PLUTSCHACK MATTHEW (DE)
CAMBIE DARIO (DE)
WOLF JAKOB (DE)
WO2016176330A1 | 2016-11-03 | |||
WO2016176330A1 | 2016-11-03 | |||
WO2017075531A1 | 2017-05-04 | |||
WO2017148874A1 | 2017-09-08 |
Claims 1. A continuous flow process for producing a compound of general formula (I) wherein R1, R2 and R3 independently from each other represent –H, C1-24 alkyl , or C2-24 alkenyl; L represents C1-12 alkylene, C2-12 alkenylene, C2-12 alkynylene, C3-15 cycloalkylene, C3-15 cycloalkenylene, or –(CH2–O–CH2)1-6–; P represents C1-24 alkylene, C2-24 alkenylene, C2-24 alkynylene, or –(CH2)m–(CH2–O–CH2)1-6–(CH2)n–; X is selected from –H, –OR4, –CN, –C(O)OR4, –OC(O)OR4, and –NR4R5; R4 and R5 independently from each other are selected from –H or C1-12 alkyl; wherein m and n are integers independently selected from 0 and 1; the process comprising the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI) F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor. 2. The continuous flow process according to claim 1, wherein the continuous flow of a mixture comprising an oxidizing agent of step C) is obtained by combining i) an aqueous solution comprising the oxidizing agent sodium hypochlorite, a base and an alkali bromide salt, and ii) an organic solution of a piperidin-1-oxyl nitroxyl radical compound and/or a pyrrolidine-1-oxyl nitroxyl radical compound. 3. The continuous flow process according to claim 1 or 2, wherein the continuous flow of a mixture comprising an oxidizing agent of step C) is obtained by combining i) an aqueous solution comprising the oxidizing agent sodium hypochlorite, sodium bicarbonate and potassium bromide, and ii) a solution of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl in 2-methyl tetrahydrofuran. 4. The continuous flow process according to any one of the claims 1 – 3, wherein following step is performed after step D) D') purifying compound of formula (V) under continuous flow conditions. 5. The continuous flow process according to any one of the claims 1 – 4, further comprising steps B1'), B2') and B3') after step B) B1') combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow comprising an aqueous base, B2') continuously performing a neutralization reaction in a continuous flow reactor at a reaction temperature below 23°C, and B3') purifying compound of formula (IV) under continuous flow conditions. 6. The continuous flow process according to any one of the claims 1 – 5, wherein the reducing agent of step E) is a boron compound selected from: NaBH4, NaBH4/Celite/LiCl, NaCNBH3, NaBH(OAc)3, Me4NBH(OAc)3, or borane dimethylsulfide. 7. The continuous flow process according to any one of the claims 1 – 6, wherein the combined continuous flow obtained from step E) comprises at least one C1-5 alcohol and an aprotic solvent. 8. The continuous flow process according to any one of the claims 1 – 7, wherein the combined continuous flow obtained from step E) comprises methanol and 2-methyl tetrahydrofuran. 9. The continuous flow process according to any one of the claims 1 – 8, wherein in step E) the continuous flow containing the compound of formula (V) is combined simultaneously with the continuous flow of a solution comprising a reducing agent and with the continuous flow of a solution comprising an amine compound of formula (VI) using a cross-shaped mixer. 10. The continuous flow process according to any one of the claims 1 – 9, wherein the continuous flow of a solution comprising acid chloride (II) and the diol compound (III) of step A) is obtained by combining a continuous flow of a solution comprising the acid chloride (II) and a continuous flow of a solution comprising the diol compound (III). 11. The continuous flow process according to claim 10, wherein the continuous flow of a solution comprising the acid chloride (II) is obtained from reacting a carboxylic acid of formula (VII) with a chlorinating agent, preferably thionyl chloride, oxalyl chloride, bis(trichloromethyl)carbonate or phosgene, in a continuous flow reactor at a reaction temperature between 23°C and 100°C wherein R1, R2 and R3 have the meanings as defined in claim 1. 12. The continuous flow process according to any one of the claims 1 – 11, further comprising step G): G) isolating the compound of formula (I) produced in step F). 13. The continuous flow process according to any one of the claims 1 – 12, further comprising step G*) after step G) or instead of step G): G*) preparing a vaccine formulation containing the compound of formula (I). 14. The continuous flow process according to any one of the claims 1 – 13, wherein R3 represents –H and/or wherein X represents –OH. 15. The continuous flow process according to any one of the claims 1 – 14, wherein R1 represents –(CH2)5–CH3 ; R2 represents –(CH2)7–CH3 ; R3 represents –H ; L represents –(CH2)4– ; P represents –(CH2)4– ; and X represents –OH . |
The reducing agent is a compound or a mixture of compounds capable of reducing aldehydes in the presence of a primary amine to amines. The reducing agent is for instance a borane compound, a borohydride, hydrogen in combination with a hydrogenation catalyst (e.g. Pt/C, Pd/C) or an electrode in combination with a protic solvent (electrochemical reduction). Preferably, the reducing agent is selected from the group consisting of sodium borohydride (NaBH 4 ), lithium borohydride (LiBH 4 ), potassium borohydride (KBH 4 ), calcium borohydride (Ca(BH 4 ) 2 ), NaCNBH 3 , NaBH(OAc) 3 , Me 4 NBH(OAc) 3 (tetramethylammonium triacetoxy borohydride), borane dimethylsulfide, hydrogen and a mixture of the afore-mentioned reducing agent. Preferred is tetramethylammonium triacetoxy borohydride.
The reducing agent also encompasses electrochemical reductions.
The reducing agent is preferably soluble in the solvent used for the reaction.
The chlorinating agent is a compound which converts acid of formula (VII) to an acid chloride of formula (II). Examples are thionyl chloride, oxalyl chloride, phosgene and phosgene derivatives, such as bis(trichloromethyl)carbonate.
The oxidizing agent is a compound or a mixture of compounds which converts primary alcohol of formula (IV) selectively to aldehyde of formula (V). Examples are pyridinium chlorochromate, sodium hypochlorite/sodium bicarbonate/potassium bromide/TEMPO ((2,2,6,6-tetramethylpiperidin-1-yl)oxyl) or dimethyl sulfoxide/oxalyl chloride/triethylamine.
Preferably, pyridinium chlorochromate is not used as oxidizing agent in the inventive continuous flow process.
The nitroxyl radical compound is a stable radical compound and a catalyst for the oxidation of primary alcohols to aldehydes. Examples are 2, 2, 5, 5 alkyl substituted piperidin-1 -oxyl and 2, 2, 6, 6 alkyl substituted pyrrolidine-1 -oxyl as well as derivatives thereof, such as TEMPO.
In a preferred embodiment, the continuous flow process is performed in an aprotic solvent. Examples for aprotic solvents are: CH 2 CI 2 , CHCI 3 , CIH 2 CCH 2 CI, CHCI 2 CHCI 2 , CCI 2 FCCI 2 F, CH 3 CN, Et 2 O, tert-butylmethylether (MTBE), 1,2-dimethoxyethane, pentane, hexane, heptanes, petroleum ether, cyclopentane, cyclohexane, benzene, toluene, PEG 400, THF, 2-methyl tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, dimethylformamide, dimethylacetamide, N-methyl pyrrolidinone (NMP) and mixtures thereof. A preferred aprotic solvent is 2-methyl tetrahydrofuran. Thus, the present invention is directed to a continuous flow process for producing a compound of general formula (I) comprising the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III) in an aprotic solvent; B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent in an aprotic solvent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI) in an aprotic solvent; and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor. In a preferred embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III) in an aprotic solvent; B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent in the aprotic solvent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI) in the aprotic solvent; and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor, wherein the aprotic solvent is 2-methyl tetrahydrofuran. In a preferred embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III) in an aprotic solvent; B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent in the aprotic solvent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI) in the aprotic solvent; and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor, wherein the aprotic solvent is 2-methyl tetrahydrofuran and the solution comprising a reducing agent in step E) is a solution of the reducing agent in N-methyl pyrrolidinone. The inventive process can also be performed without a solvent exchange. Thus, steps A) to F) can be run in the same solvent or solvent mixture. In a preferred embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III) in an aprotic solvent; B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent in the aprotic solvent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI) in the aprotic solvent; and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor, wherein in steps A) to F) the same aprotic solvent is used. In one embodiment, the reductive amination step F) is performed in a solvent mixture of at least one C 1 -C 5 alcohol and an aprotic solvent. The addition of at least one C 1 -C 5 alcohol increases the solubility of the reducing agent and increases the reaction rate. The expression “at least one” C 1 - 5 alcohol indicates that also mixtures of C 1 - 5 alcohols could be used. The term “C 1 - 5 alcohol” refers to any monool, diol, triol, tetraol or pentaol. Preferred examples of a C 1 -C 5 alcohol are: CH 3 OH, CH 3 CH 2 OH, CH 3 CH 2 CH 2 OH, CH 3 CH 2 CH 2 CH 2 OH, CH 3 CH 2 CH 2 CH 2 CH 2 OH, HOCH 2 CH 2 OH, HOCH 2 CH 2 CH 2 OH, HOCH 2 CH 2 CH 2 CH 2 OH, HOCH 2 CH 2 CH 2 CH 2 CH 2 OH, HOCH 2 CH(OH)CH 2 OH, HOCH 2 CH(OH)CH 2 CH 2 OH, HOCH 2 CH(OH)CH(OH)CH 3 , HOCH 2 CH(OH)CH(OH)CH 2 OH, HOCH 2 CH(OH)CH 2 CH 2 CH 2 OH, HOCH 2 CH 2 CH(OH)CH 2 CH 2 OH, HOCH 2 CH(OH)CH(OH)CH 2 CH 2 OH, HOCH 2 CH(OH)CH 2 CH(OH)CH 2 OH, HOCH 2 CH(OH)CH(OH)CH(OH)CH 2 OH, HC(CH 2 OH) 3 , HO–C(CH 2 OH) 3 , and C(CH 2 OH) 4 . It was found that a preferred molar ratio of C 1 - 5 alcohol to reducing agent is in the range of 1.0:0.1 to 1.0:10.0, more preferred 1.0:0.3 to 1.0:5.0, even more preferred 1.0:0.4 to 1.0:3.0, and most preferred 1.0:0.5 to 1.0:1.0. It was also found that a preferred C 1 - 5 alcohol is methanol, ethanol and a mixture thereof. The molar ratio between acid chloride (II) and diol compound (III) in step A) is preferably between 1:1 and 1:10, more preferably between 1:1.1 and 1:9, more preferably between 1:1.2 and 1:8, more preferably between 1:1.3 and 1:7, more preferably between 1:1.5 and 1:5, more preferably between 1:2 and 1:4, more preferably between 1:2.5 and 1:3.5, and most preferably between 12.7 and 1:3.2. Most preferably, the molar ratio between acid chloride (II) and diol compound (III) in step A) is about 1:3. The esterification reaction in step B) is preferably performed at a temperature between 40°C and 150°C, more preferably between 60°C and 120°C and most preferably between 70°C and 100°C. In one embodiment the esterification reaction is performed at 100 °C. In one embodiment the esterification reaction is performed at 80°C. In one embodiment the esterification reaction is performed at 150°C. In a preferred embodiment the mixture comprising an oxidizing agent of step C) is obtained by combining i) an aqueous solution comprising the oxidizing agent sodium hypochlorite, sodium bicarbonate and potassium bromide, and ii) a solution of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl in 2-methyl tetrahydrofuran. Preferably, the aqueous solution i) comprises sodium hypochlorite and sodium bicarbonate in a molar ratio between 6:1 and 7:1. The oxidization reaction of step D) is preferably performed at a constant reaction temperature under cooling in a continuous flow reactor. More preferably, the oxidization reaction of step D) is performed at a reaction temperature of 23°C under cooling in a continuous flow reactor. The oxidization reaction of step D) is preferably performed at a pH between 8.5 and 10.5, more preferably between 8.6 and 10.4, more preferably between 8.7 and 10.3, more preferably between 8.8 and 10.2, more preferably between 8.9 and 10.1, more preferably between 9.0 and 10.0, more preferably between 9.1 and 9.9, more preferably between 9.2 and 9.8, more preferably between 9.3 and 9.7 and most preferably between 9.4 and 9.6. In a preferred embodiment, the oxidization reaction of step D) is performed at a pH of 9.5. The reductive amination reaction of step F) is preferably performed at a constant reaction temperature under cooling in a continuous flow reactor. More preferably, the reductive amination reaction of step F) is performed at a reaction temperature of 23°C under cooling in a continuous flow reactor. In further preferred embodiments of the continuous flow process described herein R 3 represents –H; R 1 and R 2 independently of each other represent C 1-24 alkyl; and X represents –OH. In further preferred embodiments of the continuous flow process described herein R 3 represents –H; R 1 and R 2 independently of each other represent C 1-24 alkyl; P represents C 1-12 alkylene; and X represents –OH. In further preferred embodiments of the continuous flow process described herein R 3 represents –H; R 1 and R 2 independently of each other represent C 1-24 alkyl; L represents –(CH 2 –O–CH 2 ) 1-6 – ; and X represents –OH. In further preferred embodiments of the continuous flow process described herein R 3 represents –H; R 1 and R 2 independently of each other represent C 1-24 alkyl; P represents –(CH 2 ) 1 –(CH 2 –O–CH 2 ) 1-6 –(CH 2 ) 1 – ; and X represents –OH. In further preferred embodiments of the continuous flow process described herein R 3 represents –H; R 1 and R 2 independently of each other represent C 1-24 alkyl; L represents C 1-12 alkylene; P represents –(CH 2 ) 1 –(CH 2 –O–CH 2 ) 1-6 –(CH 2 ) 1 – ; and X represents –OH. In further preferred embodiments of the continuous flow process described herein R 3 represents –H; R 1 and R 2 independently of each other represent C 1-24 alkyl; L represents C 1-12 alkylene; P represents C 1-12 alkylene; and X represents –OH. In further preferred embodiments of the continuous flow process described herein R 3 represents –H; R 1 and R 2 independently of each other represent C 1-24 alkyl; L represents C 1-12 alkylene; and X represents –N(CH 3 ) 2 . A further aspect of the present invention is directed to a continuous flow process for producing a compound of general formula (I) wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . Thus, the present invention is also directed to a continuous flow process for producing a compound of general formula (I) comprising steps A1) and A2) instead of step A): A1) providing a continuous flow of a solution comprising a carboxylic acid of formula (VII) and a chlorinating agent; A2) continuously producing an acid chloride of formula (IV) from the continuous flow of the solution comprising the carboxylic acid of formula (VII) and the chlorinating agent in a continuous flow reactor; B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor, wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . Preferably, the chlorinating agent is selected from thionyl chloride, oxalyl chloride, bis(trichloromethyl)carbonate or phosgene. Most preferably, the chlorinating agent is thionyl chloride. Preferably, step A2) is performed at a reaction temperature between 23°C and 100°C more preferably at a reaction temperature between 40°C and 100°C, even more preferably at a reaction temperature between 60°C and 90°C and most preferably at a reaction temperature of about 80°C. Most preferably, the chlorinating agent is thionyl chloride and step A2) is performed at a reaction temperature of about 80°C. In one embodiment, preferably 0.005 molar equivalents to 0.2 molar equivalents of N,N-dimethylformamide, more preferably 0.007 molar equivalents to 0.15 molar equivalents of N,N-dimethylformamide, more preferably 0.01 molar equivalents to 0.1 molar equivalents of N,N-dimethylformamide, and most preferably 0.05 molar equivalents of N,N-dimethylformamide are added in step A2) in order to increase the reaction rate. Another embodiment of the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; B1') combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow comprising an aqueous base, B2') continuously performing a neutralization reaction in a continuous flow reactor at a reaction temperature below 23°C, B3') purifying compound of formula (IV) under continuous flow conditions, C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . Preferably, the aqueous base is an aqueous solution of an alkali metal hydroxide. Preferably, the aqueous base is a 1 molar aqueous solution of an alkali metal hydroxide. Preferably, the aqueous base is an aqueous solution of lithium hydroxide, sodium hydroxide or potassium hydroxide. Most preferably, the aqueous base is a 1 molar aqueous solution of sodium hydroxide. Preferably, step B3') is performed at a reaction temperature of 0 °C. Another embodiment of the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent and a base; C') neutralizing the continuous flow obtained in step C); D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C') in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . In other words, the present invention is directed to a continuous flow process for producing a compound of general formula (I) comprising the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor, thereby forming hydrogen chloride; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent and a base; C') neutralizing the hydrogen chloride formed in step B); D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C') in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . The present invention is directed to a continuous flow process for producing a compound of general formula (I) comprising the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a biphasic mixture of an oxidizing agent; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . In other words, the present invention is directed to a continuous flow process for producing a compound of general formula (I) comprising the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with i) a continuous flow of a solution comprising an aqueous solution comprising sodium hypochlorite, a base and an alkali bromide salt, and ii) a continuous flow of a solution comprising an organic solution of a piperidin-1-oxyl nitroxyl radical compound and/or a pyrrolidine-1-oxyl nitroxyl radical compound; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . The present invention is also directed to a continuous flow process for producing a compound of general formula (I) comprising the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising sodium hypochlorite, a base, an alkali bromide salt, and a piperidin-1-oxyl nitroxyl radical compound and/or a pyrrolidine-1-oxyl nitroxyl radical compound; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . Preferably, the nitroxyl radical compound is (2,2,6,6-tetramethyl)piperidin-1-yl)oxyl. In a preferred embodiment the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein the continuous flow of a mixture comprising an oxidizing agent of step C) is obtained by combining i) an aqueous solution comprising the oxidizing agent sodium hypochlorite, sodium bicarbonate and potassium bromide, and ii) a solution of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl in 2-methyl tetrahydrofuran; and wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . In a further embodiment, the continuous flow comprising the compound of formula (V) obtained in step D) is subjected to an intermediate purification before step E). Thus, the inventive continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; D') purifying compound of formula (V) under continuous flow conditions; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . Preferably, the intermediate purification in step D’) is performed by liquid-liquid extraction, such as an in-line membrane-based separation. Thus, in a preferred embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a biphasic mixture of an oxidizing agent; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; D') purifying compound of formula (V) under continuous flow conditions; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . Also, in a preferred embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with i) a continuous flow of a solution comprising an aqueous solution comprising sodium hypochlorite, a base and an alkali bromide salt, and ii) a continuous flow of a solution comprising an organic solution of a piperidin-1-oxyl nitroxyl radical compound and/or a pyrrolidine-1-oxyl nitroxyl radical compound; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; D') purifying the compound of formula (V) under continuous flow conditions by liquid-liquid extraction; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . Also, in a preferred embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; B1') combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow comprising an aqueous base, B2') continuously performing a neutralization reaction in a continuous flow reactor at a reaction temperature below 23°C, B3') purifying compound of formula (IV) under continuous flow conditions, C) combining the continuous flow of a solution containing the compound of formula (IV) with i) a continuous flow of a solution comprising an aqueous solution comprising sodium hypochlorite, a base and an alkali bromide salt, and ii) a continuous flow of a solution comprising an organic solution of a piperidin-1-oxyl nitroxyl radical compound and/or a pyrrolidine-1-oxyl nitroxyl radical compound; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; D') purifying the compound of formula (V) under continuous flow conditions by liquid-liquid extraction; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor, wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . In a preferred embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a basic biphasic continuous flow of an oxidizing agent; C') neutralizing the continuous flow obtained in step C); D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C)' in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . In a further preferred embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a basic biphasic continuous flow of an oxidizing agent; C') neutralizing the continuous flow obtained in step C); D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; D') purifying the compound of formula (V) under continuous flow conditions; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . In a further preferred embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising sodium hypochlorite, a base, an alkali bromide salt, and a piperidin-1-oxyl nitroxyl radical compound and/or a pyrrolidine-1-oxyl nitroxyl radical compound; C') neutralizing the continuous flow obtained in step C); D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C') in a continuous flow reactor; D') purifying the compound of formula (V) under continuous flow conditions by liquid-liquid extraction; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . In a further embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor at a temperature between 40 °C and 150 °C in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . Preferably, the esterification reaction in step B) is performed at 100°C. In a further embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein the reducing agent is a boron compound selected from: NaBH 4 , NaBH 4 /Celite/LiCl, NaCNBH 3 , NaBH(OAc) 3 , Me 4 NBH(OAc) 3 , or borane dimethylsulfide; and wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . Preferably, the combined continuous flow obtained from step E) comprises at least one C 1 -C 5 alcohol and an aprotic solvent. Thus, in a further embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein the combined continuous flow obtained from step E) comprises at least one C 1 -C 5 alcohol and an aprotic solvent; wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . Preferably, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein the combined continuous flow obtained from step E) comprises methanol and 2-methyl tetrahydrofuran; wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . In a preferred embodiment of the inventive continuous flow process the continuous flow containing the compound of formula (V) in step E) is combined simultaneously with the continuous flow of a solution comprising a reducing agent and with the continuous flow of a solution comprising an amine compound of formula (VI) using a cross-shaped mixer. Simultaneous mixing of the three continuous flows reduces the solid formation. Thus, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) simultaneously combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI) by using a cross shaped mixer; and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein the combined continuous flow obtained from step E) comprises methanol and 2-methyl tetrahydrofuran; wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . In a further embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; and G) isolating the compound of formula (I) produced in step F); wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . A further aspect of the invention is directed to a continuous flow process for producing a vaccine composition comprising the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; G) isolating the compound of formula (I) produced in step F); and G*) preparing a vaccine formulation containing the compound of formula (I); wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . In a preferred embodiment, the continuous flow process comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; and G*) preparing a vaccine formulation containing the compound of formula (I); wherein R 1 represents C 2-24 alkenyl ; R 2 and R 3 represent –H ; and L represents –(CH 2 –O–CH 2 ) 1-6 – ; P represents C 1-24 alkylene ; and X represents –OH . A further aspect of the present invention is directed to a continuous flow process for producing ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2- hexyldecanoate), thus the compound of general formula (I) wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H ; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH . Thus, the present invention is also directed to a continuous flow process for producing a compound of general formula (I) comprising steps A1) and A2) instead of step A): A1) providing a continuous flow of a solution comprising a carboxylic acid of formula (VII) and a chlorinating agent; A2) continuously producing an acid chloride of formula (IV) from the continuous flow of the solution comprising the carboxylic acid of formula (VII) and the chlorinating agent in a continuous flow reactor; B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor, wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H ; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH . Preferably, the chlorinating agent is selected from thionyl chloride, oxalyl chloride, bis(trichloromethyl)carbonate or phosgene. Most preferably, the chlorinating agent is thionyl chloride. Preferably, step A2) is performed at a reaction temperature between 23°C and 100°C more preferably at a reaction temperature between 40°C and 100°C, even more preferably at a reaction temperature between 60°C and 90°C and most preferably at a reaction temperature of about 80°C. Most preferably, the chlorinating agent is thionyl chloride and step A2) is performed at a reaction temperature of about 80°C. In one embodiment, preferably 0.005 molar equivalents to 0.2 molar equivalents of N,N-dimethylformamide, more preferably 0.007 molar equivalents to 0.15 molar equivalents of N,N-dimethylformamide, more preferably 0.01 molar equivalents to 0.1 molar equivalents of N,N-dimethylformamide, and most preferably 0.05 molar equivalents of N,N-dimethylformamide are added in step A2) in order to increase the reaction rate. Another embodiment of the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; B1') combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow comprising an aqueous base, B2') continuously performing a neutralization reaction in a continuous flow reactor at a reaction temperature below 23°C, B3') purifying compound of formula (IV) under continuous flow conditions, C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H ; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH . Preferably, the aqueous base is an aqueous solution of an alkali metal hydroxide. Preferably, the aqueous base is a 1 molar aqueous solution of an alkali metal hydroxide. Preferably, the aqueous base is an aqueous solution of lithium hydroxide, sodium hydroxide or potassium hydroxide. Most preferably, the aqueous base is a 1 molar aqueous solution of sodium hydroxide. Preferably, step B3') is performed at a reaction temperature of 0 °C. Another embodiment of the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent and a base; C') neutralizing the continuous flow obtained in step C); D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C') in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H ; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. In other words, the present invention is directed to a continuous flow process for producing a compound of general formula (I) comprising the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor, thereby forming hydrogen chloride; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent and a base; C') neutralizing the hydrogen chloride formed in step B); D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C') in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. The present invention is directed to a continuous flow process for producing a compound of general formula (I) comprising the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a biphasic mixture of an oxidizing agent; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. In other words, the present invention is directed to a continuous flow process for producing a compound of general formula (I) comprising the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with i) a continuous flow of a solution comprising an aqueous solution comprising sodium hypochlorite, a base and an alkali bromide salt, and ii) a continuous flow of a solution comprising an organic solution of a piperidin-1-oxyl nitroxyl radical compound and/or a pyrrolidine-1-oxyl nitroxyl radical compound; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. The present invention is also directed to a continuous flow process for producing a compound of general formula (I) comprising the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising sodium hypochlorite, a base, an alkali bromide salt, and a piperidin-1-oxyl nitroxyl radical compound and/or a pyrrolidine-1-oxyl nitroxyl radical compound; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. Preferably, the nitroxyl radical compound is (2,2,6,6-tetramethyl)piperidin-1-yl)oxyl. In a preferred embodiment the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein the continuous flow of a mixture comprising an oxidizing agent of step C) is obtained by combining i) an aqueous solution comprising the oxidizing agent sodium hypochlorite, sodium bicarbonate and potassium bromide, and ii) a solution of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl in 2-methyl tetrahydrofuran; and wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. In a further embodiment, the continuous flow comprising the compound of formula (V) obtained in step D) is subjected to an intermediate purification before step E). Thus, the inventive continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; D') purifying compound of formula (V) under continuous flow conditions; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. Preferably, the intermediate purification in step D’) is performed by liquid-liquid extraction, such as an in-line membrane-based separation. Thus, in a preferred embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a biphasic mixture of an oxidizing agent; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; D') purifying compound of formula (V) under continuous flow conditions; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. Also, in a preferred embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with i) a continuous flow of a solution comprising an aqueous solution comprising sodium hypochlorite, a base and an alkali bromide salt, and ii) a continuous flow of a solution comprising an organic solution of a piperidin-1-oxyl nitroxyl radical compound and/or a pyrrolidine-1-oxyl nitroxyl radical compound; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; D') purifying the compound of formula (V) under continuous flow conditions by liquid-liquid extraction; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. Also, in a preferred embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; B1') combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow comprising an aqueous base, B2') continuously performing a neutralization reaction in a continuous flow reactor at a reaction temperature below 23°C, B3') purifying compound of formula (IV) under continuous flow conditions, C) combining the continuous flow of a solution containing the compound of formula (IV) with i) a continuous flow of a solution comprising an aqueous solution comprising sodium hypochlorite, a base and an alkali bromide salt, and ii) a continuous flow of a solution comprising an organic solution of a piperidin-1-oxyl nitroxyl radical compound and/or a pyrrolidine-1-oxyl nitroxyl radical compound; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; D') purifying the compound of formula (V) under continuous flow conditions by liquid-liquid extraction; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor, wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. In a preferred embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a basic biphasic continuous flow of an oxidizing agent; C') neutralizing the continuous flow obtained in step C); D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C)' in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. In a further preferred embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a basic biphasic continuous flow of an oxidizing agent; C') neutralizing the continuous flow obtained in step C); D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; D') purifying the compound of formula (V) under continuous flow conditions; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. In a further preferred embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising sodium hypochlorite, a base, an alkali bromide salt, and a piperidin-1-oxyl nitroxyl radical compound and/or a pyrrolidine-1-oxyl nitroxyl radical compound; C') neutralizing the continuous flow obtained in step C); D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C') in a continuous flow reactor; D') purifying the compound of formula (V) under continuous flow conditions by liquid-liquid extraction; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. In a further embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor at a temperature between 40 °C and 150 °C in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. Preferably, the esterification reaction in step B) is performed at 100°C. In a further embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein the reducing agent is a boron compound selected from: NaBH 4 , NaBH 4 /Celite/LiCl, NaCNBH 3 , NaBH(OAc) 3 , Me 4 NBH(OAc) 3 , or borane dimethylsulfide; and wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. Preferably, the combined continuous flow obtained from step E) comprises at least one C 1 -C 5 alcohol and an aprotic solvent. Thus, in a further embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein the combined continuous flow obtained from step E) comprises at least one C 1 -C 5 alcohol and an aprotic solvent; wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. Preferably, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined biphasic continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein the combined continuous flow obtained from step E) comprises methanol and 2-methyl tetrahydrofuran; wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. In a preferred embodiment of the inventive continuous flow process the continuous flow containing the compound of formula (V) in step E) is combined simultaneously with the continuous flow of a solution comprising a reducing agent and with the continuous flow of a solution comprising an amine compound of formula (VI) using a cross-shaped mixer. Simultaneous mixing of the three continuous flows reduces the solid formation. Thus, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) simultaneously combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI) by using a cross shaped mixer; and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; wherein the combined continuous flow obtained from step E) comprises methanol and 2-methyl tetrahydrofuran; wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. In a further embodiment, the continuous flow process for producing a compound of general formula (I) comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; and G) isolating the compound of formula (I) produced in step F); wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. A further aspect of the invention is directed to a continuous flow process for producing a vaccine composition comprising the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; G) isolating the compound of formula (I) produced in step F); and G*) preparing a vaccine formulation containing the compound of formula (I); wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. In a preferred embodiment, the continuous flow process comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; and G*) preparing a vaccine formulation containing the compound of formula (I); wherein R 1 represents –(CH 2 ) 5 –CH 3 ; R 2 represents –(CH 2 ) 7 –CH 3 ; R 3 represents –H; and L represents –(CH 2 ) 4 – ; P represents –(CH 2 ) 4 – ; and X represents –OH. Vaccine formulation Another aspect of the present invention is directed to a method for preparing a vaccine formulation containing the compound of formula (I). The compound of formula (I) as a cationic lipid is particularly useful for forming lipid nanoparticles together with other lipid components that facilitate delivery of therapeutic nucleic acids, particularly mRNA. The term "immunogenic mRNA" refers to mRNA that encodes the viral Spike (S) glycoprotein of SARS-CoV-2 virus. Thus, the present invention is also directed to a continuous flow process comprising the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; and G*) preparing a vaccine formulation comprising an immunogenic mRNA encapsulated in a lipid nanoparticle comprising the compound of formula (I). In a preferred embodiment, the continuous flow process comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; B1') combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow comprising an aqueous base, B2') continuously performing a neutralization reaction in a continuous flow reactor at a reaction temperature below 23°C, B3') purifying compound of formula (IV) under continuous flow conditions, C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; and G*) preparing a vaccine formulation comprising an immunogenic mRNA encapsulated in a lipid nanoparticle comprising the compound of formula (I). In a further preferred embodiment, the continuous flow process comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; B1') combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow comprising an aqueous base, B2') continuously performing a neutralization reaction in a continuous flow reactor at a reaction temperature below 23°C, B3') purifying compound of formula (IV) under continuous flow conditions, C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; D') purifying the compound of formula (V) under continuous flow conditions; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; and G*) preparing a vaccine formulation comprising an immunogenic mRNA encapsulated in a lipid nanoparticle comprising the compound of formula (I). Preferably, the intermediate purifications in step B3') and step D’) are performed by liquid-liquid extraction, such as an in-line membrane-based separation. In a further preferred embodiment, the continuous flow process comprises the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent and a base; C') neutralizing the hydrogen chloride formed in step B); D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; D') optionally purifying the compound of formula (V) under continuous flow conditions; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; and G*) preparing a vaccine formulation comprising an immunogenic mRNA encapsulated in a lipid nanoparticle comprising the compound of formula (I). In preferred embodiments the lipid nanoparticle comprises a cationic lipid of formula (I); a neutral lipid; a steroid; a polymer conjugated lipid; and an immunogenic mRNA encapsulated within or associated with the lipid nanoparticle. Preferably, the lipid nanoparticle comprises the cationic lipid of formula (I) in the amount of 40 and 50 mol percent. Preferably, the neutral lipid is 1,2-Distearoyl-sn- glycero-3-phosphocholine (DSPC). Preferably, the steroid is cholesterol. Preferably, the polymer conjugated lipid is 2-[(polyethylene glycol)-2000]-N,N ditetradecylacetamide. In a preferred embodiment, the lipid nanoparticle comprises 40 and 50 mol percent of the cationic lipid of formula (I), 1 ,2-Distearoyl- sn-glycero-3-phosphocholine (DSPC), cholesterol, 2-[(polyethylene glycol)-2000]- N,N ditetradecylacetamide and an immunogenic mRNA.
The lipid nanoparticles may be formed by any suitable method known in the art. To this extent, the lipid components cationic lipid of formula (I); neutral lipid; steroid; and polymer conjugated lipid; are dissolved in at least one C1-5 alcohol, preferably ethanol. The solution containing the lipid components is then mixed with an aqueous solution of the immunogenic mRNA to obtain the lipid nanoparticle with an encapsulated or associated immunogenic mRNA.
Thus, the present invention is also directed to a continuous flow process comprising the following steps:
A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III);
B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base;
C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent;
D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor;
E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and
F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; and
G1*) preparing a solution of lipid components, wherein one lipid component is the compound of formula (I);
G2*) mixing the solution of lipid components with an aqueous solution of an immunogenic mRNA in order to obtain a vaccine formulation comprising the immunogenic mRNA encapsulated in a lipid nanoparticle comprising the compound of formula (I).
Preferably, the present invention is also directed to a continuous flow process comprising the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; and G1*) preparing a solution of the cationic lipid of formula (I); a neutral lipid; a steroid; and a polymer conjugated lipid in ethanol; G2*) mixing the solution obtained in step G1*) with an aqueous solution of an immunogenic mRNA in order to obtain a vaccine formulation comprising the immunogenic mRNA encapsulated in a lipid nanoparticle comprising the compound of formula (I). The solution containing the lipid components can be mixed with the aqueous solution of the immunogenic mRNA according to any conventional mixing method, including T-junction mixing, microfluidic hydrodynamic focusing and staggered herringbone mixing. Preferably, the T-junction mixing is used in the processes described herein. A T-junction mixer provides a controlled mixing environment compared to macroscopic mixing methods (e.g., vortexing or pipetting), thereby leading to reproducible production of lipid particles. The mixing occurs when the two input streams (lipid components and aqueous mRNA solution) in the T-junction collide, resulting in a turbulent output flow containing the lipid nanoparticles. Thus, the present invention is also directed to a continuous flow process comprising the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; and G1*) preparing a solution of the cationic lipid of formula (I); a neutral lipid; a steroid; and a polymer conjugated lipid in ethanol; G2*) rapid mixing the solution obtained in step G1*) with an aqueous solution of an immunogenic mRNA by using an in-line T-junction mixer in order to obtain a vaccine formulation comprising the immunogenic mRNA encapsulated in a lipid nanoparticle comprising the compound of formula (I). To obtain a sterile vaccine formulation for in vivo application the vaccine formulation may be subjected to sterile filtration. Thus, the present invention is also directed to a continuous flow process comprising the following steps: A) providing a continuous flow of a solution comprising acid chloride (II) and diol compound (III); B) continuously producing a compound of formula (IV) from the continuous flow of the solution comprising acid chloride (II) and diol compound (III) in a continuous flow reactor in the absence of a base; C) combining the continuous flow of a solution containing the compound of formula (IV) with a continuous flow of a mixture comprising an oxidizing agent; D) continuously producing a compound of formula (V) from the combined continuous flow obtained in step C) in a continuous flow reactor; E) combining the continuous flow containing the compound of formula (V) obtained in step D) with a continuous flow of a solution comprising a reducing agent and with a continuous flow of a solution comprising an amine compound of formula (VI); and F) continuously producing the compound of formula (I) from the combined continuous flow obtained in step E) in a continuous flow reactor; and G1*) preparing a solution of the cationic lipid of formula (I); a neutral lipid; a steroid; and a polymer conjugated lipid in ethanol; G2*) mixing the solution obtained in step G1*) with an aqueous solution of an immunogenic mRNA in order to obtain a vaccine formulation comprising the immunogenic mRNA encapsulated in a lipid nanoparticle comprising the compound of formula (I); G3*) sterile filtration of the vaccine formulation obtained in step G2*). Optionally, adjuvants, buffers, excipients and/or diluents may be added to the vaccine formulation in order to improve immunological activity, stability and bring it into an administrable form. The term “adjuvant” as used herein refers to an immunological adjuvant i.e. a material used in a vaccine composition that modifies or augments the effects of said vaccine by enhancing the immune response to a given antigen contained in the vaccine without being antigenically related to it. For the persons skilled in the art, classically recognized examples immunological adjuvants include but are not restricted to oil emulsions (e.g. Freund's adjuvant), saponins, aluminium or calcium salts (e.g. alum), non-ionic block polymer surfactants, and many others. The vaccine formulation may be administered subcutaneously, by spray, by injection, orally, intraocularly, intramuscular, intratracheally or nasally. Preferably, the vaccine formulation is administered intramuscular. Preferably the vaccine formulation is formulated as a liquid buffer solution. Preferred buffers are potassium dihydrogen phosphate, disodium hydrogen phosphate and tris (tormethamine) to maintain the pH between 7 and 8. Further suitable excipients are potassium chloride, sodium chloride, sodium acetate, sucrose and water for injection (diluent). Description of Figures Fig.1: shows the structure of cationic lipid ALC-0315. Fig.2A: shows the synthesis of ALC-0315 known from WO 2016/176330 A1. In a first step, 2-hexyldecanoyl chloride is esterified with 1,6-hexanediol in the presence of 2 equiv. triethylamine. The remaining free alcohol group is then oxidized with toxic pyridinium chlorochromate to the corresponding aldehyde, which is in a last step reduced with sodium triacetoxy borohydride and acetic acid in the presence of 4-amino-1-butanol to ALC-0315. Fig.2B: shows the synthesis of ALC-0315 known from WO 2017/075531 A1. In a first step, 2-hexyldecanoic acid is esterified with 1,6-hexanediol in the presence of dicyclohexylcarbodiimide and 4-dimethylaminopyridine. The remaining free alcohol group is then oxidized with toxic pyridinium chlorochromate to the corresponding aldehyde, which is in a last step reduced with sodium triacetoxy borohydride and acetic acid in the presence of 4-amino-1-butanol to ALC-0315. Fig.3: Schematic drawing of a synthesis of compound of formula (I) according to the invention in continuous manner. Fig.4: Schematic drawing of a synthesis of compound of formula (I) according to the invention in continuous manner. Fig.5: Schematic drawing of a synthesis of compound of formula (I) according to the invention in continuous manner using biphasic TEMPO/sodium hypochlorite/KBr as oxidizing agent and two phase separation steps. Fig.6: shows HPLC chromatogram of the crude reaction mixture of the esterification reaction in Example 3. The chromatogram shows a 6-hydroxyhexyl 2-hexyldecanoate/hexane-1,6-diyl bis(2-hexyldecanoate) ratio of 8:1 Examples Example 1: Continuous preparation of ALC-0315 The synthesis of lipid ALC-0315 was performed in a four-step continuous flow process starting from 2-hexyldecanoic acid as shown in Figure 4. First, 2-hexyldecanoic acid is converted to 2-hexyldecanoyl chloride in 2-methyl tetrahydrofuran using thionyl chloride in a flow reactor for heating (1) at temperatures ranging from 23 to 80 °C. A faster conversion to the acid chloride was observed by addition of 0.01 molar equivalents of N,N-dimethylformamide. The esterification of 2-hexyldecanoyl chloride using excess amounts of 1,6-hexanediol was carried out at elevated temperature without addition of a base (2). The mono-ester, 6-hydroxyhexyl 2-hexyldecanoate is oxidized in the third step (3) via a biphasic reaction using an aqueous solution of sodium hypochlorite, a basic aqueous solution of potassium bromide, and a solution of 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO) in 2-methyl tetrahydrofuran. The product was purified using an in-line liquid-liquid separator (3). In the final synthetic step, the aldehyde stream is combined with a methanolic solution of 4-amino-1-butanol and a borohydride, producing ((4-hydroxybutyl)azanediyl)- bis(hexane-6,1-diyl) bis(2-hexyldecanoate) (4). Example 2: Unsuccessful attempts of continuously preparing ALC-0315 The synthesis of lipid ALC-0315 was attempted in a four-step continuous flow process starting from 2-hexyldecanoic acid similar to Example 1. The second step, the esterification reaction, was performed differently with 2 equivalents of triethylamine. The formation of a heterogeneous reaction mixture was observed. The final product ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl) bis(2- hexyldecanoate) was obtained in significantly lower yields compared to Example 1. Example 3: Continuous preparation of ALC-0315 using aqueous sodium hydroxide solution as base for esterification reaction The synthesis of lipid ALC-0315 was performed in a four-step continuous flow process starting from 2-hexyldecanoic acid as shown in Figure 5. A solution of 2-hexyldecanoic acid (35.23 g, 137.4 mmol) and N,N-dimethylformamide (502 mg, 6.87 mmol) in 2-methyltetrahydrofuran (1.374 M) was pumped through 1/16” Tefzel™ tubing (I.D.1 mm) using an HPLC pump at a flow rate of 0.901 mL min -1 [Line A]. Neat thionyl chloride (18.00 g, 151.3 mmol) was pumped through Tefzel™ tubing (I.D. 1 mm) using a continuous syringe pump at a flow rate of 0.099 mL min -1 [Line B]. Line B was combined with Line A via a T-mixer providing a continuous flow of a solution which was heated at 80 °C in a 20 mL reactor (Reactor 1, 20 min residence time). A solution of hexan-1,6-diol (48.71 g, 412.2 mmol) in 2-methyltetrahydrofuran (2.50 M) was pumped through 1/16” Tefzel™ tubing (I.D. 1 mm) using an HPLC pump at a flow rate of 1.5 mL min -1 [Line C]. Line C was combined with the output from Reactor 1 via a T-mixer providing a continuous flow of a solution, which was heated at 100 °C in a 10 mL reactor (Reactor 2, 4 min residence time). A solution of sodium hydroxide in water (1 M) was pumped through 1/16” Tefzel™ tubing (I.D. 1 mm) using an HPLC pump at a flow rate of 5.5 mL min -1 [Line D]. Line D was combined with the output from Reactor 2 via a T-mixer providing a continuous flow of a solution, which was cooled at 0 °C in a 10 mL reactor (Reactor 3, 1.25 min residence time). The entire system was held under constant pressure using a backpressure regulator (e.g.2.8 bar, IDEX 40 PSI, P-761). After a steady state was reached (2 residence times, 50.5 min), the biphasic outlet was collected for 30 min and phases separated. The organic phase was used in the next step without any further purification. For analytical purposes, an aliquot (5 mL) of the organic phase (47 mL) was analysed by HPLC and NMR and purified by column chromatography. HPLC analysis of the crude mixture showed a 6-hydroxyhexyl 2-hexyldecanoate/hexane-1,6-diyl bis(2-hexyldecanoate) ratio of 8:1 (Figure 6). As a representative example, from 1.603 g of crude material 1.05 g (74%) of 6-hydroxyhexyl 2-hexyldecanoate were obtained after precipitation of 1,6-hexanediol in hexane and flash chromatography (hexane:ethylacetate 0-15%). The organic phase obtained from the previous step after gravitational separation, was pumped through 1/16” Tefzel™ tubing (I.D.1 mm) using an HPLC pump at a flow rate of 1.5 mL min -1 [Line E]. A solution of TEMPO ((2,2,6,6-tetramethyl- piperidin-1-yl)oxyl) in 2-methyltetrahydrofuran (0.50 M) was pumped through 1/16” Tefzel™ tubing (I.D. 1 mm) using an HPLC pump at a flow rate of 0.15 mL min -1 [Line F]. Line F was combined with Line E via a T-mixer [Line G] providing a continuous flow of a solution. A solution of both NaOCl and Na 2 CO 3 in water (2 M and 0.3 M respectively) was pumped through 1/16” Tefzel™ tubing (I.D. 1 mm) using a continuous syringe pump at a flow rate of 1.25 mL min -1 [Line H]. A solution of KBr and NaHCO 3 in water (0.25 M and 0.7 M respectively) was pumped through 1/16” Tefzel™ tubing (I.D.1 mm) using an HPLC pump at a flow rate of 1.5 mL min -1 [Line I]. Line G and Line H were combined in a crossmixer with Line I to provide a continuous biphasic stream which was cooled to room temperature in a 10 mL reactor (Reactor 4, 1/16” Tefzel™ tubing (I.D. 1 mm), 2.3 min residence time). The reaction mixture color turned from red (near the cross mixer) to almost colorless (toward the end) through the reactor. After reaching steady state (2 residence times) the biphasic outlet was collected for 10 minutes. After manual separation of phases, an aliquot of the organic phase was analyzed by quantitative NMR with 1,3,5-trimethoxybenzene as internal standard. Collection over 10 minutes gave 13 mL of organic phase, with 0.57 M (avg. of three experiment) aldehyde concentration, corresponding to 64% yield overall yield over 3 steps. Organic phase from reactor 4 was dried over Na 2 SO 4 and pumped through 1/16” Tefzel™ tubing (I.D. 1 mm) using a syringe pump at a flow rate of 0.0777 mL min -1 [Line J]. Tetramethylammonium triacetoxyborohydride in 1-methylpyrrolidin-2-on (0.45 M) was pumped through 1/16” Tefzel™ tubing (I.D. 1 mm) using a syringe pump at a flow rate of 0.0984 mL min -1 [Line K]. 4-Aminobutan-1-ol in methanol (0.2 M) was pumped through 1/16” Tefzel™ tubing (I.D. 1 mm) using a syringe pump at a flow rate of 0.0738 mL min -1 [Line L]. The lines J, K, L were joined in a crossmixer, which provided a continuous stream that was cooled to room temperature in a 4 mL reactor (Reactor 5, 1/16” Tefzel™ tubing (I.D. 1 mm), 16 min residence time). After reaching steady state (two residence times), the outlet was collected for 50 min and quenched with water, hexanes added, basified to pH 9.5 and the phases were separated. The organic phase dried over Na 2 SO 4 yielded 1.265 g of crude red oil after solvent removal. An aliquot of crude (476 mg) was purified on a plug of silica, by sequential washes with hexanes (with 0.1 v% of TFA), hexanes/ethyl acetate (4:1, with 0.1 v% of TFA) and pure ethyl acetate (with 0.1 v% of TFA). Washing the combined fractions of ethyl acetate with Na 2 CO 3 and removing the solvent under reduced pressure yielded 121 mg of a slightly yellow oil (yield 57% in last step, based on aminobutanol, 38% based on aldehyde) with an overall yield over the four steps of 25%. Example 4: Continuous preparation of cationic lipid of formula 6 A solution of oleic acid (3.881 g, 13.74 mmol) and N,N-dimethylformamide (50.2 mg, 0.687 mmol) in 2-methyltetrahydrofuran (1.374 M) was pumped through 1/16” Tefzel™ tubing (I.D. 1 mm) using an syringe pump at a flow rate of 0.45 µL min -1 [Line A]. Neat thionyl chloride (1.80 g, 15.13 mmol) was pumped through Tefzel™ tubing (I.D.1 mm) using a syringe pump at a flow rate of 4.95 µL min -1 [Line B]. Line B was combined with Line A via a T-mixer providing a continuous flow of a solution which was heated at 80 °C in a 2 mL reactor (Reactor 1, 20 min residence time). A solution of triethylene glycol (3.75 g, 25 mmol) in 2-methyltetrahydrofuran (2.50 M) was pumped through 1/16” Tefzel™ tubing (I.D. 1 mm) using a syringe pump at a flow rate of 74.2 µL min -1 [Line C]. Line C was combined with the output from Reactor 1 via a T-mixer providing a continuous flow of a solution which was heated at 100 °C in a 1 mL reactor (Reactor 2, 4 min residence time). An aliquot of the mono-ester was collected for analytical purposes: The collected solution was quenched with a saturated aqueous solution of sodium bicarbonate, hexanes added and the organic layer washed with brine. Removing the solvent under reduced pressure afforded 241 mg of a yellow oil. LRMS ESI m/z: [M+Na]+ calcd. C 24 H 46 O 5 437.32, found 437.36. From 1H NMR (400 MHz, CDCl 3 ), yield was estimated as 50% over two steps. A solution of sodium hydroxide in water (1 M) was pumped through 1/16” Tefzel™ tubing (I.D. 1 mm) using an HPLC pump at a flow rate of 5.5 mL min -1 [Line D]. Line D was combined with the output from Reactor 2 via a T-mixer providing a continuous flow of a solution, which was cooled at 0 °C in a 10 mL reactor (Reactor 3, 1.25 min residence time). The entire system was held under constant pressure using a backpressure regulator (4 bar, Zaiput) for three full residence times to achieve steady state conditions. The further conversion of the mono-ester to the final compound 6 is performed as described in Example 3: The organic phase obtained from the previous step after gravitational separation, is pumped through 1/16” Tefzel™ tubing (I.D. 1 mm) using an HPLC pump at a flow rate of 1.5 mL min -1 [Line E]. A solution of TEMPO ((2,2,6,6-tetramethyl- piperidin-1-yl)oxyl) in 2-methyltetrahydrofuran (0.50 M) is pumped through 1/16” Tefzel™ tubing (I.D. 1 mm) using an HPLC pump at a flow rate of 0.15 mL min -1 [Line F]. Line F is combined with Line E via a T-mixer [Line G] providing a continuous flow of a solution. A solution of both NaOCl and Na 2 CO 3 in water (2 M and 0.3 M respectively) is pumped through 1/16” Tefzel™ tubing (I.D.1 mm) using a continuous syringe pump at a flow rate of 1.25 mL min -1 [Line H]. A solution of KBr and NaHCO 3 in water (0.25 M and 0.7 M respectively) is pumped through 1/16” Tefzel™ tubing (I.D. 1 mm) using an HPLC pump at a flow rate of 1.5 mL min -1 [Line I]. Line G and Line H were combined in a crossmixer with Line I to provide a continuous biphasic stream which is cooled to room temperature in a 10 mL reactor (Reactor 4, 1/16” Tefzel™ tubing (I.D. 1 mm), 2.3 min residence time). The reaction mixture color turns from red (near the cross mixer) to almost colorless (toward the end) through the reactor. After reaching steady state (2 residence times) the biphasic outlet is collected for 10 minutes. After manual separation of phases, an aliquot of the organic phase is analyzed by quantitative NMR. The organic phase from Reactor 4 is dried over Na 2 SO 4 and pumped through 1/16” Tefzel™ tubing (I.D. 1 mm) using a syringe pump at a flow rate of 0.07 mL min -1 [Line J]. Tetramethylammonium triacetoxyborohydride in 1-methyl- pyrrolidin-2-on (0.45 M) is pumped through 1/16” Tefzel™ tubing (I.D.1 mm) using a syringe pump at a flow rate of 0.09 mL min -1 [Line K]. 4-Aminobutan-1-ol in methanol (0.2 M) is pumped through 1/16” Tefzel™ tubing (I.D. 1 mm) using a syringe pump at a flow rate of 0.07 mL min -1 [Line L]. The lines J, K, L are joined in a crossmixer, which provided a continuous stream that is cooled to room temperature in a 4 mL reactor (Reactor 5, 1/16” Tefzel™ tubing (I.D. 1 mm), 16 min residence time). After reaching steady state (two residence times), the outlet is collected for 50 min and quenched with water, hexanes added, basified to pH 9.5 and the phases were separated. The organic phase is dried over Na 2 SO 4 . An aliquot of crude (476 mg) is purified on a plug of silica, by sequential washes with hexanes (with 0.1 v% of TFA), hexanes/ethyl acetate (4:1, with 0.1 v% of TFA) and pure ethyl acetate (with 0.1 v% of TFA). Washing the combined fractions of ethyl acetate with Na 2 CO 3 and removing the solvent under reduced pressure yields compound 6. Example 5: Preparation of a vaccine formulation comprising lipid nanoparticles Cationic lipid ALC-0315 (0.43 mg) obtained in Example 1, DSPC (0.09 mg), cholesterol (0.2 mg) and ALC-0159 (2-[(polyethylene glycol)-2000]-N,N ditetradecylacetamide, 0.05 mg) were solubilized in ethanol. Lipid nanoparticles (LP) were prepared at a total lipid to mRNA weight ratio of approximately 25:1. The mRNA (30 µg) was diluted to 0.2 mg/mL in citrate buffer, pH 4. Syringe pumps were used to mix the ethanolic lipid solution with the mRNA aqueous solution at a ratio of about 1:5 to 1:3 (vol/vol) with total flow rates above 15 mL/min. The ethanol was then removed and the external buffer replaced with PBS by dialysis. Finally, the lipid nanoparticles were filtered through a 0.2 μπι pore sterile filter. Lipid nanoparticle particle size was approximately 55-95 nm diameter, and in some instances approximately 70-90 nm diameter as determined by quasi-elastic light scattering.