ORTIZ ADRIAN (US)
WO2011006621A1 | 2011-01-20 |
BUGERA, M.: "Deoxofluorination of Aliphatic Carboxylic Acids: A Route to Trifluoromethyl-Substituted Derivative", J. ORG. CHEM., vol. 84, 2019, pages 16105 - 16115
CAS , no. 2306248-65-5
T. W. GREENEP. G. M. WUTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY & SONS, INC.
"Pharmaceutical Sciences,", 1985, MACK PUBLISHING COMPANY
R. LAROCK: "Comprehensive Organic Transformations", 1989, VCH PUBLISHERS
L. FIESERM. FIESER: "Fieser and Fieser's Reagents for Organic Synthesis", 1994, JOHN WILEY AND SONS
L. PAQUETTE: "Encyclopedia of Reagents for Organic Synthesis", 1995, JOHN WILEY AND SONS
CLAIM: What is claimed is: 1. A stereoselective process for the preparation of a compound having formula (2): (2); wherein X is halo; comprising a. contacting a compound of formula ; wherein X is as defined above in compound (2); and COOR1 is an ester group; with an ester hydrolyzing agent in a solvent; to form said compound (2); and optionally followed by a process of purifying said compound (2) by (a1) contacting said compound (2) with a base in a solvent to form a salt of compound (2); and (a2) contacting said salt of compound (2) with an acid in a solvent at a low temperature to form a purified form of compound (2). 2. The process according to claim Error! Reference source not found., further comprising preparing said compound (3) comprising: (b) contacting a compound of formula ); wherein said R1 is as defined above in compound (3); with a deoxyhalogenating agent in an organic solvent, optionally at a low temperature, to form said compound (3). 3. The process according to claim 2, further comprising preparing said compound (4) comprising: contacting a compound of formula (5): (5); wherein said R1 is as defined above in compound (4); with (c1) a metal catalyst in an organic solvent at a low temperature; or (c2) a biocatalytic agent in an organic solvent and in the presence of a buffer solution; to form said compound (4). 4. The process according to claim 3, further comprising preparing compound (5) comprising: (d) contacting a compound of formula (6): (6); with an R1 agent, in the presence of a base; wherein R1 is as defined above in compound (5); in an organic solvent to form said compound (5). 5. The process according to claim 1, further comprising preparing a compound of formula ; wherein said X is as defined above in compound (2); comprising: contacting said compound (2) with a trifluoromethylating agent in an organic solvent to form said compound of formula (1). 6. The process according to any one of claims 1 to 5, wherein X is bromo or iodo. 7. The process according to any one of claims 1 to 6, wherein X is bromo. 8. The process according to any one of claims 1 to 7, wherein R1 is (C1-C6)alkyl, phenyl, or benzyl. 9. The process according to any one of claims 1 to 8, wherein R1 is benzyl. 10. The process according to any one of claims 1 to 9, wherein in (a), said ester hydrolyzing agent is an alkali metal hydroxide or a lipase enzyme. 11. The process according to any one of claims 1 to 10, wherein in (a), said ester hydrolyzing agent is an alkali metal hydroxide and said solvent is a mixture of methyl-THF and water. 12. The process according to any one of claims 1 to 11, wherein in (a), said ester hydrolyzing agent is sodium hydroxide, potassium hydroxide, or lithium hydroxide. 13. The process according to any one of claims 1 to 12, wherein in (a), said ester hydrolyzing agent is lithium hydroxide or sodium hydroxide. 14. The process according to any one of claims 1 to 10, wherein in (a), said ester hydrolyzing agent is a lipase enzyme and said solvent is acetone or (C1-C6)alcohol. 15. The process according to any one of claims 1 to 13, wherein in (a1), said base is a primary, secondary, or tertiary amine base. 16. The process according to any one of claims 1 to 14, wherein in (a1), said base is tert-butyl amine and said salt of compound (2) has a formula: ( te t-butyl amine salt). 17. The process according to any one of claims 1 to 15, wherein in (a1), said solvent is a mixture of n-heptane and MTBE. 18. The process according to any one of claims 1 to 16, wherein in (a2), said acid is sulphuric acid, phosphoric acid, or acid halide selected from HCl or HBr. 19. The process according to any one of claims 1 to 17, wherein in (a2), said solvent is water. 20. The process according to any one of claims 2 to 19, wherein in (b), said deoxyhalogenating agent is triphenyl phosphite in the presence of NBS; or triphenyl phosphine in the presence of NBS. 21. The process according to any one of claims 2 to 20, wherein in (b), said organic solvent is DMF, acetonitrile, toluene, or dichloromethane. 22. The process according to any one of claims 3 to 21, wherein in (c1), said metal catalyst is a metal hydride. 23. The process according to any one of claims 3 to 22, wherein in (c1), said solvent is THF, acetonitrile, toluene, dichloromethane, (C1-C8)alcohol, or any mixtures thereof. 24. The process according to any one of claims 3 to 21, wherein in (c2), said biocatalytic agent is a ketoreductase enzyme. 25. The process according to any one of claims 3 to 21, or 24, wherein in (c2), said solvent is (C1-C8)alcohol, or a mixture of water and (C1-C8)alcohol. 26. The process according to any one of claims 3 to 21, or 24 to 25, wherein in (c2), said buffer is selected from phosphate, triethanol amine, PIPES, BICINE, TES, TRIS, HEPES, TRICINE, CHES, or CAPS. 27. The process according to any one of claims 3 to 21, or 24 to 26, wherein in (c2), said buffer is triethanol amine. 28. The process according to any one of claims 4 to 27, wherein in (d), said R1 agent is (C1-C6)alkyl halide, phenyl halide, or benzyl halide. 29. The process according to any one of claims 4 to 28, wherein (d) is performed in the presence of a base, wherein said base is a bicarbonate, carbonate, or tri(C1-C6)alkylamine base. 30. The process according to any one of claims 4 to 29, wherein in (d), the solvent is dichloromethane, DMF, THF, or acetonitrile. 31. The process according to claim 5, wherein said trifluoromethylating agent is sulfur tetrafluoride (SF4), in the presence of hydrogen fluoride (HF), and optionally in the presence of a solvent. 32. The process according to any one of claims 5 or 31, wherein said trifluoromethylating agent is sulfur tetrafluoride (SF4), in the presence of hydrogen fluoride (HF), and said process is performed in the presence of dichloromethane. |
[0035] In one embodiment, the compound of formula (4) can be formed with a stereoselectivity for compound cis-4 having LCAP of at least 74%. In one aspect of this embodiment, the stereoselectivity can have LCAP of at least 75%. In a more particular aspect of this embodiment, the stereoselectivity can have LCAP of at least 93%. In a more particular aspect of this embodiment, the stereoselectivity can have LCAP of at least 99%. [0036] The process of this invention requires the presence of a hydride source. The term "hydride source" refers to a compound or mixture that is capable of providing a hydride anion or a synthetic equivalent of a hydride anion. A hydride source may be used in catalytic or stoichiometric amounts. In case of the use of enzymes (KRED), additional co-factors are required in a catalytic amount. Thus, this combination of co-factor and KRED enzyme work together to regenerate a hydride from isopropyl alcohol and enable the reduction of the substrate. [0037] A co-factor used with the ketoreductase enzyme in this process of the present invention is selected from Nicotinamide adenine dinucleotide (NAD), Nicotinamide adenine dinucleotide phosphate (NADP), Nicotinamide adenine dinucleotide hydrogen (NADH), and Nicotinamide adenine dinucleotide phosphate hydrogen (NADPH). The choice of co-factor may be based upon the presence or absence of a co-factor regeneration system. In embodiments where the hydride source does not comprise a co-factor regeneration system, the co-factor is in a stoichiometric amount and is a reduced co-factor which is therefore selected from NADH and NADPH for a hydride source. It is well known in the art, or information is available from the commercial supplier of the specific ketoreductase whether NADH or NADPH is the appropriate co-factor for a given ketoreductase. See, for example, https://www.codexis.com/wp-content/uploads/KRED-Product-Info rmation.pdf. In this embodiment, the reduced co-factor is present in stoichiometric amounts as compared to the compound (5). [0038] In another embodiment, the hydride source additionally comprises a co-factor regeneration system. The high cost of co-factors makes their use on a stoichiometric basis impractical. A low-cost co-factor regeneration system continually produces and regenerates the reduced form of the cofactor, requiring the co-factor to be present in only catalytic amounts. Moreover, the use of a co-factor regeneration system eliminates the need to use a reduced co- factor. The co-factor regeneration system produces the required reduced co-factor in situ. Accordingly, any cofactor or combinations of cofactors compatible with the chosen ketoreductase can be employed with a co-factor regeneration system. In this embodiment, therefore, NAD is interchangeable with NADH; and NADP is interchangeable with NADPH. Similarly, the designations "-NAD" and "-NADH", and "-NADP" and "-NADPH", respectively, are used interchangeably herein in conjunction with enzymes that use, respectively, NADH and NADPH as co-factors. [0039] Suitable buffers include phosphate, triethanol amine, PIPES, BICINE, TES, TRIS, HEPES, TRICINE, CHES, or CAPS. Preferably, the buffer is triethanol amine. [0040] Step 3: Deoxyhalogenation [0041] Treatment of a compound of formula (4) wherein R 1 is as defined in the Summary of the Invention, with a deoxyhalogenating agent provides a compound of formula (3), wherein X is halo and R 1 is as defined in the Summary of the Invention. The reaction is carried out in a suitable organic solvent such as DMF, acetonitrile, toluene, or dichloromethane, and the like, and takes place at a temperature between -10 o C to -5 o C, or -10 o C to 0 o C, preferably below 0 o C during the addition, and is then warmed to a temperature between 25 o C to 30 o C. The reaction takes between 1h to 2h, preferably 1h. Suitable deoxyhalogenating agents include triphenyl phosphite in the presence of NBS (preferred), or triphenyl phosphine in the presence of NBS. [0042] Ester Hydrolysis/Salt Formation [0043] Treatment of a compound of formula (3) wherein X is halo, with an ester hydrolyzing agent provides a compound of formula (2). The reaction with an ester hydrolyzing agent is carried out in a suitable solvent such as methyl THF/water, or acetone, and the like, and takes place at a temperature between 25 o C to 30 o C. Suitable ester hydrolyzing agents include alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide, lithium hydroxide. Preferably, the alkali metal hydroxide is lithium hydroxide or sodium hydroxide. When alkali metal hydroxides are used, the suitable solvent is polar solvent such as a mixture of methyl-THF and water. [0044] Alternatively, said ester hydrolyzing agent is a lipase enzyme. Suitable lipase enzymes include, for example, enzymes originated from a microorganism of Candida, such as Candida cylindracea and Candida rugosa, a microorganism of Chromobacterium chocolatum, pig liver and a thermophilic microorganism. Preferably, the lipase enzyme is Lipase PS Amano SD enzyme (AMANO ENZYME Inc., Nagoya, Japan), originated from Burkholderia cepacian, CAS #: 9001-62-1, LOT #: LPS1050808SD; in the presence of a buffer, such as phosphate buffer, and takes place at a temperature between 25 o C to 30 o C, for 24 h. When a lipase enzyme is used, the suitable solvent is acetone or (C 1 -C 6 )alcohol, such as propanol or isopropyl alcohol. [0045] Enzymatic resolution of the isomeric mixture may be achieved using techniques generally known in the art, including for example contacting an isomeric mixture with a suitable lipase enzyme, in order to selectively hydrolyze an ester moiety of the compound of Formula (3) or (3a), which is compound (3) wherein X is bromo and R 1 is benzyl. Due to the neutral pH conditions that are utilized with the lipase enzymes, the present inventors do not observe the by-products, such as diphenylphosphoric acid. Such by-product’s physical properties are similar to the carboxylic acid product compound (2), which makes it difficult and tedious to remove without the use of lipase enzymes. [0046] Preferably, the above ester hydrolysis step to form compound (2) followed by a process of purifying compound (2) is followed by purification of the compound (2) product. The purification process is done in two step reaction. The first step is reacting compound (2) with a base in a solvent to form a salt of compound (2); and then, in the second step, the salt of compound (2) is reacted with an acid in a solvent at a low temperature to form a purified version of compound (2). [0047] In the first step, suitable base includes an amine base, such as a primary, secondary, or tertiary amine base. Preferred base is tert-butyl amine. Metal salts, such as sodium or calcium salts, can also be made to purify compound (2), however, Aminium salt is preferred compared to metal salts because the metal salts were found to be hygroscopic. Suitable solvent in the salt formation step includes n-heptane/MTBE, and the like. Each of the reactions takes between 12h to 24h, preferably 16h. [0048] In the second step, the salt of compound (2) obtained from the first step is reacted with an acid to form purified compound (2). Suitable acid includes sulphuric acid, phosphoric acid, or acid halide selected from HCl or HBr. Preferably, the acid is HCl. Suitable solvent includes water, lower alcohol, or mixture thereof. The reaction takes place at a temperature between -5 o C to 10 o C, preferably between 0 o C to 5 o C, most preferably at 0 o C. The reaction takes between 1h to 2h, preferably 1h. [0049] Trifluoromethylation ( ) [0050] Treatment of a compound of formula (2), wherein X is halo, with a trifluoromethylating agent provides a compound of formula (1). The reaction is carried out in a suitable organic solvent such as dichloromethane, DMF, DMSO, and the like, and takes place at a temperature between -78 o C to 30 o C. It is essential to maintain the reaction temperature to not exceed 30 o C because higher temperature was found to result in lower yield of compound (1a), which is compound (1) wherein X is bromo. The reaction takes between 12h to 24h, preferably 12h. Suitable trifluoromethylatings include SF4/HF reagentThose skilled in the art would understand that the above processes of the present invention can be performed in various orders and are not limited to the orders of the s described in the generic procedures above. The present inventors contemplate that the order of the reaction s of the present invention can vary. For example: [0051] The invention will now be described in reference to the following specific Examples. These examples are not to be regarded as limiting the scope of the present invention, but shall only serve in an illustrative manner. [0052] The following abbreviations are used throughout the description and appended claims, and they have the following meanings: [0053] “DCM” means dichloromethane. [0054] “DMSO” means dimethylsulfoxide [0055] “EtOAc” means ethyl acetate [0056] “h” means hour or hours [0057] “HPLC” means high performance liquid chromatography [0058] “IPA” means isopropyl alcohol. [0059] “LCAP” means liquid chromatography area percent [0060] “LCMS” means liquid chromatography mass spectrometry [0061] “LiCl” means lithium chloride [0062] “mins” means minutes [0063] “MTBE” means methyl tertiary-butyl ether. [0064] “rt” or “RT” means room temperature [0065] “temp” means temperature [0066] “t-bu” means tert-butyl [0067] The chemicals used in the synthetic routes delineated herein include, for example, solvents, reagents, and catalysts. The methods described above may also additionally include steps, either before or after the steps described specifically herein, to add or remove suitable protecting groups in order to ultimately allow synthesis of the compounds. In addition, various synthetic s may be performed in an alternate sequence or order to give the desired compounds. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof. [0068] All reagents, starting materials, and solvents (laboratory grade or anhydrous grade) were used as received. Purity was determined using reverse-phase HPLC. Chemical shifts (δ) for protons and carbon are reported in parts per million (ppm) referenced to tetramethylsilane (δH = 0.00, δC = 0.00) or to residual proton or carbon in the NMR solvent (CDCl3: δH = 7.26 ppm, δ C = 77.2 ppm. [0069] EXAMPLES: EXPERIMENTAL PROCEDURES [0070] Example 1: Synthesis of benzyl 3-oxocyclobutane-1-carboxylate (5a) [0071] To a solution of 3-oxocyclobutane carboxylic acid (6), available in Sigma-Aldrich, (1.12 kg, 9.82 mol, 1.2 eq.) in DMF (9.8 L, 7 L/kg) in a glass reactor were added potassium bicarbonate (2.05 kg, 20.46 mol, 2.5 eq.) and benzyl bromide (1.4 kg, 8.19 mol, 1.0 eq.) under a nitrogen atmosphere at 25-30 °C. The reaction mixture was stirred at 25°C to 30°C for 16 h. After the reaction was adjudged complete by HPLC, the reaction mixture was cooled to 5°C to 10°C, quenched by the addition of water (14.0 L, 10 L/kg) and diluted with MTBE (14.0 L, 10 L/kg). The contents were warmed to 25°C to 30°C and the phases separated. The aqueous phase was extracted with MTBE (7.0 L, 5 L/kg) and the combined organic phase was washed with 20 wt% aq. LiCl solution (7.0 L, 5 L/kg) twice. The organic phase was distilled under vacuum at 35°C to 40°C to about 2 L. The resulting concentrate was swapped with isopropanol (3.5 L, 2.5 L/kg) under vacuum at 40°C to 45 °C twice to about 1.5 L to produce Benzyl (1S,3S)-3- hydroxycyclobutane-1-carboxylate (5a) (1677 g, 95.8 HPLC area % purity, 90.6% assay by HPLC) as a pale brown liquid in 94% yield. A sample was withdrawn, distilled to dryness under reduced pressure (<10 mbar) at 45°C to 50°C and the resulting liquid analyzed by NMR and LCMS. [0072] 1 H NMR (400 MHz, CDCl3): 7.33-7.43 (m, 5H), 5.21 (s, 2H), 3.39-3.48 (m, 2H), 3.28-3.34 (m, 3H). 13 C NMR (75 MHz, CDCl 3 ): 203.6, 173.9, 135.5, 128.7 (2C), 128.5, 128.3 (2C), 67.1, 51.6 (2C), 27.4. MS: m/z 222.1 (M+H2O) + [0073] Example 2: Synthesis of benzyl (1S,3S)-3-hydroxycyclobutane-1-carboxylate (4a) [0074] METHOD A: METAL HYDRIDE CATALYST KETO REDUCTION [0075] To a pre-cooled (-5 °C to 5 °C) solution of compound (5a) (1.33 kg (75.3% assay by HPLC), 4.90 mol, 1.0 eq.) in THF (10.0 L, 10 L/kg) in a 30 L glass reactor was added a 1 M solution of lithium tri-tert-butoxy aluminum hydride in THF (5.4 L, 5.39 mol, 1.1 eq.) dropwise using a cannula over 2.5 h under nitrogen atmosphere. After the addition of the reagent was complete, the reaction mixture was stirred at -5 °C to 5 °C for another 1 h. After the reaction was adjudged complete (by HPLC), the reaction mixture was cautiously quenched by the addition of aq.1.5 N HCl (16.0 L, 16 L/kg) and the contents diluted with EtOAc (10.0 L, 10 L/kg). The contents were gradually warmed to 20 °C to 30 °C and stirred at 20 °C to 30 °C for 20 minutes. The aqueous phase was separated and extracted with EtOAc (5.0 L, 5 L/kg). The combined organic phase was washed with 30 wt% aq. NaCl solution (5.0 L, 5 L/kg) and distilled under vacuum at 40-45 °C to ~ 2 L. The resulting concentrate was swapped with toluene (2.5 L, 2.5 L/kg) under vacuum at 40°C to 45°C twice to about 1.5 L to give compound (4a) (1370 g, 84.7 HPLC area % purity, 65.9% assay by HPLC) as a pale brown liquid in 89% yield. * = chiral center [0077] Triethanol amine buffer was prepared by the addition of 188 g of triethanol amine and 1.68 g of MgSO 4 to 13.0 L of demineralized water. pH of the solution was found to be 10.0 and was adjusted to 7.0 by the addition of about 0.8 L of 1.5N aq. HCl. [0078] To a solution of benzyl (1R,3R)-3-bromocyclobutane-1-carboxylate (3a) (1.43 kg (90.6% assay by HPLC), 4.89 mol, 1.0 eq.) in isopropanol (13.0 L, 10 L/kg) in a glass reactor were charged KRED-P3-G09 (104 g, 8 wt%) and NAD (26 g, 2 wt%) under a nitrogen atmosphere at 25°C to 30°C. Triethanol amine buffer (pH 7.0, 13.0 L, 10L/kg) was added and the resulting contents stirred at 25°C to 30°C for 18 h. After the reaction was adjudged complete by HPLC, the reaction mixture was suction filtered through a short bed of CELITE® and the bed washed with EtOAc (13.0 L, 10L/kg). The filtrate was distilled under vacuum at 40°C to 45°C to remove most of the organic solvent and the resulting solution was diluted with EtOAc (13.0 L, 10L/kg). The aqueous phase was separated and extracted with EtOAc (13.0 L, 10 L/kg) twice. The combined organic phase was washed with 30 wt% aq. NaCl solution (6.5 L, 5 L/kg) and distilled under vacuum at 40°C to 45°C to about 2 L. The resulting concentrate was swapped with toluene (3.3 L, 2.5 L/kg) under vacuum at 40°C to 45°C twice to about 1.5 L to give compound (4a) (1592 g, 97.1 HPLC area % purity, 78.4% assay by HPLC) as a brown liquid in 95% yield. [0079] A sample was withdrawn, distilled to dryness under reduced pressure (<10 mbar) at 45°C to 50 °C and the resulting liquid analyzed by NMR and LCMS. 1 H NMR (400 MHz, CDCl3): 7.31-7.42 (m, 5H), 5.15 (s, 2H), 4.18 (p, J = 7.0 Hz, 1H), 3.21 (bs, 1H), 2.57-2.71 (m, 3H), 2.22-2.27 (m, 2H). 13 C NMR (75 MHz, CDCl3): 174.9, 135.9, 128.6 (2C), 128.3, 128.2 (2C), 66.5, 63.1, 37.02, 36.96, 28.9. MS: m/z 207.1 (M+H) + [0080] Example 3: Synthesis of benzyl (1R,3R)-3-bromocyclobutane-1-carboxylate (3a): [0081] To a pre-cooled (-5°C to -10°C) solution of triphenyl phosphite (226 g, 0.73 mol, 1.5 eq.) in CH3CN (0.3 L, 3 L/kg) in a glass reactor was added a solution of NBS (131 g, 0.73 mol, 1.5 eq.) in CH 3 CN (1.0 L, 10 L/kg) using an addition flask drop wise under a nitrogen atmosphere. It was ensured that the reaction mixture temperature was below 0°C during the addition. To the resulting solution was added a solution of compound (4a) (128 g (78.4% assay by HPLC), 0.49 mol, 1.0 eq.) in CH3CN (0.2 L, 2 L/kg) using an addition flask drop wise ensuring the reaction mixture temperature was below 0°C. The reaction was warmed to 25°C to 30°C and stirred for 1 h. After the reaction was adjudged complete (by HPLC), the reaction mixture was distilled under vacuum at 25°C to 30°C to remove most of the volatiles. The resulting residue was diluted with MTBE (1.0 L, 10L/kg) and filtered through a short bed of CELITE and the bed washed with MTBE (1.0 L, 10L/kg). The filtrate was washed with 2 wt% aq. Na 2 S 2 O 3 (1.0 L, 10L/kg) twice and distilled under vacuum at 40°C to 45°C to about 0.4 L to give crude compound (3a) (414 g, 33.7 HPLC area % purity, 25.5% assay by HPLC) as a dark brown liquid in 81% yield.3.6 g of (1R,3R)-3-Bromocyclobutane-1-carboxylic crude acid (2a) was also formed as side product in 4% yield. [0082] Analytical data of purified compound (3a): 1 H NMR (400 MHz, CDCl 3 ): 7.36-7.40 (m, 5H), 5.17 (s, 2H), 4.68 (p, J = 7.0 Hz, 1H), 3.46 (septet, J = 5.0 Hz, 1H), 2.93-3.00 (m, 2H), 2.69-2.77 (m, 2H). 13 C NMR (75 MHz, CDCl 3 ): 174.3, 135.7, 128.6 (2C), 128.3, 128.2 (2C), 66.6, 40.7, 37.6 (2C), 36.0. [0083] Note: The present inventors found that the distillation of the reaction mixture must be controlled at a temperature of under 30 °C. Higher temperature was found to result in increased formation of acid (crude 2a-acid). [0084] Examples 4a and 4b: Synthesis of 2-methyl propan-2-aminium (1R,3R)-3- bromocyclobutane-1-carboxylic acid (2a) and tert-butyl amine salt (2a t-BuNH 2 salt) [0085] BASIC ESTER HYDROLYSIS AND ACID PURIFICATION [0086] Example 4a-1: Synthesis of 2-methyl propan-2-aminium (1R,3R)-3- bromocyclobutane-1-carboxylic acid (2a): [0087] To a solution of crude compound (3a) (372 g (25.5% assay by HPLC), 0.35 mol, 1.0 eq.) in 2-methyl-THF (0.48 L, 5 L/kg) was added a solution of LiOH ^H 2 O (59 g, 1.41 mol, 4.0 eq.) in water (0.48 L, 5 L/kg) at 25°C to 30°C. The reaction mixture was stirred at 25°C to 30°C for 16 h. After the reaction was adjudged complete (by GC), the pH of the reaction mixture was adjusted to 8.0-8.5 by the addition of 1.5 N HCl and diluted with MTBE (0.48 L, 5 L/kg). The phases were separated, and the aqueous phase washed with MTBE (0.48 L, 5 L/kg). pH of the aqueous phase was adjusted to 3.0-3.5 by the addition of 1.5 N HCl and the resulting aqueous phase extracted with MTBE (0.48 L, 5 L/kg) twice. The combined organic extracts were washed with 30 wt% aq. NaCl solution (6.5 L, 5 L/kg) and distilled under vacuum at 40°C to 45°C to about 0.2 L. The resulting concentrate was swapped with n-heptane (3.3 L, 2.5 L/kg) under vacuum at 40°C to 45°C twice to give crude compound (2a) (330 g, 42.6 GC area % purity, 27.7% assay by GC) as a brown solid in 95% yield. [0088] Example 4a-2: Synthesis of (1R,3R)-3-bromocyclobutane-1-carboxylate 2- methylpropan-2-aminium: [0089] To the crude compound (2a) product of Example 4a was then added n-heptane (0.9 L, 10.0 L/kg) and CELITE (0.33 kg, 100 wt%) and the resulting slurry stirred at 45°C to 50°C for 2 h. The hot slurry was suction filtered, and the cake washed with hot n-heptane (0.9 L, 10.0 L/kg). The filtrate was cooled to 45°C to 50°C, diluted with MTBE (0.2 L, 2 L/kg) and a solution of tert-butyl amine (59 mL, 0.56 mol, 1.1 eq.) in n-heptane (0.2 L, 2 L/kg) was then added under a nitrogen atmosphere at 25°C to 30°C and stirred for 16 h. The solids were suction filtered, washed with n-heptane (0.2 L, 2 L/kg) and dried under vacuum at 40°C to 45°C to give (1R,3R)-3-bromocyclobutane-1-carboxylate 2-methylpropan-2-aminium (Compound 2a t-BuNH 2 salt) (103 g) as an off-white solid in 96% yield. [0090] 1 H NMR (400 MHz, CDCl3): 6.95 (bs, 3H), 4.68 (p, J = 7.0 Hz, 1H), 3.16 (septet, J = 4.8 Hz, 1H), 2.81-2.88 (m, 2H), 2.61-2.69 (m, 2H), 1.33 (s, 9H). 13 C NMR (75 MHz, CDCl3): 181.0, 50.6, 42.5, 39.0, 38.9 (2C), 27.8 (3C). [0091] Example 4a-3: Salt hydrolysis to Compound (2a): [0092] To the pre-cooled (0°C to 5°C) solution of the above Compound 2a t-BuNH2 salt (12.6 g, 50 mmol, 1.0 eq.) in water (50 mL, 4 L/kg) was added 11.2N aq. HCl (5 mL, 0.4 L/kg) drop wise until the pH of the reaction mixture was about 1 to 2. The resulting solids were stirred at 0°C to 5°C for 1 h. The solids were then suction filtered, washed with cold water (50 mL, 4 L/kg) and dried under vacuum at 25°C to 30°C to give purified compound (2a) (7.4 g) as an off-white solid in 82% yield. 1 H NMR (400 MHz, CDCl3): 9.33 (bs, 3H), 4.68 (p, J = 7.0 Hz, 1H), 3.43 (septet, J = 5.0 Hz, 1H), 2.93-3.00 (m, 2H), 2.71-2.78 (m, 2H). 13 C NMR (75 MHz, CDCl3): [0093] ENZYMATIC ESTER HYDROLYSIS [0094] Example 4b-1: Synthesis of (1R,3R)-3-bromocyclobutane-1-carboxylic acid (Crude 2 [0095] To a solution of crude compound (3a) 300 g (25 % assay by HPLC), 0.27 mol, 1.0 eq.) in IPA: phosphate buffer (pH 7) (1:1), (3 L, 10 L/kg) was added Lipase PS Amano SD (18.75 g, 0.25 w/w) at 25°C to 30°C in a glass reactor. The reaction mixture was stirred at 25°C to 30°C for 10 minutes. The pH of the reaction mixture was adjusted from 6.54 to 7.0 using saturated aq. K3PO4 solution. The reaction mixture was stirred at 25°C to 30°C for 24 h. After the reaction was adjudged complete (by GC), the contents were filtered through CELITE and the CELITE bed was washed with H2O (3 L, 10 L/kg). The filtrate was distilled in vacuo at 35 °C to remove most of the volatiles. Next, the pH of the residue was adjusted from 6.76 to 3.0 using concentrated HCl. The contents were extracted with MTBE (6 L, 20 L/kg) and the organic phase concentrated completely under vacuum to give crude compound (2a) (266.86 g, 71.4 GC area % purity, 18.0% assay by GC) as a brown solid in 93.8% yield. [0096] Example 4b-2: Synthesis of 2-methylpropan-2-aminium (1R,3R)-3-bromocyclobutane- 1-carboxylate (3) [0097] To a solution of crude compound (2a) 252.6 g (46.88 g, assay corrected by HPLC), 0.17 mol, 1.0 eq.) in n-heptane:MTBE (9:1) (940 mL, 20 L/kg) in a glass reactor, was added a solution of tert-butyl amine (21 mL, 0.187 mol, 1.1 eq.) in n-heptane (200 mL, 4.3 L/kg) drop wise using syringe at 25°C to 30°C. The reaction mixture was stirred under a nitrogen atmosphere at 25°C to 30°C for 16 h and observed solids in the reaction mixture. Next, acetone (700 mL, 15 L/kg) was added into the reaction mixture to obtain a uniform slurry. The solids were suction filtered, washed with n-heptane (230 mL, 5 L/kg) and dried under vacuum at 40°C to 45°C to give compound (2a t-BuNH 2 salt) (37 g) as an off-white solid in 56% yield. [0098] 1 H NMR (400 MHz, CDCl3): 6.89 (bs, 4H), 4.65 (q, J = 0.8 Hz, 1H), 3.14 (septet, J = 4.8 Hz, 1H), 2.79-2.85 (m, 2H), 2.58-2.65 (m, 2H), 1.31 (s, 9H). [0099] Example 4b-3: Synthesis of (1R,3R)-3-bromocyclobutane-1-carboxylic acid (2a): [00100] To a solution of compound (2a t-BuNH2 salt) (35 g, 0.13 mol, 1.0 eq.) in water (140 mL, 4 L/kg) was added 11.2N aq. HCl (19.3 mL, 0.21 mol) at 25°C to 30°C drop wise until the pH of the reaction mixture was 1-2. The reaction mixture was warmed to 40-45 °C and the contents stirred at 40°C to 45°C for 1 h. Next, the contents were cooled to 25-30 °C and stirred at 25-30 °C for 1 h. Further cooled the contents to 0°C to 5°C and stirred at 0°C to 5°C for 1 h. The solids were suction filtered, washed with cold water (50 mL, 1.5 L/kg) and dried under vacuum at 25°C to 30°C to give purified compound (2a) (12 g) as an off-white solid in 50% yield. [00101] 1 H NMR (400 MHz, CDCl3): 9.33 (bs, 3H), 4.66-4.70 (m, 1H), 4.69 (p, J = 7.0 Hz, 1H), 3.43 (septet, J = 5.0 Hz, 1H), 2.95-3.01 (m, 2H), 2.72-2.79 (m, 2H). 13 C NMR (75 MHz, CDCl3): 13 C NMR (75 MHz, CDCl3): 181.1, 40.3, 37.5, 36.0. [00102] Example 5: Synthesis of (1R,3R)-1-bromo-3-(trifluoromethyl)cyclobutene (5a) [00103] To a stirred dichloromethane (DCM) (4.0 vol) solvent was charged trans-1-bromo- 3-cyclobutanecarboxylic acid (1.0 eq) and anhydrous hydrogen fluoride (0.13 vol). The solution was transferred to a suitably sized autoclave under static vacuum. Sulphur tetrafluoride (3.0 eq) was charged to the autoclave under 20 Bar of pressure. The reaction was heated at 30℃ for a period of 16 hours, and then allowed to cool back to room temperature. The reaction mixture was quenched on to ice (69.4 eq) and washed through with DCM (13.3 vol). The combined ice/DCM reaction mixture was basified by the addition of 25% potassium hydrogen carbonate solution (13.3 vol). The layers were separated and further extracted with DCM (3 x 6.7 vol). The combined organic phases were dried with magnesium sulphate and filtered. The product was isolated by distillation (boiling point 112℃ to 114℃) to give typical yield of 70% to 80% of compound (1a). The yield was 67% at 1000 gram scale. A second distillation was conducted (94% recovery) to ensure quality and purity of the product, which is colorless liquid. GC analysis (excluding DCM) showed 97.4% of the desired trans isomer product (1a) and 1.1% of the cis isomer. GC purity: 96.82%. [00104] 1 HNMR (400 MHz, CDCl 3 ) ppm: 4.60 (quin, J = 7.20 Hz, 1H), 3.16-3.30 (m, 1H), 2.84-2.93 (m, 2H), 2.74-2.67 (m, 2H). 19 FNMR (376.46 MHz, CDCl3): 2.60 (s). [00105] The foregoing invention has been described in some detail by way of illustrations and examples, for purposes of clarity and understanding. Those skilled in the art understand that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. [00106] All patents, patent applications and publications cited herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.
Next Patent: TOOTHED POWER TRANSMISSION BELT FOR USE IN OIL