The present invention relates to a process for the preparation of carbamoyiamino pyrazole derivatives using diacetoxyiodobenzene (Ph!(OAc)?) in combination with a non-nuc!eophi!ic base,

Carbamoyiamino pyrazole side chains are, e.g., found in cephalosporine antibiotics, such as Ceftolozane. Ceftolozane, having the systematic IUPAC name (6 7R)-3-([3-Aminc-4- (2-arriinoethylcarbamoylamino)-2-methylpyrazol-1 -ium-1 -yl]methyi)-7-([(2Z)-2-(5-amin 1 ,2,4-thiadiazol-3-yl)-2-(2-carboxypropan-2-yloxyimino)acetyl ]amino)-8--oxo-5-thia-1 - azabicyclo[4.2.0]oct-2-ene-2-carboxylate is depicted below:

In the prior art, the carbamoyiamino pyrazole side chain of Ceftolozane is made from 1 - methyi-1 H-pyrazoie-4,5-diamine, followed by further functionalization of the 4-amino group to build up the urea moiety (WO2004/039814 and Bioorganic & Medicinal Chemistry Letters 2008, 18, 4849 which disclose slightly different conditions in some steps. A different sequence of steps 3, 4 and 5 is also disclosed in both documents which does not change the concept of the synthetic route):

However, it is a lengthy procedure, and the synthesis of 1 -methyl- 1 H-pyrazole-4,5-diamine requires the formation of a genotoxic and potentially explosive nitroso intermediate, followed by reduction with a transition (heavy) metal and a hazardous hydrogen atmosphere. Furthermore, the described functionalization of the 4-amino group with CDI/BocEDA was not found to be reproducible by the present inventors.

Therefore, there is a need for an improved synthesis of carbamoylamino pyrazoles such as the side chain of Ceftolozane.

All known examples in the literature to the key building block 1 H-pyrazole-4,5-diamine derivative involve the reduction of nitro or nitroso intermediates as shown;

various starting materials

x = 1 or 2 {nitroso or nitro)

Only one conceptually different approach to pyrazole-4,5-diamine derivatives has been disclosed, which is based on the Curtius rearrangement of the corresponding ester via an acyl azide intermediate (Tetrahedron Letters, 2004, 45, 4105). However, it is also a lengthy sequence of steps with an unstable acyl azide intermediate, and no yields are given:

yields not given A different approach to 1 H-pyrazole-4,5-diamtne derivatives might involve a Hofmann rearrangement of 5-amino-1 H-pyrazole~4-carboxamide derivatives;

However, Hofmann rearrangements of 1 H-pyrazo!e-4-carboxamides are generally low- yielding, US5201938A1 and Rus. Chem. Bull. 1993, 42, 1552 describe the Hofmann reaction of 1 H-pyrazole-4-carboxamide derivatives with Br2/NaOH to give 1 H-pyrazole-4- amines in only 46% and 47% yield, respectively. The present inventors found that when re/1- butyl (4-carbamoyl-1 -methyl- 1 H-pyrazol-5-yl)carbamate is prepared and subjected to classical Hofmann reagents (NaOCI, NBS, 8r ₂ ), this leads to recovery of the starting material or decomposition (see comparative example 1 ):

When using the milder reagent Phi(OAc) ₂ and KOH/H ₂ 0 with rert-butyl (4-carbamoyl-1 - methyl-1 H-pyrazol-5-yl)carbamate, the inventors of the present invention could obtain the desired 4,5-diaminopyrazole derivative, but in only 48% yield, and it could be shown that the hypervalent iodine reagent decomposes the primary amine product during the reaction (see comparative example 2):

The present inventors found that the problem of aminopyrazole instability can be solved by trapping the isocyanate intermediate in situ with an alcohol to make a more stable derivative (see comparative example 3):

However, in the context of Ceftolozane side chain synthesis, this would introduce an extra step of carbamate deprotection, which is undesirable.

Thus, there is a need for an improved, more efficient synthesis of carbamoylamino pyrazoles, such as the side chain of Ceftolozane that among other things avoids genotoxic and explosive intermediates such as nitroso compounds and hazardous reagents such as transition metals or hydrogen gas.

It was now surprisingly found by the inventors of the present invention that 5-amino-1 H- pyrazoIe-4-carboxamide substrates can undergo Hofmann rearrangement with Phl(OAc)2 and low amounts of an amine nucieophiie to directly make a stable unsymmetrical urea when used in combination with a non-nucleophiiic base.

The overall synthetic sequence of the present invention is shown in an exemplary manner below: NHBoc

R-t = ₂ = Boc Ri = Boc R-i = Boc

or R, = Tr, R ₂ = H or R ₁ = Tr or = Tr

Using this novel method, 5-amino-1 H-pyrazole-4-carboxamide derivatives can be converted to 4-ureido-5-amino-pyrazole derivatives in one pot. This method can therefore give the side chains of Ceftolozane and other cephem compounds: a) without any nitro- or nitroso-intermediates or transition metals/hydrogen gas b) with a shorter reaction sequence than in the process of the prior art - meaning that fewer resources, isolation and purification steps are required Furthermore, the novel method: c) relies on a Hofmann rearrangement with useful reagents (PhI(OAc)2) and reagent stoichiometries (no large excess)

d) gives good yields, has proven scalability (kg-scale demonstrated) and tolerates different protecting groups on the 5-amino group

e) requires no chromatographic purification of any intermediates or the product.

The present invention thus relates to a process for production of a compound of formula

wherein

Ri is H, straight or branched Ci-Ce alkyl, optionally substituted by 1 to 5 hydroxy groups which may be protected or halogen atoms,

F¾ is H, straight or branched Ci-Ce alkyl or an amino protecting group, or Ri and F¾ are bonded together to form d-Ce alkyiene or C Ce alkeny!ene,

R:¾ is H, straight or branched Ci-Ce alkyl or an amino protecting group, wherein f¾ is not H if R ₂ is H,

wherein

a is 0, 1 , 2, 3, 4, 5 or 6,

Rs is H or hydroxy which may be protected, and

Re is H, Ci-Ce straight or branched alkyl, mono or di straight or branched Ci-Ce alkyiamino, Cs-Ce cycloalkyl, Ca-Ce cycloalkyl amino, Ce-Ciz aryl or C6-C12 aryi amino, protected amino, protected guanidino or a saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms, wherein the cycloalkyl or aryl is optionally substituted by one or more C<- Cs straight or branched alkyl and the heterocyclic group is optionally substituted by one or more protected amino groups comprising reacting the compound of formula

wherein R , R ₂ and i¾ are as defined above with a compound of formula

wherein a, (¾ and Re are as defined above and Phl(OAc)2 in the presence of a non-nucleophilic base to produce the compound of formula I.

Such novel process has not been suggested considering the known process for the 4- ureido-pyrazole side chain production of Ceftolozane of the literature. It is further noted that - even in fields other than Ceftolozane (or cephem) synthesis - described methods for Hofmann urea synthesis: a) have not involved 5-amino-1 H-pyrazole-4-carboxamides to the best of the inventors ^' knowledge,

AND b) involve highly toxic metals like Pb or Hg which are incompatible with a pharmaceutical process (J. Org, Chem. 1975, 40, 3554), OR

c) when employing ΡηΙ(ΟΑ require a very large excess of the amine nucleophile (used as a solvent) which limits the methods to very simple and inexpensive amines like methylamine, and do not employ a non-nucieophilic base in the process (Synth, Comm. 2005, 35, 2735; ACS Chem. Lett. 2014, 5, 1284), OR

d) when employing Phl(OAc)2 can only make symmetrical ureas by reacting 2 equivalents of the starting material which is not useful for the desired transformation (Eur J. Org. Chem. 2012, 1994; Synlett 2010, 1 104), OR e) when employing only a small excess of amine require the use of PhIO which is much more expensive and unstable than Phl(OAc)2 (PhIO requires storage at -20 °C, is explosive upon heating). (Eur J. Org. Chem. 2012, 1994).

In a preferred embodiment of the present invention Ri is straight or branched C<-Cs alkyl.

Suitable straight or branched C--C ₆ alkyl (to be used e.g. as Ri ) include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl and hexyl. In a more preferred embodiment, Ri is straight or branched C1-C4 alkyl.

Ri can e.g. also be straight or branched Ci-C _{i alkyl substituted by 1 to 5 hydroxy groups or halogen atoms, such as chlorine, bromine, iodine and fluorine, including hydroxymethyl, 1 - hydroxyethyl, 2-hydroxyethyl, 1 -hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 4- hydroxybutyl, 5-hydroxypentyl and β-hydroxyhexyl, wherein the hydroxy group(s) may be protected in each case, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, bromomethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2, 2, 2-trifIuoroethyI , 2-chloroethyl, 2,2- dichloroethy!, 2, 2, 2-trichloroethyl, 3-fluoropropyl or 2, 2, 3, 3, 3-pentafluoropropyl. In one embodiment, Ri is straight or branched C1-C4 alkyl substituted with one hydroxy group which may be protected. In another embodiment, Ri is straight or branched C1-C4 alkyl substituted with 1 , 2 or 3 halogen atoms.

Suitable hydroxy protecting groups are, e.g., C/,-C2o-tert-alkyl groups, preferably C4-C20- tert-alkyl groups which carry a tertiary carbon atom in the 1 -position, such as tert-butyl, 1 ,1-dimethylprop-1 -yl, 1 , 1-dimethylbutyl-1 -yl, 1 , 1 ,2-trimethylprop-1 -yl, 1 , 1 - dimethylpent-1 - yl, 1 , 1 ,2-trimethylbut-1-yl, 1 , 1 ,3-trimethyl-but-l -yl, 1 -ethy!-1-methyl-but-1 -yl, 1 , 1 - dimethylhex-1-yl and 1 , 1 -dimethyl-2-ethylbut-1 -yl; C3-C ₂ o-trialkylsilyl groups, preferably C ₃ - Ca-trialkylsilyl groups such as trimethylsilyl, triethylsilyl, tri-n-propylsilyi, tri-propylsilyl, tri-n- butylsilyl, dimethylethylsilyl, diethylmethylsilyl, dimethyl-n-propylsilyl, dimethyl-iso- propylsi!yl, dimethyi-n-butyisilyl, and dimethyl-tert-butylsilyl; lower alkylarylsi!yl groups, preferably diphenylmethylsilyl, phenyldimethylsilyl, diphenyl-t-butylsilyl; benzyl; 3,4- dimethoxybenzyl; benzyloxymethyi; p-(trimethylsilyl)ethoxymethyl; p-methoxybenzyl; ally!; allyloxycarbonyl; acyl; lower alkoxy lower alkyl groups, preferably methoxymethyl, ethoxy methyl, methoxyethoxymethyl or cyclic acetal groups, such as 2-furanyi, 2- tetrahydrofuranyl, 2-pyranyl, 2-tetrahydropyranyl, 1 ,3-dioxan-2-yl, 1 ,3-dioxan-4-yl and 1 ,4- dioxan-2-yl.

In a preferred embodiment of the present invention f¾ is an amino protecting group. The process of the present invention tolerates different protecting groups.

Suitable amino protecting groups in the present invention include e.g. an acyl group as mentioned below, an aryl lower alkylidene (e.g., benzylidene), and aryl lower alkyl such as mono-, di- or tripheny! lower alkyl (e.g., benzyl, phenethyl, benzhydryl, trityl). Protecting groups for hydroxy and amino functionalities and introduction of protecting groups and later elimination after completion of the reaction are processes known to the skilled person from, for example, "Greene's Protective Groups in Organic Synthesis" by Peter G. M. Wuts and Theodora W. Greene, 4 ^ih Ed. 2007, published by John Wiley and Sons, Inc.

"Lower" herein means Ci-Ce, if nothing else is obvious or indicated. So, for example, lower alkyl means herein Ci-Ce alkyl if nothing else is indicated or obvious to the skilled person; lower alkylidene means Ci-Ce alkylidene herein, if nothing else is indicated or obvious to the skilled person.

Aryl herein, e.g., refers to phenyl or naphthyl, phenyl being more preferred.

Suitable "acyl" groups in the present invention are e.g. lower alkanoyl (e.g., formyl, acetyl, propionyl, hexanoyl, pivaloyl, etc.), mono or di or tri halo lower alkanoyl (e.g., chloroacetyl , trifluoroacetyl, etc.), lower alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert- butoxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl, etc.), carbamoyl, aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.), aryl lower alkanoyl (e.g., phenylacetyl, phenylpropionyl, etc.), aryioxycarbonyl (e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.), aryloxy lower alkanoyl (e.g., phenoxyacetyl, phenoxypropionyl, etc.), arylg!yoxy!oy! (e.g., phenylglyoxy!oyl, naphthylg!yoxyloy!, etc.), and aryl lower alkoxycarbonyl which is optionally substituted by e.g. 1 -3 suitable substituent(s), such as nitro, halogen or lower alkyl substituents (e.g., benzyloxycarbonyl, phenethyloxycarbonyl, p- nitrobenzyloxycarbonyl, etc.).

Preferable examples of "amino protecting groups" include aryl lower alkyl and acyl, in which more preferred ones are aryl lower alkyl, lower alkanoyl and lower alkoxycarbonyl. Particularly preferred examples are mono-, di- or triphenyl (G-Ce) alkyl, such as triphenylmethyi {trityl, Tr) and C1-C4 alkanoyl. Other particularly preferred examples are G-

Cc alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc).

Suitable G-Ce alkylene formed by Ri and R ₂ when bonded together includes straight alkylene having 1 to 6, preferably 2 to 4 carbon atoms, such as methylene, ethylene, trimethylene and tetramethylene, in which a more preferred one is straight alkylene having 2 or 3 carbon atoms. Suitable G-C ₆ alkenylene formed by Ri and R2 includes straight alkenylene having 2 to 6, preferably 2 to 4 carbon atoms, such as vinylene and propenylene, in which a more preferred one is straight alkenylene having 2 or 3 carbon atoms.

In a preferred embodiment of the present invention R ₃ is H and R2 is not H. R3 can e.g. also be a straight or branched G-Ce alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, tert-pentyl and hexyl. In one embodiment it is straight or branched G-C4 alkyl. It can further be an amino protecting group.

R in the present invention is

wherein

a is 0, 1 , 2, 3, 4, 5 or 6. R ₅ is (if present, i.e. if a is not 0) H or hydroxy which may be protected. If a is e.g.≥ 2, then R ₅ can be the same or different for the≥ 2 (CH)R ₅ groups. Re is H, G-Ce straight or branched alkyl, mono or di straight or branched G-Ce alkylamino, G-Ce cycloalkyl, G-Ce cycloalkyl amino, G3-G ₂ aryl or G-G2 aryl amino, protected amino, protected guanidino or a saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms, wherein the cycloalkyl or aryl is optionally substituted by one or more G- C?, straight or branched a!kyl and the heterocyclic group is optionally substituted by one or more protected amino groups. In one embodiment R ₆ is H, Ci-Ce straight or branched alkyl, mono or di straight or branched d-Ce alkylamino, C3-C0 cyc!oalkyl, Cs-Ce cycloalkyl amino, C6-C12 aryl or Ce-Ci ₂ aryl amino, or protected amino, wherein the cycloalkyl or aryl is optionally substituted by one or more C1-C3 straight or branched alkyi.

Mono or di straight or branched C--Ce alkylamino in the present invention includes as suitable examples e.g. mono or di C1-C4 alkylamino, methylamino, dimethylamino, ethylamino, diethylamino, N-ethyl-N-methylamino, propylamino. butylamino and N-ethyl-N- propylamino.

Suitable examples of "protected amino" include in the present invention aryl lower alkylamino and acylamino, in which more preferred ones are aryl lower alkylamino, lower alkanoylamino and lower alkoxycarbonylamino. In the present invention, protected amino is preferably mono-, di- or triphenyl Ci-C ₃ alkylamino, Ct-C ₆ alkanoylamino and C--C ₆ alkoxycarbonylamino (e.g., tert-butoxycarbonylamino). Examples of "protected guanidino" include acylguanidino (monoacylguanidino and diacylguanidino) such as 2,3-bis (lower alkoxycarbonyl) guanidino (e.g., 2,3-bis (tert-butoxycarbonyl) guanidine), in which a more preferred one is 2,3-bis C-Cc, alkoxycarbonyl guanidino.

Suitable "saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms" in the present invention includes azetidinyl (e.g., 1-azetidinyl and 3-azetidinyl), pyrrolidinyl (e.g., 1 -pyrrolidinyl and 3-pyrrolidinyl), imidazolidinyl (e.g., 1 -imidazolidinyl and 4- imidazolidinyl), piperidinyl (e.g., 1 -piperidinyl and 4-piperidinyl) and piperazinyl (e.g., 1 - piperazinyl). In one embodiment, it is a 4- to 6-membered heterocyclic group containing 1 to 4 nitrogen atoms.

In a preferred embodiment of the present invention

wherein

a is 0, 1 , 2, 3, 4, 5 or 8,

R ₅ is H or hydroxy which may be protected, and Re is H, mono or di straight or branched Ci-Ce aikylamino or straight or branched d-Ce alkoxycarbonyiamino.

In a more preferred embodiment of the present invention

wherein

a is 1 , 2, or 3,

Rs is H, and

f¾ is straight or branched Ci-Ce alkoxycarbonyiamino.

In a particularly preferred embodiment of the present invention

Ri is methyl,

f¾ is an amino protecting group,

R;¾ is H, and

wherein a is 2,

R ₅ is H, and

Re is protected amino.

In one embodiment of the process of the present invention

Ri is methyl,

R ₂ is Boc or trityl,

R ₃ is H, and

wherein a is 2,

R ₅ is H,

and f¾ is NH-Boc.

In the process of the present invention the presence of a non-nucleophilic base is required for effective production of the compound of formula I. Preferably an organic non- nucleophilic base is used as the non-nucleophilic base in the present invention. More preferably a tertiary amine, such as ,8-diazabicycloundec-7-ene (DBU), N,N- diisopropylethylamine, or triethylamine, is used as the non-nucleophilic base in the present invention. In a particularly preferred embodiment, DBU is used as the non-nucleophilic base in the present invention. Particularly good yields are obtainable in this case. Other non-nucleophilic bases that can be used as the non-nucleophilic base herein are, e.g., pyridine which is optionally substituted by 1 -5 C--Ce, straight or branched alkyl (e.g., 2,6-di- tert-butylpyridine or 2 ₎ 6-di-tert-butyl-4-methylpyridine), diisopropylethylamine (DIPEA), triethylamine or other C<-Ce trialkylamines, quinuclidine, tetramethyl piperidine, or trimethylguanidine. In one embodiment, 1 , ,3,3-tetramethylguanidine, 1 ,5- Diazabicyclo[4.3.0jnon-5-ene (DBN), 1 ,8-diazabicycloundec-7-ene (DBU), 7-Methyl-1 ,5,7- triazabicyclo(4.4.0)dec-5-ene ( TBD) or 1 ,5,7-Triazabicyclo(4.4.0)dec-5-ene (TBD) is used in the present invention as the non-nucleophilic base.

The process of the present invention for production of the compound of formula I is preferably conducted in a non-nucleophilic solvent. The non-nucleophilic solvent is different from the non-nucleophilic base.

In a particularly preferred embodiment of this invention, production of the compound of formula I is conducted in 2-methyltetrahydrofuran or in dichloromethane. Production of the compound of formula I can also e.g. be conducted in THF, ,4-dioxane, diethyl ether, trichloromethane, dichloroethane, acetonitrile, benzene, toluene, dimethyl sulfoxide (DMSO), or dimethylformamide (DMF). The use of 2-methyltetrahydrofuran is particularly preferred if F¾ is Boc. The use of dichloromethane is particularly preferred if f¾ is trityl. For the production of formula I according to the process of the present invention, the compound of formula II is e.g. suspended in the non-aqueous medium to which the compound of formula III, the non-nucleophilic base (such as DBU) and ΡηΙ(ΟΛ are added, in one embodiment Phi(OAc) ₂ is added in 2 or more portions. Production of the compound of formula I from the compound of formula II according to the present invention e.g. takes place at an internal temperature of 0-5 °C.

As production of the compound of formula I from the compound of formula II is preferably conducted in an environment with limited water content to avoid formation of the amine instead of the urea derivative, the use of starting compounds with little or no water content in the process of the present invention is advantageous. The water content in the non- nucleophilic solvent and the non-nucleophilic base is therefore preferably less than 10 wt- % each, more preferably less than 5 wt.-% or less than 1 wt.-% each. In a further preferred embodiment of this invention, production of the compound of formula I is conducted under anhydrous conditions Herein, the term "anhydrous" refers to a reaction mixture that includes less than 1 wt-% water, preferabl less than 0.7 wt.-% water, preferably less than 0.5 wt-% water, or, preferably, is devoid of water. After the compound of formula I is produced, however, it is not excluded that water is used during work-up.

In this specification, "%" is on a weight by weight basis, if nothing else is explicitly stated or evident for a skilled person in the specific context.

The compounds of formula II and III are, e.g., used in a molar ratio of 1/1 to 1/4 in the present invention. In a preferred embodiment of the present invention the compounds of formula II and formula III are used in a molar ratio of 1/1 .2 to 1/3, The molar ratio of the compounds of formula II and formula III is, e.g., 1/1.2 to 1/2. The molar ratio of the compounds of formula II and Phl(OAc)2 is, e.g., 1/1.1 to 1/3. In another preferred embodiment of the present invention the compounds of formula II and Phl(OAc)2 are used in a molar ratio of 1/1.1 to 1/1.9. Yields above 60 % are obtainable with the present invention in the production of the compound of formula I from the compounds of formulae II and III.

Regarding the molar ratio of the compound of formula II and the non-nucleophilic base preferably the molar ratio of the compound of formula II and the non-nucleophilic base (such as DBU) is 1 :1 or smaller, such as 1 :2 to 1 : 10, more preferably 1 :2.5 to 1 :5.5, even more preferably 1 :3 to 1 :5 or 1 :3 to 1 :4 in the process of the present invention, In one embodiment, the molar ratio of the compound of formula II and the non-nucleophilic base is 1 :3. More preferably, the non-nucleophilic base is DBU and the molar ratio of the compound of formula II and of DBU is 1 :3. As the formation of compound I from compounds II and III can be done as a one pot process, the process is concise, time and resource efficient. Furthermore, the process is easily scalable allowing for industrial scale production. In one embodiment, the process of the present invention is thus an industrial process. The employed amount of DBU in the process of the present invention is e.g.≥ 1.0 kg, such as≥ 1.8 kg. In one embodiment of the process of the present invention the employed amount of the compound of formula HI is e.g. > 1.0 kg.

In a preferred embodiment of the present invention the compound of formula II is prepared by a process of converting a compound of formula

wherein f¾ and F¾ are as defined above, and R3 is straight or branched Ci-Ce alkyl or an amino protecting group into the compound of formula II. This is preferably done by using hydrogen peroxide under basic conditions. Yields of above 80 % are obtainable for this step, adding to the high efficiency of the production process of the present invention. In one embodiment in the process of converting the compound of formula IV into the compound of formula II, (¾ in the compound of formula II is the same as F¾ in the compound of formula IV. In one embodiment in the process of converting the compound of formula IV into the compound of formula II i¾ and R3 in the compound of formula IV are both amino protecting groups, of which one amino protecting group is eliminated when converting the compound of formula IV into the compound of formula II (so that one of R2 or R3 in the compound of formula II then is H). In one embodiment of the present invention, both R2 and Ra- in the compound of formula IV are Boc and in the process of converting the compound of formula IV into the compound of formula II, one of the Boc groups is eliminated from the 5-amino group and a compound of formula !l is obtained wherein R2 is Boc and R3 is H. In this process, e.g., ethanol is preferably used as solvent. In another embodiment of the present invention, F¾ is trityl and F¾ is H or straight or branched Ci-Ce alkyl in the compound of formula IV, which is converted into the compound of formula II, wherein f¾ is trityl and f¾ is the same as F¾ in the compound of formula IV. In this process, e.g., DMSO is preferably used as solvent.

In one embodiment of the present invention, the process for production of a compound of formula I comprises as a first step preparing the compound of formula IV wherein F¾ and/or F¾ is an amino protecting group by introduction of the amino protecting groups(s) to the 5-amino group of the pyrazole ring of the compound of formula

wherein Ri is as defined above. In a second step, the compound of formula IV is converted into the compound of formula II as described above. In a third step, the compound of formula I is produced from the compound of formula II as described above.

The present invention also relates to a compound of formula I

Ri is H, straight or branched Ci-C ₆ alkyl, optionally substituted by 1 to 5 hydroxy groups which may be protected or halogen atoms,

f¾ is H, straight or branched Ci-C ₆ alkyl or an amino protecting group, or Ri and (¾ are bonded together to form d-Ce alkylene or C2-C6 alkenylene,

R3 is H, straight or branched Ci-Ce alkyl or an amino protecting group, wherein i¾ is not H if f¾ is H, wherein

a is 0, 1 , 2, 3, 4, 5 or 6,

R ₅ is H or hydroxy which may be protected, and

Re is H, Ci-C ₆ straight or branched alkyi, mono or di straight or branched d-Ce alkylamino, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloaikyl amino, C ₆ -Ci ₂ aryl, C ₆ - Ci ₂ aryl amino, protected amino, protected guanidino or a saturated 3- to 8-membered heterocyclic group containing 1 to 4 nitrogen atoms, wherein the cycloalkyl or aryl is optionally substituted by one or more Cr C3 straight or branched alkyi and the heterocyclic group is optionally substituted by one or more protected amino groups, obtainable by a process comprising reacting the compound of formula

wherein Ri , F½ and F¾ are as defined above with a compound of formula wherein a, F¾ and Re are as defined above and Phl(OAc)2 in the presence of a non-nucieophilic base to produce the compound of formula I. The preferred features and embodiments of the process for production of a compound of formula I as described above also apply here. This, e.g., means that in a particularly preferred embodiment, the compound of formula I is obtainable by a process for production of the compound of formula I, wherein the non-nucleophilic base is DBU.

The process of the present invention can also include a step of deprotecting the compound of formula I if it contains protecting groups. Thus, the present invention also relates to a process for the production of a compound of formula I from a compound of formula II and a compound of formula III as described above further comprising removing one or more remaining protecting groups from the compound of formula I. It also relates to said process wherein the compound of formula II is prepared from a compound of formula IV as described above, wherein the compound of formula IV can be prepared from a compound of formula V as described above. E.g. if the 5-amino group of the pyrazole ring of the compound of formula I is protected with a protecting group, it can be deprotected in a further step. Boc deprotection is, e.g., performed by using thermal conditions (e.g. by heating (such as to > 80 °C) the solution of the compound of formula I in ethanol after addition of water. Preferably no additional reagents are used during deprotection. Good yields are thus obtainable.

The present invention further relates to a process for the preparation of a cephem antibiotic or a salt thereof, which comprises a) preparing a compound of formula I by a process as described above, and b) using the compound of formula I as an intermediate for the preparation of the cephem antibiotic or the salt thereof.

In one embodiment of the process for the preparation of the cephem antibiotic or the salt thereof step b) comprises reacting the compound of formula I, optionally after deprotection, with at least one other intermediate product and removing any remaining protection group to obtain the cephem antibiotic or the salt thereof.

In one embodiment, the present invention particularly relates to a process for the preparation of Ceftolozone or a salt thereof, which comprises a) preparing a compound of formula I by a process as described above wherein R-, is methyl, F¾ is H or an amino protecting group, f¾ is an amino protecting group, and

wherein a is 2,

f¾ is H, and

Re is protected amino,

b) using the compound of formula I as an intermediate for the preparation of Ceftolozane or salt thereof.

In one embodiment of the process for the preparation of Ceftolozane or salt thereof step b) comprises reacting the compound of formula I, optionally after deprotection, with at least one other intermediate product and removing any remaining protection group to obtain Ceftolozane or the salt thereof.

For the disclosure of processes for the preparation of cephem antibiotics or salts thereof (such as Ceftolozane or a salt thereof) using a compound of formula I as an intermediate and suitable other intermediate products, it is explicitly referred to WO2004/039814 (see in particular claim 12 (3) and process 3) and WO 2014/152763 (see in particular example 1 ).

The present invention also relates to Ceftolozane or a salt thereof obtainable by a process which comprises a) preparing a compound of formula I by a process as described above wherein Ri is methyl, f¾ is H or an amino protecting group, f¾ is an amino protecting group, and

wherein a is 2,

F¾ is H, and Re is protected amino,

using the compound of formula I as an intermediate for the preparation Ceftolozane or salt thereof.

The preferred features and embodiments of the process for production of a compound of formula I as described above also apply here. This, e.g., means that in a particuiarly preferred embodiment, Ceftolozane or the salt thereof is obtainable by a process for preparation of Ceftolozane or a salt thereof, wherein in step a) DBU is used as the non- nucieophilic base in the process for preparing the compound of formula I.

The following examples are illustrative without restricting the scope of protection. If in the examples and comparative examples a process detail is not explicitly described, a skilled person can easily find such detail according to the general practice in the art.

Abbreviations used herein

Ac acetate

Boc tert-butyloxycarbonyl

BocEDA N-Boc ethylenediamine, feri-butyl (2-aminoethyl)carbamate

B0C ₂ O di-terf-butyl dicarbonate

DBU 1 ,8-Diazabicycioundec-7-ene

DCM dichloromethane

DiPET diisopropylether

DMAP 4-dimethylamino pyridine

DMSO dimethyl sulfoxide

Et ethyl

EtOAc ethyl acetate

Equiv equivalent(s)

HPLC high pressure liquid chromatography

M molar, molarity

Me methyl

mM millimolar

MeOH methanol

Me-THF 2-methyltetrahydrofuran

NMR nuclear magnetic resonance

ppm parts per million

R any substituent

r.t. room temperature

TEA triethylamine

THF tetrahydrofuran

TLC thin layer chromatography

TMS tetramethylsilane

Tr Trityl, triphenylmethyl

UV ultraviolet General analytical methods: Reactions were monitored by HPLC on a C- 18 reverse phase column with a gradient of acetonitrile in 10 mM ammonium sulfamate aqueous buffer at pH 5.6 or 40 mM aqueous sulfamic acid, or using thin layer chromatography (TLC) on silica gei pre-coated aluminum sheets (Silica gel 60 F254, Merck). TLC visualization was accomplished by irradiation with UV light at 254 nm and/or a eerie ammonium moiybdate stain. ¹ H and ¹³ C chemical shifts are reported in ppm relative to T S (0 ppm) with the solvent resonance as the internal standard (CDCI ₃ , ¹ H: 7,28 ppm, ¹³ C: 77.16 ppm, (CD ₃ ) ₂ 0 ¹ H: 2,05 ppm, ¹³ C: 29.84, 202.28 ppm, DM SO: ¹ H: 2,50 ppm, ¹³ C: 39,51 ppm).

Example 1 - synthesis of di-tert-butyl (4-cyano-1 -methyl-1 H-pyrazol-5-yl) imidodicarbonate

In a 10 L reactor, 5-amino-1 -methyl-1 H-pyrazole-4-carbonitrile (501 .95 g, 4.1 1 mol, 1 equiv) was suspended in 2-methyltetrahydrofuran (Me-THF, 7.5 L). To this suspension, triethylamine (828.6g, mL, 8.19 moi, 2 equiv) and DMAP (85.0 g, 0.69 mol, 0.17 equiv) were added in one portion, keeping the inner temperature at 25 ^" C. in a separate 6 L reactor, di-fert-butyl dicarbonate (1368 g, 9.0 mol, 2.2 equiv) was dissolved in Me-THF (2.5 L), This solution was added to the main reactor over 23 min keeping the reaction temperature≤ 30 °C (caution: gas evolution). The reaction was heated to + 47 °C and stirred for 4.8 h, after which HPLC control indicated complete disappearance of the starting material. The reaction was cooled to + 25 °C and charged with water (2.0 L). The pH was adjusted to 3.1 with 10% aq. HCI (3257 g), and the phases separated. The aqueous phase was discarded and the organic phase charged with water (1 .75 L) and sat. aq. NaCI (1 ,75 L). The pH was adjusted to 10.2 with 1 M NaOH (813 g) and the solution stirred for 5 min. The stirring was stopped and phases separated. The aqueous phase was discarded and the organic phase charged with sat. aq. NaCI (2.5 L), stirred for 10 min and the phases separated. The aqueous phase was discarded and the organic phase was transferred to a rotary evaporator. Volatiles were removed under reduced pressure to afford the title product as a clear gum (1402 g) which slowly solidified, and was used without further purification. Characterization data for the product:

¹ H N R (300 MHz, DMSO): 8.12 (s, 1 H), 3.71 (s, 3H), 1 ,41 (s, 18H).

Example 2 - synthesis of 1-methyi-5-{tritylamino)-1 W-pyrazole-4-carbonitri!e

In a two-neck round bottom flask, 5-amino-1 -methy!-1 H-pyrazo!e-4-carbonitrile (970.9 g, 7.95 mmol, 1 equiv) was suspended in pyridine (10 mL). To this suspension trityl chloride (1.99 g, 7.15 mmol, 0.9 equiv) was added, and the reaction was heated to 60 X, whereby a clear solution was initially formed, followed by the gradual appearance of a precipitate. The reaction was stirred for 15h, after which further trityl chloride (1.1 1 g, 3.97 mmol, 0.5 equiv) was added, followed by ethanol (2.32 mL). The reaction was stirred for 23 h, after which HPLC control indicated 94% conversion of the starting material. The reaction was charged with water (50 mL) and dich!oromethane (50 mL) and pH was adjusted to 2.25 with 50% aq. H2SO4. The phases were separated, the organic phase charged was charged with water (50 mL) and pH was adjusted to 10 with 2M NaOH. The phases were separated, the organic phase was washed with sat. aq. NaCI (50 mL), dried over Na;SCv. and filtered. To the filtrate was added 100 mL diisopropylether (DIPET) and the solution was concentrated under reduced pressure to 25g, initiating crystallization. The crystal suspension was cooled at 4 °C for 1 h and filtered, washing the filter cake with cold DIPET. Drying at 30 °C under reduced pressure for 17 h gave the title product as white crystalline solid (1 .47g, 4.0 mmol, 50%).

Characterization data for the product:

¹ H NMR (300 MHz, DMSO); 7.48 (s, 1 H), 7.37-7.16 (m, 15H), 6.77 (s, 1 H), 3.53 (s, 3H). ¹³ C NMR (75 MHz, DMSO): 147.8, 144.7, 141.1 , 128.9, 127.7, 127.5, 1 14.8, 81.3, 71.8, Example 3 - synthesis of ferf-butyl (4-carbamoyl-1-methyl-1 H-pyrazol-5-yi)carbamate

In a 30 L reactor equipped with a gas exhaust (20L/h flow rate) and a reflux condenser, di- terf- butyi (4-cyano-1 -methyl- 1 H-pyrazol-5-yl) imidodicarbonate prepared according to

Example 1 (1349 g, 1 equiv) was dissolved in ethanol (8.8 L). To this solution, 1 M NaOH (1 1.9 L) was added in one portion, keeping the reaction temperature at 30 °C. A 35% aqueous H2O2 solution (2788g) was then added over 120 min (caution: gas evolution) keeping the inner temperature below 40 °C. The reaction was stirred for an additional 1 h, after which HPLC control indicated complete disappearance of the starting material and <1 % of the mono Boc-proteded intermediate ferf-butyl (4-cyano-1 -methyl- 1 H-pyrazol-5- yl)carbamate. A solution of NazS0 ₃ (720 g) in water (6L) was added to the reaction mixture over 5 min, and the mixture was stirred for 17 min. The pH was adjusted to 10.7 with 10% aq. HC! (1265 g), and the crude reaction mixture extracted with EtOAc (4 x 15 L). The combined organic layers (70 L) were divided into 2 portions and each portion concentrated under reduced pressure to ca. 10 L, stripped with EtOAc by continuous addition of solvent and evaporation while keeping the volume at ca. 10 L and seeded, initiating crystallization. Each portion of the crystal suspension was further evaporated to an end mass of ca. 3400 g and both portions were combined and kept at - 20 °C for 20 h. The crystal suspension was filtered washing the filter cake with a cold cyclohexane/EtOAc (2:1 ) solution. Drying at 40 °C under reduced pressure for 16 h gave the title product as white crystalline solid (882g, 3.67 moi, 89% over 2 steps).

Characterization data for the product:

¹ H NMR (300 MHz, (CD ₃ ) ₂ 0): 8.56 (br s, 1 H), 7.81 (s, 1 H), 7.10 (br s, 1 H), 6.50 (br s, 1 H), 3.77 (s, 3H), 1.50 (s, 9H).

¹³ C NMR (75 MHz, DMSO): 163.5, 153.0, 137.7, 137.4, 109.7, 79.9, 35.6, 27.9. - synthesis of 1-methyl-5-(trftylamii "azole-4-carboxamide

In a two-neck round bottom flask, 1 -methyl-5-(tritylamino}-1 H-pyrazole-4-carbonitrile prepared according to Example 2 (634,0 mg, 1 ,74 mmol, 1 equiv) was dissolved in DMSO (7 mL). To this solution 5 M NaOH (1.19 mL, 5.95 mmol, 3.4 equiv) was added, followed by 35% aq. H2O2 (1.4 mL, 9 equiv) dropwise (caution: reaction highly exothermic). The foaming reaction was cooled by the addition of 10 mL DMSO and stirred for 30 min, after which HPLC analysis indicated 98% conversion. The reaction was charged with water (30 mL), stirred for 30 min and filtered, washing the filter cake with water (10 mL). Drying at under reduced pressure gave the title product as white crystalline solid (560 mg, 1.46 mmol, 84%).

Characterization data for the product:

¹ H NMR (300 MHz, DMSO): 8.93 (s, 1 H), 7.63 (s, 1 H), 7.47-7.15 (m, 16H), 6.76 (br s, 1 H), 2.88 (s, 3H).

3C NMR (75 MHz, DMSO): 166.45, 149.1 , 156.6, 137.2, 128.3, 128.0, 127.0, 101 ,3, 71.7, 38.3.

Example 5 - synthesis of ferf-butyl (2-(3-(5-tert-butoxycarbonyl)amino)-1-methyl-1H- pyrazoi-4-yi)ureido)ethyl}carbamate

In a 20 L reactor, ferf-butyl (4-carbamoyl-1 -methyl-1 H-pyrazol-5-y!)carbamate prepared according to Example 3 (783.4 g, 3.26 mo!, 1 equiv) was suspended in Me-THF (8.3 L) and the reaction was cooled to 0 °C. To this suspension, ferf-butyl (2- aminoethyl)carbamate (BocEDA, 1033.5 g, 8.45 mol, 1.86 equiv) was added in one portion, followed by DBU (1788.8 g, 1 1 .6 mol, 3.3 equiv) keeping the inner temperature at 0 °C. Diacetoxyiodobenzene (665.4 g, 2.07 mol, 0.6 equiv) was added in one portion and the reaction was stirred for 68 min at 0 °C. A second portion of diacetoxyiodobenzene (663.6 g, 2.06 mol, 0.6 equiv) was added and the reaction was stirred for 4 h at 0 °C. The reaction was warmed up to 20 °C and charged with 17% aq. NaCI solution (7 L), stirred and the phases were separated. The organic phase was charged with 10% aq. Na2S(¾ solution (4.2 L) and stirred. The pH was adjusted to 3.5 with 10% aq. HCi (2969 g) and the phases separated. The organic phase was charged with 8% aq. NaHCOa solution, stirred and the phases were separated. The organic phase was evaporated under reduced pressure to dryness, the residue was redissolved in MeOH (6.7 L) and extracted with heptane (3 x 6.7 L). The combined heptane phases were discarded and the methanol phase was evaporated under reduced pressure to dryness, redissolved in acetone (3.3 L) and evaporated to dryness again. The residue was taken up in acetone (5 L) and stirred for 1 h at 20 "C, whereby crystallization was initiated. Cyclohexane (7.5 L) was added dropwise over 42 min and the crystal suspension was stirred for 52 min, cooled to - 10 °C and stirred for further 13 h. The suspension was filtered, washing the filter cake with cold (- 10 °C) solution of acetone/cyclohexane (1 :3) (4 L). Drying at 40 °C under reduced pressure for 16 h gave the title product as white crystalline solid (803 g, 2.01 mol, 62%).

Characterization data for the product:

¹ H NMR (300 MHz, DMSO): 8.72 (br s, 1 H), 7.49 (s, 1 H), 6.81 (br s, 1 H), 6.34 (br s, 1 H), 3.55 (s, 3H), 3.15-3.02 (m, 2H), 3.02-2.90 (m, 2H), 1 .51 -1.30 (m, 18H).

1 ³ C NMR (75 MHz, DMSO): 155.6, 155.4, 153.3, 130.4, 125.0, 1 16.6, 79.8, 77.6, 40.5, 39.1 , 35.3, 28.2, 27.9.

Example § - synthesis of 4-(3- 2-[{feri-butoxycarbonyl) amino]ethyl}ureido)-1 -methyl- 5-triphenylmethylaminopyrazole

In a two-neck round bottom flask, 1-methyl-5-(trityiamino)-1 H-pyrazoie-4-carboxamide prepared according to Example 4 (92 mg, 0.24 mmol, 1 equiv) was suspended in dichloromethane (2.5 mL). To this suspension, iert-butyl (2-aminoethyl)carbamate (BocEDA, 97.3 mg, 0.58 mmol, 2.4 equiv) was added in one portion, followed by DBU (134 pL, 0.9 mmol, 3.7 equiv), whereby a clear solution was obtained after several minutes of stirring. The reaction was cooled to 0 °C and diacetoxyiodobenzene (105.2 mg, 0.33 mmol, 1 .4 equiv) was added in one portion and the reaction was stirred for 75 min at 0 °C, after which HPLC indicated complete conversion. The crude reaction mixture was evaporated under reduced pressure to dryness, the residue was redissolved in MeOH (5 mL) and extracted with heptane (4 x 5 mL). The combined heptane phases were discarded and the methanol phase was evaporated under reduced pressure to dryness, redissolved in dichloromethane (10 mL) and washed with 17% aq. NaCI solution (15 mL). The phases were separated, and the organic phase allowed to stand at r.t, whereby crystallization initiated. The crystal suspension was allowed to stand at - 20 °C for 2 days and filtered. Drying at r.t. under reduced pressure for 2 h gave the title product as white crystalline solid (80 mg, 0.15 mmol, 62%).

Characterization data for the product:

¹ H NMR (300 MHz, DMSO): 8.72 (br s, 1 H), 7.49 (s, 1 H), 6.81 (br s, 1 H), 6.34 (br s, 1 H), 3.55 (s, 3H), 3.15-3.02 (m, 2H), 3.02-2.90 (m, 2H), 1 .51-1 .30 (m, 18H).

1 ³ C NMR (75 MHz, DMSO): 156.2, 155.6, 145.8, 136.5, 132.6, 129.1 , 127.3, 126.7, 1 15 0, 77.6, 72.1 , 40.6, 39.3, 34.6, 28.2.

Example 7 - synthesis of ferf-butyl (2-(3-(5-amino-1-methyl-1W-pyrazol-4- yl)ureido)ethyl)carbamate

-NHBoc

In a 3-neck round bottom flask equipped with a reflux condenser, ferf-butyl (2-(3-(5-((tert- butoxycarbonyl)amino)-1 -methyl-1 H-pyrazol-4-yl)ureido)ethyl)carbamate prepared according to Example 5 (43.6 g, 109.5 mmol, 1 equiv) was dissolved in absolute ethanol (90 mL). To this solution, water (450 mL) was added. The resulting suspension was heated to 1 10 °C with vigorous stirring, whereby the suspension slowly dissolved (solid encrusted on the reaction vessel walls was washed with additional 5 mL ethanol). After a total of 5 h, HPLC control indicated 94% conversion. The reaction was cooled to 85 °C, stirred for an additional 1.5 h and cooled to r.t. The crude reaction mixture was diluted with THF (450 mL), charged with 25% aq. NaCI solution (450 mL) and the phases were separated. The aqueous phase was extracted with THF (1 x 450 mL and 1 x 250 mL). The combined organic phases were evaporated under reduced pressure, the residue was redissolved in methanol (250 mL) and evaporated to dryness again. Drying at 50 °C under reduced pressure for 17 h gave the title product as white crystalline solid (26.3 g, 88.1 mmol, 81 %).

Characterization data for the product:

¹ H NMR (300 MHz, DMSO): 7.52 (br s, 1 H), 6,98 (s, 1 H), 6.81 (br s, 1 H), 6.09 (br s, 1 H),

4.84 (br s, 2H), 3.50 (s, 3H), 3.1 1 -3.01 (m, 2H), 3.01-2.91 (m, 2H), 1.38 (s, 9H).

3C NMR (75 MHz, DMSO): 156.8, 155.6, 140.2, 133.6, 103.4, 77.5, 40.6, 39.4, 34.7,

28.2.

Comparative example 1 - Overview of attempted Hofmann rearrangement using classical reagents

R Reagent equiv Base equiv Solvent Temp, °C Time, h Result

H Br ₂ 1 KOH 14 H ₂ 0 -5 to 80 17 3% product + decomp,

H NaOCI 1 NaOH 1.9 H ₂ 0 70 3.5 educt + decomposition

H NBS 15 KOH 6 MeOH/H ₂ 0 0 to r.t. 5 no conversion

Boc NBS 1.5 DBU 10 1 ,4-dioxane 10 to r.t. 1 decomposition

Boc NBS 1.5 KOH 10 1 ,4-dioxane r.t. to 85 1 ,5 no conversion Comparative example 2 - synthesis of fert-butyt (4-amino-1-methyl-1 W-pyrazoi-5- yl)carbamate

In a two-neck round bottom flask, fert-butyl (4-carbamoyl-1 -methyl-1 H-pyrazol-5- yl)carbamate prepared according to Example 3 (300 mg, 1 .25 mmol, 1 equiv) was dissolved in 1 ,4-dioxane (3 rriL). To this solution was added water (0.3 ml) and 50% aq. KOH solution (930μΙ_, 12.5 mmol, 10 equiv). The resulting emulsion was heated to 40 °C and a solution of diacetoxyiodobenzene (603 mg, 1.87 mmol, 1 .5 equiv) in 1 ,4-dioxane (3 ml_) and water (0.3 ml) was added dropwtse over 30 min. The reaction was stirred for 1 h at 40 °C and a second portion of diacetoxyiodobenzene (80 mg, 0.25 mmol, 0.2 equiv) was added in one portion. The reaction was stirred for 3 h at 40 °C, cooled to r.t and diluted with dichioromethane (30 mL). The pH was adjusted to 8.5 with 50% aq. H2SO4 solution, resulting in phase separation. The phases were separated and the aqueous phase washed with dichioromethane (20 mL). The combined organic phases were dried over Na2SO«„ filtered and evaporated under reduced pressure. Drying at 40 °C under high vacuum for 17 h gave the title product as pale brown gum which solidified upon standing (127 mg, 0.80 mmol, 48%).

Characterization data for the product:

¹ H NMR (300 MHz, CDCb): 7.13 (s, 1 H), 6.44 (br s, 1 H), 3.68 (s, 3H), 3.19 (br s, 2H), 1.50

(s, 9H),

Comparative example 3 -synthesis of tert-butyl methyl (1-methyl-1 W-pyrazole-4,5- diyQdicarbamate

in a two-neck round bottom flask, ferf-butyl (4-carbamoyl-1 -methyl-1 H-pyrazol-5- yi)carbamate prepared according to Example 3 (1 g, 4, 16 mmol, 1 equiv) was suspended in methanol (10 mL) and charged with water (1 mL), The resulting clear solution was cooled to 0 °C and charged with 50% aq. KOH solution (3.1 mL, 41.6 mmol, 10 equiv) (caution: exothermic). Diacetoxyiodobenzene (2.01 g, 8.24 mmol, 1.5 equiv) was added in one portion (caution: exothermic). The resulting grey suspension was stirred at 0 °C for 10 min and the cooling was removed, whereby a red solution was formed. After 1 h, HPLC control indicated complete conversion of the starting material and the reaction was diluted with EtOAc (50 mL). The crude reaction mixture was extracted with sat. aq. NaHCC (50 mL), the aqueous phase was washed with EtOAc (25 mL) and the combined organic phases were tried over Na?S04, filtered and evaporated under reduced pressure. Drying at 30 °C under reduced pressure for 48 h gave the title product as off-white crystalline solid (571 mg, 2,11 mmol, 51 %),

Characterization data for the product: H NMR (300 MHz, DMSO): 7.44 (s, 1 H), 6.65 (br s, 1 H), 8.49 (br s, 1 H), 3,78 (s, 3H), 3,73 (s, 3H), 1.5 (s, 9H).

¹³ C NMR (75 MHz, DMSO): 154.5, 153.0, 131.3, 127.1 , 1 14,4, 79.6, 51 ,6, 35.6, 27.9.