CS268531B2 - Method of carboxy-alkene acid's derivatives production - Google Patents

Abstract

Cephems and analogues of formula (I) are new. R = aryl or heterocyclyl; R1 = H or halogen; R2 = single bond, alkylene, oxa-alkylene or thia-alkylene- R3, R6 = H, salt-forming atom or gp. or ester-forming gp.; R4 = H or MeO; R5 = H or a 3-substituent as found in cephalosporins; X = O, S or SO. Provided that when R2 = thia-alkylene, then R1 = halogen. - Intermediates of formula (II) are new.

Description

A six-membered monocyclic hetero group with up to 2 and tons of nitrogen, oxygen or sulfur (optionally in protected form); R ² denotes a single bond or C 1 -C 3 alkylene, R ³ and R ^b denote hydrogen, an alkali metal atom or an ester-forming group, provided that when R represents thisalkylene, R ¹ is a halogen atom, wherein the formyloxalate of formula (II) wherein

R @ ⁶ and R @ ⁶ are as defined above, or their acetal is subjected to a wittig reaction and the compound obtained is then optionally converted to another compound within the scope of the compounds of formula I. The compounds obtainable by the method of the invention are suitable as starting materials for antibacterially active acids beta- (carboxylakenoylamino) -3-cephem-4-carboxylic acid. .

RCCOOR ⁶

I 1? 3

CR - R - COOR ^J

R-CH-XO.T ⁵

I нс

Italy (11) (13) B2 (51) Int. Cl. ⁴ C 07 OJ C 57/13 C 07 0 501/20

The present invention relates to a process for the preparation of carboxyalkenic acid derivatives of the general formula I

RCCOOR ⁶

CR - R - COOR ^J (Ό where

R represents a phenyl group or a five- or six-membered monocyclic hetero group containing one or two heteroatoms selected from nitrogen, sulfur and oxygen, optionally protected by a protecting group usually used in the penicillin or cafalosporin region, _R 1 represents a hydrogen atom or a halogen atom, r ² represents a single bond or an alkylene group having 1 to 3 carbon atoms, r 3 and r 6 represent a hydrogen atom, an alkali metal atom, an ester-forming group forming an alkyl ester of 3 to 12 carbon atoms; (C až-C ar ⁾ aralkyl ester, (C až-C lo lo) alkoxy, (C lo-C formy lo) alkoxy or C 6 a-Cry a (C která-Cryry) aryl group optionally substituted with halo ar ³ or C ester-C ester ester alkyl ester-forming group atoms, provided that when R is thiaalkylenovou group, R ¹ represents halogen · compounds obtainable according to the invention are suitable as starting materials for the production of antibacterially active ester of 7 | 3- (carboxy and lkenoylamino) -3-cephem-4-carboxylic acid of formula I '

where.

r is an aryl or heterocyclic group; represents hydrogen or halogen, R ² represents a single bond, alkylene, oxaalkylene or thiaalkylen, R ³ represents hydrogen or a modified carboxyl group, R ⁴ is hydrogen or methoxy, R ⁵ represents a hydrogen atom or a substituent in the 3-position of cephalosporin, R ⁶ represents a hydrogen atom or a modified carboxyl group; and

X represents an oxygen atom, a sulfur atom or a sulfinyl group ·

Various meanings of the substituents in the compound of formula (i) are now explained.

R is a phenyl or heterocyclic group represented by an optionally substituted 5 or 6 membered monocyclic ring group containing 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur. Representative rings are pyrryl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidyl, pyrazinyl and the like. These groups are optionally protected by protecting groups well known in the penicillin and cephalosporin areas. amino is preferably optionally substituted C7-C20 aralkyl groups, for example benzyl, benzbydril, trityl, methoxybenzyl, dimethoxybenzyl, nitrobenzyl, methylbenzyl, dimethylbenzyl, optionally substituted alkyl groups of 1 to 8 carbon atoms, for example trichloromethyl, trichloroethyl, trifluoromethyl, tetrahydropyranyl, substituted phenylthio, substituted alkylidene of 1 to 8 carbon atoms, substituted aralkylidene of 7 to 14 carbon atoms, substituted cycloalkylldene and 5 to 8 carbon atoms, acyl, for example optionally substituted alkanoyl C 1 -C 8 -carbonyl, for example formyl, acetyl, chloroacetyl, trifluoroacetyl, optionally substituted lower C 2 -C 12 alkoxycarbonyl, wherein the alkyl moiety is methyl, ethyl, propyl, cyclopropylethyl, isopropyl, butyl, pentyl, hexyl , trichloroethyl, pyridylmethyl, cyclopentyl, cyclohexyl, quinolylmethyl or the like, an optionally substituted C 8 -C 15 alkoxycarbonyl group in which the aralkyl moiety is benzyl, diphenylmethyl, nitrobenzyl or the like and further succinyl, phthaloyl, and trialkylsilyl, trialkylsilyl, trialkylsilyl, trialkylsilyl, trialkylsilyl, alike·

Preferably R is selected from the group consisting of phenyl, furyl, thienyl, oxazolyl, isoxazolyl, optionally protected aminolsoxazoles, thiazolyl and optionally protected aminothiazolyl.

R ¹ as halogen is fluorine or chlorine, especially chlorine. Preferably R ¹ represents a hydrogen atom.

The alkylene moiety in R is a lower alkylene group, preferably an alkylene group having 1 to 3 carbon atoms, especially methylene.

R ³ or R ⁶ as a modified carboxy group is preferably an ester-forming group or an alkali metal atom.

Carboxy protecting groups are known in the field of penicillin and cephalosporin and can be introduced and removed without detrimental effect on another Part of the molecule · Representative are inorganic salts, for example lithium, sodium or potassium salts, alkyl esters of 3 to 12 carbon atoms, , propyl, isopropyl, ethoxyethyl, butyl, isobutyl, tert-butyl or hexyl, aralkyl of 7 to 15 carbon atoms, e.g. phenacyl ester, dl-tert-butylhydroxybenzyl ester, aryl of 6 to 12 carbon atoms, for example, phenyl ester, tolyl ester, diisopropylphenyl ester, xylyl ester, trichlorophenyl ester and indanyl ester;

Preferred R ³ and R ⁶ as carboxy protecting groups are hydrogen, sodium, potassium, tert-butyl, phenyl, benzyl, halobenzyl, methylbenzyl or the like.

The protecting group in the compounds of the invention, and also its structure, are of no particular importance as long as the group is well protected and can thus be replaced by widely diverse equivalent groups.

Particularly suitable carboxy derivatives include alkali metal salts and pharmaceutically acceptable esters, preferred metals being those which form physiologically acceptable ions. Lithium, sodium and potassium are preferred. Pharmacologically acceptable esters it shall include the well-known alkyl esters substituted in position 1, 3 to 12 carbon atoms, for example alkanoyloxy, for example acetoxymethyl, асеtoxyethylester _t propionyloxyethylester, pivaloyloxymethyl, pivaloyloxyester, tetrahydrofůrylester, tetrahydropyranyl, alkoxyformyloxyalkylestery 3 to 8 carbon atoms such as ethoxycarbonyloxyethyl, substituted (C až-C) aralkyl esters, for example phenacyl and / or phthalidyl esters, substituted C 6-C a aryl esters, for example, phenyl, xylyl or indanyl esters, and 2-alkenyl esters, for example allyl or 2-oxo-1,3-dioxolenylmethyl esters.

Particularly preferred compounds of formula I are those wherein R is phenyl, thienyl, aminoisoxazolyl, and animothiazolyl, wherein the amino group may be protected by benzyloxycarbonyl, methylbenzyloxycarbonyl, tert-butoxycarbonyl, methoxyethoxymethyl, formyl, chloroacetyl, benzylide, dimethylaminomethylidene or dimethylaminomethylidene R is preferably hydrogen, R is preferably branched alkylene of 1 to 3 carbon atoms, especially methylene A

Examples of suitable R and R are the same or different groups selected from the group consisting of hydrogen, methyl, ethyl, tert-butyl, trichloroethyl, benzyl, methylbenzyl, diphenylmethyl, trityl or the like.

The compounds of the invention are prepared by a synthetic process.

The compounds of the formula I are novel substances which can be obtained by the Wittig reaction.

The process for the preparation of the compounds of the formula I according to the invention is characterized in that the formyloxylate of the formula II is used

R-CH-C00R ⁶

CHO (П) / where

R < 6 > and R < 6 > are as defined above, or the acetal thereof is subjected to a Wittig reaction by treatment with an alkylidene phosphorane of formula III

Ar ₃ P · CH-R ² -COO R ³ (III) / where.

R ² and R ³ have the abovementioned meaning and

Ar is an aryl group, in an inert solvent at a temperature of 50 to 120 ° C, and optionally the ester-forming group is removed from the compound of formula I to form a compound of formula I wherein R ³ and / or R ⁶ are hydrogen and the other substituents or wherein the resulting compound of formula (I) is halogenated to form a compound of formula (I) wherein R ¹ is a halogen atom and the other substituents are as defined above, or the obtained compound of formula (I) is converted to its alkali salt.

Heating to this temperature typically takes from 10 minutes to 10 hours.

Examples of typical solvents for the reaction are hydrocarbons such as pentane, hexane, octane, benzene, toluene or xylene, halogenated hydrocarbons such as dichloroethane, trichloroethane, dichloromethane, chloroform, carbon tetrachloride or chlorobenzene, ethers such as diethyl ether, methyl isobutyl ether, dioxane or tetrahydrofuran, , for example acetone, methyl ethyl ketone or cyclohexanone, esters such as ethyl acetate, isobutyl acetate or methyl benzoate, nitrated hydrocarbons such as nitromethane or nitrobenzene, nitriles such as acetonitrile or benzonitrile; carboxylic acids such as formic acid, acetic acid, propionic acid, organic bases such as diethylamine, triethylamine, pyridine, picoline, collidine or quinoline, alcohols such as methanol, ethanol, propanol, hexanol, octa nol or benzyl alcohol, or water and other industrial solvents and mixtures thereof ·

The products can be recovered from the reaction mixture by removing impurities such as solvents, unreacted starting materials or by-products by conventional methods such as extraction, evaporation, washing, concentration, precipitation, filtration or drying and isolation of the product by conventional processing such as adsorption, elution, distillation, precipitation , separation or chromatography, or a combination of these processes ·

The process of the present invention is illustrated, but not limited, by the accompanying examples.

In the examples, parts are parts by weight and the equivalent is the molar equivalent of the starting material. Cis * and trans * are the relative positions of the amide and carbocyl substituents attached to the side chain double bond. The physicochemical constants of the products are summarized and the IR gives values in cm ^-1 , NMR analyzes express the values and 3 values show the constants given in Hz. In NMR analyzes of mixtures of geometric isomers, signals cleaved into two or more signals point to chemical shifts.

Usually, the reaction mixture is washed, dried and evaporated after addition of a solvent, for example water, acid or dichloromethane, and the product is separated. All evaporations are carried out under reduced pressure.

In the text and reaction schemes, the abbreviations have the following meanings:

AOM acetoxymethyl

BH diphenylmethyl

Bu butyl

Boc tert-butyloxycarbonyl

Bzl benzyl

Cbz benzyloxycarbones 1 ring in the hetero ring of structural formula aromatic ring exo double bond at position 3,4 of the positional isomers in the acyl side chain at position 7

Me methyl

MEM methoxyethoxymethyl phenyl

PMB p-methoxybenzyl

PNB p-nitrobenzyl

POM of loyloxymethy1 beer.

Other meanings of the abbreviations are evident from the examples.

CS 268531 82

Example 1

Process for the preparation of 2- (2-benzyloxycarbonylaminothiazol-4-yl) -4-benzyloxycarbonyl-2-butanoic acid (3)

C-COOCHF2H4

II

CH i

CH-CClCH3 Fn

CbzNH

C-COOH

II

CH

CH ₂ C00CH ₂ Ph

A solution of 1.94 g of the form of lacetate (1) and 1.3 equivalents of benzyloxycarbonylmethylidentrifenylphosphorane in 8 parts of dioxane or toluene is stirred for 1 or 6 hours at 80 or 120 ° C (both temperatures). After cooling, the mixture was evaporated and the residue was purified by chromatography on silica gel using benzene-ethyl acetate (1: 1) to give 2.1 g of propenedicarboxylate (2). Yield 87%. This is a mixture of 39% cis-isomer and 61% geometric trans isomers, which can be separated by repeated chromatography.

IR (CHCl ₃ ) V: 3410, 1730 cm ^-1 (trans),

IR (CHC1 _3): 3400, 1730 си ^-1 (cis).

2. 2 parts of anisole and 2 parts of trifluoroacetic acid are added to a solution of 1.16 g of product (2) in 10 parts of dichloromethane. After stirring for 2 hours, the reaction mixture was evaporated and the residue was washed with ether-hexane to remove the mother liquors. 0.76 g of dicarboxylic acid monobenzyl ester (3) is obtained in 89% yield. The thus obtained 1: 3 mixture of geometric cis and trans isomers can be separated by chromatography on silica gel using a 1: 1 benzene-ethylate system.

NMR (CDCl ₃ -COOD) δ: 3.51 (d, 3-7 Hz, 2H), 5.13 (s, 2H),

5.26 (β, 2H), 7.06 (s, 1H), 7.0-7.5 (m, 11H) (trans)

NMR (CDCl ₃ -CD ₃₀₀ ): 3.73 (d, 37 Hz, 2H), 5.13 (β, 2H),

7.10 (a, 1H); 7.0-7.5 (m, 11H) (cis).

In a similar manner as described in this example, the butenic acid diesters listed in Table 1 were prepared from the corresponding formyl acetate using the same ratios.

CS 268531 82

reactants and solvents at the same temperature and time. If desired, the ester obtained is wholly or partially non-esterified using a conventional resolving agent, for example sodium hydroxide for alkyl esters and Lewis acids such as aluminum, titanium or tin (II) halide, for tert-alkyl esters.

Table 1.

Acids and side chains and derivatives thereof of the general formula

Ref. R R ¹ R ² IR (nujol): c · “ ¹ NMR δ: pp * 1 BOC H H 3120, 1700, 1675 m.p. 153-154 ° C (decomposition) 1.50 (α, 9H), 3.45 (d, 3-7.5 Hz, 2H), 7.00 (t, 3-7.5 Hz, 1H), 7.13 (8, 1H). 7.13 (а, 1H) / C0 ₃ SOC0 ₃ / 2 Boc H H 3150, 1700, 1630, 1600, m.p. 165-167 ° C (decomposition) 1.49 (α, 9H), 3.41 (d, 3-7.5 Hz, 2H), 6.89 (t, 3-7.5 Hz, 1H), 7.08 (в, 1H) / С0 ₃ «) С0 ₃ / 3 Chz H H 3200, 1738, 1715 1690, m.p. 169 až 172 ° C (decomposition) 3.44, 3.50, (2xd, 3-8 Hz, 2H), 5.25 (s, 2H), 7.07, 7.35 (2times, 3-8 Hz, 1H), 7.12 ( α, 1H), 7.38 (broad, 5H / CDCl ₃ -CO ₃ 00) 4 HCO H H 3400, 1718, 1690, 1630, 1550 m.p. 168 ° C (decomposition) 3.45, 3.63 (2xd, 3-7.5 Hz, 2H), 7.14, 7.32 (2x, δ -7.5 Hz, 1H), 7.23, 7.25 (2xa, 1H), 8.51 (a, 1H) (CDCl ₃ -CD ₃₀₀ ) 5 C1CH ₂ CO H H 3100, 1720, 1685, 1620, m.p. 153-155 ° C (decomposition) 3.45 (d, 3-8 Hz, 2H), 4.37 (α, 2H), 6.97, 7.05 (2Xt, 3-8 Hz, 1H), 7.23, 7.27 (2xs) , 1H) / Co ₃ soco ₃ / 6 Boc H Bzl 3160, 1740, 1724 1700, 1678, 1255 1168 3.95 (d, 3-7.5 Hz, 2H), 5.50 (α, 2H), 7.26 (t, 3-7.5 Hz, 1H), 7.30 (broad, 1H), 7.49 (Å, 1H), 7.75 (Å, 5H), 11.86 (broad, 1H), / CD ₃ SOC0 ₃ / 7 HCO (2 cis: 1 trans) H target. -Bu - 3150, 3100, 1720, 1690, 1635 m.p. Mp 185-188 ° C 1.40 (t, 9H), 3.43 (d, 3-7 Hz, 2H), 6.89, 7.00 (2xt, 3-7 Hz, 1H), 7.20, 7.26 (2хз) , 1H), 8.84 (a, in) (co ₃ soco ₃ ) 8 HCO H Bzl 1735, 1680, 1620, m.p. 153-155 ° C (decomposition) - 3.69 (d, 3-7 Hz, 2H), 5.12 (a, 2H), 7.17 (t, 3-7 Hz, 1H), 7.21 (s, 1H), 7.32 ( а, 5H), 8.46 (a, in) / co ₃ soco ₃ / 9 ClCH3CO H Me not specified 3.39 (d, 3-7.5 Hz, 2H), 3.70 (a, 3H), 4.24 (a, 2H), 7.11 (a, 1H), 7.23 (t, 3) -7.5 Hz, 1H), 9.37 (íiroký, 2H) / ₃ С0С1 / ' 10 C1CH ₂ CO H Bzl 1726, 1685, 1160 m.p. 155 ° C (decomposition) 3.95, 4.01 (2xd, 3-7.5 Hz, 2H), 4.71 (α, 2H), 5.45, 5.47 (2xa, 2H), 7.28, 7.40 ( 2xt, 3-7,5 Hz, 1H), 7.58, 7.65 (2xA, 1H), 7.70 (в, 5H), 12.9 (br, 1H) / CD ₃ S0CD ₃ /

CS 268531 82

Table 1 - continued

whose·. R R ¹ R ² IR (nujol) V: ce “ ¹ NMR (f: ρρ · 11 Cbz H Me 3400 to 2300, 1740, 1550 3.58 to 3.73 (·, 2Η), 3.63 (·. 3Η), 5.27 (», 2Η), 7.03 to 7.46 (·, 7Η), / COjSOCOg / 12 Cbz H target. -Bu 3160 to 2200, 1720, 1680, 1635, m.p. Mp 169-171 ° C 1.42 (,, 9Η), 3.53 (d, 3-7 Hz, 2H), 5.29 (,, 1H), 7.27 (t, 3-7 Hz, 1H), 7.35 (,) ·, 1H), 7.30 to 7.50 (., 5H) / С0 ₃ С0С0 ₃ / 13 Chz (cle) H target. -Bu - not specified 1.44 (α, 9H), 3.53 (d, 3-7 Hz, 2H), 5.27 (α, 2H), 7.13 (t, 3-7 Hz, 1H), 7.24 (α, 2H) β, 1H), 7.30 to 7.47 (а, 5H) / С0С1 ₃ / 14 Chz (2 cis: 1 trans) H Me- Bz 1 3150-2050, 1720, 1670, 1620, 1570, m.p. Mp 160-163 ° C 2.33 (s, 2H), 2.53, 2.70 (2xd, 3-8 Hz, 2H), 5.11 (s, 2H), 5.26 (s, 2H), 6.99 to 7 , 40 (·, 10H) / сос1 ₃ со ₃ со / 15 Dec Chz (2 cis; 3 trans) H Bz 1 1725 1675 1620 1575 m.p. Mp 164-166 ° C 3.51, 3.73 (2xd,> 7 Hz, 2H), 5.13 (in, 2H), 5.26 (s, 2H), 7.06, 7.10 (2xs, 1H), 7, 0 to 7.5 (·, 11H) (CDCl ₃ -CD ₃ OD) 16 H (HCl-salt) Me H 3330-2450, 1720 1680, 1630 3.39 (d, 3-7 Hz, 2H), 3.73 (s, 3H), 6.88 (s, 1H), 7.25 (t, 3 »7 Hz, 1H) / CD ₃ SOCD ₃ / 17 Chz H PMB 1720, 1575, 1515, m.p. Mp 145-148 ° C 3.90 (d, 3 * 8 Hz, 2H), 3.90 (8, 3H), 5.20 (8, 2H), 5.33 (s, 2H), 7.00 (s, 1H), 6.85 to 7.60 (·, 10H) (CDCl ₃ -CD ₃ OO / 18 H (HCl-sul) Me Me 3200, 1720, 1625 1605 / СНСН ₃ / 3.44 (d, J 17 HZ, 2H), 3.75 (s, 3H), 3.85, 3.88 (2X8, 3H), 6.70, 6.75 (2X8, 1H), 6 , 97, 7.43 (2xt, 3 «7 Hz, 1H) / CDCl ₃ -CD ₃ 0D / 19 Dec Boc Me Me 3415, 1720, 1541, 1155 / СНС1 ₃ / 1.52 (β, 9H), 3.54 (d, 3-6.5 Hz, 2H), 3.64, (8, 3H, 3.76 (8, 3H), 7.11 (β, 1H ), 7.18 (t, 3 * 6.5 Hz, 1H), 9.12 (Wide, 1H) / S0С1 ₃ / 20 May Boc (cle) Me Me 3410, 1720, 1541, 1150 / СНС1 ₃ / 1.51 (α, 9H), 3.54 (d, 3-6.5 Hz, 2H), 3.69 (8, 3H), 8.83 (8, 3H), 7.03 (8, 1H), 7.08 (t, 3-6.5 Hz, 1H), 9.12 (broad, 1H) / CDCl3; 21 Chz Me Me 3390, 1720, 1540 / с _{3 3} / 3.41, 3.48 (2xd, 3-8 Hz, 2H), 3.65, 3.73, 3.69 3.83 (4X8, 6H), 5.24 (s, 2H), 7.00 7.37 (7H) / CDC1 ₃ / 22nd Chz Et Et 3395, 1720 / сос1 ₃ / 1.19, 1.20, 1.22, 1.30 (4Xt, 3-8 Hz, 6H), 3.34, 3.42 (2xd, 3 * 8 Hz, 2H), 4.08, 4, 12, 4.15, 4.24 (4xq, 3-8 Hz, 4H), 5.21, 5.22, 5.24 (3xa, 2H), 7.03, 7.13 (2xt, 3-8) Hz, 1H), 7.03 (s, 1H), 7.31 (s, 3H), 10.15 (broad, 1H)

CS 268531 82

Table 1 - continued

no. R R ¹ R ² IR (nujol) V: c · * ¹ NMR (f: pp · 23 Chz 8zl Bz 1 3400, 1725 / с _{3 3} / 3.31, 3.42 (2xd, 3 * 7 Hz, 2H), 5.01, 5.03, 5.11 5.17 (4XS, 6H), 6.96-7.30 (», 17H) , 10.19 (broad, 1H) / CDCl3 24 Chz PMB Bz 1 not specified 3.40 (d, 3-7 Hz, 2H), 3.75 (a, 3H), 5.10 (a, 2H), 5.15 (a, 2H), 5.20 (s, 2H), 5.8 to 7.4 (·, 16H) / CDCl ₃ / 25 Chz BH Bzl 3490, 1725 / CDCl 3 3.34, 3.40 (2xd, 3-7 Hz, 2H), 5.02, 5.05, 5.09, 5.17 (4xs, 4H), 6.8-7.4 (Μ, 23H) ), 9.90 (Wide, IH) / CDC1 ₃ / 26 HCO (trance) Me Me 3380, 3140, 1722, 1705, 1695 / СНС1 ₃ / m.p. 100 ° C 3.46 (d, 3-7.5 Hz, 2H), 3.66 (a, 3H), 3.78 (a, 3H), 7.05 (a, 1H), 7.24 (t, 3) -7.5 Hz, 1H) 8.49. (s, IH) / ₃ COCl / 27 Mar: HCO (cis) Me Me 3390, 3150, 1715, 1700, 1535 / СНС1 ₃ / 3.56 (d, 3-7.0 Hz, 2H), 3.73 (s, 3H), 3.84, (s, 3H), 7.02 (t, 3'7 Hz, 1H), 7 12 (8 H), 8.55 (s, 1H) / CDC1 ₃ / 28 HCO (cis) ме target. - -Bu 3380, 1710, 1540 [deg.] ₃ / mp 101-104 ° C 1.47 (s, 9H), 3.50 (d, 3-7 Hz, 2H), 3.86 (α, 3H), 7.07 (t, 3-7 Hz, 1H), 7.13 (s) 8, 1H), 8.60 (8 H) / сос 1 ₃ / 29 HCO (trance) Me target. - -Bu not specified 1.44 (α, 9H), 3.27 (d, 3-7 Hz, 2H), 3.80 (α, 3H), 7.05 (a, 1H), 7.31 (t, 3-7 Hz, IH), 8.52 (a, IH), (coci ₃ ) 30 ClCHgCO Me Me not specified 3.50 (d, 3-6.5 Hz, 2H), 3.68 (a, 3H), 3.79 (a, 3H), 4.25 (a, 2H), 7.24 (a, IH) 7.24 (t, 3-6.5) Hz, 1H) / CDCl3 31 CICHjCO (cis) Me Me 3470, 1725, 1715, 1680, 1535 / снс1 ₃ / 3.60 (d, 3-7 Hz, 2H), 3.75 (α, 3H), 3.87 (α, 3H), 4.27 (α, 2H), 7.18 (α, 1H), 7.18 (t, 3-7 Hz, IH) / CDC1 ₃ / 32 ^ph 3 ^C (3 cis: 2 trans) Me Me 3380, 1720, .1703, 1500, 1480, 1425 / снс1 ₃ / 3.43 (d, 3 * 6.5 Hz, 2H), 3.26, 3.64 (2xa, 3H), 3.70, 3.75 (2xa, 3H), 6.44, 6.63 ( 2xa, IH), 6.54, 6.70 (2xa, IH), 7.01 (t, 3-6.5 Hz, IH), 7.25 (a, 15H) / Si0 ₃ /

AND

02

Example 2.

Process for the preparation of 2- (5-benzyloxycarbonylamino-1,2,4-thladiazol-3-yl) -4'-benzyloxycarbonyl-2-butenoic acid (7)

(1)

CC0C'CHPh _o

II 'снов

C-COOH

Й

CHCH ₂ COOCH ₂ Ph

1. 6 g of amine (1) are amidated with 1.2 equivalents of benzyl chloroformate with 120 ml of dichloromethane containing 2.5 equivalents of pyridine at 0 ° C for 2 hours. 11.2 g of carbamate (2), m.p. 157 DEG-158 DEG C., are obtained. The yield was 94.6%.

2. To a solution of 25.2 mL of diisobutylamine in 125 mL of tetrahydrofuran cooled to -30 to -50 ° C was added 112.3 L of a 1.6 N-hexane solution of n-butyl lithium over 21 minutes. then stirred for 1 hour 20 minutes at 0 ° C and then mixed with 11.2 g of a solution of carbamate (2) in 150 ml of tetrahydrofuran at -68 to 64 ° C for one hour and 20 minutes. It is then stirred at the same temperature for a further 3 hours. The reaction was quenched by the addition of 200 g dry ice and gradually warmed to -5 ° C.

The reaction mixture was diluted with 150 mL of water, washed with ethyl acetate, acidified to pH 2 with 2N hydrochloric acid, and extracted with dichloromethane. The extract solution was washed with water, dried, evaporated and diluted with ether. 6.33 g of the acetic acid derivative (3), m.p. 172 DEG-173 DEG C., are obtained.

GS 268531 B2 * 3. To a solution of 7 g of the acetic acid derivative (3) in 200 µl of methanol, add diphenyldiazomethane at room temperature until the acetic acid derivative can be detected. (3) Evaporate the mixture to obtain the ester (4) o mp 144-146 ° C ·

To a solution of 4.1 g of ester (4) and 3.03 g of diphenylmethyl formate in 41 ml of tetrahydrofuran cooled to 0 ° C, add 1.1 g of 60% sodium hydride. Then stir for 2 hours 20 minutes at room temperature. 60 ° C, diluted with water, acidified with 2N hydrochloric acid and extracted with ethyl acetate · The extract was washed with water, dried and evaporated to give 2.76 g of aldehyde (5) in 63.5% yield ·

IR (CHC1 _3): 3140, 1720, 1610, 1540, 1280, 1080 cm ^1,

5 · A solution of 781 mg of aldehyde (5) and 985 mg of benzyloxycarbonylmethylidenephosphorous in 17 ml of dioxane is refluxed for 3 hours · The mixture is evaporated to give 631 mg of acrylate (6) · Yield 63.5% * Product consists of a mixture cis- and transisomer in 4: 6 ratio.

IR (CDCl ₃ ): 3150, 1730, 1545, 1280 cra ^-1 .

6 0.3 ml of anisole and 0.6 ml of trifluoroacetic acid are added to a solution of 309 mg of acrylate (6) in 4.5 ml of dichloromethane. 171 mg · Yield 75.7% · The product is a 1: 6.45 mixture of cis and trans isomers.

IR (CHC1 ₃₎ M: 1730, 1621, 1540, 1280 cm ^1st

Example 3

Process for the preparation of 2 - (- 2-tert-butoxycarbonylaminothiazol-4-yl) -3-tert-butoxycarbonylmethoxy-2-propenoic acids (7)

(2) ch ₂ cooh

BdcNH

BocNH

C-CCOTCE

II

CHOH

trans (4)

Во c WH

(4) гн-хауск í

CHSPh

AND

OOH ₂ COOBu-t

C-CCOT3E

II

CHOCH ₂ COOBu-t cis / trans

cis

C-COOH 1

CH

OCH.COOBu-t

1. To a suspension of 11 g of acetic acid (1) in 120 ml of dichloromethane is added 90 ml of triethylamine. The mixture is cooled to -78 ° C, treated with 4.87 ml of 2,2,2-trichloroethyl (chloroformate) with 43 mg of N, N-dimethylaminopyridine, stirred at 0 ° C for 10 minutes and at room temperature for 2 hours, Dilute with ethyl acetate, wash with water, dry and evaporate. The residue is purified on 10% aqueous silica gel by chromatography eluting with 9: 1 benzene: ethyl acetate. 9.10 g of trichloroethyl ester (2) are obtained in a yield of 66%.

IR (CHC1 _3), Y: 3400, 1760, 1720, 1150 ^cm-first

2. A solution of 9.10 g of trichloroethyl ester (2) and 6.21 g of 2,2,2-trichloroethyl formate in 34 ml of tetrahydrofuran is added dropwise to a suspension of 2.88 g of sodium hydride in 80 ml of tetrahydrofuran. The mixture is diluted with ethyl acetate, acidified with 5.3 ml of acetic acid, washed with water, dried and evaporated. The residue was crystallized from petroleum ether to give 4.49 g of the formyl ester (3). Yield: 46%

IR (СНС1 ₃ ) У: 3420, 1735, 1620 си ” ¹ .

3. 426 mg of 60% sodium hydride are added to an ice-cooled solution of 4.49 g of the formyl ester (3) in 40 ml of Ν, Ν-dimethylformamide. The mixture was stirred until gas evolution ceased and then mixed with 3.15 g of tert-butyl bromoacetate, kept at room temperature overnight, diluted with ethyl acetate, washed with saturated sodium chloride solution, evaporated, evaporated and purified by silica gel chromatography eluting with a mixture of benzene and ethyl acetate in a ratio of 19: 1 to 2: 1.

3.03 g of diester (4) are obtained in 53% yield.

IR (CHC1 _3): 3400, 1723, 1630, 1150, 1120 · C ^'1.

4. To a solution of 3.03 g of diester (4) in 30 ml of tetrahydrofuran is added 0.70 ml of benzenethiol and 0.79 ml of triethylamine. The mixture was stirred at room temperature for 3.5 hours, evaporated and purified on silica gel using 9: 1 to 8: 2 benzene-ethyl acetate as eluent. 3.92 g of phenyltrhlpropionate (5) were obtained in 92% yield.

The product obtained is a 7: 3 mixture of two geometric isomers.

IR (CHCl ₃ ) vs 3400, 1750, 1725, 1150, 1120 cm ^-1 .

5. To a solution of 3.15 g of phenylthiopropionate (5) in 35 ml of dichloromethane cooled to -40 ° C was added 1.07 g of 80% m-chloroperoxybenzoic acid. The mixture was stirred at -40 ° C for 10 minutes and at room temperature again for 10 minutes, diluted with ethyl acetate with 2% aqueous sodium bisulfite solution and stirred at room temperature for minutes. The organic layer is collected, washed with 5% aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried, evaporated and dissolved in 150 ml of benzene and refluxed for 15 minutes, then the mixture is washed with 5% aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, It is dried, evaporated and purified on silica gel, eluting with a 9: 1 to 1: 1 mixture of benzene and ethyl acetate. Yield: 1.13 g (45%).

IR (CHCl ₃ ) ν: 3420, 1730, 1620, 1540, 1153, 1140 cm ^-1 .

6. To a solution of 0.80 g of diester (6) in 8 ml of acetic acid add 2.0 g of zinc dust. After stirring at room temperature for 1 hour, the reaction mixture was diluted with dichloromethane, treated with 2N hydrochloric acid, stirred at room temperature for 10 minutes, filtered to remove solids and the organic layer was collected. This layer was washed with water, dried and evaporated. There was thus obtained 605 mg of the cis-isomer of the monoester (7). Yield 100%.

IR (CHC1 ₃₎ * 9: 3400, 3550-2500, 1725, 1620, 1150 cm ^'1.

the trans-isomer is obtained from the mother liquor. 750 mg of the E-isomer of the monoester (7) is obtained in 30% yield.

IR (KBr) 0: 3420, 1742, 1710, 1610, 1130 cm ^-1 .

CS 268531 B1 Example 4

Process for the preparation of 2- (2-benzyloxycarbonylaminothiazol-4-yl) -4-benzyloxycarbonylpentanoic acid (3)

(2)

CbzNH. CC0CH ₂ Ph (3)

1 · A solution of 1.45 g of hydroxymethylene (1) and 2.5 g of benzyloxycarbonylethylidentrilephenylphosphorane in 20 ml of toluene is stirred at 80 ° C for 19 hours and at no ° C for 4 hours and then evaporated. chromatography on silica gel with benzene ethyl acetate 2: 1 · in 43% yield was obtained 0.808 g of diester (2), which contains compound ^{2 (3)} and a ³ (4) VP _{Om ru} g _j:

NMR (CDCl ₃ ) (δ: 1.15 (d, 3-7 Hz, 1.5H), 1.71 (s, 1.5H),

4.90 (d, 3 = 9 Hz, 0.5 H) ppm ·

To a solution of diester (2) in 20 ml of dichloromethane is added 3 ml of anisole and 3 ml of trifluoroacetic acid. After three hours stirring at room temperature the mixture was evaporated and triturated with hexane and ether to give in 85% yield 508 mg of monoester (3), which comprises Compound A and ^{3 (4)} _{in the} ratio i · i.

IR (CHC1 _3): 3400, 1725 cm ^1st

Example 5

Process for the preparation of 2- (thiazol-4-yl) -4-benzyloxycarbonyl-2-butenoic acid (3)

N ------ 1-- C-COOCH Ph _o | ¹⁰ ч _s 7 ^CHCH (1)

N ------- C-COOCHPh _э

QT i _L

CH ₂ COOOH ₂ ? H

1. To a solution of 11.5 g of the formyl ester (1) in 220 ml of benzene is added 19.5 g of benzyloxycarbonylmethylidenephosphorane. The mixture is refluxed at 85 ° C for 7 hours, evaporated to half to one third the volume, and purified by chromatography on silica gel, eluting with benzene / ethyl acetate (30: 1). Yield 97%. 15.5 g, which is a 1: 1 mixture of geometric cis and trans isomers.

IR (CHC1 ₃₎ ^9: 1 ⁷²⁰ * ¹ · c ·

2. To a solution of 15.0 g of diester (2) in 150 ml of dichloromethane was added 32 ml of trifluoroacetic acid from 0 ° C. Stir at room temperature for 1.5 h and evaporate. The residue was stirred in hexane, diluted with ethyl acetate and extracted with saturated aqueous sodium bicarbonate. The extract was acidified to pH 3-4 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was dried, evaporated and triturated with 1: 1 ether: hexane to give the monoester (3) in 55% yield. This product is a 1: 1 mixture of geometric cis and trans isomers.

NMR (CDCl ₃ -CD ₃ OD) δ: 3.53, 3.76 (d, 3-8 Hz, 2H), 5.13, 5.15 (2 x β, 2H), 7.23, 7, 38 (2 x, 3-8 Hz, 1 H), 7.35 (β, 5 H), 5.57, 7.61 (d, 3 → 2 Hz, 1 H) pp ·.

Example 6

Process for the preparation of 2- (3-tert-butoxycarbonylamino-5-isoxazolyl) -4-benzyloxycarbonyl-2-butenoic acid (7)

λΉ303

----->

BOY

O

II

NHBO

TwoOOC

_____________NH 3 C 2 PhCH, OOCCH, CH У, 7

--------> ²

НО ОСС (6)

A solution of 56 g of 3-amino-5-methylisoxazole (1) in di-tert-butylpyrocarbonate is stirred at 105-110 ° C for 17 hours. The mixture was evaporated with ether and water. The organic layer was separated, washed sequentially with water, dilute hydrochloric acid, water and saturated sodium chloride solution, dried and evaporated. The residue is washed with petroleum ether to give 75 g of tert-butylcarbonylamine (2), m.p. 108-109 ° C.

2. To a solution of 23.4 mL of diisopropylamine in 90 mL of tetrahydrofuran cooled to -20 ° C and maintained under nitrogen atmosphere was added 125 mL of a 1.6 N hexane solution of n-butyl lithium. After stirring for 15 minutes, the mixture was cooled to -78 ° C and treated with 8.3 g of a solution of tert-butoxycarbonylamino in 40 ml of tetrahydrofuran over 2 minutes. After stirring for 1 hour, 20 g dry ice was added and the solution was evaporated. The residue was dissolved in water, washed with ether, acidified with hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The extract was washed with water, dried and evaporated. The residue was washed with ether to give 4.35 g of the acetic acid derivative (3), m.p. 173-174 ° C (dec.).

3. To a solution of the acetic acid derivative (3) in 200 ml of dichloromethane add 8.63 ml of triethylamine at 0 ° C. The solution is cooled to -78 ° C and mixed with 13.1 g of trichloroethyl (chloroformate) and 0.76 g of 4-dimethylaminopyridine and stirred. Fifteen minutes. The mixture was warmed to room temperature, left overnight, evaporated, diluted with water and extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid, aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, evaporated and purified by silica gel chromatography eluting with benzene / ethyl acetate (3: 1) to give 19 g of trichloroethyl ester (4), m.p. to 147 ° C.

4. To a suspension of 6.72 g of 60% sodium hydride in 220 ml of tetrahydrofuran at -30 to -10 ° C, add a solution of trichloroethyl ester (4) and 14.4 ml of trichloroethyl formate in 100 ml of tetrahydrofuran over 40 minutes. After stirring for 1.5 hours the mixture was poured onto ice-cold hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, saturated sodium chloride solution, dried, evaporated, washed with petroleum ether to give 17.45 g of hydroxymethylidene compound (5). Melting points greater than 210 ° C

5 · A solution of 8.06 g of hydroxymethyllidene compound (5) and 11.1 g of benzyloxycarbonylmethylidentiphenylphosphorane in 350 ml of dioxane and stirred at 55 ° C for 9 hours. , aqueous sodium bicarbonate solution, water and saturated sodium chloride solution, dried, evaporated and purified by chromatography on silica gel eluting with 1: 0 to 15: 1 benzene / ethyl acetate · 6.35 g of diester (6) were obtained.

IR (CHC1 _3): 3410, 2950, 1735, 1607, 1585 · c ^'first

6 · To a solution of 1.85 g diester (6) in 20 ml dichloromethane add 5 g zinc dust and 20 ml acetic acid at 0 ° C. After stirring for 40 minutes, pour the mixture into dichloromethane and dilute hydrochloric acid, filter to remove solid. The extract was washed with water and a saturated aqueous sodium chloride solution, dried, evaporated and purified on silica gel by chromatography eluting with a 3: 1 mixture of benzene and ethyl acetate. 0.25 g of monocarboxylic acid (7) was obtained. .

IR (KBr): 3400, 3250, 2960, 1736, 1618 c and ^{the first}

The product (6) and (7), although not certain, are probably trans-isomers.

Example 7

Process for preparing 2-phenyl-4-benzyloxycarbonyl-2-butenoic acid (3)

Ph-C-COOCHPh II Ph-C-COOCHPh ₂ II CHOH -------- - II CH / Wt / wCH ₂ C00CH ₂ Ph (1) (2)

Ph-C-COOH

II

CH / WvvCH ₂ C00CH ₂ Ph

3.16 g of benzyloxycarbonylmethylidentiphenylphosphorane at room temperature are added to a solution of 1 · 94 g of 2-formylphenylacetic acid di-methyl ester in 20 ml of dioxane.

After stirring for fifty minutes at 60-65 ° C, the mixture was evaporated and purified on silica gel by chromatography eluting with dichloromethane.

1.81 g diester (2) ·

NMR (COCl ₃ ) δ ^{: 3} / 1θ * 3.58 ( ^2xd , 0-8 Hz, 2H), 5.12, 5.24 (2xs, 2H), 6.93 (s, 1H) ppm ·

2 ml of anisole and 4 ml of trifluoroacetic acid at 0 DEG C. are added to a solution of 1.79 g of diester (2) in 40 ml of dichloromethane. The mixture is stirred for 2.5 hours and the mixture is evaporated and triturated with hexane. 73% yielded 0.84 g of the monoester (3). This product is a 17: 83 mixture of geometric cis and trans isomers ·

IR (CHC1 _3), Y: 1730, 1690 · C. * ¹

Example 8

Process for the preparation of 2- (2-thienyl) -4-benzyloxycarbonyl-2-butenoic acid (2)

C-COOH

II

CH

COOOH ^ Hi

3.3 g of the diester (1) produced in the same manner as in Example 7 are dissolved in 60 ml of dichloromethane and mixed with 7 ml of anisole and 7 ml of trifluoroacetic acid at room temperature. Stir for 2.5 hours, evaporate and triturate with hexane. the solid is purified using hexane-ether · 1.19 g of the monoester (2) is obtained in a yield of 56% ·

Dieater (1): IR (СНСЦ): 1730 overload, 1722, 1165 ca ¹ . Monoeeter (2): IR (CHC1 ₃₎ 9: 1730, 1695 ca ^'1.

SUBJECT OF THE INVENTION

Claims (8)

A process for the preparation of carboxyalkenic acid derivatives of the general formula I RCCOOR ⁶ II »3, CR-R-COOl where. r represents a phenyl group or a five- or six-membered heteroaryl group containing one or two heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen, or a protected protecting group usually used in the penicillin or cephalosporin region, r ¹ represents a hydrogen atom or a halogen atom, r ³ represents a single bond or an alkylene group having 1 to 3 carbon atoms, r ³ and R ⁶ represent a hydrogen atom, an alkali metal atom, an ester group forming an alkyl ester of 3 to 12 carbon atoms, an aralkyl alkyl of 7 to 15 carbon atoms, alkoxyformyloxyalkyl of 3 to 8 atoms or a (C až-Cry a) aryl ester, which group is optionally substituted by a halogen atom, and popřípadě ³ optionally further represents an ester-forming alkenyl ester of 2 to 7 carbon atoms, provided that when R is a thiaalkylene group R ¹ is a halogen atom, with that for a myloxalate of the formula Ii R-CH-COOR ⁶ | (II) CHO kde R @ ⁶ and R @ ⁶ are as defined above, or their acetal is subjected to a Wittig reaction by treatment with an alkylidene phosphorus of formula III Ar ₃ P · CH-R ² -C00R ³ (III) CS 268531 B1 where R ² and R ³ have the abovementioned meaning and Ar is an aryl group, in an inert solvent at a temperature of 50 to 120 ° C, and optionally the ester-forming group is removed from the compound of formula 1 to form a compound of the formula Q β of formula I wherein R and / or R are hydrogen and the other substituents are as defined above, or the resulting compound of formula i is halogenated to form a compound of formula 1 wherein R * is halogen and the other substituents are as defined above or the compound of formula I obtained is converted into its alkali salt. 2. A process according to claim 1 wherein the compound of formula I wherein R and / or R is an ester-forming group as defined in item 1 is removed by treatment with an acid, Lewis acid and a cation, base or hydrogen in the presence of of the catalyst in an inert solvent at a temperature of -50 to 4100 ° C. 3. A process according to claim 1 wherein R is aminothiazoles optionally protected by benzyloxycarbonyl, tert-butoxycarbonyl, methylbenzyloxycarbonyl form, chloroacetyl or benzol, and the other substituents are as defined in point 1 · The process of item 1, wherein the compound of formula I is prepared, is as defined in item 1. wherein R @ ¹ is hydrogen and other substituents using the appropriate starting materials 5. A process according to claim 1, wherein a compound of formula (I) is prepared using the appropriate starting materials, wherein r is optionally branched alkylene of 8 to 3 carbon atoms and the other substituents are as defined in point 1. 6. A process according to claim 5, wherein a compound of formula (I) wherein R is methylene and the other substituents are as defined in (1) above is produced using the appropriate 162 starting materials. 7. A process according to any one of Claims 1 and 2, characterized in that a compound of formula I is prepared using the appropriate starting materials wherein R is hydrogen, methyl, tert-butyl, benzyl, methylbenzyl, p-methoxybenzyl or p- nitrobenzyl and other substituents have the meaning given in point 1. Process according to either of Claims 1 and 2, characterized in that a compound of the formula I is prepared using the appropriate starting materials, wherein R 1 is hydrogen, diphenylmethyl or p-methoxybenzyl and the other substituents are as defined in point 1.