SU1720487A3 - Method of producing carboxyalkenic acids - Google Patents

Abstract

The invention relates to heterocyclic compounds, in particular to the preparation of carboxyalkanoic acids in the form of R200C CH2-CH-CR-COOR1, where R is phenyl, thienyl, gizzolyl or aminoisoxazolyl, aminogadiadol, lminothiadiazolyl, and the amino group is protected by benzyl dicarcar. -f uroxy carbonyl, formyl, chlorine. shyilom; Ri, R2 are the same or different - I. methyl, ethyl, tert-butyl, benzyl, diphenylmethyl, which possess antibacterial properties. The goal is to develop a method for producing compounds with a specified action. The preparation is carried out from the compound of the f-ly R-C (CHO) H-COORi. where R and Ri are as defined above, or its acetal and alkylidene-phosphate, foran f-ly AgzR CH-COOP2, where Ra is indicated above, in an inert solvent at 50-120 ° C for 10 minutes - 10 hours, followed by if necessary, removing the carboxy group protective RI and R2 by treatment with an acid.

Description

The invention concerns a process for the preparation of new carboxyalkylene acids of the general formula

R-C-CC

sn

OR)

cis

OR2

where R is phenyl, thienyl, thiazolyl or aminoisoxazolyl, aminothiazolyl, aminothiadiazolyl, the amino group is protected by benzyloxycarbonyl, tert-butoxycarbonyl, formyl, chloroacetyl, RI and Ra are the same or different and mean hydrogen, methyl, ethyl, third -butyl, benzyl, diphenylmethyl.

Carboxyalkanoic acids can be used as an intermediate to obtain 7-beta- (carboxyalkonoylamino) -3-cephem-4-carboxylic acid

R-C-CONH CR O R2-COOR3

RS

COORi,

Xi

yoo o

4 00

vj

Gj

The purpose of the invention is to develop a preparative method for the preparation of carboxyalkenic acids of the general formula used to produce new antibacterial agents that have an effect on aerobic gram-positive bacteria.

In the description of these examples, parts refer to parts by weight and under equivalent - molar equivalent of beta-lactam starting material. The symbols cis and trans mean the relative position of the amide and carboxyl substituents linked to the double bond of the side chain. 1R (infrared spectrum, IR) shows the magnitude of cm NMR (NMR) shows the b-magnitude, and J shows the interaction constants in Hertz units. In the NMR spectrum of a geometric isomer mixture, the signals, which are split into two or more, are shown by chemical shifts, separated by a comma and a separating number and X in front of a multiple value mark.

Usually, the reaction, if necessary, after the addition of the solvent (for example, water, acid, dichloromethane) is washed, dried, and

concentrated and product separated. All concentrations are carried out under reduced pressure. The following abbreviations are accepted in the description: AOM — acetoxymethyl; BH - diphenylmethyl; Wi-butyl; BOC - tert-butoxycarbonyl; BZI is benzyl; CIZ is benzyloxycarbonyl; the circle in the hetero ring of the structural formula is an aromatic ring; exo isomer with the position of -3,4-double bond in acyl 7-side chain; Me is methyl; MEM is methoxy-ethoxymethyl; Ph is phenyl; RMB is para-methoxybenzyl; PNB is para-nitrobenzyl; and ROM - pivaloyloxymethyl.

Example 1.2- {2-benzyloxycarbonylaminothiazol-4-yl) -4-benzyloxycarbonyl-2-butenoic acid

N-yCHCOOCHPh Cbl S CHO CD

. N-yC-COOCHPhj

CbzNH 5 j1

(2) .CHjCOOCHjPh

„N-j-C-COOH

SYNCH S CH-CH2COOCH2Pb

(1) A solution of formyl acetate (1) (1.94 g) and benzyloxycarbonylmethylidentriphenylphosphorane (1.3 equivalents) in dioxane or toluene (8 hours) is stirred for 1 hour or 6 hours at 80 or 120 ° C in a water bath . After cooling, the mixture is concentrated and the residue is concentrated in a chromatographic column with silica gel, eluent SbN: EUAC, 19: 1, resulting in a propendicarboxylate (2) (2.13 g). Exit 87%. This product is a mixture of 39% cis and 61% trans geometric isomers, which can be separated after repeated

chromatography.

IR (CHCl3) v: 3410; 1730 (trance).

Spectrum and K () v: 3400; 1730 (cis).

(2) In a solution of this product (2) (1.16 g) in dichloromethane (10 hours), anisole (2 hours) and trifluoroacetic acid (2 hours) are added. After stirring for 2 hours, the reaction mixture is concentrated and the residue is washed with a mixture of ether and hexane to remove the mother liquor and the result is dicarboxylic acid monobenzyl ester (3.76 g). Yield 89%. These

geometric isomers (cis: trans 1: 3) can be separated by chromatography using a SiO2 eluent CbHe: EUAc, 1: 1.

NMR spectrum (CONR - SOZOO) (5: 3.51

(d, Hz, 2H); 5.13 (s, 2H); 5.26 (s, 2H); 7.06 (s, 1H); 7.0-7.5 (ms, 11H) (trans).

NMR spectrum (SOS SOZOO); 3.73 (d, Hz, 2H); 5.13 (s, 2H); 7.10 (s, 1H); 7.0-7.5 (m 11H) (cis).

Analogously to example 1 complex diester

butenoic acid, obtained from the corresponding formyl acetate using the same complications of reagents and solvents at the same temperature at the same

reaction time. The ester obtained, if necessary, is completely or partially deesterified using conventional reagents, for example sodium hydroxide for alkyl complexes.

esters and Lewis acids (for example, aluminum, titanium, or tin halides) for tert-alkyl or aralkyl esters, and the result is free acids.

PRI me R 2.2- {5-benzyloxycarbonylamino-1,2,4-thiadiazol-3-yl) -4-benzyloxy-arbonyl-2-butenoic acid (7)

50

UH

CHj N, -jrCH3 N-1-CH2COOH S,, CbzNHVN (3J

five

- | GH2COOCHR fc N-jpCCOOCHPI

CbzNH STjwCbzNH S N CHOH

N-jr-CCOOCHPhj.

CbzNH Y1 CH

SngSooSgrl (6)

(five)

- 5 t-soon

SbzNH S CHCH2COOCHjPh (7)

(1) Amine (1) (6 g) is amidated with benzyl chloroformate (1,2-equivalent) in dichloromethane (120 ml) containing pyridine (2.5 equivalents) at 0 ° C for 2 h, and in The result is a carbamate (7, (11.2 g) with a melting point of 157-158 ° C. Yield 94.6%.

(2) To a solution of diisobutylamine (25.2 ml) in tetrahydrofuran (125 ml), cooled to a temperature of (-30) to (-5) ° C, inject a 1.6-normal hexane solution of n-butylity (112 , 3 ml) within 21 min. After stirring for 1 hour and 20 minutes at 0 ° C, the mixture is mixed with a solution of carbamate (2) (11.2 g) in tetrahydrofuran (150 ml) at a temperature of (-68) to (64) ° C for 1 hour 20 min, and stirring is carried out at the same temperature for 3 hours. This reaction mixture is rapidly cooled with dry ice (200 g) and slowly heated to -5 ° C. This reaction mixture was diluted with water (150 ml), washed with ethyl acetate, acidified with 2-normal hydrochloric acid to pH 2, and extracted with dichloromethane. The extract solution is washed with water, dried, concentrated and diluted with ether, and the result is acetic acid (3) (6.33 g), m.p. 172-173 ° C.

(3) Diphenyldiazane-methane is introduced into a solution of acetic acid (3) (7 g) in methanol (200 ml) at room temperature until the presence of acetic acid (3) is detected. The mixture is concentrated and the ester (4) is obtained. M.p. 144-146 ° C, 8.5g.

(4) A solution of ester (4) (4.1 g) and diphenylmethylformate (3.03 g) in tetrahydrofuran (41 ml), cooled to 0 ° C, is injected with 60% sodium hydride (1.1 g). After stirring for 2 hours and 20 minutes at 60 ° C, the mixture is diluted with water, acidified with 2 normal hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried and concentrated and as a result aldehyde (5) (2.76 g) is obtained. Yield 63.5%.

IR () d: 3140; 1720; 1610; 1540; 1280; 1080cm 1.

(5) A solution of aldehyde (5) (781 mg) and benzyloxycarbonylmethylidenephosphorane (985 mg) in dioxane (17 ml) is heated under reflux for 3 hours. The mixture is concentrated and an acrylate (6) (631 mg ). Yield 63.5%. A mixture of cis-trans isomers (4: 6).

IR spectrum () b: 31.50; 1730; 1545; 1280cm 1.

(6) Anisole (0.3 ml) is added to a solution of acrylate (6) (309 mg) in dichloromethane (4.5 ml) and

trifluoroacetic acid (0.6 ml). After stirring for 1 hour at room temperature, the mixture was diluted with hexane, and the result was a semi-ether (7) (171 mg). Yield 75.7%. This complex half ester is a mixture of cis-trans isomers (1: 6.45).

IR spectrum (СНС1з) д. 1730; 1621; 1540; 1280cm 1.

Example 2-2 (Tert-butoxycarbonylaminothiazol-4-yl) -3-butoxycarbonylmethoxy-2-propenoic acid (7)

 N-jj-CH2COOTCE

BOCNH s

(2)

N-jj-C-COOTCE

BOCNh S CHOH (3)

Boc

 N-jpCH-COOTCE

Above the sn5№

(5) CH, COOBU-t

aosm

, M-COOH

F

CH2C008u-t

(1) Triethylamine (90 ml) is added to a suspension of acetic acid (1) (11 g) in dichloromethane (120 ml). The mixture is cooled at -78 ° C, mixed with 2,2,2-trichloroethyl chloroformate (4.87 ml) in NN-dimethylaminopyridine (432 mg), stirred at 0 ° C for 10 minutes, at room temperature for 2 h, diluted with ethyl acetate, washed with water, dried and concentrated. The residual product is purified by chromatographic separation using aqueous (10%) silica gel (eluted with benzene-ethyl acetate in the 9: 1 ratio), and the result is trichloroethyl ester (2) (9, 10 g). Yield 66%.

IR Spectrum (CHCbJv: 3400; 1760: 1720; 1150cm 1.

(2) A solution of trichloroethyl ether (2) (9.10 g) and 2.2.2-trichloroethylformate (6.21 g) are added dropwise to a suspension of sodium hydride (2.88 g) in tetrahydrofuran (80 ml). ) in tetrahydrofuran (34 ml). After stirring at room temperature for 2 hours, the mixture was diluted with ethyl acetate, acidified with acetic acid (5.3 ml), washed with water, dried and concentrated. The residue is crystallized from petroleum ether to form the ester of formic acid (3) (4.49 g). Yield 46%.

IR (CHCls) v: 3420 1735: 1620.

(3) In an ice-cooled solution of formic acid ester (3) (4.49 g) in N. N-dimethylformamide (40 ml), 60% sodium hydride (426 mg) are added. The mixture is stirred until gas evolution ceases, mixed with tert-butyl bromoacetate (3.15 g), maintained at room temperature overnight, diluted with ethyl acetate, washed with brine, dried, concentrated and purified by chromatographic separation. on silica gel (eluted with benzene-ethyl acetate in the ratio of 19: 1 to 2: 1) and the result is a complex diester (4) (3.03 g). Yield 53%.

IR spectrum () V: 3400; 1723; 1630; 1150; 1120 cm 1.

(4) Benzenthiol (0.70 ml) and triethylamine (0.79 ml) are added to a solution of the diester of (4) (3.03 g) in tetrahydrofuran (30 ml). The mixture is stirred at room temperature for 3.5 hours, concentrated and purified by chromatographic separation on silica gel (when used for elution: a mixture of benzene / ethyl acetate in the ratio of 9: 1-8: 2) and the result is phenyl thiopropionate (5%). ) (3.36 g). Yield 92%. This product is a mixture of two geometric isomers in a ratio of 7: 3.

IR spectrum () v: 3400; 1750; 1725; 1155; 1120cm

(5) In a solution of phenylthiopropionate (5) (3.15 g) in dichloromethane (35 ml), cooled at -40 ° C, meta-chloroperbenzoic acid (80%, 1.07 g) is added. The mixture was stirred at -40 ° C for 10 minutes and at room temperature for 10 minutes, diluted with ethyl acetate, stirred with a 2% aqueous solution of sodium hydrogen sulphite and stirred at room temperature for 5 minutes. The organic layer was removed, washed with a 5% aqueous solution of sodium hydrogencarbonate and brine, dried, concentrated, dissolved in benzene (150 ml) and heated under reflux for 15 minutes. The mixture is washed with a 5% aqueous solution of sodium hydrogencarbonate and brine, dried, concentrated and purified by chromatographic separation on silica gel (eluted with benzene-ethyl acetate 9: 1 to 1: 1). 6) (1.13 g). Yield 45%.

Spectrum IR (LBH) v: 3420; 1730; 1620; 1540; 1153; 1140cm

(6) A solution of diester (6) (0.80 g) in acetic acid (8 ml) is injected with zinc powder (2.0 g). After stirring at room temperature for 1 hour, the mixture is diluted with dichloroethane, mixed with 2N hydrochloric acid, stirred for 10 minutes at room temperature, filtered to remove solids, and the organic layer is removed. The latter is washed with water, dried and concentrated, and the cis-isomer of the monoester (7) (605 mg) is obtained. The yield is 100%.

IR (CHCl3) v: 3400; 3550-2500; 1725; 1620; 1150cm 1.

The trans isomer of the monoester (7) (750 mg) is recovered from the mother liquor. Yield 30%.

IR (KBr) v: 3420: 1742: 1710: 1610; 1130cm 1.

EXAMPLE 4.2- (2-Benoyloxycarbonylaminothiazol-4-yl) -4-benzyloxycarbonylpentenoic acid (3)

0

N-ir

/ 7

with imn snon

(ABOUT

C-COOCHPh, N CbzNH

-C-COOCHPh,

- hgkg

CbxNHS I:.:.

mg

(2)

COOCHjPh

CH-C-CH

COOCHjPh

. (1) A solution of hydroxymethylene (1) (1.46 g) and benzyloxycarbonylethylidentriphenylpho-5-sphorane (2.5 g) in toluene (20 ml) was stirred at 80 ° C for 19 hours and at 110 ° C for 4 hours and then concentrated. The residue is purified by chromatographic separation

0 silica gel (eluent CbNb: EYUAC, 2: 1) and the result is a complex diester (2) (0,808).

Yield 43% (D2 (3) / D3 () 1: 1)

NMR spectrum () d: 1.15 (d, J 7 Hz. 1.5H); 1.71 (s, 1.5H): 4.90 (fl.J 9ru, 0.5H). (2) Anisole (3 ml) and trifluoroacetic acid (3 ml) are added to a solution of the diester (2) in dichloromethane (20 ml). After stirring at room temperature for 3 hours, the mixture is concentrated and triturated in a mixture of hexane and ethyl ether, and the resultant monoester (3) (508 mg) is obtained. Yield 85% (D2 (3) / D3M) 1: 1)

IR spectrum () v: 3400: 1725. PRI me R 5. 2- (Thiazol-4-yl) -4-benzyloxycarbonyl-2-butenoic acid (3)

(1) Benzyloxycarbonylmethylidenephosphorane (19.5 g) is added to a solution of the formic ester (1) (11.5 g) in benzene (220 ml). After refluxing at 85 ° C for 7 hours, the mixture is concentrated until half to one third of the volume remains and purified by chromatographic separation on silica gel (eluted with benzene / ethyl acetate in a ratio of 30: 1) and the result is a complex diester (2) (15.5 g). Exit 97%. This product is a mixture of cis and transgeometric isomers (1: 1).

IR Spectrum () V: 1720cm 1.

(2) Trifluoroacetic acid (32 ml) was introduced into a solution of the diester of complex (2) (15.0 g) in dichloromethane (150 ml) at 0 ° C. After stirring at room temperature for 1.5 hours, the mixture is concentrated. The residue was stirred in hexane, diluted with ethyl acetate and extracted with a saturated aqueous solution of sodium hydrogencarbonate. The extract is acidified with 10% hydrochloric acid to a pH of 3-4 and extracted with ethyl acetate. The extract is dried, concentrated and triturated in a mixture of ether and hexane (1: 1 ratio) and the resultant monoester (3). Yield 55%. This product is a mixture of cis and trans (1: 1) geometric isomers.

Nuclear Magnetic Resonance Spectrum (CDCI3 - SOZOO) d: 3.53; 3.76; (d, J - 8 Hz, 2H); 5.13, 5.15 (2 x s., 2H); 7.23; 7.38 (2 x t., J - 8 Hz, 1H); 7.35 (s, 5H); 7.57; 7.61 (d, J - 2 Hz, 1H); 8.79; 8.82 (d, i - 2 Hz, 1H) ppm

Example 2- (3-Tert-butoxycarbonylamino-5-isoxazolyl) -4-benzyloxycarbonyl-2-butenoic acid (7)

jnrNHz Jpr sun / sn, VM

NHBOC. HOBO

 s n

nossn oh

(I) () (3)

HOCH-n-jj-NHBOC.

 JONNHBOC

TCEOOCCHjCf TCEOOCC / VN

(five)

PhCHjOOCCHjCH j-jj-NHBoC РСНН2ООССНгСН

TCE OOSS

(6)

II

noss

 Tt

-L

(7)

(1) Fistor Z-amino-5-methylisoxazole (1) (56 g) in di-t-butyl pyrocarbonate is stirred at 105-110 ° C for 17 h. The mixture is concentrated and diluted

5 with ether and water The organic layer is recovered, washed with water, diluted with hydrochloric acid, water and brine, dried and concentrated. Residual product concentration

10 is washed with petroleum ether and the resulting tert-butoxycarbonylamine (2) (75 g), so pl. 108-109 ° C.

(2) In a solution of diisopropylamine (23.4 ml) under nitrogen atmosphere in tetrahydro-15 furan (90 ml), cooled at -20 ° C, and-butyl lithium (1.6-normal hexa-new solution, 125 ml) was added. After stirring for 15 minutes, the mixture is cooled to -78 ° C, mixed with a solution of tert-butoc20 of sicarbonylamine (2) (8.3 g) in tetrahydrofuran (40 ml) for 2 minutes, stirred for 1 hour. cooled with dry ice (20 g) and concentrated. Residual product concentration

25 is dissolved in water, washed with ether, acidified with hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The extract is washed with water, dried and concentrated. Residual product.

The 30th concentration is washed with ether and as a result acetic acid (3) (4.35 g) is obtained. Melting point 173-174 ° C (with decomposition).

(3) In a solution of acetic acid (3) in dichloromethane (35 ml), triethylamine is added.

(8.63 ml) at 0 ° C. This mixture is cooled to -78 ° C, mixed with trichloroethyl chloroformate (13.1 g) and 4-dimethylaminopyridine (0.76 g) and stirred for

40 15 min. The mixture is heated to room temperature, allowed to stand overnight, concentrated, diluted with water and extracted with ethyl acetate. The extract is washed with dilute hydrochloric acid, aqueous

45 with a solution of sodium hydrogencarbonate, water, and brine, concentrated and purified by chromatographic separation on silica gel (eluted with benzene-ethyl acetate in relation to

50 3: 1) and the result is a trichloroethyl ester (4) with m.p. 146-147 ° C.

(4) In a suspension of 60% sodium hydride (6.72 g) in tetrahydrofuran (220 ml) at a temperature of (-30) to (-10) ° C

55 solution of trichloroethyl ether (4) and trichloroethyl formate. (14.4 ml) in tetrahydrofuran (100 ml) for 48 min. After stirring for 1.5 hours, the mixture was poured into glacial hydrochloric acid and extracted with ethyl acetate. The extract is washed with water and brine, dried, concentrated and washed with petroleum ether and the result is a hydroxymethylidene compound (5) (17.45 g), m.p. 210 ° C.

(5) A solution of hydroxymethylidene compound (5) (8.06 g) and benzyloxycarbonylmethylidentriphenylphosphorane (11.1 g) in dioxane (350 ml) was stirred at 55 ° C for 9 hours. The mixture was concentrated, dissolved in water and ethyl acetate, washed with dilute hydrochloric acid, an aqueous solution of sodium hydrogencarbonate, water and brine, dried, concentrated and purified by chromatographic separation on silica gel (with elution with a mixture of benzene and ethyl acetate in the ratio 1: 0 - 15: 1) and as a result get complex diester (6) (6,35 g).

PC-spectrum (CHCl3) v: 3410; 2950; 160 /; 1585.

(6) Zinc (g g) and acetic acid (20 ml) are introduced into a solution of the diester of a complex (6) (1.85 g) in dichloromethane (2.0 ml) at 0 ° C. After stirring for 40 minutes, the mixture is poured into dichloromethane and dilute hydrochloric acid, filtered to remove solids, and extracted with dichloromethane. The extract is washed with water and brine, dried, concentrated and purified by chromatographic separation on silica gel (. Eluting with benzene-ethyl acetate 3: 1), and the result is monocarboxylic acid (7) (0.25 d).

IR spectrum (KBr) v: 3400; 3250; 2960; 1736; 1618 cm 1.

Products (6) and (7) are pure isomers. They are not defined, but are most likely related to trans isomers.

Example. 2-Phenyl-4-benzyloxycarbonyl-2-butenoic acid (3)

Ph-c-coormt

СНгСООСН2РЬ

(21

 Ph-C-COOH

CH-vCH2COOCH2Ph

(1) Benzyloxycarbonylmethylidentriphenylphosphorane (3.16 g) was added to a solution of 2-formylphenylacetic acid diphenylmethyl ester (1) (1.94 g) in dioxane (20 ml) at room temperature. After stirring at 60-65 ° C for 50 minutes, the mixture is concentrated and purified by chromatographic separation on silica gel (eluted with

dichloromethane) and as a result, the diester (2) (1.81 g) is obtained, Yield 61%

NMR spectrum (COClS) d; 3.18; 3.58 (x A., J 8 Hz, 2H), 5.12; 5 24 (2 x s., 2H), 6 43 (s., 1H) ppm,

(2) Anisole (4 mo) and trifluoroacetic acid (4 ml) are added to a solution of the diester of complex (2) (1, / 9) in dichloromethane (40 ml) at 0 ° C. After stirring for 2.5 hours, the mixture is concentrated and triturated in hexane, and as a result, a n-monoester (3) (0.84 g) is obtained. The yield of 73% D. d.produced is the mixture of qi (- and trans- (1783) geometric isomers. IR spectrum (CHC.I; v i730; 1690.

PRI me R 8. (2 - (2 Hyenyl-4-benzyloxy- to carbonyl-2-bumenoic acid (2)

,, | IKJII- MI 20 (h-- n7soosn2rn

Oh-soon

(2) SnoSnRs

Adherent diester (1) (3.3 g), obtained similarly to preparation A-16, is dissolved in dichoromethane (60 ml), mixed with anisole (1 ml) and trifluoroacetic acid (7 ml) at 0 ° C, stirred in for 2.5 h, concentrated and triturated in hexane. The solid obtained is purified in a mixture of hexane - ether and the resultant monoester (2) (1.19 g) is obtained. Output

%%.

Complex diester (1). IR spectrum () v: 1730 narrow; 1722;

1165cm

--one

35 Mono ester (2): IR spectrum (CHC1) v: 1730; 1695cm.

40

Claims (1)

The invention The method of obtaining carboxyalkenoic acids of the general formula Rc -c sn i „, o 4 OR, , where R is phenyl, thienyl, thiazol or amino isoxazolyl, aminothiazolyl, aminothiadiazolyl, the amino group is protected by benzyloxycarbonyl, tert-butoxycarbonyl, formyl, chloroacetyl; RI and R2, the same or different - hydrogen, methyl, ethyl, tert-butyl, benzyl, diphenylmethyl, characterized in that the compound of the general formula R-CH-COOR sno where R and RI have the indicated meanings. or its acetal is reacted with alkylidenephosphorane of the general formula AgzR - CH - COOR2, where Ra has the indicated values, in an inert solvent at 50-120 ° C for 10 minutes to 10 hours, followed, if necessary, by removing the protective group for the carboxy group of RI and RZ by treating with acid. Priority featured 04.10.83 priR-aminothiazolyl, the amino group being protected by benzyloxycarbonyl, tert-butoxycarbonyl, formyl, chloroacetyl. 03.02.84 when R is phenyl, thienyl, thiazolyl or aminoisoxazolyl, aminothiadiazolyl, and the amino group is protected by benzyloxycarbonyl, tert-butoxycarbonyl, formyl, chloroacetyl.