FI56842C - SAETT ATT FRAMSTAELLA DERIVAT AV DL-7-AMINODESACETOXICEFALOSPORANSYRA - Google Patents

Description

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11 UTLÄGG NI NGSSKRI FT 00042 C (45) Γ ", t? R. T! I cy · ν π π c 1t: · 10 0 4 19 J 0 ^ (51) Kv.ik. * / Int.a * c 07 D 501/08 FINLAND - FINLAND (11) p »t« nttlh *, «mui - PwenttiMeknln * ^ 13/72 (22) H» k «ml * clouds - AniBknlngadag l6.02.72 ^ (23) Alkupiivi — Glltl | h * t * d «| 16.02.72 (41) Become public - Bllvlt offentllg 19.08.72

Registration date (44) Date of dispatch and date of issue. - 1? 7Q

Patent · ocn regiiterstyrelsen '7 Ansekan uttegd och utl. * Krift * n publicerwl 31.12.79 (32) (33) (31) Privilege claimed — Begird prlorltet 18.02.71 l8.02.7i France-France (FR) 71-05555 71 -05556 (71) Roussel Uclaf, 35 Boulevard des Invalides, Paris Jet France-France (FR) (72) Jacques Martel, Bondy, Rene Heymes, Romainville, France-France (FR) (7 * 0 Oy Jalo Ant-Wuorinen Ab (5 * +) The present invention relates to a new process for the preparation of DL-7-R-aminodesacetoxycephalosporanic acid derivatives, the general formula for which is DL-7-R-aminodesacetoxycephalosporanic acid derivatives.

S

RHN —-S 'N

COORj which exist in the form of a mixture of cis and trans isomers or of one of the isomers in which R represents a hydrogen atom or a trityl group.

R1 represents a straight or branched alkyl group or a benzyl group having 1 to 4 carbon atoms.

Compounds of the general formula B * which, in addition to the formula are limited so that when R represents a hydrogen atom, R1 is a tert-butyl, benzyl or ethyl group, are novel compounds.

Of these new compounds, mention may be made in particular of DL-7-amino-deacetoxycephalosporanic acid tert-butyl ester and the corresponding 7-tritylamino derivative, DL-7-aminodesacetoxycephalosporanic acid benzyl ester & 6Ö42 and the corresponding 7-tritylamino derivative,

The compounds of formula B 'are of particular interest as intermediates for the preparation of compounds belonging to the cephalosporan series which have antibiotic activity.

Namely, compounds of formula B * (where R is trityl) can be deprotected with an acid to give the corresponding 7-amino compounds of formula B '(where R is hydrogen), which are in particular intermediates which, by reaction with amine-reactive functional carboxylic acid derivatives and thereafter for acid hydrolysis, it is possible to prepare compounds having an effect similar to that of cefalexin (cf., inter alia, U.S. Pat. No. 3 12A 576);

Compounds of general formula B '(wherein R is hydrogen) may be converted to cephalosporin V after reaction with phenoxyacetic acid chloride J.A. According to the method of Wabber et al., J, Am. Chem. Soc., 91, 5674, (1969).

The process according to the invention thus makes it possible to prepare 7-amino-deacetoxycephalosporanic acid-type compounds by complete synthesis.

Methods for the preparation of such compounds are indeed known, but they are all based on semi-syntheses, i.e. they use an existing starting material or a kefem-type structure of the formula

S

0

The process according to the invention is characterized in that the enamine of the formula CH-NH-

S

Y-C II

wherein R 2 represents a straight or branched alkyl group having 1 to 10 carbon atoms, and Y represents a fralimido group, a benzoylamino group or a thiobenzoylamino group, is treated with hydrogen sulfide in the presence of an acid HX 2 to give a halogen, sulfate or sulfonic anion is 3,56842 m3 ® Xj ® Y-CH-CH ___ \ 111

XSH

COOR2, which is present in the form of a mixture of both threo and erythro isomers, or in the form of either isomer, the product of formula III is condensed in the presence of a tertiary amine with an ester of <x-keto-β-raethylene butanoic acid

0 CH

> - <COORj ^ XCH3 wherein R ^ represents a straight or branched alkyl group or a benzyl group having 1 to 4 carbon atoms.

A derivative of 1,3-thiazane having the general formula tt —fs "i coor2 h v is obtained.

Hq / COORj in the form of a mixture of both threo and erythro isomers, independently of the conjugation of carbon atoms 3 and 4, or in the form of either isomer, after which the dehydrating agent is reacted with a product of formula V to give a 1,3-thiazine derivative of general formula is

S

Y-CH-S '' N

1 Ί

COOR_ HN VI

J CH3 COOR1 4 56842 present in the form of a mixture of both threo and erythro isomers or of either isomer, the group Y is cleaved by functional exchange with hydrazine or acid hydrolysis to give α-carbalkoxyaminomethyl-1,3-thiataine of the general formula 5 H2NHj. - ^ ^ coor2 HN.

\ VII

CH3: oor1 which may exist in the form of a mixture of both threo and erythro isomers, or in which either the COOR2 group is selectively saponified with an alkaline agent to give α-carboxyaminomethyl-1,3-thiazine of the general formula

H 2 N-ch-'S

COOH 101 VIII

'ch3 COOR1 in the form of a mixture of both threo and erythro isomers, or of one of the isomers treated with a tritylating agent, to give an α-carboxy: ethylaminomethyl-1,3-thiazine derivative of the general formula

S

<C, H_), C-HN-CH --s' \ | f] COOH ™ γ \

CH3 IX

COOR 2 in the form of a mixture of both threo and erythro isomers, or a mixture of either isomers cyclized with a lactamizing agent to give the desired compound of general formula B ', wherein R represents a trityl radical, and this compound is optionally treated with an acidic substance of general formula B'. to prepare the desired compound, wherein R represents a hydrogen atom.

5,56842

It should be noted that some of the intermediates obtained in the process of the invention may be purified by formation of salts with either an acid or a base. Thus a) for the preparation of α-carboxyaminomethyl-1,3-thiazine of the general formula g H-N-CH

COOH HN

T \ VIII

CH-COOR1, which may exist in the form of a mixture of both threo and erythro isomers, or in the form of either a straight or branched alkyl group having 1 to 4 carbon atoms or a benzyl group, the group Y is cleaved from a 1,3-thiazine derivative of the general formula is

S

Y-CH - / \ i Γ C00R2 HN Vl ch3 COOR1 which exists in the form of both threo and erythro isomers or either isomer, in which formula Y represents a phthalimido group, a benzoylamino group or a thiobenzoylamino group and R2 represents a straight chain containing 1 to 10 carbon atoms or a branched alkyl group, by functional exchange with hydrazine or by acid hydrolysis, followed by the formation of α-carbalkoxyaminomethyl-1,3-thiazine of the general formula h2n-ch -_____

I 'VII

C00R2 HN

/ CH3 COORj, which may exist in the form of a mixture of both threo and ethytro isomers or of either isomer, is treated with an organic or inorganic acid 6 56842 HX2 »where X2 represents a halogen anion or a derivative of an organic acid, e.g. oxalic acid, to give α-carbalkoxyaminomethyl-1,3 -thiazine salt of the general formula © s 2 Hf-CH-S "" h I '* COOR2 HN VII' C »3 COOR ^ which may exist in the form of a mixture of threo and erythro isomers or of one of the isomers treated with an alkaline substance and b) DL-7-tritylaminodeacetoxycephalosporanic acid ester of general formula

S

<W3c-m. If "] _1 (β 'J® · ** R" trityHH) <T' j CH3 COOR | which occurs in the form of a mixture of both cis- and trans-isomers or of one of the isomers, in which formula Rj ^ represents a straight or a branched alkyl group or a benzyl group, O1-carboxyaminomethyl-1,3-triazine of the general formula 3

K.N-CH -f 'N

1 f 1

COOH HN

COOR1 in the form of a mixture of both threo and erythro isomers, or of one of the isomers, is treated with a tritylating agent to give a crude derivative of α-carboxytritylaminomethyl-1,3-thiazine of the general formula 7 56842

S

(C ^ HJ-HN-C ^ CH

6 5 3 I I

COOH HN

\ TY

ch3 iX

COOR1 in the form of a mixture of both threo and erythro isomers or either isomer, and the derivative is reacted with a secondary amine to produce an amine salt of an α-carboxytritylaminomethyl-1,3-thiazine derivative having the general formula; s (C, He) -C-HN-CH_ / \ ΙΓΤ] cocH hn IX 'Θ CH3 Η2Ν · ζ COOR ^ in the form of a mixture of both threo- and erythro-isomers or of one of the isomers, in which formula the group HjN ^ represents a secondary amine-derived a cation which is then hydrolysed acidically and then cyclized with a lactamizing agent to produce the desired compound.

In addition, it should be noted that HI, V, VI, VII, VIII and IX have two asymmetric carbon atoms and can thus exist in the form of a threo isomer and an erythro isomer. The Treo / erytro ratio may vary depending on working conditions. Thus, in the alkali treatment of α-carbalkoxyaminomethyl-1,3-triazine of general formula VII in the form of a mixture of threo and erythro isomers, e-carboxaminomethyl-1,3-triazine of general formula VIII can in some cases be obtained almost exclusively from threo. in the form of an isomer.

Furthermore, it should be noted that only the threo isomer of the α-carboxy-tritylaminomethyl-1,3-thiazine derivative of the general formula IX is obtained by cyclization of DL-7-tritylaminodesacetoxycephalosporanic acid esters of the general formula I having the same 6H, 7H-cis-cis than derivatives of the original natural cephalosporin.

Thus, it is important that most of the compounds of general formula IX are obtained in the form of the threo isomer, which in very good yield can be converted into the cis isomer of the compounds of general formula I, 8 56842

One embodiment, which is currently considered to be the best for carrying out the method according to the invention, satisfies the following conditions?

The acid HX 2 in the presence of which the enamine of general formula II is treated with hydrogen sulfide is anhydrous hydrochloric acid. As the acid HXj, other inorganic acids can also be used, for example sulfuric acid or also a sulfonic acid, e.g. para-toluenesulfonic acid or methanesulfonic acid; the tertiary amine in the presence of which the thioamine of general formula III is condensed with an α-keto-p-methylenebutanoic acid ester of general formula IV is triethylamine. This condensation can also be carried out in the presence of other tertiary amines and in particular N-methylpiperidine, pyridine, trimethylamine, N-methylpyrrolidine or quinoline; the dehydrating agent which is reacted with the 1,3-thiazane derivative of the general formula V to prepare the 1,3-thiazine derivative of the general formula VI is an aqueous solution of hydrochloric acid or oxalic acid; when Y in the 1,3-thiazine derivative of the general formula VI represents a phthalimido group, the group Y is preferably cleaved by functional exchange with hydrazine, and when Y represents a benzoylamino or thiobenzoylamino group, hydrogenation is preferably performed. In the latter case, it is also possible in the first step to alkylate the ketone or thioketone function with an alkyl sulphate or Meerwein reaction component to prepare the corresponding imino or thioiminoether, followed by hydrolysis in the second step with an organic or inorganic acid, e.g. acetic acid or dilute chlorine. the alkaline agent used to selectively saponify the COO1 group of α-carbalkoxyaminomethyl-1,3-thiazine of general formula VII is preferably lithium hydroxide. Potassium or sodium hydroxide or alkali metal carbonate, e.g. sodium or potassium carbonate, may also be used; The tritylating agent in which the α-carboxyaminomethyl-1,3-thiazine of the general formula VIII is treated to prepare the α-carboxytritylaminomethyl-1,3-thiazine derivative of the general formula IX is trityl chloride and this reaction is carried out in an alkaline substance and in particular a tertiary solvent. in the presence of an amine, e.g. triethylamine, trimethylamine, N-methylpiperidine, pyridine, N-methylpyrrolidine or quinoline; a dialkyl or dicycloalkylcarbodiimide, e.g. dicyclohexylcarbodiimide or 9,56842 diisopropylcarbodiimide, is used as the lactamizing agent to cyclize the α-carboxytrityl * minomethyl-1,3-thiazine derivative of the general formula IX, in nitromethane, a disubstituted amide, sulfoxide, acetone or acetonitrile, and in the presence of a tertiary amine, e.g. pyridine, collidine or dialkylaniline, wherein the reaction medium may contain another solvent, e.g. methylene chloride or chloroform; the alkaline substance used to convert the erythro isomer of α-carboxytritylaminomethyl-1,3-thiazine of general formula IX to the threo isomer is an alkali metal hydroxide, e.g. sodium or lithium hydroxide, and the reaction is carried out in an alkanol, e.g. methanol or ethanol ; the acidic substance which can be used to prepare a compound of general formula B '(wherein R is hydrogen) starting from a compound of general formula B * (wherein R is trityl) is preferably an inorganic or organic acid, e.g. hydrochloric acid or acetic acid, and is worked up in an organic solvent , e.g. in nitromethane, chloroform, methylene chloride or methanol.

In the preamble of the description, the publications in which the starting materials used in the process according to the invention are described are described.

By means of the process according to the invention it is possible to prepare the following intermediate compounds: thioararines of the general formula 0 νπ3 / 0

Y-CH-CH Xw III

^ SH

coor2 which are present in the form of a mixture of both threo and erythro isomers or of one of the isomers in which R3 represents a halogen, sulphate or sulphonium anion, R2 represents a straight or branched alkyl group having 1 to 10 carbon atoms, and Y represents a phthalimido group, benzoylamino or thiooyminoamino - a group, and in particular thio-amine hydrochloride of phthalimidomalonic acid methyl ester aldehydate, derivatives of 1,3-thiazane of the general formula

C00R2 HN2V

CH3 HO COORj 10 56842 which may exist in the form of a mixture of both threo and erythro isomers, regardless of the configuration of carbon atoms 3 and 4, or in the form of one of the isomers in which Rj represents a straight or branched alkyl group having 1 to 4 carbon atoms or a benzyl group, Rj means 1-10 a straight or branched alkyl group containing a carbon atom and Y is a phthalimido group 1 * or a benzoylamino or thiobenzoylamino group, and in particular α-methoxycarbonyl-2-phthalimidomethyl-4-ethoxycarbonyl-4-hydroxy-5-methyl-1,3-thiazane; α-methoxycarbonyl-2-phthalimidomethyl-4-tert, butoxycarbonyl-4-hydroxy-5-methyl-1,3-thiazane and α-methoxycarbonyl-2-phthalimidomethyl-4-benzyloxycarbonyl-4-hydroxy-5-methyl-1, 3-tiatsaani; Derivatives of 1,3-thiazane of general formula

S

Y '| H ^

COOR '- HN

X

ch3 COORj as well as their organic or inorganic salts, which may exist in the form of a mixture of both threo and erythro isomers or of one of the isomers, in which formula V represents an amino group, a phthalimido group, a benzoylamino or a thiobenzoylamino group. R 1 represents a straight or branched alkyl group or a benzyl group having 1 to 4 carbon atoms, R 1 'represents a straight or branched alkyl group having 1 to 10 carbon atoms, or when Y 1 represents an amino group, R 2 * represents a hydrogen atom, and in particular α-methoxycarbonyl-2-phthalimidomethyl- 4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine, α-methoxycarbonyl-2-phthalimidomethyl-4-tert, butoxycarbonyl-5-methyl-2,3-dihydro-6H- 1,3-thiazine, α-methoxycarbonyl-2-phthalimidomethyl-4-benzyloxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine, α-methoxycarbonyl-4-aminomethyl-N-ethoxycarbonyl -5-methyl-2,3-dihydro-6H-1,3-thiazine, its oxalate and its hydrochloride, α-methoxycarbonyl-2-aminomethyl-4-tert, butocycarbonyl-5-methyl-2,3-dihydro-6H -1,3-thiazine, its oxalate and its hydrochloride, amethoxycarbonyl-2-aminomethyl-4-benzyloxycarbonyl-5-methyl-2,3-dihydro 56842 6H-1,3-thiazine, and its oxalate and its hydrochloride, α-carboxy -2-Aminomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine, α-carboxy-2-aminomethyl-4-tert, butoxycarbonyl-5-methyl-2 , 3-Dihydro-6H-1,3-thiazine and α-carboxy-2-aminomethyl-4-benzyloxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine, α-carboxytritylaminomethyl -1,3-Thiazine derivatives of the general formula

S

(c6h5) 3c-hn-ch-S N

COOH HN J, Ix CH3 COOR1 and their secondary amine salts, in the form of a mixture of both threo and erythro isomers or of one of the isomers, in which R1 represents a straight or branched alkyl group having 1 to 4 carbon atoms or a benzyl group, and in particular α-carboxy-2 -tritylaminomethyl-4-ethoxycarbonyl-5- * methyl-2,3-dihydro-6H-1,3-thiazine and its diethylamine salt, α-carboxy-2-tritylaminomethyl-4-tert, butoxycarbonyl-5-methyl-2 , 3-dihydro-6H-1,3-thiazine and its diethylamine salt and α-carboxy-2-tritylaminomethyl-4-benzyloxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine and its diethylamine salt . The invention also relates to a process for the separation of DL-7-aminodesacetoxycephalosporanic acid esters of the general formula v-) - "r \ o I ch3 COORj which exist in the form of a mixture of cis- and trans-isomers or of one of the isomers in which R1 is 1- A straight or branched alkyl group or a benzyl group containing 4 carbon atoms, characterized in that the esters are separated with an optically active organic acid 12,56842 to give the desired optically active isomers. The following examples illustrate the invention.

Preparation of q-keto-B-methylene tert-butyl butyrate Step A: Sodium α-keto-g-methylene butyrate 11.5 g of α-keto-B-methylene butyl butyrate (prepared in 3 J. Chem. 5oc. p. 766, 1964 as shown) is dissolved in 77 cm of dioxane. . ... 3 ma, while stirring and cooling, add 65 cm of normal sodium hydroxide solution and allow the mixture to stand for 5 minutes. The mixture is evaporated to dryness in vacuo, the residue is dissolved in 50 cm of ethanol, evaporated to dryness, the residue is triturated with ether, dried, washed with ether and dried in vacuo to give 8.72 g of sodium α-keto-β-methylene butyrate, which is used as such in the next step.

The product is in the form of colorless crystals which are soluble in water and sparingly soluble in ordinary organic solvents.

Analysis: C 20 H 20 O 2 Na 0, 25H 2 O 140.08

Calculated: C% 42.89 H% 3.95

Found: 42.7 3.9 UV spectrum (ethanol)

1 TEASPOON

max 215 nm E.cm 542 1% max 352nm E. * 3 1 cm

Step B; α-Keto-8-methylene-tert-butyl butyrate at -40 ° C is cooled over 13 minutes with 13.6 g of sodium α-keto-β-grain. . 3. 3 leembutyrate, add 200 cm of liquid isobutylene and 5 vm of concentrate.

sulfuric acid at low temperature and the reaction mixture is brought to room temperature and allowed to stand at this temperature while stirring for 21 hours.

The mixture is cooled to -40 ° C, the excess isobutylene is removed by heating to 30 ° C and evaporated to dryness. To the residue is added 100 cm3 of methylene chloride. 3 rids and 60 cm 2 of sodium hydroxide to pH 8, the mixture is stirred, the organic phase is decanted and washed with water, the aqueous phase is extracted with methylene chloride, the combined organic phases are dried over magnesium sulphate, filtered off with suction, the filter is washed with methylene chloride and evaporated. 13.7 g of α-keto-p-methylene tert-butyl butyrate are obtained, which is used as it is in the following example.

The product is an oily liquid which is soluble in alcohols, chlorinated solvents and ether but insoluble in water, IF spectrum

The group OO occurs at 1730 and 1638 cm -1 and OC at 1650 cm * UV spectrum max. 225 nm E 1% * 231 1 cm 13 5 o 8 4 2

Example 1 DL-Tritylaminodesacetoxycephalosporanic acid tert, butyl * ester, cis compound

Step A: Thioarainal (hydrochloride) of phthalimidomalonic acid methyl esperceraldehyde, 12 g of hydrogen sulfide, 8 g of gaseous hydrogen chloride and 50 g of 2-phthalirtido-3-aminomethyl acrylate (prepared according to French Patent 1,469,529) are dissolved in 400 cm3 of i. ° C. The mixture is allowed to stand for 2 hours at room temperature, cooled, filtered off with suction, washed with a 50:50 mixture of nitromethane and ether, and then with ether and dried. A first batch of 17.1 g of the thioamine isomer of the thioamine of phthalimidomalonic acid methyl ester aldehyde hydrochloride is obtained. The solution is again allowed to stand for 3 hours to give a second batch of 3.6 g of product. The mother liquor is cooled to -10 ° C and 4 g of gaseous hydrogen chloride and 3 g of hydrogen sulfide are added and the mixture is allowed to stand at room temperature overnight to give a third batch of 18.6 g of product. The solution is finally allowed to stand for 3 days. to give a fourth batch of 3.2 g (erythro isomer), i.e. a total of 42.5 g.

The product is in the form of colorless crystals which are soluble in water, sparingly soluble in ethanol and methanol and insoluble in ether and chloroform, m.p. about 180 ° C (decomposes).

Analysis: C 18 H 19 N 2 O 2 SCl * 316.77

Calculated: C% 45.49 HZ 4.13 N% 8.85 S% 10.13 ClZ 11.20

Found: 45.2 4.1 8.7 10.2 11.3 IR spectrum (Hujol

Carbonyl at 1782 and 1718 cm *, the group ^ N-C-C-OR at -1-1748 cm and an aromatic group.

Step B: α-Methoxycarbonyl-2-phthalimidomethyl-4-tert-butoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine, threo isomer

A mixture of 32.8 g of α-keto-β-methylene tert-butyl butyrate (obtained as described above), 100 cm -1 of dioxane and 43 g of phthalimido malonic acid methyl ester aldehyde hydrochloride thioamine (first batch of product obtained in step A) is cooled. To 10 ° C with stirring and under nitrogen gas, and a solution of 18.9 cm 3 of triethylamine in 100 mother dioxane is added while maintaining the temperature below 13 ° C. The low temperature is allowed to rise to 23 [deg.] C., 100 cm <3> of ether are added, the mixture is filtered off with suction, the filter is washed with ether and the combined filtrates are evaporated to dryness. The residue is dissolved in 135 cm of ethanol, 13 cm of water are added and 3 14 56842, then 12 cm In hydrochloric acid are allowed to crystallize, stirred for 1 hour under nitrogen gas, filtered off with suction, washed with ethanol cooled to -40 ° C and then with patrol ether and dried. 27.4 g of the threo isomer of α-methoxycarbonyl-2-phthalimidomethyl-4-tert-butoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine are obtained. Concentration of the mother liquor gives 2.5 g of another batch of product, i.e. a total of 29.9 g of threo isomer.

The product is in the form of yellow crystals which are soluble in chloroform, slightly soluble in ethanol and ether and insoluble in water, m.p. 138 ° C.

Analysis: ^ 21 ^ 24 ^ 6 ^ 2 ^ * 432.5

Calculated: C% 58.33 H% 5.59 N% 6.48 S% 7.40

Found: 58.5 5.4 6.4 7.6 UV spectrum (ethanol) max 219 nm <964 i.e. ε - 41,500 1 cm

Infl. 231 nm e}% - 459 1 cm 1%

Infl. 239 nm E, - 274 l-cm max 290 nm E = 117 i.e. ε - 5,050 1 cm

Step B *: α-Methoxycarbonyl-2-phthalmidomethyl-4-tert, butoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine, erythro isomer 2.55 g of α-keto- (3- methylene tert-butyl butyrate (obtained as described in Example 1 above) and 3.96 g of phthalimidoroalonic acid methyl ester aldehyde hydrochloride thioamine (fourth batch of the product obtained in Step A) are suspended in 12 cm of ethanol, the suspension is cooled to 0-10 ° C. 3 and 1.75 cm of methylamine are added, the mixture is allowed to stand for 90 minutes at room temperature, the crystallization is allowed to begin and allowed to crystallize for 30 minutes, the precipitate is filtered off with suction, washed with ethanol and then with petroleum ether and dried in vacuo. .9 g of the erythro isomer of α-methoxycarbonyl-2-phthalimidomethyl-4-tert-butoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine.

The product is in the form of pale yellow crystals which are soluble in chloroform, sparingly soluble in ethanol and ether and insoluble in water, m.p. 138 ° C.

Analysis: C 21 H 24 ° 5N 2 S · 432.5

Calculated: C% 58.33 HZ 5.59 N% 6.48 S 7, 7.40

Found: 58.2 5.5 6.5 7.4 15 56842 UV spectrum (ethanol) 1% max, 219 ran E, »1.042 1 cm’

Inf1, 231-232 nm 1% · 392 1 era max, 239 nm E ^ ° 270 1 cm 1% max 291 ran E * 120 i.e. ε * 5 200 1 cm 17

Inf 1. 301 nm E - 100 1 cm

Step C; α-carboxy-2-aminomethyl-4-tert, butoxycarbonyl-5-methyl-2,3-dihydro-6K-1,3-thiazine, threo and erythro isomer,

Boil under reflux overnight a mixture of 28 g of α-methoxycarbonyl-2-phthalimidomethyl-4-tert-butoxycarbonyl-5-methyl-2,3-dihydro- 3,3 3 6H-1,3-thiazine, 340 cm chloroform, 65 cm methanol, 39 cm hydrazine. 3 hydrated methanol solution at a concentration of 5 g / 50 cm with stirring under a nitrogen atmosphere. Cool on ice, filter, rinse the filter with methylene chloride and evaporate the combined filtrates to dryness. The residue is dissolved in 130 cm of ether, rinse with ether, treat the filtrates with charcoal, stir for 5 minutes under nitrogen, suction, wash with ether and evaporate the filtrates to dryness.

3, 3 The residue is dissolved in 33 cm of dioxane, 16 cm of water are added, the solution o 3 is cooled to 0 ° C and 62.5 cm @ 1 of lithium hydroxide are added while maintaining the temperature at 0-2 ° C. The mixture is stirred for 5 minutes under nitrogen. its pH is adjusted to 6 by adding acetic acid, concentrated in vacuo to 3 small volumes and 65 cm of acetone are added. The mixture is stirred for 5 minutes, the precipitate is filtered off with suction, washed with acetone and then with ether and dried. 5.83 g of the threo isomer of o-carboxy-2-aminomethyl-4-tert-butoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine are obtained in the form of colorless crystals which are soluble in acidic water, slightly soluble in alcohol and insoluble in ether, m.p. about 200 ° C (decomposes),

To isolate the erythro isomer, the mother liquor is concentrated without removal of water, ether is added, the mixture is stirred for 1 hour at room temperature, the precipitate is filtered off with suction, washed with ether, mixed with ether, then with water and finally with ether and dried in vacuo at room temperature. 5.27 g of erythro isomer are obtained in the form of yellow crystals, m.p. about 170 ° C (decomposes).

16 S6842

Analysis; ^ K ^ O ^ S, 1/2 H 2 O - 297.36

Calculated: C% 48.46 H% 7.12 N% 9.42 S% 10.78

Found: 48.4 6.9 9.4 10.4 1) Threo isomer IR spectrum (Nujol ^ C = O-ether at 1727 cm-1 UV spectrum (ethanol) max. 280 nm E ^ = * 103 1 cm 2) Erythro isomer _ IR spectrum (Nujol at carbonyl sites 1718 cm \ 1689 cm ”* UV spectrum (ethanol) max. 282 nm E * ^ * 99 1 cm

Step D: α-Carboxy-2-tritylaminomethyl-4-tert, butoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine, threo isomer.

6.62 g of the threo isomer of α-carboxy-2-aminomethyl-4-tert-butoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine are mixed with 46 cm of chloroform, mixture cooled to -4 ° C with stirring under nitrogen gas, a chloroform solution of trityl chloride containing 10.4 g / 30 cm and a 2m chloroform solution of triethylamine in 30 cm are added. The reaction mixture is allowed to stand in the refrigerator for 3 hours and the temperature of the mixture is brought to 20 ° C while stirring continuously for 3 hours. It is evaporated to dryness, the residue is dissolved in 110 cm of ether. To 3 and 45 cm of water, stir, decant and wash the ether phase while stirring with a mixture of 45 cm of water and 22 cm @ 1 of hydrochloric acid.

Decant, extract the aqueous phases with ether and evaporate the combined ether phases to dryness in vacuo. The residue is triturated with 23 cm of ether, 23 cm of methanol are added, the mixture is stirred for 20 minutes, the precipitate is filtered off with suction, washed with a 1: 1 mixture of methanol and ether and then with ether and dried. 7.38 g of the threo isomer of α-carboxy-2-tritylaminomethyl-4-tert-butoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine are obtained,

The mother liquor is evaporated to a small volume, 90 cm of isopropyl ether are added, followed by 1.8 cm of 4N lithium hydroxide, 9 cm of water are added and the mixture is stirred again. The mixture is decanted, acidified to pH 4 by adding acetic acid, extracted with a mixture of 18 cm of methanol and 9 cm of water and then with water. The pH of the aqueous methanol phases is adjusted to 17 56842 by adding acetic acid, the methanol is evaporated off, the precipitate is filtered off with suction and washed with water and dried. The residue is kneaded with 5 cm of methanol, the residue is filtered off with suction, washed with methanol and dried. A second batch is obtained containing 860 mg of the threo isomer, i.e. a total of 8.24 mg.

The product is in the form of colorless crystals which are soluble in chloroform, slightly soluble in ethanol and ether and insoluble in water and methanol, m.p. 210-220 ° C (decomposes).

Analysis: C 31 H 3 O 4 .N 2 S = 530.70

Calculated: Cl 70.15 H% 6.45 N% 5.28 5% 6.05

Found: 69.9 6.6 5.5 6.3 IR spectrum (Nujol

Conjugated ester and acid at 1703 and 1691 cm, C = C at 1643 cm * and aromatic group.

UV spectrum (ethanol)

INF1. 227 nm E1 - 274 1 cm

Inf 1. 255 nm E} 7 ° »53 1 cm max 263 nm E ^ 53 1 cm max 272 nm E = 54 1 cm 1% max 285 nm E, * 57 1 cm - Step D1: Erythro isomer tritylation and conversion to the threo isomer.

. . 3.22 p of the erythro isomer obtained in step C are e-suspended in 36 cm of chloroform, the suspension is cooled to -5 ° C, a solution of 8.1 g of trityl chloride in 24 cm of chloroform is added, followed by 23.4 cm 2m chloroform solution of triethylamine and allow the mixture to stand for 3 hours in a refrigerator and then for 30 minutes at room temperature. The mixture is evaporated to dryness in vacuo,. 3 ... . 3 ..

the residue is taken up in 100 cm of ether and 20 cm of water, the aqueous phase is decanted, 10 cm of water and 20 cm @ 1 of hydrochloric acid are added to the organic phase, stirred, decanted and the aqueous phases are extracted with ether, the combined ether phases are dried over sodium sulphate and filtered off with suction. concentrated 3. 3 dry. The residue is dissolved in 100 cm of isopropyl ether and 20 cm. . 3 methanol, add 4.5 cm 4 of lithium hydroxide, stir, add 3 20 cm of water and decant. The aqueous methanol phase is acidified to 18 56842 by the addition of acetic acid. The ether phase is extracted with methanol and water. The combined aqueous methanol phases are acidified, the methanol is evaporated off under vacuum, extracted with chloroform, the chloroform phases are dried over sodium sulphate and evaporated to dryness. The residue is dissolved in 5 cm of ether and 2 cm of methanol, filtered off with suction and washed with ether. 1.28 g of the threo isomer are obtained, which is identical to the product obtained in step n.

Step E; DL-7-Tritylamino-acetacetoxycephalosporanic acid tert-butyl ester, cis Compound 7.44 g of α-carboxy-2-tritylaminomethyl-4-tert-butoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine the threo isomer is suspended in nitrogen 3.

in 700 cm of nitromethane, the suspension is cooled, a solution 3 of 3.36 g of dicyclohexylcarbodiimide in 20 cm of chloroform is added and the mixture is stirred for 15 minutes under nitrogen gas. 14 cm of pyridine are added, the mixture is stirred overnight under nitrogen gas and then for 1 hour at 25 [deg.] C., filtered off with suction, the filter is washed with ether and the filtrate is evaporated to dryness under vacuum. The residue is dissolved in 50 cm of a 1: 1 mixture of methylene chloride and ether, filtered off with suction, the filtrate is evaporated to dryness and the residue is stirred for 3 hours. 3 23 cm of ether and 23 cm of isopropyl ether are added. The mixture is cooled with ice, the precipitate is filtered off with suction, washed with isopropyl ether and dried. 5.34 g of cis of DL-7-tritylaminodeacetoxycephalosporanic acid tert-butyl ester are obtained in the form of colorless crystals which are soluble in chloroform, slightly soluble in ether and methanol and insoluble in water, m.p. 204 ° C.

Analysis: C 31 H 32 O 3 N 2 S * 512.7

Calculated: C% 72.62 H% 6.29 N% 5.46 SZ 6.25

Found: 72.3 6.3 5.5 5.9 UV spectrum (ethanol)

Inf. 225 nm E *% - 329 1 cm 1% max 265 nm E, * 117 i.e. ε 6 000 1 cm

Example 2: DL- (cis- and trans) -7-tritylaminodesacetoxycephalosporanic acid ethyl ester.

Step A: α-methoxycarbonyl-2-phthalimidomethyl-4-ethoxycarbonyl-4-hydroxy-5-methyl-1,3-thiazane, threo isomer,

M A

To 10 cm of ethanol cooled to -15 ° C is added 1.65 cm of o-keto-8-methylene ethyl butyrate (obtained as described in J, Chera. Soc., P. 766, 19 56842 1964) and 3.16 g of phthalimidomalonic acid ester aldehyde. hydrochloride thioamine (first batch of the product from Example 1, Step A, first batch of threo derivative) followed by 1.3 cm of triethylamine while maintaining the temperature at -15 ° C. The reaction mixture is brought to room temperature, allowed to stand for 30 minutes. , methylene chloride is added until it is completely dissolved and evaporated to dryness. The residue is dissolved in methylene chloride, the organic phase is washed with water, the aqueous phases are extracted with methylene chloride, the combined organic phases are dried over magnesium sulphate, filtered off with suction, the filter is washed with methylene chloride and evaporated to dryness. The residue is dissolved in 15 cm of ethanol, the crystallization is allowed to begin, the precipitate is filtered off with suction, washed with ethanol and then with ether and dried, 1.9 g of the residue are dissolved in 6 cm of methylene chloride, filtered off with suction, the filter is rinsed with methylene chloride, the filtrate is concentrated to a small volume. ethanol is added, crystallization is allowed to begin, the precipitate is filtered off with suction, washed with ethanol and then with ether and dried. 1.64 g of the threo isomer of α-methoxycarbonyl-2-phthalimidomethyl-4-ethoxycarbonyl-4-hydroxy-5-methyl-1,3-thiazane are obtained in the form of colorless crystals which are soluble in chloroform and methylene chloride, slightly soluble in ethanol and are insoluble in water and ether, m.p. 152 ° C.

Analysis: C 19 H 22 O 7 N 2 S · 422.47

Calculated: CZ 54.02 H% 5.25 N% 6.63 S% 7.58

Found: 53.8 5.2 6.5 7.8 IR spectrum (chloroform)

NH group at 3298 cm -1 OH at 3531 cm -1 O at 1742, 1725 and 1779 cm -1 and aromatic group at 1615 cm Step B: α-methoxycarbonyl-2-phthalimidomethyl-4-ethoxycarbonyl-5-methyl-2,3 -dihydro-6H-1,3-thiazine, threo isomer, "422 mg of the threo isomer of α-methoxycarbonyl-2-phthalimidomethyl-4-ethoxycarbonyl-4-hydroxy-5-methyl-1,3-thiazane are stirred 1, With 5 cm 3 of 90% ethanol, with 0.5 cm of methylene chloride and add 1 drop of 1N hydrochloric acid and allow the mixture to stand for 1 hour at room temperature.The methylene chloride is evaporated off, the precipitate is filtered off with suction, washed with 75% ethanol and dried. 176 mg of the threo isomer of α-methoxycarbonyl-2-phthalimidomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine are obtained.

The mother liquor is allowed to stand overnight, after which the precipitate is filtered off with suction, washed with 75% ethanol and then with petroleum ether. In this way a second batch containing 103 mg of threo isomer can be isolated, i.e. a total of 279 mg.

20 56842

The product is in the form of yellow crystals which are soluble in chlorinated organic solvents, sparingly soluble in ethanol and insoluble in water, m.p. 120 ° C.

Analysis: c19H20 ° 6N2S *

Calculated: C% 56.43 H% 4.99 N% 6.93 S% 7.91

Found: 56.6 5.2 6.9 7.7 UV spectrum (ethanol)

Max 219-220 nm E 1% - 1050 1 cm

INF1. 239-340 nm E1% - 296 1 cm max 290 nm E ** 125 1 cm

Step B1: α-Methoxycarbonyl-2-phthalidomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine, erythro isomer, 33 ml of ethanol cooled to -15 ° C are added 5.5 cm-o-keto-β-methylene ethyl butyrate and 10.5 g of phthalimidimal malonic acid methyl ester aldehyde hydrochloride thioamine (fourth batch of the product obtained in Example 1, step A), the mixture is cooled to -15 ° C with stirring under nitrogen and 4.6 g are added. cm of triethylamine while maintaining the temperature at -15 ° C. The temperature of the reaction mixture is brought to 27 ° C, 2 cm -1 of hydrochloric acid are added, the mixture is allowed to stand for 30 minutes, the precipitate is filtered off with suction, washed with ethanol cooled to -50 ° C. , followed by petroleum ether, dried to give 11.2 g of crude product. The mother liquor is allowed to stand overnight to give a second batch containing 3.9 g. Both batches are dissolved in 3 ... . . 3 25 cm of methylene chloride, 120 cm of ethanol are added, the methylene chloride is evaporated off, the precipitate is filtered off with suction, washed with ethanol and then with petroleum ether to give 8.95 g of α-methoxycarbonyl-2-phthalimidomethyl-4-ethoxycarbonyl-5-roethyl-2, 3-dihydro-1,3-thiazine, m.p. 160 ° C, IR spectrum (chloroform)

Carbonyl at 1779 and 1722 cm -1 N-C-COOR at 1746 cm * and NH at 3413 cm UV spectrum (ethanol) 12! max 219 nm ΕΓ - 1,120 ts.e - 45,500 i cm

Infl. 239-240 nm eJ% - 292 1 cm 12! max 291 nm Ej cm * = 141 ts, ε = 5 700 12!

Infl. 299 nm E Γ - 125 1 cm 21 56842

Proceed in the same manner starting from 31.7 g of the thioamine of phthalimidomalonic acid methyl ester aldehyde hydrochloride (mixture of the batches obtained in Step A of Example 1). A mixture of threo and erythro isomers of 1,3-thiazine, m.p. 100 ° C.

Step C: α-Methoxycarbonyl-2-aminomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6U-1,3-thiazine hydrochloride, threo isomer

Boil under reflux overnight with stirring and using nitrogen gas a mixture of 4.04 g of the threo isomer of methoxycarbonyl-2-phthalimidomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine (obtained in step B), 52 cm of chloroform, 10 cm of methanol and 6 cm of hydrazine

O

methanol solution of the hydrate at a concentration of 10 g / 100 cm. The mixture is cooled, the separated product is filtered off with suction, the filter is washed with methylene chloride and the combined organic phases are evaporated to dryness. To the residue is added 5 cm of water and then 10.5 cm @ 1 of hydrochloric acid, filtered off with suction, the filter is washed with water and the aqueous phase is evaporated to dryness. To the residue is added 3 cm of ethanol followed by 10 cm of ether, filtered off with suction, the residue is washed with an 80:20 mixture of ether and ethanol and then with ether to give 1.28 g of α-methocycarbonyl-2-aminomethyl-4-ethoxycarbonyl-5-methyl The threo isomer of -2,3-dihydro-6H-1,3-thiazine in the form of the hydrochloride. Evaporation of the mother liquor to dryness and treatment with ethanol and ether gives a second crop of 290 mg of the threo isomer, i.e. a total of 1.57 g. The product is in the form of colorless crystals which are soluble in water and ethanol and sparingly soluble in ether, m.p. 170 ° C;

Analysis: C 18 H 18 N 2 O 2 • SCl 310.8

Calculated: C% 42.51 HZ 6.16 N% 9.02 SZ 10.30 ClZ 11.41

Found: 42.6 6.3 8.8 10.0 11.4 IR spectrum (Nujol--1 -1 Carbonyl at 1752 cm, conjugated ester at 1681 cm and OC at 1637 cm UV spectrum (ethanol) 11

Infl. 226 nm ΕΓ - 90 1 cm make. 277 nm 109 i.e. 3 400 1 cm

Step C: α-Methoxycarbonyl-2-aminomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiateine oxalate, erythro isomer,

Boil under reflux overnight with stirring and under nitrogen gas a mixture of 6.07 g of α-methoxycarbonyl-2-phthalimidomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine erythro. isomer

swim ;; 22 56842 3 3 1 (obtained in step B '), 79 cm of chloroform, 15 cm of methanol and 9 cm of a methanolic solution of hydrazine hydrate at a concentration of 10 g / 100 cm f The mixture is cooled, filtered off with suction and the filter is washed with roethylene chloride, The combined filtrates are evaporated dry, the residue is triturated with 40 cm of ethyl acetate, filtered off with suction and the filter is washed with ethyl acetate,

The filtrate is treated with activated carbon, filtered, the filter is washed with ethyl acetate, 1.85 g of oxalic acid, 2 H 2 O are added and crystallization is allowed to begin. The mixture is stirred for 15 minutes under nitrogen, the precipitate is filtered off with suction and washed with ethyl acetate and dried. 4.74 g of the erythro isomer of α-methoxycarbonyl-2-aminomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine are obtained in the form of the oxalate, m.p. 140 ° C.

Analysis: 8 ^ 2® 364.38

Calculated: C% 42.86 H% 5.53 N% 7.69 S% 8.78

Found: 42.0 5.5 7.9 8.8 IR spectrum (Nujol ^

Carbonyl at 1733 cm *.

UV spectrum (ethanol) 17 max 280 nm E, * = 86 1 cm

Step D: α-Carboxy-2-aminomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine

A mixture of 20.2 g of a mixture of threo and erythro isomers of α-methoxycarbonyl-2-phthalmidomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine 3 3 3 ( obtained in step B '), 260 nm. chloroform, 50 cm of methanol and 30 cm of a methanol solution of hydrazine hydrate at a concentration of 10 g / 100 cm are refluxed overnight while stirring and using nitrogen gas. The mixture is cooled with ice, filtered off with suction, the filter is rinsed with methylene chloride and the combined filtrates are evaporated to dryness. Residue. 3. .

dissolved in 150 cm of ether, the solution is stirred for 15 minutes, filtered off with suction, the filter is washed with ether, the combined filtrates are treated with activated carbon, the mixture is stirred for 10 minutes, filtered off with suction, the filter is washed with ether and evaporated to dryness. 14 g of a mixture of the threo and erythro isomers of α-methoxycarbonyl-2-aminomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine are obtained.

3

A mixture of 14 g of the above crude product, 25 cm of ethanol. 3. 3 and 25 cm of water are cooled, 11.25 cm of 4N lithium hydroxide are added and the mixture is allowed to stand for 20 minutes, 4 cm of concentrated hydrochloric acid are added, the reaction mixture is brought to room temperature, crystallization is allowed to begin and the mixture is stirred for 30 minutes under nitrogen. A mixture of 150 cm 50 of ether and tetrahydrofuran is added, the mixture is left to stand for 10 minutes, the precipitate is filtered off with suction, washed with acetone and then with ether and dried. 7 g of α-carboxy-2-aminomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine are obtained, consisting mainly of the threo isomer,

The product is in the form of pale beige crystals which are soluble in ethanol, sparingly soluble in water and acetone and insoluble in ether, m.p. 160 ° C (decomposes).

Analysis: c10W16 ° 4N2S, 0.5H2 ° * 269.32

Calculated: C% 44.60 HZ 6.37 NZ 10.40 SZ 11.90

Found: 44.4 6.4 10.1 11.2 IR spectrum (Nujol

Streaks at 3478, 3287, 1727, 1675, 1637 and 1595 cnf1 UV spectrum (ethanol) i r max 280 - 281 nm ΕΓ - 126 1 cm

Proceed in a similar manner starting from α-methoxycarbonyl-2-aminomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine hydrochloride threoisomer (obtained in step C) and erythro- from the oxalate of the isomer (obtained in step C ') using lithium hydroxide. The threo and erythro isomers of α-carboxy-2-aminoacetyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine are obtained.

Step E: Diethylamine α-carboxy-2-tritylaminomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine salt, threo isomer _ Mixture of 2.6 g α-carboxy-2-aminomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine threo isomer and 20 cm of chloroform, cooled to -3 ° C, added 12.5 cm a chloroform solution of triethylamine at a concentration of 5.6 cm / 20 cm, followed by a solution of 4.2 g. . 3 ethyl clones in 20 cm of chloroform while keeping the temperature below 0 ° C. The mixture is allowed to stand for 55 minutes, the organic phase is washed with a 50:12 mixture of water and 1N hydrochloric acid and then with water, the aqueous phases are extracted with methylene chloride, the combined organic phases are dried over sodium sulfate, filtered off with suction, the filter is washed with methylene chloride and evaporated. The residue is dissolved in 40 cm of ether, 0.8 cm of diethylamine are added under cooling, the crystallization is allowed to begin and the mixture is allowed to stand for 10 minutes, the precipitate is filtered off with suction, washed with ether and dried. 2.715 g of diethylamine α-carboxy-2-tritylaminomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-24-56-42 thiazine suppository are obtained. The product consists mainly of threo-isomer,

The product is in the form of colorless crystals which are soluble in chloroform, sparingly soluble in methanol and insoluble in water and ether, m.p., 150 ° C (decomposes).

Analysis: e 575.78

Calculated: C% 68.85 H% 7.18 N% 7.30 S% 5.55 Found: 67.6 7.1 7.1 5.2 IR spectrum (chloroform)

Streaks at 3292, 1722, 1696, 1634 and 1601 cm UV spectrum (ethanol)

Inf 1. 230 nm E *% »205 1 cm 17 max 288 nm E, 0 = 50.

1 cm

Step F: DL- (cis- and trans -) - 7-tritylamino-acetacetoxycephalosporanic acid ethyl ester 2.3 g of diethylamine α-carboxy-2-tritylaminomethyl-4-ethoxycarbonyl-5-methyl-2,3-dihydro-6H-1 The 3-thiazine salt threo isomer 3 is dissolved in 40 cm of chloroform, 20 cm of 0.5N hydrochloric acid are added and decanted. The organic phase is washed with water, the aqueous phases are extracted with chloroform and the organic phases are dried over sodium sulfate. Evaporate to dryness, dissolve the residue in 100 cm of ether, treat the solution with activated carbon, .... 3 ...

filtered and evaporated to dryness. The residue is taken up in 200 cm of nitromethane, the solution is cooled, 0.88 g of dicyclohexylcarbodiimide is added and the mixture is allowed to stand for 4 hours at 0 [deg.] C., 2 cm -1 of pyridine are added and the mixture is allowed to stand overnight at room temperature. It is filtered off with suction, the filtrate is evaporated to dryness in vacuo at 30 [deg.] C., the residue is taken up in ether, filtered and evaporated to dryness. The residue is dissolved in 10 volumes of methanol,. . . 3 half of the methanol is evaporated off, 2 cm of ether are added, the mixture is allowed to crystallize for one hour, the precipitate is filtered off with suction, washed with 157 g of ether and dried to give 0.7 g of DL-7-tritylamino-acetoxycephalosporanic acid ethyl ester cis compound as colorless crystals. which are soluble in chloroform are sparingly soluble in ethanol and ether and insoluble in water, aul.p. 184 ° C.

Evaporation of the mother liquor, chromatography of the residue on silica gel, eluting with 5% ether in methylene chloride and recrystallization from methanol, gives 120 mg of trans, m.p., 174 DEG C., Analysis for C18: C29 H28 DEG-3N2S = 484.53

Calculated: C% 71.88 H7 5.83 N * 5.78 SZ 6.60

Found: 71.5 5.7 5.7 6.8 UV spectrum (ethanol 1) cis 25 56842

Inf1, 227 nm E ** - 340 1 cm 17 make. 260 nm E, ° 130 i.e. ε * 6 300 1 cm 2) trans compound

Infl. 226 nm eJ% - 340 1 cm 17 make. 263-264 m E. '* 132 ts, e · * 6400 1 cm

Example 3: DL-7-Tritylamino-dodec8-cephalosporanic acid benzyl ether Step A: α-Methoxycarbonyl-2-phthalimidoroethyl-4-benzyloxycarbonyl-4-hydroxy-5-methyl-1,3-thiazane, threo isomer.

21.9 g of α-keto-8-raethylene benzyl butyrate (obtained according to the method described in J. Chem. Soc. P. 791, 1964) are cooled to -1 ° C, 31.6 g of phthalimidomalonic acid methyl ester aldehyde are added. the thioamine of the hydrochloride (first and second batches of the product obtained in Step A of Example 1), followed by 14 cm of triethylamine. The temperature of the reaction mixture is raised to room temperature, the precipitate is filtered off with suction, washed with ethanol and dried. 33 g of the threo isomer of α-methoxycarbonyl-2-phthalimidomethyl-4-benzyloxycarbonyl-4-hydroxy-5-methyl-1,3-thiazane are obtained, which is used as such in the next step. The product is recrystallized for analysis from a mixture of methylene chloride and methanol.

The product is in the form of yellow crystals which are soluble in chloroform, sparingly soluble in ether and methanol and insoluble in water, m.p. 180 ° C.

Evaporation of the mother liquors to dryness, dissolving the residue in methanol and adding 1N hydrochloric acid give 1.8 g of the erythro isomer.

Analysis: ^ 2 ^ 24 ^ 7 ^ 2 ^ * 484.53

Calculated: C% 59.50 H% 4.99 NX 5.78 SX 6.61

Found: 58.9 4.9 5.8 6.4

Step B: α-Methoxycarbonyl-2-phthalimidomethyl-4-benzyloxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine, threo isomer

While stirring, dissolve 24.2 g of the threo-3,3-isomer of amethoxycarbonyl-2-thalimidomethyl-4-yl-benzyloxycarbonyl-4-hydroxy-5-methyl-1,3-thiathane in 120 cm of dioxane, add 12 cm of water and 2.5 cm In hydrochloric acid. The mixture is allowed to stand for 45 minutes at room temperature, the solvent is evaporated off under vacuum, the residue is dissolved in 50 cm <2> of methylene chloride, the organic phase is washed with water, the aqueous phases are extracted with methylene chloride and the combined organic phases are dried over magnesium sulphate, filtered off and evaporated to dryness. -methoxycarbonyl-2-phthalimido-26,56842 methyl-4-benzyloxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine threo isomer, used as such in step C,

Step B *; α-methoxycarbonyl-2-phthalimidomethyl-4-benzyloxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine, erythro isomer.

3

A mixture of 2.55 g of α-keto-8-methylenebenzylbutyrate and 10 cm of ethanol is cooled to -10 [deg.] C., 3.16 g of phthalimidomalonic acid methyl ester aldehyde hydrochloride thioamine (fourth from the product obtained in step A of Example 1 3) are added. and then 1.4 cm of triethylamine. The temperature of the reaction mixture is raised to room temperature and the resulting solution is evaporated to dryness. The residue is dissolved in methylene chloride, 20 cm of water are added, decanted, the aqueous phase is extracted with methylene chloride, the combined organic phases are dried over magnesium sulphate, filtered off with suction and evaporated to dryness.

Dissolve the residue in 20 cm of methanol, add 0.5 cm-1 in hydrochloric acid, allow the crystallization to begin and allow to crystallize over 10 minutes, suction filter and wash with methanol and dry to give 2.61 g of α-methocarbonyl-2-phthalaidaidl methyl. The erythro isomer of 4-benzyloxycarbonyl-5-methyl-2,3-dihydro-1,3-thiazine. Evaporation of the difference solutions to dryness gives a second crop of erythro isomer comprising 770 mg, te. a total of 3.38 g.

The product is recrystallized for analysis by dissolving it in methylene chloride and mixing with methanol.

The product is in the form of yellow crystals which are soluble in chloroform, sparingly soluble in methanol, ethanol and ether and insoluble in water, m.p. 138 ° C.

Analysis: C24H22 ° 6N2S * 466.52

Calculated: C% 61.80 H% 4.75 N% 6.01 S% 6.86

Found: 61.5 4.7 5.9 6.7

Step C: α-Carboxy-2-aminomethyl-4-benzyloxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine.

23.9 g of α-methoxycarbonyl-2-phthalimidomethyl-4-benzyloxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine (based on the threo... 3 and erythro isomers obtained in steps B and B '). mixture) is dissolved in 250 cm of chloroform, 3. 3 50 cm of methanol and 30 cm of a 2m methanol solution of hydrazine hydrate and the mixture are refluxed overnight under nitrogen gas. The mixture is cooled with ice, filtered off with suction, the filtrate is evaporated to dryness, the residue is stirred for 15 minutes with 130 cm of ether and filtered off with suction. The filtrate is treated with activated carbon, allowed to stand for 15 minutes, filtered off with suction and evaporated to dryness. 15.9 g of a mixture of threo and erythro isomers of α-methoxycarbonyl-2-aminomethyl-4-benzyloxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine are obtained.

27 56842. . 3 This residue (15.9 g) is dissolved in 25 cm of dioxane, 10 cm of water is added, the mixture is cooled, 12.5 cm 4 of lithium hydroxide are added and the mixture is allowed to stand for 10 minutes. It is adjusted to pH 4 by adding 3 concentrated hydrochloric acid, the dioxane is evaporated off, 80 nm of ether in 3 and 10 cm of water are added and the mixture is stirred for 2 hours. The precipitate is filtered off with suction, mixed into a dough with ether, then with water and finally with ether and dried at 45 ° C under vacuum. The residue is dissolved in 99 cm -1 of ethanol with stirring, suction filtered, dried to give 8.5 g of α-carboxy-2-aminomethyl-4-benzyloxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine. Evaporation of the mother liquor gives a second crop of 0.43 g, i.e. a total of 8.93 g.

For analysis, the product is dissolved in 10 volumes of ethyl acetate with 5% water and a small excess of triethylamine, the pH of the mixture is adjusted to 4 by adding acetic acid, the precipitate is filtered off with suction, washed with ethanol and then with ether and dried,

The product is in the form of beige crystals which are soluble in dilute sodium hydroxide, sparingly soluble in ethanol and insoluble in water and ether, m.p. about 160 ° C (decomposes).

Analysis: g H 2 O 2 S, 0.7H 2 O * 335.0

Calculated: C% 53.78 H% 5.83 NX 8.36 S% 9.57 Found: 53.7 5.6 8.5 9.1 IR spectrum (Nujol

Streaks at 1701 cm -1 (carbonyl) and 1611 cm UV spectrum (ethanol) 11 max 283 nm E, * 106.

1 cm „Step D: DL-7-tritylaminodesacetoxycephalosporanic acid benzyl ester.

3.224 g of α-carboxy-2-aminomethyl-4-benzyloxycarbonyl-5-methyl-3,3-dihydro-6H-1,3-thiazine are suspended in 20 cm of chloroform, the suspension is cooled to 3 DEG C., a solution of 5.6 cm of triethylamine in 15 cin of chloroform is added, followed by a solution of 4.2 g. trityl chloride in 20 cm of chloroform, and the mixture is stirred for 1 hour at 6 ° C. The organic phase is washed with 3 3 50 cm of water to which 16 cm @ 1 of hydrochloric acid have been added, then with 3 3 30 cm of water and evaporated to dryness. The residue is dissolved in 100 cm, 3 ethers, filtered and evaporated to dryness. The residue is dissolved in 60 cm. 3 3 of isopropyl ether and 40 cm 5 of methanol, 4 cm of 10% aqueous sodium bicarbonate solution and 16 cm of water are added, the mixture is stirred, the aqueous phase is decanted and extracted with isopropyl ether, the methanol is evaporated off from the combined aqueous methanol phases, The mixture is washed with water and dried to give α-carboxy-2-tritylaminomethyl-4-benzyloxycarbonyl-5-methyl-2,3-dihydro-6H-1,3-thiazine, 3. 1.68 g of the crude acid obtained above are dissolved in 168 cm: nitromethane, the solution is cooled to 0 ° C, 0.66 g of dicyclohexylcarbodiimide are added and the mixture is stirred for 30 minutes. 1.5 cm of pyridine are added and the reaction mixture is allowed to stand overnight at room temperature, filtered and evaporated to dryness in vacuo at 30 ° C. The residue is dissolved in 30 cm @ 2 of ether, filtered and evaporated to dryness. The residue is chromatographed on silica gel, eluted with methylene chloride and recrystallized from methanol. 151 mg of a cis derivative, 167 mg of a mixture of a cis and Trane derivative and 77 mg of a trans derivative are obtained.

The benzyl ester of cis-DL-7-tritylaminodeacetoxycephalosporanic acid is in the form of colorless crystals which are soluble in chloroform, sparingly soluble in methanol, ethanol and ether and insoluble in water, m.p. 184 ° C;

The trans derivative melts at 200 ° C.

Analysis for the Cis derivative: Calculated: C, 74.71; H, 5.53; N, 5.13; SX, 5.85.

Found: 74.5 5.5 5.0 5.4 UV spectrum (ethanol) 1) Cis derivative

Infl. 227 nm E 12 - 296

1 cm 1X

Infl. 259 nm E - 111 1 cm max 262 nm E 12 «111 1 cm

Infl. 267 nm E 12 - 106 1 cm 2) Trans derivative

Infl. 228 nm E 1% - 293 1 cm

Infl. 256 nm E 12 - 126 1 cm

Example 4; DL-7-aminodesacetoxycephalosporanic acid tert-butyl ether, cis compound 0.5 g of the cis compound of DL-7-tritylaminodesacetoxycephalo-8-propanoic acid tert-butyl 3 ester is dissolved in 5 cm of chloroform, and a stream of hydrogen chloride gas is passed through it at room temperature for 3 minutes. The chloroform is evaporated in vacuo, the residue is dissolved in ether to give 0.280 g of 29 56842 7-aminodesacetoxycephalosporanic acid tert-butyl ester hydrochloride cis compound.

3

The hydrochloride obtained above is dissolved in a mixture of 0.5 cm of methanol 3 and 1.5 cm of water, filtered off with suction, the filtrate is rinsed with a small amount of methanol and the solution is made alkaline by adding 6 drops of triethylamine. Cool on ice, filter the precipitate, wash with water and dry to give 0.222 g of the cis compound of DL-7-aminodesacetocake cephalosporanic acid tert-butyl ester in the form of colorless crystals which are soluble in chloroform, sparingly soluble in methanol and insoluble in water. C.

Analysis: c 12 H 18 N 3 N 2 S • 270.34

Calculated: C% 53.22 HZ 6.71 N% 10.37 S% 11.86

Found: 53.1 6.8 10.7 12.0 IR spectrum (chloroform)

Group NH ~ at 3401 and 3333 cm β-lactam at 1775 cm. . i. -1 conjugated ester at 1718 cm and OC and NH deformation at 1640 and 1625 cm UV spectrum. (Ethanol)

Max 219 nm E 1% - 137 1 cm

Infl. 261 nm E 1% - 220 1 cm max 271 nm E 1% ° 234 ts ‘ε“ 6 300 1 cm

Example 5: DL-7-aminodesacetoxycephalosporanic acid ethyl ester,

According to the procedure described in Example 4, the cis and trans forms of DL-7-aminodesacetoxycephalosporanic acid ethyl ester are prepared by removing the trityl group from the "cis, trane form of DL-7-tritylaminodesacetoxycephalosporanic acid ethyl ester.

Example 6: DL-7-aminodesacetoxycycephalosporanic acid benzyl ester According to the procedure described in Example 4, the cis and trans forms of DL-7-aminodesacetoxycephalosporanic acid benzyl ester are prepared by removing the trityl group 7-tritylaminodesacetoxycephalosporanic acid benzyl ester.

Example 7i L (+) - 7-aminodesacetoxycephalosporanic acid tert-butyl ester, cis compound 3 4.39 g of D (-) - tartaric acid are dissolved in 45 cm of methanol and then 7.2 g of DL-7-aminodesacetoxycephalosporanic acid tert-butyl ester are added. butyl ester cis. The mixture is heated to reflux, allowed to cool to room temperature, then kept at 20 ° C for a few minutes. After suction filtration, the tartrate obtained is washed with ethanol, ether and dried,

The tartrate is suspended in 46 cm of methanol, 3.3 cm of triethylamine are added and the mixture is stirred for 5 minutes. Insolubles are removed by filtration, the filtrate is poured into water and extracted with methylene chloride. The organic phase is dried over magnesium sulphate and the solvent is evaporated off under vacuum. The residue is crystallized from petroleum ether. There is thus obtained 2.73 g of the cis compound of L (+) - 7-aminodeacetoxycephalosporanic acid tert-butyl ester, m.p. 126 ° C. (a) * ° to + 100 + 3 ° (c - 0.5% chloroform) The cis compound of the D - (-) - 7-aminodesacetocyclo-cephalosporanic acid tert-butyl ester is obtained from L (+) - 7-aminodesacetoxycephalosporanic acid tert-butyl ether. from an aqueous aqueous solution of fattratate, m.p. 126 ° C (ct) mp -100 + 3 ° (c * 0.5%, chloroform).

Claims (3)

56842 31 Claim; Process for the preparation of DL-7-R-aminodesacetoxycephalosporanic acid derivatives of the general formula RHN - - X - o υ COOR ^ which exist in the form of a mixture of cis- and trans-isomers or of one of the isomers in which R represents a hydrogen atom or a trityl group, R ^ represents a straight or branched alkyl group or a benzyl group having 1 to 4 carbon atoms, characterized in that the enamine of the general formula CH - NH2 y - cr ii ^ coor2 wherein R2 represents a straight or branched alkyl group having 1 to 10 carbon atoms and Y represents a phthalimido group, a benzoylamino group or a thiobenzoylamino group, is treated with hydrogen sulfide in the presence of an acid HX 1 in which X 1 is a halogen, sulphate or sulphonium anion to give a thioamine having the general formula / NH 3® X 1® Y - CH - CH III co 2 R 2 which is present in both threo and in the form of a mixture of erythro isomers or either isomer, the product of formula III is condensed in the presence of a tertiary amine with an ester of α-keto-3-methylenebutanoic acid having the general formula O-CH9> -COOR ^ CH3 32 56842 in which represents a straight or branched alkyl group having 1 to 4 carbon atoms or a benzyl group to give a 1,3-thiazane derivative which the general formula is Y - coor2I V CHj HO COOR ^ in the form of a mixture of both threo and erythro isomers, regardless of the configuration of carbon atoms 3 and 4, or in the form of either isomer, followed by reacting a dehydrating agent, preferably aqueous hydrochloric acid or oxalic acid, to give a 1,3-thiazine derivative of the general formula Y - CH- "N 'I VI coor2 - ch3 COOR1 in the form of a mixture of both threo and erythro isomers or of one of the isomers, the group Y is cleaved by a functional exchange by racin or acid hydrolysis to give α-carbalkoxyaminomethyl-1,3-thiazine of general formula h9n - ch-II VII HN. COOR2 Cll3 COOR ^ which may exist in the form of a mixture of both threo and erythro isomers or of one of the isomers in which or in which the COOR2 group is selectively saponified with an alkaline agent, suitably an alkali metal hydroxide, preferably lithium hydroxide or an early metal carbonate VII, or optionally a compound with an inorganic or organic acid HX2, wherein X2 is a halogen anion or a derivative of an organic acid, to give a salt of α-carbalkoxyaminomethyl-1,3-thiazine of the general formula x Θ _ 2 © H., N - CH -f 'f VII' COOR2 HNv ^ kCH3 COOR1 which may exist in the form of a mixture of threo and erythro isomers or of one of the isomers treated with an alkaline substance, suitably an alkali metal hydroxide, preferably lithium hydroxide, or an early metal carbonate, in both cases to give α-carboxy, 3-thiazine of general formula H «N - CH-S '^' I VIII COOH COO R1 which may exist in the form of a mixture of both threo and eryto-isomers or of one of the isomers treated with a tritylating agent to give an α-carboxytritylaminomethyl-1,3-thiazine derivative of the general formula (c6h5) 3c-hn-ch-IX COOH HISk T CH3 COOR ^ present in the form of a mixture of both threo and erythro isomers or of one of the isomers cyclized with a lactamizing agent, suitably dialkyl or dicycloalkylcarbodiimide, preferably dicyclohexylcarbodiimide or diisopropyl carbide, diisopropyl carbide to react with a secondary amine to prepare an amine salt of an α-carboxytritylaminomethyl-1,3-thiazine derivative having the general formula 34 55842 / Sv (CfiH,) -, C-HN-CH -> O 5 3 »O) I TVI COO3 'HN .1 © ch3 H2N ~ COOR, in the form of a mixture of both threo and erythro isomers, or in the form of one of the isomers, where the group represents a a cation which is acid hydrolysed and then cyclized with a lactamizing agent, suitably dialkyl or dicycloalkylcarbodiimide, preferably dicyclohexylcarbodiimide or diisopropylcarbodiimide, in both cases to give the desired compound of general formula B ', wherein R represents tr and optionally treating the compound with an acidic substance, suitably an inorganic or organic acid, preferably hydrochloric acid or acetic acid, to give the desired compound of general formula B 'wherein R represents a hydrogen atom, and optionally separating the optically active organic acid with DL-7-aminodesacetoxycephalosporanic acid ester —I-TS ^ / -Ν "Υ ^ ~ Cli3 COOR1 which exists in the form of a mixture of cis and trans isomers or one of the isomers, wherein R1 is as defined above, to give the desired optically active isomers. 56842 35 The first derivative of the DL-7-R-aminodesacetoxycephalo-sporans is formed in the form of the form of a compound having the form of a mixture of cis and trans- isomeric ^ or a form of the same isomer, i vilken R is a substituent or a trityl group, R1 is a single or a saturated alkyl group of 1-4 cholatomers or a benzyl group, the parent compound of which is used in most forms of the lower form ^ CH-NH0 / 2 Y - C II ^ COOR2 in which R2 is selected from the group consisting of alkyl groups having 1-10 cholaters and Y is a phthalimido group, a benzoylamino group or a thiobenzoylamino group, having a hydrogen atom in the form of HX2, then halogenated, sulphated or sulphonated, with the aid of thioamines having the formula Y - CH - CHX, i form av en av dessa isomerer, condenser products with formula III, i närvaro a in a tertiary amine, with an ester of α-keto-β-methylenebutyrene with the following formula °> _ ^ COOR ^ Χη3 56842 36 derived from 1,3-thiazan with the formula Y-CH 2 V COOR, I 2 HN \ <^ CH3 HO COOR1 in the form of a mixture of the isomers of threo and erythro, with the configuration of the collatants 3 and 4, or in the form of a mixture of isomers, with the addition of dehydrating agents, with the addition of water chlorinated or oxalic, reacting with compounds of formula V, varying the amount of 1,3-thiazine with all of the compounds of formula Y - CH_ 1. vi coor2 mi - CH ~ 3 COOR1 is used in the form of a mixture of isomers of threo and erythro or in the form of a mixture of isomers, which represents the group Y genome and the function of the hydrazine or the genome of the hydrolysis, and gives α-carbalkoxyaminomethyl-1,3 -thiazine compounds of the formula H2N - CH-f> VII COOR2 CH3 COOR-which may be used in the form of a mixture of isomeric threo and erythro or in the form of an isomer, i vilka eller i vilken man selective förtvälar The COOR2 group is an alkaline metal hydroxide, an alkali metal hydroxide, a lithium hydroxide, or an alkali metal carbonate, or an optionally treated compound of formula VII with an organic or organic salt of HX2, or an X2 or halogenated organic compound. salt of α-carbalkoxyaminomethyl-1,3-thiazine with the formula 56842 37 * 2Θ ^ © SH, N-CH-s 'NJ · VII' JL CH3 COOR1 in the form of a mixture of the same mererna threo and erythro eller in the form of an isomer, with the addition of an alkali metal agent, an alkali metal hydroxide, anhydrous lithium hydroxide, or an alkali metal carbonate, varvid man and a-carboxyaminomethyl-1, 3-thiazine with all of the formulas H2N - <rH-1 VIII COOH HN CH3 COOR1 is a compound which is a form of a mixture of isomers of threo and an erythro or a form of a form of an isomer, and which is treated with both tritylation and the like Derivatives of α-carboxytritylamino-methyl-1,3-thiazine with all of the formulas <c6h5) 3c-hn-ch-N IX COOH HH CH3 COOR1 are preferred compounds in the form of a mixture of isomers of threo and erythro or form in the case of isomers, such as cyclic and lactic acid derivatives, heated and dialkyl- or dicycloalkylcarbodiimides, second-dicyclohexylcarbodiimides or diisopropylcarbodiimides, or optionally cyclized compounds of formula IX min for the amine salt of α-carboxytritylaminomethyl-1,3-thiazine derivatives with all the formulas