DD253819A5 - PROCESS FOR PREPARING A NEW INTERMEDIATE PRODUCT FOR CEPHALOSPORINES - Google Patents

Abstract

The invention relates to a process for the preparation of a new intermediate for cephalosporins. According to the invention, a compound of the formula (II) in which R 1 is a lower alkyl group is prepared by reacting a compound of the formula (IV) in which X is a halogen atom and R 1 has the abovementioned meaning, with thiourea in Reacting the presence of a solvent. Formulas (II) and (IV)

Description

(Syn isomer)

wherein R ^{1 represents} a lower alkyl group; R ^{2 is} a hydrogen atom or a carboxyl-protecting group; and R ^{3 represents} a substituted or unsubstituted heterocyclic group linked to the exomethylene group in the 3-position of the cephem ring via a carbon-nitrogen bond, which is a highly useful antibacterial agent. Such cephalosporins are the subject of various patent applications. (Japanese Patent Publication Nos. 99592/82 and 93085/84 and Japanese Patent Application Nos. 67871 / 83,113565 / 83 and 114313/83).

Object of the invention

The aim of the invention is to provide a simple and economical process by which cephalosporin of the formula I can be prepared in high yield.

Explanation of the essence of the invention

The object of the invention is to find easily accessible intermediates for the preparation of cephalosporin of the formula (I).

Since then, the inventors have extensively studied to develop processes for producing the cephalosporin of the formula (I) or a salt thereof. It has been found by the inventors that a useful cephalosporin (syn isomer) of the formula (I) or a salt thereof can be easily obtained in high yield by reacting a compound (syn isomer) of the general formula (II):

- GGNH,

OR "

(II) (syn-isomer)

wherein R ^{1 is} a lower alkyl group, with a compound of formula (III):

(III)

COOR '

wherein R ^{2a is} a carboxyl-protecting group and R ^{3 is} a substituted or unsubstituted heterocyclic group linked to the exomethylene group in the 3-position of the cephem ring via a carbon-nitrogen bond in the presence of boron trifluoride or a complex compound thereof and subsequently optionally the carboxyl-protecting group is removed or the product is converted to a salt as described in DDR patent application no. AP C 07 D / 268154/6.

Using the method described below, even when the compound of the formula (III) obtained in the process for producing the compound of the formula (III) is used as the starting compound for the process without isolation, excellent results are obtained as well when using an isolated compound of the formula (III) as starting material:

 A compound (syn-isomer) of the formula (II):

C-CONH,

(Syn isomer)

wherein R ^{1 has} the meaning given above, is reacted with boron trifluoride or a complex compound thereof. The compound thus obtained is reacted with the compound of the formula (III) at -50 ° C to 0 ° C in the above-mentioned organic solvent to prepare an intermediate (first reaction step),

COOR '

(assumed structure

wherein R ¹ , R ^2a and R ^{3 have} the meaning given above. Subsequently, the reaction mixture is further reacted at ⁰ ° C. to 50 ° C. and at a pH of 4.5 to 6.7 in a mixed solvent of water and the organic solvent (second reaction step). This gives a cephalosporin of the formula (I) or a salt thereof of high purity and in high yield.

Thus, even if the uninsulated compound of the formula (III) is used as the starting compound, decomposition of the intermediate product can be prevented by the above procedure and achieves the purpose of the invention described in East German Patent Application No.AP C 07D / 268154/6 become.

It is an object of the invention to provide a process for the preparation of a novel intermediate (syn-isomer) of the formula (II).

In the following the invention will be explained in more detail.

According to the invention there is provided a process for the preparation of a novel intermediate of formula (II) for the preparation of a useful cephalosporin:

(ID ί.

"S '.N

ν (syn-isomeres)

wherein R ^{1 is} a lower alkyl group. The process comprises reacting a compound of formula (IV): XCH ₂ COC-CONH ₂

N.

'·. (Syn lsomeres)

where X is a halogen atom and R ^{1 has} the meaning given above, with thiourea.

The invention will be explained in detail below. Unless otherwise stated, a straight or branched CI_ means in the present description the term "alkyl" ₁₄ alkyl, for example methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, hexyl, heptyl, octyl, dodecyl or the like The term "halogen" means fluorine, chlorine, bromine, iodine or the like. Further, the term "lower" means 1 to 5 carbon atoms.

Further, it should be noted that when words such as "alkyl", "lower" and the like appear in the various terms used in this specification, they are each as defined above unless otherwise specified.

The carboxyl-protecting group includes groups which are conventionally used as a carboxyl-protecting group in the field of penicillinia and cephalosporins. These include specifically z. Alkyl; phthalidyl; diphenylmethyl; C ₂ _ ₇ acyloxy-Ci-5-alkyl such as acetoxymethyl, pivaloyloxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-acetoxy-n-propyl, 1-pivaloyloxyethyl, 1-pivaloyloxy-n-propyl, benzoyloxymethyl , 1-benzoyloxyethyl and the like; aC ₂ _ ₅ -Acyloxybenzyl as a-pivaloyloxybenzyl, aC ₂ _5-acyloxybenzyl as a-

Pivaloyloxybenzyl, a-acetoxybenzyl and the like and others

Hereinafter, embodiments of the method according to the invention will be explained.

The compound of the formula (II) can be obtained by reacting a compound of the formula (IV) with thiourea.

The reaction is generally carried out in a solvent. As a suitable solvent, any solvent is contemplated so long as it does not adversely affect the reaction. Suitable solvents include water; Alcohols such as methanol, ethanol and the like; Ketones such as acetone and the like; Ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; Amides such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide and the like; N-methyl-a-pyridone and the like. These solvents can also be used as a mixture of two or more.

The reaction proceeds in some cases particularly smoothly by adding an acid-binding agent. Useful acid-binding agents include, for example, inorganic or organic bases such as alkali metal hydroxides, alkali metal hydrogencarbonates, triethylamine, pyridine, N, N-dimethylaniline, and the like.

The reaction proceeds completely at ⁰ ° C. to 100 ^° C., generally over a period of 1 to 48 hours, preferably 1 to 10 hours.

The thiourea may be used in an amount of one to several moles per mole of the compound of the formula (IV).

As mentioned above, the syn isomer (of the formula [H]) can be selectively obtained in high yield at a low cost.

Also included in the present invention are all solvates, adducts, crystal forms and hydrates of the compound of formula (II).

The compound of the formula (IV) can be obtained, for example, according to the stated preparation processes.

production method

CH ₃ C OCH ₂ CONIL 2

CH-COC-CONH2 ³ I! N

N i + r ology

CH-COC-COZ ³ I

NH _?

(V)

(Vl)

alkylation

Ψ CH-COC-CON ^

[VIII]

Syn isomer

(VII) Syn isomer

halogenation

XCH-COC-CONHo 2, j 2

\ 1

OR

(IV) Syn isomer

In this case, R ¹ and X.sup.1 have the abovementioned meaning; Z is a halogen atom or a group -OH or-SH; and the bonding symbol "~> means that the compound may exist as a syn or anti isomer or as a mixture thereof.

(1) Preparation of the compound of the formula (IV)

A nitroso compound of the formula (VI) can be obtained by reacting a compound of the formula (V) with a nitrosating agent.

The reaction is generally carried out in a solvent. The usable solvents include those which are inert to the reaction, such as water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran and the like. These solvents can be used as a mixture of two or more.

The preferred nitrosating agents for this reaction are nitrous acid and derivatives thereof, for example nitrosyl halides such as nitrosyl chloride, nitrosyl bromide and the like; Al kali metal nitrite such as sodium nitrite, potassium nitrite and the like; and alkyl nitrites such as butyl nitrite, pentyl nitrite and the like. If an alkali metal nitrite is used as a nitrosating agent, the reaction is preferably carried out in the presence of an inorganic and organic acid such as hydrochloric acid, sulfuric acid, formic acid, acetic acid or the like. If an alkyl nitrite is used as a nitrosating agent, the reaction is preferably carried out in the presence of a strong base such as, for example, an alkali metal alkoxide.

This reaction takes place completely at ⁰ ° C. to 30 ^° C. over a period of 10 minutes to 10 hours.

(2) Preparation of the compound of the formula (VII)

The compound of the formula (VII) can be obtained by reacting a compound of the formula (VI) with an alkylating agent.

This reaction can be carried out according to conventional methods and generally proceeds at -20 ° C to 60 ⁰ C over a period of 5 minutes to 10 hours to fully.

Any solvents may be used provided that they do not adversely affect the reaction. Suitable solvents include, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; Alcohols such as methanol, ethanol and the like; halogenated hydrocarbons such as chloroform, methylene chloride and the like; Esters such as ethyl acetate, butyl acetate and the like; Amides such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide and the like; Water; and other. These solvents can also be used as a mixture of two or more.

The alkylating agents used in the reaction include, for example, lower alkyl halides such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide and the like; dimethyl sulfate; diethyl sulfate; diazomethane; diazoethane; Methyl p-toluenesulfonate; and the same. If a Alkylierungsmittei other than diazomethane or diazoethane is used in the reaction, the reaction is preferably carried out in the presence of an inorganic or organic base, for. B.

an alkali metal carbonate such as sodium carbonate, potassium carbonate or the like, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or the like; triethylamine; pyridine; Ν, Ν-dimethylaniline; or the like through.

The compound of the formula (VII) can also be obtained by subjecting the compound of the formula (VIII) to a conventional amidation reaction using ammonia.

(3) Preparation of the compound of the formula (IV)

The compound of the formula (IV) can be obtained by reacting a compound of the formula (VII) with a halogenating agent.

The reaction is generally carried out in a solvent. Suitable solvents are those which do not adversely affect the reaction, for example halogenated hydrocarbons such as methylene chloride, chloroform and the like; organic carboxylic acids such as acetic acid, propionic acid and the like; Ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; Alcohols such as methanol, ethanol, isopropanol and the like and others. These solvents can also be used as a mixture of two or more.

The reaction proceeds at ⁰ C to 5O ⁰ C generally within a period of 30 minutes to 24 hours completely.

The usable halogenating agents include, for example, halogens such as bromine, chlorine and the like; Sulfuryl halides such as sulfuryl chloride and the like; hypohalous acids or alkali metal hypohalites such as hypochlorous acid, hypobromous acid, sodium hypochlorite and the like; N-halogenated imide compounds such as N-bromosuccinimide, N-chlorosuccinimide, N-bromophthalimide and the like; Perbromide compounds ₍ such as pyridinium hydrobromide perbromide, 2-carboxyethyltriphenylphosphonium perbromide and the like, and others.

embodiment

In the following the invention will be explained in more detail by means of examples, without limiting the invention.

example 1

(1) Dissolve 10.1 g of acetoacetamide in 35 ml of water. 6.9 g of sodium nitrite are added to the resulting solution while cooling with ice. Subsequently, 25 ml of 4N sulfuric acid were added dropwise to the resulting mixture, under stirring at 0 ° C to 5 ⁰ C for a period of 30 minutes. After completion of the dropping, the mixture is reacted at the same temperature for 30 minutes. The pH is then adjusted to 6.0 with saturated aqueous sodium bicarbonate solution.

After the insoluble portions are removed, water is removed by distillation under reduced pressure. The residue obtained is treated with 20 ml of ethyl acetate and the resulting crystals are collected by filtration. This gives 8.6 g (yield 66.2%) of 2-hydroxyimino-3-oxobutyramide having a melting point of 96-97 ° C.

IR (KBr) citT ¹ : v _{c = 0} 1 670

NMR (d -DMSO) S ' value

· Λ

2.26 (3H, s, CH CO-), 7.46 ClH, bs, -CONQ), ^{6 X} H

7.62 ClH, bs, -CON () / 12.60 ClH, s,

^X H

= N-0H)

(2) In 20 ml of water are dissolved 6.5 g of 2-hydroxyimino-3-oxobutyramide and 5.6 g of anhydrous sodium carbonate at 2O ⁰ C. Further, at 20 to 25 ° C 6.6 g of dimethyl sulfate to the resulting solution and sets the resulting mixture at the same temperature for 2 hours. The precipitate formed is collected by filtration and treated with 100 ml of methanol. Subsequently, the resultant mixture at 4O ⁰ C is stirred until 50 ⁰ C for 30 minutes. After removal of the insoluble matters, the solvent is removed by distillation under reduced pressure. 20 ml of ethanol are added to the residue thus obtained, and the crystals formed are collected by filtration. This gives 5.2 g (yield 72.2%) of 2- (Syn) -methoxyimino-3-oxobutyramide having a melting point of 156-157 ° C.

IR (KBr) cm ^-1 : v _{c = Q} 1700, 1670 NMR Cd ₆ -DMSO) δ value

2.26 (3H, s, CH ₃ CO-), 3.96 (3H, s, -OCH ₃ ),

7.46 ClH, bs, -CON ^), 7.58 ClH, bs,

CON '

(3) 7.2 g of 2- (syn -) - methoxyimino-3-oxobutyramide are suspended in 36 ml of tetrahydrofuran. To the suspension is added under stirring at 4O ⁰ C. 0.8 g of bromine. After the color caused by the bromine has disappeared, an additional 7.2 g of bromine are added to the suspension with stirring at 25 to 30 ° C. After the suspension is reacted at the same temperature for 1 hour, the solvent is removed by distillation under reduced pressure. To the residue obtained are added 50 ml of ethyl acetate and 20 ml of water. The pH is then adjusted to 6.0 with saturated aqueous sodium bicarbonate solution. The organic layer is separated and washed with 20 ml of saturated aqueous sodium chloride solution. The organic layer is then dried over anhydrous magnesium sulfate and the solvent is removed by distillation under reduced pressure. To the obtained residue is added 20 ml of a mixed solvent of diisopropyl ether-ethyl acetate (1: 1). The crystals formed are collected by filtration. This gives 9.2 g (yield 82.1%) of 4-bromo-2- (syn) -methoxyimino-3-oxo-butyramide having a melting point of 112-113 ⁰ C.

IR (KBr) cm " ¹ : ν 1715, 1660

NMR (dg-DMSO) δ value

4.02 (3H, s, -OCH ₃ ), 4.58 (2H, s, BrCH ₂ CO-), 7.72 C2H, bs, -CONH ₂ )

(4) 4.5 g of 4-bromo-2- (syn) -methoxyimino-3-oxobutyramide are suspended in 13.5 ml of ethanol. The suspension 1.5 g of thiourea was added and the resulting mixture is reacted at 20 C for 1 hour to 3O ^0th The precipitated crystals are collected by filtration, washed with ethanol and then suspended in 25 ml of water. The pH of the resulting suspension is adjusted to 6.0 with saturated aqueous sodium bicarbonate solution. Subsequently, the crystals thus formed are collected by filtration and recrystallized from 15 ml of a mixed solvent of water-methanol (1: 1). This gives 2.9 g (yield 71.8%) of 2- (2-Arninothiazol-4-yl) -2- (syn) -methoxyiminoacetamid with a melting point of 208-209 ⁰ C.

IR (KBr) cm " ¹ : v _c _ ₀ 1665

NMR Cdg-DMSO) δ _W ert

3.84 C3H, s, -OCH3), 6.75 (IH, s,

/H

7.26 (2H, bs, -NH-), 7.61 (IH, bs, -CON '),

^{Δ X} H

7.91 (IH, bs, -CDN ')

Example 2

(1) 14.4 g of 2- (Syn -) - methoxyimino-3-oxbbutyramide are suspended in 43 ml of methanol containing 3.6 g of hydrogen chloride. To the resulting suspension at 30 ° C over a period of 1 hour 16.0 g bromine added dropwise. The suspension is reacted at the same temperature for further 30 minutes, and then 43 ml of 1,4-dioxane and 22 ml of water are added to the reaction mixture while being cooled with ice. Subsequently, the pH is adjusted to 3.0-4.0 with aqueous ammonia. Top toward one gives 7.6 g of thiourea to the mixture and the mixture was reacted at 30 ⁰ C for 2 hours in order, with the pH adjusted with aqueous ammonia in a range of 3.0-5.0. The reaction mixture is subsequently cooled to 5 ⁰ C and the pH is adjusted to 6.5 with aqueous ammonia. The resulting crystals are collected by filtration and washed with a mixed solvent of water-1,4-dioxane (1: 1) to give 18.5 g (yield 64.2%) of the 1,4-dioxane adduct of 2- (m.p. 2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide having a melting point of 196-198 ⁰ C.

- / - 4.ΌΟ O

IR (KBr) cm ^-1 : v _{c = 0} 1690

NMR Cd ^ -DMSO) S value ο

), 3.83 (3H ₇ s,

-OCH ₇ ), 6.70 (IH, s, ^N ~ r ~) / 7.16 (2H,

bs, -NH ₂ ), 7.48 ClH, bs, -CON "),

• Η 7.77 ClH, bs, -

(2) 14.4 g of the 1,4-dioxane adduct of 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide obtained in the above step (1) are prepared from a mixed solvent of 18 ml of water and 18 ml Methanol recrystallized. This gives 8.6 g (yield 86.0%) of 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide having a melting point of 208-209 ° C. The physical properties (IR, NMR) of this product are identical to those of the product obtained in Example 1- (4).

(3) 1 g of the above step (1) obtained 1,4-Dioxanaddukts of 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetarnid are suspended in 5 ml of methanol at 40 ⁰ C. The resulting suspension is stirred at the same temperature for 1 hour. Subsequently, the suspension is cooled to room temperature and the crystals thus obtained are collected by filtration. There is obtained 2- (2-aminothiazol-4-yl) -2- (syn) -rnethoxyiminoacetamide with a melting point of 223.5-225 ° C (yield 89.2%).

The physical properties (NMR) of this product are identical to those of the product obtained in Example 1- (4).

Example 3

A mixed solvent of 60 ml of sulfolane and 60 ml of anhydrous methylene chloride containing 30.6 g of boron trifluoride is added with 30.0 g of 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide. The mixture is reacted at room temperature for 1 hour. The crystals formed are collected by filtration. The crystals are then suspended in 300 ml of ethyl acetate and collected by filtration after the resulting suspension is stirred for 1 hour. The crystals are washed with two 60 ml portions of ethyl acetate and dried. This gives 42.3 g of crystals.

IR (KBr) cm ^-1 : 1 680.1 650.1 620.1 200-1 000

Reference Example 1

In 41 ml of ethyl acetate is dissolved 4.10 g of pivaloyloxymethyl-7-amino-3- (5-methyl-1,2,3,4-tetrazol-2-yl) methyl-A ³ -cephem-4-carboxylate. 3.36 g of the crystals obtained in Example 3 are added to the solution. Subsequently, the solution is reacted at room temperature for 3 hours. Subsequently, 41 ml of water are added to the reaction mixture and the pH is adjusted to 4.5 with sodium bicarbonate. The organic layer is separated, washed with 20 ml of water and dried over anhydrous magnesium sulfate. Subsequently, 2.4 g Mesitylensulfonsäuredihydrat to the organic layer. The resulting mixture is reacted at room temperature for 1 hour. The crystals formed are collected by filtration and washed with 5 ml of ethyl acetate. This gives 7.18 g (yield 90.5%) of the mesitylenesulfonic acid salt of pivaloyloxymethyl-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- (5-methyl-1, 2,3,4-tetrazol-2-yl) methyl-a ³ -cephem-4-carboxylate having a melting point of 218-220 ⁰ C (decomposition).

IR (KBr) cm "" ¹ : v _{c = 0} 1 782.1 745.1 680

Reference Example 2

(1) 29.8 g of 7-amino-3- (5-methyl-1,2,3,4-tetrazol-2-yl) methyl-A ³ -cephem-4-carboxylic acid are suspended in 88.8 ml of acetone. Is then added 15.2 g!, S-DiazabicycloIöAOl ^ -undecene dropwise to the resulting suspension at ⁰ 5 C. After the resulting mixture at 5 ° C to 10 ⁰ C for 30 minutes has been implemented, is the reaction mixture cooled to ⁰ ° C and with 24.2g Pivaloyloxymethyliodid added. Subsequently, the mixture is reacted at 15 ° C to 17 ° C for 20 minutes. After 385 ml of ethyl acetate was added dropwise to the reaction mixture over a period of about 5 minutes, 2.37 g of pyridine are added to the mixture and the resulting mixture is stirred for 5 minutes. After removal of the insoluble constituents formed by filtration, the filtrate is cooled to -5 ° C. To the cooled filtrate is added 33.6 g of the crystals obtained in Example 3. The resulting mixture is reacted at -5 ° C to 0 ⁰ C for 1 hour. , ,

(2) The reaction mixture obtained in the step (1) is added to the solution previously prepared by adding 19.6 g of 85% by weight phosphoric acid to 207 ml of water and adjusting the pH to 6.5 with 30 % aqueous sodium hydroxide solution. The resulting mixture is reacted at 25 to 27 ° C for 3 hours while maintaining the pH in a range of 6.2-6.5 with 20% aqueous potassium carbonate solution. Subsequently, the pH is adjusted to 3.0, with hydrochloric acid. The insoluble components are removed by filtration. Then the organic layer is separated and washed with 148 ml of water. To the obtained organic layer is added 21.3 g of mesitylenesulfonic acid dihydrate. The mixture is stirred at 20-22 ° C for 1 hour. The precipitated crystals are collected by filtration, washed with three 44 ml portions of ethyl acetate and then dried. This gives 61.9 g (yield 78.0%) of Mesitylensulfonsäuresalzes of pivaloyloxymethyl-7- [2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido] -3- (5-methyl-1 , 2,3,4-tetrazol-2-yl) methyl-A ³ -cephem-4-carboxylate with a melting point of 218-220 ° C (decomposition).

IR (KBr) cm ^-1 : v _{c =} o 1 782.1 745.1 680

Claims (2)

Claim: 1. Process for the preparation of a new intermediate for cephalosporins of the formula (II): U C-CONH ₂ ^υΛ (syn-isomer) where R ^{1 is} a lower alkyl group, characterized in that a compound of the formula (IV): ZGH ₂ GOG - GOlIH ₂ , 1 (syn-isomer) OR wherein X is a halogen atom and R ^{1 has} the meaning given above, reacted with thiourea in the presence of a solvent. 2. The method according to item 1, characterized in that one carries out the reaction at ^{0 0} C to 100 ⁰ C. Field of application of the invention The invention relates to a process for the preparation of a new intermediate for cephalosporins. Characteristic of the known state of the art The inventors have previously found that a cephalosporin (syn isomer) represented by the following formula (I) or a salt thereof: C-CONH. , I ¹ I