FI82830B - 2-(2-Aminothiazol-4-yl)-2-(syn)alkoxyiminoacetamide, and a process for preparing it - Google Patents

Description

1,82830 2- (2-Aminothiazol-4-yl) -2- (syn) alkoxyiminoacetamide and its preparation

This invention relates to 2- (2-aminothiazol-4-yl-2- (syn) -alkoxyiminoacetamide, which is useful in the preparation of cephalosporins, and to a process for the preparation of the compound 10 The present inventors have previously found that cephalosporin (syn- isomer) of formula (I) COOk wherein R 1 is a lower alkyl group, R 2 is a hydrogen atom or a carboxyl protecting group and R 3 is a substituted or unsubstituted heterocyclic group attached to the exomethylene group at the 3-position of the cephem ring via a carbon-nitrogen bond or a salt thereof is very useful as an antibacterial agent [JP Application-25 Publications (published before the novelty study) 99592/82 and 93085/84 and JP Application Publications 67871/83, 113565/83 and 114313/83].

Since then, the present inventors have extensively studied methods for preparing cephalosporin of formula (I) or a salt thereof. As a result, they have found that a useful cephalosporin (syn-isomer) of formula (I) or a salt thereof can be easily prepared in high yield by administering a compound (syn-isomer) of formula (II) 2,82830

/OF

u M J7 n-C-CONH

2 \ J "2 HU

OF

OR * (syn isomer) wherein R1 is a lower alkyl group; react with a compound of formula (III) wherein R 2 is a carboxyl group protecting group and R 3 is a substituted or substituted carbon-type bond attached to the exomethylene group at the 3-position of the chemical ring. an inactive heterocyclic group; in the presence of boron trifluoride or a complex thereof and thereafter, if desired, by removing the carboxyl protecting group or converting the product to a salt, as described in FI patent application 843959.

Even when the compound of formula (III) obtained by the process for preparing the compound of formula (III) is used without isolation as a starting material in the process, the use of the following process leads to a favorable result, as is the case with the isolated compound of formula (III) as starting material.

The compound (syn isomer) of formula (II) is reacted with boron trifluoride to give a compound of formula (II) 30 N -C-CONH2 h2n- / JN 1113 x S ^ N 10 R (syn isomer) 35 3 82830 or a complex thereof, and the compound thus obtained is reacted at -50 to 0 ° C in the above-mentioned organic solvent with the compound of the formula (III) to form an intermediate (first reaction step).

S N

NH

10 | 2

, N -, - C-C-NH --- K'S'S

7-γ ^ αΐ2Η3 OR1 C00r2 a

15 \ S

(assumed structure) wherein R 1, R 2a and R 3 have the meanings given above, and the reaction mixture is then allowed to react further at 20 ° C to 50 ° C at a pH of 4.5 to 6.7 water and organic in a solvent-containing solvent mixture (second reaction step) to give a cephalosporin of formula (I) or a salt thereof in very pure and high yield.

Thus, when an uninsulated compound of formula (III) is used as a starting material, the above process can prevent the intermediate from decomposing and can thus achieve the object of the invention described in FI patent application 843959.

It is therefore an object of the present invention to provide a novel intermediate (syn-isomer) of formula (II) for use in the above manufacturing process.

Another object of the present invention is to provide a process for the preparation of an intermediate.

The novel compound of the invention has formula (II) 4,82830

, Ν -] - C-CONH

Η2Ν- ^ jr 1 tm 5 \ t OR1 (syn isomer) wherein R1 is a lower alkyl group.

The process according to the invention for the preparation of a novel compound of formula (II) is characterized in that the compound of formula (IV) is XCH-COC-CONH.

2 II 2 N [IV] 15 \ 1 OR (syn isomer) wherein X is a halogen atom and Railia is as defined above; is reacted with thiourea in the presence of a solvent, preferably at 0 to 100 ° C.

In this publication, unless expressly stated otherwise, the word "alkyl" means a straight-chain or branched C 1-4 alkyl group, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 25 sec-butyl, tert-butyl , pentyl, hexyl, heptyl, octyl, dodecyl or the like; the word "aryl" means, for example, phenyl, tolyl, naphthyl, indanyl, or the like; the word "aralkyl" means, for example, benzyl, phenethyl, 4-methylbenzyl, naphth-methylmethyl or the like; and the word "halogen" means fluorine, chlorine, bromine, iodine or the like. The word "lower" means 1-5 carbon atoms.

In addition, the words "alkyl", "aryl", "aralkyl", "lower" and the like, as used herein in the various expressions used herein, have the meanings set forth above, unless otherwise specified. Heterocyclic group means in particular nitrogen-containing 5- or 6-membered heterocyclic groups such as pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl and the like.

Carboxyl protecting group means groups conventionally used as a carboxyl protecting group in the penicillin and cephalosporin field. These include, for example, alkyl; phthalidyl; diphenylmethyl; C 1-6 acyloxy-C 1-6 alkyl such as acetoxymethyl, pivaloyloxymethyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 1-acetoxy-n-propyl, 1-pivaloyl-15-oxyethyl, 1-pivaloyloxy -n-propyl, benzoyloxymethyl, 1-benzoyloxyethyl and the like; α-C 2-5 acyloxybenzyl such as α-pivaloyloxybenzyl, α-acetoxybenzyl and the like; and so on.

Embodiments of the methods presented herein are illustrated below.

A compound of formula (II) may be prepared by reacting a compound of formula (IV) with a thioure.

The reaction is usually carried out in a solvent in which any solvent can be used as long as it does not adversely affect the reaction. Such 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, N, N-dimethylacetamide and the like; N-methyl-α-pyridone and the like. These solvents can also be used as mixtures of two or more solvents.

The reaction is sometimes made to proceed smoothly by the addition of an acid scavenger. Useful acid scavengers include, for example, inorganic or organic bases such as alkali metal hydroxides, alkali metal bicarbonates, triethylamine, pyridine, N, N-dimethylaniline and the like.

At 50 to 100 ° C, the reaction is usually completed in 1 to 48 hours, preferably in 1 to 10 hours.

The amount of thiourea used per mole of the compound of formula (IV) may vary from one mole to several moles.

As described above, the syn-isomer [formula (II)] can be selectively prepared in high yield and low cost.

This invention encompasses all solvates, addition products, crystalline forms and hydrates of the compounds of formula (II).

The compound of formula (IV) can be prepared, for example, according to the preparation scheme shown below.

Preparation 20 CH3COCH2CO2H2 [V] ^ Nitrosisation CH3COC-CONH2 [VI]

OF

25 OH

Alkylation NH 2 CH 3 CO - CO 2 -> CH 3 CO - CONH, [VII]

li II

Ny Ny (syn-isomer) 30 OR1 OR1 [VIII] Halogenation (syn-isomer) XCl) JcO (j: -CONH2 [IV] 35 N. (syn-isomer) OR117 82830 wherein R1 and X: Z is a halogen atom or of the formula -OR4 or -SR4 (wherein R4 is a hydrogen atom or an alkyl, aryl, aralkyl or heterocyclic group), and the bond / bond means that the compound may be a syn or an anti-isomer or a mixture thereof.

(1) Preparation of a compound of formula (VI)

A nitro compound of formula (VI) can be prepared by reacting a compound of formula (V) with a nitrosating agent.

The reaction is usually carried out in a solvent in which solvents inert under the reaction conditions, such as water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran and the like, can be used. These solvents 15 can be used as mixtures of two or more solvents.

Preferred nitrosating agents for use in this reaction include nitric acid and its derivatives, for example, nitrosyl halides, nitrosyl chloride and bromide, and the like; alkali metal nitrites such as sodium and potassium nitrite and the like; and alkyl nitrites such as butyl and pentyl nitrite and the like. When alkali metal nitrite is used as the nitrosating agent, it is preferable to carry out the reaction in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid, acetic acid or the like. When an alkyl nitrite is used as the nitrosating agent, it is preferable to carry out the reaction in the presence of a strong base such as an alkali metal alkoxide.

At 0-30 ° C, this reaction is complete over a period of time ranging from 10 minutes to 10 hours.

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

A compound of formula (VII) may be prepared by reacting a compound of formula (VI) with an alkylating agent.

This reaction can be carried out by any conventional method and at -20 to 60 ° C it is usually completed in a period ranging from five minutes to 10 hours.

Any solvent may be used as long as it does not adversely affect the reaction and includes, 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, N, N-dimethylacetamide and the like; water; etc. These solvents can also be used as mixtures of two or more solvents.

Alkylating agents useful in this reaction include, for example, lower alkyl halides such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide and the like; dimethyl and diethyl sulfate; diazomethane and ethane; methyl p-toluenesulfonate and the like. When an alkylating agent other than diazomethane or ethane is used in the reaction, it is preferable to carry out the reaction with an inorganic or organic base, for example, an alkali metal carbonate such as sodium or potassium carbonate or the like; an alkali metal hydroxide such as sodium or potassium hydroxide or the like; tri-25 ethylamine; pyridine; N, N-dimethyl aniline; or the like.

A compound of formula (VII) may also be prepared by forming an amide from a compound of formula (VIII) by a reaction known per se using ammonia.

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

A compound of formula (IV) may be prepared by reacting a compound of formula (VII) with a halogenating agent.

The reaction is usually carried out in a solvent, and 9,828,30 useful solvents include solvents 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 and propionic acid and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, isopropanol and the like; etc. These solvents can also be used as mixtures of two or more solvents.

At 10-50 ° C, the reaction is usually completed in a period ranging from 30 minutes to 24 hours.

Useful halogenating agents include, for example, halogens such as bromine, chlorine and the like; sulfuryl halides such as sulfuryl chloride and the like; Hypohalic acids or alkali metal hypohalites such as hypochlorous acid, hypobromic 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 hydrobromo-20 midiperbromide, 2-carboxyethyltriphenylphosphonium perbromide and the like; and so on.

The present invention is illustrated by the following examples.

Example 1 (1) 10.1 g of acetoacetamide was dissolved in 35 ml of water, and 6.9 g of sodium nitrite was added to the resulting solution under ice-cooling, followed by dropwise addition of the resulting mixture with stirring at 0-5 ° C. 25 ml of 4 N sulfuric acid per minute. After the dropwise addition, the mixture was allowed to react at the same temperature for 30 minutes, and then the pH was adjusted to 6.0 with saturated aqueous sodium hydrogencarbonate solution.

After removal of insoluble constituents, water was distilled off under reduced pressure. To the residue 35 thus obtained was added 20 ml of ethyl acetate, and the crystals thus obtained were collected by filtration to give 8.6 g (yield 66.2%) of 2-hydroxyimino-3-oxobutyramide having a melting point of 96 to 97 ° C.

IR (KBr) can'1: VC

/B

2.26 (3H, s, CH 3 CO-), 7.46 (1H, bs, -CON <"),

Nl 10

/B

7.62 (1H, bs, -CON (^), 12.60 (1H, s,

15 = N-OH

(2) 6.5 g of 2-hydroxyimino-3-oxobutyramide and 5.6 g of anhydrous sodium carbonate were dissolved in 20 ml of water at 20 ° C. An additional 6.6 g of dimethyl sulfate was added to the resulting solution at 20-25 ° C, and the resulting mixture was allowed to react at the same temperature for two hours. The precipitate thus formed was collected by filtration, and 100 ml of methanol was added thereto, after which the resulting mixture was stirred at 40 to 50 ° C for 30 minutes to 25 minutes. After removal of insoluble constituents, the solvent was distilled off under reduced pressure. To the residue thus obtained was added 20 ml of ethanol, and the crystals thus formed were collected by filtration to give 5.2 g (yield 72.2%) of 2- (syn) -methoxyimino-3-oxobutyramide having a melting point of 156 to 157. ° C.

IR (KBr) cm -1: vc = o 1700, 1670 NMR (d 6 -DMSO) δ δ 2.26 (3H, s, CH 3 CO-), 3.96 (3H, s, -OCH 3),

/B

7.46 (1H, bs, -CONf), 7.58 (1H, bs,

40 NH

-CON 2) 82830 (3) 7.2 g of 2- (syn) -methoxyimino-3-oxobutyramide were suspended in 36 ml of tetrahydrofuran, and 0.8 g of bromine was added to the suspension at 40 ° C with stirring. After confirming the disappearance of the bromine-induced color, an additional 7.2 g of bromine was added to the suspension at 25-30 ° C while stirring. After allowing the suspension to react at the same temperature for one hour, the solvent was distilled off under reduced pressure. To the obtained residue were added 50 ml of ethyl acetate and 20 ml of hydrogen, and the pH was then adjusted to 6.0 with saturated aqueous sodium hydrogencarbonate solution. The organic layer was separated and washed with 20 ml of saturated aqueous sodium chloride solution. The organic layer was then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the residue thus obtained was added 20 ml of a solvent mixture containing diisopropyl ether and ethyl acetate in a ratio of 1: 1, and the crystals thus formed were collected by filtration to give 9.2 g (yield 82.1%) of 4-bromo-2 (syn) - methoxyimino-3-oxobu-20 tyramide with a melting point of 112-113 ° C.

IR (KBr) cm -1: VC = δ 1715, 1660 NMR (d 6 -DMSO) δ δ 4.02 (3H, s, -OCH 3), 4.58 (2H, s, BrCH 2 CO-), δ, 72 (2H, bS, -CONH 2) 30 (4) 4.5 g of 4-bromo-2- (syn) -methoxyimino-3-oxobutyramide were suspended in 13.5 ml of ethanol. 1.5 g of thiourea was added to the suspension, and the resulting mixture was allowed to react at 20 to 30 ° C for one hour. The precipitated crystals were collected by filtration, washed with ethanol and then suspended in 25 ml of water. The pH of the resulting suspension was adjusted to 6.0 with saturated aqueous sodium hydrogencarbonate solution. The crystals thus formed were then collected by filtration and recrystallized from i2 82830 from 15 ml of a 1: 1 mixture of water and methanol to give 2.9 g (yield 71.8%) of 2- (2-aminothiazol-4-yl). ) -2- (syn) -methoxyiminoacetamide with a melting point of 208-209 ° C.

Δ IR (KBr) cm -1: 1 O> 1665 NMR (d 6 -DMSO) δ N -., Δ 3.84 (3H, s, -OCH 3), 6.75 (1H, s, Jj),

S ^ \ H

/ M

7.26 (2H, bs, -NH 2), 7.61 (1H, bs, -CON 2), 7.91 (1H, bs, -CON 2)

B

20

Example 2 (1) 14.4 g of 2- (syn) -methoxyimino-3-oxobutyramide were suspended in 43 ml of methanol containing 3.6 g of hydrogen chloride, and 30 ° C was added dropwise to the resulting suspension. 16.0 g of bromine per hour. The suspension was allowed to react at the same temperature for another 30 minutes, and then 43 ml of 1,4-dioxane and 22 ml of water were added to the reaction mixture under ice-cooling, after which the pH was adjusted to 3.0 to 4.0 with aqueous ammonia solution. Then, 7.6 g of thiourea was added to the mixture, and the mixture was allowed to react at 30 ° C for two hours, during which time the pH was maintained in the range of 3.0 to 5.0 am-35 with many aqueous solutions. The reaction mixture was then cooled to 5 ° C and the pH was adjusted to 6.5 with aqueous ammonia. The crystals thus obtained were collected by filtration and washed with a 1: 1 mixture of water and 1,4-dioxane to give 18.5 g (yield 64.2 40%) of 2- (2-aminothiazol-4-yl) -2 an adduct of (syn) -methoxyiminoacetamide and 1,4-dioxane with a melting point of 196-198 ° C.

i3 82830 IR (KBr) cm-1: vOO 1690 NMR (d6-DMSO) δ

5 H H

3.55 (8H, s, I), 3.83 (3H, s,

H H

-OCH 3), 6.70 (1H, s, T-), 7.16 (2H, 15 bs, -NH 2), 7.48 (1H, bs, -CON ("),

/B

7.77 (1H, bs, -CON <;)

20 XH

(2) 14.4 g of the adduct of 2- (2-amino-thiazol-4-yl) -2- (syn) -methoxyiminoacetamide and 1,4-dioxane obtained in the above step (1) were recrystallized from a mixed solvent, containing 18 ml of water and 18 ml of methanol to give 8.6 g (yield 86%) of 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide, m.p. 208-209 ° C.

The physical properties (IR, NMR) of the product were identical to the physical properties of the product obtained in Example 1- (4).

(3) 1 g of the adduct of 2- (2-aminothiaz-35-sol-4-yl) -2- (syn) -methoxyiminoacetamide and 1,4-dioxane obtained in step (1) above was suspended in 5 ml of 40 “Crista methanol and the resulting suspension were stirred at the same temperature for one hour. The suspension was cooled to room temperature and the crystals thus obtained were collected by filtration to give 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide (yield 89.2%), m.p. 223.5- 225 ° C.

The NMR spectrum of the product was identical to the NMR spectrum of the product obtained in Example 1- (4).

i4 82830

Example 3 To a mixed solvent of 60 ml of sulfolane and 60 ml of anhydrous methylene chloride containing 30.6 g of boron trifluoride was added 30.0 g of 2- (2-aminothiazol-4-5-yl) -2- (syn) methoxyiminoacetamide. . The mixture was allowed to react at room temperature for 1 hour, and the crystals thus formed were collected by filtration. The crystals were then suspended in 300 ml of ethyl acetate and collected by filtration after stirring the resulting suspension for 10 hours. They were washed with two 60 ml portions of ethyl acetate and dried to give 42.3 g of crystals.

IR (KBr) cm -1 1680, 1650, 1620, 1200-1000 Reference Example 1 In 41 ml of ethyl acetate was dissolved 4.10 g of pivaloyloxymethyl- [7-amino-3- (5- methyl 1,2,3,4-tetrazol-2-yl) methyl Δ3-cephem-4-carboxylate] and 3.36 g of the crystals obtained in Example 3 were added to the solution, after which the solution was allowed to react at room temperature for three hours. . Then, 41 ml of water was added to the reaction mixture, and the pH was adjusted to 4.5 with sodium hydrogen carbonate. The organic layer was separated, washed with 20 ml of water and dried over anhydrous magnesium sulfate. Subsequently, 2.4 g of mesitylene sulfonic acid dihydrate was added to the organic layer, and the resulting mixture was allowed to react at room temperature for 1 hour. The crystals thus formed were collected by filtration and washed with 5 ml of ethyl acetate to give 7.18 g (yield 90.5%) of pivaloyloxymethyl [7- [2- (2-aminothiazol-4-yl) -2- (syn ) -methoxyiminoacetamido] -3- (5-methyl-1,2,3,4-tetrazol-2-yl) methyl Δ3-cephem-4-carboxylate] mesitylenesulfonic acid salt, m.p. 218-220 ° C (dec).

IR (KBr); cm'1 VC = 0 1 782, 1 745, 1 680 l · 35 is 82830

Reference Example 2 (1) In 88.8 ml of acetone was suspended 29.6 g of 7-amino-3- (5-methyl-1,2,3,4-tetrazol-2-yl) methyl-A3-cephem. 4-Carboxylic acid and 15.2 g of 1,8-diazabicyclo [5.4.0] -7-undecene were then added dropwise to the resulting suspension at 5 ° C. After reacting the resulting mixture at 5-10 ° C for 30 minutes, the reaction mixture was cooled to 0 ° C, and 24.2 g of pivaloyloxymethyl iodide was added thereto, followed by reaction at 10-17 ° C for 20 minutes. . After 385 ml of ethyl acetate was added dropwise to the reaction mixture over about five minutes, 2.37 g of pyridine was added to the mixture, and the resulting mixture was stirred for five minutes. After removing the insoluble components thus formed (by filtration), the filtrate was cooled to -5 ° C. To the cooled filtrate was added 33.6 g of the crystals obtained in Example 3, and the resulting mixture was allowed to react at -5 to 0 ° C for 1 hour.

(2) The reaction mixture obtained in the above step (1) was added to a solution prepared by adding 19.6 g of 85% by weight of phosphoric acid 207 to any water and adjusting the pH to 6.5 with 30% aqueous sodium hydroxide solution. The resulting mixture was allowed to react at 25-27 ° C for three to 25 hours, during which time the pH was maintained between 6.2 and 6.5 with 20% aqueous potassium carbonate. The pH was then adjusted to 3.0 with hydrochloric acid, and insoluble matters were removed by filtration, after which the organic layer was separated and washed with 148 ml of water. To the obtained organic layer was added 21.3 g of mesitylenesulfonic acid dihydrate, and the mixture was stirred at 20 to 22 ° C for one hour. The crystals thus precipitated were collected by filtration, washed with three 44 ml portions of ethyl acetate and then dried to give 61.9 g (yield 78.0%) of pivaloyloxymethyl [7- [2- (2-aminothiazol-4-yl) ) -2- (syn) -methoxyiminoacetamido] -3- (5-methyl-1,2,3,4-e] 82830 tetrazol-2-yl) methyl-3-cephem-4-carboxylate] methylene sulfonic acid salt , having a melting point of 218 -220 eC (decomposes).

Δ IR (KBr) cm -1 VC = 0 1 782, 1745, 1680

Claims (3)

A compound of formula (II) 5 -N —- C-CONH v- <T! ! (syn isomer) OR where R 1 is a lower alkyl group. 2. A process for the preparation of a compound of formula (II) .N-n-C-COHH 2 h 2 n -NO 1 S 11 OR 1 (syn isomer) where R 1 is a lower alkyl group, that a compound of formula (IV) XCHoCO-COHHO 2. ii 2 N [IV] \ 1 OR (syn isomer) where X is a halogen atom and R 1 is as defined above is reacted with thiourea in the presence of a solvent, preferably at 0-100 ° C. in