HU201034B - Process for production of intermediere compositions of tiasole of cefalosporine - 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

The present invention relates to a process for the preparation of novel intermediates useful for the preparation of cephalosporins.

We have previously found that the color isomeric cafalosporins of the formula I and their salts have valuable antibacterial activity. In the formula

R ¹ is lower alkyl,

R ^{2 is} hydrogen or a protecting group for a carboxy group, and

R ^{3 is a} substituted or unsubstituted heterocyclic group which is attached to the exomethylene group 3 of the cephem skeleton by a carbon nitrogen bond.

The above compound is disclosed in 99.592 / 82. and 93.085 / 84. Japanese Patent Application Laid-Open Publication Nos. 67871/83, 113,565 / 83; and 114.313 / 83. Japanese Patent Application Ser.

Further research was carried out to develop methods for the preparation of cephalosporins of the formula I and their salts.

It has now been found that the color isomeric cephalosporins of formula (I) and their salts are readily prepared in high yield from a color isomeric compound of formula (II), wherein R ^{1 is a} lower alkyl group, with a compound of formula (III). R ^{23 is a} carboxy protecting group and R ^{3 is a} substituted or unsubstituted heterocyclic group which is attached to the 3-position exomethylene group of the cephem skeleton by carbon nitrogen bonding in the presence of boron trifluoride or its complex or by converting the resulting product into salt (T / 37621). Hungarian Patent Application Publication No. 3797/84).

The present invention relates to a process for the preparation of novel intermediates of the color isomer of the formula (II) which can be used in the above process.

In formula II, R ¹ is as defined above.

The intermediate compounds of formula (II) is prepared by reacting a formula syn isomer compound of formula (IV) wherein - X is halogen and R ¹ is as defined above - is reacted with thiourea.

Details of the process of the present invention will now be described.

Unless otherwise specified, the term C 1 -C 5 alkyl as used herein is a straight or branched C 1 -C 5 alkyl group such as methyl, ethyl, η-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, , tert-butyl or pentyl.

The halogen atom may be fluorine, chlorine, bromine or iodine.

The compound of formula (II) is prepared by reacting the compound of formula (IV) with thiourea.

The reaction is usually carried out in a solvent. Any solvent that does not interfere with the reaction can be used. As a solvent, water, alcohol such as methanol, ethanol, etc. are used. a ketone such as acetone, an ether such as diethyl ether, tetrahydrofuran, dioxane, an amide such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, N-methyl-alpha 2 pyridone and the like. can be used. A mixture of said solvents may also be used.

The reaction is usually facilitated by the addition of an acid scavenger. Useful acid scavengers include, for example, inorganic or organic bases such as alkali metal hydroxide, alkali metal bicarbonate, triethylamine, pyridine, N, N-dimethylaniline and the like. may.

The reaction is usually carried out at 0-100 ° C for 1-48 hours, preferably 1-10 hours.

Thiourea can be used in amounts of one to several moles per mole of the compound of formula IV.

The color isomeric compound of formula (II) is selectively obtained in high yield economically.

The invention also relates to the preparation of solvates, adducts, crystalline forms and hydrates of the compound of formula II.

The compound of formula (IV) may be prepared, for example, as shown in Scheme [A].

In the formulas, R ¹ and X are as defined above, Z is halogen or -OR ⁴ or -SR ⁴ , wherein R ^{4 is} hydrogen or a substituted or unsubstituted alkyl, aralkyl, aryl or heterocyclic group and the wavy line is means that the compound is a color or an anti-isomer or a mixture thereof.

The compounds of formulas (IV), (VII) and (VIII) are color isomers.

Preparation of compound of formula VI:

The compound of formula (VI) is obtained by reacting a compound of formula (V) with a nitrosating agent.

The reactant is usually carried out in an inert solvent such as water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran or a mixture thereof.

A preferred nitrosating agent for use in the reaction is nitric acid and its derivatives, such as a nitrosyl halide such as nitrosyl chloride, nitrosyl bromide, and the like. alkali metal nitrites such as sodium nitrite, potassium nitrite, etc., alkyl nitrites such as butyl nitrite, pentyl nitrite, and the like. When alkali metal nitrite is used as the nitrosating agent, the reaction is preferably carried out in the presence of an inorganic or organic acid such as hydrochloric acid, sulfuric acid, formic acid, acetic acid.

When 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.

The reaction is carried out at 0-30 ° C for 10 minutes to 10 hours.

Preparation of compound of formula VII:

The compound of formula (VII) may be prepared by alkylation of a compound of formula (VI).

The reaction may be carried out in a conventional manner and is usually carried out at a temperature of -20 ° C to 60 ° C

It can be accomplished within 5 minutes to 10 hours.

Any solvent that does not interfere with the reaction may be used, such as ethers such as diethyl ether, tetrahydrofuran, dioxane, alcohol such as methanol, ethanol, halogenated hydrocarbons such as chloroform, methylene chloride, esters, and the like.

-2EN 201034 Β ethyl acetate, butyl acetate, amides such as N, N-dimethylformamide, Ν, Ν-dimethylacetamide, water, etc. A mixture of said solvents may also be used.

Examples of alkylating agents include lower alkyl halides such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide, dimethyl sulfate, diethyl sulfate, diazomethane, diazoethane, methyl p-toluenesulfonate, and the like. may. When alkylating with an alkylating agent other than diazomethane or diazoethane, the reaction is preferably carried out in the presence of an inorganic or organic base, such as an alkali metal carbonate such as sodium carbonate, potassium carbonate, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, Ν, Ν-dimethylaniline, etc. in the presence of.

The compound of formula (VII) may also be prepared by the amidation reaction of a compound of formula (VIII) with ammonia.

Preparation of compound of formula IV:

The compound of formula (IV) may be prepared by halogenation of the compound of formula (VII).

The reaction is usually carried out in a solvent which does not hinder the reaction. Suitable solvents are, for example, halogenated hydrocarbons such as methylene chloride, chloroform, etc. organic carboxylic acids such as acetic acid, propionic acid, ether such as diethyl ether, tetrahydrofuran, dioxane, alcohols such as methanol, ethanol, isopropanol and the like. to use. Mixtures of the solvents mentioned may also be used.

The reaction is usually carried out at 0-50 ° C for 0.5-24 hours.

The halogenating agent is, for example, an elemental halogen such as bromine or chlorine, a sulfuryl halide such as sulfuryl chloride, a hypohalic acid or an alkali metal hypohalide such as hypobromic acid, hydrochloric acid, sodium hypochloride, N-halogenated imides such as N-bis succinimide, N-bromophthalimide, perbromide compounds such as pyridinium hydrobromide perbromide, 2-carboxyethyltriethylphosphonium perbromide, and the like. may.

The following Examples and Reference Examples illustrate the process of the invention without limiting the scope of the invention.

Example 7

Dissolve 10.1 g of acetoacetamide in 1.35 ml of water and add 6.9 g of sodium nitrite under ice-cooling and add 25 ml of 4 N sulfuric acid at 0-5 ° C for 30 minutes with stirring. dropwise. After completion of the dropwise addition, the mixture was reacted for 30 minutes at the above temperature and adjusted to pH 6.0 with saturated aqueous sodium bicarbonate. The insoluble material is filtered off and the water is distilled off under reduced pressure. To the resulting residue was added ethyl acetate (20 mL) and the precipitated crystals were filtered off. 8.6 g (66.2% yield) of 2- (hydroxyimino) -3-oxobutyramide, m.p. 96-97'C.

IR spectrum (KBr) cm ^-1 : uc = O 1670;

MMR (d 6 -DMSO) δ value: 2.26 (3H, s, CH ₃ CO-), 7.46 (1H, broad s, -CONH ₂ ), 7.62 (1H, broad s, -CONN 2), 12.60 (1H, s, = N-OH).

2.20 g of 2- (hydroxyimino) -3-oxobutyramide and 3.6 g of anhydrous sodium carbonate are dissolved in 20 ml of water at 20 ° C. To the solution thus obtained is added 20-25 'Con (6.6 g) of dimethyl sulfate and the mixture is reacted at the above temperature for 2 hours. The precipitate formed is filtered off, 100 ml of methanol are added to the precipitate and the resulting mixture is stirred at 40-50 ° C for 30 minutes. The insoluble material is filtered off and the solvent is distilled off under reduced pressure. The crystals were filtered off to give 5.2 g (72.2% yield) of 2- (colorimethoxyimino) 3-oxobutyramide, m.p. 156-157 ° C.

IR spectrum (KBr) cm ^-1 : vc = O 1700.1670;

MMR (d 6 -DMSO) δ value: 2.26 (3H, s, CH 3 CO-), 3.96 (3H, s, -O-CH 3), 7.46 (1H, broad s, -CONH 2), 7.58 (1H, broad s, -CONH2).

3. A suspension of 7.2 g of 2-colorimethoxyimino-3-oxobutyramide in 36 ml of tetrahydrofuran is added, and 0.8 g of bromine is added with stirring at 40 ° C. When the bromine color disappeared, another 7.2 g of bromine was added at 25-30 ° C with stirring. The suspension was reacted at the above temperature for 1 hour and the solvent was distilled off under reduced pressure. To the resulting residue was added ethyl acetate (50 mL) and water (20 mL), and the pH was adjusted to 6.0 with saturated aqueous sodium bicarbonate. The organic layer was separated and washed with saturated aqueous sodium chloride solution (20 mL). The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. To the residue was added 20 ml of a mixture of diisopropylether-ethyl acetate (1: 1) and the crystals formed were filtered off. 9.2 g (82.1% yield) of 4-bromo-2- (colorimethoxyimino) -3-oxobutyramide, m.p.

IR spectrum (KBr) cm ^-1 : ν c = 0 1715.1660;

MMR (d 6 -DMSO) δ value: 4.02 (3H, s, -OCH 3), 4.58 (2H, s, BrCH ₂ CO-), 7.72 (2H, broad s-CONH ₂ ).

4. 4.5 g of 4-bromo-2- (colorimethoxyimino) -3-oxobutyramide are suspended in 13.5 ml of ethanol. To the suspension is added 1.5 g of thiobromamide and the resulting mixture is stirred at 20-30 ° C. for 1 hour. The precipitated crystals are filtered off, washed with ethanol and suspended in 25 ml of water. The resulting suspension is adjusted to pH 6.0 with saturated aqueous sodium bicarbonate. The crystals formed are filtered off and recrystallized from 15 ml of water-methanol (1: 1). so

2.9 g (71.8% yield) of 2- (2-aminothiazol-4-yl) -2- (colormethoxyimino) acetamide are obtained, m.p. 208-209 ° C.

IR spectrum (KBr) cm ^-1 : nc = 1665;

MMR (d 6 -DMSO) δ: 3.84 (3H, s, -OCH 3), 6.75 (1H, s, (c)), 7.26 (2H, broad s, -NH ₂ ). , 7.61 (1H, broad s, -CONH ₂ ), 7.91 (1H, broad s, -CONH ₂ ).

Example 2

In 43 ml of methanol containing 3.6 g of hydrochloric acid, 14.4 g of 2- (colorimethoxyimino) -3-oxobutyramide are suspended and the suspension thus obtained is suspended.

At the temperature of 30 ° C, 16.0 g of bromine are added dropwise over 1 hour. The suspension was reacted at this temperature for a further 30 minutes and then with ice-cooling (43 ml)

1,4-dioxane and 22 ml of water were added to the reaction mixture and the pH was adjusted to 3.0-4.0 with aqueous ammonia. Thiourea (7.6 g) was added and the mixture was reacted at 30 ° C for 2 hours while maintaining the pH between 3.0 and 5.0 with aqueous ammonia. The reaction mixture was then cooled to 5 ° C and the pH was adjusted to 6.5 with 10 aqueous ammonia. The crystals thus obtained are filtered off and washed with a mixture of water, 1,4-dioxane (1: 1). 18.5 g (64.2% of theory) of 2- (2-aminothiazol-4-yl) -2- (colormethoxyimino) acetamide-1,4-dioxane adduct are obtained, m.p. 196-198 “C.

IR spectrum (KBr) cm ^-1 :? C = O 1690;

MMR (d 6 -DMSO) δ value: 3.55 (8H, s, (d)), 3.83 (3H, s, -OCH 3), 6.70 (1H, s, (c)) , 7.16 (2H, broad s, -NH ₂ ), 7.48 (1H, broad 20 s, -CONH 2), 7.77 (1H, broad s, -CONH 2).

2. 14.4 g of 2- (2-aminothiazol-4-yl) -2- (colormethoxyimino) acetamide-1,4-dioxane adduct prepared in Part 1 in 18 ml water and 18 ml recrystallized from methanol solvent mixture. Yield: 8.6 g (86.0% yield) of 2- (2-aminothiazol-4-yl) -2- (colormethoxyimino) acetamide, m.p. 208-209 ° C. The physical characteristics (IR, NMR spectrum) of the product are identical to those of Example 1 Part 4.

3. 1 g of 2- (2-aminothiazol-4-yl) -2- (colormethoxyimmo) acetamide-1, prepared according to Part 1 above,

The 4-dioxane adduct was suspended at 40 ° C in 5 ml of methanol and the resulting suspension was stirred at the above temperature for 1 hour. The slurry was cooled to room temperature and the resulting crystals were filtered off. Yield: 2- (2-aminothiazol-4-yl) -2- (colormethoxyimino) -acamine 40 (89.2%), m.p. 223.5-225 ° C. The physical characteristic (NMR spectrum) of the product is the same as that of Example 1 Part 4.

Example 3 45

To a solvent mixture of 60 ml of sulfolane containing 30.6 g of boron trifluoride and 60 ml of anhydrous methylene dichloride was added 30.0 g of 2- (2-aminothiazol-4-yl) -2- (colormethoxyimino) acetamide. The mixture is reacted for 1 hour at room temperature and the crystals formed are filtered off. The crystals are suspended in 300 ml of ethyl acetate, the suspension is stirred for 1 hour and the crystals are filtered off, washed with 2 x 60 ml of ethyl acetate and dried. 42.3 g of crystalline product are obtained. 55

IR spectrum (KBr) cm ^-1 : 1680.1650.1620.12001000.

Reference Example 7 Dissolve 4.10 g of (pivaloyloo-60-xylmethyl) -7-amino-3 - [(5-methyl-1,2,3,4-tetrazol-2-yl) methyl in ml of ethyl acetate. ^3- cephem-4-carboxylate and 3.36 g of crystalline product prepared in Example 3 are added to the solution and the solution is reacted at room temperature for 3 hours. Water (41 mL) was then added to the reaction mixture and the pH was adjusted to 4.5 with sodium bicarbonate. The organic layer was separated, washed with water (20 mL) and dried over anhydrous magnesium sulfate. Then to the organic phase

2.4 g of mesitylene sulfonic acid dihydrate are added and the resulting mixture is reacted at room temperature for 1 hour. The crystals formed are filtered off and washed with 5 ml of ethyl acetate. Yield: 7.18 g (90.5%) of (pivaloyloxymethyl) -7- [2- (2-amino-thiazole-4U) -2- (colormethoxyimino) -acetamido] -3 - [( 5-methyl-1,2,3,4-tetrazol-2-yl) -methyl] -N- ^3- cephem-4-carboxylate mesitylene sulfonic acid salt, m.p. 218-220 ° C with decomposition.

IR (KBr) ^cm-1: uc = o 1782, 1745, 1680th

Reference Example 2

29.8 g of 7-amino-3 - [(5-methyl-1,2,3,4-tetrazol-2-yl) methyl] -A ³ -cephem-4-carbonate are suspended in 1.88,8 ml of acetone and the resulting suspension is At 5 ° C, 15.2 g of 8-diazabicyclo [5.4.0] -7-undecene are added dropwise and the mixture is reacted at 5-10 ° C for 30 minutes and then cooled to 0 ° C, 24.2 ° C. pivaloyloxymethyl iodide (g) was added and the mixture was reacted at 15-17 ° C for 20 minutes. Ethyl acetate (385 mL) was added dropwise to the reaction mixture over a period of about 5 minutes, then 2.37 g of pyridine was added and the mixture was stirred for 5 minutes. The insoluble material thus formed was filtered off and the filtrate was cooled to -5 ° C. To the cooled filtrate was added 33.6 g of crystalline product prepared according to Example 3, Part 1 and the resulting mixture was reacted at -5 to 0 for 1 hour.

2. Add the reaction mixture obtained in Part 1 to a solution prepared by adding 19.6 g of 85% phosphoric acid to 207 ml of water and adjusting the pH of the solution to 30% aqueous sodium hydroxide. solution is adjusted to 6.5. The resulting mixture was reacted at 25-27 ° C for 3 hours while maintaining it at pH 6.2-6.5 with 20% aqueous potassium carbonate. The pH is adjusted to 3.0 with hydrochloric acid, the insoluble material is filtered off, the organic phase is separated off and washed with 148 ml of water. To the resulting organic phase was added 21.3 g of cytosolic sulfonic acid dihydrate and the mixture was stirred at 20-22 ° C for 1 hour. The precipitated crystals were filtered off, washed with ethyl acetate (3 x 44 mL) and dried. 61.9 g (78.0% yield) of (pivaloyloxymethyl) -7- [2- (2-aminothiazol-4-yl) -2- (synmethoxy-imino) -acetamido] -3- [(5-Methyl-1,2,3,4-tetrazol-2-yl) methyl] -N-cephem-4-carboxylate mesitylene sulfonic acid salt is obtained, m.p. 218-220 ° C with decomposition.

IR spectrum (KBr) cm- ¹ : uc = o 1782, 1745, 1680.

Reference Example 3

The reaction mixture prepared in Reference Example 2, Part 1 was poured into a solution prepared by 19.6 g of 85% phosphoric acid and

88.8 g of sodium chloride are added to 266 ml of water and the pH is adjusted to 5.3 with 30% aqueous sodium hydroxide solution. The resulting mixture was reacted at 25-27 ° C for 3 hours while 20%

Keep the pH at 4.8-5.0 with potassium carbonate aqueous solution. The pH is then adjusted to 3.0 with hydrochloric acid, the insoluble material is filtered off, the organic phase is separated off and washed with 148 ml of water. To the resulting organic phase was added 21.3 g of mesitylene sulfonic acid dihydrate and the mixture was stirred at 20-22 ° C for 1 hour. The precipitated crystals were filtered off, washed with ethyl acetate (3 x 44 mL) and dried. Yield: 61.9 g (78.0%) of (pivaloyloxymethyl) -7- [2- (2-amino-thiazol-4-yl) -2- (colormethoxy-amino) -acetamide] -3 - [( 5-methyl-2,3,4-tetrazol-2-yl) methyl] -N-cephem-4-carboxylated mesitylene sulfonic acid salt, m.p. 220 DEG C. with decomposition.

IR spectrum (KBr) cm ^-1 : ν c = O 1782, 1745, 1680.

Claims (1)

A process for the preparation of a color isomeric compound of formula II, wherein R ^{1 is a C} 1 -C 5 alkyl group, characterized in that a compound of formula IV is a compound of formula IV wherein X is halogen and R ¹ is as defined above - in the presence of solvent (iokarbamiddai reacted. Process according to claim 1, characterized in that the reaction is carried out at 0-100 ° C.