CS247197B2 - Method of new intermediate product production for cephalosporines - Google Patents

Abstract

The solution relates to the production of a new intermediate for cephalosporins that are highly effective bactericidal agent. This intermediate corresponding to the general formula II wherein R 1 is C 1-5 alkyl, is produced by reacting a compound of the general formula of Formula IV wherein X represents a halogen atom and R has as defined above, with thiourea in the presence of a solvent.

Description

The invention relates to a process for the preparation of a novel intermediate for cephalosporins.

The present inventors have previously found that cephalosporin (syn-isomer) corresponding to the general formula Ia.

-C-CONHOR ^{1 X} CH ₂ R 3

COOR ² (I) / isomer syn / wherein R is C | _ ₅ alkyl group, R is hydrogen or C ₁ _ ₅ alkyl, diphenylmethyl, phthalidyl, 1'-pivaloyloxybenzylová or C ₁ _ ₇ acyloxy C ₁ _ ₅ alkyl and R ¹ is 2- / 1,2,3,4 -tetrazolyl / 1- / 1,2,4-triazolyl / 2-3-dioxo-2,3,4-tetrahydropyrazinylová 3 , 6-dioxo-1,2,3,6-tetrahydropyridazinyl, 6-oxo-1,6-dihydropyridazinyl, 2-oxo-1,2-dihydropyridazinyl, 6-oxo-1,6-dihydropyrimidinyl, 2-oxo-1 , 2-dihydropyrimidinyl, 1,2,6-thiadiazin-1,1-dioxide-2-yl or isothiazolidin-1,1-dioxide-2-yl, which may be substituted by at least one halogen atom and / or at least one C ^ _ ₃₄ alkyl or C ₃ _ ₃ alkylthio, wherein said heterocyclic groups are attached to the exo-methylene group in the 3-position of the cephem ring by a carbon-nitrogen, or a salt thereof are very useful as an antibacterial agent and asked for it for patent protection (Japanese published přih Kokai (Nos. 99 592/82 and 93 085/84).

Since then, these authors have carried out extensive research into the production of cephalosporin corresponding to formula I or a salt thereof. As a result of this research, they have found that the beneficial cephalosporin (syn-isomer) corresponding to formula I or a salt thereof can be easily obtained in high yield by reacting the compound (syn-isomer) corresponding to formula II

H ₂ N

-C-CONH,

II ²

N / ^X OR ¹ (II) (syn-isomer) wherein R is a C 1-4 alkyl group, with a compound corresponding to formula III

(III) wherein R ^is C ₃ _ ^ alkyl, diphenylmethyl, phthalidyl, 1'- or pivaloyloxybenzylová

C ^ _ ^ acyloxy-C ₃ _ ^ alkyl and 2- / 1,2,3,4-tetrazolyl / 1- / 1,2,4-triazolyl /,

2,3-dioxo-1,2,3,4-tetrahydropyrazinyl, 3,6-dioxo-1,2,3,6-tetrahydropyridazinyl,

6-oxo-1,6-dihydropyridazinyl, 2-oxo-1,2-dihydropyridazinyl, 6-oxo-1,6-dihydropyrimidinyl, 2-oxo-1,2-dihydropyrimidinyl, 1,2,6-thiadiazine-1 l-dioxide-2-yl or isothiazolidine-1, l-dioxide 2-yl group which may be substituted by at least one halogen atom and / or at least one C ^^^^ alkyl or C ₃ _ ^ alkylthio, said heterocyclic groups are attached to the exomethylene group at the 3-position of the cephem ring by a carbon-nitrogen bond, in the presence of boron trifluoride or a complex thereof, and then optionally removing the carboxyl protecting group or converting the product to a salt as described in Czechoslovak Patent No. 247,185 .

And although the compound of formula III obtained in the process for producing the compound of formula III is used as a starting material without prior isolation, using the following method achieves the same good result as using the isolated compound of formula III as starting material:

The compound (syn-isomer) corresponding to the general formula II c-conh ₂ (II), h ₂ n ¹ OR ¹ (syn-isomer) in which R 1 is as defined above, is reacted with boron trifluoride or a complex thereof and thus the obtained compound is reacted with a compound corresponding to the general formula III at -50 ° C to 0 ° C in the above organic solvent to give an intermediate (first reaction step)

/ ture / wherein R \ R ^{^, and} _{m and} j. £ _with mountains as above, and then the reaction mixture was further reacted at 0 ° C to 50 ° C at pH 4.5 to 6.7 in a mixed solvent consisting from water and an organic solvent (second reaction step) to prepare cephalosporin corresponding to formula I or a salt thereof in high yield and high purity.

Thus, even when an unisolated compound of formula (III) is used as a starting material, the above method allows the decomposition of the intermediate to be prevented and therefore fulfills the purpose of the invention described in Czechoslovak patent No. 247 185.

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

Other objects and advantages of the invention will become apparent from the following description.

The invention will be explained in detail below.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of a novel intermediate of formula (II) for the production of beneficial cephalosporin h ₂ n c-conh ₂

N r (II)

OR ¹ in which R ¹ is a C 1 -C 4 alkyl group consisting of reacting a compound of formula IV xch ₂ coc-conh ₂

N (IV) (syn-isomer) wherein X represents a halogen atom and has the above meaning, in the presence of a thiourea solvent.

The invention will be explained in detail below.

Unless otherwise indicated, the term C 1-4 alkyl refers to a straight or branched C 1-4 alkyl group, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl, pentyl, hexyl, heptyl, octyl, dodecyl or the like The term C 1-6 alkyl refers to, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or the like. The term aryl "denotes, for example, phenyl, tolyl, naphthyl, indanyl or the like. The term ar-C 1-4 alkyl denotes, for example, benzyl, phenethyl, 4-methylbenzyl, naphthylmethyl or the like. The term C 1-4 acyl denotes a C 1-4 acyl group, for example formyl, acetyl, propionyl, n-butyryl, isobutyryl, valeryl, pivaloyl, pentanecarbonyl, cyclohexanecarbonyl or the like, and the term halogen means fluoro, chloro, bromo, iodine or the like. A heterocyclic group includes especially 5 or 6-membered nitrogen-containing heterocyclic groups such as pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl and the like.

Salts of cephalosporin corresponding to formula I include salts on basic groups and on acid groups, which are well known in the art of penicillin and cephalosporin. Salts on basic groups include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and the like, salts with organic carboxylic acids such as oxalic acid, succinic acid, formic acid, trichloroacetic acid, trifluoroacetic acid and the like salts with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluene-2-sulfonic acid, toluene-4-sulfonic acid, mesitylenesulfonic acid (2,4,6-trimethylbenzenesulfonic acid) and the like. Salts on acidic groups include, for example. alkali metal salts such as sodium, potassium, etc. alkaline earth metal salts such as calcium, magnesium, etc., ammonium salts and salts with organic bases containing nitrogen such as triethylamine, trimethylamine, aniline, Ν, dim-dimethylaniline, pyridine, dicyclohexyl amine, etc.

In the following, exemplary embodiments of the method of the invention will be described.

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

The reaction is usually carried out in a solvent. Any solvent can be used as long as this does not adversely affect the reaction, for example, 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-oC-pyridone and the like. Mixtures of two or more of these solvents may also be used.

The reaction sometimes proceeds smoothly when an acid binding agent is added, for example inorganic or organic bases such as alkali metal hydroxides, alkali metal bicarbonates, triethylamine, pyridine, Ν, dim-dimethylaniline and the like.

The reaction usually proceeds to completion at 0 ° C to 100 ° C in 1 to 48 hours, most often 1 to 10 hours.

The thioureas may be used in a ratio of one to several moles per mole of the compound of formula IV.

As described above, the syn-isomer of the compound of formula II can be selectively obtained in high yield at low cost.

The invention includes all solvates, addition compounds, crystalline forms and hydrates of the compound of Formula II.

The compound of formula (IV) may be prepared, for example, according to the manufacturing process illustrated below.

Manufacturing process

CH ₃ COCH ₂ CONH ₂ liters nitrosation

CH _o C0-C0NH ₉ ³ · ² N

AND

OH alkylation (V) (VI)

CH 2 COC-CO 2 - CH-COC-CONH - (VII) (syn-isomer) (VIII) (syn-isomer) halogenation xch ₂ coc-conh ₂ (IV) · (syn-isomer)

OR wherein R ¹ and X are as defined above, Z is a halogen atom or a group corresponding to the formula -OR 2 or -SR 2 wherein R 1 is hydrogen or C 1-6 alkyl, aryl, ar-C 1-6 alkyl or heterocyclic the group (s) indicates that the compound may be a syn- or anti-isomer or a mixture thereof.

(1) Production of a compound of formula VI

The nitroso compound of formula VI can be obtained by reacting a compound of formula V with a nitrosating agent.

The reaction is usually carried out in a solvent. Reaction-inert solvents such as water, acetic acid, benzene, methanol, ethanol, tetrahydrofuran and the like can be used. Mixtures of two or more of these solvents may also be used.

Preferred nitrosating agents for this reaction are nitric acid and derivatives thereof, for example trosyl halides such as nitrosyl chloride, nitrosyl bromide and the like, alkali metal nitrites such as sodium nitrite, potassium nitrite and the like, and alkyl nitrites such as butyl nitrite, pentyl nitrite and the like. When an 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 and the like.

When alkyl nitrite is used as the nitrosating agent, it is preferred to carry out the reaction in the presence of a strong base such as an alkali metal alkoxide.

This reaction is complete at 0 ° C to 30 ° C in 10 minutes to 10 hours.

(2) Preparation of a compound of formula VII

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

This reaction can be carried out by a conventional method. Usually, it is complete at -20 ° C to 60 ° C in 5 minutes to 10 hours.

Any solvent can be used as long as this does not adversely affect the reaction, 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, etc. Mixtures of two or more of these solvents may also be used.

As the alkylating agent, for example, lower alkyl halides such as methyl bromide, ethyl iodide, ethyl bromide and the like, dimethyl sulfate, diazomethane, diazoethane, methyl p-toluenesulfonate and the like can be used in this reaction. When an alkylating agent other than diazomethane or diazoethane is used in the reaction, it is preferable to carry out the reaction in the presence of an inorganic or organic base, for example an alkali metal carbonate such as sodium carbonate, potassium carbonate or the like, an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or similarly, triethylamine, pyridine, N, N-dimethylaniline or the like.

A compound corresponding to formula VII can also be obtained by subjecting a compound of formula VIII to a known amidation reaction using ammonia or a primary amine.

(3) Production of a compound of formula IV

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

The reaction is usually carried out in a solvent. Solvents are used 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, etc. use mixtures of two or more of these solvents.

The reaction is usually completed at 0 ° C to 50 ° C in 30 minutes to 24 hours.

As halogenating agent, for example, halogens such as bromine, chlorine and the like, sulfuryl halides such as sulfuryl chloride and the like, 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 pyridium hydrobromide perbromide, 2-carboxyethyltriphenylphosphonium perbromide and the like, etc.

The invention will be illustrated by the following non-limiting examples.

Ί

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

After removal of the undissolved residue, water was removed by distillation under reduced pressure.

20 ml of ethyl acetate were added to the residue, and the crystals thus obtained were filtered off to give 8.6 g (yield 66.2%) of 2-hydroxyimino-3-oxobutyramide, m.p. 96-97 ° C.

iC / KBr / cm ^-1 = V _c _ ₀ 1670

NMR (dg-DMSO) cf value:

2.26 (3H, s, CH ₃ CO-),

7.46 (1H, bs, -CON), ( ^H)

7.62 (1H, bs, -CON),

H

12.60 (1H, s, «-ΟΗ) (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. Then, the resulting solution was added at 20 ° C to 25 ° C

6.6 g of dimethyl sulfate and the resulting mixture was reacted at the same temperature for 2 hours.

The precipitate thus formed was filtered off and 100 ml of methanol were added thereto, followed by stirring at 40 ° C to 50 ° C for 30 minutes. After the insoluble residue was removed, the solvent was removed by distillation under reduced pressure. 20 ml of ethanol were added to the residue, and the crystals formed were filtered off. Thus 5.2 g (yield 72.2%) of 2- (syn) methoxyimino-3-oxobutyramide of melting point 156 DEG-157 DEG C. were obtained.

iC / KBr / cm ^-1: _C 9 _ _Q 1700, 1670

NMR (d, -DMSO) cf value:

O

2.26 / 3H, s, Target CO- /, 3.96 / 3H, s, -OCH ₃ /, 7.46 / 1H, bs , -CON / ^H /, 7.58 / 1H, bs , -CON H /

(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 while stirring at 40 ° C. After disappearance of the color due to bromine, an additional 7.2 g of bromine was added to the suspension at 25 ° C to 30 ° C with stirring. The suspension was allowed to react for 1 hour at the same temperature, after which the solvent was removed by distillation under reduced pressure. 50 ml of ethyl acetate and 20 ml of water were added to the obtained residue, and the pH was then adjusted to 6.0 with saturated aqueous sodium bicarbonate solution. The organic layer was separated and washed with 20 mL of saturated aqueous sodium chloride solution. Then, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure.

To the residue thus obtained was added 20 ml of a 1: 1 diisopropyl ether-ethyl acetate solvent mixture and the crystals formed were filtered off. 9.2 g (yield 82.1%) of 4-bromo-2- (syn) -methoxyimino-3-oxobutyramide, m.p. 112 DEG-113 DEG C. were obtained.

IR / KBr / cm ^-1 : 1715, 1660 • (J

NMR (.gamma.-DMSO) < f value:

4.02 (3H, s, -OCH ₃ ),

4.58 (2H, s, BrCH ₂ CO-),

7.72 (2H, bs, -CONH ₂₎ / (4) 4.5 g of 4-bromo-2- (syn) -methoxyimino-3-oxobutyramide was suspended in 13.5 ml of ethanol. To the suspension was added 1.5 g. thiourea and the resulting mixture was allowed to react at 20 ° C to 30 ° C for 1 hour. The precipitated crystals were filtered off, washed with ethanol and then suspended in 25 ml of water. The resulting suspension was adjusted to pH 6.0 with saturated aqueous sodium bicarbonate. The crystals thus formed were filtered off and recrystallized from 15 ml of a water-methanol (1: 1) solvent mixture. 2.9 g (71.8%) of 2- (2-aminothiazol-4-yl) -2- [syn] methoxyiminoacetamide, m.p. 208 DEG-209 DEG C., were thus obtained.

IR (KBr / cm &lt; ⁴ &gt;): Vu ₌ q 1665

NMR (d6-DMSO):

3.84 (3H, s, -OCH ₃ ),

N - n 6.75 (1H, s, II),

S H

7.26 / 2H, bs,

7.61 / 1H, bs,

-nh ₂ /,

-CON

7.91 / 1H, bs, -CONH

Example (1) 14.4 g of 2- (syn) -methoxyimino-3-oxobutyramide were suspended in 43 ml of methanol containing 3.6 g of hydrogen chloride. To the resulting suspension was added dropwise 16.0 g of bromine over 1 hour at 30 ° C. The suspension was allowed to react at the same temperature for an additional 30 minutes, and then 22 ml of water was added to the reaction mixture with ice-cooling, and the pH was adjusted to 3.0-4.0 with aqueous ammonia. Then the mixture was added

7.6 g of thiourea and the mixture was allowed to react for 2 hours at 30 ° C while maintaining the pH of the aqueous ammonia solution between 3.0 and 5.0. The reaction mixture was then cooled to 5 ° C and adjusted to pH 6.5 with aqueous ammonia. The crystals thus formed were filtered off and washed with a water-1,4-dioxane (1: 1) solvent mixture. Thus 18.5 g (yield 64.2%) of the addition compound 2- (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetamide with 1,4-dioxane, melting at 196-198 ° C, were obtained.

IR / KBr / cm

V _{c = 0} 1,690

NMR (d6-DMSO):

H \ \ OF H / - 3.55 / 8H, S, b 5 - H —H 3.83 / 3H, s, -OCH ₃ /, 6.70 / 1H, WITH, “T / with H 7.16 / 2H, bs, -NH ₂ /, 7.48 / 1H, bs, -CO1T /, 7.77 / 1H, bs, -CON ^ /,

(2) 14.4 g of the addition compound 2- (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetaraid with 1,4-dioxane obtained above from (1) were recrystallized from a solvent mixture 18 ml of water and 18 ml of methanol. 8.6 g (yield 86.0%) of 2- (2-aminothiazol-4-yl) -2- [syn] methoxyiminoacetamide, m.p. 208 DEG-209 DEG C., were thus obtained.

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

(3) 1 g of the addition compound 2- (2-aminothiazol-4-yl) -2- [syn] methoxyiminoacetamide with 1,4-dioxane obtained above from (1) was suspended at 40 ° C in 5 ml. of methanol. The resulting suspension was stirred at the same temperature for 1 hour. Then the suspension was cooled to room temperature and the precipitated crystals were filtered off. There was thus obtained 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamide, m.p. 223.5-225 ° C (yield 89.2%).

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

Example 3

To a solvent mixture 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-yl) -2- (syn) -methoxyiminoacetamide. The mixture was allowed to react for 1 hour at room temperature and the precipitated crystals were filtered off. The crystals were then suspended in 300 ml of ethyl acetate. The resulting suspension was stirred for 1 hour and the crystals were filtered again. They were washed with two portions of 60 ml of ethyl acetate and then dried. 42.3 crystals were obtained.

IR (KBr / cm &^lt; -1 &gt;): 1,680, 1,650, 1,620, 1,200 to 1,000

Reference Example 1

4.10 g of pivaloyloxymethyl-4- 7-amino-3- (5-methyl-1,2,3,4-tetrazol-2-yl) -methyl-N-cephem-4-carboxylate were dissolved in 41 ml of ethyl acetate. ^. 3.36 g of the crystals obtained above in Example 3 were added to the solution, and the solution was allowed to react at room temperature for 3 hours.

t

Then 41 ml of water was added to the reaction mixture and the pH was adjusted to 4.5 with sodium bicarbonate. The organic layer was separated, washed with 20 mL of water and dried over anhydrous magnesium sulfate. Then, 2.4 g of mesitylenesulfonic acid dihydrate was added to the organic layer and the resulting mixture was allowed to react for 1 hour at room temperature. The precipitated crystals were filtered off, washed with 5 ml of ethyl acetate and 7.18 g (yield 90.5%) of pivaloyloxymethyl- {7- [2- / 2-aminothiazol-4-yl] -2- [syn] methoxymethoxyacetamido] salt were obtained. -3- (5-methyl-1,2,3,4-tetrazol-2-yl) methyl- ³ -cephem-4-carboxylate | m.p. 218-220 ° C (dec.).

iC / KBr / cm ^-1 : 1782, 1745, 1680

In C — U

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- ^3- cephem- 4-carboxylic acids. To the resulting suspension was added 15.2 g of 1,8-diazabicyclo [5.4.0] -7-undecene at 5 ° C, dropwise. The reaction mixture was allowed to react at 5 ° C to 10 ° C for 30 minutes, then cooled to 0 ° C and 24.2 g of pivaloyloxymethyl iodide was added thereto, followed by reaction at 15 ° C to 17 minutes for 20 minutes. Deň: 32 ° C. Thereafter, 385 ml of ethyl acetate was added dropwise to the reaction mixture over 5 minutes, and finally 2.37 pyridine was added. The resulting mixture was stirred for 5 minutes. After the precipitate formed was filtered off, 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 ° C to 0 ° C for 1 hour.

(2) The reaction mixture obtained from above (1) was introduced into a solution which was prepared by adding 19.6 g of 85% by weight phosphoric acid to 207 ml of water and adjusting to pH 6 with 30% aqueous sodium hydroxide solution, 5. The resulting mixture was allowed to react for 3 hours at 25 ° C while maintaining the pH with a 20% aqueous potassium carbonate solution in the range of 6.2 to 6.5. The pH was adjusted to 3.0 with hydrochloric acid and the insoluble matter was filtered off, 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 ° C to 22 ° C for 1 hour. The crystals thus precipitated were filtered off, washed with three 44 ml portions of ethyl acetate and then dried. 61.9 g (78% yield) of pivaloyloxymethyl {7- [2- (2-aminothiazol-4-yl) -2- [syn] methoxyiminoacetamido] -3- (5-methyl-1,2,3) salt were thus obtained. 4-Tetrazol-2-yl (methyl- ^{3 3} -cephem-4-carboxylate) with mesitylenesulfonic acid, m.p. 218-220 ° C (dec.).

iC / KBr / cm ^-1 : V1 782, 1745, 1680

Claims (2)

1. A process for preparing the novel intermediate for the cephalosporins of the formula II / 11 / / syn-isomer / wherein R ¹ is C ₁ _ ₅ alkyl group, characterized by reacting a compound of formula IV XCH, COC-CONH II XV / XV / OR wherein X is halogen and R ¹ is as defined above, with thiourea in the presence of a solvent. 2. 3. The process of claim 1 wherein the reaction is carried out at a temperature 0 ° C to