CA1197251A - Process for producing 2-(2-aminothiazol-4- yl)glyoxylic acid derivative or a salt thereof, and intermediates therefor and process for producing the intermediates - Google Patents

Abstract

Abstract for Divisional Application I

ABSTRACT OF THE DISCLOSURE
This invention relates to a process for producing a novel compound represented by the following formula or a salt thereof which are useful intermediate for 2-(2-aminothiazol-4-yl)glyoxylic acid derivative or a salt thereof,

Description

~3L917Z5~
This invention relates -to intermediates in a process for produciny d 2-(2-aminothiazol-4-yl)glyoxylic acid deri-va-tive or a salt thereo-f, ancl a process for producing the intermediates.

This app1ication is a divisional application of co-pending application No. 430,079 filed June 9, 1983.

2-(2-Amlnothiazol-4-yl)glyoxylic acid derivative represented by the general Formula or salts thereof:
N C - C - OH (I) R ~ ~ o O
wherein pl is an amino group which may be protected, are use-ful starting materials for producing various cephalosporin antibiotics, and as processes for producing said starting compounds, there have hereto-Fore been known (1) a process by which an es-ter of 2-[2-(protected or unprotected)amino-thiazol-4-yl] ace-tic acid is oxidized with selenium dioxide or potassium permanganate (Japanese Patent Applica-tion Kokai (Laid-Open) No. 125,190/77 or 5,193~78) and (2) a process by which an ester oF acetyl~lyoxylic acid is halogenated, -the resulting halogena-tion product is reacted with thiourea, and then the reac-tion product is hydrolyzed (Japanese Pa-tent ~pplications Kokai (Laid-Open) Nos. 112,895/78and 154,785/79).

Under such circurns-tances, in orcler to ~ind a novel process for proclucing a compound represen-tecl by the ~eneral Formula (I) or a salt thereof, the present inventors have conducted extensive research. ~s a result, they have Found a novel production process, which is describe(l hereinafter, and moreover a novel intermediate used in said production process and a process for proclucing the same.

In copending application No. ~30,079 there is pro-vided a novel process for producing a 2-(2-aminothiazol-~-yl)-glyoxylic acid derivative represented by the general Formula (I) or a salt thereof.

The present invention provides a novel intermediate for use in saicl procluction process, a compound represented by the general formula (VIII) or a salt thereoF, which are hereinaf-ter described.
1~
The present invention provides a process for pro-ducing the intermediate.

This invention will be explained below in de-tail.
The invention oF the copending applica-tion relates to a novel process for producing 2-(2~minothia~o~ -yl) glyoxylic acid derivative represen-ted by the general formula (I) or a salt thereo-f through the -Following produc-tion route:

z~

Dialkyl sulfoxide or diaralkyl sulfoxide 2 2 ~ , , ~
R S O oxidation S O O
(II) (III) or a sal-t thereof or a sal-t thereof Hydrolysis ~j 1~ ~J 11 11 R S O O

(.I) or a salt thereof 1 wherein Rl is as defined above; Xl is a halogen atom; and R2 is an alkyl group or an aralkyl group.
Protec-ting groups for the amino group of R
include all qroups which can usually be used as amino-prokecting groups, and -there may be speciEically used, or exarnple, easily removable acyl groups such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyl-oxycarbonyl, p-toluenesul~onyl, p-nitrobenzyloxyca.rbonyl, o-bromobenzyloxycarbonyl, (mono-, di-, tri-)chlo.roacetyl, trifluoroacetyl, ~ormy:l, tert.-amyloxycarbonyl, -ter-t.-butoxycarbonyl, p-methoxybenzyloxycarbonyl, 3,~-methoxy-ben~yloxycarbonyl, 4-~phenylazo)benzyloxycarbonyl, 4-~4-metlloxyphellylazo)benzyloxycarbonyl, (pyridine-l-oxide-2-yl)methoxycarbonyl, 2-furyloxycarbonyl, ~L1972~
1 di.phenylmethoxycarbonyl, l,l-dime-thylpropoxycarbonyl, isopropoxycarbonyl, l-cyclopropylethoxycarbonyl, phthaloyl, succinyl, l-adamantyloxycarbonyl, 8-quinolyloxycarbonyl and the like. Further, there may be used other easily removable groups such as trityl, o-nitro-phenylsulfenyl, 2,4-dinitrophenylsulfenyl, 2-hydroxy-benzylidene, 2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naph-thylme~hylene, 3-hydroxy-4-pyridylmethylene, 1-methoxycarbonyl-2-propylidene, 1-ethoxycarbonyl-2-propylidene, 3-e-thoxycarbonyl-2-bu-tylidene, 1-acetyl-2-propylidene, l-benzoyl-2-propylidene, 1-[N-(2-methoxy-phenyl)carbamoyl]-2-propylidene, 1-[N-(4-methoxyphenyl)-carbamoyl]-2-propylidene, 2-ethoxycarbonylcyclo-hexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene, 3,3-dime-thyl-5-oxocyclo-hexylidene, (di-, -tri-)alkylsilyl groups and -the like.

As the halogen atom for Xl, there may be used, Eor example, a ~luorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
As the alky.L group Eor R2, there may be used, for e~ample, lower alkyl groups such as methyl, ethyl, n-propyl and the like, and as the aralkyl group for R , -there may be used, Eor example, ar-lower-alkyl groups such as a benzyl group ancl the l.ike.
The salt of the compound represented by the general formula (I) includes sal-ts a-t the amino group or _ L~

s~
1 salts at the carboxyl group. ~s the salts at the amino group, there may be used, for example, sal-ts with a mineral acid such as hydrochloric acld, hyclrobromic acid, hydrofluoric acid, sulfuric acld or the like;
salts with an oryanic carboxylic acid such as oxalic acid, formic acid, trichloroacetic acid, trifluoroacetic acid or the like; or salts with a sul~onic acid suc~ as methanesulfonic acid, p-toluenesulfonic acid, 1- or 2-naphthalenesulfonic acid or the like. As the salts at the carboxyl group, there may be used, for example, salts with an alkali metal atom such as sodium, po-tas-sium or the like or salts with an alkaline earth metal atom such as calcium, magnesium or the like.
The term "sal-t o~ the compound represen-ted by the general formulas (II) or (III)" means a sal-t at -the amino group in the formula (II) or (III), and includes speciEically -the same salts as -those mentioned as the salts at -the amino group of the compound represen-ted by the general Eormula (I).
The reac-tion for obtainin~ a compound represented by the general Eormula (III) or a salt -thereo:E from a compound represented by the general Eormula (II) or a salt tllereof is eEEected by reacting the compound represented by the general Eormula (I:t) or the salt thereoE with a dialkyl sul.Eoxide such as dimethyl sulEo~ide, dietllyl sul~Eoxide, di-n-propyl suloxide or -the li]ce or with a di.aral~cyl sulEoxide such as dibenzyl sulE-7ZS~

1 oYide or -the like in a solvent iner-t to -the reaction, for example, an alcohol SUCil as methanol, ethanol, isopropanol or the like, an ether such as tetrahydrofuran, dio~ane or the like, an amide such as N,N-dimethyl~ormamide, N,N-S dimethylacetamide, hexamethyl phosphoramide or the like, ora mixed solvent thereof. The dialkyl sulfoxide or the diaralkyl sulfoxide is preferably used in an amoun-t of 2.0 moles or more, more preferably 3.0 to 4.0 moles, per mole o the compound represented by the yeneral formula (II) or the sal-t thereof, and, if necessary, it may be used as a solvent. When using a compound represen-ted by the general formula ~II1 in which Xl is a chlorine atom, or a salt thereof, it is preferable to eEfect the reaction in the presence of a bromide such as hydrocJen bromide, po-tassium bromide, ammonium bromide, triethylammonium bromide or -the like, and the amo-mt of the bromide used in this reaction is pre~erably 0.5 mole or more, more preferably 0.5 to 1.0 mole, per mole o~ the compound represented by the general formula (II) or the salt -thereof. The reac-tion is completed usually in 5 minutes to 20 hours at a reac-tion temperature of 10 to 80~C. The reaction is accelerated by adding a dialkyl sulEide such as d:imethyl sulfide, diethyl sul~ide or the like, a cliallcyl disul.Eide such as dimetllyl disulEide, diethyl disulEide or the like, a cliaralkyl sul~.ide such as dibenzyl sul~ide or the like, a diaralkyl dis~ ide such as dibenzyl disulEide or -the like, an alkyl mercaptan such as methyl mercaptan, e-thyl mercaptan or the like, or an aralkyl mercap-tan such as benzyl 1 mercaptan or the like in an amount of 1.0 mole or more per mole oE the compound represented by -the general formula (II) or the salt thereof.
By subjecting to usual hydrolysis the thus obtained compound represented by the general formula (III) or a salt thereof, it can be convexted into a compound represen-ted by the general formula (I) or a sal-t thereof which are useful in producing a cephalosporin compound.
The hydrolysis in this case is effected in water or an alcohol such as me-thanol, ethanol or the like, preferably in the presence of a base. As the bases, there may be used, for example, inorganic bases such as sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate and the like, or organic bases such as trie-thylamine, pyridine and the like. These bases are used in an amount of 2.0 moles or more per mole of the compound represented by the general formula (III) or the salt thereof.
The compoundsrrepresented by the general Eormulas (I), (II) and (I:~I) or salts thereoE ~orm adducts with varlous solvents.

~ compound represented by -the ~eneral Eormula (II) or a sal-t ~hereoE can b~ procluced in the following manner:

~7Z5~

llll Halogena- 00 Halogena~
CE~3CCCH3 >- XlCH2CCCH3 ~- X C112CCCH2X a (IV) (V) (VIaJ

Ring closure ~ (VII) R ~ ~ o (II) or a salt thereoE

1 whe.rein Xl and X2a, which may be the same or different, are halogen atoms, and Rl is as defined above.
X2a in the general Eormula lVIa) represents a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or the like.
The halogena-tion or obtaining a l-halogeno-butane-2,3-dione represented by the general ormula (V) ~rom.butane-2,3-cl.ione representecl by the formula ~IV~ ancl the halogenatiorl ~or obtaining a 1,~ d.ihalogenobutane-2,3-dione represented by the gerlera:l formula (VIa) Erom a l-halo~enobutalle-2,3-dione representecl by the general :Eormula (V) are effected under -t.he same conditions. For example, they are eEEected in the absence of a solven-t or in the presence of a solvent 7ZS~
1 iner-t to the reacti.ons, e.g., an aromatic hydrocarbon such as benzene, toluene, xylene or the like, an etller such as diethyl ether, diisopropyl e.tller, tetrahydrofuran, dioxarle or the li]ce, a halogena-ted hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane or the like, a carboxylic acid such as acetic acid or the like, or a mixed solven-t -thereo~.
As the halogenating agent, there may be used a halogenatlng agent which is usually employed for halogenating a paraffin. For example, as chlorinating agents, there may be used chlorine, suluryl chloride, N-chlorosuccinimide, N~chlorophthalimide and the like, and as brominating agents, there may be used bromine, sulEuryl bromide, N-bromosuccinimide, N-bromophthalimide and the like. The amount of the halogenating agent used is preferably about equimolar -to -the compound represented by the formula (IV) or the general Eorlnula ~V). Although the reaction condi-tions may vary depending on -the kinds o~ halognnating agents to be used and ~0 the like, reaction is usuall~ eEfected at a temperature oE
10C to the reElux tempera-ture o~ the solvent for a periocl oE 30 minutes to 10 hours.
When a compound of the general :Eormula (V~a) in whicll Xl and X2a a.re the same haloyen atollls ls produced, dihalocJerlation may be e.~Eected in one step b~ di.rectly reacting a halogenating agent with a compound represented by the ~ormula (IV), in an amount oE about 2 moles per mole of said compound.

~L9372S~
1 The reaction conditions in this case are the same as mentioned above.
Preferable halogena~ions are reac-tions in which the compound represented by the formu].a (IV) is first chlorinated with sulfuryl chloride to obtain a compound represented by -the general formula (V) wherein Xl is a chlorine atom~ which is then brominated with bromine to ob-tain a compound represented by the general formula ~VIa) wherein X2a is a bromine a-tom.
Subsequen-tly, in order to obtain a compound repre-sented by the general formula (II) or a salt thereof by reactin~ a 1,4~dihalogenobutane-2,3-dione, Eor instance, l-bromo-4-chlorobu-tane-2,3-dione with a thiourea represent-ed by the general formula (VII), -the reaction is effected in the presence of a solvent inert to the reaction, Eor example, an alcohol such as methanol, ethanol, isopropanol or the like, an ether such as tetrahydrofuran, dioxane or the like, an amide such as N,N-dimethylEormamide, N,N-dimethylacetamide, hexamethyl phosphoramide or the like, or a mixed solvent thereo:E or a mixed solvent oE one or more of them and water. The amount of the -thiourea of the general Eormula ~VII) used may be 0.90 mole or more per mole oE the compound o~ tlle general formula (VIa), and is particularly pre.Eerabl~ 0.95 to 1.00 mole per mole oF said compound. This rin~ closure reaction is completed usually in 5 minutes to 20 hours at a reaction temperature oF -50 to 10C.
In copending application No.~f75,3~filed on even date there is provided herewlth - 10 _ ~7%5~

1 a compound represen-ted by the general formula (VI) and the present in-vention provicles a compound of the general Formula (VIII) shown below or a salt o-f the compound of the general Formula (VIII), s~id compound or salt being a novel and useful intermediate, and to a process for producing the same: a 1,4-dihalogenobutane-2,3-dione represented by the general formula:

~ 2 X CH2CCCH2X (VI) wherein Xl and x2 represent different halogen atoms, a 2-aminothiazole deriva-tive represented by the general Eormula or a salt thereof:

Rl~ ~ ~ (VIII) wherein Rl is as defined above and R3 is a mono-halogenomethyl, an alkylthiocarbonyl or an aralkylthio-carbonyl group.
The compounds represented by ~he general formulas (VI) and ~VIII) and salts o the compounds oE the general formula (VIII) are obtained by the process described above.
The compound represented by the general ~orMula (VIII) or the salt thereof includes the above-mentioned compounds represented by the general Eormulas (II) and (III) o.r salts thereo:E.
As the monohalogenollle-thyl group in R3, -there may be used, Eor example, a chloromethyl group, s~
1 a bromomethyl group, an iodomethyl group and the like;
as the alky].thiocarbonyl group, there may be used, for example, a me-thyl-thiocarbonyl yroup, an ethylthio--carbonyl group, a n-propylthiocarbonyl group and the like; and as the aralkylthiocarbonyl group, t.here may be used, for e~ample, a benzylthiocarbonyl group and the like.
Among the compounds of -the general formula (VIII), particularly preferable are compounds in which 10 R is an amino yroup or a formylamino group and R is a chloromethyl group or a methylthiocarbonyl group.
With respect to the N ~ group in each oE

the above-mentioned general formulas, tautomers exist as shown in the following equilibrium formulas and the tautomers also are included in -this inven-tion:

~ la~ ~ ~

wherein Rla is an imino group which may be protected, and Rl is as definecl above.
~ s the protecting group ~or the imino group in Rla, tllere may be used the monovalent aminoprotecting c3roups exp.lained in the case o~ R1.
Tlle present invention is explained below 5~

l referrin~ -to E~amples, which are not by way oE limita-tion but by way of illustration~

Example l (l) To a mixed solution of 172 g of butane-2,3-dione and 172 ml of benzene was added dropwise 163 mlof sulfuryl chloride wlth s-tlrring at 60C over a period of 3 hours. After completion of -the addi-tion, the thus obtained reaction mixture was stlrred at said tempera-ture for 1 hour and then under reflux for 1 hour, and thereaf-ter rectified under reduced pressure to obtain 12g g (51.5% yield) of 1-chlorobu-tane-2,3-dione having a boiling point of 53.5 to 55.0C/14 mmHg.
IR (neat) cm : VC O 1720.
NMR (CDCl3) ~ values:
2.45 (3H, s, -CCII3), 4.71 (2~l, s, ClCH2C-~

t2) To a mixed solut.ion of 120.5 g oE l-chloro-butane-2,3-clione and 120 ml oE dichloroethane was added dropwise 160 g o~ bromine w:ith stirrin~ under reflux over a periocl o~ 2 hours. ~;e ter completion oE
the addition, the thus ob-tained reaction mixture was ~urther stirred under re.~lu~ for 30 minutes, and then cool.ed to 20C. The depos.ited crystals were collected by ~iltration, washed with dichloroe~hane, and then dried -to obtain lO~ g (54.6~ yield) of 1-bromo-4-chiorobutane-zs~

1 2,3-dione having a melting point of 120 to 121.5C.
IR (KBr) cm : Vc 0 1760, 1735 NMR (CD30D) ~ values:

3.70 (lH, s), 3.83 (lH, s), 4.63 (l~l, s),

4.81 (lH, s) 13) A suspension consisting of 20.0 g of l-bromo-4-chlorobutane-2,3-dione and 140 ml of ethanol was cooled to -35C, and 7.3 g of thiourea was added with stirring.
The resulting reaction solu-tion was stirred at said -tem-perature for 4 hours, and the temperature of the solution was raised to -20C over a period of 30 minutes, after which the solution was further stirred at said temperature for 2 hours. Thereafter, the temperature of -the reac-tion solution was raised to lOC oVer a period of l hour and 30 minutes to deposit white crystals. The crys-tals were collected by filtration, washed with e-thanol~ and then dried to obtain 24.9 g 181.8~ yield) of l:l solva-te o~
ethanol and the hydrobromide salt oE 2-amino-4-chloro-acetyl-thiazole having a melting poin-t o~ 191C (decomp.).
IR IKBr) cm 1 vc~O 1695 NMR (d6-DMS0) ~ values:
l.09 ~311, -t, J=7.~1æ, C}13C~120~1), 3,54 12~:[, cl, J=7.5~Iz, C~l3CN20H),

5.17 ~2II, s, -fCII~Cl), ', O

II~N~ S ~ II

Br 7~

l Example 2 A mlxed solu-tion of 30.4 g of l:l solvate of ethanol and hydrobromide salt oE 2-amino-4-chloroacetyl--thiazole, 91 ml of dime-thyl sulfoxide and 11.9 g of potassium bromide was heated to 30C, and 8.9 ml of dimethyl disulfide was added. . The resulting reaction mixture was s-tirred a-t 30 to 35C for 2 hours, and -then poured into 300 ml oE ice water.
Subsequently, the resulting mi~ture was adjusted to pH 5.5 with sodium hydrogencarbonate. The deposited solid was collected by filtration and dis-solved in 80 ml of l N hydrochloric acid, and a small amoun-t of the insoluble material was removed thereErom by filtration, after wh.ich the filtrate was adjusted to pH 5.5 with sodium hydrogencarbonate. The deposited crystals were collected by filtrat.ion, washed with water, and then dried to obtain 11.7 g (61.4% yield) o~
2-~2-aminothiazol-4-yl)thioglyoxylic S-acid me-thyl ester haviny a melting point of 130C (decomp.).
IR (KBr) cm l vc=O 1675, 1650 NMR (d6-DMSO) S values:
2.45 (3H, s, -CSCEl3), 7.60 (2E-I, bs, H2N-~, 8.2~ (I.H, s, N

2~
.

1 Example 3 To 10.1 g of 2~(2-aminothiazol-4-yl)thiocJlyoxylic S-acicl methyl ester and 80 ml of water was added 10.6 g of sodium carbon~te wlth ice-cooling, and the resul-ting mixture was s-tirred at the same tempera-ture.for 1 hour.
Subsequen-tly, the thus ob-tained reaction mix-ture was adjus-ted to pH 2.5 with 6 N hydrochloric acid at the same temperature. The deposited crystals were collected by filtration, washed with waterl and then dried to obtain 6.2 g (67.8% yield) of 2-(2-aminothia~ol-4~yl)-glyoxylic acid having a melting poin-t of above 200C.
IR (KBr) cm 1 vc O 1660 NMR (d6-DMSO) ~ values:
.11 (lH, s, N 1l ) ~
~ S ~ H N
7.50 - 8.30 (2H, bs, H2N ~ ~ ) ~xample 4 A mixture of 40.3 g oE acetic anhydride and 18.4 g oE formic acid was stirred at 40 to ~5C Eor 1 hour. To the resulting mixtur~ was added 20.2 g of 2-(2-aminothiazol-~-yl)th.ioglyoxylic S-acicl metyl ester, with wa-ter-cooling, a;Eter which the resultincJ
mixture was stirred at 25C Eor 1 hour. Subsequently, 160 ml of water was aclded clropwise to the thus ob-tained reactlon mixture with ice-cooling, aEter wh.ich the resulting mixture was stirred ~ith water-cooling Eor 30 minutes, and the deposited crystaLs were collected by ~72S~I

1 EiLtration. The crystals were washed successively wi-th water and acetone and then dried to obta.in 21.9 g (94O4% yield) of 2-(2-ormylamino-thiazol-4-yl)-thioylyoxyl.ic S-acid methyl ester hav.ing a melting point of above 230C.
IR (KBr) cm 1 vc O 1690, 1670, 1650 E~ample 5 In 50 ml of water was suspended 7.8 g oE 1:1 solva-te of ethanol and hydrobromide salt of 2-amino-4-chloroacetylthiazole, and to the suspension was gradually added 2.3 y of sodium hydrogencarbonate At 20C with stirring over a period of 15 minutes. The deposi-ted crystals were collected by filtra-tion, washed with 10 ml of water, and then dried -to obtain 4.5 g (98.8 yield) of 2-amino-4-chloroacetylthiazole having a melting point of 147C (decomp.).

IR (KBr) cm 1 vc=O 1675, 1600 NMR (d6-DMSO) ~ values:
5.0 a ( 21I, s, -CCEl2Cl)~
o `20 7~47 (2H, bs, E12N-), 7.80 (lH, s,. N -~r- ) S~EI

1 Example 6 (1) In 200 ml of wa-ter is suspended 23 g of 2-(2-formylamino-thiazol-4-yl)-thioglyoxylic S-acid methyl ester, and 125 m] of a 2 N aqueous sodium hydroxide 5 solution was added -there-to dropwise with water-cooling over a period of 30 minutes, after which the resulting mixture was stirred at room temperature for 1 hour.
Af-ter completion of the reaction, the thus obtained reaction mix-ture was adjusted to pH 2.5 with 6 N hydro-chloric acid. The deposited crys-tals were collec-ted by filtration, washed successively with water and acetone, and then dried to obtain 16.2 g (81.6% yield) of 2-(2-formylaminothiazol-4-yl)glyoxylic acid having a melting point of above 210C.
I~ (KBr) cm 1 vc O 1660 NMR (d6-DMSO) ~ values:
8.31 (lH, s), 8.60 (lH, s), 12.8 (lH, bs) (2) 2-(2-Formylaminothiazol-~-yl)glyoxylic acid was hydrolyzed accorcling to a coslventional method ko obtain 2-(2--aminothiaæol-~~yl)cJlyoxylic ac:id.
rrhe physical properties oE this compound were idesltical with those of -the compouncl ob-kainecl in Example 3.

- ~8 -

Claims (21)

Claims for Divisional Application I
THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR
PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing a 2-aminothiazole derivative represented by the general formula or a salt thereof:

(VIII) wherein R1 is an amino group which may be protected by the conventional protecting group in the field of cephalosporin, and R3 is a monohalogenomethyl, an alkylthiocarbonyl or an aralkylthiocarbonyl group, which comprises reacting a 1,4-dihalogenobutane -2,3- dione represented by the general formula:
wherein Xl and X2a, which may be the same or different, are halogen atoms, with a thiourea represented by the general formula:
(VII) wherein R1 is an amino group which may be protected by the conventional protecting group in the field of cephalosporin, and, if necessary, reacting the reaction product with a dialkyl sulfoxide or a diaralkyl sulfoxide.

2. A process according to Claim 1, wherein R3 is a monohalogenomethyl group.

3. A process according to Claim 2, wherein R3 is a chloromethyl group.

4. A compound represented by the general formula or a salt thereof:

( VIII ) wherein R1 is an amino group which may be protected by the conventional protecting group in the field of cephalosporin, and R3 is a monohalogenomethyl, an alkylthiocarbonyl or an aralkylthiocarbonyl group, whenever prepared or produced by the process as claimed in Claim 1 or an obvious chemical equivalent thereof.

5. A compound of formula ( VIII ) given in Claim 1 or a salt thereof wherein R1 is as in Claim land R3 is as in Claim 2 whenever prepared or produced by the process as claimed in Claim 2 or an obvious chemical equivalent thereof.

6. A compound of formula (VIII ) given in Claim 1 or a salt thereof wherein R1 is as in Claim 1 and R3 is as in Claim 3 whenever prepared or produced by the process as claimed in Claim 3 or an obvious chemical equivalent thereof.

7. A process according to Claim 1, wherein R1 is an amino group.

8. A compound of formula (VIII) given in Claim 1 or a salt thereof wherein R3 is as in Claim 1 and R1 is as in Claim 7 whenever prepared or produced by the process as claimed in Claim 7 or an obvious chemical equivalent thereof.

9. A process according to Claim 2, wherein R1 is an amino group.

10. A compound of formula (VIII) given in Claim 1 or a salt thereof wherein R3 is as in Claim 2 and R1 is as in Claim 9 whenever prepared or produced by the process as claimed in Claim 9 or an obvious chemical equivalent thereof.

11. A process according to Claim 3, wherein R1 is an amino group.

12. A compound of formula (VIII) given in Claim 1 or a salt thereof wherein R3 is as in Claim 3 and R1 is as in Claim 11 whenever prepared or produced by the process as claimed in Claim 11 or an obvious chemical equivalent thereof.

13. A process according to Claim 1, wherein R3 is an alkylthiocarbonyl group.

14. A compound of formula (VIII) given in Claim 1 or a salt thereof wherein R1 is as in Claim 1 and R3 is as in Claim 13 whenever prepared or produced by the process as claimed in Claim 13 or an obvious chemical equivalent thereof.

15. A process according to Claim 13, wherein R3 is a methylthiocarbonyl group.

16. A compound of formula (VIII) given in Claim 1 or a salt thereof wherein R1 is as in Claim 1 and R3 is as in Claim 15 whenever prepared or produced by the process as claimed in Claim 15 or an obvious chemical equivalent thereof.

17. A process according to Claim 13, wherein R1 is an amino group.

18. A compound of formula(VIII) given in Claim 1 or a salt thereof wherein R3 is as in Claim 13 and R1 is as in Claim 17 whenever prepared or produced by the process as claimed in Claim 17 or an obvious chemical equivalent thereof.

19. A process according to Claim 15, wherein R1 is an amino group.

20. A compound of formula(VIII) given in Claim 1 or a salt thereof wherein R3is as in Claim 15 and R1 is as in Claim 19 whenever prepared or produced by the process as claimed in Claim 19 or an obvious chemical equivalent thereof.

21. A process according to Claim 1, wherein the reaction with a thiourea is effected at -50° to 10°C.