NZ212304A - 1,4-dihalogenobutane-2,3-diones - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £12304 Priority Date<s)f: A? .".^7. fP:j. [? Ai5.'.%2 Complete Specification Filed: Class: CQ7X&3lj.Q-.jJki PubHcetion Date: H.3.QEGJ98S P.O. Journal, No: NO DRAWINGS 2 12304 Under the provisions of Regtfc (latlon 23 (I) the ; Specification has been ante-doted to __ZiL~<55. jrfg. 19.££..■. // ^ ?■' \ & \o> PATENTS FORM NO. 5 PATENTS ACT 1953 COMPLETE SPECIFICATION "NOVEL INTERMEDIATES FOR PRODUCING 2-(2-AMINOTHIAZOL-4-YL) GLYOXYLIC ACID DERIVATIVE OR A SALT THEREOF, AND PROCESS FOR PRODUCING THE INTERMEDIATES" WE, TOYAMA CHEMICAL CO., LTD., a corporation organised under the laws of Japan, of 2-5, 3-chome Nishishinjuku, Shinjuku-ku, Tokyo 160, Japan, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed to be particularly described in and by the following statement:- This invention relates to a novel intermediate for producing a 2-(2-(aminothiazol-4-yl) glyoxylic acid derivative or a salt thereof, and a procfess for producing the intermediate. , 2-(2-Aminothaizol-4-yl) glyoxylic acid derivative represented by the general formula or salts thereof: wherein is an amino group which may be- protected, are useful starting materials for producing various cephalosporin antibiotics, and as processes for producing said starting compounds, there have heretofore been known (1) a process by which an ester of 2-(2-(protected or unprotected)aminothiazol-4-yl) acetic acid is oxidized with selenium dioxide or potassium permanganate (Brit. Pat. No. 1576625, 1576626, 1580189 or 1580190) and (2) a process by which an ester of acetylglyoxylic acid is halogenated, the resulting halogenation product is reacted with thiourea, and then the reaction product is hydrolyzed (European Patent Application No. 614 6 and Brit. Pat. No. 1601328) Under such circumstances, in order to find a novel process for producing a compound represented by - 1A - 212304 the general formula (I) or a salt therof, the present inventors have conducted extensive research. As a result, they have found a novel production process, which is described in NEW ZEALAND patent specification No. 204609, and moreover a novel intermediate used in said production process and a process for producing the same.

An object of this invention is to provide a novel intermediate for use in said production process (a compound represented by the general formula (II) which is Hereinafter described).

Another object is to provide a process for producing the intermediate.

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

This invention will be explained below in detail.

The compounds of the present invention are novel 1,4-dihalogenobutane-2,3-dione represented by the general formula: i 8 ¥ 2 X CH C C CH_X (II) Z 2 1 2 wherein X and X represent different halogen atoms. 1 2 As the halogen atom for X and X , there may be used, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

The compounds of the present invention represented by the general formula (II) are prepared by the following process: 1 c ch3ccch3 III 00 Halogena-tion ^ x1ch2ccch3 (iv) 00 III Halogena-tion ^ X^CH 2uccjh2X (II) (III) 1 2 wherein X and X are as defined above.

The halogenation for obtaining a 1-halogeno-butane-2,3-dione represented by the general formula (IV) from butane-2,3-dione represented by the formula (III) and the halogenation for obtaining a 1,4-dihalogen-obutane-2,3-dione represented by the general formula (II) from a l-halogenobutane-2,3-dione represented by the general formula (IV) are effected under the same conditions. For example, they are effected in the absence or the presence of a solvent inert to the reactions, e.g., an aromatic hydrocarbon such as benzene, toluene, xylene or the like, an ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or the like, a halogenated 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 solvent thereof. As the halogenating agent, there may be used a halogenating agent which is usually employed for halogenating a paraffin. For example, as chlorinating agents, there may be used chlorine, sulfuryl chloride, N-chlorosuccinimide, N-chlorophthalimide and the like, and as brominating agents, there may be used bromine, sulfuryl bromide, N-bromosuccinimide, N-bromo-phthalimide and the like. The amount of the halogenating agent used is preferably about equimolar to the compound 3 2 1 represented by the formula (III) or the general formula (IV). Although the reaction conditions may vary depending on the kinds of halogenating agents to be used and the like, reaction is usually effected at a temperature of 10°C to the reflux temperature of the solvent for a period of 30 minutes to 10 hours.

Preferable halogenations are reactions in which the compound represented by the formula (III) is first chlorinated with sulfuryl chloride to obtain a compound represented by the general formula (IV) wherein X1 is a chlorine atom, which is then brominated with bromine to obtain a compound represented by the general formula 2 til) wherein X is a bromine atom.

The compound thus obtained represented by the general formula (II) can be converted to 2-(2-aminothiazol-4-yl)glyoxylic acid derivatives represented by the general formula (I) or a salt thereof through the following production route: 1 ?? 2 X CH2CCCH2X^ (II) Ring Closure r1csnh2 (vii) Dialkyl sulfoxide or diaralkyl , sulfoxide ~ N CCH0X N C - C - SR A } i — > i* ) I >x C / n nn T? C ^ A C R S O Oxidation R S O 0 (v) (vi) or a salt thereof or a salt thereof Hydrolysis n —-—c - c - oh (I) or a salt thereof 112 2 wherein R , X and X are as defined above; R is an alkyl group or an aralkyl group. '11] 2^ The present invention is explained below referring to Examples and Referential Examples which are not by way of limitation but by way of illustration.

Example 1 (1) To a mixed solution of 172 g of butane-2,3-dione and 172 ml of benzene was added dropwise 163 ml of sulfuryl chloride with stirring at 60°C over a period of 3 hours. After completion of the addition, the thus obtained reaction mixture was stirred at said temperature for 1 hour and then under reflux for 1 hour, and thereafter rectified under reduced pressure to obtain 124 g (51.5% yield) of l-chlorobutane-2,3-dione having a boiling point of 53.5° to 55.0°C/14 mmHg.

IR (neat) cm 1: vc_0 1720 NMR (CDC13) 6 values: 2.45 (3H, s, "<jCH3) , O 4.71 (2H, s, C1CH-C-) -£ (2) To a mixed solution of 120.5 g of l-chlorobutane-2 , 3-dione and 120 ml of dichloroethane was added dropwise 160 g of bromine with stirring under reflux over a period of 2 hours. After completion of the addition, the thus obtained reaction mixture was further stirred under reflux for 30 minutes, and then cooled to 20°C. The deposited crystals were collected by filtration, washed with dichloroethane, and then dried to obtain 109 g (54.6% yield) of l-bromo-4-chlorobutane-2,3-dione having 21230 a melting point of 120° to 121.5°C.

IR (KBr) cm ~1: vc=Q 1760, 1735 NMR (CD3OD) 6 values: 3.70 (1H, s) , 3.83 (1H, s), 4.63 (1H, s), 4.81 (1H, s) Referential Example 1 A suspension consisting of 20.0 g of l-bromo-4- chlorobutane-2,3-dione and 140 ml of ethanol was cooled to -35°C, and 7.3 g of thiourea was added with stirring.

The resulting reaction solution was stirred at said temperature for 4 hours, and the temperature of the solution was raised to -20°C over a period of 30 minutes, after which the solution was further stirred at said temperature for 2 hours. Thereafter, the temperature of the reaction solution was raised to 10°C over a period of 1 hour and minutes to deposit white crystals. The crystals were collected by filtration, washed with ethanol, and then dried to obtain 24.9 g (81.8% yield) of 1:1 solvate of ethanol and the hydrobromide salt of 2-amino-4-chloroacetyl- thiazole having a melting point of 191°C (decomp.).

IR (KBr) cm"1: vc=0 1695 NMR (dg-DMSO) <5 values: 1.09 (3H, t, J=7.5Hz, CH3CH2OH), 3.54 (2H, q, J=7.5Hz, CH3CH2OH), .17 (2H, s, -CCH_C1), l~ 8.40 (4H, bs, N — ) ® JL A H3N S H o Br Referential Example 2 A mixed solution of 30.4 g of 1:1 solvate of ethanol and hydrobromide salt of 2-amino-4-chloroacetyl-thiazole, 91 ml of dimethyl sulfoxide and 11.9 g of potassium bromide was heated to 30°C, and 8.9 ml of dimethyl disulfide was added. The resulting reaction mixture was stirred at 30° to 35°C for 2 hours, and then poured into 300 ml of ice water.

Subsequently, the resulting mixture was adjusted to pH 5.5 with sodium hydrogencarbonate. The deposited solid was collected by filtration and dissolved in 80 ml of 1 N hydrochloric acid, and a small amount of the insoluble material was removed therefrom by filtration, after which the filtrate was adjusted to pH 5.5 with sodium hydrogencarbonate. The deposited crystals were collected by filtration, washed with water, and then dried to obtain 11.7 g (61.4% yield) of 2-(2-aminothiazol-4-yl)thioglyoxylic S-acid methyl ester having a melting point of 130°C (decomp.).

IR (KBr) cm"1: vc=0 1675, 1650 NMR (d^-DMSO) 6 values: 2.45 (3H, s, -CSCH-j) , I — 0 7.60 (2H, bs, H2N-), Referential Example 3 To 10.1 g of 2-(2-aminothiazol-4-yl)thioglyoxvlic S-acid methyl ester and 80 ml of water was added 10.6 g of sodium carbonate with ice-cooling, and the resulting mixture was stirred at the same temperature for 1 hour. Subsequently, the thus obtained reaction mixture was adjusted to pH 2.5 with 6 N hydrochloric acid at the same temperature. The deposited crystals were collected by filtration, washed with water, and then dried to obtain 6.2 g (67.8% yield) of 2-(2-aminothiazol-4-yl)-glyoxylic acid having a melting point of above 200°C.

IR (KBr) cm"1: vc=Q 1660 NMR (dg-DMSO) 6 values: 8.11 (1H, s n 7.50 - 8.30 (2H, bs 2 ^2 1230*

Claims (7)

WHAT WE CLAIM IS: -

1. A compound represented by the general formula: >0 r2 : cH„ca x ch2ccch2x l 2 wherein X and X are different halogen atoms.

2. A compound according to Claim 1, wherein X"*" is a 2 chlorine atom and X is a bromine atom.

3. A process for producingaX4-dihalogenobutane-2,3-dione represented by the general formula: 00 x1ch2ccch2x2 1 2 wherein X is a halogen atom, and X is a halogen atom different from x\ which comprises reacting butane-2,3-dione with a halogenating agent, and then reacting the resulting compound represented by the general formula: 00 x1ch2I1cch3 wherein X^ is as defined above, with a halogenating agent. - 9 - 212304

4. A process according to Claim 3, wherein X"*" is a 2 chlorine atom and X is a bromine atom.

5. A process according to Claim 3, wherein the halogenations are effected at 10°C to the reflux temperature of solvent.

6. A process for producing 1,4-dihalogenobutane-2,3-dione substantially as herein described with reference to Example I.

7. A compound produced by the method of any one of Claims 3 to 6. TOYAMA CHEMICAL CO., LTD. By its attorneys Baldwin^ SonCarey - 10 - = , r , \. c 6 ' • \ '\* ■