CA1231343A - 2-(2-aminothiazol-4-yl)-2 (syn)-alkoxyiminoacetamide intermediates - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

This invention relates to a novel intermediate for a cephalosporin, and a process for producing the intermediate.

Description

~3~3~3 This invention relates to a novel intermediate for a cephalosporin, and a process for producing the intermediate.

This application is a divisional application for cop ending application No. 464295 filed September 1984.

The present inventors previously found that a cephalosporin (syn-isomer) represented by the formula [I] or a pharmaceutically acceptable salt thereof-112N~ C_coNH US
S No lo~LN~H2R 3 rip COO
(syn-isomer) wherein Al is a lower alkyd group, I is a hydrogen atom or a carboxyl-protecting group; and R3 is a substituted or unsubsti-tuned heterocyclic group attached to the exomethylene group at the 3-position of the cephem ring through a carbon-nitrogen bond, are very useful as an anti-bacterial agent (Japanese Patent Application Cook (Laid-Open) Nos. 99r592!82 and 93,085/84 and Japanese Patent Application Nos. 67,871-/83, 113,565/83 and 114,313/83).
Since then, the present inventors have conducted extent size research on processes for producing the cephal~sporin repro-sensed by the formula [I] or a pharmaceutically acceptable salt thereof. As a result, they have found that the useful cephalosporin (syn-isomer) represented by the formula [I] or a pharmaceutically acceptable salt thereof can be readily obtained in a high yield by reacting a compound (syn-isomer) represented by the formula [II]:

~3~L3~

S ) N [II]
OR (syn-isomer) wherein Al is a lower alkyd group, with a compound represented by the formula [III]:

~12~ S
Clara [III

COO

wherein Roy is a carboxyl-protecting group; and R3 is a subset-tuned or unsubstituted heterocyclic group attached to the exomethylene group at the 3-position of the cephem ring through a carbon-nitrogen bond, in the presence of boron trifluoride or a complex compound thereof, and then, if desired, removing the car-boxyl-protecting group or converting the product to the forum-ceutically acceptable salt as described in the aforesaid Canadian application No. 464295. And, even when the compound represented by the formula [III] obtained in the process of producing the compound represented by the formula [III] is used without isolation as the starting compound of the process, the use of the following method gives a favorable result as in the case of an isolated compound of the formula [III] being the starting compound.

A compound (syn-isomer) represented by the formula [II]

112N I D [ ICKY]

. ~s~n-isomer~

'I 3 I
wherein Al has the same meaning as defined above, is reacted with boron trifluoride or a complex compound thereof, the compound thus obtained is reacted with the compound represented by the formula [III] at -50C to 0C in the above-mentioned organic sol-vent to produce an intermediate (first reaction stage), l SO CRY

(presumed sequitur wherein Al, Roy and R3 have the same meanings as defined above, and then the reaction mixture is subjected to further reaction at 0C to 50C at a pi of 4.5 to 6.7 in a mixed solvent of water and the organic solvent (second reaction stage), whereby a cephalosporin represented by the formula [It or a foremost-gaily acceptable salt thereof is produced in high purity and high yield.

Thus, even when the unsalted compound of formula ~III] is used as the starting compound, the above method can pro-vent the intermediate from being decomposed, and hence, can full fill the object of the invention as described ion the aforesaid Canadian application No. 464295.

The present invention provides an intermediate (sync-isomer) represented by the formula IT mentioned below.

The present invention also provides a process for pro-during the intermediate represented by the formula IT mentioned below.

~3~3~l3 This invention provides a novel intermediate repro sensed by the formula IT for producing a useful cephalosporin:

I' 2 N ~11 2 . [ I I
(sync some) wherein Al has the same meaning as defined above, and further provides a process for producing the intermediate represented by the formula [II] which comprises reacting a compound represented by the formula [ IV ]

XCH2COC-Cc~H~
N 1 (syn~isomer) [ IV]
OR

wherein X is a halogen atom and Al has the same meaning as defined above, with Thor.

This invention will be further explained in detail below.
Unless otherwise specified, in this specification, the term "alkyd" means a straight or branched chain Of alkali group, for example, methyl, ethyl, n-propyl~ isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ponytail, Huxley, hotly, octal, or dodecyl. The term "aureole" means, for example, phenol, toll, naphthyl or indanyl; the term "aralkyl" means, for example, bouncily, phenethyl, 4-methylbenzyl or naphthylme-thyl and the term "halogen" means fluorine, chlorine, bromide, iodine or the like., Also, the term "lower" means 1 to 5 carbon atoms.

~æ~ 3 Moreover, when there are words such as "alkyd", "aureole", "aralkyl~ lower and the like in various terms used in this specification, they have the same meanings as mentioned above us-less otherwise specified. And the heterocyclic group includes specifically nitrogen-containing 5- or 6-membered heterocyclic groups such as pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, personnel and triazinyl.

The carboxyl-protecting group includes groups which are conventionally used as carboxyl-protecting group in the fields of penicillin and cephalosporin. They specifically include, for example, alkyd; phthalidyl; diphenylmethyl; C2 7acyloxy-C1 alkali such as acetoxymethyl, pivaloyloxymethyl, propionyloxymehtyl, butyryloxymethyl, isobutyryloxymethyl, valeryloxymethyl, l-ace-toxyethyl, l-acetoxy-n-propyl, l-pivaloyloxyethyl, l-pivaloyloxy-n-propyl, benzoyloxymethyl and l-benzoyloxyethyl -C2 5acyloxybenzyl such as ~-pivaloyloxybenzyl and Caustics-bouncily, etc.

The embodiments of the processes of this invention will be described below.

The compound represented by the formula [II] can be obtained by reacting a compound represented by the formula [IVY
with Thor.
The reaction is usually conducted in a solvent, and as this solvent, any solvent may be used as jar as it does not effect the reaction adversely. This includes water; alcohols such as methanol, ethanol and the like; kittens such as acetone and the like; ethers such as deathly ether, tetrahydrofuran, Dixon and the like; asides such as N,N-dimethylformamide, NUN-dimethylacetamide and the like; N-methyl- pardon and the like. These solvents may also be used in admixture of two or more.

LYLE
The reaction sometimes proceeds smoothly by adding an acid-binding agent. And the acid-binding agent to be used includes, for example, inorganic or organic bases such as alkali metal hydroxides, alkali metal hydrogen carbonates, triethylamlne, pardon, N,N-dimethylaniline and the like.

The reaction is usually completed at 0C to 100C in a period of 1 to 48 hours, preferably 1 to 10 hours.

The Thor can be used in a proportion of one to several moles per mole of the compound of the formula [IV].

As described above, the syn-isomer (the formula [II]
can be selectively obtained in a high yield at a low cost.

The present invention covers all of the solvents, adduces, crystal forms and hydrates of the compound of the for-mute [II].

The compound of the formula [IV] can be produced, for example, according to the production process shown below.

The compound of the formula [II] covers all of the sol-Yates, adduces, crystal forms and hydrates thereof.

L3~l~

Production Process CH3COCH2 CCNH2 [V
I¦" Notarization .
CH3CoC--C0~12 tVI3 N
....... .
Oil Alkali lion C~l3coc-coz -- CH3COC-CON~2 VOW]
oriole I oriole (,s~n-isomer) [VIII ] . ~lalogena-tion (syn-lsomer) , ' XCH COO- one IVY]
N (syn-isomer) . OR

wherein I and X has the same meaning as defined above; Z is a halogen atom or a group represented by the formula -or or -SR4 yin which I is a hydrogen atom or an alkyd, aureole, aralkyl or heterocyclic group; and the bond means that the compound may be a sync or anti-isomer or a mixture thereof.

(1) Production of the compound of formula [VI]

A nutrias compound represented by the formula [VIM can ~3~3~

be obtained by reacting a compound represented by the formula [I]
with a nitrosating agent.

The reaction is usually conducted in a solvent, and the solvent used includes solvents inert to the reaction such as water, acetic acid, Bunsen, methanol, ethanol, tetrahydrofuran and the like. These solvents may be used in admixture of two or more.

The preferred nitrosating agents used in this reaction are nitrous acid and derivatives thereof, for example, notoriously halides such as notoriously chloride, notoriously bromide and the like;
alkali metal nitrites such as sodium nitrite, potassium nitrite and the like; and alkyd nitrites such as bottle nitrite, ponytail 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 or the like. When an alkyd nitrite is used as the nitrosating agent, it is prefer-able to effect the reaction in the presence of a strong base swishes an alkali metal alkoxide.

~23~3~3 This reaction is completed at 0C -to 30C in a period of 10 minutes to 10 hour.

(2) Production of the compound of the formula [VOW
The compound represented by the formula [VII]
can be obtained by reacting a compound represented by the formula [VIM with an alkylating gent.
This reaction can be conducted according to a convention method and is usually completed at -20C to 60C in a period of 5 minutes to 10 hours.
Any solvent may be used as far as it does not affect the reaction adversely, and it includes, for example, ethers such as deathly ether, tetrahydrofuran, Dixon and the like; alcohols such as methanol, ethanol and the like; halogenated hydrocarbons such as chloroform, ethylene chloride and the like; esters such as ethyl acetate, bottle acetate and the like; Midas such as NUN-- dimethylformamide, N,N-dimethylacet~nide and the like;
water; etc. These solvents may also be used in admixture of two or more.
The alkylating agent used in the reaction includes, for example, lower alkyd halides such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide and the like; dim ethyl sulfate; deathly sulfate; diazomethane;
diazoethane; methyl p-toluenesulfonate; and the like.
When an alkylating agent other than diazomethane or diazoethane is used in the reaction, it is preferable to effect the reaction in the presence of an inorganic or g

3~3 1 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 the like; triethylamine; pardon; NUN-dimethylaniline; or the like.
The compound-represented by the formula [VII]
can also be obtained by subjecting the compound ox the formula VOW] to an amidation reaction known per so using ammonia.
(3) Production of the compound of the formula IVY
The compound represented by the formula IVY can be obtained by reacting a compound represented by the formula VOW] with a halogenating agent.
The reaction is usually conducted in a solvent, and the solvent used includes solvents which do not affect the reaction adversely, for example, halogenated hydrocarbons such as ethylene chloride, chloroform and toe like; organic carboxylic acids such as acetic acid, . .
prop ionic acid and the like; ethers such as deathly ether tetrahydrofuran, Dixon and the like; alcohols such as methanol, ethanol, isopropanol and the like; etc.
These solvents may also be used in admixture of two or more.
The reaction is usually completed at 0C to 50C
in a period of 30 minutes to 24 hours.
The halogenating agent to be used includes, for example, halogens such as bromide, chlorine and the like;
sulfuryl halides such as sulfuryl chloride and the like;

hopeless acids or alkali metal hypohalites such as hypochlorous acid, phypobromous acid, sodium hypochlorite and the like; N-halogenated imide compounds such as N-bromosuccinimide, N-chlorosuccinimide, N-bromophthalimide and the like; per bromide compounds such as pyridinium hydrobromide-perbromide, 2-carboxyethyltriphenylphosphoniumperbromide and the like, etc.

This invention will be illustrated below referring to Examples. However, this invention is not limited thereto.

(1) In 35 ml of water was dissolved 10.1 g ox Aztec-etamide, and 6.9 g of sodium nitrite was added to the resulting I solution with ice-cooling, after which 25 ml of 4 N sulfuric acid was added drops to the resulting mixture with stirring at 0C
to 5C over a period of 30 minutes. After completion of the drops addition the mixture was subjected to reaction at the same temperature for 30 minutes, and the pi was -then adjusted -to 6.0 with saturated aqueous sodium hydrogen carbonate solution.
After the insoluble had been removed, water was removed by distillation under reduced pressure. To the residue thus obtained was added 20 ml of ethyl acetate, and crystals thus obtained were collected by filtration to obtain 8.6 g (yield 66.2~) of 2-hydroxyimino-3-oxobutyramide having a melting point of 96-97C.

IR~KBr) cm : rC=0 1670 ~3~3~3 NOR (d6-DMSO~ value:
2026 (OH, s, CHICO-), 7.46 lo by, -CON ), 7.62 lo by, -CON / ), 12.60 (lo, s, -N-OH) 1 (2) In 20 ml or water were dissolved 6.5 g ox. 2-hydroxyimino-3-oxobutyramide and 5.6 g of aiders sodium carbonate at OKAY. Furthermore 6.6 g o, dimly sulfate was added -to the resulting solution at 20C to 25C, and the resulting mixture was subjected to reaction at the same temperature for 2 hours. The precipitates thus formed were collected by filtration, and 100 ml of methanol was added to the precipitates, wherea~ter the resulting mixture was stirred at 40C to 50C for 30 minutes. After the insoluble had been removed, the solvent was removed by distillation under reduced pressure. To the residue thus obtained was added 20 ml of ethanol, and the crystals thus wormed were collected my filtration to obtain 5.2 g (yield, 72.2%) of 2-(syn~-methoxyimino~3-oxobutyramide having a malting point of 156-157C.

I~lKBr) cm : vC=O 1700, 1670 , NOR (d6~DMSO) & value:

2.26 (OH, s, SCHICK, 3.96 L3Ht s, -OUCH, 7.46 llH, by, -CON / ), 7.58 US, by, -CON /
H

i' ~L2313L~3 1 (3) In 36 ml of -tetrahydrofuran was suspended 7.2 g of 2-(syn)-methoxyimino-3-oxobutyramide, and 0.8 g of bromide was added to the suspension with stirring at 40C.
After the disappearance ox the color due to bromide was confirmed, 7.2 g of bromide was further added to the suspension with stirring at 25C to 30C. After the suspension was subjected to reaction at the same temperature for 1 hour, the solvent Wow removed by distillation under reduced pressure. To the residue obtained were added 50 ml of ethyl acetate and 20 ml of water, and the pi was then adjusted to 6.0 with saturated aqueous sodium hydrogen-carbonate solution. I've organic layer was separated and washed with 20 ml of saturated aqueous sodium chloride solution. The organic layer was then dried over an hydrous 15 magnesium sulfate, and the solvent was removed by distill Jo lotion under reduced pressure. To the residue thus obtained was added 20 ml of a mixed solvent of diisopropyl ether-ethyl acetate , and the crystals thus formed were collected by filtration to obtain 9.Z g yield, 82.1%) of 4-bromo-2-~syn)-methoxyimino-3-oxobutyramide having a melting point of 112-113~C.

IR(RBr) cm 1- Vc O 1715, 1660 NOR (d6~DMSO~ value:

4.02 (OH, s, -OUCH), 4.58 (OH, s, BrCH2CO~),`
7.72 OH by, -COWAN) (4) In 13.5 ml of ethanol was suspended 4.5 g of 33~3~3 1 4-bromo-2-~syn~-methoxyimino-3-oxo~utyramide. To the suspension was added 1.5 g of Thor, and the resulting mixture was subjected to reaction at 20C to 30C or 1 hour. the precipitated crystals were collected by filtration, washed with ethanol and thereafter suspended in 25 ml of water. The pi of -the resulting suspension was adjusted to 6.0 with saturated aqueous sodium hydrogen-carbonate solution. Then, the crystals thus formed were collected my filtration and recrystallized from 15 ml of a mixed solvent of water-methanol ~1:1) to obtain 2.9 g (yield, 71.8~) of 2-12-aminothiazol-4~yll-2-~syn~-methoxyiminoacetamide having a melting point of 208-209C.

IR(KBr) cm : Vc O 1665 NOR ~d6-DMSO~ value: .

3.84.~3H, s, -OUCH), foe lo s, S H Jo 7.26 OH by, -NH2), 7.61 llH, by, -CON ), 7.91 lo by -CON \

, .. . .

(1) In 43 ml of methanol containing 3.6 g of hydrogen chloride was suspended 14.4 g of 2-(syn)-methoxyimino-3-oxobutyramide, and 16.0 g of bromide was added drops to the resulting suspension at 30C over a period of 1 hour. The suspension was subjected to reaction at the same temperature for a further 30 minutes, and I ml of 1,4-dioxzne and 22 ml of water were thereafter added to the reaction mixture with ice-cooling, after which the pi was adjusted to 3.0-4.0 with aqueous ammonia. Then, 7.6 g of Thor was added to the mixture, and the mixture was subjected to reaction at 30C for 2 hours while maintaining the pi in a range of 3.0-5.0 with aqueous ammonia. The reaction mixture was then cooled to 5C, and -the pi was adjusted to 6.5 with aqueous ammonia. The crystals thus obtained were collected by filtration and washed with a mixed solvent of water-1,4-dio~ane (1:1) to obtain 18.5 g yield, 64.2%) of the Dixon adduce of Amman-thiazol-4-yl)-2 ~syn~-metho~yiminoacetamide having a molting point of 196-198~C.

IR(~Br) cm : Vc O 1690 NOR (d6-DMSO~ value:

H H
H O I, 3.83 (OH, s, H O H

-OUCH), 6.70 (lo, s, ), 7.16 (OH, S H

.... .. . . . ...... . . ... . . .. . . . . ... . ....... _, .. , . , .. ..... .. . . . . .. .. . _ . . _ ..

~3~L3 us, -NH2), 7.48 (lo, by, -CON < ), 7.77 (lo, by, -CON /
H

1 (2) 14.4 g of the Dixon adduce of 2-(2-aminothia~ol-4-yl)-2-(syn)-methoxyiminoacPtamide obtained in above (1) was recrystallized from a mixed solvent of 18 ml of water and 18 ml of methanol to obtain 8.6 g (yield, 86.0%) of 2-~2-~minothiazol-4-yl)-2-~syn~-methoxyiminoacetamide having a melting point of 208-209C.
The physical properties SIR, NOR) of the product were identical with those of the product obtained in Example l-.
(3) 1 g of the Dixon adduce of Amman-thiazol-4-yl)-2-~synl-methoxyiminoace-tamide obtained in above I was suspended in 5 ml of methanol a-t 40C, and the resulting suspension was stirred at the same tempera-. lure for 1 hour. The suspension was cooled to room .
15 temperature, and the crystals thus obtained were collected by filtration to obtain 2-(2-aminothiazol~4-yl]-2~(synj-me~hoxyiminoacetamide having a melting point of 223.5-225 DC
(yield, 89.2%). ...
. The physical property (NOR) of the product was identical with that of the product obtained in Example l-.

To a mixed solvent of 60 ml of sulfolane and 60 ml of an hydrous ethylene chloride which contained 30.6 g of boron trifuloride was added 30.0 g of 2-~2-aminothiazol-4-yl)-2-(syn)-methoxyiminoacetamide. The mixture was subjected to react -lion 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 the resulting suspension had been stirred for 1 hours. They were washed with two 60-ml portions of ethyl acetate and dried to obtain 42.3 g of crystals.

IR(KBr) cm : 1680, 1650, 1620, 1200-1000

Claims (6)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing a compound represented by the formula [II]:
[II]
(syn-isomer) wherein R1 is a lower alkyl group, which comprises reacting a compound represented by the formula [IV]:

[IV]
(syn-isomer) wherein X is a halogen atom; and R1 has the same meaning as defined above, with thiourea in the presence of a solvent.

2. A compound represented by the formula [II]:

[II]
(syn-isomer) wherein R1 is a lower alkyl group whenever prepared or produced by the process as claimed in claim 1 or an obvious chemical equivalent thereof.

3. A process according to claim 1, wherein the reac tion is conducted at 0°C to 100°C.

4. A compound represented by the formula [II]:

[II]
(syn-isomer) wherein R1 is a lower alkyl group whenever prepared or produced by the process as claimed in claim 3 or an obvious chemical equivalent thereof.

5. A process according to claim 1, in which R1 is methyl.

6. A compound of the formula [II] given in claim 1 wherein R1 whenever prepared or produced by the process as claimed in claim 5 or an obvious chemical equivalent thereof.