JPS58984A - Production of 2-alkyl-7-amino-2(or 3)-cephem-4-carboxylic acid - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI(R2 is alkyl; X is S, sulfoxide; dotted line shows 2- or 3-cephem) or its ester or salt. EXAMPLE:2,2,2-Trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride. USE:Antibiotic. PREPARATION:An iminohalogenating agent such as phosphorus trichloride and an iminoetherifying agent are subsequently made to act on a novel 2-alkyl-7- substituted-2(or 3)-cephem-4-carboxylic acid, or its ester or salt and, when necessary, hydrolysis is effected to give the compound of formulaI. The novel compound of formula II is obtained, e.g., by making a Lewis acid act on a corresponding 2-alkyl-6-substituted-2,3-methylpenam-3-carboxylic acid or its 1-oxide.

Description

Detailed Description of the Invention This invention provides 2-alkyl-7-substituted-2 (t or 3) represented by the general formula (in the formula, F1 means an acylamino group, R2 means an alkyl group, and Xem, respectively). −
After reacting the ester or branched salt at the carboxylic acid group of cephem-4-carboxylic acid or the carboxylic acid group with an esterifying agent and then an iminoetherifying agent, the obtained compound may be added as necessary. Upon hydrolysis reaction, 2 expressed by the general formula (in the formula ~, X and the dotted line have the same meanings as before)
-Alkyl-7-akenno2(t or 5)-cephem-
2-Alkyl-7-anno-2 (Tatasha 5)-cephem-4-, which consists of obtaining 4-carboxylic acids or their esters or their salts at the carboxy group
This invention relates to a method for producing carboxylic acids.

The raw material of this invention is a new substance, for example, the corresponding 2-alk-6-substituted-2,5-methylenebenam-5
-Carboxylic acids can be produced by reacting their 1-okinides or esters or salts of their carboxyl groups with a Lewis acid.

In the definition of the above formula, the acyl group in the azila i) group of R1 means all of the following: aliphatic acyl, acyl containing an aromatic ring, or acyl containing a heterocycle. Further, the aliphatic acyl is saturated or unsaturated alkanoyl, which may have a side chain or be cyclic, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, hivaloyl, acryloyl, crotonoyl, 2- Methyl acryloyl, cyclopentylcarbonyl, cyclohexylcarbonyl,
Cycloheptylcarnyl, naccinyl, cyclopentylacetyl, cyclohexylacetyl, cycloheptylacetyl, cyclohexylpropionyl, cycloheptylpropionyl, dihydrobenzoyl, 2,4,6. −
Examples of such groups include cyclohebutatrienyl acetyl, dihydrophenyl acetyl, etc., and these saturated or unsaturated alkanoyl groups may be interrupted with an oxygen atom or a sulfur atom, such as methoxyacetyl, methylthioacetyl, etc. , 2-probenyltheoaryuthyl, cyclohexylthioacetyl, cyclohexyloxyacetyl, dihydrophenoxyacetyl, dihydrophacyldeoacetyl, methoxycarbonyl, ethoxycarbonyl, chlorboxycarbonyl, butoxycarbonyl,
Examples include 115M enoxycarbonyl and cyclopeptyloxycarbonyl. Examples of acyl containing an aromatic ring include benzoyl, toluoyl, arylyl such as toluoyl, 1-methylnaphthoyl, phthaloyl, and tetrahydronaphthoyl, and phenylacetyl, phenylpropionyl, phenylbutyryl, diacetyl, and xylylacetyl. , t7tylacetyl, tetrahydronaphthylacetyl, etc., and the alkyl moiety of the aralkayl may be replaced with a hydrogen atom or a sulfur atom; examples of such groups include, for example. Phenoxyacetyl, phenylthioacetyl, benzyloxycarbonyl.

xylyloxycarbonyl, naphthoxycarbonyl, phenoxycarbonyl, 2-phenoxypropionyl, 2
- Phenoxybutyryl, etc. can be mentioned. Furthermore, the acyl containing a heterocycle includes a saturated or linearly unsaturated heteromonocyclic or heteropolycyclic residue containing at least one or more heteroatoms such as a hydrogen atom, a sulfur atom, a nitrogen atom, or other heteroatoms;
For example, thibacil, inzotheenyl, furil, s.

6-dihuman-2H-vinonyl, inobenzo7tunyl,
Chromenyl, +t-tentenyl, 2H-pyrrolyl, 5H-pyrrolyl, pyrrolyl, i2dazolyl, pyrazolyl, pyridyl, pyrimidinyl, bidinyl, pyridazinyl, isoindolyl, indolyl, inquizolyl, quinolyl, inquinoturu, inxazolyl, inthiazolyl, ochinasiazolyl, pyrrolidinyl, pyrrolinyl, ζdazolidinyl, piperidinyl, piperazinyl, diazolyl, triazolyl, oxasilyl, thiazolyl, thiadiazolyl,
Heterocyclic carbonyl containing a heterocycle such as tetrazolyl, benzoxasilyl, pebenzokitediazolyl, benzothiazolyl, mendithiadiazolyl, benzotriazolyl, penzinotazolyl, cytononyl, and the above-mentioned heterocycle or heterocycle substituted oxy or hetero acetyl, tetrapionyl, butyryl, isobutyryl, valeryl, which has a group such as ring-substituted thio- or heterocyclic-substituted amino or N-alkyl heterocyclic-substituted amino, etc.
Alkanoyl such as isovaleryl, piparoyl, acryloyl, ethyl)noyl, 2-methylacrytetrayl, such as IB(or a2H)-tetraflylacetyl, chenylacetyl, chenylpurpionyl, 7lylacetyl, bipezinyl Examples include acetyl, pyridinyl acetyl, pyridinylprobionibel, mendithiazolylacetyl, oxinazolylacetyl, benzoxacylylacetyl, etc., and the alkyl moiety of the alkanoyl having this heterocycle as a non-substituted The atom may be replaced by a sulfur atom before the oxygen atom, such groups include, for example, dicarbonyl in pyridylmeth, 2-7suoxycarbonyl, 8-
Examples include quinolyloxycarbonyl. Furthermore, these aliphatic acyl, acyl containing an aromatic ring or Australian lI
Acyl containing l is substituted with #C at any position except for 1
Examples of such substitutions include methyl, ethyl, propyl, inpropyl, 1 or more.
-/' Alkyl such as dibenyl, 2-propenyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, alkoxy such as methoxy, ethoxy, propoxy, isopropo, alkylthio such as ethylthio, ethylthio, aryl such as phenyl, xylyl, tolyl, etc. ,
aralkyl such as hensyl, 7-enethyl, amino, mercapto, nitri, azide, halogen such as chloro, fluoro, bromine, carboxy, sulfohydroxy, hydroxyanno, mono(or di)methylano, mono(or di)ethylamino, mono( or mono(4L< is di)alkylamino group, mono(or di) such as di)propylamino, mono(or di)inpropylamino
Mono(or di)arylamino such as phenylamino, mono(4L<di)tolylazno, mono(or di)benzylamino, mono(or di)alkylamino such as mono(di)7enetelamino, etc. Furthermore, aliphatic acyl having such non-substitutions, acyl containing aromatic group, and acyl containing heterocyclic ring include, for example, trichloroethoxycarbonyl, tribromoethoxycarbonyl, 1-cyclopropylethoxycarbonyl,
rioo74 chill, 2-chloropropioni 4,)! 7 fluoroacetyl, aminoadipoyl, α-1Z nophenyla-7tyl, carbamoyl, phenylcarbamoyl, α-
Hydroxyfaacea heptyl, p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl,
0-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, p-hydroxyphenylacetyl,
2-p-amino-2-(-5,6-cyhydro-211-fran-3-yl)acetyl, 2-amino-2-(p-hydroxy7j-nyl)acetyl, 2,6-cymethoxybennoyl, p-amino Doamidobenzenesulfonyl, 3-7enyl-5-methyl-a-+at+ylycarl-el,
3-(2-chlorophenyl)-5-methyl-4-oxacylylcarbonyl, 5-(2,6-dichlorophenyl)
-5-methyl-4-oxasilylcarbonyl, 5-(2
-chloro-6-fluorophenyl)-5-methyl-4-
Examples include oxacylylcarbonyl. If there is a free amino group, hydrophilic group, mercapto group, carboxy group, etc. in the acyl group like this, such amino group, hydroxy group, mercapto group, carboxy group, etc. can be used as a protecting group. Four protected cases are within the scope of the present invention. In this case, the holding group for the amino group includes all groups that can be used as amino-protecting groups, such as trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl (5P-)luenesulfonyl, p-nitrobenzyloxy Carbonyl, o-phtxmobenzyloxycarbonyl, O-nitrophenylsulfenyl, chloroacetyl, trifluoroacetyl, formyl, α-bifurinyl, vinyloxycarbonyl, 6th-butoxycarbonyl% p-methoxydibenzyloxy Carbonyl, A, 4-dimethoxybenzyloxycarbonyl, a-(:yacylaso)benzyloxy7carbonyl, 4-(a-methoxyphenylazo)benzyloxycarbonyl, pyridine-1-oxide-2-methoxycarbonyl, 2-pyridylmethoxy carbonyl,
2-7 liluo dicarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropo dicarbonyl, improboxycarbonyl, 1-cyclopropylethoxycarbonyl, 2-cyano-1-dimethylethoxycarbonyl, phthaloyl, naccinyl , 1-adamantyloxycarbonyl, ♂-quinolyloxycarbonyl, isobornyloxycarbonyl, 9-fluorenylmethoxycarbonyl, and the like, and furthermore, for example,
Trityl % 2-nitrophenylthio, 2,4-dinitrophenylthio, benzylidene, 4-2) o hensilia' :/, 2-hydrocypendinyl, 2-hydroxy-5-chlorobenzyl, 2-hydroxy- 1
-naphthermetele/, 6-hydroxy-4-pyridylmethylene, 1-methomodicarbonyl-2-glopylidene,
1-ethoxycarbonyl-2-glupylidene, 3-ethoxycarbonyl-2-pudelidene, 1-acetyl-2-
Propylidene, 1-benzoyl-2-propylidene,
+-(N-(2-/ t'?diphenyl)carbamoyl)-2-glupylidene, +-(M-(4-methoxyphenyl)carbamoyl)-2-propylide/, dicarbonylcyclohexy in 2-eth! groups such as lf/, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylitine, S,S-dimethyl-5-oxycyclohexylidene (for example, 1-methoxycarbonyl-2-glupylidene is Nil-1-
Propen-2-yl may be inserted into Tot+, and for example 2-ethoxycarbonylcyclohexylitine is 2
-ethoxycarbonyl-1-cyclohenyl (sometimes expressed as cenyl), di- or trial-rusilyl, and other amino group-conserving groups other than acyl groups. In addition, protecting groups for hydroxy groups and mercapto groups generally include all groups that can be used as protecting groups for hydroxy groups and mercapto groups, such as formyl, acetyl,
Benzyloxycarbonyl, 4-nitrobenzyloxy7
carbonyl, 4-bromobenzyloxycarbonyl, 4
-methoxybenzyloxycarbonyl, S, 4-dimethoxybenzyloxycarbonyl, a-(,yacylaso)be/zyloxycarbonyl, 4-(<-methoxyphenylazo)benzyloxycarbonyl, tss class butoxycarbonyl, 1.1- Dimethylpropoquine, improboxyl.

Dicarbonyl, diphenylmethoxycarbonyl, 2-pyridylmethoxycarbonyl, 2,2.2-)! j dichlorotoxycarbonyl, 2,2.2-)limoethoxycarbonyl, S-iodobutylcarbonyl, 2
- Acyl groups such as furfuryloxycarbonyl, 1-adamantyloxycarbonyl, cycarzenyl in 1-cyclopropylethate, 6-cow-noryloxycarbonyl, trifluoroacetyl, benzyl, trityl, methoxymethyl, 2-2 'Trophenyl? Examples include groups such as #, 2,4-dinitrophenylthio, etc. Furthermore, examples of carboxyl-protecting groups include all groups that can be used as ordinary carboxyl-protecting groups, such as groups whose ester moiety is methyl, ethyl, etc. , propyl, isopropyl s II s
aButyl, butyl, benzyl, diphenylmethyl%
) diphenylmethyl, p-nitrobenzyl, p-methoxybenzyl, benzoylmethyl, acetylmethyl, p
-Nitrobe/zoylmethyl, P-bromobenzoylmethyl, p-methanesulfonylbenzoylmethyl, phthalimidomethyl, trichloroethyl, trifuromoethyl, I
, 1-dimethyl-2-propynyl, 7 methyl in acetate,
Propionyloxy7methyl, pivaloyloxymethyl, 1,1-dimethylprobyl, 1,1-dimethyl-2-
7'robenyl, 5-methyl-5-butenyl, naccinimidomethyl, 1-cyclopropylethyl, 6,5-di-5-butyl-4-hydroxybenzyl, methylsulfenylmethyl, phenylsulf-7enylmethyl, methylthio Methyl, phenylthiomethyl, dimethylaminomethyl,
Pyridine-1-oquinide-2-methyl, quinoline-1
-Oquinide-2-methyl, methylsulfinylmethyl, di(p-methoxyphenyl)methyl, 2--/ano-1,1-dimethylethyl, and other esters; Kaname 7
105259, such as dimethyldichlorosilane, or At1Ii, as described in DE 2062925, for example, dimethyldichlorosilane.
JEII of titanium chloride! Examples include Hatago, in which a carboyac group is retained by a nonmetallic compound.

Examples of the alkyl group in R211c$P include methyl, ethyl, propyl, butyl, and the like.

The esters include all active esters and inactive esters, for example, the ester moiety is methyl, ethyl, propyl, inpropyl, butyl, Msg butyl, cyclohexyl, cyanomethyl, vinyl, 1-. 20
Veni #, 2-fobenyl, +, 1-dimethyl-2-7'
Saturated or slightly unsaturated alkyl such as lopenyl, 5-y'fyl, 1,1-dimethyl-2-propynyl, phenyl,
Aryl such as xylyl, tolyl, naphthyl, benzyl,
Aral moieties such as phenethyl, saturated or unsaturated alkyls, and carbon atoms in the alkyl moiety of the aral moiety are replaced with sulfur atoms, nitrogen atoms, oxygen atoms, carbonyl, etc., methoxymethyl, ethyloxymethyl,
Methylthioethyl, methylthiomethyl, dimethylaminomethyl, dimethylaminomethyl, phenoxymethyl, phenylthiomethyl, methylsulfenylmethyl, facils 47 alemethyl, benzoylmethyl, toluoylmethyl, etc., and further, these groups can be used as suitable substituents, For example, 1114L<
has more than chloromethyl, p-momethyl, trichloroethyl, cyanomethyl, 2-cyano-1,1-dimethylethyl, p-nitrophenyl, 2,4.5-trichlorophenyl, 2,4.6-)9chlorophenyl , pentachlorophenyl, p-methanesulfonylphenyl, 4
-(phenyl7/)phenyl, 2,4-dinitrophenyl, p-chlorobenzyl, 0-nitrobenzyl, p-meth)oxybenzyl, p-nitrobenzyl, 44.5-)rimethomodibenzyl, bis(p-meth)oxybenzyl, )=? methyl, pentachlorobenzyl, trichlorobenzyl, 5
, 5-di-5-butyl-4-hydroxybenzyl, p-
Nitrophenylthiomethyl, p-poa phenylthiomethyl, p-nitrobenzoylmethyl, p-chlorobenzoylmethyl, etc., other substituted or unsubstituted thioalcohols, N-hydroxykohiro (acid imide, N-hydroxy 7-thallimide, Tetrahydrobilanol, 1-Schiff tetrapropylethanol, 1-7 aer-3-methyl-5
-pizzolone, 6-hydroxypyridine, 2-hydroxymethylpyridine-1-oxtide, 1-hydroxypiperidine, 1-H)°roxy2(IH)-pyridone,
Dimethylhydroimydylamine, diethylhydroxylamine, glycolamide, 8-hydroxymethyl, chloride, 2-hydroxymethylquinoline-1-oxinide, methoxyacetylene, ethoxyacetylene, 5th-class butylethynyl dimethylamine, 1s3 butylethynyl diethylamine, ethyl ethynyl diethylamine, 2-
Ethyl-5-(5-sulfophenyl)inquinazolium hydroxide inner salt, 1,5°9.9.10-pentachlor-9,10-dihydroanthracene, 9.9.
10-Trichloro-9,10-dihydroanthracene-
Esters of 1,8,9,10,10-pentachloro-9,10-dihydroane-1thracene, etc. with 9.10.10-)'Jhalogeno-9.10-dihydroanthracene-conductors, etc.

In the reaction of this invention, a 2-alkyl-7-substituted-2 (or 5)-cephem-4-carboxylic acid or an ester having a carboxy group thereof is converted into a salt, an iminohalogenating agent, and then an iminoether. Let the agent work and make friends
This is carried out by subjecting the compound obtained according to NK to a hydrolysis reaction.

Examples include phosphorus dichloride, thionyl chloride, and phosgene. The reaction temperature is not particularly limited, but it is often carried out at a super-rich temperature or under cooling. Examples of the iminoetherification agent that acts on the reaction product obtained in this way include alcohols, alcohols, and metal alcohols,
Examples of alcohols include methanol, ethanol, propanol, impropanol, butanol, 5113-butanol, and other furkanols. , *Alkoxides of the genus include sodium alkoxides derived from the alcohols mentioned above, alkali metal alkoxides such as potassium alkoxides, and alkaline earth metal alkoxides such as calcium alkoxides and barium alkoxides. is exemplified. Although the reaction temperature is not particularly limited, the reaction is usually carried out under cooling to room temperature.

The reaction product thus obtained is subjected to a hydrolysis reaction, if necessary. The hydrolysis reaction will proceed sufficiently if the reaction solution obtained in one step is directly poured into water, but hydrophilic solvents such as methanol and ethanol, bases such as alkali metals, trialkylamines, dihydrochloric acid, acetic acid, etc. The acid may be added to the water in advance.

The temperature of this reaction is not limited to Ili, but 9O is preferred in row 1 under mild conditions such as cooling or heating.

In this reaction, the ester or salt at the carboxy group may be converted into another ester or salt or a free carboxyl group during the reaction or during the post-treatment of the reaction, but of course, in this case as well, Included. Previously, in this reaction 4, as 2-furkyl-7-substituted-2 (3)-cepheme-4-carboxylic acids α) or esters or salts at its carboxyl group, 2-cephem form, s-* fem form Although it is possible to use the stereoisomer at the 2-position of the 3-cephe4 compound either as a single a or as a linear mixture, it is possible that they are rearranged during the reaction or post-treatment, resulting in the formation of the desired compound. may be obtained, but in either case it is included in the am of JiI14. Also, if one of these isomers is produced in this reaction, it is necessary! Depending on the situation, each can be made into a single product by a conventional method such as recrystallization.

The salts of the thus obtained 2-alkyl-7-amino-2(Takasarawa 3)-cephem-4-carboxylic acid J11(2) or the ester kilF- at its carboxyl group can be converted into a desired salt by a conventional method. can.

2-alkyl-7-a (no 2
(Also 5)-7F-4-carboxylic acid a(2) or its ester or salt at the carboxy group is l
It is a substance of the Ik genus and has anti-layer properties and is useful as a medicine, and is also useful as an intermediate for producing other anti-layer substances.

Next, the present invention will be explained with reference to examples.

Example 1 2-Methyl-7-(2-yacylacetamide)-S-
2.2.2-)lichloroethyl ester of cephem-4-carboxylic acid 2.14 f was dried with Silolmeth 720
sfK-suspended, and while cooling to -5 to -10°C, 1.4 Ap of pyridine o, ssp, and s chloride were added to the solution and stirred. #I decomposition of substance #I: The reaction temperature was returned to room temperature and stirred for 4 hours. Then, 1.47 p of anhydrous methanol was added dropwise to this #I solution while cooling to -10 to -15°C. After stirring at the same temperature for 1 hour and then at 2-6°C for 1.5 hours, the precipitated crystals were collected, washed with a small amount of dichloromethane, then ether, and dried.rnp4B5-187°C (decomposed).
1.26 p (70%) of colorless crystals of the hydrochloride of 2.2.2-)lichloroethyl ester of +02-methyl-7-ino5-77emu-4-carlinic acid are obtained.

Infrared MA collection spectrum (Nujol) 181 Otsu 176Ω6M-1 Magnetic resonance collection spectrum (di-dimedelsulfoxide, /) 140 (AH, d, J = 7.5Hz) 5.92 (1
11, Otori) 4.95 (2H, a) 445 (2H, s) 3.04 (, 1, H, dL, J = 61 Kg) The above raw material compound, 2-methyl-7-(2-7 dynyl acetate) Kendo)-3-77Emu 4-Carbonken 2.2.2-)
Similar results are obtained when the following compound is used in place of the Soro ethyl ester.

By adjusting the above and PJm, the hydrochloride of 2-methyl-7-annor-5-cephem-4-carboxylic acid balanitrobe/dyl ester (mp 174-181°C (decomposition)) is obtained.

Example 2 Trimethylchlorosilane 55d was added to a solution in which 2-methyl-F-(J2-7.r-earlyacedoaudo)-6-se7emu4-carvonellI&15p was diluted with dichloromethane 400-diluted for 10 minutes. After stirring, 41.5-dimethylaniline was added to the mixture and heated under reflux for 1 hour. The reaction solution was then cooled to -40 to -30°C, and 6. After adding by and stirring at the same temperature for 2 hours, 1115 mt of methanol was added thereto and stirred at the same temperature for 1 hour. Next, add 250ml of water to the reaction solution and add 10~0ml of water.
After stirring at ℃ for 30 minutes, separate the aqueous layer. Set this to 0-1
The pH was adjusted to 5 to 4 with IM sodium hydroxide aqueous S solution at 0°C, the precipitated crystals were collected, washed sequentially with water, acetone, and ethyl ether, and then dried. -7-Amino-5-cephem-4-carvone 69rt- is obtained.

Similar results can be obtained by using the following compound as a substitute for the above raw material compound, 2-methyl-7-(2-phenylacedoyl)-5-cephem-4-carboxylic acid.

Claims (1)

[Scope of Claims] 2-al-7-substituted-2(t or 3)- represented by the general formula (in the formula, R1 means azila ζ) group, horse means alkyl group, and fem, respectively)
Cephem-4-carboxylic acids or esters or salts of their carboxylic groups are reacted with an iminohalide and an etherification compound, and if necessary, a good compound obtained is subjected to a hydrolysis reaction. , 2-alkyl-7-aq(1 or 3)-ceraem- represented by the general formula (in the formula, R2, X and dotted lines have the same meanings as before)
A method for producing 2-alkyl-7-amino-2(Makuwa 5)-cephem-4-carboxylic acids, which involves obtaining 4-carboxylic W&@ or an ester or salt thereof at its carboxy group.