JPS60149590A - Preparation of cephem compound - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as an intermediate for cephalosporin syntheses, having antibacterial properties, by reacting a novel four-membered ring lactam (derivative) with a halogenating agent to give a novel compound, subjecting this compound to ring enlargement reaction under heating. CONSTITUTION:A novel compound shown by the formula I (R is acylamino; R' is hetero ring thio; X is uncleophilic group) or its derivative at the carboxyl group [e.g., alpha-(2-benzothiazolyldithio-3-phenoxyacetamido-4-oxoazetidin-1-yl)-a lpha- (1-acetoxy-2-propen-2-yl) acetic acid benzhydryl ester, etc.] is reacted with a halogenating agent (e.g., hydrobromic acid, etc.), to give a novel compound (derivative) (e.g., 6-phenoxyacetamido-2beta-bromomethyl-2alpha-acetoxymethylpenam- 3alpha-carboxylic acid benzhydryl ester, etc.) shown by the formula II (Hal is halogen), and, this compound is reacted in DMF at 40-150 deg.C, to give the desired compound. The compound shown by the formula I , for example, is obtained from penicillin.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides an intermediate having antibacterial properties useful for synthesizing cephalosporins from penicillins. Amino group; R'
is a mercapto protecting group;

Derivatives of the carboxyne group of the above compounds include esters [alkyl esters (methyl, ethyl, trichloroethyl esters, etc.), aralkyl esters (benzyl, methoxobenzyl, nitrobenzyl, diphenylmethyl, trityl esters, etc.), aryl esters (phenyl, (naphthyl esters, etc.), metal esters (trimethylnryl, trimethyltin monoester, etc.), other esters), acid anhydrides, salts (sodium.

potassium, magnesium, aluminum salts, etc.).

Carboquine derivatives of thiol esters, amides, hydrazides, and azidonates. If possible, these carboquine derivatives may have halogens, sulfur groups, oxygen groups, nitrogen groups, carbon groups, or other substituents as shown in 1) IJ. It may have a bond.

Among these carboxyne derivatives, 9 groups are inert to the reaction and can be removed after 2 reactions without causing any adverse changes in other parts of the molecule (haloalkyl-, acylalkyl, alkoxyalkyl).

Derivatives containing alkyloxyalkyl, aralkyl-esters, dialkylhydrazides, alkali metal salts, alkylamine salts, etc.) are of interest.

If there is a group that undergoes unfavorable changes during the reaction within these groups, it can be protected in advance and then deprotected.

The group represented by X in the above formula is generally called a nuclear group. For example, halogens include chlorine, bromine, fluorine, etc. 1-acyloxy includes organic acyloxy such as formyloxy, acetyloxy, 10-pionyloxy, benzoyloxy, and sulfonyloxy, and inorganic acyloxy such as carbonic acid and sulfuric acyloxy; alcoquines include metquin, ethquin, etc. , butyloxy, etc.; Arylthio includes phenylthio, nitrophenylthio, toluylthio, 13. 'A-Thiadiazolylthio, 2~
Methyl-43,q-thiadiazol-j-ylthio9,
2-Hydroxymethyl-13,'l--thiadiazol-j-ylthio,/-methyl-42゜3, goetetrazol-5-ylthio,/, 2,3-A-lyazole-5
Examples of carbocyclic or heterocyclic arylthio include -ylthio, pyridazin-3-ylthio, and l-oxidepyridine-euylthio.

The mercapto-protecting group represented by R' in the above formula includes a group that can be eliminated under predetermined conditions to form a penum ring or a cephem ring, such as alkylthio, aralkylthio,
Aliphatic groups such as arylthio are aromatic thio groups; thiocyanato, arylamino.

Examples include leaving groups such as sulfonyl and sulfo.

Any of them may further have an unsaturated bond if possible, and may have a substituent such as an oxygen group, a nitrogen group, a sulfur group, a carbon group, or a halokene.

Alternatively, the main chain may contain a different atom.

As the halokene shown in HaIl, chlorine and chlorine are suitable, but 1. Iodine, nyudo/X lokeshi, etc. may also be used.

Examples of the mercapto-protecting group represented by R' include alkylthio, arylthio (aryl such as Ar), acyl, anno, thionano, sulfo, anilino, and other mercapto-protecting groups.

To produce these compounds, for example, = (1) Formula that can be produced from penicillin by a known method: (wherein R and X have the same meanings as above, provided that S-O bond (!: C'-CH
3 bonds are in the ns position), the compound represented by the formula: (In the formula, R, R' and X has the same meaning as defined above) or a derivative thereof at the carboxy group is produced.

The raw material is heated gently to form an S-oxide group and a -
Compounds in which the CH2X group is simultaneously inverted may also be produced. 1 word.

cause a reaction. Since these compounds also produce the target compounds under the same conditions, they can be used as raw materials.

These raw materials are co-heated with a compound represented by HR' (mercapto or sulfenic acid scavenger) in a nitrogen stream to produce the desired compound. There are no particular restrictions on the solvent.) Those that do not contain active hydrogen (for example, hydrocarbons, 110 hydrocarbons, ethers, ketones, etc.)
(amide, sulfoxide solvents, etc.) are suitable.

(21 (formula that can be produced by the method of 11 etc.: (in the formula R, R
' and X have the same meanings as above) is a derivative with C at its carboxy chain! 10 saponification agents (especially chlorine, bromine, etc.) 10 gen.

When a halide such as copper halide or silver halide) is reacted, cyclization occurs and the compound represented by the formula 2: (wherein R, X and HaA have the same meanings as above) or its carboxy moiety ( An example of a suitable method is to dissolve the compound (I) in an inert organic solvent (such as a hydrocarbon, an alcohol, or an ether solvent). ) The reaction completes in 5 hours after the addition of a solution containing (fOj) to obtain the desired compound.Amides such as acetamide can be added to the reaction system to facilitate the reaction. It is also presumed that these amides are also useful in suppressing side reactions.

(3) Compound (II) produced in this way and a derivative at the other carboxy group undergo a ring expansion reaction to produce a compound having a 71-m ring, which is the core of the middle phalosvorin antibiotic. . In the ring expansion reaction, the starting material is t
For example, a polar solvent such as dimethyl sulfoxide is dissolved in a non-polar solvent such as toluene, for example, tθ'C~
This is easily done by heating to /30°C.

A base may also accelerate the reaction.

(4) The same product is compound (I) and its carboxy group derivatives can be used with HR-removal agents (e.g. halogens, organic acids such as carboxylic acids, sulfonic acids, inorganic acids such as mineral acids, organic Salts of bases, alkali metal hydroxides, alkali metal alkoxides, organic bases, boron trifluoride,
Metal salts of acids, mercury oxide.

It can also be produced by reacting with cuprous oxide (such as cuprous oxide, especially silver fluoride). In this case, heating is not an essential requirement.

Compound (■) produced in this way, compound (■),
After removing by-products, excess reagents, and solvents from the reaction solution by conventional methods, each cephem compound can be purified by conventional methods such as reprecipitation, recrystallization, and chromatography.

Compound (I) and compound (II) are both new substances, exhibit antibacterial properties, and are suitable for daily use against humans.
g can be used for the prevention and treatment of bacterial infections. -Lf co, in the form of a derivative at the carboxyne group.

It can be used as an intermediate in the chemical production of cephalosporins.

Examples of production and usage of the compound of the present invention will be described below with reference to Examples. To dry the solution, use sulfuric acid,
This is done using magnesium sulfate.

Example/ (1) B-phenoquine acetamide β-acetquine methylruyl α-methylpenam-3α-carboxylic acid benzhydryl/a-oxide 2tθ■ toluene/3
ml and reflux in a stream of nitrogen/hour.

The reaction solution is concentrated and purified by thin layer chromatography to obtain 220m9 of O-phenoquineacetamidoyu β-methyl-,2a-acetoquinemethylpenam-3α-carboxylic acid benzhydryl/β-oxide.

NMR: δCDC/3/Otsu'I-s 3H, i7'1
s3H,3,7gd(7)-1z) / H, Hiroshi, 2g
d(71(z)/H,4450s2H,'AI/
s/H.

iN? d (jHz) / H, Otsu, /7cld(,2
; 5+1/, )/H8(2) Otsu-phenoquine methylase β-acetoquine methylose α-methylpenam-
3σ-norluponic acid benzhydryl/α-oxide 2
3/ml and 3 ml of Niemercaptobenz, and reflux for 15 hours in a nitrogen stream. By concentrating the reaction solution, α-(2-penzothiazolylsithio3)
-phenoquinace1-amido-geoxoazetidine-/-yl)-12-(/-acetoquine-2-propene-
Obtain 2 ml of benzhydryl acetate.

NMR: δCD”' /.91 s3H, 44J7s
．． 2H, 44J'θB, IH.

Similarly, O-phenoquine acetamide-, 2 (1-
Acetquin methyl-β-methylpenam-3a-carboxylic acid benzhydryl/β-oxide (2,2θytt
When y>tr-mercaptobenzothiazole S~ is refluxed in 7 ml of toluene for 2.3 hours, the same product is obtained. 2gO
get da.

(3) α-(2-Benzothiazolyldithio-3-phenoquinacetamido-j-oxoazetidin-/-yl)
-α-(/-acetoxy-niphropen-2-yl)benzhydryl acetate 2 θ~ is dissolved in methylene chloride 10 θ■, and acetamide 10θ■ is added and stirred at room temperature.
A solution of bromine in carbon tetrachloride (/mmOle/ml) was
Add 2ynl and stir for 7 hours. The reaction solution is diluted with methylene chloride (7. After washing with water and drying, the solvent is distilled off to obtain O-phenoquine aceto-E-β-promomethyl-α-acetoxymethylpenam-3a-carboxylic acid benzhydryl 739~ and the raw material. Get 36my.

NMR: δCD0' 2. g7 s3H, 3,I
Iθd C , lHz) /H.

3, Otsu/d(, 5:, 51-1z)/H. tAlod(
Otsu 1-IZ)/H, Gege. Da d (Otsu 1-1□)/H,
'A3g s2H. 3. /f s/river (4) α-(2-
Benzothiazolyldithio-3-phenoxyanatamidegeoxoazetidin-/-yl)-α-(/-acetoxy-nipropen-niyl)benzhydryl acetate 703m! f Dissolve in 3 ml of anatonitrile, add 3.2 mg of silver fluoride; and add 6 at room temperature in a nitrogen stream. 23 hours are mixed. The reaction solution was diluted with ethyl acetate, and the insoluble matter rr-
After erasing it.

Evaporate the solvent. The residue was purified by chromatography on phosphoric acid 13Q containing /θ% water to give 35 μl of penshydryl 7-phetoxyacetamidocephalosboranate. Yield: 43%.

(5) O-phenoxyacetate 1-a EF-2β-fluoromonothylyl α-acetoxymethylpenam-3a-carboxylic acid benzhydryl 3; Maintain at θθ° (7 for 7 hours. Dilute the reaction solution with ethyl acetate, wash with brine, dry, and evaporate the solvent. Residue 'A'l fl
If the product is purified by chromatography on f/θ% hydrous lycagel/30C/, 7-fetuchinacetamidyl 7-benzhydryl allosporanate//θg is obtained.

CDC/NMR: δ 32, θθs3H. 3.3od (91-1
z)/H.

3 Otsu jd (91-1z) /H, 4/. Otsu θs
2H. Long time. rθcl(71(z)/H.

310d (717)/H, 503d (2Jl-1z)
/H, J'JJdd (3 Hz at λ) / H0 Example (1) O-phenylacetamide β-acetoquine methyl-2a-methylpenam-3α-carboxylic acid 2.2.
2-1- IJ chloroethyl/α-oxide 3 fug
is refluxed in toluene/jθml/hour, and then the solvent is distilled off. Recrystallization of the residue from ether gives 72 g of O-phenylacetamitoyl β-methyl-Uα-acetoxymethylpenamyl 3α-carboxylic acid 2°λ, 2-)lichloroethyl/β-oxide.

NMR: δCDCl3 / Otsu3s3H, 2,00s3H
,3,32SyuH93,9J'd(Otsuj)lz) /H
, gtga (Otsu, 3Hz) / H, 'A! ;! ;
d (At1z)/H, 4'J4'd (Otsu Hz)/H
,J:/2d(,2tlz)/H,Otsu,0Jdd(2;
5)/H0 (2) Otsu-phenylacetamide β-methylrouyl α
-acetoxymethylpenam-3α-carboxylic acid 2, 2.
2-Trichloroethyl/θoq is refluxed with 3 t of 2-meth'captobenzothiazole in toluene Atttl for 3 hours. By concentrating the reaction solution, α-(2-hendithiazolyldithio-3-zenylacedo-2dogeoxoazetidin-/-yl)-a-(/-acetidine-eupropene-yyl)acetic acid, 2 .2.2-Trichloroethyl/
ll-θ■ is obtained.

NMR: δCDC/3. z, θ/s3K, 3.7
0 s2H, 44J' Os, 2H8(3) α-(2-
Benzothiazolyldithio-3-phenylacetamide-
t-oxoazetidin-/-yl)-α-(/-acetoxy-nipropen-2-yl)acetic acid, 2.2-)
Dissolve 7110 μl of dichloroethyl in 3 ml of methylene chloride, add 53 μl of acetamide, and while stirring at room temperature, prepare a solution of bromine in carbon tetrachloride (/mmole/ml) θ
Add /2wrlrz and stir for 7 hours. After removing the insoluble matter, diluting with methylene chloride, washing with water and drying, the solvent is distilled off to obtain O'-phenylacetamidoyl β-bromomethyl-,2,a-acetoxymethylpenam-3α-carboxylic acid. 2.2. ．． 2-trichloroethyl tt3■ is obtained.

NMR: δCDCj? 32. θ83H, 3,3θd (total (z)/H.

3,! ;Od (6 clothes)/H, 3, Otsu θS2H, Ku 3θd
(Otsu Hz) / H.

1AA3d (Otsu I'z)/H,'A73 sJH,3,
/3s/H.

(4) O-phenylacetamitoyl β-phyromomethylalpha-acetoxymethylpenam-3α-carboxylic acid λ, 2. ．． Dissolve in 2-trichloroethyl g t my + dibutyl sulfoxide and heat in a nitrogen stream/θ0°C for 2 hours. The reaction solution was extracted with ethyl acetate.

After washing with water and drying, the solvent is distilled off. Purification of the residue by thin layer chromatography yields 7-phenylacetamidocephalosporanic acid, 2. ．． 2. ．． 2-trichloroethyl/4”
W'a- get.

NMR7DC'2. / Os 3H, 3,10d (
9Hz)/H.

32zas, 2H, 3gJd (9Hz)/H, J near θd
d(SuSrulj田)/H, 3,,2,~'A! ; m
3 H0 Example 3 (1) O-phenoquine acetamide β-adetothoxymethyl-2a-methylpenam-3α-benzyl carboxylate/α-oxide/A;//I with niemercaptobenzothiazole ottqsy and toluene! Reflux for 2j hours in a stream of nitrogen in Oml. If the reaction solution is concentrated, α-(
2-Benzothiazolyldithio-3-phenoxyacetamido-t-oxoazetidin-/-yl)-α-(/-
Acetoquin-neepropen-2-yl)benzyl acetate/
Get 9 off.

NMR: δCD”J, 2,00s3H, II θs
, 2H, 'A73 S, 2H9J Near, j s,
2H0 (2) α-(,2-Benzothiazolyldithio-3-phenoquinacetamido-t-oxoazetidin-/-yl)-α-(/-acetoquin-neepropen-nieyl)
Dissolve in 10 ml of benzyl acetate/q3QletM methylene, and add θg of acetamide.

Add bromine to carbon tetrachloride solution (/ynm) with stirring at room temperature.
ole/d) 2. / ml 'J' plus 9a
Mix it up.

The reaction solution is filtered, the P solution is washed with water, dried, and the solvent is distilled off.

The ether-soluble component in the residue is benzyl phenoxiatriamide-coalpha-acetoquinemethyl-2beta-bromomethylpenam-3a-carboxylate. Foamy matter.

NMR: δCDCl32θθs3H,3O0s2H,'
A2θd(J:)l-lz) /H, guotsuθ(1(3,
3+]z) / H, Hirotsu OS Yu H95 Yu θS Yu H0 (3) Otsu-Phenoxyanatamide β-Fromomethylruyu α-acetoxymethylpenam-3α-Carboxylic acid benzyl/IIIQ in dimethyl sulfoxide 10ml
Stir and heat to 0°C/hour/θ0°C in a nitrogen stream.

Dilute the reaction solution with ethyl acetate and wash with water.

After drying, concentrate. If the residue /, 3'l'/ is purified by chromatography on phosphoric acid gel containing /θ% water, 7-
Funinoquine acetamidocephalosporanate benzyl θ
Get 3y.

NMR: δCD”, 2.0/s3H, 3,,23d
(?Hz) /)(.

3 Otsu θd (91-1j /H, 'A30 s2H, 44
7θd (7Hz) /H.

4490 d (2,3 Hz) / H, 5θ2d (7
Hz) /H,,j,23S2H.

J, S'0dd(,2,5i5+-12)/H.

Example (1) -Phenoxyacetamide-λβ-chloromethyl-2a-methylpenam-36-carboxylic acid henzhydryl/α-oxide and 2-mercaptobenzothiazole/119 were dissolved in 23 ml of toluene and refluxed for 7 hours. do. After washing the reaction solution with water and drying, the solvent was distilled off to obtain /2-(,2-benzothiazolyldithio-3-phenoxia-11-amido-oxoazetidin-/-yl)-a-<i-chlorose. -propen-2-yl) benzhydryl acetate (79 mg) was obtained.

■R Niji""'33'110. /7f3. /730. /
3 lights.

ax / θθ, /g 93cm O NMR: δCDC' 443dl-12) 2H, lA
(2) The product Otsu/9~ of the above (1) is converted into methylene chloride/θ
ml, add 30 ml of acetamide and 091 ynl of a 7M bromine-carbon tetrachloride solution, and stir for 50 minutes under water cooling. The reaction solution from which precipitated crystals have been removed is washed with an aqueous sodium hydrogen carbonate solution, dried, and then the solvent is distilled off. If the residue 0 ~ is purified by chromatography on a solica gel λθ7 containing /θ% water, it becomes 2β
-bromomethyl-2α-chloromethylpenam-3α-carboxylic acid benzhydryl 3fθ■ is obtained.

NMR: δCDC'3.2~'A'l m! H,'
41.33 s, 2H, 3,, 2s/H, 3, 4'~
JJ'rn2H, Otsug~76m-H8 Patent applicant Shionogi & Co., Ltd. Representative Patent attorney Mitsutaka Iwasaki

Claims (1)

[Scope of Claims] A compound tf represented by the formula (wherein R is an acylamino group, He is a heterocyclic thio group, and X represents a nuclear group) is obtained by reacting a halogenating agent with a derivative of its carboxyne group to form a compound of the formula : (In the formula, R and A method for producing a compound represented by the same definition as above, or a derivative thereof at the carboxine group. A compound represented by the formula C (in which R, R' and A method for producing a compound represented by (in which R and X have the same meanings as above) or a derivative thereof at the carboxy group.