JPS5899486A - Preparation of cephalosporin derivative - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as a precursor of an antibacterial agent, continuously, in a short time, in high efficiency, by hydrolyzing 7-aminocephalosporanic acid with an aqueous solution of caustic alkali in the presence of a lower alcohol, and acylating the reaction product. CONSTITUTION:7-Aminocephalosporanic acid is made to react with an aqueous solution of caustic alkali (e.g. caustic soda, caustic potash, etc.) in the presence of a lower alcohol (e.g. methanol) to obtain 7-amino-3-hydroxymethyl-3-cephem- 4-carboxylic acid, which is reacted with an acryl halide (e.g. a reactive derivative of phenoxyacetic acid, etc.) to afford the compound of formulaI(R is acyl). The compound of formulaIcan be converted to the compound of formula II (X is halogen) useful as an intermediate of cephalosporin antibiotic substance by reacting with a halogenating agent (e.g. thionyl chloride, thionyl bromide, etc.).

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention uses 1-muom as a starting material and relates to a conversion reaction at the 3-position and the T-position.

Many methods have been reported to convert the 3- and T-positions of the general KT-mu to create more powerful antibacterial agents.
The present inventors have conducted various studies on methods for synthesizing specific Kl-halomethyl compounds, and as a result have found that the desired product can be synthesized efficiently by carrying out the first step continuously, and have completed the present invention.

00H (In the formula, %R represents an acyl group, and X represents a halogen atom.) Next, each process 11 will be explained in detail.

First step? As a method for converting the acetoxymethyl group at the 3-position of -Aom or its 1-acylamino derivative into a hydroxymethyl group, enzymatic hydrolysis or hydrolysis using caustic alkali has been reported. Enzymatic methods include methods using wheat embryo esterase or Rhizopyum esterase as described in Belgian Patent No. 71@12, and orange esterase as described in the specification of Kokoku Patent No. 1116222. A method using esterase obtained from the pericarp of the fruit is known.

Also, as a method of water dissolution in a caustic alkali aqueous solution, Th@
Journal of Antibiotics vo
A method of reacting in a 2t1% caustic soda aqueous solution as described above has been reported.

Among these methods, the former has operational difficulties such as preparing the enzyme and removing it after the reaction, and the latter uses a strong base such as caustic alkali. -There is a drawback that the yield is reduced due to cleavage of the lactam product. The present inventors found that when a lower alcohol was added during the ice-melting reaction using caustic alkali, this reaction was surprisingly accelerated, and thus the reaction time could be shortened! - It was found that the cleavage of tscutam concentrate can be significantly prevented. The lower alcohol used in this case is methanol, ethanol, tetrapanol, etc., preferably methanol. Also, caustic soda,
The molar ratio of the caustic alkali used, such as caustic potash, is 1 to 2 molar ratios to 1.0 m, preferably 1.0 to 1.0 m, using caustic soda. i~1. S molar ratio. The reaction temperature is -SO°C to room temperature, preferably 0°C to 00°C. The one hour reaction is completed in several minutes to several tens of minutes.

The thus obtained T-a-denocepha I-hydroxymethyl-3-cephem-4-carboxylic acid was acylated under the conditions of the usual acylation reaction of T-a-denocephatetrasporin derivatives without isolation. It is possible to perform conversion. The type of such acylating agent is not particularly limited as long as it is a reactive derivative of carboxylic acid that is generally used in cephalosporin compounds, but preferably phenox-V acetic acid or) W 2- (2-form or reactive derivatives such as 2-chloroacetylaminothiazol)-4-yl 2-(syn)methoxyiminoacetic acid 1 such as acid halides or viruses, reacted as Mayer m-directing conductors, and the resulting 1-
Acylamino-3-hydroxy/? Lou 3 - Cephem -
4-carboxylic acids can be isolated by conventional methods. That is, after the reaction is completed, the solution can be easily isolated by making the liquid acidic, extracting with a suitable solvent such as ethyl acetate, and concentrating.

The method for converting the 3-position of the 1-azilaino-3-hydroxy compound obtained in the pre-step of the second step into the halomethyl compound is according to the method described in Japanese Patent Publication No. Sho 1t-47@78-+l@3FyK. , the 4-position carboxy group is protected with a removable ester such as diphenylmethyl, β, /, β-trichloroethyl, c-fur group, and after the chlorination reaction is completed, the ester moiety is removed to obtain the desired product. However, such a method is not industrially advantageous because the process is long and the operation method is laborious. The present inventors exposed 1-acylaof-3-hydroxymethyl-3-cephem-4-carboxylic acid to a chlorating agent such as thionyl chloride, and found that only the 3-hydroxymethyl group was preferentially chlorinated. I found something to accept.

Examples of halogenating agents in this reaction include thionyl chloride, thionyl bromide, and phosphorus tribromide. Examples include phosphorus pentachloride, but thionyl chloride is preferred. The reaction temperature is 0° C. to room temperature, but the preferred reaction time for O-IC is 30 minutes to 1 hour. After the reaction is complete, 1 is distilled off.

It can be isolated as a crystalline powder by adding an insoluble solvent, or it can be isolated as a salt of 1G carboxylic acid with a suitable base.

Thus obtained by the method of the present invention. 1-Adylamino-3-halomethyl-3-cephem-4-carboxylic acid is useful as an intermediate for cephalosporin antibiotics. For example, by reacting methanol or ethanol, %3-methoxymethyl, 5-alkoxymethyl forms such as dimethyl form in 3-ethyl alcohol, or methyl mercaptan, S
The corresponding 3-substituted mercaptomethyl compound is reacted with a mercaptan such as -mercapto-1-methyl-1H-tetrazole, and the corresponding 3-substituted mercaptomethyl compound is reacted with a (an).
It is possible to induce each of the two methyl forms.

Next, the present invention will be specifically explained with reference to Examples, but these Examples and Reference Examples are not intended to limit the present invention in any way.

Example 1゜(1-1) T-mu Omu 44#, water 1.e- and methanol S.-
was added, cooled to 15 cK, and IM-caustic soda aqueous solution tWO- was gradually added while stirring well.

The contents dissolve and become a homogeneous solution. After it became a homogeneous solution, 1N aqueous sodium hydroxide solution 1 [40] was added, and stirring was continued for 10 minutes at the same temperature.
at the same time! The pH of the reaction solution is 7. ! K to keep it at i -11. Approximately 11 yen of public funds were spent on the full petition. Stir further for %i minutes, add 200% of ethyl acetate,
Salt II*1 EOpH. Preparation o. Acetic acid8. Ya.

Separate and extract the aqueous layer with ethyl acetate. When the extracts are combined and the S medium is condensed under reduced pressure, crystals are precipitated. , this is P
Collect, wash with ethyl acetate, and dry. When the R solution is further concentrated, a small amount of crystals precipitates, so KP is similarly collected and dried to obtain a total of 4LNI of 3-hydroxymethyl-1β-phenoxyacedorudo-3-cephem-4-carboxylic acid.
.

Ta. Yield 82-MMRδ (DM80--T L6-ODOl-M
) Tomi (2) Yo [, a, CJ) e 4mm (2Hg 8m” on
, ) , 41@(I H, @ , 0Oi1100
), S, 00 (, 11! e a # J”
5Hsi, IQH), L11@(11,d4sJc”
s*ll Hg) #41”-7,4(S H#
! a #)i=nilprot7), #T@(I
H, A, J After adding thionyl chloride & chloride and stirring for 15 minutes, ethyl acetate was added to the reaction solution and washed with water (x3). After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain the target compound (L@j) in the form of a powder. I got it.

WMR (ODOj violent) δ:S,・o(zu, MUBq, Δ δ =04@ppm, J ml@
Hg, 2nd place CI! 1) #4! i4 (2”
N8, s position 011) * 40 (2H * I,
OOHmOO).

5.11 (mouth 1 # & , J w= i Il+
, @11), LTO(IH,14,Jffl
,elephant! i Htx #1st place B) I ll-7-7,
4(l H, m,)z=Nirup 謔TON), 1LO
7CI HM 6 e J-L! i Hsi) Carboxylic acid (2-1) TI-Aminocephalosporanic acid t(+II) in methanol lll- and water t@- in a suspension under cooling to -10 to -SC ■-Aqueous caustic soda solution ILIm was added to the suspension. After stirring at the same temperature for S minutes, acetone SO- is added.Meanwhile, acetone SO- and irises 9M-dimethylformade 1
The reagent obtained by stirring the mixture with - at 40°C for 1 hour was suspended in ethyl acetate sI-, and Kl-(!-formamino-4-thiazolyl)l-(syn)-methoxyinnoacetic acid &41 was added thereto. Stir for a minute at room temperature to prepare a homogeneous acylation reagent. After stirring this acylating reagent under water cooling for the above-mentioned 1-aminocephalosporanic acid hydration period, water and ethyl acetate were added to separate the aqueous layer. Add ethyl acetate-tetrachloromethane (2:1) mixed solvent (250-) to the aqueous layer,
Add KIN hydrochloric acid to this mixture to adjust the pH to 15 and separate the organic layer. The aqueous layer is further extracted with ethyl acetate-tetrahydrofuran (!IT), the extracts are combined, dried over anhydrous magnesium sulfate, the S solution is concentrated, and the precipitated powder is collected.
, the target compound was obtained. Yield 1m, 1tt (-11-
).

MMR (DM&0-di) J j Ll@ (2H*
a m 2nd position cHt) ello (F-11, s
s 0OIIl) e 41g (2H*I, 1
position OBI) e 10F (t II * eL e
J m I HM * @ place H) #11! (eye'
# a, a, J Tomi 1, UI Hg, 7th place H
).

! ! M < N > m s, s chant (I II
w & j J side a, I 11m
, li).

%2・(tn, s, !00).

(Yi-2) TI-(2-(2-forma-4-thiazolyl)-
1-(syn)-methoxyiminoacetamide]-3-hydroxymethyl-3-7femu-4-carboxylic acid (1,
To a suspension of S29) in tetrahydrofuran (S Osg), thionyl chloride (1 y!-) is added under ice-salt cooling, and the mixture is stirred for 1.1 hours while keeping the internal temperature at 0 to 5°C. The precipitate was removed by P and the F solution was concentrated to obtain the powdered target compound (
1,211N) was obtained.

WMR (DM80-414) a: 11 (2H@
brs s 2nd place C1l, ), SJI (1m
l, a, 001s), 48m (2Hl,
3rd place ONri, 11m (eyes L, ll, J
ym l II.

6th place H) * IJI (I M, 6 Am J W
S s KI Hz ) * T, 32 (% Beam fanatic), river (11!-san!1-(,), 11@1 (SR,
,a,Jgtsndust.

Mri a 118 (I II, s, 200
).

Rust example 1゜3-chloromethyl-1β-phenoxyacetamide-3
-cephem-4-carvone [QIO# methanol 3-
Add boron trifluoride etherate (1 drop of chloride) to the solution and stir at room temperature for 1 hour, then rinse with ethyl acetate for 5 minutes and then wash with water. Shake the ethyl acetate layer with 10% sodium chloride water and transfer the carboxylic acid to the aqueous layer. Ethyl acetate was added to the aqueous layer, 8M hydrochloric acid was added, the pH was adjusted to s K , and the carboxylic acid was extracted again with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the target compound in powder form (rL*1
1) was obtained.

MMRCODOIm) δ+ LX@ (* II,
a, 00Mg).

&42 (I H* brs, 2nd place cJ1t)
s tie (2Hes, s position"2) s 452
(2III #I * oou, oo) e4.1
! (Eye!, (1, J wg lilz, ・place a), 1Lys (I H, Aa, JzI,
L5Bm, 1st place") e 1F -L3(SH
, m, 7zx group proton) #7.1@ (1m
, s, M! ).

Reference example 2 8-chloromethyl-Tβ-phenoxyacetamide-3
-Cephem-4-carvone@asay and ethyl S-mercapto-1-methyl-1R-tetraacetate are added, the precipitate is removed, and the carboxylic acid in FII is extracted with 10-aqueous sodium bicarbonate. After washing the extracted aqueous solution with ethyl acetate, it was diluted with 8M hydrochloric acid.
The carboxylic acid precipitated in H11 is extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated to about 2
When the temperature reached -, diisopropyl ether was added and the precipitated powdery target product was collected.

Yield 8.41 #NMR (DM80-44) δ: &1@(2H,
#, 2nd place CIIg) * & @4 (I II,
s s IJ-OHa )-t two (2II
, #13th place 0H2) s 4@0 (2if,
s #0011200), LQ・(mouth 1,
(1, J-5H & 6th place) #5.II (mouth 16
dm JxS, 11. I Hg, 1st place H)
, LT -T,S (Sa, m,)z=nyl proton) $ 11. all (SH.

6. J W 11 Hg * NH) *Patent applicant: Sankyo Co., Ltd. Agent: Patent attorney Shoji Kashide

Claims (1)

[Claims] 1, 1-Aminocephalosborane (rllcT-muam) is reacted with caustic alkaline water fII in the presence of a lower alcohol to produce 1-amino-3-human tetraxymethyl-3.
1. A method for producing a cephalosporin derivative having the following general formula (wherein R represents an acyl group): 2.1-Aranocephalosporanic acid (1-muGA) was reacted with an aqueous caustic alkali solution in the presence of a lower alcohol to form 1-amino-1-hydroxymethyl-3-cephem-4-carboxylic acid, and then − to react with acyl halide. The obtained 1,-azilaano 1- is reacted with a halogenating agent to form a dooxymethyl-3-cephem-4-carboxylic acid having a general formula (wherein a is an acyl group and X is a halogen atom). A method for producing a cephalosporin conductor having the following properties: A patent characterized in that a compound having the general formula (wherein R represents an acyl group) is reacted with a halogenating agent (wherein R represents the same meaning as described above, and X represents a halogen atom) A method for producing a cephalosporin derivative having the following.