JPS6051153A - Mandelic acid derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula (R is H, benzyl, benzohydryl, t-butyl or silyl; A is amino acid residue which may have protected amino group) or its salt. EXAMPLE:D-O-(L-Alanyl)mandelic acid benzyl ester. USE:Useful as an acylation agent. It is used for the production of cephalosporin and penicillin by the acylation of 7-aminocephalosporinic acid and 6-aminopenicillanic acid. PREPARATION:The objective compound of formula can be produced either by reacting mandelic acid with a reactive derivative of an amino acid (which may have protected amino group) at the carboxyl group, or by esterifying the mandelic acid reacting with an amino acid or its reactive derivative (which may have protected amino group), and if necessary, removing the protecting group.

Description

[Detailed description of the invention] The present invention relates to novel mandelic acid derivatives and salts thereof.

More specifically, the present invention describes the general formula (wherein R is a hydrogen atom, benzyl, benzhydryl, t
-butyl or silyl, and A represents an amino acid residue whose amino group may be protected. ) and its salts.

In general formula (1), the amino acid residue represented by A refers to an acyl group derived from the carbosyl group of an amino acid,
Preferred amino acids are α-amino acids, particularly natural amino acids, such as glycine, L-alanine, proline, leucine, and isoleucine. The protecting group for the amino group in the amino acid residue may be any protecting group for the amino group used in normal peptide synthesis, such as penzyloxycarbonyl, p-methoxybenzyloxycarbonyl, trityl, t-butoxycarbonyl, 2, 2
,2. -1-lychloroethoxycarbonyl, formyl,
Examples include 1-methyl-2-hydroxycarbonylvinyl.

The mandelic acid derivative (1) of the present invention is produced, for example, by the method shown in the reaction formula below: → ○−o −m−→ O−〇 −1−→
0-Q-Crucible, the first step is a step of esterifying compound (U), in which compound (II) is esterified with benzyl alcohol, hensyl halide, diphenyldiazomethane, tertiary butanol, or a silylating agent (for example, trimethylsilyl). trialkylsilyl halides such as chloride, etc.)
It is carried out by reacting with. Preferred examples of the halide in benzyl halide include chloride, bromide, and iodide.

The compound (III) obtained in the first step is substantially a known compound and is described in Journal Chemical Society, 218B (192B).

The second step is a step of reacting compound (III) with an amino acid or a reactive derivative thereof. The reactive derivatives of amino acids used in this process are the usual reactive derivatives at the carboxyl group, such as acid halides (e.g. acid chloride, acid bromide), mixed acid anhydrides (e.g. anhydride with monoethyl carbonate). ), active esters (eg, cyanomethyl ester, 4-nitrophenyl ester), active amides (eg, amide with imidazole), and the like.

When using free amino acids, it is preferred to use a suitable condensing agent, such as N,N'-disubstituted carbodiimides such as N,N'-dicyclohexylcarbodiimide, N,N''- Dehydrating agents such as azolide compounds such as carbonyldiimidazole and N,N'-thionyldiimidazole are used. When these condensing agents are used, the reaction is thought to proceed via reactive derivatives of carboxylic acids.

This reaction is usually carried out in an inert solvent. Specifically, the solvent includes organic solvents such as water, acetone, dioxane, acetonitrile, chloroform, benzene, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, and pyridine, and mixed solvents thereof. can be given.

This reaction is preferably carried out at room temperature or under cooling (-20°C to
(0°C).

In addition, in compound (I-1), when the protecting group in the amino acid residue of A is hensyloxycarbonyl, considering converting this compound (1-1) to compound (1-2), , R1 is preferably benzhydryl or t-butyl.

The third step is to deprotect the compound (1-1), and when R] is benzyl, it is preferably carried out by hydrogenation (catalytic reduction, etc.). Palladium, platinum, Raney nickel, etc. are used as catalysts in this case.

Further, when R1 is tertiary butyl or benzhydryl, it is preferable to remove the protecting group by acid treatment, and the acid used is a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid or formic acid. Further, when R1 is formyl, in addition to hydrogenation and acid treatment similar to those described above, a method of adding hydrazine to decompose it is used. The catalytic reduction is carried out by contacting with a catalyst at room temperature or under heating (preferably 30 to 50°C). The acid treatment is carried out in the presence of ethyl acetate, ether, acetic acid, etc., and the temperature during the treatment is usually about 0° C. to room temperature. In addition, hydrazine treatment is usually carried out in the presence of a solvent (for example, lower alcohols such as methyl alcohol and ethyl alcohol) at 0°C to
It is preferable to carry out the reaction at room temperature.

The fourth step is a step of deprotecting compound (I-2) to form compound (I-3). The deprotecting group in this step may be removed according to a known method depending on the type of protecting group. For example, tertiary butoxycarbonyl and 1-methyl-2-ethoxycarbonylvinyl can be prepared by acid treatment, pol-mil can be prepared by acid treatment, catalytic reduction, and hydrazine decomposition, and 2,2.2-)lychloroethoxycarbonyl can be prepared by methanol. Treatment with zinc and p
-Methoxybenzyloxycarbonyl may be eliminated by acid treatment or catalytic reduction.

In the fifth step, compound (II) and a reactive derivative at the carboxyl group of an amino acid [for example, N-carboxy α
-amino acids (e.g., 4-methyl-oxazolidine-2,5
-dione)] to obtain compound (I-, 3).

The reaction may be carried out by a method known per se.

The sixth step is a step in which compound (II) is reacted with a derivative of the carboxyl group of an amino acid whose amino group is protected to obtain compound (1-2).

The seventh step is a step in which compound (III) is reacted with a reactive derivative of the carbosyl group of an amino acid whose amino group is not protected to obtain compound (1-4).

The reaction may be carried out by a method known per se.

The eighth step is a step in which compound (I-4) is deprotected to obtain compound (I-3), and the deprotecting group may be removed in the same manner as in the third step.

Mandelic acid derivatives <1) are useful as acylating agents, such as 7-aminocephalosporic acid,
Cephalosporin and penicillin can be produced by acylating the ester, 6-aminopenicillanic acid, and the ester. Specifically, PCT/
It is used as a raw material for the production of oral cephalosporins as disclosed in J P 83100437.

Hereinafter, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited to these in any way.

In the following description, BOC means t-butycarbonyl group, and φ means phenyl group.

Example 1 Synthesis of 0-(BOC-L-alanyl)mandelic acid benzyl ester: (First method) 2.42 g of D-mandelic acid benzyl ester, 62 mg of 4-dimethylaminopyridine, and 1.0 g of BOC-L-alanine. 89 g are dissolved in 25 ml of methylene chloride. −
Dicyclohexylcarbodiimide IMo at 5°C to 0°C
+/Add 11 ml of methylene chloride solution and stir at the same temperature for 30 minutes. After the reaction, dicyclohexylurea was filtered off,
The filtrate is washed with saturated sodium bicarbonate solution, 10% citric acid solution/8 solution, and saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. Ethyl acetate is added to the residue, and the precipitated dicyclohexylurea is filtered off again. The filtrate was dried under reduced pressure, and n-hexane was added to the residue to obtain 2.75 g (yield: 67%) of the title compound.

I R (nujol, cm-') ;3370,17
40.169ONM, R (CDC13, δ value) 1.41 (s, 91L -C(C1,?),)4.
8~5.2 (br, IH, -N)I-)5.16
(s, 2H, -C1l, -φ)6.01 (s, I
II, φ-CI+-)7.24.7.38 (2x s
, Loll, -φ) (Second method) D-mandelic acid benzyl ester 242mgXBOC-
L-alanine-N-oxysuccinimide ester 28
6 mg was dissolved in 25 ml of tetrahydrofuran and refluxed for 4 hours. After the reaction, add ethyl acetate, add saturated sodium bicarbonate solution,
Wash with saturated saline. After drying with anhydrous sodium sulfate,
The solvent is distilled off under reduced pressure. The residue was purified using 10 g of silica gel (effluent: Hensen-ethyl acetate 10:1) and crystallized from n-hexane to give the title compound 2.
Get 00mg.

(Third method) 189 mg of BOC-L-alanine is dissolved in 2 ml of tetrahydrofuran, 1 ml of IM-triethylamine/tetrahydrofuran solution is added, and the mixture is cooled to -15°C.

IM-ethyl chlorocarbonate/tetrahydrofuran solution 1m
1 and stir for 5 minutes. Next, 121 mg of 4-dimethylaminopyridine and 243 mg of D-mandelic acid hensyl ester were added, and the mixture was stirred at -15-0°C for 2 hours and at room temperature for 3 hours. After the reaction, ethyl acetate and water are added, and the ethyl acetate layer is washed with saturated aqueous sodium bicarbonate and saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in 10 g of silica gel (2 parts of the effluent: 1 part of Hensen-ethyl acetate)
0:1) and crystallization from n-hexane to obtain 120 mg of the title compound.

Example 2 Synthesis of D-〇-(BOC-L-alanyl)mandelic acid; 12 g of the benzyl ester obtained in Example 1 was dissolved in 100 ml of ethyl acetate, and 1 g of 5% palladium on carbon was added for catalytic reduction. After the reaction, the catalyst is filtered off and the filtrate is distilled off under reduced pressure. By adding n-hexane to the residue and crystallizing it, 8 g (yield: 85%) of the title compound is obtained.

IR (nujol, cm-1); 3500, 3425
,1725.169ONMR (CDCl2.δ value) 1.38 (s, 9H,C(CH,3)3)1-4
0 (d13111J=7112. C113-Cll
)4-40 (m, LH3CII3-Cll-)6.
00 (s, IH, φ shallow) 7.2~7.5 (m, 611. φ, -COOII
)9.27 (br, s, LH, -Nll-) Example 3 Synthesis of D-0-(L-alanyl)mandelic acid hensyl ester; 3 g of powdered L-alanine was added to 200 ml of anhydrous tetrahydrofuran and phosgene was added under stirring. Add 7 g dissolved in 50 ml of anhydrous tetrahydrofuran and stir at 40°C until a homogeneous solution is obtained. Distill the solvent under reduced pressure and dry ether 100ml D-mandelic acid benzyl ester 7.4
g.

Add 50 mB of 4-dimethylaminopyridine and stir overnight. The ether is distilled off, ethyl acetate is added, and the mixture is washed with aqueous sodium bicarbonate and brine. After drying over anhydrous sodium sulfate, the solvent was distilled off to obtain 2.7 mg of the title compound.

NMR (CDC"・"(a), 1, 18 (d, 31L J-7Hz, -94ICI
Ig) 4-3 (m, III, Cl1a-CU
)5.08 (s, 211.-0CR,-)6.0
9 (s, III, -CIIO-)7.0-7.4
5 (m, 1011. φ) 8~10 (br,, 2
11. Nil, ) Example 4 Synthesis of C1-(L-alanyl)mandelic hydrochloride; 2.4 g of the compound obtained in Example 2 are dissolved in 5 marks 1 of 99% formic acid. 4N hydrogen chloride/isopropanol solution under ice cooling 15
Add m1 and stir for 10 minutes. After the reaction, the reaction solution is poured into ether, and the resulting crystals are washed with ether and dried to obtain 1.2 g (yield: 62%) of the title compound.

IR (KBr, 'cm-'); 1755,17
45NMR (DMSO-d phantom δ value) 1.49 (d, 311. J=7112. CIIJ
-Cll)4.20 (m, LH, Cl3-C11
-) 6.01 (s, IH, φ-C river- for 7.2~7
．． 75 (m, 511. -φ-)8.00~9.8
0 (br, 411.-Nll3.-CO2H) [α)
%: --130,63° (C=3% Meknorun production example - 5N-hensyloxycarbonyl-L-alanyl)
Synthesis of mandelic acid benzhydryl ester; D-(-)-mandelic acid benzhydryl ester-,1
9g, N-benzyloxycarbonyl-cycloalanine 0.83g, 4-dimethylaminopyridine 20mg
is dissolved in 15 ml of methylene chloride. 3.7 ml of dicyclohexylcarbodiimide lMo1/methylene chloride solution is added at -5°C to 0°C, and the mixture is stirred at the same temperature for 30 minutes. After the reaction, the same treatment as in the first method of Example 1 was carried out to obtain 1.8 g of the title compound as an oily substance.

l R (nujol, cm-'): 1740.1
69ONMR (CDCI3.δ value) 1.40 (d, 3t(, J=7Hz, Cll −
CH-)” 4.57 (m1111.cl+3-cl++5.08
(s, 2H, -C1l-)1 5.30 (br, Ill -NflCH-)6.0
9 (s, Itl, φ-CI+-)6.84 (s,
1)1. -CO,CH-)7~7.4 (m, 20H
, phenyl) Production Example 6 Synthesis of D-0-(pormyl-shi-alanyl)mandelic acid tertiary butyl ester: 12 formyl-shi-alanine in 00 ml of methylene chloride
．． 6g, D-mandelic acid t-butyl ester 24.
Add 2g, 50+ng of 4-dimethylaminopyridine,
At 0° C., 100 ml of IN-dicyclohexylcarbodiimide methylene chloride solution is added dropwise. The mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour, the precipitate was filtered off, the solvent was concentrated under reduced pressure, ethyl acetate was added, the precipitated urea body was filtered off, and the ethyl acetate was distilled off under reduced pressure to obtain 34 g of the title compound. (Yield ioo%) NMR (CDCI, δ value) 1.4 (s, 911.-(Cll3)3) [1,45(d, 311. J=7flz, -CII
CI+5) -4,87(q, III, J=711z, -C1 for C
13) 5.99 (s, III, -CIIO-)6
．． 2 (br, ill, -Nll→7.36 (s
, 511. φ) 8.12 (s, 5IL -CHO) Production Example 7 O-(N-benzyloxycarbonyl-cy-alanyl)
Synthesis of mandelic acid; 524 mg of the compound obtained in Production Example 5 was mixed with methylene chloride 5
Dissolve in ml. Under water cooling, 3.8 ml of trifluoroacetic acid
Add and stir for 1 hour. After the reaction, the mixture was dried under reduced pressure, ethyl acetate was added to the residue, and the mixture was extracted with saturated aqueous sodium bicarbonate. The resulting aqueous layer is made acidic with a 10% aqueous citric acid solution and extracted with ethyl acetate. The ethyl acetate solution was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 260 mg (yield: 73%) of the title compound.

IR(nujoI, cm")'; 1730,1
68ON MR (CDC13, δ value) 1.40 (d, 311. J=711z, CH-
C1l -) - 4,50 (m, IHlCJ-CH) 5.06 (s, 2tl, -CH,) 5.3-5.
7 (br, IH, -NH-)5.98 (s, I
IL φ-C11-)7.29,7.37 (2Xs,
IOH, -φ)8.30 (br, s, IIL
-CO2H) Production Example 8 Synthesis of D-0~(BOC-L-alanyl)mandelic acid 2g of BOC-L-alanine was dissolved in 30ml of anhydrous tetrahydrofuran, 1.1g of triethylamine was added, and -
Ethyl chloroformate was dissolved in anhydrous tetrahydrofuran at 20°C.
Add the melted solution to 0ml dropwise and stir at the same temperature for 30 minutes. To this were added 1.61 g of D~mandelic acid and 50 mg of 4-dimethylaminopyridine, and the mixture was stirred at 0°C for 30 minutes and at room temperature for 2 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added and dissolved, washed with water and brine, and dried over anhydrous sodium sulfate.Then, the solvent was distilled off under reduced pressure and hexane was added to give the title compound (Example 2). The same compound) 830■ is obtained. (yield 2
4%) Production Example 9 3.6 g of the compound obtained in Production Example 5 was dissolved in 40 ml of ethyl acetate, and 180 mg of palladium oxide was added thereto for catalytic reduction. After the reaction, the catalyst was removed by filtration, hydrogen chloride was blown into the filtrate,
The precipitated crystals were collected by filtration, and 2.2 g of the same compound as in Production Example 4 was obtained.
(yield 85%).

Production Example 10 Add 4.5 g of powdered L-alanine to 200 ml dry tetrahydrofuran and add 6 g of phosgene to 50 ml under strong P & stirring.
Drop the solution dissolved in 1 of tetrahydrofuran for 40'
The mixture was stirred at c until homogeneous. The solvent was distilled off under reduced pressure and D-
Add 7.6 g of mandelic acid and 200 ml of anhydrous ether and stir overnight. The precipitated crystals were separated by filtration and washed with ether and tetrahydrofuran to obtain the same substance as in Production Example 4 of 700 mH. (Yield 5.4%) Production Examples 11 to 13 Mandelic acid derivatives (1) shown in Table 1 were obtained according to Production Examples 1.2.4 or 5.7.9.

(〉See Table 1 below) Masatomi Neichi: (Voluntary) Commissioner of the Patent Office, January 22, 1980, 2. Name of the invention: Mandelic acid derivative 3. Person making the amendment 4. Agent ■ 541 Address 4-53-3 Hirano-cho, Higashi-ku, Osaka 406 New Life Hirano-cho Telephone (06) 227-1156 1 6. Number of inventions increased by amendment 7. Detailed explanation of U invention in the specification subject to amendment Column 8 of J, contents of amendment (1) "and" on page 2, line 4 of the specification was replaced with "1 and"
Correct.

(2) The following statement is inserted between lines 17 and 18 on page 2 of the same book.

"The salt of mandelic acid derivative (1) may be any pharmacologically acceptable salt, such as hydrochloride, sulfate,
Examples include mineral acid salts such as phosphates and nitrates, and organic acid salts such as oxalates, fumarates, maleates, citrates, tartrates, methanesulfonates, and toluenesulfonates. ” Procedural amendment (Own ship January 11, 1980 1, Indication of the case 1982 Patent Application No. 160060 2, Name of the invention Mandelic acid derivative 3, Person making the amendment Relationship to the case Name of patent applicant (Name) Kyoto Yakuhin Kogyo Co., Ltd. 4, Agent ■541 Address 406 New Life Hirano-cho, 4-53-3 Hirano-cho, Higashi-ku, Osaka Telephone (06) 227-1156 6. Number of inventions increased by amendment (none) ) 7. Column 8 of "Detailed Description of the Invention" of the specification to be amended, ?ili Correct contents (1) Delete "L-" on page 2, line 7 of the specification.

(2) rO-(BOC-J is rD on page 9, line 9 of the same book)
-0- (Corrected to BOC-J.

(3) On page 10, line 12 of the same book, “φ-CIl-J [
Correct it to φ- and )l-J.

(4) “-φ” on page 10, line 13 of the same book is changed to “-φ×2
” is corrected.

(5) In the same book, page 11, line 3, "I get 200 mg of r" is corrected to "I get 200 mg of r."

(6) In the same book, page 11, line 18, ``obtain 1120mg'' is corrected to ``obtain r120mg''.

(8) 12 of the same book, page 13, line 7. Correct J to get 1mg to get r2.7mg.

(9) IO-(L-J to FD on page 13, line 16 of the same book)
-C1- (Corrected to L-j.

(10) “φ-C Lee” on page 14, line 7 of the same book [φ
- and jj-J.

(11) “-φ-” on page 14, line 8 of the same book as “-φ”
Correct.

(12) Same book, page 14, line 12, rO-(N-J is r
D-0-(Corrected to N-J.

(13) Same book, page 16, line 13, rO-(N-J is r
D-0-(Corrected to N-j.

(14) “-φ” on page 17, line 11 of the same book is changed to “-φ×
Corrected to 2.

Claims (1)

[Claims] General formula (wherein R is a hydrogen atom, benzyl, benzhydryl, t
-butyl or silyl, and A represents an amino acid residue whose amino group may be protected. ) Mandelic acid derivative or its salt.