JPS6277360A - Butyric acid compound and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R1 is H or hydroxyl-protecting group; R2 is (substituted) lower alkyl, aryl or heterocyclic group; R3 is H or carboxyl-protecting group]. EXAMPLE:(2S,3R)-threo- and (2R,3R)-erythro-3-hydroxy-2-phenylthiomethylbutyric acid methyl ester. USE:Synthetic intermediate for beta-lactam antibiotic substance. PREPARATION:The compound of formula I can be produced by condensing an acetoacetic acid compound of formula II (R31 is carboxyl-protecting group) with formaldehyde and a thiol of formula R2-SH in the presence of a base in an inert solvent, reducing the resultant 3-oxobutyric acid derivative of formula III with a reducing agent such as sodium borohydride and, if necessary, hydrolyzing the product and/or introducing a protecting group to the hydroxyl group.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to the general formula CI, which is an important synthetic intermediate for β-lactam antibiotics. a substituted lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group, a heterocyclic group, or a substituted heterocyclic group, and R3 means a hydrogen atom or a protecting group for a carboxyl group), salts thereof, and their salts. Concerning 4 manufacturing methods.

Describing R1 and R2+R:i in the above formula in detail, various commonly used protecting groups can be used as the protecting group for the hydroxyl group in R1, but preferably 1, for example, tertiary butyloxycarbonyl. lower alkoxysulfonyl groups such as, for example, 2-ethyloxycarbonyl iodide, halogenoalkoxycarbonyl groups such as 2,2,2-trichloroethyloxycarbonyl 5
For example, aralkyloxysulfonyl groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, 0-nitrobenzyloxycarbonyl, p-nitropenzyloxycarbonyl, trimethylsilyl, tert-butyldimethylsilyl, etc. It is an alkylsilyl group.

R2: lower alkyl group such as methyl, ethyl, tertiary butyl, cap-substituted lower alkyl group such as triphenylmethyl,
It means an aryl group or substituted aryl group such as phenyl, substituted phenyl, a heterocyclic group or substituted heterocyclic group such as pyridyl, disubstituted pyridyl, tininyl, substituted chenyl, thiazolyl, pennthiazolyl, and in the definition of R2, the group Examples of substituent groups include lower alkyl groups such as methyl and ethyl, /\rogen such as fluorine, chlorine, and bromine, sulfonamide groups, lower alkoxy groups, 21-col, cyano groups, alkoxycarboxyl groups, and carbamoyl groups. There are many groups, etc., and these replacements, () are the same or different ones combined and
3 to 3 may be substituted.

R, may be any group that serves as a protecting group for a hydrogen atom or a carboxyl group, and the protecting group is:
Straight-chain or branched lower alkyl groups such as methyl, ethyl, isopropyl, tert-butyl, halogens such as 2-ethyl iodide, 2.2.2-hlychloroethyl, lower alkyl lower alkoxymethyl groups such as meth+dimethyl, nidoxymethyl, imbutoxymethyl; lower aliphatic acyloxymethyl groups such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl; Examples include aralkyl groups and substituted aralkyl groups such as benzyl, benzhydryl, p-methoxybenzyl, 0-nitrobenzyl, and p-nitrobenzyl, and alcohols represented by the formula R30H include menthol, borneol, isoborneol, cholesterol, etc. It may be a group derived from something.

The carbonic acid compound in the formula (I) in which R3 is a hydrogen atom can be in the form of a salt if necessary. Such salts include lithium, sodium, potassium,
Examples include salts of inorganic metals such as calcium and magnesium, and salts with organic amines such as ammonium, cyclohexylammonium, dicyclohexylammonium, diisopropylammonium, and triethylammonium.

The manufacturing method of the present invention will be explained in detail below by dividing into each step.

First, acetoacetic acids represented by the general formula are condensed with formaldehyde and thiols represented by the general formula R2-3H (IV) in the presence of a base in an inert solvent to form a 3-
Produce oxobutyric acid derivatives. This product is reduced without any particular isolation and purification, and if desired is hydrolyzed and/or a protecting group is introduced into the hydroxyl group, thereby leading to a 3-hydroxybutyric derivative represented by the general formula.

Integrated reaction〉 Ether solvents such as diethyl ether, tetrahydrofuran, and dioxane Alcohol solvents such as methanol, ethanol, and isopropyl alcohol Water and mixed solvents Bases: Organic acids such as sodium acetate and potassium acetate Alkali metal salts Diethylamine, Organic amines such as pyridine and lutidine Temperature: 15°C to room temperature, preferably 0°C to room temperature Time: 1
Reduction reaction for 5 hours to 5 hours, usually 1 to 2 hours Various methods commonly used to reduce a carbonyl group to a hydroxyl group are possible.

Reducing agent: Boron hydride compounds such as sodium borohydride, lithium borohydride, potassium borohydride, zinc borohydride, diporan, and complexes of borane and various amines can be used. Further, reduction and reaction can also be carried out by adding a metal salt such as magnesium acetate, magnesium trifluoroacetic acid, or zinc chloride to these reaction systems as a reaction aid.

Temperature knee: 80°C to 50°C, preferably 0°C to 4°C. As a reduction method, it is also possible to induce the target 3-hydroxybutyric acid derivative by a catalytic reduction method using a platinum-based catalyst, palladium-based catalyst, etc. After the reaction is completed, the target compound can be taken out by normal methods. .

Compound (1) of the present invention is prepared by adding a 3-hydroxybutyric acid derivative represented by the general formula (wherein R1, R:l are the same as above) in an inert solvent in the presence of one base. (Vn) It can also be obtained by reacting with a halogen methylsulfuric F-conductor having the formula (X, ha, l: 1 gene atom, R2 is the same as above).

Solvent: tetrahydrofuran, diethyl ether, dimethoxyethane Base: strong groups such as sodium hydride, phenyllithium, butyllithium, and preferably lithium diethylamide, lithium cyclohexylamide, lithium diethylamide, lithium dimethylamide or lithium diimpropylamide After the reaction is completed, the target compound can be removed by a conventional method. Free hydroxyl groups can be protected by general methods such as acylation and silylation, and can also be made into an M-free state if desired.

To convert the compounds of the present invention into free carboxylic acids, various methods commonly used for converting esters into carboxylic acids can be used. For example, tetrahydrofuran, dioxane, methanol in the presence of water, This can be achieved by an alkaline hydrolysis method of reacting with a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc. in an inert solvent such as ethanol or a mixed solvent thereof at temperatures ranging from -15°C to room temperature. .

In addition, a method using an acid such as trifluoroacetic acid, formic acid, or boron trifluoride etherate in the presence of anisole, resorcin dimethyl ether, thioanisole, etc., or a catalytic reduction method using a platinum-based catalyst, a palladium-based catalyst, etc. may be used as necessary. It is possible to use

The target compound can be removed by conventional means.

Next, the steric structure of the compound obtained in the present invention will be described. The butyric acid compound (i) of the present invention has two isomers, erythro and threo, due to the steric stirrups at the 2- and 3-positions, and Since both the 3- and 3-positions are asymmetric carbons, optical isomers exist. Stereoisomers of erythro and threo can be easily separated by means commonly used in the field of organic chemistry. For example, thin layer chromatography using silica gel, alumina, etc., column chromatography, high performance liquid chromatography ( ) It can be separated by chromatography such as IPLC (abbreviated as IPLC) or crystallization method. For industrial production, a crystallization method is preferred, and good results can be obtained by introducing a transparent salt or a derivative that is easily crystallized. Such salts include salts of butyric acid salts with inorganic metals such as lithium, sodium, potassium, calcium, and magnesium, or ammonia, cyclohexylamino, dicyclohexylamine, diinoprobylamine, triethylamine, 1,8-diazahycyclo [5,4,0]-7-undecene (DB
U) and other organic amines can be mentioned.

In addition, when a threo isomer is desired in the compound of the present invention, the erythro isomer can be converted to the threo isomer, and such a method is also included in the present invention.For example, the method shown in the following reaction formula can be mentioned.

(1) 1910 bodies (
■)(IX)
(1) Also, reso "io ((in the formula, R1, R
2, R3 and n are the same as above).
An erythro-threo mixture having a high mixing ratio of the 1970-isomer or erythro-isomer of the compound represented by I) is oxidized in an inert B medium to lead to a sulfoxide-isomer or sulfone-isomer (τ). Examples of the oxidizing agent include kanjo, kanjo, metachloro kanji, and kofu, which are commonly used in the oxidation of sulfite compounds.

Organic peracids such as overboilizers, periodates, onno, inorganic thickening agents such as peroxide solution can be used.

Temperature: 80°C to 100°C, preferably 0°C to room temperature solvent.
Hydrocarbons such as hexane and benzene Halogenated hydrocarbons such as dichloromethane and chloroform Ethers such as diethyl ether and tetrahydrophthene Alcohols such as methanol, ethanol and tertiary butanol Ethyl acetate, acetone, N, N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetic acid, water Equivalent time: 15 minutes to 24 hours, usually 1 to 5 hours The oxidized product (■) is purified without particular afternoon purification. 2-Methylidene can be easily extracted by heating or by heating in an inert solvent such as an aromatic hydrocarbon such as benzene, toluene, or xylene or without a suitable solvent 1 after an extraction operation. A butyric acid derivative (IX) can be obtained.

Temperature: 80°C to 200°C, preferably 90°C to 130°C Time = 1 to 5 hours, usually 1 to 2 hours
X) in the presence of a base, the general formula R25H(IV) (wherein,
It is possible to react with a thiol represented by (R2 is the same as above) in an inert solvent and, if necessary, to separate by the means described above to obtain the threo form of the target compound (I).

Bases Organic amines such as nitriethylamine, DBU, and tetramethylquanidine are preferred Solvents Halogenated hydrocarbons such as dichloromethane and chloroform Alcohols such as methanol and ethanol Ethers such as diethyl ether, tetrahydrofuran, and dioxane Benzene 1 Hexane, etc. Hydrocarbon temperature: 0°C to 40°C, preferably 20°C to 30°C Time:
5 hours to 48 hours, usually 16 to 30 hours after completion of the reaction 1
The target compound of this reaction can be taken out by a conventional method.

The separated erythro or threo isomer can be further divided into optically active forms by conventional optical resolution methods.For example, the acetic acid derivative of the present invention can be optically resolved as a salt with an optically active base. . The optically active bases used in this case include quinine, cinchonidine,
Examples include brucine, ephedrine, natural amino acids and their esters. Further, a method of forming an ester with the butyric acid derivative of the present invention and an optically active alcohol such as menthol, borneol, isoborneol, cholesterol, etc., separating the diastereomers, and then hydrolyzing the ester to obtain an optically active butyric acid derivative. can be mentioned. Furthermore, the general formula (wherein R1 and R3 are the same as above)
Optically active (-)-(R) as a drunkenness derivative represented by
By carrying out a reaction according to the method of the present invention using a -3-hydroxy intoxicant conductor, it is possible to obtain an optically active threo form of an acetic acid conductor represented by the following formula: (where R1, R2, and R3 are the same as above) . The general formula (1) produced by the present invention
) and (n) are useful as synthetic intermediates for various cartapenem derivatives or penem derivatives having antibacterial activity.

The present invention will be explained in detail below using Examples and Reference Examples. The following abbreviations will be used.

ph=phenylSiB! 01 = tertiary butyldimethylsilyl PNB
= varanitrobenzyl THF = tetrahydrofuran TEA = ) ethylamine DMF-dimethylformamide NC3 = N-chlorosuccinimide DCC = dicyclohexylcarbodiimide Example 1 (2S,3R) ~Threo and (2R,3R)-erythro 3-hydroxy -2-Phenylthiomethylacetic acid methyl ester Dissolve 30 ml of isopropylamine in 200 ml of dry tetrahydrofuran (THF), cool to -60°C under an argon stream, and add n-butyllithium (15 t
3132.5+ ol of hexane solution is added dropwise so that the internal temperature does not rise above -50°C. Then, over 30 minutes, the temperature will rise to -30℃.
After stirring at the same temperature for 10 minutes, the mixture was cooled again to -BO°C. To this, a solution of 2.5 g of methyl 3-hydroxybutyrate in 20 ml of dry THF was added dropwise over 10 minutes and stirred at the same temperature for 30 minutes. Then, iodomethylphenylsulfide) After dropping 20 ml of 26.6 g of hexamethylphosphoric amide solution and stirring at the same temperature for 30 minutes and at -40"O for 10 minutes,
400 ml of ffi-hydrated ammonium chloride water is extracted with ethyl acetate. After drying with sodium sulfate, the solvent was distilled off, and the resulting residue was subjected to column chromatography on 100 g of silica gel, and the title compound was obtained from the chloroform eluate as a compound with an erythrose ratio of <4:n for 9.5S. The wood product was used in the next reaction without being separated as a mixture.

Example 2 (3R)-Ill-hydroxy-2-methylidene methyl ester (2S,3R)-threo-3-tert-butyldimethylsilyloxy-2-phenylthiomethyl 15.57 g
was dissolved in 450 ml of methylene chloride, 13.4 g of methylene chloride was added little by little under cooling with water, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with saturated carbonated hydrogen-resistant sodium water and dried over sodium sulfate, and then 'E' was distilled off to obtain 16.86 g of an oily substance. The crystal is immediately 1 without intervening.
This was dissolved in 160ml of toluene and heated at 120°C for 1 hour. The f8 medium was distilled off, and the residue was subjected to column chromatography using 50 g of silica gel. The portion eluted with benzene was removed first, and the portion eluted with chloroform was condensed once under reduced pressure to obtain 6.5 g of the title compound.

NMRδ(CDCI;)Ppffl+ 1.39 (3H, d, J=6.54(OH)CH:)3
．． 79(3H,s,C02C)l:)5.83,6.2
1 (each'/lH, s, ))\Example 3 (2S,3R)-threo- and (2R,3R)-erythro 3-hydroxyloxy 2-phenylthionotylbyric acid methyl ester obtained in Example 2 4.5g of compound in 95ml of chloroform
4.58 ml of thiophenol and 1.87 g of triethylamine (TEA) were added under cooling with water, and then stirred at room temperature for 21 hours. 5z* after cooling the reaction solution
Wash with an aqueous solution of sodium doxate, further wash with water, and dry with sodium sulfate. The solvent was distilled off, the resulting residue was subjected to column chromatography using 30 g of silica gel, and the chloroform eluate was concentrated under reduced pressure to obtain 6.7 g of the title compound as an oil as a mixture of erythrose-threo (3-nea).

NMRδ(C:DCl:+)ppm +1.21(d
, J-6,34, threo form (DH)CH3) 1.22
(d, J=8.34.(0)1)CH of erythro body:;
)3, Ei8(s, C00CR in threo type: )3.
69 (s, C0CJCH= )7.23-
7.40(5H,m,Ar-H)Example 4 (,'2S,3R)-Threo- and (2S,3R)-
Erythro 3-hydroxy-2-phenylthiomethylbutyric acid 5.64 g of the compound obtained in Example 3 and 55 m of carbon tetrachloride
1, and add 4.1 ml of iodotrimethylan to this.
Remove from pressure and heat in a sealed tube at 50°C for 15 hours. Add 10 ml of water in a cold machine and stir at room temperature for 8 hours. Carbon tetrachloride is distilled off, saturated sodium bicarbonate water is added, and the mixture is washed with ether. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ether.

The ether layer is washed with aqueous sodium thiosulfate and dried over sodium sulfate. The solvent was distilled off and the residue was purified using silica gel 2.
4.13 g of the title compound as an oil was obtained as a mixture of 0 g of column clots and erythrose (3 nia).

NMRδ (CDClz) ppm: 1.28 (d, J = 6.34Hz, (0)1 of threo form
) CH3) 1.29 (d, J = 8.35 Hz, elinuroform (OH) CH3) 2.60 to 2.84 (LH, m,
Cz-H) 3.19-3.29 (2H, m, C:HzS
Ph) 4.00-4.25 (IH, m, CzJj)7.
00-7.40 (5H, +o, Ar-H) Travel Example 5 (2S, 3R)-Threo-3-hydroxy-2-phenylthiomethyl PIB acid 4.13 g of the compound obtained in Example 4 was added to 100 ml of ethanol.
1, add 4.5 ml of dicyclohexylamine, and after emitting sound, ethanol is distilled off. The residue was washed with ether, and the obtained crystals (1.3 g) were recrystallized from benzene to obtain colorless crystals of dicyclohexylamine salt. melting point 14
5-149°C [α10-21.80° (C:=4.0C
HC: b) Add 2 IN hydrochloric acid to 520 mg of this dicyclohexylamine salt.
ml and extracted with ether. After drying the ether layer with magnesium sulfate, the solvent was distilled off to obtain the oily title compound 2.
30 mg was obtained.

NMRδ (CDCI3) pPm: 1.26 (3H, d, J=6.34.CH3) 2.89
~2.84 (IH, m, C2-H) 3.19-3.29
(2)1. m, C) I2SPh) 4.11-4.24 (
IH, m, C knee H) 7.25-7.40 (5H, m,
Ar-H) Example 6 (2S,3R)-Threo-3-tertiary-butyldimethylmonlyloxy-2-phenylthiomethylbutyric acid 230 mg of the compound obtained in Example 5 was dissolved in dimethylformamide (DMF
), add 290 mg of imitasol and 365 mg of tertiary butyldimethylchlorosilane, and stir at room temperature for 14 hours.6 Add 15 ml of water and 30 ml of methanol to the reaction mixture, and stir at room temperature for 3 hours. The reaction solution was extracted with a mixed solvent of benzene-ethyl acetate (1:l) and dried over magnesium sulfate.

The residue obtained by distilling off ε-V was subjected to column chromatography using 5 g of silica gel, and the Hensen's dissolved area was concentrated under reduced pressure to obtain the title compound 100+ag as an oil. Melting point 63-67°C [α]D-+, s9° (C=1.0.CHCl:)IR
(KBr disk) cm= :170ONMR
δ(CDCI:+)ppm: 0.06, 0.1 (3H,s, S i (CHJ
)20J3(9H,s,5iC(C)Iko)31.1
? 3(3)1. d, J=6.3H2, (OH)CH3
) 2.80 to 2.90 (IH, m, C2-jl 2.9
5-3.50 (2H, m, CH25Ph) 4.20-4
．． 40 (IH, m, C3-H) 7.20-7.40 (5
H, m, Ar - Example 7 (±)-erythro and [±]-threo-3-hydroxy-2-phenylthiomethylbutyric acid tert-butyl Dissolve 83 g of sodium acetate in 350 ml of methanol at room temperature,
Add 59g of 37% formalin to this and 55g of thiophenol.
g and 79 g of tertiary-butyl acetoacetate were sequentially added thereto and stirred at the same temperature for 1 hour. The reaction solution was cooled with water, 9 g of sodium borohydride was added little by little, and the mixture was stirred at the same temperature for 2 hours. The solvent was distilled off, n-hexane was added to the residue, insoluble matter was filtered off, and the n-hexane was distilled off to obtain 71 g of an oily substance. According to NMR, this compound was a mixture of the title 1970 isomer and the threo isomer (4:1).

NMRδ(CDCI= ) ppm +1.20(d,
J=8.3Hz, (OH)CH of erythro form: )1.
24(d, J=6.3Hz, (OH)OH1 in threo form
ll) 1.45 (9H, s, C (GHz):) 7.10
-7.30 (5H, m, Ar-H) Example 8 (±)-threo and (±)-erythro 3-hydroxy-2-phenylthiomethylbutyric acid 20 g of the compound obtained in Example 7 was mixed with 50 ml of phenol and Dissolve in 100 ml of fluoroacetic acid and stir at room temperature for 30 minutes. After distilling off the solvent, it is dissolved in a saturated aqueous sodium bicarbonate solution and washed with ether.

The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ether. After drying with sodium sulfate, the solvent was concentrated under reduced pressure to give 15 g of colorless crystals.
or can be obtained. According to NMR, this compound was a mixture of the title erythro form and threo form (4:1). Rough recrystallization from benzene was performed to obtain (±)-dilithro-3-hydroxy-2-phenylthiomethylbutyric acid. Melting point 79-80
°C IR (KBr, disk) cr l :3350 J7
0ONMRδ(CDC:h) PPff1 :1.2
9 (3H, d, J = 6.35) 1z, CHs, ) 2.1
30-2.80 (IH, a, c2-H) 3.20 (2H
,brd,J=5.4Hz,C! 1j2SPh) 4.0
0-4.25 (IH, m, C34) 7.00-7.30
(5H, m, Ar-H) Further, dicyclohexylamine was added to the filtrate for crystallization, and recrystallization was performed from coarse ethanol to obtain a dicyclohexylamine salt in the form of leaf-colored crystals. Melting point: 155-157°C.

This dicyclohexylamine salt is acidified with 1N hydrochloric acid and extracted with ether. After drying over sodium sulfate, the solvent was distilled off to obtain oily (±)-threo-3-hydroxy-2-phenylthiomethylbutyric acid.

NMRδ (CDCl2) ppm: 1.26 (3H, d, J=6.34Hz, CH3)2.
89~2.84 (l) I, m, CzJj) 3.19~3
．． 29 (2H, m, (JjXSPh) 4.11-4.2
4 (IH, m, C34) 125-7.40 (5H, m,
Ar-1i) Example 9 (±)-Erythro 3-tert-butyldimethylsilyloxy-2-phenylthiomethylbutyric acid obtained in Example 8 (±
)-Erythro compound was subjected to reaction and post-treatment in the same manner as in Example 6 to obtain the title compound as colorless crystals. Melting point 91-92 ° C NMR δ (CDCIs) ppm + 0.0B, 0.1 (each 31 (, s, 5i (C) 13)
20.9 (9H,s, 5iC(C:)I3)31.2
8 (3H, d, J-6, 3Hz, (OH)CHs)2.
55-2.78 (IH, m, Cz-H) 3.10-3.
21 (2H, m, CH25Ph) 4.12-4.36 (
IH, m, C: +-H) 7.30-7.45 (5H, m
, Ar-H) Example i.

(±)-threo-3-tert-butyldimethylsilyloxy-2-phenylthiomethylbutyric acid Example 6 using the (±)-threo compound obtained in Example 9
The reaction and post-treatment were carried out in the same manner as above to obtain the title compound as colorless crystals. Melting point 93-94° CIR (KBr, di
sk) cm-1:170ONMRδCCDGlz)ρp
IIl: 0.08, 0.1 (respectively 3H, s, 5i (CH3)?0
．． 93(9)1. s, 5iC(CH3)3123(3H
, d, J==6.3Hz, (DH)()js)2, Ei
O~2.90 (IH, 10, C2-H) 2.95~3.
50(2)1. Φ, CH, 5Ph) 4.20-4.40
(IH, m, C3-H) 7.20-7.40 (5H, a
+, Ar-H) Example 11 The same reaction as in Example 7 was carried out using (±)-erythro and (±)-threo-3-hydroxy-2-phenylthiomethylbutyric acid methylacetoacetate as raw materials, and the title erythro A mixture of (4:1) was obtained.

N) IRδ (CDC: I3) ppm: 1.21 (d,
J=8.3Hz, (OH)Clh in threo form)1.2
2(d, J=t3.34Hz, (OH)C of erythro form
H3) 3.88 (s, C00C in threo type) 13 ) 3
．． 69(s, C00C of erythro form!!3) Reference Example I C3S, 4S) -3-[(R)-1-(tert-butyldimethylthuryloxy)ethyl] -1-(4-nitropencil roquine) )-4-Phenylthio-2-acetidinone (2S, 3R)-threo-3-tert-butyldimethylsilyloxy-2-phenylthiomethyl butyrotate (140 mg) was added to 1.4 ml of chloroform (purified through an alumina column). Dissolve at room temperature and gradually add 136 mg of NC3 and stir for 7 minutes. 6 Cool the reaction mixture on ice and add 89 mg of 0-4-nitropenzylhydroxylamine and 0.1 g of chloroform.
4ml solution and then a solution of 85 mg of DCG in 0.14 ml of chloroform were added, and the mixture was stirred at room temperature for 20 minutes. Then, a solution of 0.8 ml of TEAo in 0.14 ml of chloroform was added, and the mixture was stirred at the same temperature for 20 minutes. 5m of water in the reaction solution
l, extracted with chloroform, and dried over sodium sulfate. The residue obtained by evaporating the solvent was subjected to column chromatography using 3 g of silica gel, and the benzene eluate was filtered under reduced pressure e112i.
Then, 30 mg of the title compound was obtained as an oil.

rα]o −79, 20° (C: = 0.5. 3
)2)0.93 (9H,s,5i(OH3)3)1.
42 (3)1. d, J-Ei, 58.0H3) 3.2
5,3.29 (IH, dd, j=5.138.5.
69) 1z , C3-H) 5.16 (2H,s, -0
C1b-)5.24 (1)! , d, J=5.69Hz
, C4-jl 7.23~? ,55 (78,m, At
-H) 8.15 (2H, d, J=8.87.Ar-j
Reference Example 2 (3S,4S)-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-1-hydroxy-4-
Phenylthio-2-azetidinone 30 mg of the compound obtained in Reference Example 1 was dissolved in 5 parts of methanol, 30 mg of lOx palladium on carbon was added, and catalytic reduction was carried out at normal pressure for 3 cycles for 40 minutes. Further, 30 mg of the above catalyst was added and catalytic reduction was carried out at normal pressure for 1 hour. The catalyst was removed using Celite, and the solvent was distilled off under reduced pressure to obtain 16 mg of the title compound in the form of amber crystals. Melting point 132-135°C.

[(!] CD -84,00° (C-0,35, methanol) IR (KBr disk) cm-': 344
0,1754 Reference Example 3 (3S,4S)-3-[(R)-1(tert-butyldimethylsilyloxy]ethyl]-4-phenylthio-2-
Azetidinone 15 mg of the compound obtained in Reference Example 2 was added to 1.2 ml of methanol.
, fl@I in 0.5 ml of water, add 75 µm of titanium trichloride solution at room temperature to pH IN with sodium hydroxide.
Add while keeping the temperature around 7. After further stirring for 30 minutes at the same temperature, 5 ml of water was added, extracted with ethyl acetate, and dried over Macnenoum sulfur. The residue obtained by distilling off f6 was subjected to preparative thin layer chromatography (20X20XO, 5cz
>t: The product was developed and purified using chloroform-methanol (93:7) to obtain 13 mg of the title compound.

fans -77,57' (C=0.86.CHC
l: )IR (KEr disk) cm-1: I? E
i2NMRδ(CDCl2)PPIII:0:13
(8H,s,5i(CJj3h)0.93 C8H,
s, 5ICCHz) 3) 1.43 (3) 1. d, J=
8.35) 1z, Gp3) 5.13 (IH, d, J=
5.03Hz, Ca-! lri 6.30 (IH, bro
ad, s, -NH) 7.28-7.44 (5H, m,
Ar-H) The (±]threo-3-tertiary butyldimethyllinyloxy-2-phenylthiomethyl obtained in Example 10 was treated in the same manner as in Reference Example 1, and the corresponding [±]threo-3-(1- tertiary-butyldimethylsilyloxy]ethyl-1-(4-nitrohensyloxy)-4-phenylthio-2-7ceticinone was obtained in a yield of 123%-cql. This was treated in the same manner as in Reference Example 2 to obtain ( ±)Threo-3-(
+-tertiary butyldimethylsilyloxy)-1-hydroxy-4-phenylthio-2-acetidinone i80
Obtained in %. This was treated in the same manner as in Reference Example 3.
- Phenylthio-2-azetidinone recovered XJ88g -
I got c. The three types of (earth)threo bodies mentioned above can be optically resolved using the methods described above.

It is also possible to process the (±) erythro body obtained in Example 9 in the same manner as above to produce the corresponding (±) 1970 bodies, and to perform optical resolution at each stage.

β-lactam compounds obtained from the compounds of the present invention by treatment as in Reference Examples include penem, l-rubabenem and other β-lactam compounds.
It is an important compound as a synthetic intermediate for lactam antibiotics. In particular, the side m [(
3 having the same configuration as Fri-hydroxyethyl group]
S-r(R)-hydrodiethyl 1-azetidine-2-
The conductor or the compound (A) whose hydroxyl group is protected with a protecting group is the 11-form of the natural product chenamycin and the (5R, SS, 8R)-8-(
It is an extremely important compound in the synthesis of (hydroxyethyl)penem-3-carboxylic acid derivatives. When introducing these compounds, the leaving group (RO) of formula (A) and the nucleophile (N
It is known that in the displacement reaction with u), a compound of formula (B) is generated in the middle, and a nucleophile (Nu) reacts with this to generate a compound of formula (C) [Can, J.Cha
m, y61, 1899 (1983); Organic Synthetic Chemistry 41 No. 1, p. 83 (1983) J, therefore (A) 4
The steric configuration of position RO may be either the R configuration or the S configuration.

(In the formula, R11 is a hydrogen atom or a hydroxyl group: J
The s group can be easily converted into a leaving group with higher activity than the substituent group -5-R2 (RO means a leaving group) at the 4-position of the above-mentioned 8-lactam compound (X), so penem, It is an extremely useful compound as a synthetic intermediate for 1-lactam antibiotics and other β-lactam antibiotics.

A leaving group is a group that can be easily eliminated and replaced by a nucleophilic reagent residue in a nucleophilic transfer reaction, and typical examples include a halogen atom, an acetoxy group, and a Hensensulfokol group. can be mentioned.

It is also possible to change the 1-position of these β-lactam compounds. That is, if a protecting group is present at the 1-position, this can be removed if desired.

Demovability includes reductive decomposition by hydrogenation, sodium amalgam, aluminum amalgam, metallic sodium in ammonia, (NiL)2Ce(No:)t, K2
Methods include decomposition using S20B, TiGlx and other reducing agents, hydrolysis using an acid or base, and liquefied decomposition using ozone.

A more detailed explanation is as follows.

R1 is -0-R4, R4 is a benzyl group, p-
Nitrobe〉'zyl group, benzyloxycarbonyl group, p
- In the case of compounds such as nitrobenzyloxysulfonyl groups and benzhydryl groups, palladium-supported carbon, platinum oxide,
It can be deprotected by catalytic reduction using other known metal catalysts to give N-hydroxy-2-azetidinone derivatives of the general formula. As a reaction solvent, methanol, ethanol, dioxane, tetrahydrofuran (T
HF), preferably in methanol, under a hydrogen pressure of 1 to 4 atmospheres, at 0 to 50°C, preferably 10 to 30°C, for 30 minutes to 10
You can react and obtain the desired object within a period of time, usually between 1 and 5 poems. The product can be isolated by conventional extraction and recrystallization.

Furthermore, the above N-hydroxy-2-acetinone derivative can be converted into a 2-azetidinone derivative of the general formula using a binary agent such as titanium trinide. Methanol, ethanol, dioxane, THF, water, and a buffer solution (including mixed solvents) are used as reaction solvents at 10 to 50°C, preferably at 15 to 30°C in aqueous methanol while neutralizing with an aqueous sodium hydroxide solution. Add Tic +3 aqueous solution for 20 minutes~
The desired product can be obtained by reacting for 5 hours, preferably 30 minutes to 2 hours, and extracting with an organic solvent such as ethyl acetate, Hensen, or chloroform.

In addition, as mentioned above, the 2-acetinone derivative has N-
Without isolating the hydroxy-2-7 zetidinone derivative, it can be obtained directly by reducing a compound in which R3 is -0-R4 with sodium chloride in liquid ammonia. The raw material, 2-azetidinone derivative, can be added directly to the liquid ammonia of metallic sodium; however, if the raw material is poorly soluble, dissolve the raw material in a small amount of THE and add it little by little to obtain good results. The reaction is carried out at -50 to -30°C for 5 minutes to 1 hour, and after the reaction, ammonium chloride is added, and further C
After adding an extraction solvent such as H2Cl and expelling ammonia with nitrogen gas, the desired product can be obtained by a normal extraction operation.

Claims (5)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 means a hydrogen atom or a protecting group for a hydroxyl group, and R_2 is a lower alkyl group, a substituted lower alkyl group, an aryl group, a substituted aryl group. , means a heterocyclic group or a substituted heterocyclic group, and R_3 means a hydrogen atom or a protecting group for a carboxyl group) and its salts (2) The compound according to claim 1, wherein the substituents at the 2- and 3-positions have a 2S, 3R configuration. (3) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ By reacting acetoacetic acids represented by formaldehyde and thiols represented by the general formula R_2-SH, the general formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. ▼ which are characterized by forming the 3-oxobutyric acid derivative represented by, further reducing it, and optionally hydrolyzing and/or introducing a protecting group into the hydroxyl group. In the formula, R_1 means a hydrogen atom or a protecting group for a hydroxyl group, R_2 means a lower alkyl group, substituted lower alkyl group, aryl group, substituted aryl group, heterocyclic group, or substituted heterocyclic group, and R_3 means hydrogen A method for producing a butyric acid compound and its salts (representing a protecting group for an atom or carboxyl group, R_3_1 means a protecting group for a carboxyl group) (4) A general method characterized by reacting a compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ with a halogenomethyl sulfide derivative represented by the general formula X-CH_2S-R_2, and then hydrolyzing it if desired. Method for producing butyric acid compounds and their salts represented by the formula ▲Mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R
_1 means a hydrogen atom or a protecting group for a hydroxyl group, R_2 means a lower alkyl group, substituted lower alkyl group, aryl group, substituted aryl group, heterocyclic group, or substituted heterocyclic group, R_3 means a hydrogen atom or a carboxyl group R_3_1 means a protecting group for a carboxyl group, X means a halogen atom) (5) General formula ▲ Numerical formulas, chemical formulas, tables, etc. are available ▼ The 2-methylidenebutyric acid derivative represented by the general formula R_2-
A method for producing the threo isomer of a butyric acid compound or its salt represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ characterized by reacting with thiols represented by SH and further hydrolyzing if desired (in the formula , R_1 means a hydrogen atom or a protecting group for a hydroxyl group, R_2 means a lower alkyl group, substituted lower alkyl group, aryl group, substituted aryl group, heterocyclic group or substituted heterocyclic group, R_3 means a hydrogen atom or (8) The erythro form of a butyric acid compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ is oxidized to form the compound represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ This product is then heated to produce a 2-methylidenebutyric acid derivative represented by the general formula ▲Mathematical formula, chemical formula, table, etc.▼, which is then converted into a 2-methylidenebutyric acid derivative represented by the general formula R_2-SH in the presence of a base. A method for producing the threo isomer of butyric acid compound or its salt, which is characterized by reacting with the compound and further hydrolyzing and separating as desired.
In the formula, R_1 means a hydrogen atom or a protecting group for a hydroxyl group, R_2 means a lower alkyl group, substituted lower alkyl group, aryl group, substituted aryl group, heterocyclic group, or substituted heterocyclic group, and R_3 means hydrogen means a protecting group for an atom or carboxyl group, n means 1 or 2)