JPS61158986A - Penam derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I (R<1> is alkyl, aryl, or aralkyl; R<3> is H, or ester residue; R<4> is akyl, aryl, or aralkyl). EXAMPLE:5-Methylseleno-6-methoxypenam-3-carboxylic acid methyl ester. USE:An intermediate for producing 6-oxypenam useful as beta-lactamase inhibitor, etc. PREPARATION:A reactive derivative of a carboxylic acid shown by the formula R<1>O-CH2COOH is reacted with a compound (e.g., 2-methylseleno-4-methoxy carbonyl-1,3-thiazoline, etc.) shown by the formula II (R<3> is ester residue) in the presence of a base such as triethylamine.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a 6-oxypenam compound, and more specifically, in the following general formula, R' represents an alkyl group, an aryl group, or an aralkyl group, R2 represents a hydrogen atom or a benzoyloxy group, The present invention relates to a 6-oxypenam compound represented by the following formula, in which Rs represents an ester residue, a method for producing the same, and a novel intermediate in the method.

In recent years, resistance of bacteria to fused ring type β-lactam antibiotics such as penicillin and cephalosporin has become a problem, and the development of effective β-lactamase inhibitors has been eagerly awaited.

The main purpose of the present invention is to provide an efficient and highly stereoselective intermediate for the production of 6-oxypenams, which is expected to be useful as a β-lactamase inhibitor, and a general synthesis method for the production of 6-oxypenams. The objective is to provide a unique manufacturing method.

The present inventors have been researching the cycloaddition method of ketene and imine as a β-lactam ring formation method, but in particular, the reaction using a cyclic 2-thiazoline compound as the imine constructs the penum skeleton at once. This is an interesting method in that it can be done. Among them, as a method for producing a penam compound having an oxy substituent at the 6-position, conventionally, (a) a 2-
Thiazoline-4-carboxylic acid ester, (b) 2-phenyl (or furyl)-2-thiazoline-4-carboxylic acid ester, or (C) 2-methylthio-2-thiazoline in the presence of a base, ketene precursor α-methoxy (
A method of reacting with acetic acid chloride (or furyl) is known (A, K. Bose et al., J. Org, Che.
m.

39.2877 (1974): J, Heterocy
clicChem, 10.791 (1973)], but the method using the starting material (a) has a low yield due to the low reactivity of the thiazoline compound, and the method using the starting material (b) has a low yield due to the low reactivity of the thiazoline compound. It has poor versatility because the 5-position substituent (phenylbo or furyl) cannot be removed from (c), and although the yield is relatively good, (c) selectively removes the 2-methylthio group from the resulting penam compound. There are drawbacks, such as the fact that it is difficult to

The present inventors first made 2-methylthio-2-thia,
The corresponding benam compound can be obtained in high yield, and furthermore, this reaction proceeds stereoselectively, and when optically active 48 monomer is used as the thiazoline compound, 38% 5R%
6- represented by the following formula (IV) having a 6S configuration
It has been found that medoxypenam compounds can be obtained.

(IT) However, since it is difficult to selectively remove the methylthio group from the compound of formula (IV), it is of low value as an intermediate for deriving a more useful penam or penem compound.

Therefore, the present inventors have made efforts to find a thiazoline compound that can be stereoselectively cyclized in high yield and that can easily and selectively remove the 5-position substituent from the resulting penam compound. As a result of repeated research, in the following general formula, R4 represents an alkyl group, an aryl group, or an aralkyl group, and Rs has the above meaning. -'') is reacted with a reactive derivative of a carboxylic acid represented by the following general formula R'0-CH,C0OH (II), in which R1 has the above-mentioned meaning, in the presence of a base. , in the following general formula, R1, R1 and R4 have the above-mentioned meanings. A compound represented by the formula (
When the compound (ii) is reacted with trifi-butyltin hydride in the presence of a radical generator, the seleno group at the 5-position is easily separated, and in the following general formula, R' and Rs have the above meanings. It was discovered that a 6-oxybenem compound having the following formula was produced, and the present invention was completed.

Furthermore, in the present invention, when the compound of the above formula (1-a) is reacted with benzoyl peroxide, the following formula
.

In the formula, R1 and R1 have the above-mentioned meanings, and when this compound is treated with a base, a 6- It has also been found that oxybenem compounds are obtained.

The method of the present invention described above proceeds stereoselectively. For example, when optically active 48 monomer is used as the thiazoline compound in 21), the reaction proceeds stereoselectively as shown in the reaction formula below, and 38% PenaA (1-a'), 2R of 38,5R,68 via selenopenum (■') with 5B-,6S-configuration.

38.5R, 68 pentyloxybenam (■-b'
) and 5R,68 penem compounds (V') can be obtained.

Reaction Formula A In each of the above formulas, R1, RRlRl and R4 have the above-mentioned meanings, and X represents a group of a reactive derivative of a carboxyl group.

The stereochemical characteristics in the method of the present invention are determined by the formula (1v
The steric configuration at the 5- and 6-positions of the penum compound () is essentially determined by the steric configuration of the compound of formula (1), which is the starting material. That is, if the 4-position of the thiazoline compound of the formula (ship) is in the S-configuration, the 5- and 6-positions of the resulting compound of the formula ([Y) will be in the S-configuration.Furthermore, if the formula (rV) The elimination of the seleno group at the 5-position from the compound of formula (1-a) also proceeds stereoselectively, and the 5-
The 6- and 6-positions have trans configurations of 5R and 6S, respectively. The subsequent benzoyloxylation also proceeds highly stereoselectively, and the above formula (1-b) having 2R benzoyloxy groups
The compound is obtained. The double bond formation reaction by elimination of benzoic acid from the compound of formula (I-b) also proceeds with steric retention, and penem (V') in the trans configuration with 5R and 6S at the 5th and 6th positions, respectively, is formed. can get.

In addition, in the above-mentioned reaction acid A, optically active 4 is used as a starting material.
Although each reaction in the case of using a compound of formula (I') which is 8-unit is illustrated, in the method of the present invention, 4R-unitary or racemic compound may be used as a compound of formula (4R), and thereby each corresponding steric A product of configuration can be obtained.

Therefore, the formulas (1), (IV), (1-1L), (I
It should be understood that -b) and (V) include everything from optically active forms to racemic forms.

Formulas (1-a), (I-b) provided by the present invention
) and (V) are useful as synthetic intermediates for various penam or venem compounds expected to be useful as β-lactamase inhibitors and/or antibacterial agents.

In the above formula, the "alkyl group" represented by R1 or R4 may be linear or branched, such as methyl, ethyl, n-propyl, inpropyl, n-butyl, Inbutyl, 5ec
-1 carbon atom such as butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-octyl, inoctyl, dodecyl, tetradecyl, etc.
Lower straight-chain or branched alkyl groups having ~15, preferably 1 to 4 carbon atoms are included; r7! j-
For example, phenyl, α-naphthyl, β
-naphthyl group, etc.; further, "aralkyl group" includes aryl-substituted carbon atoms such as benzyl, phenethyl, phenylpropyl, naphthylethyl group, etc.
Four straight or branched lower alkyl groups are included.

On the other hand, examples of the "ester residue" represented by R3 include methyl, ethyl, propyl, isopropyl,
Linear or branched lower alkyl groups such as n-butyl, isobutyl, and tert-butyl; substituted or unsubstituted aralkyl groups such as benzyl, 4-nitrobenzyl, 4-methoxybenzyl, and 2,4-dimethoxybenzyl; etc.

The method of the present invention will be explained in more detail below.

The reaction between the reactive derivative of the carboxylic acid of formula (H) and the compound of formula I) is usually carried out in an inert organic solvent, and examples of organic solvents that can be used include 1, ethyl ether, and tetrahydrofuran. , dioxannato ethers; chlorinated hydrocarbons such as methylene chloride, chloroform, dichloroethylene, carbon tetrachloride; aliphatic or aromatic hydrocarbons such as n-hexane, toluene, benzene, and mixed solvents thereof, etc. Among them, methylene chloride, chloroform, ethyl ether, etc.>1
Preferably used.

The ratio of the reactive derivative of the carboxylic acid of the formula (It) to the notiazoline compound of the formula (I) is not strictly limited and may be varied over a wide range depending on the type of the compound used. It is convenient to use the reactive derivative of the carboxylic acid of formula (It) in the range of 1 to 5 mol, preferably in the range of 3.0 to 3.5 mol, per mol of the compound of formula (It).

As the reactive derivative of the carboxylic acid of formula (II), for example, acid halides and mixed acid anhydrides with ethyl or isopropyl carbonate, trifluoroacetic acid, p-toluenesulfonic acid, diethyl phosphoric acid, etc. are generally used. Acid chloride is particularly preferably used. The reaction between the reactive derivative of the carboxylic acid of formula (Ir) above and the compound of formula I is carried out in the presence of a base, and bases that can be used include triethylamine, triethylamine, Examples include tertiary amines such as diisopropylethylamine and dimethylaniline, and triethylamine is particularly preferably used. The amount of base used is
Usually, the appropriate amount is within the range of 1 to 6 mol, preferably within the range of 1.5 to 3.0 mol, per 1 mol of the reactive derivative of the carboxylic acid of formula (U). The reaction temperature is determined by the formula used (…)
Although it depends on the reactive derivative of the carboxylic acid, the base, the solvent, etc., mild temperature conditions of 0 to 50°C, preferably about θ°C to room temperature turbidity are convenient. Reaction times are generally 10 to 72 hours under heated conditions, more commonly 15 to 72 hours.
~36 hours is sufficient.

The compound of formula (IV) thus obtained is treated with di-n-butyltin hydride (in the presence of a radical initiator) to remove the seleno group bonded to the 5-position of the compound of formula (IV). can be forced to leave. Azobisinobutyronitrile (AIBN) is suitable as the radical initiator used in this reaction, and the amount used is generally 0.01 mol per mol of the compound of formula (IT).
~0.5 mol, preferably about 0.05-0.2 mol is convenient. Further, the IJ-n-butyltin hydride can be used in an amount of usually 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of the compound of formula (IY). The reaction can usually be carried out in an organic solvent. Examples of organic solvents that can be used include ethers such as ethyl ether, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as benzene and toluene; and acetonitrile, among which tetrahydrofuran and acetonitrile are preferably used.

The reaction temperature is within the range of 50 to 120°C, and the reflux temperature of the commonly used solvent is used. A reaction time of 1 to 12 hours, more preferably 3 to 5 hours, is sufficient.

By the above reaction, a 6-oxypenam compound represented by the following general formula, in which R1 and R1 have the above-mentioned meanings, is obtained, which is then reacted with benzoyl peroxide to obtain a 6-oxypenam compound represented by the following general formula: In which R1 and R1 have the above meanings, it can be changed to a 2-benzoyloxy-6-oxybenam compound represented by.

This reaction can usually be carried out in an organic solvent such as an aromatic hydrocarbon such as benzene or toluene; or a chlorinated hydrocarbon such as methylene chloride, chloroform or carbon tetrachloride;
Among them, carbon tetrachloride is preferably used. Formula (1-a)
The ratio of benzoyl peroxide to the compound of formula (1-IL) is not strictly limited and can vary widely, but is generally within the range of 1 to 10 mol, preferably 1 to 10 mol, per 1 mol of the compound of formula (1-IL). is conveniently used in a range of 2 to 4 moles. The reaction humidity depends on the solvent used, but
The reflux temperature of the solvent is usually used within the range of 40 to 120°C. The reaction time is generally about 1 to 10 hours, and usually about 4 to 6 hours is sufficient.

The compound of formula ([V), (1-a) and/or (1-b) obtained above can be prepared, if necessary, by a method known per se, such as extraction, 20-magnetography, recrystallization, and combinations thereof. It can be separated and/or purified by the following methods.

Furthermore, the ester residues of these compounds can be hydrolyzed to free benamcarboxylic acid, if necessary. The present inventors investigated the ester residue (R1
), for example, in the case of lower alkyl groups such as methyl, I
It has been found that scales can be easily removed by treatment with an enzyme such as 'orcin 1iver cste-rase. The hydrolyzate can be isolated as the Eshenmoser base salt, or by further treatment of this salt with potassium 2-ethylhexanoate, as the potassium salt, or as the free carboxylic acid. Further, when the ester residue is a substituted or unsubstituted aralkyl group such as benzyl, it can be eliminated by catalytic hydrogenation using radium carbon or the like as a catalyst according to a conventional method.

The penam compound of formula (1-a) or (I-b) obtained as described above is useful as an intermediate for various penam or penem compounds having an oxy substituent at the 6-position.

For example, the penam compound of formula (1-b) can be treated with a base, which is expected to be useful as a β-2 catamase inhibitor, and can also be used as a synthetic intermediate to produce more useful compounds. In the following formula, R1 and 7R3 have the meanings given above, and can be changed to penem compounds of the following formula.

Examples of the base that can be used for converting the compound of formula (1-b) to the compound of formula (V') include triethylamine,
Examples include organic bases such as diisopropylethylamine, 1°8-diazabicyclo(5,4,0)-7-undecene, and 1,4-diazabicyclo(112)octane; inorganic bases such as sodium carbonate and potassium carbonate;
, 8-diazabicyclo(5,4,0)-7-undecene is preferably used. Although the amount of the base used is not strictly limited, generally the compound 1 of the formula (1-b)
It is convenient to use within the range from 1 to 3 mol, preferably from 1 to 1.5 mol, based on the mole. This reaction is usually carried out in an inert organic solvent. Examples of organic solvents that can be used include diethyl ether, tetrahydrofuran,
Examples include ethers such as dioxane; aromatic hydrocarbons such as benzene and toluene; chlorinated hydrocarbons such as methylene chloride and chloroform; and dimethylformamide, among which methylene chloride is preferably used. The reaction temperature depends on the type of solvent and/or base used, but is generally -10 to 20 degrees Celsius, and generally -5 to 10 degrees Celsius.
The appropriate temperature is around room temperature, and the reaction time is generally 10 to 60 minutes.
Time purity is enough.

The resulting compound of formula (V) can be separated and/or purified by methods known per se, such as extraction, chromatography, recrystallization and combinations thereof.

The novel thiazoline compound represented by the above formula (1), which is a starting material for the method of the present invention, has the following reaction formula, where Y represents a halogen atom such as iodine, and R1 and R4 have the above-mentioned meanings.

According to methods known per se [C, Rreti et al., J.
, inorg, nucl, chem, 36.37
25 (1974), F. Cr1stiani et al., J.
C.S., Perkin II, 324 (1977)]
It can be made into pears.

Further, as a result of studying an efficient method for producing the compound of formula (VIA), the present inventors found that by reacting cysteine with carbon selenide, the following reaction formula: Reaction formula C In the formula, R8 has the meaning given above.

It has been found that the compound of formula (■) can be obtained with good yield according to the method. According to this method, an optically active compound of formula (■) can be obtained from optically active cysteine. A detailed description of this reaction is provided in Example 11.

Next, the method of the present invention will be explained in more detail with reference to Examples.

Example 15-Methylseleno-6-medoxypena 2-methylseleno-4-methoxycarbonyl-1,3-thiazolif (2 mmole, 4761+9; 4S/4R
=75/25, [α1%'-35,3° (C=1,3
7, CHClm ) ) methylene chloride (1d)
Triethylamine (4 mmol
e.

0.56 m) followed by methoxyacetic acid chloride (
A solution of 2,4 mmole, 0.2214) in methylene chloride (1,5 Nj) was added dropwise under a nitrogen stream over about 15 minutes, and after stirring at room temperature for 22 hours, triethylamine (1 mmole, 0.14 wl) and Methoxyacetic acid chloride (1 mmole, 0.09 ad
) in methylene chloride (1d) and diluted with 1d at room temperature.
Stirred for 4 hours. The reaction mixture was washed with 5% hydrochloric acid, saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound ( 0.5F, yield 80.6%) was obtained as a yellow oil. The optical isomer ratio of the product is 38.58.68/3R,
5R, 6R = 75/25.

[α]” (C=1.01, CHCl5); + 110
．． 1°' H-NMR (CDCIs, 100MHz);
6m26 (3H.

5XSeCHa), 3.66 (3H,S, 0CRs
), 3.81 (3B, S, COtCHm ),
3.62-4.02 (2B% ms C” Ht),
4.60 (IH, S, C'-H), 4.89 (I
H, dd, J=7.8.6.4, C”-H) IR (CHCIs): 1780.175QcrFL
'MS(M); Calculated value (CoH+5NO4SSe) 31
0.9729, measured value 310.973 (1 Example 2 Table 81 shows examples of compounds obtained by the same method as in Example.

Example 3. 6-Medoxypenammoo 3-carboxylic acid 5-methylseleno-6-medoxypenammoo 3-carphonic acid methyl ester (1,35 mmole).

418#P:38,5S,68/3R,5R,6R=7
5/25) and azobisin butyronitrile (0,03
To a solution of rrmole, 5 rq) in tetrahydrofuran (5d) under a nitrogen atmosphere, tri-n-butyltin hydride (1,35 mmole, 0.37d) was added.
The mixture was heated under reflux for 3 hours. The solvent was distilled off under reduced pressure, and acetonitrile/n-hexane (1:1) solvent (140i1) was added to the residue.
was added and mixed thoroughly. Separate the acetonitrile layer,
After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (229 x 3
S, 5R, 6S/3R, 5S, 6R = 75/25, yield 78.4) was obtained as a pale yellow oil.

[α]” (C=1.0, CHCl, ); +11
9.4゜'H-NMR (CDC1m, 100MH2);
δ3.42 (IH, d1Jax=6.3, HA) 3.
47 (IH.

d1JBX=3.4, HB), 3.54 (3H, S.

0CHs), 3.78 (3H-, 8% COICHI
), 4.50 (IH, %d, J=1.≦), 5°03
(IH, dd.

JAX=6.3, JBx=3.4, Hx), 5.10(
IH.

d, J=1.5, C'-H) IR (rseat): 1770.1740. ! 'MS
(M); Calculated value (C3HIINO4S) 217.04
08 Measured value 217.0377 Example 4. Examples of compounds obtained in the same manner as in Example 3 are shown in Table 2.

'nmflJ5. 2-benzoyloxy-6-methoxy♂- 6-medoxybenamum 3-carboxylic acid methyl ester A/
(1mmole, 2171i9; 38.5R, 6S
/3R,58,6R=75/25) and benzoyl peroxide (4 mmole, 96 glq) in carbon tetrachloride (1511j) was refluxed for 6 hours. After cooling, methylene chloride (2(1)) was added to the reaction solution, and the mixture was washed with a 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (68,4v:2R,3S
, SR, 6S/28, 3R, 58, 6R=75/25,
Yield: 64.2%) was obtained as colorless needle crystals.

Melting point: 111-112゜[α]" (C=1.02, CHCIg); -27.1
''HNMR (CDC1g, 100MHz): a3
．． 55 (3HXS, 0CHs), 3.83 (3
H,5XCOtCHn), 4.61 (1)1.
d, J=2.0, C'-H), 5.27(IH, d
, J=2.0, C'-H), 5.36(1)1°S, C
'-H), 6.83 (LH, S, C''-Fl),
IR(CHCIg); 1790.1750.1725
α-1MS (M'): Calculated value (CtsH+wNOe
S) 337.0619 Measured value 337.0612 Example 6. Examples of compounds obtained in the same manner as in Example 5 are shown in Table 3.

'A k ml 7. 6-Medoxy 2-Penem-3
-Cal-2-benzoyloxy-6-methoxypenam-3
-carboxylic acid methyl ester (0,O55rrmole
.

18.7 possible; 2R, 3S, 5R16S/2S, 3R15
1,8-diazabicyclo (5,4,0
)-7-undecene (0,06 mmole.

9.4m) was added thereto, and the mixture was stirred at 0°C for 30 minutes. Under reduced pressure
The solvent was distilled off, and the residue was purified by column chromatography to give the title compound (10,:3y 5
R, 6S158, 6Rmi 75/25, yield 86.7chi)
I got it.

[α]2d (C=0.35, CHClm): +58
．． 6゜' H-NMR (CDC1s, 100MHz)
; δ3.58 (3H.

S, 0GHs), 3.83 (3H, 51COtCH
s), 4.99 (IH, dd, J=1.5.1.0
, C'-H), 5.69 (I H, d, J=1.5
, C''-H), 7.16 (IH, d, J=1.0, C
"-H) IR(CHCIm); 1790.1720c!IL'
″″1) MS (M ); Calculated value (CaHsNOaS)
215.0251, measured value 215.0227 Example 8. Following the same method as in Example 7, 2-pensoyloxy-6-medoxyhenamoo 3-carboxylic acid benzyl ester (2R, 38°5R, 6S/2S, 3R,
58,6R=50150) to pale yellow oily 6-medoxy 2-penem-3-carboxylic acid benzyl ester (5
R,6S158.6R=50150) was obtained; yield 94
．． 8%.

'H-NMR (CDCI, 100MH2): δ3.
57 (3H.

8% 0CHs), 4.99 (IH, dd, J=
1.0.1.5, C'-H), 5.27 (2H% 8
% CO*CHtCaHs ), 5.67 (I H,
dSJ = 1.5, C'-H), 7.17 (IH, d
, J=1.0. C"-H), 7.30-7.45
(5HX mX C0tCHtCaHs)IR(CHC
Ig); 1790.1710cru-'MS(M
): Calculated value (CI4H13NO4S) 291.0565
, measured value 291.0581 Potassium 6-medoxybenamcarboxylic acid methyl ester (,o,
3 mmole, 65.1”P: 38%
5 R% 6 S/ 3 R% 5S, 6R=75/25
) in 0.1M phosphate buffer (pH 7.5) 28.5
aZlc suspension 1 and porcin 1iver
esterase (Sigma, 160 units
/q.

A solution of 0.15 d of prot, ) dissolved in 0.1 M phosphate buffer (5 d) was added, and the mixture was stirred at room temperature for 1 hour.

The reaction mixture was adjusted to pH 2.5 with 10% hydrochloric acid, and then extracted with ethyl acetate. After drying the extract over anhydrous sodium sulfate, the solvent was distilled off and the residue was diluted with methylene chloride (1,5
3.3.6.9° 9-pentamethyl-2,10-diazabicyclo-[4,4,0]-1-dece7 (0,25nynole, 51.3k) A methylene (1.5 mg) solution was added and the mixture was allowed to stand at room temperature for 5 minutes, and then the molten residue was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 6-medoxypenamyl 3-
Carboxylic acids 3, 3, 6.

9.9-pentamethyl-2,10-diazabicyclo-(
4,4,0]-1-decene (62■) was obtained as colorless needles. This material was suspended in ethyl ether (3 wl), and under stirring, potassium 2-ethylhexanoate A (0,1
A solution of 3 mmole, 331F) in tetrahydro7rane (4M) was added. After reacting at room temperature for 1 hour, the resulting precipitate was filtered and diluted with tetrahydrofuran-ethyl ether (1 hour).
:1) Washed with a mixed solution and recrystallized from water to acetone to obtain the title compound (29.9μ, yield 41.4%) as colorless needles: 3S, 5R.

6S/3R,58,6R=75/25° Melting point: 186~
188℃ (decomposition) [α]” (C=0.31, CH*OH); +61
．． 9゜'HNMR (D*O1100MHz): δ3.3
7-3.50 (2H, mXC"-H), 3.55 (3
HXS%0CH1), 4.66 (IH, d, J=1.
2, C'-H), 4.91 (IH, ddXJ=5.4.
4.4, C''-H), 5.15 (IH, d, J=1
．． 2, C'-H) IR (KBr); 1750.1590
cIrL-'2-benzoyloxy-6-methoxypenam-3-carboxylic acid benzyl ester (o, o32IT
rrIole113.2++v; 2R, 3S, 5R, 6
8/2S, 3R.

5S, 6R) in tetrahydrofuran (1,28a#) was added with IQ% Pd-C (26,4■), and hydrogenation was carried out at normal pressure and room temperature for 24 hours while stirring.

The reaction solution was filtered and the residue was washed with methanol. The washing solution and washing solution were combined, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (8
,4q, 2 R13S, 5R,6S/28,3R,
5S, 6R=75/25, yield 81.6%) was obtained as colorless amorphous crystals.

Melting point: 118-120°C [α]: (C=0.14, CIHCIm): 36
．． 4゜' H-NMR (CDC1s, 100MHz)
; δ3.55 (3H, S, OCR, l), 4.62
(I H, m, C' - H), 5.27 (I H, d
, J=1.9, c8-! 5.41 (I H,S,
C'-H), 6.88 (IH, S, C"-H), 7.
3Q ~7.60 (3H.

IR(CHCIg): 1785.1730cIrL-
Heavy MS (M'): Calculated value (C+4H+5NOaS)
323.0463, measured value 323.0473 D-cystine methyl ester (17 rrmole.

Niseleno carbon (17 mmole, 2.88 f
) was added. After stirring for 20 minutes under water cooling, transfer the reaction solution to a celiac)
After filtration, the filtrate was washed with saturated aqueous ammonium sulfate and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1,5F) as a yellow oil.

39.5%).

ra〕e” c C=0.32, CHCl3): +
59.3゜' HNMR (CDC1s, 100MH2)
;δ3.77(2)TXd, J=7.8, C11-H
), 3.86 (3H.

S, C0ICHs), 4.83 (I H,t, J
=7.8, C'-H), 8-83 (I HXb r
S%NH)I R(CHCIs); 1750
crn-'VLSCM); calculation [direct(C5HyNO
t5Se) 224.9362, measured value 224.93
70 2-methylthio-4-methoxycarbonyl-1, instead of 2-methylseleno-4-methoxycarbonyl-1,3-thiazoline (4S/4R=75/25) in Example 1.
Using 3-thiazoline (48/4R=75/25),
A similar reaction was carried out to obtain the title compound (38,5R
, 6S) was obtained (yield 57.6%).

[α]υ (C=0.8, CHCIm): 125.8
゜' H-NMR (CDC13,400MHz); J2
．． 36 (3HXS, SCH*'), 3.67 (3
H, S, 0CHs), 3, 76 (IH, ddSJA
X=7.8, JAB=11.5, ratio, ), C81 (3
H, S, coscHs), 3.90 (IHXddX
JBX = 6°8, JAB = 11.5, DanB), 4.7
0 (IH, SXC@-H'), 4.88 (I H, d
dXJAx=7.8, JBx=6.8, HX)IR(C
HCIg): 1780, 1755cR
-凰MS(M”'); Calculated value (CeHtsNO*St'
) 263.0286, measured value 263.0303 011: Selenium A (0.19 mole.

15? ) and indium borohydride (062 mol
Ethanol (507) was added little by little under a nitrogen stream to the mixture of (e, 7.859), and the mixture was stirred at room temperature for 5 minutes. After further adding methanol (137 mg) and stirring for 10 minutes, 2-methylthio-4-methoxycarbonyl-
1,3-thiazoline (0,105mole, 2O
A methanol (270a7) solution of f) was added and stirred for 15 hours. The number of yellow needle crystals produced was counted. The p solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain yellow needle crystals (total of 2Of crystals No. 1 and No. 2).

85.3%).

Melting point: 131-132℃'T(-NMR(CDCl2.100MHz): δ
3.77 (2H, d, J=7.8, C"-Fl), 3
．． 83 (3HXS.

C0ICHs), 4.83 (IHXt, J=7.8
, C4-H), 8.83 (IHXbrs, NH)IR(
KBr); 1725cm-■ 4-methoxycarbonyl-1,3-thiazolidine-2-
Selenone (43mmole, 8.969) and triethylamine (44rrwnole, 6.13wl)
) (D In methanol (43m) solution, methyl iodide A/
(44mmole.

2.7614) was added and stirred at room temperature for 30 minutes. The reaction solution was poured into saturated brine (5Q ysrl ) and extracted with methylene chloride. After drying the extract over anhydrous sulfuric acid (IJ), the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (9.14r, 96%) as a pale yellow oil.

'HNMR (CDCIs, 100MHz): δ149(
3H.

8% to 5eCH 3.61 (I H% dlJAX
=9.3, Cs- and 0.3.64 (II(, d, J
Bx=8.3, c'-p, )3.81 (3HXS,
C0tCHs), s, o 6 (I H.

dd, JAX=9.3, JBX=8.3, C4-flea) IR (CHCIg): 1740, 1555 1MS
(M); Calculated value (CaHoNOtSSe) 238.95
19, measured value 238.9519 2-methylseleno-4-methoxycarbonyl-1,3-
A methanol solution of 0.4 N potassium hydroxide (12.5 m
1) and water (4-) were added, and the mixture was stirred at room temperature for 1 hour.

The solvent was distilled off under reduced pressure, and the residue was dimethylformamide (6d
) and benzyl bromide (5 rrmole.

0.62 ml) was added and stirred at room temperature for 15 hours.

Water (50 aJ) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extracted layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1,11?, 70) as a pale yellow oil. .7ch) was obtained.

'HNMR (CDC1s, 1nOMHz): δ2.48
(3HS8XSeCHs), 3.60 (IH, d.

JAX=9.3, C'-H, ), 3.62 (IH,
d.

JBx=8.3, C'-■-15,08 (I H, dd
.

JAx=9.3, JBX8.3, C'-H,), 5.2
3(2H,S, C0tCHtCsHs), 7.36
(5H.

8% C0tCHtCsHs) IR (neat): 1740,1555cIIL'
MS (M), calculated value (C + tHINOtsse) 314
．． 9830° Measured value 314.9786°

Claims (1)

[Claims] 1. General formula R^1O-CH_2COOH (II) In the formula, R^1 represents an alkyl group, an aryl group, or an aralkyl group. ,
There are chemical formulas, tables, etc. ▼ (III) In the formula, R^3 represents an ester residue, and R^4 represents an alkyl group, aryl group, or aralkyl group. Reacts with the compound shown in the presence of a base. A method for producing a compound represented by the general formula ▲ mathematical formula, chemical formula, table, etc. ▼ (IV) where R^1, R^3 and R^4 have the above meanings. 2. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) In the formula, R^1 represents an alkyl group, aryl group, or aralkyl group, R^3 represents a hydrogen atom or an ester residue, and R^ 4 represents an alkyl group, an aryl group, or an aralkyl group. 3. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (IV) In the formula, R^1 represents an alkyl group, aryl group, or aralkyl group, R^3 represents an ester residue, and R^4 represents an alkyl group. represents a group, an aryl group, or an aralkyl group in the presence of a radical generator.
-By reacting with butyltin hydride, a compound represented by the general formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I-a) In the formula, R^1 and R^3 have the above meanings. , and if necessary, the compound of the above general formula (I-a) is reacted with benzoyl peroxide to introduce a benzoyloxy group at the 2-position of the penum ring. General formula ▲ Numerical formula, chemical formula, There are tables etc.▼(I) In the formula, R^2 represents a hydrogen atom or a benzoyloxy group, and R^1 and R^3 have the above meanings. A method for producing a penum compound represented by the following. 4. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I-b) In the formula, R^1 represents an alkyl group, aryl group, or aralkyl group, and R^3 represents a hydrogen atom or an ester residue. The compound shown in 5. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I-b) In the formula, R^1 represents an alkyl group, aryl group, or aralkyl group, and R^3 represents an ester residue. Production of a venem compound represented by the general formula ▲Mathematical formula, chemical formula, table, etc., characterized by treating the compound with a base▼(V) In the formula, R^1 and R^3 have the above meanings Method. 6. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) In the formula, R^3 represents a hydrogen atom or an ester residue, and R
A thiazoline derivative represented by: ^4 represents an alkyl group, an aryl group, or an aralkyl group. 7. General formula characterized by reacting cysteine ester with carbon diselenide ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VII) In the formula, R^3 represents an ester residue. Production method.