JPH05201968A - Synthetic intermediate for 1beta-substituted carbapenem - Google Patents

Abstract

PURPOSE:To provide a compound useful as a synthetic intermediate for 1- substituted carbapenem derivative which is known as an excellent antibacterial agent. CONSTITUTION:The compound of formula I [R<1> is H or OH-protecting group; R<2> is 1-6C alkyl, 1-6C alkoxy, halogen, etc.; R<3> is CYNR<5>R<6> (Y is O or S; R<5> and R<6> are 1-6C alkyl, aryl, aralkyl, etc.); R<4> is H or amino-protecting group)], e.g. (2R)-2-[(3S,4S)--3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-2-oxo-4- azetidinyl]thiopropionic acid S-(2-diethylaminocarbonylphenyl) ester. The compound of formula I can be produced by reacting a silyl enol ether of formula II (R<8> to R<10> are 1-4C alkyl or phenyl; Z is 0 or S) with an azetidinone derivative of formula III (R<11> is acyloxy, alkylsulfonyl, etc.) in the presence of a Lewis acid (e.g. zinc oxide) in a solvent (e.g. methylene chloride) at -10 to +70 deg.C.

Description

Detailed Description of the Invention

[0001]

The compound (I) of the present invention is a useful intermediate in the synthesis of 1-substituted carbapenem derivatives which are excellent antibacterial agents.

[0002]

2. Description of the Related Art Introducing a substituent at the 1β-position of a carbapenem antibiotic having strong antibacterial activity not only makes it chemically stable but also protects against dihydropeptidase I (DHP-I) existing in the body. It was found to be stable. 1
Carbapenem antibiotics having a substituent at the β-position have not been obtained naturally, so it is necessary to make them synthetically, and the synthetic method has received a great deal of attention, and various synthetic methods have been studied. As one of the synthetic methods, silyl enol ether obtained from thiopropionic acid S-phenyl ester and (3R, 4R) -3-[(1R) -1-t-butyldimethylsilyloxy) ethyl] -4-acetoxy-
The 2R-isomer (a), which is a key intermediate of 1β-methylcarbapenem antibiotics, has been synthesized by reaction with 2-azetidinone or its 1-trimethylsilyl derivative. [T.Shibata et al, Tetrahedron Letters, 26 , 4793
(1985); CUKim et al, Tetrahedron Letters, 28 , 507 (19
87); A. Martel et al, Can. J. Chem., 66 , 1537 (1988)]. However, in these methods, the ratio of desirable 2R-thiopropionic acid derivative and its 2S-isomer is 1.
6/1, 1/19, 1/9, which was not a satisfactory method for synthesizing the desired 2R-isomer.

[0003]

[Chemical 2]

[0004]

DISCLOSURE OF THE INVENTION The present inventors have more selective a 2R-thiopropionic acid derivative in which a silyl enol ether derived from thiopropionic acid S-phenyl ester in which a phenyl group has an amide group as a substituent is desirable. The present invention has been completed.

[0005]

The present invention has the general formula

[0006]

[Chemical 3]

Is a compound having

In the above formula, R ¹ represents a hydrogen atom or a hydroxyl-protecting group, R ² represents a linear or branched alkyl group having 1 to 6 carbon atoms, a straight chain having 1 to 6 carbon atoms or A branched-chain alkoxy group, a halogen atom, a phenyl group having an unsubstituted or a substituent selected from the following α group or a phenoxy group having an unsubstituted or a substituent selected from the following α group, R ³ is CYNR ⁵ R ⁶ groups (in the formula,
Y represents an oxygen atom or a sulfur atom, R ⁵ and R ⁶ are each independently a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, an unsubstituted or substituted substituent selected from the α group below. Or an aralkyl group which is unsubstituted or has a substituent selected from the following α group, or R ⁵ and R
⁶ together formula _{- (CH 2) m (X} ) L (CH 2) n - group (wherein, m
And n are the same or different and represent 0 to 5 (provided that m + n is 2 or more), L is 0 or 1, X is oxygen, a sulfur atom or an NR ⁷ group (R ⁷ is a carbon number of 1 to 6). Straight-chain or branched-chain alkyl groups, straight-chain or branched-chain aliphatic acyl groups having 1 to 6 carbon atoms, unsubstituted or the following α
An aromatic acyl group having a substituent selected from the group is shown. ) Is shown. ) Is shown. ) As a substituent and which may have a substituent selected from the following α group, R ⁴ represents a hydrogen atom or an amino-group protecting group, Z represents oxygen or Indicates a sulfur atom. In the above general formula, the halogen atom of R ² and α group is fluorine, chlorine and bromine, and preferably fluorine and chlorine.

The hydroxyl group-protecting group for R ^{1 is} a hydroxyl group-protecting group commonly used in the synthesis of carbapenem derivatives, and is preferably a tri-group such as t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylsilyl and triethylsilyl groups. It is a substituted silyl group, an aralkyloxycarbonyl group such as benzyloxycarbonyl or p-nitrobenzyloxycarbonyl group, or an optionally substituted acetyl group such as acetyl, chloroacetyl or methoxyacetyl.

The amino-protecting group for R ^{4 is} an amino-protecting group commonly used in the synthesis of carbapenem derivatives, and is preferably t-butyldimethylsilyl, t-butyldiphenylsilyl, trimethylsilyl or triethylsilyl group. Is a tri-substituted silyl group.

Examples of the linear or branched alkyl group having 1 to 6 carbon atoms of R ² , R ⁵ , R ⁶ and R ⁷ include methyl, ethyl, propyl, i-butyl, pentyl and hexyl groups. And preferably a methyl group or an ethyl group.

Examples of the alkyl moiety of the straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms for R ² include those similar to the above-mentioned alkyl groups, and preferably methoxy,
It is an ethoxy group.

Examples of the alkyl moiety of the linear or branched aliphatic acyl group having 1 to 6 carbon atoms for R ⁷ include methyl, ethyl, propyl, i-butyl, pentyl group, and the like. , Methyl and ethyl groups.

Examples of the alkyl moiety of the α-group alkylamino group having 1 to 4 carbon atoms and the dialkylamino group having 2 alkyl groups having 1 to 4 carbon atoms include those similar to the above alkyl groups. Suitably, propyl and i-
It is a butyl group.

The substituents selected from Le group and an unsubstituted or below α group - [0015] ants having substituents selected from unsubstituted or below α group of R ⁵ and R ⁶ CYNR of ⁵ R ⁶ groups R ³ The aryl portion of the aromatic aralkyl group which has an unsubstituted aralkyl group or a substituent selected from the following α group of the aralkyl group having R ⁷ is preferably a phenyl group.

The alkylenedioxy group having 1 to 3 carbon atoms in the α group is preferably a methylenedioxy group.

Specific examples of the compound having the general formula (I) of the present invention include the compounds shown in Tables 1 to 8, but the present invention is not limited to these compounds.

In Tables 1 to 4, the formula (I-
1) and Tables 5 to 8 use the formula (I-2).

[0019]

[Chemical 4]

[0020]

[Table 1]

[0021]

[Table 2]

[0022]

[Table 3]

[0023]

[Table 4]

[0024]

[Table 5]

[0025]

[Table 6]

[0026]

[Table 7]

[0027]

[Table 8]

In the table, Me is a methyl group, ^t Bu is a t-butyl group, Ph is a phenyl group, Ar is a substituted phenyl group, and (m) Me is m.
- position to have a methyl group in, PNZ the p- nitrobenzyloxycarbonyl group, m-CH _3: shows that with m-position to the methyl group.

In the above table, preferred compounds include 1-
1, 1-2, 1-3, 1-6, 1-16, 1-26, 1
-27, 1-28, 1-29, 1-30, 1-31, 1
-37, 1-38, 1-39, 1-40, 1-42, 1
-55, 1-56, 1-59, 1-60, 1-63, 1
-66,1-68,1-69,1-70,1-71,1
-75,2-3,2-4,2-5,2-8,2-21,
2-25, 2-46, 2-47, 2-48, 2-49,
2-50, 2-51, 2-61, 2-63, 2-65,
2-69, 2-70, 2-71, 2-72, 2-76,
2-84, 2-85, 2-86, 2-87, 2-88,
2-89, 2-92, 2-94 and 2-96, more preferably 1-1, 1-2, 1-3, 1-6, 1-
16, 1-26, 1-27, 1-28, 1-29, 1-
30, 1-31, 1-40, 1-56, 1-60, 1-
63,1-66,1-68,1-69,1-70,1-
71,2-3,2-4,2-5,2-8,2-21,2
-25,2-61,2-63,2-65,2-69,2
-70, 2-71 and 2-72, most preferably
1-2, 1-3, 1-56, 1-60, 1-67, 2-
3,2-4,2-5,2-8. The compounds of the present invention can be prepared by a variety of methods, the general techniques of which are well known in the art for the preparation of compounds of this type.

For example, the compound has the formula (II)

[0031]

[Chemical 5]

(In the formula, R ² , R ³ and Z are as described above, R ⁸ , R ⁹ and R ¹⁰ are the same or different and each represents an alkyl group having 1 to 4 carbon atoms or a phenyl group.)
A compound of formula (III)

[0033]

[Chemical 6]

It is prepared by reacting a compound of the formula (wherein R ¹ and R ⁴ are as described above, R ¹¹ is an acyloxy, alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl group).

More preferably, the compound of formula (III) has the formula
(IIIa)

[0036]

[Chemical 7]

Since it has a configuration as shown in,
Formula (Ia)

[0038]

[Chemical 8]

The compound of ## STR7 ## is obtained.

Examples of the alkyl group represented by R ⁸ , R ⁹ and R ¹⁰ include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and t-butyl groups. Examples of preferred groups of formula SiR ⁸ R ⁹ R ¹⁰ include t-butyldimethylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl and t-butyldiphenylsilyl groups.

The acyloxy group represented by R ¹¹ is an aliphatic or aromatic carboxylacyloxy group. In the case of aliphatic acyloxy groups, these are preferably 1-6.
An alkanoyloxy, haloalkanoyloxy or alkenoyloxy group, each having 2 to 4 carbon atoms, and preferably an alkanoyloxy group.
Examples of such groups include acetoxy, propionyloxy and butyryloxy groups. In the case of an aromatic acyloxy group, it is an arylcarbonyloxy group, and the aryl moiety is as defined and exemplified above. A preferred group is the benzoyloxy group. In the case of alkylsulfonyl and alkylsulfinyl groups, the alkyl moiety has 1 to 6, preferably 1 to 4 carbon atoms, examples of alkyl moieties of such groups include:
Included are methyl, ethyl, propyl and isopropyl groups. In the case of arylsulfonyl and arylsulfinyl groups, the aryl moiety may be as defined and exemplified above, examples of aryl moieties of such groups include phenyl and p-tolyl groups. Preferably R ¹¹ is an acetoxy, benzoyloxy, phenylsulfonyl, phenylsulfinyl, tolylsulfinyl or methylsulfinyl group.

In this reaction, a silyl enol ether of formula (II) is reacted with an azetidinone derivative of formula (III). The reaction usually takes place preferably in the presence of a solvent and a Lewis acid.

Examples of Lewis acids used in the reaction include zinc chloride, zinc bromide, zinc iodide and boron trifluoride etherate. Of these, zinc chloride or zinc iodide is preferable.

The reaction usually takes place preferably in the presence of a solvent. If the solvent used does not adversely affect the reaction or the reagent used and can dissolve the reagent at least to some extent, its properties are not particularly limited. Examples of suitable solvents include
Halogenated hydrocarbons, especially halogenated aliphatic hydrocarbons,
Examples include methylene chloride, chloroform and 1,2-dichloroethane; ethers such as tetrahydrofuran and 1,2-dimethoxyethane; and nitrites such as acetonitrile. Of these, methylene chloride, chloroform or 1,2-dichloroethane is preferably used.

The reaction can be carried out over a wide range of temperatures and the exact reaction temperature is not critical to the invention. In general, it is convenient to carry out the reaction at a temperature of -10 ° C to 70 ° C, more preferably 10 ° C to 50 ° C. The time required for the reaction also varies widely depending on many factors, notably the reaction temperature and the nature of the reagents and solvents used. However, if the reaction is carried out under the preferred conditions as outlined above, a period of 10 minutes to 24 hours is usually sufficient.

The compound of formula (I) thus obtained can be recovered from the reaction mixture by any conventional method.
For example, as an example of a suitable recovery method, a solvent such as methylene chloride or ethyl acetate is added to the reaction mixture, the mixture is separated, the organic layer is washed with water, and finally, thin layer chromatography or flash chromatography through silica gel is performed. The desired compound is isolated by a suitable means such as chromatography or purified by means such as crystallization or recrystallization.

The formula used as the starting material in this reaction
The silyl enol ether of (II) is a compound of formula (IV): R ² CH ₂ COZR ³ (IV) (wherein R ² , R ³ and Z are as defined above) is a compound of formula (V): R ⁸ R ⁹ R ¹⁰ SiW (V) (wherein R ⁸ , R ⁹ and R ¹⁰ are as defined above)
Represents a halogen atom such as a chlorine atom, or a leaving group such as a sulfonyloxy group such as a trifluoromethanesulfonyloxy group), and can be prepared by reacting in the presence of a base.

The reaction is usually and preferably effected in the presence of solvent. There is no particular limitation on the nature of the solvent used as long as it does not adversely affect the reaction or related reagents and can dissolve the reagents to a certain extent. Examples of suitable solvents include ethers such as diethyl ether, 1,2-dimethoxyethane and tetrahydrofuran; and hydrocarbons, especially aliphatic hydrocarbons such as hexane or cyclohexane, any two of these solvents. Mixtures of the above may also be used.

The yield of the reaction may be one or more of the following solvents:
It can be improved by adding to the solvent of one or more kinds. Examples of such a solvent to be added include hexamethylphosphoric triamide (HMPA), N, N-dimethylformamide, N, N-dimethylacetamide, N, N ¹ -dimethylpropyleneurea, N-methylpyrrolidone and N-
Methyl piperidone is mentioned.

Examples of the base used in this reaction include diisopropylamine, hexamethyldisilazane,
Mention may be made of the lithium, sodium or potassium salt of dicyclohexylamine or 2,2,6,6-tetramethylpiperidine.

The addition of one or more bases and the above-mentioned bases may improve the yield of the compound of formula (II). Examples of such bases include tertiary amines such as triethylamine.

The reaction can be carried out over a wide range of temperatures and the exact reaction temperature is not critical to the invention. In general, it is convenient to carry out the reaction at a temperature of -90 ° C to 20 ° C, more preferably -78 ° C to -20 ° C. The time required for the reaction also varies widely depending on many factors, notably the reaction temperature and the nature of the reagents and solvents used. However, if the reaction is carried out under the preferred conditions as outlined above, 5 minutes to 4 hours, more preferably 1
A period of 0 to 30 minutes is usually sufficient.

The compound of formula (II) obtained can be recovered from the reaction mixture by conventional methods. For example, water in the reaction mixture,
A saturated aqueous solution of sodium hydrogen carbonate or triethylamine is added, the mixture is extracted with an organic solvent, and then purified by a means such as column chromatography or distillation to recover the product in good yield.

When R ³ represents a phenyl group, R ² represents a methyl group and Z represents a sulfur atom, the resulting compound of formula (IV) is a substituted S -phenylthiopropionate, which is It can be used as a starting compound in the reaction.

It is prepared as shown in Reaction Schemes A and B below.

[0056]

[Chemical 9]

[0057]

[Chemical 10]

[0058]

[Chemical 11]

[0059]

[Chemical 12]

In the above formula, R ^3a , R ⁵ and R ⁶ are as defined above. R ¹² is an aryl group (as defined above), eg a phenyl or tolyl group, R ¹³ is a lower alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, eg a methyl or ethyl group. Represent.

In Reaction Scheme A, a substituted S -phenylthiopropionate, a compound of formula (IVa) can be prepared from a compound of formula (VI) and a compound of formula (VI) is 2,2 ¹ -dithio. It is easily obtained by reacting a benzoic acid derivative with a halogenating agent such as thionyl chloride.

In step A1, the secondary amine R ⁵ R ⁶ N
H is reacted with a compound of formula (VI) in the presence of an organic amine such as triethylamine or an inorganic base such as sodium carbonate to give a compound of formula (VII). In step A2, the compound of formula (VII) is reacted with propionic anhydride in the presence of a metal having reducing activity such as zinc.

Alternatively, in the reaction process table B, the formula (V
The compound of formula (IVa) is prepared using the thiosalicylic acid derivative of III) as a starting material.

In step B1 of this reaction scheme, the compound of formula (VIII) is protected with a thiol group of the compound of formula (VIII) by reacting it with an aromatic acyl halide such as benzoyl chloride. In step B2, the compound of formula (IX) is treated with 2-chloro-
In the presence of a dehydrating condensing agent such as 1-methyl-pyridium iodide is reacted with a secondary amine R ⁵ R ⁶ NH, give an amide compound of formula (X).

In step B3, the aromatic acyl protecting group R ¹² CO is removed by treating the compound of formula (X) with a base such as sodium methoxide to give the compound of formula (XI).

In step B4, a compound of formula (XI) is prepared by reacting with an active derivative of propionic acid such as propionyl chloride or propionic anhydride in the presence of a base.
Of the compound of formula (IV
The desired substituted S -phenylthiopropionate of a) is obtained.

Alternatively, the compound of formula (XI) is
II) from the anthranilic acid derivative by conventional means (eg,
(As disclosed in Organic Syntheses Coll. Vol. III, page 809) via steps B5 and B6. In step B5, the compound of formula (XII) is diazotized and then reacted with potassium S -ethyldithiocarbonate to give the compound of formula (XIII). Process B
In 6, the compound of formula (XIII) is hydrolyzed with a base such as potassium hydroxide to give the compound of formula (XI).

In reaction process table B, R ³ is a substituted phenyl group,
A method for preparing a compound of formula (IV) in which Y is an oxygen atom and Z is a sulfur atom, that is, a compound of formula (IVa) is shown. Corresponding compounds in which Y is a sulfur atom or Z is an oxygen atom can be prepared as shown in Reaction Schemes C and D below.

In the above formula, R ^3a , R ⁵ and R ⁶ are as defined above, and Hal represents a halogen atom.

In the reaction process table C, the carbonyl group-forming portion of the amide group at the 2-position of the compound of formula (IVa) is converted to a thiocarbonyl group by reaction with a Labesson's reagent or a thiolating agent such as phosphorus pentasulfide. This reaction is known in the art and may be carried out using a general and known solvent, reaction temperature and reaction time.

In the step D1 of the reaction process table D, the formula (I
The compound of formula (Va) is halogenated, preferably chlorinated, with a conventional halogenating agent such as oxalyl chloride, oxalyl bromide, thionyl chloride or thionyl bromide and a conventional halogenating condition, and preferably chlorinated the carboxyl group at the 2-position to give a compound of the formula (XVI)
To obtain the compound of This compound of formula (XVI) is then converted to formula R
Reaction with a secondary amine of ⁵ R ⁶ NH in the presence of an organic tertiary amine such as triethylamine or an inorganic base such as sodium carbonate provides the desired compound of formula (XVII).

The azetidinone derivative of formula (I) of the present invention can be easily converted into the corresponding carbapenem compound by reaction with a suitable mercaptan derivative of formula R ¹⁴ SH, which reaction can be carried out in a conventional manner (see, for example 60-1976
(As described in No. 4) and the formula (XV
The compound of III) is obtained. This is then cyclized by a conventional method (for example, as described in JP-A-62-54427) to give a carbapenem derivative of formula (XIX) as shown in the following reaction process tables E and E ^1. obtain.

In these formulas, Z, R ¹ , R ² , R ³ and R ⁴ are as defined above, and R ¹⁴ represents various organic groups of the type usually used at the designated position of the carbapenem derivative. .. As can be seen from the reaction process table E ¹ , the configuration at the carbon to which the azetidine 3-position and the group represented by R ² are bonded is retained, and therefore these important compounds can be conveniently and efficiently prepared.

On the other hand, the compound of formula (C) described in the above-mentioned US Pat. Nos. 4,895,939 and 4,772,683 is the mercaptan of the formula R ¹⁴ SH in the first step of Reaction Process Table E. It is not suitable for this reaction because it does not react easily and therefore the compound of formula (XVII) cannot be easily formed. On the other hand, T.Shib
ata et al. [Tetrahedron Letters, 26 , 4793 (1985)], CU
Kim et al. [Tetrahedron Letters, 28 , 507 (1987)] and
In the reaction described by A. Martel et al. [Can. J. Chem., 66 , 1537 (1988)], the desired 2 R -isomer is relatively high in a mixture with large amounts of the undesired 2 S -isomer. It is difficult and expensive to isolate because it is obtained in low yields.

[0075]

The S-phenyl ester moiety of the compound (I) of the present invention is easily replaced with a suitable mercaptan derivative RSH according to a conventional method (JP-A-60-19764) to produce a compound (XVIII). It is possible to

The obtained compound (XVIII) is a carbapenem derivative (X) according to the conventional method (Japanese Patent Publication No. 62-54427).
IX). Thus, the compound (I) of the present invention is a useful intermediate in the synthesis of 1β-methylcarbapenem derivative (XV).

[0077]

【Example】

[0078]

Example 1 (2R) -2-[(3S, 4S) -3-[(R) -1-]
(T-Butyldimethylsilyloxy) ethyl] -2-o
Xo-4-azetidinyl] thiopropionic acid S- (2
-Diethylaminocarbonylphenyl) ester and
(2S) isomer of silyl enol ether obtained in Reference Example 1 911 mg
(2.40 mmol) and (3R, 4R) -3-[(R) -1- (t
-Butyldimethylsilyloxy) ethyl] -4-acetoxy-2-azetidinone (340 mg, 1.21 mmol) in methylene chloride (12 ml) was added with anhydrous zinc chloride (330 mg, 2.42 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with water and dried, and then the solvent was distilled off. The residue was separated and purified on a Rover column [hexane-ethyl acetate (1: 1)] to give 61 mg (10%) of 2S-isomer and 48 of 2R-isomer.
7 mg (82%) were obtained. mp125-126.5 ° C (hexane-ethyl acetate) [2S-
Isomer]; mp130.5-132 ° C (isopropyl ether) [2R-isomer] IR spectrum (KBr) cm ^-1 : [2S-isomer] 3182, 1765, 1711, 16
29,953,774 [2R-isomer] 3086,1762,1700,16
37,965,829 NMR spectrum (270 MHz, CDCl ₃ ) δppm: [2S-isomer] 0.06 (3H, s), 0.07 (3H, s), 0.87 (9H, s),
1.05 (3H, t, J = 7Hz), 1.26 (3H, d, J = 6Hz), 1.26 (3H, t, J = 7H
z), 1.28 (3H, d, J = 7Hz), 2.71-2.83 (2H, m), 3.00-3.21 (2H, n
onet-like, J = 7Hz), 3.35-3.80 (2H, broad), 3.63 (1H, d, J = 9
Hz), 4.14 (1H, quintet, J = 6Hz), 7.00-7.30 (1H, br.s), 7.30
-7.35 (1H, m), 7.42-7.53 (3H, m) [2R-isomer] 0.08 (6H, s), 0.87 (9H, s), 1.03 (3H, t, J =
7Hz), 1.21 (3H, d, J = 6Hz), 1.25 (3H, t, J = 7Hz), 1.29 (3H, d,
J = 7Hz), 2.96-3.15 (4H, m), 3.20-3.85 (2H, broad), 3.96 (1
H, dd, J = 2Hz, 4Hz), 4.19 (1H, quintet, J = 6Hz), 5.90-6.10 (1
H, br.s), 7.30-7.35 (1H, m), 7.41-7.51 (3H, m) mass spectrum (m / z): [2R]-and [2S] -isomers, 492 (M ⁺ , C) ₂₅ H ₄₀ N ₂ O ₄ SSi) Elemental analysis: C ₂₅ H ₄₀ N ₂ O ₄ SSi Calculated value: C, 60.94; H, 8.18; N, 5.69; S, 6.51 Actual value (2S-isomer): C , 60.72; H, 8.01; N, 5.70; S, 6.
57 Found (2R-isomer): C, 60.85; H, 8.10; N, 5.62; S, 6.
50 Furthermore, the compounds of Examples 2 to 9 were produced by the same method as in Example 1.

[0079]

Example 2 (2R) -2-[(3S, 4S) -3-[(R) -1-]
(T-Butyldimethylsilyloxy) ethyl] -2-o
Xo-4-azetidinyl] thiopropionic acid S- (2
-Dimethylaminocarbonylphenyl ) ester 2R-isomer yield (%) 79 YR and 2S-isomer yield ratio 4.9 Crystal shape Needle crystal mp (° C) 99-101 Reconstituted solvent (EtOAc-hex ) NMR spectrum δ ppm (CDCl ₃ ): 0.08 (6H, s), 0.88 (9H, s),
1.21 (3H, d, J = 6Hz), 1.29 (3H, d, J = 7Hz), 2.79 (3H, s), 2.96
-3.08 (2H, m), 3.10 (3H, s), 3.94 (1H, dd, J = 2.5Hz), 4.19 (1
H, dq, J = 5.6Hz), 6.10-6.20 (1H, brs), 7.31-7.36 (1H, m), 7.
40-7.70 (3H, m)

[0080]

Third Embodiment (2R) -2-[(3S, 4S) -3-[(R) -1-]
(T-Butyldimethylsilyloxy) ethyl] -2-o
Xo-4-azetidinyl] thiopropionic acid S- (2
-Dipropylaminocarbonylphenyl ) ester Yield of 2R-isomer (%) 74 Yield ratio of 2R and 2S-isomer 3.5 Crystal shape Needle mp (° C) 112-113 Reconstituted solvent (EtOAc- hex) NMR spectrum δppm (CDCl ₃ ) 0.08 (6H, s), 0.72 (3H, t, J = 7Hz), 0.88 (9H, s), 1.00 (3H, t,
J = 7Hz), 1.22 (3H, d, J = 6Hz), 1.20-1.40 (3H, broad), 1.46
(2H, sextet, J = 7Hz), 1.70 (2H, sextet, J = 7Hz), 2.91-3.06
(2H, m), 3.10-3.80 (2H, broad), 3.96 (2H, dd, J = 2.4Hz), 4.
19 (1H, dq, J = 5.6Hz), 5.90-6.20 (1H, brs), 7.29-7.35 (1H,
m), 7.40-7.51 (3H, m)

[0081]

Example 4 (2R) -2-[(3S, 4S) -3-[(R) -1-]
(T-Butyldimethylsilyloxy) ethyl] -2-o
Xo-4-azetidinyl] thiopropionic acid S- (2
-Diisobutylaminocarbonylphenyl ) ester 2R-isomer yield (%) 70 2R and 2S-isomer yield ratio 4.6 Crystal shape Needle crystal mp (° C) 144-146 Reconstituted solvent (EtOAc-hex ) NMR spectrum δppm (CDCl ₃ ) 0.08 (6H, s), 0.74 (6H, d, J = 7Hz), 0.87 (9H, s), 1.02 (6H, d,
J = 7Hz), 1.21 (3H, d, J = 6Hz), 1.20-1.40 (3H, broad), 1.81
(1H, Septet, J = 7Hz), 2.12 (1H, Septet, J = 7Hz), 2.80-3.06
(4H, m), 3.20-3.57 (2H, broad), 3.92-4.05 (1H, brs), 4.
13-4.28 (1H, broad), 5.95-6.15 (1H, broad), 7.29-7.35 (1
H, m), 7.42-7.50 (3H, m)

[0082]

Fifth Embodiment (2R) -2-[(3S, 4S) -3-[(R) -1-]
(T-Butyldimethylsilyloxy) ethyl] -2-o
Xo-4-azetidinyl] thiopropionic acid S- (2
-N, N-methylphenylaminocarbonylphenyl)
Yield (%) of ester 2R-isomer 64 Yield ratio of 2R and 2S-isomer 2.6 Crystal shape Needle crystal mp (° C) 158-159.5 Recrystallization solvent (EtOAc-hex) NMR spectrum δppm (CDCl ₃ ) 0.08,0.09 (6H, eachS), 0.88 (9H, m), 1.23 (3H, d, J = 6Hz),
1.34 (3H, d, J = 7Hz), 3.01-3.12 (2H, m), 3.49 (3H, s), 4.00-
4.08 (1H, brs), 4.20 (1H, dq, J = 6.6Hz), 6.05-6.20 (1H, br
s), 6.95-7.63 (9H, m)

[0083]

Sixth Embodiment (2R) -2-[(3S, 4S) -3-[(R) -1-]
(T-Butyldimethylsilyloxy) ethyl] -2-o
Xo-4-azetidinyl] thiopropionic acid S- (2
-Pyrrolidinocarbonylphenyl ) ester 2R-isomer yield (%) 85 2R and 2S-isomer yield ratio 7.1 Crystal shape foam NMR spectrum δppm (CDCl ₃ ) 0.08 (6H, s), 0.88 (9H, s), 1.21 (3H, d, J = 6Hz), 1.29 (3H, d,
J = 7Hz), 1.75-2.00 (4H, m), 2.95-3.06 (2H, m), 3.18 (2H, t,
J = 7Hz), 3.60 (2H, t, J = 7Hz), 3.96 (1H, dd, J = 2.4Hz), 4.20 (1
H, dq, J = 5.6Hz), 6.10-6.25 (1H, brs), 7.37-7.53 (4H, m)

[0084]

Example 7 (2R) -2-[(3S, 4S) -3-[(R) -1-]
(T-Butyldimethylsilyloxy) ethyl] -2-o
Xo-4-azetidinyl] thiopropionic acid S- (2
- piperidinocarbonyl phenyl) ester 2R- isomer yield (%) 75 2R and 2S- isomers of the yield ratio 4.8 crystalline form glassy material NMR spectrum _{δppm (CDCl 3) 0.07,0.08 (6H} , each s), 0.87,0.88 (9H, each s), 1.16-1.
25 (3H, m), 1.28,1.33 (3H, each d, J = 7Hz), 1.37-1.52 (2H,
broad), 1.54-1.77 (4H, broad), 2.95-3.26 (4H, m), 3.47-3.
60 (1H, broad), 3.80-3.95 (1H, broad), 3.97 (1H, dd, J = 2.4
Hz), 4.12-4.26 (1H, broad), 6.00-6.16 (1H, broad), 7.26-
7.52 (4H, m)

[0085]

Example 8 (2R) -2-[(3S, 4S) -3-[(R) -1-]
(T-Butyldimethylsilyloxy) ethyl] -2-o
Xo-4-azetidinyl] thiopropionic acid S- (2
- morpholinocarbonyl phenyl) ester 2R- isomer yield (%) 83 2R and 2S- isomers yield 7.9 crystalline form glassy material NMR spectrum _{δppm (CDCl 3) 0.08 (6H} , s), 0.88 (9H, s), 1.21 (3H, d, J = 7Hz), 1.22-1.38
(3H, m), 2.97-3.08 (2H, m), 3.12-3.32 (2H, m), 3.50-3.60
(2H, m), 3.70-3.84 (4H, broad), 3.93-4.01 (1H, brs), 4.19
(1H, dq, J = 5.5Hz), 5.90-6.10 (1H, broad), 7.20-7.38 (1H,
m), 7.42-7.55 (3H, m)

[0086]

Example 9 (2R) -2-[(3S, 4S) -3-[(R) -1-]
(T-Butyldimethylsilyloxy) ethyl] -2-o
Xo-4-azetidinyl] thiopropionic acid S- (2
-(2H-1,3,4,5,6,7-hexahydroase
Yield of pino ) carbonylphenyl) ester 2R-isomer (%) 87 Yield ratio of 2R and 2S-isomer 9.5 Crystal shape Glassy substance NMR spectrum δppm (CDCl ₃ ) 0.08 (6H, s), 0.88 (9H, s), 1.22 (3H, d, J = 6Hz), 1.20-1.40
(3H, broad), 1.50-1.96 (8H, broad), 2.97-3.10 (2H, m), 3.0
6-3.32 (2H, broad), 3.40-3.90 (2H, broad), 3.96 (1H, dd, J =
2.4Hz), 4.20 (1H, dq, J = 6.6Hz), 6.05-6.25 (1H, broad), 7.3
0-7.37 (1H, m), 7.42-7.52 (3H, m)

[0087]

Example 10 (2R) -2-[(3S, 4S) -3-[(R) -1-]
(T-Butyldimethylsilyloxy) ethyl] -2-o
Xo-4-azetidinyl] thiopropionic acid S- (2
-Diethylaminocarbonyl-6-phenyl) ester 2R-isomer yield (%) 88 2R and 2S-isomer yield ratio 12.3 Crystal shape Needle crystal mp (° C) 150-150.5 Reconstituted solvent (i -Pr ₂ O) NMR spectrum δppm (CDCl ₃ ): 0.06 (3H, s), 0.86 (9 / 2H,
s), 0.89 (9 / 2H, s), 1.02 (3H, t, J = 7Hz), 1.19-1.29 (7.5H,
m), 1.35 (1.5H, d, J = 7Hz), 2.35 (3H, s), 2.92-3.16 (4H, m),
3.28-3.41 (1H, m), 3.74 (1H, dq, J = 14and7Hz), 3.95-4.00 (1
H, m), 4.17 (1H, quitet, J = 6Hz), 6.00-6.30 (1H, brs), 7.14
(1H, dd, J = 3and6Hz), 7.34-7.41 (2H, m)

[0088]

Example 11 (2R) -2-[(3S, 4S) -3-[(R) -1-]
(T-Butyldimethylsilyloxy) ethyl] -2-o
Xo-4-azetidinyl] thiopropionic acid S- (2
-Diethylaminothiocarbonylphenyl ) ester Yield of 2R-isomer (%) 81 Yield ratio of 2R and 2S-isomer 4.8 Crystal shape Needle mp (° C) 163-165 Reconstituted solvent (EtOAc-hex ) NMR spectrum δ ppm (CDCl ₃ ): 0.09 (6H, s), 0.89 (9H, s),
1.09 (3H, t, J = 7Hz), 1.22 (3H, d, J = 6Hz), 1.26 (3H, dJ = 7H
z), 1.38 (3H, t, J = 7Hz), 2.96-3.06 (2H, m), 3.20 (1H, dq, J = 1
4and7Hz), 3.36 (1H, dq, J = 14and7Hz), 3.97 (1H, dd, J = 2and5
Hz), 4.20 (1H, dq, J = 5,6Hz), 4.46 (1H, dq, J = 14and7Hz), 7.2
2-7.26 (1H, m), 7.33-7.46 (3H, m)

[0089]

Twelfth Embodiment (2R) -2-[(3S, 4S) -3-[(R) -1-]
(T-Butyldimethylsilyloxy) ethyl] -2-o
Xo-4-azetidinyl] propionic acid S- (2-di
Yield of ethylaminocarbonylphenyl) ester 2R-isomer (%) 61 Yield ratio of 2R and 2S-isomer 6.8 Crystal shape NMR spectrum of glassy substance δppm (CDCl ₃ ): 0.09 (6H, s), 0.88 (9H, s),
1.10 (3H, t, J = 7Hz), 1.22 (3H, t, J = 7Hz), 1.25 (3H, dJ = 6H
z), 1.32 (3H, d, J = 7Hz), 2.95 (1H, dq, J = 4and7Hz), 3.00 (1H,
d, J = 6Hz), 3.22 (2H, q, J = 7Hz), 3.42-3.63 (1H, m), 4.08-4.1
6 (1H, m), 4.18 (1H, quintet, J = 6Hz), 6.45 (1H, brs), 7.17 (1
H, d, J = 8Hz), 7.26-7.28 (2H, m), 7.38-7.43 (1H, m)

[0090]

Reference Example 1 Z (0) -1-t-butyldimethylsilyloxy-1-
(2-Diethylaminocarbonyl) phenylthio-1-
Propene and its E (O) -isomer 729 mg (2.75 mmol) of the compound obtained in Reference Example 10, t-
A solution of 832 mg (5.52 mmol) of butyldimethylsilyl chloride and 621 mg (3.47 mmol) of hexamethylphosphoric triamide in 6 ml of tetrahydrofuran was cooled to −78 ° C., and 3.0 ml (3.0 mmol) of a 1.0 M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran was added thereto. It dripped in 7 minutes. After stirring for 10 minutes at the same temperature, 2 ml of saturated sodium bicarbonate water was added to terminate the reaction. Hexane was added to the reaction mixture. The organic layer was taken and washed with water to remove tetrahydrofuran and hexamethylphosphoric triamide. The residue obtained by distilling off the solvent was subjected to column chromatography using 20 g of alumina and eluted with methylene chloride-hexane (1: 1) to give 922 mg (88) of the title compound as a colorless oily substance.
%) Was obtained. From NMR spectrum (270MHz) it is Z
A mixture of (O) and E (O) -isomers in a ratio of 4: 1
Met. NMR spectrum (270 Mz, CDCl ₃ ) δppm :, 0.10 (1.2H, s),
0.11 (4.8H, s), 0.80 (7.2H, s), 0.89 (1.8H, s), 1.07 (3H, t, J
= 7Hz), 1.27 (3H, t, J = 7Hz), 1.70 (0.8H, d, J = 7Hz), 1.78 (0.2
H, d, J = 7Hz), 3.16 (1.6H, q, J = 7Hz), 3.18 (0.4H, q, J = 7Hz),
3.46-3.65 (2H, broad), 5.35 (1H, q, J = 7Hz), 7.11-7.20 (2H,
m), 7.22-7.32 (1H, m), 7.37-7.45 (1H, m) Further, the compounds of Reference Examples 2 to 9 were produced in the same manner as in Reference Example 1.

[0091]

Reference Example 2 Z (0) -1-t-butyldimethylsilyloxy-1-
(2-Dimethylaminocarbonyl) phenylthio-1-
Propene and its E (O) -isomer Z (O)-and E (O)-isomer ratio 4 NMR spectrum δppm 0.10 (1.2H, s), 0.11 (4.8H, s), 0.79 (1.8H, s) ), 0.89 (7.2H,
s), 1.70 (2.4H, d, J = 7Hz), 1.78 (0.6H, d, J = 7Hz), 2.88 (3H,
s), 3.12 (3H, s), 5.33 (0.2H, q, J = 7Hz), 5.35 (0.8H, q, J = 7H
z), 7.15-7.20 (2H, m), 7.24-7.33 (1H, m), 7.40-7.47 (1
H, m)

[0092]

Reference Example 3 Z (0) -1-t-butyldimethylsilyloxy-1-
(2-dipropylaminocarbonyl) phenylthio-1
-Propene and its E (O) -isomer Z (O)-and E (O)-isomer ratio 2 NMR spectrum δppm 0.10 (2H, s), 0.11 (4H, s), 0.73 (3H, t, J = 7Hz), 0.81 (3H, s),
0.89 (6H, s), 1.00 (3H, t, J = 7Hz), 1.43-1.60 (2H, m), 1.62-
1.80 (2H, m), 1.70 (2H, d, J = 7Hz), 1.77 (1H, d, J = 7Hz), 3.05
(1.3H, t, J = 7Hz), 3.08 (0.7H, t, J = 7Hz), 3.46-3.60 (2H, br
s), 5.35 (0.67H, q, J = 7Hz), 5.37 (0.33H, q, J = 7Hz), 7.10-
7.19 (2H, m), 7.22-7.31 (1H, m), 7.36-7.44 (1H, m)

[0093]

Reference Example 4 Z (0) -1-t-butyldimethylsilyloxy-1-
(2-diisobutylaminocarbonyl) phenylthio-
1-Propene and its E (O) -isomer Z (O)-and E (O)-isomer ratio 7 NMR spectrum δppm 0.11 (6H, s), 0.75 (5.3H, d, J = 7Hz), 0.77 (0.7H, d, J = 7Hz),
0.82 (1.1H, s), 0.90 (7.9H, s), 1.03 (6H, d, J = 7Hz), 1.71
(2.6H, d, J = 7Hz), 1.76 (0.4H, d, J = 7Hz), 1.80-1.95 (1H,
m), 2.07-2.25 (1H, m), 2.99 (1.75H, d, J = 8Hz), 3.02 (0.25
H, d, J = 8Hz), 3.10-3.70 (2H, brs), 5.36 (0.88H, q, J = 7Hz),
5.42 (0.12H, q, J = 7Hz), 7.09-7.22 (2H, m), 7.23-7.30 (1H,
m), 7.34-7.42 (1H, m)

[0094]

Reference Example 5 Z (0) -1-t-butyldimethylsilyloxy-1-
(2-N, N-methylphenylaminocarbonyl) phen
Nylthio-1-propene and its E (O) -isomer Z (O)-and E (O)-isomer ratio 9 NMR spectrum δppm 0.10 (0.6H, s), 0.15 (5.4H) ，
s), 0.84 (0.9H, s), 0.92 (8.1)
H, s), 1.69 (2.7H, d, J = 7Hz),
1.79 (0.3H, d, J = 7Hz), 3.35-
3.55 (3H, brs), 5.34 (0.9H,
q, J = 7 Hz), 5.39 (0.1H, q, J = 7H)
z), 6.85-7.27 (8H, broad),
7.31-7.38 (1H, broad)

[0095]

Reference Example 6 Z (0) -1-t-butyldimethylsilyloxy-1-
(2-Pyrrolidinocarbonyl) phenylthio-1-pro
Pen and its E (O) -isomer Z (O)-and E (O) -isomer ratio 5 NMR spectrum δppm 0.10 (6H, s), 0.79 (1.5H, s), 0.88 (7.5H, s) , 1.69 (2.5H, d, J
= 7Hz), 1.79 (0.5H, d, J = 7Hz), 1.80-2.02 (4H, m), 3.25 (2H,
t, J = 7Hz), 3.65 (2H, t, J = 7Hz), 5.33 (0.17H, q, J = 7Hz), 5.3
6 (0.83H, q, J = 7Hz), 7.12-7.33 (3H, m), 7.39-7.47 (1H, m)

[0096]

Reference Example 7 Z (0) -1-t-butyldimethylsilyloxy-1-
(2-piperidinocarbonyl) phenylthio-1-pro
Pen and its E (O) -isomer Z (O)-and E (O)-isomer ratio 3 NMR spectrum δppm 0.10 (1.5H, s), 0.11 (4.5H, s), 0.80 (2.3H, s) ), 0.89 (6.7H,
s), 1.40-1.73 (6H, broad), 1.69 (2.25H, d, J = 7Hz), 1.77 (0.
75H, d, J = 7Hz), 3.15-3.28 (2H, broad), 3.55-3.95 (2H, broa
d), 5.34 (0.25H, q, J = 7Hz), 5.34 (0.75H, q, J = 7Hz), 7.10-7.
19 (2H, m), 7.22-7.32 (1H, m), 7.38-7.46
(1H, m)

[0097]

Reference Example 8 Z (0) -1-t-butyldimethylsilyloxy-1-
(2-morpholinocarbonyl) phenylthio-1-pro
Pen and its E (O) -isomer Z (O)-and E (O)-isomer ratio 5 NMR spectrum δppm 0.10 (1H, s), 0.11 (5H, s), 0.7
9 (1.5H, s), 0.89 (7.5H, s), 1.
70 (2.5H, d, J = 7Hz), 1.78 (0.5
H, d, J = 7 Hz), 3.18-3.40 (2H, b
road), 3.52-3.85 (2H, brs),
3.65-3.90 (4H, brs), 5.34 (0.
17H, q, J = 7Hz), 5.35 (0.83H,
q, J = 7 Hz), 7.13-7.21 (2H, m),
7.25-7.36 (1H, m), 7.40-7.47
(1H, m)

[0098]

Reference Example 9 Z (0) -1-t-butyldimethylsilyloxy-1-
(2- (2H-1,3,4,5,6,7-hexahydro
Azepino) carbonyl) phenylthio-1-propene and
And its E (O) -isomer Z (O)-and E (O)-isomer ratio 3 NMR spectrum δppm 0.10 (1.5H, s), 0.12 (4.5H, s), 0.79 (2.3H, s), 0.90 (6.7H,
s), 1.53-1.72 (6H, broad), 1.69 (2.25H, d, J = 7Hz), 1.78 (0.
75H, d, J = 7Hz), 1.75-1.90 (2H, broad), 3.19-3.35 (2H, broa
d), 3.55-3.80 (2H, broad), 5.33 (0.25H, q, J = 7Hz), 5.34 (0.
75H, q, J = 7Hz), 7.10-7.19 (2H, m), 7.21-7.33 (1H, m), 7.38-
7.46 (1H, m)

[0099]

Reference Example 10 Z (0) -1-t-butyldimethylsilyloxy-1-
(2-Diethylaminocarbonyl-6-methyl) phenyl
Ruthio-1-propene and its E (O) -isomer Z (O)-and E (O)-isomer ratio 11 NMR spectrum δppm 0.21 (3H, s), 0.23 (3H, s), 0.96 (9H, s), 1.03 (3H, t, J = 7Hz),
1.27 (3H, t, J = 7Hz), 1.49 (3H, d, J = 7Hz), 2.51 (3H, s), 3.08
(1H, dq, J = 14and7Hz), 3.11 (1H, dq, J = 14and7Hz), 3.43 (1H,
dq, J = 14and7Hz), 3.70 (1H, dq, J = 14and7Hz), 4.12 (1H, q, J =
7Hz), 7.08-7.13 (1H, m), 7.25-7.32 (2H, m)

[0100]

Reference Example 11 Z (0) -1-t-butyldimethylsilyloxy-1-
(2-Diethylaminothiocarbonyl) phenylthio-
1-Propene and its E (O) -isomer Z (O)-and E (O)-isomer ratio 20 NMR spectrum δppm 0.12 (3H, s), 0.14 (3H, s), 0.80 (9 / 21H, s), 0.91 (180 / 21H,
s), 1.11 (3H, t, J = 7Hz), 1.40 (3H, t, J = 7Hz), 1.70 (60 / 21H,
d, J = 7Hz), 1.78 (3 / 21H, d, J = 7Hz), 3.29 (1H, dq, J = 7and14H
z), 3.44 (1H, dq, J = 7and14Hz), 3.67 (1H, dq, J = 7and14Hz),
4.57 (1H, dq, J = 7and14Hz), 5.38 (1H, q, J = 7Hz), 7.10-7.25
(3H, m), 7.31-7.40 (1H, m)

[0101]

[Reference Example 12] Thiopropionic acid S- (2-diethylamino carbonate
) Phenyl ester A method 71.62 g of ice-cooled 2,2'-dithiobenzoyl chloride
In a 300 ml suspension of methylene chloride (0.209 mol), 34.84 g (0.476 mol) of diethylamine and 70.0 ml (0.5
A solution of 02 mol) in 50 ml of methylene chloride was added dropwise over 1 hour, and the mixture was stirred at the same temperature for 30 minutes. The residue obtained by distilling methylene chloride under reduced pressure was diluted with ethyl acetate and water,
It was washed successively with saturated saline. The solvent was distilled off again to obtain an amide compound. A mixture of about 4 g of the amide compound thus obtained, zinc powder 14.36 g (0.220 mol), and propionic anhydride 80.0 ml (0.624 mol) was heated at 100 ° C. for 5 minutes to carry out the reaction. Activation of zinc was performed. Then, a solution of the remaining amide compound in 100 ml of benzene was added dropwise at the same temperature over 20 minutes, and the mixture was heated under reflux for 90 minutes. The crystals precipitated after cooling were filtered off, and the crystals were washed with ethyl acetate. The filtrate and washing liquid were combined, washed with water, and then the solvent was distilled off,
The residue was distilled under reduced pressure and 106.97 g of the title compound (2 steps, 96
%) Was obtained. bp 167 to 170 ° C./0.95 to 1.1 mmHg IR spectrum (liq) cm ⁻¹ : 1710,1635,1292,932 NMR spectrum (270 MHz, CDCl ₃ ) δppm: 1.02 (3H, t, J = 7H
z), 1.20 (3H, t, J = 7Hz), 1.23 (3H, t, J = 7Hz), 2.66 (2H, q, J = 7
Hz), 2.90-3.20 (2H, broad), 3.10-4.00 (2H, broad), 7.29-
7.36 (1H, m), 7.40-7.52 (1H, m) Mass spectrum (m / z), 266 (M ⁺ +1), 265 (M ⁺ , C ₁₄ H
₁₉ NO ₂ S) Method B a. A solution of 3.13 g (20.3 mmol) of thiosalicylic acid and 2.46 g (24.4 mmol) of triethylamine in 60 ml of methylene chloride was ice-cooled, and 2.85 g (20.3 mmol) of benzoyl chloride was added dropwise. After dropping, the mixture was stirred at room temperature for 1 hour, and the reaction solution was diluted with 0.2 N hydrochloric acid to 2
It was washed once with saturated saline. 5.24g after distilling off the solvent
Crude crystals of benzoylthiobenzoic acid were obtained (quantitative yield). This was dissolved in 100 ml of methylene chloride, and under ice-cooling, 2.45 g (21.3 m) of 2-chloro-1-methylpyridinium iodide.
mol), diethylamine 1.78 g (24.4 mmol) and triethylamine 4.51 g (44.7 mmol) were sequentially added, and the mixture was stirred at room temperature for 20 hours. The solvent was evaporated and the obtained residue was partitioned between ethyl acetate and dilute hydrochloric acid, and the organic layer was washed with water. The solvent was distilled off, and the residue was subjected to column chromatography using 120 g of silica gel and eluted with hexane-acetone (4-3: 1) to obtain 4.86 g (76%) of N, N-diethyl 2-benzoylthiobenzamide as an oil. Obtained as a substance. NMR spectrum (60MHz, CDCl ₃ ) δppm: 0.99 (3H, t, J = 7Hz), 1.0
2 (3H, t, J = 7Hz), 3.09 (2H, q, J = 7Hz), 3.0-3.9 (2H, broad),
7.2-7.7 (7.5H, m), 7.9-8.2 (1.5H, m) b. A solution of 4.86 g (15.5 mmol) of the compound obtained in a in 60 ml of methanol was ice-cooled and 0.84 g of sodium methoxide (15.
(5 mmol) was added and stirred for 20 minutes. After about 15 drops of concentrated hydrochloric acid was added to neutralize the reaction solution, ethanol was further added to distill off the solvent. To remove water, 20 ml of ethanol and 30 ml of benzene were added and the solvent was distilled off again. The residue containing N, N-diethyl-2mercaptobenzamide thus obtained was suspended in 60 ml of methylene chloride, and under cooling with ice, 4.30 g (46.5 mmol) of propionyl chloride and triethylamine were added.
6.26 g (62.0 mmol) was added and stirred for 2.5 hours. The reaction was terminated by adding water and diluted with methylene chloride. The organic layer was washed with dilute hydrochloric acid and water, the solvent was distilled off, and the residue was purified by column chromatography using 100 g of silica gel.
Obtained 3.26 g (79%) of the title compound. This compound was the same as that obtained by Method A. A of Reference Example 12
The compounds of Reference Examples 13 to 21 were produced by the method B or method B.

[0102]

[Reference Example 13] Thiopropionic acid S- (2-dimethylamino carbonate
) Phenyl ester yield (2 steps,%) 78 IR spectrum Carbonyl absorption (cm ⁻¹ ) 1709,
1639

[0103]

[Reference Example 14] Thiopropionic acid S- (2-dipropylaminocarbonyl)
) Phenyl ester yield (2 steps,%) 93 IR spectrum Carbonyl absorption (cm ⁻¹ ) 1705
1632

[0104]

Reference Example 15 S- (2-diisobutylaminocarbothiothiopropionate
Nyl) phenyl ester yield (2 steps,%) 99 IR spectrum Carbonyl absorption (cm ⁻¹ ) 1712,
1635

[0105]

Reference Example 16 S- (2-N, N-methylphenylthiothiopropionate
Minocarbonyl) phenyl ester yield (2 steps,%) 96 IR spectrum Carbonyl absorption (cm ^-1 ) 1705
1645

[0106]

Reference Example 17 S- (2-pyrrolidinocarbonyl ) thiopropionate
Yield of ester (2 steps,%) 74 IR spectrum Carbonyl absorption (cm ⁻¹ ) 1702
1630

[0107]

[Reference Example 18] S- (2-piperidinocarbonyl ) thiopropionate
Yenyl ester yield (2 steps,%) 98 IR spectrum Carbonyl absorption (cm ⁻¹ ) 1702
1630

[0108]

Reference Example 19 S- (2-morpholinocarbonyl) thiopropionate
Yenyl ester yield (2 steps,%) 89 IR spectrum Carbonyl absorption (cm ⁻¹ ) 1702
1635

[0109]

[Reference Example 20] Thiopropionic acid S- (2- (2H-1, 3, 4, 5,
6,7-Hexahydroazepino) carbonyl) phenyl
Ester yield (2 steps,%) 93 IR spectrum Carbonyl absorption (cm ⁻¹ ) 1705
1630

[0110]

[Reference Example 21] Thiopropionic acid S- (2-diethylaminocarbonyl)
-6-Methyl) phenyl ester yield (2 steps,%) 38 IR spectrum Carbonyl absorption (cm ^-1 ) 1703.
1635

[0111]

Reference Example 22 S- (2-diethylaminothiocarbothiothiopropionate
Nyl ) phenyl ester 276 mg (1.04 mmol) of the compound of Reference Example 12 was added to toluene (5 m
l), and Lawson's reagent 216 mg (0.534 mmol)
Was added and heated at 100 ° C. for 2 hours with stirring. After the completion of the reaction, the reaction mixture was cooled and chromatographed (eluted with methylene chloride: hexane = 3: 0-3: 1) using 25 g of silica gel as it was to obtain 286 mg of S-2-diethylaminothiocarbonylphenylthiopropionate. Melting point: 6
7.5-68.5 ℃ IR spectrum (nuj) cm ^-1 : 1712,1505,1308,1242,928 NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.08 (3H, t, J = 7H
z), 1.20 (3H, t, J = 7Hz), 1.37 (3H, t, J = 7Hz), 2.66 (2H, q, J = 7
Hz), 3.19 (1H, dq, J = 14and7Hz), 3.38 (1H, dq, J = 14and7Hz),
3.70 (1H, dq, J = 14and7Hz), 4.53 (1H, dq, J = 14and7Hz), 3.29
(1H, dq, J = 7and14Hz), 3.67 (1H, dq, J = 7and14Hz), 4.57 (1H,
dq, J = 7and14Hz), 5.37 (1H, q, J = 7Hz), 7.10-7.25 (3H, m), 7.
31-7.47 (3H, m) mass spectrum (m / z): 281 ( M +, C 14 H 19 NOS 2) yield (2 steps,%) 38 IR spectrum carbonyl absorption (cm ^-1) 1703,163
5

[0112]

[Reference Example 23] Propionic acid (2-diethylaminocarbonyl) phene
Nyl ester 2-propionyloxybenzoic acid 2.40 g (12.4 mmol)
Was dissolved in 24 ml of methylene chloride, 2.0 ml (23 mmol) of oxalyl chloride and 0.050 ml of dimethylformamide were added thereto under ice cooling, and the mixture was stirred for 1 hour. The solvent and excess oxalyl chloride were distilled off under reduced pressure. In the residue,
20 ml of methylene chloride was added, and under ice cooling, 1.36 g (13.5 mmol) of triethylamine and 986 of diethylamine were added.
mg (13.5 mmol) was added and stirred for 1 hour. After the reaction,
Ethyl acetate was added and washed with water. The solvent was distilled off, and the residue was chromatographed on 25 g of silica gel (methylene chloride: ethyl acetate =
10: 1 to 7: 1) was carried out to obtain 3.0 g of 2-diethylaminocarbonylphenylpropionate (yield 97%) as an oily substance. IR spectrum (liq) cm ^-1: 1765,1638,1430,1293,1142 NMR spectrum _{(60MHz, CDCl 3) δppm:} 1.06 (3H, t, J = 7H
z), 1.20 (6H, t, J = 7Hz), 2.52 (2H, q, J = 7Hz), 3.15 (2H, q, J = 7
Hz), 3.49 (2H, q, J = 7Hz), 7.0-7.6 (4H, m) Mass spectrum (m / z): 249 (M ⁺ , C ₁₄ H ₁₉ NO ₃ )

[0113]

Reference Example 24 (3S, 4S) -3-[(1R) -1-t-butyldime
Cylsilyloxyethyl] -4-[(1R)-[(2
S, 4S) -2- [4- (2-p-nitrobenzyloxy
Ciethyl) piperazin-1-ylcarbonyl] -1-p
Nitrobenzyloxycarbonylpyrrolidyl-4-i
]] Thiocarbonylethyl] azetidin-2-one 99 mg (0.20 mmol) of the compound obtained in Example 1, (2S,
4S) -2- {4- [2- (p-nitrobenzyloxycarbonyl) oxyethyl] -1-piperazinylcarbonyl} -4-mercapto-1- (p-nitrobenzyloxycarbonyl) pyrrolidine 135 mg (0.22 mmol) , And triethylamine 30 mg (0.30 mmol) methylene chloride 2 ml
The solution was stirred at room temperature for 17 hours. The residue obtained by distilling off the solvent was dissolved in ethyl acetate and washed successively with 2N caustic soda, water and saturated saline. After evaporating the solvent, the residue was subjected to column chromatography using 25 g of silica gel and eluted with acetone-hexane (3: 2) to obtain 182 mg (quantitative yield) of the title compound as a foam.

[0114]

Reference Example 25 (3S, 4S) -3-[(R) -1-hydroxyethyl
] -4-[[(R) -1-[(2S, 4S) -2-4]
-2- (4-nitrobenzyloxycarbonyloxy)
Ethyl-1-piperazinylcarbonyl-1- (4-nit
Robenzyloxycarbonyl) pyrrolidin-4-ylchi
Ocarbonylethyl] azetidin-2-one (3S, 4S) -3-[(R) -1- (t-butyldimethylsilyloxy) ethyl] -4-[(R) -1-
[(2S, 4S) -2- [4- [2- (4-Nitrobenzyloxycarbonyloxy) ethyl] -1-piperazinylcarbonyl] -1- (4-nitrobenzyloxycarbonyl) pyrrolidin-4-yl -Thiocarbonyl] ethyl] -2-azetidinone (8.1 g) was added to methanol (80
3N hydrochloric acid (24m) while stirring under ice cooling.
l) was added dropwise. After the dropwise addition, the mixture was stirred at the same temperature for 30 minutes and left in a refrigerator overnight, then the reaction mixture was ice-cooled and the pH was adjusted to 5 to 6 with sodium hydrogen carbonate. Then, the mixture was concentrated under reduced pressure, a small amount of water was added to the residue, and the mixture was extracted with ethyl acetate.
Further, the aqueous layer was saturated with sodium chloride and extracted with the same solvent. The extracts were combined and the solvent was evaporated under reduced pressure. The residue is silica gel 15
By subjecting to column chromatography using 0 g and eluting with a mixed solvent of ethyl acetate: methanol = 20 to 10: 1, the target compound (5.9 g) was obtained as a colorless foamy compound. IR spectrum (CHCl ₃ ) cm ⁻¹ : 1752,1710,1650,1607,152
2,1443,1405,1347,1263 NMR spectrum (270 MHz, CDCl ₃ ): 1.27 (3H, d, J = 6.83Hz),
1.28 (3H, d, J = 6.35Hz), 1.82-1.99 (1H, m), 2.10-2.18 (1H,
m), 2.40-2.95 (7H, m), 3.03 (1H, dd, J = 1.95,6.35Hz), 3.37-
3.80 (5H, m), 3.78 (1H, dd, J = 1.95,6.84Hz), 3.95-4.48 (6H,
m), 4.68,4.73 (1H, t × 2, J = 8.06,7.33Hz), 5.06,5.32 (1H, d
× 2, J = 13.43Hz), 5.21 (1H, s), 5.26 (2H, s) 5.99 (1H, br.
s), 7.45,7.50 (2H, d × 2, J = 8.30,8.79Hz), 7.56 (2H, d, J = 8.
79Hz), 8.18-8.26 (4H, m)

Claims (1)

[Claims] 1. A general formula: [Wherein R ¹ represents a hydrogen atom or a protective group for a hydroxyl group, R ² represents a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched chain having 1 to 6 carbon atoms] An alkoxy group, a halogen atom, a phenyl group having no substituent or a substituent selected from the following α group, or a phenoxy group having no substituent or a substituent selected from the following α group, R ³ is CYNR ⁵ R ⁶ A group (in the formula, Y represents an oxygen atom or a sulfur atom, R ⁵ and R ⁶ each independently have 1 to 6 carbon atoms)
A straight or branched chain alkyl group, an unsubstituted or substituted aryl group having a substituent selected from the following α group, or an unsubstituted or aralkyl group having a substituent selected from the following α group , R ⁵ and R ⁶ together form the formula −
_{(CH 2) m (X)} L (CH 2) n - group (wherein, m and n to 0 me identical or different 5 (however, m + n indicates 2 or more).
L is 0 or 1, X is an oxygen atom, a sulfur atom or an NR ⁷ group (R ⁷ is a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched chain having 1 to 6 carbon atoms) Of the above-mentioned aliphatic acyl group, which is unsubstituted or has a substituent selected from the following α group). ) Is shown. ) As a substituent and which may have a substituent selected from the following α group, R ⁴ represents a hydrogen atom or an amino-protecting group, and Z represents oxygen or Indicates a sulfur atom. ] The compound which has. [Α group] halogen atom, cyano group, nitro group, hydroxyl group,
An amino group, an alkylamino group having 1 to 4 carbon atoms, a dialkylamino group having two alkyl groups having 1 to 4 carbon atoms, and an alkylenedioxy group having 1 to 3 carbon atoms.