JP3175857B2 - 1β-substituted carbapenem synthetic intermediate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The compound (I) of the present invention is a useful intermediate for 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 a strong antibacterial activity not only makes it chemically stable but also inhibits dihydropeptidase I (DHP-I) existing in a living body. It was found to be stable. 1
Since carbapenem antibiotics having a substituent at the β-position have not been obtained naturally, it is necessary to prepare them by synthesis, and the synthesis methods have attracted much attention, and various synthesis methods have been studied. As one of the synthesis 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 desired ratio of the 2R-thiopropionic acid derivative to its 2S-isomer is 1.
The ratio was 6/1, 1/19, 1/9, which was not satisfactory as a method for synthesizing a desirable 2R-isomer.

[0003]

Embedded image

[0004]

DISCLOSURE OF THE INVENTION The present inventors have selected a 2R-thiopropionic acid derivative, which is preferably a silyl enol ether derived from thiopropionic acid S-phenyl ester having a phenyl group having an amide group as a substituent. And completed the present invention.

[0005]

According to the present invention, there is provided a compound of the general formula

[0006]

Embedded image

Is a compound having

In the above formula, R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group, and R ² represents a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkyl group having 1 to 6 carbon atoms. A branched chain alkoxy group, a halogen atom, an unsubstituted or substituted phenyl group having a substituent selected from the following α group, or an unsubstituted or phenoxy group having a substituted moiety selected from the following α group, and R ³ represents CYNR ⁵ R ⁶ groups (wherein,
Y represents an oxygen or sulfur atom, and R ⁵ and R ⁶ are each independently a linear or branched alkyl group having 1 to 6 carbon atoms, an unsubstituted or substituted group selected from the following α group. - or an aralkyl group having substituents selected from group or an unsubstituted or below α group, 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 (where m + n is 2 or more), L is 0 or 1, X is oxygen, sulfur atom or NR ⁷ group (R ⁷ is carbon number 1 to 6). Linear or branched alkyl groups, linear or branched aliphatic acyl groups having 1 to 6 carbon atoms, unsubstituted or
An aromatic acyl group having a substituent selected from the group is shown. ). ). ) As a substituent, and a phenyl group which may have a substituent selected from the following α group, R ⁴ represents a hydrogen atom or an amino-protecting group, Z represents oxygen or Indicates a sulfur atom. In the above general formula, the halogen atoms of R ² and α group are fluorine, chlorine and bromine, preferably fluorine and chlorine.

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

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

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

Examples of the alkyl moiety of the linear or branched alkoxy group having 1 to 6 carbon atoms for R ² include the same as the above-mentioned alkyl groups.
An ethoxy group.

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

Examples of the alkyl group of the α-group alkylamino group having 1 to 4 carbon atoms and the dialkylamino group having two alkyl groups having 1 to 4 carbon atoms are the same as the above-mentioned alkyl groups. Preferably, propyl, 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 moiety of the aromatic acyl group having no aralkyl group and the unsubstituted R ⁷ or a substituent selected from the following α group 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.

Tables 1 to 4 have the formula (I-
1) For Tables 5 to 8, the formula (I-2) is used.

[0019]

Embedded image

[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
PNZ indicates a p-nitrobenzyloxycarbonyl group and m-CH ₃ : a methyl group at the m-position.

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 various methods, the general techniques of which are known in the art for preparing such compounds.

For example, the compound has the formula (II)

[0031]

Embedded image

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

[0033]

Embedded image

Wherein R ¹ and R ⁴ are as described above, and R ¹¹ represents an acyloxy, alkylsulfonyl, arylsulfonyl, alkylsulfinyl or arylsulfinyl group.

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

[0036]

Embedded image

Has a configuration as shown in
Formula (Ia)

[0038]

Embedded image

Is obtained.

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

The acyloxy group represented by R ¹¹ is an aliphatic or aromatic carboxylacyloxy group. In the case of aliphatic acyloxy groups, these are preferably from 1 to 6
Alkanoyloxy, haloalkanoyloxy or alkenoyloxy groups, preferably having 2 to 4 carbon atoms, with alkanoyloxy groups being preferred.
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 a benzoyloxy group. In the case of alkylsulfonyl and alkylsulfinyl groups, the alkyl moiety has 1 to 6, preferably 1 to 4 carbon atoms, and examples of the alkyl moiety of such groups include:
Methyl, ethyl, propyl and isopropyl groups are included. In the case of arylsulfonyl and arylsulfinyl groups, the aryl moiety may be as defined and exemplified above, and examples of aryl moieties in such groups include phenyl and p-tolyl groups. Preferably, R ¹¹ is an acetoxy, benzoyloxy, phenylsulfonyl, phenylsulfinyl, tolylsulfinyl or methylsulfinyl group.

In this reaction, the silyl enol ether of the formula (II) is reacted with an azetidinone derivative of the formula (III). This 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 preferred.

The reaction usually takes place preferably in the presence of a solvent. There is no particular limitation on the properties of the solvent, as long as the solvent does not adversely affect the reaction or the reagent used and can dissolve the reagent at least to some extent. 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 nitriles such as acetonitrile. Among them, 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 in the present invention. Generally, it is convenient to carry out the reaction at a temperature between -10C and 70C, more preferably between 10C and 50C. The time required for the reaction also varies widely depending on many factors, especially the reaction temperature and the nature of the reagents and solvents used. However, a period of 10 minutes to 24 hours is usually sufficient if the reaction is carried out under favorable conditions as outlined above.

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

The formula used as starting material in this reaction
Silyl enol ether (II) is the formula _{^{(IV): R 2 CH 2}} COZR 3 (IV) ( wherein, R ^2, R ³ and Z are as previously defined) compounds 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 leaving group such as a halogen atom such as a chlorine atom or a sulfonyloxy group such as a trifluoromethanesulfonyloxy group) in the presence of a base.

This reaction is usually carried out preferably in the presence of a solvent. There is no particular limitation on the nature of the solvent used, as long as it does not adversely affect the reaction or the related reagents and can dissolve the reagents at least to some 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, and any two of these solvents Mixtures of the above may also be used.

The reaction yield is determined by using one or more of the following solvents:
It can be improved by adding to one or more of the above solvents. Examples of solvents that such additives, hexamethylphosphoric triamide (HMPA), N, N- dimethylformamide, N, N- dimethylacetamide, N, N ¹ - dimethyl propylene urea, N- methyl-pyrrolidone and N-
Methylpiperidone.

Examples of the base used in this reaction include diisopropylamine, hexamethyldisilazane,
Lithium, sodium or potassium salts of dicyclohexylamine or 2,2,6,6-tetramethylpiperidine.

The addition of one or more bases and the aforementioned bases may improve the yield of the compound of formula (II) in some cases. 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 in the present invention. Generally, it is convenient to carry out the reaction at a temperature between -90C and 20C, more preferably between -78C and -20C. The time required for the reaction also varies widely depending on many factors, especially 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 minute
A period of 0 to 30 minutes is usually sufficient.

The compound of formula (II) obtained can be recovered from the reaction mixture by a conventional method. For example, water,
A saturated aqueous solution of sodium hydrogencarbonate or triethylamine is added, the mixture is extracted with an organic solvent, and then purified by means such as column chromatography or distillation, whereby the product can be recovered 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, It can be used as a starting compound in a reaction.

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

[0056]

Embedded image

[0057]

Embedded image

[0058]

Embedded image

[0059]

Embedded image

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

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 -dithiophene. 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 a reducing activity such as zinc.

Alternatively, in Reaction Scheme 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 thiol group of the compound of formula (VIII) is protected by reacting the compound of formula (VIII) with an aromatic acyl halide such as benzoyl chloride to obtain a compound of formula (IX) In step B2 to obtain a protected compound of formula (IX), the compound of formula (IX) is
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 compound of formula (XI) is obtained by treating the compound of formula (X) with a base such as sodium methoxide to remove the aromatic acyl protecting group R ¹² CO.

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

Alternatively, the compound of formula (XI) is
II) from anthranilic acid derivatives by conventional means (eg,
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 a compound of formula (XIII). Step B
In 6, the compound of formula (XIII) is hydrolyzed with a base such as potassium hydroxide to give the compound of formula (XI).

Reaction scheme B shows that R ³ is a substituted phenyl group,
A method for preparing a compound of the formula (IV) in which Y is an oxygen atom and Z is a sulfur atom, that is, a compound of the formula (IVa) is shown. The corresponding compounds wherein 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 Reaction Scheme C, the carbonyl-forming portion of the amide group at position 2 of the compound of formula (IVa) is converted to a thiocarbonyl group by reaction with a thiolating agent such as Labesson's reagent or phosphorus pentasulfide. This reaction is known in the art, and may be performed using a common and known solvent, reaction temperature and reaction time.

In Step D1 of Reaction Scheme D, the compound of the formula (I
The carboxyl group at the 2-position of the compound of Va) is halogenated, preferably chlorinated, using a conventional halogenating agent such as oxalyl chloride, oxalyl bromide, thionyl chloride or thionyl bromide and usual halogenation conditions to obtain a compound of the formula (XVI)
Is obtained. This compound of formula (XVI) is then converted to a compound of formula R
Reaction of the secondary amine of ⁵ R ⁶ NH with an organic tertiary amine such as triethylamine or an inorganic base such as sodium carbonate gives the desired compound of formula (XVII).

The azetidinone derivative of the formula (I) of the present invention can be easily converted to the corresponding carbapenem compound by reaction with a suitable mercaptan derivative of the formula R ¹⁴ SH. 1960-1976
No. 4) and the formula (XV
The compound of III) is obtained. This was cyclized by then conventional methods (e.g., as described in JP-62-54427), as shown in Scheme Tables E and E ¹ below, the carbapenem derivative of formula (XIX) 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 kind commonly used at the designated position of the carbapenem derivative. . As can be seen from the reaction process chart E ^1, the configuration at the carbon to which the group represented by azetidine 3-position and R ² attached is held, therefore, these important compounds conveniently, efficiently produced.

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

[0075]

The compound (XVIII) is prepared by easily substituting the S-phenyl ester moiety of the compound (I) of the present invention with an appropriate mercaptan derivative RSH according to a conventional method (Japanese Patent Application Laid-Open No. 60-19764). It is possible to

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

[0077]

【Example】

[0078]

Example 1 (2R) -2-[(3S, 4S) -3-[(R) -1-
(T-butyldimethylsilyloxy) ethyl] -2-o
Oxo-4-azetidinyl] thiopropionic acid S- (2
-Diethylaminocarbonylphenyl) ester and its
911 mg of the silyl enol ether obtained in Reference Example 1 of (2S) isomer
(2.40 mmol) and (3R, 4R) -3-[(R) -1- (t
-Butyldimethylsilyloxy) ethyl] -4-acetoxy-2-azetidinone (330 mg, 2.42 mmol) was added to a solution of 347 mg (1.21 mmol) of methylene chloride in 12 ml of methylene chloride, 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 the solvent was distilled off. The residue was separated and purified on a row bar column [hexane-ethyl acetate (1: 1)] to give 61 mg (10%) of the 2S-isomer and 48 of the 2R-isomer.
7 mg (82%) were obtained. mp 125-126.5 ° C (hexane-ethyl acetate) [2S-
Isomer]; mp 130.5-132 ° 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 ) δ ppm: [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
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: 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 Further, the compounds of Examples 2 to 9 were produced in the same manner as in Example 1.

[0079]

Example 2 (2R) -2-[(3S, 4S) -3-[(R) -1-
(T-butyldimethylsilyloxy) ethyl] -2-o
Oxo-4-azetidinyl] thiopropionic acid S- (2
-Dimethylaminocarbonylphenyl ) ester 2R-isomer yield (%) 79 Yield ratio of 2R to 2S-isomer 4.9 Crystal shape Needle crystal mp (° C) 99-101 Reconstituted solvent (EtOAc-hex) ) 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), 2.79 (3H, s), 2.96
-3.08 (2H, m), 3.10 (3H, s), 3.94 (1H, dd, J = 2.5Hz), 4.19 (1H
(H, dq, J = 5.6Hz), 6.10-6.20 (1H, brs), 7.31-7.36 (1H, m), 7.
40-7.70 (3H, m)

[0080]

Example 3 (2R) -2-[(3S, 4S) -3-[(R) -1-
(T-butyldimethylsilyloxy) ethyl] -2-o
Oxo-4-azetidinyl] thiopropionic acid S- (2
-Dipropylaminocarbonylphenyl ) ester 2R-isomer yield (%) 74 Yield ratio between 2R and 2S-isomer 3.5 Crystal form Needle crystal 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
Oxo-4-azetidinyl] thiopropionic acid S- (2
-Diisobutylaminocarbonylphenyl ) ester 2R-isomer yield (%) 70 2R and 2S-isomer yield ratio 4.6 Crystal shape needles 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]

Example 5 (2R) -2-[(3S, 4S) -3-[(R) -1-
(T-butyldimethylsilyloxy) ethyl] -2-o
Oxo-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 form Needle crystal mp (° C) 158-159.5 Reconstituted 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]

Example 6 (2R) -2-[(3S, 4S) -3-[(R) -1-
(T-butyldimethylsilyloxy) ethyl] -2-o
Oxo-4-azetidinyl] thiopropionic acid S- (2
-Pyrrolidinocarbonylphenyl ) ester 2R-isomer yield (%) 85 Yield ratio of 2R to 2S-isomer 7.1 Crystal form 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
Oxo-4-azetidinyl] thiopropionic acid S- (2
-Piperidinocarbonylphenyl ) ester 2R-isomer yield (%) 75 2R and 2S-isomer yield ratio 4.8 Crystal form Glassy substance NMR spectrum δ ppm (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, m
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
Oxo-4-azetidinyl] thiopropionic acid S- (2
-Morpholinocarbonylphenyl ) ester 2R-isomer yield (%) 83 Yield ratio of 2R to 2S-isomer 7.9 Crystal form Glassy substance NMR spectrum δ ppm (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]

Embodiment 9 (2R) -2-[(3S, 4S) -3-[(R) -1-
(T-butyldimethylsilyloxy) ethyl] -2-o
Oxo-4-azetidinyl] thiopropionic acid S- (2
-(2H-1,3,4,5,6,7-hexahydroaze
Pino) carbonylphenyl) ester 2R-isomer yield (%) 87 Yield ratio of 2R to 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
Oxo-4-azetidinyl] thiopropionic acid S- (2
-Diethylaminocarbonyl-6-phenyl) ester 2R-isomer yield (%) 88 Yield ratio of 2R to 2S-isomer 12.3 Crystal form Needle crystal mp (° C) 150-150.5 Resolved solvent (i -Pr ₂ O) NMR spectrum δ ppm (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
Oxo-4-azetidinyl] thiopropionic acid S- (2
-Diethylaminothiocarbonylphenyl ) ester 2R-isomer yield (%) 81 Yield ratio of 2R and 2S-isomer 4.8 Crystal form Needle crystal 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 = 14 and 7Hz), 7.2
2-7.26 (1H, m), 7.33-7.46 (3H, m)

[0089]

Example 12 (2R) -2-[(3S, 4S) -3-[(R) -1-
(T-butyldimethylsilyloxy) ethyl] -2-o
Oxo-4-azetidinyl] propionic acid S- (2-di
Ethylaminocarbonylphenyl ) ester 2R-isomer yield (%) 61 Yield ratio of 2R to 2S-isomer 6.8 Crystal form Glassy substance NMR spectrum δ ppm (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 (1H
(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 acid triamide in 6 ml of tetrahydrofuran was cooled to −78 ° C., and 3.0 ml (3.0 mmol) of a 1.0 M lithium bis (trimethylsilyl) amide solution in tetrahydrofuran was added thereto. It was dropped in 7 minutes. After stirring at the same temperature for 10 minutes, 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, eluted with methylene chloride-hexane (1: 1), and 922 mg (88 mg) of the title compound as a colorless oily substance.
%). From the NMR spectrum (270 MHz)
A mixture of (O) and E (O) -isomers with a ratio of 4: 1
Met. NMR spectrum (270 Mz, CDCl ₃ ) δ ppm: 0.10 (1.2 H, 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 (0.2H
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 δ ppm 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 δ ppm 0.11 (6H, s), 0.75 (5.3H, d, J = 7 Hz), 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) fe
Nylthio-1-propene and its E (O) -isomer Z (O)-and E (O)-isomer ratio 9 NMR spectrum δ ppm 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 = 7 Hz),
1.79 (0.3H, d, J = 7Hz), 3.35-
3.55 (3H, brs), 5.34 (0.9H,
q, J = 7 Hz), 5.39 (0.1 H, q, J = 7 H)
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 δ ppm 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 δ ppm 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 δ ppm 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 = 7 Hz), 1.78 (0.5
H, d, J = 7 Hz), 3.18-3.40 (2H, b
load), 3.52-3.85 (2H, brs),
3.65-3.90 (4H, brs), 5.34 (0.
17H, q, J = 7 Hz), 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
Luthio-1-propene and its E (O) -isomer Z (O)-and E (O)-isomer ratio 11 NMR spectrum δ ppm 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 δ ppm 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-diethylaminocarboni
Le) phenyl ester Method A Ice-cooled 2,2'-dithiobenzoyl chloride 71.62 g
(0.209 mol) in 300 ml of methylene chloride
Amine 34.84 g (0.476 mol) and triethylamine 70.0 ml (0.5
02mol) in 50 ml of methylene chloride over 1 hour
Then, the mixture was further stirred at the same temperature for 30 minutes. Methylene chloride
The residue obtained by evaporation under reduced pressure is diluted with ethyl acetate and water,
Washed sequentially with saturated saline. Remove the solvent again and remove
The compound was obtained. Of the amide compound thus obtained
About 4 g of this, 14.36 g (0.220 mol) of zinc dust, anhydrous propylene
A mixture of 80.0 ml (0.624 mol) of on acid was added at 100 ° C for 5 minutes.
Upon heating and reaction, the zinc was activated simultaneously. Incidentally
At the same temperature, a solution of the remaining amide compound in 100 ml of benzene
The mixture was added dropwise over 20 minutes, and the mixture was further heated under reflux for 90 minutes. cold
The precipitated crystals are filtered off, and the crystals are washed with ethyl acetate.
Was. The filtrate and the washing solution were combined, washed with water, and then the solvent was distilled off.
The residue was distilled under reduced pressure to give 106.97 g of the title compound (2 steps, 96
%). bp 167-170 ° C / 0.95-1.1 mmHg IR spectrum (liq) cm^-1 : 1710,1635,1292,932 NMR spectrum (270MHz, CDCl_Three) δppm ： 1.02 (3H, t, J = 7H
z), 1.20 (3H, t, J = 7 Hz), 1.23 (3H, t, J = 7 Hz), 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⁺, C₁₄H
₁₉NO_TwoS) Method B a. 3.13 g (20.3 mmol) of thiosalicylic acid and triethylamido
A solution of 2.46 g (24.4 mmol) of methylene chloride in 60 ml of ice
Then, 2.85 g (20.3 mmol) of benzoyl chloride was added dropwise. Dripping
Thereafter, the mixture was further stirred at room temperature for 1 hour, and the reaction solution was added with 0.2 N hydrochloric acid for 2 hours.
It was washed once with saturated saline. 5.24 g after distilling off the solvent
(Quantitative yield) of crude crystals of benzoylthiobenzoic acid
Was. Dissolve this in 100 ml of methylene chloride and add
5.45 g of 2-chloro-1-methylpyridinium iodide (21.3m
mol), diethylamine 1.78 g (24.4 mmol) and triethyl
After sequentially adding 4.51 g (44.7 mmol) of amine, the mixture was added at room temperature for 20 hours.
While stirring. The residue obtained by distilling off the solvent is ethyl acetate.
And diluted hydrochloric acid, and the organic layer was washed with water. Distill solvent
Column chromatography using 120 g of silica gel
And hexane-acetone (4-3: 1)
Eluted and 4.86 g (76%) of N, N-diethyl 2-benzene
Zoylthiobenzamide was obtained as an oil. NMR
Spectrum (60MHz, CDCl_Three) 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. 4.86 g (15.5 mmol) of the compound obtained in a in methanol
The 60 ml solution was cooled on ice and 0.84 g of sodium methoxide (15.
5 mmol) and stirred for 20 minutes. Add about 15 drops of concentrated hydrochloric acid
And neutralize the reaction mixture, and then add ethanol to dissolve
The agent was distilled off. To remove water, add 20 ml ethanol and
30 ml of benzene was added and the solvent was again distilled off. in this way
, N-diethyl-2 mercaptobenzure
The residue containing the amide was suspended in 60 ml of methylene chloride and cooled under ice-cooling.
4.30 g (46.5 mmol) of propionyl chloride and triethylamine
6.26 g (62.0 mmol) was added and the mixture was stirred for 2.5 hours. Add water
The reaction was terminated by diluting with methylene chloride. Dilute organic layer
After washing with hydrochloric acid and water, the solvent is distilled off.
Purified by column chromatography using 100 g
3.26 g (79%) of the title compound were obtained. This compound is prepared using Method A
Identical to that obtained by A of Reference Example 12
Production of compounds of Reference Examples 13 to 21 by Method B or Method B
did.

[0102]

[Reference Example 13]Thiopropionic acid S- (2-dimethylaminocarboni
Le) phenyl ester Yield (2 steps,%) 78 IR spectrum Carbonyl absorption (cm^-1) 1709,
1639

[0103]

Reference Example 14 S- (2-dipropylaminocarbonithioic acid )
L) phenyl ester yield (2 steps,%) 93 IR spectrum carbonyl absorption (cm ^-1 ) 1705
1632

[0104]

Reference Example 15 S- (2-diisobutylaminocarboxy ) thiopropionate
Nyl) phenyl ester yield (2 steps,%) 99 IR spectrum carbonyl absorption (cm ^-1 ) 1712,
1635

[0105]

Reference Example 16 Thiopropionic acid S- (2-N, N-methylphenyla
Mino) phenyl ester yield (2 steps,%) 96 IR spectrum carbonyl absorption (cm ^-1) 1705,
1645

[0106]

REFERENCE EXAMPLE 17 S- (2-Pyrrolidinocarbonyl ) thiopropionic acid
Enyl ester yield (2 steps,%) 74 IR spectrum carbonyl absorption (cm ^-1 ) 1702
1630

[0107]

Reference Example 18 S- (2-piperidinocarbonyl ) thiopropionic acid
Enyl ester yield (2 steps,%) 98 IR spectrum carbonyl absorption (cm ^-1 ) 1702
1630

[0108]

Reference Example 19 S- (2-morpholinocarbonyl) thiopropionic acid
Enyl 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 Thiopropionic acid S- (2-diethylaminothiocarbo)
Nyl ) phenyl ester 276 mg (1.04 mmol) of the compound of Reference Example 12 was added to toluene (5 m
l), into which 216 mg (0.534 mmol) of Lawesson's reagent was added.
And heated at 100 ° C. with stirring for 2 hours. After completion of the reaction, the reaction mixture was cooled and chromatographed using 25 g of silica gel (eluted with methylene chloride: hexane = 3: 0 to 3: 1) 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 = 7 Hz), 1.37 (3H, t, J = 7 Hz), 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] (2-diethylaminocarbonyl) propionic acid
Nyl ester 2.40 g (12.4 mmol) of 2-propionyloxybenzoic acid
Was dissolved in 24 ml of methylene chloride, and 2.0 ml (23 mmol) of oxalyl chloride and 0.050 ml of dimethylformamide were added thereto under ice cooling, followed by stirring for 1 hour. The solvent and excess oxalyl chloride were distilled off under reduced pressure. To 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 subjected to 25 g of silica gel chromatography (methylene chloride: ethyl acetate =
10: 1 to 7: 1) to give 3.0 g (97% yield) of 2-diethylaminocarbonylphenylpropionate as an oil. IR spectrum (liq) cm ^-1 : 1765, 1638, 1430, 1293, 1142 NMR spectrum (60 MHz, CDCl ₃ ) δ ppm: 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-butyldimene
Tylsilyloxyethyl] -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-nitrobenzyloxy)
Carbonyl) oxyethyl] -1-piperazinylcarbo
Nil} -4-mercapto-1- (p-nitrobenzylo
135 mg (0.22 mmol) of (xycarbonyl) pyrrolidine, and
2 ml of methylene chloride of 30 mg (0.30 mmol) of triethylamine
The solution was stirred at room temperature for 17 hours. Obtained by distilling off the solvent
The residue is dissolved in ethyl acetate and 2N caustic soda, water, saturated
Washed sequentially with saline. After distilling off the solvent, the residue is
For column chromatography using 25 g of Kagel
And eluted with acetone-hexane (3: 2).
182 mg (quantitative yield) of the title compound were obtained.

[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-nitro
Robenzyloxycarbonyl) pyrrolidin-4-ylchi
Ocarbonylethyl] azetidin-2-one (3S, 4S) -3-[(R) -1- (t-butyldimene)
Tylsilyloxy) ethyl] -4-[(R) -1-
[(2S, 4S) -2- [4- [2- (4-nitroben
Diloxycarbonyloxy) ethyl] -1-piperazine
Nylcarbonyl] -1- (4-nitrobenzyloxyca
Rubonyl) pyrrolidin-4-yl-thiocarbonyl] d
Tyl] -2-azetidinone (8.1 g) in methanol (80
3N hydrochloric acid (24 ml) with stirring under ice-cooling.
l) was added dropwise. After dropping, the mixture is stirred at the same temperature for 30 minutes,
After standing in the refrigerator overnight, the reaction mixture was cooled on ice and
The pH was adjusted to 5 to 6 with sodium chloride. Then concentrate under reduced pressure
The residue was added with a small amount of water and extracted with ethyl acetate.
Further, the aqueous layer was saturated with common salt and extracted with the same solvent. Extract
In addition, the solvent was distilled off under reduced pressure. Residue is silica gel 15
Column chromatography using 0 g of ethyl acetate.
Elution with a mixed solvent of chill: methanol = 20 to 10: 1
This gave the target compound (5.9 g) as a colorless foamy compound. IR spectrum (CHCl_Three)cm^-1 ： 1752,1710,1650,1607,152
2,1443,1405,1347,1263 NMR spectrum (270MHz, CDCl_Three): 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)

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 205/08 C07D 477/00 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula [In the formula, R ¹ represents a hydrogen atom or a protecting group for a hydroxyl group, R ² represents a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkyl group having 1 to 6 carbon atoms. Represents 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 (wherein, Y represents an oxygen or sulfur atom, and R ⁵ and R ⁶ each independently represent a group having 1 to 6 carbon atoms;
A linear or branched alkyl group, an unsubstituted or 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-
A (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, sulfur atom or 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) Represents an unsubstituted or substituted aromatic acyl group selected from the following α group.) ). ) As a substituent, and a phenyl group which may have a substituent selected from the following α group, R ⁴ represents a hydrogen atom or an amino-protecting group, Z represents oxygen or Indicates a sulfur atom. ] The compound which has this. [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.