JPH06293765A - Synthetic intermediate for 1beta-substituted carbapenem antibiotic substance - Google Patents

Abstract

PURPOSE:To obtain the subject compound useful as a practical synthetic intermediate for a carbapenem derivative having excellent antibacterial activity. CONSTITUTION:A 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 sulfur atom; R<5> and R<6> are 1-6C alkyl, phenyl, etc.), H, etc.; R<4> is H or carboxyl- protecting group; (k) is 0-2], e.g. (1R,5S,6S)-2-(2-diethylcarbamoyphenylthio)-1- methyl-6[(R)-1-trimethylsilyoxyethyl]-1-carbapen-2-em-3-carboxylic acid 4- nitrobenzyl ester. The compound of formula I can be produced by reacting a compound of formula II (R<1n> is OH-protecting group) with an acid chloride of formula III and reacting the resultant N-oxyl derivative of formula IV with a phosphorous acid triester or phosphonous acid diester.

Description

Detailed Description of the Invention

[0001]

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

[0002]

2. Description of the Related Art Carbapenem antibiotics having strong antibacterial activity not only become chemically stable when a substituent is introduced at the 1β-position, but also against dihydropeptidase I (DHP-I) present in the body. Was also 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 synthetic method has received a great deal of attention, and various synthetic methods have been studied.

As one of the methods for synthesizing 1β-methylcarbapenem derivatives, 1β-substitution by BG Christensen et al.
The method of using 2-ketocarbapenamu as an intermediate (Heterocycle
s, 21, 29 (1984)), or the intramolecular Wittig method using phosphite triesters of Ota et al. (JP-A-61-508).
There is 1). However, in the former method, 1β-substitution-
Due to the instability of 2-keto carbapenum, it needs to be adjusted before use. Further, in the latter method of Oita et al., Since the Wittig reaction is carried out at a high temperature, depending on the desired 2-position substituent of the carbapenem, the decomposition reaction may be prioritized and the ring closure reaction may be difficult to proceed. As a method for overcoming these difficulties, there is an excellent method by Sugimura et al. Shown in the following reaction formula (Japanese Patent Laid-Open No. 1-25780), but the following points are problems.

[0004]

[Chemical 4]

That is, the yield (22) of the addition elimination reaction (A → B) between the mercaptan and the 4-chlorophenylsulfinyl group (22)
%) Is low.

[0006]

DISCLOSURE OF THE INVENTION The inventors of the present invention have found that one of the compounds of the present invention is a sulfide (Ia; k = 0).
That the sulfinyl compound (Ib; k = 1) and the sulfonyl compound (Ic; k = 2) obtained by oxidization of the compound undergo an addition-elimination reaction with mercaptan in the presence of a metal salt in a good yield to obtain a compound B or the like. Heading The present invention has been completed.

[0007]

The present invention has the general formula

[0008]

[Chemical 5]

Is a compound having

In the above formula, R ¹ represents a hydrogen atom or a hydroxyl-protecting group, R ² represents a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, a straight chain having 1 to 6 carbon atoms or Represents a branched alkoxy group, a halogen atom, a phenyl group or a phenoxy group, and R ³ represents a CYNR ⁵ R ⁶ group (in the formula,
Y represents an oxygen or sulfur atom, R ⁵ and R ⁶ each independently represent a linear or branched alkyl group having 1 to 6 carbon atoms or a phenyl group, or R ⁵ and R ⁶ are combined. Te formula _{- (CH 2) m (X} ) L (CH 2) n - group (wherein, m and n are 0 to 5 I same or different (provided that, m + n is 2 or more).
L is 0 or 1, X is an oxygen atom, R ^{3 ′} is a hydrogen atom, a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, a straight-chain or branched chain having 1 to 6 carbon atoms. A chain alkoxy group, a hydroxyl group, a halogen atom, a cyano group, or a nitro group, R ⁴ represents a hydrogen atom or a carboxyl group-protecting group, and k represents 0, 1, or 2.

In the above general formula, the hydroxyl-protecting group for R ^{1 is} a hydroxyl-protecting group commonly used in the synthesis of carbapenem derivatives, and is preferably t-butyldimethylsilyl or t-butyldimethylsilyl.
Trisubstituted silyl groups such as butyldiphenylsilyl, trimethylsilyl, triethylsilyl groups, aralkyloxycarbonyl groups such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl group, acetyl, chloroacetyl, substituted with methoxyacetyl A good acetyl group.

The halogen atom for R ² is fluorine, chlorine and bromine, preferably fluorine and chlorine.

Halogen atoms [0013] R ^{3 'is} fluorine, chlorine and bromine, preferably chlorine, bromine.

As the protective group for the carboxyl group of R ⁴ ,
A protecting group for a carboxyl group commonly used in the synthesis of carbapenem derivatives, preferably a lower alkyl group such as methyl, ethyl, t-butyl, benzyl, diphenylmethyl, 4-
Aralkyl groups such as nitrobenzyl and 2-nitrobenzyl, alkenyl groups such as allyl, 2-chloroallyl and 2-methylallyl, 2,2,2-trichloroethyl, 2,2,2-
Halogenated alkyl groups such as tribromoethyl or 2
An example is a-(trimethylsilyl) ethyl group.

Examples of the linear or branched alkyl group having 1 to 6 carbon atoms represented by R ² , R ⁵ , R ⁶ and R ^{3 ′} include methyl, ethyl, propyl, i-butyl, pentyl and hexyl. And preferred are methyl, ethyl and propyl.

Examples of the alkyl moiety of the straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms represented by R ² and R ^{3 ′} include those similar to the above-mentioned alkyl groups, and preferably methoxy and ethoxy. It is a base.

Specific examples of the compound having the general formula (I) of the present invention include the compounds shown in Tables 1 and 2, but the present invention is not limited thereto.

The formula (I-1) is used for Table 1 and the formula (I-2) is used for Table 2.

[0019]

[Chemical 6]

[0020]

[Table 1]

[0021]

[Chemical 7]

[0022]

[Table 2] In the table, TBS is t-butyldimethylsilyl group, TMS is trimethylsilyl group, Ph is phenyl group, and PNB is 4-.
A nitrobenzyl group, PNZ is a 4-nitrobenzyloxycarbonyl group, A11 is an allyl group, and m-Me is a methyl group at the m-position.

In the above table, preferred compounds include 1-
1,1-2,1-3,1-4,1-5,1-6,1-
7, 1-8, 1-9, 1-28, 1-29, 1-30,
1-31, 1-32, 1-33, 1-34, 1-35,
1-36, 1-46, 1-47, 1-48, 1-49,
1-50, 1-51, 1-52, 1-53, 1-54,
1-64, 1-65, 1-66, 1-67, 1-68,
1-69, 1-79, 1-80, 1-81, 1-82,
1-83, 1-84, 2-3, 2-4, 2-5, 2-
7, 2-10, 2-11, 12-12, 2-14, 2-1
7, 2-18, 2-19, 2-21, 24, 2-2
6,2-28, 2-31, 2-33, 2-35, 2-3
8, 2-40, 2-42, 2-45, 2-47, 2-4
9, 2-52, 2-54, 2-56, 2-59, 2-6
1 and 2-63, and more preferably 1-4, 1-
5, 1-6, 1-31, 1-32, 1-33, 1-4
9, 1-50, 1-51, 2-5, 2-12, 2-1
9,2-26,2-33,2-40,2-47,2-5
4 and 2-61, most preferably 1-31, 1-3
2,1-33,1-49,1-50,1-51,2-2
6, 2-33, 2-40, 2-47, 2-54, 2-6
It is 1.

The compound (I) according to the present invention can be synthesized by the following method.

Method A

[0026]

[Chemical 8]

In the above formula, R ¹ , R ³ , R ⁴ and k have the same meanings as described above, and R ^1a has the same meaning as the hydroxyl-protecting group for R ¹ .

R ⁸ represents a lower alkyl group or a lower alkoxy group. Examples of the lower alkyl group for R ⁸ include methyl, ethyl, propyl, isopropyl, butyl and isobutyl.

The lower alkoxy group for R ⁸ is, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or t-butoxy.

R ⁹ represents a lower alkoxy group or an aryloxy group. The lower alkoxy group for R ^{9 has} the same meaning as the lower alkoxy group for R ⁸ .

Examples of the aryloxy group of R ⁹ include phenoxy, 4-methylphenoxy and 4-methoxyphenoxy.

Compound (II) of Method A (Japanese Patent Application No. 4-1740)
No. 99 publication) R ¹ = TBS, R ² = CH ₃ , R ³ = 2
-CONEt _2, R ³ '= a H compound (II) Z
(O) -1-t-butyldimethylsilyloxy-1-
Obtained from the reaction of (diethylcarbamoylphenylthio) -1-propene with (3R, 4R) -3-[(R) -1- (t-butyldimethylsilyloxy) ethyl] -4-acetoxyazetidinone, The compound can be obtained in a yield of 77% only by a purification method by recrystallization without purification by column chromatography. Therefore, this compound is a useful intermediate in the industrial production of 1β-methylcarbapenem derivatives.

In the method A, the N-oxylyl derivative (IV) obtained by reacting the compound (II) with the acid chloride (III) is further reacted with a phosphorous acid triester or a phosphonous acid diester to give the compound (Ia). ) Is a known method (Tetrahedron Letters 25 2793 (1984) or Japanese Patent Application No.
180779).

Step 1 The compound (IV) is obtained by reacting the compound having the general formula (II) with 2 to 5 molar equivalents of the acid chloride (III) in the presence of a base.

The base used is not particularly limited as long as it does not participate in the reaction, and examples thereof include tertiary amines, and examples of the tertiary amine include diisopropylethylamine, diisopropylmethylamine, triethylamine, 1- Ethylpiperidine, 1-methylmorpholine, 1-ethylpyrrolidine, 1,4-diazabicyclo [2,2,2] octane, 1,5-diazabicyclo [5,4,0] undecene-5 or 1,5-diazabicyclo [4] , 3,0] Nonene-5, such as cyclic or chain amines.

The solvent used is not particularly limited as long as it does not participate in this reaction, but halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane: diethyl ether, ethers such as tetrahydrofuran: benzene Hydrocarbons such as toluene and nitriles such as acetonitrile and propionitrile are preferred.

The reaction temperature is usually -78 ° C to 50 ° C, preferably -30 ° C to 30 ° C. The reaction time varies depending on the raw material compounds and reaction reagents, but is usually 5 minutes
3 hours.

After completion of the reaction, the desired compound can be isolated from the reaction mixture by a conventional method after decomposing excess acid chloride with alcohol. For example, water is added to the reaction mixture, the target compound (4) is extracted with an organic solvent immiscible with water, such as the above-mentioned reaction solvent or ethyl acetate, the solvent is distilled off from the extract, and column chromatography, etc., if necessary. Can be purified to obtain a pure product.

Step 2 The compound having the general formula (IV) is reacted with 2 to 6 molar equivalents of the trivalent phosphorus compound (V) without solvent or in a solvent to obtain phosphorane (VI).

The solvent used is not particularly limited as long as it does not participate in this reaction, but hydrocarbons such as benzene, toluene, xylene: chloroform, methylene chloride, 1,2-dichloroethane, etc. Examples are carbon halides, ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile, esters such as ethyl acetate, and amides such as dimethylformamide.

The reaction temperature is usually -10 ° C to 100 ° C, preferably 0 ° C to 100 ° C. The reaction time varies depending on the raw material compound and the reaction reagent, but is usually 10 minutes to
30 hours.

After completion of the reaction, phosphorous (VI) is obtained by distilling off excess phosphorus compound (V) and its oxygen adduct under reduced pressure or by adding a non-polar solvent such as hexane to precipitate the product. To be

The VI of the crude product thus obtained can be used as it is in the next step without purification, but if necessary, it can be purified by using column chromatography or the like.

Third Step By heating the phosphorane (VI), the compound (Ia) is obtained.

The solvent used is not particularly limited as long as it does not participate in this reaction, but substituted aromatic hydrocarbons such as toluene, xylene, mesitylene or chlorobenzene can be mentioned. The reaction temperature is usually 100 to 20.
It is 0 degreeC, Preferably it is 120-170 degreeC. The reaction time varies depending on the raw material compound and the reaction reagent, but is usually 1
~ 30 hours.

After completion of the reaction, the solvent is distilled off and the residue is purified by recrystallization or by chromatography to give compound (I
a) is obtained.

Method B is a method of oxidizing compound having the general formula (Ia) to synthesize compound (Ib).

Step 4 S-oxide (Ib) is obtained by reacting compound (Ia) with an oxidizing agent. Examples of the oxidizing agent include peroxides such as m-chloroperbenzoic acid, peracetic acid, hydrogen peroxide, and t-butylhydroperoxide, but m-chloroperbenzoic acid and t-butylhydroperoxide are preferable. . t-
When butyl hydroperoxide is used as a catalyst for the reaction, vanadyl acetylacetonate [VO (acac)
₂ ] and molybdenum acetylacetonate can be used, but vanadyl acetylacetonate is preferable. Further, in order to remove the acidic substance derived from peroxide generated by participating in this reaction,
The oxidation reaction can be carried out in the presence of an alkali metal carbonate or an aqueous solution thereof. The solvent used is not particularly limited as long as it does not participate in this reaction, and alcohols such as methanol and ethanol, dichloromethane,
Examples thereof include halogenated carbons such as chloroform and 1,2-dichloroethane, and preferably halogenated carbons. The reaction temperature is 10 to 50 ° C., preferably 0.
~ 25 ° C. The reaction time varies depending on the reaction temperature and the like, but is usually 30 minutes to 6 hours.

After completion of the reaction, a reducing agent such as 10% sodium sulfite is added to decompose excess oxide, and the mixture is diluted with a solvent such as methylene chloride. The obtained organic solvent layer is washed with water and dried. Obtained by distilling off the solvent.

The residue is purified by recrystallization or by chromatography to obtain the compound (Ib).

Method C is a method for synthesizing compound (Ic) by further oxidizing the compound having general formula (Ib).

The fifth step can be performed in the same manner as the fourth step. The compound (Ic) obtained in the fifth step can also be synthesized by directly using an excess of an oxidizing agent as compared with the compound (Ia).

Method D is a known method (TWGreen and PG) in the step of removing the protective group R ¹ for the hydroxyl group of compound (Id).
M Wuts, “Protective Groups in Organic Synthesis.
2ndEdition ”John Wiley and Sons, Inc., 1991, p10).

Compound (Ia) included in Compound I of the present invention
(Ib) and (Ic) derived from the above are suitable mercaptans (R ¹⁰ ) in the presence of magnesium salts, for example, cyclohexylisopropyl magnesium bromide or diisopropylamine and magnesium bromide ether complex.
It is converted to compound VII in good yield by addition-elimination reaction with SH).

[0055]

[Chemical 9]

Examples of R ¹⁰ SH include

[0057]

[Chemical 10]

And the like.

[0059]

INDUSTRIAL APPLICABILITY The compounds (I
The compounds (Ib) and (Ic) derived from a) could be converted to the compound (VII) in good yield.

When R ^{1 of} (VII) thus obtained is a hydroxyl-protecting group, it is removed by a conventional method, and further, a carboxyl-protecting group R ⁴ is removed to exhibit excellent antibacterial activity. Can lead to substituted carbapenems. Therefore, the compound (I) of the present invention is a useful intermediate in the synthesis of 1-substituted carbapenem antibiotics.

[0061]

【Example】

Example 1 (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylthio) -1-methyl-6-
[(R) -1-Trimethylsilyloxyethyl] -1-
Carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0062]

[Chemical 11]

492 mg (1.09 m) of the compound of Reference Example 1
mol) and triethylamine 0.46 ml (3.30 m)
Mol) in 8 ml of methylene chloride was cooled in a salt-ice bath to give 4-nitrobenzyloxyoxalyl chloride 79
7 mg (3.27 mmol) was added and reacted at the same temperature for 15 minutes. Furthermore, 0.25 ml of isopropanol (3.
27 mmol) was added and the mixture was stirred for 10 minutes at the same temperature to decompose excess acid chloride. The reaction solution was diluted with ethyl acetate and washed twice with water and twice with saturated saline. The solvent was evaporated, the obtained residue was suspended in toluene, and the insoluble material was removed by filtration. Toluene was distilled off, 784 mg (4.40 mmol) of dipropylethylphosphonite was added to the residue, and the mixture was stirred at room temperature for 140 minutes. The excess reagent was distilled off, the residue was dissolved in 65 ml of xylene, and the mixture was heated under reflux for 3 hours. The solvent was distilled off, and the residue was subjected to column chromatography using 50 g of silica gel and eluted with ethyl acetate-hexane (1: 2),
The target product containing a small amount of impurities was obtained. This was further purified under the same conditions to obtain 535 mg (78%) of the target compound,
Mp20 when re-bonded with isopropyl ether
Colorless crystals of 2 to 203 ° C were obtained.

IR spectrum (KBr) cm ^-1 : 1761,1695,163
0,1342,1207 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.10 (9H, s), 1.01
(3H, t, J = 7Hz), 0.95-1.20 (6H, m), 1.20 (3H, d, J = 6Hz), 3.06
(2H, q, J = 7Hz), 3.05-3.28 (3H, m), 3.45-3.80 (1H, brs), 4.1
8-4.25 (2H, m), 5.27 (1H, d, J = 14Hz), 5.47 (1H, d, J = 14Hz),
7.32-7.65 (4H, m), 7.68 (2H, d, J = 9Hz), 8.21 (2H, d, J = 9Hz) Mass spectrum (m / z): 625 (M ⁺ , C ₃₁ H ₃₉ N ₃ O ₇ SSi) Example 2 (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylthio) -1-methyl-6-
[(R) -1-t-Butyldimethylsilyloxyethyl] -1-carbapene-2-em-3-carboxylic acid 4-
Nitrobenzyl ester

[0065]

[Chemical 12]

When the raw material used in Reference Example 1 was reacted and treated in the same manner as in Example 1, the target compound was obtained in a yield of 80%, which was recombined with isopropyl ether to give mp16.
Crystals of 6 to 166.5 ° C were obtained.

IR spectrum (nujol) cm ⁻¹ : 1762,1693,16
33,1340,1210 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.06 (6H, s), 0.84
(9H, s), 1.01 (3H, t, J = 7Hz), 0.93-1.20 (6H, m), 1.16 (3H, d,
J = 6Hz), 3.00-3.30 (3H, m), 3.07 (2H, q, J = 7Hz), 3.40-3.90
(1H, m), 4.21-4.33 (2H, m), 5.28 (1H, d, J = 14Hz), 5.44 (1H,
d, J = 14Hz), 7.27-7.65 (4H, m), 7.67 (2H, d, J = 9Hz), 8.21 (2
H, d of t, J = 9 Hz) Mass spectrum (m / z): 667 (M ⁺ , C ₃₄ H ₄₅ N ₃ O ₇ SSi) Example 3 (1R, 5S, 6S) -2- [2- ( 2H-
1,3,4,5,6,7-Hexahydro1-azepinyl) carbonylphenylthio] -1-methyl-6-
[(R) -1-t-Butyldimethylsilyloxyethyl] -1-carbapene-2-em-3-carboxylic acid 4-
Nitrobenzyl ester

[0068]

[Chemical 13]

Example 9 of Japanese Patent Application No. 4-174099
The target compound was obtained by reacting and treating the compound of Example 1 in the same manner as in Example 1, and recrystallized with isopropyl ether to give crystals of mp 210 to 211 ° C.

IR spectrum (KBr) cm ⁻¹ : 1757,1700,163
2,1341,1212,1138 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.06 (6H, s), 0.85
(9H, s), 0.95-1.08 (3H, m), 1.16 (3H, d, J = 6Hz), 1.40-1.85
(8H, m), 3.04-3.34 (5H, m), 3.45-3.65 (1H, brs), 4.20-4.36
(2H, m), 5.29 (1H, d, J = 14Hz), 5.46 (1H, d, J = 14Hz), 7.30-7.
65 (4H, m), 7.68 (2H, d, J = 9Hz), 8.22 (2H, d, J = 9Hz) Mass spectrum (m / z): 693 (M ⁺ , C ₃₆ H ₄₇ N ₃ O ₇ SSi ) Example 4 (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylthio) -1-methyl-6-
[(R) -1-hydroxyethyl] -1-carbapene-
2-M-3-carboxylic acid 4-nitrobenzyl ester

[0071]

[Chemical 14]

1.072 g (1.71 g) of the compound of Example 1
mmol) methanol-methylene chloride (2: 1) 30
41 mg of citric acid hydrate (0.195 mm
ol) was added and the mixture was stirred at room temperature for 20 minutes. The reaction solution was concentrated, and the obtained residue was subjected to column chromatography using 25 g of silica gel and eluted with ethyl acetate to obtain 970 mg (quantitative yield) of a colorless foamy substance.

IR spectrum (neat) cm ⁻¹ : 3600 to 3200 (b
r), 1771,1707,1612,1352,1207 NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.00 (3H, t, J = 7H
z), 0.94-1.15 (6H, m), 1.30 (3H, d, J = 6Hz), 3.05 (2H, q, J = 7H
z), 3.10-3.28 (3H, m), 3.45-3.80 (1H, brs), 4.20 (1H, quin
t, J = 7Hz), 4.25 (1H, dd, J = 2Hz, 9Hz), 5.27 (1H, d, J = 14Hz),
5.48 (1H, d, J = 14Hz), 7.31-7.65 (4H, m), 7.67 (2H, d, J = 9H
z), 8.22 (2H, d , J = 9Hz) Mass Spectrum (m / z): 553 ( M +, C 28 H 31 N 3 O 7 S) Example 5 (1R, 5S, 6S) -2- ( 2-Diethylcarbamoylphenylsulfinyl) -1-methyl-6
-[(R) -1-trimethylsilyloxyethyl] -1
-Carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0074]

[Chemical 15]

304 mg of the compound of Example 1 (0.486
122 mg of baking soda in 6 ml of methylene chloride solution.
(1.45 mmol) was added, and 105 mg (0.487 mmo) of 3-chloroperbenzoic acid having a purity of 80% under stirring with ice cooling.
1) was added and the mixture was stirred at the same temperature for 1 hour. The reaction solution was diluted with methylene chloride and washed with ice-cooled dilute aqueous sodium hydrogen carbonate. The residue obtained by evaporating the solvent was subjected to column chromatography using 25 g of silica gel and eluted with ethyl acetate-hexane (2: 1) to give 260 m of the target compound as a foamy substance.
g (83%) was obtained.

IR spectrum (film) cm ⁻¹ : 1788,1734,16
30,1522,1061 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.08 (5.4H, s), 0.
10 (3.6H, s), 1.04-1.27 (12H, m), 2.98-3.53 (5.6H, m), 3.67
(0.4H, d of q, J = 11Hz, 7Hz), 4.16-4.23 (1H, m), 4.26 (0.6
H, dd, J = 10Hz, 3Hz), 4.34 (0.4H, dd, J = 10Hz, 3Hz), 5.35 (0.4
H, d, J = 14Hz), 5.38 (0.6H, d, J = 14Hz), 5.46 (0.4H, d, J = 14H)
z), 5.50 (0.6H, d, J = 14Hz), 7.27-7.36 (1H, m), 7.50-7.73 (4
H, m), 7.84-7.90 (0.4H , m), 8.15-8.26 (2.6H, m) mass spectrum (m / z): 641 ( M +, C 31 H 39 N 3 O 8 SSi) Example 6 (1R, 5S, 6S) -2- (2-Diethylcarbamoylphenylsulfinyl) -1-methyl-6
-[(R) -1-t-Butyldimethylsilyloxyethyl] -1-carbapene-2-em-3-carboxylic acid 4-
Nitrobenzyl ester

[0077]

[Chemical 16]

When the compound of Example 2 was reacted and treated in the same manner as in Example 5, the target compound was obtained as a foamy substance in a yield of 87%.

IR spectrum (nujol) cm ⁻¹ : 1788,1735,16
30,1523,1058 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.03,0.04,0.05,
0.06 (6H, each s), 0.83 (4.5H, s), 0.84 (4.5H, s), 1.05-1.2
7 (12H, m), 2.98-3.56 (5.5H, m), 3.59 (0.5H, d of q, J = 10H
z, 7Hz), 4.20-4.38 (1H, m), 4.30 (0.5H, dd, J = 11Hz, 3Hz), 4.
39 (0.5H, dd, J = 11Hz, 3Hz), 5.34 (0.5H, d, J = 14Hz), 5.38 (0.
5H, d, J = 14Hz), 5.45 (0.5H, d, J = 14Hz), 5.49 (0.5H, d, J = 14H)
z), 7.29-7.36 (1H, m), 7.50-7.71 (4H, m), 7.85-7.89 (0.5H,
m), 8.15-8.25 (2.5H, m ) mass spectrum (m / z): 683 ( M +, C 34 H 45 N 3 O 8 SSi) Example 7 (1R, 5S, 6S) -2- (2 -Diethylcarbamoylphenylsulfinyl) -1-methyl-6
-[(R) -hydroxyethyl] -1-carbapene-2
-M-3-carboxylic acid 4-nitrobenzyl ester

[0080]

[Chemical 17]

554 mg of the compound of Example 4 (1.00 m
10 ml of a methylene chloride solution in 10 ml of methylene chloride was ice-cooled, 1.5 ml (1.5 mmol) of 1M aqueous sodium hydrogen carbonate solution and 215 mg (1.00 mmol) of 80% m-chloroperbenzoic acid were sequentially added, and the mixture was stirred at the same temperature for 90 minutes. Aqueous sodium sulfite solution was added to the reaction solution and stirred for 10 minutes to terminate the reaction. The reaction mixture was diluted with methylene chloride, washed with ice-cold aqueous sodium hydrogen carbonate, and concentrated. The residue was subjected to column chromatography using 50 g of silica gel and eluted with ethyl acetate to obtain 145 mg (25%) of the target compound with low polarity (isomer with S—O coordination) and 96 mg (17% of target compound with high polarity). )
Respectively as a foamy substance.

IR spectrum (film) cm ^-1 : low polar s-oxide, 3500-3300,1786,1732,1624,1522,1200,1061; high polar s-oxide, 3500-3300,1786,1734,1624, 1522,119
8,1061 NMR spectrum (270 MHz, CDCl ₃ ) δppm: low-polarity s-oxide, 1.02-1.11 (6H, m), 1.24 (6H, t, J = 7Hz), 3.01 (1H, d of
q, J = 10Hz, 7Hz), 3.12 (2H, q, J = 7Hz), 3.18-3.30 (1H, m), 3.3
2 (1H, dd, J = 3Hz, 6Hz), 3.39-3.52 (1H, m), 4.19 (1H, quint, 6
Hz), 4.28 (1H, dd, J = 3Hz, 10Hz), 5.38 (1H, d, J = 14Hz), 5.52
(1H, d, J = 14Hz), 7.33 (1H, dd, J = 1Hz, 8Hz), 7.58 (1H, d of
t, J = 1Hz, 8Hz), 7.66 (1H, d of t, J = 1Hz, 8Hz), 7.70 (2H, d, J
= 9Hz), 8.16 (1H, dd, J = 1Hz, 8Hz), 8.24 (2H, d, J = 9Hz); high polarity s-oxide, 0.83 (3H, d, J = 7Hz), 1.09 (3H, t , J = 7Hz),
1.18 (3H, t, J = 7Hz), 1.28 (3H, d, J = 6Hz), 3.18 (2H, q, J = 7H
z), 3.20-3.35 (1H, m), 3.40-3.53 (1H, m), 3.47 (1H, dd, J = 3H
z, 6Hz), 3.70 (1H, d of q, J = 10Hz, 7Hz), 4.25 (1H, quint, 6H
z), 4.38 (1H, dd, J = 3Hz, 10Hz), 5.34 (1H, d, J = 13Hz), 5.48 (1
H, d, J = 13Hz), 7.28-7.32 (1H, m), 7.48-7.56 (2H, m), 7.65 (2
H, d, J = 9Hz), 7.85-7.91 (1H, m), 8.22 (2H, d, J = 9Hz) Mass spectrum (m / z): high polarity s-oxide, 551 (M ⁺ -H)
₂ O) Example 8 (1R, 5S, 6S) -2- [2- (2H-
1,3,4,5,6,7-Hexahydro-1-azepinyl) carbonylsulfenylsulfinyl) -1-methyl-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-carbapene- 2-M-3-carboxylic acid 4-nitrobenzyl ester

[0083]

[Chemical 18]

The compound obtained in Example 3 was reacted and treated in the same manner as in Example 5 to obtain the target compound as a foamy substance. Yield 89%.

IR spectrum (film) cm ⁻¹ : 1790, 1734, 16
28,1524,1347,1061, NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.03, 0.04, 0.05,
0.06 (total 6H, each s), 0.75 (1.5H, d, J = 7Hz), 0.83 (4.5
H, s), 0.84 (4.5H, s), 1.13 (1.5H, d, J = 6Hz), 1.16 (1.5H, d, J
= 6Hz), 1.28 (1.5H, d, J = 7Hz), 1.44-1.80 (8H, m), 3.00 (0.5
H, d of q, J = 10Hz, 7Hz), 3.11-3.37 (3.5H, m), 3.41-3.50 (1
H, m), 3.60-3.77 (1H, m), 4.19-4.31 (1.5H, m), 4.38 (0.5H, d
d, J = 10Hz, 3Hz), 5.33 (0.5H, d, J = 14Hz), 5.40 (0.5H, d, J = 14
Hz), 5.46 (0.5H, d, J = 14Hz), 5.49 (0.5H, d, J = 14Hz), 7.27-
7.32 (0.5H, m), 7.36 (0.5H, dd, J = 7Hz, 1Hz), 7.48-7.60 (1.5
H, m), 7.63-7.73 (2.5H, m), 7.93-7.96 (0.5H, m,), 8.15 (0.5
H, dd, J = 8Hz, 1Hz), 8.22 (1H, d, J = 9Hz), 8.23 (1H, d, J = 9Hz) Mass spectrum (m / z): 709 (M ⁺ , C ₃₆ H ₄₇ N ₃ O ₈ SSi) Example 9 (1R, 5S, 6S) -2- (2-diethylcarbamoylphenylsulfonyl) -1-methyl-6-
[(R) -1-t-Butyldimethylsilyloxyethyl] -1-carbapene-2-em-3-carboxylic acid 4-
Nitrobenzyl ester

[0086]

[Chemical 19]

157 mg (0.235) of the compound of Example 2
A solution of 3 mmol of methylene chloride in methylene chloride was cooled with ice, and 78 mg (0.93 mmol) of sodium bicarbonate and 78 mg (0.52 mmol) of 80% m-chloroperbenzoic acid were sequentially added.
After stirring at the same temperature for 20 minutes and further at room temperature for 3.5 hours, an aqueous sodium sulfite solution was added and the reaction was terminated by stirring for 10 minutes. The reaction mixture was diluted with methylene chloride, washed with aqueous sodium hydrogen carbonate, and concentrated. The residue was subjected to column chromatography using 15 g of silica gel and eluted with ethyl acetate-hexane (4: 6) to give the target compound 148 as a foamy substance.
mg (90%) was obtained.

IR spectrum (film) cm ⁻¹ : 1794, 1748, 16
36,1524,1320,1266,1161 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.03 (3H, s), 0.05
(3H, s), 0.83 (9H, s), 1.06 (3H, t, J = 7Hz), 1.16 (3H, d, J = 6H
z), 1.20-1.43 (6H, m), 3.01-3.19 (2H, m), 3.24-3.84 (4H,
m), 4.19-4.28 (1H, m), 4.42-4.52 (1H, m), 5.39 (2H, s), 7.25
-7.34 (1H, m), 7.48-7.65 (2H, m), 7.62 (2H, d, J = 9Hz), 8.11
(1H, d, J = 8Hz), 8.21 (2H, d, J = 9Hz) Mass spectrum (m / z): 700 (M ⁺ (C ₃₄ H ₄₅ N ₃ O ₉ SSi) +1) Reference example 1 ( R) -2-[(3S, 4S) -3-
[(R) -1- (trimethylsilyloxy) ethyl]-
2-oxo-4-azetidinyl] thiopropionic acid S-
2-diethylcarbamoylphenyl ester

[0089]

[Chemical 20]

Compound (R) -2-[(3S, 4S) -3-[(R) -1-] described in Japanese Patent Application No. 3-172220
t-Butyldimethylsilyloxyethyl] -2-oxo-4-azetidinyl] thiopropionic acid S-2-diethylcarbamoylphenyl ester 1.002 g (2.0
3 mmol) in 20 ml of tetrahydrofuran solution
5 ml of hydrochloric acid was added and heated at 50 ° C. for 3 hours. After cooling, the reaction solution was diluted with ethyl acetate and partitioned with water. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate, water and saturated brine, and the solvent was evaporated. The obtained desilylated product was treated with tetrahydrofuran 10
Dissolve in 0.3 ml of triethylamine 0.60 ml (4.3
0 mmol), trimethylsilyl chloride 0.53 ml
Was added, and the mixture was stirred at room temperature for 80 minutes and at 40 ° C for 100 minutes.
After cooling, the reaction solution was diluted with ethyl acetate, washed twice with ice water and further washed with saturated saline, and the solvent was evaporated. The residue was subjected to column chromatography using 100 g of silica gel and eluted with ethyl acetate-hexane (60-80: 100) to give 742 mg (81%) of the title compound as a foam.

IR spectrum (film) cm ⁻¹ : 3250,1760,17
00,1625 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.12 (9H, s), 1.03
(3H, t, J = 7Hz), 1.23 (3H, d, J = 6Hz), 1.25 (3H, t, J = 7Hz), 1.2
2-1.31 (3H, m), 2.95-3.12 (4H, m), 3.25-3.85 (2H, m), 3.90
(1H, dd, J = 2Hz, 4Hz), 4.14 (1H, quint, J = 6Hz), 6.07-6.18 (1
H, brs), 7.32-7.35 (1H, m), 7.41-7.61 (3H, m) Mass spectrum (m / z): 450 (M ⁺ , C ₂₂ H ₃₄ N ₂ O ₄ SSi) Reference example 2 (1R , 5S, 6S) -2-[(2S, 4
S) -3-Dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-pyrrolidinylthio]-
1-Methyl-6-[(R) -1-trimethylsilyloxyethyl] -1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0092]

[Chemical 21]

(2S, 4S) -2-Dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4
-Mercaptopyrrolidine 68 mg (0.19 mmol)
2 ml of tetrahydrofuran solution of is cooled in an ice bath and 0.19 ml of 1M bromomagnesium isopropyl cyclohexyl amide tetrahydrofuran solution (0.19 mmo
1) was added dropwise in 2 minutes. The mixture was stirred at the same temperature for 10 minutes, and 1 ml of a tetrahydrofuran solution of the compound of Example 5 was added.
Was added. After stirring at the same temperature for 15 minutes, ice water was added and the reaction solution was diluted with ethyl acetate and washed successively with an aqueous ammonium chloride solution and saturated saline. The solvent was evaporated and the obtained residue was subjected to column chromatography using 10 g of silica gel and eluted with ethyl acetate to give 94 mg (78%) of the title compound as a foamy substance.

IR spectrum (film) cm ⁻¹ : 1773,1711,16
55,1522,1345,1142,845 NMR spectrum (270MHz, CDCl ₃ ) δppm: 0.13 (4.5H, s), 1.1
4 (4.5H, s,), 1.25-1.29 (6H, m), 1.89-2.00 (1H, m), 2.67-2.
80 (1H, m), 2.94 (1.5H, s), 2.98 (1.5H, s), 3.00 (1.5H, s), 3.
11 (1.5H, s), 3.22-3.27 (1H, m), 3.30-3.40 (1H, m), 3.46-3.
57 (1H, m), 3.60-3.76 (1H, m), 4.02-4.30 (3H, m), 4.72 (0.5
H, t, J = 8Hz), 4.76 (0.5H, t, J = 8Hz), 5.07 (0.5H, d, J = 14Hz),
5.22 (1H, s), 5.25 (1H, d, J = 14Hz), 5.30 (0.5H, d, J = 14Hz),
5.46 (1H, d, J = 14Hz), 7.44 (1H, d, J = 9Hz), 7.52 (1H, d, J = 9H
z), 7.65 (2H, d, J = 9Hz), 8.20 (1H, d, 9Hz), 8.21 (3H, d, J = 9H
z) Mass spectrum (m / z): 754 ( M + (C 35 H 43 N 5 O 11 SSi) -CH 3) Reference Example 3 (1R, 5S, 6S) -2 - [(2S, 4
S) -2-Dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-pyrrolidinylthio]-
1-Methyl-6-[(R) -1-t-butyldimethylsilyloxyethyl] -1-carbapene-2-em-3-
Carboxylic acid 4-nitrobenzyl ester

[0095]

[Chemical formula 22]

A) Using the compound of Example 6 under the same conditions as in Reference Example 2, the title compound was obtained as a foamy substance in a yield of 86%.

B) Using the compound of Example 8 under the same conditions as in Reference Example 2, the title compound was obtained as a foamy substance in a yield of 83%.

C) Compound of Example 9 (50 mg, 0.07)
1 mmol), (2S, 4S) -Dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-
53 mg of mercaptopyrrolidine (0.086 mmo
l), magnesium bromide ether complex 76 mg (0.2
25 μl (0.144 mmol) of diisopropylethylamine was added to a tetrahydrofuran suspension of 94 mmol) and the mixture was stirred for 94 hours. Dilute the reaction solution with ethyl acetate,
After washing with water and saturated saline, the solvent was distilled off. The residue was purified by silica gel column chromatography to give the title compound 53 mg (69%). IR spectrum (film) cm ^-1 : 1775,1713,1657,1522,134
5,1142,837 NMR spectrum _{(270MHz, CDCl 3) δppm:} 0.07-0.09 (6H, m),
0.85 (4.5H, s), 0.87 (4.5H, s), 1.23-1.29 (6H, m), 1.88-2.0
0 (1H, m), 2.67-2.81 (1H, m), 2.94 (1.5H, s), 2.98 (1.5H, s),
2.99 (1.5H, s) 3.11 (1.5H, s), 3.23-3.41 (2H, m), 3.46-3.57
(1H, m), 3.61-3.78 (1H, m), 4.03-4.32 (3H, m), 4.73 (0.5H,
t, J = 8Hz), 4.77 (0.5H, t, J = 8Hz), 5.07 (0.5H, d, J = 13Hz), 5.
22 (1H, s), 5.25 (1H, d, J = 13Hz), 5.30 (0.5H, d, J = 13Hz), 5.4
5 (1H, d, J = 13Hz), 7.45 (1H, d, 9Hz), 7.52 (1H, d, J = 9Hz), 7.6
5 (2H, d, J = 9Hz), 8.20 (1H, d, 9Hz), 8.21 (3H, d, J = 9Hz) Mass spectrum (m / z): 754 (M ⁺ (C ₃₈ H ₄₉ N ₅ O ₁₁ SSi) -C ₄ H ₉ ) Reference Example 4 (1R, 5S, 6S) -2-[(2S, 4
S) -2-Dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl) -4-pyrrolidinylthio]-
1-methyl-6-[(R) -1-hydroxyethyl]-
1-carbapene-2-em-3-carboxylic acid 4-nitrobenzyl ester

[0099]

[Chemical formula 23]

A) (i) 467 mg of the compound of Example 4
(0.843 mmol) and 80% m-chloroperbenzoic acid (201 mg, 0.932 mmol) were used to carry out the reaction and treatment of Example 7 to obtain 464 mg of crude s-oxide. This was used for the next reaction without chromatographic purification.

(Ii) (2S, 4S) -Dimethylcarbamoyl-1- (4-nitrobenzyloxycarbonyl)-
4-Mercaptopyrrolidine 347 mg (0.982 mm
ol) in 3 ml of tetrahydrofuran and ice-cooled
Bromomagnesium isopropyl cyclohexyl amide tetrahydrofuran solution 0.97 ml (0.97 mmo
l) was added dropwise over 4 minutes and stirred for a further 10 minutes. 464 mg of crude s-oxide obtained in (i) was added to this solution.
2 ml of tetrahydrofuran solution of was added, and the mixture was further stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added, water was added, and the mixture was extracted 3 times with ethyl acetate. The organic layers were combined, washed successively with saturated brine and the concentrated oily residue was subjected to column chromatography using 50 g of silica gel and eluted with methanol-ethyl acetate (1: 9) to give 365 mg (62%) of the title compound. Was obtained as a foam.

B) 55 mg (0.07) of the compound of Reference Example 2
To a solution of 1 mmol) in 2 ml of methanol was added citric acid hydrate 8 mg (0.039 mmol), and the mixture was stirred at room temperature for 35 minutes. The solvent was evaporated and the obtained residue was subjected to column chromatography using 5 g of silica gel and eluted with methanol-ethyl acetate = 1: 9 to give 42 m of the title compound.
g (84%) was obtained as a glass.

IR spectrum (film) cm ⁻¹ : 3500-3300,17
71,1707,1649,1522,1345,1140,855 NMR spectrum (270MHz, CDCl ₃ ) δppm: 1.25 (1.5H, d, J = 7H
z), 1.28 (1.5H, d, J = 7Hz), 1.34 (3H, d, J = 6Hz), 1.86-1.99 (1
H, m), 2.40-3.20 (1H, broad), 2.67-2.81 (1H, m), 2.94 (1.5
H, s), 2.99 (3H, s), 3.11 (1.5H, s), 3.23-3.29 (1H, m), 3.34-
3.76 (3H, m), 4.04-4.29 (3H, m), 4.73 (0.5H, t, J = 8Hz), 4.78
(0.5H, t, J = 8Hz), 5.07 (0.5H, d, J = 14Hz), 5.21 (1H, s), 5.22
(0.5H, d, J = 14Hz), 5.23 (1H, d, J = 14Hz), 5.48 (1H, d, J = 14H
z), 7.43 (1H, d, J = 8Hz), 7.51 (1H, d, J = 8Hz), 7.64 (2H, d, J = 8
Hz), 8.20 (1H, d, J = 9Hz), 8.17-8.22 (3H, m) Reference Example 5 (R) -2-[(3S, 4S) -3-
[(R) -1- (t-Butyldimethylsilyloxy) ethyl] -2-oxo-4-azetidinyl] thiopropionic acid S-2-diethylcarbamoylphenyl ester

[0104]

[Chemical formula 24]

1) Thiopropionic acid S- (2-, described in Reference Example 12 of JP-A-4-174099.
Diethylcarbamoyl) phenyl ester 3.20 g
1.7 ml of triethylamine (12.2 mmol) was added to a solution of 12 ml of N, N-dimethylformamide (12. 1 mmol) and 3.64 g (24.1 mmol) of t-butyldimethylchlorosilane and 12 ml of tetrahydrofuran.
1) was added and the mixture was stirred at room temperature for 3 minutes. This solution is -78 ° C
After cooling, 12.1 ml of a 1.0 M solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran was added dropwise over 20 minutes. After stirring at the same temperature for 30 minutes, about 10 ml of saturated heavy hydrogen water was added to terminate the reaction. The reaction solution was extracted with hexane, and the organic layer was collected and sequentially washed twice with water, 2N Na
It was washed once with OH, three times with water, and once with saturated saline. After drying the solution with magnesium sulfate, the solvent was distilled off and the residue was dissolved again in hexane. After adding 9.0 g of chromatographic alumina and stirring for 15 minutes, the alumina was filtered off and the alumina was washed with hexane. The filtrate and washings were combined and the solvent was distilled off to obtain 4.24 g of Z (O) -1-t-butyldimethylsilyloxy-1- (2-diethylcarbamoyl) phenylthio-1-propene. From the NMR spectrum (270 MHz), the ratio of Z (O) and E (O) -isomers was 20 or more.

2) 4.24 g of the compound obtained in 1 and (3
R, 4R) -3-[(R) -1- (t-butyldimethylsilyloxy) ethyl] -4-acetoxy-2-azetidinone (1.57 g, 5.47 mmol) in 55 ml of methylene chloride was added to anhydrous zinc chloride. 1.49g (10.9m
(mol) was added and the mixture was heated under reflux for 40 minutes. The reaction solution was returned to room temperature and concentrated under reduced pressure. Dissolve the residue in ethyl acetate and add 3 to water.
And washed once with saturated saline. After drying, the solvent was distilled off, and about 10 ml of diisopropyl ether was added to the residue to precipitate crystals to obtain 2.08 g (yield 77%) of the title compound. mp 130.5-132 ° C NMR spectrum (270 MHz, CDCl ₃ ) δppm: 0.08 (6H, s), 0.87
(9H, s), 1.03 (4H, 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), 3.20-3.8
5 (2H, broad), 3.96 (1H, dd, J = 2,4Hz), 4.19 (H, quintet, J = 6
Hz), 5.90-6.10 (1H, br.s), 7.30-7.35 (1H, m), 7.41-7.51 (3
H, m) mass spectrum (m / z): 492 (M ⁺ , C ₂₅ H ₄₀ N
₂ O ₄ SSi)

Claims (3)

[Claims] 1. A general formula: [Wherein R ¹ represents a hydrogen atom or a hydroxyl-protecting group, R ² represents a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, a straight-chain or branched chain having 1 to 6 carbon atoms] An alkoxy group, a halogen atom, a phenyl group or a phenoxy group, R ³ is a —CYNR ⁵ R ⁶ group (in the formula, Y represents an oxygen atom or a sulfur atom, and R ⁵ and R ⁶ each independently have a carbon number of 1 to 1). 6 straight chain or branched chain alkyl groups or phenyl groups are shown, or R ⁵ and R ⁶ are taken together to form the formula-(CH ₂ ).
_m (X) _L (CH ₂ ) _n -group (wherein m and n are the same or different and are 0
To 5 (provided that m + n is 2 or more), L represents 0 or 1, and X represents an oxygen atom. R ^{3 ′} represents a hydrogen atom, a linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkoxy group having 1 to 6 carbon atoms, a hydroxyl group, a halogen atom, Cyano group,
A nitro group or an amino group, R ⁴ represents a hydrogen atom or a protecting group for a carboxy group, and k represents 0, 1, or 2]. 2. A general formula: [In the formula, R ¹ represents a hydrogen atom or a hydroxyl-protecting group (a tri-substituted silyl group, an aralkyloxycarbonyl group or an acetyl group which may be substituted with halogen or alkoxy), and R ² has 1 to 1 carbon atoms. 3 linear or branched alkyl groups, 1 or 2 linear or branched alkoxy groups having 1 to 2 carbon atoms, a halogen atom, a phenyl group or a phenoxy group, wherein R ³ is a -CYNR ⁵ R ⁶ group (In the formula, Y represents an oxygen atom, R ⁵ and R ⁶ each independently represent a linear or branched alkyl group having 1 to 3 carbon atoms or a phenyl group, or R ⁵ and R ⁶ are the same. turned by the formula _{- (CH 2) m (X} ) L (CH 2) n - group (wherein, m and n are 0 to 5 I same or different (provided that, m + n is 2 or more).
, L is 0 or 1, and X is an oxygen atom. R ^{3 ′} represents a hydrogen atom, a linear or branched alkyl group having 1 to 3 carbon atoms, a linear or branched alkoxy group having 1 to 2 carbon atoms, a halogen atom or a nitro group. R ⁴ represents a hydrogen atom or a protecting group for a carboxy group (which may be substituted with a halogen, and may be substituted with a linear or branched alkyl group having 1 to 4 carbon atoms, an aralkyl group, or a halogen). A preferable straight chain or branched alkenyl group having 2 to 4 carbon atoms or a 2- (trimethylsilyl) ethyl group) and k is 0, 1, or 2]. 3. A general formula: [In the formula, R ¹ represents a hydrogen atom or a protective group of a hydroxyl group (indicates a tri-substituted silyl group, an aralkyloxycarbonyl group, or an acetyl group which may be substituted with halogen or alkoxy), and R ² represents a methyl group. , R ³ is −
CYNR ⁵ R ⁶ group (in the formula, Y represents an oxygen atom, R ⁵ and R ⁶ each independently represent a linear or branched alkyl group having 1 to 3 carbon atoms or a phenyl group, or R ⁵ And R ⁶ together form a-(CH ₂ ) _m (X) _L (CH ₂ ) _n- group (in the formula, m and n are the same or different and are 0 to 5 (provided that m + n
Is 2 or more. ), L is 0 or 1, and X is an oxygen atom. R ^{3 ′} represents a hydrogen atom, a linear or branched alkyl group having 1 to 3 carbon atoms, a linear or branched alkoxy group having 1 to 2 carbon atoms, a halogen atom or a nitro group. R ⁴ represents a hydrogen atom or a protecting group for a carboxy group (which may be substituted with a halogen, and may be substituted with a linear or branched alkyl group having 1 to 4 carbon atoms, an aralkyl group, or a halogen). A straight-chain or branched alkenyl group having 2 to 4 carbon atoms or 2-
(Representing (trimethylsilyl) ethyl group) and k represents 0, 1, or 2].