JP2620846B2 - 1-butenyl sulfide derivative and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the general formula (1)

Embedded image And a method for producing the same. The 1-butenyl sulfide derivative of the present invention is obtained by reacting chlorosulfonyl isocyanate with a protected hydroxyl group or as it is , by reacting it with a compound of the general formula (2a)

Embedded image Or a chlorosulfonyl isocyanate, if necessary, to give a compound having the general formula (2a), and then removing the chlorosulfonyl group to obtain a compound of the general formula (2b)

Embedded image A 2-azetidinone derivative having the formula:

[0002] The 2-azetidinone derivative represented by the general formula (2b) can be used as a carbapenem or penem compound having a hydroxyethyl group at the 6-position, and is used in the field of antibiotics. In particular, it is an epoch-making method for producing carbapenem and penem having an optically active hydroxyethyl group.

[0003]

2. Description of the Related Art Naturally produced thienamycin (Thienamycin)
It is considered that a carbapenem antibiotic represented by enamycin needs a 1 '-(R) -hydroxyethyl group at the 6-position in order to exert a potent and broad antibacterial activity [K. Hirai et al. Tetrahedron L
etters, 23, 4021, 1982]. Penem antibiotics in which the methylene group at the 1-position of the carbapenem skeleton is substituted with a sulfur atom have not been found in nature and have been obtained by synthesis. It is considered that the penem antibiotic having a similar skeleton to the carbapenem also has a 1 '-(R) -hydroxyethyl group at the 6-position for its activity. In fact 1-thiathienamycin (S. OHTA et al. Antimi
crob. Agents Chemother. , 21
492, p. 492) and Sch29482 [A. K.
Gangly et al. Antimicrob. Chem
other. , (Suppl. C), vol. 9, p. 1, 1982
Years) have been found to have strong antibacterial activity. Therefore, development of a novel method for producing a compound having a 1 '-(R) -hydroxyethyl group at the 6-position of the penem ring has been eagerly desired.

[0004]

SUMMARY OF THE INVENTION The present inventors have planned to develop a method for efficiently producing a penem antibiotic having a 1 '-(R) -hydroxyethyl group at the 6-position, and have studied the solution. As a first method, a compound having a 1 '-(R) -hydroxyethyl group at the 3-position of the 2-azetidinone skeleton is synthesized with good yield using an optically active raw material, and this compound is used as a target penem antibiotic. The second method is a method for synthesizing a target penem antibiotic by performing efficient optical resolution in the process of deriving a 2-azetidinone skeleton to a penem skeleton.

[0005] At the 3-position of the 2-azetidinone ring, 1 '-(R)
Many methods for introducing a hydroxyethyl group are already known. For example, A. Yoshida et al., Chem. P
harm. Bull. 29, 2899, 1981; Shiozaki et al. Tetrahedron
Letters, Vol. 22, p. 5205, 1981, but the methods known up to now are not very suitable because the yield is not so good or the reaction steps are complicated. The method of obtaining a compound having a 1 '-(R) -hydroxyethyl group at the 3-position of the 2-azetidinone ring by optical resolution has disadvantages such as poor yield in the purification / separation step and difficulty in purification. .

[0006]

According to the present invention, there is provided a compound represented by the general formula (1):

Embedded image A 1-butenyl sulfide derivative having the general formula (6)

Embedded image Having lithium carbonate act on a compound having the general formula (1 ′ )

Embedded image And a method for producing a 1-butenyl sulfide derivative having the formula:

The 1-butenyl sulfide derivative of the present invention has the general formula (2)

Embedded image It is useful as a raw material for producing a 2-azetidinone derivative represented by the formula: More specifically, the 1-butenyl sulfide derivative of the present invention represented by the general formula (1) can be produced by the following Production Method A, Production Method B, Production Method C or Production Method D.

The above-mentioned general formula (1) of the present invention

Embedded image When a 1-butenyl sulfide derivative represented by the formula (1) is used, it can be reacted with chlorosulfonyl isocyanate to produce a azetidinone derivative having a hydroxyl functional group at the 1'-position and a trans-coordination at the 3,4-position.

When an optically active reagent is used as a starting material in the production method A, B or C, an optically active 1-butenyl sulfide derivative and, consequently, an optically active 2-azetidinone derivative can be produced. The optically active 1-butenyl Nils sulfide derivative by carrying out the steps in the asymmetric reduction in process D, it is therefore optically active 2-azetidinone derivative can be produced. In the production method A, B, C or D,
Optically active 1 is obtained by optical resolution during the manufacturing process.
-Butenyl sulfide derivative, and thus optically active 2-
An azetidinone derivative is obtained.

[Production method A]

Embedded image

(Step 1) and (Step 2) (3R) -1,3-butanediol is reacted with p-toluenesulfonyl chloride or methanesulfonyl chloride in the presence of a base to give tosylate (3) and mesylate (3), respectively. After that, heating in the presence of an inorganic base with a compound represented by the general formula R ² SH (wherein R ² has the same meaning as described above) in an ether-based or aromatic hydrocarbon-based solvent, or using a compound represented by the general formula R ² SY (Wherein R ² has the same meaning as described above, and Y represents an alkali metal), whereby a sulfide derivative represented by the formula (4) can be obtained by heating.

(Step 3) In the step of protecting the hydroxyl group of the sulfide derivative obtained in step 2, compound (4) and a silylating agent such as t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triethylsilyl chloride, etc. Acetyl chloride, acetyl bromide, trifluoroacetic acid, acetic anhydride, etc., allyl chloride or para-nitrobenzyloxycarbonyl chloride, allyloxycarbonyl chloride Protected compound (5) can be obtained by reacting a protecting agent such as trichloroethyloxycarbonyl chloride in the presence of a base such as pyridine, triethylamine, dimethylaminopyridine or imidazole.

Compound (5) in which the 3-hydroxyl group is protected
Is a known compound [H. A. Khan et al. Te
Trahedron Letters, 23, 508
3 1982 and P.M. Loiseau et al. Phar
m. Acta Helv. 58, 115, 1983; See Ueno et al. Bull. Chem. Soc. J
pn. 53, 3615, 1980].

(Step 4) (Step 5) The compound (5) obtained in the step 3 is halogenated with N-chlorosuccinimide or sulfuryl chloride, and then heated with carbonate or salt, potassium chloride, lithium chloride, especially lithium carbonate. As a result, an optically active 1-butenyl sulfide derivative represented by the general formula (1a ′ ) is obtained.

The above compound (5) is converted into a sulfoxide with an oxidizing agent such as metachloroperbenzoic acid, aqueous hydrogen peroxide, perbenzoic acid and peracetic acid, and then heated in acetic anhydride to obtain the compound of the general formula (1a ' ). The 1-butenyl sulfide derivative represented is obtained.

In the dehydrohalogenation reaction of the above-mentioned compound (6a), an alkali metal alkoxide may be used instead of a carbonate or an alkali metal salt, but it cannot be obtained with an amine such as sodium amide as a base.

[Production method B]

Embedded image

(Step 6) Step 6 represents the reduction reaction of (R)-(-)-3-hydroxybutyric acid ester, and this reduction is carried out at 0 ° C. or lower by reacting a reducing agent such as lithium aluminum hydride. Butanol derivative (8) can be easily obtained.

(Step 7) Step 7 can be carried out in the same manner as in Step 1 described above. Compound (8) is dissolved in a base such as pyridine, and paratoluenesulfonyl chloride or methanesulfonyl chloride is added at 0 ° C. or lower, and the mixture is stirred at room temperature. Then, a sulfonic acid ester (3) is obtained. The butenyl sulfide derivative represented by the general formula (1) obtained by the production method A or B is a mixture of a cis isomer and a trans isomer with respect to a double bond.
There is no problem in obtaining the azetidinone derivative.

This compound ( 1a ') is dissolved in an ether-based or chlorine-based solvent, and is 1.1 equivalents or more, preferably 1.2 equivalents.
Add ~ 1.4 equivalents of chlorosulfonyl isocyanate. Chlorsulfonyl isocyanate is dissolved in an ether-based or chlorine-based solvent, and the reaction temperature is 0 ° C or lower, preferably -20 ° C or lower. After completion of the reaction, but chlorosulfonyl group is easily removed by adding a concentrated reducing agent and a free radical capturing 捉 agents, reducing agents, for example thiophenol,
Mercaptoethanol, mercaptan, sodium bisulfite, ammonium bisulfite, and sodium borohydride are preferred. Particularly preferred are thiophenol and sodium bisulfite.

The free-radical capturing The 捉 agent such as pyridine to neutralize the chlorosulfonic acid to produce sodium bicarbonate, sodium phosphate, amines and the like. General formula (2C) thus obtained

Embedded image There are two types of isomers in the 2-azetidinone derivative (2C) represented by That is, (1′R, 3S, 4
R) and (1'R, 3R, 4S). The former has the same configuration as carbapenems such as thienamycin,
Needless to say, it is a useful raw material for synthesis. Both isomers are very easy to separate and purify. Examples of purification methods include column chromatography, preparative thin-layer chromatography, and recrystallization, and (1′R, 3S, 4R) and (1′R, 3R, 4) obtained by the present invention.
S) Compound (2C) is easily separated by recrystallization.

Instead of chlorosulfonyl isocyanate, for example, trichloroacetyl isocyanate, benzyl isocyanate, allyl isocyanate and p-toluenesulfonyl isocyanate can be considered, but chlorosulfonyl isocyanate is most suitable in consideration of removal of a protecting group and reactivity. When trifluoroacetyl isocyanate or trichloroethoxysulfonyl isocyanate is used, the 2-azetidinone derivative can be obtained after the completion of the reaction, for example, by column chromatography of florisil or zinc treatment.

The thus-obtained 2-azetidinone derivative represented by the general formula (2C) can be easily oxidized to give the general formula (9)

Embedded image Is obtained. Needless to say, this compound (9) can be derived into penem and carbapenem by a known method.

[Production method C]

Embedded image

(Step 8) In the step of condensing 1-butyn-3-ol with the general formula R ² SH (where R ² has the same meaning as described above), an inorganic base such as sodium hydroxide or potassium hydroxide is used. This is a method of heating (preferably 80 to 150 ° C.) in the presence to obtain 1-butenyl sulfide of the present invention represented by the general formula (1 ″ ). In this synthesis method, only the cis form is obtained.

(Step 9) In this step, a 1-butenyl sulfide derivative represented by the general formula ( 1 ' ) is obtained by the same operation as in the above step 3. The obtained reaction product can be purified by distillation or column chromatography. (Step 10) This step is the same operation as Step 9, and is performed by the general formula ( 10 )
The compound represented by is obtained. (Step 11) Compound (1 ′ ) is obtained in the same manner as in step 8 in step 11 . Pure compound ( 1 ' ) is obtained by distilling the obtained reaction product or subjecting it to column chromatography.

[Production method D]

Embedded image

(Step 12) A compound represented by the general formula ( 11 ) and a mercaptan represented by the general formula R ² SH (where R ² has the same meaning as described above) are dissolved in an organic solvent, and a catalytic amount of an organic acid is present. The enone compound represented by the general formula ( 12 ) is obtained by heating below. Compound ( 12 ) can be distilled or purified by column chromatography. As the organic acid used in this step, paratoluenesulfonic acid and camphorsulfonic acid are preferable, and the reaction temperature is preferably 50 to 60C.

(Step 13) Compound ( 1 ″ ) is obtained by dissolving the enone compound ( 12 ) in an organic solvent and adding a reducing agent such as sodium borohydride, and by using an asymmetric reducing reagent in this reduction reaction. An optically active compound ( 1 " ) is obtained.

(Step 14) The step of protecting the hydroxyl group is the same as the steps 3, 9 and 1 described above.
This is the same operation as 0. The 1-butenyl sulfide derivative represented by the general formula (1 ' ) thus obtained is dissolved in an organic solvent, chlorosulfonyl isocyanate is added thereto under cooling, and the reaction is carried out in the same manner as in the reaction under the optically active form. A 2-azetidinone derivative represented by (2) can be obtained. General formula (2b) thus obtained

Embedded image The 3,4 cis form and the 3,4 trans form present in the 2-azetidinone derivative having the following formula can be separated by recrystallization or column chromatography or preparative thin-layer chromatography and are 3,4 trans forms (1′R, 3S). , 4R) and (1'S, 3R, 4S) and (1'S, 3S, 4R) and (1'R, 3R, 4S) isomers are recrystallized or column chromatography, The former and the latter can be separated by using layer chromatography.

(1'R, 3S, 4R) and (1'S,
The mixture of (3R, 4S) is oxidized as described above to give a sulfonyl derivative represented by the general formula (9), followed by a substitution reaction with a thiocarboxylic acid by a known method, recrystallization, column chromatography or fractionation of the compound obtained. By thin layer chromatography (1′R, 3S, 4
R) form and (1'S, 3R, 4S) form.

[0032]

EXAMPLES The present invention will be further described below with reference to Reference Examples and Examples.

Reference Example 1 3- (1′R-tert-butyldimethylsilyloxy) ethyl-4-phenylsulfinyl-2-azetidinone

Embedded image 0.37 ml of chlorsulfonyl isocyanate (4.2
(4 mmol) was dissolved in 8 ml of dry ether, and 1.00 g of (3R) -tert-butyldimethylsilyloxy-1-butenylphenyl sulfide (3.
(40 mmol) in ether (2 ml) was added slowly. After stirring at room temperature for 4 hours, the solvent was distilled off under reduced pressure. The residue was dissolved in 5 ml of acetone, and 0.75 g (6.80 mmol) of thiophenol and subsequently 0.67 g (8.48 mmol) of pyridine were added thereto under ice cooling, followed by stirring at room temperature for 15 minutes. Water was added to the reaction solution, which was extracted with methylene chloride.
The extract was washed with water and dried to obtain a crude product, which was purified by silica gel column chromatography. Of the two isomers obtained, the ( 1'R, 3S, 4R ) form was precipitated from cold hexane, while the ( 1'R, 3R, 4S ) form was separated as an oil. [Reference Examples 2-3] Reference Examples 2 and 3 were carried out in the same manner as Reference Example 1 except that the substituent (Y) was changed. Table 1 shows the yield, properties, melting point, and instrument data of the obtained compound.

[Table 1]

Reference Example 4 (1'S, 3S, 4R and 1'R, 3R, 4S) -3-
(1′-tert-butyldimethylsilyloxy) ethyl-4-tert-butylthio-2-azetidinone

Embedded image N-chlorosulfonyl isocyanate (0.26 ml,
3 mmol) in ether (3 ml).
At −60 ° C., a mixture of (Z) -3-tert-butyldimethylsilyloxy-1-tert-butylthio-1-butene (0.55 g, 2 mmol) and ether (2 ml) was gradually added dropwise. After the mixture was stirred at -40 to -50 ° C for 1 hour, a mixture of tert-butyl mercaptan (0.45 ml, 4.4 mmol), pyridine (0.27 ml) and acetone (2 ml) was added at -60 ° C. The mixture was stirred for 30 minutes. The reaction product was washed successively with 0.5N hydrochloric acid, saturated sodium bicarbonate and saturated saline, dried and concentrated. The residue was purified by silica gel column chromatography to obtain 77 mg (24%) of the title compound. NMR (CDCl ₃ ) δ: 0.10 (6H, s), 0.91 (9H, s), 1.33 (3H, d, J = 1.33 Hz), 1.35 (9H, s), 3 .17 (1H, m), 4.13 (1H, dq, J = 4 Hz, 7 Hz), 4.73 (1H, d, J = 2 Hz), 6.60 (1H, br.s)

Reference Example 5 (1'R, 3S, 4R and 1'S, 3S, 4R and 1 '
R, 3R, 4S and 1'S, 3R, 4S) -3- (1 '
-Tert-butyldimethylsilyloxy) ethyl-4
-Tert-butylthio-2-azetidinone

Embedded image (E) -3-tert-butyldimethylsilyloxy-
1-tert-butylthio-1-butene (0.55 g,
2 mmol) and N-chlorosulfonyl isocyanate (0.21 ml, 2 mmol) were operated in the same manner as in Reference Example 4 to obtain 0.155 g (25%) of the title compound. NMR (CDCl ₃ ) δ: 0.09 (6H, s), 0.89 (9H, s), 1.21 (0.5H, d, J = 7 Hz), 1.28 (0.5H, d, J = 7 Hz), 1.35 (9H, s), 3.0 (1H, m), 4.20 (1H, m), 4.21 (0.5H, d, J = 7 Hz), 4.94 (0.5H, d, J = 7Hz), 6.20 (0.5H, br.s), 6.30 (0.5H, br.s)

Reference Example 6 (1'R, 3S, 4R and 1'S, 3R, 4S) -3-
(1'-tert-butyldimethylsilyloxy) ethyl-4-phenylthio-2-azetidinone (A) and (1'S, 3S, 4R and 1'R, 3R, 4S) -3-
(1'-tert-butyldimethylsilyloxy) ethyl-4-phenylthio-2-azetidinone (B)

Embedded image (Z) -3-tert-butyldimethylsilyloxy-
1-phenylthio-1-butene (0.298 g, 1 mmol) and N-chlorosulfonyl isocyanate (0.1
ml, 1.15 mmol) in the same manner as in Reference Example 4 to obtain 0.088 g of a mixture of the title compounds (A) and (B).
(28%). From the NMR spectrum data, the mixing ratio of compound A to compound B was 1: 5. NMR (CDCl ₃ ) δ: (Compound A) 0.05 (6H, s), 0.85 (9H, s), 1.15 (3H, d, J = 7 Hz), 3.01 (1H, dd, J = 2 Hz, 5 Hz), 4.20 (1 H, dq, J = 5 Hz, 7 Hz), 5.02 (1 H, d, J = 2 Hz), 6.75 (1 H, br.s), 7.35 ( 5H, m) (Compound B) 0.10 (6H, s), 0.91 (9H, s), 1.32 (3H, d, J = 7 Hz), 3.14 (1H, m), 4. 10 (1H, dq, J = 3 Hz, 7 Hz), 4.84 (1H, d, J = 2 Hz), 6.50 (1H, br.s), 7.30 (5H, m)

Reference Example 7 (1'R, 3S, 4R and 1'S, 3R, 4S) -3-
(1'-tert-butyldimethylsilyloxy) ethyl-4-phenylthio-2-azetidinone (A) and (1'S, 3S, 4R and 1'R, 3R, 4S) -3-
(1'-tert-butyldimethylsilyloxy) ethyl-4-phenylthio-2-azetidinone (B)

Embedded image (E) -3-tert-butyldimethylsilyloxy-
1-phenylthio-1-butene (75 g, 0.25 mol) and N-chlorosulfonyl isocyanate (26 m
1, 0.3 mol) in the same manner as in Reference Example 4 to obtain 33.6 g (40%) of a mixture of the title compounds (A) and (B). This mixture was washed with cold n-pentane to obtain 19.3 g (23%) of compound (A) as colorless crystals. The filtrate was concentrated to give compound (B) as a colorless oily substance.
4.3 g (17%) were obtained. The spectral data of compound (A) and compound (B) completely coincided with those obtained in Reference Example 6.

Reference Example 8 (1'R, 3S, 4R and 1'S, 3R, 4S) -3-
(1′-tert-butyldimethylsilyloxy) ethyl-4- (4-chlorophenyl) thio-2-azetidinone (A) and (1 ′S, 3S, 4R and 1′R, 3R,
4S) -3- (1'-tert-butyldimethylsilyloxy) ethyl-4- (4-chlorophenyl) thio-2
-Azetidinone (B)

Embedded image 3-tert-butyldimethylsilyloxy-1- (4
-Chlorophenyl) thio-1-butene (13.8 g, 4
2.6 mmol) in ether (30 ml),
At 60 ° C., N-chlorosulfonyl isocyanate (4.
A mixture of 7 ml, 53.9 mmol) and ether (17 ml) was slowly added dropwise. The mixture was stirred for 1.5 hours,
Concentrated. The residue was dissolved in acetone (70 ml),
Pyridine at 40 ° C. (3.5 ml, 42.6 mmol)
And thiophenol (9.7 ml, 94.5 mmol)
Was added dropwise. The reaction was gradually brought to 0 ° C., water was added, and the mixture was extracted with methylene chloride. The extract was dried and concentrated. The residue was purified by silica gel column chromatography, and a mixture of the title compounds (A) and (B) (mixing ratio: A
/ B = 3/1). The mixture of compounds (A) and (B) was washed with cold pentane to give compound (A)
Was obtained as colorless crystals. NMR (CDCl ₃ ) δ: (Compound A) 0.08 (6H, s), 0.83 (9H, s), 1.20 (3H, d, J = 7 Hz), 3.0 (1H, m) 4.15-4.28 (1H, m), 5.04 (1H, d, J = 2 Hz), 6.1 (1H, s), 7.30-7.45 (4H, m) (compound B) 0.07 (6H, s), 0.86 (9H, s), 1.31 (3H, d, J = 7 Hz), 3.11 (1H, m), 4.15-4.28 ( 1H, m), 4.87 (1H, d, J = 2 Hz), 6.1 (1H, br.s), 7.30-7.45 (4H, m)

Reference Example 9 (1'R, 3S, 4R) -3- (1'-tert-butyldimethylsilyloxy) ethyl-4-phenylthio-
2-azetidinone

Embedded image (R)-(-)-3-tert-butyldimethylsilyloxy-1-phenylthio-1-butene (1.00 g,
Reference Example 8 containing 3.40 mmol) and N-chlorosulfonyl isocyanate (0.37 ml, 4.24 mmol).
The title compound was obtained in a yield of 44%.

Embedded image

Reference Example 10 (1'R, 3S, 4R) -3- (1'-tert-butyldimethylsilyloxy) ethyl-4- (4-methoxyphenyl) thio-2-azetidinone

Embedded image (R)-(-)-3-tert-butyldimethylsilyloxy-1- (4-methoxyphenyl) thio-1-butene was operated in the same manner as in Reference Example 8 to obtain the title compound.

Embedded image

Reference Example 11 (1'R, 3S, 4R) -3- (1'-tert-butyldimethylsilyloxy) ethyl-4- (4-chlorophenyl) thio-2-azetidinone

Embedded image (R)-(-)-3-tert-butyldimethylsilyloxy-1- (4-chlorophenyl) thio-1-butene was operated in the same manner as in Reference Example 8 to obtain the title compound.

Embedded image

Reference Production Example 1 (R) -3-t-butyldimethylsilyloxy-1-chloro-1-p-chlorophenylthiobutane

Embedded image (R) -3-t-butyldimethylsilyloxy-1-p
0.50 g (1.61 mmol) of -chlorophenylthiobutane was dissolved in 12 ml of carbon tetrachloride, and 0.24 g (1.77 mmol) of N-chlorosuccinimide was added thereto, followed by stirring at room temperature for 1.5 hours. The precipitated succinimide was collected by filtration, and the filtrate was concentrated to give the title compound (0.56 g, yield 97%). Properties: colorless oil IR spectrum (film, cm ^-1 ): 2950, 29
20, 2850, 1470, 1250, 1130, 10
90, 830, 820, 770 ¹ H-NMR spectrum (CDCl ₃ , δ): 0.03
(3H, s), 0.07 (3H, s), 0.86 (9
H, s), 1.12 (3H, d, J = 6.0 Hz),
1.65-1.77 (2H, m), 1.95-2.08
(1H, m), 4.15 (1H, m), 4.54 (1
H, dd, J = 9.0, 4.4 Hz), 7.20-7.
40 (4H, m)

Example 1 (R)-(-)-3-tert-butyldimethylsilyloxy-1-phenylthio-1-butene

Embedded image

(A) (R)-(-)-3-tert-
A mixture of butyldimethylsilyloxy-1-phenylthiobutane (2.20 g, 7.42 mmol) and N-chlorosuccinimide (1.09 g, 8.16 mmol) was mixed with carbon tetrachloride (50 ml) and brought to room temperature. And stirred for 1 hour. The insolubles were removed by filtration, the filtrate was concentrated, the residue was dissolved in dimethylformamide (20 ml), and lithium chloride (0.35 g, 8.16 mmol) and lithium carbonate (0.55 g, 7.42 mmol) were added. The mixture was stirred at 80 ° C. for 2 hours. After cooling, insolubles were separated by filtration, water was added to the filtrate, and the mixture was extracted with ether. The ether layer was washed with water, dried over anhydrous magnesium sulfate, concentrated and the resulting residue was purified by silica gel column chromatography to give 1.58 g (72%) of the title compound as a colorless oil.
%)Obtained. The compound was a mixture of E / Z = 2.5 / 1.

Embedded image

(B) (R)-(-)-3-tert-
Butyldimethylsilyloxy-1-phenylthiobutane (1.00 g, 3.22 mmol) was added to chloroform (5 g).
ml) and sulfuryl chloride (0.4 ml) at 0 ° C.
4 g, 3.22 mmol) and stirred at room temperature for 1 hour. The reaction was concentrated, the residue was dissolved in dimethylformamide (5 ml), lithium chloride (0.17 g) and lithium carbonate (0.27 g) were added, and the mixture was cooled to 80 ° C.
After cooling for 2 hours, insolubles were filtered off after cooling, water was added to the filtrate, and the mixture was extracted with ether. The ether layer was washed with water, dried over anhydrous magnesium sulfate and concentrated, and the obtained residue was purified by silica gel column chromatography to give 0.62 g (62%) of the title compound as a colorless oil. The spectral data of this product was completely consistent with that obtained in (a). [Examples 2 to 9 ] In the same manner as in Example 1 (a), substituents (R ¹ , R
^The following compounds were synthesized using the raw materials obtained by changing ⁶ ).
Table 2 shows the reaction conditions, yield, ratio of trans-cis form, and Table 3
Shows the device data.

[0046]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

Example 10 (R) -3-t-butyldimethylsilyloxy-1-p
-Chlorophenylthio-1-butene

Embedded image The title compound was obtained as a mixture of trans-form and cis-form under the reaction conditions and yields shown in Table 2 in the same manner as in Example 1, and the resulting trans-cis mixture was subjected to silica gel column chromatography (elution solvent: hexane). Separate each,
Obtained as trans-form and cis-form. Physical properties of transformer

Embedded image Physical properties of cis form

Embedded image

Reference Production Example 2 (R)-(-)-3-t-butyldimethylsilyloxy-1-p-chlorophenylthiobutane-S-oxide

Embedded image (R) -3-t-butyldimethylsilyloxy-1-p
1.00 g (3.22 mmol) of -chlorophenylthiobutane was dissolved in 30 ml of methylene chloride, and 0.695 g (3.22 mmol) of 80% m-chloroperbenzoic acid was added. After stirring at room temperature for 2 hours, the reaction solution was washed successively with sodium bicarbonate and water, and dried over magnesium sulfate. The residue obtained by evaporating the solvent was separated and purified by silica gel column chromatography to obtain 0.980 g of the title compound (93% yield).
Obtained. Properties: colorless oil IR spectrum (film, cm ^-1 ): 1040 (S →
O)

Example 11 trans- (R) -3-t-butyldimethylsilyloxy-1-p-chlorophenylthio-1-butene

Embedded image 0.20 g (0.61 g) of the S-oxide obtained in Reference Production Example 2
(Mmol) was added to 5 ml of acetic anhydride and heated under reflux for 3 hours. After evaporating the solvent, the residue was separated and purified by thin-layer chromatography to obtain 0.020 g (yield 10%) of the title compound.

Reference Production Example 3 (R)-(-)-3-hydroxy-1-paratoluenesulfonyloxybutane

Embedded image (R)-(-)-1,3-butanediol (10.00
g, 0.111 mol) and pyridine (9.66 g, 0.1 g).
122 mol) in methylene chloride (150 ml)
P-Toluenesulfonic acid chloride (23.27 g, 0.
122 mol) at 0 ° C. The mixture was stirred at room temperature for 15 hours, and the reaction was transferred into cold water (200 ml). The methylene chloride layer was separated, and the aqueous layer was extracted with methylene chloride. The methylene chloride layers were combined and washed sequentially with water, diluted hydrochloric acid, saturated sodium bicarbonate, and saturated saline. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give the title compound as a colorless oil.
1.68 g (80%) were obtained.

Embedded image

Reference Production Example 4 (R)-(-)-3-hydroxy-1-methanesulfonyloxybutane

Embedded image (R)-(-)-1,3-butanediol (0.500
g, 5.55 mmol), pyridine (0.483 g,
6.1 mmol) and methanesulfonyl chloride (0.1 mmol).
(699 g, 6.10 mmol) in the same manner as in Reference Production Example 3 to obtain 0.392 g (42%) of the title compound as a colorless oil.

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Reference Production Example 5 (R)-(-)-3-hydroxy-1-phenylthiobutane

Embedded image (R)-(-)-3-hydroxy-1-paratoluenesulfonyloxybutane (2.00 g, 8.19 mmol) and sodium thiophenolate (1.30 g,
9.82 mmol), tetrahydrofuran (40 ml)
The mixture was heated to reflux for 1 hour, and after cooling, water was added to the reaction mixture.
Extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

Reference Production Examples 6 to 11 The sodium thiophenolate derivatives shown in Tables and (R)-
(-)-3-Hydroxy-1-paratoluenesulfonyloxybutane was operated in the same manner as in Reference Production Example 5 to obtain the sulfide compounds in the table. Table 4 shows the properties, yields, and equipment data of each compound obtained in this example and Reference Production Example 5 .

[Table 6]

[Table 7]

Reference Production Example 12 R-(-)-3-hydroxybutyl-p-chlorophenyl sulfide

Embedded image 0.20 g (1.19 mmol) of R-(-)-3-hydroxybutylmethanesulfonate, 0.210 g (1.25 mmol) of sodium p-chlorothiophenoxide
Was dissolved in 5 ml of tetrahydrofuran and heated under reflux for 1 hour. Thereafter, the same treatment as in Reference Production Example 5 was carried out to obtain 0.22 g (yield 87%) of the title compound.

Reference Production Example 13 R-(-)-3-tert-butyldimethylsilyloxy-1-phenylthiobutane

Embedded image R-(-)-3-hydroxy-1-phenylthiobutane (1.44 g, 7.90 mmol), tert-butyldimethylsilyl chloride (1.31 g, 8.69 mmol), 4-dimethylaminopyridine (1 .06g, 8.
69 mmol) in dimethylformamide (10
ml) and stirred for 3 hours. The reaction product was diluted with ether, washed sequentially with water, diluted hydrochloric acid, saturated sodium hydrogen carbonate and saturated saline, and dried over anhydrous magnesium sulfate. The residue obtained by concentration was purified by silica gel column chromatography to give the title compound as a colorless oil (86%).

Embedded image Reference Production Examples 14 to 19 The following compounds were synthesized in the same manner as in Reference Production Example 13 . The properties, yields and instrument data are shown in Table 5.

[Table 8]

[Table 9]

Reference Production Example 20 (R)-(-)-3-benzyloxy-1- (4-chlorophenylthio) butane

Embedded image (R)-(-)-3-Hydroxy-1- (4-chlorophenylthio) butane (1.00 g, 4.61 mmol)
Was dissolved in tetrahydrofuran (20 ml), and sodium hydride (5.53 mmol) was gradually added. Then benzyl bromide (0.79 g, 4.61 mmol) was added and the mixture was heated at reflux for 2 hours. After cooling, the mixture was diluted with ether, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 1.23 g (87%) of the title compound as a colorless oil.

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Reference Production Example 21 (R)-(-)-3-acetoxy-1- (4-chlorophenylthio) butane

Embedded image Dissolve a mixture of (R)-(-)-3-hydroxy-1- (4-chlorophenylthio) butane (1.00 g, 4.6 mmol) and pyridine (0.44 g, 55 mmol) in tetrahydrofuran (10 ml) Then, acetyl chloride (0.44 g, 55 mmol) was added at 0 ° C. After stirring at room temperature for 30 minutes, methylene chloride was added to the reaction product, which was washed with water and dried over anhydrous magnesium sulfate. The residue obtained by concentration was purified by silica gel column chromatography to give the title compound as a colorless oil (0.97 g, 81%).
%)Obtained.

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Reference Production Example 22 (R)-(-)-3- (2,2,2-trichloroethyloxy) carbonyloxy-1- (4-chlorophenylthio) butane

Embedded image (R)-(-)-3-Hydroxy-1- (4-chlorophenylthio) butane (0.50 g, 2.31 mmol)
And pyridine (0.22 g, 2.77 mmol) and 2,
2,2-trichloroethyl chloroformate (0.54
(0 g, 2.54 mmol) to give 0.88 g (97%) of the title compound as a colorless oil.

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Reference Production Example 23 (R)-(-)-3- (4-Nitrobenzyloxy) carbonyloxy-1- (4-chlorophenylthio) butane

Embedded image (R)-(-)-3-Hydroxy-1- (4-chlorophenylthio) butane, pyridine and paranitrobenzyloxycarbonyl chloride were operated in the same manner as in Reference Production Example 21 to give the title compound as a colorless oil. (73%).

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Reference Production Example 24 (Z) -1-tert-butylthio-3-hydroxy-1-butene

Embedded image 1-butyn-3-ol (9.44 ml, 0.12 mol), potassium hydroxide (0.56 g, 0.01 mol) and tert-butyl mercaptan (11.25 ml,
0.1 mol) was stirred at 90-100 ° C for 30 minutes. After cooling, add ether to the mixture, wash with water, dry,
Concentration afforded 15 g of the title compound. This crude product was used for the next reaction without purification. NMR (CDCl ₃ ) δ: 1.22 (3H, d, J = 7 Hz), 1.35 (9H, s), 4.62 (1H, m), 5.60 (1H, d, d, J = 7Hz, 10Hz), 6.10 (1H, d, J = 10Hz)

Reference Production Example 25 (Z) -3-tert-butyldimethylsilyloxy-
1-tert-butylthio-1-butene

Embedded image (Z) -1-tert-butylthio-3-hydroxy-
1-Butene (5.83 g, 36.4 mmol) was dissolved in dimethylformamide (37 ml), and tert.
t-butyldimethylsilyl chloride (5.89 g), 4
-Dimethylaminopyridine (0.5 g) and triethylamine (5 ml) were sequentially added, and the mixture was stirred overnight. Ether was added to the reaction mixture, and the mixture was washed successively with water, diluted hydrochloric acid, saturated sodium hydrogen carbonate, and saturated saline, dried and concentrated, and the obtained residue was distilled under reduced pressure to give the title compound as a colorless oil. 8.5 g (85%). Boiling point: 120-130 ° C. at 0.5 mmHg NMR (CDCl ₃ ) δ: 0.1 (6H, s), 0.90 (9H, s), 1.21 (3H, d, J = 7 Hz), 1 .37 (9H, s), 4.65 (1H, m), 5.61 (1H, dd, J = 7 Hz, 10 Hz), 6.01 (1H, d, J = 10 Hz)

Example 12 (Z) -3-Hydroxy-1-phenylthio-1-butene

Embedded image 1-butyn-3-ol (4.2 g, 60 mmol),
Thiophenol (5.5 g, 50 mmol) and potassium hydroxide (0.28 g, 5 mmol) were used as Reference Production Example 24.
In the same manner as in the above, 9.0 g (100%) of the title compound was obtained. NMR (CDCl ₃ ) δ: 1.30 (3H, d, J = 7 Hz), 4.75 (1H, quint, J = 7 Hz), 4.25 (1H, dd, J = 7 Hz, 10 Hz), 6. 17 (1H, d, J = 10 Hz), 7.20 (5H, m)

Example 13 (Z) -3-tert-butyldimethylsilyloxy-
1-phenylthio-1-butene

Embedded image (Z) -3-hydroxy-1-phenylthio-1-butene (9 g, 50 mmol), tert-butyldimethylsilyl chloride (7.53 g, 50 mmol), triethylamine (7 ml, 50 mmol) and 4-dimethylaminopyridine (0.225 g) was operated in the same manner as in Reference Production Example 25 to obtain 13.4 g (90%) of the title compound. Boiling point: 155-160 ° C. at 0.9 mmHg NMR (CDCl ₃ ) δ: 0.09 (6H, s), 0.90 (9H, s), 1.25 (3H, d, J = 7 Hz), 4 .73 (1H, quint, J = 7 Hz), 5.74 (1H, dd, J = 7 Hz, 10 Hz), 6.07 (1H, d, J = 10 Hz)

Example 14 3-tert-butyldimethylsilyloxy-1- (4
-Chlorophenylthio) -1-butene

Embedded image A mixture of 3-tert-butyldimethylsilyloxy-1-butyne (5.587 g, 30.3 mmol) and parachlorophenylmercaptan (4.504 g, 31.14 mmol) was stirred at 78 ° C. for 1.5 hours. After cooling, the mixture was subjected to column chromatography (silica gel 10).
0 g, eluted with hexane containing 0.01% triethylamine) to give 4.254 g (43%) of the title compound.
%)Obtained. NMR (CDCl ₃ ) δ: 0.07 (6H, s), 0.90 (9H, s), 1.23 (1.9 H, d, J = 6.4 Hz), 1.25 (1.1 H, s) d, J = 6.4 Hz), 4.76 (1 H, m), 5.86 (0.37 H, dd, J = 7.8 Hz, 9.5 Hz), 5.91 (0.63 H, dd, J) = 4.9 Hz, 14.9 Hz), 6.06 (0.37H, d, J = 9.5 Hz), 6.29 (0.63H, d, J = 14.9 Hz), 7.24 (5H) , S)

Reference Production Example 26 (E) -1-tert-butylthio-3-oxo-1-
Butene

Embedded image 1-methoxy-3-oxo-1-butene (2.6 g, 2
6 mmol), tert-butyl mercaptan (3 m
1,26.7 mmol), paratoluenesulfonic acid (2
6 mg) was dissolved in benzene (40 ml) and the mixture was stirred at 50-55 ° C for 2 hours. After cooling, the solvent was distilled off, and the obtained crude product was purified by distillation to obtain 1.5 g (36.5%) of the title compound. Boiling point: 130-150 ° C. at 9 mmHg NMR (CDCl ₃ ) δ: 1.45 (9H, s), 2.20 (3H, s), 6.28 (1H, d, J = 15 Hz), 7.81 (1H, d, J = 15Hz)

Reference Production Example 27 (E) -3-oxo-1-phenylthio-1-butene

Embedded image 1-methoxy-3-oxo-1-butene (51.38
g, 0.51 mol), thiophenol (63 ml, 0.1 g).
61 mol) and p-toluenesulfonic acid (1 g) Reference
Operating in the same manner as in Production Example 26 , 88.34 g of the title compound was obtained.
(97%). Boiling point: 110-112 ° C at 2 mmHg NMR (CDCl ₃ ) δ: 2.15 (3H, s), 5.97 (1H, d, J = 15 Hz), 7.65 (1H, d, J = 15 Hz)

Reference Production Example 28 (E) -1- (4-Methylphenylthio) -3-oxo-1-butene

Embedded image 1-methoxy-3-oxo-1-butene (0.095
g, 1 mmol), 4-methylphenylmercaptan (0.127 g, 1 mmol) and paratoluenesulfonic acid (1 mg) were operated in the same manner as in Reference Production Example 26 to obtain 0.096 g (50%) of the title compound. . NMR (CDCl ₃ ) δ: 2.05 (3H, s), 2.30 (3H, s), 5.8 (1H, d, J = 15 Hz), 7.1 (4H, m), 7.55 (1H, d, J = 15Hz)

Reference Production Example 29 1- (4-chlorophenylthio) -3-oxo-1-butene

Embedded image 1-methoxy-3-oxo-1-butene (5.00 g,
50 mmol), 4-chlorophenyl mercaptan (7.95 g, 55 mmol) and p-toluenesulfonic acid (30 mg, 0.15 mmol) Reference Production Example 26
6.3 g (51%) of the title compound was obtained. NMR (CDCl ₃ ) δ: 2.2 (1.5 H, s), 2.3 (1.5 H, s), 5.9 (0.5 H, d, J = 15 Hz), 6.4 (0. 5H, d, J = 9 Hz), 7.1 (0.5 H, d, J = 9 Hz), 7.35 (4H, m), 7.6 (0.5 H, d, J = 15 Hz)

Reference Production Example 30 3-oxo-1-triphenylmethylthio-1-butene

Embedded image 1-methoxy-3-oxo-1-butene (1 g, 10 mmol), triphenylmethylmercaptan (2.76)
g, 10 mmol) and p-toluenesulfonic acid (10
mg) in the same manner as in Reference Production Example 26 to obtain 1.54 g (45%) of the title compound. NMR (CDCl ₃ ) δ: 1.94 (3H, s), 6.16 (0.5H, d, J = 11 Hz), 6.23 (0.5H, d, J = 16 Hz), 6.74 ( 0.5H, d, J = 11Hz), 7.13 (0.5H, d, J = 16Hz), 7.16-7.45 (15H, m)

Reference Production Example 31 (E) -3-tert-butyldimethylsilyloxy-
1-tert-butylthio-1-butene

Embedded image (A) (E) -1-tert-Butylthio-3-oxo-1-butene (1.58 g, 10 mmol) was dissolved in methanol (20 ml), and sodium borohydride (0. 19 g, 5 mmol) was added slowly. After stirring at 0 ° C. for 30 minutes, the mixture was diluted with ether, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude product (1.6 g) was used without purification.

Embedded image

(B) The above crude product (1.6 g), te
rt-butyldimethylsilyl chloride (1.5 g, 10
Mmol), triethylamine (1.4 ml, 10 mmol) and 4-dimethylaminopyridine (45 mg) were dissolved in dimethylformamide (10 ml), and the mixture was stirred at room temperature for 20 hours. The reaction product was diluted with ether, washed successively with water, diluted hydrochloric acid, saturated sodium bicarbonate, and saturated saline, dried over anhydrous magnesium sulfate and concentrated, and the obtained crude product was distilled to obtain the title compound.
0 g (73%) were obtained. Boiling point: 120-130 ° C. at 0.5 mmHg NMR (CDCl ₃ ) δ: 0.07 (6H, s), 0.91 (9H, s), 1.20 (3H, d, J = 7 Hz), 1 0.33 (9H, s), 4.30 (1H, quint, J = 7 Hz), 5.78 (1H, dd, J = 7 Hz, 15 Hz), 6.26 (1H, d, J = 15 Hz)

Example 15 (E) -3-tert-butyldimethylsilyloxy-
1-phenylthio-1-butene

Embedded image (E) -3-oxo-1-phenylthio-1-butene (180 g, 1 mol) and sodium borohydride (19
g) and Reference Production Example 31 (a), to give a crude product (180 g).

Embedded image The crude product (180 g), tert-butyldimethylsilyl chloride (150 g, 1 mol), triethylamine (101 g, 1 mol) and 4-dimethylaminopyridine (3.8 g) were operated in the same manner as in Reference Production Example 31 (b). And
223.5 g (75%) of the title compound were obtained. Boiling point: 150-160 ° C NMR at 0.9 mmHg (C
DCl ₃ ) δ: 0.09 (6H, s), 0.92 (9
H, s), 1.25 (3H, d, J = 7 Hz), 4.3
7 (1H, quint., J = 7 Hz), 5.82 (1
H, dd, J = 7 Hz, 15 Hz), 6.33 (1H,
d, J = 15 Hz), 7.22 (5H, m)

Example 16 (E) -3-tert-butyldimethylsilyloxy-
1- (4-methylphenylthio) -1-butene

Embedded image (E) -1- (4-methylphenylthio) -3-oxo-1-butene and sodium borohydride as Reference Production Example 3
1 The same operation as in (a) was performed to obtain 0.25 g of a crude product.

Embedded image The above crude product (0.25 g), tert-butyldimethylsilyl chloride (0.21 g, 1.4 mmol), triethylamine (0.14 g, 1.4 mmol) and 4
-Dimethylaminopyridine (10 mg) as Reference Production Example 3
1 In the same manner as in (b), 0.25 g of the title compound (6
3%). NMR (CDCl ₃ ) δ: 0.08 (6H, s), 0.90 (9H, s), 2.32 (3H, s), 4.35 (1H, m), 5.80 (1H, dd) , J = 7 Hz, 16 Hz), 6.3 (1H, d, J = 16 Hz), 7.1 and 7.24 (2H, AB type d, J = 4 Hz, respectively)

Example 17 3-tert-butyldimethylsilyloxy-1- (4
-Chlorophenylthio) -1-butene

Embedded image 1- (4-Chlorophenylthio) -3-oxo-1-butene (15 g, 70 mmol) and sodium borohydride (11 g, 27 mmol) were operated in the same manner as in Reference Production Example 31 (a) to obtain a crude product. Was obtained 14.8 g.

Embedded image The above crude product (14.8 g), tert-butyldimethylsilyl chloride (13 g, 70 mmol), triethylamine (8.7 g, 87 mmol) and 4-dimethylaminopyridine (1 g) were used as Reference Production Example 31 (b). By the same operation, 14.93 g (64.5%) of the title compound was obtained. Its NMR spectrum data and Rf value by thin layer chromatography were completely identical to those obtained in Example 14 .

Reference Production Example 32 (R)-(-)-3-tert-butyldimethylsilyloxy-1-butanol

Embedded image Methyl (R)-(-)-3-tert-butyldimethylsilyloxybutyrate (2.323 g, 0.01 mol) was dissolved in ether (20 ml) and the solution was dissolved in ether (3
0 ml) was slowly added dropwise at −78 ° C. to lithium aluminum hydride (0.380 g, 0.01 mol). The mixture was stirred at -78 ° C for 2 hours, and 5% anhydrous sodium sulfate was added at the same temperature to decompose excess lithium aluminum hydride. The insolubles were removed by filtration, and the filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 2.010 g (98%) of the title compound as a colorless oil.

Embedded image

Reference Production Example 33 (R)-(-)-3-tert-butyldimethylsilyloxy-1-paratoluenesulfonyloxybutane

Embedded image (R)-(-)-3-tert-butyldimethylsilyloxy-1-butanol (1.022 g, 5 mmol)
Was dissolved in pyridine (10 ml), and this mixture was slowly added to paratoluenesulfonyl chloride (0.953) at 0 ° C.
g, 5 mmol). The mixture was stirred for 20 hours,
The mixture was diluted with ether (100 ml) and washed sequentially with water, diluted hydrochloric acid, saturated sodium hydrogen carbonate, and saturated saline. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give 1.747 g of the title compound (9.
7.5%).

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[0077]

According to the present invention, there is provided a 1-butenyl sulfide derivative which is useful as an intermediate for producing carbapenem-based and penem-based antibiotics, and a carbapenem-based compound which is easily optically active via the derivative. Synthesize penem antibiotics.

 ──────────────────────────────────────────────────続 き Continuation of the front page (72) Inventor Mitsuto Okitsu 1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka Prefecture Biotechnology Research Institute, Suntory Limited (56) References TETRAHEDRON LETTE RS, VOL. 24, NO. 44, p. 4825-4828 (1983) TETRAHEDRON LETTE RS, VOL. 24, NO. 44, p. 4829 −4832 (1983)

Claims (5)

(57) [Claims] 1. General formula (1): 1-butenyl sulfide derivative having the formula: 2. A compound represented by the general formula (1a): The 1-butenyl sulfide derivative according to claim 1, which is a (3R) form having the following formula: 3. The protecting group for a hydroxyl group of R ¹ is t-butyldimethylsilyl group, t-butyldiphenylsilyl group, triethylsilyl group, benzyl group, paranitrobenzyl group, acetyl group, trifluoroacetyl group, allyl group. The 1-butenyl sulfide derivative according to claim 1 or 2, which is a paranitrobenzyloxycarbonyl group, an allyloxycarbonyl group or a trichloroethyloxycarbonyl group. 4. General formula (6): Wherein lithium carbonate is allowed to act on a compound having the general formula (1 ′): A method for producing a 1-butenyl sulfide derivative having the formula: 5. A compound of the general formula (6a): From a compound having the general formula (1a '): Claim give 1 butenyl Nils sulfide derivatives with
Production method as described.