JPS61207373A - Production of 2-azetidinone derivative - Google Patents

Abstract

PURPOSE:To obtain efficiently the titled compound useful as an intermediate for synthesizing a penem antibiotic, by reacting 1-butenylsulfide derivative with chlorosulfonyl isocyanate and optionally removing an amino-protecting group. CONSTITUTION:A compound shown by the formula 1 (R<1> is hydroxyl-protecting group; R<2> is triphenylmethyl, t-butyl, or (aromatic ring-substituted)phenyl is reacted with chlorosulfonyl isocyanate in an ether or chlorine solvent at <=0 deg.C, preferably <=-20 deg.C, and optionally an amino-protecting group is removed (concentrated and treated with reducing agent and free-radical scavenger), to give the aimed compound shown by the formula 2. An optical active compound such as a compound shown by the formula 1a obtained from (3R)-1,3-butanediol as a starting raw material is used as the compound shown by the formula I, to give the aimed optically active compound.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention is based on the general formula (1) (wherein R1 represents a hydroxyl protecting group, and R2 represents a triphenylmethyl group, a [-butyl group, a phenyl group, or an aromatic A 2-azetidinone derivative having the general formula (2a) R1 (wherein R and R have the same meanings as above) is obtained by reacting chlorosulfonyl isocyanate with a 1-butenyl sulfide derivative having a ring-substituted phenyl group). The general formula (2
The present invention relates to a method for producing a 2-azetidinone derivative having the general formula (2b) (wherein R and R have the same meanings as above) by preparing a compound having the formula (a) and then removing the chlorosulfonyl group.

The 2-azetidinone derivative represented by the general formula (2b) has a hydroxyethyl group at the 6-position, which leads to carbapenem and penem compounds, and is therefore used in the field of antibiotics.

In particular, this is an innovative method for producing carbapenems and penems having an optically active hydroxyethyl group.

(Prior art) Naturally produced chenamycin
It is thought that a 1'-B)-hydroxyethyl group is required at the 6-position in order for carbapenem antibiotics, represented by n), to exhibit strong and broad antibacterial activity [K,H
irai et al. Tetrahedron Letters,
Vol. 23, p. 4021, 1982].

Penem antibiotics in which the methylene group at position 1 of the carbapenem skeleton is replaced with a sulfur atom have not been found in nature, but have been obtained synthetically. Penem antibiotics, which have a similar skeleton to this carbapenem, also have a 1-2) hydroxyethyl group at the 6-position, which is thought to be important for their activity. Fact l-Thiachenamycin (S, OiA et al.
I cr ob, Agent Chemoth
Er,.

21, 492, 1982) and 5ch29482 [A,
K, Ganguly et al. J, Antimicrob
, Chemother+.

(SuppH, C) Vol. 9, p. 1, 1982] have been found to have strong antibacterial activity. Therefore, the development of a new method for producing a compound having an l-(t)-hydroxyethyl group at the 6-position of the penem ring is eagerly awaited.

(Problems to be Solved by the Invention) The present inventors planned the development of an efficient method for producing a penem antibiotic having a 1-(6)-hydroxyethyl group at the 6-position, and studied methods for solving the problem.

The first method uses optically active raw materials and yields (2
The second method is to synthesize a compound having a 1-(t)-hydroxyethyl group at the 8-position of the azetidinone ring, and use this compound to synthesize the target penem antibiotic. This is a method to synthesize the target penem antibiotic by performing efficient optical resolution during the process of inducing the penem skeleton from the azetidinone skeleton.

Many methods are already known for introducing a 1'-■)-hydroxyethyl group into the 3-position of the 2-azetidinone ring.

For example, A. Yoshida et al. Chem. Phar
M, Buln, 29'& 2899 1981 and M, 5hiozaki et al. Tetrahedron L
etters, Vol. 22, p. 5205, 1981, etc., but the methods known to date are not very suitable for reasons such as poor yields and complicated reaction steps.

Also, by optical resolution, 1-■) was found at the 3-position of the 2-azetidinone ring.
-The method for obtaining compounds with hydroxyethyl groups is through purification and
It has drawbacks such as poor yield in the separation process and difficulty in purification.

Structure of the Invention (Means for Solving Problems) The present invention is based on the general formula (2) (wherein R1 is a hydroxyl protecting group, and R2 is a triphenylmethyl group, a t-butyl group, a phenyl group, or an aromatic ring-substituted phenyl group) , R3 represents a hydrogen atom or a chlorosulfonyl group).

More specifically, the 2-azetidinone derivative represented by the general formula (2) of the present invention can be produced by the following production method A1 production method B1 production method C or the production method.

The feature of this production method is that the l-butenyl sulfide derivative represented by the general formula (1) (in which R1 and R2 have the same meanings as above) is reacted with chlorosulfonyl isocyanate to form an acid functional group at the 1-position. This is a method for producing an azetidinone derivative having trans-3,4-position.

If an optically active reagent is used as a starting material in production method A, B or C, an optically active 2-azetidinone derivative can be produced. Furthermore, optically active 2-azetidinone derivatives can be produced by performing asymmetric reduction during the production process.

In production methods A, B, C, or D, optically active 2-azetidinone derivatives are obtained by optical resolution during the production process.

[Manufacturing method A]

(6) (1a) (The inset in the above reaction formula represents a tosyl group or a mesyl group,
X represents a halogen atom, and R1 and R2 have the same meanings as above. ) (Step 1) and (Step 2) (8R)-1,3-butanediol is reacted with p-toluenesulfonyl chloride or methanesulfonyl chloride in the presence of a base to form tosylate (3-mesylate (
3) and then heated in an ether or aromatic hydrocarbon solvent with a compound represented by the general formula RSH C (in which R2 represents the same meaning as above) in the presence of an inorganic base, or by heating in the presence of an inorganic base. In the formula, R2 represents the same meaning as above and Y represents an alkali metal) by heating with a salt represented by the formula (
The sulfide derivative represented by 4) is obtained.

(Step 3) In the step of protecting the hydroxyl group of the sulfide derivative obtained in Step 2, compound (4) and a benzyl chloride other than silyl such as t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triethylsilyl chloride, etc.
Aralkyl halides such as benzyl bromide and paranitrobenzyl chloride, acetyl chloride, acetyl bromide, acylating agents such as trifluoroacetic anhydride and acetic anhydride, allyl chloride or paranitrobenzyloxycarbonyl chloride, allyloxycarboxyl chloride, The 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.

The a-form of compound (5) in which the hydroxyl group at the 3-position is protected is a known compound [H, A, Khan et al. Tetrahed
ron Letters, Volume 23, Page 5083 1982
and P. Loiseau et al. Pharm, Acta
He1v, vol. 58, p. 115 1983 and Y.
Ueno et al. Bull, Chem, Soc, JP
n,, vol. 53, p. 3615, 1980].

(Step 4) (Step 5) The compound (5) obtained in Step 3 is halogenated using N-chlorosuccinimide or sulfuryl chloride, and then heated with carbonate or common salt, potassium chloride, and lithium chloride to obtain the general formula (1a). ) is the optically active l
-butenyl sulfide derivatives are obtained.

The general formula (la
) is obtained.

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

[Production method B] (In the above formula, A and R' represent the same meanings as above, and R4 represents a lower alkyl group) (Step 6) Step 6 is a reduction reaction of R)-←)-3-hydroxybutyric acid ester This reduction can be easily converted into a butanol derivative (8) by using a reducing agent such as lithium aluminum hydride at a temperature below O'C.

(Step 7) Step 7 can be carried out in the same manner as Step 1 described above, by dissolving compound (3) in a base such as pyridine, adding paratoluenesulfonyl chloride or methanesulfonyl chloride at 0°C or lower, and stirring at room temperature. This is a method for producing sulfonic acid ester (3).

Although the butenyl sulfide derivative represented by the general formula (1) obtained by production method A or B is a mixture of cis and trans forms with respect to a double bond, there is no problem in carrying out the present invention.

This compound (1) is dissolved in an ether or chlorine solvent, and 1.1 equivalent or more, preferably 1.2 to 1.4 equivalents of chlorsulfonyl isocyanate is added.Chlorsulfonyl isocyanate is an ether or chlorine solvent. The chlorsulfonyl group is easily removed by concentrating the reaction and adding a reducing agent and a free radical scavenger. For example, thiophenol, mercaptoethanol, mercaptan, sodium bisulfite, ammonium bisulfite, and sodium borohydride are preferred.

Particularly good are thiophenol and sodium bisulfite.

Examples of free radical scavengers that neutralize the generated chlorosulfonic acid include pyridine, sodium hydrogen carbonate, sodium phosphate, and amines.

The 2-azetidinone derivative (2C) represented by the general formula (2C) (in which R1 and R2 have the same meanings as described above) thus obtained has two types of isomers. That is, (1'R, BS, 4R) body and (IR, 8
R,4S) body. The former has the same steric configuration as carbapenems such as chenamycin, and it goes without saying that it is a useful synthetic raw material.

Furthermore, both isomers are extremely easy to separate and purify. Purification methods include column chromatography, preparative thin layer chromatography, and recrystallization.
, 4S) Compound (2c) is easily separated by recrystallization.

In place of chlorosulfonyl isocyanate, for example, trichloroacetyl isocyanate, benzyl isocyanate, allyl isocyanate, para-toluenesulfonyl isocyanate can be used, but chlorsulfonyl isocyanate is most suitable in consideration of removal of protecting groups, reactivity, etc.

When trifluoroacetyl isocyanate or trichloroethoxysulfonyl isocyanate is used, a 2-azetidinone derivative can be obtained by, for example, florisil column chromatography or zinc treatment after the reaction is completed.

2 represented by the general formula (2c) obtained in this way
By oxidizing the -azetidinone derivative, a sulfonyl derivative represented by the general formula (9) (wherein R1 and R2 have the same meanings as above) can be easily obtained. This compound (9
) can be induced into penem and carbapenem by known methods (1 line).
(1) (R in the above formula
and R represent the same meanings as above) (Step 7) - In the step of condensing -butyn-3-ol with the general formula RSH (in the formula, R2 represents the same meanings as above), an inorganic base,
For example, 1-butenyl sulfide represented by the general formula αQ is obtained by heating in the presence of sodium hydroxide or potassium hydroxide, preferably at 80 to 150°C. This synthetic method yields only the cis isomer.

(Step 8) In this step, the general formula (1) is
A 1-butenyl sulfide derivative represented by is obtained. The obtained reaction product can be purified by distillation or column chromatography.

(Step 9) This step is the same operation as Step 8, and the general formula (11)
The compound represented by can be changed.

(Step io) In step IO, compound (1) is obtained in the same manner as in step 7. Pure compound (1) can be obtained by distilling the obtained reaction product or subjecting it to column chromatography.

[Manufacturing method D]

[In the above formula, R and R represent the same meanings as above, and R represents a lower alkyl group] (Step 11) A compound represented by the general formula (1) and R in the general formula RSHC
An enone compound represented by the general formula θ can be obtained by dissolving a mercaptan represented by (2 has the same meaning as above) in an organic solvent and heating it in the presence of a catalytic amount of an organic acid. Compound (13) can be purified by distillation or column chromatography.

The organic acid used in this step is preferably para-toluenesulfonic acid or camphorsulfonic acid, and the reaction temperature is preferably 50 to 60°C.

(Step 12) The compound (131) is dissolved by dissolving it in an organic solvent and adding a reducing agent such as sodium borohydride.
10 is obtained. By using an asymmetric reducing reagent in this reduction reaction, an optically active compound α1 can be obtained.

(Step 13) The step of protecting this hydroxyl group is as described in steps 3, 8 and 1 above.
This is the same operation as 0.

The l-butenyl sulfide derivative represented by the general formula (1) obtained in this way is dissolved in an organic solvent, chlorosulfonyl isocyanate is added under cooling, and the general formula ( 2)
It can be a 2-azetidinone derivative represented by:

The 3°4cis isomer and the 3,4trans isomer present in the 2-azetidinone derivative having the general formula (2b) (wherein R1 and R2 have the same meanings as above) obtained in this manner can be removed by recrystallization or column chromatography. Can be separated by preparative thin layer chromatography3,
It is a 4-trans form (1'R.

3S, 4R) and (Is, 3R, 4S) and (Is,
The four isomers, 8S, 4R) and (1'R, 8R, 4S), can be obtained by recrystallization or column chromatography.
By using preparative thin layer chromatography, it can be separated into the former two and the latter two.

(IR, 8S, 4R) and (Is, 3R, 4S)
The mixture is oxidized as described above, and the sulfonyl derivative represented by the general formula (9) is subjected to a substitution reaction with a thiocarboxylic acid by a known method. By (1'R, 8S, 4R) body and (Is
, 3R, 4S) bodies.

[Example 1] 3-(IR-t-butyldimethylsilyloxy)ethyl-
4-Phenylsulfinyl-2-azetidinone chlorosulfonyl isocyanate 0.87rne(4,
(24 mmol) was dissolved in 8d dry ether, and 1.00 y(3,
40 mmol) in ether (2d) was added slowly. After stirring at room temperature for 4 hours, the solvent was distilled off under reduced pressure.

Dissolve the residue in 5 g of acetone and remove 0 thiophenol under water cooling.
．． 75y (6.80 mmol) followed by 0.75y of pyridine.
67y (8.48 mmol) was added and stirred at room temperature for 15 minutes. Water was added to the reaction solution, and the mixture was extracted with methylene chloride. The extract was washed with water and the crude product obtained was purified by silica gel column chromatography. Of the two isomers obtained, the l'R, 3S, and 4R forms precipitated from cold hexane, while the 1'R, 3R, and 4S forms could be separated as an oily substance.

Table 1 shows the yield, properties, melting point, and instrumental data of the compound obtained in the same manner as in Example 1.

(Left below) [Example 4] (is, BS, 4R and IR, 8R, 4S) -8
-(1-tert-Butyldimethylsilyloxy)ethyl-4Lert-butylthio-2-azetidinone N-chlorosulfonylisocyanate (0,2643 mmol) was dissolved in ether (ad) and at -50 to -60°C (Z ) -a -tert-butyldimethylsilyloxy-t-tert-butylthio-1-butene (0,55
A mixture of 2 mmol) and ether (2-) was slowly added dropwise. The mixture was stirred at -40 to -50°C for 1 hour and then heated to -60°C with tert-butyl mercaptan (0
, 45d, 44 mmol), pyridine C0, 27d)
and acetone (2rnl) was added and stirred for 80 minutes. The reaction product was washed successively with 0.5N hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride, dried, and then concentrated. The residue was purified by silica gel column chromatography to obtain 77ffi9 (24%) of the title compound.

NMRCCDCI3) δ: 0.10 (6H, s), 0
．． 91 (9B, ri, 1.38 (3H, d, J=1.
38Hz), 1.95 (9H, S), 3.17 (IH,
m), 4.18 (LH, di, J=4Hz, 7Hz
), 4.73 (IH, d, J=2Hz), 6.60 (
IH, br, 3) [Example 5] (IR, 8S, 4R and 1'S, 8S, 4R and 1'R, l, 4S and is, 8R, 4S) -3-(
1'-tert-butyldimethylsilyloxy)ethyl-4-tert-butylthio-2-azetidinone (E) -3-tert-butyldimethylsilyloxy 1-tert-butylthio-1-buteneC0,5592
mmol) and N-chlorosulfonyl isocyanate,
The title compound was obtained in O,155y (25%).

NMR (CDC13) δ: 0.09 (6H,S), 0
．． 89 (9H, heat), 1,21 (0,5H, d, J=
7Hz), 1.28 (0.5H, d.

J=7Hz), 1.35 (9H,i), 3.0 (L
H.

m), 4.20 (IH, m), 4.21 (0,5
H,d.

J=7Hz), 4.94(0,5H,d, J=7Hz
), 6.20 (0,5H,br, '3), 6.80
(0,5H,br.

S) [Example 6] (IR, 8S, 4R and Is, 8R, 4S)-3-
(1-tert-butyldimethylsilyloxy)ethyl-4-phenylthio-2-azetidinone (8) and (l
S.

35.4R and IR, 8S, 4R)-8-(1-te
r t-butyldimethylsilyloxy)ethyl-4-phenylthio-2-azetidinone (B) (to) (B) tZ) -8-ter t-butyldimethylsilyloxy-1-phenylthio-1-butene (0, 298y,
1 mmol) and N-chlorosulfonyl isocyanate (
0.1 ml, 1.15 mmol) was operated in the same manner as in Example 4, and a mixture of the title compound (8) and g3) was
88y (28%) was obtained. According to NMR spectrum data, the mixing ratio of Compound A and Compound B was 1:5.

NMRCCDCI3) δ: (Compound A) 0.05 (6
H, m), 0.85 (9H, h), 1.15 (3H, d
, J=7Hz) 3.01(IH, dd, J-2Hz
, 5Hz), 4°20 (IH, dy, J=5Hz,
7Hz), 5.02 (IH, d, J=2Hz), 6
．． 75 (IH.

br, f), 7.135 (5H, m) (Compound B) 0.10 (6H, 5), 0.919H,
s), IJ2(3H,d, J=7Hz)-(4-chlorophenyl)thio-1-butene (13,8y, 42.
6 mmol) in ether C80 ml), -60
N-chlorosulfonyl isocyanate (4,7
ml! , 53.9 mmol) and ether (17me
) was gradually added dropwise. The mixture was stirred for 1.5 hours and concentrated. The residue was dissolved in acetone (701 nI) at -40°C with pyridine (3.5 d, 42.6 mmol) and thiophenol (9.7 m/, 94.5 d).
) was added dropwise. The reaction mixture was gradually brought to O'C, water was added,
Extracted with methylene chloride. The extract was dried and concentrated. The residue was purified by silica gel column chromatography to obtain 8.4y of a mixture of the title compound (5) and [F] (mixing ratio: A/B = 8/l). The mixture of the first compound and (B) was washed with cold pentane, and the compound (
3.581 as a colorless crystal? Obtained.

NMR (CDC13)j: (Compound A) 0.08
(6H, box), 0.83 (9H, g), 1.20 (8
H, d, J=7Hz), 3.0 (If(,m),
4.15-4.28 (LH, m), 5.04 (IH, d
, J=2Hz), 6.1 (IH.

3), 7.30-7.45 (4H, m) (compound B)
0.07C6H, ≦ 0.86 (9H, *), 1.31
(3H, d, J=7Hz), 3.1.1 (l H, m
), 4.15-4.28 (LH, m), 4.87 (I
H, d, J=2Hz), 6.1 (1, H.

br,! j), 7.80-7.45 (4H, m) [
Example 9] (IR, 8S, 4R)-3-(1'-tert-butyldimethylsilyloxy)ethyl-4-phenylthio-2-azetidinone shin)-←)8-tert-butyldimethylsilyloxy-1- Phenylthio-1-butene (1,01°3.40
mmol) and N-chlorosulfonyl isocyanate C0
, 87ml (1.4.24 mmol) was operated in the same manner as in Example 8 to obtain the title compound in a yield of 44%.

Properties: Colorless prismatic crystal Melting point: 124-125°C 20.

[α], +64.8 (C=0.12.chloroform) IRKB! - Summer: 1764 m NMR (CDC63) J: 0.05 (3H, fi),
0.07 (3H, '4), 0.87 (9H, 8), 1.
20 (3H, d, J = 6.1H2), 4.24 (LH,
m), 5.39 (IH.

d, J=2.4Hz), 5.98(IH,br,
5), 7.30-7.60 (5H, m) [Example 101 (lR9:3Ss 4R) 8 (1ter t-
butyldimethylsilyloxy)ethyl-4-(4-methoxyphenyl)-thio-2-azetidinone (2)-(he)-8-tert-butyldimethylsilyloxy-1-(4-methoxyphenyl)thio-1- Butene was operated in the same manner as in Example 8 to obtain the title compound.

Properties: Colorless needle crystals Melting point: 108-104°C [α], +43.30 (C=0.4.chloroporum) NMR (CDC#3) δ: 0.06 (3H,S),
0.08 (3H, S), 0.87 (9H, S), 1.2
1 (8H, d, J=6.0Hz) 2.96 (IH,
m), 3.82 (3H, S), 4.2° (LH, m),
4.94 (LH, d, J = 2.4Hz) 5.93
(IH, br, S) [Example 111 (1'R, as, 4R)-3-(1'-tert-
butyldimethylsilyloxy)ethyl-4-(4-chlorophenyl)thio-2-azetidinone(t)-←>-8-tert-butyldimethylsilyloxy-1-(4-chlorophenyl)fA-, -1-butene The same procedure as in Example 8 was carried out to obtain the title compound.

Properties: Colorless needle crystals Melting point: 156-1580 20.

[α], +66.4 (C=0.1.chloroform) IRKBrl: 1764 cm NMR (CDCJ?3) δ: 0.07 (6H,S),
0.86 (9H, S), 1.21 (8H, d,
J = 6.0Hz), 3.01 (IH, m), 4.20 (
LH, m), 5.00 (LH, d, J=2.4Hz)
, 6.45 (IH, br, S), 7.20-7.50
(4H, m) Reference Example 1 (8R)-1-chloro-3-t-butyldimethylsilyloxybutyl-do-chlorophenylsulfide C3R)-
t-Butyldimethylsilyloxybutyl-chlorphenyl sulfide 0.50? (1,61 mmol) in 12 Wll of carbon tetrachloride! To this was added 0.24y (1.77 mmol) of N-chlorosuccinimide, and the mixture was stirred at room temperature for 1.5 hours.

The precipitated succinimide was collected by filtration, and the filtrate was concentrated to obtain the title compound 0.56y (yield 97%).

Properties: colorless oil IR spectrum (film, cm'): 295
0°2920, 2850.1470.1250.113
o, 1090°830, 820.770'H-NMR spectrum/l/ (CDCII 3.δ)
: 0.08 (3H, s), 0.07 (IH, 3), 0
．． 86 (9H, j), 1.12 (1, d.

J=6.0Hz), 1.65-1.77 (2H, m
), 1.95-2.08 ('IH, m), 4.15 (I
H, m), 4.54 (IH, dd, J=9.0.4.
4Hz), 7.20-7.40 (4H,m) Reference Example 2 <8R)-t-butyldimethylsilyloxy-1-butenylphenyl sulfide axis method: ←)-8R-t-butyldimethylsilyloxy Butylphenyl sulfide N-chlorsuccinimide 1.0 9y (8.1 6
mmol) was dissolved in 50-carbon tetrachloride and reacted under the reaction conditions shown in the table. The precipitated succinimide was removed by filtration, and the solvent of the P solution was distilled off.

The resulting residue was dissolved in dimethylformamide 20-
Lithium chloride 0.85y (8.16 mmol),
0.55y (7.42 mmol) of lithium carbonate was added and stirred at 80°C for 2 hours.

After cooling, water was added to the reaction solution and extracted with ether.

The extract was washed with water, dried over magnesium sulfate, the solvent was distilled off, and purified by silica gel column chromatography to obtain the title compound as a mixture of trans and cis forms.

Properties: Colorless oil (yield 72%) Trans form 2.5 Cis form! IR spectrum (film, cm): 298
0.

2955, 2880, 1590, 1490, 1
450, 1265.

1100, 845, 790, 745, 700 High resolution mass (M/Z): 'H-NMR spectrum: trans isomer (CDCl
a, δ) 0, 06 (6H, S), 0.91 (9H, S)
, 1.25 (3H, d.

J = 6.0Hz), 4.42 (IH, m), 5.92 (
IH, dd.

J=15.5, 6.0Hz), 6.38(IH, dd,
J=15.5.

1, 4f(z), 7.2 5-7.4 2 (5 H
, m) Cis form (CDC13, δ): 0.08 (6H
, S), 0.92 (9H, S), 1.26 (3H, d
, J=6.0Hz), 4.8 1 (IH.

m), 5.86 (IH, dd, J=9.5,
8.0Hz), 6.18 (IH.

dd, J=9.5, 1.5Hz), 7.25
-7.42 (5H, m) (b) method: (-j - 3R
- Dissolve 1.0 (H! (3.22 mmol) of t-butyldimethylsilyloxybutylphenyl sulfide in 5-chloroform, add 0.449 (3.22 mmol) of sulfuryl chloride under water cooling, and stir at room temperature for 1 hour. The residue obtained by distilling off the solvent was treated in the same manner as in method (a) to obtain the title compound.

Yield: 62% As in Reference Example 2, Table 2 shows the reaction conditions, yield, and ratio of trans/cis isomers, and Table 3 shows equipment data.

(Leaving space below) Reference Example 6 (3R)-+-Butyldimethylsilyloxy-1-butenyl-do-chlorophenylsulfide The title compound was prepared in the same manner as in Reference Example 2 under the reaction conditions and yields shown in Table 2 to produce the trans form and cis form of the title compound. It is obtained as a mixture of bodies.

The trans and cis mixture obtained here was separated by silica gel column chromatography (elution solvent: hexane) to obtain trans and cis forms, respectively.

Physical properties of trans isomer IR spectrum (film, cm): 296 (
L2940, 2850.1475.1250.1095
．． 880°-NMR spectrum CCDCl3. J):
0.06 (6H,S), 0.91 (9H,S),
1.25 (3H, d, J=6.0Hz,), 4.42
(LH, m), 5.92 (LH, dd, J=15.5,
6.0Hz), 6.8B (IH, dd, J=15.5,
1.4Hz), 7.25-7.42 (5H, m) Physical properties of cis isomer 2940, 2860.1480.1255.1150.
880'H-NMR spectrum (cDc13.a)
: o, o8(6H,S), 0.92(9H,S)
, 1.26 (3H, d, J=6.0Hz), 4.81
(LH, m), 5.86 (IH, dd, J=9.5
．． 8.0Hz), 6.18 (1B, dd, J=7
．． 5.1.5Hz), 7.25-7.42 (5H, m) Reference Example 11 (3R)-(he)-[-butyldimethylsilyloxybutyl-do-chlorophenylsulfide-S-oxy(aR
)-t-butyldimethylsilyloxybutyl-P-ri-lorphenylsulfide 1.0 Oy (3.22 mmol)
was dissolved in 30 d of methylene chloride, and 0.695 y (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 distilling off the solvent was separated and purified by silica gel column chromatography to obtain 0.980 gI of the title compound.
(yield 93%).

Properties: colorless oil IR spectrum (film, cm): 1040
(S→0) Reference Example 12 Trans-(3R)-t-butyldimethylsilyloxy-
1-Butenyl-do-chlorophenylsulfy Reference Example 11
0.20y (0.61 mmol) of the S-oxide obtained above was added to 5me of acetic anhydride and heated under reflux for 3 hours.

After distilling off the solvent, the residue was separated and purified by thin layer chromatography to obtain 0.020y (yield: 10%) of the title compound.

Reference Example 13 R-H-8-Hydroxybutyl-p-1-luenesulfonate To 150 rnl of dry methylene chloride was added R-←)-i,a-butanediol lo, 00p (0,111 mol) and pyridine 9.66p (0 , 122 mol), then P
-Toluenesulfonyl chloride 23.279 (0,12
2 mol) was added. After stirring at room temperature for 15 hours, the reaction solution was diluted with water and extracted with methylene chloride. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound 21.68y. Yield 80%.

Properties: Colorless oily substance 20, 0 [α], 11.5 (C=2.8.Chloroform) IR spectrum (film + cm)'
3400+1605, 1360.1180.950.
900'H-NMR spectrum (CDC13, J):
1.19 (3H, d.

J=7.0H2), 1.60~2.10 (2H, m
), 1.87 (LH, S), 2.45 (8H, S), 3
．． 65-4.81 (2H, m), 7.58 (4H.

Q+ J=8-OHz) Reference Example 14 R-(he)-3-hydroxybutyl-methanesulfonate dry methylene chloride 1 ornl! R-←)-1,8-butanediol 0.50 Of (5,55 mmol),
0.483y (6.10 mmol) of pyridine and 0.699y (6.10 mmol) of methanesulfonyl chloride were added and treated in the same manner as in Reference Example 1 to obtain 0.392y of the title compound (yield 42%). .

Properties: Colorless oil [α]”0 knee 26.8° (C=1.0.chloroform) IR spectrum (film + cm)’
3400+2970, 1620.1830.1170
．． 9401H-NMR spectrum (CDCa, δ)
: 1.22 (3H, d.

J=7.0Hz), 1.65-2.10 (2H, m
), 2.73 (LH, S), 3.00 (8H, S), 3
．． 90 (IH, m), 4.20-4.50 (2H.

m) Reference Example 15 R-(to)-3-hydroxybutylphenyl sulfide tetrahydrofuran 40- to R-←)-3-hydroxybutyl-do-toluenesulfonate 2.00y(8,1
9 mmol), sodium thiophenoxide 1.30y (
9.82 mmol) was added thereto and heated under reflux for 1 hour. - After cooling, water was added to the reaction solution and extracted with methylene chloride. The extract was washed with water and dried over magnesium sulfate. The oily substance obtained by distilling off the solvent was subjected to silica gel column chromatography (
The title compound was obtained by separation and purification using chloroform (elution solvent).

The compounds shown in Table 4 were synthesized using a similar synthetic method. The properties, yield and equipment data for each are shown in Table 4.

(Left below) Reference Example 16 R-←) -3-hydroxybutyl-P-chlorophenylsulfide R-(-)-1-hydroxybutyl methanesulfonate 0.20y (1,19 mmol), radium p-chlorothiophenoxy (0.21011.25 mmol) was dissolved in 5-tetrahydrofuran and heated under reflux for 1 hour. The following treatment was carried out in the same manner as in the reference example, and the title compound was obtained at 0.22y.
(yield 87%).

Reference Example 17 R←) -,3-t-Butyldimethylsilyloxybutyl phenyl sulfide RH-3-hydroxybutylphenyl sulfide 1.44y (7,90
mmol), t-butyldimethylsilyl chloride 1°a
ly (8.69 mmol) in dimethylformamide 1O
1.065' (8.69 mmol) of 4-dimethylaminopyridine was added to the solution dissolved in fnl at room temperature and stirred for 3 hours. The reaction solution was diluted with water and extracted with ether. The extract was washed with water and then dried over magnesium sulfate.

After distilling off the solvent, the obtained oily substance was separated and purified by silica gel column chromatography to obtain the title compound.

The compounds shown in Table 5 were obtained in the same manner as in Reference Example 17. Its properties, yield and equipment data are shown in Table 5.

(Left below) Reference Example 18 <5R)-benzyloxybutyl-p-chlorfe (3
R)-Hydroxybutyl-P-chlorophenylsulfide 1.00i (4.61 mmol), 60% sodium hydride 0.22y (5,53 mmol) and benzyl bromide 0.79j;' (4.61 mmol) are dried Added to 20me of tetrahydrofuran. After heating under reflux for 2 hours, the mixture was cooled and diluted with water. Dry with magnesium sulfate,
The oil obtained by distilling off the solvent was purified by silica gel column chromatography. 1.23y of the title substance was obtained as a colorless oil (yield: 87%).

[α]D, -25,5° (C=2.5.chloroform)
iR spectrum (film, cm): 2960
゜2920, 2850.1475.1090.8101
H-R spectrum < CDCl3. δ): 1.22(
3H, d.

J=6.0Hz), 1.53-2.08 (2H, m),
2.88-3.17 (2H, m), 3.61 (LH, m
), 4.47 (28, dd, J = 12.5. l O
, OHz), 7.15 (4H, S), 7.23 (5H
, S) Reference Example 19 (3R)-Acetoxybutyl-P-chlorphenylsulfide (8R)-Hydroxybutyl-P-chlorphenylsulfide 1.00 F/(4,6 mmol) and pyridine 0.44 y(5, 5 mmol) in dry tetrahydrofuran 1 Ornl! After stirring, 0.44 p (5.5 mmol) of acetyl chloride was added to the mixture under ice-cooling. After stirring at room temperature for 30 minutes, water was added and extracted with methylene chloride. The extract was washed with water and then dried over magnesium sulfate. The oily substance obtained by distilling off the solvent was purified using silica gel column chromatography to obtain 0.97y (yield: 81%) of the title compound as a colorless oily substance.

[α]” 1.00 (C=4.0.Chloroform) IR spectrum (film, cm) 2960
゜2920. 1,735. 1480. 1370
．． 1240. 1095゜'HNMRX h') Tor (CDCe3.a): 1.25 (3H, d
.

J=6.0Hz), 1.70-1.95 (2H, m
), 2.03 (3H, S), 2.80-3.00
(2H,m), 5.00 (LH,m), 7.
25 (4H.

S) Reference Example 20 (3R)-Trichloroethoxycarbonyloxybutyl-p-chlorophenyl-sulfide (3R)-hydroxybutyl-p-chlorophenyl sulfide 0.50.9
' (2,81 mmol), pyridine 0,22y (2,7
'i mmol) in 20 me of dry methylene chloride and cooled on ice.2. 2. 0.540 g I (2.54 mmol) of 2-trichloroethyl chloroformate was added dropwise.

After stirring at room temperature for 1 hour, water was added and extracted with methylene chloride.

The oily substance obtained by distilling off the solvent was purified using solitary gel column chromatography to obtain the title compound at 0.81 (yield: 9).
7%) obtained.

Properties: Colorless oily substance 1755, 1475.1880.1250.1090.
810'HNMR spectrum/l/ (CDCe3.a
): 1.32 (3H, d.

J=6.0Hz), 1.65-2.20 (2H, m
), 1.78-3.11 (2H, m), 4.71 (2
H, S), 4.90 (IH, m), 7.20 (4H,
S) Reference Example 21 (8R)-7'-Nitropenzyloxyluponyloxybutyl-r-chlorophenylsulfide The same procedure as in Reference Example 20 was carried out using arnitropenzyloxyluponyl chloride.

Properties: colorless oil (yield 73%) 20, 0 [α], 11.9 (C=2.8.chloroform) IR spectrum (film, cm): 29
60°1755, 1475.1380.1250.10
90.810'HNMR SHE') CCDCe3.
a): 1.31 (3H, d.

J=6.0Hz), 1.60-2.15 (2H, m
), 2.80-3.10 (2H, m), 4.15 (LH
, m), 5.20 (2H, S), 7.20 (4H, S)
, 7.30-7.65 (2H, m), 8.05-8
．． 30 (2H, m) Reference Example 22 (Z) -1-tert-butylthio-3-hydroxy-1-butene l-butyn-3-ol (9,44me, 0.12 mol), potassium hydroxide (0, 56p, 0.01 mol)
and tert-butyl mercaptan (11,25me,
0.1 mol) was stirred at 90-100'c for 30 minutes. After cooling, ether was added to the mixture, washed with water, dried, and concentrated to obtain the title compound e15p. This crude product was used in the next reaction without purification.

NMR (CDI3) δ: 1.22 (:13H, d,
J=7Hz), 1.35 (9H.

S), 4.62 (LH, m), 5.60 (L H, c
l, d.

J=7Hz, 1OHz), 6.10 (IH, d.

J=10Hz) Reference Example 23 (Z) -1-tert-butylthio-3-tert-
Butyldimethylsilyloxy-1-butene (Z) -1
-tert-Butylthio-3-hydroxy-1-butene (5,83?, 86.4 mmol) was dissolved in dimethylformamide (37d) and tert-butyldimethylsilyl chloride (5,89y), 4-dimethylaminopyridine (0,5y) and triethylamine (5d) were added sequentially and stirred overnight. Ether was added to the reaction mixture, and the mixture was washed successively with water, dilute hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride, dried, and concentrated. The resulting residue was distilled under reduced pressure to obtain the title compound as a colorless oil. 8.5y (85%) was obtained.

Boiling point: 120-130℃ NMR at 0.5mmHg (
CDCII3)a: 0.1(6H,S), 0.90(
9H, S), 1.21 (3H, d, J=7Hz), 1.
37 (9H, S), 4.65 (IH, m), 5.61 (
IH, dd, J=7Hz, 1OHz), 6.01 (I
H, d, J = 10 Hz) Reference example 24 (Z)-8-hydroxy-1-phenylthio-1-butene -butyn-3-ol (4,2y, 60 mmol),
Thiophenol (5,5y, 50 mmol), potassium hydroxide (0,28y, 5 mmol) and thiophenol (5,5y, 50 mmol) were operated in the same manner as in Reference Example 22, and the title compound was dissolved in 9.0p ( 100%) obtained.

NMR(CDCl3)δ: 1.30 (3H,d,
J=7Hz), 4.75 (IH.

quint, J=7Hz), 4.25(IH, dd
.

J=7Hz, lOHz), 6.17 (LH, d.

J=10Hz), 7.20 (5H,m) Reference Example 25 (Z) -3-tert-butyldimethylsilyloxy-l-phenylthio-1-butene (Z) -8-hydroxy-1-phenylthio-1- Butene (9y, 50 mmol), tert-butyldimethylsilyl chloride (7,53y, 50 mmol),
Triethylamine (7rnl, 50 mmol) and 4-
Dimethylaminopyridine C0,2259) as Reference Example 23
In the same manner as above, 13.4y (90%) of the title compound was obtained.

Boiling point: 155-160'cNMR at 0.9mmHg
(CD(J'3)J:0.09(6H,S),0.90
(9H, S), 1.25 (3H, d, J=7Hz), 4
．． 78 (l H.

quint, J”7H2), 5.74 (IH, dd.

J=7Hz, 10Hz), 6.07(IH, d, J=1
0H2) Reference Example 26 3-tert-butyldimethylsilyloxy-1-(4
-chlorophenyl)thio-1-butene 3-tert-butyldimethylsilyloxy-1-butyne (5,587?
, 30.3 mmol) and parachlorophenylmercaptan (4,504y, 81.14 mmol) was stirred at 78° C. for 1.5 hours. After cooling, this mixture was subjected to column chromatography (silica gel 100y, 0
．． Eluted with hexane containing 0.01% triethylamine)
Purification was performed to obtain 4.254y (43%) of the title compound.

NMR (CDC13) δ: 0.07 (6H,S)
, 0.90 (9H, S), 1.23 (1,9H, d, J
=6.4Hz), 1.25(1,1H.

d, J=6.4Hz), 4.76(IH,m),
5.86 (0.37H, dd, J=7.8Hz, 9.5
Hz), 5.91 (0.61H, dd, J=4.9H
z.

14.9Hz), 6.06 (0.87H, d, J=9.
5Hz), 6.29 (0.68H, d, J=14.9H
z), 7.24 (5H,S) Reference Example 27 (E) -1-tert-butylthio-3-oxo-1
-Butene l-methoxy-3-oxo-1-butene C2,69゜2
6 mmol), tert-butyl mercaptan (9 m
l, 26.7 mmol), para-toluenesulfonic acid (2
A mixture of 6 fng) was dissolved in 40 rnl of benzene, and the mixture was stirred at 50-55° for 2 hours. After cooling, the solvent was distilled off, and the resulting crude product was purified by distillation to obtain the title compound. 1.5y (36.5%) was obtained.

Boiling point: 180-150°CNMR at 9 mmHg (
CDC13) δ: 1.45 (9H, S), 2.20 (8
B, S), 6.28 (IH, d, J=15Hz),
7.18 (LH, d.

J=15Hz) Reference Example 28 [F])-3-oxo-1-phenylthio-1-butene ■-Methoxy3-oxo-1-butene (51,38p
, 0.51 mol), thiophenol (6ad, 0.6
1 mol) and p-toluenesulfonic acid (1y) in the same manner as in Reference Example 27 to obtain the title compound at 88.84? \、
(97%) obtained.

Boiling point: 110-112°CNMR at 2 mmHg (
CD (J3)a: 2.15 (9H, S), 5.97
(LH, d, J=15Hz), 7.65 (LH, d,
J=15H2) Reference Example 29 (E)-1-(4-methylphenyl)thio-3-oxo-1-butene l-methoxy-3-oxo-1-butene (0,095P
, 1 mmol), 4-methylphenylmercaptan (0
, 127y, 1 mmol) and p-toluenesulfonic acid (1~) in the same manner as in Reference Example 27 to give the title compound 0.
．． 096y (50%) was obtained.

NMR (CDC13') δ: 2.05 (3H,S), 2
．． 80 (8H, S), 5.8 (IH, d, J=15H
2), 7.1 (4H, m), 7.55 (LH, d,
J=15Hz) Reference Example 80 1-(4-chlorophenyl)thio-3-oxo-1-butene l-methoxy-3-oxo-1-butene (5,00P,
50 mm IJ mol L 4-chlorophenylmercaptan C
7,959,55 mmol) and p-toluenesulfonic acid (801y1g, 0.15 mmol) in the same manner as in Reference Example 27 to obtain 6.8y (51%) of the title compound.

NMRCCDCI8) δ: 2.2 (1,5H,S
), 2.8 (1,5H, S ), 5.9 (0,5H,
d, J=15Hz), 6.4 (0,5H, d.

J=9Hz, ), -7,1(0,5H,d, J=9H
z ), 7.35 (4H, m), 7.6 (0,5H, d
, J=15Hz) Reference Example 31 3-oxo-1-triphenylmethylthio-1-butene l-methoxy-3-oxo-1-butene (Iy.

10 mmol), triphenylmethyl mercaptan (2
, 76y, 10 mmol) and p-toluenesulfonic acid (1 (lv)) in the same manner as in Reference Example 27 to obtain the title compound (1.549C45%).

NMR (CDC18) δ: 1.94 (3H,S), 6.
16 (0.5H, d, J=11Hz), 6.28 (
0.5H, d, J=16Hz), 6.74 (0.5H,
d, J=11Hz), 7.13(0,5H,d, J=1
6Hz), 7.16-7.45 (15H, m) Reference Example 32 (E) -8-tert-butyldimethylsilyloxy-t-tert-butylthio-1-butene (a) (E)
-1-tert-Butylthio-3-oxo-1-butene (1,58y, 10 mmol) was dissolved in methanol (20 mmol).
Sodium borohydride (0.19y, 5 mmol) was gradually added under stirring at 0°C.

After stirring for 80 minutes at 0°C, 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 (1,6y) was used without purification.

(b) the above crude product (1,6), tert-butyldimethylsilyl chloride (1,FM', 10 mmol),
Triethylamine (1,4mf, 10mmol), 4-
A mixture of dimethylaminopyridine (45fng) was dissolved in dimethylformamide (10d) and the mixture was stirred at room temperature for 20 hours. Dilute the reaction with ether,
Washed sequentially with water, dilute hydrochloric acid, saturated sodium bicarbonate, and saturated salt, dried over anhydrous magnesium sulfate, and concentrated.
The resulting composition was distilled to yield the title compound at 2.05' (73
%)Obtained.

Boiling point: 120-130°ONMR at 0.5mmHg
(CDC7?3) a: 0.07 (6H, S), 0.9
1(9H,S), 1.20C8H,d, J=7Hz)
, 1.83 (9H, S), 4.30 (IH, quint
, J=7Hz), 5.78(LH, dd, J=7
Hz, 15Hz), 6.26 (LH, d, J=15
Hz) Reference Example 33 [F])-3-tert-butyldimethylsilyloxy-1-7enylthio ■-butene [F])-3-oxo-1-phenylthio-1-butene (180y, 1 mol) and hydrogen Sodium boronate (19
y) in the same manner as in Reference Example 32 (a) to obtain a crude product (180y).

Crude product (181'), tert-butyldimethylsilyl chloride (150y, 1 mol), triethylamine (
IOIy, 1 mol) and 4-dimethylaminopyridine (
3,8y) was operated in the same manner as in Reference Example 82(b) to obtain 223.5y (75%) of the title compound.

Boiling point: 150-160'CNMR at 0.9mmHg
(CDC63) J: 0.09 (6H, S), 0.92
(9H, S), 1.25 (IH, d, J=7Hz), 4
．． 87 (LH.

quint, , J=7Hz), 5.82 (IH, dd.

J=7Hz, 15Hz), 6.33 (IH, d.

J=15Hz), 7.22 (5H, m) Reference Example 34 (E) -3-tert-butyldimethylsilyloxy-1-(4-methylphenyl)thio i-phthene (E)
-1-(4-methylphenyl)thio-3-oxo-1-
Reference example 82 of butene (11) and sodium borohydride
Operate in the same manner as in (a) to obtain 0.25y of crude product 1
child .

Refer to crude product (lal (0,259), tert-butyldimethylsilyl chloride (0,21y, 1.4 mmol), triethylamine (0,11', 1.4 mmol) and 4-dimethylaminopyridine (lorng) Working in the same manner as Example 82 (b), the title compound was prepared at 0.2
5y (68%) was obtained.

NMRCCDC18)/j: 0.08 (6H,S),
0.90 (9H, S), 2.32 (8H, S), 4.8
5 (IH, m), 5,80 (LH, dd, J=7H2
, 16H2), 6.3 (IH, d, J=16Hz),
7.1 and 7.24 (respectively 2H, AB type d, J = 4Hz
) Reference Example 35 3-tert-butyldimethylsilyloxy-1-(4
-chlorophenyl)thio-1-butene 1-(4-chlorophenyl)thio-3-oxo-1-butene (15y, 7
0 mmol) and sodium borohydride (liy, 27
mmol) was treated in the same manner as in Reference Example 32(a) to obtain 14.8y of crude product.

The above crude product (14,8y), tert-butyldimethylsilyl chloride (18y, 70 mmol), triethylamine (8,7y, 87 mmol) and 4-dimethylaminopyridine (12) were added in the same manner as in Reference Example 82 (b). 14.93y (64.5%) of the title compound was obtained.

The NMR spectral data and the Rf value obtained by thin layer chromatography of this product completely matched those obtained in Reference Example 26.

Reference Example 36 (2)-←)-3-hydroxy-1-paratoluenesulfonyloxybutane (R) = (→-1,8-butanediol (10,00
y.

0.111 mol) and pyridine (9,66y, 0.12
para-toluenesulfonic acid chloride (23,27 gt, 0
．． 122 mol) was added gradually at 80°C. The mixture was stirred at room temperature for 15 hours and the reaction was washed with cold water (200 m/ml).
) moved inside. The methylene chloride layer was separated, and the aqueous layer was extracted with methylene chloride. The methylene chloride layer also contains water,
It was washed successively with dilute hydrochloric acid, saturated sodium hydrogen carbonate, and saturated sodium chloride. It was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography to obtain the title compound as a colorless oil.
1.68y (80%) gained rko.

[α]"0 Knee 11.5° (C22.8.Chloroform) IR"": 3400.1605.1860.1180
．． 950.900ax NMR (CDC13) δ: 1.19 (8H, d,
J=7.0Hz), 1.60-2.10 (2H, m)
, 1.87 (LH, S), 2.45 (3H.

S), 3.65-4.31 (2H, m), 7.53 (4
H.

q, J=8.0Hz) Reference Example 37 @)-←)-3-hydroxy-■-methanesulfonyloxybutane (2)-←)-1,8-butanediol (0,500y
.

5.55 mmol), pyridine (0,483y, 6.
1 mmol) and methanesulfonyl chloride (0,69
9y.

6.10 mmol) was operated in the same manner as in Reference Example 36 to obtain 0.392y (42%) of the title compound as a colorless oil.

[α] 20 Knee 26.8° (C = 1.0.Chloroform) IRfilm: 3400, 2970, 1620.1
8 (0,1170°ax 4O NMR (CDC13) δ: 1.22 (8H, d,
J=7.0Hz), 1.65-2.10 (2H, m)
, 2.78 (IH, S), 3.00 (3) L S),
3. ．． 90 (IH, m), 4.20-4.50 (2H
, m) Reference Example 38 (2)-H-3-hydroxy-1-phenylthiobutane@)-H-3-hydroxy-1-paratoluenesulfonyloxybutane (2,00y, 8.19 mmol)
and sodium thiophenolate (1,30y, 9.
A mixture of 82 mmol) and tetrahydrofuran (40 me) was heated under reflux for 1 hour, and after cooling, water was added to the reaction mixture and 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 Examples 39-44 Sodium thiophenolate derivatives and ■)-(→
-3-Hydroxy-1-paratoluenesulfonyloxybutane was operated in the same manner as in Reference Example 38 to obtain the sulfide compounds shown in the table.

[Reference Example 45] (R) -(-) -3-tert-butyldimethylsilyloxy-1-phenylthiobutane (R) -(-1-3-hydroxy-1-phenylthiobutane (1,44 g, 7 .90 mmol), jar
t-Butyldimethylsilyl chloride (1,11F, 8.
69 mmol), 4-dimethylaminopyridine (1,0
6F, 8.69E mol) was dissolved in dimethylformamide (10 mN) and stirred for 3 hours. The reaction mixture was diluted with ether, washed successively with water, diluted hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride, and dried over anhydrous magnesium sulfate. The residue obtained by concentration was purified by silica gel column chromatography to obtain the title compound.

[α]20: -21,30° (C=2.8.Chloroform) I R""" 2950.2980.2890
．． 2850, 1580, 1480° (to)''l.

1255.1180.835 NMR (CD(J?3)J: 0.06(6H,S)
, 0.89 (9H,S).

1.14 (3H, d, J=6.0Hz), 1.53
-1.95 (2H, m), 2.81-3.14 (2H,
m).

8.90 (lH, m), 7.22 (5H, br, S).

The following compound was synthesized in the same manner as in Reference Example 45.

(Margins below) [Reference Example 52] (R) -(-) -8-ter t-butyldimethylsilyloxy-1-butanol (R) -(→-3-jert-butyldimethylsilyloxymethyl methylbutyrate (2, 323 g, 0.01 mol) in ether (20 mg) and the solution was dissolved in ether (323 g, 0.01 mol) in ether (20 mg).
Lithium aluminum hydride (0 mg) suspended in
, 380 g, 0.01 mol) at -78°C. The mixture was stirred at -78°C for 2 hours, and at the same temperature, 5% anhydrous sodium sulfate was added to decompose excess lithium aluminum hydride. Insoluble matter was removed, and the limbs were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the title compound as a colorless oil (2.01.0198%).

20 ・ [Q! ] , -23,5° (C=2.064.chloroform)"Im: 8820,2945.2910,
2880, 2850° 1R (rl 1460, 1455, 1860, 1245, 1
130.

1095.82O NMR: 0.03 (3H, S), 0.04 (3H,
S), 0.84 (9H, S).

1.14 (3H, d, J=5.94Hz), 1.52-
1.79 (2H.

772), 2.81 (LH, br, S), 3.58-
3.82 (2H, 777).

3.98-4.10 (LH, m) [Reference Example 53] (R) -(-) -3-tert-butyldimethylsilyloxy-1-paratoluenesulfonyloxybutanecy-1-butanol (39) ( 1,022 F, 5 mmol) was dissolved in pyridine (10 ml) and para-toluenesulfonyl chloride (0,953 F, 5 mmol) was slowly added to this mixture at O'C. mix 20
Stir for an hour, dilute in ether (100 mn), water,
It was washed successively with dilute hydrochloric acid, saturated sodium bicarbonate, and saturated sodium chloride. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (40).
1.747197.5%) was obtained.

[α]20: -18,0° (C=1.144.Chloroform) IR""": 2955.2945,29
00,2852,1600°1475,1463,18
60,1260,1190°1008.940.89O NMR (CDCl2) δ: -0,04 (8H,S),
0.00(lIH,s).

3.88-9.95 (IH, l, 1.61-1.84
(2H, m), 2.48 (3H, S), 183-3.9
5 (LH, 1, 4, 09 (2H, t, J = 5.94),
7. (2(2H, d, J=8.58).

7.77(2I(,d,J=8.58) [Reference Example 54] (R)-(-1-8-benzyloxy-1-(4-chloro(ta-(-1-8-hydroxy- I-(4-chloro)phenylthiobutane (1,00 f, 4.61 mmol) was dissolved in tetrahydrofuran (20 mg) and sodium hydride (5,58 mmol) was slowly added.

Then benzyl bromide (0.79g, 4.61E mol)
was added and the mixture was heated under 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 1.28f (87%) of the title compound as a colorless oil.

20.

[α], -25,5° (C=2.5.Chloroform) IRfil”: 2960.2920,2850
．． 1475.1090.810NMRCCDC(Is
) a: 1.22 (3H, d, J=6.0
Hz), 1.58-2.08 (2H, m),
2.88-3.17 (2H, m) 8.61 (LH,
1, 4, 47 (2H, dd, J=10Hz, 12.5
Hz), 7.15 (4H, S).

7.28 (5H, S) [Reference Example 55] (R) -(→-3-acetoxy1-(4-chlorophenyl)thiobutane (R) -(-1-3-hydroxy-1-(4-chloro) Phenylthiobutane (1,00g, 4.6R mol)
and pyridine (0.44f, 55E mol) was dissolved in tetrahydrofuran (107711) and heated to O゛C.
Acetyl chloride (0.44F, 55 mmol) was added at . After stirring at room temperature for 30 minutes, methylene chloride was added to the reaction mixture, washed with water, and dried over anhydrous magnesium sulfate. The residue obtained by concentration was purified by silica gel column chromatography to obtain the title compound as a colorless oil with a concentration of 0.97
% (81%).

[α]20: -1,0° (C=4.0.Chloroform) IR, 2960, 2920, 1735, 1480, 1
370° (J”-1 1240,1095,81O NMR, (CDCl5) δ: 1.25 (3H, d,
J-6,0Hz), 1.70-1.95 (2H,77
i1), 2.03 (3H,S).

2.8O-100 (2H, 7F+), 5.00 (IH.

m), 7.25(4H,S) [Reference Example 56] (R)-(-1-3-(2,2,2-trichloroethyloxy)carbonyloxy-1-(4-chlorophenyl)thiobutane (R ) -(-1-8-hydroxy-1-(4-chloro)phenylthiobutane (29) (0,50ff,
2.31 mmol) and pyridine C0,22f, 2.77
0.88f (97%) of the title compound was obtained as a colorless oil from 2.2.2-trichloroethylchloroformate (0.540f, 2.54 mmol).

[α] 20 Knee 5.6° (C=1.4.Chloroform)
Film.

IR, 2960, 1755, 1475, IJ80.12
50°1090,81O NMR (CDCff3) δ: 1.82 (3H, d, J
=6.0Hz), 1.65-2.20(2H,77i1
), 1.78-8.11 (2H.

m), 4.71 (2H, S), 4.90 (LH, m).

7゜20(4H,S) [Reference Example 57] (Mother -(-) -8-(4-nitrobenzyloxy)carbonyloxy-1-(4-chloro)phenylthiobutane (R+ -(-1-3 -Hydroxy-1-(4-chloro)phenylthiobutane, pyridine, and paranitrobenzyloxycarbonyl chloride were operated in the same manner as in Reference Example 55 to obtain the title compound as a colorless oil.

20° [α], -11,9° (C=28.chloroform) IR
,2960,1755,1475,1380,1250
°c, -1 1090,81O NMR (CDCff3) δ: 1,31 (3H, d, J
=6.0Hz), 1.60-2.15(21(,m),
2.80-110. (2H.

m), 4.15 (IH, m), 5.20 (2H, S)
.

7.20 (4H, S), 7.80-7.65 (2H.

m>, 8.05-8.30 (2H, m) and Reference Example 58
] (R) -(→-8-tert-butyldimethylsilyloxy-1-phenylthio-1-butene (al (R1-←18-tert-butyldimethylsilyloxy-1-phenylthiobutane (2,2Of.

7.42 mmol) and N-chlorosuccinimide (1
, 09F, 8.16 mmol) was dissolved in carbon tetrachloride (
50 ml> and stirred at room temperature for 1 hour. The insoluble material was divided into mouths, the mouth liquid was concentrated, the residue was dissolved in dimethylformamide (20 ml), and lithium chloride (0.35N
, 8. 16 mmol), lithium carbonate (0,55 f
, 7.42 mmol) and the mixture was heated to 80°C.
The mixture was stirred for 2 hours. The insoluble material was then divided into mouthfuls, water was added to the oral fluid, 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 obtain 1.581f (72%) of the title compound as a colorless oil. The compound was a mixture of E/Z=2.5/L.

xRf'4. ”:29so, 295s, 2sgo, 1
590,1490゜0m 1450, 1265, 1100.845.790
, 745.

NMR (CDCe3) δ: (E form) 0.06 (6H, S
), 0.91 (9H.

S), 1.25 (3H, d, J=6.0Hz).

4.22 (LH, m), 5.92 (IH, dd, J=6
．． 0 Hz, 15.5 Hz), 6.38 (LH, dd.

J-1,4Hz, 15.5Hz), 7.25-7.42
(5H, m) (2 bodies) 0.08 (6H, S), 0.92 (9H, S
), 1.26 ([(, d, J=6.0Hz), 4.81
(LH, 772), 5.86 (LH.

dd, J”8.0 Hz, 9.5 Hz),
6.18 (LH.

dd, J-1,5Hz, 9.5Hz), 7.25-7
．． 42(5H,7F+) (b) (R)-() -8-tert-butyldimethylsilyloxy-1-phenylthiobutane (1,0O
f, 8.22 mmol) in chloroform (5 ml!
>1), sulfuryl chloride (0,
44y, 3.22 mmol) was added thereto, and the mixture was stirred at room temperature for 1 hour.

The reaction was concentrated and the residue was dissolved in dimethylformamide (5 m
Lithium chloride A (0,17y) and lithium carbonate (0,27y) were added, and the mixture was stirred at 80°C for 2 hours. Extracted into ether. The ether layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography to obtain 0.629 (62%) of the title compound as a colorless oil.

The spectral data of this product completely matched that obtained in (a).

The following compound was synthesized by the same operation as in Reference Example 58.

Claims (1)

[Claims] 1) General formula ▲ Numerical formulas, chemical formulas, tables, etc. 1-butenyl sulfide derivative having a ring-substituted phenyl group) is reacted with chlorosulfonyl isocyanate, or if necessary, after reacting with chlorsulfonyl isocyanate, the protecting group of the amino group is removed. A method for producing a 2-azetidinone derivative having the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 and R^2 have the same meanings as above, and R^3 represents a hydrogen atom or a chlorosulfonyl group). 2) The group R^2 is a triphenylmethyl group, a t-butyl group,
2. The production method according to claim 1, which is a phenyl group, a lower alkylphenyl group, a lower alkoxyphenyl group, a nitrophenyl group, or a halogen-substituted phenyl group. 3) The production method according to claim 1, in which a weak base is used to deprotect the amino group. 4) The production method according to claim 1, in which a reducing agent is used to deprotect the amino group. 5) The production method according to claim 1, wherein the 1-butenyl sulfide derivative is an optically active derivative.