JPS6287559A - Novel halosulfone and production thereof - Google Patents

Abstract

NEW MATERIAL:The halosulfone of formula I [R<1> is (substituted) phenyl; R<2> is H or lower acyl; X is halogen]. EXAMPLE:6-Chloro-1-hydroxy-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexe n-1-yl)-9- phenylsulfonyl-2,7-nonadiene. USE:Useful as a synthetic intermediate for vitamin A or its acetate useful as a medicine and feed additive. It can be produced easily in high yield from a raw material available easily at a low cost. PREPARATION:The compound of formula I can be produced by reacting a novel hydroxysulfone of formula II (R<3> is lower acyl) with a halogenation agent (e.g. thionyl chloride) in a solvent such as benzene in the presence of a tertiary amine at 10-30 deg.C and, if necessary, hydrolyzing the reaction product.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a compound of the general formula (wherein R1 represents optionally substituted phenyl Me and R2 represents a hydrogen atom or a lower afur group).

X represents a halogen atom. ) and a method for producing the same.

Halonurphone represented by the general formula (1) provided by the present invention is useful as a synthetic intermediate for vitamin A or its acetate, which is used as a medicine and feed additive, as described below.

[Conventional technology]

It is conventionally known that vitamin A or its acetate can be produced by the following method.

[In the formula, Ac is 7-t! f A, represents a group; H
elveticaChemica Acta, 30+
1911 (1947)] Vitamin A hydrolysis
, Tami7A acetate [In the formula, Ph represents a phenyl group, X represents a halogen atom, and Ae represents an acetyl group; Chemie
Ingeniuor Teehnik, ! 5, 6
46 (1973)] [The stone problem that the invention seeks to solve] The above-mentioned conventional methods for producing vitamin A or its acetate all use β-ionone as a starting material. It is manufactured industrially by ring-closing reaction using a large amount of ion, but it is not always available at a low price because the yield is not very high and it is difficult to separate by distillation from by-products such as α-iono. Not an industrial raw material.

Therefore, one object of the present invention is to develop a new vitamin A1 and its acetate which can be easily produced in good yield from inexpensive and easily available industrial raw materials and which can be easily derived in good yield and into vitamin A1 and its acetate. to provide the compound. Another object of the invention is to provide a method for producing the new compounds.

[Means for solving problems]

According to the present invention, the above object is achieved by providing a halosulfone of the general formula CD, wherein R1 is as defined above and sRs represents a lower acyl group. ) to the hydroxysulfone represented by /
- This is achieved by providing a method for producing a halosulfone represented by the general formula (I), which is characterized in that a halogenating agent is applied and the product is hydrolyzed as necessary.

R1 in the above general formula. R'', R3 and
Lower alkyl groups such as 7'α-biru, n-7'-biru, i-butyl, n-butyl; halogen atoms such as chlorine, bromine, iodine; and methoxy, ethoxy, l-propoxy, n-propoxy, l- Examples include lower alkoxy groups such as butoxy and n-butoxy. Further, the substituent may be located at any position such as the ortho position, the meta position, or the rose position, and may be one or two or more. R2 represents a hydrogen atom or a lower acyl group such as formyl, acetyl or propionyl. R3 represents the same lower acyl group as R2. Further, %X represents a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom.

By allowing a halogenating agent to act on the hydroxysulfone represented by the general formula (II), a halosulfone in which R2 is a lower acyl group in the general formula (1) can be produced. As the halogenating agent, for example, thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide, etc. are used. The amount of the halogenating agent to be used is preferably about 1 to 3 halides per hydroxysulfone represented by the general formula (Il). This reaction is preferably carried out in an organic solvent in the presence of a tertiary amine. Examples of organic solvents include hydrocarbons such as benzene and toluene; methylene chloride, 1.2
- Halogenated hydrocarbons such as dichloroethane; ethers such as diethyl ether and diisopropyl ether; and esters such as ethyl acetate and butyl acetate. The amount of organic solvent used is preferably such that the concentration of hydroxysulfone represented by general formula (II') is about 0.1 to 5 mol/l. As the tertiary amine, for example, pyridine, triethylamine, etc. are advantageously used. These tertiary amines have about 0.01 to 50% of the hydroxysulfone represented by the general formula (■).
Although it is preferable to use an equivalent amount, the tertiary amine can also serve as an organic solvent by using an excess amount. The reaction is preferably carried out within a temperature range of about -10°C to 30°C. In the general formula (I'') obtained by the above reaction, R2
The separation of rosulfo/ in which is a lower acyl group can be carried out by a conventional method. For example, after pouring the reaction mixture into water, saturated aqueous sodium bicarbonate solution, dilute sulfuric acid, etc., benzene, methylene chloride, diethyl ether, etc.
Extract with ethyl acetate etc., wash the extract with water and dry with anhydrous sodium sulfate.

Next, low-boiling substances were distilled off from the extract under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain general formula (1) i? Halosulfones in which R2 is a lower acyl group can be isolated.

In general formula (1), R2 is a hydrogen atom...rosulfone is produced by hydrolyzing halosulfone in general formula (1) obtained by the above method, in which R2 is a lower acyl group. This hydrolysis reaction can be carried out by reacting a halosulfone in which R2 is a lower acyl group in general formula (1) with an alkali metal hydroxide or carbonate. As the alkali metal hydroxide or carbonate, for example, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, etc. are used.

The amount of alkali metal hydroxide or carbonate to be used is determined by the general formula (
Approximately 1 to 2 equivalents are suitable for sulfo/ in which R2 is a lower acyl group in 1). This reaction is preferably carried out in a solvent, such as alcohols such as methanol and ethanol, or mixtures of these alcohols with water and/or hydrocarbons such as benzene and toluene. The amount of solvent used is preferably such that the concentration of halosulfone in which R2 is a lower acyl group in general formula (1) is about 0.1 to 10 mol/l. When using a mixture of alcohols and water and/or hydrocarbons as a solvent, ascites and/or hydrocarbons are preferably used to an extent that does not cause phase separation in the reaction system. The reaction is suitably carried out within a temperature range of about -10°C to 30°C.

Six general formulas (R in 1'l) obtained by the above reaction
A halosulfone in which 2 is a hydrogen atom can be separated by a conventional method. For example, saturated ammonium chloride aqueous solution, dilute hydrochloric acid, dilute sulfuric acid, etc. are added to the reaction mixture to neutralize the remaining alkali metal hydroxide or carbonate, and if necessary, the alcohol used as a solvent is distilled off. After adding water to the residue, it is extracted with benzene, methylene chloride, diethyl ether, ethyl acetate, etc., and the extract is washed with water and dried over anhydrous sodium sulfate. Next, by distilling off the low-temperature compounds from the extract under reduced pressure and subjecting the residue to silica gel column chromatography, the halosulfone in which R2 is a hydrogen atom in general formula (I) can be isolated.

Hydroxysulfo/ represented by the general formula (II) used as a raw material is a new compound, for example, a compound represented by the general formula (wherein R1 is as defined above) and the general formula % formula % () (In the formula, R3 is as defined above.) It is produced by reacting the compound represented by the above in the presence of an anionizing agent. In the reaction between the compound represented by the general formula ([11) and the compound represented by the general formula (■)], the anionizing agent to be present in the reaction system is A base that generates a carbanion at the α-position, such as organic lithiums such as methyllithium and n-butyllithium; Grignard reagents such as methylmagnesium chloride, ethylmacnesium chloride, and ethylmacnesium chloride; lithium hydride; Alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal amides such as lithium amide, sodium amide and potassium amide; lithium methoxide, sodium methoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, etc. These include lower alkoxides of alkali metals.

The amount of anionizing agent used is about 0.2 to 1 molar equivalent to the compound represented by the general formula (Ill'l).
is an aliphatic or aromatic hydrocarbon such as hexane, heptane, benzene, toluene; linear or cyclic ether such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane; dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, hexamethylphosphoryltri Preferably, it is carried out in an organic solvent such as an amide. The solvent is appropriately selected in combination with the anionizing agent. The reaction is usually carried out within a temperature range of about -100°C to 150°C, and is advantageously carried out under an inert gas atmosphere such as urium, nitrogen, or argon. Although it varies depending on the agent, solvent, reaction temperature, etc., for example, using an anionizing agent and n-butyllithium in tetrahydrofuran solvent, about -
When the reaction is carried out at a temperature of 78°C to -50”C, the
It's time.

The compound represented by the general formula (11) can be easily produced in good yield from linalool, which is an inexpensive industrial raw material. For example, a compound of the general formula (■) (in which R1 is a phenyl group) can be produced by the following method.

In other words, geranyl chloride is produced by treating linalool with thionyl chloride. :1 Geranyl phenyl sulfone is obtained by reacting the geranyl chloride with sodium benzene sulfinate. β-cyclogeranylphenyl sulfone is obtained by carrying out a ring-closing reaction in the presence of a geranylphenyl sulfone acid catalyst, such as a mixed acid of sulfuric acid and acetic acid. In addition, during the ring-closing reaction, β
-α- isomer of cyclogeranylphenyl sulfone
Although cyclogeranylphenyl sulfone may be a byproduct, high purity β-cyclogeranylphenyl sulfone can be omitted by crystallizing the mixture of both products in a solvent such as hexane.

In addition, α-cyclogeranylphenyl sulfone is converted into the desired β-cyclogeranylphenyl sulfone by returning it to the above-mentioned closure reaction system. The total yield of β-cyclogeranylphenyl sulfone from linalool is typically about 80%.

The compound represented by the general formula (1'i') can be easily prepared by reacting, for example, selenium dioxide with the lower carboxylic acid ester of geraniol (Tetr
ahedron Letters, 281 (197
See 3)].

The halosulfone represented by the general formula (1) can be easily converted into vitamin A, and further into vitamin A acetate, in good yield by, for example, the following method.

(In the above formula, R1, R2 and X are as defined above.) That is, vitamin A can be obtained by treating halosulfone represented by general formula (1) with a base. As the base, for example, potassium alkoxide such as potassium methoxide, potassium ethoxide, potassium n-butoxide, potassium hydroxide, etc. are used. The amount of the base to be used is preferably about 2 to 20% # relative to 1 mole of lerhalosulfone represented by the general formula (1). This reaction is preferably carried out in an organic solvent, and hydrocarbons such as hexane, cyclohexane, benzene, and toluene are used as the organic solvent. The amount of the organic solvent used is preferably such that the malleability of the no-losulfone represented by the general formula (1) is about 0.05 to 1 mol/l.

Preferably, the reaction is carried out within a temperature range of about 10-120°C. After the reaction is completed, a precipitate is filtered from the reaction mixture as required, and then water, a saturated ammonium chloride aqueous solution, etc. are added to the reaction mixture, and the organic layer is separated. Vitamin A can be obtained by subjecting the obtained organic layer to purification means such as recrystallization and column chromatography.

Vitamin A acetate can be derived by acetylating the vitamin A thus obtained by a conventional method. This acetylation reaction is performed on the organic layer containing vitamin A separated from the reaction mixture obtained by the above-mentioned vitamin A production reaction or on the vitamin A separated and purified from the organic layer, preferably in an organic solvent. This is carried out by using an acetylating agent in the presence of a class amine. Examples of acetylating agents include acetic anhydride,
Acetyl chloride etc. are used. The amount of the acetylating agent to be used is preferably about 1 to 10 times the amount of vitamin A. Examples of organic solvents include hydrocarbons such as benzene and toluene;・Rogenated hydrocarbons; ethers such as diethyl ether and diisopropyl ether; esters such as ethyl acetate and butyl acetate are used, and these organic solvents have a vitamin A concentration of about 0.1 to 5 mol/l! It is preferable to use an amount of about 1 to 10 equivalents to vitamin A. Examples of tertiary amines include triethylamine and pyridine. However, by using an excess amount, the tertiary amine can also serve as an organic solvent. The reaction is about -10
It is preferable to carry out the process at a temperature in the range of 1'C to 30'C.

After the reaction is completed, the precipitate is filtered from the reaction mixture if necessary, and then dilute sulfuric acid, water, a saturated aqueous sodium bicarbonate solution, etc. are added to the reaction mixture, and the layer is separated. Vitamin A acetate can be obtained by subjecting the obtained organic layer to purification means such as recrystallization and column chromatography.

〔Example〕

Hereinafter, we would like to congratulate the present invention'5rO on the following examples.The present invention is not limited by these embodiments. -8
-Hydroxy-3,7-dimethyl-9-(2,6,6-
Dolimethyl-1-cycloheyacen-1-yl)-9-phenylsulfonyl-2,6-)f scene 7.38
t (15 m, mol), benzene:/60 tnl and 12 ml of pyridine were added, 1.32 mA' of thionyl chloride was added dropwise while stirring in an ice-water bath, and then 16 mA' of thionyl chloride was added at room temperature.
Stir the hole for an hour. To the ice-cooled reaction mixture VC, a diluted acid solution was added, and the organic layer was separated. The aqueous layer was extracted twice with 7 Otnt and 7 Otnt in a total of 140 m4, and 7/:
These organic layers were combined, washed successively with ice-cooled 3% aqueous sulfuric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off from the organic layer, and the residue was purified by column chromatography using silica gel (eluent: a mixture of hexane and ethyl acetate in a volume ratio of 5:1) to obtain a white waxy substance.7. I got 182. According to the instrumental analysis data shown below, this product was found to be
-cyclohexen-1-yl)-9-phenylsulfonyl-2,7-nonadiene. Yield 9
4%.

CD C1C 13N δ(CH3)3SiO8i(CH3)3 '0
．． 72-2.05 (m, 28)i), 4.17-4.
57 (m, 4H).

5.23 (t, 1M), 5.88 (m, 1) 1),
7.35-7.91 (r!1°5H) IR (film) ν (crn-1): 1745 (C
=OL1150(SO2), 685(C6H5)F
D-MS m/e: 506 (M”), 507 (M
++1)=470(M"-Hα), 365(M"-
C6H5SO2) Potassium hydroxide (purity 85%) 0.0226 t (0,342
mmol) and methanol were added and stirred at room temperature to prepare a methanol solution of potassium hydroxide.

This solution Kl-acetoxy-6-chloro-3,7-dimeter-9-(2,6,6-)rimether-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,7-
0.0373 f (0,0736 mmol) of Nonagene was added to the mixture, and a solution soaked in a mixed solution of 2 rnl of '-ru and 2 rnl of benzene was added, followed by stirring in an ice water bath for 30 minutes. Add saturated ammonium chloride aqueous solution to the reaction mixture,
The solvent was distilled off, water was added to the solution, and the mixture was extracted with diethyl ether. The extract was washed with a saturated aqueous ammonium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off from this extract, and 0.02% of a yellow oil was obtained.
Obtained 97F. According to the instrumental analysis data shown below, this product is 6-chloro-1-hydroxy-3,7-dimethyl-9-(2,6,6-drimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2, 7-, /
I recognized that 6 with f-diene. Yield 87%.

CDα3''R'(CH3)3SiO8i(CHs)3'0.
75-2.20 (m, 26) 1), 4. (16c
d, 2H) +4.21 to 4.55 (m, 2H),
5.30 (t, LH).

5.91 (m, LH), 7.36-7.90 (
m, 5H) IR (film) y (crn'): 33
00(OR), 1745(C=0)-1150(S02
), 685(CsHs)FD-MS m/e: 4
65 (M"+1), 428 (M"-HQ').

323 (M+-C6H5SO2) Example 2 1-acetoxy-8-hydroxy-3,7-dimenal-9-(2,6,6-drimethyl-1-cyclohexen-1-yl)-9-phenyl in a 50 d round-bottom flask. Sulfonyl-2,6-)fje: /2.44? (5,0
0 mmol), 0.12 pyridine and 201 d of methylene chloride, and while cooling in an ice water bath, add 0.12 pyridine and 201 d of methylene chloride.
．． Drop 29 ml (3.3 mmol) 1. , and stirred at the same temperature for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. Wash the extract with saturated aqueous sodium bicarbonate solution,
It was dried with anhydrous magnesium sulfate.

The solvent was distilled off from the extract, and the remaining silica gel was used for nine-column chromatography (mixture of hexane and ethyl acetate at a ratio of 9:1 to 5:1).
Purified from vc, l-7-e togin-6-chloro3,
7-dimethyl-9(2,6,6bdimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,
1.27y of 7-nonadiene was obtained. Yield 50%.

Example 3 50i/! 1-acetoxy-8-hydroxy-3,7-dimether-9-(2,6,6-drimethyl-i-7chlorohexen-1-yl)-9-phenylsulfonyl-2,6-nonacyl: r- 2.44y (
Add 0.12f of pyridine and 2r)ml of methylene chloride, and while cooling in an ice water bath, add 0.31rnA' (3.3rnmol) of phosphorus tribromide.
) was added dropwise and stirred at the same temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The extract was washed sequentially with a saturated sodium bicarbonate water bath gauze and a saturated sodium chloride aqueous solution.

It was dried with anhydrous magnesium sulfate. The solvent was distilled off from the extract, and the residue was subjected to six-column chromatography using silica gel (eluent: hexane and enal acetate in a volume ratio of 9
A white waxy substance 2.34F was obtained.

According to the following instrumental analysis data, this product is 1-acetoxy-2-promo 3,7-cymethyl-9-(2,6,6
-Drimether-1-cyclohexen-1-yl)-9-
It was confirmed that it was phenylsulfonyl-2,7-nonadiene. Yield 85%.

CDα3 NMR” (CH3)3SiO8i (CIXL3)31.
71-2. C13 (m, 28M), 4.32~4
．． 57 (m, Ji).

5.24 (m, In), 5.90 (m, 1) l), 7.
4:3-7.90 (m.

5h) IR (film) ν (IM'): 1730 (C=0),
1135 (S02).

670 (C5) is) FD-MS mle: 550 (M”), 47 (
1 (M”-HBr).

409 (M''-C6H5S (J2) Example 4 50 ml round-bottom flask - 1-acetoxy-8-hydroquine-3,7-dimethyl-9- (2,6,6-trimethyl-1-cyclohexen-1-yl) -9-(p
-)lyl)sulfonyl-2,6-nonadiene 61010
1l 1.26mmol), Virigi 70.96m
1 (12 mmol) and benzene 15rlLl, and while cooling in an ice water bath, add 0.11i (12 mmol) of f-onyl chloride.
, 5 mmol) and then stirred at room temperature for 16 hours. IN hydrochloric acid and benzene were added to the reaction mixture to separate the layers.

The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was removed from it to obtain 630 kg of a yellow oil. According to the following instrumental analysis data, this product is 1-acetoycin-6-chloro-3, fucymethyl-9- (2,6
,6-)dimethyl-1-cyclohen-1-yl)-
It was confirmed that it was 9-(p-tolyl)sulfonyl-2,7-nonadiene. In addition, NMR analysis revealed that the purity of the nuclear oil was 89%. Yield 88%.

0.70-1.93 (m, 28H), 2.40
(s, 3H).

4.15-4.43 (ml 4) f), 5.17
(t, IH).

5.82 (d, IH), 7.21 (d, 2H), 7.6
4(d, 2H)IR(7(#mu) ν(crn'):
1740 (C=0).

1150 (SO2) Reference Example 1 100 n/' capacity flask cyclokeranyl phenyl sulfone 1.1368S substituted with argon gas
'(5,Qmmol) and tetrahydrofuran 2011
/ Gold pot, cooled to -78°C, then n-butyllithium hexane bath solution (1.5 mol/l) 2.2
ml (:3゜3mrnol) was added dropwise, and 3ml was added at the same temperature.
Stir for 7 hours. Next, add 8-acetoxy-
2,6-dimethyl-2,6-octarenine-1-al 0.63? (3, Oramol) Tetrahydrofluff 5! (7) Melt If! L was added dropwise at -78°C, stirred at the same temperature for 2 hours, and further stirred at -50°C for 2 hours. -7
After cooling to 8°C, water was added to the reaction mixture, and then the temperature was raised to room temperature. The resulting mixture was diluted with 100% benzene.
r! Extracted with Ll three times with a total of 300 wl. Extract M was washed with water and dried over anhydrous sodium sulfate. Benzene was distilled off from this extract, and the residue was purified by column chromatography using silica gel (eluent: a mixture of hexane and ethyl acetate in a volume ratio of 5:1) to obtain a colorless transparent oil. A product of 1.362F was obtained. According to the following instrumental analysis data, this product is 1-acetoxy-8-hydroxy-3,7-dimethyl-9-(2,6,6-drimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,6 - Confirmed to be Nonagene. Yield 93%.

0.62-1.94 (m, 28H), 3.73
(br,, LH) 13.81 (d, LH), 4.4
1(d, 2!(), 4.90(d, IH).

5.21 (m, 2H), 7.38-7.99
(m, 5H) IR (film) I/ (cnl-
1) : 3500((JH) +1735(C=C'
) +1140(SO2)F D -M A S S
m/e: 488 (M) Reference Example 2 5.40 ? (1
9,4 mmol) and toluene 50+t/ were added, and then a diethyl ether solution of ethylmagnesium bromide (1,06 mol/j!) 12.1 m/(12,
8 mmol) was added dropwise at an internal temperature of 20 to 25°C. After the addition was completed, the mixture was stirred for 3 hours at an internal temperature of 40 to 45°C. Next, cool the VC1 so that the internal temperature is -40 to -30°C, and add 80% to this solution.
-acetoxy-2,6-dimethyl-2,6-octane:
A solution of r-7-1-7-#2.01r (9.57 mmol) in 5 at of toluene was added dropwise. After the dropwise addition was completed, the mixture was vigorously stirred for another 2 hours at the same temperature. 10 to the reaction mixture
% aqueous hydrochloric acid solution was added and the toluene layer was separated. This toluene layer was washed with water, further washed with saturated aqueous sodium chloride, and purified with anhydrous magnesium sulfate. Toluene was distilled off from this toluene layer, and the residue was purified by column chromatography using silica gel (bath solution: mixture of hexane and ethyl acetate (mixture of 7:3). 1-acetoxy-8-hydroxy-3
,7-dimethyl-9-(2,6,6-drimethyl-1-
Cyclohexen-1-yl)-9-phenylsulfonyl-2,6-nonadiene 4231 was obtained. Yield: 91 cm. In addition, the obtained 1-acetoxy-8-hydroquine-3,7
-Simethyl-9-(2,6,6-)rifthyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2
, 6-nonadiene were compared with those obtained in Reference Example 1, IR and F D
-MASS matched, but some differences were observed in NMR as shown below.

This was obtained using 1-acetoxy-8-hydroxy-3
,7-dimethyl-9-(2,6,6-)dimethyl-1-
Cyclohegysen-1-yl)-9-phenylsulfonyl-2,6-nonadiene is meant to be a mixture of diastereomers.

0.61-2.03 (m, 28H); 2.87
(br,, 1M); 3.95, 4.20 (d, total II (); 4.50 (d, 2H); 4.85, 4.
97 (d, together with IH); 5.25, 5.6
2 (m.

total of 2H); 7.40 to 8.03 (m, 5H) Reference Example 3 Into a third flask of 501E/' volume purged with argon gas, β-cyclogeranyl-1)-)lylsulfone 1.75
2 F (6,00 mmol) and 30 tons of tetrahydro7ran were added, and after cooling to -78°C, a hexane solution of n-butyllithium (1,5 mol/4) 2□
4d (3.6 mmol) was added dropwise, and the mixture was stirred at the same temperature for 2 hours.

In this solution, 8-acetoxy-2,6-dimethyl-2.
6-octarenine-1-al630~(3,00m
A solution of 78 mol of tetrahydrochloride was heated to 78°C.
and stirred at the same temperature for 3 hours. Water was added to the reaction mixture, and the temperature was raised to room temperature. The resulting mixture was mixed with 30 d of benzene three times for a total of 90 ml of benzene. The benzene extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off from this extract, and the residue was purified by nine column chromatography using silica gel (eluent: a mixture of hexane and ethyl acetate in a volume ratio of 5:1 to 3:1) to obtain a white solid. A mold of 1.22 f was obtained. According to the following instrumental analysis data, this product is 1-acetocoir-8-hydroxy-3
,7-dimethyl-9-(2,6,6-)dimethyl-1-
It was confirmed that it was cyclohexen-1-yl)-9-(p-tolyl)sulfonyl-2,6-nonadiene. Yield: 81 cm.

CDα3 NMRδ(CH3)3Si(JSI(CH3)3'0
．． 61-2.01 (m, 28H), 2.37
(8, 3I() 13.71(br,, IH), 3
．． 94(d, IH).

4.49 (d, 2H), 4.97 (d, LH), 5.1
6 (m, 2H) t7.26 (d, 2) 1), 7.86 (
d, 2H) IR (film) ν(m'): 348
0((JH).

1735 (C-li) + 1140 (S (J2) Reference Example 4 1-7 in a 50!WJ flask purged with argon gas
Setoxy-6-chloro-3,7-dimethyl-9-(2,
6,6-)dimethyl-1-cyclohexene-1-1)
-9-phenylsulfonyl-2,7-nonadiene 0.4
951? (0,977 mmol) and 15jIe of cyclohexane were added, and after stirring for a while, 0.70 ml of potassium methoxide was added to this solution. (10rnm, ol)
was added, and then stirred at 38°C for 2 hours. To the reaction mixture were added 30 x ti of diimpropyl ether and 151 Il of a saturated aqueous ammonium chloride solution, the mixture was separated, and the aqueous layer was extracted with 20 x ti of diisopropyl ether. The organic layers were combined, washed with saturated ammonium chloride aqueous solution, and anhydrous sulfur was dried over magnesium.

The organic solvent was distilled off from this organic layer, and the residue was
A 0.05% strength by weight solution of di-tert-butyl-4-methylphenol in hexane with 4 tttl and triethylamine l, lvtl with 100wII purged with argon gas! I put it in a flask. To this mixture was added 0.55 g of acetic anhydride under water cooling, and the mixture was stirred at room temperature for one day. Add 50ml of hexane/and saturated hydrogen carbonate to the reaction mixture)
After adding 101 ml of IJum aqueous solution and stirring for a while, the hexane layer was separated. This hexane layer was washed with saturated hydrogen carbonate and thorium aqueous solution M.

It was dried over anhydrous 61 magnesium. By distilling off hexane from this hexane layer, a red oil of 0.34% was produced.
I got 62r. When this oil was subjected to FLI-MS analysis, a peak at % m/e = 328 was detected. This confirmed that the main component of the kernel oil was vitamin A acetate. Next, using high performance liquid chromatography to quantify the produced vitamin A acetate using methyl stearate as an internal standard, the yield of vitamin A acetate was 1-acetoxy-6-chloro-3,7-
cymethyl-9-(2,6,6-drimethyl-1-cyclohexen-1-1)-9-phenylsulfonyl-2,
It was in the 70 range based on Hunonadien.

Reference Example 5 In Reference Example 4, 1-acetoxy-6-chloro-3,7
-Simethyl-9-(2,6,6-drimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2
, 7-7 Nadiene 0.4951 r (0,977 mmo
l) instead of 1-acetoxy-6-pheromo 3゜7
-Simethyl-9-(2,6,6-)dimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2
,7-No6 diene 0.5538 ? (1,01rn
The reaction and separation operations were carried out in the same manner, except that a mixture of 10 m/mol of cyclohexane and 5 d of toluene was used instead of 15 m6 of cyclohexane.

0.3195f of red oil was obtained. FD this oily substance
- When subjected to MS analysis, a peak of m/e=328 was detected. This confirmed that the main component of the kernel oil was vitamin A acetate.

Next, when the vitamin A acetate produced by high performance liquid chromatography was quantified in the same manner as in Reference Example 4, the yield of vitamin A acetate was 1-acetoxy-6.
-Promo 3,7-dimethyl-9-(2,6,6-)dimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-70% based on 2,7-nonadiene
Met.

Reference Example 6 In Reference Example 5, 1-acetoxy-6-promo 3.7
-Simethyl-9-(2,6,6-)dimethyl-1-cyclohexene'-1-1l)-9-phenylsulfonyl-
2,7-nonadiene 0.5538r (1,01rnmo
l) instead of 1-acetyl-6-chloro-3゜7-dimethyl-9-(2,6,6-drimethyl-1-cyclohexen-1-yl)-9-(p-)lyl)sul*2 −
2,7-nonazine 0.5127r (0,985mmo
The reaction and separation operations were carried out in the same manner except that 1) was used, and 0.0% of the red oil was obtained. : 3325 g' was obtained 4. When this oil was subjected to FD-MS analysis, it was found that m/e-328
peak was detected. This confirmed that the main component of the kernel oil was vitamin A acetate. Next, when the vitamin A acetate produced was quantified by high performance liquid chromatography in the same manner as in Reference Example 4, the yield of vitamin A acetate was 1-acetoxy-6-chloro(1
-3,7-dimethyl-9-(2,6,6-)dimethyl-
1-cyclohexen-1-yl)-9-(p-1lyl)
It was 68% based on sulfonyl-2,7-nonadiene.

Reference Example 7 6-chloro-1-hydroxy-3,7-dimethyl-9-(2
,6,6-drimethyl-1-cyclohexen-1-yl)-9-phenylsulfo,=2,7-nonadiene0
．． 0232F (0,050 mmol) and cyclohexene 5ynl, then potassium methoxide 0.0
352y (0.50 mmol) was added, and the mixture was stirred at 35°C for 2 hours. The reaction mixture was diinozolobyl ether 2
0al? and 1Qg/saturated ammonium chloride. The organic matter was separated, dried over anhydrous magnesium sulfate, and concentrated to about 1 liter. This concentrated solution was analyzed by FD-MS.
Upon analysis, a peak of m/e=286 was detected. It was confirmed that this liquid contains vitamin A.

〔Effect of the invention〕

According to the method of the present invention, /S rosulfone represented by the general formula (1) can be easily produced in good yield from inexpensive and easily available industrial raw materials, as is clear from the above examples. Furthermore, the halosulfone represented by the general formula (1) of the present invention can be easily derived into vitamin A and further into its acetate in a good yield, as is clear from the above reference examples.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 represents an optionally substituted phenyl group, and R^2 represents a hydrogen atom or a lower acyl group. Representation, X
represents a halogen atom. ) is a halosulfone. 2. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R^1 represents an optionally substituted phenyl group, and R^3 represents a lower acyl group.) There are general formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by applying a halogenating agent and hydrolyzing the product as necessary ▼ (wherein R^1 is as defined above, R^2 represents a hydrogen atom or a lower acyl group, and X represents a halogen atom.) A method for producing a halosulfone represented by: