JPS6287561A - Production of vitamin a and carboxylic acid ester thereof - Google Patents

Abstract

PURPOSE:To obtain the titled compound useful as pharmaceutical, feed additive, etc., easily in high yield from an easily available inexpensive raw material, by treating a halosulfone with a base and, if necessary, acylating the product. CONSTITUTION:Vitamin A can be produced by reacting a halosulfone of formula (R<1> is phenyl; R<2> is H or lower acyl; X is halogen) with a base (e.g. potassium methoxide) in a solvent such as cyclohexane at 10-120 deg.C. If necessary, obtained vitamin A is made to react with an acylation agent (e.g. acetic anhydride) at -10-+30 deg.C in the presence of a tertiary amine to obtain the objective carboxylic acid ester. The amount of the base is 2-20mol per 1mol of the halosulfone. The halosulfone of formula is a novel compound which can be produced by reacting hydroxysulfone with a halogenation agent and, if necessary, hydrolyzing the product.

Description

[Detailed description of the invention]

[Industrial Field of Application] The present invention relates to a method for producing a vitamin or a carboxylic acid ester thereof. Vitamin A and its carboxylic acid esters represented by acetate and halumitate are used in large quantities as medicines, feed additives, etc. [Prior art] Conventionally, vitamin A or its carboxylic acid esters have been prepared by the following methods. It is known that teyoshi is manufactured. [In the formula, Ac represents 7-t=thyl group; Helve
tieaChemica Acta, 30.1911
(I947)] Vitamin A Edge Water Decomposition Vitamin A Aceate [In the formula, Ph represents a phenyl group, X represents a /・logen atom, and Ac represents an acetyl group; Chemie
Ingentuor Technik, 45.64
6 (I973)] [Problems to be Solved by the Invention] All of the above-mentioned conventional methods for producing vitamins or their carboxylic acid esters use β-ionone as a starting material. This β-ionone is produced industrially by ring-closing reaction of boolean ionone using a large amount of concentrated sulfuric acid, but the yield is not very high, and the distillation separation from α-ionone etc. produced as a by-product is difficult. It is not necessarily an industrial raw material that can be obtained at low cost due to the difficulty of manufacturing. SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a method for easily producing vitamin A or its carboxylic acid ester in good yield from inexpensive and easily available industrial raw materials. [Means for Solving the Problems] According to the present invention, the above object is achieved by the general formula (wherein R represents an optionally substituted phenyl group, R represents a hydrogen atom or a lower acyl group, , X represents a halogen atom) is treated with a base, and if necessary, the produced vitamin A is annealized. This is achieved by the above general formula (I
) is a halosulfone represented by the general formula (wherein R is as defined above, and R represents a lower anru group)
) by reacting a halogenating agent with a halogenating agent and optionally hydrolyzing the product. Achieved 1. 1 (, R, R, and X in the above general formula are explained in detail.
Moon. ■71 represents a phenyl group which may be substituted, and the substituent here is a lower alkyl group such as methyl, ethyl, i-furoyl, n-7'robyl, 1-butyl, n-butyl; Halogen atoms such as chlorine, bromine, iodine; and methoxy, ethquine, i 7' loboxy, n
Examples include lower alkoxy groups such as -propoxy, l-butoxy, and n-butoxy. In addition, the substituent is at the ortho position,
It may be present at either the meta position or the para position, and may be present in one or more than two positions. R represents a hydrogen atom or a lower acyl group such as formyl, acetyl or propionyl. R represents the same lower acyl group as R. Further, X represents a halogen atom such as a chlorine atom, a bromine atom, or an iodine atom. Examples of the carboxylic acid ester of vitamin A produced by the method of the present invention include vitamin A acetate, vitamin A palmitate, and the like. Examples of the base to be present in the reaction system in the reaction of inducing vitamin A from the halosulfone represented by the general formula (I) according to the present invention include potassium alkoxides such as potassium methoxide, potassium ethoxide, and potassium n-butoxide; Potassium oxide etc. are used. Use of one group: 11゛ is a halosulfone 1 represented by general formula (I)
About 2 to 20 moles per mole is preferred. 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 concentration of rosulfone is approximately Q, 0
It is preferable that the amount of electricity is 5 to 1 mol/pu. Preferably, the reaction is carried out within a temperature range of about 10 to 120°C. After the reaction is completed, a precipitate is filtered from the reaction mixture as required, and then water, a saturated IJ 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. By acylating the vitamin A thus obtained by a conventional method, a carboxylic acid ester of vitamin A can be derived. In this acylation reaction, vitamin A is separated and purified from the organic layer containing vitamin A separated from the reaction mixture obtained by the above-mentioned reaction for producing vitamin A, preferably in an organic solvent. This is carried out by introducing an acylating agent in the presence of a tertiary amine. As the acylating agent, acetic anhydride, acetyl chloride, balmitoyl chloride, etc. are used. The amount of acylating agent used is approximately 1 to 1 for vitamin A.
0 bottle is preferred. 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 diimpropyl ether; and esters such as ethyl acetate and butyl acetate. 0.1
It is preferable to use 1 of + length so that it becomes ~5 mol/C. As the tertiary amine, for example, triethylamine, pyridine, etc. are used. It is preferable to use these tertiary amines in an amount of about 1 to 10 equivalents relative to vitamin A, but by using excess -1IL, the tertiary amines can be
It is also possible for the grade amine to also serve as an organic solvent. Preferably, the reaction is carried out at a temperature range of about -1O<0>C to 30<0>C. After the reaction is completed, the precipitate is filtered out from the reaction mixture, and then dilute sulfuric acid, water, a saturated aqueous sodium bicarbonate solution, etc. are added to the reaction mixture to separate the filter layer. A carboxylic acid ester of vitamin A can be obtained by subjecting the obtained organic layer to purification means such as recrystallization and column chromatography. The norosulfone represented by the general formula (I) used as a raw material is a new compound, and as mentioned above, the no-losulfone represented by the general formula (II)
By reacting a halogenating agent with the hydroxysulfone represented by and hydrolyzing the product as necessary, p
will be outfitted. First, by allowing a halogenating agent to act on the hydroxysulfone represented by the general formula (II), the halogenating agent that can produce halosulfo/ in which R2 is a lower acyl group in the general formula (I) is as follows.
For example, thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide, etc. are used. The amount of 41 to be used is preferably about 1 to 3 equivalents relative to the hydroxysulfone represented by the general formula (■). 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-dichloroethane
Any halogenated hydrocarbons; ethers such as diethyl ether and diimpropyl ether; esters such as ethyl acetate and butyl acetate are used. The amount of organic solvent used is preferably such that the concentration of hydroxysulfone represented by general formula (n) is about 0.1 to 5 mol/-e. As the tertiary amine, pyridine, triethylamine, etc. are advantageously used. 71. The tertiary amine is hydroginesulfo/
It is preferable to use JAk in an amount of about 0.01 to 50 equivalents, but by using an excess of JAk, the tertiary amine can also serve as an organic solvent. Preferably, the reaction is carried out within a temperature range of about -10°C to 30°C. In the general formula (I) obtained by this reaction, R
Gasu

The halosulfone, which is an acyl group, can be separated by a conventional method. For example, the reaction mixture is poured into water, a saturated sodium bicarbonate water bath solution, a sulfur trowel, etc., and extracted with benzene, methylene chloride, diethyl ether, ethyl acetate, etc., and the extraction liquid is washed with water and anhydrous. Dry with sodium sulfate. Next, by distilling off low-boiling substances from the extract under reduced pressure and subjecting the residue to silica gel column chromatography, a halosulfone in which 1ζ is a lower acyl group in general formula (I) can be isolated. . In addition, in general formula (I), R is a hydrogen atom...rosulfone can be obtained by hydrolyzing halosulfone in general formula (I), in which R is a lower alkyl group, obtained by the above method. Manufactured. This hydrolysis reaction is carried out by reacting a halosulfone in which R is a lower acyl group in general formula (I) 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 preferably about 1 to 2 equivalents relative to the sulfone in which R is a lower acyl group in general formula (I). This reaction is preferably carried out in a solvent, and the solvent may be an alcohol such as methanol or ethanol, or a mixture of these alcohols with water and/or a hydrocarbon such as benzene or toluene! i-2! Il etc. are used. The fecal amount of the solvent is generally about 0.1 to 10 mol/ml of halosulfone in which R is a lower acyl group per person (I).
It is preferable that the rent be equal to p. In polymerizations that conveniently use a mixture of alcohols and water and/or hydrocarbons as a solvent, it is preferable to use the loading and/or hydrocarbons to an extent that does not cause phase separation in the reaction system. The reaction is suitably carried out at a temperature of about -10°C to 30°C. The halosulfone obtained by this reaction in general formula (I) in which R2 is a hydrogen atom can be separated by a conventional method. For example, add saturated ammonium chloride aqueous solution, Kihana Fil:, dilute sulfuric acid, etc. to the reaction mixture to neutralize the remaining alkali metal hydroxide or carbonate, and use it as a solvent if necessary. After distilling off the alcohol and adding water to the residue, it was extracted with benzene, methylene chloride, diethyl ether, 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,
By subjecting the residue to silica gel column chromatography, it is possible to separate gold halosulfones in general formula (I) in which R is a hydrogen atom. A novel compound of hydroxysulfone 4 represented by the general formula (II), for example, a compound represented by the general formula (wherein R is as defined above) and a compound represented by the general formula (wherein, ■L is as defined above). Table 1 is obtained by reacting the compound shown in Table 1 with the compound shown in Table 1.) in the presence of an anionizing agent. The anionizing agent that can be used has the general formula (
A base that generates a carbanion at the α-position of the -So2R group in the compound represented by I), for example, an organic lithium such as methyllithium or n-butyllithium;
Grignard reagents such as methylmagnesium chloride, ethylmagnesium chloride, and ethylmagnesium bromide; alkali gold hydrides such as lithium hydride, sodium hydride, and potassium hydride; lithium amide, sodium chloride, and potassium hydride Alkali metal amides such as amides; alkali metal lower alkoxides such as lithium methoxide, sodium methoxide, potassium methoxide, potassium ethoxide, potassium t-butoxide, etc. The amount of anionizing agent used is about 0.2 to 1 mole relative to the compound represented by the general formula (Ill). This reaction reacts with aliphatic or aromatic hydrocarbons such as hexane, heptane, benzene, and toluene; linear or cyclic ethers such as diethyl ether, diimpropyl ether, tetrahydrofuran, and dioxane; dimethylformamide, N-methylpyrrolidone, and It is preferable to carry out the reaction in an organic solvent such as IJ amide (sulfoxide, hexamethylphosphoryl). The solvent is appropriately selected in combination with the anionizing agent. The reaction is usually carried out within a temperature range of about -100 DEG C. to 150 DEG C., and is advantageously carried out under an atmosphere of an inert gas such as helium, nitrogen or argon. The reaction time varies depending on the anionizing agent, solvent, reaction temperature, etc. used, but for example, n-butyllithium is used as the anionizing agent and the reaction is carried out in a tetrahydrofuran solvent at a temperature of about -78°C to -50°C. In case about 4
It's time. The compound represented by the general formula (Ill) can be easily produced in good yield from linalool using inexpensive industrial raw materials. For example, a compound in which R1 is a phenyl group in general formula (III) is produced by the following method. That is, shigeranyl chloride is obtained by reacting linalool with thionyl chloride, and shigeranyl phenyl sulfone is obtained by reacting the geranyl chloride with sodium benzenesulfinate. Cyβ-cyclogeranylphenyl sulfone is obtained by subjecting geranylphenyl sulfone to a ring-closing reaction in the presence of an acid catalyst such as a mixed acid of sulfur and acetic acid. It should be noted that α-cycloclaranylphenylsulfone, which is an isomer of β-cyclochelanylphenylsulfone, may be produced as a by-product during the ring-closing reaction.
By crystallizing the mixture of both products in a solvent such as hexane, β-cyclogeranylphenyl sulfone of high purity can be obtained. Further, α-cyclogeranylphenyl sulfone is converted into the desired β-cyclogeranylphenyl sulfone by returning it to the ring-closing reaction system. ! J f a-Lucara+7) The total yield of β-cyclogeranyl phenyl sulfone is usually about 80%. Further, the compound represented by the general formula (IV) can be easily produced by reacting, for example, selenium dioxide with a lower carboxylic acid ester of geraniol (Tetrah
edron Letters, 281 (I973)
reference〕. [Example] Hereinafter, the present invention will be explained with reference to Examples, but the present invention is not limited to these Examples. −
Acetoxy-6-chloro-3,7-dimether-9-(2
,6,6-)rifthyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,7-nonadiene0.
4951? (0,977 mmol) and 15 rItl of cyclohexane were added, and after stirring for a while, 0.70 f of potassium methoxide (lommof
) and then stirred at 38°C for 2 hours. To the reaction mixture, 30 rttl of diimpropyl ether and 151 ml of a saturated aqueous ammonium chloride solution were added to separate an organic layer, and the aqueous layer was extracted with 20 d of diimpropyl ether.The organic layers were combined, washed with a saturated aqueous ammonium chloride solution, and anhydrous. It was dried with sulfuric acid. The organic solvent is distilled off from this organic layer, and what remains? 11'fr:2. s-Gt
- Hexane bath solution 41 with a density of 0.05N mass % of -butyl-4-methylphenol and triethylamine l, l m
The mixture was heated with argon gas and placed in a 100g capacity flask. Add 9.59% of acetic anhydride to this mixture under water cooling.
m was added thereto, and the mixture was stirred at room temperature for 1 day. Add 50ffi of hexane to the reaction mixture and 10 liters of saturated aqueous sodium bicarbonate solution.
After stirring for a while, the hexane layer was separated. The hexane layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. By distilling off hexane from this hexane layer, no red oil was produced.
．． 3462F was obtained. When this oil was subjected to FD-MS analysis, a peak at m/e=328 was detected. It has been shown that the main component of this oily substance is vitamin A acetate. Next, when we quantified vitamin A acetate produced using methyl stearate as an internal standard using high-performance liquid chromatography, we found that the yield of vitamin A acetate was 1.
-7 Setoxy 6-chloro 3,7-dimeteru 9-(
The yield was 70% based on 2,6,6-dolimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,7-nonadiene. Example 2 In Example 1, 1-acetoxy-6-chloro-3,7
-dimethyl-9-(2,6,6-trimethyl-1-cyclohexene-3-(ru)-9-phenylsulfonyl-
2,7-nonadiene 0.4951 F (0,977 m
rnol) instead of 1-acetoxy-6-bromo-
3,7-dimeter-9-(2,6,6-4-limethyl-J
-cyclohesocene-1-1)-9-722lsulfonyl-2,7-nonadiene0.55385'(I,01m
rnol), cyclohexane 15 is substituted with cyclohexane 10 door 1 and utor x n 5
rd The reaction and separation were carried out in the same manner as R except that all non-tM compounds were used, and the red oily substance was 0.3ffi9!
This oil was subjected to Fl)-MS analysis, and a peak of m/e-328 was detected. From this, it was determined that the main component of the oil was vitamin A acetate. Next, when vitamin A acetate produced by high performance liquid chromatography VC in the same manner as in Example 1 was rated at 1, the yield of vitamin A acetate was 1.
-acetoxy-6-bromo-3,7-cymethyl-9-(
2,6,6-drimethyl-1-cyclohexene-1-(
70% based on 2,7-7nadiene)-9-phenylsulfonyl-2,7-nadiene. 6-chloro-1-hydroxy-3,7-cymenal-9-(2,6
,8-trimethyl-1-cyclohexene-1-(ru)-
9-phenylsulfonyl-2,7-/nathien 0.02
Add 32 F (0,050 mn1o1) and 5 g of cyclohexane, then add 0.0352 mn of potassium methoxide.
f (0.50 rnmol) was added, and the mixture was stirred at 35°C for 2 hours. The reaction mixture was dissolved in diisopropyl ether 20
1 and 10xe of saturated ammonium chloride. The organic layer was separated and dried over anhydrous magnesium sulfate.
It was concentrated to about 1 d. When this concentrated solution was subjected to FD-MS analysis, a lake of n-x/e=286 was detected. From this, it was confirmed that the concentrate contained vitamin A. IA-0,0137? (0.05 mmo!) was added thereto, and the mixture was stirred for 0.5 hours under water cooling, and then for 5 hours under water cooling. The reaction mixture was poured into a large amount of water for 8E and extracted with hexane. After washing the hexane extract with water, it was dried on an anhydrous 1.1c branch mag. Anhydrous magnesium sulfate was filtered off, and hexane was distilled off from the filtrate under reduced pressure to obtain 0.0282y of a reddish-yellow oil. This oil contains 0.0183F of vitamin palmitate, as determined by liquid chromatography (column: μ-porasil, eluent: a mixture of isopropyle ether and hexane in a volume ratio of 2:98). This was confirmed. In Example 2, 1-acetoxy-6-bromo-3,7
-dimeter-9-(2,6,6-drimether-1-cyclohexen-1-yl)-9-phenyl
(I,01mmo!) in place of 1-7 setoxy-6
-chloro3,7-dimethyl-9-(2,6,6-drimethyl-1-cyclohexen-1-yl)-9-(p-
tolyl) sulfonyl-2,7-nonadiene 0.5127
The reaction and other procedures were carried out in the same manner except that f(o,') 85 mmol) was used, and 0.3 of a red oily substance was obtained.
325F was obtained. When this oil was subjected to FD-IVIS analysis, a peak at m/e=328 was detected. It was found that the main component of the oily substance was vitamin A acetate. Next, when the vitamin A acetate produced was quantified by high performance liquid chromatography in the same manner as in Example 1, the yield of vitamin A acetate was 1-acetoxy-6-chloro-3,7-dimethyl-
9-(2,6,6-')rifthyl-1-cyclohexen-1-yl)-9-(p-)lyl)sulfonyl-2,7
- Based on Nonagen! . It was 68%. In case 1, potassium methoxide was 0.70 f (
Potassium n-butoxide 1 in place of J Ommol)
The reaction and separation operations were carried out in the same manner except that ゜x2r (I layer mmol) was used, and a red oily substance of 0.3481V was obtained.
I got it. When the vitamin A acetate produced was determined by high performance liquid chromatography in the same manner as in Example 1, the yield of vitamin A acetate was 1-acetoxy-
6-chloro-3,7-dimethyl-9- (2,6,6-
It was 72% based on trimethyl-1-cyclohexen-1-yl)-9-phenyl-2,7-nonadiene. Example 6 1-
Acetoxy-6-chloro-3,7-dimethyl-9- (
2,6,6-)rifnal-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,7-/tenene0
．． 4913? (0,970 mmol) and 1'5 td"fz of cyclohexane, stirred for a while, and added 0.0% potassium hydroxide (purity 85%) to this solution.
66y (I0 mmol) k was added thereto, and the mixture was stirred at 65° C. for 1.5 hours and further at reflux for 2 hours. After cooling, 30 dllt- of diisopropyl ether was added to the reaction mixture.
(i) Add 15wLl of saturated ammonium chloride aqueous solution, separate the organic layer, and remove the aqueous layer with 20rn of diisopropyl ether.
Extracted with l. The organic layers were combined, washed with saturated aqueous ammonium chloride solution, and dried over anhydrous magnesium sulfate. The organic solvent was distilled off from this organic layer, and 1 ft2. S-G-
t-Butyl-4-methylphenol+7) 0.05
It was placed in an argon-substituted 00v flask with 5 layers of hexane and 1.1 ml of ethylamine. Add 0.6 ml of acetic anhydride to this mixture under water cooling.
8 pieces of cod were added, and the mixture was stirred for 1 day across the width of the room. Add 50rne of hexane and 10w of saturated aqueous sodium hydrogen carbonate solution to the reaction mixture.
After adding te and stirring for a while, hexane M was separated. This hexane layer was washed with Kinmaro Q Sodium Boron water bath and dried over anhydrous magnesium sulfate. To this-
? A red oil was obtained by exchanging hexane from the sand layer. When the same product as in Example 1 was produced by high-performance liquid chromatography and 7 pieces of vitamin A acetate were cut into squares, the yield of vitamin A acetate was 1-acetoxy-6-lycz o -3°7.
-dimenal-9-(2,6,6-drimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2
, 7-nonacyenwo article was 64%. Example 1 β-cyclogeranyl phenyl sulfone IO, 80 g
Add f(38,8nol) and 100m of toluene, and then add dietherether/L'lJ solution of etelmag insium fluoride (I,06rnol/z) 24.
2 mg (25.6n+mol) at an internal temperature of 20-25℃
It was dripped. After the dropwise addition was completed, the mixture was stirred at an internal temperature of 40 to 45°C for 3 hours. Next, the bath liquid was cooled to an internal temperature of -40 to -30°C, and 4.02 f (I
A solution of 5 liters of toluene lO (9,]rnmol) was added dropwise. After the dropwise addition was completed, the mixture was vigorously stirred for another 2 hours at the same temperature. A 10% hydrochloric acid water bath solution was added to the reaction mixture, and the toluene layer was separated. This toluene layer was washed with water, further washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The toluene was distilled off from this toluene layer, and the residue was purified by column chromatography using silica gel (common liquid: a mixture of hexane and 6 & ether in a volume ratio of 7:3), which was then purified to be colorless and transparent. 8.46f of oil was obtained. According to the following instrumental analysis data, this product is 1-acetoxy-8-hydroxy-3,7-dimether-9-(
2,6,6-1 Rimeter-1-cyclohexene-1-(
It was determined that a mixture of diastereomers of -9-phenylsulfonyl-2,6-nonadiene was obtained. Yield: 91 cm. 0.61-2.03 (nl, 28H); 2.87 (h
r, l 3.95°4.20 (d, combined IM
); 4.50 (d, 2) i); 4.85°4.
97 ((I, together with IH); 5.25, 5.62 (
nl, total 2H); 7.40-8.03 (m, 5
H) IR (Fill A) ν(+z'): 3500(O
H), 1735cc=o)+l 40 (S02) FD-MASS m/e: 488 (M”) 100m
1-acetoxy-8-hydroxy-3,7-dimethyl-9-(2,6,6-t'Jmethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,6 - Nonagene 7.381 (I5mmo
l ), benzene 5Qmi & pyridine 12rytl
Add 1.32% of thionyl chloride while cooling in an ice water bath.
rxl was added dropwise and then stirred at room temperature for 16 hours. A water-cooled 3% sulfuric acid aqueous solution was added to the reaction mixture, and the organic layer was separated.
Extracted from 40 catfish. These organic NIs were combined, washed 111 times with an ice-cooled 3% sulfuric acid water bath, a saturated sodium bicarbonate water bath, and a saturated sodium chloride water bath, and dried over anhydrous magnesium sulfate. The solvent was removed from the organic layer and the shallowly soaked mixture was subjected to column chromatography using silica gel (
Eluate: A mixture of hexanoate and acid-resistant enal in a volume ratio of 5:1) was used to obtain 7.18f of a white waxy substance. According to the instrumental analysis data shown below, this item is 1
-acetoxy-6-chloro-3゜7-dimether-9-(
2,6,6-1 Rimeter-1-cyclohexene-1-1
The product was confirmed to be 2,7-nonadiene)-9-phenylsulfonyl-2,7-nonadiene. Yield 94%. 0.72-2.05 (n, 28d), 4.17~
4.57(m, 4f(). 5.23(t, 1)i), 5.88(m, 1li)
, 7.35-7.91 (m, 5H) IR (film) y (m-'): 1745 (C=U
), 1150 (SO2), 685 (C6da) FD-MS m/e: 506 (tvl”)
, 507 (&i"+1). 47o(M"-kiCe), 365(M"-06)
1sSOz) 10"'8 eggplant-shaped flask
mm01) and methyl 11 were added thereto, and stirred with stirring to prepare a water rg1t:potassium/kamethanol solution. This bath solution contains 1-acetoxy-6-chloro-3,7-
dimeter-9-(2,6,6-1rimenal-1-cyclohexen-1-yl)-9-phenylsulfonyl-2,
7-Nonadiene 0037: l (0°0736mmol
)'s evening/-k 2mg and beni' sevenin 0.2mg
The bath solution was added to the mixed solution with a bath knife, and the mixture was stirred for 30 minutes using a hot spring. A saturated ammonium chloride aqueous bath solution was added to reaction mixture 1, the solvent was then distilled off, water was added to the residue, and then extracted with diethyl ether. The extract was washed with a saturated ammonium chloride water bath and dried over % anhydrous magnesium sulfate. The solvent was distilled off from this extract to obtain a yellow oil, IJ, 0297ffe, which was determined to be 6-chloro-1-hydroxy-
3,7-dimethyl-9-(2,6,6-trimethyl-1
-Cyclohexen-1-yl)-9-phenylsulfonyl-2,7-nonadiene confirmed Q yield 8
7%. fJ, 75-2.20 (m, 261-1), 4.
06(d,2)i), 4.21-4.55(nl
, 2f(), 5.30(t,l), 5.91(
m, 1H). 7.36 to 7.90 (m, 5H) IR (Fi A・
) ν (cm ”): 3300 (OH), 174
5 (C=O), 1150 (SO2), 685 (
CaHs) FD r% ISm/e: 465 (
M” + 1) t 428 (84”-ratio Or32
3 (iVL"-C6HsSO2) Silver Example 2 5.00 r (I8,0 r
rtmol) and tetrahydrofuran 601,
After cooling to -78°C, a hexane solution of n-butyllithium (I,5rnol/z) 6.6wt1 (9,
9 mmol) was added dropwise, and the mixture was stirred at the same temperature for 3 hours. Next, 8-acetoxy-2,6-dimethyl-
2,6-octarenine-1-al 1.8'l (9,0
A solution of 15 g of tetrahydrofuran (rnrnol) in tetrahydrofuran was added dropwise at -78°C, stirred at the same temperature for 2 hours, and then -
The mixture was stirred at 50°C for 2 hours. After cooling to -78°C, water was added to one reaction mixture, and then the temperature was raised to room temperature. The resulting mixture was extracted with 100 mJ of benzene three times for a total of 300 d. The extract was washed with water and dried with 7X fib H sodium free. Benzene was distilled off from this extract, and the residue was subjected to column chromatography using silica gel (
Effluent: A mixed solution of hexane and r + ether in a volume ratio of 5:1) to obtain 4.01F of a colorless and transparent oil. According to the instrumental analysis data of manure, this substance is 1-acetoxy-8-hydroxy-3,7-dimether-9-(
2゜6.6-t! 7methyl-1-cyclohexene-1-
yl)-9-phenylsulfo; 2.6-/f
I confirmed that it works with Jien. Yield 93%. Around C3 NMRδ(CH3)3siUSi(CHs)3”0.6
2-1.94 (rn, 28H) + 3.73 (br,
IH), 3.81 (d, iH), 4.41 (dt
2H), 4.9o(d,xH)+5.21(m
*2H), 7.38-7.99 (mt 5H)I
R (film) ν (preparation-1): 3500 (OH),
1735 (C=Lt), 1140 (SO2) FD
-MASS m/e: 488 (M”) 501 @ 1-acetoxy-8-hydroxy-3,7 in an eggplant flask
-Simethyl-9-(2,6,6-drimethyl-1-cyclohexen-1-yl)-9-phenylsulfonyl-2
,6-/f Scene 2.44f (5,0mII)0
1), pyridine (), 122 and methylene chloride 20j
1J and while cooling in an ice water bath, the tribromide concentration was 70.3.
1 xl (3.3 mmol) was added dropwise for 1 to 1 hour, and then stirred at the same temperature for 1.5 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. Extract 17: +hv: Washed with saturated aqueous sodium taurate solution and saturated aqueous sodium chloride solution. It was dried with anhydrous magnesium sulfate. The solvent was distilled off from the extract, and the residue was purified by column chromatography using silica gel (eluent: a mixture of hexane and ethyl acetate at a height ratio of 9:1 to 3:1), A white waxy substance 2.34F was obtained. According to the following instrumental analysis data, this product is 1-acetoxy-2-bromo-3,7-dimedel-9-(2°6.6
-1-limethyl-1-cyclohexen-1-yl)-9-
It was confirmed that it was phenylsulfonyl-2,7-nonashene. Yield 85%. 1.71-2.03 (m, 28) 1), 4.32-4
．． 57(m, 4f(). 5.24(m, 4)i), 5.90(m, IM),
7.43-7.90 (III, 5H) IR (film) ν (clN-J: 1730 (C=
0), 1135 (Su2), 670 (06H3
) FD-MS m/e: 550 (M”), 470 (M
"-HBr). 409 (M"-CaHsSOz) Sugiba Example 3 β-
Cyclogeranyl-p-tolylsulfone 1.752 j'
(6,00rnmol) and tetrahedral o7 run 3
After cooling to -78°C, add n-butyllithium hexane bath solution (I,5rriol/z).
Drop 2.4 soap (01 for 3,6m) and 2:1 at the same width.
Stirred i-tl 35. Next, 8-acetoxy-2,6-dimethyl-2,6-octarenine-1 was added to this solution.
A solution of 15 tze of tetrahuman CI7 rough 630w (3,00 mmol) was added dropwise at -78°C, and the mixture was stirred for 3 hours at the same temperature. Water was added to the reaction mixture, and the mixture was stirred to a boiling point.・The resulting mixture was extracted with 30 liters of benzene (JOml), the benzene extract was washed with water, and dried with anhydrous fJt M mag fushiwam.This extract was removed. The shallowly soaked product was purified by column chromatography using silica gel (elution: hexane, !7 mixed solution with ethyl acetate in a volume ratio of 5:1 to 3:1) to obtain 1.22F as a white solid. According to the following instrumental analysis data, 1-7cetoxy-8-hydroxy-3,7-dimethyl-9-(2,6
,6-drimether-1-cyclohexen-1-yl)-
It was confirmed to be 9-(I)-tolyl)sulfonyl-2,6-nonadiene. Yield: 81 cm. o, el ~2. ol(m, 2sH), 2. a7(
g, 3M), 3.71 (br -, IH), 3.
94 (d + 1'), '4-49 (d-2H)
t4.97(d, 1f(), 5.16(m, 2H)
, 7.26(d,2). 7.86 (d, 214) IR(7(Am)v(m-1): 3480(OH
), 1-a7toxy-8-hydroxy-3,7-dimethyl-9-(
2,6゜6-trimethyl-l-cyclohexen-1-yl)-9-(p-4lyl)sulfonyl-2,6-nonadiene 610'i (I,26m1nol), 0.96 g of pyridine? (I2mn+ol) and benzene 15
υ, and while cooling in an ice water bath, add Theoni Chloride #0.
11 #I/ (I, 5xumol) was added and then stirred at room temperature for 16 hours. IN hydrochloric acid and benzene were added to the reaction mixture to separate the layers. After washing the free layer with water and drying with anhydrous KM'magnesium, the liquid was distilled off to obtain a yellow oil of 630"W. According to the lower BEr's g5 analytical data,
1-acetoxy-6-chloro-3,7-cymethyl-9-
(2,6,6-trimethyl-1-cyclohexene-1
-yl)-9-(p-1lyl)sulfonyl-2,7-nonadiene. In addition, NMR analysis revealed that the purity of the oily substance was 89%. Yield 8
8%. 0.70-1.93 (Ill, 28H), 2.4 (
I(S, 31(), 4.15~4, = 13(m, 4
1(l), 5.17(t, IH), 5.82(
ci, IH). 7.21(d, 2H), 7.64(d, 21()I
R (film) ν (pre-'): 1740 (C=0
), 1150 (SO2) [Effects of the invention]

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (In the formula, R^1 represents an optionally substituted phenyl group, and R^2 is a hydrogen atom or a lower Represents an acyl group, X
represents a halogen atom. ) A method for producing vitamin A or its carboxylic acid ester, which comprises treating a halosulfone represented by the formula below with a base, and optionally acylating the produced vitamin A. 2. Halosulfone represented by the general formula (I) has the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (In the formula, R^1 represents an optionally substituted phenyl group, R^3 represents a lower acyl group), and optionally hydrolyzes the product.