JPH0246017B2 - JIMECHIRUOKUTENJIOORUJUDOTAIOYOBISONOSEIZOHOHO - Google Patents

Description

[Detailed description of the invention]

The present invention relates to dimethyloctenediol derivatives and methods for producing the same. More specifically, the present invention relates to the general formula [In the formula, R ¹ and R ² are (1)—CH ₂ R ³ , provided that they do not belong to the same group at the same time.

【formula】

[Formula] and (4)—CH ₂ —S—R represents a group arbitrarily selected from the four groups ¹⁰ , where R ³ represents an aryl group, and R ⁴ and R ⁵ represent a hydrogen atom or a lower alkyl group. Representation,
R ⁶ represents a lower alkyl group or a lower alkoxy lower alkyl group, or R ⁶ and R ⁴ or R ⁵
are combined to represent an alkylene group having 4 to 5 carbon atoms, R ⁷ , R ⁸ and R ⁹ represent a lower alkyl group or an aryl group, and R ¹⁰ represents a lower alkyl group. ] The present invention relates to a 2,6-dimethyl-2[Z]-octene-1,8-diol derivative represented by the following and a method for producing the same. In this specification, Z indicates a cis configuration. 2,6-dimethyl-2(Z)-octene-1 represented by the general formula () provided by the present invention,
8-Diol derivatives are new compounds that have not been described in the literature, and they are useful as intermediates for the synthesis of various isoprene-based compounds.In particular, they are widely distributed in mammalian bodies and play extremely important functions in maintaining the life of living organisms. It is useful as a carbon chain extender intermediate for the synthesis of dolichols, which are known to play a role. Mammal dolichols have the general formula (In the formula,

[Formula] represents a trans isoprene unit,

[Formula] represents a cis isoprene unit. The same shall apply hereinafter in this specification. ), the number n of cis isoprene units in the formula is generally distributed from 12 to 18, and n =
14, n=15 and n=16 are the main congeners. Although it is extremely difficult to fully synthesize mammalian dolichols, which have such complex and unique molecular structures, using current organic synthesis technology, some of the present inventors and their co-researchers have previously synthesized mammalian dolichols, which have such complex and unique molecular structures. Pinus densiflora), Japanese black pine (Pinus
13 By hydrolyzing the extract extracted with an organic solvent from the leaves of animals of the Pinaceae family, such as Pinaceae (Pinaceae) such as (Pinaceae), and treating it by chromatography, fractional dissolution, or other appropriate separation method. A general formula with ~21 isoprene units in the same trans and cis configuration as mammalian dolichorules. (In the formula,

[expression] and

[Formula] is as defined above, and m represents an integer of 10 to 18. ) can be obtained from a homologue mixture of polyprenol and/or its acetate ester, the polyprenyl fraction has no α-terminal saturated isoprene unit compared to mammalian dolichols, and has a cis exhibiting a distribution of polyprenyl congeners very similar to the distribution of polyprenyl congeners in mammalian dolichols, except for one less unsaturated isoprene unit, said polyprenyl fraction being optionally a constituent thereof; It has been found that individual polyprenyl analogs (with a uniform number of isoprene units) can be separated relatively easily. As a result of intensive research to produce mammalian dolichols from the polyprenyl compounds described above, the present inventors found that 2,6-dimethyl represented by the general formula () is useful as a soprene chain elongation compound that meets that purpose. -2(Z)-octene-1,8
-We have created a diol derivative. As mentioned above, R ¹ and R ² in the general formula () do not belong to the same group at the same time.
(1)—CH ₂ R ₃ ,

【formula】

It can be a group arbitrarily selected from the following four groups: [Formula] and (4)—CH ₂ —S—R ¹⁰ . Here, R ³ represents an aryl group such as a phenyl group or a tolyl group, preferably a phenyl group. R ⁴ and R ⁵ represent a hydrogen atom or a lower alkyl group such as a methyl group or an ethyl group, preferably a hydrogen atom or a methyl group. R ⁶ represents a lower alkyl group such as a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, or a lower alkoxy lower alkyl group such as a methoxyethyl group. . Further, R ⁶ and R ⁴ or R ⁵ are bonded to form an alkylene group having 4 to 5 carbon atoms, preferably -
(CH ₂ ) ₄ - or - (CH ₂ ) ₅ -. base

Particularly preferred examples of the formula include methoxymethyl group, ethoxymethyl group, 1-ethoxyethyl group, methoxyethoxymethyl group, tetrahydrofuryl group, and tetrahydropyranyl group. R ⁷ , R ⁸ and R ⁹ are the same or different from each other,
Each is a lower alkyl group such as methyl, ethyl, n-propyl, n-butyl, t-butyl, etc. or an aryl group such as phenyl, tolyl, etc. base

Particularly preferred examples of the formula include dimethyl t-butylsilyl group and triphenylsilyl group.
R ¹⁰ is a lower alkyl group such as a methyl group, ethyl group, n-propyl group, n-butyl group,
Particularly preferred is a methyl group. According to the present invention, a compound represented by the general formula () is a compound represented by the general formula () (In the formula, R ¹¹ represents a lower alkyl group, and R ¹ is as defined above.) 2-methyl-2(Z)-butene-1,
4-Diol derivatives and general formula (In the formula, X represents a halogen atom, and R ² is as defined above.) It can be produced by reacting a Grignard reagent represented by the following in the presence of a copper salt. This reaction is carried out in an ether solvent such as diethyl ether, tetrahydrofuran or 1,2-dimethoxyethane, preferably tetrahydrofuran. The usage ratio of the compound represented by the general formula () and the compound represented by the general formula () is ():()
= 2:1 to 1:6, preferably 1:1 to 1:2 (molar ratio). This reaction needs to be carried out in the presence of a copper salt, and the copper salts that can be used include
CuCl, CuBr, CuI, Cu( _OCOCH3 ) ₂ , Cu
(CH ₃ COCHCOCH ₃ ) ₂ , Li ₂ CuCl ₄ , CuCl ₂ and the like. Li ₂ CuCl ₄ is preferably used. The amount of copper salt used is about 0.001 to 1 mol, preferably 0.01 to 0.05 per mol of the compound represented by the general formula ().
It is a mole. The reaction temperature is -78°C to +30°C, preferably -20°C to +5°C. The compound represented by the general formula () used in this reaction has a lower alkyl group such as a methyl group, ethyl group, or n-propyl group as the group R ¹¹ , and these can be produced, for example, by the following synthetic route. can. That is, the hydroxyl group of propargyl alcohol is converted into a group R ¹ (as defined above) by a method known per se.
(), and then the carbanion produced by eliminating acetylenic hydrogen with a strong base such as n-butyllithium is condensed with methyl chloroformate () to give the condensation product ().
(Z)-α,β-unsaturated ester ( ), this is reduced with, for example, diisobutylaluminum hydride, and then hydrolyzed to synthesize (Z)-allylic alcohol () (), and this alcohol is converted into acetic acid, propionic acid, butyric acid, etc. according to a method known per se. A compound represented by the general formula () can be obtained by reacting () with a lower carboxylic acid or a reactive derivative thereof such as an acid anhydride or an acid halide. In addition, the Grignard reagent shown by the general formula () is magnesium and the general formula (In the formula, X and R ² are as defined above.) A halide (e.g. chloride, bromide, preferably bromide) represented by
It can be prepared by reaction in an ethereal solvent such as tetrahydrofuran or 1,2-dimethoxyethane, preferably at about 20 to 80°C (see, for example, European Patent Application Publication No. 0054753A1). The Grignard reagent represented by the general formula () thus prepared can be directly subjected to a reaction with the compound represented by the general formula () without being separated. Suitable examples of the compound of the present invention represented by the general formula () include the following compounds. In the above formula, THP represents a 2-tetrahydropyranyl group, THF represents a 2-tetrahydrofuryl group, ^tBu represents a tertiary butyl group, and ^iPr represents an isopropyl group. The same shall apply hereinafter in this specification. The compound of the present invention is useful, for example, as a compound for elongating isoprene chains in the production of mammalian dolichols, and mammalian dolichols can be synthesized from the polyprenol represented by general formula (B) or a mixture of its homologs by the following method. enable. (In the formula, p represents an integer of 9 to 17.) R ¹ and R ² are as defined above. That is, a polyprenol represented by the general formula (B) or a mixture of its homologs is reacted with phosphorus tribromide in the presence of a catalytic amount of pyridine to form polyprenyl bromide (), which is converted into polyprenyl bromide (),
It is converted into polyprenylphenyl sulfone by reaction with sodium benzenesulfinate in dimethylformamide (), while the hydroxyl protecting group (R ¹ ) at position 1 is selected from the compound of the present invention represented by the general formula (). The hydroxyl group is converted into a bromine atom () in the same manner as in the case of bromination of polyprenol, and this brominated product is reacted with, for example, tetrahydrofuran and hexamethylphosphoric triamide. The polyprenylphenyl sulfone is reacted with a carbanion produced by the action of a base such as n-butyllithium in a mixed solvent (), and the resulting condensation reaction product is reacted with lithium in a mixed solvent of ethylamine and tetrahydrofuran. Mammalian dolichols can be obtained by reductively desulfonating ( ) by reacting with and then removing the terminal hydroxyl group protecting group (R ² ) ( ). Note that the above-mentioned removal of R ¹ can be performed, for example, as follows. That is, R ¹ is the above-
In the case of CH ₂ R ³ , by reaction with lithium in a mixed solvent of ethylamine and tetrahydrofuran, and when R ¹ is

[Formula] When R ¹ is

When [Formula] is, by reaction with tetra-n-butylammonium fluoride in tetrahydrofuran,
Furthermore, when R ¹ is the above-mentioned -CH ₂ -S-R ¹⁰ , R ¹ can be separated by reaction with mercuric chloride in a mixed solvent of acetonitrile and water. In addition to the methods described above, a wider range of known methods can be used to eliminate the group R ² . The mammalian dolichols thus obtained are used as pharmaceuticals,
It is useful as a physiologically active substance or as a base in the cosmetics field. The present invention will be explained below using Examples and Reference Examples. Reference example 1 Synthesis reaction of 4-acetoxy-2-methyl-2(Z)-butenylbenzyl ether 56 g of propargyl alcohol, benzyl chloride
A mixture of 63.3 g, 30 g of NaOH, and 400 ml of benzene was heated to reflux for 5 hours with stirring. After cooling, the reaction solution was poured into water and extracted with ethyl ether.
Wash the ethyl ether layer with saturated aqueous NaCl solution,
Dry with anhydrous _MgSO4 . After removing the solvent, 58.1 g of propargyl benzyl ether was obtained by distillation.
bp50-54°C/0.7 Torr. Reaction 32ml of a 15% hexane solution of n-butyllithium was added dropwise to a solution of 7.3g of propargyl benzyl ether in 50ml of tetrahydrofuran at -30°C. After 1 hour, 4.7 g of methyl chlorocarbonate was added, and the temperature was raised to room temperature. The reaction solution was poured into diluted hydrochloric acid and extracted with ethyl ether. The ethyl ether layer was washed twice with saturated aqueous NaHCO ₃ and dried over anhydrous MgSO ₄ . The solvent was distilled off and Kugelrohr distillation (120-140℃/
0.3 Torr), 3.95 g of methyl 4-benzyloxy-2-butyrate was obtained. Reaction 3.81 g of cuprous iodide in 25 ml of tetrahydrofuran
A 5% solution of methyllithium in ethyl ether was added dropwise to the suspension at 0°C. The reaction solution passed through a yellow suspension and became a transparent solution, and at this point, the dropwise addition of methyllithium was stopped. The resulting dimethyllithium cuprate solution was cooled to -78°C, and methyl 4-benzyloxy-2-butyrate 3.71
2 ml of tetrahydrofuran solution was added. After stirring at the same temperature for 1 hour, 8 ml of methanol and then 10 ml of dilute hydrochloric acid were added, and the temperature was raised to room temperature. Ethyl ether was added to the reaction solution, filtered through Celite, and the ethyl ether layer was washed with water and saturated _NaHCO3 aqueous solution, dried over anhydrous _MgSO4 , the solvent was distilled off, and Kugelrohr distillation (120-150℃/
(Z)-44-benzyloxy-3 at 0.3Torr)
2.95 g of methyl-2-butenoate was obtained. Reaction A solution of 3.81 g of methyl (Z)-4-benzyloxy-3-methyl-2-butenoate in 20 ml of ethyl ether was added dropwise to 52 ml of a 15% hexane solution of diisobutylaluminum hydride at 0°C. After stirring at room temperature for 30 minutes, the mixture was poured into cold water, diluted hydrochloric acid was added to dissolve the white precipitate, and then extracted with ethyl ether.
The ethyl ether layer was washed with saturated _NaHCO3 water and
Dry with anhydrous _MgSO4 . The solvent was distilled off, and (Z)-4-benzyloxy-3-methyl-2- was obtained by Kugelrohr distillation (110-140°C/0.3 Torr).
1.96 g of buten-1-ol was obtained. Reaction: Add (Z)-4-benzyloxy-3- to a solution of 1.20 g of acetic anhydride and 1.01 g of pyridine in 10 ml of benzene.
Add 1.89g of methyl-2-buten-1-ol,
The mixture was heated under reflux for 1 hour. After cooling, ethyl ether was added, and the mixture was washed successively with water, diluted hydrochloric acid, water, and saturated aqueous NaHCO ₃ solution, and dried over anhydrous MgSO ₄ . After distilling off the solvent, it was purified by column chromatography using silica gel to obtain 4-acetoxy-2-methyl-2(Z)-butenylbenzyl ether 2.00
I got g. The analysis results of this compound are shown below. NMR δ ^CDCl _3ppn 1.80 (s, 3H), 1.99 (s, 3H), 4.05 (s, 2H), 4.47 (s, 2H), 4.56 (d,
2H), 5.51 (t, 1H), 7.34 (s, 5H) IRcm ^-1 (KBr film) 1740 (C=O); 1230 (C-O); 740, 700 (C ₆ H ₅ ). Reference Examples 2 and 3 Compounds in which R ¹ and R ¹¹ are the groups shown in Table 1 in the general formula () were synthesized by the same method as in Reference Example 1. The analytical values are shown in Table 1.

[Table] Example 1 Synthesis of 2-[8-benzyloxy-2,6-dimethyl-2(Z)-octenyloxy]-tetrahydro-2H-pyran Suspension of 0.32 g (13 mmol) of magnesium in 0.5 ml of tetrahydrofuran 50 ~ under argon atmosphere
A solution of 2.57 g (10 mmol) of 4-bromo-3-methylbutylbenzyl ether in 3 ml of tetrahydrofuran was added dropwise at 60°C. After the dropwise addition, the mixture was stirred at 70°C for 1 minute, and after being allowed to cool, 3.5 ml of tetrahydrofuran was added. A Grignard reagent solution was prepared as described above. (In addition, when a Grignard reagent prepared separately in the same manner was examined by acid titration after hydrolysis, it was found that the yield of the Grignard reagent preparation reaction described above was approximately 65 ± 5%. Three ports replaced with argon. To the flask 2-[4-
Acetoxy-2-methyl-2[Z]-butenyloxy]-tetrahydro-2H-pyran 1.14g
(5 mmol), 5 ml of tetrahydrofuran and
2 ml of a 0.1M tetrahydrofuran solution of Li ₂ CuCl ₄ was added thereto, and a solution of the Grignard reagent prepared from the above 4-bromo-3-methylbutylbenzyl ether was added dropwise at 0° C. for 10 minutes. 1 at the same temperature
After stirring for an hour, saturated aqueous NH ₄ Cl solution was added, poured into water, and extracted with ethyl ether. The ethyl ether layer was washed with saturated aqueous NH ₄ Cl and dried over anhydrous MgSO ₄ . Remove the solvent and Kugelrohr distillation (180
~220℃/3Torr), the distillate was purified by column chromatography using silica gel (hexane/isopropyl ether = 95/5 to 90/10 was used as the developing solution) to obtain 1.19 g of a colorless and transparent liquid. Ta.
The analysis results of this liquid are shown below. NMR δ ^CDDCl _3ppn 0.82 (d, 3H), 1.10-2.15 (m, 16H), 3.20-4.10 (m, 6H), 4.42 (s, 2H), 4.51 (m, 1H), 5.33 (m, 1H), 7.36(s,
5H) IRcm ^-1 (KBr film) 1140-1040 (C-O-C), 730, 690
(C ₆ H ₅ ) FD-MASS 346 (M ⁺ ) From the above analysis results, this liquid is 2-[8-benzyloxy-2,6-dimethyl-2(Z)-octenyloxy]-tetrahydro-2H - Confirmed that it was Piran. The yield was 69%. Examples 2 to 5 By the same method as in Example 1, in the general formula (), R ¹ is a group listed in Table 2 and R ¹¹ =CH ₃
In the compound and general formula (), R ² is as shown in Table 2.
A compound represented by the corresponding general formula () (having the groups described in Table 2 as R ¹ and R ² ) was synthesized from a compound having the group described in 1 and where X=Br. Table 2 shows its physical property values and yield.

[Table] Examples 6 to 12 In the general formula (), R ¹ is a group described in Table 2 and R ¹¹ = CH ₃
In the compound and general formula (), R ² is as shown in Table 2.
The compound represented by the corresponding general formula () (R ¹
and has a group listed in Table 2 as R ² . ) was synthesized. Table 3 shows its physical property values and yield.

【table】

[Table] Examples 13 to 16 The same procedure as in Example 1 except that the copper salts listed in Table 4 were added to 2 ml of the 0.1M tetrahydrofuran solution of Li ₂ CuCl ₄ in Example 1 in the amounts listed in the table. 2-[8-benzyloxy-2,6-dimethyl-2(Z)-octenyloxy]-tetrahydro-2H-pyran was obtained in the yield shown in the same table.

[Table] Example 17 The operation of adding the solution of Grignard reagent prepared from 4-bromo-3-methylbutylbenzyl ether in Example 1 dropwise at 0°C for 10 minutes, and then stirring at the same temperature for 1 hour, The reaction was carried out in the same manner as in Example 1 except that the temperature was changed to -20°C instead of 0°C. As a result, the yield of 2-[8-benzyloxy-2,6-dimethyl-2(Z)-octenyloxy]-tetrahydro-2H pyran was 58%.
I got it. Reference Example 4 Synthesis reaction of mammalian dolichols 12.4 g of polyprenol represented by formula (B) isolated from Japanese red pine (a mixture of homologs mainly containing m = 12, 13, 14, and 15) and 1 ml of pyridine were mixed with hexane. Add phosphorus tribromide to this solution at 0°C.
2.0g was added dropwise. After the dropwise addition, the mixture was stirred at the same temperature for 2 hours, and the reaction mixture was poured into a saturated aqueous Na ₂ CO ₃ solution and extracted with hexane. The hexane layer was washed with saturated aqueous _NaHCO3 and dried over anhydrous _MgSO4 . 12.0 g of a yellow liquid obtained by distilling off hexane was used in the next reaction. Reaction The above yellow liquid and 3.3 g of anhydrous sodium benzenesulfinate were added in 100 ml of N,N-dimethylformamide at room temperature for 20 hours, and then at 50°C for 1 hour.
Stir for hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with benzene. The benzene layer was washed with water and dried over anhydrous _MgSO4 . Distill the solvent,
Purification was performed by column chromatography using silica gel to obtain 9.4 g of a pale yellow liquid. FD-MASS analysis of this liquid is M ⁺ = 1162, 1230, 1298,
1366 was mainly observed, and it was confirmed that the peak was a mixture of sulfone homologs represented by formula (XI). Reaction 1.04 g of 2-[8-benzyloxy-2,6-dimethyl-2(Z)-octenyloxy]-tetrahydro-2H-pyran synthesized in Example 1 and 0.13 g of pyridine paratoluenesulfonate were added to 20 ml of ethanol. The mixture was dissolved and reacted at 55°C for 3 hours. After cooling, 0.21 g of Na ₂ CO ₃ was added, and ethanol was distilled off under reduced pressure. Dissolve the residue in ethyl ether and
The ethyl ether solution was washed with saturated aqueous _NaHCO3 and dried over anhydrous _MgSO4 . 0.79 g of the residue obtained by distilling off the ethyl ether was used in the next reaction. Reaction The reaction residue and 0.02 g of pyridine were dissolved in 10 ml of ethyl ether, and 0.33 g of phosphorus tribromide was dissolved at 0°C.
g was added thereto, and the mixture was stirred at the same temperature for 1 hour. saturation
The mixture was poured into an aqueous Na ₂ CO ₃ solution and extracted with ethyl ether. The ethyl ether layer was washed with saturated aqueous NaHCO ₃ and dried over anhydrous MgSO ₄ . Distill the solvent,
The remaining 0.85 g of yellow liquid was used as it was in the next reaction. When this liquid was analyzed by FDMASS, M ⁺ =
A peak of 325 was detected and R ² in equation ()
It was confirmed that it was a bromide with =C ₆ H ₅ CH ₂ . Reaction 3.01g of the sulfone homologue mixture represented by formula (XI) synthesized by reaction was added to 15ml of tetrahydrofuran.
and hexamethylphosphoric triamide 1.5
Dissolve n-butyllithium in hexane solution (1.6M) under argon atmosphere at -10℃.
After stirring at the same temperature for 15 minutes, 1 ml of a solution of 0.85 g of bromide, synthesized by the reaction and having the formula () where R ² =C ₆ H ₅ CH ₂ in tetrahydrofuran, was added dropwise. After the dropwise addition was completed, the mixture was stirred at the same temperature for 1 hour, and then stirred at room temperature overnight. The reaction solution was poured into water and extracted with methylene chloride. The methylene chloride layer was washed with water, further dried over anhydrous MgSO ₄ , the solvent was distilled off, and the residue was purified by column chromatography using silica gel to obtain 2.97 g of a pale yellow liquid. The result of FD-MASS analysis of this liquid is M ⁺ =
It mainly gave peaks of 1338, 1406, 1474, and 1542, and was confirmed to be a homologue mixture of the compound in formula (XI) where R ² =C ₆ H ₅ CH ₂ . In the formula () synthesized by reaction and reaction, R ² =
A solution of 2.97 g of a homologue mixture of the compound C ₆ H ₅ H ₂ in 20 ml of tetrahydrofuran was added dropwise to a solution of 0.30 g of lithium in 20 ml of diethylamine at -30°C. After stirring at the same temperature for 1 hour, 3 ml of isoprene was added, followed by saturated aqueous NH ₄ Cl solution. The reaction solution was poured into water and extracted with ethyl ether. The ethyl ether layer was washed with dilute hydrochloric acid, saturated aqueous _NaHCO3 , and anhydrous.
Dry with _MgSO4 . The solvent was distilled off and purified by column chromatography using silica gel.
2.29 g of a colorless and transparent liquid was obtained. The result of FD-MASS analysis of this liquid is M ⁺ =
1108, 1176, 1244, and 1312 were mainly given, and it was confirmed that they were dolichols represented by formula (A).

Claims (1)

[Claims] 1. General formula [In the formula, R ¹ and R ² are (1)—CH ₂ R ³ , provided that they do not belong to the same group at the same time.
[Formula] [Formula] and (4) - CH ₂ - S - R ¹⁰ represents a group arbitrarily selected from the following groups, where R ³ represents an aryl group, and R ⁴ and R ⁵ represent a hydrogen atom or a lower represents an alkyl group,
R ⁶ represents a lower alkyl group or a lower alkoxy lower alkyl group, or R ⁶ and R ⁴ or R ⁵
are combined to represent an alkylene group having 4 to 5 carbon atoms, R ⁷ , R ⁸ and R ⁹ represent a lower alkyl group or an aryl group, and R ¹⁰ represents a lower alkyl group. ] 2,6-dimethyl-2(Z)-octene-1,8-diol derivative shown. 2 General formula 2-methyl-2(Z)-butene-1,
4-Diol derivatives and general formula A general formula characterized by reacting a Grignard reagent represented by in the presence of a copper salt. [In the above formula, R ¹¹ represents a lower alkyl group, X represents a halogen atom, and R ¹ and R ² is (1)—CH ₂ R ₃ , provided that they do not belong to the same group at the same time.
[Formula] [Formula] and (4) - CH ₂ - S - R ¹⁰ represents a group arbitrarily selected from the following groups, where R ³ represents an aryl group, and R ⁴ and R ⁵ represent a hydrogen atom or a lower represents an alkyl group,
R ⁶ represents a lower alkyl group or a lower alkoxy lower alkyl group, or R ⁶ and R ⁴ or R ⁵
are combined to represent an alkylene group having 4 to 5 carbon atoms, R ⁷ , R ⁸ and R ⁹ represent a lower alkyl group or an aryl group, and R ¹⁰ represents a lower alkyl group. ].