JPS6338972B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an optically active diol derivative represented by the general formula ArOCH ₂ CH (OH) CH ₂ OH - () (wherein Ar is an aromatic group). .

The optically active diol derivative represented by the general formula () obtained in the present invention has an optically active β-
It is a useful compound that can be converted into a blocker (see, for example, J.Org.Chem. 43.3641 (1978)). β
-The optically active form of Brotzker is more active than the racemic form [see J.Med.Chem., 11 , 1118 (1968). ] Therefore, there is a need for a method for selectively obtaining optically active substances.

Conventionally, a method using optically active 3-tosyloxy-1,2-propanediol acetonide has been known as a typical method for synthesizing optically active diol derivatives (). However, this compound can be produced by (a) a method that requires more steps than D-mannitol [see J.Org.Chem., 43 , 3461 (1978); ]
and (b) a method in which a half ester obtained by reacting glycerin 1,2-acetonide with phthalic anhydride is optically resolved with an optically active amine, and then glycerin 1,2-acetonide is regenerated and tosylated ( However, these methods require complicated steps and expensive reagents, and are problematic as industrial methods.

The present inventors have discovered that optically active diol derivatives,
The method of the present invention has been completed through intensive research into a method that can be synthesized in a short and easy manner.

The present invention is for producing an optically active diol, and in this case, the desired product can be obtained without any racemization.

The present _invention is carried out under basic conditions using the general formula _: . ) by reacting an optically active halohydrin derivative represented by the general formula ArOH - () (wherein Ar is an aromatic group) with an alcohol represented by the general formula ArOH - () (wherein Ar is an aromatic group). It produces active diol derivatives.

The optically active halohydrin derivative represented by the general formula (), which is a raw material of the present invention, is a 1,2-
It is a compound that can be easily obtained by asymmetric hydrolysis of diacyloxy-3-halopropane using lipase (see Reference Examples below), for example, optically active 1,2-diacetoxy-3-chloropropane, 1, 2-diacetoxy-3-bromopropane, 1,2-dipropionyloxy-3-chloropropane, 1-acetoxy-2-hydroxy-3
-chloropropane, 1-hydroxy-2-acetoxy-3-chloropropane, and the like. The amount of these halohydrin derivatives used is preferably at least the equivalent molar amount to the aromatic alcohol.

The aromatic alcohol represented by the general formula (), which is one of the raw materials, is a compound that is easily available as an industrial raw material. Roxyphenol, 4-
Acetylaminophenol, 2-chloro-5-methylphenol, 2-acetyl-4-butyrylaminophenol, 1-naphthol, 4-hydroxyindole, 5-hydroxyindole, 5-
Hydroxycoumarinamide and the like can be mentioned.

The present invention requires that it be carried out in the presence of a base. As the base, for example, alkali metal alkoxides such as sodium methoxide and sodium ethoxide can be used, but alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate can also be used. , alkaline earth metal hydroxides such as calcium hydroxide, etc. can be used. The amount of base used is 5 equivalent moles or more based on the halohydrin derivative.
It is preferable to use a molar amount because the reaction proceeds smoothly.

In carrying out the present invention, it is desirable to use a solvent, including alcoholic solvents such as methanol and ethanol, diethyl ether, tetrahydrofuran,
Ether solvents such as dioxane, mixed solvents of these solvents and water, and single solvents of water can be used, but aqueous solvents mainly composed of water are preferable since the yield can be improved. The reaction usually proceeds smoothly at room temperature to 80°C.

Hereinafter, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Example 1 [α] 1,2 with ²⁵ _D -4.5° (c1.10, MeOH)
-Diacetoxy-3-chloropropane 1.4g, 4-
Chlorophenol 454mg, calcium hydroxide 1.33g
Add 30ml of water to 1g of Hyflo Super Cell,
Stirred at 50-60°C for 2 hours. After cooling, the solids were filtered off and the filtrate was extracted with methylene chloride. The organic layer was dehydrated with sodium sulfate and then concentrated to obtain crystals. Recrystallize from ethyl acetate/hexane to obtain [α] ²⁵ _D
3-(4-chlorophenoxy)-1,2-propanediol with +7.63° (c1.2, MeOH) 421
mg (59%).

Example 2 [α] 1,2 with ²⁵ _D −5.24° (c1.0, MeOH)
-Diacetoxy-3-chloropropane 1.03g, 2
-20 ml of water was added to 446 mg of allyloxyphenol and 976 mg of calcium hydroxide, the atmosphere was replaced with argon, the mixture was sealed tightly, and the mixture was stirred at 60°C for 2 hours. After cooling, the mixture was extracted with ethyl acetate. After dehydration and concentration, it was dissolved in methylene chloride and subjected to silica gel chromatography. Elute with methylene chloride containing 6-10% ethyl acetate, [α] ²⁰ _D +8.00 (c0.10, EtOH) [see literature value (J.Org.Chem., 43 , 3641 (1978)): [α] ²⁰ _D +
3-(2-aryloxyphenoxy)-1,2-propanediol with 7.7゜(c0.094, EtOH)]
Obtained 246 mg (37%).

Example 3 [α] 1,2 with ²⁵ _D −5.1° (c1.0, MeOH)
-Diacetoxy-3-chloropropane 1.6g, 1-
40 ml of water was added to 576 mg of naphthol, 1.48 g of calcium hydroxide, and 1 g of Hyflo Supercel, and the mixture was heated to 50°C over 1 hour from room temperature and stirred at 50 to 55°C for 2 hours. After cooling, the mixture was extracted with ethyl acetate and filtered. The solid matter on the filter paper was washed with ethyl acetate, and the filtrate aqueous layer was re-extracted using this ethyl acetate. The ethyl acetate layers were combined, dried, and concentrated. Dissolve the concentrate in a small amount of ethyl acetate and methylene chloride, perform silica gel chromatography, and elute with methylene chloride containing 1-3% ethyl acetate, [α] ²⁵ _D +
450 mg (52%) of 3-(1-naphthoxy)-1,2-propanediol with 7.12° (c1.08, MeOH)
I got it.

Example 4 [α] 1,2 with ²⁵ _D -6.22° (c1.0, MeOH)
-Diacetoxy-3-bromopropane 1.04g, 1
- 20 ml of water was added to 302 mg of naphthol, 794 mg of calcium hydroxide, and 0.5 g of Hyflo Supercel, and the mixture was heated to 50°C over 1 hour from room temperature and stirred at 50 to 60°C for 2 hours. After cooling, extraction with ethyl acetate was carried out in the same manner as in Example 3. [α] ²⁵ _D +5.78° (c1.1,
3-(1-naphthoxy)-1 with MeOH),
247 mg (54%) of 2-propanediol was obtained.

Example 5 [α] 1 with ²⁵ _D −5.52° (c1.23, MeOH),
2-diacetoxy-3-chloropropane 192mg,
66 mg of 5-hydroxyindole, 185 mg of calcium hydroxide, and 0.1 g of Hyflo Super Cell to 3.5 g of water.
ml and stirred at 50-60°C for 2 hours. After cooling,
Extracted with ethyl acetate, dried and concentrated. The concentrate was dissolved in methylene chloride and subjected to silica gel chromatography, eluting with methylene chloride containing ^2-10 % ethyl _acetate .
51 mg (49.5%) of 5-(2,3-dihydroxypropyloxy)indole with (MeOH) was obtained.

Reference Example 1 In a 500 ml Erlenmeyer flask, 0.14 mg of lipoprotein lipase Amano 40 was dissolved in 150 ml of 0.2 M sodium phosphate buffer (PH7). there
6 g of 1,2-diacetoxy-3-chloropropane was added and shaken on a reciprocating rotary shaker overnight at room temperature. Extract with hexane, wash with water to remove alcohol, dehydrate and concentrate to obtain [α] ²⁵ _D -4.9° (c1.02,
1.235 g (20.6%) of (S)-1,2-diacetoxy-3-chloropropane with (MeOH) was obtained.

Reference Example 2 0.03 mg of lipoprotein lipase Amano 40 was dissolved in 90 ml of 0.2 M sodium phosphate buffer (PH7) and placed in a 500 ml Erlenmeyer flask. 3.6 g of 1,2-diacetoxy-3-chloropropane was added thereto, and the mixture was shaken on a reciprocating rotary shaker at room temperature overnight.
After extraction with 50 ml of hexane five times to remove unreacted diacetate, extraction with ethyl acetate, dehydration, concentration, and alcohol (1-hydroxy-2-
It was estimated to be a mixture of acetoxy-3-chloropropane and 1-acetoxy-2-hydroxy-3-chloropropane. ) 761 mg (27%) was obtained.

Example 6 [α] 1,2 with ²⁵ _D -5.03° (c1.3, MeOH)
-Diacetoxy-3-chloropropane 560mg, 4
-Hydroxyindole 200mg, calcium hydroxide 570mg and Hyflo Super Cell 600mg plus water 30ml
was added and stirred at 50-60°C for 2 hours. After cooling, the mixture was extracted with ethyl acetate, dehydrated, and concentrated. The concentrate was dissolved in methylene chloride and subjected to silica gel chromatography, eluting with ^methylene chloride containing 2-10% ethyl _acetate .
147 mg (47%) of 4-(2,3-dihydroxypropyloxy)indole with MeOH) were obtained. This was recrystallized from ethyl acetate/hexane.
mp120-121℃.

Example 7 Add 10 ml of water to 305 mg of alcohol, 150 mg of 1-naphthol, 377 mg of calcium hydroxide, and 0.3 g of Hyflo Supercel obtained in Reference Example 2, and heat at 50 to 60°C.
The mixture was stirred for 3.5 hours. After cooling, extract with ethyl acetate,
Dehydrated and concentrated. The concentrate was dissolved in methylene chloride and subjected to silica gel column chromatography, eluting with methylene chloride containing 2-10% ethyl acetate to obtain 3- with [α] ²⁵ _D -5.87° (c1.1, MeOH). 109 mg (48%) of (1-naphthoxy)-1,2-propanediol was obtained.

Example 8 [α] 1,2- with ²⁵ _D -4.9° (c1, MeOH)
Diacetoxy-3-chloropropane 780mg, 2-
20 ml of water was added to 248 mg of methoxyphenol and 740 mg of calcium hydroxide, and the mixture was stirred at 50 to 60°C for 2 hours. After cooling, the mixture was extracted with ethyl acetate, dehydrated, and concentrated. The concentrate was dissolved in methylene chloride, subjected to silica gel column chromatography, and dissolved in ethyl acetate.
Elute with methylene chloride containing 20-50% [α]
3-(2-methoxyphenoxy)-1,2-propanediol with ²⁵ _D +7.93° (c1.45, MeOH)
Obtained 145 mg (36.5%). Recrystallized from ethyl acetate/hexane, mp 96-97℃ and [α] ²⁵ _D +
113 mg (28.5
%) was obtained.

Claims (1)

[Claims] 1. An optically active halohydrin derivative represented by the general formula XCH ₂ CH (OY) CH ₂ OZ is reacted with an alcohol represented by the general formula ArOH under basic conditions. A method for producing an optically active diol derivative represented by the general formula ArOCH ₂ CH(OH)CH ₂ OH (where Ar is a phenyl group, substituted phenyl group, naphthyl group or indolyl group, X is a halogen atom,
Y and Z are a hydrogen atom, an acetyl group or a propionyl group, and either one is an acetyl group or a propionyl group. ). 2. The method according to claim 1, which comprises carrying out the process in an aqueous solvent.