JPH0222272A - Production of optically active compound - Google Patents

Abstract

PURPOSE:To obtain a 3,8-dihydroxy compound by dividing 3,4-dihydro-8-- protected-hydroxy-3-optically active acyloxy-2H-1-benzopyrane into 3R isomer and 3S isomer and eliminating the acyl group and the OH-protecting group. CONSTITUTION:A compound of formula I (A* is acyl group derived from optically active amino acid; Z is H or protecting group) is divided into 3R isomer and 3S isomer by column chromatography and the acyl group and the OH- protecting group are eliminated from the isomers in an arbitrary order to obtain (3R)- or (3S)-3,8-dihydroxy compound. The compound of formula I can be produced by reacting a compound of formula I wherein OA is OH with a compound of formula II (e.g., L-alanine having protected amino group) or by reacting a compound of formula III with a compound of formula II and reacting the product successively with a peracid and an alkali halide, etc. The obtained 3,8-di-OH compound is useful as an intermediate for a drug for circulatory system.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 3,4-dihydro-3,8-dihydroxy-
(3) is an optical isomer of 2H-1-benzobilane (1).
R) isomer (hereinafter abbreviated as (1)-R isomer) and (3S
) isomer (hereinafter abbreviated as (1)-8 isomer).

x-351 is represented by the following formula, and since there is an asymmetric carbon atom at the 6th position of the benzobylane ring and the 2nd position of the side chain, four types of optical isomers exist.

H In other words, K-351 has (2'S), (38), (
2'R) #(6R), (2'S), (i) and (2'
There are four optical isomers: R), (38). Among these optical isomers, (2'R), (3R) compounds (hereinafter abbreviated as -351 for R-R-) and (2'R-)
'S), (3R) (hereinafter S -R-K-3
It has been recognized that two isomers (abbreviated as 51) have particularly excellent medicinal efficacy (see above specification).

Methods for stereospecifically preparing these isomers are described in the above specification. That is, 3,4-dihydro-
8-Hydro='l-C5-nitroxy-2H-1-benzobilane (racemic form) is reacted with an optically active amino acid or its reactive derivative, such as N-mesyl-L-phenylalanine, to form an ester (3R ), and hydrolyzed it to obtain (3R)-3,4-dihydro-8-hydroxy-6-nitroxy-2H-1-benzobilane (■), which was treated with (2R)- or (28)
The desired (
2'R), (3R) -351 and (2'R)
, (3S) gives -351.

However, in this method, the (6R) and (3S) esters are separated and only the (6R) ester is separated, so it is impossible to increase the yield of this step above 50%. In addition, since the Rf values of these two isomers in thin layer chromatography are very similar, it is not preferable to use chromatography as a separation method, which has the disadvantage of requiring recrystallization, which is industrially disadvantageous. There is.

In order to overcome the above-mentioned drawbacks, the present inventors investigated and found that -551 and 5-R-
It is an important compound for producing -351 (SR
) -3,4-dihydro a -f3-hydroxy-6-nitroxy 2H-1-benzobilane (It) Novel and We have discovered an industrially useful manufacturing method.

(1) General formula The present invention is based on the general formula O7゜ (wherein A is an acyl group derived from an optically active amino acid,
Z represents a hydrogen atom or a hydroxyl group protecting group) is subjected to column chromatography to separate a compound having an R configuration at the 6-position and a compound having an S configuration. (6R)- or (6R)- or (
3S) -! This is a method for producing 1,4-dihydro-6,8-dihydroxy-2H-1-benzobilane.

Compounds of the formula ring can be produced by the following two methods.

(in the formula, Z has the above-mentioned meaning) to a compound represented by the general formula (V) * A -OH(V) (in the formula, Z has the above-mentioned meaning) or the reactivity in its carboxyl group Let the derivatives act.

(2) A compound represented by the general formula (in which Z has the above meaning) is reacted with a compound of formula (1) to form a compound represented by the general formula (in which each symbol has the above meaning); (1)-8 by treating this with peracid to remove the protecting group of the hydroxyl group according to the general formula.
It is a method of manufacturing the body.

The compound of formula (1) can be obtained by ring-closing 0-vanillin using acrylonitrile according to the method described in JP-A No. 59-29681, and then hydrolyzing the cyano group to form the general formula (each symbol in the formula is (having the above-mentioned meaning), and this compound is allowed to act as an alkali or a quaternary ammonium alkali.

The present invention can further be produced by converting a compound represented by the general formula (in which Z has the meaning described above) into an azide and then hydrolyzing it.

Azidation of the compound of formula X is carried out in the presence of a compound of general formula A1 represented by -OH ( ) is reduced using yeast, and then, if necessary, the transition compound represented by (each symbol in the formula has the above-mentioned meaning) is isolated, and then hydrolyzed to produce a compound with high yield. It can also be manufactured.

The method of the present invention is shown by the following reaction formula.

Examples of optically active amino acids that lead to A in compounds 2, 2, 2, and 2 include L-alanine and L-phenylalanine, and the amine groups of these amino acids are preferably protected.

As the protecting group for the amine group, those commonly used in the field of peptide synthesis can be used, including acyl groups such as acetyl group, globionyl group, benzoyl group, p-nitrobenzoyl group, mesyl group, benzenesulfonyl group, It is preferable to use a sulfonyl group such as a tosyl group, an alkyloxycarbonyl group, a cycloalkyloxycarbonyl group, an aralkyloxycarbonyl group, an aryloxycarbonyl group, and the like.

Examples of the hydroxyl protecting group for 2 of compounds 2, 2 and 2 include lower alkyl groups, aryl groups, lower alkoxycarbonyl groups, lower acyl groups, haloacyl groups, alkylsulfonyl groups, and arylsulfonyl groups. Can be mentioned.

Next, the reactions in each step will be explained.

(1) Compound (I[D) is obtained by reacting the optically active amino acid of formula (1) with compound (transformation).

The reaction is carried out by reacting the free acid of an optically active amino acid on the compound (conversion) in the presence of a dehydrating agent or condensing agent, or by
IV) with a reactive derivative of an optically active amino acid. Examples of the dehydrating agent used in this reaction include N.

Examples of the cyclocarbodiimide and the condensing agent include chlorocarbonate esters and phosphite esters. Reactive derivatives of amino acids include, for example, acid chlorides, azides, acid anhydrides, mixed acid anhydrides, active esters such as phenyl esters, cyanomethyl esters, N-
Other compounds used in peptide synthesis such as oxysuccinimide ester and N-oxyphthalic acid imide ester can be used.

In the condensation reaction, compound QV), an optically active amino acid and a dehydrating agent or a condensing agent, or a compound of formula (1) and a reactive derivative of an optically active amino acid are reacted in a solvent at 0 to 100°C in the presence or absence of a base. This is done by reacting for ~30 hours.

Examples of solvents include halogenated hydrocarbons such as chloroform and methylene chloride, hydrocarbons such as n-hexane, benzene, and toluene, ethers such as ether, dioxane, and tetrahydrofuran, pyridine, and ethyl acetate; and bases such as triethylamine. , pyridine, dimethylaminopyridine and the like.

The ester thus obtained ([[D] can be easily separated into 8- and 8-isomers by column chromatography due to the difference in Rf value. As a carrier used in the column,
Examples include silica gel, silanized silica gel, and alumina. Elution solvent: toshiteha, benzene, toluene,
Hydrocarbons such as n-hexane, alcohols such as methanol and ethanol, ethyl acetate, acetone, chloroform,
Acetonitrile, water, etc. can be used alone or in combination. A conventional elution method can be used. For example, when eluting with a mixed solvent of benzene-ethyl acetate or hexane-acetate F-/I/, 8 bodies are eluted first and then 8 bodies are eluted. . The target product can be separated and purified from the eluate by a conventional method.

(2) Hydrolyzing 8 or 8 bodies of compound (I[[),
Then, when the protecting group of the hydroxyl group is removed, the desired (1) −
8 bodies or ([)-8 bodies are obtained.

As the hydrolysis, alkaline hydrolysis is preferred. Bases used for hydrolysis include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide and barium hydroxide, and alkali carbonates such as sodium carbonate and potassium carbonate. Examples include metals. The reaction is carried out by stirring the compound (DD and base) in a solvent at 0 to 100°C for several minutes to several hours. Examples of solvents include alcohols such as methanol, ethanol, and propanol, tetrahydrofuran,
Ethers such as dioxane, acetone, acetonitrile, etc. can be used.

Removal of the protecting group for the hydroxyl group requires different reaction conditions depending on the protecting group used, but for example, when the hydroxyl group is protected by a lower alkyl group, it can be removed using hydrogen halide, such as hydrogen bromide.

The reaction is, for example, hydrolyzed into an aqueous solution of hydrogen bromide ([[
D-8 body or ([[Add D-8 body, room temperature to 200℃
The process progresses in a few minutes to a few hours at ℃.

Either of the above hydrolysis reaction and elimination reaction may be performed first (or both reactions may be performed simultaneously).

(3) Compound (2) is obtained by reacting compound (2) with optically active amino acid (V).

The reaction can be carried out in the same manner as in (1) above.

(4) Compound (4) is reacted with a peracid to obtain compound -.

As the peracid, hydrogen peroxide, peracetic acid, perbenzoic acid, methachloroperbenzoic acid, etc. are used.

The reaction is to mix compound ① and peracid in a solvent at 0 to 100℃ for 1 to 4
Proceed by stirring for 0 hours.

As the solvent, for example, halogenated hydrocarbons such as chloroform and methylene chloride, hydrocarbons such as n-hexane, benzene and toluene, and ethers such as diethyl ether, dioxane and tetrahydrofuran are used.

(5) When the compound (I) is reacted with an alkali or a quaternary ammonium halide,
is obtained.

Examples of halogen alkalis used include sodium iodide, potassium iodide, and potassium bromide; examples of quaternary ammonium halides include tetra-n-butylammonium bromide, tetra-1-butylammonium chloride, and tetra-n-butylammonium bromide. -Butylammonium iodide and the like are used.

The reaction proceeds by stirring in a solvent at room temperature to 200°C for 0.5 to 10 hours. Examples of solvents used include acetone, dimethylformamide, Improvyl alcohol, t-butyl alcohol, pyridine, and toluene.

Compound (I[I) thus obtained can be converted into (I)-R form or (1)-8 form by the method described above.

(6) Compound (XII) is obtained by azidating compound (X) in the presence of compound -. As the azidating agent, diphenylphosphoric azide or the like is used. Alternatively, an active acyl derivative of compound (X), for example, a mixed acid anhydride obtained by reacting ethyl chlorocarbonate in the presence of a base, is reacted with sodium azide in a solvent to form an acid azide, and then compound (X) is obtained. Compound (XU) can also be obtained by heating in the presence of. The reaction proceeds in a solvent in the presence or absence of a base at 0 to 200°C for 0.5 to 10 hours. Various solvents can be used, and the alcohol of formula (2) can also be used in excess to serve as a solvent. As the base, for example, triethylamine, pyridine, dimethylaminopyridine, etc. can be used.

(7) When compound (Xll) is hydrolyzed, compound ((
company) is obtained.

Hydrolysis is carried out using an acid or an alkali, with acid hydrolysis being preferred. As the acid, it is preferable to use mineral acids such as hydrochloric acid and sulfuric acid.

The reaction is completed in a solvent at 0 to 100°C in 0.5 to 10 hours. Examples of solvents include chloroform, halogenated hydrocarbons such as methylene chloride, n-hexane, benzene,
Hydrocarbons such as toluene, ethers, ethers such as dioxane, tetrahydrofuran, etc. are used.

(8) When compound ① is reduced by yeast, a compound (X[[l) with R configuration at the 6th position is obtained. As the yeast used at this time, yeast belonging to the genus Saccharomyces is preferable, particularly baker's yeast [Saccharomyces cerevisiae (Saccharomyces cerevisiae)].
charomyces cervisiae)] is preferred. In addition, microorganisms commonly used in the process of reducing ketone bodies to alcohol can also be used. This reaction is completed by reacting compound (1) with yeast in an amount of 2 times or more by weight in an aqueous medium at 0 to 60°C, preferably around room temperature, for 0.5 to 20 hours. In addition to sugars such as glucose and sucrose, substances that promote the progress of this reaction, such as emulsifiers, alcohols, and acetone, can also be added to this reaction system.

(9) When the protecting group for the hydroxyl group of compound (X[II) is removed, the desired (1)-R form is obtained.

The reaction can be carried out in the same manner as in (2) above.

The (1)-R form obtained by the present invention can be led to compound (■) by protecting the hydroxyl group at the 8-position, acting with acetyl nitrate, and then removing the protecting group of the hydroxyl group ( (Refer to the specification of Japanese Patent Publication No. 6o-54617).

In addition, for the other target compound (1)-8, the hydroxyl group at the 8-position is preferably protected, and then the hydroxyl group at the 6-position is converted into a sulfonic acid ester, and then reacted with an organic quaternary ammonium nitrate. Compound (II) can be obtained by removing the protecting group of the hydroxyl group (see JP-A-61-15847).

Therefore, compound (1) that can be advantageously produced by the present invention
Since both the -R form and the (1)-8 form can be led to compound (II), the method of the present invention eliminates the need to discard about 50% of the product in an intermediate step unlike the conventional method. This is an industrially extremely advantageous method.

Example 1 (a) 0.95 g of 3.4-dihydro-3-hydroxy-8-methoxy-2H-1-benzopyran was dissolved in 7 ml of pyridine, and N-mesyl-L-phenylalanyl was dissolved under stirring while cooling. After adding chloride 1.80.111D, the mixture was stirred at room temperature for 20 hours. After 0.7 ml of water was added to the reaction solution and the mixture was further stirred at room temperature for 20 minutes, pyridine was distilled off under reduced pressure. Chloroform and 2N-hydrochloric acid were added to the residue, and the chloroform layer was separated, washed with a saturated aqueous solution of hydrogen carbonate and water, dried, and the chloroform was distilled off. The obtained oil was applied to a silica gel column, eluted with a mixed solvent of benzene-ethyl acetate (5:1), and treated in a conventional manner to give (3S) -5 from the previous eluate.
,4-dihydro-3-(N-mesyl-L-phenylalanyloxy)-8-methoxy-2H-1-benzopyran 0.97. ! i+ (yield 45.3%) was obtained, and (6R)-3,4-dihydro-3-(N-mesyl-L-phenylalanyloxy)-8-methoxy-
2H-1-benzopyran 0.99 g (yield 46.6%
)was gotten.

(8 bodies) Colorless glassy substance Specific optical rotation: [α) D-36,8° (C=3.65, CH
Cl, )IR value CHCIscm-'aX 1767.1329.1149'' H-NMR value: δCDCl5, ppm2.62 (
3H%S, cH8so, -)2.78~5.26 (
4H,m, -0H2-Ar and C4-2H) 3.88
(5H,s, CH30-)4-OB~4-44
(3H-ml, -Cdan-NH and C2-2H) 4.82
(H, d, J=9Hz, -NH-)5.26-5.
34 (H, out, C, -H) 6, 62-6.80 (2H
lm, Ca H and C,-H)6.88 (H,t
, J=8Hz%C6-H)714~7.40(5H,
m, aromatic H) Mass spectrum value: m/z 405 (
M”) (8 bodies) Colorless needle crystal Melting point 126.0-1275°G, KBr IR value, ν 1.-1 ax 3212.1743.1321.1166″H-Texture value: δCDC 8, ppm 2 .65 (3H,s, CH35O2-)2.74~
3.24 (4H,m, -CH2-Ar and C,-2
H) 3.88 (3H,s, CH,0-)4,12~
4.48 (5H, m, )CdanNH and C, -2H)
4.82 (I H%d, J = 9Hz, -NH-
)5.24-5.64 (I H, m, C1-H)6.
62-6.80 (2H, m, C, -H and C) -H
)6.88 (I H,t, J==8Hz, c,
H) Mass spectrum value: m/z 405 (M
+) Elemental analysis value: C7゜H, No., CHN calculated value as 8 (餉) 59.25 5.72 5.45 Actual value (
餉 59.89 5.81 3.48(t)) (a
The (3S)-ester compound 864rn9 obtained in ) was dissolved in 10 mj of methanol, and while stirring at room temperature, 2.2 ml of a 2N aqueous sodium hydroxide solution was added, and the mixture was stirred for 1 hour. After adding 4N hydrochloric acid to the reaction solution to make it neutral, methanol was distilled off.

Chloroform and water were added to the residue, and the chloroform layer was separated, washed with water and dried, and the chloroform was distilled off. The residue was purified by silica gel column chromatography [eluent: ethyl acetate-n-hexane (1:1)], and ethyl acetate-n-hexane (1:1) was used.
- melting point 102-103.5 when recrystallized from hexane
(SF3)-5,4-dihydro-3-hydroxy-
8-Methoxy-2H-1-benzopyran 366my (
A yield of 95.3%) was obtained.

, KBr IR value, ν 1. −1 ax ゛H-Group JR value: δ. circle. , 3, ppm2.10 (I
H%d, J=8Hz, -OH)2.74-5.1
6 (2H,m5C42H)3.88 (6H,s,
CH30-) 4.14-4.22 (2H, m, C
2-2H) 4.2(] ~ 4.32 (I H, mSC,
-H) 6.64 to 6.78 (2H, m, C5-H and C7-H) 6.86 (I H,t, J = 8Hz
%CoH) Elemental analysis value: C+oH+CH as tOs Calculated value%) 66.65 6.71 Actual value ((6
) 66.70 6.60 (c) 712 m9 of the C58)-8-methoxy compound obtained in (b) was added to 4.3 ml of 47% aqueous hydrogen bromide solution, and reacted for 70 minutes at a bath temperature of 115°C. The reaction mixture was cooled with ice water, adjusted to pH 2 by adding an aqueous sodium hydroxide solution while stirring, and extracted with ethyl acetate. The extract was washed with saturated brine, dried and the solvent was distilled off. The residue was subjected to silica gel column chromatography (eluent: chloroform-acetone (1:1)
)] and recrystallized from acetone-n-hexane to give (38)-3,4-dihydro-3,8-dihydroxy-2H-1-be/Sohiran 592 da( A yield of 90.2%) was obtained.

IR value KBr, -・ aπ ax 3560 (OH) 'H-NMR value: δCD, OD, ppm2.52~5
．． 18 (2H, m, C4-2H) 5.80-4.28
(3H, m, C, -2H and C, -H) 6.44-6.
78 (!IH, m, aromatic H) elemental analysis value: CgH
,. CH calculated value as O8 ((6) 65.05 6.07 actual value%)
65.05 6.06 Example 2 (a) Reaction in the same manner as in Example 1(b) using the (6R)-ester compound 860 obtained in Example 1(a),
After treatment and recrystallization from ethyl acetate-n-hexane,
(3R)3-hydroxy-8 with melting point 102~10&5°C
-Methoxy-3,4-dihydro-2H-1-benzobilane 676~ (yield 98.0%) was obtained.

Specific optical rotation [α]23-H6,1° (c=4, CHCIg
) IR value: Same as (38) H-NMR value: Same as (5S) Elemental analysis value:
C+oH+□○, CH Calculated value (%) 66.65 6.71 Actual value (%)
66.69 6.77(b) Obtained in (a) (
Example 1 using 780 μ of 6R)-8-methoxy compound
When reacted and treated in the same manner as (c) and recrystallized from acetone-n-hexane, (6R
)-3,4-dihydro-6,8-dihydroxy-2H-
1-benzopyran 662~ (yield 92.0%) was obtained.

Specific optical rotation: [α) -45,8° (C=3, 'I'H
F) IR value = same as S-form 'H-NMR value = same elemental analysis value as R-form' co) (to o, OH Calculated value (candle 65.05 6.07 Actual value (%J 65.15 6 .05 Example 3 (a) 1.67 g of 2-allyl-6-medoxyphenol
was dissolved in 16 ml of pyridine, 4.0 g of N-mesyl-L-phenylalanyl chloride was added to the solution under stirring under water cooling, and the mixture was stirred at room temperature for 15 hours. 2.5 ml of water was added to the reaction solution, and the mixture was stirred at room temperature. After stirring for 20 minutes, pyridine was distilled off under reduced pressure.The residue was dissolved in chloroform, washed successively with 2N-hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and water, dried, and chloroform was distilled off to obtain crude crystals. 3゜8
g was obtained. When this was recrystallized from methanol, 3.6 g of 2-allyl-6-methoxyphenyl-N-mesyl-L-phenylalanyle-
A yield of 90.8%) was obtained.

, KBr IR value, ν 1. -1 max 6267.1767.1327.1144' H-NM
R value: δCDCL, ppm2.70 (5H,s,
CHsSOz )3.06~3.46 (2H,m,
-CH2-CH=CH2)5.24 (2H,d,
J = 7Hz, -CH2-Ar)3.80 (3H,
s, CH30-)4.62~4-74 (H1m
-y CHNH) 4.88 to 5.12 (3H, m,
-NH and -CH=CH,)5.76-5.96 (H
, m, -CH=CH1)6.82~6.92 (2H
, m, c, -H and C, -H)7, 18 (j H,
t, J = BHz%C4-H)7.34(5H,s,
Aromatic H) Elemental analysis value: HN as C, oH, 3NOsS Calculated value tA) 61.68 5.95 3.60 Actual value (□□□ 61.72 6.00 5.61(b)
1.8 g of the ester obtained in (a) was added to chloroform.
The solution was dissolved in 4 ml, 1.4 J of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 20 hours.

The precipitated white precipitate was dissolved by adding 20 at of chloroform, washed with an aqueous sodium bisulfite solution, a saturated aqueous sodium bicarbonate solution, and then water, dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography [eluent: chloroform-methanol (100:1)] to give 2-
(2,3-epoxy)propyl-6-methoxyphenyl-N-mesyl-L-phenylalanyle-) 1.8.
9 (yield 96.0%) was obtained.

IR value: I/KBr" max - 3260.1771.1314.1145 Mass spectrum value: m/z 405 (M) (C) 1.0 g of the epoxy compound obtained in (b) was dissolved in 5 d of acetone, Add 0.37 g of sodium iodide and boil at a bath temperature of 55°C.
Stir for hours.

Acetone was distilled off from the reaction solution, and the residue was dissolved in chloroform, washed with water, and then dried. The oil obtained by distilling off the solvent was separated and purified by column chromatography in the same manner as in Example 1(a), yielding 473 8-units (yield 47.6%) and 476 8-units (yield 47%). .6%) was obtained.

(8 bodies) Specific rotation: [a] -374° (c=13s, r:H
cl, ) IR value: Same as the 8 bodies obtained in 1(a)'
H-NMR value: Same mass spectrum value as 8 bodies obtained with Na): m/z 405 (M”) (8 bodies) Melting point: 125-127°C Specific optical rotation: [α] -1,8° (c=5.33, CH
Cl3) IR value: Same as 8 bodies obtained in 1(a)'H
-NMR value: Same mass spectrum value as 8 bodies obtained with Na): m/z 405 (M”) Example 4 (a) 15.0 g of 3-(8-methoxy-2H-1-benzopyran)carboxylic acid , diphenyl phosphate azide 2
0.0 g and triethylamine 7,49 were added to 170 m/t-butyl alcohol, and the mixture was refluxed at a bath temperature of 100°C for 3 hours.

The t-butyl alcohol was distilled off from the reaction solution under reduced pressure, and the residue was dissolved in benzene and washed twice with a 2N aqueous sodium hydroxide solution and then twice with saturated brine. The solvent was distilled off, the residue was purified by silica gel column chromatography (eluent: chloroform), and recrystallized from ether-n-hexane to give 6-(
N-t-butyloxycarbonylamino)-8-methoxy-2H-1-benzopyran 15°2.9 (yield 75
．． 3%) was obtained.

IR value: Br, cIL-'3331.1732' H-NMR value: δCDCl, ppm 1.50 (9
H, s, -c(CH3)! >3.86 (5H,s,
CHIO-)4.80 (2H,s, C2-2H)6
．． 02 (I H, br, s, -NH- or C4-
H) 6.48 (I H, br, s, -NH- or C
4-H) 6.58-6.74 (2H, m, C5=H and C, -H) 6.84 (I H, t, J = 811
z, CoH) Elemental analysis value: CHN Calculated value (as C15H19NO4) 64.97 6.915.05 Actual value (3
) 64.94 6.84 5.0!1 (bl France)
10.4 g of the 6-amine compound obtained above was dissolved in 45 ml of tetrahydrofuran, and 64 ml of 6N-hydrochloric acid was added at room temperature, followed by stirring for 4 hours.

After the reaction, sodium hydrogen carbonate was added little by little while stirring under water cooling to adjust the pH to 7, followed by extraction with benzene. After washing the extract with water and drying, the solvent was distilled off, and the residue was subjected to silica gel column chromatography [eluent: Hensen-chloroform (2
:1)) and recrystallized from benzene-n-hexane to give 6,4-dihydro-8-methoxy-3-oxo-2H-1-benzobilane 5.1 with a melting point of 78-81°C.
g (yield 76.3%) was obtained.

, KBr IR value, ν, (m-'aX'H-NMR value: δCDCl,, ppm3.62 (
2H,s, C4-2H)3.92 (3H,s,
CH30-)4.47 (2H% s, C2-2H)6
．． 74 (IH%d, J=81'lz, C, -H or C7-H) 6.86 (IH,d, J=8Hz,
C6-H or C7-H)7,01 (1H,t, J
=8Hz, C, -H) Elemental analysis value: clOHl. 03
As CH Calculated value %) 67.41 5.66 Actual value ((6
) 67.58 5.58 (cl (3.0 g of 3-oxo compound obtained in bl) and stirred for hours.

Ethyl acetate was added to the reaction solution, stirred for 10 minutes, filtered, and the ethyl acetate layer was separated from the p solution. This solution was washed with saturated brine, dried, and the solvent was distilled off. The resulting crude crystals were washed with n-hexane and subjected to silica gel column chromatography [eluent: chloroform-methanol (
When purified with 30:1)), 2.84g of colorless crystals were obtained.
(Yield 96.6%) was obtained. This is ethyl acetate-n
- When recrystallized from hexane, (5R) -3-hydroxy-8-
2.61 g (yield: 86.0%) of methoxy-6,4-dihydro-2H-1-benzobilane was obtained.

Specific optical rotation: [α] + 15.0° (C = 4, CHCl,)
IR value: Same as the compound of Example 2(a) 'H-NMR value: Same as the compound of Example 2(a) Optical purity: 88.4%
ee (measured by chiral high performance liquid chromatography after induction into 5-mesyloxylated metal) Elemental analysis value: C1°HI20. As CH Calculated value k) 66.65 6.71 Actual value ^)
66.46 6.70 When this compound was further recrystallized from ethyl acetate-n-hexane, a product with a recovery rate of 90% and an optical purity of 91.6%ee was obtained.

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (III) (In the formula, A^* is an acyl group derived from an optically active amino acid, and Z is a hydrogen atom or a protecting group for a hydroxyl group. ) is subjected to column chromatography to separate a compound whose 3-position is R and a compound whose 3-position is S,
(3R)- or (3S)-3,4-dihydro-3,8-dihydroxy-2H-1, which is characterized in that the protecting groups for the acyl group and hydroxyl group of these compounds are then removed in any order. -Production method of benzopyran. 2. The first one in which the optically active amino acid leading to A^* is L-alanine or L-phenylalanine with a protected amino group.
A method as claimed. 3. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) (In the formula, Z represents a hydrogen atom or a protecting group for a hydroxyl group.) The compound represented by the general formula A^*-OH (V) (formula The formula thus obtained is obtained by reacting a compound represented by (A^* indicates an acyl group derived from an optically active amino acid) or a reactive derivative of its carboxyl group.
Process according to claim 1, characterized in that a compound of III is used. 4. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VI) (in the formula, Z represents a hydrogen atom or a hydroxyl group protecting group). ^* indicates an acyl group derived from an optically active amino acid) or a reactive derivative of its carboxyl group is reacted with the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VII) (in the formula (Each symbol has the meaning given above) is a compound represented by a peracid, and the obtained general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (VIII) (Each symbol in the formula has the meaning given above) The method according to claim 1, characterized in that the compound represented by formula III is reacted with a halide alkali or a quaternary ammonium halide, and the thus obtained compound of formula III is used. 5. The compound represented by the general formula ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ (IX) (in the formula, Z represents a hydrogen atom or a protecting group for a hydroxyl group) is reduced using yeast, and then the hydroxyl group is removed as necessary. (3R) characterized by removing a protecting group
-3,4-dihydro-3,8-dihydroxy-2H-1
-Production method of benzopyran. 6. The method according to claim 5, characterized in that the reduction is carried out using baker's yeast in an aqueous medium. 7. General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (X) (In the formula, Z represents a hydrogen atom or a hydroxyl group protecting group) After making the compound represented by an acid azide compound, the general formula Alk-OH ( X I ) (In the formula, Alk represents a lower alkyl group) is reacted with the compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (XII) (Each symbol in the formula has the above meaning. 6. Process according to claim 5, characterized in that the compound of formula IX obtained in this way is used.