JP2802996B2 - Production method of optically active compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 3,4-dihydro-3,8-dihydroxy-2H-
New 1-benzopyran (I) optical isomers (3R) isomer (hereinafter abbreviated as (I) -R isomer) and (3S) isomer (hereinafter abbreviated as (I) -S isomer) Related to manufacturing method.

The (I) -R form and the (I) -S form are represented by the following formulas, and are useful as circulating agents, for example, 3,4-dihydro-8.
The optical isomer of-(2'-hydroxy-3'-isopropylamino) propoxy-3-nitroxy-2H-1-benzopyran (hereinafter abbreviated as K-351) (Japanese Patent Laid-Open No. 60-208)
973).

K-351 is represented by the following formula. Since there are asymmetric carbon atoms at the third position of the benzopyran ring and the second position of the side chain, there are four types of optical isomers.

That is, (2'S), (3S),
(2'R), (3R), (2'S), (3R) and (2 '
There are four optical isomers, R) and (3S). Among these optical isomers, compounds (2′R) and (3R) (hereinafter abbreviated as RR · K-351) and (2′R)
It has been recognized that two isomers of compounds (S) and (3R) (hereinafter abbreviated as SR-K-351) have particularly excellent medicinal effects (see the above specification). .

A method for stereospecifically producing these isomers is described in the above specification. That is, 3,4-dihydro-
8-Hydroxy-3-nitroxy-2H-1-benzopyran (racemate) is reacted with an optically active amino acid or a reactive derivative thereof, for example, N-mesyl-L-phenylalanine to form an ester, which is (3R). The compound was separated and hydrolyzed to obtain (3R) -3,4-dihydro-8-hydroxy-3-nitroxy-2H-1-benzopyran (II), to which (2R)-or (2S ) The sulfonyl ester of -2,3-epoxypropanol is reacted with isopropylamine to give the desired (2'R), (3R) K-
351 and K-351 which are (2'R) and (3S) are obtained.

However, in this method, since the (3R) and (3S) esters are separated and only the (3R) ester is fractionated, it is impossible to increase the yield of this step to 50% or more. Further, since the R _f values in thin-layer chromatography of these two isomers are very similar, it is not preferable to use chromatography as a separation method, and an industrially disadvantageous recrystallization method must be performed. There is a disadvantage that it must be done.

The present inventors have studied to overcome the above-mentioned drawbacks, and as a result, have found that R-K-351 and S-R-
An important compound for producing K-351 (3R)-
3,4-dihydro-8-hydroxy-3-nitroxy-2H
A novel and industrially useful method for producing (I) -R-form and (I) -S-form which can be specifically converted to -1-benzopyran (II) has been found.

The present invention has the general formula (Wherein A ^* represents an acyl group derived from an optically active amino acid, Z represents a hydrogen atom or a protecting group for a hydroxyl group), and the compound at the 3-position is R by column chromatography. A compound and a compound that is S are fractionated,
Then, the protecting groups for the acyl group and the hydroxyl group of these compounds are eliminated in an arbitrary order, and are characterized in that (3R)-or (3S) -3,4-dihydro-3,8-dihydroxy-2H-1. −
This is a method for producing benzopyran.

Compounds of formula III can be prepared in two ways:

(1) General formula (Wherein Z has the above-mentioned meaning) and a compound represented by the general formula (V) A ^* -OH (V) (where A ^* has the above-mentioned meaning) or a reaction at a carboxyl group thereof Activated derivative.

(2) General formula (Wherein Z has the above-mentioned meaning) by reacting a compound of the formula V with a compound of the general formula (Each symbol in the formula has the same meaning as described above), which is reacted with a peracid to form a compound represented by the general formula (Wherein each symbol has the same meaning as described above), and a halogeno alkali or a quaternary ammonium halide is allowed to act on this compound (VIII).

The present invention further provides a compound of the general formula (Wherein Z has the above-mentioned meaning) is a method for producing an (I) -R-form by reducing a compound represented by the formula (I) with yeast, and then removing a hydroxyl-protecting group, if necessary. .

The compound of the formula IX can be obtained by subjecting o-vanillin to ring closure with acrylonitrile according to the method described in JP-A-59-29681, and then hydrolyzing the cyano group to give a compound of the general formula (Wherein Z has the meaning described above), which can be produced by subjecting this compound to azido conversion and hydrolysis.

The azidation of the compound of formula X is carried out in the presence of a compound of the general formula Alk-OH (XI) (where Alk represents a lower alkyl group), (The symbols in the formula have the same meanings as described above.) The compound can also be produced in a high yield by isolating and then hydrolyzing the compound.

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

Examples of optically active amino acids that lead to A ^* of the compounds of formulas III, V, VII and VIII include L-alanine, L-phenylalanine and the like, and it is preferable to protect the amino group of these amino acids. As the protecting group for the amino group, those usually used in the field of peptide synthesis can be used, and an acyl group such as an acetyl group, a propionyl group, a benzoyl group, a p-nitrobenzoyl group, a mesyl group,
It is preferable to use a sulfonyl group such as a benzenesulfonyl group and a tosyl group, an alkyloxycarbonyl group, a cycloalkyloxycarbonyl group, an aralkyloxycarbonyl group, and an aryloxycarbonyl group.

Hydroxyl protecting groups for Z in compounds of formulas III, IV and VI-XII include lower alkyl, aryl, lower alkoxycarbonyl, lower acyl, haloacyl,
Examples thereof include an alkylsulfonyl group and an arylsulfonyl group.

 Next, the reaction of each step will be described.

(1) Compound (III) is obtained by reacting compound (IV) with an optically active amino acid of formula V.

The reaction is carried out by reacting compound (IV) with the free acid of an optically active amino acid in the presence of a dehydrating agent or a condensing agent, or by reacting compound (IV) with a reactive derivative of an optically active amino acid. . Examples of the dehydrating agent used in this reaction include N, N'-dicyclocarbodiimide, and examples of the condensing agent include chlorocarbonates and phosphites. 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-oxysuccinimide esters,
Those used in the synthesis of other peptides, such as N-oxyphthalimide ester, can be used.

The condensation reaction is carried out by subjecting the compound (IV), an optically active amino acid and a dehydrating agent or a condensing agent, or a compound of the formula I and a reactive derivative of the optically active amino acid to 0-100 ° C. in a solvent in the presence or absence of a base. It is carried out by reacting for 1 to 30 hours.

As the solvent, for example, chloroform, halogenated hydrocarbons such as methylene chloride, n-hexane, benzene, hydrocarbons such as toluene, ethers, dioxane, ethers such as tetrahydrofuran, pyridine, ethyl acetate and the like,
Examples of the base include triethylamine, pyridine, dimethylaminopyridine and the like.

The ester (III) thus obtained can be easily separated into R-form and S-form by column chromatography due to the difference in _Rf value. As the carrier used for the column,
Examples include silica gel, silanized silica gel, and alumina. As the elution solvent, benzene, toluene,
Hydrocarbons such as n-hexane, alcohols such as methanol and ethanol, ethyl acetate, acetone, chloroform,
Acetonitrile, water and the like can be used alone or in combination. As the elution method, a usual method can be adopted. For example, when eluting with a mixed solvent of benzene-ethyl acetate or hexane-ethyl acetate, the S form is eluted first, and then the R form is eluted. The target substance can be separated and purified from the eluate by a usual method.

(2) hydrolyzing the R-form or S-form of compound (III),
Then, when the protecting group for the hydroxyl group is eliminated, the desired (I) -R
Or (I) -S form.

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

The reaction conditions for the elimination of the hydroxyl-protecting group vary depending on the protecting group used.For example, when the hydroxyl group is protected by a lower alkyl group, the elimination can be carried out using a hydrogen halide, for example, hydrogen bromide. it can. The reaction proceeds, for example, by adding the hydrolyzed (III) -R form or (III) -S form to an aqueous solution of hydrogen bromide, at room temperature to 200 ° C. for several minutes to several hours.

Either the hydrolysis reaction or the elimination reaction may be performed first, or both reactions may be performed simultaneously.

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

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

(4) Compound (VIII) is obtained by reacting compound (VII) with a peracid.

As the peracid, hydrogen peroxide, peracetic acid, perbenzoic acid, methachloroperbenzoic acid and the like are used. The reaction proceeds by stirring compound (VII) and the peracid in a solvent at 0 to 100 ° C for 1 to 40 hours. Examples of the solvent include 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.

(5) Compound (VIII) is reacted with halogenoalkali or quaternary ammonium halide to give compound (III).

Examples of halogenoalkali include sodium iodide,
Potassium iodide, potassium bromide and the like are used. As the quaternary ammonium halide, for example, tetra-n-butylammonium bromide, tetra-t-butylammonium chloride, tetra-n-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. As the solvent, for example, acetone, dimethylformamide, isopropyl alcohol,
T-butyl alcohol, pyridine, toluene and the like are used.

The compound (III) thus obtained can be converted to the (I) -R form or (I) -S form by the above-mentioned method.

(6) Azide compound (X) in the presence of compound (XI) gives compound (XII). As the azidating agent, diphenylphosphoric acid azide and the like are used. Further, an active azide derivative of compound (X), for example, a mixed acid anhydride obtained by the action of ethyl chlorocarbonate in the presence of a base is reacted with sodium azide in a solvent to form an acid azide, and then the compound (XI) Compound (XII) 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 as the solvent.
It is also possible to use the alcohol of I) in excess to double as a solvent. As the base, for example, triethylamine, pyridine, dimethylaminopyridine and the like can be used.

(7) The compound (XII) is hydrolyzed to give the compound (I
X) is obtained.

The hydrolysis is carried out using an acid or an alkali, but hydrolysis with an acid is preferred. As the acid, a mineral acid such as hydrochloric acid or sulfuric acid is preferably used. The reaction is carried out in a solvent at 0 to 10
Finish in 0.5-10 hours at 0 ° C. Examples of the solvent include halogenated hydrocarbons such as chloroform and methylene chloride, n
-Hydrocarbons such as hexane, benzene, and toluene; ethers such as ether, dioxane, and tetrahydrofuran;

(8) Reduction of compound (IX) with yeast gives compound (XIII) having an R configuration at the 3-position. As the yeast used at this time, yeast belonging to the genus Saccharomyces is preferable, and especially baker's yeast [Saccharomyces cerevisiae (Sacc.
haromyces cervisiae)] is preferred. In addition, microorganisms commonly used in the step of reducing ketone bodies to alcohols can also be used. This reaction is completed by reacting the compound (IX) with 2 times or more by weight of yeast in an aqueous medium at 0 to 60 ° C, preferably at about room temperature, for 0.5 to 20 hours. In addition to substances such as glucose, sucrose and the like, emulsifiers, alcohols, acetone, and other substances that promote the progress of the reaction can be added to the reaction system.

(9) The desired protecting group (I) -R is obtained by removing the hydroxyl-protecting group of compound (XIII).

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

The (I) -R form obtained according to the present invention can be converted into the compound (II) by protecting the hydroxyl group at the 8-position, reacting with acetyl nitrate, and then removing the hydroxyl-protecting group. (See Japanese Patent Publication No. 60-54317).

Further, the other target compound (I) -S isomer is preferably protected by protecting the hydroxyl group at the 8-position, then sulfonating the hydroxyl group at the 3-position, and then reacting with a nitrate of an organic quaternary ammonium, and The compound (II) can be obtained by removing the protecting group for the hydroxyl group accordingly (see JP-A-61-15847).

Therefore, the compound (I) -R form and (I) -S form which can be advantageously produced according to the present invention can be converted to the compound (II). In this step, it is not necessary to discard about 50% of the product, and all of the product can be used, which is an industrially 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 chloride 1.80 was dissolved under cooling and stirring. g was added and stirred at room temperature for 20 hours. After the reaction, 0.7 ml of water was added, and the mixture was further stirred at room temperature for 20 minutes, and then pyridine was distilled off under reduced pressure. Chloroform and 2N for residue
-Hydrochloric acid was added, the chloroform layer was separated, washed with a saturated aqueous solution of sodium 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)
-3,4-Dihydro-3- (N-mesyl-L-phenylalanyloxy) -8-methoxy-2H-1-benzopyran
0.97 g (45.3% yield) was obtained.
-3,4-Dihydro-3- (N-mesyl-L-phenylalanyloxy) -8-methoxy-2H-1-benzopyran
0.99 g (46.3% yield) was obtained.

(S form) Colorless glassy substance Specific rotation: ▲ [α] ²² _D ▼ -36.8 ゜ (c = 3.33, CHCl ₃ ) 1737, 1329, 1149 _{2.62 (3H, s, CH 3} SO 2 -) 2.78~3.26 (4H, m, -CH 2 -Ar , and _{C 4 -2H) 3.88 (3H,} s, CH 3 O-) 4.08~4.44 (3H, m, C H -NH and _{C 2 -2H) 4.82 (H,} d, J = 9Hz, -NH-) 5.26~5.34 (H, m, C 3 -H) 6.62~6.80 (2H, m, C 5 -H and _{C 7 -H) 6.88 (H,} t, J = 8Hz, C 6 -H) 7.14~7.40 (5H, m, aromatic H) Masukupekutoru ^{value: m / z405 (M +)} (R form) colorless needles Crystal Melting point: 126.0-127.5 ° C Specific rotation: ▲ [α] ²² _D ▼ -1.8 ゜ (c = 3.33, CHCl ₃ ) 3212, 1743, 1321, 1166 _{2.65 (3H, s, CH 3} SO 2 -) 2.74~3.24 (4H, m, -CH 2 -Ar , and _{C 4 -2H) 3.88 (3H,} s, CH 3 O-) 4.12~4.48 (3H, m, C H NH and _{C 2 -2H) 4.82 (1H,} d, J = 9Hz, -NH-) 5.24~5.34 (1H, m, C 3 -H) 6.62~6.80 (2H, m, C 5 -H and C ₇₋ H) 6.88 (1H, t, J = 8 Hz, C ₆ −H) 7.06 to 7.15 7.20 to 7.33 Mass spectrum: m / z 405 (M ⁺ ) Elemental analysis: C N calculated as C ₂₀ H ₂₃ NO ₆ S (%) 59.25 5.72 3.45 Found (%) 59.09 5.81 3.48 (b) Obtained with (a) (3S) -ester compound 864m
g was dissolved in 10 ml of methanol, and 2.2 ml of a 2N aqueous solution of sodium hydroxide was added thereto with stirring at room temperature, followed by stirring for 1 hour. The reaction solution was neutralized by adding 4N-hydrochloric acid, and then methanol was distilled off. Chloroform and water were added to the residue, the chloroform layer was separated, washed with water and dried, and chloroform was distilled off. The residue was purified by silica gel column chromatography [eluent: ethyl acetate-n-hexane (1: 1)] and recrystallized from ethyl acetate-n-hexane to give a melting point of 102-1.
(3S) -3,4-dihydro-3-hydroxy-8 at 03.5 ° C
-Methoxy-2H-1-benzopyran 366 mg (yield 95.3)
%)was gotten.

Specific rotation ▲ [α] ²³ _D ▼ -16.4 ゜ (c = 4, CHCl ₃ ) 3483 2.10 (1H, d, J = 8Hz, -OH) 2.74~3.16 (2H, m, C 4 -2H) 3.88 (3H, s, CH 3 O-) 4.14~4.22 (2H, m, C 2 -2H) _{4.20~4.32 (1H, m, C 3} -H) 6.64~6.78 (2H, m, C 5 -H and _{C 7 -H) 6.86 (1H,} t, J = 8Hz, C 6 -H) elemental analysis: C ₁₀ H ₁₂ O ₃ Calculated CH (%) 66.65 6.71 Found (%) 66.70 6.60 (c) (3S) -8-methoxy compound obtained in (b) in 4.3 ml of 47% aqueous hydrogen bromide solution Add 712mg and at bath temperature 115 ° C
The reaction was performed for 70 minutes. The reaction mixture was cooled with ice water, adjusted to pH 2 by adding an aqueous sodium hydroxide solution with stirring, and then extracted with ethyl acetate. The extract was washed with saturated saline, dried, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (eluent: chloroform-acetone (1: 1).
1)] and recrystallized from acetone-n-hexane to give (3S) -3,4-dihydro-3,8 with a melting point of 154 to 156.5 ° C.
592 mg of dihydroxy-2H-1-benzopyran (yield 90.
2%).

Specific rotation: ▲ [α] ²² _D ▼ + 45.6 ゜ (c = 3, THF) 3360 (OH) _{2.52~3.18 (2H, m, C 4} -2H) 3.80~4.28 (3H, m, C 2 -2H and _{C 3 -H) 6.44~6.78 (3H,} m, aromatic H) Elemental analysis: C ₉ H Calculated CH (%) as ₁₀ O ₃ 65.05 6.07 Actual value (%) 65.03 6.06 Example 2 (a) Example 1 (864 mg of the (3R) -ester compound obtained in Example 1 (a)) was used. Reaction and treatment in the same manner as in b), and recrystallization from ethyl acetate-n-hexane gave a melting point of
376 mg of (3R) -3-hydroxy-8-methoxy-3,4-dihydro-2H-1-benzopyran at 102-103.5 ° C (yield 9
8.0%).

Specific rotation ▲ [α] ²³ _D ▼ + 16.1 DEG _{(c = 4, CHCl 3)} IR value: (3S) same ¹ H-NMR value integral: (3S) same elemental analysis integral: C ₁₀ H Calculated CH (%) as ₁₂ O ₃ 66.65 6.71 Found (%) 66.69 6.77 (b) (3R) -8-methoxy compound obtained in (a)
Reaction and treatment were carried out in the same manner as in Example 1 (c) using 780 mg,
Recrystallization from acetone-n-hexane gave a melting point of 154-1.
(3R) -3,4-dihydro-3,8-dihydroxy-
662 mg (92.0% yield) of 2H-1-benzopyran was obtained.

Specific rotation: ▲ [α] ²² _D ▼ -45.8 ゜ (c = 3, THF) IR value: same as S form ¹ H-NMR value: same as R form Elemental analysis value: C ₉ H ₁₀ O ₃ as C H Calculated value (%) 65.05 6.07 Actual value (%) 65.15 6.05 Example 3 (a) Dissolve 1.67 g of 2-allyl-6-methoxyphenol in 16 ml of pyridine, and add N-mesyl-L- under ice-cooling and stirring.
4.0 g of phenylalanyl chloride was added, and the mixture was stirred at room temperature for 15 hours. After adding 2.5 ml of water to the reaction solution and stirring at room temperature 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 solution of sodium hydrogencarbonate and dried, and the chloroform was distilled off to obtain 3.8 g of crude crystals. This was recrystallized from methanol to give 2-allyl-6-methoxyphenyl-N-mesyl-L-phenylalanylate having a melting point of 141-142 ° C.
3.6 g (90.8% yield) was obtained.

Specific rotation: ▲ [α] ²² _D ▼ -32.4 ゜ (c = 4, CHCl ₃ ) 3267, 1767, 1327, 1144 _{2.70 (3H, s, CH 3} SO 2 -) 3.06~3.46 (2H, m, -C H 2 -CH = CH 2) 3.24 (2H, d, J = 7Hz, -CH 2 -Ar) 3.80 (3H, _{s, CH 3 O-) 4.62~4.74 (} H, m, C H -NH-) 4.88~5.12 (3H, m, -NH and _{-CH = C H 2) 5.76~5.96 (} H, m, -C H _{= CH 2) 6.82~6.92 (2H,} m, C 3 -H and _{C 5 -H) 7.18 (1H,} t, J = 8Hz, C 4 -H) 7.34 (5H, s, aromatic H) elemental analysis : C ₂₀ H ₂₃ NO ₅ S CH N Calculated value (%) 61.68 5.95 3.60 Observed value (%) 61.72 6.00 3.61 (b) 1.8 g of the ester obtained in (a) was subjected to chloroform.
The solution was dissolved in 14 ml, and 1.4 g of m-chloroperbenzoic acid was added, followed by stirring at room temperature for 20 hours.

The precipitated white precipitate was dissolved by adding 20 ml of chloroform, washed with an aqueous solution of sodium hydrogen sulfite and an aqueous solution of saturated sodium hydrogen carbonate and then 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
1.8 g (96.0% yield) of -epoxy) propyl-6-methoxyphenyl-N-mesyl-L-phenylalanilate were obtained.

Specific rotation: ▲ [α] ²² _D ▼ -31.8 ゜ (c = 4, CHCl ₃ ) 3260, 1771, 1314, 1145 Mass spectral value: m / z 405 (M ⁺ ) (c) 1.0 g of the epoxy compound obtained in (b) was dissolved in 5 ml of acetone, and 0.37 g of sodium iodide was added thereto, and the bath temperature was 55%. ° C
For 3 hours.

Acetone was distilled off from the reaction solution, the residue was dissolved in chloroform, washed with water and 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) to obtain 473 mg of the R-form (yield 47.3%) and the S-form 4
76 mg (47.6% yield) was obtained.

(S-form) Specific rotation: ▲ [α] ²² _D ▼ -37.4 ゜ (c = 3.33, CHCl ₃ ) IR value: ¹ H-NMR value: 1 (a) same as S-form obtained in (a) Mass spectrum value: m / z 405 (M ⁺ ) (R-form) Melting point: 125-127 ° C. Specific rotation: ▲ [α] ²² _D ▼ -1.8 ゜ (c = 3.33, CHCl ₃ ) IR value: the same ¹ H-NMR value as the R-form obtained in 1 (a): the same as the R-form obtained in 1 (a) Mass spectrum value: m / z 405 (M ⁺ ) Example 4 ( a) 3- (8-methoxy-2H-1-benzopyran)
15.0 g of carboxylic acid, 20.0 g of diphenylphosphoric acid azide and 7.4 g of triethylamine were added to 170 ml of t-butyl alcohol, and the mixture was refluxed at a bath temperature of 100 ° C. for 3 hours.

From the reaction solution, t-butyl alcohol was distilled off under reduced pressure.
The residue was dissolved in benzene and washed twice with a 2N aqueous solution of sodium hydroxide and then twice with a saturated saline solution. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform) and recrystallized from ether-n-hexane to give 3- (Nt-m.p.
(Butyloxycarbonylamino) -8-methoxy-2H-
15.2 g (75.3% yield) of 1-benzopyran was obtained.

3331, 1732 1.50 (9H, s, -C ( CH 3) 3) 3.86 (3H, s, CH 3 O-) 4.80 (2H, s, C 2 -2H) 6.02 (1H, br.s, -NH- or C ₄ -H) 6.48 (1H, br.s, -NH- or _{C 4 -H) 6.58~6.74 (2H,} m, C 5 -H and _{C 7 -H) 6.84 (1H,} t, J = 8Hz, C 6 -H) elemental analysis: C ₁₅ C H N calcd H ₁₉ NO ₄ (percent) 64.97 6.91 5.05 Found (%) 64.94 6.84 5.03 (b) (a) obtained in 3-amino compound 10.4g It was dissolved in 45 ml of tetrahydrofuran, 34 ml of 6N hydrochloric acid was added at room temperature, and the mixture was stirred for 4 hours.

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

1725 _{3.62 (2H, s, C 4} -2H) 3.92 (3H, s, CH 3 O-) 4.47 (2H, s, C 2 -2H) 6.74 (1H, d, J = 8Hz, C 5 -H or C ₇ -H) 6.86 (1H, d, J = 8Hz, C 5 -H or _{C 7 -H) 7.01 (1H,} t, J = 8Hz, C 6 -H) elemental analysis: C, as C ₁₀ H ₁₀ O ₃ H Calculated value (%) 67.41 5.66 Actual value (%) 67.58 5.58 (c) 3.0 g of the 3-oxo compound obtained in (b) and 15 g of dry yeast (trade name: Super Camellia, manufactured by Nisshin Seifun KK) The mixture was stirred at room temperature for 4 hours.

After the reaction, ethyl acetate was added, and the mixture was stirred for 10 minutes and passed through, and the ethyl acetate layer was separated from the liquid. The solution was washed with a saturated saline solution, dried, and the solvent was distilled off. The obtained crude crystals were washed with n-hexane and purified by silica gel column chromatography [eluent: chloroform-methanol (30: 1)] to give 2.84 g of colorless crystals (yield 93.6 g).
%)was gotten. This was recrystallized from ethyl acetate-n-hexane to give colorless needles having a melting point of 100 to 102 ° C.
2.61 g (86.0% yield) of (3R) -3-hydroxy-8-methoxy-3,4-dihydro-2H-1-benzopyran was obtained.

Specific rotation: ▲ [α] ²² _D ▼ + 15.0 ° (c = 4, CHCl ₃ ) IR value: ¹ H-NMR value same as the compound of Example 2 (a): Compound of Example 2 (a) Same as optical purity: 88.4% ee (measured by chiral high performance liquid chromatography after derivation to 3-mesyloxy compound) Elemental analysis: Calculated C H as C ₁₀ H ₁₂ O ₃ (%) 66.65 6.71 Actual measurement (%) 66.46 6.70 This compound was further recrystallized from ethyl acetate-n-hexane to obtain a compound having an optical purity of 91.6% ee with a recovery of 90%.

──────────────────────────────────────────────────続 き Continued on the front page (58) Field surveyed (Int.Cl. ⁶ , DB name) C07D 311/64 REGISTRY (STN) CA (STN)

Claims (7)

(57) [Claims] (1) General formula (Wherein A ^* represents an acyl group derived from an optically active amino acid, Z represents a hydrogen atom or a protecting group for a hydroxyl group), and the compound at the 3-position is R by column chromatography. A compound and a compound that is S are fractionated,
Then, the protecting groups for the acyl group and the hydroxyl group of these compounds are eliminated in an arbitrary order, and are characterized in that (3R)-or (3S) -3,4-dihydro-3,8-dihydroxy-2H-1. −
Method for producing benzopyran. 2. The method according to claim 1, wherein the optically active amino acid that leads to A ^* is L-alanine or L-phenylalanine whose amino group is protected. 3. The general formula (Wherein Z represents a hydrogen atom or a protecting group for a hydroxyl group) represented by the general formula A ^* -OH (V) (where A ^* represents an acyl group derived from an optically active amino acid). Compound or its reactive derivative at the carboxyl group, and the thus obtained formula II
2. The method according to claim 1, wherein the compound of I is used. 4. General formula (Wherein Z represents a hydrogen atom or a protecting group for a hydroxyl group) represented by the general formula A ^* -OH (V) (where A ^* represents an acyl group derived from an optically active amino acid). Compound or its reactive derivative at the carboxyl group, (Each symbol in the formula has the same meaning as described above), which is reacted with peracid to obtain a compound represented by the general formula (1) a compound represented by the formula III, wherein a halogeno alkali or a quaternary ammonium halide is allowed to act on a compound represented by the formula (wherein each symbol has the above-mentioned meaning), and the compound of the formula III thus obtained is used. The method described in. 5. The general formula (Wherein Z represents a hydrogen atom or a hydroxyl-protecting group), using a yeast, and then, if necessary, removing the hydroxyl-protecting group. (3R)-
A method for producing 3,4-dihydro-3,8-dihydroxy-2H-1-benzopyran. 6. The method according to claim 5, wherein the reduction is carried out using baker's yeast in an aqueous medium. 7. The general formula A compound represented by the general formula Alk-OH (XI) (wherein, Alk represents a lower alkyl group) after a compound represented by the formula (Z represents a hydrogen atom or a protecting group for a hydroxyl group) is taken as an acid azide compound. And the resulting general formula The method according to claim 5, characterized in that the compound of the formula (IX) is hydrolyzed and the compound of the formula IX thus obtained is used.