JPS58141787A - Preparation of optically active alpha-hydroxyketone compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing an optically active α-hydroxyketone compound.

More specifically, the present invention relates to a racemic α-hydroxyketone compound represented by formula (I) cg3°.
aaaharomycsg cerevisiaa (
Baker'5east) to selectively reduce the formula (II&).

([[b) "308 Obtain a mixture of diastereomers of a diol compound represented by CH30, fractionally recrystallize this to obtain an optically active diol compound represented by formula (na), and then oxidize this compound. This is a method for producing an optically active α-hydroxyketone compound represented by the formula ().

The present invention. QIOsu:nwachini)-2(group-acetyl-5,8-dimethoxy-1,2,8゜4-tetrahydro-24-naphthol) has attracted attention due to its remarkable anticancer activity. It is an extremely useful compound as a raw material for the synthesis of anthracycline compounds such as daunorubicin, adriamycin, 4-demethoxydaunorubicin, and 4-demethoxyadriamycin.

A method for producing the compound represented by formula (2) is a method in which racemic compound (I) is optically resolved using optically active α-phenylethylamine (F, Mude camons).

German Offen, 2601785)
*Method using asymmetric bromolactonization reaction (S.

Tsraahima, Chem, Pha/m, Bu
ll,, ju, 2851 (1979) l.

Method using asymmetric reduction reaction (B, Terashi
ma.

Tetrahedron Lett, 19gQ g74
9. , 8. Terashima, .

1bid, 1980.2758) etc., but as a result of intensive research by the present inventors, 8acch
aromyceθcerevisiae (Baker
CoMeuberg succeeded in producing ffl in a simpler and more efficient manner, and the actual asymmetric reduction is known.

Adv, Carbohydrate Chem, 4
．． 75 (1949) J, B6. Tones.

C, J., Sih, D., Psrlman, %
Applications ofBiochemistry
al B:systems in Organic
Chemistry Part Engineering, Joha Wi
ley and 5ons, New York, 1
975), but there have been no examples of its application to anthracycline compounds.

Under such circumstances, the present inventors added Sacchar to the racemic α-hydroxyketone compound represented by formula (I).
omycea cerevlsiae (Baker'
2(R)-(1'(5)-hydroxy)ethyl-5,8-dimethoxy-1,-2,8,4-tetrahydro-2 of the formula (n?,) (R)-naphthol and its epimer, the formula (
IIb) 2 (B) -(1'(#)-Hydroxy)ethyl-5,8-dimethoxy-1,2,8,
4-tetrahydro-2(S)-naphthol was obtained at a production ratio of 1:1, and by fractional recrystallization of this diastereomer mixture, a compound of formula (na) with an optical purity of 1 oon was successfully obtained, and further By oxidizing the compound of formula (II&), f-3-2(R)-acetyl-5,8-dimethoxy-1,2,8,4-tetrahydro-2 having an optical purity of 1004 is obtained by oxidizing the compound of formula (II&). (R)-
It was discovered that naphthol can be obtained.

The method of the present invention will be explained in detail below. The first step is the formula (I
) is a process for obtaining a mixture of diastereomers of diol compounds represented by the formulas (na) and (ntl) from the α-hydroxyketone compound represented by Sac
charomyces cereviae (Bak
er' II yeast) (7) 7 jL+:
) The most common method is to add a racemic α-hydroxyketone compound represented by formula (I) to the fermentation liquid and continue the fermentation. There is no particular restriction on the temperature as long as the fermentation can continue, but it is usually preferably carried out at 25 to 85°C.
Generally, the number of days for fermentation is approximately half a day to eight days, but other pentose and hexose can also be used, and the amount used is 0.1 to 10 times that of yeast. Double doses are used.

The solvent used for the fractional recrystallization of the mixture of diastereomers of the diol compound represented by the formula (na) and the formula (nl) of No. 21 is alcohol such as methanol, ethanol, benzene-ether, dichloroethane, etc. A mixed solvent of these and hexane is suitable.

The unnecessary diol compound represented by formula ([1)), which is the main component of the recrystallization mother liquor, can be led to the compound represented by formula (1) by the following steps, and the method of the present invention can be applied again. It can be used repeatedly.

CH30CH3゜(■)(v) That is, by concentrating the recrystallization mother liquor and treating the resulting residue with sodium metaperiodate in anatone,
When the compound represented by ([b)] is cleaved with glycol, the β-tetralone form represented by formula (IV) is quantitatively obtained, and this is reacted with ethynylmagnesium bromide to form the ethynyl form represented by 2M. After that, the acetylene moiety is hydrated with a mercury catalyst to obtain the compound represented by formula (I) in good yield.

Next, in the second step, an optically active α-hydroxyketone compound represented by the formula (II &) is obtained from an optically active diol compound represented by the formula (II &). A common oxidizing agent for ketones,
For example, chromic acid-sulfuric acid, pyridinium chlorochromate, dimethyl sulfoxide/dicyclohexy J Reca!
Levodiimide/trifluoroacetic acid/pyridine, Feti
zon reagent (Fetizon, :J, Qrg, C
hew, 86.1889 (1971)).

DM80/Pyridine-Sulfur trioxide/Triethylamine
('J, R, Par ikh, J, Am,
Chew, Boa, , 89-5505 (19
67)) can be used, especially IFetLzO
n reagent, DMS 'o7 pyridine) no sulfur trioxide/
Triethylamine is preferred.

In addition, when the recrystallization mother liquor containing the compound of formula (III) as the main component obtained in the second step is concentrated and the resulting residue is subjected to a similar oxidation reaction, enantiomers of the compound of formula (III) as the main component are obtained. A compound is obtained.

This product is racemized by treatment with acid and has the formula (1
) and can be used repeatedly by applying the method of the present invention again.

As described above, according to the present invention, the homogeneous acetyl-5,
8-dimethoxy-1,2゜3.4-tetrahydro-2(
b)-Naphthol can be produced with an optical purity of 1004, and the unnecessary isomer produced in the middle can be repeatedly used by the above two methods, so it can be said that this method is industrially excellent.

The present invention will be described in detail below with reference to Examples.

Example-1 Sacchar in a solution of 25t of sucrose and 200CH of water
omyccertvisiaa (1i1H Engineering GMA
: Y2O-1) Add 17.59 and stir while keeping warm at 80-85℃. Within 80 minutes, carbon dioxide gas is generated rapidly and fermentation starts, so finely ground 2-acetyl-5゜8-dimethoxy 1 .2.8. 1 t of 4-tetrahydro-2-naphthol was added and fermentation was continued with stirring at 80-85°C. After 48 hours, the fermented liquid was filtered through Celite, and the Okinawa product was washed with ethanol and ethyl acetate. After distilling off the ethanol washing liquid,
The mixture was combined with the furnace liquid and extracted with ethyl acetate.

The ethyl acetate layer was washed with brine, then dried and distilled off over magnesium sulfate, and the residue was purified by silica gel chromatography (solvent: methylene chloride) to obtain 2(6)-(1'(S
)-hydroxy)ethyl-5,8-dimethoxy-1,2
, 8,4-tetrahydro-2)-naphthol and 2 (
S) -(1'(S)-hydroxy)ethyl-5,8-
Dimethoxy-1,2,8,4-tetrahydro-2(S)
- 908 wg of a mixture of naphthol was obtained. The mixture of e8 was recrystallized 8 times from benzene-hexane, and the optical purity was 1.
004-2 (R) -(1'(8)-hydroxy)
818 wg of ethyl-5,8-dimethoxy-1,2,8,4-tetrahydro-2(R) naphthol was obtained.

Melting point 154-155°C Elemental analysis CH Actual value 66.564 8.024 Example-2 2(R) [1'(8)-? : F O * C) 2% J+/-5゜8-dimethoxy-1,2,8,4-tetrahydro-2(6)-naphthol 100 capes in anhydrous DM
Dissolve in SO 1oc, add 1.2 t of triethylamine, and add pyridine-sulfur trioxide 68031F anhydrous D under stirring.
A solution of MSO2CC was added and stirred at room temperature for 2 hours. After cooling, 3 cc of 04-hydrochloric acid was added and extracted with chloroform.

The chloroform layer was washed successively with 54-hydrochloric acid, water, hydrogenated sodium chloride solution, and water, dried over magnesium sulfate (11), and then evaporated. The residue was purified by thin layer chromatography (C silica gel, solvent, benzene:ethyl acetate = 8:1) to obtain colorless crystals 9Qq.

(904) Melting point 126-12'7.5C Optical rotation [α], = -45,81 (0 = 0.90,
CHCl3,) This product was recrystallized from 9 cyclohexane to obtain 7764 units of pure 2(6)-acetyl-5,8-dimethoxy-1,2,8,4-tetrahydro-2(t)-naphthol. Ta.

Melting point 128-128.5° Optical rotation [α], = -46.8° (c = 0.54,
CHCts) Reference Example-11.

Crude 2-(1′-hydroxy)ethyl-5°8-dimethoxy-1,2,8,4-tetrahydro-2-naphthol ([αID-1-27,0′C-0,91°CHCL
3) Melting point 105-120℃) with acetone o, a
A solution of 841q of sodium metaperiodate in 0.6 cc of water was added at room temperature and stirred for 1 hour. The reaction solution was diluted with water, extracted with ethyl acetate, the organic layer was washed with water, dried over magnesium sulfate, and evaporated to give colorless crystals.
lv (994) Melting point: 98-96°C This product was recrystallized from ethanol to obtain pure 1°4-dimethoxy-6-tetralone.

Melting point 98.5-99.5°C Reference example-2 486q% magnesium in argon stream anhydrous THIF1
Prepare an ethylmagnesium bromide solution from 2CC, ethyl bromide 71/1,660c, and add the ethylmagnesium bromide solution obtained above at room temperature while blowing dry acetylene gas into i6 THFgac to obtain ethynyl bromide. Synthesize magnesium and add 1,4-dimethoxy-6-
A solution of 412 wg of tetralone in τHF7CC was added and stirred at room temperature for 16 hours.

After the reaction was completed, 104-ammonium chloride aqueous solution was added, and the mixture was extracted with ether. The extract was washed with brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (silica gel, solvent: benzene:ethyl acetate = 10:1) to obtain colorless crystals of 8585w. (
76) Melting point: 10G-108℃ Recrystallize this product from isopropyl ether to obtain pure 2-ethynyl-6,8
-dimethoxy-1,2,8,4-tetrahydro-2-naphthol was obtained. Melting point, 105-106°C Reference Example-8 V
4-tetrahydro-2tft-tlt8'14tdO'
) A solution of 11.5 cc of TM was added at room temperature and stirred for 5 hours. The reaction solution was diluted with brine and extracted with ethyl acetate. The extract was washed with sodium hydrogen aqueous solution and brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by thin layer chromatography on silica gel, solvent: ether: hexane = 1
:1) Obtained 84.7 capes of 141 color crystals (86 tatami mats) Melting point: 99-101°C This crystal was recrystallized from ether to give pure 2-acetyl-5,8-dimethoxy-1,2,8°4 −
Tetrahydro-2-naphthol was obtained with a melting point of 102-10
8℃

Claims (1)

[Claims] Formula (1) is a racemic α-hydroxyketone compound represented by % formula %.
acoharomyces cerevieae (B
aker'5yeast) to selectively reduce the formula (II &). A mixture of diastereomers of the diol compound represented by ([1)) is obtained, which is fractionally recrystallized to obtain an optically active diol compound represented by the formula (II&), and then a mixture of diastereomers of the diol compound represented by ξ is obtained. A method for producing an optically active α-hydroxyketone compound represented by formula (III) a 0 .