JPS5925348A - Preparation of optical active 4-demethoxydaunomycin - Google Patents

Abstract

PURPOSE:To obtain easily the titled compound having excellent carcinostatic action from a high-purity optical active alpha-hydroxyketone compound which is obtained by carrying out optical resolution using an optical active alpha-glycol having a symmetric structure as a resolving agent. CONSTITUTION:A racemic modification of an alpha-hydroxyketone shown by the formula I is treated with an optical active substance of an alpha-glycol shown by the formula II (R is p-chlorobenzyloxymethyl) to give a mixture of diastereomeric acetal derivative shown by the formula III-A and formula III-B (two Rs are in trans-position to each other), which are separated by selective crystallization, deacetalized, to give an optical active substance shown by the formula IV or formula V. The compound shown by the formula IV is acetalized, brominated, hydrolyzed to give a compound shown by the formula VI, which is further isomerized to give the desired compound shown by the formula VII. An unnecessary enantiomer prepared in the course of the optical resolution is usable repeatedly, and the recovery of the resolving agent can be carried out easily by a simple operation.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing optically active 4-demethoxydaunomycinone. More specifically, the present invention provides a racemic form of an α-hydroquine ketone compound represented by the formula [1], which is represented by the formula [1D (wherein R1, represents a tp-chlorobenzyloxymethyl group)]. The optically active form of α-glycol was reacted with the formula [IL[-A:] (in the formula, the two H groups are trans-coordinated with each other) and the formula [Kawa-B] OH (in the formula, 2 The two R groups are trans-coordinated with each other.) A mixture of diastereomeric acetal conductors represented by and the thus obtained α- represented by the above formula [IV-A]
The hydroquine ketone compound is acetalized to form a tar derivative of the formula [■] o O) ( ), and then brominated to form a compound of the formula [■I] 0 0HBr, which is then hydrolyzed. By doing this, a compound represented by the formula [1:VII:] OLlkiOH is obtained, which is deacetalized to form the formula [V11
1] A method for producing optically active 4-demethoxydaunomycinone represented by the formula [IX], which is characterized by forming the compound represented by the formula [IX] and further isomerizing it.

Here, the above-mentioned formulas [■], [:l1l-A] and Cm-B1 will be explained in more detail.

The optically active form of α-glycol represented by the formula [II] is represented by the formula [11a] or [■b][:lla:l
It can be expressed as [:nb] (in the formula, R has the same meaning as in JJU). Here, the coordination of the asymmetric carbon atom is as shown in the above formula, in the compound [
: [a] has the (R,R) coordination, and the compound ['ub] has the (3°S) coordination.

Therefore, what is the mixture of diastereomeric acetal visiting conductors represented by the formula ['+u-A] and the formula [111-B'l that is generated when α-glycol [Ua] is used as an optical resolving agent? , formula [+na-A”JJ
J and formula [■a-1j] [u+a-p, ] [ura-B]
(In the formula, R has the same meaning as above.) α-Glycol [IIb]
When used as an optical resolving agent, the formula [1lb-A]
and the formula [11[1)-J310HooH [IHo-A ] [llab-B
] (wherein R has the same meaning as above).

The optically active compound [■] Sunai] obtained by the present invention is optically active 4-demethoxidr-unomycinone, which is one of the anosthracycline antibiotics that is attracting attention due to its remarkable anticancer effect. ] oou.

C1 (BOOOHO) is an aglycone of 4-deme]xidaunorubicin, a non-natural anthracyclino antibiotic that is 8 to 10 times stronger than daunorubicin.

The following two methods are known as methods for producing the optically active compound represented by the formula rlX].

In method A, the optically active compound [XI] obtained by optical resolution of the corresponding racemic compound and phthalic anhydride are subjected to a Friedel-Krach reaction to lead to an optically active compound represented by the above formula 11'1V-A]. , and further introduced a hydroxyl group to 7 la'f to synthesize optically active 4-demethoquinodaunomycinone represented by the formula [IX].

[F,Arcamonθet al,, IDxper
ientia, 34.

1255 (1978) and West German Patent (Publication) No. 26
+l + Specification No. 785] CHB [XI] J3°C in method B optically resolves the intermediate represented by the formula [xrr], and further undergoes 7 steps to form an optically active compound [X111]? The mixture is subjected to Diels and Alder reactions and further undergoes four steps to synthesize optically active 4-demethoxydaunomycinone represented by the above formula [IX].

[C, Hl Hassall et al, J, Ch.
em.

Soa,,Chem,Com+nun,, 158(1
982)] 4th step -> [I To obtain an optically pure compound [IV-A] from
It turned out to be very difficult.

In addition, in method B, the optically active intermediate compound [X
II+'] has the disadvantage that a large number of steps are required to produce it.

Under such circumstances, the present inventors developed a racemic compound [I
] Various optical resolution methods were investigated.

The following examples are known as conventional optical resolution methods using functional groups.

a) A method of optically resolving as an Oquine rib conductor by the action of optically active hydroxyamines [R.

Pappo st al,, Tetrahedron
Lett,, 17Q9.

1827 (1978)] b) Method of optically resolving hydrazino derivatives by the action of optically active hydrazies 7 [W, N.

Speckamp et al., Rθc, Trav
, Chim, 91.

861 (1972): ] C) Method of optically resolving as an imine derivative by reacting optically active amines [F, Arcamone et al.

West German Patent (Publication) No. 2601728] d) Method for optically resolving optically active α-amino alcohols as functional xazolidine derivatives CR, Kelly et
al,, Tetrahearon Lett117
09 (197B)] 8) Method of optically resolving as an acetal derivative by reacting optically active α-glycols [E, J.

Corey et al., Chem, and in
d, 1664 (1961).

M, 5anz-Burata et allAfini
dad, 27. (393°698, 705 (19
70), H. Rapport et al., J.
Am.

CH31n, Soc, 98.1758 (197
1)] f) A method of optically resolving as a thioayatal derivative by acting on optically active α-dithiols [E, J, (oreyeta1..J, Azn, Chem, Soc,
.

84, 29118 (1962)] However, in the method of lr, IL, b and C,
Corresponding derivatives ＼When derived, syn and arlt
It is possible for the i isomer to exist, and in the d method, a new asymmetric center is generated when it is made into an oxazolidine derivative. or,
Even in the θ and f methods, a new asymmetric center occurs when α-glycols or α-dithiols having an asymmetric structure are used. a
In either case of the -f method, the number of diastereomers that can be theoretically produced is two or more, which is a factor that complicates the problem.

Therefore, in order to develop an effective optical resolving agent, it is essential to overcome the above-mentioned difficulties and to find a resolving agent that satisfies the following conditions. Namely, 1) It should be possible to synthesize in a short number of steps starting from a high-value raw material.

2) The two enantiomers can be produced equally and easily by hand (if this condition is met, the properties of the rare stereomers that will be produced are such that both enantiomers can be used appropriately and the optimal resolution can be achieved). Article f' can be selected.

With ordinary resolving agents, there is often only one type of diastereomer that can be isolated in a pure and high yield.
This condition is important so that it can be an effective optical resolution agent. ) Based on these conditions, as a result of intensive research on a method for optically resolving compound [■] in a rotary manner, we found that the formula ['lll α- They discovered that the optically active form of glycol is extremely superior.

That is, since the optically active form of compound [II'] is α-glycol with a symmetrical structure, the acetal derivatives produced are only two types of diastereomers, and the optically active form of compound [II'] is It has been found that Lf is an excellent optical resolution agent that satisfies the above-mentioned conditions such as better yield than mannitol or tartaric acid, which are cheap and easily available, and can be easily manufactured.

Furthermore, in conventional optical resolution examples using α-glycols, the diastereomers and acetal derivatives produced are all separated by gas chromatography, which has little practical value. When the optically active form of α-glycol CIl, which is the optical resolving agent of the present invention, is applied to the optical resolution of compound [1], the diastereomeric acetal derivative produced can be separated only by crystallization. It turned out to be an excellent method that can be manufactured industrially.

That is, by developing a new resolution method via the acetal derivative of compound [I], the present inventors have made it possible to obtain optically pure compound [■v-A], and furthermore, by developing a new resolution method using an acetal derivative of compound [I], This paved the way for the production of the pure compound rTX] and completed the present invention.

The method of the present invention will be explained in detail below.

In the acetalization reaction of racemate [■], usual acetalization conditions can be used. That is, the compound [t
] and a small excess of the optically active form of compound [II'] in the presence of a catalytic acid in a hydrocarbon solvent to azeotropically remove the water produced (f). .

As the acid, hydrogen chloride, sulfuric acid, hydrogen bromide, p-toluenesulfonic acid, boron trifluoride etherate, phosphoric acid, ion exchange resin, etc. are used, and p-toluenesulfonic acid is preferably used. Benzene, toluene, etc. are used as the hydrocarbon solvent. The diastereomer mixture thus obtained is separated by adding ether etc. to the crude product after distilling off the solvent and stirring, mainly to obtain the above formula [■a-A] or formula [■b-B''' J
row 4r by selectively crystallizing the compound of
If necessary, recrystallize from acetonitrile or the like to obtain a compound with even higher optical purity [ma-Al>, Iko [■■
b-B ]. Compound [111a
After addition of -Al or [IITb-B] as a crystal, the solution is concentrated and the residue is recrystallized from ether etc. to obtain the other diastereomer compound [13a-B]. or [1llb-A
'] can be obtained.

Separated diastereomers [nt-, Al (i.e. [l■a-A -J or [l1ll)-A]
) can be subjected to conventional deacetalization conditions, ie, acetal exchange or acid hydrolysis reaction, to obtain the optically active compound [1v-A']. On the other hand, the compound [■I-
B] (i.e. C[11a-B])
When B] is similarly subjected to p61 acetalization reaction, a compound [:+v-B] which is an enantiomer of compound [1v-A'] is obtained.

The deacetalization reaction is carried out in the presence of an acid such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, boron etherate, etc., in a mixed solvent such as methanol, acetonate, dioxane, tetrahydrofurano, water, etc. using room temperature 4
C) C) The reaction can be easily carried out by heating.

Due to the deacetalization reaction, the optically active form of ('[1) is liberated as an asymmetric source.
It can be reused as is.

Therefore, the partially active compound [v-E] force; Itatami et al. I'
Compounds with partial activity [tv-B
] The isolated compound ['IV-Bl
Treatment with lyoacid-Murukobiki-111=8-6=04-)-
1. It can be used repeatedly by applying the method of the present invention again.

Optically active compound [IV
-A], compound [v] can be obtained by a normal acetalization reaction. For example, compound 11'V'] can be easily reacted in the presence of ethylene glycol and an acid catalyst in a hydrocarbon solvent (e.g. benzene, toluene, etc.) while removing the water produced azeotropically. An acetal rust conductor CV'J can be obtained.

Then, compound [V] is converted to compound [v■] by reacting with a brominating agent.

As the brominating agent, bromine, N-bromosuccinimide, etc. are preferably used. The reaction generally proceeds above room temperature, but is accelerated by heating. If necessary, it is possible to take measures such as adding a radical initiator such as azobisisobutyronitrile or benzoyl peroxide or irradiating visible light to accelerate the reaction. In order to scavenge the generated hydrogen bromide, cyclohexenoxide or acetamide may be used as a scavenger, if necessary. The reaction solvent should be one that will hinder the progress of the bromination reaction.1. 10-genide alkyl solvents (such as carbon tetrachloride, chloroform, dichloromethane, etc.), aromatic solvents such as benzene, ether solvents such as diethyl ether, tetrahydrofurano, dioxane, diglyme, dimethylformamide, etc. amide solvent, n-hexane, two aliphatic solvents, acetic acid,
Water and the like can be used alone or in any mixture.

If this bromination reaction is carried out under heating in a water-containing solvent, then -C hydrolysis reaction proceeds following the bromination reaction,
Compound [V■] is obtained. [y.

ArCam0nθθt a],, IDxperien
tia, -84+ 1255 (1973); It',
Jor1neonθt an,, J, Am, Ch
em.

soc, 108, 1561 (1981)] The hydrolysis reaction from compound [■I] to compound [V■] can be carried out by the following two methods.

The first method is to hydrolyze the compound [Vt] with moist silica gel [: , T, Aun, Chem, So
c., 93.

1967 (1976)] or by hydrolysis with an alkali in the presence of U in a water-containing ether solvent. Dioxane, potassium metal, or alkaline earth metal hydroxide such as calcium hydroxide or barium hydroxide is used as the upper-chill solvent, and this reaction proceeds suitably at around room temperature. ['J, P.

Geeson et al., J., Chem., S.
oa, Chem, Commun.

421 (1982), 'A, S, ni θnds et
all, Tetrahedron Lθtters,
4779 (1981); P, N, C0nfal
one atal,, J, A, m, Chem, S
oc, 103, 4251 (1981)] The second method is to convert the compound [VD into the trifluoroacetoxy derivative [XIV] by reacting it with a metal salt of trifluoroacetate in a solvent, followed by metathurisis. I can do it.

/-] As the trifluoroacetic acid metal salt, salts of alkali metals such as sodium/lium and potassium, alkaline earth metal salts or silver salts are preferable, and as reaction solvents, acetone, dimethylformamide, dimethylsulfokide, etc. are preferable.] Used for good fortune,
The reaction proceeds in the container at around room temperature.

The methane rinsing reaction proceeds easily at room temperature in methanol or a mixed solvent of methanol/tetrahydrylj afuranostop to give the compound [vu] [Special Patent No. 41M-1982-82157; T, H, Sm1
thetal, J. Al11. Chsm, 5
oc198, 1969 (1976): J, Org
,, C1+om,, -4i, 865B (197
7)] The compound [vn'l] thus obtained was removed by a conventional acetal exchange reaction or acid hydrolysis reaction I
It is often done. The Chikarasou acetalization reaction is carried out using methanol, acetone, dioxane, tetrahydrofuran, water, or a mixed solvent thereof in the presence of an acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonate, or trifluoroboric etherate. It progresses easily at around room temperature. The isomerization reaction of the resulting compound [vJ usually occurs simultaneously with the detarring reaction using the above acid at a production ratio of 1:1. Optically active 4-demethoxydautzmainone [: IXI] can be obtained by separating and purifying this product by column chroma I/graphing or the like.

As described above, the method of the present invention can be used to synthesize compounds [: I
v-A ] was obtained with high purity, making it easy to produce optically active 4-demethoxydaunomycinone. However, the unnecessary enantiomer generated in the optical resolution step 2 can be used repeatedly, and the compound used as the chiral source [■
] Since the recovery of the optically active substance of
We can say that this is the method.

The present invention will be described in detail below using Examples JJ and Reference Examples, but the content of the present invention is not limited to the following Examples.

C precedent 1 (1) 50! Wash 1.96r% sodium hydride with dry hexanoate, add 20-rHF, and add (R
,R)-(-)-2,13-0-techθopropyli
denθ−Tl+rei℃O1([α]D−4,2(
C=5.31. ri o o +l; rum)) 3?
, THF6 mt solution was prepared for 15 minutes, and allowed to rise to room temperature for 30 minutes. A solution of p-chlorohensyl chloride 8.94r%Tin''15- was added dropwise over 15 minutes, and then stirred at 50°C for 3 hours.After cooling, water and benzene were added for liquid separation and extraction. The 113 layer was washed sequentially with water, 596 hydrochloric acid, water, saturated aqueous water, and water, dried, and the solvent was distilled off. ，
R) 6,541! (8696') was obtained.

0 [“]D +8.1° (C=6.17.chloroform), mass spectrometry (t4+): 410 (2) Bis(p-chlorobenzyl) body obtained in the above C example 1-(1) 4. 5f was dissolved in 7.7.1 THF and 12.4 ml of dioxane, 1 rnl of concentrated hydrochloric acid was added, and the mixture was stirred at 60°C for 6 hours.After cooling, 4.5 t of finely powdered potassium carbonate was added little by little. After stirring, strain
The solvent was distilled off. The residue was subjected to column chromatography (50 t of silica gel, 0 melting point, melting point 76-78°C, [α]D + 6.3° (. = 8.08
．． chloroporum), mass spectrometry (Mt)2 70 Reference Example 2 In the same manner as in Reference Example 1, (s,5)-1-( [IIb] was obtained.

Melting point 74-77°C, [α]D-6.5° (ca, ot
.

chloroform), mass spectrometry (M+): 870', A stream side I (1) Racemic α-hydroquine ketone compound [1]
While removing water azeotropically, a suspension of 2.4 M, optically active α-glycol [IIal 8.08 P, 81 yy of p-h luenosulfonoic acid, and 100 ml of benzene was produced (214-6°C). The mixture was heated under reflux for 18 hours. Cool to room temperature, add 100 green onions,
Further finely ground potassium carbonate 5? After stirring for 1 hour, the mixture was filtered and the solvent was distilled off. Apply the residue to silica gel chroma 1~
51', solvent, silica gel, solvent, nine-fold 7. A 1:1), acetal derivative ['1lla-A:] and [a-B] 6 are compounded 5,2y and 8f.

[α]L) +4.8° (C=0.65.Chloroporm) Add 200 rnl of ether to this, and add a little 11
Crystal seeds were added and the mixture was stirred at room temperature for 15 hours.

The precipitated crystals were collected, washed with cold ether, and then dried.

Apparatus 2.854 y (47 qc), melting point 132-6
℃ This crystal was recrystallized twice from acetonitrile to obtain an acetal derivative [rua-A'].

~2°C, ['α]D-53,6° (C=0.50.
Chloroform) Furthermore - anti-paleo crystal melting point 141
．． It showed [α]D-58,6 (C=0.51, chloroform) at 5-2°C.

CH as photoelement analysis Ca811a4C1iO9 Calculated value 64.69% 4.86% Actual value 64.42964.9096 The washing liquid after ether treatment was combined and distilled off to obtain bi 2
．． 4 (16y (4g%)), 3 times 11 from ether
) was crystallized to obtain an acetal derivative [1a-B].

Conversion gain fitO, 925f (1896), melting point 120 ~
PiC, [rt) I) + 665° (G=0.50
, riD O form) Furthermore, -IW recrystallization gives a melting point of 120 ~ ~ BiC, (, a, +66.8° (C = 05
1, Il'l OhoJL/mu was shown.
c n-element system analysis C881184 (calculated value as brown 0. 6469% 486% actual aim 1 (direct 6452%
4.83% 2-1) Acetal derivative (llft-A) 200 Hywo7
Cell: / 200xtico-dissolved LiF2. Eu2
OQ, 1 (3 ml) was added and heated under reflux for 13 hours.

After cooling, add saturated Rousseau aqueous solution and extract with chloroform.
Ko. After washing the organic layer with water and drying, the solvent was distilled off, and the residue was purified by chroma[・
Purified by graph r-fl. (Silica gel 15y,
General (ffl benocene:dichloromethane-3:1) yield: 97.8 MP (98%), melting point: 214-7°C
1[a]l, -81,9°1c=0.116, ri o.

Form) recrystallized from benzene to form an optically active compound [1 C)~) 80.1 scraps! (80%).

Melting point 218-9°C, (a) D-89,9° (C-〇,
102, chloroform) CH Calculated value as elemental analysis C20H1606 68.18
964.5896 Actual value 68.85% 4.6'2
The asymmetric source portion obtained by 96 chromatography was further purified by thin layer chromatography (silica gel, solvent: benzene), and the optically active α-glycol [■a] represented by the formula was purified by short-path vacuum distillation. 81.6 square meters (71,696) of acetal were obtained.

Boiling point 260℃ (bath temperature) / 0.01~0.02F
.

[α] + 7.8° (C = 5.97, chloroform) (2
-2) 4'e:=ffl;@! IS,>y Seta-Jl/Derivative [nIa-A] 100ml Cool, add saturated soda water, and extract with chloroform. The organic layer was washed with water, dried, and then subjected to column chromatography. (Silica gel 7.52:rBK
, benozeno; dichloromethane-3:l), yield 48. ?
ν (97%), melting point 214-8°C, [α:II)-84
, 7° (C=0.118, chloroform) Benzene, 1 j + recrystallized to form an optically active compound ("rv
-A] 88.1 my. Melting point: 218-90°C, [α:]D-90. lli°(,c=0.106,
The asymmetric source portion obtained by chromatographic purification was further purified by thin layer chromatography (silica gel; solvent, dichloromethane) to obtain optically active α-glycol Clla.
] was obtained. Apparatus 89.4η (75%), melting point 76
0 to 8°・[“]i)+5.7・(C=2.98, chloroform) (3) Optically active compound [Iv-A:] (Melting point 2
18-219°C, [α]D -90,0° (C=0.
102, chloroform) 160 w, ethylene glycol
(84) 0.24 ml of 11-toluene, 7 ml of sulfonic acid, and 16 ml of benzene were refluxed for 5 hours according to a conventional method. Most of the solvent was distilled off, dichloromethane was added after cooling, the mixture was washed with saturated sodium chloride water and water, dried, and the solvent was distilled off to obtain an ethylene acetal derivative [V].

Obtained m17711&(98%), melting point 222-5°C When recrystallized from benzene, melting point 224-6°C1[α]9-
81.0° (C=0.120, chloroform).

CH original cumulative 1'i (calculated value as 1221+2oQ7
66.66% 5.09% Actual value 65.59% 50
5% (4) Ethylene acetal derivative [■] (melting point 2゛24-6°C, (α) D-81,0° (Iji = 0.12
0 chloroform) 90 MQ to 15 ml of chloroform
20#7f of azobisisobutyronitrile, 12 tsl of water, and 6 ml of bromine-carbon tetrachloride solution (0.05 molar solution) were added and refluxed for 1 hour, and then 1 hour of bromine-carbon tetrachloride solution was added. .5 ml was added and refluxed for 80 minutes (7. Furthermore, 1.5 tsl of bromine-carbon tetrachloride solution was added and refluxed for 1 hour. The reaction solution was cooled, extracted by adding chloroform, and the extract was washed with water and dried. After the solvent was distilled off, 9 ml of 8096-driful acetic acid was added to the residue, and the mixture was stirred at room temperature for 15 hours, then poured into ice water and extracted with chloroform.The extract was washed with water.
The residue (110k4) was purified by Noriyoku Gel chromatography (Noriyoku Gel 20&, γ8-linked chloromethane) and purified with 4-demethoxy. Dautzmycinone [Ix']
I got it. Obtained R4,2~(4196') When this product is recrystallized from chloroporum ether, the melting point is 184~1
85.5°C, [α1. +157° (C=0.114, Geoki Reno).

Elemental analysis C2oH+607. +/a CH as H2O Calculated value 64.17 4.48 Actual value 64.29 4.30 Example 2 1) In the same manner as in Example 1-+1), racemic-α-hytroquine ketone compound [11500νIV, optical A ] To[II[b-Bl ) mixture 1021! lv, [α]
9-5.4° (C=0.61, chloroform) was obtained.
, :.

This was treated with ether to form crystals 449 ilr (4596
1), a melting point of 188-8°C was obtained. This crystal was recrystallized from acetonitrile to obtain an acetal derivative [111b-Bl
I got it.

Conversion gain: 387η (8996), melting point: 140.5-14
1.5℃, [α'], +58.8° ((! = 0.
59, chloroform) Furthermore, when anti-paleo crystals have a melting point of 141-2°C, [α]9-1-58.8° (c = 0, 5
5, chloroform).

CH Calculated value as elemental analysis C38H34Cmu09 64.
69% 4.869 (actual value 64.76964.74
% After the ether treatment, the ρ washing liquid is concentrated and put into a device 50
0-(509i) and was recrystallized twice from ether to obtain an acetal derivative [■b-A]. Exchange n M218u#/
(21%), melting point 119.5-1205°C, [α]-
66,0° (c=o5r, chloroform) Furthermore, when anti-old crystals have a melting point of 120~IO°C, [α
'1. -66.4° (C=0.58, chloroform).

CH Elemental analysis Caa[(a4Gn9(!: LT)fft
N value 64.69% 4.86% actual value (34,6
49 (4,92% (2-1')) 100η of the acetal derivative CIIIL)-A was reacted in the same manner as in Example 1-(2-1).

Chroma 1 - Amount obtained after 49. o:,? , (98%), melting point 215-7°C, [α]D -84,6° (c = 0.
112°chloroform) This product was recrystallized from benzene to obtain the photoactive compound [V-
A] 38.2fff (7696) was obtained.

Melting point 218-9℃, [α:]D90.1 (C=0.1
08, Chloroform) (2-2) In the same manner as in Example 1-(2-2), 100~ of acetal conductor [ml)-A] was reacted.

Post-chromatography top 48.5 vpy (9796), melting point 21
5-8℃, [α]D -88,2° (C=0.106
, chloroporum) was recrystallized from benzene to obtain an optically active compound [t
VA] 88.4 nry (77%) was obtained.

Melting point 218-9℃, [α]D -90,0° (c=Q
, 110, chloroform) Reference Example 3 (1) In the same manner as in Example 1-(2-1), ace1
Tar derivative [u+a-B,] 100 my was reacted. After chromatography, 48.4η (9796),
Melting point 215-7℃, [α], +84.2° (C=0, 1
06, chloroform) This product was recrystallized from benzene to obtain the optically active compound [I
V-B ] B 9.5 my (79q6) obtained t
, :.

Melting point 218-20℃ [α]n +89-5° (c=0
, 102, Chloroporum) Word calculation as element publication C20H1606 (Direct 6
8.1896 4.58% Actual value 67.90964.
5396 (2) In the same manner as in Example 1-(2-1), react the acetal visiting conductor Cmb-B]100rnvj
child.

After chromatography ffi 49.1'I N・f (999
6'), melting point 215-7℃, [α], +88.7°
(0=0.104, li-coloform) This product was recrystallized to obtain an optically active compound [I V-B 1
39, □V (784X) was obtained. [α]. -F2
O, 8° (C = 0.120, chloroform)

Claims (2)

[Claims] (1) The racemic form of the α-hydroxyketone compound represented by the formula is treated with an optically active form of α-glycol represented by the formula % (wherein R represents a p-chlorobenzyloxymethyl group). , a diastereomeric diastereomeric compound of the formula (in which the two R groups are in trans configuration to each other) and the formula (in which the two R groups are in trans configuration to each other) A mixture of acetal derivatives and (7) an α-hydroxyketone characterized in that each diastereomer is separated and then subjected to a deacetalization reaction to obtain an optically active α-hydroxyketone compound represented by the formula OOH or the formula Optical resolution method of compounds. (2) Optical activity of α-glycol represented by the racemic formula % of an α-hydroxyketone compound represented by the formula % (wherein R represents a p-chlorobenzyloxymethyl group) and the formula %formula% (wherein the two R, !4!, are in trans coordination with each other) and formula%formula% (wherein the two R groups are in trans coordination with each other) A mixture of diastereomeric acetal derivatives represented by formula % or ODI ( -Hydroxyquinone compound was obtained, and the thus obtained α-hydroxyquine compound was converted into a monocetal to form an ethylenoacetal derivative with the formula %('2Jk). A compound represented by the formula is obtained by hydrolyzing the compound represented by the formula (-tonimari formula), deacetalized to form the compound represented by the formula, and further isomerized. A method for producing optically active 4-demethoxydaunomycinone shown by