JPS6241586B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is expressed by the following formula (1) 2-acetyl-5,8-dimethoxy represented by
This is a new method for producing 1,2,3,4-tetrahydro-2-naphthol. More specifically, the present invention is based on the following formula () 2-acetyl-5,8-dimethoxy represented by
Carbonyl of 3,4-dihydronaphthalene (〓
CO) part is reduced and the following formula () 2-(1'-hydroxy)ethyl-5,
8-dimethoxy-3,4-dihydronaphthalene was obtained, and then the double bond between the 1st and 2nd positions of this compound was epoxidized to give the general formula () 2-(1'-hydroxy)ethyl-5,
8-dimethoxy-1,2-epoxy-1,2,
3,4-tetra-hydronaphthalene is obtained, and then the 1,2-epoxy part of this compound is

Reduce [formula] and the following formula () 2-(1'-hydroxy)ethyl-5,
8-dimethoxy-1,2,3,4-tetrahydro-2-naphthol is obtained, and then the 1'-
2-acetyl-5 represented by the above formula (1), which is characterized by oxidizing the hydroxy moiety (–CHOH),
This is a new method for producing 8-dimethoxy-1,2,3,4-tetrahydro-2-naphthol. Here, compound (1) is 2(R) monolithic, 2(S) monolithic or a mixture thereof, and compound () is 1′(S) monolithic,
1'(R) or a mixture thereof, compound () is 1'(S), 1(S), 2(S),
1'(S), 1(R), 2(R) together, 1'(R), 1
(R), 2 (R) integral, 1' (R), (S), 2 (S)
The compound () is 1'(S), 2(R) monolithic, 1'(S), 2(S) monolithic, 1'(R), monolithic or a mixture of any combination of the above four isomers. 2(S)
It includes monolithic, 1'(R), 2(R) monolithic, or a mixture of any combination of the above four isomers. Regarding (→→→-(1)), the following relationship exists. Further, the present invention provides the carbonyl (〓CO) moiety of 2-acetyl-5,8-dimethoxy-3,4-dihydronaphthalene represented by the above formula () to (-)-1
(R), 2(S)-N-alkyl- or aralkyl-substituted efnidoline and N-monoalkyl- or aryl-substituted anilines are subjected to asymmetric reduction with lithium aluminum tobilide partially decomposed, and the following formula (') is obtained. (-)-2-(1'(S)-hydroxyethyl)-5,8-dimethoxy-3,4-dihydronaphthalene represented by , and the following formula (′) 2(S)-(1'(S)-hydroxy) represented by
Ethyl-5,8-dimethoxy-1(S),2
(S)-epoxy-1,2,3,4-tetrahydronaphthalene was obtained, and then the 1,2-
Epoxy part

Reduce [formula] to the following formula (') (-)-2(R)-(1'(S)-hydroxy)ethyl-5,8-dimethoxy-1,2,
3,4-tetrahydro-2(R)-naphthol was obtained, and then the 1'-hydroxy moiety (〓
The following formula (1) is characterized by oxidizing CHOH) (-)-2(R)-acetyl-5,8 represented by
-dimethoxy-1,2,3,4-tetrahydro-
This is a new method for producing 2(R)-naphthol. Compound (1) obtained by the present invention, especially (-)-
2(R)-acetyl-5,8-dimethoxy-1,
2,3,4-tetrahydro-2(R)-naphthol (1') is a compound used in the synthesis of adriamycin (2), daunorubicin (3), etc., which are anthracycline antibiotics that have recently attracted attention due to their remarkable anticancer effects. It is an extremely useful compound as a raw material (F.Arcamone,
Lloydia, 40 , 45 (1977). TRKelly“Synthetic
Approaches to Anthracycline Antibintics,”in
“Annual Reports in Medicinal Chemistry,”
Am Chem Soc., 1979). That is, from 1′, 2
and adriamycinone, an aglycone of 3.
(4) and daunomycinone

【table】 ~

[Table] Synthetic routes for 2 and 3 from 5) have also been established (C, M, Wong, etal , Can.J.Chem, 49 ,
2712 (1971). C. M. Wong, etal , Ibid ., 51 .
466 (1973). T, H, Smith, etal , J.Org.
Chem, 42 , 3653 (1977). ). 2 and 3 are known to cause heart damage in some cases if used frequently, and 4-demethoxyadriamycin (6) and 4-demethoxyadriamycin (6) are non-natural anthracyclines with fewer side effects such as heart damage. Methoxydaunorubicin (7) has been developed as an anticancer drug with excellent pharmacological activity, but 6 and 7 have also been synthesized using 1' as a starting material (F, Arcamone,
etal , Cancer Treat. Rep. 60 , 829 (1976). F,
Arcamone, etal German Offen, 261785. F,
Arcamone, Lloydia 40 , 45 (1977). ). As mentioned above, in the production of natural and non-natural anthracyclines, the object compound (1) of the present invention, especially 1', is an extremely important compound as a raw material for the production of optically active forms. 5-
This is a method for producing optically active compound 1' from dimethoxybenzaldehyde, and in particular, the method for producing optically active substance 1' is a racemic form (C, M,
Wong, etal , Can J, Chem, 49 , 2712
(1971). C, M, Wong, etal Ibid , 51 , 466
(1973). ) using optically active α-phenylethylamine (F, Arcamo-ne,
etal , German Offen, 2601785) or (S)
-N-α,β obtained from proline and 5,8-dimethoxy-3,4-dihydro-2-naphthoic acid (8)
A method using asymmetric bromolactonization reaction of -unsaturated acyl-(S)-proline (S,
Terashima, etal , Chem, Pharm, Bull
(Tokyo), 27 , 2351 (1979). ) is merely being attempted. Under such circumstances, the present inventors discovered that 2-acetyl-
The present invention was completed by developing a method for efficiently producing the object compound of the present invention using 5,8-dimethoxy-3,4-dihydronaphthalene.
The present invention will be explained in detail below. Formula () which is the first step in the production method of the present invention
This method reduces the carbonyl moiety (〓CO) of a compound to obtain a compound of formula (), but in this method, the ketone (〓CO) is converted into a secondary alcohol (〓CHOH).
The usual method of reducing That is, as a reducing agent, sodium borohydride, zinc borohydride, lithium aluminum hydride, lithium-tri-t-butoxyaluminum hydride,
Sodium, bis(methoxyethoxy)aluminum hydride, etc. are usually used, and ether,
In a solvent such as an ether solvent such as tetrahydrofuran, dimethoxymethane, or dimethoxyethane, or an aromatic hydrocarbon solvent such as toluene, at -70 to +25°C from 1 to
Allow to react for 4 hours. In addition, as a reducing agent (-)-1(R), 2
When lithium aluminum hydride partially decomposed with (S)-N-alkyl- or aralkyl-substituted ephedrin and N-monoalkyl- or aryl-substituted anilines is used, the optically active compound (') can be obtained in good asymmetric yield. Usually 1 equivalent of (-)-1(R),2(S)-N-methylefedrine (K, Nakajima, Nippon Kagaku Zasshi 81 , 1476
(1960)) and lithium aluminum hydride partially decomposed with 2 equivalents of N-ethylaniline.
The crude compound (') is obtained by reducing the reaction mixture at °C for 3 hours and separating the neutral part from the reaction product. In addition, from the basic part of the reaction product, (-)-1
(R), 2(S)-N-methylefedrin and N-
Ethylaniline is recovered quantitatively. When the crude compound (′) is recrystallized from hexane, the compound (′) mp88- with 100% optical purity is obtained.
89°C, [α] ²⁰ _D -20.5° (C=1.07 ethanol) is obtained. In addition to (-)-1(R), 2(S)-N-methylephedrin, (-)-1(R), 2(S)-N-alkyl or aralkyl-substituted ephedrin includes (-)- 1(R), 2(S)-N-ethylephedrine (O. Cervinka, etal , Coll.
Czech Chem, Comm, 32 , 3897 (1967). ),
(-)-1(R), 2(S)-N-propylephedrin, (-)-1(R), 2(S)-N-isobutylephedrin, (+)-1(R), 2 (S)-
N-benzylephedrin (S, Yamada,
etal , Yakugaku Zasshi, in press), but (-)-1(R),2(S)-N-methylefedrine is the best chiral source. Again N-
In addition to N-ethylaniline, monoalkyl- or aryl-substituted anilines include N-methylaniline, N-propylaniline, N-isopropylaniline, N-butylaniline, N-isobutylaniline, and N-ethyl-3,5-dimethylaniline. , N-ethyl-2,6-dimethylaniline, diphenylamine, carbazole, etc. can be used, but the asymmetric yield of compound (') was highest when N-ethylaniline was used. Also, N-t
- When butylaniline, pyrrolidine, piperidine, morpholine, pyrrole, imidazole, benztriazole, etc. are used in place of N-ethylaniline, the reduction reaction does not proceed, or even if it does proceed, the asymmetric yield is low. Katta. The ratio of (-)-1(R), 2(S)-N-alkyl or aralkyl-substituted ephedrin to N-monoalkyl or arylaniline may be other than the above 1:2, but the chiral source may be From the viewpoint of efficient use, a ratio of 1:2 is desirable. Asymmetric reduction is also possible in the following case, although it is not as efficient as the above case. That is, compound () is converted into 3 equivalents of (-)-1(R),2(S)-N-alkylephedrin, e.g. (-)-1(R),2
Lithium aluminum hydride (S, Yamada,
etal , Chem, pharm, Bull, (Tokyo), 25 , 1273
(1977). ), the optical purity is 15.
% of compound (') in a yield of 34% and 1 equivalent of (-)-1(R), 2(S)-N-alkylephedrine such as (-)-1(R), 2(S)- N
- Lithium aluminum hydride partially decomposed with methyl ephedrin and 2 equivalents of m-xylenol (J, P, Vigneron, etal , Tetrahedron, 32 ,
939 (1976). ), the enantiomer of compound (') with an optical purity of 13% was obtained in a yield of 68%,
In addition, lithium partially decomposed with 1 equivalent of (S)-2-anilinomethylpyrrolidine. aluminum.
Hydride (T, Mukai yama, etal Bull, Chem,
Soc, Japan, 51 , 1869 (1978). ), compound (') with optical purity of 54% was obtained in 60% yield. The second step is the epoxidation reaction of the 1st and 2nd double bonds, but this reaction is a normal double bond epoxidation reaction.

[Formula] is used. The epoxidizing agent is usually t-butyl hydroperoxide, cumene hydroperoxide, etc., molybdenum dioxyacetylacetonate (MoO ₂
(acac) ₂ ), vanadium oxyacetylacetonate (VO(acac) ₂ ), and other reagents used in the presence of catalysts (K, B, Scharpless, etal , J, Am Chem
Soc, 95 6136 (1973), H. Yamamoto, etal ,
Bull, Chem Soc. Japan 52 , 1701 (1979). ),
Examples include organic peracids such as perbenzoic acid, m-chloroperbenzoic acid, and peracetic acid. The reaction is usually carried out at -20 to +25°C for 30 minutes to 4 hours in an aromatic hydrocarbon solvent such as benzene or toluene, or a halogenated hydrocarbon solvent such as chloroform or methylene chloride. Since the compound () obtained in this reaction is unstable, it is usually directly subjected to the next step without being purified. Compound (') with 100% optical purity is oxidized with a reagent such as t-butyl hydroperoxide in the presence of a catalyst of vanadium oxyacetylacetonate in a solvent such as benzene to obtain optically active compound ('). It is usually obtained together with small amounts of the 1(R) and 2(R) isomers (see Examples), and since this mixture is an unstable oil, it is immediately subjected to the next step without purification. The third step is the reduction reaction of the 1,2-epoxy moiety of compound (), but this reaction

alcohol of [formula]

A reduction reaction to the formula is used. Typically, lithium aluminum hydride, sodium bis(methoxyethoxy)aluminum hydride, etc. are used as a reducing agent in a solvent such as an ether solvent such as tetrahydrofuran, or an aromatic hydrocarbon solvent such as benzene or toluene.
React at ~+25°C for 1-4 hours. When optically active compound (') is subjected to this reduction reaction, optically active compound (') is obtained. Usually, when this reduction reaction is carried out using a compound (') mixed with a small amount of 1(R), 2(R)-isomer, 2
Compound (') mixed with (S)-epimer is obtained, and this crude product can be purified by means such as column chromatography and recrystallization. Further, the mixture containing the 2(S)-epimer can be subjected to the next oxidation reaction as it is. The fourth step is the step of oxidizing the 1'-hydroxy moiety (〓CHOH) of the compound (), but this oxidation reaction usually oxidizes the secondary alcohol to a ketone (〓
The CHOH→〓C=O) method is used. Oxidizing agents usually include chromic acid-sulfuric acid, pyridinium chlorochromate (E, J. Corey, et al .
Tetrahedron Letters, 1975 , 2647. ), dimethyl sulfoxide-dicyclohexylcarbodiimide trifluoroacetic acid-pyridine (K, E,
Pfitzner, etal , J. Am Chem Soc, 87 ,
5661, 5670 (1965). ), silver carbonate-celite,
(Fetizon reagent) (Fetizon, etal , J, Org.
Chem, 36 , 1339 (1971). ), etc., and the reaction is usually carried out in a solvent such as acetone, dichloromethane, dimethyl sulfoxide, benzene, etc. at 0 to 80°C for 1 to 24 hours. When optically active compound (') is oxidized with Fetizon reagent, optically active compound (1') of the present invention is obtained. When a compound (') mixed with the 2(S)-epimer as described above is used, a compound (1') mixed with the 2(S)-epimer of compound (1') is obtained. As described above, according to the present invention, anthracycline antibiotics can be synthesized from 2-acetyl-5,8-dimethoxy-3,4-dihydronaphthalene () by a simple reaction procedure that is industrially possible. 2-acetyl-5,8-dimethoxy-1,2,3,4- which can be an extremely useful starting material
Tetrahydro-2-naphthol (1) can be produced.
In particular, the optically active form (1') of compound (1) has an optical purity of 100.
%. The compound () is 5,8-dimethoxy-3,4-dihydro-2-naphthoic acid (S, Terashi-ma, Chem, Pharm, Bull,
(Tokyo), 27 , 2351 (1979). ) can be easily manufactured from That is, the present invention has the following advantages from an industrial standpoint.
This is an excellent synthesis method. Aspects of the present invention will be illustrated below with examples. Reference example 2-acetyl-5,8-dimethoxy-3,4-
Dihydronaphthalene (): Argon gas flow 5,
8-dimethoxy-3,4-dihydro-2-naphthoic acid (234mg, 1.00m mole) in ether (10ml)
An ether solution of methyllithium (1.1 mmole/ml, 16 ml,
17.6m mole) in 30 minutes. The reaction solution was stirred at room temperature for 3 hours, then thoroughly stirred with 5% hydrochloric acid (40%
ml). After saturating the salt, the aqueous solution was extracted with ether (30 ml x 4), and the ether extracts were combined with saturated sodium bicarbonate aqueous solution (50 ml x 4), 10% sodium thiosulfate aqueous solution (50 ml), and water (50 ml). ) and saturated brine (50 ml), and dried over anhydrous magnesium sulfate.
Overconcentration gave a pale yellow oil (252 mg). The obtained crude oil was separated and purified by thin layer chromatography (silica gel, solvent, benzene-ethyl acetate 8:1), and pale yellow crystals (172
mg, 74%). Recrystallized from isopropyl ether to give pure pale yellow needle crystals (125mg,
54%), mp 104-105°C. IRν ^CHCl3 _nax cm ^-1 : 1655 (ketone). NMR (in
CDCl ₃ ): 2.43 (3H, s, COCH ₃ ), 2.20-3.10
(4H, m, C H ₂ C H ₂ ), 3.77 (3H, s, OC
H ₃ ), 3.81 (3H, s, OC H ₃ ) 6.77 (1H,
d, J=9.6Hz, one of aromatic protons),
6.88 (1H, d, J=9.6Hz, one of aromatic
protons), 7.83 (1H, bs, = CH) Anal, Calcd.
for C ₁₄ H ₁₆ O ₃ :C, 72.39; H, 6.94, Found;
C, 72.43; H, 6.89 Example 1-1 2-(1′(RS)-hydroxy)ethyl-5,
8-Dimethoxy-3,4-dihydronaphthalene (): (1.16 g,
5.0 mmole) was dissolved, and sodium borohydride (284 mg, 7.5 mmole) was added thereto. The reaction solution was stirred at room temperature for 4 hours. After adding water (2 ml), the reaction solution was concentrated under reduced pressure, ethyl acetate (30 ml) and saturated brine (20 ml) were added to the concentrated solution, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (15 ml x 3), and the ethyl acetate layers were combined and washed with saturated brine (20 ml). After drying with anhydrous magnesium sulfate and over-distillation, the crude product is a pale yellow oil (1.21
g, quantitative yield). This thing is
Crystallization occurred when hexane was added. Hexane (40
ml), pure colorless crystals (1.09
g, 93%), mp77-78°C. Further recrystallization from hexane was repeated to obtain an analytical sample of colorless crystals, mp 78-79°C. IRν ^CHCl3 _nax cm ^-1 : 3600, 1260, 1100 (alcohol). NMR (in CDCl ₃ ): 1.31 (3H, d, J=6
Hz, CH( _OH ) CH3 ), 2.06-2.44(2H, m,
C H ₂ C=), 2.44 (1H, s, O H ), 2.68-2.94
(2H, m, CH ₂ CH ₂ C=), 3.71 (6H, s, two
OC H ₃ ), 4.42 (1H, q, J = 6Hz, C H
(OH)), 6.60 (2H, s, aromatic protons),
6.78 (1H, brs, = CH ), Anal , Calcd for
_{C14H18O3 :} C, _71.77 ; H, 7.74. Found：C,
71.90; H, 7.73. Example 1-2 (-)-2-(1'(S)-hydroxy)ethyl-5,8-dimethoxy-3,4-dihydronaphthalene ('): Lithium aluminum hydride (1.44 g, 38 mmole) under argon stream ) was suspended in ether (70 ml), and (-)-1(R),2
(S)-N-methylefedrine (K,
Nakajima, Japanese Chemical Journal, 81 , 1476 (1960). )
(mp86.5-87.5℃, [α] ^20D _- 29.5゜(C=4.54,
An ether solution (100 ml) of methanol) (6.81 g, 38 mmole) was added, and the mixture was heated to reflux with stirring for 1 hour.
Then N-ethylaniline (9.21g, 76m
A reducing reagent was prepared by adding an ether solution (60 ml) of mol.
The ether solution of the reducing reagent was cooled to −78°C,
(2.20g, 9.47m mole) in ether solution (200
ml) was gradually added, and the mixture was stirred and reacted at the same temperature for 3 hours. After the reaction, add 1N-hydrochloric acid (152ml, 152m
mole) and extracted with ethyl acetate (150 ml x 2). Combine the extracts and add 1% hydrochloric acid water (150ml x
2) Washed sequentially with 5% aqueous sodium bicarbonate solution (150 ml), water (150 ml x 3), and saturated brine (150 ml), and dried over anhydrous magnesium sulfate. After distillation, the crude ' was obtained as pale yellow crystals (2.58 g, quantitative yield), [α] ²⁰ _D -17.8° (C = 1.83, ethanol).
obtained as. Assuming that the optical purity of [α] ²⁰ _D −20.5° (C=1.07, ethanol) obtained from this sample by the procedure described below is 100%, the optical purity of this sample is 87%. The obtained crystals were recrystallized from hexane (130 ml), and the pure product with optical purity of 100% was converted into colorless needle crystals (1.8 g, 81%), mp88-89℃,
[α] ²⁰ _D -20.5° (C=1.07, ethanol) was obtained. IRν ^CHCl3 _nax cm ^-1 : 3600, 1260, 1100 (alcohol). NMR (in CDCl ₃ ): 1.32 (3H, d, J=6
Hz, CH( _OH ) CH3 ), 2.00-2.36(2H, m,
C H ₂ C=), 2.12 (1H, s, O H ), 2.64-2.88
(2H, m, CH ₂ CH ₂ C=), 3.74 (6H, s, two
OC H3 ), 4.40 ( _1H , q, J=6Hz, C H
(OH), 6.60 (2H, s, aromatic protons),
6.72 (1H, brs, = C H ), Anal . Calcd
_{C14H18O3 :} C, _71.77 ; H, 7.74. Found：C,
71.57; H, 7.76. On the other hand, the remaining 1N-hydrochloric acid layer extracted with ethyl acetate was made alkaline (PH > 12) with a 10% aqueous sodium hydroxide solution and extracted with ethyl acetate (150 ml x 2). The ethyl acetate extracts were combined, washed with saturated brine (150 ml), and dried over anhydrous potassium carbonate.
When filtered and distilled, (-)-1(R), 2(S)-
A 1:2 mixture of N-methylefedrin and N-ethylaniline was obtained as a pale yellow oil (16.3 g, quantitative recovery). Example 2-1 2(RS)-(1'(SR)-hydroxy)ethyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2(RS)-naphthol (): Under argon stream ( 117mg, 0.50m mole) and vanadium oxyacetylacetonate (1.9mg,
0.007m mole) was dissolved in benzene (10ml), and a benzene solution of t-butyl hydroperoxide (22mg/ml, 2.5ml, 0.60ml) was added to this under stirring at room temperature.
mole) and stirred at room temperature for 45 minutes. When the benzene is distilled off after the reaction is completed, crude product 1 is obtained.
A mixture of (SR), 2(SR)-isomers was obtained as an unstable oil. This mixture shows its NMR spectrum (in
The first proton in CDCl ₃ ) is 4.50ppm.
4.41ppm, and from the area ratio and part 1
(SR), 2 (SR) isomer ratio was calculated to be 96:4. This result agreed well with the value calculated from the optical purity of 1'. Crude tomato part 1 (SR), 2
The mixture of (SR)-isomers was dissolved in tetrahydrofuran (5 ml) and this solution was injected into a suspension of lithium aluminum hydride (38 mg, 1.0 mmole) in tetrahydrofuran (5 ml).
Stirred at room temperature for 4 hours. After the reaction is complete, add 2N NaOH
A solution (10 ml) was added to separate the organic layer, and the aqueous layer was extracted with ethyl acetate (15 ml x 3). The extracts were combined, washed with water (15 ml) and saturated brine (15 ml), and dried over anhydrous magnesium sulfate. After filtration and distillation, a crude product was obtained as colorless crystals (131 mg). This product was separated and purified by thin layer chromatography (silica gel, solvent, benzene-ethyl acetate 1:1), and colorless crystals (108 mg, 86%) were obtained.mp138
-141℃. The analysis sample obtained here was recrystallized from ether as colorless needle crystals.
Obtained as mp145-146℃. IRν ^KBr _nax cm ^-1 : 3340, 1260, 1100, 1070 (alcohol). NMR (in CDCl ₃ - CD ₃ OD): 1.26 (3H, d, J
=6.0Hz, CH(OH) CH3 ), _1.30-2.05 (2H,
m, CH ₂ C H ₂ C (OH)), 2.70-3.00 (4H, m,
_CH2C (OH) _CH2CH2 ), 3.20―3.80 (3H _,
m, C H (OH) CH ₃ and O H ) , 3.76 (3H,
s, OCH ₃ ), 3.78 (3H, s, OCH ₃ ), 6.68
(2H, s, aromatic protons). Anal . Calcd ,
for C ₁₄ H ₂₀ O ₄ :C, 66.64; H, 7.99. Found;
C, 66.34; H, 7.94. Example 2-2 (-)-2(R)-(1'(S)-hydroxy)
Ethyl-5,8-dimethoxy-1,2,3,4-
Tetrahydro-2(R)-naphthol ('):
Under argon flow, '(mp88-89℃, [α] ²⁰ _D -
20.5゜(C=1.07, ethanol)) (703mg, 3.00m
benzene (55 m mole) and vanadium oxyacetylacetonate (11 mg, 0.042 m mole)
ml), and to this was added a benzene solution of t-butyl hydroperoxide (22 mg/mL) under stirring at room temperature.
ml), 13.5ml, 3.3m mole) and 1.5ml at the same temperature.
Time reacted. After the reaction was completed, benzene was distilled off to obtain a mixture of crude ' and its 1(R) and 2(R) isomers as an unstable oil. This was dissolved in tetrahydrofuran (40 ml), and this tetrahydrofuran solution was added to a suspension of lithium aluminum hydride (456 mg, 12 mmole) in tetrahydrofuran (40 ml).
Stir for hours. After the reaction was completed, 10% aqueous sodium hydroxide solution (65 ml) was added, and the aqueous layer was diluted with ethyl acetate (50 ml).
ml x 3). Combine the extract with water (50ml x
3) Washed with saturated brine (100 ml) and dried over anhydrous magnesium sulfate. After distillation, a mixture of crude ' and its 2(S)-epimer was obtained as colorless crystals (730 mg, 97% from '). A portion (380 mg) of the colorless crystals (730 mg) was separated and purified by column chromatography (silica gel, solvent, benzene-ethyl acetate 1:1), and a mixture of ' and its 2(S)-epimer was separated and purified as colorless needle-shaped crystals. (325
mg, 82% from '), mp140-150℃, [α] ²⁰ _D -
39.3° (C=1.04, ethanol). The IR and NMR spectra of this product matched those of the pure product '' below. Since 1′ with optical purity of 90% can be obtained from this product, ′ and its 2(S)
-Ratio of epimers, i.e. ' and its 1
The ratio of (R),2(R)-epimers was calculated to be 95:5. The remainder (350 mg) of the colorless crystals (730 mg) was crystallized from ether (35 ml) to obtain pure colorless needle crystals (252 mg, 70%), mp154-155℃, [α] ²⁰ _D -
49.7° (C=0.50, ethanol). IR
ν ^CHCl3 _nax cm ^-1 : 3580, 1260, 1105, 1090 (alcohol). IRν ^KBr _nax cm ^-1 : 3360, 1260, 1085 (alcohol) NMR (in CDCl ₃ - CD ₃ OD): 1.23 (3H,
d, J=6Hz, CH(OH) CH3 ), _1.40-2.05
(2H, m, C H ₂ C (OH)), 2.50-2.88 (4H,
m, CH ₂ C (OH) CH ₂ C H ₂ ), 3.20 (2H, s,
O H XZ), 3.62 (1H, q, J=6Hz, C H
(OH)CH ₃ ), 3.72 (3H, s, OC H ₃ ), 3.74
(3H, s, OC H ₃ ), 6.60 (2H, s, aromatic
protons). Anal , Calcd, for C ₁₄ H ₂₀ O ₄ :C,
66.64; H, 7.99. Found: C, 66.48; H,
8.06. Example 3-1 2(RS)-acetyl-5,8-dimethoxy-
1,2,3,4-tetrahydro-2(RS)-naphthol (1):a) (101 mg, 0.40 m mole) was dissolved in benzene (10 ml), silver carbonate-Celite reagent (Fetizon reagent) (1 m mole /g, 2.0 mmole) and heated under reflux for 30 minutes. After the reaction was completed, the silver-celite was removed and washed with benzene (50 ml).
The washing liquids were combined and distilled under reduced pressure to obtain a reddish brown solid (100
mg) was obtained. This was subjected to thin layer chromatography (silica gel, solvent, benzene:ethyl acetate 5:1).
Separation and purification was performed to obtain 1 as colorless crystals (90 mg, 90%). This product was recrystallized from chloroform-ether to produce pure 1 as colorless needle crystals, mp100-
101℃ (C, M, Wong, etal , Can.J.Chem,
49 , 2712 (1971). ,mp100-102℃；TH
Smith, etal J, Org Chem, 42 , 3653
(1977). , mp97℃). IRν ^nujol _na
x cm ^-1 :
1700 (ketones). NMR (in CDCl ₃ ): 1.85-2.10 (2H, m, CH ₂ C
H ₂ C (OH) CH ₂ ), 2.30 (3H, s, CO C H
₃ ), 2.70-3.00 (4H, m, CH ₂ CH ₂ C(OH)C
H ₂ ), 3.67 (1H, s, O H ), 3.72 (3H, s,
OC H ₃ ), 3.76 (3H, s, OCH ₃ ), 6.58 (2H,
s, aromatic protons). This NMR spectrum was obtained from the literature (S. Terashima et al ., Chem.
Pharm, Bull (Tokyo), 27 , 2351 (1979). ) matched. b) (50.5mg, 0.20m mole) was dissolved in dimethyl sulfoxide (1ml), and to this was added a benzene solution (1ml) of pyridine (15.8mg, 0.20m mole) and trifluoroacetic acid (11.4mg, 0.10m mole) under stirring at room temperature.
mole) in benzene (1 ml) and dicyclohexylcarbodiimide (124 mg, 0.60 m mole)
was added and reacted at the same temperature for 39 hours. The precipitated white solid was removed and washed with benzene. The washings were combined, washed with water (10 ml x 3) and saturated brine (10 ml), and dried over anhydrous magnesium sulfate. Too late,
Distillation gave an oil. This product was separated and purified by thin layer chromatography (silica gel, solvent, ethyl acetate:benzene 1:5) to obtain 1 as a semisolid (30.4 mg, 61%). When this product is recrystallized from chloroform-ether, pure 1
was obtained as colorless needle crystals, mp 100-101°C. The spectrum of this sample matched that of the sample obtained in a). Example 3-2 (-)-2(R)-acetyl-5,8-dimethoxy-1,2,3,4-tetrahydro-2(R)
-Mixture of naphthol 1':' and its 2(S)-epimer (mp140-150℃, [α] ²⁰ _D -39.3゜(C
= 1.04, ethanol) (135 mg, 0.54 m mole) was dissolved in benzene (13 ml) and Fetizon reagent (1 m
mole/g, 2.7 g, 2.7 mmole) was added, and the mixture was heated under reflux for 30 minutes. After the reaction was completed, the silver-celite was removed and washed with benzene (40 ml). The washing liquids were combined and concentrated under reduced pressure to obtain a reddish-brown oil (140 mg).
This was separated and purified by thin layer chromatography (silica gel, solvent, benzene-ethyl acetate 5:1), and 1' was obtained as colorless crystals (105 mg, 84%), mp123-127
°C, [α] ²⁰ _D -42.5° (C = 0.89, chloroform)
obtained as. The IR and NMR spectra of this product were consistent with those below. Also, [α] ²⁰ _D -
If 1' showing 47.10 (C=1.11, chloroform) has an optical purity of 100%, this product has an optical purity of 90%. On the other hand, pure product' (mp154-155℃, [α] ^20D _-
49.6゜(C=1.08, ethanol) (134mg, 0.53m
mole) was treated in the same manner as above, and the benzene washing solution was concentrated under reduced pressure, resulting in a reddish brown oil (130
mg) was obtained. This product was separated and purified by thin layer chromatography in the same manner as above, and pure 1' was obtained as colorless crystals (91 mg, 69%), mp127-128.5℃, [α] ²⁰ _D -
44.0° (C=1.92, chloroform). When this product was recrystallized twice from chloroform-ether, the elemental analysis sample of 1' was colorless needle crystals, mp 128-129℃, [α] ²⁰ _D -47.1゜ (C = 1.11,
Chloroform) (S, Terashima, etal , Chem
Pharm Bull (Tokyo), 27 , 2351 (1979).
mp128-129°C, [α] ²⁰ _D -48.2° (C=0.982, chloroform)). IRν ^CHCl _3nax
cm ^-1 :
1710 (ketone). NMR (in _CDCl3 ): 1.86-2.10
(2H, m, C H ₂ C (OH)), 2.29 (3H, s, CO
C H ₃ ), 2.70-3.10 (4H, m, C H ₂ CH ₂ C
(OH) CH2 ) _, 3.58 (1H,s, OH ), 3.72
(3H,s,OC H3 )3.76( _3H ,s,OC H
₃ ), 6.62 (2H, s, aromatic protons). These spectra are from the literature (S, Terashima, et al.
Chem.Pharm, Bull (Tokyo), 27 , 2351
(1979). ) matched.

Claims (1)

[Claims] 1 formula 2-acetyl-5,8-dimethoxy represented by
Carbonyl of 3,4-dihydronaphthalene (〓
CO) part is reduced and the formula 2-(1'-hydroxy)ethyl-5,
8-dimethoxy-3,4-dihydronaphthalene was obtained, and then the double bond between the 1st and 2nd positions of this compound was epoxidized to give the formula 2-(1'-hydroxy)ethyl-5,
8-dimethoxy-1,2-epoxy-1,2,
3,4-tetrahydronaphthalene was obtained, and the 1,2-epoxy moiety [formula] of this compound was then reduced to give the formula 2-(1'-hydroxy)ethyl-5,
8-dimethoxy-1,2,3,4-tetrahydro-2-naphthol is obtained, and then the 1'-
Formulas characterized by oxidizing the hydroxy moiety (〓CHOH) 2-acetyl-5,8-dimethoxy represented by
New method for producing 1,2,3,4-tetrahydro-2-naphthol 2 Formula 2-acetyl-5,8-dimethoxy represented by
Carbonyl of 3,4-dihydronaphthalene (〓
CO) moiety with (-)-1(R), 2(S)-N-alkyl- or aralkyl-substituted ephedrin and N-
Asymmetric reduction with lithium aluminum hydride partially decomposed with monoalkyl- or aryl-substituted anilines gives the formula (-)-2-(1'(S)-hydroxy)ethyl-5,8-dimethoxy-3,4-dihydronaphthalene represented by
By epoxidizing the double bond between the positions, the formula 2(S)-(1'(S)-hydroxy) represented by
Ethyl-5,8-dimethoxy-1(S),2
(S)-epoxy-1,2,3,4-tetrahydronaphthalene was obtained, and then the 1,2-
Reducing the epoxy part [formula], the formula (-)-2(R)-(1'(S)-hydroxy)ethyl-5,8-dimethoxy-1,2,
3,4-tetrahydro-3(R)-naphthol was obtained, and then the 1'-hydroxy moiety (〓
A formula characterized by oxidizing CHOH) (-)-2(R)-acetyl-5,8 represented by
-dimethoxy-1,2,3,4-tetrahydro-
A new method for producing 2(R)-naphthol.