JPH03246277A - Racemization of octahydroisoquinoline derivative - Google Patents

Abstract

PURPOSE:To racemize the subject compound useful as a synthetic intermediate for pharmaceuticals by oxidizing and reducing an optically active isomer of an octahydroisoquinoline derivative using a specific compound. CONSTITUTION:An optically active octahydroisoquinoline derivative is racemized by oxidizing an optically active isomer of an octahydroisoquinoline derivative of formula (R<1> is H or univalent hydrocarbon group; R<2> is H, OH, lower alkyl or alkoxy) with N-bromosuccinimide in a solvent such as dichloromethane and reducing the oxidation product with an alkali metal borohydride in a solvent such as methanol at 15-40 deg.C. The amount of N-bromosuccinimide is 2-2.2mol- equivalent and that of alkali metal borohydride is >=1mol-equivalent based on the compound of formula.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for racemizing octahydroisoquinoline derivatives useful as pharmaceutical intermediates and a method for producing optically active octahydroisoquinoline derivative compounds.

[Prior Art] Physiologically active natural organic compounds have significantly different physiological activities depending on the steric structure of their optical isomers, and sometimes exhibit actions completely opposite to their original purpose or harmful effects.

Therefore, the physiological activities of such derivatives of natural organic compounds often differ greatly depending on the steric structure of the optical isomer. For example, dextromethorphan is an artificial derivative of the opium alkaloid represented by the formula (n), which has a dextrorotatory morphian structure and is a useful compound as an antitussive, but its levorotatory compound has an analgesic effect. It also has narcotic properties.

- As an example, dextromethorphan is first synthesized as a racemic form of 3-hydroxy-N-methylmorphian;
By optically resolving this by some method to obtain dextrorotatory d-3-hydroxy-N-methylmorphine and then methylating it, or by nitrating the natural product d-N-methylmorphine and then After reduction, it is diazotized to obtain an optically active d-3-hydroxy-N-methylmorphian, which is then similarly methylated (Helv, Chem.

Acta, 32.821 (1949)).

In addition, as a racemization method that is one of the means to effectively utilize the enantiomers remaining after optical resolution, a racemization method is known in which L-octahydroisoquinoline derivatives are heated in an alcohol solvent under a hydrogen atmosphere using a platinum carbon catalyst. There is (Unexamined Japanese Patent Publication No. 6)
2-190.166).

[Problems to be Solved by the Invention] However, synthesis from natural products requires a large number of steps, separation of isomers, etc., resulting in poor yields in each step, and is industrially disadvantageous. In addition, in the method of producing an optically active substance by optical resolution of a racemate, the enantiomer thereof is not utilized in obtaining the desired optically active substance, and thus is poor in economic efficiency.

Also, according to racemization method using platinum carbon catalyst etc.
% complete racemate cannot be obtained, and it is not practical in terms of ease of operation and reaction time and reaction temperature.

Therefore, an object of the present invention is to provide a method that can advantageously perform racemization, and to provide a racemic product that can optically resolve the enantiomer having the opposite steric configuration to the desired one after optically resolving the racemate. The purpose of the present invention is to provide a method for efficiently producing a desired optically active substance.

[Means for Solving the Problems] Therefore, as a result of various studies to solve these problems, the present inventors have discovered that N-bromosuccinimide and alkali metal borohydride are important synthetic intermediates for pharmaceuticals. However, they discovered that it is possible to completely racemize the unused enantiomer and furthermore, optically resolve the racemate, thereby completing the present invention.

That is, the present invention relates to the following general formula (I) (wherein R' represents hydrogen or a lower alkyl group, and R
1 represents hydrogen, a hydroxyl group, a lower alkyl group, or an alkoxy group) is oxidized with N-bromosuccinimide, and then reduced with an alkali metal borohydride. After racemizing the derivative and optically resolving the racemic form of the octahydroxyisoquinoline derivative to obtain the desired optically active form, the remaining enantiomer is racemized using the above racemization method, and this is optically resolved again. This is a method for producing an optically active octahydroxyisoquinoline derivative compound.

The reaction formula of the present invention is as follows.

(However, in the formula, R1 represents hydrogen or a lower alkyl group, and R
(2 represents hydrogen, a hydroxyl group, a lower alkyl group, or an alkoxy group, and X represents a halogen) The octahydroisoquinoline derivative used as a raw material in the present invention is a compound represented by the above general formula (I),
In the formula, R1 is hydrogen or a lower alkyl group, preferably hydrogen or an alkyl group having 1 to 3 carbon atoms, and R2 is hydrogen, a hydroxyl group, a lower alkyl group, or an alcohol, preferably hydrogen or a carbon alkyl group. It is an alkyl group or an alkoxy group of number 1 to 3.

In the present invention, the amount of N-bromosuccinimide used in the oxidation reaction may be at least twice the molar equivalent of the raw material octahydroisoquinoline, and is usually 2 to 2.
Approximately 2 molar equivalents are preferable.

The solvent used in the oxidation reaction in the present invention is preferably a halogen organic solvent such as dichloromethane or chloroform. The amount of this solvent to be used is preferably about 20 to 40 times the weight of N-bromosuccinimide.

In the present invention, the amount of the alkali metal borohydride used in the reduction reaction may be 1 molar equivalent or more, and usually about 1 to 2.2 molar equivalents, relative to the octahydroisoquinoline.

In the present invention, the solvent used in the reduction reaction is preferably a mixed solvent of alcohol and water, and the proportion of alcohol is preferably 75 to 95% by weight. As the alcohol, methanol and ethanol are preferred.

Furthermore, in order to carry out the oxidation reaction in the present invention, octahydroisoquinolines are dissolved in about 10% of a predetermined amount of an organic solvent, and a suspension of the remaining organic solvent and a predetermined amount of N-bromosuccinimide is added to this. A preferred method is to add the mixture with stirring, usually over a period of 5 to 20 minutes, and then to react at 15 to 50° C. with stirring for about 2 to 6 hours.

Next, in order to perform a reduction reaction in the present invention, after the oxidation reaction is completed, the solvent is distilled off, and the residue is dissolved in a predetermined amount of a mixed solvent. A preferred method is to add an alkali metal borohydride to the mixture, usually over a period of 5 to 20 minutes, and then react with stirring at 15 to 40°C for about 2 to 8 hours.

After the reaction is completed in this manner, the solvent is distilled off from the reaction mixture, the residue is made alkaline with aqueous ammonia, etc., and then extracted using an organic solvent as an extraction solvent to obtain the desired racemate. The extraction solvent may be a commonly used non-aqueous organic solvent.

By distilling off the extraction solvent, the desired racemic form of octahydroisoquinolines is obtained.

This racemate can be optically resolved again to obtain a useful optically active form. That is, after optically resolving the racemic form of the octahydroxyisoquinoline derivative to obtain the desired optically active form, the remaining enantiomer is racemized using the racemization method described above, and this is optically resolved again to obtain the desired optically active form. This is a method for obtaining active octahydroxyisoquinoline derivatives and producing octahydroxyisoquinoline derivative compounds useful as pharmaceuticals such as morphinan derivatives from these desired optically active octahydroxyisoquinoline derivatives.

[Example] Hereinafter, the present invention will be described in detail based on Examples.

Example 1 dL-1-p-methoxybenzyl-2-methyl-
1,2,5,6,7,8-hexahydroisoquinoline 2
2.0g (82 mmol), water 251n! , 250 methanol was charged, 3.6 g of sodium borohydride was added little by little over about 15 minutes at room temperature while stirring, and the reaction was further allowed to proceed at room temperature for 3 hours with stirring.

After the reaction was completed, the solvent was distilled off under reduced pressure, 150% of water and 300% of benzene were added to the residue, and the mixture was thoroughly shaken and the benzene layer was separated. The aqueous layer was made basic by adding aqueous ammonia, and then extracted twice with 1007 nl of benzene.

The benzene layer thus obtained and the benzene extract were combined and washed with 3x-ammonia water.

After washing, it was dried over anhydrous sodium sulfate, and then benzene was distilled off to obtain 21.5 g (79 ml J mol, yield 97x) of an orange oil. The obtained orange oil was distilled under reduced pressure to obtain dl-1-p-methoxybenzyl-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline. The boiling point, mass spectrometry spectrum and 'H-NMR (CDC1a) of this product were measured. The results are shown below.

Boiling point: 152-154°C/0.15mmHg Mass spectrometry spectrum: m/e: 271 H-NMR (CDC13): δ = 1.49-1.93
(m, 101(); 2.33<s, 3H): 2.4
6 (m, IH); 2.75 (d, 2H); 2.83 (
m, IH); 2.90 (m, IH); 3.70
(s.

3H); 6.76 (d, 2H); 7.14 (d, 2
H) 17.5 g (65 mmol) of the obtained dL-1-p-methoxybenzyl-2-methyl 1,2.3.4.5.6.7.8-octahytroinquinoline and L-(+) −
9.8 g (65 mmol) of tartaric acid and 50 mmol of methanol
The mixture was dissolved under heating and left at room temperature for 4 hours. The precipitated crystals were collected by filtration and dried to give 11.2 g (27 mmol,
A yield of 81.9N) was obtained.

The filtrate at this time was designated as mother liquor A. The melting point and optical rotation of the obtained crystals were measured. The results are shown below.

Melting point 173-174°C [α]”D −+ 4 5, 9°
(C=1.methanol) This crystal was dissolved in 407 nl of water, 3x-ammonia water (20-mL) was added, and the precipitated oil was extracted with 80-mL of benzene. After washing the extract with water, it was dried over anhydrous sodium sulfate, and then benzene was distilled off to give d-
1-pmethoxybenzyl-2-methyl-1,2,3,4
, 5,6,7,8-octahydroisoquinoline was obtained quantitatively. The optical rotation of the obtained crystal was as follows.

[α]”D = +3 3. 1 ° (C
=1. Methanol) Example 2 Mother liquor A obtained in Example 1 was concentrated to obtain 16.5 g of oil.
I got it. The optical rotation of this oil is [α]20D =
1 2. 8° (C=1.methanol).

Dissolve this oil in 80 - of water and 3x - 3 - ammonia water.
0- was added, and the precipitated oil was extracted with 1207 nl of benzene. The extract was washed with water, dried over anhydrous sodium sulfate, and then benzene was distilled off to give L-1-p-methoxybenzyl-2-methyl-1,2,3,4,5°6,7.
10.0 g (37 mmol) of 8-octahydroisoquinoline was obtained. The obtained L-1-p-methoxybenzyl-
The optical rotation of 2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline was [α]”D-28; 2° (C=1.methanol).

Next, 1-1-p-methoxybenzyl-2-methyl-1 was added to 11 reactors equipped with a thermometer, a reflux condenser, and a stirrer.
, 10.0 g of octahydroisoquinoline and 50 g of dichloromethane were charged, and 13.2 g of N-bromosuccinimide (7
A suspension of 4 ml J mol) in 350 ml of dichloromethane was added little by little over about 10 minutes, and the mixture was further stirred at room temperature for 3 hours.

After stirring, dichloromethane was distilled off under reduced pressure, the residue was dissolved in 100ml of methanol and 10ml of water, and 3.1g (74 mmol) of sodium borohydride was added little by little to this solution over about 15 minutes, followed by heating at room temperature. The mixture was stirred for 3 hours. After stirring, the solvent was distilled off under reduced pressure and the residue (Residue A
) were added with 50 l of water and 501 nl of benzene, and after shaking and mixing thoroughly, the benzene layer was separated. In addition, aqueous ammonia was added to the aqueous layer to make it basic, and then 40 ml of benzene was added.
Extracted twice. The obtained benzene layer and benzene extract were combined, dried over anhydrous sodium sulfate, and then the benzene was distilled off to give 9.4 g (35 mm) of a brown oil.
J%, yield 94.7N, purity 86.4N).

The brown oil thus obtained was distilled under reduced pressure to give dll.
-p-methoxybenzyl-2-methyl-1,2,3゜4
, 5.6.7.8-octahydroisoquinoline was obtained.

The optical rotation, boiling point, and mass spectrometry spectrum of this product were measured. The results are shown below.

[α]”D=0° (C=1.methanol) Boiling point: 152-1546C/0.15mmH
g Mass spectrometry spectrum m/e: 271 Obtained dL-1-p-methoxybenzyl-2-methyl-1,2,3,4,5,6,7,8-octahydroisoquinoline 8°0 g (30 mmol ) and 4.4 g (30 mmol) of L-(+)-tartaric acid were dissolved in 2 G of methanol under heating and allowed to stand at room temperature. The precipitated crystals were collected by filtration and dried to give 5.2 g of crystals (12 ml J mol, yield 82.
3%). The melting point and optical rotation of the obtained crystals were measured. The results are shown below.

Melting point 173-174°C [α]20o-+ 4 5. 8° (C=
1. Methanol) Example 3 4.6 g of the residue A from Example 2 and dL-1-p-methoxybenzyl-2-methyl-1,2 were added to a 500-cm reactor equipped with a thermometer, a reflux condenser, and a stirrer. ,5,6,7゜8
-hexahydroisoquinoline 13.4 g (49
2.7 g of sodium borohydride (2.7 g of sodium borohydride)
64 mlJ mol) was added little by little over about 15 minutes, and after further stirring at room temperature for 3 hours, the solvent was distilled off under reduced pressure. After adding 70 mm of water and 80 mm of benzene to the obtained residue and thoroughly shaking the mixture, the benzene layer was separated. In addition, the water layer has 3
The mixture was made basic by adding 50 ml of X-ammonia water, and then extracted twice with 50 d of benzene. The obtained benzene layer and benzene extract were combined, washed with 3x-ammonia water and water, dried over anhydrous sodium sulfate, and then benzene was distilled off to obtain 14.7 g (54 mlJ mol) of an oily substance. I got it. This oil was distilled under reduced pressure to give dll-p-methoxybenzyl-2-methyl-1,2°3,4.5.6
．． 7.8-octahydroisoquinoline was obtained.

The optical rotation, boiling point, and mass spectrometry spectrum of the obtained dl-1-p-methoxybenzyl-2-methyl-1°2,3.4.5.6.7.8-octahytroinquinoline were measured. The results are shown below.

[α]”D = 0 ° (C = 1. Methanol) Boiling point: 153-156 °C / 0.20 mmHg Mass spectrometry spectrum m/e: 271 Obtained at-1-p-methoxybenzyl-2-methyl 1 , 2.3.4.5.6.7.8-octahydroisoquinoline 8.8 g (32 mmol) and L-(+)-tartaric acid 4.9 g (32 mmol) were heated in 30-methanol. It was dissolved and left at room temperature for 4 hours. The precipitated crystals were collected by filtration and dried to obtain 5.5 g of crystals (13 mmol, yield 81.7 N).The melting point and The optical rotation was measured.The results are shown below.

Melting point 173-174°C [α]”D = + 4 5. 8 ° (
C=1. Methanol) Example 4 d-1-p-methoxybenzyl-2-methyl 1,2 was added to a 200-cm reactor equipped with a thermometer, a reflux condenser, and a stirrer.
．． 3.4.5.6.7. 4.4 g (16 mmol) of 8-octahydroisoquinoline and 60 d of 85X-phosphoric acid were charged, and the mixture was heated and stirred at 145 to 155° C. for 28 hours.

After the reaction is completed, the reaction solution is dispersed in ice water, concentrated aqueous ammonia is added to make it strongly alkaline, then 100% of water and 200% of benzene are added and shaken well, and the aqueous layer and benzene layer are separated. Furthermore, for the water layer, add this to benzene 10
Extracted twice with 0.07nl.

The benzene layer thus obtained and the benzene extract were combined, dried over anhydrous sodium sulfate, and then benzene was distilled off to obtain 4.1 g of a yellow oil.
was added, and the precipitated crystals were collected by filtration and dried to obtain white crystals of d-3-hydroxy-N-methylmorphian. 2g
(12 mlJ mol, yield 76, 7N) was obtained. Melting point, mass spectrometry spectrum, optical rotation and 'H-NMR of this product
(CDC13) was measured. The results are shown below.

Melting point = 197-198°C Mass spectrometry spectrum: m/e: 257 [α] 20D
” + 5 5.8 ° (C=1.methanol)H-NM[CI)C7!3): δ=1.1
0-1.83 (m, 10H); 2.07 (m.

IH); 2.26 (m, 2H); 2.34 (s, 3
H); 2°41 (s, LH); 2.65 (dd, I
H); 2.90 (m, IH); 3,12 (d, I
H); 6.60 (dd, IH); 6°70 (d
, IH); 6.97 (d, IH) [Effect of the invention] According to the present invention, in an octahydroisoquinoline derivative which is an intermediate for producing an optically active N-methylmorphian derivative useful as a pharmaceutical, 50% of the It is possible to advantageously racemize the unused enantiomer that occupies the molecule, and if this is optically resolved again, it is possible to improve the yield of the desired optically active form. It is possible to improve the yield of octahydroisoquinoline derivative compounds and is extremely economical.

Claims (3)

[Claims] (1) The following general formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (However, in the formula, R^1 represents hydrogen or a lower alkyl group,
R^2 represents hydrogen, a hydroxyl group, a lower alkyl group, or an alkoxy group) The optically active form of an octahydroisoquinoline derivative represented by R^2 is oxidized with N-bromosuccinimide, and then reduced with an alkali metal borohydride. Racemization method for optically active octahydroisoquinoline derivatives. (2) A method for producing a morphian derivative which undergoes racemization according to claim 1. (3) After optically resolving the racemic form of the octahydroxyisoquinoline derivative to obtain the desired optically active form, the remaining enantiomer is racemized using the racemization method described in claim 1,
A method for producing an optically active octahydroxyisoquinoline derivative compound, which comprises optically resolving this compound again.