JPH0532663A - Production of yohinban derivative - Google Patents

Abstract

PURPOSE:To stereoselectively obtain the subject compounds useful as an intermediate for synthesis of medical drugs by reacting an alkalline or alkalline earth compound of a yohinban derivative with a lower-alkyl chlorocarbonate. CONSTITUTION:An alkalline or alkalline earth compound of a yohinban derivative of formula I (R is H or lower alkyl; A is lower alkyl) is acylated at 0 deg.C-room temperature by using a lower-alkyl chlorocarbonate to obtain the objective compound of formula II. Based on 1 mol compound of formula I, 1-3mol lower-alkyl chlorocarbonate is used. Useful as an intermediate for synthesis of rauwolfia alkaloids such as reserpine and deserpidine and the rauwolfia alkaloids are useful as an antihypertensive agent, a tranquilizer, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a yohimbane derivative.

[0002]

2. Description of the Related Art Low Wolfia alkaloids such as reserpine and deserpidine are known as hypotensive agents, tranquilizers and the like. The present inventor has previously established a simple stereoselective synthetic method for yohimbinone and arroyohinbinone, and has made it possible to practically perform simple total synthesis of yohimbine and aroyohimbin. After that, further research was conducted to find out a general method for synthesizing low-wolfia alkaloids including reserpine and deserpidine, and the present invention was reached.

The present invention has the general formula

[Chemical 3] (Wherein R represents a hydrogen atom or a lower alkoxy group, A represents a lower alkyl group), and an alkali or alkaline earth metal compound of a yohimbane derivative represented by the formula is reacted with a lower alkyl chlorocarbonate.

[Chemical 4] A method for producing a yohimbane derivative represented by the formula (wherein R and A have the above-mentioned meanings).

Lithium compounds are preferred as the alkali metal compound of the yohimbane derivative of formula I and magnesium compounds are preferred as the alkaline earth metal compound. Examples of the lower alkyl group of lower alkyl chlorocarbonate include a methyl group, an ethyl group, a propyl group and a butyl group, and preferably a methyl group. The acylation reaction is carried out at 0 ° C. to room temperature using 1 to 3 mol of lower alkyl chlorocarbonate to 1 mol of the compound of formula I.

The compounds of formula I have the general formula

[Chemical 5] (In the formula, R and A have the above-mentioned meanings) An indolopyridine enamide derivative is subjected to a reductive photocyclization reaction,
The reaction product can be obtained, for example, by reduction with a large excess of lithium aluminum hydride by a conventional method, and then acid treatment with, for example, dilute hydrochloric acid. The product (I) can be isolated and purified by column chromatography or the like.

The raw material indolopyridine enamide derivative (III) is represented by the general formula

[Chemical 6] It is obtained by reacting an indolopyridine represented by the formula (wherein R has the above-mentioned meaning) in the presence of a lower alkoxy-substituted benzoic acid halide or a dehydrohalogenating agent.

The reductive photocyclization reaction can be carried out by irradiating the indolopyridine enamide derivative (III) in a polar solvent in the presence of sodium borohydride with a high-pressure mercury lamp. As the polar solvent, for example, acetonitrile, alcohol, etc. and a mixture thereof are used. The light irradiation time is several minutes to several hours, preferably 30 to 60 minutes. This reaction is preferably carried out in an atmosphere of an inert gas such as nitrogen.

The metalation of the yohimbane derivative (I) is an important condition for stereoselective acylation, and the compound of formula I can be prepared, for example, from lithium di-lower alkylamide (LD).
It is obtained as lithium enolate by uniformly reacting with A) at a low temperature of 80 ° C. Reaction of this with lower alkyl chlorocarbonates, preferably in the presence of magnesium halide and the like, provides compounds of formula II. If desired, the reaction product can be catalytically reduced in the presence of a catalyst such as platinum oxide to saturate the double bond.

As LDA, lithium dimethyl amide, lithium diethyl amide, lithium dipropyl amide, lithium dibutyl amide, lithium methyl ethyl amide, lithium propyl butyl amide and the like, preferably lithium diisopropyl amide, are used. LDA is, for example, di-lower alkylamine, n-alkyllithium,
It is preferably obtained by reacting with n-putyllithium. Tetrahydrofuran and crown ether are preferable as the solvent for this reaction. The reaction is carried out in a short time of about 1 hour, and the product can be isolated and purified by column chromatography or the like.

Reference Example 18-Methoxy-18,19-didehydro-17-oxo-yohimban 1 described in Example 3 of JP-A-60-56978
350 mg of 7,18-dimethoxy-16,17,18,19-tetradehydro-21-oxo-yohimban is reduced with a large excess of lithium aluminum hydride by a conventional method. The product was immediately dissolved in 15 ml of methanol as it was, 2 ml of 10% hydrochloric acid was added with stirring, and the mixture was stirred at room temperature for 30 minutes.
Leave for a minute. After completion of the reaction, the mixture is neutralized with saturated aqueous sodium hydrogen carbonate and extracted with methylene chloride. The extract is washed with water and dried over anhydrous sodium sulfate, and the solvent is distilled off. Recrystallization of the residue from an ether-methanol mixture gave 18
-Methoxy-18,19-didehydro-17-oxo.
130 mg of yohimban (40% yield) is obtained.

NMR δ (CDCl ₃ ): 8.12 (1H, s, NH) 5.80 (1H, d, J = 2.5Hz, 19-H) 5.16 (1H, m, 5eq-H) 4.90 (1H, dd, J = 11.5, 5Hz, 3-
H) 3.80 (1H, br, dd, J = 5, 2.5 Hz, 2
0-H) 3.57 (3H, s, OCH 3) 3.08~2.70 (5H, m, 5ax-H, 6-
_{H 2, 15-H, 16eq} -H) 2.58 (1H, d -like, J = 14Hz, 16ax-H ) 2.24 (1H, br, d, J = 11.5Hz, 14e
q-H) 2.00 (1H, q, J = 11.5 Hz, 14ax-
H)

Example 16-Methoxycarbonyl-18-methoxy-18,1
9-didehydro-17-oxo-yohimban (18-methoxy-18,19-didehydro-yohimbinone) 0.078 ml of diisopropylamine and 0.1 ml of n-butyllithium in 10 ml of anhydrous tetrahydrofuran at -78 ° C.
Add 09 ml of lithium diisopropylamide (LD
A) is prepared. After standing for 10 minutes, 35 mg of 18-methoxy-18,19-didehydro-17-oxo-yohimban obtained in Reference Example was added to anhydrous tetrahydrofuran 3
The solution dissolved in ml is added dropwise. After standing at -78 ° C for 1 hour, a solution of 20 mg of anhydrous magnesium bromide dissolved in 5 ml of anhydrous tetrahydrofuran is added and the mixture is allowed to stand for 40 minutes. Then, 0.01 ml of methyl chlorocarbonate is added and left at room temperature for 1 hour. Water is added to the reaction solution, which is extracted with methylene chloride. The extract is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off. The obtained residue was purified by column chromatography to give 16-methoxycarbonyl-18-methoxy-18,19-didehydro-
5 mg of 17-oxo yohimban (12% yield) are obtained. In addition, unreacted raw materials are separated and collected in this purification process.

1R ν CHC1 ₃ max cm ^-1 :
_{3500,1740,1695,1630,1600 NMR δ (CDC1 3):} 12.35 (1 / 3H, s, enolic OH) 7.80 (2 / 3H, s, 2 / 3NH) 7.74 (1 / 3H, s, 1 / 3NH) 5.73 (2 / 3H, brs, 2/3 19-H) 5.17 (1 / 3H, brs, 1/3 19-H) 3.90 and 3.68 ( 1H, s, 1/3 OCH ₂ × each
2) 3.77 and 3.65 (each 2H, s, 2 / 3OCH ₃ ×)
2)

[0014]

INDUSTRIAL APPLICABILITY The compound of the present invention is useful as an intermediate in a general synthesis method of low-orphia alkaloids including reserpine, deserpidine and the like.

Claims (1)

What is claimed is: 1. A general formula: (Wherein R represents a hydrogen atom or a lower alkoxy group, A represents a lower alkyl group), and an alkali or alkaline earth metal compound of a yohimbane derivative represented by the formula is reacted with a lower alkyl chlorocarbonate. [Chemical 2] A method for producing a yohimbane derivative represented by the formula (wherein R and A have the above meanings).