JPS5927340B2 - N- dimethylallyl -3- benzazocinno seizouhou - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing N-dimethylaryl-3-benzazosine represented by general formula (I).

, <! An-1゜''1゜0-1 (wherein R1 represents a lower alkyl group) The compound in which R1 is a methyl group, that is, N-dimethylallyl 1,2,3|4|5,6-hexahydro 6,
11-dimethyl ■8-hydroxy 2,6=methanol 3-benzazosine is commonly called pentalicine.
It is a compound that is widely used medically, especially as a powerful analgesic.

Although several reports have already been made regarding the manufacturing method of the compound, the present inventor has completed the present invention as a result of intensive studies to establish an industrially more effective manufacturing method.
The process of the present invention and raw material synthesis can be expressed as a chemical formula as follows.

\ 1411-! 1V Ha --? In the above chemical formula, the steps according to the present invention are (a) → (1) and (Hb) → (1), and the step of primitive needle synthesis is (
)→(a) and ()→()→(b).

First, the process of raw material synthesis will be explained.

8-Hydroxy-3-benzazocin-14-one represented by the general formula (), which is a starting material in the synthesis of raw materials, is a known substance (V) [Japanese Patent Application No. 149262/1989 filed by the present inventor]. [described in the specification] according to the following formula.

That is, N-benzyl-8-hydroxy-3-benzazosin-4-one (■) was subjected to a conventional debenzylation reaction (
(for example, catalytic reduction, heating with mineral acids, etc.) with good yield. First, 8-hydroxy-3-benzazocin-4-one represented by the general formula (■) is reacted with dimethylallyl halide in an appropriate solvent under an alkali metal catalyst to form a compound corresponding to the general formula (■a). get.

The solvent used in this reaction may be any solvent as long as it does not directly affect the reaction, and is usually an ether type such as ether, tetrahydrofuran, or dioxane, an aromatic hydrocarbon type such as benzene, toluene, or xylene, or methanol. ,
An alcoholic solvent such as ethanol is used. The alkali metal catalyst to be used is variously selected depending on the solvent, and in addition to alkali metal alcoholates such as sodium ethoxide, sodium methoxide, potassium ethoxide, and potassium methoxide, sodium hydride and sodium amide are used. The reaction time is sufficient for 1 to 20 hours, and the reaction temperature is around the boiling point of the solvent used. Next, the reaction to obtain the compound represented by the general formula (■) by reacting benzyl halide with 8-hydroxy-3-benzazosin-4-one represented by the general formula (■) is carried out using methanol,
This is carried out by heating in the presence of an alkali metal carbonate in an alcoholic solvent such as ethanol or a polar solvent such as dimethylformamide.

Examples of alkali metal carbonates include potassium carbonate and sodium carbonate. After completion of the reaction, the compound represented by the general formula (■) is isolated as crystals using a method known per se. Next, the compound represented by the general formula (■) thus obtained is reacted with dimethylallyl halide under an alkali metal catalyst to obtain the compound represented by the general formula (■b). (2) The same means as the means for converting in a) are adopted. Next, the steps according to the present invention will be explained.

N-dimethylallyl-1,2,3,4,5,6, which is the target compound of the present invention, is obtained by reducing the compound represented by general formula (■a) or (■b), and which is represented by general formula (1). -hexahydro-6,11dialkyl-8-hydroxy-2,6
Although various reducing agents can be used for the reaction to obtain -methano-3-benzazosine, the method shown below gave the most favorable results. First, general formula (■a) or general formula (■b)
This is carried out by dissolving the compound represented by the above in a relatively high boiling point solvent, adding a sodium bis(2-methoxyethoxy)aluminum hydride solution thereto, and heating the solution.

The solvent to be used is selected from solvents that do not directly affect the reaction, such as benzene, toluene, and xylene, and xylene is more preferred. The reaction temperature and reaction time cannot be definitively determined depending on the solvent used, but it is around the boiling point of the solvent,
10 to 100 hours is sufficient. Of course, generally known reducing agents such as lithium aluminum hydride can be used, but with such reducing agents, reduction of 1 carbonyl group or elimination of dimethylallyl group or benzyl group of R2 does not proceed at all, or Alternatively, the progress may be insufficient or undesirable side reactions such as reduction of the double bond of the 2-dimethylallyl group may occur, resulting in the target product (1).
is not obtained or the yield is extremely low (see Comparative Examples). The present invention uses sodium bis(
By using aluminum hydride (2methoxyshethoxy), the above-mentioned drawbacks of general reducing agents are overcome, and a method for obtaining the target product (1) in a good yield is provided.

In particular, the method of the present invention can reduce the carbonyl group and eliminate the substituent R2 at the same time while preserving the easily-reduced double bond of the dimethylallyl group. ) is an excellent method that has not been seen before. After completion of the reaction, the target compound of the reaction, a compound represented by general formula (1), is isolated as crystals using a method known per se. Since the starting materials and intermediate compounds of the invention are all new compounds, they were elucidated using various instrumental analysis data.

The present invention will be explained below by way of examples.

Note that the reference example shows a method for producing a specific starting material, and the comparative example shows an example using another reducing agent. Reference Example 1 Method for producing 1,2,3,4,5,6-hexahydro-6,11-dimethyl-8-hydroxy-2,6-methano-3-benzazocin-4-one.

N-benzyl-1,2,3,4,5,6-hexahydro-6,11-dimethyl-8-hydroxy 2,6-methano-3-benzazocin-4-one (500 w) and acetic acid (20 m)
Catalytic reduction is carried out at 80° C. for 21 hours using 10% palladium-carbon 300% solution in l/l. After the reaction, the catalyst is filtered off and the solvent is distilled off to give a pale caramel-like product. Crystallization from n-hexane, washing with chloroform, and recrystallization from ethanol gives colorless crystals with a melting point of 275-27rC (decomposed). Reference Example 2 Method for producing N-dimethylallyl-1,2,3,4,5,6hexahydro-6,11-dimethyl-8-dimethylallyloxy-2,6-methano-3-benzazocin-4-one .

Mixture of 475 η of 1,2,3,4,5,6-hexahydro-6,11-dimethyl-8-hydroxy-2,6-methano-3-benzazosin-4-one and 200 ml of dioxane of 495 w of 50% sodium hydride. Reflux the liquid for 2.5 hours.

After cooling, add 1.55% dimethylallyl bromide to the above mixture.
ml and reflux for 5 hours. After the reaction, excess sodium hydride is decomposed with ammonium chloride, and the solvent is distilled off. The residue was dissolved in chloroform, washed with water and saturated saline, and then dried (mirabilite). Chloroform was distilled off, the resulting solid was washed with n-hexane, and a white solid was obtained.
get. Recrystallization from benzene-n-hexane gives colorless crystals with a melting point of 129-131°C. 8-benzyloxy-1,2,3,4,5,6hexahydro-6,11
-dimethyl-2,6-methano-3-benzazosine-4
-Production method of on.

1,2,3,4,5,6-hegisahydro-6,11-dimethyl-8-hydroxy-2,6-methano-3-benzazocin-4-one 140η, benzyl chloride 91
A methanol mixture of 9 Trl and 51 η of potassium carbonate is refluxed for 3 days.

Separate the inorganic substances and distill off the methanol to give a pale yellow solid. Dissolve in chloroform, wash with water and saturated saline, and dry (mirabilite). Chloroform was distilled off and the residue was
-Washing with hexane gives a colorless powder of 150Trl9. Recrystallization from benzene gives crystals with a melting point of 194°C. Reference example 4 N-dimethylallyl-1,2,3,4,5,6hexahydro-6,11-dimethyl-8-benzyloxy-2,
Method for producing 6-methano-3-benzazosin-4-one.

A mixed solution of compounds 90~ obtained in Reference Example 3 and 90 mg of 50% sodium hydride in dioxane 6rfLl is refluxed for 2.5 hours.

After cooling, dimethylallyl bromide O. 09d was added and the same treatment as in Reference Example 2 was carried out to obtain 98Tfl9 as a colorless solid. When recrystallized from benzene-n-hexane, the melting point is 1.
Gives colorless crystals at 51-152°C. Riumbis-(2
-methoxyethoxy)aluminum hydride in 20 ml of xylene is stirred under reflux for 42 hours.

After the reaction is completed, the mixture is acidified with a 10% aqueous hydrochloric acid solution while cooling, and the organic layer is separated. Wash the organic layer with water, combine the aqueous layers, neutralize with aqueous ammonia, and extract with chloroform. After washing with water and drying (mirabilite), chloroform was distilled off, and the resulting caramel was subjected to column chromatography using silica gel.
v) flows out. The resulting material (285η) is crystallized from acetone to give colorless crystals with a yield of 216η (66%). This product was identified using an infrared absorption spectrum, a magnetic resonance spectrum, and a mixing test with a specimen obtained by a known method.
(b) A mixture of compound 45Tfl9 obtained in Reference Example 4 and 350 g of 70% sodium bis(2-methoxyethoxy)aluminum hydride in 3 ml of xylene is reacted in the same manner as in the method (a) above under a nitrogen stream for 60 hours.

After the reaction is completed, the same treatment as in method (a) is carried out to obtain a caramel-like substance. This product was purified by silica gel thin layer chromatography (developing solvent: methanol: ethyl acetate:
Benzene = 1:5:4v/v), 18mg (yield 52%
) to obtain crystals. The instrumental analysis data for this substance are completely consistent with those obtained by method (a). (c) A mixed solution of 5 ml of benzene containing the compound 100Tf9 obtained in Reference Example 2 and 900 η of 70% sodium bis(2-methoxyethoxy)aluminum hydride is refluxed and stirred for 5 hours under a nitrogen gas stream.

After the reaction, the same treatment as in method (a) above is carried out to obtain 6η crystals. This product is identified as the specimen obtained by method (a). On the other hand, the organic layer during the reaction treatment was washed with saturated saline and dried (mirabilite), and the solvent was distilled off to form a hydrochloride, giving crystals (70Trl9).
If recrystallized from methanol-ether, the melting point is 117°C.
gives colorless crystals.

This product is N-dimethylallyl-1,2,3,4,5,6-
Confirmed as hexahydro-6,11-dimethyl-8-dimethylallyloxy-2,6-methano-3-benzazosine. This product 32η is 70? Sodium bis-(2-methoxyethoxy)aluminum hydride 300η xylene 2
ml of the mixed solution for an additional 42 hours and the same treatment as in method (a) yields colorless crystals 19η.

Total yield 25η (35% yield). The instrumental analysis data for this substance are completely consistent with those obtained by method (a). Comparative example (a
) The compound 195η obtained in Reference Example 2 was mixed with anhydrous dioxane 10
d, and add 50% of lithium aluminum hydride to this.
The mixture was heated and stirred at 70 to 80°C for 10 hours.

Claims (1)

[Claims] 1 General formula (II) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (However, in the formula, R_2 is a dimethylallyl group or a benzyl group, R_1
represents a lower alkyl group)
II) with sodium bis-(2-methoxyethoxy)aluminum hydride (
I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (However, R_1 in the formula is the same as above) A method for producing N-dimethylallyl-3-benzazosine.