JPS61286377A - Production of hexahydronicotine - Google Patents

Abstract

PURPOSE:To produce the titled compound in high selectivity under mild conditions, by reducing a 1-benzylnicotinium salt with sodium borohdride, hydrolyzing the resultant compound in the presence of a nickel catalyst, and subjecting the resultant compound to hydrogenolysis in the presence of a catalyst. CONSTITUTION:A 1-benzylnicotinium salt is reduced with sodium borohydride to give 1-benzyl-1,2,5,6-tetrahydronicotine, which is then hydrogenated in the presence of a nickel catalyst to afford a mixture of 2'S, 3R-1- benzylhexahydronicotoine with 2'S,3S-1-benzylhexahydronicotine, which is then separated by reversed phase chromatography using a mixture solution of methanol and water as a development solvent. The respective compounds are then subjected to hydrogenolysis in the presence of a catalyst to give 2'S,3R- hexahydronicotine expressed by formula I and 2'S,3S-hexahydronicotine expressed by formula II.

Description

[Detailed description of the invention] (Industrial application field) The present invention relates to a method for producing hexahydronicotine.

In the field of tobacco health and medical research, nicotine has been studied in more detail than ever before. Among these, various nicotine derivatives including hexahydronicotine have been studied in order to study the steric and structural characteristics of nicotine. In addition, hexahydronicotine is bacterium
It is also an important substance as a synthetic intermediate for icide and fungicide.

(Prior Art) Hexahydronicotine is conventionally obtained by reducing nicotine with sodium in ethanol (Ber, 1
8. 2969 (1885)), and 2: r f :/
hydrochloride using Raney nickel or platinum as a catalyst,
Obtained by catalytic hydrogenation under high temperature and high pressure (US Patent 2,
834,784 (1958) J, A, C, S, 5
2.3385 (1930)).

(Problems to be Solved by the Invention) However, the conventional production method requires extremely severe reaction conditions, and therefore the reaction product is obtained as a mixture of various types including octahydronicotine which has also been reduced at the 2' position. They have the disadvantage that their separation is difficult.

The present invention does not have the drawbacks associated with conventional known production methods, has mild reaction conditions, has high selectivity, and has a 2/8
, 3R- and 2'S, 38-hexahydronicotine [The purpose is to provide an easy production method.

(Means for Solving the Problem) That is, 1 the present invention reduces 1-benzylnicotinium salt obtained by a known method with sodium borohydride (hereinafter referred to as [Na HH4J) and hydrogenates it with 2'S, 3R-1-benzylhexahydronicotine (hereinafter referred to as "rRBHH") and 2'S, 3B-
1-benzylhexahydronicotine (rSB
I()-IJ) is obtained as a mixture.

The mixture thus obtained was separated by reverse phase chromatography using a methanol/water mixture as a developing solvent, and then each was hydrolyzed in the presence of a catalyst to produce 2'S shown in formula 1, This is a manufacturing method for obtaining 3R-hexahydronicotine (hereinafter referred to as "compound 1") and 2'S, 3S-hexahydronicotine (hereinafter referred to as "compound 2") shown in formula 2. The manufacturing method will be described in detail below based on manufacturing examples described later.

Formula 1 Formula 2 1-Benzylnicotinium obtained by a known method! , desired t L < tri, 1-benzylnicotinium bromide is dissolved in 10 to 20 times, preferably 12 times the amount of water or a protic solvent such as methanol or ethanol, preferably water, and cooled with water. , 3 to 10 times, preferably 5 times the amount of NaBH4 to 1-benzylnicotinium bromide is slowly added over about 1 hour.

After the reaction, the solution is made acidic by adding a small amount of hydrochloric acid, then made alkaline by adding an alkaline aqueous solution such as sodium hydroxide, extracted with an organic solvent such as ether or chloroform, and dried with sodium sulfate, etc. The solvent was distilled off under reduced pressure and then heated at 153°C92tnw.
BZTH was distilled under reduced pressure under Hg conditions with a yield of 7.
Obtained from 0 to 80%.

Obtainable BZTH, 10 to 30 times the amount of BZTHK,
Dissolved in preferably 15 times the amount of methanol, added nickel, preferably activated Raney-Ninkel catalyst, in an amount of 0.01 to 15 times, preferably 0.2 times the amount of BZTH, and heated at room temperature, normal pressure, and hydrogen gas. The reaction is allowed to proceed under atmosphere for 5 to 24 hours, preferably for 10 hours. After the reaction, the nickel was filtered off and the solvent was distilled off under reduced pressure, yielding BHH, 5BHH.
It is obtained as a mixture with a yield of 90-95%.

The obtained mixture of RBHI (and 5BHH) was mixed with methanol and water in a solvent ratio of 1:1 to 5:1, preferably 3:
1) was subjected to reverse phase chromatography using I(
BHH, 5BHH to B Z T f4, 6 each
The yields were 5-75% and 15-30%.

Next, each of the obtained RBHH+' S B HH was dissolved in ether, and after passing dry hydrogen chloride gas,
Each hydrochloride is collected by filtration, and then dissolved in 10 to 20 times the amount of methanol, preferably 15 times the amount of each hydrochloride.
．． One time the amount of catalyst, preferably palladium-activated carbon, is added, and the reaction is allowed to proceed for 2 to 10 hours, preferably 4 hours, at room temperature, normal pressure, and hydrogen gas atmosphere. After the reaction, the catalyst is filtered off and the solvent is distilled off under reduced pressure. The catalyst used here is not limited to palladium, but other catalysts may also be used. Dissolve the obtained oily substance in an appropriate amount of water and hydroxylate it.) Add an aqueous alkali solution such as IJum, add an alkaline earth metal, extract with an organic solvent such as ether or chloroform, and sulfuric acid). After drying, the solvent is distilled off under reduced pressure. Next, by recrystallizing with petroleum ether at low temperature, Compound 1 and Compound 2 were each made into 90-98φ
, with a yield of 85-95.

(Manufacturing example) 500ml! In a beaker, 6.7 ji (20 mm
l) 1-benzylnicotinium bromide in 8Q water
mt, and slowly add NaBH43,8ji (100 mmol) to the solution while stirring under water cooling over 1 hour. After the reaction, add an appropriate amount of hydrochloric acid to make the solution acidic (pH<3), then hydroxylate it.Add an aqueous solution of IJium to make it alkaline (pH>11), extract with ether, and sulfuric acid. Dry and remove the solvent under reduced pressure. Then, when it was subjected to vacuum distillation under the conditions of 153°C and 2 mm Hg, B Z T H was 4.1
,! 9 (yield 80%) was obtained.

The obtained BZTH4,,1,! i' (16 mmol)
is dissolved in 60 methanol in a 100 rnt sealant. 0.8 g of Raney nickel (R-4) activated by a known method is added to the solution, and hydrogen gas is injected while stirring. After gas replacement was performed three times to bring the gas phase into a hydrogen atmosphere, the mixture was stirred at room temperature and normal pressure for 10 hours. After the reaction, Raney nickel was filtered off and the solvent was distilled off under reduced pressure to obtain 3.9 g (yield: 95 cm) of R, B HH and 5BHH as a mixture.

C18 reverse phase chromatograph (ODS, 22 mm φ x 50
cIrL) to separate RBHH and 5BHH, 2.8 g (yield 72%) and 0.9 g (yield 23%)
) obtained.

Then, the obtained RBHH2.8 g (11 mmo 1
) in 10-ether and then injecting dry hydrogen chloride gas. The obtained RBHH hydrochloride was collected by filtration, and 1
Dissolve in 0-methanol. 100- Add 0.2g of 5% palladium-activated carbon to Schlenk and add methanol 3
After adding 5-, hydrogen gas is injected while stirring. In order to bring the gas phase under a hydrogen atmosphere, the gas was replaced three times, and then stirred for 5 minutes under a hydrogen atmosphere. Then R, B
A methanol solution containing HH hydrochloride is added, and the mixture is stirred at room temperature and normal pressure for 4 hours. After the reaction, the palladium-activated carbon is filtered off, and the solvent is distilled off under reduced pressure. The obtained oily substance is dissolved in 10-m water, made alkaline (pH>11) by adding an aqueous sodium hydroxide solution, extracted with ether, dried over sodium sulfate, and the solvent is distilled off under reduced pressure. Recrystallization from petroleum ether at low temperature (0° C.) yields 1.8 g (95% yield) of Compound 1.

Hydrolysis of 0.9 g (3.5 mmo+) of 5BHH using the method described above yields 0.5.9 g (90% yield) of compound 2.

(Effects of the Invention) As explained in detail above, the manufacturing method according to the present invention,
It has the advantage that the reaction conditions are mild in all steps, the selectivity of the reaction is extremely high, and the separation of two types of diastereomers is easy.

Claims (3)

[Claims] (1) A method for producing hexahydronicotine, which comprises reducing a 1-benzylnicotinium salt with sodium borohydride and then hydrogenating the resulting compound using nickel as a catalyst, and hydrolyzing the resulting compound in the presence of a catalyst. (2) After reducing l-benzylnicotinium salt with sodium borohydride and hydrogenating it using nickel as a catalyst, the 2'S,3R-1-benzylhexahydronicotine obtained by separation and purification is processed using palladium as a catalyst. The method for producing hexahydronicotine according to claim 1, which comprises hydrogenolyzing. (3) After reducing 1-benzylnicotinium salt with sodium borohydride and hydrogenating it using nickel as a catalyst, the 2'S,3S-1-benzylhexahydronicotine obtained by separation and purification is processed using palladium as a catalyst. The method for producing hexahydronicotine according to claim 1, which comprises hydrogenolyzing.