WO2023007712A1

WO2023007712A1 - (r,s)-nicotine production method

Info

Publication number: WO2023007712A1
Application number: PCT/JP2021/028399
Authority: WO
Inventors: 敦永井
Original assignee: 日本たばこ産業株式会社
Priority date: 2021-07-30
Filing date: 2021-07-30
Publication date: 2023-02-02

Abstract

Provided is an (R,S)-nicotine production method including a step for isolating a specific compound from a pseudooxynicotine equilibrium mixture and a step for reducing said compound. Preferably, the isolation step includes isolating a compound represented by formula (b) from the equilibrium mixture.

Description

Method for producing (R,S)-nicotine

The present invention relates to a method for producing (R,S)-nicotine.

Nicotine is a kind of alkaloid contained in plants and is a natural product. Nicotine has two optical isomers, (R)-nicotine and (S)-nicotine, and most nicotine extracted from plants is the S-isomer. By the way, various investigations have been made to chemically synthesize nicotine. For example, Patent Document 1 describes a racemic mixture of (R)-nicotine and (S)-nicotine from 1-methyl-3-nicotinoyl-2-pyrrolidone or a salt thereof using a one-pot process. )-nicotine”) or a salt thereof. Patent Document 2 describes the reaction of N-methyl-2-pyrrolidone or a salt thereof with a nicotinic acid salt compound in the presence of a solvent and a base to form 1-methyl-3-nicotinoyl-2-pyrrolidone or a salt thereof. , discloses the reduction of said 1-methyl-3-nicotinoyl-2-pyrrolidone or a salt thereof with a solution of Na ₂ S ₂ O ₄ to produce racemic nicotine or a salt thereof. Patent Document 3 discloses a method for producing racemic nicotine starting from N-vinyl-2-pyrrolidinone and a nicotinic acid ester.

U.S. Pat. No. 8,884,021 U.S. Pat. No. 9,809,567 U.S. Pat. No. 9,556,142 WO2014/174505

There is a demand for producing (R, S)-nicotine (racemic nicotine) by a simpler method. In view of such circumstances, an object of the present invention is to provide a method for producing (R,S)-nicotine by a simpler method.

The inventors have found that the above problems can be solved by isolating a specific compound and reducing it. That is, the above problems are solved by the present invention described below.
Aspect 1
isolating a specific compound from an equilibrium mixture of pseudooxynicotine; and reducing said compound.
A method for producing (R,S)-nicotine.
Aspect 2
The production method according to aspect 1, wherein the isolation step comprises isolating a compound represented by formula (b) described below from the equilibrium mixture.
Aspect 3
3. The process according to aspect 2, wherein said isolating step comprises distilling an equilibrium mixture of pseudooxynicotine to isolate said compound of formula (b).
Aspect 4
The production method according to any one of aspects 1 to 3, wherein the isolation step and the reduction step are performed under an inert atmosphere.
Aspect 5
The production method according to any one of aspects 1 to 4, wherein the isolation step and the reduction step are performed consecutively.
Aspect 6
The production method according to any one of aspects 1 to 5, wherein hydrogen is used as a reducing agent in the reduction step.
Aspect 7
The production method according to any one of aspects 1 to 6, wherein substantially no amino alcohol is produced in the reduction step.
Aspect 8
(R,S)-nicotine obtained by the production method according to any one of aspects 1 to 7.
Aspect 9
A process for producing a compound represented by formula (b), comprising distilling an equilibrium mixture of pseudooxynicotine to isolate the compound represented by formula (b) as described below.

According to the present invention, it is possible to provide a method for producing (R,S)-nicotine by a simpler method.

¹ H-NMR of compound b obtained in Example 1 Diagram showing ¹ H-NMR assignments ¹³ C-NMR of compound b obtained in Example 1

The present invention will be described in detail below. In the present invention, "X to Y" includes X and Y which are the end values.

1. Method of Manufacture The method of manufacture comprises isolating a specific compound from an equilibrium mixture of pseudooxynicotine and reducing the compound.
(1) Isolation step Pseudooxynicotine is a compound represented by PON in the following formula. Pseudooxynicotine exists as an equilibrium mixture under the conditions used in this production method (Patent Document 4: International Publication No. 2014/174505). The conditions used in this production method are not limited as long as the isolation and reduction can be carried out, but in one embodiment, the conditions are room temperature or higher. In the present invention, the mixture of the four compounds in the scheme below is referred to as the pseudooxynicotine equilibrium mixture or simply the equilibrium mixture. Pseudooxynicotine can be produced by a known method, for example, a method of reacting N-methyl-2-pyrrolidone or a salt thereof with a nicotinic acid salt compound in the presence of a solvent and a base, followed by acid hydrolysis and alkalinization. is mentioned.

In this step, the compound represented by the chemical formula (b) in the above scheme (3-(1-methyl-4,5-dihydro-1H-pyrrol-2-yl)pyridine, hereinafter simply referred to as "compound b", other (similar to the compound of ) is preferably isolated. The inventors have surprisingly found that only compound b can be easily removed from the equilibrium mixture by distillation. Furthermore, since this compound b does not contain an oxygen atom as will be described later, by-products are less likely to be produced in the reduction step.

Distillation is preferably carried out under reduced pressure. The pressure in distillation is more preferably 80 Pa or less, still more preferably 70 Pa or less, and particularly preferably 60 Pa or less. The lower limit of the pressure is not limited as long as the distillation is possible, but is preferably 20 Pa or higher, more preferably 30 Pa or higher, and particularly preferably 40 Pa or higher. The distillation temperature is preferably 60° C. or higher, more preferably 80° C. or higher, and its upper limit is preferably 140° C. or lower, more preferably 130° C. or lower. Compound b is isolated in this step, and isolation in the present invention means that the substance obtained in the isolation step is pure compound b, and that the substance substantially consists of compound b. include. In one embodiment, the substance consists essentially of compound b, which means that the substance does not contain 100 ppm or more of other components. Isolation is therefore also screening for the compound of interest.

(2) Reduction Step Since the compound isolated from the equilibrium mixture is preferably compound b, this step will be described below using the reduction of compound b as an example.

1) Conditions The reduction step is preferably carried out in the presence of a solvent. Moreover, it is preferable to use a catalyst for the reduction step. Although not limited, the reduction step preferably uses a metal catalyst and a hydrogen donor. As the metal catalyst, known metal catalysts such as transition metals can be used, but palladium on carbon (Pd/C) is preferable from the viewpoint of availability. The hydrogen donor is not limited, but is preferably hydrogen (gas) or ammonium formate, more preferably hydrogen (gas). Although the solvent is not limited, an alcohol such as methanol or an ester such as ethyl acetate is preferred. As one aspect, the reduction step includes adding about 1 to 20% by weight of Pd/C (the amount of Pd to compound b is preferably 0.1 to 2% by weight) with respect to compound b, and removing an excess amount of hydrogen. It can be carried out by mixing in methanol solvent.

This step can be performed at room temperature (about 10 to 30°C) or higher. Although the upper limit of the temperature is not limited, it can be, for example, reflux conditions. Moreover, this step can be carried out at normal pressure. The reduction step can also be performed in a hydrogen atmosphere by substituting hydrogen in the system.

This reduction reaction reduces the double bond on the pyrrolidine ring of compound b to produce (R,S)-nicotine. If the equilibrium mixture is directly subjected to the reduction reaction, an aminoalcohol is produced as a by-product in addition to (R,S)-nicotine, resulting in a decrease in yield and complication of subsequent purification steps. The present inventors have found that if only a single substance can be extracted from an equilibrium mixture and the substance can be reduced with substantially no oxygen atoms present in the substrate or reactant, the by-product aminoalcohol is generated in principle. I came up with the idea that the yield would not decrease without In fact, it was found that (R,S)-nicotine can be efficiently produced by isolating the compound b containing no oxygen atoms from the equilibrium mixture and reducing it.

2) By-products As described above, this step has the advantage that aminoalcohols, which are by-products, are not substantially produced. Substantially no by-products means that the target product does not contain 100 ppm or more of by-products in one aspect. For example, in Example 2, no compound presumed to be an amino alcohol by-product was detected on TLC. In this case, considering the detection limit of TLC, the content of by-products can be said to be less than 100 ppm. Therefore, (R,S)-nicotine can be obtained in high yield by this production method. An aminoalcohol is a compound having an alkane skeleton containing a hydroxy group and an amino group, and in one aspect is a compound having the following structure.

3) Consecutive Implementation with Distillation Step It is preferable that the reduction step be carried out continuously with the distillation step. This is because decomposition of the compound b can be suppressed. Preferably, both steps are performed sequentially under an inert atmosphere. To perform both steps continuously means to perform both steps without providing another step between them. In one aspect, the other step is a storage step or the like.

(3) Other steps The production method may further include a known purification step. In addition, this production method may further comprise a step of separating the R-isomer or S-isomer from the obtained (R,S)-nicotine.

2. (R,S)-Nicotine The (R,S)-nicotine obtained by this production method has the advantage of containing extremely few impurities as described above. Therefore, (R,S)-nicotine is useful in fields such as pharmaceuticals and smoking articles.

[Production Example 1] Synthesis of pseudooxynicotine 2.4 g of NaH (100 mmol, 2.0 eq) was added to a two-necked eggplant flask, washed twice with 30 mL of toluene, and activated. After adding 10 mL of cyclopentyl methyl ether (CPME) into the flask, add a solution of 5.0 g (50 mmol, 1.0 equivalent) of N-methylpyrrolidone dissolved in 20 mL of CPME, and heat at 60° C. for 30 minutes. Stirred. Then, a solution of 9.1 g of ethyl nicotinate (60 mmol, 1.2 equivalents) dissolved in 20 mL of CPME was added to the flask, and the mixture was heated and stirred at 85° C. for reaction. After completion of the reaction, 6M HCl was added for neutralization, and after confirming neutrality, intermediate 1 (8.8 g, yield 86%) was extracted with ethyl acetate.

50 mL of 6 M H ₂ SO ₄ was added to 4 g of the intermediate 1 (20 mmol) and heated under reflux for 72 hours. After completion of the reaction, sodium hydroxide was added until the pH reached 13. The reaction solution was separated using ether, and after washing the oil phase with brine, the oil phase was dried using magnesium sulfate. The solvent was distilled off from the oil phase using a rotary evaporator to obtain the desired pseudooxynicotine in a yield of 56%.

[Example 1] Selective acquisition of compound b 3-(1-methyl-4,5-dihydro-1H-pyrrol-2-yl)pyridine The equilibrium mixture of pseudooxynicotine obtained in Example 1 was subjected to Kugelrohr distillation. to obtain compound b as a distillate. Distillation conditions were as follows.
Pressure: 40-60Pa
Temperature: Gradually heated from 80°C to 125°C.
The obtained liquid after distillation was analyzed by ¹ H-NMR and ¹³ C-NMR and identified as compound b. The analytical results are shown in FIGS. 1 and 2. FIG.

Example 2 Reduction Into a flask under a nitrogen atmosphere was weighed 2 wt% Pd/C (7.54 mg) with respect to compound b. The Pd concentration in Pd/C was 10 wt%, so the amount of Pd relative to compound b was 0.2 wt%. After evacuating the inside of the flask, the inside of the system was replaced with nitrogen gas again. 3 mL of methanol solvent was added to the flask, and the inside of the system was replaced with hydrogen. A solution prepared by dissolving 377 mg of compound b (2.35 mmol) in 5 mL of methanol solvent was added dropwise, and the contents were stirred at room temperature to conduct a reaction. After completion of the reaction, the palladium carbon was filtered and the methanol solvent was distilled off. After purification by silica gel chromatography, the desired (R,S)-nicotine was obtained in 70% yield. A by-product, a compound presumed to be an aminoalcohol, was not detected on TLC.

Claims

isolating a specific compound from an equilibrium mixture of pseudooxynicotine; and reducing said compound.
A method for producing (R,S)-nicotine.
wherein said isolating step comprises isolating a compound of formula (b) from said equilibrium mixture;

The manufacturing method according to claim 1.
The production method according to claim 2, wherein the isolating step comprises distilling an equilibrium mixture of pseudooxynicotine to isolate the compound represented by the formula (b).
The production method according to any one of claims 1 to 3, wherein the isolation step and the reduction step are performed under an inert atmosphere.
The production method according to any one of claims 1 to 4, wherein the isolation step and the reduction step are performed continuously.
The production method according to any one of claims 1 to 5, wherein hydrogen is used as a reducing agent in the reduction step.
The production method according to any one of claims 1 to 6, wherein substantially no amino alcohol is produced in the reduction step.
(R,S)-nicotine obtained by the production method according to any one of claims 1 to 7.
distilling the equilibrium mixture of pseudooxynicotine to isolate the compound of formula (b);

A method for producing a compound represented by formula (b).