WO2023007710A1 - Method for producing (r,s)-nicotine - Google Patents

Abstract

Provided is a method for producing (R,S)-nicotine which includes a step in which an equilibrium mixture of pseudooxynicotines is reacted with formic acid. The step preferably includes selectively reducing the compound represented by formula (a) out of the equilibrium mixture of pseudooxynicotines.

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. S)-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 problem can be solved by subjecting an equilibrium mixture of pseudooxynicotine to a reaction with formic acid. That is, the above problems are solved by the present invention described below.
Aspect 1
A method for producing (R,S)-nicotine, comprising subjecting an equilibrium mixture of pseudooxynicotine to a reaction with formic acid.
Aspect 2
The production method according to aspect 1, wherein the step comprises selectively reducing a compound represented by formula (a) described below from an equilibrium mixture of pseudooxynicotine.
Aspect 3
The production method according to aspect 1 or 2, wherein the step does not use a metal as a catalyst.
Aspect 4
The production method according to any one of aspects 1 to 3, wherein substantially no amino alcohol is produced in the step.
Aspect 5
The production method according to any one of aspects 1 to 4, wherein in said step, an equimolar amount or more of formic acid is used with respect to the total molar amount of said equilibrium mixture.
Aspect 6
The production method according to any one of aspects 1 to 5, wherein the step does not use an additional basic substance.
Aspect 7
The production method according to any one of aspects 1 to 6, wherein no solvent is used in the steps.
Aspect 8
(R,S)-nicotine obtained by the production method according to any one of aspects 1 to 7.

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

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 the step of subjecting an equilibrium mixture of pseudooxynicotine to a reaction with formic acid.
(1) Equilibrium mixture of pseudooxynicotine In this production method, an equilibrium mixture of pseudooxynicotine is used as a starting material. 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 above reaction can be carried out, but in one embodiment, the conditions are room temperature or higher and normal pressure. 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.

(2) Formic acid In this production method, formic acid is used as a reaction substrate. Subjecting the equilibrium mixture to reaction with formic acid produces (R,S)-nicotine. Although this reaction mechanism is not limited, it is speculated as follows. The compound represented by (a) in the equilibrium mixture (hereinafter also referred to as "compound a"; the same applies to other compounds) has a quaternary ammonium ion and a counter anion OH ^- . When formic acid approaches compound a, formic acid is activated by the hydroxy ions of compound a, essentially becoming a hydride equivalent. (R,S)-nicotine is produced by the reduction of the iminium ion in the vicinity of the hydride equivalent. Therefore, compound a in the equilibrium mixture is selectively reduced by formic acid to produce (R,S)-nicotine. When compound a is converted to (R,S)-nicotine, it is presumed that compound a is sequentially supplied from the equilibrium mixture because the equilibrium is biased. That is, in this production method, the equilibrium mixture and formic acid are present in the reaction system, and compound a is selectively converted to (R,S)-nicotine.

Therefore, the amount of formic acid is theoretically equimolar or greater than the molar amount of pseudooxynicotine, that is, the total molar amount of the equilibrium mixture (the total molar amount of pseudooxynicotine, compound 1, compound b, and compound a). Any amount is sufficient, but it is preferably 1.5-fold molar amount or more, more preferably 2-fold molar amount or more. The upper limit is not limited, but is preferably 100-fold molar amount or less, 50-fold molar amount or less, 40-fold molar amount or less, 30-fold molar amount or less, 20-fold molar amount or less, or 10-fold molar amount or less. It is preferably not more than 5 times the molar amount. Further, as described later, a solvent may be used in this step. When a solvent is used, the upper limit of the amount of formic acid can be less than or equal to the amount of solvent.

(3) Metals In this step, (R,S)-nicotine can be produced without using metals. The metal here means a metal that participates in the reaction, such as a catalyst, and does not include metals that do not participate in the reaction, such as metals used as materials for reactors. Therefore, in this step, it is preferable not to use a metal involved in the reaction, and more preferably not to use a metal as a catalyst. Conventionally, it has been understood that carbonyl and imino groups cannot be reduced by hydrogen sources such as formic acid alone. For example, as described in Patent Document 1, the reduction requires the use of a boranate complex or a specific transition metal to generate active hydrogen. However, the inventors have surprisingly found that said reduction can be carried out without the use of metals as catalysts. The reason for this is presumed to be that a hydride equivalent derived from formic acid is produced in this step, as described above.

When using metals as catalysts, it is necessary to remove them from the perspective of metal tolerance limits in the final product. If no metal is used in this step, the step of removing the metal can be omitted or simplified. In addition, when a metal is used as a catalyst, compounds other than compound a in the equilibrium mixture are also reduced, resulting in the formation of by-products. However, when the metal is not used, the isolation step can be simplified or omitted.

(4) Basic substance No additional basic substance may be used in this step. Additional basic substances are pseudooxynicotine, compound 1, compound a, compound b, (R,S)-nicotine, and basic substances other than solvents.

The basic substance generates hydride by abstracting the hydrogen from the carboxylic acid site of formic acid, making formic acid an active species. However, in this step the reduction can be carried out without additional basic substances. Therefore, compared with the method of adding an additional basic substance, it can be carried out at low cost under mild and convenient conditions. The reason why it is not necessary to use an additional basic substance is not limited, but it is presumed that the substrate itself or the product itself functions as a base. However, if necessary, an additional basic substance may be used within a range that does not impair the effects of the present invention. Examples of the basic substance include triethylamine and pyridine.

(5) Conditions This step can be carried out 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. Furthermore, although the atmosphere in which this step is performed is not limited, it is preferably an inert atmosphere.

This step can be performed without a solvent or in the presence of a solvent. Solvents that can be used are not limited, but include, for example, aprotic solvents such as dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, 1,4-dioxane, and alcohols such as ethanol. The presence of a solvent as a reaction field increases the reaction efficiency.

(6) By-products This step also 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 1, a compound presumed to be an amino alcohol by-product was not 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.

(7) Others 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.

In addition, the compound represented by the formula (A) can also be used as a starting material in this production method.

In the formula, X ^- is a counter anion. The anion is not limited and may be an organic anion or an inorganic anion, preferably an inorganic anion. Examples of the inorganic anion include OH ⁻ , and halide ions such as Cl ⁻ , Br ⁻ and I ⁻ , and OH ⁻ is more preferable.

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 was partitioned with ether, washed with brine, and the organic phase was dried with magnesium sulfate. The solvent was distilled off from the organic phase using a rotary evaporator to obtain the desired pseudooxynicotine in a yield of 56%.

[Example 1] Synthesis of (R,S)-nicotine using formic acid 178.2 mg of the pseudooxynicotine (1 mmol, 1 equivalent) was weighed into a two-necked 20 mL eggplant flask. To this was added 0.12 mL formic acid (3.2 mmol, 3.2 eq), 6 mL dimethylformamide and 0.36 mL triethylamine (2.6 mmol, 2.6 eq) and stirred at room temperature to allow the reaction to proceed. gone. After completion of the reaction, excess formic acid was distilled off using a rotary evaporator to obtain the desired (R,S)-nicotine. Yield was 78%. The yield was calculated assuming the equilibrium mixture was all compound a. The by-product aminoalcohol was not detected by TLC. Thus, compound a could be selectively reduced from an equilibrium mixture of pseudooxynicotine to produce (R,S)-nicotine.

[Comparative Example 1]
An attempt was made to synthesize (R,S)-nicotine in the same manner as in Example 1, except that acetic acid was used instead of formic acid. However, (R,S)-nicotine was not produced.

Claims (8)

A method for producing (R,S)-nicotine, comprising the step of subjecting an equilibrium mixture of pseudooxynicotine to a reaction with formic acid. said step comprising selectively reducing a compound of formula (a) from an equilibrium mixture of pseudooxynicotine;

The manufacturing method according to claim 1. The production method according to claim 1 or 2, wherein the step does not use a metal as a catalyst. The production method according to any one of claims 1 to 3, wherein substantially no amino alcohol is produced in the step. The production method according to any one of claims 1 to 4, wherein in said step, an equimolar amount or more of formic acid is used with respect to the total molar amount of said equilibrium mixture. The production method according to any one of claims 1 to 5, wherein no additional basic substance is used in said step. The production method according to any one of claims 1 to 6, wherein no solvent is used in the steps. (R,S)-nicotine obtained by the production method according to any one of claims 1 to 7.