WO2023007710A1 - Procédé de production de (r,s)-nicotine - Google Patents

Procédé de production de (r,s)-nicotine Download PDF

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Publication number
WO2023007710A1
WO2023007710A1 PCT/JP2021/028395 JP2021028395W WO2023007710A1 WO 2023007710 A1 WO2023007710 A1 WO 2023007710A1 JP 2021028395 W JP2021028395 W JP 2021028395W WO 2023007710 A1 WO2023007710 A1 WO 2023007710A1
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WO
WIPO (PCT)
Prior art keywords
nicotine
production method
formic acid
equilibrium mixture
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2021/028395
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English (en)
Japanese (ja)
Inventor
茜 有尾
敦 永井
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Japan Tobacco Inc
Original Assignee
Japan Tobacco Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Japan Tobacco Inc filed Critical Japan Tobacco Inc
Priority to PCT/JP2021/028395 priority Critical patent/WO2023007710A1/fr
Publication of WO2023007710A1 publication Critical patent/WO2023007710A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • 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.
  • 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.
  • an object of the present invention is to provide a method for producing (R,S)-nicotine by a simpler method.
  • 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.
  • X to Y includes X and Y which are the end values.
  • the method of manufacture comprises the step of subjecting an equilibrium mixture of pseudooxynicotine to a reaction with formic acid.
  • 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.
  • 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.
  • compound a in the equilibrium mixture is selectively reduced by formic acid to produce (R,S)-nicotine.
  • 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.
  • 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.
  • 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.
  • (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.
  • carbonyl and imino groups cannot be reduced by hydrogen sources such as formic acid alone.
  • the reduction requires the use of a boranate complex or a specific transition metal to generate active hydrogen.
  • 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.
  • the step of removing the metal can be omitted or simplified.
  • compounds other than compound a in the equilibrium mixture are also reduced, resulting in the formation of by-products.
  • the isolation step can be simplified or omitted.
  • 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.
  • 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.
  • This step can be carried out at room temperature (about 10 to 30°C) or higher.
  • the upper limit of the temperature is not limited, it can be, for example, reflux conditions.
  • this step can be carried out at normal pressure.
  • 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.
  • aprotic solvents such as dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, 1,4-dioxane
  • alcohols such as ethanol.
  • aminoalcohols which are by-products
  • Substantially no by-products means that the target product does not contain 100 ppm or more of by-products in one aspect.
  • a compound presumed to be an amino alcohol by-product was not detected on 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.
  • the production method may further include a known purification step.
  • this production method may further comprise a step of separating the R-isomer or S-isomer from the obtained (R,S)-nicotine.
  • the compound represented by the formula (A) can also be used as a starting material in this production method.
  • 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.
  • (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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de production de (R,S)-nicotine qui comprend une étape dans laquelle un mélange d'équilibre de pseudo-oxynicotines est mis en réaction avec de l'acide formique. L'étape comprend de préférence la réduction sélective du composé représenté par la formule (a) à partir du mélange d'équilibre de pseudo-oxynicotines.
PCT/JP2021/028395 2021-07-30 2021-07-30 Procédé de production de (r,s)-nicotine Ceased WO2023007710A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JP2021/028395 WO2023007710A1 (fr) 2021-07-30 2021-07-30 Procédé de production de (r,s)-nicotine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/JP2021/028395 WO2023007710A1 (fr) 2021-07-30 2021-07-30 Procédé de production de (r,s)-nicotine

Publications (1)

Publication Number Publication Date
WO2023007710A1 true WO2023007710A1 (fr) 2023-02-02

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2021/028395 Ceased WO2023007710A1 (fr) 2021-07-30 2021-07-30 Procédé de production de (r,s)-nicotine

Country Status (1)

Country Link
WO (1) WO2023007710A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014174505A2 (fr) * 2013-04-22 2014-10-30 Perrigo Api Ltd. Procédé de préparation de nicotine comprenant la réduction enzymatique de 4-(méthylamino)-1-(pyridine-3-yl) butan-1-one
CN110627769A (zh) * 2019-09-27 2019-12-31 深圳黑尔格科技有限公司 亚胺盐衍生物、其制备方法及尼古丁的制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014174505A2 (fr) * 2013-04-22 2014-10-30 Perrigo Api Ltd. Procédé de préparation de nicotine comprenant la réduction enzymatique de 4-(méthylamino)-1-(pyridine-3-yl) butan-1-one
CN110627769A (zh) * 2019-09-27 2019-12-31 深圳黑尔格科技有限公司 亚胺盐衍生物、其制备方法及尼古丁的制备方法

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