WO2023007712A1 - Procédé de production de (r,s)-nicotine - Google Patents

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

Info

Publication number
WO2023007712A1
WO2023007712A1 PCT/JP2021/028399 JP2021028399W WO2023007712A1 WO 2023007712 A1 WO2023007712 A1 WO 2023007712A1 JP 2021028399 W JP2021028399 W JP 2021028399W WO 2023007712 A1 WO2023007712 A1 WO 2023007712A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
nicotine
production method
equilibrium mixture
pseudooxynicotine
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/JP2021/028399
Other languages
English (en)
Japanese (ja)
Inventor
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/JP2021/028399 priority Critical patent/WO2023007712A1/fr
Publication of WO2023007712A1 publication Critical patent/WO2023007712A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

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. )-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 isolating a specific compound from an equilibrium mixture of pseudooxynicotine; and reducing said compound.
  • 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.
  • 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.
  • X to Y includes X and Y which are the end values.
  • the method of manufacture comprises isolating a specific compound from an equilibrium mixture of pseudooxynicotine and reducing the compound.
  • 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.
  • 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.
  • 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.
  • 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.
  • the reduction step preferably uses a metal catalyst and a hydrogen donor.
  • 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).
  • the solvent is not limited, an alcohol such as methanol or an ester such as ethyl acetate is preferred.
  • 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.
  • 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.
  • no compound presumed to be an amino alcohol by-product was 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 reduction step be carried out continuously with the distillation step. This is because decomposition of the compound b can be suppressed.
  • 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.
  • the other step is a storage step or the like.
  • 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.
  • (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.
  • 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. 1 The analytical results are shown in FIGS. 1 and 2.
  • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de production de (R,S)-nicotine comprenant une étape pour isoler un composé spécifique à partir d'un mélange d'équilibre de pseudooxynicotine et une étape pour réduire ledit composé. De préférence, l'étape d'isolement consiste à isoler un composé représenté par la formule (b) à partir du mélange d'équilibre.
PCT/JP2021/028399 2021-07-30 2021-07-30 Procédé de production de (r,s)-nicotine Ceased WO2023007712A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/JP2021/028399 WO2023007712A1 (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/JP2021/028399 WO2023007712A1 (fr) 2021-07-30 2021-07-30 Procédé de production de (r,s)-nicotine

Publications (1)

Publication Number Publication Date
WO2023007712A1 true WO2023007712A1 (fr) 2023-02-02

Family

ID=85086588

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2021/028399 Ceased WO2023007712A1 (fr) 2021-07-30 2021-07-30 Procédé de production de (r,s)-nicotine

Country Status (1)

Country Link
WO (1) WO2023007712A1 (fr)

Citations (3)

* 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
CN107011321A (zh) * 2017-03-27 2017-08-04 华健 一种人工合成消旋体尼古丁的制备方法
CN112876454A (zh) * 2020-03-25 2021-06-01 深圳梵活生命科学股份有限公司 一种人工合成（r，s)-尼古丁盐的制备方法

Patent Citations (3)

* 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
CN107011321A (zh) * 2017-03-27 2017-08-04 华健 一种人工合成消旋体尼古丁的制备方法
CN112876454A (zh) * 2020-03-25 2021-06-01 深圳梵活生命科学股份有限公司 一种人工合成（r，s)-尼古丁盐的制备方法

Similar Documents

Publication Publication Date Title
EP3044212B1 (fr) Procédé pour la production à grande échelle de 1h-1,2,3-triazole et de son intermédiaire 1-benzyl-1h-1,2,3-triazole
JP2009057376A5 (fr)
KR20100029332A (ko) 하이드록시클로로퀸의 신규 제조방법
CN118772081B (zh) 一种制备n-甲基-2,3-二氢苯并噻嗪-4-酮的方法
JP2009062360A (ja) シナカルセットの製造方法
JPH01193246A (ja) ２，３―ジクロロピリジンの製造法
WO2023007712A1 (fr) Procédé de production de (r,s)-nicotine
TWI855165B (zh) 製備(r)-4-胺基茚烷及其對應醯胺的方法
US5099067A (en) Use of ammonium formate as a hydrogen transfer reagent for reduction of chiral nitro compounds with retention of configuration
JP4397990B2 (ja) ３−アルキルフラバノノール誘導体の精製法
EA011763B1 (ru) Способы получения венлафаксина и формы i венлафаксина гидрохлорида
KR100743617B1 (ko) 고광학순도를 갖는 키랄 3-히드록시 피롤리딘 및 그유도체를 제조하는 방법
JPH053858B2 (fr)
JP2004131399A (ja) シス−ヘキサヒドロイソインドリンの製造法
WO2023007710A1 (fr) Procédé de production de (r,s)-nicotine
CN119285542B (zh) 一种利用自然光诱导羰基化反应构建6-氯-4-苯基喹啉-2(1h)-酮化合物的方法
CN117820139B (zh) 一种2-叔丁基胺基苯甲醛类衍生物的制备方法
JP4099630B2 (ja) パーフルオロアルキル化合物の製造方法
JP4314602B2 (ja) 光学活性３−ヒドロキシピロリジン誘導体の製造方法
JP3382681B2 (ja) 含フッ素化合物およびその製法
CN113968883A (zh) 光学色酮衍生物及其制备方法
JP4896476B2 (ja) メチルオキシメチルアミノピリジン誘導体及びその製造方法
JP4825969B2 (ja) 第３級アルコールの製造方法
JP4480802B2 (ja) 臭素化剤
JPH01121268A (ja) ３，５−ジクロロピリジンの製造法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21951911

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21951911

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP