WO2009082884A1 - Procédés pour préparer des composés de morpholine n-substitués - Google Patents

Procédés pour préparer des composés de morpholine n-substitués Download PDF

Info

Publication number
WO2009082884A1
WO2009082884A1 PCT/CN2008/070072 CN2008070072W WO2009082884A1 WO 2009082884 A1 WO2009082884 A1 WO 2009082884A1 CN 2008070072 W CN2008070072 W CN 2008070072W WO 2009082884 A1 WO2009082884 A1 WO 2009082884A1
Authority
WO
WIPO (PCT)
Prior art keywords
organic compound
substituted morpholine
compound according
hydrazine
substituted
Prior art date
Application number
PCT/CN2008/070072
Other languages
English (en)
Chinese (zh)
Inventor
Feng Li
Qian Li
Jing Sun
Litao Kang
Original Assignee
Northcarolina Chemlabs(Shanghai)
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 Northcarolina Chemlabs(Shanghai) filed Critical Northcarolina Chemlabs(Shanghai)
Publication of WO2009082884A1 publication Critical patent/WO2009082884A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/06—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals
    • C07D295/067—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain

Definitions

  • the present invention relates to a process for preparing an N-substituted morpholine organic compound.
  • N-substituted morpholine organic compound can be prepared by the following two routes:
  • Route 1 As shown in Figure 1, an amino or substituted amino compound such as 3-aminopropanol is combined with dichlorodiethyl ether to form a morpholine ring. To prepare a substituted compound such as N-bromopropyl, chloropropyl or allyl, a substitution reaction is carried out at the alcoholic hydroxyl group (as shown in Figure 2). Therefore, the one-step reaction can only prepare a few compounds such as N-alkyl and hydroxypropyl-substituted morpholine, and has no versatility. If the target product needs to introduce a halogen atom, a two-step reaction is required, and the desired ammonia-based raw material is particularly difficult to obtain, and the reaction yield is low. The final product is in the form of a hydrohalide salt and the post-treatment crystallization process is unstable.
  • Route 2 As shown in Figure 3, a combination of morpholine and a halogenated hydrocarbon is prepared. This route has only one step reaction, and a variety of substituent groups can be conveniently introduced on N, which is highly versatile, and halogenated hydrocarbon raw materials are easily obtained at low cost.
  • the invention discloses a preparation process of an N-substituted morpholine organic compound, comprising the following steps: adding an equimolar amount of morpholine, a halogenated hydrocarbon and an alkalizing agent in an organic solvent, and a molar amount of morpholine molar amount 1 %-10% of the alkali metal halide obtains the reaction solution, and the reaction produces an N-substituted morpholine organic compound, and the N-substituted morpholine organic compound is purified to obtain a pure N-substituted morpholine organic compound.
  • RX is a halogenated hydrocarbon
  • X is a halogen
  • R is a hydrocarbon group or a halogenated hydrocarbon group.
  • the organic solvent is selected from the group consisting of methyl tert-butyl ether, 1, 4-dioxane, acetone, methanol, ethanol, isopropanol, hydrazine, hydrazine-dimethylformamide, ethyl acetate, dichloro
  • organic solvents such as methane, chloroform, carbon tetrachloride, acetonitrile, n-hexane, and cyclohexane.
  • the alkalizing agent is selected from one or more of sodium hydride, calcium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate or calcium carbonate.
  • the alkali metal halide is selected from one or more of potassium bromide, sodium bromide, potassium iodide, and sodium iodide.
  • the reaction temperature may be from 0 ° C to the reflux temperature of the organic solvent.
  • the reaction time can be controlled at 0.5-48 hours.
  • a halogenated hydrocarbon is a compound formed by substituting a hydrogen atom in a hydrocarbon molecule with a halogen (fluorine, chlorine, bromine or iodine).
  • monohalogenated or dihalogenated hydrocarbons including monohalogenated alkanes such as bromoethane, alpha-halogenated olefins such as allyl chloride, allyl bromide, and alpha-halogenated aromatic hydrocarbons.
  • monohalogenated alkanes such as bromoethane
  • alpha-halogenated olefins such as allyl chloride, allyl bromide
  • alpha-halogenated aromatic hydrocarbons for example, 4-methylbenzyl chloride, benzyl bromide, 4-methoxy bromide, dihaloalkane, such as 1-chloro-3-bromopropane.
  • bromoethane, 1-chloro-3-bromopropane, allyl bromide, 4-methoxybenzyl bromide and 4-methylchlorobenzyl are exemplified, and halogens in halogenated hydrocarbons are optional.
  • fluorine, chlorine, bromine, iodine according to the method and principle disclosed by the present invention, those skilled in the art can fully realize the use of the reaction system of the present invention, and adopt other halogenated hydrocarbons suitable for the existing one-step reaction instead of the implementation.
  • the halogenated hydrocarbons exemplified in the examples are reacted to obtain the corresponding hydrazine-substituted morpholine organic compounds.
  • the hydrazine-substituted morpholine organic compound is one of the above halogenated hydrocarbons, and one halogen is morpholinyl (molecular formula: ) Substituted product.
  • the molar concentration of the morpholine, halogenated hydrocarbon and alkalizing agent is 0.24 mol/liter based on the total volume of the reaction solution.
  • the alkalizing agent and the inorganic salt solid are removed by filtration, and the filtrate is collected.
  • the filtrate was concentrated under reduced pressure and the solvent was evaporated.
  • the organic phase is washed with a weakly basic solution such as saturated sodium bicarbonate solution or saturated sodium carbonate to remove a small amount of halogenated reagent and hydrohalic acid which may remain.
  • the organic phase was washed with saturated brine to remove a little aqueous solution which was mixed in the organic phase during the previous washing, and the organic phase was completely separated.
  • the organic phase is separated, and the obtained organic phase is concentrated under reduced pressure to dilute dichloromethane to obtain a crude purified N-substituted morpholine organic compound. Further, the above-mentioned preliminary purified N-substituted morpholine organic compound can be further purified.
  • the initially purified N-substituted morpholine organic compound is liquid at room temperature, it is collected by distillation under reduced pressure with N-substituted morpholine. A fraction corresponding to the boiling point of the organo-organic compound is obtained as a pure N-substituted morpholine organic compound.
  • the initially purified N-substituted morpholine organic compound is a solid at room temperature
  • a pure N-substituted morpholine organic compound can be obtained by recrystallization, and a mixed solvent of dichloromethane or n-hexane can be used for recrystallization. .
  • the process of the present invention facilitates the industrialization of pharmaceutical intermediates, particularly for the industrialization of key intermediates of the antitumor drug gefitinib.
  • the present invention is the same in that the present invention still uses N-substituted morpholine organic compounds by reacting morpholine with a halogenated hydrocarbon.
  • the difference is that the preparation process conditions provided by the present invention are changed, an equivalent amount of an alkalizing agent is added, and an alkali metal halide having a molar amount of 1 to 10% by mole of morpholine is added to remove the tetrahydrofuran and toluene.
  • the other organic solvent replaces tetrahydrofuran and toluene, and can be reacted to obtain a product even at room temperature.
  • the reaction was stirred at 0 ° C for 8 hours.
  • the reaction was stopped, filtered, and the solid was washed with methyl tert-butyl ether.
  • the filtrate was combined to distill off methyl t-butyl ether, 60 ml of dichloromethane was added, and washed with 20 ml of saturated sodium hydrogen carbonate solution, and washed with 20 ml of saturated brine. 1 time. Distillation of dichloromethane gave 17.7 g of a pale yellow liquid.
  • the mixture was distilled under reduced pressure, and a fraction of 72 ° C was collected to obtain a pale yellow liquid (11.3 g, yield: 73.9%).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention porte sur des procédés pour préparer des composés de morpholine N-substitués comprenant les étapes suivantes consistant à : ajouter de la morpholine, un hydrocarbure halogéné et un basifiant en quantité équimolaire et un halogénure de métal alcalin dont la quantité molaire est de 1 % à 10 % de celle de la morpholine dans un solvant organique pour faire une solution de réaction, amener à réagir et purifier pour obtenir des morpholines N-substituées. Les procédés ont des avantages de coût et de technique évidente, tels que des conditions réactionnelles douces, un fonctionnement aisé, un rendement stable (> 60 %), des réactifs non coûteux et faciles, et sont faciles à industrialiser.
PCT/CN2008/070072 2007-12-27 2008-01-10 Procédés pour préparer des composés de morpholine n-substitués WO2009082884A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2007101733832A CN101215274B (zh) 2007-12-27 2007-12-27 N取代吗啉类有机化合物的制备工艺
CN200710173383.2 2007-12-27

Publications (1)

Publication Number Publication Date
WO2009082884A1 true WO2009082884A1 (fr) 2009-07-09

Family

ID=39621792

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2008/070072 WO2009082884A1 (fr) 2007-12-27 2008-01-10 Procédés pour préparer des composés de morpholine n-substitués

Country Status (2)

Country Link
CN (1) CN101215274B (fr)
WO (1) WO2009082884A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102675246B (zh) * 2012-05-18 2014-04-23 济南诚汇双达化工有限公司 一种盐酸普莫卡因的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4946996A (en) * 1985-08-08 1990-08-07 The Dow Chemical Company Preparation of an allyl amine and quaternary diallyl ammonium compounds therefrom
CN1391563A (zh) * 1999-09-21 2003-01-15 阿斯特拉曾尼卡有限公司 治疗用喹唑啉衍生物
CN1597667A (zh) * 1999-02-10 2005-03-23 阿斯特拉曾尼卡有限公司 用作血管生成抑制剂的喹唑啉衍生物
CN1675201A (zh) * 2002-06-24 2005-09-28 阿卡蒂亚药品公司 N－取代哌啶衍生物作为血清素受体试剂

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0221245D0 (en) * 2002-09-13 2002-10-23 Astrazeneca Ab Chemical process

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4946996A (en) * 1985-08-08 1990-08-07 The Dow Chemical Company Preparation of an allyl amine and quaternary diallyl ammonium compounds therefrom
CN1597667A (zh) * 1999-02-10 2005-03-23 阿斯特拉曾尼卡有限公司 用作血管生成抑制剂的喹唑啉衍生物
CN1391563A (zh) * 1999-09-21 2003-01-15 阿斯特拉曾尼卡有限公司 治疗用喹唑啉衍生物
CN1675201A (zh) * 2002-06-24 2005-09-28 阿卡蒂亚药品公司 N－取代哌啶衍生物作为血清素受体试剂

Also Published As

Publication number Publication date
CN101215274B (zh) 2011-05-04
CN101215274A (zh) 2008-07-09

Similar Documents

Publication Publication Date Title
US20170166517A1 (en) Process for Preparing N-(4-Cyclohexyl-3-trifluoromethyl-benzyloxy)-acetimidic Acid Ethyl Ester
CA2954276C (fr) Procede de preparation d'acides 4-alkoxy-3-hydroxypicoliniques
AU2018383864A1 (en) Method for synthesis of Roxadustat and intermediate compounds thereof
JP6985367B2 (ja) 新規化合物および方法
TWI397380B (zh) 含磷之α胺基酸之製造方法及其製造中間體
US11325922B2 (en) Process for the preparation of Crisaborole in a stable crystal form
WO2009082884A1 (fr) Procédés pour préparer des composés de morpholine n-substitués
WO2012103105A1 (fr) Procédés de préparation du raltégravir et de ses intermédiaires dans lesdits procédés
WO2021130163A1 (fr) Procédé de synthèse de melphalan
KR20040043176A (ko) 5-치환 이소벤조퓨란의 제조 방법
CA2910011A1 (fr) Procede de preparation d'ivabradine
KR102632488B1 (ko) 연속 흐름 화학에 의한 bbmo의 합성 방법
CN115784941B (zh) 一种三官能度腈氧化物、制备方法及其应用
CN112321451B (zh) 一种用于制备盐酸西那卡塞药物中间体的方法
CN117794567A (zh) 用于制备纯2-硝基-4-甲基磺酰基苯甲酸的方法
WO2017083719A1 (fr) Procédés de synthèse, sans métal de transition, de composés biaryle
CN101309910A (zh) 获得用于得到药学活性化合物的缬氨酸衍生物的方法
WO2023100110A1 (fr) Procédé de préparation de brivaracétam
JP2004238322A (ja) （ｒ）−３−アミノペンタンニトリルメタンスルホン酸塩の製造方法
EP3092222A1 (fr) Procédé de préparation de fingolimod amélioré
TW201305104A (zh) ３－氯－４－甲基苯甲酸異丙酯及其製造方法
JP3021598B2 (ja) 光学活性２―アリール環状エーテル類の製造方法
KR20220015173A (ko) 메소트리온 전구체의 제조 방법
EP1281708B1 (fr) Procédé pour la preparation de 5-formylphthalide
CN117024410A (zh) 一种艾乐替尼中间体及其制备方法

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: 08700096

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: 08700096

Country of ref document: EP

Kind code of ref document: A1