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WO1997032835A1 - Processus de production de composes de fluor - Google Patents

Processus de production de composes de fluor Download PDF

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Publication number
WO1997032835A1
WO1997032835A1 PCT/JP1997/000706 JP9700706W WO9732835A1 WO 1997032835 A1 WO1997032835 A1 WO 1997032835A1 JP 9700706 W JP9700706 W JP 9700706W WO 9732835 A1 WO9732835 A1 WO 9732835A1
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WO
WIPO (PCT)
Prior art keywords
group
hydrogen
lower alkyl
atom
hydrogen atom
Prior art date
Application number
PCT/JP1997/000706
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English (en)
Japanese (ja)
Inventor
Toshikazu Simizu
Atsusi Nagaoka
Mitsuo Oda
Chiaki Seki
Tsuneo Yamashita
Kazuhiro Shimokawa
Original Assignee
Eisai Chemical Co., Ltd.
Daikin Industries, Ltd.
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 Eisai Chemical Co., Ltd., Daikin Industries, Ltd. filed Critical Eisai Chemical Co., Ltd.
Publication of WO1997032835A1 publication Critical patent/WO1997032835A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B39/00—Halogenation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups

Definitions

  • the present invention relates to a fluoro compound useful as an intermediate of a drug (for example,
  • the alcoholic hydroxyl group is fluorinated with N, N-getyl-1,1.2,3,3.3-hexafluoropropylamine or an analog thereof to obtain a fluoro compound. And a method for producing the same.
  • fluorinating agents have been developed and used to obtain fluoro compounds by fluorinating various compounds.
  • fluorine (F 2 ), hydrogen fluoride (HF), tetraalkylammonium fluoride (Bu 4 N + F_, etc.), alkali metal fluorides (KF, CsF, etc.) have been used for a long time.
  • monopyridine hydrofluoride (Olar reagent) and (C 2 H 5 ) 2 NSF 3 (DAST) have been widely used at the research stage because many compounds can be fluorinated efficiently.
  • ⁇ , ⁇ -Jetyl-1,1,2,3,3.3-hexafluoropropylamine is cheaper and more stable than DAS ⁇ , so it can be fluorinated on an industrial scale. Suitable for. Furthermore, the selectivity of fluorinated products is higher than that of fluorinating agents other than DAST. However, even if the above reaction was carried out using ⁇ , ⁇ -getyl-1,1,2,3,3,3-hexafluoropropylamine, about 20% of the by-product olefin compound was produced, Hinders the reaction. It is also known that when the reaction is carried out using other starting materials, an ether form is formed together with the olefin form (Ishikawa et al., Bull.Chein. Soc. J APAN), 52 (11), 3377 ( 1979)].
  • An object of the present invention is to produce a fluoro compound by fluorination using N, N-getyl-1,1,2,3,3,3-hexafluoropropylamine, which is a by-product, an olefin compound to an ether compound.
  • An object of the present invention is to provide a method for suppressing the formation of fluorinated compounds and producing a fluoro compound as efficiently as fluorination using DAST.
  • hydrogen fluoride and a tertiary amino acid are used together with a fluorinating agent, NN-ethyl-1,1,2.3,3.3-hexafluoropropylamine or an analog thereof. The fluorination is performed using
  • the present invention provides a compound represented by the general formula (I):
  • R 1 represents a hydrogen atom, a lower alkyl group, lower alkenyl group, halogenation lower alkyl group, a lower alkoxyalkyl group, a lower Arukokishikaru Boniruarukiru group, Shiano lower alkyl group or Ararukiru group:
  • R 2 is A hydrogen atom, an optionally substituted piperazinyl group, a piperidyl group, a pyrrolidinyl group, a morpholinyl group, an optionally substituted amino group or a heteroaryl group;
  • R 3 and R 4 are the same or different and are each a hydrogen atom Represents a halogen atom, a cyano group, a lower alkyl group or a lower alkoxy group.
  • the benzyl alcohol derivative represented by the formula (1) is reacted with tertiary amine, especially triethylamine and hydrogen fluoride in the presence of N, N-ethyl-1,1, General
  • the present invention provides a compound represented by the general formula (III):
  • ⁇ Is the same or different, and represents a hydrogen atom or a halogen atom, an alkoxy group, an amino group, an amide group, a nitro group, a cyano group, a carbonyl group, a carboxyl group, a thiol group, An alkyl group having 1 to 20 carbon atoms, an alkenyl group having 2 to 20 carbon atoms, an allene group, an aryl group, a carbon atom having 6 to 6 carbon atoms, which may be substituted with a thioether group, a sulfonyl group, a sulfoxide group or a phosphonyl group.
  • R 11 and R 12 are both hydrogen atoms
  • R 13 is not a hydrogen atom, and R 13 forms a saturated or unsaturated 3- to 8-membered ring together with R 11 and R 12 May be.
  • R 1 R 12 and R 13 have the same meanings as described above.
  • the present invention relates to N, N-Jetyl-1.1,2,3,3,3-hexafluoropropylamine or an analog thereof, hydrogen fluoride and Provided is a fluorinated reagent composition comprising gradeamine.
  • the lower alkyl group is, for example, a carbon atom such as a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a t-butyl group, a pentyl group, and a hexyl group. It is an alkyl group of numbers 1 to 6.
  • the lower alkenyl group is, for example, an alkenyl group having 2 to 6 carbon atoms such as a vinyl group, a propenyl group and a butenyl group.
  • the halogenated lower alkyl group is, for example, a fluoroalkyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a fluoropropyl group, a cyclobutyl group, a cyclopentyl group, etc., wherein the lower alkyl group is one or more halogen atoms. It is a substituted group.
  • the lower alkoxyalkyl group is a group in which the lower alkyl group such as a methoxymethyl group, a methoxyethyl group, a methoxypropyl group and the like is substituted by a lower alkoxy group having 1 to 6 carbon atoms.
  • the lower alkoxycarbonylalkyl group is an alkoxycarbonylalkyl group having 3 to 10 carbon atoms as a whole, such as a methoxycarbonylmethyl group, an ethoxyquincarbonylethyl group, a t-butoxycarbonylmethyl group, and the like.
  • the cyano lower alkyl group is a group in which the lower alkyl group is substituted with one or more cyano groups, such as a cyanomethyl group and a cyanoethyl group.
  • aralkyl group examples include an aralkyl group having 7 to 16 carbon atoms such as a benzyl group, a methylbenzyl group, a phenyl group, and a phenylpropyl group.
  • piperazinyl group which may be substituted include, for example, 4- (t-butoxycarbonyl) piperazine-11-yl group, 4-benzyloxycarbonyl piperazine-11-yl group, 4-ethoxycarbonylpi Perezin 1-yl Group, 4-benzylpiperazine-l-yl group, 4-formylpiperazine-l-yl group, 4-acetylbiperazine-l-yl group, 4-benzylbiperazine-l-yl group, 4-l (p- Nitrobenzoyl) piperazine-1-yl group, 4-methanesulfonylbiperazine-11-yl group, 4- (p-toluenesulfonyl) piperazine-1-yl group, 4-arylpiperazine-11-yl group, 4 One-year-old xypiperazine-11-yl group, 4-trimethylsilylpiperazin-1-yl group and other piperazine-11-yl
  • heteroaryl group examples include an imidazolyl group, a thiazolyl group, an oxazolyl group, a pyridyl group, and a virazyl group.
  • heterocycles containing N, 0 or S include:
  • R X represents a trifluoromethyl group or a halogen atom, particularly a fluorine atom or a chlorine atom
  • R represents a lower alkyl group.
  • two Rs are, together with the nitrogen atom to which they are bound, a ring May be formed.
  • R 'NS F 3 (In the formula, R ′ represents a lower alkyl group. However, two R ′s may form a ring together with the nitrogen atom to which they are attached.)
  • R represents a fluorine atom or an aryl group, preferably a phenyl group.
  • R ′ ′′ represents an aryl group, preferably a phenyl group, and X represents 1, 2, or 3.
  • N, N-Jetyl-1.1,2,3,3,3-hexafluoropropylamine or a tertiary amine used with an analog thereof is not particularly limited, and a wide range of known tertiary amines is used. You can choose from.
  • tertiary amines are the amines shown below:
  • N, N-getyl-1,1,2,3,3,3-hexafluoropropylamine or analogs thereof are as follows:
  • N, N-ethyl-1,1,2,3,3,3-hexafluoropropylamine or its analogs, hydrogen fluoride and tertiary amine are as follows. It is as follows.
  • N, N Jethyl, 1, 1.2, 3.3, 3-hexa Fluoropropylamine or an analog thereof can be used in an amount of 1 to 10 equivalents.
  • N-N-Jetyl-1,1,2,3,3,3-hexafluoropropylamine or its analogs consist of hydrogen fluoride and tertiary amine per mole of the analog
  • the complex can be used in an amount of 0.3 to 30 mol, preferably 1 to 20 mol.
  • the molar ratio between hydrogen fluoride and tertiary amine is 10: 1 to 1: 1 and preferably 5: 1 to 1: 1.
  • benzyl alcohols represented by the formula (I) used as a starting material in the first production method of the present invention preferred are compounds in which R 1 is a lower alkyl group and R 2 is an optionally substituted piperazinyl. Or a piperidyl group, benzyl alcohol of the formula (I) wherein R 3 is a hydrogen atom, a halogen atom or a lower alkyl group, and R 4 is a hydrogen atom, a halogen atom or a lower alkoxy group.
  • R 1 is a lower alkyl group
  • R 2 is an optionally substituted piperazinyl group
  • R 3 and R 4 are the same or different halogen atoms. Jil alcohol.
  • the most preferred compounds are those in which R 1 is an ethyl group, R 2 is a 4- (t-butoxy) carborylbiperazine-1-yl group, R 3 is a bromine atom, and R 4 is a chlorine atom.
  • the most preferred compound is a benzyl alcohol of the formula (I) in which R 1 is an optically active substance consisting of an atomic group selected from other than a hydrogen atom. It has been difficult to stereospecifically obtain a desired benzyl fluoride derivative reflecting the optical purity of the raw material by the conventional fluorination technology of secondary benzyl alcohol. That is, a decrease in the optical purity due to the reaction was inevitable.
  • the benzyl fluoride derivative can be stereospecifically obtained without racemization by almost completely reversing the configuration of the alcohol.
  • preferred alcohols are the following alcohols:
  • the reaction conditions in the production method of the present invention are as follows.
  • the reaction is preferably performed in the absence of moisture.
  • the reaction temperature depends on the reactivity of the starting materials, and is preferably between 100 ° C and 150 ° C, preferably between 78 ° C and 100 ° C, more preferably between 78 ° C and 50 ° C. You can choose from a range.
  • the reaction pressure depends on the state of the starting material at the reaction temperature (either solid or gaseous) and can be used from depressurization to pressurization, but atmospheric pressure or pressurization due to the simplicity of the reactor. For example, pressures up to 10 atmospheres are preferred.
  • the reaction can be performed either in the presence or absence of a solvent.
  • a solvent hydrocarbons, ethers, halogenated hydrocarbons, nitriles, amides, alkylsulfoxides, etc.
  • Preferred solvents are pentane, hexane, benzene, toluene, xylene, petroleum benzene, petroleum ether.
  • ADVANTAGE OF THE INVENTION According to the manufacturing method of this invention, generation
  • Hexafluoropropene-Jethylamine 200 mg, 0.46 mmo 1
  • Triethylfluorinated triethylamine 5 66 mg, 3.52 mmol
  • double-mouthed form (1. Oml)
  • 60 mg (0.44 mmo 1) of 1-phenyl-1-propanol was stirred for 3 hours.
  • Table 1 shows the results of Examples 1 to 3 and Comparative Examples 1 to 3.
  • the reactor is charged with the molar equivalent of tris-fluoric acid described in Table 2 and the molar equivalent of hexafluoropropene-getylamine (Ishikawa reagent) described in Table 2 is added thereto and cooled on ice (about 0 ° C). did.
  • the solution was dripped slowly so that the temperature inside the vessel did not rise. After completion of the dropwise addition, the mixture was stirred under ice cooling for 3 hours.
  • 2-Fluoroadamanone was obtained from 68 mg (0.44 mmo 1) of 2-adamantanol in the same manner as in Example 1 with a yield of 76% and adamanten with a yield of 4%.
  • Table 3 shows the results of Examples 10 to 13 and Comparative Examples 5 to 8.

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

Abstract

Cette invention concerne un processus de production de dérivés de fluorure de benzyle correspondant à la formule générale (II) où R1 représente hydrogène, alkyle inférieur, etc., et R2 représente hydrogène, pipérazinyle, pipéridyle, pyrrolidinyle, morpholinyle, amino ou hétéroaryle, tandis que R3 et R4 représentent chacun hydrogène, halogéno, cyano, alkyle inférieur ou alcoxy inférieur. Ce processus consiste à faire réagir un dérivé d'alcool de benzyle correspondant à la formule générale (I) avec un N,N-diéthyl-1,1,2,3,3,3-hexafluoropropylamine, ceci en présence d'un amine tertiaire et de fluorure d'hydrogène. Ce processus permet de produire des composés de fluor avec la même efficacité que la fluoration par DAST, tout en inhibant la formation de produits dérivés comme des oléfines et des éthers.
PCT/JP1997/000706 1996-03-07 1997-03-07 Processus de production de composes de fluor WO1997032835A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8/50453 1996-03-07
JP05045396A JP3759649B2 (ja) 1996-03-07 1996-03-07 フルオロ化合物の製造方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6348625B1 (en) * 2000-11-10 2002-02-19 Gloria Long Anderson Method for preparing some 1-adamantancecarboxamides
US6727264B1 (en) 2001-07-05 2004-04-27 Synaptic Pharmaceutical Corporation Substituted anilinic piperidines as MCH selective antagonists

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1903021B1 (fr) * 2005-03-28 2015-09-30 Tosoh F-Tech, Inc. Procede de fabrication de composes fluores
WO2006103986A1 (fr) * 2005-03-28 2006-10-05 Tosoh F-Tech, Inc. Procede de fabrication d’un derive de fluoroproline optiquement actif
US10196341B2 (en) * 2011-08-19 2019-02-05 The Trustees Of Princeton University C-halogen bond formation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3137701A (en) * 1962-04-19 1964-06-16 Upjohn Co Process for the preparation of 6-deoxy-6-fluoromorphines, 6-deoxy-6-fluorocodeines, and related compounds
JPS61246138A (ja) * 1985-04-25 1986-11-01 Sagami Chem Res Center フツ化アリル誘導体の製造方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3137701A (en) * 1962-04-19 1964-06-16 Upjohn Co Process for the preparation of 6-deoxy-6-fluoromorphines, 6-deoxy-6-fluorocodeines, and related compounds
JPS61246138A (ja) * 1985-04-25 1986-11-01 Sagami Chem Res Center フツ化アリル誘導体の製造方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, Vol. 52(11), 1979, p. 3377-3380. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6348625B1 (en) * 2000-11-10 2002-02-19 Gloria Long Anderson Method for preparing some 1-adamantancecarboxamides
US6727264B1 (en) 2001-07-05 2004-04-27 Synaptic Pharmaceutical Corporation Substituted anilinic piperidines as MCH selective antagonists
US7067534B1 (en) 2001-07-05 2006-06-27 H. Lundbeck A/S Substituted anilinic piperidines as MCH selective antagonists

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JPH09241190A (ja) 1997-09-16
JP3759649B2 (ja) 2006-03-29

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