WO2010041402A1 - テトラフルオロ化合物の製造方法 - Google Patents
テトラフルオロ化合物の製造方法 Download PDFInfo
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- WO2010041402A1 WO2010041402A1 PCT/JP2009/005130 JP2009005130W WO2010041402A1 WO 2010041402 A1 WO2010041402 A1 WO 2010041402A1 JP 2009005130 W JP2009005130 W JP 2009005130W WO 2010041402 A1 WO2010041402 A1 WO 2010041402A1
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- NLEXXOXXILNCLL-UHFFFAOYSA-N CC(C)(C)OC(OCC(C(COC(OC(C)(C)C)=O)(F)F)(F)F)=O Chemical compound CC(C)(C)OC(OCC(C(COC(OC(C)(C)C)=O)(F)F)(F)F)=O NLEXXOXXILNCLL-UHFFFAOYSA-N 0.000 description 1
- JCHXIWIEMLOIEJ-UHFFFAOYSA-N CC(OCC(C(COC(C)=O)(F)F)(F)F)=O Chemical compound CC(OCC(C(COC(C)=O)(F)F)(F)F)=O JCHXIWIEMLOIEJ-UHFFFAOYSA-N 0.000 description 1
- CDZXJJOGDCLNKX-UHFFFAOYSA-N OCC(C(CO)(F)F)(F)F Chemical compound OCC(C(CO)(F)F)(F)F CDZXJJOGDCLNKX-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/30—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/48—Preparation of compounds having groups
- C07C41/50—Preparation of compounds having groups by reactions producing groups
- C07C41/52—Preparation of compounds having groups by reactions producing groups by substitution of halogen only
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/287—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
Definitions
- the present invention relates to a method for producing a tetrafluoro compound from an alkyne compound and a method for producing a tetrafluoro nitrogen-containing heterocyclic compound using the method.
- Patent Documents 1 and 2 Non-Patent Documents 1 to 4, etc.
- these methods require reduction using expensive LiAlH 4 or the like.
- An object of the present invention is to provide a method for producing a tetrafluoronitrogen-containing heterocyclic compound such as tetrafluoropyrrolidine with good yield and at low cost.
- the present inventors have produced a tetrafluoro compound represented by the formula (II) with high yield by reacting an alkyne compound represented by the following formula (I) with a fluorine gas.
- the present inventors have found that a tetrafluoro nitrogen-containing heterocyclic compound can be produced at a low cost and in a high yield by using this method for the production of tetrafluoro nitrogen-containing heterocyclic compounds such as tetrafluoropyrrolidine.
- R 1 and R 2 each independently represents a hydrogen atom or an OH protecting group
- R 3 to R 6 each independently represents a hydrogen atom or an alkyl group
- n 1 and n 2 Each independently represents an integer of 1 or more
- a fluorine gas is reacted with the formula (II)
- the present invention also provides [2] (A) Formula (I)
- R 1 and R 2 each independently represents a hydrogen atom or an OH protecting group
- R 3 to R 6 each independently represents a hydrogen atom or an alkyl group
- n 1 and n 2 Are each independently an integer of 1 or more
- a tetrafluoro compound can be produced from an alkyne compound in a high yield, and as a result, a tetrafluoro nitrogen-containing heterocyclic compound can be produced at a low cost and in a high yield using that method.
- the alkyne compound represented by the formula (II) is reacted with fluorine gas.
- the tetrafluoro compound represented by these is manufactured.
- the alkyne compound represented by the formula (I) used in the present invention is as follows.
- the substituents R 1 and R 2 each independently represent a hydrogen atom or a protecting group for an OH group.
- a protecting group generally used for protecting the OH group can be used. Specific examples thereof include a lower alkyl group such as a methyl group; a lower alkoxyalkyl group such as a methoxymethyl group and an ethoxyethyl group; an optionally substituted benzyl group (the substituent includes a nitro group, a lower alkoxy group, and the like).
- R 3 to R 6 each independently represent a hydrogen atom or an alkyl group.
- the alkyl group include methyl group, ethyl group, n-propyl group, i-propyl group, n-butyl group, s-butyl group, i-butyl group, t-butyl group, n-pentyl group, and n-hexyl group.
- it is a C1-6 alkyl group.
- n1 and n2 each independently represents an integer of 1 or more, preferably 1 to 3.
- the fluorination reaction of the alkyne compound represented by the formula (I) in the solvent is performed by fluorinating the alkyne compound represented by the formula (I) using a fluorine gas.
- a fluorine gas usually, the alkyne compound represented by the formula (I) is added to a solvent, and this solution is reacted with bubbling fluorine gas under stirring.
- the fluorine gas may be used as it is, or may be diluted with an inert gas (nitrogen gas, helium gas, etc.).
- the amount to be used is generally 1 to 10 mol, preferably 2 to 4 mol, per 1 mol of the compound represented by the formula (I).
- the reaction temperature is usually -196 to 25 ° C, preferably -78 to 10 ° C.
- the reaction time is usually 1 to 10 hours, preferably 2 to 4 hours.
- the solvent used in fluorination will not be specifically limited if it is a solvent inactive with respect to fluorine gas.
- perfluoroalkanes such as perfluoropentane, perfluorohexane, perfluoroheptane, and perfluorooctane
- perfluorocycloalkanes such as perfluorocyclopentane, perfluorocyclohexane, perfluorocycloheptane, and perfluorocyclooctane
- Those substituted with atoms eg, CFCl 3 and the like
- perfluoroether perfluoroalkylamine
- trifluoroacetic acid acetonitrile and the like.
- solvents may be used alone or in combination of two or more.
- a mixed solvent such as CFCl 3 and acetonitrile is used.
- the amount of the solvent used is 1 to 20 L, preferably 5 to 10 L, per mole of the alkyne compound represented by the formula (I).
- a compound having an OH group protecting group it can be deprotected to form an OH group by a known method or the like.
- the manufacturing method of the tetrafluoro nitrogen-containing heterocyclic compound represented by Formula (IV) It has the following processes. Step 1 above. As shown, the tetrafluoro compound represented by the formula (II) is produced by reacting the compound represented by the formula (I) with a fluorine gas. In addition, when the tetrafluoro compound represented by the formula (II) has an OH group protecting group, it may be deprotected to form an OH group in the first step.
- the tetrafluoro nitrogen-containing heterocyclic compound represented by these or its salt is manufactured.
- R 7 and R 8 are, for example, halogen atoms such as chlorine atom and bromine atom; methanesulfonyloxy group, ethanesulfonyloxy group, trifluoromethanesulfonyloxy group, benzenesulfonyloxy And a group capable of leaving the nucleophile such as an organic sulfonyloxy group such as a p-toluenesulfonyloxy group.
- R 1 and R 2 are hydrogen atoms
- the compound represented by the formula (II) is converted into an OH group by hydrolysis when R 1 and R 2 are protecting groups for OH groups.
- the compound represented by the formula (III) can be obtained by reacting with a reagent such as thionyl chloride, methanesulfonyl chloride, 4-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, etc. in a solvent.
- a reagent such as thionyl chloride, methanesulfonyl chloride, 4-toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, etc.
- the amount of the reagent to be converted to the leaving group is usually 2 to 10 mol, preferably 2 to 3 mol, relative to 1 mol of the compound represented by the formula (II).
- the reaction temperature is generally ⁇ 78 to 200 ° C., preferably ⁇ 5 to 20 ° C.
- the reaction time is usually 1 to 24 hours, preferably 2 to 4 hours.
- Examples of the solvent that can be used for conversion to the leaving group include tetrahydrofuran, acetonitrile, toluene, chloroform, and dichloromethane. These solvents may be used alone or in combination of two or more.
- the amount of the solvent used is 1 to 10 L, preferably 1 to 3 L, per 1 mol of the tetrafluoro compound represented by the formula (II).
- R 3 to R 6 , n1 and n2 are the same as defined in the formula (I).
- R 9 is a hydrogen atom or an amino-protecting group.
- protecting groups generally used for protecting N can be used. Specific examples thereof include t-butyl group; allyl group; trisubstituted silyl groups such as trimethylsilyl group, triethylsilyl group, t-butyldimethylsilyl group, triisopropylsilyl group, dimethylhexylsilyl group, t-butyldiphenylsilyl group, etc.
- An optionally substituted benzyl group (the substituent includes a nitro group, a lower alkoxy group, etc.); a lower alkoxycarbonyl group such as a t-butoxycarbonyl group; a halogeno lower alkoxycarbonyl group; Good benzyloxycarbonyl groups (substituents include nitro groups, lower alkoxy groups, etc.); acyl groups such as acetyl groups and benzoyl groups.
- Examples of the tetrafluoro nitrogen-containing heterocyclic compound represented by the formula (IV) include the following.
- Examples of the salt of the tetrafluoro nitrogen-containing heterocyclic compound represented by the formula (IV) include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid And salts with organic acids such as maleic acid, succinic acid, citric acid and tartaric acid.
- inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, fumaric acid
- organic acids such as maleic acid, succinic acid, citric acid and tartaric acid.
- a compound represented by the formula (III) By reacting a compound represented by the formula (III) with a primary amine compound represented by the formula NH 2 R 9 (wherein R 9 represents a hydrogen atom or a protecting group for an amino group), The tetrafluoro nitrogen-containing heterocyclic compound represented can be obtained.
- the primary amine compound represented by the formula NH 2 R 9 include t-butylamine, allylamine, trimethylsilylamine, benzylamine, t-butoxycarbonylamine, and benzoylamine.
- the amount of the primary amine compound to be used is generally 1 to 10 mol, preferably 1 to 3 mol, per 1 mol of the compound represented by the formula (III).
- the reaction temperature is usually 0 to 200 ° C., preferably 0 to 80 ° C.
- the reaction time is usually 1 to 24 hours, preferably 5 to 20 hours.
- chloroform, ethanol, etc. are mentioned, for example. These solvents may be used alone or in combination of two or more.
- the amount of the solvent used is 1 to 10 L, preferably 1 to 3 L, relative to 1 mol of the tetrafluoro compound represented by the formula (II).
- an appropriate method can be appropriately selected according to the kind of the protecting group.
- the deprotection method include the method described in PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 2nd. Ed.
- the protecting group is a t-butyl group, t-butoxycarbonyl group or the like, it may be treated with an acid such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid or methanesulfonic acid.
- the protecting group is a benzyl group or the like, hydrogenolysis can be performed in the presence of a palladium catalyst or the like.
- the desired product can be isolated by purification by a conventional post-treatment operation and, if desired, known and conventional purification means such as distillation, recrystallization, column chromatography and the like.
- A% represents an area ratio percentage
- Example 2 A crude product containing the compound (3) obtained in Example 1 (19.45 g (120 mmol, 77 mmol in terms of pure content)) and pyridine (23.7 g, 300 mmol) in a methylene chloride solution in a range of ⁇ 5 to 5 ° C.
- reaction solution was added to saturated sodium bicarbonate water. Subsequently, extraction was performed three times with methylene chloride, and the organic layer was washed with water and then dehydrated with magnesium sulfate. After the dehydrating agent was filtered off, the solvent was distilled off under reduced pressure to obtain 1.54 g of a crude product of 2,2,3,3-tetrafluorobutane-1,4-diol diacetate. To the crude product was added 5 ml of dilute sulfuric acid, and the mixture was heated to reflux for 3 hours. The reaction solution was cooled and then added to ice-cooled saturated sodium bicarbonate water.
- 2-butyne-1,4-diol 1.53 g of 2-butyne-1,4-diol bis (2,2,2-trifluoroacetate) instead of diacetate was used in the same manner as in Example 1, and 2 , 2,3,3-Tetrafluorobutane-1,4-diol (0.18 g) was obtained.
- 1,4-bis (methoxymethoxy) -2-butyne (0.96 g, 5.5 mmol) was weighed into a reaction vessel having a cooling device and a gas inlet, and dissolved in a mixed solvent of 10 ml of acetonitrile and 30 ml of trichlorofluoromethane. .
- the solution was cooled to ⁇ 50 ° C. while blowing nitrogen (50 ml / min) and purged with nitrogen for 15 minutes. Thereafter, fluorine gas diluted to 10% with nitrogen was blown in at a rate of 50 ml / min for 123 minutes.
- 1,4-bis (pivaloyloxy) was used in the same manner as in Example 4 except that 1.40 g of 1,4-bis (pivaloyloxy) -2-butyne was used instead of 1,4-bis (methoxymethoxy) -2-butyne. 2.11 g of a crude product of -2,2,3,3-tetrafluorobutane was obtained. From analysis by gas chromatography, 1,4-bis (pivaloyloxy) -2,2,3,3-tetrafluorobutane in the crude product was 18 A%.
- 1,4-bis (t-butoxycarbonyloxy) -2-butyne (1.57 g) was used in place of 1,4-bis (methoxymethoxy) -2-butyne, and 1,4-bis (methoxymethoxy) -2-butyne was used in the same manner as in Example 4.
- 2.29 g of a crude product of bis (t-butoxycarbonyloxy) -2,2,3,3-tetrafluorobutane was obtained. From analysis by gas chromatography, 1,4-bis (t-butoxycarbonyloxy) -2,2,3,3-tetrafluorobutane in the crude product was 18 A%.
- 1,4-bis (t-butyldimethylsilyloxy) -2-butyne (1.73 g) was used in place of 1,4-bis (methoxymethoxy) -2-butyne, and 1,4 bis (methoxymethoxy) -2-butyne was synthesized in the same manner as in Example 4. 2.49 g of a crude product of bis (t-butyldimethylsilyloxy) -2,2,3,3-tetrafluorobutane was obtained. From analysis by gas chromatography, 1,4-bis (t-butyldimethylsilyloxy) -2,2,3,3-tetrafluorobutane in the crude product was 25 A%.
- 1,4-bis (methoxysulfonyl) -2-butyne was used in place of 1,4-bis (methoxymethoxy) -2-butyne and 1.30 g of 1,4-bis (methylsulfonyloxy) -2-butyne was used in the same manner as in Example 4. 1.97 g of a crude product of methylsulfonyloxy) -2,2,3,3-tetrafluorobutane was obtained. From analysis by gas chromatography, 1,4-bis (methylsulfonyloxy) -2,2,3,3-tetrafluorobutane in the crude product was 7 A%.
- 1,4-bis (perfluorobenzyloxy) -2-butyne (2.35 g) was used instead of 1,4-bis (methoxymethoxy) -2-butyne, and 1,4-bis (meth) was synthesized in the same manner as in Example 4. 3.06 g of a crude product of (perfluorobenzyloxy) -2,2,3,3-tetrafluorobutane was obtained. From analysis by gas chromatography, 1,4-bis (perfluorobenzyloxy) -2,2,3,3-tetrafluorobutane in the crude product was 19 A%.
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
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Abstract
Description
本願は、2008年10月7日に出願された日本国特許出願第2008-260485号に対し優先権を主張し、その内容をここに援用する。
[1]式(I)
[2](A)式(I)
(B)式(II)で表されるテトラフルオロ誘導体を式(III)
(C)式(III)で表される化合物と式NH2R9(式中、R9は水素原子又はアミノ基の保護基を示す)で表されるアミン化合物とを反応させて、式(IV)
を有することを特徴とする、式(IV)で表されるテトラフルオロ含窒素複素環化合物又はその塩の製造方法に関する。
式(I)
置換基R1及びR2は、夫々独立して、水素原子又はOH基の保護基を示す。
OH基の保護基としては、一般にOH基を保護するのに用いられている保護基が使用できる。その具体例としては、メチル基等の低級アルキル基;メトキシメチル基、エトキシエチル基等の低級アルコキシアルキル基;置換されていてもよいベンジル基(置換基としてはニトロ基、低級アルコキシ基等が挙げられる);低級アルコキシカルボニル基;ハロゲノ低級アルコキシカルボニル基;置換されていてもよいベンジルオキシカルボニル基(置換基としてはニトロ基、低級アルコキシ基等が挙げられる);アセチル基、ベンゾイル基等のアシル基;トリフェニルメチル基;テトラヒドロピラニル基;メタンスルホニル基;p-トルエンスルホニル基;トリメチルシリル基、トリエチルシリル基、t-ブチルジメチルシリル基、トリイソプロピルシリル基、ジメチルヘキシルシリル基、t-ブチルジフェニルシリル基等のトリ置換シリル基等が例示される。
アルキル基としては、メチル基、エチル基、n-プロピル基、i-プロピル基、n-ブチル基、s-ブチル基、i-ブチル基、t-ブチル基、n-ペンチル基、n-ヘキシル基、ノニル基、イソノニル基、デシル基、ドデシル基、トリデシル基、テトラデシル基、ペンタデシル基、ヘキサデシル基、ヘプタデシル基、オクタデシル基等が挙げられる。好ましくは、C1-6のアルキル基である。
n1及びn2は、夫々独立して1以上の整数を示し、好ましくは、1~3である。
フッ素ガスは、そのまま用いてもよく、不活性ガス(窒素ガス、ヘリウムガス等)で希釈して用いてもよい。使用量は、式(I)で表される化合物1モルに対して、通常1~10モル、好ましくは、2~4モルである。反応温度は、通常-196~25℃、好ましくは-78~10℃である。反応時間は、通常1~10時間、好ましくは2~4時間である。
例えば、ペルフルオロペンタン、ペルフルオロヘキサン、ペルフルオロヘプタン、ペルフルオロオクタン等のペルフルオロアルカン;ペルフルオロシクロペンタン、ペルフルオロシクロヘキサン、ペルフルオロシクロヘプタン、ペルフルオロシクロオクタン等のペルフルオロシクロアルカン;上記のうち、一部のフッ素を他のハロゲン原子に置き換えたもの(例、CFCl3等);ペルフルオロエーテル;ペルフルオロアルキルアミン;トリフルオロ酢酸;アセトニトリルなどが挙げられる。これらの溶媒は単独で用いてもよく、2種類以上を混合して用いても良い。好ましくは、CFCl3とアセトニトリルのような混合溶媒が挙げられる。用いる溶媒の量としては、式(I)で表されるアルキン化合物1モル当り1~20L、好ましくは5~10Lである。
なお、OH基の保護基を有している化合物の場合は、公知の方法等により脱保護してOH基とすることができる。
以下の工程を有する。
第1工程
上記1.で示されるように、式(I)で表される化合物とフッ素ガスとを反応させることにより式(II)で表されるテトラフルオロ化合物を製造する。なお、式(II)で表されるテトラフルオロ化合物がOH基の保護基を有している場合は、第1工程において、脱保護してOH基としてもよい。
式(II)で表されるテトラフルオロ誘導体を式(III)
式(III)で表される化合物と式NH2R9で表されるアミン化合物とを反応させて、式(IV)
上記式(IV)のR9がアミノ基の保護基の場合は、第3工程の後、さらに、溶媒中、式(IV)で表される化合物を脱保護して式(V)
第2工程において得られる式(III)において、R7及びR8は、例えば、塩素原子、臭素原子等のハロゲン原子;メタンスルホニルオキシ基、エタンスルホニルオキシ基、トリフルオロメタンスルホニルオキシ基、ベンゼンスルホニルオキシ基、p-トルエンスルホニルオキシ基等の有機スルホニルオキシ基等、求核試薬に対して脱離する基である。
式(II)で表される化合物を、R1及びR2が水素原子である場合は、そのまま、R1及びR2がOH基の保護基である場合は、加水分解してOH基に変換した後、溶媒中で、塩化チオニル、メタンスルホニルクロリド、4-トルエンスルホニルクロリド、無水トリフルオロメタンスルホン酸等の試薬と反応させることにより、式(III)で表される化合物を得ることができる。
脱離基に変換する試薬の使用量は、式(II)で表される化合物1モルに対して、通常2~10モル、好ましくは、2~3モルである。反応温度は、通常-78~200℃、好ましくは-5~20℃である。反応時間は、通常1~24時間、好ましくは2~4時間である。
また、脱離基に変換する際に使用しうる溶媒としては、例えば、テトラヒドロフラン、アセトニトリル、トルエン、クロロホルム、ジクロロメタンなどが挙げられる。これらの溶媒は単独で用いてもよく、2種類以上を混合して用いても良い。用いる溶媒の量としては、式(II)で表されるテトラフルオロ化合物1モル当り1~10L、好ましくは1~3Lである。
第3工程において得られる式(IV)において、R3~R6,n1及びn2は前記式(I)における定義と同じである。R9は水素原子又はアミノ基の保護基である。
R9のアミノ基の保護基としては、一般にNを保護するために用いられている保護基が使用できる。その具体例としては、t-ブチル基;アリル基;トリメチルシリル基、トリエチルシリル基、t-ブチルジメチルシリル基、トリイソプロピルシリル基、ジメチルヘキシルシリル基、t-ブチルジフェニルシリル基等のトリ置換シリル基;置換されていてもよいベンジル基(置換基としてはニトロ基、低級アルコキシ基等が挙げられる。);t-ブトキシカルボニル基等の低級アルコキシカルボニル基;ハロゲノ低級アルコキシカルボニル基;置換されていてもよいベンジルオキシカルボニル基(置換基としてはニトロ基、低級アルコキシ基等が挙げられる。);アセチル基、ベンゾイル基等のアシル基等が挙げられる。
式NH2R9で表される1級アミン化合物としては、t-ブチルアミン、アリルアミン、トリメチルシリルアミン、ベンジルアミン、t-ブトキシカルボニルアミン、ベンゾイルアミン等が挙げられる。
また、使用しうる溶媒としては、例えば、クロロホルム、エタノールなどが挙げられる。これらの溶媒は単独で用いてもよく、2種類以上を混合して用いても良い。用いる溶媒の量としては、式(II)で表されるテトラフルオロ化合物1モルに対して1~10L、好ましくは1~3Lである。
式(IV)で表される化合物の脱保護は、保護基の種類に応じて、適宜適切な方法を選ぶことができる。脱保護の方法としては、例えば、プロテクティヴ・グループス・イン・オーガニックシンセシス第2版(PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 2nd. Ed.)記載の方法があげられる。例えば、保護基がt-ブチル基、t-ブトキシカルボニル基等の場合は、トリフルオロ酢酸、塩酸、硫酸、p-トルエンスルホン酸、メタンスルホン酸等の酸で処理すればよい。また、保護基がベンジル基等の場合は、パラジウム触媒などの存在下で水素化分解を行うことができる。
反応終了後は、通常の後処理操作、及び所望により蒸留、再結晶、カラムクロマトグラフィー等の公知慣用の精製手段により精製して、目的物を単離することができる。
さらに、化合物(2)の粗生成物1.29gに希硫酸5mlを加え加熱還流させながら加水分解を行い、反応終了後、水とエーテルを加え、有機層を飽和食塩水で洗浄し、硫酸マグネシウムで脱水した。溶媒を留去して化合物(3)(2,2,3,3-テトラフルオロブタンジオール)の粗生成物0.48gを得た。ガスクロマトグラフィーにより、組成物中の化合物(3)は64%であった。
実施例1で得られた化合物(3)を含む粗生成物19.45g(120mmol、純分換算で、77mmol)、ピリジン23.7g(300mmol)の塩化メチレン溶液に-5~5℃の範囲で無水トリフルオロメタンスルホン酸72.8g(257mmol)を滴下し、同温度で1時間、さらに室温で1時間反応した後、水洗し、硫酸マグネシウムで乾燥後、溶媒を留去して目的物である2,2,3,3-テトラフルオロ-1,4-ビス(トリフルオロメタンスルホニルオキシ)-ブタンを含む粗生成物を得た。
得られた上記粗生成物、ベンジルアミン12.8g(120mmol)、及びトリエチルアミン30.4g(300mmol)のエタノール溶液を20時間還流した。室温に冷却後、溶媒を留去し、エーテルを加え、有機層をアルカリ、及び飽和食塩水で洗浄後、硫酸マグネシウムで乾燥した。
硫酸マグネシウムを濾過したエーテル溶液に0℃~室温の範囲で、塩化水素ガスを1時間吹き込んだ。
その後、窒素ガスを吹き込み余分な塩化水素を除去した後、析出した結晶を濾過、エーテルで洗浄し、目的とする3,3,4,4-テトラフルオロ-1-ベンジル-ピロリジン塩酸塩16.9g(純分換算収率82%)を得た。
得られた3,3,4,4-テトラフルオロ-1-ベンジル-ピロリジン塩酸塩16.9g、及び10%Pd/C 1.8gのエタノール溶液を常圧下で水素ガスと接触するように室温で3時間、攪拌した。濾過後、溶媒を留去し、目的とする3,3,4,4-テトラフルオロ-ピロリジン塩酸塩11g(収率98%)を得た。
Claims (3)
- (A)式(I)
(B)式(II)で表されるテトラフルオロ誘導体を式(III)
(C)式(III)で表される化合物と式NH2R9(式中、R9は水素原子又はアミノ基の保護基を示す)で表されるアミン化合物とを反応させて、式(IV)
を有することを特徴とする、式(IV)で表されるテトラフルオロ含窒素複素環化合物又はその塩の製造方法。
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US13/121,267 US8481774B2 (en) | 2008-10-07 | 2009-10-02 | Method for producing tetrafluoro compound |
JP2010532796A JP5379149B2 (ja) | 2008-10-07 | 2009-10-02 | テトラフルオロ化合物の製造方法 |
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US4474700A (en) | 1981-07-02 | 1984-10-02 | E. I. Du Pont DeNemours and Company | β-Substituted polyfluoropropionate salts and derivatives |
WO2003101449A2 (en) | 2002-06-04 | 2003-12-11 | Pfizer Products Inc. | Process for the preparation of 3,3,4,4-tetrafluoropyrrolidine and derivatives thereof |
US20050043292A1 (en) * | 2003-08-20 | 2005-02-24 | Pfizer Inc | Fluorinated lysine derivatives as dipeptidyl peptidase IV inhibitors |
JP2008260485A (ja) | 2007-04-13 | 2008-10-30 | Toyota Motor Corp | 車両 |
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BE825446A (fr) * | 1974-02-25 | 1975-08-12 | Procede de coprecipitation de malachite et de bismuth, procede de preparation d'un complexe acetylure cuivreux a partir du coprecipite obtenu, et complexe ainsi produit | |
DE19753458A1 (de) * | 1997-12-02 | 1999-06-10 | Basf Ag | Verfahren zur Herstellung eines Katalysators und nach diesem Verfahren erhältliche Katalysatoren |
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US4474700A (en) | 1981-07-02 | 1984-10-02 | E. I. Du Pont DeNemours and Company | β-Substituted polyfluoropropionate salts and derivatives |
WO2003101449A2 (en) | 2002-06-04 | 2003-12-11 | Pfizer Products Inc. | Process for the preparation of 3,3,4,4-tetrafluoropyrrolidine and derivatives thereof |
US20050043292A1 (en) * | 2003-08-20 | 2005-02-24 | Pfizer Inc | Fluorinated lysine derivatives as dipeptidyl peptidase IV inhibitors |
JP2008260485A (ja) | 2007-04-13 | 2008-10-30 | Toyota Motor Corp | 車両 |
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EP2348010A1 (en) | 2011-07-27 |
CN102171175A (zh) | 2011-08-31 |
US20110178323A1 (en) | 2011-07-21 |
CN102171175B (zh) | 2014-05-14 |
US8481774B2 (en) | 2013-07-09 |
EP2348010A4 (en) | 2012-06-27 |
JPWO2010041402A1 (ja) | 2012-03-01 |
EP2348010B1 (en) | 2014-02-26 |
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