WO2012011516A1 - 光学活性1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンの製造方法 - Google Patents
光学活性1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンの製造方法 Download PDFInfo
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- WO2012011516A1 WO2012011516A1 PCT/JP2011/066512 JP2011066512W WO2012011516A1 WO 2012011516 A1 WO2012011516 A1 WO 2012011516A1 JP 2011066512 W JP2011066512 W JP 2011066512W WO 2012011516 A1 WO2012011516 A1 WO 2012011516A1
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- trifluoromethyl
- phenyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/013—Preparation of halogenated hydrocarbons by addition of halogens
- C07C17/04—Preparation of halogenated hydrocarbons by addition of halogens to unsaturated halogenated hydrocarbons
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C22/00—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom
- C07C22/02—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings
- C07C22/04—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings
- C07C22/08—Cyclic compounds containing halogen atoms bound to an acyclic carbon atom having unsaturation in the rings containing six-membered aromatic rings containing fluorine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Definitions
- the present invention relates to a method for producing optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane useful as a raw material for producing pharmaceuticals, agricultural chemicals, industrial products and the like.
- the optically active 1- [3,5-bis (trifluoromethyl) phenyl] ethyl group is important as a structural unit of a compound useful for pharmaceuticals and agricultural chemicals, and 1-bromo is used as a raw material for the production of a compound containing this group.
- -1- [3,5-bis (trifluoromethyl) phenyl] ethane is a very useful compound.
- 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane is used as a raw material to produce a compound that acts as an NK-1 receptor antagonist (non- Patent Documents 1 and 2).
- Racemic 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane can be synthesized by the method shown in Scheme 1 below (Patent Document 1). This method reduces 3,5-bis (trifluoromethyl) acetophenone with sodium borohydride in methanol to convert it to an alcohol compound, which is brominated with phosphorus tribromide in toluene. It includes a process.
- Racemic 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane can also be synthesized by the method of Scheme 2 below (Non-patent Document 3).
- 3 ′, 5′-bis (trifluoromethyl) acetophenone is reduced with sodium borohydride in methanol to give an alcohol compound, which is then brominated by treatment with hydrobromic acid and sulfuric acid. It includes a process.
- Patent Document 1 and Non-Patent Document 3 do not specifically show a method for producing optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane.
- Optically active 1- [3,5-bis (trifluoromethyl) phenyl] ethanol is an asymmetric reduction reaction of bis-3 ′, 5 ′-(trifluoromethyl) phenylacetophenone, or bis-3,5- ( One of the enantiomers can be obtained with high optical purity by the asymmetric methylation reaction of (trifluoromethyl) benzaldehyde. Therefore, if a high optical purity alcohol as a starting material can be converted into 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane while maintaining high optical purity, the production method can be This is a simple and efficient production method. However, a method for efficiently producing 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane using an optically active alcohol as a starting material while maintaining high optical purity has not been known.
- Non-patent Document 5 As a general method for brominating a hydroxyl group, a method is known in which alkyl alcohol or benzyl alcohol is converted to a leaving group such as a sulfonate ester and brominated by a bromide ion substitution reaction (non-patent). Reference 4). Further, when phosphorus tribromide is allowed to act on optically active 1-phenylethanol in diethyl ether in the presence of an excess amount of pyridine at a low temperature, 1-phenylbromo is obtained in a high yield (conversion rate 93.9%). It has been reported that ethane can be obtained (Non-patent Document 5).
- Non-patent Document 6 a method of exchanging a hydroxyl group with a halogen using 1,2-dibromo-1,1,2,2-tetrachloroethane and triphenylphosphine
- Non-patent Document 7 A method for exchanging a hydroxyl group with a halogen has also been reported (Non-patent Document 7).
- these methods are applied to optically active 1- [3,5-bis (trifluoromethyl) phenyl] ethanol to maintain 1-bromo-1- [3,5-bis (trimethyl) while maintaining high optical purity. It has not been previously known that fluoromethyl) phenyl] ethane can be produced.
- a method for preparing an optically active compound a method in which a racemate is resolved by chiral column chromatography is generally performed.
- the method of supplying the optically active substance by optically resolving the racemate may cause decomposition of the target product. It may be accompanied by racemization, and it is expected that the optically active substance cannot be supplied stably.
- Non-Patent Document 2 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane is used as a raw material as a racemate, and a mixture of the obtained diastereomers is used. A method is adopted in which the optically separated target is separated by two-stage optical resolution.
- the object of the present invention is to use optically active 1- [3,5-bis (trifluoromethyl) phenyl] ethanol as a raw material while maintaining high optical purity and optically active 1-bromo-1- [3,5-bis.
- the object is to provide a method for producing (trifluoromethyl) phenyl] ethane efficiently and in high yield.
- Non-Patent Document 4 optically active (R) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol.
- R optically active
- a bromine substitution exchange reaction takes place between the desired benzyl bromide once generated and the bromide ion present in the reaction system, and the resulting 1-bromo-1- [3,5-bis (tri Fluoromethyl) phenyl] ethane was almost completely racemized (see Comparative Example 1).
- a) a method using a combination of phosphorus halide and bromide as a brominating agent, and b) 1,2-dibromo-1,1,2 in the presence of a solvent 2-tetrachloroethane and a method using a combination of organophosphorus compounds such as triphenylphosphine, or c) a method using a combination of N-bromosuccinimide and dialkyl sulfide in the presence of a solvent.
- optically active 1- [3,5-bis (trifluoromethyl) phenyl] ethanol
- a process for producing optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane wherein a) a combination of phosphorus halide and hydrogen bromide as a brominating agent B) 1,2-dibromo-1,1,2,2-tetrachloroethane and general formula (I): P (R 1 ) (R 2 ) (R 3 ) (wherein R 1 , R 2 , and R 3 each independently represents a C 6-10 aryl group, a C 6-10 aryloxy group, a C 1-10 alkyl group, a C 1-10 alkoxyl group, a C 3-6 cycloalkyl group, or a C 3-6 cycloalkoxyl.
- the optically active 1- [3,5-bis (trifluoromethyl) phenyl] ethanol is (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol.
- optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane is (R) -1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane
- optically active 1- [3,5-bis (trifluoromethyl) phenyl] ethanol is (R) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol
- optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane is (S) -1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane Serial method is provided.
- the above method wherein the phosphorus halide is phosphorus tribromide; the above method using hydrobromic acid as hydrogen bromide; bromide as hydrogen bromide
- the above method using an acetic acid solution of hydrogen; the above using phosphorus tribromide in the range of 0.4 to 0.6 equivalents relative to optically active 1- [3,5-bis (trifluoromethyl) phenyl] ethanol.
- the above method in which the reaction is carried out in the presence of a solvent; the above method in which the organic phosphorus compound represented by the general formula (I) is triphenylphosphine; 1,2-Dibromo-1,1,2,2-tetrachloroethane is used in the range of 1.0 to 1.2 equivalents based on optically active 1- [3,5-bis (trifluoromethyl) phenyl] ethanol.
- the above method in which the reaction is carried out in the presence of a solvent; the above method in which the dialkyl sulfide is dimethyl sulfide; and N-bromosuccinimide is optically active 1- [ 3,5-bis (trifluoromethyl) phenyl]
- the above method used in an amount of 1.4 to 1.6 equivalents based on ethanol; dimethyl sulfide is optically active 1- [3,5-bis (trifluoromethyl) Phenyl]
- the above method used in the range of 1.7 to 1.9 equivalents with respect to ethanol; the above method wherein the solvent is a halogenated hydrocarbon; the above method wherein the solvent is dichloromethane; the reaction temperature is from 0 to 30
- a method as described above is provided which is in ° C.
- the present invention provides optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane.
- the present invention also provides optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane that can be obtained by the above production method.
- the optical purity of the optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane is 97.0% ee to 99.5% ee.
- optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane which is useful as a raw material for producing pharmaceuticals, agricultural chemicals, and industrial products, is optically active 1- [ It can be produced from 3,5-bis (trifluoromethyl) phenyl] ethanol in a single step with a high yield while maintaining the optical purity of the raw material without complicated operations.
- the method of the present invention is a method for producing optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane, wherein a) a combination of phosphorus halide and hydrogen bromide as a brominating agent B) 1,2-dibromo-1,1,2,2-tetrachloroethane and general formula (I): P (R 1 ) (R 2 ) (R 3 ) (wherein R 1 , R 2 , and R 3 each independently represents a C 6-10 aryl group, a C 6-10 aryloxy group, a C 1-10 alkyl group, a C 1-10 alkoxyl group, a C 3-6 cycloalkyl group, or a C 3-6 cycloalkoxyl.
- the optically active 1- [3,5-bis (trifluoromethyl) phenyl] ethanol used as a raw material in the method of the present invention is an asymmetric reduction reaction of bis-3,5- (trifluoromethyl) phenylmethylketone, or bis It can be produced by a known method such as asymmetric methylation reaction of -3,5- (trifluoromethyl) benzaldehyde, and any one of the enantiomers can be obtained with high optical purity.
- phosphorus bromide such as phosphorus tribromide, phosphorus pentabromide, and phosphorus oxybromide can be used.
- phosphorus bromide phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, etc. It may be used. Two or more types of phosphorus halides may be used in combination. Of these, phosphorus bromide is preferred, and phosphorus tribromide is particularly preferred.
- hydrogen bromide in addition to hydrobromic acid, an acetic acid solution of hydrogen bromide such as a 30% acetic acid solution can be used.
- the combination of phosphorus halide and hydrogen bromide is preferably a combination of phosphorus tribromide and acetic acid solution of hydrogen bromide.
- Phosphorus halides such as phosphorus tribromide can be used in the range of 0.5 to 2.0 equivalents relative to the raw material alcohol, but preferably 0.4 to 0.6 equivalents.
- Hydrogen bromide can be used, for example, in the range of 0.7 to 3.0 equivalents relative to the starting alcohol, but preferably 0.8 to 1.2 equivalents.
- the above reaction can be carried out in the presence or absence of a solvent.
- the type of solvent used is not particularly limited as long as it does not participate in the reaction.
- the solvent include aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, chlorobenzene, 1,2-dichlorobenzene, nitrobenzene; n-pentane, n-hexane, cyclohexane, n-heptane, n-octane, Aliphatic hydrocarbons such as n-decane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform and carbon tetrachloride.
- benzene, toluene, xylene, dichloromethane, 1,2-dichloroethane, n-pentane, n-hexane, and n-heptane can be used, and n-heptane can be more preferably used.
- These solvents can be used alone or in combination, and the amount of the solvent used is not particularly limited.
- the reaction temperature is not particularly limited, but it may be usually in the range of ⁇ 50 to 150 ° C., more preferably ⁇ 20 to 80 ° C., and particularly preferably 0 to 15 ° C.
- the reaction time is usually preferably 5 minutes to 48 hours, more preferably 30 minutes to 36 hours, and particularly preferably 12 to 24 hours.
- a crude product can be obtained by performing a normal post-treatment operation.
- the obtained crude product is subjected to purification operations such as activated carbon treatment, distillation, column chromatography, etc., if necessary, to give optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl.
- Ethane can be obtained with high chemical and optical purity.
- the optical purity of optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane is, for example, 95% ee or more, preferably 96% ee or more, but is not particularly limited. Absent.
- phosphorus halides such as phosphorus tribromide and hydrogen bromide such as hydrobromic acid used in the method using the combination of (a) above are used in general bromination reactions, and kainic acid and citric acid.
- examples of the C 6-10 aryl group include a phenyl group, a naphthyl group, and an azulenyl group.
- examples of the C 6-10 aryloxy group include a phenoxy group, a naphthyloxy group, and an azulenyloxy group.
- Examples of the C 1-10 alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl group, isobutyl group, t-butyl group, pentyl group, hexyl group, octyl group. Group, nonyl group, decyl group and the like.
- Examples of the C 1-10 alkoxyl group include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an s-butoxy group, an isobutoxy group, a t-butoxy group, a pentoxy group, and a hexyloxy group. Octyloxy group, nonyloxy group, decyloxy group and the like.
- Examples of the C 3-6 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like.
- Examples of the C 3-6 cycloalkoxyl group include a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, and the like.
- R 1 , R 2 , and R 3 are preferably C 6-10 aryl groups, and R 1 , R 2 , and R 3 are phenyl groups. In some cases, i.e., triphenylphosphine is more preferred.
- 1,2-Dibromo-1,1,2,2-tetrachloroethane can be used, for example, in the range of 1.0 to 3.0 equivalents relative to the starting alcohol, but preferably 1.0 to 1.2. Equivalent amounts should be used.
- the organophosphorus compound represented by the general formula (I), such as triphenylphosphine, can be used in the range of, for example, 1.0 to 3.0 equivalents relative to the raw material alcohol, but preferably 1.0 to 1. Two equivalents should be used.
- the above reaction can be preferably performed in the presence of a solvent.
- the type of solvent used is not particularly limited as long as it does not participate in the reaction.
- the solvent include aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, chlorobenzene, 1,2-dichlorobenzene, and nitrobenzene; n-pentane, n-hexane, cyclohexane, n-heptane, and n-octane.
- aliphatic hydrocarbons such as n-decane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride.
- benzene, toluene, xylene, dichloromethane, or 1,2-dichloroethane is preferable, and toluene, dichloromethane, or 1,2-dichloroethane is more preferable.
- These solvents can be used alone or in combination, and the amount of the solvent used is not particularly limited.
- the reaction temperature is not particularly limited, but it may be usually in the range of ⁇ 50 to 150 ° C., more preferably ⁇ 20 to 80 ° C., and particularly preferably 0 to 30 ° C.
- the reaction time is preferably preferably 5 minutes to 48 hours, more preferably 30 minutes to 36 hours, and particularly preferably 1 to 12 hours.
- a crude product can be obtained by performing a normal post-treatment operation.
- the obtained crude product is subjected to purification operations such as activated carbon treatment, distillation, column chromatography, etc., if necessary, to give optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl.
- Ethane can be obtained with high chemical and optical purity.
- the optical purity of optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane is, for example, 95% ee or more, preferably 96% ee or more, but is not particularly limited. Absent.
- the two alkyl groups in the dialkyl sulfide may be the same or different, but are preferably the same.
- the alkyl group the above C 1-10 alkyl group, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, s-butyl group, isobutyl group, t-butyl group, pentyl group, A hexyl group, an octyl group, a nonyl group, a decyl group, etc. are mentioned.
- a methyl group can be used as the two alkyl groups.
- N-bromosuccinimide can be used, for example, in the range of 1.0 to 3.0 equivalents relative to the raw material alcohol, preferably 1.0 to 1.8 equivalents, more preferably 1.4 to 1. 6 equivalents should be used.
- a dialkyl sulfide such as dimethyl sulfide can be used in the range of 1.0 to 3.0 equivalents relative to the raw material alcohol, preferably 1.5 to 2.0 equivalents, more preferably 1.7 to 1 equivalents. .9 equivalents should be used.
- the above reaction can be preferably performed in the presence of a solvent.
- the type of solvent used is not particularly limited as long as it does not participate in the reaction.
- the solvent include aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, chlorobenzene, 1,2-dichlorobenzene, and nitrobenzene; n-pentane, n-hexane, cyclohexane, n-heptane, and n-octane.
- aliphatic hydrocarbons such as n-decane; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and carbon tetrachloride.
- benzene, toluene, xylene, dichloromethane, or 1,2-dichloroethane is preferable, and toluene, dichloromethane, or 1,2-dichloroethane is more preferable.
- These solvents can be used alone or in combination, and the amount of the solvent used is not particularly limited.
- the reaction temperature is not particularly limited, but it may be usually in the range of ⁇ 50 to 150 ° C., more preferably ⁇ 20 to 80 ° C., and particularly preferably 0 to 30 ° C.
- the reaction time is preferably preferably 5 minutes to 48 hours, more preferably 30 minutes to 36 hours, and particularly preferably 1 to 12 hours.
- a crude product can be obtained by performing a normal post-treatment operation.
- the obtained crude product is subjected to purification operations such as activated carbon treatment, distillation, column chromatography, etc., if necessary, to give optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl.
- Ethane can be obtained with high chemical and optical purity.
- the optical purity of optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane is, for example, 95% ee or more, preferably 96% ee or more, but is not particularly limited. Absent.
- Example 1 The absolute configuration of 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane shown in Example 1 below is a commercially available known absolute configuration as shown in Examples 1-4 and 1-5. To ⁇ - [3,5-bis (trifluoromethyl) phenyl] ethylamine, which was determined by comparing the sign of specific rotation.
- (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol has (S) -1- [3,5-bis (trifluoromethyl) phenyl having an optical purity of 99.5% and 98%.
- optical purity % ee
- conversion rate (%) % ee of product /% ee of raw material alcohol.
- Example 1-1 (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol (1.0 g, 3.87 mmol,> 99.5% ee) in an argon atmosphere on a water bath at 20 ° C. or lower with three odors Phosphorus bromide (0.52 g, 1.94 mmol) was added dropwise, and the mixture was stirred at 19-22 ° C. for 30 minutes. The reaction mixture was cooled, hydrogen bromide (30% acetic acid solution) (0.76 mL, 3.87 mmol) was added dropwise at 0 ° C. or lower, and the mixture was stirred at 13-15 ° C. for 18 hours.
- Phosphorus bromide 0.52 g, 1.94 mmol
- Example 1-2 Three odors of (R) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol (1.0 g, 3.87 mmol,> 99.5% ee) in water bath at 20 ° C. or lower under argon atmosphere Phosphorus bromide (0.52 g, 1.94 mmol) was added dropwise, and the mixture was stirred at 19-22 ° C. for 30 minutes. The reaction mixture was cooled, hydrogen bromide (30% acetic acid solution) (0.76 mL, 3.87 mmol) was added dropwise at 0 ° C. or lower, and the mixture was stirred at 13-15 ° C. for 18 hours.
- Phosphorus bromide 0.52 g, 1.94 mmol
- Example 1-3 In a heptane suspension (2 mL) of (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol (1.0 g, 3.87 mmol,> 99.5% ee) under an argon atmosphere, 0 to Phosphorus tribromide (0.52 g, 1.94 mmol) was added dropwise at 5 ° C., and the mixture was stirred at 0 to 5 ° C. for 30 minutes. Hydrogen bromide (30% acetic acid solution) (0.76 mL, 3.87 mmol) was added dropwise to the reaction solution at 0 to 5 ° C., and the mixture was stirred at 10 ° C. for 17 hours.
- Example 1-4 A dimethylformamide solution of 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane (first peak: 96.8% ee, 102 mg, 0.32 mmol) obtained in Example 1-1 ( 1 mL) was added sodium azide (62.0 mg, 0.95 mmol), and the mixture was stirred at ⁇ 18 to ⁇ 15 ° C. for 3 hours.
- Example 1-5 The ⁇ - [3,5-bis (trifluoromethyl) phenyl] ethylamine obtained in Example 1-5 is in the S form by comparing the sign of specific rotation with that of a commercially available standard amine. There was found. That is, since the amine is obtained from 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane via a nucleophilic substitution reaction of an azide ion, it is obtained in Example 1-1. It was confirmed that 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane was R form (chiral HPLC analysis: first peak).
- a bromination reaction using phosphorus tribromide was performed under the conditions shown in Table 1 in the same manner as in Examples 1-1 and 1-2.
- the isolation yield, optical purity (% ee), and conversion (% ee of product /% ee of raw material) are shown in Table 1.
- (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol has (S) -1- [3,5-bis (trifluoromethyl) phenyl having an optical purity of 99.5% and 98%.
- optical purity % ee
- conversion rate (%) % ee of product /% ee of raw material alcohol.
- Example 2-1 Under an argon atmosphere, 1,2-dibromo-1,1,2,2-tetrachloroethane (7.57 g, 23.2 mmol) was dissolved in toluene (12.5 mL), and triphenylphosphine (6. 1 g, 23.2 mmol) was added and stirred for 30 minutes. A toluene solution (12.5 mL) of (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol (5.0 g, 19.4 mmol,> 99.5% ee) was added at 0 ° C. for 10 minutes. After dripping over the above, the temperature was raised to room temperature and stirred at the same temperature for 1 hour.
- Example 2-2 Under an argon atmosphere, 1,2-dibromo-1,1,2,2-tetrachloroethane (7.57 g, 23.2 mmol) was dissolved in toluene (12.5 mL), and triphenylphosphine (6. 1 g, 23.2 mmol) was added and stirred for 30 minutes. A toluene solution (12.5 mL) of (R) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol (5.0 g, 19.4 mmol,> 99.5% ee) was added at 0 ° C. for 10 minutes. After dripping over the above, the temperature was raised to room temperature and stirred at the same temperature for 1 hour.
- Example 2-3 Under an argon atmosphere, dimethyl sulfide (105 ⁇ L, 1.40 mmol) was added dropwise over 3 minutes to a suspension of N-bromosuccinimide (206 mg, 1.16 mmol) in anhydrous dichloromethane (3.8 mL) under ice cooling. . At ⁇ 20 ° C., a solution of (S) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol (200 mg, 0.78 mmol,> 99.5% ee) in anhydrous dichloromethane (2 mL) was added dropwise. And stirred at room temperature for 9 hours.
- Example 2-4 Under an argon atmosphere, dimethyl sulfide (53 ⁇ L, 0.70 mmol) was added dropwise over 3 minutes to a suspension of N-bromosuccinimide (103 mg, 0.58 mmol) in anhydrous dichloromethane (2.0 mL) under ice cooling. . At ⁇ 20 ° C., a solution of (R) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol (100 mg, 0.39 mmol,> 99.5% ee) in anhydrous dichloromethane (1 mL) was added dropwise. And stirred at room temperature for 6 hours.
- Example 2-5 Dimethylformamide solution of 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane (first peak:> 99.5% ee, 106 mg, 0.33 mmol) obtained in Example 2-1 To (1 mL) was added sodium azide (64.4 mg, 0.99 mmol), and the mixture was stirred at ⁇ 18 to ⁇ 15 ° C. for 4 hours.
- Example 2-6 The ⁇ - [3,5-bis (trifluoromethyl) phenyl] ethylamine obtained in Example 2-6 is in the S form by comparing the sign of specific rotation with a commercially available standard amine. There was found. That is, since the amine is obtained from 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane via a nucleophilic substitution reaction of an azide ion, it is obtained in Example 2-1. It was confirmed that 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane was R form (chiral HPLC analysis: first peak).
- DCM dichloromethane
- 1,2-DCE 1,2- dichloroethane
- NBS N-bromosuccinimide
- THF tetrahydrofuran
- DMF N, N- dimethylformamide
- TMSCl trimethylsilyl chloride
- PyHBr 3 pyridinium tribromide
- HMDS 1,1,1,2,2,2-hexamethyldisilane
- DEAD diethyl azodicarboxylate
- Example 3 (comparative example) With reference to Japanese Patent No. 39386651, dichloromethane of (R) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol (optical purity> 99.5% ee, 1.6 g, 6.20 mmol) (20 mL) The solution was added with methanesulfonyl chloride (0.58 mL, 7.44 mmol), triethylamine (1.30 mL, 9.3 mmol), and dimethylaminopyridine (76 mg, 0.62 mmol) under ice-cooling and stirring. And stirred for 30 minutes. 1N hydrochloric acid and chloroform were added to the reaction solution at the same temperature, and the organic layer was separated.
- Example 4 (comparative example) (R) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol (optical purity> 99.5% ee, 100 mg, 0.39 mmol) in dehydrated diethyl ether (1.0 mL) solution under argon atmosphere Dehydrated pyridine (69.4 mg, 0.89 mmol) was added. A solution of phosphorus tribromide (117.2 mg, 0.43 mmol) in dehydrated diethyl ether (0.5 mL) was slowly added dropwise at ⁇ 15 to ⁇ 20 ° C., stirred at the same temperature for 2 hours, and then at ⁇ 5 ° C.
- the method of the present invention is an industrially applicable condition for optically active 1-bromo-1- [3,5-bis (trifluoromethyl) phenyl] ethane, which is useful as a raw material for producing pharmaceuticals, agricultural chemicals, and industrial products. And can be produced efficiently and in high yield.
Abstract
Description
ハロゲン化リンとしては三臭化リン、五臭化リン、オキシ臭化リンなどの臭化リンを用いることができるが、臭化リンのほか、三塩化リン、五塩化リン、オキシ塩化リンなどを用いてもよい。2種以上のハロゲン化リンを組み合わせて用いてもよい。これらのうち臭化リンが好ましく、三臭化リンが特に好ましい。臭化水素としては、臭化水素酸のほか、臭化水素の酢酸溶液、例えば30%酢酸溶液などを用いることができる。ハロゲン化リン及び臭化水素の組み合わせとしては三臭化リンと臭化水素の酢酸溶液との組み合わせが好ましい。
一般式(I)で表される有機リン化合物において、C6-10アリール基としては、例えば、フェニル基、ナフチル基、アズレニル基等が挙げられる。C6-10アリールオキシ基としては、例えば、フェノキシ基、ナフチルオキシ基、アズレニルオキシ基等が挙げられる。C1-10アルキル基としては、例えば、メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、s-ブチル基、イソブチル基、t-ブチル基、ペンチル基、ヘキシル基、オクチル基、ノニル基、デシル基等が挙げられる。C1-10アルコキシル基としては、例えば、メトキシ基、エトキシ基、n-プロポキシ基、イソプロポキシ基、n-ブトキシ基、s-ブトキシ基、イソブトキシ基、t-ブトキシ基、ペントキシ基、ヘキシルオキシ基、オクチルオキシ基、ノニルオキシ基、デシルオキシ基等が挙げられる。C3-6シクロアルキル基としては、例えば、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等が挙げられる。C3-6シクロアルコキシル基としては、例えば、シクロプロポキシ基、シクロブトキシ基、シクロペンチルオキシ基、シクロヘキシルオキシ基等が挙げられる。
ジアルキルスルフィドにおける2個のアルキル基は同一でも異なっていてもよいが、同一であることが好ましい。アルキル基としては上記のC1-10アルキル基、例えば、メチル基、エチル基、n-プロピル基、イソプロピル基、n-ブチル基、s-ブチル基、イソブチル基、t-ブチル基、ペンチル基、ヘキシル基、オクチル基、ノニル基、デシル基等が挙げられる。好ましくは2個のアルキル基としてメチル基を用いることができる。
アルゴン雰囲気下、(S)-1-[3,5-ビス(トリフルオロメチル)フェニル]エタノール(1.0g, 3.87mmol、>99.5%ee)に水浴上、20℃以下で三臭化リン(0.52g,1.94mmol)を滴下し、19~22℃で30分撹拌した。反応液を冷却し、0℃以下で臭化水素(30%酢酸溶液)(0.76mL,3.87mmol)を滴下し、13~15℃で18時間撹拌した。反応液を氷水に注加し、n-ヘキサン(15mL×2)で抽出した。有機層を合わせ、飽和重曹水(15mL×1)で洗浄、次いで飽和食塩水(15mL×1)で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗体をカラムクロマトグラフィー(シリカゲル8g、展開溶媒:n-ヘキサン)で精製することにより1.06gの(R)-1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンを無色油状物として得た。
収率:85%
キラルHPLC分析:光学純度96.8%ee(第一ピーク)、転化率97.3%
[α]D 25 +56.6(c=1.18,CHCl3)
1H-NMR (CDCl3):δ 2.08 (3H, d, J = 7.1 Hz), 5.21 (1H, q, J = 7.1 Hz), 7.81 (1H, s), 7.87 (2H, s).
アルゴン雰囲気下、(R)-1-[3,5-ビス(トリフルオロメチル)フェニル]エタノール(1.0g, 3.87mmol、>99.5%ee)に水浴上、20℃以下で三臭化リン(0.52g,1.94mmol)を滴下し、19~22℃で30分撹拌した。反応液を冷却し、0℃以下で臭化水素(30%酢酸溶液)(0.76mL,3.87mmol)を滴下し、13~15℃で18時間撹拌した。反応液を氷水に注加し、n-ヘキサン(15mL×2)で抽出した。有機層を合わせ、飽和重曹水(15mL×1)で洗浄、次いで飽和食塩水(15mL×1)で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗体をカラムクロマトグラフィー(シリカゲル8g、展開溶媒:n-ヘキサン)で精製することにより1.13gの(S)-1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンを無色油状物として得た。
収率:91%
キラルHPLC分析:光学純度96.3%ee(第二ピーク)、転化率>96.8%
[α]D 25 -55.6(c=1.23,CHCl3)
1H-NMRスペクトルは例1-1に示したものと同じであった。
アルゴン雰囲気下(S)-1-[3,5-ビス(トリフルオロメチル)フェニル]エタノール(1.0g, 3.87mmol、>99.5%ee)のヘプタン懸濁液(2mL)に0~5℃で三臭化リン(0.52g,1.94mmol)を滴下し、0~5℃で30分撹拌した。反応液に0~5℃で臭化水素(30%酢酸溶液)(0.76mL,3.87mmol)を滴下し、10℃で17時間撹拌した。反応液を氷水に注加し、n-ヘキサン(15mL×2)で抽出した。有機層を合わせ、飽和重曹水洗浄(15mL×1)、飽和食塩水洗浄(15mL×1)し、無水硫酸ナトリウムで乾燥後、減圧濃縮し得られた粗体をカラムクロマトグラフィー(シリカゲル8g、展開溶媒:n-ヘキサン)で精製することにより1.12gの(R)-1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンを無色油状物として得た。
収率:90%
キラルHPLC分析:光学純度97.7%ee(第二ピーク)、転化率>98.2%
1H-NMRスペクトルは例1-1に示したものと同じであった。
例1-1で得られた1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタン(第一ピーク:96.8%ee,102mg, 0.32mmol)のジメチルホルムアミド溶液(1mL)にアジ化ナトリウム(62.0mg,0.95mmol)を加え-18~-15℃にて3時間撹拌した。反応溶液を酢酸エチル/ヘキサン(1:1)で希釈し、有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮することで118.8mgの1-アジド-[3,5-ビス(トリフルオロメチル)フェニル]エタンの粗生成物を得た。
1H-NMR (CDCl3):δ 1.61 (3H, d, J = 6.8 Hz), 4.79 (1H, q, J = 6.8 Hz), 7.78 (2H, s), 7.84 (1H, s).
例1-4で得られた1-アジド-[3,5-ビス(トリフルオロメチル)フェニル]エタンの粗生成物にパラジウム-フィブロイン(18mg)とメタノール(6mL)を加え水素で置換し、室温で撹拌した。1時間撹拌後、セライトろ過、濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=50:1~5:1)にて精製し、58.9mgのα-[3,5-ビス(トリフルオロメチル)フェニル]エチルアミンを無色油状物として得た。
収率:74%(2工程)
[α]D 25 -15.4(c=1.01,CHCl3)
1H-NMR (CDCl3):δ 1.42 (3H, d, J = 6.8 Hz), 1.58 (2H, br-s), 4.30 (1H, q, J = 6.8 Hz), 7.75 (1H, s), 7.85 (2H, s).
標品:(S)-α-[3,5-ビス(トリフルオロメチル)フェニル]エチルアミン
セントラル硝子社製
Lot.0102000
光学純度:99%ee
[α]D 25 -15.9(c=1.15,CHCl3)
アルゴン雰囲気下、1,2-ジブロモ-1,1,2,2-テトラクロロエタン(7.57g,23.2mmol)をトルエン(12.5mL)に溶解し、0℃にてトリフェニルホスフィン(6.1g,23.2mmol)を加え30分間撹拌した。(S)-1-[3,5-ビス(トリフルオロメチル)フェニル]エタノール(5.0g,19.4mmol, >99.5%ee)のトルエン溶液(12.5mL)を0℃で10分以上かけて滴下した後、室温まで昇温し、同温にて1時間撹拌した。反応液にn-ヘキサン(25mL)を加え、セライトろ過した。ろ液を水、飽和重曹水、飽和食塩水で順次洗浄し、硫酸ナトリウムで乾燥後、減圧留去した。得られた残渣を減圧蒸留(56oC,0.7mmHg)することで、5.52gの(R)-1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンを無色油状物として得た。
収率:89%
キラルHPLC分析:光学純度>99.5%ee(第一ピーク),転化率>99.5%
[α]D 25 +59.1(c=1.03,CHCl3)
1H-NMR (CDCl3):δ 2.08 (3H, d, J = 7.1 Hz), 5.21 (1H, q, J = 7.1 Hz), 7.81 (1H, s), 7.87 (2H, s).
アルゴン雰囲気下、1,2-ジブロモ-1,1,2,2-テトラクロロエタン(7.57g,23.2mmol)をトルエン(12.5mL)に溶解し、0℃にてトリフェニルホスフィン(6.1g,23.2mmol)を加え30分間撹拌した。(R)-1-[3,5-ビス(トリフルオロメチル)フェニル]エタノール(5.0g,19.4mmol,>99.5%ee)のトルエン溶液(12.5mL)を0℃で10分以上かけて滴下した後、室温まで昇温し、同温にて1時間撹拌した。反応液にn-ヘキサン(25mL)を加え、セライトろ過した。ろ液を水、飽和重曹水、飽和食塩水で順次洗浄し、硫酸ナトリウムで乾燥後、減圧留去した。得られた残渣を減圧蒸留(56oC,0.7mmHg)することで、5.45gの(S)-1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンを無色油状物として得た。
収率:88%
キラルHPLC分析:光学純度99.0%ee(第二ピーク),転化率>99.5%
1H-NMRスペクトルは例2-1に示したものと同じであった。
アルゴン雰囲気下、N-ブロモコハク酸イミド(206mg,1.16mmol)の無水ジクロロメタン(3.8mL)懸濁液に、氷冷下にてジメチルスルフィド(105μL,1.40mmoL)を3分間かけて滴下した。-20℃にて、(S)-1-[3,5-ビス(トリフルオロメチル)フェニル]エタノール(200mg,0.78mmol、>99.5%ee)の無水ジクロロメタン(2mL)溶液を滴下し、室温にて9時間攪拌した。反応液にn-ヘキサンを加え、有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒:n-ヘキサン)で精製し、144 mgの(R)-1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンを無色油状物として得た。
収率:58%
キラルHPLC分析:光学純度>99.5%ee(第一ピーク),転化率>99.5%
1H-NMRスペクトルは例2-1に示したものと同じであった。
アルゴン雰囲気下、N-ブロモコハク酸イミド(103mg,0.58mmol)の無水ジクロロメタン(2.0mL)懸濁液に、氷冷下にてジメチルスルフィド(53μL,0.70mmoL)を3分間かけて滴下した。-20℃にて、(R)-1-[3,5-ビス(トリフルオロメチル)フェニル]エタノール(100mg,0.39mmol、>99.5%ee)の無水ジクロロメタン(1mL)溶液を滴下し、室温にて6時間攪拌した。反応液にn-ヘキサンを加え、有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮し得られた残渣をシリカゲルカラムクロマトグラフィー(展開溶媒:n-ヘキサン)で精製し、82mgの(S)-1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンを無色油状物として得た。
収率:66%
キラルHPLC分析:光学純度>99.5%ee(第二ピーク),転化率>99.5%
1H-NMRスペクトルは例2-1に示したものと同じであった。
例2-1で得られた1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタン(第一ピーク:>99.5%ee,106mg, 0.33mmol)のジメチルホルムアミド溶液(1mL)にアジ化ナトリウム(64.4mg,0.99mmol)を加え-18~-15℃にて4時間撹拌した。反応溶液を酢酸エチル/ヘキサン(1:1)で希釈し、有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮することで111.5mgの1-アジド-[3,5-ビス(トリフルオロメチル)フェニル]エタンの粗生成物を得た。
1H-NMR (CDCl3):δ 1.61 (3H, d, J = 6.8 Hz), 4.79 (1H, q, J = 6.8 Hz), 7.78 (2H, s), 7.84 (1H, s).
例2-5で得られた1-アジド-[3,5-ビス(トリフルオロメチル)フェニル]エタンの粗生成物にパラジウム-フィブロイン(18mg)とメタノール(6mL)を加え水素で置換し、室温で撹拌した。1時間撹拌後、セライトろ過、濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(クロロホルム:メタノール=50:1~5:1)にて精製し、77.6mgのα-[3,5-ビス(トリフルオロメチル)フェニル]エチルアミンを無色油状物として得た。
収率:91%(2工程)
[α]D 25 -15.9(c=1.31,CHCl3)
1H-NMR (CDCl3):δ 1.42 (3H, d, J = 6.8 Hz), 1.58 (2H, br-s), 4.30 (1H, q, J = 6.8 Hz), 7.75 (1H, s), 7.85 (2H, s).
標品:(S)-α-[3,5-ビス(トリフルオロメチル)フェニル]エチルアミン
セントラル硝子社製
Lot.0102000
光学純度:99%
[α]D 25 -15.9(c=1.15,CHCl3)
日本国特許第3938651号を参考に、(R)-1-[3,5-ビス(トリフルオロメチル)フェニル]エタノール(光学純度>99.5%ee, 1.6g, 6.20mmol)のジクロロメタン(20mL)溶液に氷冷攪拌下、塩化メタンスルホニル(0.58mL,7.44mmol)、トリエチルアミン(1.30mL,9.3mmol)、ジメチルアミノピリジン(76mg,0.62mmol)を加え、同温にて30分間攪拌した。反応液に同温にて1N塩酸とクロロホルムを加え有機層を分取した。水層をクロロホルム(20mL×3)で抽出し、有機層を合わせ飽和食塩水にて洗浄後、無水硫酸ナトリウムにて乾燥し、減圧濃縮し、無色油状物として(R)-メタンスルホン酸 1-[3,5-ビス(トリフルオロメチル)フェニル]エチルエステル(2.23g)を得た。次に得られた(R)-メタンスルホン酸 1-[3,5-ビス(トリフルオロメチル)フェニル]エチル エステル(2.23 g)のN,N-ジメチルホルムアミド(20mL)溶液に臭化ナトリウム(1.26g,12.25mmoL)を加え、50℃にて1時間攪拌した。反応液に室温にて水(30mL)を加え、ヘキサン(30mL×3)で抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムにて乾燥後、減圧濃縮して得られた残渣をシリカゲルカラムクロマトグラフィー(ヘキサン:酢酸エチル=10:1)にて精製し、1.85gの1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンを無色油状物として得た。比旋光度より、得られた1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンがラセミ化していることを確認した。
収率:93 %(2工程)
[α]D 25 -0.19(c=1.01,CHCl3)
1H-NMRスペクトルは例1-1に示したものと同じであった。
(R)-1-[3,5-ビス(トリフルオロメチル)フェニル]エタノール(光学純度>99.5%ee,100mg,0.39mmol)の脱水ジエチルエーテル(1.0mL)溶液にアルゴン雰囲気下、脱水ピリジン(69.4mg,0.89mmol)を加えた。-15~-20℃にて三臭化リン(117.2mg, 0.43mmol)の脱水ジエチルエーテル(0.5mL)溶液をゆっくり滴下し、同温にて2時間攪拌した後、-5℃で48時間静置させた後、氷冷下、反応液に冷却水 (3mL)を加え室温で15分攪拌した後、ジエチルエーテル (10mL)で抽出した。有機層を減圧濃縮し得られた残渣をシリカゲルカラムクロマトグラフィー(シリカゲル3.0g, 展開溶媒:n-ヘキサン)で精製し、17.6 mgの1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンを無色油状物として得た。
収率:14%
1H-NMRスペクトルは例1-1に示したものと同じであった。
Claims (14)
- 光学活性1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンの製造方法であって、臭素化剤として(a)ハロゲン化リン及び臭化水素の組み合わせ、(b)1,2-ジブロモ-1,1,2,2-テトラクロロエタン及び一般式(I):P(R1)(R2)(R3)(式中、R1、R2、及びR3はそれぞれ独立にC6-10アリール基、C6-10アリールオキシ基、C1-10アルキル基、C1-10アルコキシル基、C3-6シクロアルキル基、又はC3-6シクロアルコキシル基を示す)で表される有機リン化合物の組み合わせ、又は(c)N-ブロモコハク酸イミド及びジアルキルスルフィドの組み合わせのいずれかを用いて光学活性1-[3,5-ビス(トリフルオロメチル)フェニル]エタノールを臭素化する工程を含む方法。
- 光学活性1-[3,5-ビス(トリフルオロメチル)フェニル]エタノールが(S)-1-[3,5-ビス(トリフルオロメチル)フェニル]エタノールであり、かつ光学活性1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンが(R)-1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンである請求項1に記載の方法。
- 光学活性1-[3,5-ビス(トリフルオロメチル)フェニル]エタノールが(R)-1-[3,5-ビス(トリフルオロメチル)フェニル]エタノールであり、かつ光学活性1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンが(S)-1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタンである請求項1に記載の方法。
- ハロゲン化リンが三臭化リンである請求項1ないし3のいずれか1項に記載の方法。
- 臭化水素として臭化水素酸又は臭化水素の酢酸溶液を用いる請求項1ないし4のいずれか1項に記載の方法。
- 溶媒の非存在下又は存在下で行う請求項1ないし5のいずれか1項に記載の方法。
- 溶媒としてヘプタンを用いる請求項6に記載の方法。
- 上記(b)又は(c)の組み合わせを用いて溶媒の存在下に臭素化を行う請求項1ないし3のいずれか1項に記載の方法。
- 溶媒が芳香族炭化水素類又はハロゲン化炭化水素類である請求項8に記載の方法。
- 溶媒がトルエン、ジクロロメタン、又は1,2-ジクロロエタンである請求項9に記載の方法。
- 一般式(I)で表される有機リン化合物がトリフェニルホスフィンである請求項8ないし10のいずれか1項に記載の方法。
- ジアルキルスルフィドがジメチルスルフィドである請求項8ないし10のいずれか1項に記載の方法。
- 光学活性1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタン。
- 光学純度が97.0%ee~99.5%eeである請求項13に記載の光学活性1-ブロモ-1-[3,5-ビス(トリフルオロメチル)フェニル]エタン。
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EP11809686.6A EP2597079A4 (en) | 2010-07-22 | 2011-07-21 | PROCESS FOR PREPARING OPTICALLY ACTIVE 1-BROM-1- [3,5-BIS- (TRIFLUOROMETHYL-) PHENYL-] ETHANE |
US13/811,651 US9272966B2 (en) | 2010-07-22 | 2011-07-21 | Method for preparing optically active 1-bromo-1[3,5-bis(trifluoromethyl)phenyl]ethane |
IN1326CHN2013 IN2013CN01326A (ja) | 2010-07-22 | 2011-07-21 | |
CN2011800357009A CN102985395A (zh) | 2010-07-22 | 2011-07-21 | 光学活性1-溴-1-[3,5-双(三氟甲基)苯基]乙烷的制备方法 |
JP2012525419A JP5793143B2 (ja) | 2010-07-22 | 2011-07-21 | 光学活性1−ブロモ−1−[3,5−ビス(トリフルオロメチル)フェニル]エタンの製造方法 |
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US (1) | US9272966B2 (ja) |
EP (1) | EP2597079A4 (ja) |
JP (1) | JP5793143B2 (ja) |
CN (2) | CN105837401A (ja) |
HK (1) | HK1223908A1 (ja) |
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CN114105796B (zh) * | 2021-12-11 | 2023-11-28 | 上海化工研究院有限公司 | 一种稳定性同位素氘标记异亮氨酸的合成方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007044829A2 (en) | 2005-10-06 | 2007-04-19 | Dr. Reddy's Laboratories Ltd. | Preparation of aprepitant |
JP3938651B2 (ja) | 2000-04-13 | 2007-06-27 | セントラル硝子株式会社 | 光学活性α−メチル−ビス−3、5−(トリフルオロメチル)ベンジルアミンの製造方法 |
WO2008129951A1 (ja) | 2007-04-13 | 2008-10-30 | Kowa Company, Ltd. | 新規なジベンジルアミン構造を有するピリミジン化合物及びこれを含有する医薬 |
WO2009062371A1 (fr) * | 2007-10-15 | 2009-05-22 | Shanghai Hengrui Pharmaceutical Co., Ltd. | Dérivés de carbamate et utilisation en tant que médicament |
JP2010077116A (ja) * | 2008-08-25 | 2010-04-08 | Kowa Co | 新規なジベンジルアミン構造を有するピリミジン化合物及びこれを含有する医薬 |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6750344B1 (en) * | 1997-09-05 | 2004-06-15 | Isis Pharmaceuticals, Inc. | Amine compounds and combinatorial libraries comprising same |
US7790737B2 (en) * | 2007-03-13 | 2010-09-07 | Kowa Company, Ltd. | Substituted pyrimidine compounds and their utility as CETP inhibitors |
KR20100094554A (ko) * | 2007-12-06 | 2010-08-26 | 쉐링 코포레이션 | 감마 세크레타제 조절인자 |
TWI492749B (zh) * | 2010-06-04 | 2015-07-21 | Kowa Co | Optically active dibenzylamine derivatives and methods for their manufacture |
EP2626351A4 (en) * | 2010-10-04 | 2014-03-12 | Kowa Co | AGENT CAPABLE OF INHIBITING THE EXPRESSION OF LIPID METABOLISM-RELATED MRNA |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP3938651B2 (ja) | 2000-04-13 | 2007-06-27 | セントラル硝子株式会社 | 光学活性α−メチル−ビス−3、5−(トリフルオロメチル)ベンジルアミンの製造方法 |
WO2007044829A2 (en) | 2005-10-06 | 2007-04-19 | Dr. Reddy's Laboratories Ltd. | Preparation of aprepitant |
WO2008129951A1 (ja) | 2007-04-13 | 2008-10-30 | Kowa Company, Ltd. | 新規なジベンジルアミン構造を有するピリミジン化合物及びこれを含有する医薬 |
WO2009062371A1 (fr) * | 2007-10-15 | 2009-05-22 | Shanghai Hengrui Pharmaceutical Co., Ltd. | Dérivés de carbamate et utilisation en tant que médicament |
JP2010077116A (ja) * | 2008-08-25 | 2010-04-08 | Kowa Co | 新規なジベンジルアミン構造を有するピリミジン化合物及びこれを含有する医薬 |
Non-Patent Citations (9)
Title |
---|
"Guide Book of Japanese Pharmacopoeia", 1996, HIROKAWA PUBLISHING CO. |
INDIAN J. CHEM., SEC B, vol. 44B, 2005, pages 557 - 562 |
J. AM. CHEM. SOC., vol. 125, 2003, pages 2129 - 2135 |
J. ORG. CHEM., vol. 26, 1961, pages 3645 - 3649 |
J. ORG. CHEM., vol. 71, 2006, pages 7378 - 7390 |
See also references of EP2597079A4 |
SYNTHESIS COMMUN., 1983, pages 139 - 141 |
TETRAHEDRON LETT., vol. 42, 1972, pages 4339 - 4342 |
TETRAHEDRON LETT., vol. 48, 2007, pages 8001 - 8004 |
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CN102985395A (zh) | 2013-03-20 |
US9272966B2 (en) | 2016-03-01 |
JP5793143B2 (ja) | 2015-10-14 |
IN2013CN01326A (ja) | 2015-04-24 |
CN105837401A (zh) | 2016-08-10 |
EP2597079A1 (en) | 2013-05-29 |
JPWO2012011516A1 (ja) | 2013-09-09 |
EP2597079A4 (en) | 2015-11-11 |
US20130190540A1 (en) | 2013-07-25 |
HK1223908A1 (zh) | 2017-08-11 |
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