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WO2017098975A1 - Method for producing biphenyl compound - Google Patents

Method for producing biphenyl compound Download PDF

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Publication number
WO2017098975A1
WO2017098975A1 PCT/JP2016/085502 JP2016085502W WO2017098975A1 WO 2017098975 A1 WO2017098975 A1 WO 2017098975A1 JP 2016085502 W JP2016085502 W JP 2016085502W WO 2017098975 A1 WO2017098975 A1 WO 2017098975A1
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Prior art keywords
biphenyl
amino
tert
butoxycarbonyl
methyl
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PCT/JP2016/085502
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French (fr)
Japanese (ja)
Inventor
大輔 笹山
村岡　秀郎
秋山　雅紀
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住友化学株式会社
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Publication of WO2017098975A1 publication Critical patent/WO2017098975A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses

Definitions

  • the present invention relates to a method for producing a biphenyl compound.
  • Boc represents a tert-butoxycarbonyl group.
  • Methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate represented by the formula is useful as an intermediate for its production.
  • N-tert-butoxycarbonyl- ⁇ is used as a method for producing methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate.
  • N-tert-butoxycarbonyl- ⁇ is used as a method for producing methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate.
  • N-tert-butoxycarbonyl- ⁇ is used as a method for producing methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate.
  • N-tert-butoxycarbonyl- ⁇ is used as a method for producing methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert
  • the present invention provides a new method for producing methyl (2Z) -3- (1,1'-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate.
  • 4-phenylbenzaldehyde and glycine are used as starting materials, and a novel intermediate methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] Methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate was obtained by a method via -3-hydroxypropanoate. Can be manufactured.
  • the production method of the present invention comprises: [Step 1] By reacting 4-phenylbenzaldehyde and glycine in the presence of sodium hydroxide or potassium hydroxide, and mixing the resulting reaction mixture with hydrochloric acid, 2-amino-3- (1,1 Obtaining '-biphenyl-4-yl) -3-hydroxypropionate hydrochloride; [Step 2] 2-amino-3- (1,1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride and di-tert-butyl dicarbonate are reacted under basic conditions to give 3- Obtaining (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid; [Step 3] 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid is reacted with dimethyl sul
  • Step 1 In Step 1, 4-phenylbenzaldehyde and glycine are reacted in the presence of potassium hydroxide or sodium hydroxide, and the resulting reaction mixture is mixed with hydrochloric acid to give 2-amino-3- (1,1 '-Biphenyl-4-yl) -3-hydroxypropionate hydrochloride is obtained.
  • the amount of 4-phenylbenzaldehyde used is preferably 1.7 to 3.3 moles, more preferably 2.0 to 2.5 moles per mole of glycine in terms of yield and economy.
  • the amount of sodium hydroxide or potassium hydroxide to be used is preferably 1.0 to 2.0 mol, more preferably 1.0 to 1.5 mol with respect to 1 mol of glycine in terms of yield and economy. .
  • Solvents include water, alcohol solvents (eg, methanol, ethanol); aromatic hydrocarbon solvents (eg, toluene, benzene, xylene); halogenated hydrocarbon solvents (eg, chloroform, dichloromethane, carbon tetrachloride); ether solvents (eg, diethyl) Ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane); aprotic polar solvent (for example, dimethylformamide, dimethylacetamide); a mixed solvent thereof and the like.
  • solvents include water, alcohol solvents (eg, methanol, ethanol); aromatic hydrocarbon solvents (eg, toluene, benzene, xylene); halogenated hydrocarbon solvents (eg, chloroform, dichloromethane, carbon tetrachloride); ether solvents (eg, diethyl) Ether, tert-butyl
  • alcohol solvents, aromatic hydrocarbon solvents, and mixed solvents thereof are preferable, and mixed solvents of methanol and toluene are particularly preferable.
  • the amount of the solvent used is preferably 40 to 80 mL, more preferably 40 to 60 mL, with respect to 1 g of glycine.
  • the reaction is carried out by mixing glycine, sodium hydroxide or potassium hydroxide, 4-phenylbenzaldehyde and a solvent.
  • the reaction temperature is preferably in the range of 10 to 50 ° C., more preferably in the range of 10 to 30 ° C., although it depends on the type of solvent.
  • reaction mixture thus obtained and hydrochloric acid are mixed, if necessary, a solvent immiscible with water is mixed, and the aqueous layer is separated, whereby 2-amino-3- (1,1′-biphenyl) is separated.
  • -4-yl) -3-hydroxypropionate hydrochloride can be obtained as an aqueous solution.
  • Isolation of 2-amino-3- (1,1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride can be performed by subjecting the reaction mixture to a post-treatment such as crystallization.
  • the purification can be carried out by a purification process such as extraction, recrystallization, etc.
  • Step 2 In step 2, 2-amino-3- (1,1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride and di-tert-butyl dicarbonate are reacted under basic conditions to give 3 -(1,1'-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid is obtained.
  • An aqueous solution of 2-amino-3- (1,1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride is adjusted to a pH of 7 to 10, preferably 7, using a base such as sodium hydroxide in advance. It is preferable to adjust to 5 to 9.0, more preferably 7.5 to 8.5.
  • the amount of di-tert-butyl dicarbonate used is 1 mol of 2-amino-3- (1,1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride in terms of yield and economy. On the other hand, it is preferably 1 to 4 mol.
  • Solvents include aromatic hydrocarbon solvents (for example, toluene, benzene, xylene); halogenated hydrocarbon solvents (for example, chloroform, dichloromethane, carbon tetrachloride); ether solvents (for example, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 1 , 4-dioxane); aprotic polar solvents (for example, dimethylformamide, dimethylacetamide); water; mixed solvents thereof and the like.
  • aromatic hydrocarbon solvents for example, toluene, benzene, xylene
  • halogenated hydrocarbon solvents for example, chloroform, dichloromethane, carbon tetrachloride
  • ether solvents for example, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 1 , 4-dioxane
  • aprotic polar solvents for
  • a mixed solvent of an aromatic hydrocarbon solvent and water is preferable, and a mixed solvent of toluene and water is particularly preferable.
  • the amount of the solvent used is preferably 15 to 30 mL with respect to 1 g of 2-amino-3- (1,1'-biphenyl-4-yl) -3-hydroxypropionate hydrochloride.
  • the reaction is carried out by adjusting the pH of the reaction mixture to 7-10, preferably 7.5-9.0, more preferably 7.5-8.5 using a base, while 2-amino-3- (1, 1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride and a solvent are mixed, and di-tert-butyl dicarbonate is added thereto, preferably added dropwise and mixed.
  • Examples of the base used for pH adjustment include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; organic bases such as triethylamine, trimethylamine, and diisopropylethylamine. .
  • inorganic bases such as sodium hydroxide and potassium hydroxide are preferable, and sodium hydroxide is particularly preferable.
  • the reaction temperature is preferably in the range of 10 to 60 ° C., more preferably in the range of 20 to 50 ° C., although it depends on the type of solvent.
  • the progress of the reaction can be confirmed by analytical means such as thin layer chromatography and high performance liquid chromatography.
  • the 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid contained in the reaction mixture thus obtained is obtained by crystallizing the reaction mixture. It can be isolated by subjecting it to post-treatment such as conversion.
  • the purification is performed by extracting 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid, chromatography treatment such as silica gel column chromatography, although it can be carried out by purification treatment such as recrystallization, the reaction mixture of 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid is used as it is. You may use for the next process, and you may use the organic layer after extraction for the next process as it is.
  • Step 3 In step 3, 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid is reacted with dimethyl sulfate in the presence of a base to give methyl 3 -(1,1'-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate is obtained.
  • the amount of dimethyl sulfate used is 1 mol of 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid in terms of yield and economy.
  • the amount is preferably 1 to 10 moles.
  • the base examples include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; organic bases such as triethylamine, trimethylamine and diisopropylethylamine.
  • inorganic bases such as sodium hydrogen carbonate and potassium hydrogen carbonate are preferable, and sodium hydrogen carbonate is particularly preferable.
  • the amount of base used is 1 mol of 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid in terms of yield and economy. On the other hand, it is preferably 2 to 5 mol.
  • Solvents include aromatic hydrocarbon solvents (for example, toluene, benzene, xylene); halogenated hydrocarbon solvents (for example, chloroform, dichloromethane, carbon tetrachloride); ether solvents (for example, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 1 , 4-dioxane); aprotic polar solvents (for example, dimethylformamide, dimethylacetamide); water; mixed solvents thereof and the like.
  • aromatic hydrocarbon solvents for example, toluene, benzene, xylene
  • halogenated hydrocarbon solvents for example, chloroform, dichloromethane, carbon tetrachloride
  • ether solvents for example, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 1 , 4-dioxane
  • aprotic polar solvents for
  • a mixed solvent of an aromatic hydrocarbon solvent and water is preferable, and a mixed solvent of toluene and water is particularly preferable.
  • the amount of the solvent used is preferably 20 to 50 mL with respect to 1 g of 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid.
  • phase transfer catalyst examples include tetrabutylammonium bromide and benzyltrimethylammonium chloride. Of these, tetrabutylammonium bromide is preferable.
  • phase transfer catalyst used is 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid 1 in terms of yield and economy.
  • amount of phase transfer catalyst used is 0.01-0.2 mol with respect to mol.
  • the reaction is carried out using 3- (1,1′-biphenyl) while adjusting the pH of the reaction mixture to 6 to 10, preferably 6.0 to 9.0, more preferably 6.0 to 8.0 using a base.
  • -4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid, a base and a solvent are mixed, and dimethyl sulfate is added thereto, preferably added dropwise and mixed. .
  • the reaction temperature is preferably in the range of 20 to 60 ° C, more preferably in the range of 25 to 50 ° C, although it depends on the type of solvent.
  • the progress of the reaction can be confirmed by analytical means such as thin layer chromatography and high performance liquid chromatography.
  • dimethyl sulfate may be decomposed with a base such as triethylamine.
  • Methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate contained in the reaction mixture thus obtained is Can be isolated by post-treatment such as crystallization. Further, the purification is performed by extracting methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate, chromatography such as silica gel column chromatography, etc. It can be performed by purification treatment such as treatment, recrystallization and the like.
  • Methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate may be used in the next step as the reaction mixture or after extraction.
  • the organic layer may be used in the next step as it is.
  • Step 4 In step 4, methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate is reacted with methanesulfonyl chloride in the presence of a base.
  • the corresponding mesyl body is reacted with methanesulfonyl chloride in the presence of a base.
  • the amount of methanesulfonyl chloride used is methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropano in terms of yield and economy.
  • the amount is preferably 1.0 to 5.0 moles, more preferably 1.0 to 1.5 moles per mole of ate.
  • the base examples include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; triethylamine, trimethylamine, pyridine, 2,6-lutidine, diisopropylethylamine, N-methylmorpholine, DBU (1,8 -Organic bases such as diazabicyclo [5.4.0] undec-7-ene), DBN (1,5-diazabicyclo [4.3.0] non-5-ene) and imidazole.
  • organic bases such as triethylamine and pyridine are preferable, and triethylamine is particularly preferable.
  • the amount of base used is methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate 1 in terms of yield and economy.
  • it is 1.0-5.0 mol with respect to mol.
  • Solvents include aromatic hydrocarbon solvents (for example, toluene, benzene, xylene); halogenated hydrocarbon solvents (for example, chloroform, dichloromethane, carbon tetrachloride); ether solvents (for example, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 1 , 4-dioxane); mixed solvents thereof and the like.
  • aromatic hydrocarbon solvents for example, toluene, benzene, xylene
  • halogenated hydrocarbon solvents for example, chloroform, dichloromethane, carbon tetrachloride
  • ether solvents for example, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 1 , 4-dioxane
  • mixed solvents thereof and the like Among these, an aromatic hydrocarbon solvent is preferable from the viewpoint of good reactivity and yield, and tolu
  • the amount of the solvent used is preferably 5 to 15 mL with respect to 1 g of methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate. is there.
  • the reaction temperature depends on the type of solvent, but is preferably in the range of ⁇ 10 to 30 ° C., more preferably in the range of ⁇ 10 to 10 ° C.
  • the progress of the reaction can be confirmed by analytical means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.
  • the reaction is performed by mixing methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate, base, methanesulfonyl chloride and solvent. Done.
  • the mesyl body is reacted with sodium methylate.
  • the reaction mixture containing the mesyl body may be washed with an acidic aqueous solution such as hydrochloric acid or sulfuric acid water.
  • the amount of sodium methylate used is methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropano in terms of yield and economy.
  • the amount is preferably 1 to 5 moles per mole of ate.
  • Sodium methylate may be used in the form of a methanol solution.
  • the reaction temperature is preferably in the range of ⁇ 10 to 30 ° C., more preferably in the range of ⁇ 5 to 10 ° C., although it depends on the type of solvent.
  • the progress of the reaction can be confirmed by analytical means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.
  • reaction mixture can be isolated by subjecting to a post-treatment such as crystallization.
  • the purification can be performed by extracting methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate, silica gel column chromatography, etc. It can be performed by subjecting it to a purification treatment such as chromatography or recrystallization.
  • Methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate has the following route
  • Methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate is prepared by a known method (for example, optically active phosphine compound and rhodium compound).
  • optically active phosphine compound used in the hydrogenation reaction examples include 1-[(R) -ferrocenyl-2- (S) -ethyl-1- (dimethylamino) phenyl]-(R) -phosphino-1′-dicyclo Xylphosphinoferrocene, 1-[(S) -ferrocenyl-2- (R) -ethyl-1- (dimethylamino) phenyl]-(S) -phosphino-1′-dicyclohexylphosphinoferrocene, ( ⁇ ) -1,2-bis [(2R, 5R) -2,5-dimethylphosphorano] benzene, (+)-1,2-bis [(2S, 5S) -2,5-dimethylphosphorano] benzene, -)-1,2-bis [(2R, 5R) -2,5-diethylphosphorano] benzene, (+)-1,2-bis
  • the amount of the optically active phosphine compound used in the hydrogenation reaction is usually 1 to 5 mol, preferably 1.01 to 2 mol, per 1 mol of the rhodium compound.
  • Methyl (2R) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] propanoate is used in a known reduction method (for example, using a reducing agent such as sodium borohydride). Reduction) can lead to tert-butyl [(2R) -1- (1,1′-biphenyl-4-yl) -3-hydroxypropan-2-yl] carbamate.
  • Example 1 While mixing glycine (4.59 mol, 344.8 g), potassium hydroxide (5.23 mol, 296.4 g), methanol (613.0 mL) and toluene (10192 mL), stirring at 15 ° C., 4-phenylbenzaldehyde A solution of (10.7 mol, 1949.9 g) in toluene (6984.3 mL) was added over 1 hour. The reaction mixture was stirred for 12 hours and the reaction mixture was added to 7.5% hydrochloric acid (7427.6 g). The reaction mixture adhering to the vessel was washed out with toluene (1122.7 mL) and added to hydrochloric acid.
  • the obtained mixed liquid was adjusted to 35 ° C., methanol (7061.1 mL) was added and stirred, and the aqueous layer was separated after standing.
  • the obtained aqueous layer was washed three times with toluene (4498.8 mL), and liquid separation was repeated, and the aqueous layer was separated to give 2-amino-3- (1,1′-biphenyl-4-yl) -3.
  • -An aqueous solution of hydroxypropionate hydrochloride was obtained.
  • Example 2 To the aqueous solution of 2-amino-3- (1,1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride obtained in Example 1, toluene (6231.5 mL) and 30% aqueous sodium hydroxide solution ( 1451.3 g) was added to adjust the pH of the aqueous layer to 8. While stirring the resulting mixture at 35 ° C., a solution of di-tert-butyl dicarbonate (5.05 mol, 1102.6 g) in toluene (2056.4 mL) and 30% aqueous sodium hydroxide solution (447.0 g) were added. The mixture was added dropwise while adjusting so that the pH of the mixture was maintained at 8.
  • a 30% aqueous sodium hydroxide solution (685.9 g) was further added dropwise while stirring for 8 hours, and then 35% hydrochloric acid (1507.1 g) was added to the mixture at 25 ° C.
  • the pH of the layer was adjusted to 1 or less.
  • the mixture was separated and the organic layer was separated.
  • the aqueous layer was further extracted four times with toluene (6231.5 mL), and all the separated organic layers were combined to give 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino.
  • a toluene solution of 3-hydroxypropionic acid was obtained.
  • Example 3 To a toluene solution of 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid obtained in Example 2, toluene (778.9 mL), 5% Aqueous sodium hydrogen carbonate solution (10793.4 g) and tetrabutylammonium bromide (0.23 mol, 74.0 g) were added, and dimethyl sulfate (6.89 mol, 868.9 g) and 5% hydrogen carbonate at 35 ° C. with stirring. A sodium aqueous solution (10793.4 g) was added dropwise at the same time while adjusting the pH of the mixture to 7.
  • Example 4 The toluene solution of methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate obtained in Example 3 was reduced to about 20% by weight. After concentrating under cooling, the resulting crystals are cooled to 1 ° C. and collected to give methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3- Hydroxypropanoate was obtained as a colorless solid.
  • the organic layer was washed twice with water (3411.8 mL), and the obtained organic layer was concentrated until the target concentration was about 20% by weight.
  • heptane (6484.4 mL) was added dropwise at 45 ° C. to crystallize the desired product. After the mixture was cooled to 0 ° C., the crystals were filtered, then washed with a cooled toluene-heptane mixture (weight ratio 1: 1, 1194.1 g), and further washed with cooled heptane (1745.8 mL).

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Abstract

A method for producing methyl (2Z)-3-(1,1'-biphenyl-4-yl)-2-[(tert-butoxycarbonyl)amino]- prop-2-enoate, comprising the steps of: reacting 4-phenylbenzaldehyde with glycine in the presence of sodium hydroxide or potassium hydroxide to produce a reaction mixture, and then mixing the reaction mixture with hydrochloric acid to produce 2-amino-3-(1,1'-biphenyl-4-yl)-3-hydroxypropionic acid hydrochloride; reacting 2-amino-3-(1,1'-biphenyl-4-yl)-3-hydroxypropionic acid hydrochloride with di-tert-butyl dicarbonate under basic conditions to produce 3-(1,1'-biphenyl-4-yl)-2-[(tert- butoxycarbonyl)amino]-3-hydroxypropionic acid; reacting 3-(1,1'-biphenyl-4-yl)-2-[(tert-butoxycarbonyl)amino]-3- hydroxypropionic acid with dimethyl sulfate in the presence of a base to produce methyl 3-(1,1'-biphenyl-4-yl)-2- [(tert-butoxycarbonyl)amino]-3-hydroxypropanoate; and reacting methyl 3-(1,1'-biphenyl-4-yl)-2-[(tert- butoxycarbonyl)amino]-3-hydroxypropanoate with methanesulfonyl chloride in the presence of a base to produce a corresponding mesyl-form compound, and then reacting the mesyl-form compound with sodium methylate to produce methyl (2Z)-3-(1,1'-biphenyl-4-yl)-2-[(tert-butoxycarbonyl)amino]- prop-2-enoate. According to the method, it becomes possible to produce methyl (2Z)-3-(1,1'-biphenyl-4-yl)-2- [(tert-butoxycarbonyl)amino]prop-2-enoate which is useful as an intermediate for the production of a medicine or the like.

Description

ビフェニル化合物の製造方法Method for producing biphenyl compound
　本発明は、ビフェニル化合物の製造方法に関する。 The present invention relates to a method for producing a biphenyl compound.
　式
Figure JPOXMLDOC01-appb-I000001
formula
Figure JPOXMLDOC01-appb-I000001
（本出願において、Ｂｏｃはｔｅｒｔ－ブトキシカルボニル基を表す。）
で示される化合物は、医薬等の製造中間体として有用である（ＷＯ２０１３／０２６７７３参照）。 (In this application, Boc represents a tert-butoxycarbonyl group.)
Is useful as an intermediate for the production of pharmaceuticals and the like (see WO2013 / 026773).
　そして、式
Figure JPOXMLDOC01-appb-I000002

で示されるメチル　（２Ｚ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロプ－２－エノエートは、その製造中間体として有用である。 And the formula
Figure JPOXMLDOC01-appb-I000002

Methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate represented by the formula is useful as an intermediate for its production.
　メチル　（２Ｚ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロプ－２－エノエートの製造方法としては、Ｎ－ｔｅｒｔ－ブトキシカルボニル－α－ホスホノグリシントリメチルエステルを用いる方法が知られている（Organic Letters, 2014, 16(5), 1426-1429, Supporting Information及びChirality, 8(2), 173-188, 1996）が、リンを含む廃棄物処理が必要なことから工業的な使用には適していない。 As a method for producing methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate, N-tert-butoxycarbonyl-α is used. -Methods using phosphonoglycine trimethyl esters are known (Organic Letters, 2014, 16 (5), 1426-1429, Supporting Information and Chirality, 8 (2), 173-188, 1996) It is not suitable for industrial use because it requires waste disposal.
　本発明はメチル　（２Ｚ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロプ－２－エノエートを製造する新たな方法を提供する。 The present invention provides a new method for producing methyl (2Z) -3- (1,1'-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate.
　本発明によれば、４－フェニルベンズアルデヒド及びグリシンを出発原料とし、新規な中間体であるメチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエートを経由する方法により、メチル　（２Ｚ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロプ－２－エノエートを製造できる。本発明の製造方法は、
［工程１］　４－フェニルベンズアルデヒドとグリシンとを水酸化ナトリウム又は水酸化カリウムの存在下で反応させ、得られた反応混合物と塩酸とを混合することにより、２－アミノ－３－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロピオン酸塩酸塩を得る工程；
［工程２］　２－アミノ－３－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロピオン酸塩酸塩とジ－ｔｅｒｔ－ブチルジカーボネートとを塩基性条件下で反応させて３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロピオン酸を得る工程；
［工程３］　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロピオン酸とジメチル硫酸とを塩基の存在下で反応させてメチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエートを得る工程；及び
［工程４］　メチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエートを塩基の存在下でメタンスルホニルクロリドと反応させて対応するメシル体を得、次いでメシル体をナトリウムメチラートと反応させてメチル　（２Ｚ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロプ－２－エノエートを得る工程；
を含むメチル　（２Ｚ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロプ－２－エノエートの製造方法である。 According to the present invention, 4-phenylbenzaldehyde and glycine are used as starting materials, and a novel intermediate methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] Methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate was obtained by a method via -3-hydroxypropanoate. Can be manufactured. The production method of the present invention comprises:
[Step 1] By reacting 4-phenylbenzaldehyde and glycine in the presence of sodium hydroxide or potassium hydroxide, and mixing the resulting reaction mixture with hydrochloric acid, 2-amino-3- (1,1 Obtaining '-biphenyl-4-yl) -3-hydroxypropionate hydrochloride;
[Step 2] 2-amino-3- (1,1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride and di-tert-butyl dicarbonate are reacted under basic conditions to give 3- Obtaining (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid;
[Step 3] 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid is reacted with dimethyl sulfate in the presence of a base to give methyl Obtaining 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate; and [Step 4] methyl 3- (1,1 ′ -Biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate is reacted with methanesulfonyl chloride in the presence of a base to give the corresponding mesyl form, Reaction with sodium methylate methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop - obtaining a enoate;
Is a process for producing methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate containing
　以下、本発明について詳細に説明する。 Hereinafter, the present invention will be described in detail.
　メチル　（２Ｚ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロプ－２－エノエートの製造ルートは以下の通りである。
Figure JPOXMLDOC01-appb-I000003
The production route for methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate is as follows.
Figure JPOXMLDOC01-appb-I000003
工程１：
　工程１では、４－フェニルベンズアルデヒドとグリシンとを水酸化カリウム又は水酸化ナトリウムの存在下で反応させ、得られた反応混合物と塩酸とを混合することにより、２－アミノ－３－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロピオン酸塩酸塩を得る。 Step 1:
In Step 1, 4-phenylbenzaldehyde and glycine are reacted in the presence of potassium hydroxide or sodium hydroxide, and the resulting reaction mixture is mixed with hydrochloric acid to give 2-amino-3- (1,1 '-Biphenyl-4-yl) -3-hydroxypropionate hydrochloride is obtained.
　４－フェニルベンズアルデヒドの使用量は、収率及び経済性の点からグリシン１モルに対し、好ましくは１．７～３．３モル、より好ましくは２．０～２．５モルである。 The amount of 4-phenylbenzaldehyde used is preferably 1.7 to 3.3 moles, more preferably 2.0 to 2.5 moles per mole of glycine in terms of yield and economy.
　水酸化ナトリウム又は水酸化カリウムの使用量は、収率及び経済性の点からグリシン１モルに対し、好ましくは１．０～２．０モル、より好ましくは１．０～１．５モルである。 The amount of sodium hydroxide or potassium hydroxide to be used is preferably 1.0 to 2.0 mol, more preferably 1.0 to 1.5 mol with respect to 1 mol of glycine in terms of yield and economy. .
　反応は通常溶媒中で行われる。溶媒としては、水、アルコール溶媒（例えばメタノール、エタノール）；芳香族炭化水素溶媒（例えばトルエン、ベンゼン、キシレン）；ハロゲン化炭化水素溶媒（例えばクロロホルム、ジクロロメタン、四塩化炭素）；エーテル溶媒（例えばジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、テトラヒドロフラン、１，４－ジオキサン）；非プロトン性極性溶媒（例えばジメチルホルムアミド、ジメチルアセトアミド）；これらの混合溶媒等が挙げられる。中でも、反応性及び収率が良好である点から、アルコール溶媒、芳香族炭化水素溶媒、これらの混合溶媒が好ましく、メタノール及びトルエンの混合溶媒が特に好ましい。溶媒の使用量は、グリシン１ｇに対し、好ましくは４０～８０ｍＬ、より好ましくは４０～６０ｍＬである。 The reaction is usually performed in a solvent. Solvents include water, alcohol solvents (eg, methanol, ethanol); aromatic hydrocarbon solvents (eg, toluene, benzene, xylene); halogenated hydrocarbon solvents (eg, chloroform, dichloromethane, carbon tetrachloride); ether solvents (eg, diethyl) Ether, tert-butyl methyl ether, tetrahydrofuran, 1,4-dioxane); aprotic polar solvent (for example, dimethylformamide, dimethylacetamide); a mixed solvent thereof and the like. Among these, from the viewpoint of good reactivity and yield, alcohol solvents, aromatic hydrocarbon solvents, and mixed solvents thereof are preferable, and mixed solvents of methanol and toluene are particularly preferable. The amount of the solvent used is preferably 40 to 80 mL, more preferably 40 to 60 mL, with respect to 1 g of glycine.
　反応は、グリシン、水酸化ナトリウム又は水酸化カリウム、４－フェニルベンズアルデヒド及び溶媒を混合することにより行われる。 The reaction is carried out by mixing glycine, sodium hydroxide or potassium hydroxide, 4-phenylbenzaldehyde and a solvent.
　反応温度は、溶媒の種類にもよるが、好ましくは１０～５０℃の範囲内、より好ましくは１０～３０℃の範囲内である。 The reaction temperature is preferably in the range of 10 to 50 ° C., more preferably in the range of 10 to 30 ° C., although it depends on the type of solvent.
　このようにして得られた反応混合物と塩酸とを混合し、必要に応じて水と混和しない溶媒を混合し、水層を分離することにより、２－アミノ－３－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロピオン酸塩酸塩を水溶液として得ることができる。２－アミノ－３－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロピオン酸塩酸塩の単離は、反応混合物を結晶化等の後処理に付すことにより行うことができる。また、その精製は２－アミノ－３－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロピオン酸塩酸塩を抽出、再結晶等の精製処理により行うことができるが、２－アミノ－３－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロピオン酸塩酸塩の水溶液をそのまま次工程に供してもよい。
工程２：
　工程２では、２－アミノ－３－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロピオン酸塩酸塩とジ－ｔｅｒｔ－ブチルジカーボネートとを塩基性条件下で反応させて、３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロピオン酸を得る。 The reaction mixture thus obtained and hydrochloric acid are mixed, if necessary, a solvent immiscible with water is mixed, and the aqueous layer is separated, whereby 2-amino-3- (1,1′-biphenyl) is separated. -4-yl) -3-hydroxypropionate hydrochloride can be obtained as an aqueous solution. Isolation of 2-amino-3- (1,1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride can be performed by subjecting the reaction mixture to a post-treatment such as crystallization. The purification can be carried out by a purification process such as extraction, recrystallization, etc. of 2-amino-3- (1,1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride. An aqueous solution of -3- (1,1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride may be directly used in the next step.
Step 2:
In step 2, 2-amino-3- (1,1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride and di-tert-butyl dicarbonate are reacted under basic conditions to give 3 -(1,1'-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid is obtained.
　２－アミノ－３－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロピオン酸塩酸塩の水溶液を、予め水酸化ナトリウム等の塩基を用いてｐＨを７～１０、好ましくは７．５～９．０、より好ましくは７．５～８．５に調整しておくのが好ましい。 An aqueous solution of 2-amino-3- (1,1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride is adjusted to a pH of 7 to 10, preferably 7, using a base such as sodium hydroxide in advance. It is preferable to adjust to 5 to 9.0, more preferably 7.5 to 8.5.
　ジ－ｔｅｒｔ－ブチルジカーボネートの使用量は、収率及び経済性の点から、２－アミノ－３－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロピオン酸塩酸塩１モルに対し、好ましくは１～４モルである。 The amount of di-tert-butyl dicarbonate used is 1 mol of 2-amino-3- (1,1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride in terms of yield and economy. On the other hand, it is preferably 1 to 4 mol.
　反応は通常溶媒中で行われる。溶媒としては、芳香族炭化水素溶媒（例えばトルエン、ベンゼン、キシレン）；ハロゲン化炭化水素溶媒（例えばクロロホルム、ジクロロメタン、四塩化炭素）；エーテル溶媒（例えばジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、テトラヒドロフラン、１，４－ジオキサン）；非プロトン性極性溶媒（例えばジメチルホルムアミド、ジメチルアセトアミド）；水；これらの混合溶媒等が挙げられる。中でも、経済性の点から、芳香族炭化水素溶媒及び水の混合溶媒が好ましく、トルエンと水の混合溶媒が特に好ましい。溶媒の使用量は、２－アミノ－３－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロピオン酸塩酸塩１ｇに対し、好ましくは１５～３０ｍＬである。 The reaction is usually performed in a solvent. Solvents include aromatic hydrocarbon solvents (for example, toluene, benzene, xylene); halogenated hydrocarbon solvents (for example, chloroform, dichloromethane, carbon tetrachloride); ether solvents (for example, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 1 , 4-dioxane); aprotic polar solvents (for example, dimethylformamide, dimethylacetamide); water; mixed solvents thereof and the like. Among these, from the viewpoint of economy, a mixed solvent of an aromatic hydrocarbon solvent and water is preferable, and a mixed solvent of toluene and water is particularly preferable. The amount of the solvent used is preferably 15 to 30 mL with respect to 1 g of 2-amino-3- (1,1'-biphenyl-4-yl) -3-hydroxypropionate hydrochloride.
　反応は、塩基を用いて反応混合物のｐＨを７～１０、好ましくは７．５～９．０、より好ましくは７．５～８．５に調整しながら、２－アミノ－３－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロピオン酸塩酸塩及び溶媒を混合し、そこにジ－ｔｅｒｔ－ブチルジカーボネートを添加、好ましくは滴下して混合する方法等により行われる。 The reaction is carried out by adjusting the pH of the reaction mixture to 7-10, preferably 7.5-9.0, more preferably 7.5-8.5 using a base, while 2-amino-3- (1, 1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride and a solvent are mixed, and di-tert-butyl dicarbonate is added thereto, preferably added dropwise and mixed.
　ｐＨ調整に使用される塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム等の無機塩基；トリエチルアミン、トリメチルアミン、ジイソプロピルエチルアミン等の有機塩基などが挙げられる。中でも、収率及び経済性の点から、水酸化ナトリウム、水酸化カリウム等の無機塩基が好ましく、水酸化ナトリウムが特に好ましい。 Examples of the base used for pH adjustment include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; organic bases such as triethylamine, trimethylamine, and diisopropylethylamine. . Among these, from the viewpoint of yield and economy, inorganic bases such as sodium hydroxide and potassium hydroxide are preferable, and sodium hydroxide is particularly preferable.
　反応温度は、溶媒の種類にもよるが、好ましくは１０～６０℃の範囲内、より好ましくは２０～５０℃の範囲内である。 The reaction temperature is preferably in the range of 10 to 60 ° C., more preferably in the range of 20 to 50 ° C., although it depends on the type of solvent.
　反応の進行度合いは、薄層クロマトグラフィー、高速液体クロマトグラフィー等の分析手段により確認することができる。 The progress of the reaction can be confirmed by analytical means such as thin layer chromatography and high performance liquid chromatography.
　このようにして得られた反応混合物に含まれる３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロピオン酸は、反応混合物を結晶化等の後処理に付すことにより単離することができる。また、その精製は３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロピオン酸を抽出、シリカゲルカラムクロマトグラフィー等のクロマトグラフィー処理、再結晶等の精製処理により行うことができるが、３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロピオン酸の反応混合物をそのまま次工程に供してもよいし、抽出後の有機層をそのまま次工程に供してもよい。
工程３：
　工程３では、３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロピオン酸を塩基の存在下でジメチル硫酸と反応させ、メチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエートを得る。 The 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid contained in the reaction mixture thus obtained is obtained by crystallizing the reaction mixture. It can be isolated by subjecting it to post-treatment such as conversion. In addition, the purification is performed by extracting 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid, chromatography treatment such as silica gel column chromatography, Although it can be carried out by purification treatment such as recrystallization, the reaction mixture of 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid is used as it is. You may use for the next process, and you may use the organic layer after extraction for the next process as it is.
Step 3:
In step 3, 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid is reacted with dimethyl sulfate in the presence of a base to give methyl 3 -(1,1'-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate is obtained.
　ジメチル硫酸の使用量は、収率及び経済性の点から、３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロピオン酸１モルに対し、好ましくは１～１０モルである。 The amount of dimethyl sulfate used is 1 mol of 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid in terms of yield and economy. The amount is preferably 1 to 10 moles.
　塩基としては、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム、炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウム等の無機塩基；トリエチルアミン、トリメチルアミン、ジイソプロピルエチルアミン等の有機塩基等が挙げられる。中でも、収率及び経済性の点から、炭酸水素ナトリウム、炭酸水素カリウム等の無機塩基が好ましく、炭酸水素ナトリウムが特に好ましい。 Examples of the base include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; organic bases such as triethylamine, trimethylamine and diisopropylethylamine. Among these, from the viewpoint of yield and economy, inorganic bases such as sodium hydrogen carbonate and potassium hydrogen carbonate are preferable, and sodium hydrogen carbonate is particularly preferable.
　塩基の使用量は、収率及び経済性の点から、３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロピオン酸１モルに対し、好ましくは２～５モルである。 The amount of base used is 1 mol of 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid in terms of yield and economy. On the other hand, it is preferably 2 to 5 mol.
　反応は通常溶媒中で行われる。溶媒としては、芳香族炭化水素溶媒（例えばトルエン、ベンゼン、キシレン）；ハロゲン化炭化水素溶媒（例えばクロロホルム、ジクロロメタン、四塩化炭素）；エーテル溶媒（例えばジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、テトラヒドロフラン、１，４－ジオキサン）；非プロトン性極性溶媒（例えばジメチルホルムアミド、ジメチルアセトアミド）；水；これらの混合溶媒等が挙げられる。中でも、経済性の点から、芳香族炭化水素溶媒と水との混合溶媒が好ましく、トルエンと水との混合溶媒が特に好ましい。溶媒の使用量は、３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロピオン酸１ｇに対し、好ましくは２０～５０ｍＬである。 The reaction is usually performed in a solvent. Solvents include aromatic hydrocarbon solvents (for example, toluene, benzene, xylene); halogenated hydrocarbon solvents (for example, chloroform, dichloromethane, carbon tetrachloride); ether solvents (for example, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 1 , 4-dioxane); aprotic polar solvents (for example, dimethylformamide, dimethylacetamide); water; mixed solvents thereof and the like. Among these, from the viewpoint of economy, a mixed solvent of an aromatic hydrocarbon solvent and water is preferable, and a mixed solvent of toluene and water is particularly preferable. The amount of the solvent used is preferably 20 to 50 mL with respect to 1 g of 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid.
　芳香族炭化水素溶媒及び水の混合溶媒を使用する場合、必要により相関移動触媒存在下で行ってもよい。相関移動触媒としては、テトラブチルアンモニウムブロミド、ベンジルトリメチルアンモニウムクロリド等が挙げられる。中でも、テトラブチルアンモニウムブロミドが好ましい。 When using a mixed solvent of an aromatic hydrocarbon solvent and water, it may be carried out in the presence of a phase transfer catalyst if necessary. Examples of the phase transfer catalyst include tetrabutylammonium bromide and benzyltrimethylammonium chloride. Of these, tetrabutylammonium bromide is preferable.
　相関移動触媒の使用量は、収率及び経済性の点から、３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロピオン酸１モルに対し、好ましくは０．０１～０．２モルである。 The amount of phase transfer catalyst used is 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid 1 in terms of yield and economy. Preferably it is 0.01-0.2 mol with respect to mol.
　反応は、塩基を用いて反応混合物のｐＨを６～１０、好ましくは６．０～９．０、より好ましくは６．０～８．０に調整しながら、３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロピオン酸、塩基及び溶媒を混合し、そこにジメチル硫酸を添加、好ましくは滴下して混合する方法等により行われる。 The reaction is carried out using 3- (1,1′-biphenyl) while adjusting the pH of the reaction mixture to 6 to 10, preferably 6.0 to 9.0, more preferably 6.0 to 8.0 using a base. -4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid, a base and a solvent are mixed, and dimethyl sulfate is added thereto, preferably added dropwise and mixed. .
　反応温度は、溶媒の種類にもよるが、好ましくは２０～６０℃の範囲内、より好ましくは２５～５０℃の範囲内である。 The reaction temperature is preferably in the range of 20 to 60 ° C, more preferably in the range of 25 to 50 ° C, although it depends on the type of solvent.
　反応の進行度合いは、薄層クロマトグラフィー、高速液体クロマトグラフィー等の分析手段により確認することができる。 The progress of the reaction can be confirmed by analytical means such as thin layer chromatography and high performance liquid chromatography.
　反応終了後、必要により、過剰のジメチル硫酸を例えばトリエチルアミン等の塩基で分解してもよい。 After completion of the reaction, if necessary, excess dimethyl sulfate may be decomposed with a base such as triethylamine.
　このようにして得られた反応混合物に含まれるメチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエートは、反応混合物を結晶化等の後処理に付すことにより単離することができる。また、その精製はメチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエートを抽出、シリカゲルカラムクロマトグラフィー等のクロマトグラフィー処理、再結晶等の精製処理により行うことができる。メチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエートは反応混合物のまま次工程に供してもよいし、抽出後の有機層をそのまま次工程に供してもよい。
工程４：
　工程４では、メチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエートを塩基の存在下でメタンスルホニルクロリドと反応させ、対応するメシル体：
Figure JPOXMLDOC01-appb-I000004
Methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate contained in the reaction mixture thus obtained is Can be isolated by post-treatment such as crystallization. Further, the purification is performed by extracting methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate, chromatography such as silica gel column chromatography, etc. It can be performed by purification treatment such as treatment, recrystallization and the like. Methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate may be used in the next step as the reaction mixture or after extraction. The organic layer may be used in the next step as it is.
Step 4:
In step 4, methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate is reacted with methanesulfonyl chloride in the presence of a base. The corresponding mesyl body:
Figure JPOXMLDOC01-appb-I000004
を得、次いでメシル体をナトリウムメチラートと反応させてメチル　（２Ｚ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロプ－２－エノエートを得る。 Then, the mesyl compound is reacted with sodium methylate to obtain methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate Get.
　メタンスルホニルクロリドの使用量は、収率及び経済性の点から、メチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエート１モルに対し、好ましくは１．０～５．０モル、より好ましくは１．０～１．５モルである。 The amount of methanesulfonyl chloride used is methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropano in terms of yield and economy. The amount is preferably 1.0 to 5.0 moles, more preferably 1.0 to 1.5 moles per mole of ate.
　塩基としては、炭酸ナトリウム、炭酸カリウム、炭酸セシウム、炭酸水素ナトリウム、炭酸水素カリウム等の無機塩基；トリエチルアミン、トリメチルアミン、ピリジン、２，６－ルチジン、ジイソプロピルエチルアミン、Ｎ－メチルモルホリン、ＤＢＵ（１，８－ジアザビシクロ［５．４．０］ウンデカ－７－エン）、ＤＢＮ（１，５－ジアザビシクロ［４．３．０］ノナ－５－エン）、イミダゾール等の有機塩基等が挙げられる。中でも、トリエチルアミン、ピリジン等の有機塩基が好ましく、トリエチルアミンが特に好ましい。 Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate; triethylamine, trimethylamine, pyridine, 2,6-lutidine, diisopropylethylamine, N-methylmorpholine, DBU (1,8 -Organic bases such as diazabicyclo [5.4.0] undec-7-ene), DBN (1,5-diazabicyclo [4.3.0] non-5-ene) and imidazole. Among these, organic bases such as triethylamine and pyridine are preferable, and triethylamine is particularly preferable.
　塩基の使用量は、収率及び経済性の点から、メチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエート１モルに対し、好ましくは１．０～５．０モルである。 The amount of base used is methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate 1 in terms of yield and economy. Preferably it is 1.0-5.0 mol with respect to mol.
　反応は通常溶媒中で行われる。溶媒としては、芳香族炭化水素溶媒（例えばトルエン、ベンゼン、キシレン）；ハロゲン化炭化水素溶媒（例えばクロロホルム、ジクロロメタン、四塩化炭素）；エーテル溶媒（例えばジエチルエーテル、ｔｅｒｔ－ブチルメチルエーテル、テトラヒドロフラン、１，４－ジオキサン）；これらの混合溶媒等が挙げられる。中でも、反応性及び収率が良好である点から、芳香族炭化水素溶媒が好ましく、トルエンが特に好ましい。溶媒の使用量は、メチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエート１ｇに対し、好ましくは５～１５ｍＬである。 The reaction is usually performed in a solvent. Solvents include aromatic hydrocarbon solvents (for example, toluene, benzene, xylene); halogenated hydrocarbon solvents (for example, chloroform, dichloromethane, carbon tetrachloride); ether solvents (for example, diethyl ether, tert-butyl methyl ether, tetrahydrofuran, 1 , 4-dioxane); mixed solvents thereof and the like. Among these, an aromatic hydrocarbon solvent is preferable from the viewpoint of good reactivity and yield, and toluene is particularly preferable. The amount of the solvent used is preferably 5 to 15 mL with respect to 1 g of methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate. is there.
　反応温度は、溶媒の種類にもよるが、好ましくは－１０～３０℃の範囲内、より好ましくは－１０～１０℃の範囲内である。 The reaction temperature depends on the type of solvent, but is preferably in the range of −10 to 30 ° C., more preferably in the range of −10 to 10 ° C.
　反応の進行度合いは、薄層クロマトグラフィー、ガスクロマトグラフィー、高速液体クロマトグラフィー等の分析手段により確認することができる。 The progress of the reaction can be confirmed by analytical means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.
　反応は、メチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエート、塩基、メタンスルホニルクロリド及び溶媒を混合することにより行われる。 The reaction is performed by mixing methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate, base, methanesulfonyl chloride and solvent. Done.
　反応終了後、メシル体とナトリウムメチラートとを反応させる。この際、ナトリウムメチラートとの反応に先立ち、メシル体を含む反応混合物を塩酸や硫酸水等の酸性の水溶液で洗浄してもよい。 After completion of the reaction, the mesyl body is reacted with sodium methylate. At this time, prior to the reaction with sodium methylate, the reaction mixture containing the mesyl body may be washed with an acidic aqueous solution such as hydrochloric acid or sulfuric acid water.
　ナトリウムメチラートの使用量は、収率及び経済性の点から、メチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエート１モルに対し、好ましくは１～５モルである。 The amount of sodium methylate used is methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropano in terms of yield and economy. The amount is preferably 1 to 5 moles per mole of ate.
　ナトリウムメチラートはメタノール溶液の形態で用いてもよい。 Sodium methylate may be used in the form of a methanol solution.
　反応温度は、溶媒の種類にもよるが、好ましくは－１０～３０℃の範囲内、より好ましくは－５～１０℃の範囲内である。 The reaction temperature is preferably in the range of −10 to 30 ° C., more preferably in the range of −5 to 10 ° C., although it depends on the type of solvent.
　反応の進行度合いは、薄層クロマトグラフィー、ガスクロマトグラフィー、高速液体クロマトグラフィー等の分析手段により確認することができる。 The progress of the reaction can be confirmed by analytical means such as thin layer chromatography, gas chromatography, high performance liquid chromatography and the like.
　このようにして得られた反応混合物に含まれるメチル　（２Ｚ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロプ－２－エノエートは、反応混合物を結晶化等の後処理に付すことにより単離することができる。また、その精製はメチル　（２Ｚ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロプ－２－エノエートを抽出、シリカゲルカラムクロマトグラフィー等のクロマトグラフィー処理、再結晶等の精製処理に付すことにより行うことができる。 Methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate contained in the reaction mixture thus obtained is The reaction mixture can be isolated by subjecting to a post-treatment such as crystallization. The purification can be performed by extracting methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate, silica gel column chromatography, etc. It can be performed by subjecting it to a purification treatment such as chromatography or recrystallization.
　メチル　（２Ｚ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロプ－２－エノエートは、次のルート
Figure JPOXMLDOC01-appb-I000005
Methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate has the following route
Figure JPOXMLDOC01-appb-I000005
により、医薬等の製造中間体として有用なｔｅｒｔ－ブチル　［（２Ｒ）－１－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロパン－２－イル］カーバメートに導くことができる。 Can lead to tert-butyl [(2R) -1- (1,1′-biphenyl-4-yl) -3-hydroxypropan-2-yl] carbamate, which is useful as an intermediate for producing pharmaceuticals and the like.
　メチル　（２Ｚ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロプ－２－エノエートを公知の方法（例えば光学活性ホスフィン化合物とロジウム化合物との組合せによる触媒の存在下で水素と反応させることによる水素化反応）に供することにより、メチル　（２Ｒ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロパノエートに導くことができる。 Methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate is prepared by a known method (for example, optically active phosphine compound and rhodium compound). (2R) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxy) by subjecting to a hydrogenation reaction by reacting with hydrogen in the presence of a catalyst by a combination of Carbonyl) amino] propanoate.
　水素化反応に用いられる光学活性ホスフィン化合物としては、１－［（Ｒ）－フェロセニル－２－（Ｓ）－エチル－１－（ジメチルアミノ）フェニル］－（Ｒ）－ホスフィノ－１’－ジシクロへキシルホスフィノフェロセン、１－［（Ｓ）－フェロセニル－２－（Ｒ）－エチル－１－（ジメチルアミノ）フェニル］－（Ｓ）－ホスフィノ－１’－ジシクロへキシルホスフィノフェロセン、（－）－１，２－ビス［（２Ｒ，５Ｒ）－２，５－ジメチルホスホラノ］ベンゼン、（＋）－１，２－ビス［（２Ｓ，５Ｓ）－２，５－ジメチルホスホラノ］ベンゼン、（－）－１，２－ビス［（２Ｒ，５Ｒ）－２，５－ジエチルホスホラノ］ベンゼン、（＋）－１，２－ビス［（２Ｓ，５Ｓ）－２，５－ジエチルホスホラノ］ベンゼン、（－）－１，２－ビス［（２Ｒ，５Ｒ）－２，５－ジイソプロピルホスホラノ］ベンゼン、（Ｒ，Ｒ）－２，３－ビス（ｔｅｒｔ－ブチルメチルホスフィノ）キノキサリン、（＋）－１，２－ビス［（２Ｓ，５Ｓ）－２，５－ジイソプロピルホスホラノ］ベンゼン、（Ｒ）－（－）－４，１２－ビス（ジフェニルホスフィノ）－［２，２］－パラシクロファン、（Ｓ）－（＋）－４，１２－ビス（ジフェニルホスフィノ）－［２，２］－パラシクロファン、（４Ｒ，５Ｒ）－（－）－ビス（ジフェニルホスフィノメチル）－２，２－ジメチル－１，３－ジオキソラン、（４Ｓ，５Ｓ）－（＋）－ビス（ジフェニルホスフィノメチル）－２，２－ジメチル－１，３－ジオキソラン、（Ｒ，Ｒ）－１，２－ビス［（２－メトキシフェニル）（フェニルホスフィノ）］エタンおよび（Ｓ，Ｓ）－１，２－ビス［（２－メトキシフェニル）（フェニルホスフィノ）］エタン等が挙げられる。 Examples of the optically active phosphine compound used in the hydrogenation reaction include 1-[(R) -ferrocenyl-2- (S) -ethyl-1- (dimethylamino) phenyl]-(R) -phosphino-1′-dicyclo Xylphosphinoferrocene, 1-[(S) -ferrocenyl-2- (R) -ethyl-1- (dimethylamino) phenyl]-(S) -phosphino-1′-dicyclohexylphosphinoferrocene, (−) -1,2-bis [(2R, 5R) -2,5-dimethylphosphorano] benzene, (+)-1,2-bis [(2S, 5S) -2,5-dimethylphosphorano] benzene, -)-1,2-bis [(2R, 5R) -2,5-diethylphosphorano] benzene, (+)-1,2-bis [(2S, 5S) -2,5-diethylphosphorano] benzene , (-)-1, -Bis [(2R, 5R) -2,5-diisopropylphosphorano] benzene, (R, R) -2,3-bis (tert-butylmethylphosphino) quinoxaline, (+)-1,2-bis [ (2S, 5S) -2,5-diisopropylphosphorano] benzene, (R)-(−)-4,12-bis (diphenylphosphino)-[2,2] -paracyclophane, (S) — ( +)-4,12-bis (diphenylphosphino)-[2,2] -paracyclophane, (4R, 5R)-(−)-bis (diphenylphosphinomethyl) -2,2-dimethyl-1, 3-dioxolane, (4S, 5S)-(+)-bis (diphenylphosphinomethyl) -2,2-dimethyl-1,3-dioxolane, (R, R) -1,2-bis [(2-methoxy Phenyl) (phenylphosphite) )] Ethane and (S, S)-1,2-bis [(2-methoxyphenyl) (phenyl phosphino)] ethane, and the like.
　水素化反応に用いられる光学活性ホスフィン化合物の使用量は、ロジウム化合物１モルに対し、通常１～５モル、好ましくは１．０１～２モルである。 The amount of the optically active phosphine compound used in the hydrogenation reaction is usually 1 to 5 mol, preferably 1.01 to 2 mol, per 1 mol of the rhodium compound.
　メチル　（２Ｒ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロパノエートを、公知の還元方法（例えば水素化ホウ素ナトリウム等の還元剤を用いた還元）により、ｔｅｒｔ－ブチル　［（２Ｒ）－１－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロパン－２－イル］カーバメートに導くことができる。 Methyl (2R) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] propanoate is used in a known reduction method (for example, using a reducing agent such as sodium borohydride). Reduction) can lead to tert-butyl [(2R) -1- (1,1′-biphenyl-4-yl) -3-hydroxypropan-2-yl] carbamate.
　以下、実施例を挙げて本発明をより具体的に説明する。
実施例１
　グリシン（４．５９ｍｏｌ、３４４．８ｇ）、水酸化カリウム（５．２３ｍｏｌ、２９６．４ｇ）、メタノール（６１３．０ｍＬ）及びトルエン（１０１９２ｍＬ）を混合し、１５℃で撹拌しながら、４－フェニルベンズアルデヒド（１０．７ｍｏｌ、１９４９．９ｇ）のトルエン（６９８４．３ｍＬ）溶液を１時間かけて加えた。反応混合物を１２時間撹拌し、反応混合物を７．５％塩酸（７４２７．６ｇ）に加えた。容器に付着した反応混合物をトルエン（１１２２．７ｍＬ）で洗い出し、塩酸中に加えた。得られた混合液を３５℃に調整し、メタノール（７０６１．１ｍＬ）を加えて撹拌し、静置後に水層を分取した。得られた水層をトルエン（４４９８．８ｍＬ）で３回洗浄、分液を繰り返し、水層を分取することで２－アミノ－３－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロピオン酸塩酸塩の水溶液を得た。
実施例２
　実施例１で得た２－アミノ－３－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロピオン酸塩酸塩の水溶液に、トルエン（６２３１．５ｍＬ）及び３０％水酸化ナトリウム水溶液（１４５１．３ｇ）を加えて水層のｐＨを８に調整した。得られた混合物を３５℃で撹拌しながら、ジ－ｔｅｒｔ－ブチルジカーボネート（５．０５ｍｏｌ、１１０２．６ｇ）のトルエン（２０５６．４ｍＬ）溶液と３０％水酸化ナトリウム水溶液（４４７．０ｇ）とを、混合物のｐＨが８を維持するように調整しながら同時に滴下した。混合物のｐＨが８を維持するように、さらに３０％水酸化ナトリウム水溶液（６８５．９ｇ）を滴下しながら８時間撹拌した後、２５℃で混合物に３５％塩酸（１５０７．１ｇ）を加えて水層のｐＨを１以下に調整した。混合物を分液し、有機層を分取した。さらに水層をトルエン（６２３１．５ｍＬ）で４回抽出し、分取した有機層を全て合わせて３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロピオン酸のトルエン溶液を得た。
実施例３
　実施例２で得た３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロピオン酸のトルエン溶液に、トルエン（７７８．９ｍＬ）、５％炭酸水素ナトリウム水溶液（１０７９３．４ｇ）及びテトラブチルアンモニウムブロミド（０．２３ｍｏｌ、７４．０ｇ）を加え、撹拌しながら３５℃でジメチル硫酸（６．８９ｍｏｌ、８６８．９ｇ）と５％炭酸水素ナトリウム水溶液（１０７９３．４ｇ）とを、混合物のｐＨを７に調整しながら同時に滴下した。さらに同温度で６時間撹拌した後、混合物を分液し、有機層を分取した。有機層にトルエン（７７８．９ｍＬ）及びトリエチルアミン（４．５９ｍｏｌ、４６４．７ｇ）を加えて３時間撹拌し、過剰のジメチル硫酸を分解した。有機層に室温で水（５３９６．５ｍＬ）を加え、撹拌後、分液して有機層を分取した。得られた有機層を濃縮した後、トルエン（１３８４９．５ｍＬ）を加えてメチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエートのトルエン溶液を得た。
実施例４
　実施例３で得たメチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエートのトルエン溶液を約２０重量％まで減圧下で濃縮した後、１℃に冷却して生じた結晶をろ取し、メチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエートを無色固体として得た。
1H-NMR(CDCl3, δ); 1.44 (9H, s), 3.73 (3H, s), 4.01 (1H, d, J=4.8Hz), 5.24(1H, s), 7.32 (1H, d, J=7.6Hz), 7.7.26-7.36 (3H, m), 7.44 (2H, t, J=7.6Hz), 7.56-7.59 
(4H, m)
実施例５
　実施例３で得たメチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエートのトルエン溶液にトリエチルアミン（５．５１ｍｏｌ、５５７．７ｇ）を加え、０℃で撹拌しながらメタンスルホニルクロリド（５．５１ｍｏｌ、６３１．３ｇ）を滴下した。同温度で３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエートが消失するまで撹拌した後、０℃で２８％ナトリウムメチラートのメタノール溶液（１０．７５ｍｏｌ、２０７３．４ｇ）を加えた。さらに同温度で約１時間撹拌した後、０℃で水（６８２３．５ｍＬ）を滴下した。次いで、同温度で３５％塩酸（９４２．８ｇ）を加え、反応混合物のｐＨを７に調整した。室温で分液し、有機層を分取した。有機層を水（３４１１．８ｍＬ）で２回洗浄し、得られた有機層を目的物濃度が約２０重量％になるまで濃縮した。得られた混合物に４５℃でヘプタン（６４８４．４ｍＬ）を滴下し、目的物を結晶化させた。混合物を０℃に冷却した後、結晶をろ過し、次いで冷却したトルエン－へプタン混合液（重量比１:１、１１９４．１ｇ）で洗浄し、さらに冷却したヘプタン（１７４５．８ｍＬ）で洗浄して得られた結晶を乾燥してメチル　（２Ｚ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロプ－２－エノエート（１１３６．２ｇ、グリシンからの収率：７０％）を得た。
1H-NMR（CDCl3, δ)； 1.41 (9H, s), 3.55 (3H, s), 6.31 (1H, brs), 7.30 (1H, brs), 7.33-7.45 (3H, m), 7.57-7.63 (6H, m) Hereinafter, the present invention will be described more specifically with reference to examples.
Example 1
While mixing glycine (4.59 mol, 344.8 g), potassium hydroxide (5.23 mol, 296.4 g), methanol (613.0 mL) and toluene (10192 mL), stirring at 15 ° C., 4-phenylbenzaldehyde A solution of (10.7 mol, 1949.9 g) in toluene (6984.3 mL) was added over 1 hour. The reaction mixture was stirred for 12 hours and the reaction mixture was added to 7.5% hydrochloric acid (7427.6 g). The reaction mixture adhering to the vessel was washed out with toluene (1122.7 mL) and added to hydrochloric acid. The obtained mixed liquid was adjusted to 35 ° C., methanol (7061.1 mL) was added and stirred, and the aqueous layer was separated after standing. The obtained aqueous layer was washed three times with toluene (4498.8 mL), and liquid separation was repeated, and the aqueous layer was separated to give 2-amino-3- (1,1′-biphenyl-4-yl) -3. -An aqueous solution of hydroxypropionate hydrochloride was obtained.
Example 2
To the aqueous solution of 2-amino-3- (1,1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride obtained in Example 1, toluene (6231.5 mL) and 30% aqueous sodium hydroxide solution ( 1451.3 g) was added to adjust the pH of the aqueous layer to 8. While stirring the resulting mixture at 35 ° C., a solution of di-tert-butyl dicarbonate (5.05 mol, 1102.6 g) in toluene (2056.4 mL) and 30% aqueous sodium hydroxide solution (447.0 g) were added. The mixture was added dropwise while adjusting so that the pH of the mixture was maintained at 8. In order to maintain the pH of the mixture at 8, a 30% aqueous sodium hydroxide solution (685.9 g) was further added dropwise while stirring for 8 hours, and then 35% hydrochloric acid (1507.1 g) was added to the mixture at 25 ° C. The pH of the layer was adjusted to 1 or less. The mixture was separated and the organic layer was separated. The aqueous layer was further extracted four times with toluene (6231.5 mL), and all the separated organic layers were combined to give 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino. A toluene solution of 3-hydroxypropionic acid was obtained.
Example 3
To a toluene solution of 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid obtained in Example 2, toluene (778.9 mL), 5% Aqueous sodium hydrogen carbonate solution (10793.4 g) and tetrabutylammonium bromide (0.23 mol, 74.0 g) were added, and dimethyl sulfate (6.89 mol, 868.9 g) and 5% hydrogen carbonate at 35 ° C. with stirring. A sodium aqueous solution (10793.4 g) was added dropwise at the same time while adjusting the pH of the mixture to 7. After further stirring at the same temperature for 6 hours, the mixture was separated, and the organic layer was separated. Toluene (778.9 mL) and triethylamine (4.59 mol, 464.7 g) were added to the organic layer and stirred for 3 hours to decompose excess dimethyl sulfate. Water (5396.5 mL) was added to the organic layer at room temperature, and after stirring, liquid separation was performed to separate the organic layer. The obtained organic layer was concentrated, toluene (13849.5 mL) was added, and methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxy was added. A toluene solution of propanoate was obtained.
Example 4
The toluene solution of methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate obtained in Example 3 was reduced to about 20% by weight. After concentrating under cooling, the resulting crystals are cooled to 1 ° C. and collected to give methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3- Hydroxypropanoate was obtained as a colorless solid.
1 H-NMR (CDCl 3 , δ); 1.44 (9H, s), 3.73 (3H, s), 4.01 (1H, d, J = 4.8Hz), 5.24 (1H, s), 7.32 (1H, d, J = 7.6Hz), 7.7.26-7.36 (3H, m), 7.44 (2H, t, J = 7.6Hz), 7.56-7.59
(4H, m)
Example 5
To a toluene solution of methyl 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate obtained in Example 3, triethylamine (5.51 mol, 557.7 g) was added, and methanesulfonyl chloride (5.51 mol, 631.3 g) was added dropwise with stirring at 0 ° C. After stirring at the same temperature until 3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate disappeared, 28% sodium was added at 0 ° C. Methylate in methanol (10.75 mol, 2073.4 g) was added. Furthermore, after stirring at the same temperature for about 1 hour, water (6823.5 mL) was dripped at 0 degreeC. Subsequently, 35% hydrochloric acid (942.8 g) was added at the same temperature to adjust the pH of the reaction mixture to 7. Liquid separation was performed at room temperature, and the organic layer was separated. The organic layer was washed twice with water (3411.8 mL), and the obtained organic layer was concentrated until the target concentration was about 20% by weight. To the obtained mixture, heptane (6484.4 mL) was added dropwise at 45 ° C. to crystallize the desired product. After the mixture was cooled to 0 ° C., the crystals were filtered, then washed with a cooled toluene-heptane mixture (weight ratio 1: 1, 1194.1 g), and further washed with cooled heptane (1745.8 mL). The crystals thus obtained were dried to give methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate (1136.2 g, Yield from glycine: 70%) was obtained.
1 H-NMR (CDCl 3 , δ); 1.41 (9H, s), 3.55 (3H, s), 6.31 (1H, brs), 7.30 (1H, brs), 7.33-7.45 (3H, m), 7.57- 7.63 (6H, m)
　本発明により、医薬等の製造中間体として有用な式
Figure JPOXMLDOC01-appb-I000006
According to the present invention, a formula useful as an intermediate for production of pharmaceuticals
Figure JPOXMLDOC01-appb-I000006
で示される化合物の製造中間体である（２Ｚ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロプ－２－エノエートを製造できる。 (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate, which is an intermediate for producing the compound represented by

Claims (2)

  1. 　４－フェニルベンズアルデヒドとグリシンとを水酸化ナトリウム又は水酸化カリウムの存在下で反応させ、得られた反応混合物と塩酸とを混合することにより、２－アミノ－３－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロピオン酸塩酸塩を得る工程；
    　２－アミノ－３－（１，１’－ビフェニル－４－イル）－３－ヒドロキシプロピオン酸塩酸塩とジ－ｔｅｒｔ－ブチルジカーボネートとを塩基性条件下で反応させて３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロピオン酸を得る工程；
    　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロピオン酸とジメチル硫酸とを塩基の存在下で反応させてメチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエートを得る工程；及び
    　メチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエートを塩基の存在下でメタンスルホニルクロリドと反応させて対応するメシル体を得、次いでメシル体をナトリウムメチラートと反応させて、メチル　（２Ｚ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロプ－２－エノエートを得る工程；
    を含むメチル　（２Ｚ）－３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］プロプ－２－エノエートの製造方法。     By reacting 4-phenylbenzaldehyde and glycine in the presence of sodium hydroxide or potassium hydroxide, and mixing the resulting reaction mixture with hydrochloric acid, 2-amino-3- (1,1′-biphenyl- Obtaining 4-yl) -3-hydroxypropionate hydrochloride;
    2-Amino-3- (1,1′-biphenyl-4-yl) -3-hydroxypropionate hydrochloride and di-tert-butyl dicarbonate were reacted under basic conditions to give 3- (1,1 Obtaining '-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid;
    3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropionic acid and dimethyl sulfate are reacted in the presence of a base to give methyl 3- (1 , 1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate; and methyl 3- (1,1′-biphenyl-4-yl)- 2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate is reacted with methanesulfonyl chloride in the presence of a base to give the corresponding mesyl form, then the mesyl form is reacted with sodium methylate, Methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate is obtained. Process;
    Of methyl (2Z) -3- (1,1′-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] prop-2-enoate containing
  2. 　メチル　３－（１，１’－ビフェニル－４－イル）－２－［（ｔｅｒｔ－ブトキシカルボニル）アミノ］－３－ヒドロキシプロパノエート。 Methyl 3- (1,1'-biphenyl-4-yl) -2-[(tert-butoxycarbonyl) amino] -3-hydroxypropanoate.
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JP2003342251A (en) * 2002-03-18 2003-12-03 Sumitomo Chem Co Ltd Method for producing biarylalanine
WO2016199688A1 (en) * 2015-06-10 2016-12-15 住友化学株式会社 Method for producing carbamate compound

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GB762240A (en) * 1953-06-30 1956-11-28 Hoechst Ag Process for the manufacture of n-acylated amino-alcohols
JPS60190749A (en) * 1984-03-12 1985-09-28 Mitsui Toatsu Chem Inc Preparation of alpha-acetamidocinnamic acid
JP2003342251A (en) * 2002-03-18 2003-12-03 Sumitomo Chem Co Ltd Method for producing biarylalanine
WO2016199688A1 (en) * 2015-06-10 2016-12-15 住友化学株式会社 Method for producing carbamate compound

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ZHI-TAO HE ET AL.: "Copper-Catalyzed Asymmetric Hydroboration of alpha-Dehydroamino Acid Derivatives: Facile Synthesis of Chiral beta- Hydroxy-alpha-amino Acids", ORGANIC LETTERS, vol. 16, 14 February 2014 (2014-02-14), pages 1426 - 1429, XP055392189 *

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