WO2010067824A1 - 光学活性カルボン酸の製造方法 - Google Patents
光学活性カルボン酸の製造方法 Download PDFInfo
- Publication number
- WO2010067824A1 WO2010067824A1 PCT/JP2009/070613 JP2009070613W WO2010067824A1 WO 2010067824 A1 WO2010067824 A1 WO 2010067824A1 JP 2009070613 W JP2009070613 W JP 2009070613W WO 2010067824 A1 WO2010067824 A1 WO 2010067824A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- solvent
- general formula
- water
- compound
- compound represented
- Prior art date
Links
- 0 *OC([C@]1CC=CCC1)=O Chemical compound *OC([C@]1CC=CCC1)=O 0.000 description 2
- VUSWCWPCANWBFG-UHFFFAOYSA-N OC(C1CC=CCC1)=O Chemical compound OC(C1CC=CCC1)=O VUSWCWPCANWBFG-UHFFFAOYSA-N 0.000 description 1
- VUSWCWPCANWBFG-ZCFIWIBFSA-N OC([C@@H]1CC=CCC1)=O Chemical compound OC([C@@H]1CC=CCC1)=O VUSWCWPCANWBFG-ZCFIWIBFSA-N 0.000 description 1
- VUSWCWPCANWBFG-LURJTMIESA-N OC([C@H]1CC=CCC1)=O Chemical compound OC([C@H]1CC=CCC1)=O VUSWCWPCANWBFG-LURJTMIESA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/353—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C61/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C61/16—Unsaturated compounds
- C07C61/22—Unsaturated compounds having a carboxyl group bound to a six-membered ring
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Definitions
- the present invention relates to a method for producing an intermediate of a compound that exhibits an inhibitory action on activated blood coagulation factor X (FXa) and is useful as a preventive and / or therapeutic agent for thrombotic diseases.
- FXa activated blood coagulation factor X
- activated blood coagulation factor X (sometimes referred to as activated factor X or FXa) and is useful as a prophylactic and / or therapeutic agent for thrombotic diseases, for example, the following formula (X)
- Patent Documents 1 to 4 A p-toluenesulfonic acid monohydrate of Compound X represented by the formula is known (Patent Documents 1 to 4).
- Compound A uses 3-cyclohexene-1-carboxylic acid (hereinafter sometimes referred to as Compound I) using (R) - ⁇ -phenylethylamine (hereinafter sometimes referred to as (R) -PEA). It is known that it can be obtained by optically dividing (Non-patent Document 1). Non-Patent Document 1 does not describe a solvent used in optical resolution, and describes that recrystallization is required five times or more.
- Non-patent Document 2 It has also been reported that Compound A is obtained by an asymmetric hydrolysis reaction with an enzyme (Non-patent Document 2).
- this method requires a large amount of solvent, and when assuming industrial production, an efficient method is essential from the viewpoint of volumetric efficiency.
- stereoisomer (R) -3-cyclohexene-1-carboxylic acid is produced as a by-product. It is not described at all.
- Non-patent Document 3 a method for obtaining compound A stereoselectively by an asymmetric Diels-Alder reaction using D-pantolactone as an asymmetric auxiliary group has also been reported (Non-patent Document 3).
- D-pantolactone is expensive, and a cheaper method has been demanded when industrial production is assumed.
- the object of the present invention is to provide (R) - ⁇ -phenylethylamine salt of (S) -3-cyclohexene-1-carboxylic acid or (S) -3-cyclohexene-1-carboxylic acid from 3-cyclohexene-1-carboxylic acid It is to provide a method for efficiently and inexpensively manufacturing a product.
- a method for producing (R) - ⁇ -phenylethylamine salt of (S) -3-cyclohexene-1-carboxylic acid and / or (S) -3-cyclohexene-1-carboxylic acid efficiently at low cost Is provided.
- an unnecessary stereoisomer (R) -3-cyclohexene-1-carboxylic acid for obtaining (S) -3-cyclohexene-1-carboxylic acid from 3-cyclohexene-1-carboxylic acid is converted into 3 A process for racemizing to cyclohexene-1-carboxylic acid is provided.
- R 1 represents a C1-C6 alkyl group
- V the compound represented by the general formula (V) is reacted with a base in a solvent.
- C1-C6 alkyl refers to a linear or branched alkyl group having 1 to 6 carbon atoms.
- C1-C6 alkyl includes, for example, methyl, ethyl, propyl or isopropyl.
- examples of the “C1 to C6 alkyl alcohol” include methanol, ethanol, propanol, and isopropyl alcohol.
- hydrophilic solvent refers to a mixed solvent of water and a solvent other than water. Mixing of water and a solvent other than water may be before the reaction or may be in the middle of the reaction, and is not particularly limited as long as water and a solvent other than water act as a solvent.
- N 1- (5-chloropyridin-2-yl) -N 2 -((1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2- ⁇ [(5-methyl- 4,5,6,7-tetrahydrothiazolo [5,4-c] pyridin-2-yl) carbonyl] amino ⁇ cyclohexyl) ethanediamide
- N 1- (5-Chloropyridin-2-yl) -N 2 -(( 1S, 2R, 4S) -4-[(dimethylamino) carbonyl] -2- ⁇ [(5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c] pyridine-2-yl) carbonyl] amino ⁇ cyclohexyl) ethanediamide
- Y the formula (Y)
- WHO) World Health Organization
- R 1 represents a C1-C6 alkyl group.
- the compound represented by the general formula II (hereinafter sometimes referred to as compound II) is a crystalline diastereomeric salt obtained by allowing (R) -PEA to act on compound I as an optically active base in a solvent. Can be obtained as Compound II with higher purity can be obtained by further repeating recrystallization of this salt (step a).
- Compound I and (R) -PEA can be synthesized by a known method, or can be purchased from commercial sources.
- the solvent in the salt resolution is not particularly limited, but for example, water; alcohol solvents such as methanol, ethanol or isopropyl alcohol; ethers such as diethyl ether, dipropyl ether, diisopropyl ether, tetrahydrofuran, methyl t-butyl ether or cyclopentyl methyl ether Solvent; ester solvent such as methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate or phenyl acetate; halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane or tetrachloroethane; acetone, methyl ethyl ketone , Ketone solvents such as diethyl ketone or methyl isobutyl ketone; aromatic charcoal such as benzene, chlorobenzene,
- water-containing acetone or a mixed solvent of water and ethyl acetate (hereinafter sometimes referred to as water-containing ethyl acetate).
- the water content when water-containing acetone is used as the solvent for salt separation is not particularly limited, but is preferably 3% to 90%, more preferably 4% to 70%.
- the water content when water-containing ethyl acetate is used as the solvent is not particularly limited, but is preferably 0.1% to 3%, more preferably 0.5% to 3%.
- the amount of the salt-resolving solvent is not particularly limited, but is preferably 5 to 30 times (v / w), more preferably 5 to 10 times (v / w) with respect to Compound I.
- the temperature of crystallization by salt splitting varies depending on the solvent used, but is ⁇ 10 ° C. to the boiling point of the solvent, preferably 0 ° C. to 60 ° C.
- the temperature may be kept constant, or may be cooled stepwise after being maintained for several hours at the temperature at which crystals are precipitated.
- cooling stepwise for example, it is maintained at 40 ° C. to 60 ° C. for 2 to 6 hours, and then slowly cooled (for example, 5 to 10 ° C./hour, preferably 20 to 40 ° C., 5 ° C./hour).
- cooling is preferably performed at a rate of 10 ° C / hour from -10 ° C to 20 ° C.
- the time for crystallization of salt separation may be in the range of 1 hour to 48 hours, preferably in the range of 16 hours to 30 hours.
- the amount of (R) -PEA is not particularly limited, but for example, the compound I may be reacted at 0.5 to 2 equivalents, preferably 0.5 to 1 equivalents.
- the temperature at which the crystallized compound II is filtered is not particularly limited, but is preferably ⁇ 20 ° C. to 50 ° C., more preferably ⁇ 10 ° C. to 30 ° C.
- the precipitated crystals can be isolated by, for example, filtration, centrifugation, or a gradient method.
- the isolated crystals can be washed with a suitable solvent as necessary.
- Compound II obtained by optical resolution using (R) -PEA of Compound I can be further heated and dissolved in a solvent, and then cooled and recrystallized to further increase the optical purity.
- the solvent for recrystallization is not particularly limited.
- water alcohol solvents such as methanol, ethanol or isopropyl alcohol
- ethers such as diethyl ether, dipropyl ether, diisopropyl ether, tetrahydrofuran, methyl t-butyl ether or cyclopentyl methyl ether Solvent; ester solvent such as methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate or phenyl acetate; halogenated hydrocarbon solvent such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane or tetrachloroethane; acetone, methyl ethyl ketone , Ketone solvents such as diethyl ketone or methyl isobutyl ketone; aromatic charcoal such as benzene, chlorobenzene, to
- ethyl acetate, acetone, a mixed solvent of ethanol and diisopropyl ether, a mixed solvent of ethyl acetate and acetone, hydrous acetone or hydrous water Ethyl acetate is mentioned.
- the water content when water-containing acetone is used is not particularly limited, but is preferably 3% to 90%, more preferably 4% to 70%.
- the water content when water-containing ethyl acetate is used as the solvent is not particularly limited, but is preferably 0.1% to 3%, more preferably 0.5% to 3%.
- the solvent for recrystallization a different type of solvent from the solvent used in salt resolution may be used, but the same solvent is preferably used.
- the amount of the solvent in the recrystallization is not particularly limited, but is preferably 5 to 30 times (v / w), more preferably 5 to 10 times (v / w) with respect to Compound II.
- the crystallization temperature for recrystallization varies depending on the solvent used, but is ⁇ 10 ° C. to the boiling point of the solvent, preferably 0 ° C. to 60 ° C.
- the temperature may be kept constant, or may be cooled stepwise after being maintained for several hours at the temperature at which crystals are precipitated.
- cooling stepwise for example, it is maintained at 40 ° C. to 60 ° C. for 2 to 6 hours, and then slowly cooled (for example, 5 to 10 ° C./hour, preferably 20 to 40 ° C., 5 ° C./hour).
- cooling is preferably performed at a rate of 10 ° C / hour from -10 ° C to 20 ° C.
- the recrystallization time may be in the range of 1 to 48 hours, preferably in the range of 16 to 30 hours.
- the temperature at which the compound II crystallized by recrystallization is filtered is not particularly limited, but is preferably ⁇ 20 ° C. to 50 ° C., more preferably ⁇ 10 ° C. to 30 ° C.
- the number of recrystallizations is not particularly limited as long as the target compound is obtained with good purity and good yield, but according to the method of the present invention, it is at least 5 times or less, preferably 3 times or less, more preferably Compound II having a high purity can be obtained by recrystallization of an extremely small number of times of 2 or less. Therefore, the method of the present invention comprises compound II, and further, compound A obtained by using compound II as described in detail below, and thus an activated blood coagulation factor X inhibitor described in Patent Documents 1 to 4 and the like It is very useful as a method for industrially producing a useful compound.
- Compound A can be obtained by reacting compound II with an acid such as hydrochloric acid or sulfuric acid (step b).
- the acid used in step (b) is not particularly limited, and examples thereof include hydrochloric acid, sulfuric acid, benzenesulfonic acid, methanesulfonic acid, and p-toluenesulfonic acid, and preferably hydrochloric acid or sulfuric acid.
- the solvent used in step (b) is not particularly limited.
- water alcohol solvents such as methanol, ethanol or isopropyl alcohol; diethyl ether, dipropyl ether, diisopropyl ether, tetrahydrofuran, methyl t-butyl ether or cyclopentylmethyl Ether solvents such as ether; ester solvents such as methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate or phenyl acetate; halogenated hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane or tetrachloroethane Ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone or methyl isobutyl ketone; benzene, chlorobenzene, toluene or
- the amount of the solvent used in the step (b) is not particularly limited, but is preferably 5 to 30 times (v / w), more preferably 5 to 10 times (v / w) with respect to Compound II.
- the reaction temperature used in step (b) varies depending on the solvent used, but is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from 0 ° C. to 30 ° C.
- the reaction time used in step (b) may be in the range of 10 minutes to 24 hours, preferably in the range of 15 minutes to 8 hours.
- Compound A synthesized in this way is useful as an intermediate of a compound useful as an activated blood coagulation factor X (FXa) inhibitor described in Patent Documents 1 to 4, for example.
- FXa activated blood coagulation factor X
- Compound I is represented by general formula (IV) by reacting a compound represented by general formula (III) (hereinafter sometimes referred to as compound III) with a C1-C6 alkyl alcohol in the presence of an acid catalyst.
- a compound hereinafter sometimes referred to as compound IV
- step c A compound (hereinafter sometimes referred to as compound IV) was obtained (step c), and the compound IV was reacted with a base in a solvent to represent an ester represented by formula (V) (hereinafter sometimes referred to as compound V).
- Step d and then compound V can be obtained by hydrolysis in C1-C6 alkyl alcohol (step e).
- the acid catalyst used in step (c) is not particularly limited, and examples thereof include hydrochloric acid, sulfuric acid, benzenesulfonic acid, methanesulfonic acid, and p-toluenesulfonic acid, and preferably hydrochloric acid and sulfuric acid.
- the C1-C6 alkyl alcohol used in the step (c) is not particularly limited, and examples thereof include methanol, ethanol, propanol, and isopropyl alcohol, and preferably methanol or ethanol.
- the solvent used in step (c) is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction, but water; alcohol solvents such as methanol, ethanol or isopropyl alcohol; diethyl ether, dipropyl ether, Ether solvents such as diisopropyl ether, tetrahydrofuran, methyl t-butyl ether or cyclopentyl methyl ether; ester solvents such as methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate or phenyl acetate; dichloromethane, chloroform, carbon tetrachloride , Halogenated hydrocarbon solvents such as dichloroethane or tetrachloroethane; ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone or methyl isobutyl
- the amount of the solvent used in the step (c) is not particularly limited, but is preferably 5 to 30 times (v / w), more preferably 5 to 10 times (v / w) with respect to Compound III.
- the reaction temperature in step (c) varies depending on the solvent used, but is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from room temperature to the boiling point of the solvent.
- reaction time in step (c) may be in the range of 1 to 24 hours, preferably in the range of 3 to 20 hours.
- the solvent used in step (d) is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
- water alcohol solvents such as methanol, ethanol, isopropyl alcohol; diethyl ether, dipropyl Ether solvents such as ether, diisopropyl ether, tetrahydrofuran, methyl t-butyl ether, cyclopentyl methyl ether; ester solvents such as methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and phenyl acetate; dichloromethane, chloroform, four Halogenated hydrocarbon solvents such as carbon chloride, dichloroethane, tetrachloroethane; ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone;
- the amount of the solvent used in the step (d) is not particularly limited, but is preferably 1 to 30 times (v / w), more preferably 5 to 10 times (v / w) with respect to Compound III.
- the base used in step (d) is not particularly limited, but for example: alkali metal such as sodium, potassium or lithium or alkaline earth metal hydroxide such as magnesium or calcium, carbonate, bicarbonate or alkoxide Metal hydrides such as sodium hydride, potassium hydride or lithium hydride; alkyllithium reagents such as n-butyllithium or methyllithium; or 1,8-diazabicyclo [5.4.0] undec-7-ene; And basic heterocyclic compounds such as (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) or dimethylaniline.
- alkali metal such as sodium, potassium or lithium or alkaline earth metal hydroxide such as magnesium or calcium, carbonate, bicarbonate or alkoxide
- Metal hydrides such as sodium hydride, potassium hydride or lithium hydride
- alkyllithium reagents such as n-butyllithium or methyllithium
- this step includes quaternary ammonium salt such as tetrabutylammonium bromide or benzyltriethylammonium chloride, alkali metal or alkaline earth metal iodide such as potassium iodide or sodium iodide, and crown ether.
- quaternary ammonium salt such as tetrabutylammonium bromide or benzyltriethylammonium chloride
- alkali metal or alkaline earth metal iodide such as potassium iodide or sodium iodide
- crown ether such as potassium iodide or sodium iodide
- alkoxides, metal hydrides or basic heterocyclic compounds are preferable, and sodium ethoxide, sodium hydride or DBU is more preferable.
- the amount of the base used in step (d) is not particularly limited, but is preferably 1 equivalent to 30 equivalents, more preferably 1 equivalent to 5 equivalents, relative to compound III.
- the reaction temperature in step (d) varies depending on the solvent used, but is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from 50 ° C. to the boiling point of the solvent.
- reaction time in step (d) may be in the range of 1 to 24 hours, preferably in the range of 6 to 20 hours.
- the hydrolysis in the step (e) is performed using an acid or an alkali, and an acid such as hydrochloric acid or sulfuric acid is used for the acidic hydrolysis.
- an acid such as hydrochloric acid or sulfuric acid
- alkaline hydrolysis alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; alkali metal carbonate such as sodium carbonate or potassium carbonate; base such as alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate And the base is usually used as an aqueous solution.
- alkaline hydrolysis is preferred.
- the solvent used in step (e) is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
- water alcohol solvents such as methanol, ethanol or isopropyl alcohol; diethyl ether, dipropyl Ether solvents such as ether, diisopropyl ether, tetrahydrofuran, methyl t-butyl ether or cyclopentyl methyl ether; ester solvents such as methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate or phenyl acetate; dichloromethane, chloroform, four Halogenated hydrocarbon solvents such as carbon chloride, dichloroethane or tetrachloroethane; ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone or methyl isobutyl ketone;
- the amount of the base used in the step (e) is not particularly limited, but is preferably 1 equivalent to 30 equivalents, more preferably 1 equivalent to 5 equivalents, relative to the compound III.
- the reaction temperature in step (e) varies depending on the solvent used, but is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from 50 ° C. to the boiling point of the solvent.
- reaction time in step (e) may be in the range of 1 to 24 hours, preferably in the range of 6 to 20 hours.
- the solvent used in this step is not particularly limited as long as it dissolves the starting materials to some extent and does not inhibit the reaction.
- water alcohol solvents such as methanol, ethanol or isopropyl alcohol; diethyl ether, dipropyl ether, Ether solvents such as diisopropyl ether, tetrahydrofuran, methyl t-butyl ether or cyclopentyl methyl ether; ester solvents such as methyl formate, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate or phenyl acetate; dichloromethane, chloroform, carbon tetrachloride Halogenated hydrocarbon solvents such as acetone, dichloroethane or tetrachloroethane; ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone or methyl isobutyl
- the amount of the solvent used in this step is not particularly limited, but is preferably 1 to 50 times (v / w), more preferably 5 to 10 times (v / w) with respect to Compound III.
- the base used in this step is not particularly limited, but for example: alkali metal such as sodium, potassium or lithium or alkaline earth metal hydroxide such as magnesium or calcium, carbonate, bicarbonate or alkoxide; hydrogen Metal hydrides such as sodium hydride, potassium hydride or lithium hydride; alkyllithium reagents such as n-butyllithium or methyllithium; or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) ), A basic heterocyclic compound such as 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) or dimethylaniline.
- alkali metal such as sodium, potassium or lithium or alkaline earth metal hydroxide such as magnesium or calcium, carbonate, bicarbonate or alkoxide
- hydrogen Metal hydrides such as sodium hydride, potassium hydride or lithium hydride
- alkyllithium reagents such as n-butyllithium or methyllithium
- DBU
- the amount of the base used in this step is not particularly limited, but is preferably 0.1 to 10 equivalents, preferably 1 to 5 equivalents with respect to Compound III.
- the reaction temperature in this step varies depending on the solvent used, but is from ⁇ 78 ° C. to the boiling point of the solvent, preferably from 50 ° C. to the boiling point of the solvent.
- the reaction time of this step may be in the range of 1 to 24 hours, preferably in the range of 6 to 20 hours.
- the unnecessary stereoisomeric compound III obtained in the step (a) is converted into the compound I and again converted into the compound II and the compound A, and further, Patent Documents 1-4.
- the optical purity (% ee) of the obtained compound was determined as follows.
- the optical purity (% ee) of the carboxylic acid in the diastereomeric salt was determined after derivatization to the corresponding carboxylic acid.
- the optical purity (% ee) of the carboxylic acid, methyl ester form and ethyl ester form was measured by GC.
- Example 1 (S) -3-Cyclohexene-1-carboxylic acid / (R) - ⁇ -phenylethylamine salt 3-cyclohexene-1-carboxylic acid (1.0 kg) containing 4.8% aqueous acetone (7. 5L), and slowly add a solution (500 ml) of (R) - ⁇ -phenylethylamine (624.3 g) in 4.8% aqueous acetone at 50 ° C. and stir at that temperature for 4 hours. did. The suspension was cooled to 35 ° C., stirred at the same temperature for 16 hours, and further stirred at 10 ° C. for 3 hours.
- the suspension was subjected to vacuum filtration to obtain 837.1 g of the title compound as white crystals. Its optical purity was 63% de.
- 4.8% aqueous acetone (5.6 L) was added to 700 g of the obtained salt, stirred for 13 hours at 30 ° C. for 5 hours under heating to reflux, and then stirred for 3 hours under ice cooling.
- the suspension was subjected to vacuum filtration to obtain 519.4 g of the title compound as white crystals. Its optical purity was 81% de.
- 4.8% aqueous acetone (4.0 L) was added to 500 g of the obtained salt, and the mixture was stirred for 5 hours at 30 ° C. for 13 hours under reflux with heating, and then stirred at 10 ° C.
- Example 7 Ethyl-3-cyclohexene-1-carboxylate ethyl (R) -3-cyclohexene-1-carboxylate (1.0 g, 97% ee) was dissolved in N, N-dimethylformamide (10 ml). 1,8-diazabicyclo [5.4.0] undec-7-ene (1.0 ml) was added at room temperature, and the mixture was stirred at 120 ° C. for 18 hours. After cooling the reaction solution to room temperature, a 10% aqueous citric acid solution was added dropwise, followed by extraction with cyclopentyl methyl ether, and the organic layer was washed with water and then dried over anhydrous magnesium sulfate.
Abstract
Description
[1]一般式(I)
[2]さらに、一般式(II)で表される化合物を、再結晶溶媒として含水アセトンまたは含水酢酸エチルを用いて再結晶させる工程を含む、[1]に記載の方法;
[3]溶媒及び再結晶溶媒として含水酢酸エチルを用いることを特徴とする、[2]に記載の方法;
[4]含水酢酸エチルの含水率が0.5%~3.0%である、[3]に記載の方法;
[5]一般式(II)で表される化合物を酸で処理して、一般式(A)
[6][1]の製造方法において得られる一般式(III)
[7]一般式(IV)で表される化合物から一般式(V)で表される化合物を得る工程の溶媒が、N,N-ジメチルホルムアミドである、[6]に記載の方法;
[8]一般式(IV)で表される化合物から一般式(V)で表される化合物を得る工程の塩基が1,8-ジアザビシクロ[5.4.0]ウンデク-7-エンである、[6]または[7]に記載の方法;
[9]加水分解に用いる溶媒がメタノールまたはエタノールである、[6]~[8]のいずれか1に記載の方法;
[10]加水分解に用いる塩基が水酸化ナトリウムである、[6]~[9]のいずれか1に記載の方法;
[11][1]の製造方法において得られる一般式(III)
[12]溶媒が、N,N-ジメチルホルムアミドである、[11]に記載の方法;
[13]塩基が、水素化ナトリウムである、[11]または[12]に記載の方法;
に関する。
(工程a)
一般式IIで表される化合物(以下、化合物IIと称する場合がある。)は、溶媒中、化合物Iに光学活性な塩基として(R)-PEAを作用させることで結晶性のジアステレオマー塩として得ることができる。この塩の再結晶をさらに繰り返すことでより純度の高い化合物IIを得ることができる(工程a)。
(工程b)
化合物IIに塩酸または硫酸等の酸を作用させることにより、化合物Aを得ることができる(工程b)。
(工程c、工程dおよび工程e)
化合物Iは、一般式(III)で表される化合物(以下、化合物IIIと称する場合がある。)に酸触媒下、C1~C6アルキルアルコールを反応させて、一般式(IV)で表される化合物(以下、化合物IVと称する場合がある。)を得(工程c)、該化合物IVを溶媒中、塩基と反応させて式(V)で表されるエステル(以下、化合物Vと称する場合がある。)を得(工程d)、次いで化合物VをC1~C6アルキルアルコール中、加水分解を行なう(工程e)ことで得ることができる。
(工程f)
化合物Iは、化合物IIIを、溶媒中、塩基と反応させても得ることができる。
以下に実施例を記載するが、本発明はこれらに限定されるものではない。
光学純度分析条件;検出器:FID、カラム:J&W Cyclodex(登録商標)、30m×0.25mm、試料気化室温度:250℃、カラム温度:90℃、検出部温度:250℃、キャリアーガス:ヘリウム、流速1ml/min]
3-シクロヘキセン-1-カルボン酸(1.0kg)を4.8%含水アセトン(7.5L)に溶解し、50℃にて(R)-α-フェニルエチルアミン(624.3g)を4.8%含水アセトンに溶解した溶液(500ml)を徐々に加え、そのままの温度にて4時間攪拌した。懸濁液を35℃まで冷却し、そのままの温度にて16時間攪拌後、更に10℃にて3時間攪拌した。懸濁液を減圧濾過に附し、標題化合物を白色結晶として837.1g得た。その光学純度は、63%deであった。続いて、得られた塩700gへ4.8%含水アセトン(5.6L)を加え、加熱還流下、5時間、30℃にて13時間攪拌後、氷冷下、3時間攪拌した。その懸濁液を減圧濾過に附し、標題化合物を白色結晶として519.4g得た。その光学純度は、81%deであった。さらに、得られた塩500gへ4.8%含水アセトン(4.0L)を加え、加熱還流下、5時間、30℃にて13時間攪拌後、10℃にて、3時間攪拌した。その懸濁液を減圧濾過に附し、標題化合物を白色結晶として398.5g得た。その光学純度は、91%deであった。最後に、得られた塩300gへ4.8%含水アセトン(2.4L)を加え、加熱還流下、5時間、30℃にて13時間攪拌後、10℃にて、3時間攪拌した。その懸濁液を減圧濾過に附し、標題化合物を白色結晶として240.0g得た。その光学純度は、97%deであった。
1H-NMR(D2O)δ:1.50-1.63(1H,m)、1.66(3H,d,J=6.9hz)、1.86-1.95(1H,m)、1.98-2.25(4H,m)、2.32-2.43(1H,m)、4.56(1H,q,J=6.9Hz)、5.70-5.80(2H,m)、7.40-7.55(5H,m)
元素分析:C15H21N1O2として
理論値(%)C;72.84,H;8.56,N;5.66
実測値(%)C;72.88,H;8.58,N;5.72
(実施例2)(S)-3-シクロヘキセン-1-カルボン酸・(R)-α-フェニルエチルアミン塩
3-シクロヘキセン-1-カルボン酸(30g)を3%含水酢酸エチル(150ml)に溶解し、55℃にて(R)-α-フェニルエチルアミン(23.0g)を3%含水酢酸エチルに溶解した溶液(30ml)を徐々に加え、そのままの温度にて6時間攪拌した。懸濁液を25℃にて5時間、更に-10℃にて2時間30分間攪拌した。懸濁液を減圧濾過に附し、標題化合物を白色結晶として32.9g得た。その光学純度は、49%deであった。続いて、得られた塩32.7gへ3%含水酢酸エチル(196ml)を加え、55℃にて3時間攪拌後、25℃にて5時間、更に-10℃にて2時間30分間攪拌した。その懸濁液を減圧濾過に附し、標題化合物を白色結晶として24.7g得た。その光学純度は、78%deであった。さらに、得られた塩24.6gへ3%含水酢酸エチル(148ml)を加え、55℃にて3時間攪拌後、25℃にて5時間、更に-10℃にて2時間30分間攪拌した。その懸濁液を減圧濾過に附し、標題化合物を白色結晶として20.3g得た。その光学純度は、95%deであった。
各種スペクトルデータは、実施例1と一致した。
(参考例1)(S)-3-シクロヘキセン-1-カルボン酸・(R)-α-フェニルエチルアミン塩
3-シクロヘキセン-1-カルボン酸(10.0g)をアセトン(70ml)に溶解し、50℃にて(R)-α-フェニルエチルアミン(6.2g)のアセトン溶液(10ml)を徐々に加え、そのままの温度にて4時間攪拌した。懸濁液を30℃まで冷却し、そのままの温度にて16時間攪拌後、更に10℃にて3時間攪拌した。懸濁液を減圧濾過に附し、標題化合物を白色結晶として9.5g得た。その光学純度は、45%deであった。
各種スペクトルデータは、実施例1と一致した。
(参考例2)(S)-3-シクロヘキセン-1-カルボン酸・(R)-α-フェニルエチルアミン塩
3-シクロヘキセン-1-カルボン酸(10.0g)を酢酸エチル(50ml)に溶解し、50℃にて(R)-α-フェニルエチルアミン(6.2g)の酢酸エチル溶液(10ml)を徐々に加え、そのままの温度にて4時間攪拌した。懸濁液を30℃まで冷却し、そのままの温度にて16時間攪拌後、更に10℃にて3時間攪拌した。懸濁液を減圧濾過に附し、標題化合物を白色結晶として9.8g得た。その光学純度は、40%deであった。
各種スペクトルデータは、実施例1と一致した。
(実施例3)(S)-3-シクロヘキセン-1-カルボン酸
(S)-3-シクロヘキセン-1-カルボン酸・(R)-α-フェニルエチルアミン塩(1.0g,97%de)にメチルt-ブチルエーテル(20ml)、1規定塩酸溶液をpH1になるまで加え、室温にて1時間攪拌した。有機層を無水硫酸マグネシウムにて乾燥後、溶媒を留去し、標題化合物を無色油状物として504mg得た。
1H-NMR(CDCl3)δ: 1.64-1.75(1H,m)、1.99-2.20(3H,m)、2.24-2.30(2H,m)、2.56-2.63(1H,m)、5.63-5.70(2H,m)
(実施例4)メチル(R)-3-シクロヘキセン-1-カルボキシレート
(R)-3-シクロヘキセン-1-カルボン酸(1.0g,97%de)をメタノール(10ml)に溶解し、室温にて5規定塩酸水溶液(1ml)を加えた。反応液を6時間加熱還流した後、溶媒を留去した。得られた残渣へメチルt-ブチルエーテルを加えた後、有機層を飽和炭酸水素ナトリウム溶液および水にて洗浄後、無水硫酸マグネシウムにて乾燥した。溶媒留去後、得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル-ノルマルヘキサン=1:1)に附し、標題化合物を無色油状物として1.08g得た。その光学純度は97%eeであった。
1H-NMR(CDCl3)δ: 1.60-1.77(1H,m)、1.95-2.13(3H,m)、2.23-2.29(2H,m)、2.50-2.62(1H,m)、3.70(3H,s)、5.64-5.71(2H,m)
(実施例5)エチル(R)-3-シクロヘキセン-1-カルボキシレート
(R)-3-シクロヘキセン-1-カルボン酸(1.0g,97%de)をエタノール(10ml)に溶解し、室温にて5規定塩酸水溶液(1ml)を加えた。反応液を6時間加熱還流した後、溶媒を留去した。得られた残渣へメチルt-ブチルエーテルを加えた後、有機層を飽和炭酸水素ナトリウム溶液および水にて洗浄後、無水硫酸マグネシウムにて乾燥した。溶媒留去後、得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル-ノルマルヘキサン=1:1)に附し、標題化合物を無色油状物として1.13g得た。その光学純度は97%eeであった。
1H-NMR(CDCl3)δ: 1.26(3H,t,J=7.2Hz)、1.62-1.75(1H,m)、1.95-2.15(3H,m)、2.21-2.30(2H,m)、2.49-2.59(1H,m)、4.14(2H,q,J=7.2Hz)、5.64-5.72(2H,m)
(実施例6)メチル-3-シクロヘキセン-1-カルボキシレート
メチル(R)-3-シクロヘキセン-1-カルボキシレート(1.0g,97%ee)をN,N-ジメチルホルムアミド(10ml)に溶解し、室温にて1,8-ジアザビシクロ[5.4.0]ウンデク-7-エン(1.1ml)を加え、120℃にて18時間攪拌した。反応液を室温まで冷却後、10%クエン酸水溶液を滴下後、シクロペンチルメチルエーテルにて抽出し、有機層を水にて洗浄後、無水硫酸マグネシウムにて乾燥した。溶媒留去後、得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル-ノルマルヘキサン=1:1)に附し、標題化合物を無色油状物として0.91g得た。その光学純度は0%eeであった。H-NMRスペクトルデータは、実施例4と一致した。
(実施例7)エチル-3-シクロヘキセン-1-カルボキシレート
エチル(R)-3-シクロヘキセン-1-カルボキシレート(1.0g,97%ee)をN,N-ジメチルホルムアミド(10ml)に溶解し、室温にて1,8-ジアザビシクロ[5.4.0]ウンデク-7-エン(1.0ml)を加え、120℃にて18時間攪拌した。反応液を室温まで冷却後、10%クエン酸水溶液を滴下後、シクロペンチルメチルエーテルにて抽出し、有機層を水にて洗浄後、無水硫酸マグネシウムにて乾燥した。溶媒留去後、得られた残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル-ノルマルヘキサン=1:1)に附し、標題化合物を無色油状物として0.89g得た。その光学純度は0%eeであった。H-NMRスペクトルデータは、実施例5と一致した。
(実施例8)3-シクロヘキセン-1-カルボン酸
メチル-3-シクロヘキセン-1-カルボキシレート(1.0g)をメタノール(10ml)に溶解し、室温にて5N水酸化ナトリウム水溶液(5ml)を加え、そのままの温度にて16時間攪拌した。反応液へ塩酸を加えた後、シクロペンチルメチルエーテルにて抽出し、有機層を水にて洗浄後、無水硫酸マグネシウムにて乾燥した。溶媒留去後、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=3:1)に附し、標題化合物を無色油状物として855mg得た。H-NMRスペクトルデータは、実施例3と一致した。
(実施例9)3-シクロヘキセン-1-カルボン酸
エチル-3-シクロヘキセン-1-カルボキシレート(1.0g)をエタノール(10ml)に溶解し、室温にて5N水酸化ナトリウム水溶液(5ml)を加え、そのままの温度にて16時間攪拌した。反応液へ塩酸を加えた後、シクロペンチルメチルエーテルにて抽出し、有機層を水にて洗浄後、無水硫酸マグネシウムにて乾燥した。溶媒留去後、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=3:1)に附し、標題化合物を無色油状物として800mg得た。H-NMRスペクトルデータは、実施例3と一致した。
(実施例10)3-シクロヘキセン-1-カルボン酸
(R)-3-シクロヘキセン-1-カルボン酸(1.0g,97%ee)をN,N-ジメチルホルムアミド(10ml)に溶解し、室温にて60%水素化ナトリウム(634mg)を加え、120℃にて18時間攪拌した。反応液を室温まで冷却後、10%クエン酸水溶液を滴下後、シクロペンチルメチルエーテルにて抽出し、有機層を水にて洗浄後、無水硫酸マグネシウムにて乾燥した。溶媒留去後、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=3:1)に附し、標題化合物を無色油状物として892mg得た。その光学純度は0%eeであった。H-NMRスペクトルデータは、実施例3と一致した。
Claims (13)
- さらに、一般式(II)で表される化合物を、再結晶溶媒として含水アセトンまたは含水酢酸エチルを用いて再結晶させる工程を含む、請求項1に記載の方法。
- 溶媒及び再結晶溶媒として含水酢酸エチルを用いることを特徴とする、請求項2に記載の方法。
- 含水酢酸エチルの含水率が0.5%~3.0%である、請求項3に記載の方法。
- 一般式(IV)で表される化合物から一般式(V)で表される化合物を得る工程の溶媒が、N,N-ジメチルホルムアミドである、請求項6に記載の方法。
- 一般式(IV)で表される化合物から一般式(V)で表される化合物を得る工程の塩基が1,8-ジアザビシクロ[5.4.0]ウンデク-7-エンである、請求項6または請求項7に記載の方法。
- 加水分解に用いる溶媒がメタノールまたはエタノールである、請求項6~8のいずれか1項に記載の方法。
- 加水分解に用いる塩基が水酸化ナトリウムである、請求項6~9のいずれか1項に記載の方法。
- 溶媒が、N,N-ジメチルホルムアミドである、請求項11に記載の方法。
- 塩基が、水素化ナトリウムである、請求項11または請求項12に記載の方法。
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2746570A CA2746570A1 (en) | 2008-12-12 | 2009-12-09 | Process for producing optically active carboxylic acid |
EP09831928A EP2368870A1 (en) | 2008-12-12 | 2009-12-09 | Process for producing optically active carboxylic acid |
CN2009801567789A CN102317248A (zh) | 2008-12-12 | 2009-12-09 | 光学活性羧酸的生产方法 |
JP2010542119A JP5683273B2 (ja) | 2008-12-12 | 2009-12-09 | 光学活性カルボン酸の製造方法 |
BRPI0922434A BRPI0922434A2 (pt) | 2008-12-12 | 2009-12-09 | processo para produzir ácido carboxílico opticamente ativo |
IL213472A IL213472A0 (en) | 2008-12-12 | 2011-06-09 | Process for producing optically active carboxylic acid and uses of the same |
US13/157,590 US20110257401A1 (en) | 2008-12-12 | 2011-06-10 | Process for producing optically active carboxylic acid |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2008-316849 | 2008-12-12 | ||
JP2008316849 | 2008-12-12 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US13/157,590 Continuation US20110257401A1 (en) | 2008-12-12 | 2011-06-10 | Process for producing optically active carboxylic acid |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2010067824A1 true WO2010067824A1 (ja) | 2010-06-17 |
Family
ID=42242811
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2009/070613 WO2010067824A1 (ja) | 2008-12-12 | 2009-12-09 | 光学活性カルボン酸の製造方法 |
Country Status (9)
Country | Link |
---|---|
US (1) | US20110257401A1 (ja) |
EP (1) | EP2368870A1 (ja) |
JP (1) | JP5683273B2 (ja) |
KR (1) | KR20110106840A (ja) |
CN (1) | CN102317248A (ja) |
BR (1) | BRPI0922434A2 (ja) |
CA (1) | CA2746570A1 (ja) |
IL (1) | IL213472A0 (ja) |
WO (1) | WO2010067824A1 (ja) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104447294A (zh) * | 2014-11-24 | 2015-03-25 | 苏州乔纳森新材料科技有限公司 | 一种3-环己烯-1-甲酸的手性拆分方法 |
WO2017104782A1 (ja) * | 2015-12-17 | 2017-06-22 | 第一三共株式会社 | オキサジアゾール化合物の製造方法 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BRPI0809205B8 (pt) | 2007-03-29 | 2021-05-25 | Daiichi Sankyo Co Ltd | composição farmacêutica |
CN102348680B (zh) | 2009-03-13 | 2014-11-05 | 第一三共株式会社 | 用于制备光学活性二胺衍生物的方法 |
JP2016503389A (ja) | 2012-11-23 | 2016-02-04 | 第一三共株式会社 | (1s,4s,5s)−4−ブロモ−6−オキサビシクロ[3.2.1]オクタン−7−オンの調製方法 |
CN105198776A (zh) * | 2015-10-30 | 2015-12-30 | 天津药物研究院药业有限责任公司 | 依度沙班中间体及其制备方法 |
SK50282016A3 (sk) | 2016-10-11 | 2018-05-02 | Saneca Pharmaceuticals A.S. | Spôsob izolácie a čistenia naltrexónu |
CN111099989B (zh) * | 2019-12-27 | 2022-08-05 | 郑州手性药物研究院有限公司 | S-3-环己烯甲酸及其精制方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001151724A (ja) * | 1999-11-19 | 2001-06-05 | Kuraray Co Ltd | 光学活性な2,2,4−トリメチル−3−シクロヘキセンカルボン酸の製造方法 |
WO2003000680A1 (fr) | 2001-06-20 | 2003-01-03 | Daiichi Pharmaceutical Co., Ltd. | Derives de diamine |
WO2003000657A1 (fr) | 2001-06-20 | 2003-01-03 | Daiichi Pharmaceutical Co., Ltd. | Derives de diamine |
WO2003016302A1 (fr) | 2001-08-09 | 2003-02-27 | Daiichi Pharmaceutical Co., Ltd. | Derives de diamine |
WO2004058715A1 (ja) | 2002-12-25 | 2004-07-15 | Daiichi Pharmaceutical Co., Ltd. | ジアミン誘導体 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5149855A (en) * | 1989-12-26 | 1992-09-22 | Mitsubishi Rayon Co., Ltd. | Process for racemizing optically active carboxylic acid esters |
US5677469A (en) * | 1995-05-18 | 1997-10-14 | Sepracor, Inc. | Process for resolving chiral acids with 1-aminoindan-2-ols |
JP4483165B2 (ja) * | 2002-10-01 | 2010-06-16 | 山川薬品工業株式会社 | 光学活性な3−(メチルアミノ)−1−(2−チエニル)プロパン−1−オールの製造方法および製造の中間体 |
JP4728636B2 (ja) * | 2004-12-15 | 2011-07-20 | 大東化学株式会社 | 光学活性アミノ酸類の製造方法 |
-
2009
- 2009-12-09 CN CN2009801567789A patent/CN102317248A/zh active Pending
- 2009-12-09 CA CA2746570A patent/CA2746570A1/en not_active Abandoned
- 2009-12-09 BR BRPI0922434A patent/BRPI0922434A2/pt not_active IP Right Cessation
- 2009-12-09 EP EP09831928A patent/EP2368870A1/en not_active Withdrawn
- 2009-12-09 WO PCT/JP2009/070613 patent/WO2010067824A1/ja active Application Filing
- 2009-12-09 JP JP2010542119A patent/JP5683273B2/ja active Active
- 2009-12-09 KR KR1020117012535A patent/KR20110106840A/ko not_active Application Discontinuation
-
2011
- 2011-06-09 IL IL213472A patent/IL213472A0/en unknown
- 2011-06-10 US US13/157,590 patent/US20110257401A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001151724A (ja) * | 1999-11-19 | 2001-06-05 | Kuraray Co Ltd | 光学活性な2,2,4−トリメチル−3−シクロヘキセンカルボン酸の製造方法 |
WO2003000680A1 (fr) | 2001-06-20 | 2003-01-03 | Daiichi Pharmaceutical Co., Ltd. | Derives de diamine |
WO2003000657A1 (fr) | 2001-06-20 | 2003-01-03 | Daiichi Pharmaceutical Co., Ltd. | Derives de diamine |
WO2003016302A1 (fr) | 2001-08-09 | 2003-02-27 | Daiichi Pharmaceutical Co., Ltd. | Derives de diamine |
WO2004058715A1 (ja) | 2002-12-25 | 2004-07-15 | Daiichi Pharmaceutical Co., Ltd. | ジアミン誘導体 |
Non-Patent Citations (8)
Title |
---|
BARRY M. TROST ET AL., TETRAHEDRON LETT., vol. 32, 1991, pages 1613 - 1616 |
CIHANGIR TANYELI ET AL., TETRAHEDRON: ASYMMETRY, vol. 15, 2004, pages 2057 - 2060 |
CSJ: THE CHEMICAL SOCIETY OF JAPAN: "Kogaku Iseitai no Bunri 'Kikan Kagaku Sosetsu No.6", JAPAN SCIENTIFIC SOCIETIES PRESS, pages: 45 - 54 * |
HAROLD M. SCHWARTZ ET AL., J. AM. CHEM. SOC., vol. 100, 1978, pages 5199 - 5203 |
JOURNAL OF ORGANIC CHEMISTRY, vol. 31, 1966, pages 240 - 243 * |
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 100, no. 16, 1978, pages 5199 - 5203 * |
TETRAHEDRON ASYMMETRY, vol. 15, 2004, pages 2057 - 2060 * |
TETRAHEDRON LETTERS, vol. 32, no. 13, 1991, pages 1613 - 1616 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104447294A (zh) * | 2014-11-24 | 2015-03-25 | 苏州乔纳森新材料科技有限公司 | 一种3-环己烯-1-甲酸的手性拆分方法 |
WO2017104782A1 (ja) * | 2015-12-17 | 2017-06-22 | 第一三共株式会社 | オキサジアゾール化合物の製造方法 |
Also Published As
Publication number | Publication date |
---|---|
KR20110106840A (ko) | 2011-09-29 |
JP5683273B2 (ja) | 2015-03-11 |
US20110257401A1 (en) | 2011-10-20 |
CA2746570A1 (en) | 2010-06-17 |
EP2368870A1 (en) | 2011-09-28 |
CN102317248A (zh) | 2012-01-11 |
JPWO2010067824A1 (ja) | 2012-05-24 |
BRPI0922434A2 (pt) | 2015-12-15 |
IL213472A0 (en) | 2011-07-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5683273B2 (ja) | 光学活性カルボン酸の製造方法 | |
EP2719676B1 (en) | Method for producing bicyclic compound via iminium salt | |
JP5980780B2 (ja) | クライゼン転位反応による二環性化合物の製造方法 | |
JP6285968B2 (ja) | (2s,5r)−6−ベンジルオキシ−7−オキソ−1,6−ジアザ−ビシクロ[3.2.1]オクタン−2−カルボン酸のナトリウム塩およびその調製 | |
KR20080020613A (ko) | (치환된) (r)- 또는 (s)-만델산의 동적 분할 방법 | |
TW201708191A (zh) | 用於製備前列腺素醯胺之新穎方法(二) | |
TW201536724A (zh) | 光學活性二環γ-胺基酸衍生物之製造方法 | |
JP6504530B2 (ja) | 光学活性な2−(2−フルオロビフェニル−4−イル)プロパン酸の製造法 | |
JPWO2014034957A1 (ja) | (r)−1,1,3−トリメチル−4−アミノインダンの製造方法 | |
JP2011057665A (ja) | 光学活性な1−アミノ−2−ビニルシクロプロパンカルボン酸エステルの製造方法 | |
WO2018061034A1 (en) | Novel process for the preparation of 1-(3-ethoxy-4-methoxy-phenyl)-2-methylsulfonyl-ethanamine | |
JP4451537B2 (ja) | 置換脂環式−1,3−ジオンの製造方法 | |
JP2006298872A (ja) | 1−フルオロ−1−フェニルチオエテンの製造方法 | |
JP5704763B2 (ja) | トランス−4−アミノシクロペンタ−2−エン−1−カルボン酸誘導体の製造 | |
KR100654923B1 (ko) | 고순도의 광학활성아미드를 연속적으로 제조하는 방법 | |
WO2010071122A1 (ja) | シクロヘキセン誘導体の製造方法 | |
EP3145904A1 (en) | Improved process for preparing substituted crotonic acids | |
CN117886708A (zh) | 一种苯磺酸米洛巴林的合成方法 | |
WO2016208709A1 (ja) | 1-(アシルオキシ)アルキルカルバメート誘導体の新規な製造方法 | |
JP2009269875A (ja) | フッ素化エステル化合物の製造方法及びその中間体 | |
JP2009019004A (ja) | 光学活性アリールオキシカルボン酸誘導体の製造方法 | |
JP2006001925A (ja) | 3,4,5−トリフルオロベンジルアルコールの製造方法 | |
JP2016065024A (ja) | カルボン酸の光学分割方法 | |
KR20060125218A (ko) | 광학활성 벤족사진 유도체의 제조방법 | |
JP2002201169A (ja) | 4−シアノ−3−オキソブタン酸エステルの製造法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200980156778.9 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09831928 Country of ref document: EP Kind code of ref document: A1 |
|
ENP | Entry into the national phase |
Ref document number: 2010542119 Country of ref document: JP Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009831928 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 20117012535 Country of ref document: KR Kind code of ref document: A |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2746570 Country of ref document: CA |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1341/MUMNP/2011 Country of ref document: IN |
|
ENP | Entry into the national phase |
Ref document number: PI0922434 Country of ref document: BR Kind code of ref document: A2 Effective date: 20110613 |