WO2009122997A1 - (s)-3-(1-シアノ-1,1-ジフェニルメチル)-ピロリジンの製造法 - Google Patents
(s)-3-(1-シアノ-1,1-ジフェニルメチル)-ピロリジンの製造法 Download PDFInfo
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- WO2009122997A1 WO2009122997A1 PCT/JP2009/056065 JP2009056065W WO2009122997A1 WO 2009122997 A1 WO2009122997 A1 WO 2009122997A1 JP 2009056065 W JP2009056065 W JP 2009056065W WO 2009122997 A1 WO2009122997 A1 WO 2009122997A1
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- 0 *C(N(CC1)C[C@@]1C(c1ccccc1)(c1ccccc1)C#N)=O Chemical compound *C(N(CC1)C[C@@]1C(c1ccccc1)(c1ccccc1)C#N)=O 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/12—Oxygen or sulfur atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the present invention relates to a process for producing (S) -3- (1-cyano-1,1-diphenylmethyl) -pyrrolidine and its important intermediate.
- (S) -3- (1-cyano-1,1-diphenylmethyl) -pyrrolidine is an important intermediate in the production of a muscarinic receptor antagonist (darifenacin) described in, for example, WO2003 / 080599.
- the present invention has the following formula (1):
- R 1 represents a methyl group, a phenyl group, a tert-butoxy group, or a benzyloxy group
- S -1-protected-3- (1-cyano-1,1-diphenyl Methyl) -pyrrolidine.
- R 2 has a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a substituent, an alkenyl group having 2 to 20 carbon atoms which may have a substituent, or a substituent. It may have an aralkyl group having 7 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms which may have a substituent, an alkyloxy group having 1 to 20 carbon atoms which may have a substituent, or a substituent.
- R 2 is the same as above.
- R 3 represents an optionally substituted alkyl group having 1 to 20 carbon atoms or an optionally substituted aryl group having 6 to 20 carbon atoms.
- the method is characterized by reacting diphenylacetonitrile represented by the formula in the presence of a base.
- (S) -1-protected-3- (1-cyano-1,1-diphenylmethyl) -pyrrolidine having a protective group that can be easily deprotected under milder conditions than before is produced. It becomes possible to do. Therefore, (S) -3- (1-cyano-1,1-diphenylmethyl) -pyrrolidine can be produced more efficiently than before.
- each process will be described in turn below. Unless otherwise specified, each step is independent, and in the present invention, it is not always necessary to carry out all the steps to obtain the target compound.
- the (S) -4-chloro-3-hydroxybutyronitrile represented by the formula (6) can be easily produced, for example, by the method described in JP-A-2-85249 or JP-B-5-69818. .
- the metal catalyst examples include Raney metal or alloy, rhodium catalyst, palladium catalyst, or platinum catalyst.
- a metal catalyst may be used independently and may be used in mixture.
- the amount of the metal catalyst used is preferably 0.001 to 10 times the weight, more preferably 0.01 to 1 times the weight of the compound (6).
- the solvent in this step is not particularly limited as long as it is a solvent used in a normal catalytic reduction reaction.
- Preferred are water, methanol, ethanol, n-propanol, isopropanol, n-butanol, ethylene glycol, acetic acid, 1,4-dioxane, toluene, ethyl acetate and the like. More preferred is methanol or ethanol.
- a solvent may be used independently and may be used in mixture. When mixed and used, the mixing ratio is not particularly limited.
- the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore it is preferably 50 times weight or less, more preferably 20 times weight or less with respect to the compound (6).
- Further acid may be added for the purpose of accelerating the reduction reaction.
- the acid include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid and the like, preferably hydrochloric acid.
- the amount of acid used is preferably 0.1 to 10 times the molar amount, more preferably 0.5 to 3 times the molar amount relative to the compound (6).
- the reaction product of this step includes the case where a primary amine as a primary product of reduction is mainly obtained depending on the metal catalyst used, reaction temperature and time, and (S) -3-pyrrolidinol represented by the above formula (7). May be obtained. Therefore, a base may be further added for the purpose of complete cyclization.
- Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, magnesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, trisodium phosphate, tripotassium phosphate , Triethylamine, diisopropylethylamine, pyridine and the like.
- Sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and triethylamine are preferable, and triethylamine is more preferable.
- the amount of base used is preferably 0.1 to 10 times the molar amount, more preferably 0.5 to 3 times the molar amount relative to the compound (6).
- the pressure of hydrogen added during the reduction reaction is preferably 0.5 to 100 atm, and more preferably 1 to 10 atm.
- the reaction temperature in this step may be appropriately set depending on the type and amount of metal catalyst used and the hydrogen pressure.
- the temperature is preferably 0 to 100 ° C, more preferably 10 to 60 ° C.
- reaction time of this step is set by the type and amount of metal catalyst used, hydrogen pressure, and reaction temperature.
- the time is preferably 1 to 100 hours, more preferably 5 to 40 hours.
- reaction solution After completion of the reduction reaction, the reaction solution may be directly used in the next step, or a solution obtained by filtering the metal catalyst by vacuum filtration or the like may be used in the next step.
- R 2 may have a hydrogen atom, an alkyl group having 1 to 20 carbon atoms which may have a substituent, an alkenyl group having 2 to 20 carbon atoms which may have a substituent, or a substituent.
- a good aralkyl group having 7 to 20 carbon atoms, an aryl group having 6 to 20 carbon atoms which may have a substituent, an alkyloxy group having 1 to 20 carbon atoms which may have a substituent, and a substituent An alkenyloxy group having 2 to 20 carbon atoms, an aralkyloxy group having 7 to 20 carbon atoms which may have a substituent, or an aryloxy group having 6 to 20 carbon atoms which may have a substituent. is there.
- Examples of the alkyl group having 1 to 20 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and a tert-butyl group.
- Examples of the alkenyl group having 2 to 20 carbon atoms include a vinyl group, an allyl group, and a methallyl group.
- Examples of the aralkyl group having 7 to 20 carbon atoms include benzyl group, 1-phenethyl group, (2,3-dihydrobenzofuran-5-yl) methyl, and the like.
- Examples of the aryl group having 6 to 20 carbon atoms include a phenyl group, a naphthyl group, and a biphenyl group.
- Examples of the alkyloxy group having 1 to 20 carbon atoms include a methoxy group, an ethoxy group, an isopropoxy group, and a tert-butoxy group.
- Examples of the alkenyloxy group having 2 to 20 carbon atoms include vinyloxy group, allyloxy group, and methallyloxy group.
- Examples of the aralkyloxy group having 7 to 20 carbon atoms include benzyloxy group and 1-phenethyloxy group.
- Examples of the aryloxy group having 6 to 20 carbon atoms include a phenoxy group and a biphenyloxy group.
- substituents include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, nitro group, nitroso group, cyano group, amino group, hydroxyamino group, alkylamino group having 1 to 12 carbon atoms, carbon number 1-12 dialkylamino groups, C7-12 aralkylamino groups, C7-12 diaralkylamino groups, C1-12 alkylsulfonylamino groups, sulfonic acid groups, sulfonamido groups, azide groups Trifluoromethyl group, carboxyl group, acyl group having 1 to 12 carbon atoms, aroyl group having 7 to 12 carbon atoms, hydroxyl group, alkyloxy group having 1 to 12 carbon atoms, aralkyloxy group having 7 to 12 carbon atoms, Aryloxy group having 6 to 12 carbon atoms, acyloxy group having 1 to 12 carbon atoms, aroyloxy
- R 2 is preferably a hydrogen atom, methyl group, ethyl group, n-propyl group, methoxymethyl group, chloromethyl group, trifluoromethyl group, (2,3-dihydrobenzofuran-5-yl) methyl group, phenyl group 4-methylphenyl group, 4-chlorophenyl group, 4-nitrophenyl group, methoxy group, ethoxy group, isopropoxy group, tert-butoxy group, allyloxy group, benzyloxy group, or phenoxy group, more preferably methyl Group, phenyl group, tert-butoxy group or benzyloxy group, particularly preferably tert-butoxy group.
- the present inventors can extract and isolate using a small amount of an organic solvent by protecting the amino group without isolating (S) -3-pyrrolidinol as in this step.
- the inventors have found that (S) -1-protected-3-pyrrolidinol can be easily produced.
- Protecting the amino group is preferably acyl protection or carbamate protection, and can be carried out by adding an acylating agent or carbamate agent to the reaction solution obtained in Step 1.
- acylating agents include esters such as methyl formate and methyl trifluoroacetate, acetyl chloride, acetyl bromide, propionyl chloride, butanoyl chloride, (2,3-dihydrobenzofuran-5-yl) acetyl chloride, benzoyl chloride, 4 -Acid halides such as methylbenzoyl, 4-chlorobenzoyl chloride and 4-nitrobenzoyl chloride, or acid anhydrides such as acetic anhydride and trifluoroacetic anhydride.
- Carbamate agents include methoxycarbonyl chloride, ethoxycarbonyl chloride, isopropoxycarbonyl chloride, allyloxycarbonyl chloride, benzyloxycarbonyl chloride, phenyloxycarbonyl chloride and the like, or anhydrides such as ditert-butyl dicarbonate. Can be mentioned.
- acetyl chloride acetic anhydride
- benzoyl chloride benzyloxycarbonyl chloride
- ditert-butyl dicarbonate ditert-butyl dicarbonate
- the amount of the acylating agent or carbamating agent used is preferably 1 to 10 times the molar amount, more preferably 1 to 3 times the molar amount relative to (S) -3-pyrrolidinol.
- a base may be further added for the purpose of accelerating the reaction by neutralizing by-product acid.
- Examples of the base include metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate and calcium carbonate; metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and cesium hydrogen carbonate; lithium hydroxide, Metal hydroxides such as sodium hydroxide and potassium hydroxide; tertiary amines such as triethylamine, ethyldiisopropylamine and pyridine can be exemplified.
- Sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, triethylamine, and pyridine are preferable, and triethylamine is more preferable.
- the amount of the base used is preferably 0.5 to 20 times the molar amount, more preferably 0.5 to 5 times the molar amount relative to (S) -3-pyrrolidinol.
- a reaction solvent is not particularly required, but it may be used when the reaction is accelerated by adding the reaction solvent.
- the reaction solvent is not particularly limited as long as it does not affect the reaction.
- water alcohol solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, ethylene glycol; tetrahydrofuran Ether solvents such as diethyl ether, 1,4-dioxane and ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; aliphatic hydrocarbon solvents such as pentane, hexane, heptane and methylcyclohexane; tetrachloride Halogen solvents such as carbon, chloroform, methylene chloride, 1,2-dichloroethane and chlorobenzene; ester solvents such as ethyl acetate, isopropyl acetate and tert-butyl acetate; sulfoxide solvents such as dimethyl sulf
- water Preferably, water; aromatic hydrocarbon solvents such as benzene and toluene; ether solvents such as tetrahydrofuran, 1,4-dioxane and methyl tert-butyl ether; ester solvents such as ethyl acetate, isopropyl acetate and tert-butyl acetate More preferably, it is toluene or ethyl acetate. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited.
- the amount of the solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore it is preferably 50 times weight or less, more preferably 20 times weight or less with respect to (S) -3-pyrrolidinol.
- the reaction temperature in this step is preferably ⁇ 10 to 90 ° C., more preferably 0 to 50 ° C. for the purpose of shortening the reaction time and suppressing side reactions. Moreover, there is no restriction
- the time is preferably 1 to 24 hours, more preferably 3 to 12 hours.
- the method of adding an acylating agent or carbamate forming agent, a base, and a reaction solvent to the reaction solution in Step 1 and the order of addition thereof are not particularly limited.
- the organic solvent is not particularly limited as long as it has low compatibility with water.
- Examples include methylene, 1,2-dichloroethane, chlorobenzene, ethyl acetate, isopropyl acetate, and tert-butyl acetate.
- toluene or ethyl acetate is used.
- the amount of the organic solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore it is preferably 50 times weight or less, more preferably 20 times weight or less with respect to the compound (8).
- the extract of (S) -1-protected-3-pyrrolidinol represented by the formula (8) may be used in the next step as it is, but the solvent is distilled off by an operation such as heating under reduced pressure to obtain the target product. May be separated.
- the target product obtained in this way has sufficient purity that can be used in the subsequent step, but for the purpose of further increasing the yield of the subsequent step or the purity of the compound obtained in the subsequent step, crystallization, fractionation
- the purity may be further increased by a general purification method such as distillation or column chromatography.
- R 2 is the same as described above.
- R 3 is an alkyl group having 1 to 20 carbon atoms which may have a substituent, or an aryl group having 6 to 20 carbon atoms which may have a substituent.
- Examples of the alkyl group having 1 to 20 carbon atoms include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, and a tert-butyl group.
- Examples of the aryl group having 6 to 20 carbon atoms include a phenyl group, a naphthyl group, and a biphenyl group.
- substituents include halogen atoms such as fluorine atom, chlorine atom, bromine atom and iodine atom, nitro group, nitroso group, cyano group, amino group, hydroxyamino group, alkylamino group having 1 to 12 carbon atoms, carbon number 1-12 dialkylamino groups, C7-12 aralkylamino groups, C7-12 diaralkylamino groups, C1-12 alkylsulfonylamino groups, sulfonic acid groups, sulfonamido groups, azide groups Trifluoromethyl group, carboxyl group, acyl group having 1 to 12 carbon atoms, aroyl group having 7 to 12 carbon atoms, hydroxyl group, alkyloxy group having 1 to 12 carbon atoms, aralkyloxy group having 7 to 12 carbon atoms, Aryloxy group having 6 to 12 carbon atoms, acyloxy group having 1 to 12 carbon atoms, aroyloxy
- R 3 is preferably a methyl group, a trifluoromethyl group, a phenyl group, a 4-methylphenyl group, a 4-chlorophenyl group, a 2-nitrophenyl group, a 3-nitrophenyl group, or a 4-nitrophenyl group, and more preferably Is a methyl group.
- the sulfonylation can be performed by treating with a sulfonylating agent in the presence of a base.
- the sulfonylating agent is preferably methanesulfonyl chloride, anhydrous trifluoromethanesulfonyl, benzenesulfonyl chloride, 4-methylbenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 3-nitrobenzenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride. Etc. More preferred is methanesulfonyl chloride.
- the amount of the sulfonylating agent to be used is preferably 2 to 10-fold mol amount, more preferably 2 to 5-fold mol amount based on the compound (8).
- Bases used in this step include triethylamine, tri-n-butylamine, N-methylmorpholine, N-methylpiperidine, diisopropylethylamine, pyridine, N, N-dimethylaminopyridine, 1,4-diazabicyclo [2,2,2 Tertiary amines such as octane; metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, magnesium hydroxide; metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; Examples thereof include metal hydrogen carbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate.
- tertiary such as triethylamine, tri-n-butylamine, N-methylmorpholine, N-methylpiperidine, diisopropylethylamine, pyridine, N, N-dimethylaminopyridine, 1,4-diazabicyclo [2,2,2] octane Amines, more preferably triethylamine.
- the amount of the base used is preferably 2 to 20 times the molar amount, more preferably 2 to 10 times the molar amount relative to the compound (8).
- the base may be used as a reaction solvent in this step.
- a reaction solvent may be further added for the purpose of ensuring fluidity.
- reaction solvent examples include water; ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, and ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; pentane, hexane, heptane, methylcyclohexane, and the like.
- Aliphatic hydrocarbon solvents such as carbon tetrachloride, chloroform, methylene chloride, 1,2-dichloroethane and chlorobenzene; ester solvents such as ethyl acetate, isopropyl acetate and tert-butyl acetate; sulfoxides such as dimethyl sulfoxide Amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide; urea solvents such as dimethylpropylene urea; phosphonic acid triamide solvents such as hexamethylphosphonic acid triamide; acetone; Ketone solvents such as methyl ethyl ketone; acetonitrile, nitrile solvents such as propionitrile can be used.
- halogen solvents such as carbon tetrachloride, chloroform, methylene chloride, 1,2-dichloroethane and chlorobenzene
- ester solvents such as e
- ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane and ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; ester solvents such as ethyl acetate, isopropyl acetate and tert-butyl acetate More preferably, it is toluene or ethyl acetate.
- aromatic hydrocarbon solvents such as benzene and toluene
- ester solvents such as ethyl acetate, isopropyl acetate and tert-butyl acetate More preferably, it is toluene or ethyl acetate.
- ester solvents such as ethyl acetate, isopropyl acetate and tert-butyl acetate More preferably, it is toluene or ethyl acetate.
- these may be used alone
- the amount of the reaction solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore it is preferably 50 times weight or less, more preferably 20 times weight or less relative to the compound (8).
- the reaction temperature in this step is preferably ⁇ 40 to 80 ° C., more preferably ⁇ 20 to 50 ° C. for the purpose of shortening the reaction time and suppressing side reactions.
- the reaction time in this step is not particularly limited and is preferably 0.1 to 24 hours, and more preferably 0.5 to 12 hours.
- the order of addition and the addition method of the compound (8), base, sulfonylating agent, and reaction solvent are not particularly limited.
- a general treatment for obtaining a product from the reaction solution may be performed.
- the reaction solution after completion of the reaction is neutralized by adding water or an aqueous acid solution such as an aqueous hydrochloric acid solution or an aqueous sulfuric acid solution, or an aqueous alkali solution such as an aqueous sodium hydroxide solution or an aqueous potassium carbonate solution, if necessary.
- the extraction operation is performed using a solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, hexane and the like.
- the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained.
- the target product thus obtained has sufficient purity that can be used in the subsequent step, but for the purpose of further increasing the yield of the subsequent step or the purity of the compound obtained in the subsequent step, crystallization, The purity may be further increased by a general purification method such as fractional distillation or column chromatography.
- R 2 is the same as described above.
- the amount of diphenylacetonitrile represented by the formula (3) is preferably 1 to 10 times the molar amount, more preferably 1 to 3 times the molar amount relative to the compound (2).
- the base examples include metal amides such as lithium amide, sodium amide, lithium diisopropylamide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and magnesium chloride diisopropylamide; methyllithium, n-butyllithium, tert-butyl Organolithium reagents such as lithium, sec-butyllithium and phenyllithium; Grignard reagents such as methylmagnesium bromide, n-butylmagnesium chloride, sec-butylmagnesium chloride and tert-butylmagnesium chloride; lithium methoxide, sodium methoxide, Potassium methoxide, lithium ethoxide, sodium ethoxide, potassium ethoxide, magnesium ethoxide, sodium isopropoxide, potassium isopropoxy Metal alkoxides such as lithium tert-butoxide, sodium tert-butoxide, potassium
- the amount of the base used is preferably 0.5 to 20 times the molar amount, more preferably 1 to 5 times the molar amount relative to the compound (2).
- a reaction solvent may be further added for the purpose of ensuring fluidity.
- the reaction solvent include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane and ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; fats such as pentane, hexane, heptane and methylcyclohexane.
- Group hydrocarbon solvents such as carbon tetrachloride, chloroform, methylene chloride, 1,2-dichloroethane and chlorobenzene; ester solvents such as ethyl acetate, isopropyl acetate and tert-butyl acetate; sulfoxide systems such as dimethyl sulfoxide Solvent; Amide solvent such as N, N-dimethylformamide and N, N-dimethylacetamide; Urea solvent such as dimethylpropylene urea; Phosphonic acid triamide solvent such as hexamethylphosphonic acid triamide; Acetone, Ketone solvents such as ethyl ketone; acetonitrile, can be used nitrile solvents such as propionitrile.
- halogen solvents such as carbon tetrachloride, chloroform, methylene chloride, 1,2-dichloroethane and chlorobenzene
- ester solvents such as ethyl
- ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane and ethylene glycol dimethyl ether; aromatic hydrocarbon solvents such as benzene and toluene; ester solvents such as ethyl acetate, isopropyl acetate and tert-butyl acetate
- An amide solvent such as N, N-dimethylformamide and N, N-dimethylacetamide, more preferably tetrahydrofuran, toluene, ethyl acetate, or N, N-dimethylacetamide. These may be used alone or in combination of two or more. When using 2 or more types together, the mixing ratio is not particularly limited.
- the amount of the reaction solvent used is too large, it is not preferable in terms of cost and post-treatment, and therefore it is preferably 50 times weight or less, more preferably 20 times weight or less relative to the compound (2).
- the reaction temperature in this step is preferably ⁇ 40 to 80 ° C., more preferably ⁇ 20 to 50 ° C. for the purpose of shortening the reaction time and suppressing side reactions.
- the reaction time in this step is not particularly limited and is preferably 0.1 to 24 hours, and more preferably 0.5 to 12 hours.
- the addition order and addition method of the compound (2), the compound (3), the base, and the reaction solvent are not particularly limited.
- a general treatment for obtaining a product from the reaction solution may be performed.
- the reaction solution after completion of the reaction is neutralized by adding water or an aqueous acid solution such as an aqueous hydrochloric acid solution or an aqueous sulfuric acid solution as necessary, and a common extraction solvent such as ethyl acetate, diethyl ether, methylene chloride, toluene, Extraction is performed using hexane or the like.
- the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained.
- the target product thus obtained has sufficient purity that can be used in the subsequent step, but for the purpose of further increasing the yield of the subsequent step or the purity of the compound obtained in the subsequent step, crystallization,
- the purity may be further increased by a general purification method such as fractional distillation or column chromatography.
- Conditions for deprotection performed in this step may be set appropriately depending on the type of protecting group.
- PROTECTIVE GROUPS in ORGANIC SYNTHESIS ⁇ ⁇ ⁇ Third edition written by JOHN WILEY & SONS, INC., Theodora W. Greene (Protective Groups in Organic) The method for deprotecting the acyl protecting group or the carbamate protecting group described on pages 503 to 564 of Synthesis 3rd edition) may be used.
- the formyl group and trifluoroacetyl group can be deprotected by alkaline hydrolysis.
- the benzyloxycarbonyl group can be deprotected by hydrogenation in the presence of a metal catalyst such as palladium carbon.
- the allyloxycarbonyl group can be deprotected by hydrolysis in the presence of a metal catalyst such as ruthenium.
- both of the acyl protecting group and the carbamate protecting group may be deprotected by acid hydrolysis or acid alcoholysis.
- the acid include inorganic acids such as hydrogen chloride, hydrogen bromide, perchloric acid, and sulfuric acid; and organic acids such as formic acid, methanesulfonic acid, and p-toluenesulfonic acid.
- the amount of the acid used is preferably 0.5 to 30-fold mol amount, more preferably 1 to 10-fold mol amount based on the compound (4).
- the alcohol include methanol, ethanol, n-propanol, isopropanol, n-butanol, and ethylene glycol.
- the amount of water or alcohol used is preferably 50 times or less, more preferably 20 times or less the weight of the compound (4).
- the water and alcohol may be a mixture. The mixing ratio in that case is not particularly limited.
- reaction temperature and reaction time in this step may be appropriately set according to the type of protecting group.
- tert-butoxycarbonyl can be deprotected at a reaction temperature of 0 to 50 ° C. in about 1 to 12 hours.
- a benzoyl group it can be deprotected at a reaction temperature of 50 to 100 ° C. in about 12 to 36 hours.
- the order of addition and the addition method of the compound (4), acid, water or alcohol are not particularly limited.
- a general treatment for obtaining a product from the reaction solution may be performed.
- the reaction solution after completion of the reaction is neutralized by adding water or an alkaline aqueous solution such as an aqueous sodium hydroxide solution or an aqueous potassium carbonate solution as necessary, and is extracted by a common extraction solvent such as ethyl acetate, diethyl ether, methylene chloride. Extraction is performed using toluene, hexane or the like. When the reaction solvent and the extraction solvent are distilled off from the resulting extract by an operation such as heating under reduced pressure, the desired product is obtained.
- the target product thus obtained has sufficient purity that can be used in the subsequent step, but for the purpose of further increasing the yield of the subsequent step or the purity of the compound obtained in the subsequent step, crystallization,
- the purity may be further increased by a general purification method such as fractional distillation or column chromatography.
- the solvent may be distilled off from the reaction solution after completion of the reaction under reduced pressure, crystallized as an acid salt with the compound (5), and isolated.
- Example 1 Production of (S) -1- (tert-butoxycarbonyl) -3-pyrrolidinol 2.41 g of (S) -4-chloro-3-hydroxybutyronitrile was dissolved in 12.4 ml of methanol and concentrated. 2.51 g of hydrochloric acid and 0.48 g of 10% palladium carbon (containing 50 wt% water) were added. After stirring at 25 ° C. for 23 hours and at 50 ° C. for 6 hours under the condition of hydrogen pressure (4 atm), 0.48 g of 5% palladium carbon (containing 50 wt% water) was further added and stirred at 50 ° C. for 11 hours. .
- the filtrate obtained by filtering off the catalyst under reduced pressure was concentrated under reduced pressure, and then 6.4 ml of methanol, 1.6 ml of distilled water and 2.29 g of triethylamine were added to the concentrate, followed by stirring at 25 ° C. for 20 hours and at 40 ° C. for 8 hours. .
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Abstract
Description
1)(S)-1-ベンジル-3-(1-シアノ-1,1-ジフェニルメチル)-ピロリジンをパラジウム触媒存在下に水素化することにより製造する方法(特許文献1)。
2)(S)-1-(4-メチルベンゼンスルホニル)-3-(1-シアノ-1,1-ジフェニルメチル)-ピロリジンをフェノールと臭化水素酸存在下に加熱還流することにより製造する方法(特許文献2)。
本工程では、式(6):
本工程では、前記式(7)で表される(S)-3-ピロリジノールを単離することなくアミノ基を保護することにより、下記式(8):
本工程では、前記式(8)で表される(S)-1-保護-3-ピロリジノールをスルホニル化することにより、下記式(2):
本工程では、前記式(2)で表される(S)-1-保護-3-(スルホニルオキシ)-ピロリジンと下記式(3):
本工程では、前記式(4)で表される(S)-1-保護-3-(1-シアノ-1,1-ジフェニルメチル)-ピロリジンを脱保護することにより、下記式(5):
カラム:ナカライ製 {コスモシル5C18ARII 250×4.6mm}
移動相A:0.1%リン酸水溶液,移動相B:アセトニトリル(移動相A%/移動相B%=90/10~40/60)
流速:1.0ml/min
検出:UV 210nm
カラム温度:40℃
保持時間:
(S)-1-(tert-ブトキシカルボニル)-3-ピロリジノール 11.8分、
(S)-1-(tert-ブトキシカルボニル)-3-(メタンスルホニルオキシ)-ピロリジン 14.4分、
(S)-1-(tert-ブトキシカルボニル)-3-(1-シアノ-1,1-ジフェニルメチル)-ピロリジン 30.5分、
(S)-3-(1-シアノ-1,1-ジフェニルメチル)-ピロリジン 10.3分、
(S)-1-ベンゾイル-3-(1-シアノ-1,1-ジフェニルメチル)-ピロリジン 19.8分。
3-(1-シアノ-1,1-ジフェニルメチル)-ピロリジンのアミノ基をtert-ブトキシカルボニル(以下、Boc)保護した後に測定を行った。
カラム:ダイセル化学社製 {CHIRALCEL OD-H 250×4.6mm}
移動相:ヘキサン/イソプロピルアルコール=98/2(容量比)
流速:1.0ml/min
検出器:UV210nm
カラム温度:30℃
保持時間:
(R)-3-(1-シアノ-1,1-ジフェニルメチル)-ピロリジンのBoc保護体 20.3分、
(S)-3-(1-シアノ-1,1-ジフェニルメチル)-ピロリジンのBoc保護体 22.3分。
(S)-4-クロロ-3-ヒドロキシブチロニトリル2.41gをメタノール12.4mlに溶解し、濃塩酸2.51gと10%パラジウム炭素(含水50wt%品)0.48gを加えた。水素加圧(4気圧)の条件下、25℃で23時間、50℃で6時間撹拌した後、更に5%パラジウム炭素(含水50wt%品)0.48gを加えて50℃で11時間撹拌した。
実施例1で製造した(S)-1-(tert-ブトキシカルボニル)-3-ピロリジノール3.61gをトルエン30mlに溶解し、トリエチルアミン1.58gを加えた。この溶液に、氷冷下で塩化メタンスルホニル1.64gを10分間かけて滴下して、更に25℃で1時間撹拌した。反応液に蒸留水15mlを加えて目的物を有機層に抽出し、得られた有機層を蒸留水15mlで洗浄した。この有機層を減圧濃縮して、標題化合物を褐色油状物質4.10gとして得た(含量74.6wt%、収率89%)。
(S)-1-(tert-ブトキシカルボニル)-3-(メタンスルホニルオキシ)ピロリジン1.56gを含むトルエン溶液2.23gを減圧濃縮して、濃縮物にテトラヒドロフラン1.51gとカリウムtert-ブトキシド0.79gを加えた。還流条件下でジフェニルアセトニトリル1.37gとテトラヒドロフラン1.63gからなる溶液を1時間かけて滴下して、更に21時間撹拌した。室温まで冷却した反応液に、蒸留水2.8mlとトルエン5mlを加えて目的物を有機層に抽出し、得られた有機層を蒸留水2.5mlで2回洗浄した。この有機層を減圧濃縮、真空乾燥して標題化合物を橙色油状物質2.47gとして得た(含量77.7wt%、収率90%)。
(S)-1-(tert-ブトキシカルボニル)-3-(1-シアノ-1,1-ジフェニルメチル)-ピロリジン1.13gをテトラヒドロフラン5.62gに溶解し、47%臭化水素酸1.55gを加えた。この溶液を40℃で6時間撹拌し、室温まで冷却した後に2.42gまで減圧濃縮した。濃縮物にトルエン0.42gと酢酸エチル2.39gを加えて3.15gまで減圧濃縮し、種結晶を加えると標題化合物が結晶として析出した。20℃で5分間撹拌した後、トルエン1.49gと酢酸エチル4.02gを加えて、20℃で1時間撹拌した。結晶を減圧濾別し、酢酸エチル2mlで洗浄後、真空乾燥することにより標題化合物を白色結晶0.26gとして得た(化学純度99.9area%、光学純度100%ee、収率26%)。
(S)-1-ベンゾイル-3-(メタンスルホニルオキシ)ピロリジン0.81gに、テトラヒドロフラン1.51gとカリウムtert-ブトキシド0.40gを加えた。還流条件下でジフェニルアセトニトリル1.37gとテトラヒドロフラン1.63gからなる溶液を1時間かけて滴下して、更に21時間撹拌した。室温まで冷却した反応液に、蒸留水2.8mlとトルエン5mlを加えて目的物を有機層に抽出し、得られた有機層を蒸留水2.5mlで2回洗浄した。この有機層を減圧濃縮、真空乾燥して標題化合物を白色固体1.19gとして得た(含量80.0wt%、収率86%)。
(S)-1-ベンゾイル-3-(1-シアノ-1,1-ジフェニルメチル)-ピロリジン171mgに47%臭化水素酸3.22gを加えて、110℃~120℃で38時間撹拌した。室温まで冷却した反応液を減圧濃縮した後、濃縮物に蒸留水5mlと酢酸エチル5mlを加えて目的物を水層に抽出した(収率66%)。水層にイソプロパノール5mlを加えて減圧濃縮すると結晶が析出したので、イソプロパノール5mlを再度加えて減圧濃縮し、更に酢酸エチル1mlを加えて20℃で30分間撹拌した。結晶を減圧濾別し、酢酸エチル2mlで洗浄後、真空乾燥することにより標題化合物を白色結晶113mgとして得た(含量59.8wt%、収率53%)。
(S)-3-(1-シアノ-1,1-ジフェニルメチル)-ピロリジン臭化水素酸塩78mg(含量60.8wt%)に蒸留水1mlとトルエン1ml、30wt%水酸化ナトリウム水溶液38mgを加えて撹拌し、目的物を有機層に抽出した。得られた有機層を蒸留水1mlで2回洗浄した後、減圧濃縮、真空乾燥して標題化合物を無色透明油状物質32mgとして得た(含量100wt%、収率88%)。
Claims (8)
- 前記式(1)において、R1がtert-ブトキシ基である(S)-1-(tert-ブトキシカルボニル)-3-(1-シアノ-1,1-ジフェニルメチル)-ピロリジン。
- 下記式(4):
- 下記式(8):
- 下記式(2):
- 下記式(4):
Priority Applications (3)
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EP09726472A EP2261205A4 (en) | 2008-04-02 | 2009-03-26 | PROCESS FOR PRODUCING (S) -3- (1-CYANO-1,1-DIPHENYLMETHYL) -PYRROLIDINE |
CN2009801121566A CN101983187A (zh) | 2008-04-02 | 2009-03-26 | (s)-3-(1-氰基-1,1-二苯基甲基)吡咯烷的制备方法 |
JP2010505753A JP5450387B2 (ja) | 2008-04-02 | 2009-03-26 | (s)−3−(1−シアノ−1,1−ジフェニルメチル)−ピロリジンの製造法 |
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- 2009-03-26 JP JP2010505753A patent/JP5450387B2/ja not_active Expired - Fee Related
- 2009-03-26 EP EP09726472A patent/EP2261205A4/en not_active Withdrawn
- 2009-03-26 WO PCT/JP2009/056065 patent/WO2009122997A1/ja active Application Filing
- 2009-03-26 CN CN2009801121566A patent/CN101983187A/zh active Pending
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THEODORA W. GREENE: "PROTECTIVE GROUPS in ORGANIC SYNTHESIS,Third edition", JOHN WILEY & SONS, INC., pages: 503 - 564 |
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JP5450387B2 (ja) | 2014-03-26 |
EP2261205A1 (en) | 2010-12-15 |
CN101983187A (zh) | 2011-03-02 |
EP2261205A4 (en) | 2012-06-06 |
JPWO2009122997A1 (ja) | 2011-07-28 |
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