WO2004103990A1 - Procede de production d'un compose de n-monoalkyle-3-hydroxy-3-arylpropylamine optiquement actif et son intermediaire - Google Patents

Procede de production d'un compose de n-monoalkyle-3-hydroxy-3-arylpropylamine optiquement actif et son intermediaire Download PDF

Info

Publication number
WO2004103990A1
WO2004103990A1 PCT/JP2004/006602 JP2004006602W WO2004103990A1 WO 2004103990 A1 WO2004103990 A1 WO 2004103990A1 JP 2004006602 W JP2004006602 W JP 2004006602W WO 2004103990 A1 WO2004103990 A1 WO 2004103990A1
Authority
WO
WIPO (PCT)
Prior art keywords
oxo
group
monoalkyl
hydroxy
methyl
Prior art date
Application number
PCT/JP2004/006602
Other languages
English (en)
Japanese (ja)
Inventor
Kazunori Iwakura
Takayuki Higashii
Seiji Bando
Original Assignee
Sumitomo Seika Chemicals Co. Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sumitomo Seika Chemicals Co. Ltd. filed Critical Sumitomo Seika Chemicals Co. Ltd.
Publication of WO2004103990A1 publication Critical patent/WO2004103990A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • 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
    • 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 method for producing optically active N-monoalkyl-13-hydroxy-3-arylpropylamines and intermediates. More specifically, the present invention relates to a method for producing optically active N-monoalkyl-3-hydroxy-3-arylpropylamines which are highly reactive and are useful as intermediates for various medicines and the like, and an intermediate for the production thereof (Z) One N-protected N-monoalkyl-3-oxo-3-arylpropenylamines. Background art.
  • optically active N-monoalkyl-3-hydroxy-3-arylpropylamines can be obtained by optically resolving a racemate thereof using a resolving agent such as an optically active organic acid.
  • a resolving agent such as an optically active organic acid.
  • N, N-dialkyl_3-oxo-3-arylproenylamines were asymmetrically reduced (eg, Chem. Pharm. Bull. 1995, 43, 748, Synlett 1997, 11, 1306, J Am. Chem. Soc. 2000, 122, 6510), and a method of dealkylation using a dealkylating agent (for example, JP-A-5-213838) is known.
  • this method has a problem that the dealkylating agent is required to be twice or more moles relative to the substrate, which is economically disadvantageous.
  • the present invention is useful as a process for producing optically active N-monoalkyl-13-hydroxy-3-arylpropylamines industrially at low cost and easily, and useful as an intermediate in producing the conjugate.
  • (Z) N-protected N-monoalkyl-3-oxo-3-arylproenylamines. That is, the present invention relates to the following formula (1):
  • Ar is an aryl group which may have a substituent or a heteroaryl group which may have a substituent
  • R 1 is an alkyl group having 1 to 5 carbon atoms which may have a substituent
  • R 2 represents an amino protecting group.
  • N-protected N-monoalkyl-3-oxo-3-propyl propylamines represented by the formula:
  • Optically active N represented by the formula (2) after asymmetric reduction with an asymmetric catalyst —Protected—N-monoalkyl-3-hydroxy-3-arylpropylamines, followed by deprotection.
  • An optically active N-monoalkyl-3-hydroxy-acid represented by the formula (3).
  • the present invention relates to a process for producing 3-arylpropylamines and an intermediate for the production thereof, (Z) -N-protected 1-N-monoalkyl-3-oxo-3-3-arylprovenylamines.
  • the process for producing optically active N-monoalkyl-3-hydroxy-3-arylpropylamines comprises the steps of (Z) -N-protected 1-N-monoalkyl-3-oxoxo.
  • each step will be described specifically.
  • Step 1_1 In this step, (Z) -N-protected N-monoalkyl-13-oxo-3-arylarylenylamines are asymmetrically reduced with an asymmetric catalyst to achieve optically active N-protection. — Produce N-monoalkyl-1-hydroxy-3-arylpropylamines. .
  • the (Z) -N-protected 1-N-monoalkyl-13-oxo-3-allylproenylamines used in this step are compounds represented by the formula (1).
  • Ar represents an aryl group which may have a substituent or an aryl group which may have a substituent.
  • R 1 represents an alkyl group having 1 to 5 carbon atoms which may have a substituent, and R 2 represents an amino protecting group.
  • aryl group examples include a phenyl group, a naphthyl group, and a phenanthryl group.
  • heteroaryl group examples include a furyl group, a phenyl group, a pyrrolyl group, a pyridyl group, a benzofuryl group, and an indenyl group.
  • alkyl group having 1 to 5 carbon atoms examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, and an n-pentyl group.
  • substituent of the above aryl, heteroaryl or alkyl group examples include, for example, hydroxyl, methyl, ethyl, propyl, trifluoromethyl, methoxy, nitro, amino, methylsulfonylamino.
  • substituent of the above aryl, heteroaryl or alkyl group examples include, for example, hydroxyl, methyl, ethyl, propyl, trifluoromethyl, methoxy, nitro, amino, methylsulfonylamino.
  • benzoyloxy group fluorine atom, chlorine atom, bromine atom, iodine atom and the like.
  • amino protecting group examples include a methoxycarbonyl group, an ethoxycarbonyl group, a 2,2,2-trichloroethyloxycarbonyl group, an n-propyloxycarbonyl group, an isopropyloxycarbonyl group, and an n-butyloxy group.
  • Alkyloxy groups such as carbonyl group, isobutyloxycarbonyl group and tert-butyloxycarbonyl group; aralkyloxycarbonyl groups such as benzyloxycarbonyl group; aryl groups such as phenyloxycarbonyl group.
  • (Z) -N-protected 1-N-monoalkyl-13-oxo-3-3-arylpropenylamines include N-methyl-1-N- (2,2,2-trichloroethyloxylponyl) 1-3-oxo_3-phenylphenylenylamine, N-methyl-1-N-phenylcarboxyl 3-oxo-1-3-phenylpropenylamine, N-ethyl-N-methoxycarboxyl 3-oxo-3- ( 4-Tolyl) propenylamine, N-ethyl-N-ethoxycarbone 3-oxo-3- (4-trifluoromethylphenyl) probenylamine, N-methyl-N-methoxy 3 —Oxo-1 3 _ (4-methoxyphenyl) propenylamine, N- (n-propyl) —N-ethoxycarpinolu 3-Oxo—3— Phenyl) propenyl
  • the azetidine amide coordinated transition metal complex is represented by the formula (5):
  • R 3 and R 4 may each have a hydrogen atom, an alkyl group having 1 to 5 carbon atoms which may have a substituent, an aralkyl group which may have a substituent or a substituent.
  • Y represents a hydrogen atom or a protecting group
  • M represents a transition metal atom
  • X represents a counter ion
  • m represents an integer of 0 to 4
  • n represents 0 or represents 1.!
  • ⁇ OyoBishi 2 each independently or. * is showing the ligand together, is an optically active compound represented by indicating the asymmetric carbon atom.).
  • alkyl group having 1 to 5 carbon atoms examples include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, and an n-pentyl group.
  • aralkyl group examples include a benzyl group, a 2-phenylethyl group, a 2-naphthylethyl group, a diphenylmethyl group and the like.
  • aryl group examples include a phenyl group, a naphthyl group, a biphenyl group, and a phenanthryl group.
  • Examples of the substituent of the above group include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; an alkoxy group such as a methoxy group, an ethoxy group, an n-propoxy group and a tert-butoxy group; a phenoxy group Alkyl groups such as methyl group, ethyl group, isopropyl group, n-butyl group and tert-butyl group; alkylthio groups such as n-methylthio group, n-propylthio group and tert-butylthio group An arylthio group such as a phenylthio group; a nitro group and a sulfonyl group.
  • a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom
  • an alkoxy group
  • Examples of the protecting group include a methoxycarbonyl group, an ethoxycarbonyl group, a 2,2,2-trichloroethyloxycarbonyl group, an n-propyloxycarbonyl group, an isopropyloxycarbonyl group, and an n-butyl group.
  • Alkyl such as oxycarbonyl group, isobutyloxycarbonyl group, tert-butyloxycarbonyl group
  • An aralkyloxycarbonyl group such as a benzyloxycarbonyl group; an aryloxycarbonyl group such as a phenyloxycarbonyl group; and a benzyl group.
  • transition metal atom examples include ruthenium, rhodium, iridium and the like.
  • Examples of the counter ion include a fluorine ion, a chloride ion, an iodine ion, a perchlorate ion, a hexafluorophosphate ion, a tetrafluoroborate ion, a trifluoromethylbenzenesulfonate ion, and a trifluoromethanesulfonate ion.
  • L 1 and L 2 may be any as long as they coordinate with a transition metal, and examples thereof include aromatic compounds such as benzene, p-cymene, mesitylene, hexamethylbenzene, naphthalene, and anthracene; ethylene, butadiene, Olefin compounds such as cyclohexene, 1,5-cyclobutadiene tacitane, cyclooctatriene, and pentamethylcyclopentagenenyl; amine compounds such as dimethylethylenediamine and diphenylethylenediamine; carbon monoxide, nitric oxide, chlorine, and bromine And the like. These may be independently coordinated to L 1 and L 2 , or may be coordinated together. Among them, benzene, p-cymene or cyclooctagene, in which L 1 L 2 is in a form, is preferably used.
  • azetidine amide coordinated transition metal complex examples include (S) -N-phenyl_2-azetidinecarpoxamide ruthenium chloride (p-cymene) complex and (S) -N-naphthyl-2-azetidine Carpoxamide ruthenium chloride (p-cymene) complex, (S) —N— (2-fluorophenyl) —2-azetidinecarboxamide ruthenium (benzene) complex, (S) -N— (4 —Cyanobenzyl) —2-zetidinecarboxamide ruthenium chloride (p-cymene) complex, (S) —N-benzyl—2_ (N-methoxycarbonyl) azetidinecarpoxamide ruthenium chloride (p-cymene) Complexes and the like.
  • the azetidine alcohol phosphine coordinated transition metal complex is a compound represented by the formula (6).
  • R 3 , R 4 , M, X—, m, n, L 1 and L 2 are the same as in the equation (5).
  • R 5 to R 8 represent an aryl group which may have a substituent. * Indicates an asymmetric carbon atom.
  • aryl group examples include a phenyl group, a naphthyl group, a biphenyl group, and a phenanthryl group.
  • substituents examples include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; an alkoxy group such as a methoxy group, an ethoxy group, an n-propoxy group and a tert-butoxy group; and an aryloxy group such as a phenoxy group.
  • halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom
  • alkoxy group such as a methoxy group, an ethoxy group, an n-propoxy group and a tert-butoxy group
  • aryloxy group such as a phenoxy group.
  • alkyl groups such as methyl group, ethyl group, isopropyl group, n-butyl group, tert-butyl group
  • alkylthio groups such as n-methylthio group, n-propylthio group, tert-butylthio group
  • phenylthio group And a nitro group, a sulfonyl group and the like.
  • azetidine alcohol phosphine coordinated transition metal complex examples include (S) -N, di-bis (diphenylphosphino) and ⁇ -dimethyl-2-azetidine alcohol (rhodium) -1,5-cyclohexyl.
  • Dugen complex triflate salt (S) - ⁇ , ⁇ _bis (diphenylphosphino) _ ⁇ , ⁇ -Jetyl-2-azetidine alcohol (rhodium chloride) norponadiene complex, (S) - ⁇ , ⁇ bis (diph 1-dimethyl-2-azetidine alcohol (rhodium iodide) triphenylphosphine complex, (S) - ⁇ , ⁇ -bis [di (4-methoxyphenyl) phosphino] 1 ⁇ , ⁇ — Diphenyl-2-azetidine alcohol (iridium chloride) _1,5-cyclohexanediene complex, (S) - ⁇ , polycarbonate (diphenylphosphino) — ⁇ , —diphenyl ⁇ 2-azetidine alcohol ruthenium chloride complex, (S) mono-, di-bis (diphenylphosphino) mono, a diphenyl 2- 2-azetidine alcohol
  • the amount of the asymmetric catalyst used may be a catalytic amount based on (Z) -N-protected-N-monoalkyl-13-oxo-13-arylproenylamines, and is preferably 0.0001 to 0.
  • the molar amount is 1-fold, more preferably 0.0005 to 0.02-fold.
  • the hydrogen supply source include alcohols such as methanol, ethanol, and 2-propanol; formic acid and salts thereof; and hydrogen. Among them, hydrogen, 2-propanol or formic acid is preferably used. The case where hydrogen, 2-propanol or formic acid is used as a hydrogen supply source will be specifically described below.
  • Asymmetric reduction using hydrogen as a hydrogen source includes, for example, dissolving (Z) -N-protected-N-monoalkyl-3-oxo-3-arylproenylamines and an asymmetric catalyst in a reaction solvent, A method in which hydrogen is charged into the reaction system preferably at 0.001 to 150 MPa, more preferably at 0 :!
  • reaction solvent examples include alcohols such as methanol, ethanol, and 2-propanol; halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; and ethers such as methyl ether and tert-butyl methyl ether. Can be These may be used alone or as a mixture.
  • the reaction temperature is preferably ⁇ 20 to 150 ° C., more preferably 0 to 100 ° C.
  • Asymmetric reduction using 2-propanol as a hydrogen source includes, for example, (Z) _N-protected 1-N-monoalkyl-13-oxo-3-arylpropenylamines, 2-propanol and the presence of a base.
  • the following is a method of performing a reduction reaction using an asymmetric catalyst.
  • the amount of 2-propanol used is preferably 0.1 to 100 times the weight, more preferably 0 to 100 times the weight of (Z) -N-protected mono-N-monoalkyl-3-oxo-3-arylpropenylamines. 1 to 50 times the weight.
  • lithium oxide sodium hydroxide, potassium hydroxide, hydroxylamine Metal hydroxide compounds such as calcium; sodium methoxide, potassium ethoxide
  • metal alkoxides such as sodium tert-butoxide and potassium potassium tert-butoxide
  • metal hydride compounds such as hydrogen hydride and sodium hydride.
  • the amount of the base to be used is preferably 0.1 to 10 moles, more preferably 0.5 to 4 moles, relative to the asymmetric catalyst.
  • the reaction temperature is preferably from ⁇ 20 to 150 ° C., more preferably from 0 to 100 ° C.
  • asymmetric reduction using formic acid as a hydrogen source includes, for example, (Z) -N-protected-N-monoalkyl-13-oxo-3-arylproenylamines in the presence of formic acid and triethylamine.
  • the amount of formic acid used is preferably 0.05 to 100 times the weight of (Z) -N-protected 1-N-monoalkyl-13-oxo-13-arylproenylamines. More preferably, the weight is 0.1 to 50 times the weight.
  • the amount of triethylamine used is preferably 0.05 to 10 moles, more preferably 0.2 to 5 moles with respect to formic acid. If the amount of triethylamine used is less than 0.2 mole or more than 10 mole, the reaction may be slow and not complete.
  • reaction solvent examples include alcohols such as methanol, ethanol, and 2-propanol; halogenated hydrocarbons such as methylene chloride and 1,2-dichloroethane; ethers such as methyl ether and tert-butyl methyl ether; morpholine, Amines such as peridine; acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide and the like; These may be used alone or as a mixture. '
  • the reaction temperature is preferably from ⁇ 20 to 150 ° C., more preferably from 0 to 100 ° C.
  • the reaction solution containing the product, optically active N-protected 1-N-monoalkyl-1-hydroxy-3-arylpropylamines was concentrated and remained.
  • a water-insoluble reaction solvent such as toluene and dimethyl ether and water are added to the residue, and the mixture is separated to obtain an organic layer.
  • the optically active N-protected-N-monoalkyl-13-hydroxy-3-arylpropylamines can be isolated by washing and concentrating the obtained organic layer with water. Further, the obtained optically active N-protected-N-monoalkyl-13-hydroxy-13-arylpropylamines can be purified by a method such as silica gel column chromatography or distillation.
  • optically active N-protected N-monoalkyl-3-hydroxy-3-arylpropylamines include N-methyl-N- (2,2,2-trichloroethyloxycarponyl) _3-hydroxy-3-phenyl Enylpropylamine, N-methyl-N-phenyloxycarbonyl, 3-hydroxy-3-phenylpropylamine, N-ethyl-N-methoxycarbonyl-3-hydroxy-3- (4-tolyl) propylamine, N -Ethyl-N-ethoxycarbonyl-3-Hydroxy-3- (4-Trifluoromethylphenyl) propylamine, N-Methyl-1-N-Methoxycarbonyl 3-hydroxy-3- (4-methoxyphenyl) propylamine , N— (n—propyl) —N—ethoxycarbonyl—3-hydroxy—3- (4-nitrophenyl) propylamine, N— (tert-butyl)
  • Step 1-2 the target compound is obtained by deprotecting the optically active N-protected-N-monoalkyl-1-hydroxy-3-arylpropylamines obtained in the above step 1-1. Produces optically active N-monoalkyl-13-hydroxy-13-arylpropylamines.
  • Examples of the deprotecting agent for deprotection include alkalis such as sodium hydroxide, potassium heptaoxide, lithium hydroxide, sodium methoxide, and potassium ethoxide; and acids such as hydrochloric acid, sulfuric acid, and acetic acid.
  • alkalis especially sodium hydroxide, are preferably used from the viewpoint of easy deprotection.
  • the amount of the deprotecting agent to be used is preferably 0.2 to 20-fold mol based on the optically active N-protected-N-monoalkyl-13-hydroxy-13-arylpropylamines. Preferably it is 0.5 to 5 times mol.
  • reaction solvent examples include aliphatic hydrocarbons such as pentane, hexane, cyclohexane, and heptane; aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene; getyl ether, tert-butyl methyl ether; Ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopropanol; esters such as methyl acetate, ethyl acetate and butyl acetate; and water. Of these, alcohols, especially isopropanol, are preferably used.
  • the amount of the above reaction solvent used depends on the optically active N_protected—N-monoalkyl-3-hydro It is preferably from 0.05 to 100 times by weight, more preferably from 0.2 to 50 times by weight, based on xyl 3-arylpropylamines.
  • the reaction temperature is preferably from 0 to 100, more preferably from 15 to 50 ° C.
  • optically active N-monoalkyl-3-hydroxy-3-arylpropylamines can be purified by a method such as silica gel gel chromatography, distillation and the like.
  • a method such as silica gel gel chromatography, distillation and the like.
  • an optically active N-monoalkyl-3-hydroxy-3-arylpropyl propylamine represented by the formula (3) is obtained.
  • optically active N-monoalkyl-3-hydroxy-3-arylpropylamines include, for example, N-methyl-3-hydroxy-3-phenylpropylamine, N-ethyl-3-hydroxy-3- (4 —Tolyl) propylamine, N-ethyl-3-hydroxy-3— (4-trifluoromethylphenyl) propylamine, N-methyl-3-hydroxy-3- (4-methoxyphenyl) propylamine, N— (n —Propyl) —3—Hydroxy— 3- (4-Ditrophenyl) propylamine, N— (tert-butyl) -1-hydroxy-3 -— (3-methylsulfonylaminophenyl) propylamine, N-methyl-3-hydroxy 3- (4-Benzoyloxyphenyl) propylamine, N-ethyl-3-hydroxy 3- (4-chlorophenyl) propyl Mine, N-methyl-1-hydroxy-3- (4,6-dimethoxy
  • the method for producing an optically active N-monoalkyl-13-hydroxy-3-arylarylamine comprises: (Z) -N-protected-N-monoalkyl-3-oxo-13- N-protected N-monoalkyl-1-3-oxo_3-arylpropylamines by reducing arylproenylamines, followed by asymmetric reduction with an asymmetric catalyst for optically active N-protected N- Monoalkyl-3-hydroxy-3-arylpropylamines, followed by deprotection.
  • each step will be described specifically.
  • Step 2-1 the (Z) -N-protected-N-monoalkyl-3-oxo-l-3-arylpropylenylamine is reduced to give an N-protected N-monoalkyl Produce 1-3-oxo-13-arylpropylamines.
  • a reduction method using a catalyst in a hydrogen atmosphere may be mentioned.
  • hydrogen is preferably dissolved in an amount of 0.001 to 150 MPa, More preferably, 0.1 to: a method in which the reaction system is filled with LO OM Pa and reacted.
  • the catalyst examples include metal catalysts such as palladium carbon, palladium acetate, platinum carbon, and Raney nickel.
  • metal catalysts such as palladium carbon, palladium acetate, platinum carbon, and Raney nickel.
  • palladium carbon is preferably used in terms of ease of handling.
  • the amount of the above catalyst used is preferably from 0.0001 to 0.1 times, more preferably from 0.0001 to 0.1 times, based on (Z) -N-protected-N-monoalkyl-3-oxo-13-arylproenylamines. It is 0.0005 to 0.05 times by mole.
  • Alcohols such as methanol, ethanol, and 2-propanol Hydrogen; halogenated carbons such as methylene chloride and 1,2-dichlorobenzene; ethers such as ethyl ether and tert-butyl methyl ether; These may be used alone or as a mixture. Among them, methanol and ethanol are preferably used from the viewpoint of reactivity.
  • the amount of the reaction solvent used is preferably from 0.1 to 100 times by weight, more preferably from (Z) -N-protected 1-N-monoalkyl-13-oxo-3--3-arylproenylamines. 0.5 to 50 times the weight.
  • the reaction temperature is preferably from 0 to 150 ° C, more preferably from about 20 to 100 ° C. If the reaction temperature exceeds 150 ° C, impurities may be formed or the product may be N-protected N-monoalkyl-13-hydroxy-3-arylpropylamines in racemic form. is there.
  • the catalyst is removed from the reaction solution by filtration, and the obtained reaction solution is concentrated to isolate N-protected-1N-monoalkyl-13-oxo-13-arylpropylamines. . Further, the obtained N-protected 1-N-monoalkyl 3-oxo-13-arylpropylamines can be purified by a method such as silica gel column chromatography and distillation.
  • N-protected mono-N-monoalkyl-3-oxo-3-arylpropylamines represented by the formula (4) are obtained.
  • N-protected 1-N-monoalkyl-13-oxo-13-arylpropylamines include, for example, N-methyl-N- (2,2,2-trichloroethyoxyloxycarbonyl) -3 —Oxo-3-phenylpropylamine, N-methyl-N-phenyloxycarbonyl—3-oxo-1-3-phenylpropylamine, N-ethyl-N-methoxycarbonyl 3-oxo-1 3 _ (4 —Tolyl) Propylamine, N-Ethyl-N-Ethoxycarbonyl 3-Oxo-3- (4-Trifluoromethylphenyl) propylamine, N-Methyl-N-Methoxycarbonyl, 13-Oxo _3— (4-Methoxyphenyl) Propylamine, N _ (n-Propyl) 1 N-Ethoxycarbonyl 3-Oxo-1 3- (4-Ditrophenyl) Pyramine
  • Step 2-2 the N-protected mono-N-monoalkyl-3-oxo-3-arylpropylamines obtained in the above-mentioned Step 2-1 are successively immiscible with an asymmetric catalyst. Simultaneous reduction to produce optically active N-protected-N-monoalkyl-13-hydroxy-3-arylpropylamines.
  • the method for asymmetric reduction using an asymmetric catalyst is the same as in the above-mentioned step 1-1, and therefore the description is omitted.
  • Step 2-3 the optically active N_protected 1-N-monoalkyl-13-hydroxy-3-arylpropylamines obtained in the above step 2-2 are deprotected to give the desired product.
  • the deprotection can be performed by the same method as in the above step 1-2.
  • the (Z) 1 N-protected 1 N-monoalkyl-13-oxo-13-arylpropenylamines represented by the above formula (1) used in the first and second embodiments of the present invention are novel Compound.
  • the (Z) -N-protected-N-monoalkyl-3-oxo-3-arylbenzoylamines of the present invention are (Z) -N-monoalkyl-13-oxo-3-aliphenylopenylamine. Can be produced by reacting a compound with an amino-protected compound.
  • (Z) —N—monoalkyl—3-oxo—3-arylpropenylamines include, for example, N-methyl-3-oxo-1-3-phenylprobenylamine, N-ethyl-3-oxo-3 — (4-Tolyl) propenylamine, N-ethyl-3- 3-oxo-3- (4-trifluoromethylphenyl) propenylamine, N-methyl-3-oxo-3 -— (4-methoxyphenyl) Propenylamine, N- (n-propyl) -13-oxo-13- (4-nitrophenyl) propenylamine, N- (tert-butyl) -13-oxo-3- (3-methylsulfonylaminophenyl) Probenylamine, N-Methyl-3-oxo-l3- (4-benzyloxyphenyl) propenylamine, N-Ethyl-3-oxo- 3
  • the amino-protected compound used in the present invention is a compound represented by the formula (8) or (9).
  • Equation (8)
  • R 2 represents the same group as in formula (1).
  • W represents a halogen atom.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • amino-protected compounds include methyl methyl carbonate, ethyl methyl carbonate, 2,2-, 2-trichloroethyl carbonate, n-propyl carbonate, isopropyl carbonate, and isopropyl carbonate.
  • examples include n-butyl, isobutyl carbonate, tert-butyl carbonate, benzyl carbonate, phenyl carbonate, ditert-butyl dicarbonate, and the like. Of these, isopentyl carbonate and benzyl chlorocarbonate are preferably used.
  • the amount of the amino group-protected compound to be used is preferably 0.5 to 10-fold mol, more preferably 0 to 10 mol, per (Z) -N-monoalkyl-13-oxo-13-arylproenylamines. It is 8 to 3 times mol.
  • reaction solvent examples include: aliphatic hydrocarbons such as pentane, hexane, cyclohexane, and heptane; aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene; getyl ether, tert-butyl methyl ether; Ethers such as tetrahydrofuran and dioxane; esters such as methyl acetate, ethyl acetate and butyl acetate; and water.
  • aliphatic hydrocarbons such as pentane, hexane, cyclohexane, and heptane
  • aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene
  • getyl ether, tert-butyl methyl ether Ethers such as tetrahydrofuran and dioxane
  • esters such as methyl acetate, e
  • the amount of the above-mentioned reaction solvent to be used is preferably 0.05 to 100 times by weight, more preferably 0.2 to (Z) -N-monoalkyl-13-oxo-13-arylproenylamines. ⁇ 20 times the weight.
  • the reaction temperature is preferably from 120 to 150 ° C., more preferably from 110 to: L 0 Ot :.
  • the reaction solution is concentrated, and a water-insoluble organic solvent such as toluene and water are added, and the mixture is separated to obtain an organic layer.
  • the water-insoluble organic solvent is distilled off from the obtained organic layer.
  • a 4-neck flask was charged with 114.8 mg (0.42 mmo 1) of N-methyl-N-isobutyloxy-3-hydroxy-2- (2-phenyl) propylamine and 5 ml of 2-propanol, and a .30% by weight aqueous sodium hydroxide solution. 0.2 g was added and reacted at 30 ° C for 24 hours.
  • N-methyl-N-isobutyloxy-3-hydroxy-3- (2-phenyl) propylamine 42 mg (0. 15 mmo1) and 2 ml of 2-propanol were charged, 0.1 g of a 30% by weight aqueous sodium hydroxide solution was added, and the mixture was reacted at 30 ° C for 24 hours.
  • N-methyl-N-isobutyloxy-13-hydroxy-3- (2-phenyl) propylamine 119 mg (0 mg) was added to a 5-Oml four-necked flask equipped with a stirrer, a condenser, a thermometer and a dropping funnel. 44mmo 1) and 2-mole mouthpiece 5m1 were added, and 0.2g of 30% by weight aqueous sodium hydroxide solution was added. And reacted at 30 ° C. for 24 hours.
  • an optically active N-monoalkyl-3-hydroxy-3-arylpropylamine is industrially inexpensively and easily produced, and is useful as an intermediate in producing the compound.
  • (Z) N—Protected N-monoalkyl-1 3-oxo-3—arylproenylamines can be provided.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention concerne un procédé de production d'un composé de N-monoalkyle-3-hydroxy-3-arylpropylamine optiquement actif par la formule (3), dans laquelle le symbole * désigne un atome de carbone asymétrique et R1 représente un alkyle C1-5 éventuellement substitué, caractérisé par une réduction asymétrique d'un composé (Z)-protégé-N-monoalkyle-3-oxo-3-arylpropenylamine représenté par la formule (1), dans laquelle Ar désigne un aryle éventuellement substitué, etc. ; R1 désigne la même chose ; et R2 désigne un groupe de protection amino avec un catalyseur asymétrique permettant d'obtenir un composé optiquement actif représenté par la formule (2), dans laquelle le symbole * désigne les mêmes éléments que précités. L'invention permet d'éliminer le groupe protecteur.
PCT/JP2004/006602 2003-05-22 2004-05-11 Procede de production d'un compose de n-monoalkyle-3-hydroxy-3-arylpropylamine optiquement actif et son intermediaire WO2004103990A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2003144742A JP2004346008A (ja) 2003-05-22 2003-05-22 Ｎ−モノアルキル−３−ヒドロキシ−３−アリールプロピルアミン類の製造方法および中間体
JP2003-144742 2003-05-22

Publications (1)

Publication Number Publication Date
WO2004103990A1 true WO2004103990A1 (fr) 2004-12-02

Family

ID=33475217

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2004/006602 WO2004103990A1 (fr) 2003-05-22 2004-05-11 Procede de production d'un compose de n-monoalkyle-3-hydroxy-3-arylpropylamine optiquement actif et son intermediaire

Country Status (2)

Country Link
JP (1) JP2004346008A (fr)
WO (1) WO2004103990A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006104249A1 (fr) * 2005-03-29 2006-10-05 Zeon Corporation Methode de fabrication de l’alcool 1-(2-thienyl)-3-alkylaminopropylique
WO2007020797A1 (fr) * 2005-08-19 2007-02-22 Sumitomo Seika Chemicals Co., Ltd. (e)-n-monoalkyl-3-oxo-3-(2-thiényl)propénamine et procédé servant à produire celle-ci et (e,z)-n-monoalkyl-3-oxo-3-(2-thiényl)propénamine et procédé servant à produire celle-ci
WO2008004191A2 (fr) 2006-07-03 2008-01-10 Ranbaxy Laboratories Limited Procédé de préparation de duloxétine et de ses sels
JP2010235604A (ja) * 2009-03-12 2010-10-21 Kanto Chem Co Inc 新規な有機金属錯体およびアミン化合物の製造方法
WO2011118625A1 (fr) * 2010-03-24 2011-09-29 住友精化株式会社 Méthode de production d'une n-monoalkyl-3-hydroxy-3-arylpropylamine optiquement active

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10503772A (ja) * 1994-07-29 1998-04-07 アボツト・ラボラトリーズ 置換２，５−ジアミノ−３−ヒドロキシヘキサンの製造方法
WO2001058843A1 (fr) * 2000-02-08 2001-08-16 Asahi Kasei Kabushiki Kaisha Procede de preparation d'alcools secondaires optiquement actifs possedant des groupes fonctionnels azote ou oxygene
WO2004016603A1 (fr) * 2002-08-06 2004-02-26 Sumitomo Seika Chemicals Co., Ltd. Procede de production de n-monoalkyl-3-hydroxy-3-(2-thienyl) propanamine, et d'intermediaires
JP2004155770A (ja) * 2002-10-18 2004-06-03 Toru Yokozawa 光学活性アミノアルコールの製造方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10503772A (ja) * 1994-07-29 1998-04-07 アボツト・ラボラトリーズ 置換２，５−ジアミノ−３−ヒドロキシヘキサンの製造方法
WO2001058843A1 (fr) * 2000-02-08 2001-08-16 Asahi Kasei Kabushiki Kaisha Procede de preparation d'alcools secondaires optiquement actifs possedant des groupes fonctionnels azote ou oxygene
WO2004016603A1 (fr) * 2002-08-06 2004-02-26 Sumitomo Seika Chemicals Co., Ltd. Procede de production de n-monoalkyl-3-hydroxy-3-(2-thienyl) propanamine, et d'intermediaires
JP2004155770A (ja) * 2002-10-18 2004-06-03 Toru Yokozawa 光学活性アミノアルコールの製造方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SAKURABA S. ET AL.: "Efficient asymmetric hydrogenation of beta- and gamma-amino ketone derivatives leading to practical synthesis of fluoxetine and eprozinol", CHEM. PHARM. BULL., vol. 43, no. 5, 1995, pages 748 - 753, XP001071298 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006104249A1 (fr) * 2005-03-29 2006-10-05 Zeon Corporation Methode de fabrication de l’alcool 1-(2-thienyl)-3-alkylaminopropylique
WO2007020797A1 (fr) * 2005-08-19 2007-02-22 Sumitomo Seika Chemicals Co., Ltd. (e)-n-monoalkyl-3-oxo-3-(2-thiényl)propénamine et procédé servant à produire celle-ci et (e,z)-n-monoalkyl-3-oxo-3-(2-thiényl)propénamine et procédé servant à produire celle-ci
US8183392B2 (en) 2005-08-19 2012-05-22 Sumitomo Seika Chemicals Co., Ltd. (E)-N-monoalkyl-3-oxo-3-(2-thienyl) propenamine and process for producing the same and process for producing (E,Z)-N-monoalkyl-3-oxo-3-(2-thienyl) propenamine
JP5361187B2 (ja) * 2005-08-19 2013-12-04 住友精化株式会社 （ｅ）−ｎ−モノアルキル−３−オキソ−３−（２−チエニル）プロペンアミンおよびその製造方法、ならびに（ｅ，ｚ）−ｎ−モノアルキル−３−オキソ−３−（２−チエニル）プロペンアミンの製造方法
JP2013256501A (ja) * 2005-08-19 2013-12-26 Sumitomo Seika Chem Co Ltd （ｅ）−ｎ−モノアルキル−３−オキソ−３−（２−チエニル）プロペンアミンおよびその製造方法、ならびに（ｅ，ｚ）−ｎ−モノアルキル−３−オキソ−３−（２−チエニル）プロペンアミンの製造方法
US8722906B2 (en) 2005-08-19 2014-05-13 Sumitomo Seika Chemicals Co., Ltd. (E)-N-monoalkyl-3-oxo-3-(2-thienyl) propenamine and process for producing the same and process for producing (E,Z)-N-monoalkyl-3-oxo-3-(2-thienyl) propenamine
WO2008004191A2 (fr) 2006-07-03 2008-01-10 Ranbaxy Laboratories Limited Procédé de préparation de duloxétine et de ses sels
JP2010235604A (ja) * 2009-03-12 2010-10-21 Kanto Chem Co Inc 新規な有機金属錯体およびアミン化合物の製造方法
WO2011118625A1 (fr) * 2010-03-24 2011-09-29 住友精化株式会社 Méthode de production d'une n-monoalkyl-3-hydroxy-3-arylpropylamine optiquement active
CN102822161A (zh) * 2010-03-24 2012-12-12 住友精化株式会社 制造光学活性n-单烷基-3-羟基-3-芳基丙胺化合物的方法
JPWO2011118625A1 (ja) * 2010-03-24 2013-07-04 住友精化株式会社 光学活性なｎ−モノアルキル−３−ヒドロキシ−３−アリールプロピルアミン化合物の製造方法
US8981122B2 (en) 2010-03-24 2015-03-17 Sumitomo Seika Chemicals Co., Ltd. Method for producing optically active N-monoalkyl-3-hydroxy-3-arylpropylamine compound

Also Published As

Publication number Publication date
JP2004346008A (ja) 2004-12-09

Similar Documents

Publication Publication Date Title
JP5113118B2 (ja) 有機合成用試薬、及び当該試薬を用いた有機合成反応方法
TWI464165B (zh) 用於製備藥劑之方法及中間物
US9040738B2 (en) Intermediate compounds of tamiflu, methods of preparation and uses thereof
US10343955B2 (en) Process for the preparation of deuterated ethanol from D2
KR20060126965A (ko) 활성 아민기 존재하에서 ｏ-카바모일 화합물을 제조하는방법
WO2019123994A1 (fr) Nouvel agent de protection du diphénylméthane alkyle
WO2015037460A1 (fr) PROCÉDÉ DE PRODUCTION DE 3-(BIPHÉNYLE-4-YL)-2-[(t-BUTOXYCARBONYL)AMINO]PROPAN-1-OL OPTIQUEMENT ACTIF
WO2003097632A1 (fr) Derives de propanolamine, procede de preparation de 3-n-methylamino-1-(2-thienyl)-1-propanols et procede de preparation de derives de propanolamine
MX2008013539A (es) Produccion de intermediarios de amino alcohol quiralmente puros, derivados de los mismos, y usos de los mismos.
Tang et al. Synthesis of a water-soluble cationic chiral diamine ligand bearing a diguanidinium and application in asymmetric transfer hydrogenation
US9771317B2 (en) Process for preparing lacosamide and related compounds
CN107382783B (zh) 一种手性β-氨基酸衍生物及其制备方法
WO2004103990A1 (fr) Procede de production d'un compose de n-monoalkyle-3-hydroxy-3-arylpropylamine optiquement actif et son intermediaire
JP5207226B2 (ja) タモキシフェン類縁体を有効成分として含有するプロテアソーム阻害剤
CN102381988B (zh) 利伐斯的明的中间体化合物的制备方法及中间体化合物
JP6531235B1 (ja) 新規アルキルジフェニルメタン保護剤
WO2016115962A1 (fr) Procédé de préparation d'intermédiaire de nébivolol et procédé de préparation de nébivolol
JP2008115178A (ja) ジフェニルアラニン−Ｎｉ（ＩＩ）錯体の製造方法
EP2192110B1 (fr) Procédé de fabrication d'un dérivé de n-(halopropyl)amino acide optiquement actif
KR100701743B1 (ko) 밤부테롤의 신규한 제조 방법
JP4182242B2 (ja) 光学活性なアゼチジンメタノールホスフィン配位遷移金属錯体、中間体、製造法および用途
JP2000247990A (ja) フェロセニルアミノホスフィン及び該ホスフィンを含む触媒
JP2002173476A (ja) １，４−フェニレンジアミン誘導体及びその製造法
BRPI0716247A2 (pt) processo para preparar de derivados de n-metiladamantil por uma reaÇço de ligaÇço catalisada por palÁdio seguida por aminaÇço redutiva
WO2008010578A1 (fr) Procédé de fabrication d'un dérivé du styrène

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase