WO2000021932A1 - NEW PROCESSES FOR PRODUCING β-ALANINE DERIVATIVE - Google Patents
NEW PROCESSES FOR PRODUCING β-ALANINE DERIVATIVE Download PDFInfo
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- WO2000021932A1 WO2000021932A1 PCT/JP1999/005520 JP9905520W WO0021932A1 WO 2000021932 A1 WO2000021932 A1 WO 2000021932A1 JP 9905520 W JP9905520 W JP 9905520W WO 0021932 A1 WO0021932 A1 WO 0021932A1
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- Prior art keywords
- ester
- acid
- alanine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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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 processes for the preparation of ⁇ -alanine derivative. More particularly, it relates to processes for the preparation of ⁇ -alanine derivative which is glycoprotein Ilb/IIIa antagonist, inhibitor of blood platelets aggregation and inhibitor of the binding of fibrinogen to blood platelets.
- the object of the present invention is to provide the producing process by which ⁇ -Alanine derivative, shown the following formula [I] or [II] or a salt thereof, can be produced in a good yield.
- the present invention provides a process for producing the ⁇ -Alanine derivative illustrated in the Processes 1 and 2 as shown below.
- R is amino protective group
- R is acyl group
- R is protected carboxy
- Suitable salts of the object compound (I) are conventional pharmaceutically acceptable and non-toxic salts, and include a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.], an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N-dibenzylethylenediamine salt, etc.], an organic acid addition salt [e.g.
- a metal salt such as an alkali metal salt [e.g. sodium salt, potassium salt, etc.], an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N-dibenzyl
- formate acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.]
- an inorganic acid addition salt e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.
- a salt with an amino acid e.g. arginine salt, aspartic acid salt, glutamic acid salt, etc.] and the like.
- the preferable number of the "one or more” in the term “one or more suitable substituent (s) " may be 1 to 3.
- Suitable "protected carboxy” may be carboxy protected by a conventional protecting group such as an esterified carboxy group, or ' the like, and concrete examples of the ester moiety in said esterified carboxy group may be the ones such as lower alkyl ester [e.g.
- acetoxymethyl ester propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-acetoxyethyl ester, 1-propionyloxyethyl ester, pivaloyloxyethyl ester, 2-propionyloxyethyl ester, hexanoyloxymethyl ester, etc.], lower-alkanesulfonyl (lower) - alkyl ester [e.g. 2-mesylethyl ester, etc.] or mono(or di or tri) halo (lower) alkyl ester [e.g.
- higher alkyl ester e.g. heptyl ester, octyl ester, 3,5- dimethyloctyl ester, 3, 7-dimethyloctyl ester, non
- lower alkenyl ester e.g. (C2-Cg) alkenyl ester (e.g. vinyl ester, allyl ester, etc.)]
- lower alkynyl ester e.g. (C2 ⁇ Cg) alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.)]
- ar (lower) alkyl ester which may have one or more suitable substituent (s) [e.g. phenyl (lower) alkyl ester which may have 1 to 4 lower alkoxy, halogen, nitro, hydroxy, lower alkyl, phenyl, or halo (lower) alkyl, (e.g.
- benzyl ester 4-methoxybenzyl ester, 4-chlorobenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3, 4-dimethoxybenzyl ester, 4-hydroxy-3, 5-di-tert-butylbenzyl ester, 4-trifluoromethylbenzyl ester, etc.)]; aryl ester which may have one or more suitable substituent (s) [e.g. phenyl ester which may have 1 to 4 lower alkyl, or halogen, (e.g.
- cycloalkyloxycarbonyloxy (lower) alkyl ester which may have lower alkyl (e.g., cyclopentyloxycarbonyloxymethyl ester, cyclohexyloxycarbonyloxymethyl ester, cycloheptyloxycarbonyloxymethyl ester, 1-methylcyclohexyloxycarbonyloxymethyl ester, 1- (or 2-) [cyclopentyloxycarbonyloxy] ethyl ester, 1- (or 2-) [cyclohexyloxycarbonyloxy] ethyl ester,
- the preferred one may be lower alkyl ester, ar (lower) alkyl ester, aryl ester which may have one or more suitable substituent (s) , cycloalkyloxycarbonyloxy (lower) alkyl ester or lower alkanoyloxy ( lower) alkyl ester, and the more preferred one may be methyl ester, ethyl ester, butyl ester, pentyl ester, isopentyl ester, isohexyl ester, benzyl ester, phenethyl ester, phenyl ester, indanyl ester, pivaloyloxymethyl ester or 1-cyclohexyloxycarbonyloxyethyl ester .
- Suitable “amino protective group” may include acyl group as explained below, a conventional protective group such as ar ( lower) alkyl which may have 1 to 3 suitable substituent (s) (e.g. benzyl, phenethyl, 1-phenylethyl, benzhydryl, trityl, etc.), [5- (lower) alkyl-2-oxo-l, 3-dioxol-4-yl] (lower) alkyl [e.g. (5-methyl-2-oxo-l, 3-dioxol-4-yl) methyl, etc.] or the like; and the like.
- suitable substituent e.g. benzyl, phenethyl, 1-phenylethyl, benzhydryl, trityl, etc.
- acyl group and “acyl” may include aliphatic acyl, aromatic acyl, arylaliphatic acyl and heterocyclic- aliphatic acyl derived from carboxylic acid, carbonic acid, carbamic acid, sulfonic acid, and the like.
- acyl group may be illustrated as follows : aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2 , 2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl , hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.); lower or higher alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl
- aryloxy (lower) alkanoyl e.g., phenoxyacetyl , phenoxypropionyl, etc.
- arylcarbamoyl e.g., phenylcarbamoyl, etc
- arylthiocarbamoyl e.g., phenylthiocarbamoyl, etc.
- arylglyoxyloyl e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc )
- arylsulfonyl which may have 1 to 4 lower alkyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.); or the like
- heterocyclic acyl such as heterocycliccarbonyl; heterocyclic (lower ) alkanoyl (e.g., heterocyclicacetyl, heterocyclicpropanoy
- heterocyclic moiety in the terms “heterocycliccarbonyl” , “heterocyclic (lower) alkyl” , “heterocyclic (lower) alkenoyl” and “heterocyclicglyoxyloyl” as mentioned above, and “heterocyclic group” mean saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
- the preferable heterocyclic group may be heterocyclic group such as unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1 , 2 , 4-triazolyl, 1H-1,2,3- triazolyl, 2H-1 , 2 , 3-triazolyl, etc.), tetrazolyl (e.g., 1H- tetrazolyl, 2H-tetrazolyl, etc.), etc.; saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyr
- nitrogen atom(s) for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, dihydroquinolyl, isoquinolyl, indazolyl, quinoxalinyl, dihydroquinoxalinyl, benzotriazolyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1 , 2, 4-oxadiazolyl, 1,3,4- oxadiazolyl, 1, 2 , 5-oxadiazolyl, etc), etc.; saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3
- the acyl moiety as mentioned above may have one to ten, same or different, suitable substituent (s) such as lower alkyl (e.g., methyl, ethyl, propyl, etc.); lower alkoxy (e.g., methoxy, ethoxy, propoxy, etc); lower alkylthio (e.g., methylthio, ethylthio, etc.); lower alkylamino (e.g., methylamino, ethylamino, propylamino, etc.); cyclo (lower) alkyl [e.g. cyclo (C -Cg) alkyl (e.g.
- cyclo (lower) alkenyl
- Suitable "protected hydroxy” may include acyl as mentioned above, phenyl (lower) alkyl which may have one or more suitable substituent (s) (e.g., benzyl, 4-methoxybenzyl, trityl, etc), trisubstituted silyl [e.g., tri (lower) alkylsilyl (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.), etc.], tetrahydropyranyl and the like.
- suitable substituent e.g., benzyl, 4-methoxybenzyl, trityl, etc
- trisubstituted silyl e.g., tri (lower) alkylsilyl (e.g., trimethylsilyl, t-butyldimethylsilyl, etc.), etc.
- amino protective group may be lower alkoxycarbonyl or ar (lower) alkoxycarbonyl, and the most preferred one may be t-butoxycarbonyl or benzyloxycarbonyl .
- Suitable "acyl group” of R can be referred to aforementioned "acyl group” .
- the more preferred one may be lower alkanoyl, and the most preferred one may be acetyl.
- the object compound (I) or a salt thereof can be prepared by subjecting a compound (II) or a salt thereof to elimination reaction of carboxy protective group, and then the acylation reaction of amino group.
- the elimination reaction of carboxy protective group This reaction is carried out in accordance with a conventional method such as hydrolysis, reduction or the like.
- the hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
- Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g. lithium, sodium, potassium, etc.], an alkaline earth metal [e.g. magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonate thereof, trialkylamine [e.g. trimethylamine, triethylamine, etc], picoline, 1, 5-diazabicyclo [ 4.3.0] non-5-ene, 1, 4-diazabicyclo [2.2.2] octane, 1, 8-diazabicyclo [5.4.0] undec- 7-ene, or the like.
- the preferred one may be lithium anhydride.
- Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc].
- organic acid e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.
- an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.
- the elimination using Lewis acid such as trihaloacetic acid is preferably carried out in the presence of cation trapping agents [e.g. anisole, phenol, etc.].
- the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adversely influence the reaction.
- a liquid base or acid can be also used as the solvent.
- the reaction temperature is not critical and the reaction is usually carried out under cooling to warming.
- the reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.
- Suitable reducing agents to be used in chemical reduction are a combination of metal [e.g. tin, zinc, iron, etc] or metallic compound [e.g. chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc . ] .
- metal e.g. tin, zinc, iron, etc
- metallic compound e.g. chromium chloride, chromium acetate, etc.
- organic or inorganic acid e.g. formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc .
- Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.], palladium catalysts [e.g. spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium, sulfate, palladium on barium carbonate, etc.], nickel catalysts [e.g. reduced nickel, nickel oxide, Raney nickel, etc.], cobalt catalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts [e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reduced copper, Raney copper, Ulman copper, etc.] and the like.
- platinum catalysts e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.
- palladium catalysts e.g. spongy
- the reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, or a mixture thereof.
- a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane tetrahydrofuran, etc., or a mixture thereof.
- reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling to warming.
- Suitable acylating agent to be used in the present acylation reaction may include the compound of the formula :
- Suitable reactive derivative at the amino group of the compound obtained by elimination reaction of carboxy protective group mentioned above may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound obtained by elimination reaction of carboxy protective group mentioned above with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound obtained by elimination reaction of carboxy protective group mentioned above with a silyl compound such as N, O-bis (trimethylsilyl) - acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound obtained by elimination reaction of carboxy protective group mentioned above with phosphorus trichloride or phosgene, and the like.
- Suitable reactive derivative of the compound (IV) may include an acid halide, an acid anhydride (e.g., acetic anhydride, etc.), an activated ester, and the like.
- an acid halide e.g., acetic anhydride, etc.
- an activated ester e.g., an activated ester, and the like.
- the preferred one may be acid anhydride, and most preferred one may be acetic anhydride.
- the suitable example may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc), dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, alkanesulfonic acid (e.g., methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc); aromatic carboxylic acid (e.g., benzoic acid, etc.) ; a symmetrical acid anhydride; an activated amide with imidazole, 4-substituted imidazole
- These reactive derivatives can optionally be selected from them accordingly to the kind of the compound obtained by elimination reaction of carboxy protective group mentioned above to be used.
- the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvents which do not adversely affect the reaction, or the mixture thereof.
- the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N ' -dicyclohexylcarbodiimide; N-cyclohexyl-N ' -morpholinoethylcarbodiimide; N-cyclohexyl-N ' - (4-diethylaminocyclohexyl) carbodiimide; N, N ' -diisopropylcarbodiimide; N-ethyl-N ' - (3- dimethylaminopropyl) carbodiimide; N, N-carbonyl-bis (2- methylimidazole) ; pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene ; 1-alkoxy-l-chlor
- the reaction may also be carried out in the presence of an organic or inorganic base such as an alkali metal, bicarbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorphorine, N, N-di (lower) alkylbenzylamine, or the like.
- an organic or inorganic base such as an alkali metal, bicarbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorphorine, N, N-di (lower) alkylbenzylamine, or the like.
- the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
- the object compound (III) or a salt thereof can be prepared by subjecting a compound (I) or a salt thereof to elimination reaction of the amino protective group.
- reaction can be carried out in a similar manner to that of Process 1 mentioned in the above, and therefore the reaction mode and reaction conditions [e.g. base, acid, catalyst, solvent, reaction temperature, etc.] of this reaction are to be referred to those as explained in Process
- the object compound (III) thus obtained is in a salt form, it can be converted into a free form in a conventional manner (e.g., neutralization, column chromatography, recrystallization, desalting resin column chromatography, etc).
- a conventional manner e.g., neutralization, column chromatography, recrystallization, desalting resin column chromatography, etc.
- the compounds obtained by the above Processes 1 and 2 can be isolated and purified by a conventional method such as pulverization, recrystallization, column-chromatography, reprecipitation or the like.
- each of the compounds (I), (II) and (III) may include one or more stereoisomer such as optical isomer (s) and geometrical isomer (s) due to asymmetric carbon atom(s) and double bond(s) and all such isomers and mixture thereof are included within the scope of this invention.
- the compounds (I), (II) and (III) or a salt thereof include solvated compound [e.g., enclosure compound (e.g., hydrate, etc. ) ] .
- the compounds (I), (II) and (III) or a salt thereof include both its crystal form and non-crystal form.
- the above invention would make it possible to produce ⁇ - alanine derivative in a good yield and/or to obtain a certain stereoisomer thereof which has a specific configuration in a good yield.
- the compound (I) or a salt thereof is useful as an intermediate for preparing the compound (III) or a salt thereof .
- the production of the compound (I) or a salt thereof in a good yield is useful as the effective production of the intermediate for the compound (III) or a salt thereof which is useful as glycoprotain Ilb/IIIa antagonist or so.
- aqueous LiOH (116 ml) solution was added to the solution within 15 minutes at 0-3°C.
- acetic anhydride (6.89 ml) was added to the mixture within 15 minutes at 0-4°C.
- the mixture was stirred for 30 minutes at 0°C, then diethyl ether (150 ml) was added.
- the aqueous layer was separated, and the pH of it was adjusted to 2.5 with aqueous 20% KHSO ⁇ , then extracted with ethyl acetate.
- Example 5 N- [ (R) -1- [3- (l-tert-Butoxycarbonyl-4-piperidyl) - propionyl] -3-piperidylcarbonyl] -2 (R) -acetylamino- ⁇ -alanine was obtained from N- [ (R) -1- [3- ( l-tert-Butoxycarbonyl-4- piperidyl) propionyl] -3-piperidylcarbonyl] -2 (R) - benzyloxycarbonylamino- ⁇ -alanine methyl ester according to a similar manner to that of Example 1.
- Example 6 N- [ (R) -1- [3- (1-tert-Butoxycarbonyl-4-piperidyl) - propionyl] -3-piperidylcarbonyl] -2 (R) -acetylamino- ⁇ -alanine was obtained from N- [ (R) -1- [ 3- ( l-tert-Butoxycarbonyl-4- piperidyl) propionyl] -3-piperidylcarbonyl] -2 (R) - benzyloxycarbonylamino- ⁇ -alanine ethyl ester according to a similar manner to that of Example 1, and was the same compound obtained in Example 5.
- Example 8 To a solution of N- [ (R) -1- [3- (l-tert-butoxycarbonyl-4- piperidyl) propionyl] -3-piperidylcarbonyl] -2 (S) - acetylamino- ⁇ -alanine (14.9 g) in ethyl acetate (150 ml) was added dropwise 4N HCl in ethyl acetate (74.8 ml) for 10 minutes at 0°C. After the mixture was stirred for 1 hour and 20 minutes, a white solid was collected by filtration, and dried in vacuo.
- the powder was dissolved in water (150 ml), and the solution was neutralized to pH 6.5 with saturated aqueous NaHC03 • ⁇ l ⁇ e solution was concentrated to about 100 ml, then applied to ODS column (Disogel-120SP®, 1 P) , and eluted with 4-6% CH3CN/water. The eluent was concentrated in vacuo, and the residue was dissolved 0.5% aqueous ethanol (200 ml) .
- Example 13 A mixture of N- [ (R) -1- [3- (4-pyridyl) -2-propenoyl] -3- piperidylcarbonyl] -2 (S) -acetylamino- ⁇ -alanine benzyl ester (233 mg), Pt0 2 (60 mg) in ethanol (10 ml), 4N HCl in ethyl acetate (121 ⁇ l) and Pt0 2 (50% wet, 1.2 g) was stirred vigorously under hydrogen (1 atm) atmosphere. After 3.5 hours, the catalyst was removed by filtration, and the filtrate was evaporated in vacuo. The residue was dissolved in water (10 ml) .
- Di-t-butyl dicarbonate (18.3 g) was added to the mixture at 20°C and stirred overnight.
- PH was adjusted to 7 with HCl, organic layer was washed with 10% aqueous citric acid (40 ml), 5% aqueous sodium chloride (40 ml), dried over magnesium sulfate (5 g) and concentrated in vacuo.
- the residue was resolved in toluene (20 ml), concentrated in vacuo to 25 ml.
- the mixture was stirred at 40°C for 3 hours, n-heptane (20 ml) was added to the mixture and stirred at 0°C overnight.
- Example 14 N-[(R)-l-[3-( 1-tert-butoxycarbony1-4-piperidyl) propionyl] -3-piperidylcarbonyl] -2 (S) -acetylamino- ⁇ -alanine (20.0 g) was treated under atmosphere RH 50%, 25°C for 40 hours to give N- [ (R) -1- [3- (4-piperidyl) propionyl] -3-piperidyl carbonyl] -2 (S) -acetylamino- ⁇ -alanine trihydrate (21.6 g) , whose stability against humidity was very good.
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Abstract
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Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002346433A CA2346433A1 (en) | 1998-10-12 | 1999-10-07 | New processes for producing .beta.-alanine derivative |
KR1020017004562A KR20010075623A (en) | 1998-10-12 | 1999-10-07 | New processes for producing β-alanine derivative |
HU0104067A HUP0104067A3 (en) | 1998-10-12 | 1999-10-07 | New processes for producing betha-alanine derivative |
JP2000575841A JP2002527424A (en) | 1998-10-12 | 1999-10-07 | Novel production method of β-alanine derivative |
BR9914780-7A BR9914780A (en) | 1998-10-12 | 1999-10-07 | Process of preparing a compound of formula (i) and compound produced by such a process |
EP99970380A EP1121346A1 (en) | 1998-10-12 | 1999-10-07 | New processes for producing beta-alanine derivative |
AU60044/99A AU769718B2 (en) | 1998-10-12 | 1999-10-07 | New processes for producing beta-alanine derivative |
US09/806,483 US6538007B1 (en) | 1998-10-12 | 1999-10-07 | N-[(R)-1-[3-(4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine trihydrate, compositions thereof, and methods for its use |
HK02104562.8A HK1043120A1 (en) | 1998-10-12 | 2002-06-19 | NEW PROCESSES FOR PRODUCING β -ALANINE DERIVATIVE |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AUPP6465A AUPP646598A0 (en) | 1998-10-12 | 1998-10-12 | New processes for producing alpha-alanine derivative |
AUPP6465 | 1998-10-12 |
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US09/806,483 A-371-Of-International US6538007B1 (en) | 1998-10-12 | 1999-10-07 | N-[(R)-1-[3-(4-piperidyl)propionyl]-3-piperidylcarbonyl]-2(S)-acetylamino-β-alanine trihydrate, compositions thereof, and methods for its use |
US10/318,087 Continuation US20030114488A1 (en) | 1998-10-12 | 2002-12-13 | New processes for producing beta-alanine derivatives |
Publications (1)
Publication Number | Publication Date |
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WO2000021932A1 true WO2000021932A1 (en) | 2000-04-20 |
Family
ID=3810687
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP1999/005520 WO2000021932A1 (en) | 1998-10-12 | 1999-10-07 | NEW PROCESSES FOR PRODUCING β-ALANINE DERIVATIVE |
Country Status (16)
Country | Link |
---|---|
US (2) | US6538007B1 (en) |
EP (1) | EP1121346A1 (en) |
JP (1) | JP2002527424A (en) |
KR (1) | KR20010075623A (en) |
CN (1) | CN1329595A (en) |
AR (1) | AR020768A1 (en) |
AU (1) | AUPP646598A0 (en) |
BR (1) | BR9914780A (en) |
CA (1) | CA2346433A1 (en) |
CZ (1) | CZ20011324A3 (en) |
HK (1) | HK1043120A1 (en) |
HU (1) | HUP0104067A3 (en) |
TR (1) | TR200101040T2 (en) |
TW (1) | TW490460B (en) |
WO (1) | WO2000021932A1 (en) |
ZA (1) | ZA200102781B (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001060813A1 (en) * | 2000-02-17 | 2001-08-23 | Fujisawa Pharmaceutical Co., Ltd. | Beta-alanine derivatives and their use as receptor antagonists |
EP2404899A1 (en) | 2004-02-25 | 2012-01-11 | Astellas Pharma Inc. | Contrast medium for thrombus detection |
WO2018089360A1 (en) | 2016-11-08 | 2018-05-17 | Bristol-Myers Squibb Company | Pyrrole amides as alpha v integrin inhibitors |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20010051730A1 (en) * | 1993-09-22 | 2001-12-13 | Fujisawa Pharmaceutical Co., Ltd. | Beta-alanine derivative and a process for the preparation thereof |
US20050107350A1 (en) * | 2003-08-22 | 2005-05-19 | Pharmacia Corporation | Method for the treatment or prevention of bone disorders with a cyclooxygenase-2 inhibitor alone and in combination with a bone disorder treatment agent and compositions therewith |
CN105017134A (en) * | 2015-07-26 | 2015-11-04 | 陈吉美 | Preparation method for 4-pyridineacrylic acid |
CN110078657A (en) * | 2019-04-10 | 2019-08-02 | 湖州复华春生物医药科技有限公司 | A kind of synthetic method of chirality 3- amino piperidine and its derivative |
CN109970585A (en) * | 2019-04-29 | 2019-07-05 | 安徽安力肽生物科技有限公司 | A kind of preparation method of Beta-alanine ester type compound |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995008536A1 (en) * | 1993-09-22 | 1995-03-30 | Fujisawa Pharmaceutical Co., Ltd. | N-(3-piperidinylcarbonyl)-beta-alanine derivatives as paf antagonists |
WO1996029309A1 (en) * | 1995-03-17 | 1996-09-26 | Fujisawa Pharmaceutical Co., Ltd. | N-ACYLPIPERIDINYLCARBONYLAMINOCARBOXYLIC ACIDS AND THEIR USE AS GLYCOPROTEIN IIB/IIa ANTAGONISTS AND FIBRINOGEN-BLOOD PLATELETS BINDING INHIBITORS |
WO1997033869A1 (en) * | 1996-03-13 | 1997-09-18 | Fujisawa Pharmaceutical Co., Ltd. | N-[(r)-1-{3-(4-piperidyl)propionyl-3-piperidylcarbonyl]-2(s)-acetylamino-beta-alanine as fibrinogen receptor antagonist |
-
1998
- 1998-10-12 AU AUPP6465A patent/AUPP646598A0/en not_active Abandoned
-
1999
- 1999-10-04 TW TW088117056A patent/TW490460B/en not_active IP Right Cessation
- 1999-10-07 TR TR2001/01040T patent/TR200101040T2/en unknown
- 1999-10-07 CA CA002346433A patent/CA2346433A1/en not_active Abandoned
- 1999-10-07 KR KR1020017004562A patent/KR20010075623A/en not_active Application Discontinuation
- 1999-10-07 US US09/806,483 patent/US6538007B1/en not_active Expired - Fee Related
- 1999-10-07 BR BR9914780-7A patent/BR9914780A/en not_active Application Discontinuation
- 1999-10-07 JP JP2000575841A patent/JP2002527424A/en not_active Withdrawn
- 1999-10-07 CZ CZ20011324A patent/CZ20011324A3/en unknown
- 1999-10-07 HU HU0104067A patent/HUP0104067A3/en unknown
- 1999-10-07 EP EP99970380A patent/EP1121346A1/en not_active Withdrawn
- 1999-10-07 WO PCT/JP1999/005520 patent/WO2000021932A1/en active IP Right Grant
- 1999-10-07 CN CN99814265A patent/CN1329595A/en active Pending
- 1999-10-08 AR ARP990105130A patent/AR020768A1/en unknown
-
2001
- 2001-04-04 ZA ZA200102781A patent/ZA200102781B/en unknown
-
2002
- 2002-06-19 HK HK02104562.8A patent/HK1043120A1/en unknown
- 2002-12-13 US US10/318,087 patent/US20030114488A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1995008536A1 (en) * | 1993-09-22 | 1995-03-30 | Fujisawa Pharmaceutical Co., Ltd. | N-(3-piperidinylcarbonyl)-beta-alanine derivatives as paf antagonists |
WO1996029309A1 (en) * | 1995-03-17 | 1996-09-26 | Fujisawa Pharmaceutical Co., Ltd. | N-ACYLPIPERIDINYLCARBONYLAMINOCARBOXYLIC ACIDS AND THEIR USE AS GLYCOPROTEIN IIB/IIa ANTAGONISTS AND FIBRINOGEN-BLOOD PLATELETS BINDING INHIBITORS |
WO1997033869A1 (en) * | 1996-03-13 | 1997-09-18 | Fujisawa Pharmaceutical Co., Ltd. | N-[(r)-1-{3-(4-piperidyl)propionyl-3-piperidylcarbonyl]-2(s)-acetylamino-beta-alanine as fibrinogen receptor antagonist |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001060813A1 (en) * | 2000-02-17 | 2001-08-23 | Fujisawa Pharmaceutical Co., Ltd. | Beta-alanine derivatives and their use as receptor antagonists |
US6812235B2 (en) | 2000-02-17 | 2004-11-02 | Fujisawa Pharmaceutical Co., Ltd. | Beta-alanine derivatives and their use as receptor anatgonists |
EP2404899A1 (en) | 2004-02-25 | 2012-01-11 | Astellas Pharma Inc. | Contrast medium for thrombus detection |
WO2018089360A1 (en) | 2016-11-08 | 2018-05-17 | Bristol-Myers Squibb Company | Pyrrole amides as alpha v integrin inhibitors |
Also Published As
Publication number | Publication date |
---|---|
EP1121346A1 (en) | 2001-08-08 |
HK1043120A1 (en) | 2002-09-06 |
CZ20011324A3 (en) | 2001-08-15 |
HUP0104067A3 (en) | 2002-04-29 |
JP2002527424A (en) | 2002-08-27 |
US20030114488A1 (en) | 2003-06-19 |
AUPP646598A0 (en) | 1998-11-05 |
CN1329595A (en) | 2002-01-02 |
US6538007B1 (en) | 2003-03-25 |
CA2346433A1 (en) | 2000-04-20 |
HUP0104067A2 (en) | 2002-03-28 |
BR9914780A (en) | 2001-10-30 |
TR200101040T2 (en) | 2001-08-21 |
ZA200102781B (en) | 2002-07-04 |
TW490460B (en) | 2002-06-11 |
AR020768A1 (en) | 2002-05-29 |
KR20010075623A (en) | 2001-08-09 |
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