WO2002051815A1 - Derives de pyrimidine et procede de preparation de ceux-ci - Google Patents
Derives de pyrimidine et procede de preparation de ceux-ci Download PDFInfo
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- WO2002051815A1 WO2002051815A1 PCT/JP2001/011371 JP0111371W WO02051815A1 WO 2002051815 A1 WO2002051815 A1 WO 2002051815A1 JP 0111371 W JP0111371 W JP 0111371W WO 02051815 A1 WO02051815 A1 WO 02051815A1
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- Prior art keywords
- dihydropyrimidine
- oxo
- ylacetic acid
- amino
- salt
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
- C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a novel pyrimidine derivative represented by the general formula (I) useful as a pharmaceutical intermediate and Z or a method for producing a pharmaceutical using the same.
- a pyrimidine derivative compound represented by or a salt thereof A pyrimidine derivative compound represented by or a salt thereof,
- WO 98/24806 describes that the compound represented by the general formula (E) or a non-toxic salt thereof is useful as a serine protease (particularly, elastase) inhibitor.
- WO98 / 24806 describes the formula (V-1) by the method described in J. Med. Chem., Vol. 39, 98-108 (1995) (method shown in reaction formula 1). 5-benzyloxycanolepo- / reamino-6-oxo-1-phen-2- ⁇ -1,6-dihydropyrimidine-11-ylacetic acid shown in the following formula was prepared and used as a key intermediate. It is described that a compound represented by the formula ( ⁇ -1) is produced by the above method. Koseo 1
- E t 3 N represents triethylamine
- DPPA diphenylphosphate azide
- B n OH represents benzyl alcohol
- C b z represents a benzyloxycarbyl group
- EDC stands for 1-Ethyl-3- (3-dimethylaminopropyl) carpoimide
- HOB t represents 1-hydroxybenzotriazole
- NMM stands for N-methylmorpholine
- DMF stands for dimethylformamide
- a Curtius rearrangement reaction is carried out in order to produce a compound represented by the formula (X-6) from a compound represented by the formula (X-4).
- a large amount of nitrogen gas is generated during the progress of the reaction. This nitrogen gas is not a problem in small-scale synthesis at the laboratory level. 1 It was a major problem in industrial large-scale synthesis. From such a point, a method for producing a pyrimidine derivative without performing the Curtius rearrangement reaction has been desired.
- a pyrimidine derivative represented by the formula (E-1) is obtained by combining an amidine compound represented by the formula (X-1) and a methoxymethylene represented by the formula (X-2) It is produced in eight steps from the reaction of dimethyl malonate. Therefore, in the industrial mass synthesis of the pyrimidine derivative represented by the formula (E-1), a more efficient method capable of producing the pyrimidine derivative in a short step has been desired.
- (2) WO00 / 55140 discloses an improved method for producing a compound represented by the formula (X-6) from the compound represented by the formula (X-4) in the reaction scheme 1. In other words, this method is a method for producing a pyrimidine derivative without performing Curtius rearrangement (see Reaction Scheme 3). ⁇ TM ⁇ , 3
- E t 3 N represents triethylamine
- DBU stands for 1,8-diazabicyclo [5.4.0] -7-indene.
- THF represents tetrahydrofuran
- C bz C 1 represents a benzyloxycarboluc mouth ride.
- L DA represents lithium diisopropylamide
- TME DA represents N, N, N ,, N'-tetramethylethylenediamine
- Boc represents a tert-butyloxycarbonyl group
- a c O Et represents ethyl acetate
- NMM stands for N-methylmorpholine
- C b z represents a benzyloxycarbonyl group.
- the present inventors have conducted intensive studies for the purpose of efficiently producing the compound represented by the general formula ( ⁇ ) on an industrial production scale, and as a result, have obtained the compound represented by the general formula (I-—). It was found that the object was achieved by passing through, and the present invention was completed.
- the 5-amino-6-oxo-11,6-dihydropyrimidine-11-inoleacetic acid derivative represented by the formula (IA) or a salt thereof is a novel compound which has not been known at all.
- the Curtius rearrangement does not go through. Further, the compound represented by the general formula (E) is changed from a compound represented by the formula ( ⁇ -1) or a compound represented by the formula ( ⁇ -2) and a compound represented by the general formula (m) by 2 to 3 Manufactured in short stages. Therefore, this method is suitable for industrial mass synthesis. It's a very efficient method.
- a 5-benzoylamino-6-oxo-2-1,6-dihydropyrimidine-11-ylacetic acid derivative represented by the general formula (I-B) or a salt thereof is a novel compound which has never been known before. Compound.
- a 4-chloro-5-benzyloxycarbonylamine 6-oxo-1,6-dihydropyrimidine-11-inoleacetic acid derivative represented by the following formula or a salt thereof is obtained, and further subjected to hydrogenolysis to obtain a compound represented by the general formula ( The compound represented by I-A) was also successfully produced.
- the compound represented by the formula (E) is a short step of four steps from the compound represented by the formula (IV-1) or the compound represented by the formula (IV-2) and the compound represented by the general formula ( ⁇ ). It is manufactured in. Therefore, this method is also a very efficient method for industrial mass synthesis.
- the pyrimidine derivative represented by the general formula (I) or a salt thereof of the present invention is a completely novel compound, and these compounds are useful as serine protease (especially, elastase) inhibitors.
- RS serine protease
- the present invention is a.
- R 1 represents an amino group, a benzoylamino group or a benzyloxycarbonylamino group
- R 2 represents a hydrogen atom, a hydroxyl group or a chlorine atom
- (3) represents a C 1-4 alkyl group substituted by Cy c 1
- Cy c 1 contains a C 3-10 monocyclic or bicyclic carbocycle, 1-4 nitrogen atoms, 1-2 oxygen atoms and Z or 1-2 sulfur atoms.
- ⁇ ⁇ represents a 0-membered monocyclic or bicyclic heterocyclic ring, Cy c 1 may be substituted by 1 to 5 R 4 ,
- R 1 represents a benzyloxycarbonylamino group
- R 2 represents a hydroxyl group or a chlorine atom.
- a pyrimidine derivative compound represented by or a salt thereof A pyrimidine derivative compound represented by or a salt thereof,
- the present invention relates to a method for producing a 1,6-dihydropyrimidine-11-yl) acetoamide derivative compound or a non-toxic salt thereof.
- the C1-4 alkyl group refers to a methyl, ethyl, propyl, petyl group and isomers thereof.
- the halogen atom is a fluorine, chlorine, bromine and iodine atom.
- the C 3-10 monocyclic or bicyclic carbocyclic ring means a C 3-10 monocyclic or bicyclic carbocyclic aryl or a partially or wholly saturated one thereof. included.
- examples include hebutadiene, cyclooctadiene, benzene, pentalene, azulene, perhydroazulene, perhydropentalene, indene, hydrogenated indene, indane, naphthalene, tetrahydronaphthalene, perhydronaphthalene and the like.
- a 3- to 10-membered monocyclic or bicyclic heterocyclic ring containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms is 1
- Examples of the 3- to 10-membered monocyclic or bicyclic heterocyclic aryl containing 1 to 4 nitrogen atoms, 1 to 2 oxygen atoms and / or 1 to 2 sulfur atoms include, for example, pyrrole, imidazole , Triazonole, tetrazole, virazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, thiin, chepin, oxazole, isoxazonole, thiazole, oxazole, oxazole, oxazole, oxazole Oxazepine, oxaziazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, indolizine,
- heterocycle include aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidin, tetrazoline, tetrazolidine, pyrazoline, virazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydrovirazine, tetrahydrovirazine.
- alkyl, alkoxy, and alkylene groups include straight-chain and branched ones.
- isomers in double bonds, rings and fused rings are included unless otherwise indicated.
- the compound of the present invention represented by the general formula (I) or a non-toxic salt thereof can be produced by the following methods or the methods described in Examples.
- the 5- (benzoisle) amino-6-oxo-1,6-dihydropyrimidine-11-dicarboxylic acid derivative represented by the formula or a salt thereof has the formula ( ⁇ -1)
- the reaction between the compound represented by the formula ( ⁇ -1) or the compound represented by the formula ( ⁇ -2) and the compound represented by the general formula (m) or a salt thereof is carried out, for example, in an organic solvent (methanol, ethanol, etc.).
- the reaction is carried out at a temperature of 20 to 150 in the presence or absence of a base (sodium ethylate, sodium methylate, etc.).
- the reaction of the compound represented by the formula (IV-1) or a salt thereof or the compound represented by the formula (IV-2) or a salt thereof with the compound represented by the general formula (m) or a salt thereof includes, for example, an organic solvent ( Dimethyl carbonate, getyl carbonate, methanol / le, ethanol, etc.), base (sodium hydride, potassium hydride, sodium ethyate) And sodium methylate) in the presence or absence of phenol at a temperature of 20 to 150 ° C.
- an organic solvent Dimethyl carbonate, getyl carbonate, methanol / le, ethanol, etc.
- base sodium hydride, potassium hydride, sodium ethyate
- sodium methylate in the presence or absence of phenol at a temperature of 20 to 150 ° C.
- 4-Chloro-5-benzyloxycarbamine 6-oxo-1,6-dihydropyrimidine-11-ylacetic acid or a salt thereof represented by the formula: can be obtained by halogenating a compound represented by the general formula (I—C). It can be produced by subjecting to a chemical reaction.
- This halogenation reaction is known, for example, in an organic solvent (dichloromethane, chloroform, etc.) in the presence of a halogenating agent (phosphorous oxychloride, thiol chloride, etc.) at a temperature of 120 to 100 ° C.
- a halogenating agent phosphorous oxychloride, thiol chloride, etc.
- 5-Amino-6-oxo-1,6-dihydropyrimidine 1-1 shown by The acetic acid derivative or a salt thereof can be produced by the following methods ( a ) to (d).
- This deprotection reaction is known.
- the reaction is carried out at a temperature of 20 to 150 ° C. in an organic solvent (methanol, ethanol, etc.) in the presence of a base (sodium methylate, sodium ethylate, etc.). It is performed by
- the compound represented by the general formula (IA) or a salt thereof is a compound represented by the formula ( ⁇ -1) or a compound represented by the formula ( ⁇ -2) and a compound represented by the general formula (m) Or subjecting them to a reaction to obtain a compound represented by the general formula (I-B) or a salt thereof, and then subjecting the compound to a deprotection reaction without isolation (ie, one pot) Can also be manufactured.
- the compound represented by the general formula (I-A) can be produced by subjecting the compound represented by the general formula (I-D) produced by the method described above or a salt thereof to hydrogenolysis. it can.
- This hydrogenolysis is known, for example, an inert solvent [ether type (eg, tetrahydrofuran, dioxane, dimethoxetane, getyl ether, etc.), alcohol type (eg, methanol, ethanol, etc.), benzene type (eg, benzene, Toluene, etc.), ketones (eg, acetone, methylethylketone, etc.), nitriles (eg, acetonitrile, etc.), amides (eg, dimethylformamide, etc.), water, ethyl acetate, acetic acid, or a mixture of two or more thereof.
- ether type eg, tetrahydrofuran, dioxane, dimethoxetane, getyl ether, etc.
- alcohol type eg, methanol, ethanol, etc.
- benzene type eg, benzene, Tol
- Solvent in the presence of a hydrogenation catalyst (eg, palladium-carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, nickel, Raney nickel, ruthenium chloride, etc.), and an inorganic acid (eg, hydrochloric acid, sulfuric acid) , Hypochlorous acid, boric acid, tetraflu Rohou acid, etc.) or organic acids (e.g., acetic acid, p- Torue).
- a hydrogenation catalyst eg, palladium-carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, nickel, Raney nickel, ruthenium chloride, etc.
- an inorganic acid eg, hydrochloric acid, sulfuric acid
- organic acids e.g., acetic acid, p- Torue
- the reaction is carried out in the presence or absence of sulfonic acid
- the reduction reaction of dinitro groups is known, for example by hydrogenolysis
- Hydrocracking is carried out by the method described above.
- Reduction reactions using a metal or a salt thereof are known.
- a metal or a salt thereof in the presence or absence of hydrochloric acid, a metal or a salt thereof (zinc, iron, tin) , Tin chloride, iron chloride, etc.) at a temperature of 50 to 150 ° C.
- the method of using an acid or a compound is, for example, a method in which a compound represented by the general formula (IA) is mixed with an inert organic solvent (eg, chloroform, methylene chloride, dimethyl ether, tetrahydrobran) or in an inert solvent. Reaction with acid halides (oxalyl chloride, thiol chloride, etc.) at 120 ° C to reflux temperature in a solvent, and the resulting acid halide is reacted with a tertiary amine (pyridine, triethylamine, dimethylaniline).
- an inert organic solvent eg, chloroform, methylene chloride, dimethyl ether, tetrahydrobran
- acid halides oxalyl chloride, thiol chloride, etc.
- pyridine triethylamine, dimethylaniline
- the method using a mixed acid anhydride is, for example, a method in which a compound represented by the general formula (I-A) is dissolved in an inert organic solvent (eg, chloroform, methylene chloride, dimethyl ether, tetrahydrofuran) or without solvent.
- an inert organic solvent eg, chloroform, methylene chloride, dimethyl ether, tetrahydrofuran
- Tertiary amines pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, N-methylmorpholine, etc.
- acid halides pivaloyl chloride, tosyl chloride, mesyl chloride, etc.
- acid derivatives Etyl chloroformate (ethyl ethyl carbonate), isobutyl chloroformate (isobutyl carbonate), etc.
- the mixture is reacted at 0 to 40 ° C., and the obtained mixed anhydride is reacted with a compound represented by the formula ( ⁇ ) in an inert organic solvent (chloropho / rem, methylene chloride, getyl ether, tetrahydrofuran, etc.).
- the reaction is carried out at 0 to 40 ° C.
- the method using a condensing agent is, for example, a method in which a compound represented by the general formula (I-A) and a compound represented by the formula ( ⁇ ) are mixed with an organic solvent (chloroform, methylene chloride, dimethylhonolemamide, or jetino).
- an organic solvent chloroform, methylene chloride, dimethylhonolemamide, or jetino
- the reactions 1) and 2) are preferably carried out under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.
- the reaction 3) can be carried out under an inert gas (argon, nitrogen, etc.) atmosphere, under anhydrous conditions or in the presence of water.
- the compound represented by the formula ( ⁇ -1), the formula ( ⁇ -2), the general formula ( ⁇ ), the formula (IV-1), the formula (IV-2), the general formula (V) or the general formula (VI) It is publicly known.
- the compound represented by the formula ( ⁇ -1) has CAS registration number 15646-40-5, CAS registration number 60777-96-0, and the compound represented by formula ( ⁇ -2) has CAS registration number 171616.
- -90-3 among the compounds represented by the general formula (m), the compound in which R 3 is a fuel group has CAS registration number 32683-07-1, and the compound represented by the formula (IV-1) has CAS registration number.
- the compound represented by the formula (IV-2) is a compound represented by CAS registration number 3005-66-1, and the compound represented by the general formula (V) in which R 3 is a phenyl group.
- the compound having the CAS registration number 148747-59-5 and R 3 being a phenyl group is a compound represented by the formula (VII) in WO01 / 23361. Are specifically described in WO00 / 55145.
- the product of each reaction is isolated, washed, dried and purified at each step, and the next reaction May be performed, or these operations may not be performed at all, or may be stopped at an appropriate stage and proceed to the next step.
- the reaction product in each reaction can be purified by a usual purification means, for example, a method such as distillation under normal pressure or reduced pressure, high performance liquid chromatography, thin layer chromatography, column chromatography, washing, and recrystallization.
- Salts of the compound of the present invention include alkali metal salts, alkaline earth metal salts, ammonium salts, organic amine salts, acid adduct salts and the like.
- the present compound is converted into a salt by a known method.
- Suitable salts include salts of alkali metals (potassium, sodium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, and organic amines (tetramethylammonium, triethylamine, methylamine, dimethylamine, Salts of cyclopentinoleamine, benzinoleamine, phenetinoleamine, piperidine, monoethanolanolamine, diethanolamine, tris (hydroxymethyl) amino, lysine, arginine, N-methyl-D-glucamine, etc.
- Acid adduct salts inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate, or acetate, trifluoroacetate, lactate, tartrate, oxalate
- Fumarate maleate, citrate, benzoate, methanesole Emissions, ethanesulfonate, benzenesulfonate, Torue Nsuruhon, isethionate, glucuronate, Darukon salt, etc.
- the non-toxic salt of the compound represented by the general formula (E) of the present invention includes the above-mentioned salts of alkali metal, salts of alkaline earth metals, ammonium salts, salts of organic amines, salts of acid adducts, and solvates. It is a non-toxic salt.
- the compound of the present invention and a salt thereof can also be converted to a solvate (water, methanol, etc.) by a known method.
- the method of the present invention relates to a compound represented by the general formula (E), in particular, a compound represented by the formula (E-1): (RS) -N-[(1- (5-tert-butyl-l, 1,3,4-) Oxaziazione 1- 2-innole power pilloninole) 1- 2-methinolep pill] 1 2-(5-amino 6-oxo 1 2 _ phenyl 2,6-dihydropyrimidine 1-yl) acetoamide or its non- It is an excellent method for producing toxic salts compared to conventional methods.
- a pyrimidine compound in which the amino group at the 5-position is protected was used for the reaction, so that after the amidation, the deprotection reaction of the amino group was essential.
- a pyrimidine compound in which the amino group at the 5-position is not protected is used in the reaction (without deprotection of the amino group) to give a compound represented by the general formula (E):
- the production of the compound represented by the formula (E-1) has become possible.
- the conventional method allows the final reaction step only at a low concentration of 0.2 mo 1ZL
- the method of the present invention allows a high concentration of 1.0mo 1ZL, which facilitates mass synthesis in industrialization.
- N- (2,2-dimethylmethoxytinole) benzamidine represented by the formula (X-1) can be obtained in eight steps from (WO98 / 24806) or N- (2,2-dimethoxy).
- Ethyl) can be obtained from phenylamidine in 7 to 10 steps (method of WO00 / 55145), but in the method of the present invention, in 2 to 4 steps from benzamidinoacetic acid represented by the general formula (m), The compound represented by the formula (E-1) can be obtained.
- the method of the present invention is more suitable for industrial mass synthesis than the conventional method. It can be said that it was a method. Detailed description of the drawings
- FIG. 1 shows single crystal structure data of the compound produced in Example 4 (4).
- FIG. 2 shows single crystal structure packing data of the compound produced in Example 4 (4).
- the solvent in kakkou indicated by TLC at the point of separation by chromatography indicates the elution solvent or developing solvent used, and the ratio indicates the volume ratio.
- the solvent in kakkoko shown in the NMR section indicates the solvent used for the measurement.
- the aqueous layer was acidified with 6N hydrochloric acid and extracted with ethyl acetate.
- the extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated.
- Toluene was added to the obtained residue, and the mixture was stirred and crystallized.
- the precipitated crystals were filtered and dried to give the compound of the present invention (9.31 g) having the following physical data.
- Example 4 (1) or 4 (2) was dried at 80 ° C under reduced pressure to give the compound of the present invention having the following physical data.
- Example 4 (1) or 4 (2) The compound produced in Example 4 (1) or 4 (2) was recrystallized from methanol to obtain the present compound having the following physical properties.
- FIG. 1 shows single crystal structure data of the compound produced in Example 4 (4)
- FIG. 2 shows single crystal structure packing data.
- Example 4 (1) or 4 (2) The compound (970 mg) produced in Example 4 (1) or 4 (2) was dissolved in water (1 Oml), and 2N hydrochloric acid (1.7 m 1) was added. The reaction mixture was ice-cooled, and the precipitated solid was filtered, washed with water, and dried under reduced pressure at 50 ° C to obtain the compound of the present invention (784 mg) having the following physical data.
- Example 4 To a suspension of 1-hydroxybenzotriazonole monohydrate (1.68 g) in acetonitrile (10 ml), at a temperature of 7.5 ° C or lower, (RS) —2— (2-amino-1-3-methylbutyryl) —5 — Tert-butyl-1,3,4-oxadiazole 'hydrochloride (2.88 g), 1-ethyl-13- (3-dimethylaminopropyl) carbodiimid-hydrochloride (2.11 g), Example 4 (1) Alternatively, the compound produced in Example 4 (2) (2.87 g) was added to the mixture. The reaction mixture was stirred at the same temperature for 3.5 hours.
- Example 4 A solution of the compound (1.23 g) prepared in (5), Example 6 (1) or 6 (2) and 1-benzotriazolyl mesylate (1.28 g) in dimethylformamide (3 m 1) And a solution of (RS) —2- (2-amino-3-methylbutyryl) -5-tert-butyl-1,3,4-oxadiazole hydrochloride (1.44 g) in dimethylformamide (2 ml) at 15 ° C Was added. Triethylamine (1.67 ml) was added dropwise to the reaction mixture at 15 ° C. The reaction mixture was stirred at 15 to 0 ° C for 2 hours.
- Example 4 a solution of the compound prepared in Example 6 (1) or 6 (2) (49 Omg) and 1-benzotriazolyl mesylate (426 mg) in dimethylformamide (8 ml), and triethylamine at 0 (0.33 m 1) was added. The reaction mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added a solution of (RS) -2- (2-amino-3-methylbutyryl) -15-tert-butyl-1,3,4-oxadiazole hydrochloride (628 mg) in dimethylformamide (2 ml). added. Triethylamine (0.33 ml) was added dropwise to the reaction mixture at 0 ° C.
- Example 8 To a solution of 28% sodium methylate in methanol (3.86 g) in methanol (15 ml) was added the compound prepared in Example 8 (3.67 g) under an argon atmosphere. The reaction mixture was heated at reflux for 20 hours. The reaction mixture was cooled with water, and the precipitated solid was filtered, washed with methanol, and dried under reduced pressure to obtain a sodium salt (1.26 g) of the present compound. This sodium salt (1.19 g) was dissolved in water (4 ml), 1N hydrochloric acid (3.8 ml) was added, and the mixture was stirred for 30 minutes. The precipitated solid was collected by filtration and dried to give the present compound (647 mg) having the following physical data.
- Example 9 The same operation as in Example 9 was carried out using the compounds produced in Examples 8 (1) to 8 (18) instead of the compound produced in Example 8, to obtain the following compounds of the present invention.
- Example 9 (1) The same operation as in Example 9 was carried out using the compounds produced in Examples 8 (1) to 8 (18) instead of the compound produced in Example 8, to obtain the following compounds of the present invention.
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Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP01995000A EP1346985A4 (en) | 2000-12-26 | 2001-12-25 | PYRIMIDINE DERIVATIVES AND PROCESS FOR THE PREPARATION THEREOF |
JP2002552912A JPWO2002051815A1 (ja) | 2000-12-26 | 2001-12-25 | ピリミジン誘導体化合物およびそれらの製造方法 |
HU0303631A HUP0303631A2 (hu) | 2000-12-26 | 2001-12-25 | Pirimidinszármazékok és eljárás előállításukra |
US10/451,670 US20040063936A1 (en) | 2000-12-26 | 2001-12-25 | Pyrimidine derivatives and process for preparing the same |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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JP2000-395012 | 2000-12-26 | ||
JP2000395012 | 2000-12-26 |
Publications (1)
Publication Number | Publication Date |
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WO2002051815A1 true WO2002051815A1 (fr) | 2002-07-04 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/JP2001/011371 WO2002051815A1 (fr) | 2000-12-26 | 2001-12-25 | Derives de pyrimidine et procede de preparation de ceux-ci |
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Country | Link |
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US (1) | US20040063936A1 (ja) |
EP (1) | EP1346985A4 (ja) |
JP (1) | JPWO2002051815A1 (ja) |
HU (1) | HUP0303631A2 (ja) |
WO (1) | WO2002051815A1 (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003106434A1 (ja) * | 2002-06-14 | 2003-12-24 | 味の素株式会社 | ピリミジン化合物の製造方法 |
WO2005042499A1 (ja) * | 2003-11-04 | 2005-05-12 | Ajinomoto Co., Inc. | ピリミジン誘導体および中間体の製造方法 |
US7358368B2 (en) | 2003-11-04 | 2008-04-15 | Ajinomoto Co., Inc. | Azlactone compound and method for preparation thereof |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1529778A1 (en) * | 2003-11-04 | 2005-05-11 | Ajinomoto Co., Inc. | Production method of pyrimidine derivative, intermediate therefor |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0528633A1 (en) * | 1991-08-15 | 1993-02-24 | Zeneca Limited | Pyrimidinyl acetamides as elastase inhibitors |
WO1996033974A1 (fr) * | 1995-04-27 | 1996-10-31 | The Green Cross Corporation | Composes heterocycliques amides et leur utilisation medicinale |
WO1999032459A1 (fr) * | 1997-12-22 | 1999-07-01 | Yoshitomi Pharmaceutical Industries, Ltd. | Inhibiteurs de la chymase |
WO2000055145A1 (fr) * | 1999-03-12 | 2000-09-21 | Ono Pharmaceutical Co., Ltd. | Derives de 1,3,4-oxadiazole et leur procede de fabrication |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6011158A (en) * | 1994-12-13 | 2000-01-04 | Corvas International, Inc. | Aromatic heterocyclic derivatives as enzyme inhibitors |
MX9704439A (es) * | 1994-12-13 | 1997-10-31 | Corvas Int Inc | Derivados heterociclicos aromaticos como inhibidores de enzima. |
-
2001
- 2001-12-25 HU HU0303631A patent/HUP0303631A2/hu unknown
- 2001-12-25 WO PCT/JP2001/011371 patent/WO2002051815A1/ja not_active Application Discontinuation
- 2001-12-25 JP JP2002552912A patent/JPWO2002051815A1/ja active Pending
- 2001-12-25 US US10/451,670 patent/US20040063936A1/en not_active Abandoned
- 2001-12-25 EP EP01995000A patent/EP1346985A4/en not_active Withdrawn
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0528633A1 (en) * | 1991-08-15 | 1993-02-24 | Zeneca Limited | Pyrimidinyl acetamides as elastase inhibitors |
WO1996033974A1 (fr) * | 1995-04-27 | 1996-10-31 | The Green Cross Corporation | Composes heterocycliques amides et leur utilisation medicinale |
WO1999032459A1 (fr) * | 1997-12-22 | 1999-07-01 | Yoshitomi Pharmaceutical Industries, Ltd. | Inhibiteurs de la chymase |
WO2000055145A1 (fr) * | 1999-03-12 | 2000-09-21 | Ono Pharmaceutical Co., Ltd. | Derives de 1,3,4-oxadiazole et leur procede de fabrication |
Non-Patent Citations (5)
Title |
---|
OHMOTO K. ET AL.: "Design and synthesis of new orally active inhibitors of human neutrophil elastase", BIOORG. MED. CHEM., vol. 9, no. 5, May 2001 (2001-05-01), pages 1307 - 1323, XP002908877 * |
OHMOTO K. ET AL.: "Design and synthesis of new orally active nonpeptidic inhibitors of human neutrophil elastase", J. MED. CHEM., vol. 43, no. 26, 28 December 2000 (2000-12-28), pages 4927 - 4929, XP002908875 * |
OHMOTO K. ET AL.: "Development of orally active nonpeptidic inhibitors of human neutrophil elastase", J. MED. CHEM., vol. 44, no. 8, April 2001 (2001-04-01), pages 1268 - 1285, XP002908876 * |
OHMOTO K. ET AL.: "Improved synthesis of a new nonpeptidic inhibitor of human neutrophil elastase", SYNLETT, no. 2, February 2001 (2001-02-01), pages 299 - 301, XP002908878 * |
See also references of EP1346985A4 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003106434A1 (ja) * | 2002-06-14 | 2003-12-24 | 味の素株式会社 | ピリミジン化合物の製造方法 |
WO2005042499A1 (ja) * | 2003-11-04 | 2005-05-12 | Ajinomoto Co., Inc. | ピリミジン誘導体および中間体の製造方法 |
US7358368B2 (en) | 2003-11-04 | 2008-04-15 | Ajinomoto Co., Inc. | Azlactone compound and method for preparation thereof |
Also Published As
Publication number | Publication date |
---|---|
HUP0303631A2 (hu) | 2004-03-01 |
US20040063936A1 (en) | 2004-04-01 |
EP1346985A4 (en) | 2004-02-18 |
JPWO2002051815A1 (ja) | 2004-04-22 |
EP1346985A1 (en) | 2003-09-24 |
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