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Matched Legal Cases: ['Application No. 2001', 'Application No. 2001', 'Application No. 2001', 'Application No. 2001', 'Application No. 2002', 'Application No. 2002', 'art 29']

Patent US7816528 - Preparation of aminopyrimidine compounds - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign in<nobr>Advanced Patent Search</nobr>PatentsA 2-(N-methyl-N-methanesulfonylamino)pyrimidine compound of the formula (3): [R is a hydrocarbyl group], is prepared by the steps of: (I) reacting an isobutyrylacetate ester with 4-fluorobenzaldehyde and urea in the presence of a protonic compound and a metal salt; (II) oxidizing the reaction product...http://www.google.com/patents/US7816528?utm_source=gb-gplus-sharePatent US7816528 - Preparation of aminopyrimidine compoundsAdvanced Patent SearchPublication numberUS7816528 B2Publication typeGrantApplication numberUS 11/933,626Publication dateOct 19, 2010Filing dateNov 1, 2007Priority dateJul 13, 2001Fee statusPaidAlso published asCA2453505A1, CA2453505C, CN1301977C, CN1527821A, CN1763016A, CN100349877C, DE60217126D1, DE60217126T2, EP1417180A1, EP1417180A4, EP1417180B1, US7304156, US8222412, US8614320, US20040176401, US20080058520, US20110160455, US20120277432, WO2003006439A1Publication number11933626, 933626, US 7816528 B2, US 7816528B2, US-B2-7816528, US7816528 B2, US7816528B2InventorsAkio Matsushita, Mizuho Oda, Yasuhiro Kawachi, Jun-ichi ChikaOriginal AssigneeAstrazeneca Uk LimitedExport CitationBiBTeX, EndNote, RefManPatent Citations (83), Non-Patent Citations (49), Referenced by (5), Classifications (22), Legal Events (1) External Links: USPTO, USPTO Assignment, EspacenetPreparation of aminopyrimidine compoundsUS 7816528 B2Abstract A 2-(N-methyl-N-methanesulfonylamino)pyrimidine compound of the formula (3): [R is a hydrocarbyl group], is prepared by the steps of: (I) reacting an isobutyrylacetate ester with 4-fluorobenzaldehyde and urea in the presence of a protonic compound and a metal salt; (II) oxidizing the reaction product of the step (I); (III) reacting the oxidation product of the step (II) with an organic sulfonyl halide or an organic sulfonyl anhydride; and (IV) reacting the reaction product of the step (III) with N-methyl-N-methanesulfonamide.
1. A hydroxypyrimidine compound having the formula (1):
in which R is selected from the group consisting of an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl-alkyl group having an alkyl moiety of 1 to 3 carbon atoms an aryl group and a methylphenyl group.
2. The hydroxypyrimidine compound of claim 1, wherein R is an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl-alkyl group having an alkyl moiety of 1 to 3 carbon atoms, or an aryl group.
3. A method for preparing the hydroxypyrimidine compound of claim 1, which comprises oxidizing a dihydropyrimidinone compound having the formula (4):
wherein R is selected from the group consisting of an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl-alkyl group having an alkyl moiety of 1 to 3 carbon atoms an aryl group and a methylphenyl group.
4. The method of claim 3, wherein the dihydropyrimidinone compound is oxidized using nitric acid.
5. The method of claim 3, wherein the dihydropyrimidinone compound is prepared by reacting an isobutyrylacetate ester having the formula (5):
in which R is the same as defined in claim 3,
with 4-fluorobenzaldehyde and urea in the presence of
a protonic compound selected from the group consisting of an inorganic acid or its salt, an organic sulfonic acid, an organic carboxylic acid and an alcohol; and
a metal salt selected from the group consisting of copper(I) chloride, copper(II) chloride, copper(II) acetate, iron(II) chloride, iron(III) chloride, aluminum chloride, nickel(II) bromide, tin(IV) chloride, titanium tetrachloride and magnesium bromide.
6. The method of claim 5, wherein the protonic compound is a protonic acid.
7. The method of claim 6, wherein the protonic acid is sulfuric acid.
8. The method of claim 5, wherein the metal salt is copper(I) chloride.
RELATED APPLICATIONS This is a Divisional Application of U.S. application Ser. No. 10/483,430, filed Jan. 12, 2004, now U.S. Pat. No. 7,304,156, which is a U.S. National Phase Application of International Application No. PCT/JP02/07129, filed Jul. 12, 2002, which claims the benefit of Japanese Patent Application No. 2001-213417, filed Jul. 13, 2001, Japanese Patent Application No. 2001-213418, filed Jul. 13, 2001, Japanese Patent Application No. 2001-310900, filed Oct. 9, 2001, Japanese Patent Application No. 2001-360339, filed Nov. 27, 2001, Japanese Patent Application No. 2002-7015, filed Jan. 16, 2002, and Japanese Patent Application No. 2002-42076, filed Feb. 19, 2002, all of which are herein incorporated by reference in their entireties.
BACKGROUND OF THE INVENTION Bioorg. Med. Chem., 5, 437(1997) describes that the 2-(N-methyl-N-methanesulfonylamino)pyrimidine compound is employable as an intermediate compound for producing a cholesterol reducing agent (HMG-CoA reductase inhibitor: S-4522) having the following formula:
reacting methyl isobutyrylacetate with 4-fluoro-benzonitrile to produce methyl 2-[l-amino-1-(4-fluoro-phenyl)methylene]-4-methyl-3-oxopentanate; and
reacting the 2-[1-amino-1-(4-fluorophenyl)methyl-ene]-4-methyl-3-oxopentanate with N-cyano-N-methyl-methanesulfonamide which is obtained by reaction between N-methylmethanesulfonamide and cyanogen chloride, to produce 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methanesulfonyl-N-methylamino)pyrimidine.
R′SO2X (2)
(R′SO2)2O (2a)
wherein R is the same as above, and X is a halogen atom or an organic sulfonyloxy group,
with an amine compound having the formula (7):
[R is a hydrocarbyl group].
Examples of the sulfonyl halides include methanesulfonyl fluoride, methanesulfonyl chloride, ethanesulfonyl chloride, 1-propanesulfonyl chloride, 2-propanesulfonyl chloride, trifluoromethanesulfonyl fluoride, trifluoromethanesulfonyl chloride, nonafluorobutanesufonyl fluoride, tridecafluorohexanesulfonyl fluoride, heptadecafluorooctanesulfonyl fluoride, uncosafluorodecanesulfonyl fluoride, benzenesulfonyl chloride, 1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, p-toluenesulfonyl fluoride, p-toluenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, p-chlorobenzenesulfonyl chloride, and 2-nitrobenzenesulfonyl chloride. Preferred are trifluoromethanesulfonyl fluoride, benzenesulfonyl chloride, 1-naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, p-toluenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, and p-chlorobenzenesulfonyl chloride. Particularly preferred are p-toluenesulfonyl chloride, 2,4,6-trimethylbenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, and p-methoxybenzenesulfonyl chloride.
The reaction can be conducted in two separate liquid phases in the presence of a phase transfer catalyst. Examples of the phase transfer catalysts include tetramethylammonium chloride, tetramethylammonium bromide, tetraethylammonium fluoride, tetraethylammonium chloride, tetraethylammonium bromide, tetrapropylammonium bromide, tetrapropylammonium iodide, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapentylammonium bromide, tetrahexylammonium bromide, tetraheptylammonium bromide, tetraoctylammonium bromide, benzyldimethyltetradecylammonium chloride, benzyltriethylammonium chloride, phenyltrimethylammonium chloride, phenyltrimethylammonium iodide, and hexadecyltrimethylammonium chloride. Preferred are tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodided, benzyltriethylammonium chloride, and hexadecyltrimethylammonium chloride. Most preferred are tetrabutylammonium bromide, benzyltriethylanmonium chloride, and hexadecyltrimethylammonium chloride.
UV λmax (CH3CN, nm): 194.3, 278.6
EXAMPLE 3 Preparation of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine In a 50 mL-volume glass flask equipped with a stirrer and a thermometer was placed 11 mL (144 mmol.) of nitric acid (60-61%, sp.gr.: 1.38). To the nitric acid was slowly added at room temperature 4.00 g (13.7 mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinone prepared in the same manner as in Example 1, and the mixture was subjected to reaction for 30 minutes at room temperature. After the reaction was complete, the reaction mixture was neutralized by placing the mixture in 140 mL of saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was then extracted with ethyl acetate. The organic liquid portion was separated and concentrated under reduced pressure. The residue was crystallized from toluene. The crystalline product was collected on a filter and washed with toluene to obtain 3.64 g of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine as a colorless crystalline product having the below-mentioned characteristics. The yield was 92% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinone).
UV λmax (CH3CN, nm): 196.6, 243.2, 317.9
IR (KBr, cm−1): 2991, 2887, 1717, 1653, 1589, 1433, 1280, 1223.
EXAMPLE 5 Preparation of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine In a 200 mL-volume glass flask equipped with a stirrer and a thermometer was placed 54.0 g (735 mmol.) of nitric acid (60-61%, sp.gr.: 1.38). To the nitric acid was slowly added at room temperature 30.6 g (105 mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinone prepared in the same manner as in Example 1, and the mixture was subjected to reaction for 30 minutes at room temperature. After the reaction was complete, the reaction mixture was poured into 162 mL of water. The aqueous mixture was neutralized by adding 61 g of aqueous sodium hydroxide solution (48 wt. %) to precipitate a crystalline product. The crystalline product was collected by filtration and dried to obtain 27.6 g of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxy-carbonylpyrimidine as a colorless crystalline product. The yield was 91% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-3,4-2(1H)-dihydropyrimidinone).
UV λmax (CH3CN, nm): 194.7, 276.5
1H-NMR (DMSO-d6, δ (ppm)): 1.33 (6H, d, J=6.8 Hz), 3.1-3.2 (1H, m), 3.76 (3H, s), 7.15 (2H, t, J=8.5 Hz), 7.6-7.7 (2H, m).
EXAMPLE 11 Preparation of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine In a 25 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 1.00 g (3.43 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 0.5 mL (3.9 mmol.) of thionyl chloride, 3.44 mL of toluene, and 0.11 mL of N,N-dimethylformamide. The mixture was heated to 80� C. for 3 hours, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature, and poured into an ice/water mixture. The resulting aqueous mixture was neutralized with a saturated aqueous sodium hydrogen carbonate solution. The neutralized aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure, to obtain 0.80 g of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine as a colorless crystalline product. The yield was 76% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isoproply-5-methoxycarbonylpyrimidine).
EXAMPLE 12 Preparation of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonyl-amino)pyrimidine In a 25 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 546 mg (5 mmol.) of N-methylmethanesulfonamide, 551 mg (5 mmol.) of sodium t-pentoxide, 10 mL of acetonitrile, and 309 mg (1 mmol.) of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine. The mixture was heated to 81-82� C. for 3 hours under refluxing, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the cooled mixture was added 10 mL of water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated, and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (2:1, volume ratio)). There was obtained 339 mg of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine. The yield was 89% (based on the amount of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine).
UV λmax (CH3CN, nm): 193.7, 276.8
EXAMPLE 14 Preparation of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine In a 200 mL-volume glass flask were placed 27.6 g (95.1 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 12.5 g (123 mmol.) of triethylamine, and 95 mL of acetonitrile. The mixture of the flask was chilled to 0-5� C. in an ice bath. To the chilled mixture was slowly added 20.0 g (105 mmol.) of p-toluenesulfonyl chloride, and the resulting mixture was subjected to reaction at 20-25� C. for one hour. After the reaction was complete, to the reaction mixture was added 95 mL of water. The aqueous reaction mixture was extracted with toluene and the toluene portion was separated. The toluene portion was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The dried mixture was filtered and concentrated under reduced pressure. The residue was crystallized from methanol, to give 35.9 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine as a colorless crystalline product having the below-mentioned characteristics. The yield was 85% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
UV λmax (CH3CN, nm): 194.9, 275.2
HRMS: 444.1155 (theoretical value (C22H21FN2O5S(M+)) 444.1194)
There was obtained 37.7 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(2,4,6-trimethylbenzenesulfonyloxy)pyrimidine as a pale yellow crystalline product having the below-mentioned characteristics. The yield was 84% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
There was obtained 47.1 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(2,4,6-triisopropylbenzenesulfonyloxy)pyrimidine as a pale yellow crystalline product having the below-mentioned characteristics. The yield was 89% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
There was obtained 39.9 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-methoxybenzenesulfonyloxy)pyrimidine as a colorless crystalline product having the below-mentioned characteristics. The yield was 91% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
There was obtained 28.0 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(2-nitrobenzenesulfonyloxy)pyrimidine as an opaque crystalline product having the below-mentioned characteristics. The yield was 62% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
EXAMPLE 21 Preparation of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine In a 25 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 196 mg (1.8 mmol.) of N-methylmethanesulfonamide, 198 mg (1.8 mmol.) of sodium t-pentoxide, 7.5 mL of acetonitrile, and 667 mg (1.5 mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine. The mixture was heated to 81-82� C. for 1.5 hours under refluxing, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the cooled mixture was added 10 mL of water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated, and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (2:1, volume ratio)). There was obtained 428 mg of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)-pyrimidine. The yield was 75% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine).
EXAMPLE 22 Preparation of (2-amino-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine In a 25 mL-volume glass flask equipped with a stirrer, a thermometer and a gas inlet were placed under ice-chilling 1.00 g (2.71 mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine and 8.1 mL of tetrahydrofuran. The mixture was stirred at room temperature for 12 hours under gaseous ammonia atmosphere, for carrying out reaction. After the reaction was complete, 10 mL of water was added to the reaction mixture. The aqueuos mixture was then subjected to extraction with toluene. The toluene portion was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The dried toluene portion was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (2:1, volume ratio)). There was obtained 0.63 g of 2-amino-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine. The yield was 80% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine). 6-isopropyl-5-methoxycarbonylpyrimidine
EXAMPLE 23 Preparation of (4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-N-methylaminopyrimidine In a 50 mL-volume glass flask equipped with a stirrer, a thermometer and a dropping funnel was placed 6.00 g (16.3 mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine. Into the flask was slowly dropped under ice-chilling 5.06 g (65.2 mmol) of aqueous 40 wt. % methylamine solution. The resulting mixture was stirred for one hour at the same temperature for carrying out reaction. After the reaction was complete, 16 mL of water was added to the reaction mixture. The aqueuos mixture was then subjected to extraction with toluene. The toluene portion was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The dried toluene portion was filtered and concentrated under reduced pressure to give 4.81 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-N-methylaminopyrimidine. The yield was 97% (based on the amount of 4-(4-fluoro-phenyl)-6-isopropyl-5-methoxycarbonyl-2-methanesulfonyloxypyrimidine).
EXAMPLE 24 Preparation of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine In a 300 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 8.7 g (30.0 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 3.0 g (30.0 mmol.) of triethylamine, and 150 mL of toluene. The mixture in the flask was chilled to 0� C. in an ice bath. To the chilled mixture was slowly added 8.46 g (30.0 mmol.) of trifluoromethanesulfonic anhydride, and the resulting mixture was subjected to reaction for 3 hours at the same temperature. After the reaction was complete, to the reaction mixture was added 90 mL of water. From the aqueous reaction mixture, an organic liquid portion was separated. The organic liquid portion was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (8:2, volume ratio)). There was obtained 8.46 g of 4-(4-fluorophenyl)-6-isoproply-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine having the below-mentioned characteristics as a colorless oil. The yield was 74% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
1H-NMR (CDCl3, δ (ppm)): 1.33 (6H, d, J=6.6 Hz), 3.1-3.2(1H, m), 3.80 (3H, s), 7.1-7.2 (2H, m), 7.7-7.8 (2H, m)
EXAMPLE 25 Preparation of 4-(4-flurophenyl)-6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine In a 300 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 2.9 g (10.0 mmol.) of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine, 1.7 g (16.8 mmol.) of triethylamine, and 50 mL of toluene. The mixture in the flask was chilled to 0� C. in an ice bath. To the chilled mixture was slowly added 2.4 g (14.1 mmol.) of trifluoromethanesulfonyl chloride, and the resulting mixture was subjected to reaction for 3 hours at the same temperature. After the reaction was complete, to the reaction mixture was added 30 mL of water. From the aqueous reaction mixture, an organic liquid portion was separated. The organic liquid portion was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (8:2, volume ratio)). There was obtained 2.8 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine having the below-mentioned characteristics as a colorless oil. The yield was 66% (based on the amount of 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-5-methoxycarbonylpyrimidine).
EXAMPLE 26 Preparation of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine In a 50 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 3.0 g (7 mmol.) of 4-(4-fluorophenyl-6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine, 1.13 g (10.5 mmol.) of N-methylmethanesulfonamide, 1.45 g (10.5 mmol.) of potassium carbonate (available from Wako Junyaku Co., Ltd., special grade), and 14 mL of butyl acetate. The mixture was heated to 122-125� C. for 3 hours under refluxing, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the reaction mixture were added 10 mL of water and 7 mL of acetone, and the organic liquid portion was separated. The organic liquid portion was washed with a saturated aqueous sodium chloride solution and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (5:1, volume ratio)). There was obtained 2.1 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine as a white crystalline product. The yield was 78% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-trifluoromethanesulfonyloxypyrimidine).
EXAMPLE 27 Preparation of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine In a 50 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 1.1 g (2.5 mmol.) of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine, 0.55 g (5.0 mmol.) of N-methylmethanesulfonamide, 0.69 g (5.0 mmol.) of potassium carbonate (available from Wako Junyaku Co., Ltd., special grade), 0.32 g (1.0 mmol.) of tetrabutylammonium bromide, 20 mL of toluene and 5 mL of water. The mixture was heated to 85� C. for 28 hours under refluxing, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the reaction mixture were added 10 mL of water and 7 mL of acetone, and the organic liquid portion was separated. The organic liquid portion was analyzed by high performance liquid chromatography. It was confirmed that 0.6 g of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesulfonylamino)pyrimidine was produced. The yield was 63% (based on the amount of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(p-toluenesulfonyloxy)pyrimidine).
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"Synthesis of syn- and anti-3,5-Dihydroxy-6-heptenoates from 2-Deoxy-d-ribose: Intermediates for Polyols Synthesis" Synlett 2:215-218 (2003).Referenced byCiting PatentFiling datePublication dateApplicantTitleUS7989643Nov 24, 2009Aug 2, 2011Astrazeneca Uk Ltd.Process for the preparation of 2-(6-substituted-1,3-dioxane-4-yl)acetic acid derivativesUS8034932Dec 22, 2005Oct 11, 2011Astrazeneca Uk LimitedHydroxy-3-methylglutaryl/3-/ coenzyme A reductase inhibitor; anticholesterol agents;dyslipidemia; chemical intermediate for rosuvastatinUS8063213Jun 3, 2004Nov 22, 2011Astrazeneca Uk LimitedReacting (1-6C)alkyl ester of (E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl) acetic acid with hydrochloric acid, salt formation with sodium or potassium hydroxide, basification, desolventization, salt exchangeUS8222412 *Sep 23, 2010Jul 17, 2012Astrazeneca Uk LimitedPreparation of aminopyrimidine compoundsUS8614320Jun 14, 2012Dec 24, 2013Astrazeneca Uk LimitedPreparation of aminopyrimidine compounds* Cited by examinerClassifications U.S. Classification544/315, 544/330, 544/318International ClassificationC07D239/36, C07D239/30, C07D239/69, C07D239/22, C07D239/34, A61P3/06, C07D239/42, A61K31/505, C07DCooperative ClassificationC07D239/42, C07D239/30, C07D239/22, C07D239/36, C07D239/34European ClassificationC07D239/34, C07D239/30, C07D239/36, C07D239/22, C07D239/42Legal EventsDateCodeEventDescriptionMar 19, 2014FPAYFee paymentYear of fee payment: 4RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google