Classifications

• • 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
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/42—One nitrogen atom

Definitions

• This invention relates to the field of compound preparation, and in particular to novel crystalline forms of rosuvastatin oxime ester and methods for their preparation. Background technique
• Rosuvastatin calcium bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-indolyl sulfonylaminopyrimidine)-5-yl] ( 3R,5S)-dihydroxy-(E)-6-hept-enoic acid] calcium salt, the structure of which is shown in formula I,
• Rosuvastatin Calcium is a super statin drug that is comparable to first-cholesterol and triglycerides.
• Rosuvastatin and the intermediate rosuvastatin oxime esters have enantiomers and diastereomers with molecules having two chiral centers at positions 3 and 5.
• ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5R)-3 the structure of 5-dihydroxyhept-6-enoic acid decyl ester is as shown in Formula II
• the structure of decyl sulfonylamino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate is as shown in Formula III
• WO 2005/040134 reports reducing rosuvastatin by lactonization or by converting amorphous rosuvastatin and an intermediate into a crystalline rosuvastatin intermediate and subsequent conversion to an amorphous form. The diastereomeric content of the intermediate.
• the method disclosed in WO 2007/040940 is to reduce the content of diastereomers of the rosuvastatin intermediate by recovering rosuvastatin diol ester and crystallizing rosuvastatin ketone-ester. Chiral purity of the rosuvastatin intermediate. However, it is very difficult to remove unreacted starting materials from the reaction.
• the present invention provides rosuvastatin oxime ester (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine -5-yl]
• the method can obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[ ⁇ ] with enantiomeric impurities less than 0.50% and diastereomeric impurities less than 0.30%.
• the present invention provides the following technical solutions:
• the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidin-5-yl] (3R,5S) Crystal form of -3,5-dihydroxyhept-6-enoate, X-ray powder diffraction pattern at 2 ⁇ 1 The position has a peak, and the 2 ⁇ are 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927, and 26.3293.
• the X ⁇ value of the X-ray powder diffraction pattern may vary slightly between machines or between samples, and the values may differ by about 1 unit, or by about 0.8 units, or by about 0.5 units, or by a difference of about 0.3. Units, or a difference of approximately 0.1 units, so the values quoted cannot be interpreted as absolute values. It should also be understood that the relative intensities of the peaks may vary depending on the orientation of the sample under test, and thus the XRD trace intensities included in the present invention are illustrative and are not intended for absolute comparison.
• the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R a crystal form of 5S)-3,5-dihydroxyhept-6-enoic acid ester having an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.8, wherein the 2 ⁇ is 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927 and 26.3293.
• the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R a crystal form of 5S)-3,5-dihydroxyhept-6-enoate having an X-ray powder diffraction pattern having a peak at 2 ⁇ 0.5, wherein the 2 ⁇ is 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927 and 26.3293.
• the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R a crystal form of 5S)-3,5-dihydroxyhept-6-enoate having an X-ray powder diffraction pattern having a peak at a position of 2 ⁇ 0.3, and the 2 ⁇ is 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927 and 26.3293.
• the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R a crystal form of 5S)-3,5-dihydroxyhept-6-enoate having an X-ray powder diffraction pattern having a peak at a position of 2 ⁇ 0.2, wherein the 2 ⁇ is 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927 and 26.3293.
• the present invention also provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S a crystalline form of -3,5-dihydroxyhept-6-enoic acid ester for the preparation of rosuvastatin or a pharmaceutically acceptable salt thereof; (E)-7-[4-(4-fluorophenyl) X-ray of -6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate
• the powder diffraction pattern has peaks at 2 ⁇ ⁇ 1 position, which are 9.3280, 17.4066, 17.9806, 19.5084, 20.2123, 21.6525, 24.3325, 24.6927, and 26.3293.
• the present invention also provides the above ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R, A method for the conversion of a crystalline form of 5S)-3,5-dihydroxyhept-6-enoate to rosuvastatin or rosuvastatin lactone or a pharmaceutically acceptable salt according to US Publication No. 2005/080134 get on. This conversion can be carried out by alkaline hydrolysis of the oxime ester.
• the present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S a method for crystallizing a crystalline form of -3,5-dihydroxyhept-6-enoate, comprising the steps of: Step 1: obtaining (E)-7-[4-(4-fluorophenyl)-6- Isopropyl-2-[indolyl(decyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid decyl ester;
• Step 2 Take (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-dihydroxyhept-6-enoic acid decyl ester is mixed with an excess of solvent to obtain a first solution, which is obtained after crystallization, separation and drying;
• the solvent is ( 1-4 alcohol, C 3-8 ester, C 3-8 ketone, C 3-8 ether, C 6-1 .
• Aromatic hydrocarbon ethylene glycol diethyl ether, ethylene glycol dioxime ether, water, acetonitrile One or a mixture of two or more;
• the present invention provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (
• the solvent in step 2 is decyl alcohol, a mixture of acetonitrile and water, a mixture of acetone and water, MTBE ( ⁇ Tert-butyl ether), a mixture of sterol and water, a mixture of ethanol and water, a mixture of ethanol and MTBE, a mixture of acetonitrile and MTBE, a mixture of decyl alcohol and MTBE, MEK (mercaptoethyl ketone), 4-mercapto a mixture of 2-pentanone, MTBE and terpene, a mixture of one or more of ethyl ketone, MEK (mercaptoethyl ketone), 4-mercapto a mixture of 2-pentanone, MTBE
• the present invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidin-5-yl] (3R)
• the solvent used is not limited to the above-mentioned species, and according to the principle that the structural similar properties are similar, it is known that (3 1-4 alcohol, C 3-8 ester, C 3-8 ketone, C 3-8 ether, C 6-1 .
• a mixture of one or more of an aromatic hydrocarbon, ethylene glycol diethyl ether, water, acetonitrile can be used as a solvent to facilitate The effect of crystallization, therefore, one or both of C M alcohol, C 3-8 ester, C 3-8 ketone, C 3-8 ether, C 6-10 aromatic hydrocarbon, ethylene glycol diethyl ether, water, acetonitrile
• the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine- Crystal form of 5-(5R,5S)-3,5-dihydroxyhept-6-enoate
• the solvent in the step 2 is MTBE, MEK, 4-mercapto-2-pentanone, terpene, a mixture of acetone and water, a mixture of one or more of a mixture of acetonitrile and water.
• the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
• the solvent in step 2 is 4-mercapto-2-pentanone and/or MTBE.
• the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
• the solvent is decyl alcohol, in g/mL
• the mass to volume ratio of the crude decyl enoate to sterol is 1:1 to 10.
• the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
• the solvent is a mixture of decyl alcohol and water, wherein the volume ratio of sterol to water Less than 6: 1.
• the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
• the solvent is a mixture of acetonitrile and MTBE, wherein the volume ratio of acetonitrile to MTBE is less than 1: 10.
• the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
• the solvent is a mixture of decyl alcohol and MTBE, wherein the volume ratio of sterol to MTBE is less than 1: 10.
• the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
• the crystallization in step 2 is specifically taking the first solution and heating to 50 ° C or higher. , cool down.
• (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R) is provided by the present invention.
• the cooling temperature is -20 - 40 °C.
• the cooling temperature is -10 to 30 °C.
• the cooling temperature is -5 to 10 °C.
• the filtration in step 2 is vacuum filtration.
• step 2 After filtration, the filter cake is collected, and the filter cake is dried, and the drying in step 2 is dried under reduced pressure or warmed up. Dry.
• the drying in step 2 is carried out under a negative pressure at 40 to 50 °C.
• the present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine-5 which is obtained by the above preparation method.
• the present invention also provides ( ⁇ )-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S a method for preparing a crystal form of -3,5-dihydroxyhept-6-enoate, comprising the steps of: Step 1: obtaining (E)-7-[4-(4-fluorophenyl)-6- Isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid decyl ester;
• Step 2 Take (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine-5 at 0-40 °C a solution of (3R,5S)-3,5-dihydroxyhept-6-enoic acid decyl ester is suspended in an excess of a second solvent, and is obtained after separation and drying;
• the second solvent is selected from the group consisting of C M alcohols, C 3-8 esters, C 3-8 ketones, C 3-8 ethers, C 6-1 .
• Aromatic hydrocarbons ethylene glycol diethyl ether, ethylene glycol dioxime ether, acetonitrile, water.
• the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine-
• the second solvent is decyl alcohol, a mixture of acetonitrile and water, a mixture of acetone and water.
• MTBE nonyl tert-butyl ether
• sterol and water a mixture of ethanol and water
• a mixture of ethanol and MTBE a mixture of acetonitrile and MTBE
• MEK mercaptoethyl ketone
• 4-mercapto-2-pentanone a mixture of MTBE and toluene, a mixture of one or more of a mixture of ethyl acetate and petroleum ether.
• the present invention provides (E)-7-[ 4- ( 4 -fluorophenyl)-6-isopropyl- 2 -[[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R)
• the solvent used is not limited to the above-mentioned species, and according to the principle that the structural similar properties are similar, it is known that ( ⁇ , alcohol, ester, C) ⁇ 8 ketone, ether, C car aromatic hydrocarbon, ethylene glycol diethyl ether, water, acetonitrile or a mixture of two or more can be used as a solvent to facilitate the pulping and thereby obtain the crystal form, therefore, C M alcohol And a mixture of one or more of an aromatic hydrocarbon, ethylene glycol diethyl ether, water, acetonitrile, and a mixture of two or more of C, 8 ester
• the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
• the second solvent is MTBE, MEK, 4-mercapto-2-pentanone , terpene, a mixture of acetone and water, a mixture of one or more of a mixture of acetonitrile and water.
• the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl
• the solvent is 4-mercapto-2-pentanone and/or MTBE.
• the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
• the second solvent is decyl alcohol, in terms of g/mL
• the mass to volume ratio of crude hydroxyhept-6-enoate and sterol is 1: 1 ⁇ 10.
• the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
• the second solvent is a mixture of decyl alcohol and water, wherein sterol and water are The volume ratio is less than 6:1.
• the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
• the second solvent is a mixture of acetonitrile and MTBE, wherein the volume of acetonitrile and MTBE The ratio is less than 1:10.
• the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
• the second solvent is a mixture of decyl alcohol and MTBE, wherein the volume of sterol and MTBE The ratio is less than 1:10.
• the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine
• the separation in step 2 is filtration.
• the filtration in step 2 is vacuum filtration.
• step 2 the drying is carried out under reduced pressure or at elevated temperature.
• the drying in the step 2 is drying under a negative pressure of 40 to 50 °C.
• the present invention also provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(indolyl)amino]pyrimidine-5 which is obtained by the above preparation method.
• the present invention provides rosuvastatin oxime ester (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl (3R,5S)-3,5-Dihydroxyhept-6-enoic acid decyl ester and a preparation method thereof.
• the method can obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2 with enantiomeric impurities less than 0.50% and diastereomeric impurities less than 0.30% by solvent.
• Figure 1 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl prepared in Example 1.
• Figure 2 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl prepared in Example 2.
• Figure 3 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl prepared in Example 3.
• the invention discloses rosuvastatin oxime ester and a preparation method thereof, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
• the method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
• the reagents used in the rosuvastatin oxime ester provided by the present invention and the preparation method thereof can be purchased from the market.
• the present invention determines X-ray powder diffraction spectra by placing a sample in crystalline form on a Siemans single silicon crystal (SSC) wafer mount and coating the sample as a thin layer by means of a microscopic slide.
• the sample was rotated at 30 revolutions per minute (to improve count statistics) and illuminated with X-rays generated by an elongated focusing copper tube operating at a wavelength of 1.5406 angstroms at 40 kV and 40 mA.
• the calibrated X-ray source passes through an automatically adjustable divergence slit set to V20 (20 mm diameter), and the reflected radiation passes directly through a 2 mm anti-scatter slit and a 0.2 mm detection slit.
• the sample received 4 seconds of radiation (continuous scan mode) for every 0.02 degrees 2 turns in the range of 2 to 40 degrees 2 turns in the ⁇ - ⁇ mode.
• the running time is 2 hours, 6 minutes and 40 seconds.
• the instrument is equipped with a scintillation counter as the detector.
• Diffrac AT Socabim
• the invention is not limited, and a suitable temperature range is within the scope of the invention.
• Example 1 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine- 5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate crystallization from benzene
• Example 5 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from MTBE
• Example 6 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) - 3,5-Dihydroxyhept-6-enoate crystallization from MEK
• Example 7 (E)- 7- [4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from ethyl acetate: petroleum ether (1:1)
• Example 8 ( ⁇ )-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid methyl ester crystallized from 4-mercapto-2-pentanone
• Example 9 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) - 3,5-Dihydroxyhept-6-enoate crystallization from ethylene glycol diterpene ether
• Example 10 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine-5-] (3R,5S)- 3,5-Dihydroxyhept-6-enoate crystallization from sterol
• Example 11 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid methyl ester from MEK pulping
• Example 12 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of acetonitrile and MTBE (volume ratio 1:15)
• Example 13 ( ⁇ )-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of decyl alcohol and water (5:1 by volume)
• Example 14 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester from a mixture of decyl alcohol and MTBE (volume ratio 1: 20)
• Example 15 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of acetone and water lOg (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) After total dissolution with 20 ml of a mixture of acetone and water, then cooled to room temperature (25 ° C ), and then placed in a
• Example 16 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of ethanol and MTBE
• Example 17 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of 4-mercapto-2-pentanone, MTBE and toluene
• Example 18 (E)- 7 -[ 4 -( 4 -Fluorophenyl)-6-isopropyl- 2 -[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of decyl alcohol and water
• Example 19 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine-5-yl](3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from toluene
• Example 20 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of ethanol and water lOg (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoate (1.0% diastereomer 0.7% enantiomer) After total dissolution with 20 ml of a mixture of ethanol and water, then cooled to room temperature (30 ° C ), placed in a refrigerator (-10 ° C), frozen and crystallized,
• Example 21 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of MTBE and toluene
• Example 22 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of decyl alcohol and MTBE
• Example 23 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of acetonitrile and water
• Example 2 4 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from ethyl acetate and petroleum ether
• Example 26 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of ethanol and MTBE
• Example 27 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of acetonitrile and MTBE (1:25 by volume)
• Example 28 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of acetone and water
• Example 29 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate oxime pulping from MTBE
• Example 30 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from decyl alcohol
• Example 31 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate decylate from a mixture of decyl alcohol and water (1:1 by volume)
• Example 32 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime pulp from a mixture of decyl alcohol and MTBE (volume ratio 1:30)
• Example 33 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of decyl alcohol and water (volume ratio of 2:1)
• Example 34 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate decylate from a mixture of decyl alcohol and MTBE (volume ratio less than 1:10)
• Example 35 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from a mixture of decyl alcohol and water (volume ratio less than 6: 1) lOg (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl](3R,5S)-3 , 5-dihydroxyhept-6-enoic acid decyl ester (1.0% diastereomer 0.7% enantiomer) After heating with a mixture of 20 ml of decyl alcohol and water (volume ratio less than 6:1), The
• Example 36 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from a mixture of acetonitrile and MTBE (volume ratio less than 1:10)
• Example 37 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from ethylene glycol diterpene ether
• Example 38 (E)- 7- [4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidine-5-yl](3R,5S) -3,5-Dihydroxyhept-6-enoate crystallization from MEK
• Example 39 (E)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-[indolyl(sulfonyl)amino]pyrimidin-5-yl] (3R,5S) -3,5-Dihydroxyhept-6-enoic acid oxime ester is slurried from mercapto tert-butyl ether

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Plural Heterocyclic Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=50386917

Family Applications (1)

Country Status (2)

Citations (2)

Family Cites Families (2)

• 2012
  • 2012-09-29 CN CN201210379910.6A patent/CN103709107B/zh not_active Expired - Fee Related
  • 2012-10-24 WO PCT/CN2012/083419 patent/WO2014047996A1/fr not_active Ceased

Patent Citations (2)

Also Published As

Similar Documents

Legal Events