CN103848790B - Crystal formation of Rosuvastatin ester and preparation method thereof - Google Patents

Crystal formation of Rosuvastatin ester and preparation method thereof Download PDF

Info

Publication number
CN103848790B
CN103848790B CN201210516337.9A CN201210516337A CN103848790B CN 103848790 B CN103848790 B CN 103848790B CN 201210516337 A CN201210516337 A CN 201210516337A CN 103848790 B CN103848790 B CN 103848790B
Authority
CN
China
Prior art keywords
methyl
base
fluorophenyl
isopropyl
mesyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201210516337.9A
Other languages
Chinese (zh)
Other versions
CN103848790A (en
Inventor
黄庆云
黄欢
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Anhui Qingyun Medicine Co ltd
Original Assignee
ANHUI QINGYUN PHARMACEUTICAL AND CHEMICAL Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ANHUI QINGYUN PHARMACEUTICAL AND CHEMICAL Co Ltd filed Critical ANHUI QINGYUN PHARMACEUTICAL AND CHEMICAL Co Ltd
Priority to CN201210516337.9A priority Critical patent/CN103848790B/en
Priority to PCT/CN2012/087703 priority patent/WO2014086072A1/en
Publication of CN103848790A publication Critical patent/CN103848790A/en
Application granted granted Critical
Publication of CN103848790B publication Critical patent/CN103848790B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • 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
    • 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
    • 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

Landscapes

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

Abstract

The present invention relates to field of compound preparation; particularly to (E) 7 [4 (4 fluorophenyl) 6 isopropyl 2 [methyl (mesyl) amino] pyrimidine 5 base] (3R; novel crystal forms of 5S) 3,5 dihydroxy heptyl 6 olefin(e) acid esters and preparation method thereof.The method can pass through solvent crystallization; and then obtain enantiomerism impurity less than 0.50%; the diastereomeric impurities (E) 7 [4 (4 fluorophenyl) 6 isopropyl 2 [methyl (mesyl) amino] pyrimidine 5 the base] (3R less than 0.30%; the crystal formation of 5S) 3,5 dihydroxy heptyl 6 olefin(e) acid esters.

Description

Crystal formation of Rosuvastatin ester and preparation method thereof
Technical field
The present invention relates to field of compound preparation, particularly to the novel crystal forms and preparation method thereof of Rosuvastatin ester.
Background technology
(double [[(N-methyl methane sulfonylamino is phonetic for 4-(4-fluorophenyl)-6-isopropyl-2-for (E)-7-for rosuvastain calcium Pyridine)-5-base] (3R, 5S)-dihydroxy-(E)-6-hept-olefin(e) acid] calcium salt), its structure, as shown in formula I, is that Shionogi company opens A kind of HMG-CoA reductase inhibitor sent out, is used for treating (particularly) high-cholesterol disease, hyperlipoproteinemia and arteriosclerosis The associated conditions such as disease.Rosuvastain calcium belongs to superstatin class medicine, can be more solid than first generation medicine more effectively reduces LDL-gallbladder Alcohol and triglyceride.
There is enantiomer and diastereomer in Rosuvastatin and intermediate Rosuvastatin ester, its molecule is in place Put 3 and 5 and there are two chiral centres.Wherein, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5R)-3, the structure of 5-dihydroxy hept-6-olefin(e) acid ester as shown in formula II, (E)-7-[4-(4-fluorophenyl)- 6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] structure of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ester As shown in formula III, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3S, The structure of 5R)-3,5-dihydroxy hept-6-olefin(e) acid ester as shown in formula IV, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] structure of (3S, 5S)-3,5-dihydroxy hept-6-olefin(e) acid ester is as shown in formula V.These mappings Isomer and diastereomer can detect with reversed-phase HPLC.
US RE37, the synthetic method of the Rosuvastatin disclosed in 314E and intermediate relate to Rosuvastatin important in The synthetic method of mesosome.The ketone-ester of Rosuvastatin is reduced to obtain diol ester by the method in 5, carbon, going back in this position Former is the standard exemplary steps in statins (statins) synthesis.But, this reduction step can produce diastereo-isomerism Impurity.
Disclosed in WO 2005/040134, method report is by lactonizing, or by by amorphous rosuvastatin and Intermediate changes into crystal type Rosuvastatin intermediate and is subsequently converted to amorphous form, reduces in the middle of Rosuvastatin The non-corresponding content of isomer of body.
Method report disclosed in WO 2007/040940 is by reclaiming Rosuvastatin diol ester, and crystallizes Rosuvastain Spit of fland ketone-ester thing, reduces the content of the diastereomer of Rosuvastatin intermediate, thus improves Rosuvastatin intermediate Chiral purity.But from this reaction, remove unreacted initiation material there is the biggest difficulty.
[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] is phonetic for (E)-7-prepared by existing method Pyridine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ester is grease, it is impossible to by the Methods For Purification of recrystallization.
Summary of the invention
In view of this, the present invention provides Rosuvastatin ester to be (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] novel crystal forms and preparation method thereof of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ester.Should Method is obtained in that enantiomerism impurity is less than 0.50%, the diastereomeric impurities (E)-7-[4-(4-fluorobenzene less than 0.30% Base)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ester Crystal formation.
In order to realize foregoing invention purpose, the present invention provides techniques below scheme:
The invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine- 5-yl] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, its X-ray powder diffraction figure has peak in 2 positions, θ ± 1 Value, described 2 θ are 9.2445,9.6413,11.9698,13.7766,15.7766,16.3961,17.2367,17.8864, 18.4518、19.3910、20.0676、20.5769、21.5166、22.3291、22.8866、23.5785、24.1036、 24.7740、 26.0137、27.0325、29.1436、30.4514、30.8838、31.9431、33.0464、33.9875、 35.7625,36.6411,37.6839,39.7936,40.8743 and 46.4935.
It should be understood that 2 θ values of X-ray powder diffraction figure can vary slightly between machine or between sample, its numerical value can About 1 unit, or about 0.8 unit of difference, or about 0.5 unit of difference, or difference about 0.3 can be differed Individual unit, or about 0.1 unit of difference, therefore cited numerical value can not be construed to absolute value.It shall again be understood that peak Relative intensity can change, XRD trace (trace) intensity being therefore included in the present invention according to the orientation of sample in test For illustrative, it is not meant for definitely comparing.
As preferably, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, its X-ray powder diffraction figure is in 2 θ ± 0.8 Position has peak value, described 2 θ to be 9.2445,9.6413,11.9698,13.7766,15.7766,16.3961,17.2367, 17.8864、18.4518、19.3910、20.0676、20.5769、21.5166、22.3291、22.8866、23.5785、 24.1036、24.7740、26.0137、27.0325、29.1436、30.4514、30.8838、31.9431、33.0464、 33.9875,35.7625,36.6411,37.6839,39.7936,40.8743 and 46.4935.
As preferably, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, its X-ray powder diffraction figure is in 2 θ ± 0.5 Position has peak value, described 2 θ to be 9.2445,9.6413,11.9698,13.7766,15.7766,16.3961,17.2367, 17.8864、18.4518、19.3910、20.0676、20.5769、21.5166、22.3291、22.8866、23.5785、 24.1036、24.7740、26.0137、27.0325、29.1436、30.4514、30.8838、31.9431、33.0464、 33.9875,35.7625,36.6411,37.6839,39.7936,40.8743 and 46.4935.
As preferably, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, its X-ray powder diffraction figure is in 2 θ ± 0.3 Position has peak value, described 2 θ to be 9.2445,9.6413,11.9698,13.7766,15.7766,16.3961,17.2367, 17.8864、18.4518、19.3910、20.0676、20.5769、21.5166、22.3291、22.8866、23.5785、 24.1036、24.7740、26.0137、27.0325、29.1436、30.4514、30.8838、31.9431、33.0464、 33.9875,35.7625,36.6411,37.6839,39.7936,40.8743 and 46.4935.
As preferably, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, its X-ray powder diffraction figure is in 2 θ ± 0.2 Position has peak value, described 2 θ to be 9.2445,9.6413,11.9698,13.7766,15.7766,16.3961,17.2367, 17.8864、18.4518、19.3910、20.0676、20.5769、21.5166、22.3291、22.8866、23.5785、 24.1036、24.7740、26.0137、27.0325、29.1436、30.4514、30.8838、31.9431、33.0464、 33.9875,35.7625,36.6411,37.6839,39.7936,40.8743 and 46.4935.
[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] is phonetic to present invention also offers (E)-7- Pyridine-5-base] crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester is used for preparing Rosuvastatin or its medicine can accept Salt；Above-mentioned (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)- The crystal formation X-ray powder diffraction figure of 3,5-dihydroxy heptyl-6-olefin(e) acid ethyl esters has the peak value, described 2 θ to be in 2 positions, θ ± 1 9.2445、9.6413、11.9698、13.7766、15.7766、16.3961、17.2367、17.8864、18.4518、 19.3910、20.0676、20.5769、21.5166、22.3291、22.8866、23.5785、24.1036、24.7740、 26.0137、27.0325、29.1436、30.4514、30.8838、31.9431、33.0464、33.9875、35.7625、 36.6411,37.6839,39.7936,40.8743 and 46.4935.
Above-mentioned (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] that the present invention also provides for Pyrimidine-5-base] crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester to Rosuvastatin or Rosuvastain statin lactone or The method of the conversion of drug acceptable salt, can be carried out according to US publication 2005/080134.This conversion can be by the aqueous alkali of ethyl ester Solution is carried out.(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, The basic hydrolysis of 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester can by the alkali metal of one or more equivalents or alkaline earth metal alkali, as NaOH or Ca (OH) 2, is hydrolyzed in the organic solvent below such as: oxolane, ACN (acetonitrile), (1-4C) alcohol (acetone, methyl ethyl ketone, methyl are different for (MeOH, EtOH, IPA (isopropanol), propanol, butanol etc.), (3-8C) ketone or (3-8C) ester Propyl group ketone, ethyl acetate).Hydrolysis also can be excellent by water or the mixture of above-mentioned solvent or water and the mixture of above-mentioned solvent Choosing at room temperature or is carried out by heating.
[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] is phonetic to present invention also offers (E)-7- Pyridine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, its X-ray powder diffraction figure is in 2 positions, θ ± 1 Having peak value, described 2 θ is 17.0352,18.0864,19.3245,19.7326,20.5246 and 21.8532.
It should be understood that 2 θ values of X-ray powder diffraction figure can vary slightly between machine or between sample, its numerical value can About 1 unit, or about 0.8 unit of difference, or about 0.5 unit of difference, or difference about 0.3 can be differed Individual unit, or about 0.1 unit of difference, therefore cited numerical value can not be construed to absolute value.It shall again be understood that peak Relative intensity can change, XRD trace (trace) intensity being therefore included in the present invention according to the orientation of sample in test For illustrative, it is not meant for definitely comparing.
As preferably, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, its X-ray powder diffraction figure in 2 θ ± 0.8 position has peak value, described 2 θ to be 17.0352,18.0864,19.3245,19.7326,20.5246 and 21.8532.
As preferably, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, its X-ray powder diffraction figure in 2 θ ± 0.5 position has peak value, described 2 θ to be 17.0352,18.0864,19.3245,19.7326,20.5246 and 21.8532.
As preferably, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, its X-ray powder diffraction figure in 2 θ ± 0.3 position has peak value, described 2 θ to be 17.0352,18.0864,19.3245,19.7326,20.5246 and 21.8532.
As preferably, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, its X-ray powder diffraction figure in 2 θ ± 0.2 position has peak value, described 2 θ to be 17.0352,18.0864,19.3245,19.7326,20.5246 and 21.8532.
[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] is phonetic to present invention also offers (E)-7- Pyridine-5-base] crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester is used for preparing Rosuvastatin or its medicine can connect By salt；Above-mentioned (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, The crystal formation X-ray powder diffraction figure of 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester has the peak value, described 2 θ to be in 2 positions, θ ± 1 17.0352,18.0864,19.3245,19.7326,20.5246 and 21.8532.
[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] is phonetic to present invention also offers (E)-7- Pyridine-5-base] crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester is used for preparing Rosuvastatin or its medicine can connect By salt.
[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] is phonetic to the invention provides one (E)-7- Pyridine-5-base] (3R, 5S)-3, the method for crystallising of the crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ester, comprise the steps:
Step 1: obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ester crude product；
Step 2: take (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ester crude product obtains the first solution after mixing with the solvent of excess, crystallizes, separates, does After dry and get final product；
Solvent is C1-4Alcohol, C3-8Ester, C3-8Ketone, C3-8Ether, C6-10A kind of or both above mixing in aromatic hydrocarbons, water, acetonitrile Compound.
In some embodiments of the invention, in step 2, solvent is the mixture of methanol, acetonitrile and water, acetone, water and The mixture of MTBE, the mixture of first alcohol and water, the mixture of second alcohol and water, MEK, 4-methyl-2 pentanone and the mixing of toluene A kind of or both mixture above in the mixture of thing, ethyl acetate and petroleum ether.
In other embodiments of the present invention, in step 2, solvent is MTBE, MEK, 4-methyl-2 pentanone, toluene, third A kind of or both mixture above in the mixture of ketone and the mixture of water, acetonitrile and water.
As preferably, step 2 crystallizes and specially takes described first solution, be heated to more than 50 DEG C, cooling.
As preferably, chilling temperature is-20～40 DEG C.
In some embodiments of the invention, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) Amino] pyrimidine-5-base] structure of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ester is as shown in formula III
Formula III
Wherein, R is ethyl, propyl group, normal-butyl or the tert-butyl group.
Preferably, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ester is (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) Amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester or (E)-7-[4-(4-fluorophenyl)-6-isopropyl- 2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester.
[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] is phonetic to present invention also offers (E)-7- Pyridine-5-base] (3R, 5S)-3, the method for crystallising of the crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, comprise the steps:
Step 1: obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester；
Step 2: take (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester obtains the first solution after mixing with the solvent of excess, crystallize, separate, Dried and get final product；
Solvent is C1-4Alcohol, C3-8Ester, C3-8Ketone, C3-8Ether, C6-10A kind of or both above mixing in aromatic hydrocarbons, water, acetonitrile Compound.
In some embodiments of the invention, in step 2, solvent is the mixture of methanol, acetonitrile and water, acetone, water and The mixture of MTBE, the mixture of first alcohol and water, the mixture of second alcohol and water, MEK, 4-methyl-2 pentanone and the mixing of toluene A kind of or both mixture above in the mixture of thing, ethyl acetate and petroleum ether.
It is appreciated that (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia that the present invention provides Base] pyrimidine-5-base] (3R, 5S)-3, in the preparation method of the crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, solvent for use not only limits In mentioned kind, according to the principle that the close character of structure is close, it is known that C1-4Alcohol, C3-8Ester, C3-8Ketone, C3-8Ether, C6-10Aromatic hydrocarbons, second A kind of or that both are above mixture in glycol diethyl ether, water, acetonitrile all can play the effect beneficially crystallized as solvent, because of This, C1-4Alcohol, C3-8Ester, C3-8Ketone, C3-8Ether, C6-10A kind of in aromatic hydrocarbons, ethylene glycol diethyl ether, water, acetonitrile or both are above Mixture is the most within the scope of the present invention.
In some embodiments of the invention, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[first that the present invention provides Base (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3, in the method for crystallising of the crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, During in step 2, solvent is the mixture of the mixture of MTBE, MEK, 4-methyl-2 pentanone, toluene, acetone and water, acetonitrile and water A kind of or mixture that both are above.
In other embodiments of the present invention, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-that the present invention provides [methyl (mesyl) amino] pyrimidine-5-base] method for crystallising of crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester In, in step 2, solvent is methylisobutylketone and the mixture of petroleum ether, 4-methyl-2 pentanone or toluene.
In some embodiments of the invention, in terms of g/mL, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester and methylisobutylketone and stone The mass volume ratio of the oil mixture of ether, 4-methyl-2 pentanone or toluene is 1:3；Wherein, methylisobutylketone and the body of petroleum ether Long-pending ratio is 1:1.
In other embodiments of the present invention, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-that the present invention provides [methyl (mesyl) amino] pyrimidine-5-base] the crystallization side of crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester In method, solvent selected from the mixture of acetonitrile and methyl tertiary butyl ether(MTBE), the mixture of MEK, ethyl acetate and petroleum ether, methanol, third The mixture of ketone and water, the mixture of methanol and water, the mixture of ethanol and water, the mixture of acetonitrile and water, oxolane with The mixture of petroleum ether.Wherein, acetonitrile is 2:6 with the volume ratio of methyl tertiary butyl ether(MTBE)；Ethyl acetate and the volume ratio of petroleum ether It is 1: 1；Methanol is less than 6:1 with the volume ratio of water, and in some embodiments of the invention, methanol is 5:2 with the volume ratio of water, In other embodiments of the present invention, methanol is 2:1 with the volume ratio of water；Oxolane is 1:1 with the volume ratio of petroleum ether.
In some embodiments of the invention, in terms of g/mL, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester and glycol dimethyl ether Mass volume ratio is 1:1.5.
In other embodiments of the present invention, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-that the present invention provides [methyl (mesyl) amino] pyrimidine-5-base] method for crystallising of crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester In, solvent is MTBE.In terms of g/mL, [4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] is phonetic for (E)-7- Pyridine-5-base] mass volume ratio of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester and MTBE is 1:5.
In other embodiments of the present invention, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-that the present invention provides [methyl (mesyl) amino] pyrimidine-5-base] method for crystallising of crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester In, step 2 crystallizes and specially takes the first solution, be heated to more than 50 DEG C, cooling.
As preferably, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia that the present invention provides Base] pyrimidine-5-base] (3R, 5S)-3, in the method for crystallising of the crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, chilling temperature is-20 ～40 DEG C.
Preferably, chilling temperature is-10～30 DEG C.
It is furthermore preferred that chilling temperature is-5～10 DEG C.
The present invention provide (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine- 5-yl] (3R, 5S)-3, in the method for crystallising of the crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, after crystallization, step 2 was separated into Filter.
As preferably, step 2 is filtered into filtration under diminished pressure.
Collect filter cake after filtration, and filter cake is dried, step 2 be dried into drying under reduced pressure or heat up dry.
As preferably, step 2 is dried into being dried in negative pressure, under conditions of 40～50 DEG C.
The invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine- 5-yl] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, its X-ray powder diffraction figure has peak in 2 positions, θ ± 1 Value, described 2 θ are 9.2445,9.6413,11.9698,13.7766,15.7766,16.3961,17.2367,17.8864, 18.4518、19.3910、20.0676、20.5769、21.5166、22.3291、22.8866、23.5785、24.1036、 24.7740、26.0137、27.0325、29.1436、30.4514、30.8838、31.9431、33.0464、33.9875、 35.7625,36.6411,37.6839,39.7936,40.8743 and 46.4935.
It should be understood that 2 θ values of X-ray powder diffraction figure can vary slightly between machine or between sample, its numerical value can About 1 unit, or about 0.8 unit of difference, or about 0.5 unit of difference, or difference about 0.3 can be differed Individual unit, or about 0.1 unit of difference, therefore cited numerical value can not be construed to absolute value.It shall again be understood that The relative intensity at peak can change according to the orientation of sample in test, and the XRD trace (trace) being therefore included in the present invention is strong Degree, for illustrative, is not meant for definitely comparing.
As preferably, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, its X-ray powder diffraction figure is in 2 θ ± 0.8 Position has peak value, described 2 θ to be 9.2445,9.6413,11.9698,13.7766,15.7766,16.3961,17.2367, 17.8864、18.4518、19.3910、20.0676、20.5769、21.5166、22.3291、22.8866、23.5785、 24.1036、24.7740、26.0137、27.0325、29.1436、30.4514、30.8838、31.9431、33.0464、 33.9875,35.7625,36.6411,37.6839,39.7936,40.8743 and 46.4935.
As preferably, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, its X-ray powder diffraction figure is in 2 θ ± 0.5 Position has peak value, described 2 θ to be 9.2445,9.6413,11.9698,13.7766,15.7766,16.3961,17.2367, 17.8864、18.4518、19.3910、20.0676、20.5769、21.5166、22.3291、22.8866、23.5785、 24.1036、24.7740、26.0137、27.0325、29.1436、30.4514、30.8838、31.9431、33.0464、 33.9875,35.7625,36.6411,37.6839,39.7936,40.8743 and 46.4935.
As preferably, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, its X-ray powder diffraction figure is in 2 θ ± 0.3 Position has peak value, described 2 θ to be 9.2445,9.6413,11.9698,13.7766,15.7766,16.3961,17.2367, 17.8864、18.4518、19.3910、20.0676、20.5769、21.5166、22.3291、22.8866、23.5785、 24.1036、24.7740、26.0137、27.0325、29.1436、30.4514、30.8838、31.9431、33.0464、 33.9875,35.7625,36.6411,37.6839,39.7936,40.8743 and 46.4935.
As preferably, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, its X-ray powder diffraction figure is in 2 θ ± 0.2 Position has peak value, described 2 θ to be 9.2445,9.6413,11.9698,13.7766,15.7766,16.3961,17.2367, 17.8864、18.4518、19.3910、20.0676、20.5769、21.5166、22.3291、22.8866、23.5785、 24.1036、24.7740、26.0137、27.0325、29.1436、30.4514、30.8838、31.9431、33.0464、 33.9875,35.7625,36.6411,37.6839,39.7936,40.8743 and 46.4935.
[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] is phonetic to present invention also offers (E)-7- Pyridine-5-base] crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester is used for preparing Rosuvastatin or its medicine can accept Salt；Above-mentioned (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)- The crystal formation X-ray powder diffraction figure of 3,5-dihydroxy heptyl-6-olefin(e) acid ethyl esters has peak value, described 2 θ to be 9.2445 in 2 positions, θ ± 1, 9.6413、11.9698、13.7766、15.7766、16.3961、17.2367、17.8864、18.4518、19.3910、 20.0676、20.5769、21.5166、22.3291、22.8866、23.5785、24.1036、24.7740、26.0137、 27.0325、29.1436、30.4514、30.8838、31.9431、33.0464、33.9875、35.7625、36.6411、 37.6839,39.7936,40.8743 and 46.4935.
Above-mentioned (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] that the present invention also provides for Pyrimidine-5-base] crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester to Rosuvastatin or Rosuvastain statin lactone or The method of the conversion of drug acceptable salt, can be carried out according to US publication 2005/080134.This conversion can be by the aqueous alkali of ethyl ester Solution is carried out.(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, The basic hydrolysis of 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester can by the alkali metal of one or more equivalents or alkaline earth metal alkali, as NaOH or Ca (OH) 2, is hydrolyzed in the organic solvent below such as: oxolane, ACN (acetonitrile), (1-4C) alcohol (acetone, methyl ethyl ketone, methyl are different for (MeOH, EtOH, IPA (isopropanol), propanol, butanol etc.), (3-8C) ketone or (3-8C) ester Propyl group ketone, ethyl acetate).Hydrolysis also can be excellent by water or the mixture of above-mentioned solvent or water and the mixture of above-mentioned solvent Choosing at room temperature or is carried out by heating.
[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] is phonetic to present invention also offers (E)-7- Pyridine-5-base] (3R, 5S)-3, the method for crystallising of the crystal formation of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, comprise the steps:
Step 1: obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester crude product；
Step 2: take (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester crude product obtains the first solution after mixing with the solvent of excess, crystallizes, divides From, dried and get final product；
Solvent is C1-4Alcohol, C3-8Ester, C3-8Ketone, C3-8Ether, C6-10A kind of or both above mixing in aromatic hydrocarbons, water, acetonitrile Compound.
In some embodiments of the invention, in step 2, solvent is the mixture of methanol, acetonitrile and water, acetone, water and The mixture of MTBE, the mixture of first alcohol and water, the mixture of second alcohol and water, MEK, 4-methyl-2 pentanone and the mixing of toluene A kind of or both mixture above in the mixture of thing, ethyl acetate and petroleum ether.
It is appreciated that (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia that the present invention provides Base] pyrimidine-5-base] (3R, 5S)-3, in the preparation method of the crystal formation of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, solvent for use is not only It is limited to mentioned kind, according to the principle that the close character of structure is close, it is known that C1-4Alcohol, C3-8Ester, C3-8Ketone, C3-8Ether, C6-10Aromatic hydrocarbons, A kind of or that both are above mixture in ethylene glycol diethyl ether, water, acetonitrile all can play the effect beneficially crystallized as solvent, Therefore, C1-4Alcohol, C3-8Ester, C3-8Ketone, C3-8Ether, C6-10One in aromatic hydrocarbons, ethylene glycol diethyl ether, water, acetonitrile or both more than Mixture the most within the scope of the present invention.
In some embodiments of the invention, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[first that the present invention provides Base (mesyl) amino] pyrimidine-5-base] method for crystallising of crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester In, in step 2, solvent is the mixture of the mixture of MTBE, MEK, 4-methyl-2 pentanone, toluene, acetone and water, acetonitrile and water In a kind of or mixture that both are above.In other embodiments of the present invention, (E)-7-[4-(4-that the present invention provides Fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid In the method for crystallising of the crystal formation of the tert-butyl ester, in step 2, solvent is 4-methyl-2 pentanone and/or MTBE.
In other embodiments of the present invention, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-that the present invention provides [methyl (mesyl) amino] pyrimidine-5-base] preparation of crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester In method, the second solvent is 4-methyl-2 pentanone and/or MTBE.
In other embodiments of the present invention, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-that the present invention provides [methyl (mesyl) amino] pyrimidine-5-base] the preparation side of crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester In method, the second solvent is methanol, in terms of g/mL, and (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] mass volume ratio of (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester crude product and methanol be 1: 1～ 10。
In other embodiments of the present invention, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-that the present invention provides [methyl (mesyl) amino] pyrimidine-5-base] the preparation side of crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester In method, the second solvent is the mixture of first alcohol and water, and wherein, methanol is less than 6:1 with the volume ratio of water.
In other embodiments of the present invention, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-that the present invention provides [methyl (mesyl) amino] pyrimidine-5-base] the preparation side of crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester In method, the second solvent is the mixture of acetonitrile and MTBE, and wherein, the volume ratio of acetonitrile and MTBE is less than 1:10.
In other embodiments of the present invention, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-that the present invention provides [methyl (mesyl) amino] pyrimidine-5-base] the preparation side of crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester In method, the second solvent is the mixture of methanol and MTBE, and wherein, the volume ratio of methanol and MTBE is less than 1:10.
In other embodiments of the present invention, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-that the present invention provides [methyl (mesyl) amino] pyrimidine-5-base] the preparation side of crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester In method, step 2 is separated into filtration.
As preferably, step 2 is filtered into filtration under diminished pressure.
Collect filter cake after filtration, and filter cake is dried.Step 2 it is dried into drying under reduced pressure or heats up dry.
As preferably, step 2 is dried be negative pressure, under conditions of 40～50 DEG C dry.
[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] is phonetic to present invention also offers (E)-7- Pyridine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, its X-ray powder diffraction figure is in 2 positions, θ ± 1 Having peak value, described 2 θ is 17.0352,18.0864,19.3245,19.7326,20.5246 and 21.8532.
It should be understood that 2 θ values of X-ray powder diffraction figure can vary slightly between machine or between sample, its numerical value can About 1 unit, or about 0.8 unit of difference, or about 0.5 unit of difference, or difference about 0.3 can be differed Individual unit, or about 0.1 unit of difference, therefore cited numerical value can not be construed to absolute value.It shall again be understood that peak Relative intensity can change, XRD trace (trace) intensity being therefore included in the present invention according to the orientation of sample in test For illustrative, it is not meant for definitely comparing.
As preferably, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, its X-ray powder diffraction figure in 2 θ ± 0.8 position has peak value, described 2 θ to be 17.0352,18.0864,19.3245,19.7326,20.5246 and 21.8532.
As preferably, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, its X-ray powder diffraction figure in 2 θ ± 0.5 position has peak value, described 2 θ to be 17.0352,18.0864,19.3245,19.7326,20.5246 and 21.8532.
As preferably, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, its X-ray powder diffraction figure in 2 θ ± 0.3 position has peak value, described 2 θ to be 17.0352,18.0864,19.3245,19.7326,20.5246 and 21.8532.
As preferably, the invention provides (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia Base] pyrimidine-5-base] (3R, 5S)-3, the crystal formation of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, its X-ray powder diffraction figure in 2 θ ± 0.2 position has peak value, described 2 θ to be 17.0352,18.0864,19.3245,19.7326,20.5246 and 21.8532.
[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] is phonetic to present invention also offers (E)-7- Pyridine-5-base] crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester is used for preparing Rosuvastatin or its medicine can connect By salt；Above-mentioned (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, The crystal formation X-ray powder diffraction figure of 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester has the peak value, described 2 θ to be in 2 positions, θ ± 1 17.0352,18.0864,19.3245,19.7326,20.5246 and 21.8532.
Above-mentioned (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] that the present invention also provides for Pyrimidine-5-base] crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester is to Rosuvastatin or Rosuvastain statin lactone Or the method for the conversion of drug acceptable salt, can carry out according to US publication 2005/080134.This conversion can be by the alkali of ethyl ester Hydrolysis is carried out.(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, The basic hydrolysis of 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester can by the alkali metal of one or more equivalents or alkaline earth metal alkali, Such as NaOH or Ca (OH) 2, the organic solvent below such as is hydrolyzed: oxolane, ACN (acetonitrile), (1-4C) alcohol (acetone, methyl ethyl ketone, methyl are different for (MeOH, EtOH, IPA (isopropanol), propanol, butanol etc.), (3-8C) ketone or (3-8C) ester Propyl group ketone, ethyl acetate).Hydrolysis also can be excellent by water or the mixture of above-mentioned solvent or water and the mixture of above-mentioned solvent Choosing at room temperature or is carried out by heating.
The present invention provides Rosuvastatin ester to be (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl Base) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ester and preparation method thereof.The method is by by solvent It is obtained in that enantiomerism impurity is less than 0.50%, the diastereomeric impurities (E)-7-[4-(4-fluorophenyl)-6-less than 0.30% Isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ester；Logical Cross and solvent is selected to obtain enantiomerism impurity less than 0.30%, diastereomeric impurities (E)-7-less than 0.10% [4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl- The crystal formation of 6-olefin(e) acid ester；By more preferably selecting of solvent being obtained in that, enantiomerism impurity is less than 0.10%, diastereo-isomerism is miscellaneous Matter (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] less than 0.10% The crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ester.
Accompanying drawing explanation
Fig. 1 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia prepared in embodiment 1 Base] pyrimidine-5-base] the X-ray powder diffraction figure of crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester；
Fig. 2 shows (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) ammonia prepared in embodiment 18 Base] pyrimidine-5-base] the X-ray powder diffraction figure of crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester.
Detailed description of the invention
The invention discloses Rosuvastatin ester and preparation method thereof, those skilled in the art can use for reference present disclosure, It is suitably modified technological parameter to realize.Special needs to be pointed out is, those skilled in the art are come by all similar replacements and change Saying and be apparent from, they are considered as being included in the present invention.Preferred embodiment has been passed through in method and the application of the present invention Be described, related personnel substantially can in without departing from present invention, spirit and scope to method described herein and should With being modified or suitably changing and combine, realize and apply the technology of the present invention.
In Rosuvastatin ester that the present invention provides and preparation method thereof, agents useful for same all can be buied by market.
The present invention is by laying crystal form on Siemans mono-silicon crystal (SSC) wafer paster (wafter mounts) Sample and by micro-micro slide by this sample invent by Siemans mono-silicon crystal (SSC) wafer paster (wafter Mounts) lay the sample of crystal form on and by micro-micro slide, this sample be coated with as a thin layer to measure X-ray powder End diffraction spectrum.Use instrument be Philips Xper ' t x-ray diffractometer, with by 1.5406 angstroms wavelengths with 40kV And 40mA operation one elongated focusing copper pipe produce X-ray irradiate.Sample spends 2 θ angle ranges through 2 to 40 in θ-θ mode The most often increase by 0.02 degree of 2 θ corner connection by radiation (continuous scan pattern) in 4 seconds.The operation time is 2 hours 6 minutes 40 seconds.This instrument is joined There is the super detector of Philips.With Philips software by Highscore software data processing
The present invention does not limits, and suitable temperature range is the most within the scope of the present invention.
Below in conjunction with embodiment, the present invention it is expanded on further:
Embodiment 1 (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester crystallizes from toluene
Diastereo-isomerism body detecting method:
HPLC condition:
Chromatographic column: Agilent C8(4.5*15mm, 5um)
Gradient elution: A:1ml 85% phosphoric acid is dissolved in 1000ml water
B: isopropanol
C: methanol
Actual conditions is shown in Table 1.
Table 1 condition of gradient elution
Flow velocity: 0.8ml/min
Detection wavelength X=242nm
Column temperature: 30 DEG C
Prepared by sample:
Take sample to add 90% methanol in right amount and make the solution of 0.5mg/ml.Sample introduction 20 μ L.
Enantiomerism body detecting method:
Chromatographic column: CHIRALCEL OJ-H (4.6*250mm, 5 μm)
Flowing phase: (normal hexane: ethanol: trifluoroacetic acid)-(80:20:0.1)
Flow:1.0ml/min λ=242nm column temperature: 30 DEG C
Sample preparation: take sample and add flowing in right amount and make the solution of 0.2mg/ml mutually.Sample introduction 20 μ L.
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (1.0% diastereomer 0.7% enantiomer) 20ml toluene heats After the most molten, being then cooled to room temperature (30 DEG C), place into (0 DEG C) in refrigerator freezing crystallize, filter after separating out crystal, filter cake is in 45 DEG C decompression drying, obtains 8.1g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, yield is 70% ~ 75%, and purity is more than 98.5%.Isomer and diastereomeric Isomer is respectively less than 0.5%.Wherein enantiomer level is 0.50%, and diastereomer level is 0.32%.Obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy The X-ray powder diffraction figure of base hept-6-e pioic acid methyl ester as it is shown in figure 1, in 2 θ be 9.2445,9.6413,11.9698, 13.7766、15.7766、16.3961、17.2367、17.8864、18.4518、19.3910、20.0676、20.5769、 21.5166、22.3291、22.8866、23.5785、24.1036、24.7740、26.0137、27.0325、29.1436、 30.4514、30.8838、31.9431、33.0464、33.9875、35.7625、36.6411、37.6839、39.7936、 There is peak 40.8743 and 46.4935 positions, are specifically shown in Table 1.
Table 1X ray powder diffraction data
Embodiment 2:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester is from oxolane: crystallize petroleum ether
The detection method of diastereomer and enantiomer is with embodiment 1.
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (1.0% diastereomer 0.7% enantiomer) uses 30ml mixed solvent After (oxolane: petroleum ether=1:1) heating is the most molten, it is then cooled to room temperature (25 DEG C), places into (4 DEG C) in refrigerator freezing analysis Crystalline substance, filters after separating out crystal, and filter cake, in 45 DEG C of decompression dryings, obtains 7.9g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester, yield is 75% ~ 80%, Purity is more than 99%.Isomer and non-corresponding isomer are respectively less than 0.5%, and wherein enantiomer level is 0.48%, diastereomeric Isomer level is 0.31%.(E)-7-[4-(4-the fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] obtained Pyrimidine-5-base] (3R, 5S)-3, the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-e pioic acid methyl ester, in 2 θ be 9.2454, 9.6431、11.9687、13.7757、15.7773、16.3959、17.2375、17.8859、18.4532、19.3943、 20.0654、20.5747、21.5159、22.3283、22.8859、23.5779、24.1063、24.7755、26.0173、 27.0356、29.1443、30.4564、30.8853、31.9442、33.0447、33.9849、35.7653、36.6443、 37.6827, there is peak 39.7943,40.8734 and 46.4952 positions.
Embodiment 3:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester slurrying from toluene
The detection method of diastereomer and enantiomer is with embodiment 1.
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (1.0% diastereomer 0.7% enantiomer) 30ml toluene heats After the most molten, being then cooled to room temperature (25 DEG C), place into (4 DEG C) in refrigerator freezing crystallize, filter after separating out crystal, filter cake is in 45 DEG C decompression drying, obtains 7.9g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester, 75% ~ 83%, purity is more than 98.5%.Isomer and non-corresponding isomer It is respectively less than 0.3%.(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-obtained Base] (3R, 5S)-3, the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-e pioic acid methyl ester, in 2 θ be 9.2439,9.6427, 11.9678、13.7759、15.7764、16.3958、17.2354、17.8852、18.4528、19.3930、20.0659、 20.5754、21.5162、22.3287、22.8858、23.5776、24.1045、24.7723、26.0158、27.0353、 29.1442、30.4523、30.8843、31.9445、33.0474、33.9859、35.7638、36.6415、37.6843、 39.7945, there is peak 40.8752 and 46.4958 positions.
Embodiment 4:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester is from ethyl acetate: crystallize petroleum ether (1:1)
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (1.0% diastereomer 0.7% enantiomer) uses 30ml mixed solvent After the mixed solvent heating of (ethyl acetate: petroleum ether=1:1) is the most molten, it is then cooled to room temperature (20 DEG C), place in refrigerator (- 5 DEG C) freezing crystallize, filter after separating out crystal, filter cake in 45 DEG C of decompression dryings, obtain 7.5g (E)-7-[4-(4-fluorophenyl)- 6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester, yield Being 75% ~ 80%, purity is more than 99%, and isomer and non-corresponding isomer are respectively less than 0.3%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-e pioic acid methyl ester, 2 θ values and embodiment 1 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 5:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester crystallizes from ether
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (1.1% diastereomer 0.7% enantiomer) 30ml ether heats After the most molten, be then cooled to room temperature (15 DEG C), place in refrigerator (-20 DEG C) freezing crystallize, filter after separating out crystal, filter cake in 45 DEG C of decompression dryings, obtain 7.5g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine- 5-yl] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester, yield 75% ~ 80%, purity is more than 99%.Isomer and non-corresponding are different Structure body is respectively less than 0.3%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-e pioic acid methyl ester, 2 θ values and embodiment 1 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 6:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester crystallizes from MEK
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (0.52% diastereomer 0.3% enantiomer) adds with 20ml MEK After heat is the most molten, it is then cooled to room temperature (28 DEG C), places into (-10 DEG C) in refrigerator freezing crystallize, filter after separating out crystal, filter cake In 45 DEG C of decompression dryings, obtain 7g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine- 5-yl] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester, wherein enantiomer level is 0.25%, diastereomer Level is 0.12%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, 2 θ values and embodiment 2 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 7:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester is from ethyl acetate: crystallize petroleum ether (1:1)
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (0.52% diastereomer, 0.3% enantiomer) 20ml acetic acid second Ester: after the mixed solvent heating of petroleum ether (1:1) is the most molten, is then cooled to room temperature (23 DEG C), places in refrigerator (0 DEG C) freezing Crystallize, separates out and filters after crystal, filter cake in 45 DEG C of decompression dryings, obtain 7.6g (E)-7-[4-(4-fluorophenyl)-6-isopropyl- 2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, wherein enantiomerism Body level is 0.28%, and diastereomer level is 0.13%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, 2 θ values and embodiment 2 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 8:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester crystallizes from 4-methyl-2 pentanone
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (0.52% diastereomer, 0.3% enantiomer) 30ml 4-first After base-2 pentanone heating is the most molten, it is then cooled to room temperature (10 DEG C), places into (-10 DEG C) in refrigerator freezing crystallize, separate out crystal Rear filtration, filter cake, in 45 DEG C of decompression dryings, obtains 7.8g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl Base) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, wherein enantiomer level is 0.20%, Diastereomer level is 0.10%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, 2 θ values and embodiment 2 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 9:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester crystallizes from glycol dimethyl ether
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (0.52% diastereomer 0.3% enantiomer) uses 15ml ethylene glycol After dimethyl ether heating is the most molten, it is then cooled to room temperature (40 DEG C), places into (-5 DEG C) in refrigerator freezing crystallize, separate out mistake after crystal Filter, filter cake, in 45 DEG C of decompression dryings, obtains 8.0g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) Amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, wherein enantiomer level is 0.08%, non- Enantiomer level is 0.05%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, 2 θ values and embodiment 1 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 10:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester crystallizes from methanol
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (1.0% diastereomer 0.7% enantiomer) 20ml methanol heats After the most molten, being subsequently cooled to 30 DEG C, place into (-5 DEG C) in refrigerator freezing crystallize, filter after separating out crystal, filter cake subtracts in 45 DEG C Pressure is dried, and obtains 7.9g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, wherein enantiomer level is 0.48%, and diastereomer level is 0.31%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, 2 θ values and embodiment 1 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 11:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester crystallizes from MEK
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (1.0% diastereomer 0.7% enantiomer) 50ml MEK heats After the most molten, being subsequently cooled to 30 DEG C, place into (-5 DEG C) in refrigerator freezing crystallize, filter after separating out crystal, filter cake subtracts in 45 DEG C Pressure is dried, and obtains 7.9g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, yield 85%.Enantiomer 0.61%, non-corresponding isomer 0.35%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, 2 θ values and embodiment 1 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 12:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester is from acetonitrile: methyl tertiary butyl ether(MTBE) (2:6) crystallizes
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (1.0% diastereomer 0.7% enantiomer) 20ml acetonitrile: first After base tertbutyl ether (2:6) heating is the most molten, it is subsequently cooled to 30 DEG C, places into (-5 DEG C) in refrigerator freezing crystallize, separate out crystal Rear filtration, filter cake, in 45 DEG C of decompression dryings, obtains 7.9g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl Base) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, yield 85%.Enantiomer 0.61%, non- Corresponding isomer 0.35%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, 2 θ values and embodiment 1 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 13:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester crystallizes from the mixture of acetonitrile and water
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (0.52% diastereomer 0.3% enantiomer) 20ml acetonitrile: first After base tertbutyl ether (2:6) heating is the most molten, it is then cooled to room temperature (30 DEG C), places into (0 DEG C) in refrigerator freezing crystallize, separate out Filtering after crystal, filter cake, in 45 DEG C of decompression dryings, obtains 7g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (first sulphur Acyl group) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, wherein enantiomer level is 0.25%, diastereomer level is 0.12%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, 2 θ values and embodiment 2 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 14:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester is from oxolane: petroleum ether (volume ratio is 1:1) crystallizes
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (0.52% diastereomer 0.3% enantiomer) 20ml tetrahydrochysene furan Mutter: after petroleum ether (volume ratio is 1:1) heating is the most molten, be then cooled to room temperature (30 DEG C), place into (0 DEG C) in refrigerator freezing analysis Crystalline substance, filters after separating out crystal, and filter cake, in 45 DEG C of decompression dryings, obtains 7g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[first Base (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, yield 85%.Enantiomer 0.61%, non-corresponding isomer 0.35%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, 2 θ values and embodiment 2 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 15:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester crystallizes from the mixture of acetone and water
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (1.0% diastereomer 0.7% enantiomer) 20ml acetone and water Mixture heating the most molten after, be then cooled to room temperature (25 DEG C), place in refrigerator (-5 DEG C) freezing crystallize, after separating out crystal Filtering, filter cake, in 45 DEG C of decompression dryings, obtains 7.9g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl Base) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, wherein enantiomer level is 0.48%, Diastereomer level is 0.31%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, 2 θ values and embodiment 1 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 16:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester is from methylisobutylketone: petroleum ether (volume ratio is 1:1) crystallizes
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (1.0% diastereomer 0.7% enantiomer) uses 30ml methyl tert-butyl Ketone: after petroleum ether (volume ratio is 1:1) heating is the most molten, be then cooled to room temperature (25 DEG C), places into (-5 DEG C) in refrigerator freezing Crystallize, separates out and filters after crystal, filter cake in 45 DEG C of decompression dryings, obtain 7.9g (E)-7-[4-(4-fluorophenyl)-6-isopropyl- 2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, wherein enantiomerism Body level is 0.39%, and diastereomer level is 0.30%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, 2 θ values and embodiment 1 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 17:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester crystallizes from the mixture (volume ratio is 2:1) of first alcohol and water
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester (1.0% diastereomer 0.7% enantiomer) 20ml first alcohol and water Mixture (volume ratio is 2:1) heating the most molten after, be then cooled to room temperature (25 DEG C), place in refrigerator (-5 DEG C) freezing analysis Crystalline substance, filters after separating out crystal, and filter cake, in 45 DEG C of decompression dryings, obtains 7.9g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, wherein enantiomer Level is 0.32%, and diastereomer level is 0.21%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, 2 θ values and embodiment 1 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 18:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester crystallizes from the mixture of first alcohol and water
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester (0.52% diastereomer 0.3% enantiomer) uses 20ml methanol After the most molten with the mixture of water (volume ratio be less than 6:1) heating, it be then cooled to room temperature (20 DEG C), place into (4 DEG C) in refrigerator Freezing crystallize, filters after separating out crystal, and filter cake, in 45 DEG C of decompression dryings, obtains 7g (E)-7-[4-(4-fluorophenyl)-6-isopropyl Base-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester, wherein mapping Isomer level is 0.25%, and diastereomer level is 0.12%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, and 2 θ values are 17.0352,18.0864,19.3245,19.7326,20.5246 and 21.8532.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 19:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester crystallizes from the mixture of second alcohol and water
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester (1.0% diastereomer 0.7% enantiomer) 20ml second alcohol and water Mixture heating the most molten after, be then cooled to room temperature (30 DEG C), place in refrigerator (-10 DEG C) freezing crystallize, separate out crystal Rear filtration, filter cake, in 45 DEG C of decompression dryings, obtains 7.9g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl Base) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester, wherein enantiomer level is 0.48%, Diastereomer level is 0.31%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-e pioic acid methyl ester, 2 θ values and embodiment 18 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 20:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester crystallizes from the mixture (volume ratio is 2:1) of second alcohol and water
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester (1.0% diastereomer 0.7% enantiomer) 20ml first alcohol and water Mixture (volume ratio is 2:1) heating the most molten after, be then cooled to room temperature (30 DEG C), place in refrigerator (-10 DEG C) freezing Crystallize, separates out and filters after crystal, filter cake in 45 DEG C of decompression dryings, obtain 7.9g (E)-7-[4-(4-fluorophenyl)-6-isopropyl- 2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester, wherein enantiomerism Body level is 0.31%, and diastereomer level is 0.23%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-e pioic acid methyl ester, 2 θ values and embodiment 18 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 21:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] crystallization from the mixture (volume ratio is less than 6:1) of second alcohol and water of (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester (1.0% diastereomer 0.7% enantiomer) 20ml first alcohol and water Mixture (volume ratio be less than 6:1) heating the most molten after, be then cooled to room temperature (30 DEG C), place into (-10 DEG C) in refrigerator cold Freezeout is brilliant, filters after separating out crystal, and filter cake, in 45 DEG C of decompression dryings, obtains 7.9g (E)-7-[4-(4-fluorophenyl)-6-isopropyl Base-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester, wherein mapping is different Structure body level is 0.36%, and diastereomer level is 0.25%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-e pioic acid methyl ester, 2 θ values and embodiment 18 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 22:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester is from the mixture of acetonitrile and methyl tertiary butyl ether(MTBE) (volume ratio 2:8) Crystallization
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester (0.52% diastereomer 0.3% enantiomer) 50ml acetonitrile: first After base tertbutyl ether (2:8) heating is the most molten, it is then cooled to room temperature (18 DEG C), places into (4 DEG C) in refrigerator freezing crystallize, separate out Filtering after crystal, filter cake, in 45 DEG C of decompression dryings, obtains 7g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (first sulphur Acyl group) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester, wherein enantiomer level is 0.25%, diastereomer level is 0.12%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-e pioic acid methyl ester, 2 θ values and embodiment 18 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 23:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester crystallizes from toluene
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester (1.0% diastereomer 0.7% enantiomer) adds with 30ml toluene After heat is the most molten, it is then cooled to room temperature (10 DEG C), places into (-20 DEG C) in refrigerator freezing crystallize, filter after separating out crystal, filter cake In 45 DEG C of decompression dryings, [4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] is phonetic to obtain 7.9g (E)-7- Pyridine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester, wherein enantiomer level is 0.48%, and diastereomeric is different Structure body level is 0.31%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, 2 θ value and embodiments 18 are similar to.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 24:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester crystallizes from MEK
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester (1.0% diastereomer 0.7% enantiomer) adds with 20ml MEK After heat is the most molten, it is then cooled to room temperature (10 DEG C), places into (-20 DEG C) in refrigerator freezing crystallize, filter after separating out crystal, filter cake In 45 DEG C of decompression dryings, [4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] is phonetic to obtain 7.9g (E)-7- Pyridine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester, wherein enantiomer level is 0.42%, and diastereomeric is different Structure body level is 0.24%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, 2 θ value and embodiments 18 are similar to.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 25:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester crystallizes from MTBE
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester (1.0% diastereomer 0.7% enantiomer) uses 50ml MTBE Heat the most molten after, be then cooled to room temperature (10 DEG C), place in refrigerator (-20 DEG C) freezing crystallize, filter after separating out crystal, filter Cake, in 45 DEG C of decompression dryings, obtains 7.9g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] Pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester, wherein enantiomer level is 0.39%, diastereomeric Isomer level is 0.27%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, 2 θ value and embodiments 18 are similar to.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 26:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester is from ethyl acetate: petroleum ether (1:2) crystallizes
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester (1.0% diastereomer 0.7% enantiomer) uses 40ml acetic acid Ethyl ester: after petroleum ether (1:2) heating is the most molten, be then cooled to room temperature (10 DEG C), places into (-20 DEG C) in refrigerator freezing crystallize, Filtering after separating out crystal, filter cake, in 45 DEG C of decompression dryings, obtains 7.9g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[first Base (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester, wherein enantiomer water Putting down is 0.34%, and diastereomer level is 0.22%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, 2 θ value and embodiments 18 are similar to.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 27:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester crystallizes from 4-methyl-2 pentanone
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester (0.52% diastereomer 0.3% enantiomer) 30ml 4-first After base-2 pentanone heating is the most molten, it is then cooled to room temperature (23 DEG C), places into (-15 DEG C) in refrigerator freezing crystallize, separate out crystal Rear filtration, filter cake, in 45 DEG C of decompression dryings, obtains 7g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl Base) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester, wherein enantiomer level is 0.25%, diastereomer level is 0.12%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, 2 θ value and embodiments 18 are similar to.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 28:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester crystallizes from methanol
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester (1.0% diastereomer 0.7% enantiomer) adds with 20ml methanol After heat is the most molten, it is then cooled to room temperature (20 DEG C), places into (-8 DEG C) in refrigerator freezing crystallize, filter after separating out crystal, filter cake In 45 DEG C of decompression dryings, [4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] is phonetic to obtain 7.9g (E)-7- Pyridine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester, wherein enantiomer level is 0.48%, and diastereomeric is different Structure body level is 0.31%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, 2 θ value and embodiments 18 are similar to.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 29:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester crystallizes from glycol dimethyl ether
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester (1.0% diastereomer 0.7% enantiomer) uses 15ml ethylene glycol After dimethyl ether heating is the most molten, it is then cooled to room temperature (20 DEG C), places into (-8 DEG C) in refrigerator freezing crystallize, after separating out crystal Filtering, filter cake, in 45 DEG C of decompression dryings, obtains 7.9g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl Base) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester, wherein enantiomer level is 0.42%, diastereomer level is 0.32%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, 2 θ value and embodiments 18 are similar to.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 30:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester crystallizes from the mixture (volume ratio is 2:1) of first alcohol and water
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester (0.52% diastereomer 0.3% enantiomer) with 20ml methanol and After mixture (volume ratio the is 2:1) heating of water is the most molten, it is then cooled to room temperature (25 DEG C), places in refrigerator (5 DEG C) freezing Crystallize, filters after separating out crystal, and filter cake, in 45 DEG C of decompression dryings, obtains 7g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester, wherein enantiomer Level is 0.25%, and diastereomer level is 0.12%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-e pioic acid methyl ester, 2 θ values and embodiment 18 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 31:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] crystallization from the mixture (volume ratio is less than 6:1) of first alcohol and water of (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester (1.0% diastereomer 0.7% enantiomer) 20ml first alcohol and water Mixture (volume ratio be less than 6:1) heating the most molten after, be then cooled to room temperature (20 DEG C), place into (0 DEG C) in refrigerator freezing Crystallize, separates out and filters after crystal, filter cake in 45 DEG C of decompression dryings, obtain 7.9g (E)-7-[4-(4-fluorophenyl)-6-isopropyl- 2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester, wherein enantiomerism Body level is 0.48%, and diastereomer level is 0.31%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-e pioic acid methyl ester, 2 θ values and embodiment 18 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 32:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester crystallizes from the mixture of acetone and water
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester (0.52% diastereomer 0.3% enantiomer) uses 20ml acetone After the most molten with the heating of the mixture of water, it is then cooled to room temperature (15 DEG C), places into (-20 DEG C) in refrigerator freezing crystallize, separate out Filtering after crystal, filter cake, in 45 DEG C of decompression dryings, obtains 7g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (first Sulfonyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester, wherein enantiomer level is 0.25%, diastereomer level is 0.12%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, 2 θ value and embodiments 18 are similar to.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
Embodiment 33:(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester crystallizes from ether
By 10g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester (0.52% diastereomer 0.3% enantiomer) adds with 30ml ether After heat is the most molten, it is then cooled to room temperature (15 DEG C), places into (-20 DEG C) in refrigerator freezing crystallize, filter after separating out crystal, filter cake In 45 DEG C of decompression dryings, obtain 7g (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine- 5-yl] (3R, 5S)-3,5-dihydroxy heptyl-6-e pioic acid methyl ester, wherein enantiomer level is 0.25%, diastereomer Level is 0.12%.
(the E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] obtained , there is peak (3R, 5S)-3 in 2 θ positions in the X-ray powder diffraction figure of 5-dihydroxy heptyl-6-e pioic acid methyl ester, 2 θ values and embodiment 18 Similar.
Wherein, the detection method of diastereomer and enantiomer is with embodiment 1.
The above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art For Yuan, under the premise without departing from the principles of the invention, it is also possible to make some improvements and modifications, these improvements and modifications also should It is considered as protection scope of the present invention.

Claims (5)

1. (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3, The crystal formation of 5-dihydroxy heptyl-6-olefin(e) acid ethyl ester, it is characterised in that its X-ray powder diffraction figure has peak value, such as Fig. 1 in 2 θ positions Shown in, described 2 θ are 9.2445,9.6413,11.9698,13.7766,15.7766,16.3961,17.2367,17.8864, 18.4518、19.3910、20.0676、20.5769、21.5166、22.3291、22.8866、23.5785、24.1036、 24.7740、26.0137、27.0325、29.1436、30.4514、30.8838、31.9431、33.0464、33.9875、 35.7625,36.6411,37.6839,39.7936,40.8743 and 46.4935.
(E) the most according to claim 1-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] Pyrimidine-5-base] crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester is used for preparing Rosuvastatin or its medicine can connect By salt.
3. (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3, The crystal formation of 5-dihydroxy heptyl-6-enoic acid ter-butyl ester, it is characterised in that its X-ray powder diffraction figure has peak value in 2 θ positions, such as figure Shown in 2, described 2 θ are 17.0352,18.0864,19.3245,19.7326,20.5246 and 21.8532.
(E) the most according to claim 3-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] Pyrimidine-5-base] crystal formation of (3R, 5S)-3,5-dihydroxy heptyl-6-enoic acid ter-butyl ester is used for preparing Rosuvastatin or its medicine can Accept salt.
5. the method for crystallising of crystal formation as described in claim 1 or claim 3, it is characterised in that comprise the steps:
Step 1: obtain (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ester crude product；
Step 2: take described (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ester crude product obtains the first solution after mixing with the solvent of excess, crystallizes, separates, does After dry and get final product；
Solvent described in step 2 is the mixture of methanol, acetonitrile and water, the mixture of acetone, water and MTBE, mixing of second alcohol and water One in the mixture of the mixture of compound, MEK, 4-methyl-2 pentanone and toluene, ethyl acetate and petroleum ether or both with On mixture, or
MTBE, 4-methyl-2 pentanone, a kind of or both mixture above in toluene；Or
Methylisobutylketone and the mixture of the mixture of petroleum ether, acetonitrile and methyl tertiary butyl ether(MTBE), ethyl acetate and petroleum ether The mixture of mixture, oxolane and petroleum ether or glycol dimethyl ether；
Crystallize described in step 2 and specially take described first solution, be heated to more than 50 DEG C, cooling；
The temperature of described cooling is-20～40 DEG C；
Wherein, acetonitrile is 2:6 with the volume ratio of methyl tertiary butyl ether(MTBE)；Ethyl acetate is 1:1 with the volume ratio of petroleum ether；Tetrahydrochysene furan The volume ratio with petroleum ether of muttering is 1:1；
Wherein, in terms of g/mL, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5- Base] mass volume ratio of (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester and glycol dimethyl ether is 1:1.5；
In terms of g/mL, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester is 1:5 with the mass volume ratio of MTBE；
In terms of g/mL, (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (mesyl) amino] pyrimidine-5-base] (3R, 5S)-3,5-dihydroxy heptyl-6-olefin(e) acid ethyl ester and methylisobutylketone and the mixture of petroleum ether, 4-methyl-2 pentanone Or the mass volume ratio of toluene is 1:3；Wherein, methylisobutylketone is 1:1 with the volume ratio of petroleum ether；
Step 2 is dried in negative pressure, be dried under conditions of 40～50 DEG C.
CN201210516337.9A 2012-12-05 2012-12-05 Crystal formation of Rosuvastatin ester and preparation method thereof Expired - Fee Related CN103848790B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201210516337.9A CN103848790B (en) 2012-12-05 2012-12-05 Crystal formation of Rosuvastatin ester and preparation method thereof
PCT/CN2012/087703 WO2014086072A1 (en) 2012-12-05 2012-12-27 Crystal form of rosuvastatin ester and method of preparing same

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201210516337.9A CN103848790B (en) 2012-12-05 2012-12-05 Crystal formation of Rosuvastatin ester and preparation method thereof

Publications (2)

Publication Number Publication Date
CN103848790A CN103848790A (en) 2014-06-11
CN103848790B true CN103848790B (en) 2016-08-03

Family

ID=50856953

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201210516337.9A Expired - Fee Related CN103848790B (en) 2012-12-05 2012-12-05 Crystal formation of Rosuvastatin ester and preparation method thereof

Country Status (2)

Country Link
CN (1) CN103848790B (en)
WO (1) WO2014086072A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1898233A (en) * 2003-10-24 2007-01-17 阿斯利康(英国)有限公司 Process for the manufacture of the calcium salt of rosuvatatin (e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-enoic acid and crystallin
CN102617481A (en) * 2012-03-16 2012-08-01 湖南欧亚生物有限公司 Preparation method of rosuvastatin calcium

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070179166A1 (en) * 2003-12-24 2007-08-02 Valerie Niddam-Hildesheim Process for preparation of statins with high syn to anti ratio
EP2467363A1 (en) * 2009-08-17 2012-06-27 Aurobindo Pharma Limited Process for the manufacture of rosuvastatin calcium using crystalline rosuvastatin ethyl ester
HU230987B1 (en) * 2010-11-29 2019-08-28 Egis Gyógyszergyár Nyrt. Process for the preparation of pharmaceutical intermediates with high purity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1898233A (en) * 2003-10-24 2007-01-17 阿斯利康(英国)有限公司 Process for the manufacture of the calcium salt of rosuvatatin (e)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3r,5s)-3,5-dihydroxyhept-6-enoic acid and crystallin
CN102617481A (en) * 2012-03-16 2012-08-01 湖南欧亚生物有限公司 Preparation method of rosuvastatin calcium

Also Published As

Publication number Publication date
CN103848790A (en) 2014-06-11
WO2014086072A1 (en) 2014-06-12

Similar Documents

Publication Publication Date Title
US8487105B2 (en) Process for preparing pitavastatin, intermediates and pharmaceuctically acceptable salts thereof
TWI344957B (en) Chemical process and intermediates
US20190106401A1 (en) Coformer salts of (2s,3s)-methyl 7-fluoro-2-(4-fluorophenyl)-3-(1-methyl-1h-1,2,4-triazol-5-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate and methods of preparing them
JP6511083B2 (en) Crystal of pyrrole derivative
WO2007099561A1 (en) Process for preparing rosuvastatin calcium
JP2016029102A (en) Crystal form of quinoline compound and method for its production
US8912333B2 (en) Polymorphs of pitavastatin calcium
JP2012072175A5 (en)
KR20190133724A (en) (S) -2-((2-((S) -4- (difluoromethyl) -2-oxooxazolidin-3-yl) -5,6-dihydrobenzo [f] imidazo [1 , 2-d] [1,4] oxazepin-9-yl) amino) propanamide, polymorphs and solid forms, and methods for preparing the same
AU2016239028A1 (en) P-toluenesulfonate for MEK kinase inhibitor, and crystal form thereof and preparation method therefor
CN103848790B (en) Crystal formation of Rosuvastatin ester and preparation method thereof
WO2012106584A2 (en) Pitavastatin salts
CN103848784B (en) Crystal formation of Pitavastatin ester and preparation method thereof
WO2013098773A1 (en) Crystalline forms of pitavastatin calcium
CN103709107B (en) New crystal of Rosuvastatin methyl esters and preparation method thereof
EP2598485B1 (en) Novel montelukast 4-halobenzylamine salt and method for preparing montelukast sodium salt by using the same
CN110776451B (en) Preparation method of I-type atorvastatin calcium
TWI801759B (en) Hexadecyl treprostinil crystals and methods for preparation thereof
EP2888231B1 (en) Process for preparation of crystalline etoricoxib
TWI723455B (en) Lubiprostone crystals and methods for preparing the same
EP2373609A1 (en) Use of amphiphilic compounds for controlled crystallization of statins and statin intermediates
CN104529909B (en) A kind of method for crystallising of rosuvastain calcium intermediate
US20050215600A1 (en) Polymorphs of torsemide hydrochloride and process for production thereof
CN104557898A (en) Azilsartan tetrahydrofuran solvate and preparation method thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C41 Transfer of patent application or patent right or utility model
TR01 Transfer of patent right

Effective date of registration: 20170215

Address after: Shuangfeng Avenue Hefei Shuangfeng Industrial Zone in Anhui Province, 231131 Jinchuan Road, No. 025

Patentee after: ANHUI QINGYUN MEDICINE CO.,LTD.

Address before: Shuangfeng Avenue Hefei Shuangfeng Industrial Zone in Anhui Province, 231131 Jinchuan Road, No. 025

Patentee before: ANHUI QINGYUN PHARMACEUTICAL & CHEMICAL Co.,Ltd.

CF01 Termination of patent right due to non-payment of annual fee
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20160803

Termination date: 20211205