CN101426794A - Methods for preparing eszopiclone crystalline form A, substantially pure eszopiclone and optically enriched eszopiclone - Google Patents
Methods for preparing eszopiclone crystalline form A, substantially pure eszopiclone and optically enriched eszopiclone Download PDFInfo
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- CN101426794A CN101426794A CNA2007800139084A CN200780013908A CN101426794A CN 101426794 A CN101426794 A CN 101426794A CN A2007800139084 A CNA2007800139084 A CN A2007800139084A CN 200780013908 A CN200780013908 A CN 200780013908A CN 101426794 A CN101426794 A CN 101426794A
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- lunesta
- solvent
- water
- free alkali
- virahol
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- GBBSUAFBMRNDJC-INIZCTEOSA-N eszopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-INIZCTEOSA-N 0.000 title claims abstract description 218
- 238000000034 method Methods 0.000 title claims abstract description 109
- 229960001578 eszopiclone Drugs 0.000 title abstract description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 103
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 78
- 239000002904 solvent Substances 0.000 claims abstract description 71
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 70
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 58
- 239000000203 mixture Substances 0.000 claims abstract description 40
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 39
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims abstract description 33
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims abstract description 29
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims abstract description 29
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims abstract description 29
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims abstract description 29
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 29
- 230000003287 optical effect Effects 0.000 claims abstract description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000013557 residual solvent Substances 0.000 claims abstract description 20
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims abstract description 18
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims abstract description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 12
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940116333 ethyl lactate Drugs 0.000 claims abstract description 4
- 239000012458 free base Substances 0.000 claims abstract description 4
- 229940012618 lunesta Drugs 0.000 claims description 206
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 65
- 239000003513 alkali Substances 0.000 claims description 62
- 239000013078 crystal Substances 0.000 claims description 58
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 30
- 239000000126 substance Substances 0.000 claims description 28
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 27
- 238000001816 cooling Methods 0.000 claims description 26
- 239000002002 slurry Substances 0.000 claims description 24
- 238000010438 heat treatment Methods 0.000 claims description 22
- 238000002425 crystallisation Methods 0.000 claims description 21
- 230000008025 crystallization Effects 0.000 claims description 20
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 17
- GBBSUAFBMRNDJC-MRXNPFEDSA-N (5R)-zopiclone Chemical compound C1CN(C)CCN1C(=O)O[C@@H]1C2=NC=CN=C2C(=O)N1C1=CC=C(Cl)C=N1 GBBSUAFBMRNDJC-MRXNPFEDSA-N 0.000 claims description 14
- 239000012296 anti-solvent Substances 0.000 claims description 14
- 238000010992 reflux Methods 0.000 claims description 14
- 229960000820 zopiclone Drugs 0.000 claims description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical group COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- 125000003944 tolyl group Chemical group 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 3
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 claims description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 2
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
- OAIYNRAQCIOEBD-UHFFFAOYSA-N butyl acetate;hydrate Chemical compound O.CCCCOC(C)=O OAIYNRAQCIOEBD-UHFFFAOYSA-N 0.000 claims 2
- 239000003651 drinking water Substances 0.000 claims 2
- 235000020188 drinking water Nutrition 0.000 claims 2
- 125000001033 ether group Chemical group 0.000 claims 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims 1
- 239000003495 polar organic solvent Substances 0.000 claims 1
- -1 i-butanolisobutanol Chemical compound 0.000 abstract description 3
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 abstract 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 38
- 239000007787 solid Substances 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 238000001556 precipitation Methods 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 13
- 238000001035 drying Methods 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- 239000003960 organic solvent Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 206010013786 Dry skin Diseases 0.000 description 7
- 238000001291 vacuum drying Methods 0.000 description 7
- 238000002441 X-ray diffraction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 238000004140 cleaning Methods 0.000 description 5
- 238000005755 formation reaction Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 150000003839 salts Chemical group 0.000 description 5
- 239000013256 coordination polymer Substances 0.000 description 4
- 229940049920 malate Drugs 0.000 description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 2
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000000147 hypnotic effect Effects 0.000 description 2
- 206010022437 insomnia Diseases 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- OCQAXYHNMWVLRH-UHFFFAOYSA-N 2,3-dibenzoyl-2,3-dihydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(O)(C(O)=O)C(O)(C(=O)O)C(=O)C1=CC=CC=C1 OCQAXYHNMWVLRH-UHFFFAOYSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- DMHXOWQGBAAYTK-UHFFFAOYSA-N N1(CCNCC1)C(=O)O.CC1=C(C=C(C(=O)O)C=C1)C(=O)O Chemical compound N1(CCNCC1)C(=O)O.CC1=C(C=C(C(=O)O)C=C1)C(=O)O DMHXOWQGBAAYTK-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 238000005251 capillar electrophoresis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- 229940045641 monobasic sodium phosphate Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 239000000932 sedative agent Substances 0.000 description 1
- 230000001624 sedative effect Effects 0.000 description 1
- 238000011894 semi-preparative HPLC Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides methods for preparing eszopiclone Form A, substantially chemically pure eszopiclone, or eszopiclone with low level(s) of residual solvent(s). The present invention also provides eszopiclone with low level(s) of residual solvent(s). The present invention also provides a process for optical enrichment of eszopiclone free base. For instance, one of the embodiments of the invention is directed to a method of preparing eszopiclone Form A, wherein the method comprises crystallizing eszopiclone free base from a solvent selected from the group consisting of isopropanol (IPA), methyl isobutyl ketone (MIBK), acetone, n-butanol, i-butanolisobutanol, 2-butanol, tetrahydrofuran (THF), dimethyl carbonate, methanol, ethanol, ethyl lactate, dimethylformamide (DMF), carbon tetrachloride, toluene, iso-butyl acetate and mixtures thereof.
Description
The related application of cross reference
The application requires the rights and interests in U.S. Provisional Application No.60/793303 (April 20 2006 applying date) and 60/884109 (January 9 2007 applying date), and its disclosure is hereby incorporated by.
Invention field
The present invention relates to prepare Lunesta, the optically enriched Lunesta of Lunesta (eszopiclone) crystal form A, substantially pure and have the method for Lunesta of the residual solvent (one or more) of lower concentration.
Background of invention
Zopiclone (zopiclone) be a kind of can be used for bringing out calm the nerves (sedative), hypnosis (hypnotic) or calm (tranquilizing) effect, for the useful non-benzodiazepine of Cure for insomnia disease (insomnia)
Class (benzodiazepine), it is a kind of racemic compound, has chemical name: 4-methyl isophthalic acid-piperazinecarboxylic acid 6-(5-chloro-2-pyridyl)-6,7-dihydro-7-oxygen-5H-pyrrolo-[3,4-b] pyrazine-5-base ester, (±)-6-(5-chloro-2-pyridyl)-6,7-dihydro-7-oxygen-5H-pyrrolo-[3,4-b] pyrazine-5-base-4-methylpiperazine-1-manthanoate, perhaps 6-(5-chloropyridine-2-yl)-5-(4-methylpiperazine-1-yl) carbonyl oxygen base-7-oxygen-6,7-dihydro-5H-pyrrolo-[3,4-b] pyrazine is represented with following formula I.
Lunesta is the S-enantiomer of Zopiclone, and according to United States Patent (USP) 6,444,673 B1, it has bigger activity and lower toxicity than racemize Zopiclone.This medicine in the U.S. by Sepracor
TM 
(be called in the past
) sell under the title, have CAS number of registration 138729-47-2.Lunesta has chemical name: (+)-6-(5-chloro-2-pyridyl)-7 (S)-(4-methylpiperazine-1-base-carbonyl oxygen base)-6,7-dihydro-5H-pyrrolo-[3,4-b] pyrazine-5-ketone is also represented with Formula Il.
The Lunesta that is in free alkali form and salt form is disclosed in United States Patent (USP) 6,444, in 673 and 6,864,257.
Lunesta can prepare by the optical resolution of racemize Zopiclone.Blaschke, people such as G., Chirality (1993) 5:419-421 disclose and have used 0.5 normal D-(+)-oxysuccinic acid preparation not have the Lunesta of its enantiomer.By this method, diastereomeric salt is crystallization from methanol-acetone mixt, and this salt and at CH then neutralizes
2Cl
2Extraction of free base in the/ethyl acetate, and precipitate by concentrating this solution.At United States Patent (USP) 6,339, use in 086 1 normal D-(+)-oxysuccinic acid to improve of the preparation of described use oxysuccinic acid by the Lunesta of racemize Zopiclone optical resolution.In the method for the optical resolution of another racemize Zopiclone,, a kind of semipreparative HPLC method has been described among Chirality (1995) 7:267-271 people such as C.F.F.Gimenez.A kind of capillary electrophoresis method that is used for the Zopiclone stage enantiomer separation is disclosed in High, and J.ResolutionChromatography (2000) 23 (6): among the 413-429.Perhaps, US 2005/0043311 A1 discloses use D-(+)-O, and O '-dibenzoyl base (dibenzoyl)-tartrate is from the isolating Lunesta of racemize Zopiclone.According to this method, Lunesta is a crystalline from acetonitrile.
These methods have been described the Lunesta that the enantiomer that containing of free alkali form or salt form do not expect is provided.Therefore, the improved method of the Lunesta optical purity of diastereomeric salt or free alkali form need be improved in this area.
Zopiclone exists with several crystal formations; These crystal formation feature descriptions are in Chem.Commun. (2001) 2204-2205 and J.Phys.IV France 11 (2001) pr 10-93-pr 10-97, and at Drug Development and Industrial Pharmacy (2000) 26 (5): mention among the 531-537.Described crystal formation is oblique crystal dihydrate crystal formation I, oblique crystal anhydrous crystal forms II and iris type III.
Lunesta crystal form A (it has X-ray diffraction (XRD) figure that is equivalent to disclosed Zopiclone crystal form II I in the Chem.Commun publication) is to characterize by following main XRD peak: 5.1,10.1,11.3,12.6,16.1,18.1,19.1,20.2,21.4,25.7,27.7 ± 0.2 ° of 2 θ.Crystal form II I is the coalescent group of a kind of racemize (conglomerate), and this shows that same X-ray diffraction (XRD) figure also shows by single enantiomer.Have been found that according to US 6,444,673 and U.S. patent No.6,339,086 disclose, the crystallization of Lunesta free alkali in acetonitrile or ethyl acetate produces polymorphic A.
But acetonitrile is expensive, and the solvability of Lunesta in ethyl acetate is low and need the large volume solvent to bring out dissolving completely.In addition, for Lunesta is reclaimed from the solution ethyl acetate, need concentrate and bring out the Lunesta precipitation.This area need a kind ofly allow to use more practical solvent to come the method for industrial preparation Lunesta crystal form A.
Summary of the invention
The invention provides a kind of method for preparing the Lunesta crystal form A, comprise crystallization Lunesta free alkali from solvent, this solvent is selected from Virahol (IPA), methyl iso-butyl ketone (MIBK) (MIBK), acetone, propyl carbinol, isopropylcarbinol, 2-butanols, tetrahydrofuran (THF) (THF), methylcarbonate, methyl alcohol, ethanol, ethyl lactate, dimethyl formamide (DMF), tetracol phenixin, toluene, isobutyl acetate and its mixture.
The invention provides a kind of preparation method of chemical pure Lunesta basically, it comprises crystallization Lunesta free alkali from solvent, and this solvent is selected from methyl iso-butyl ketone (MIBK), isobutyl acetate, acetone, isopropylcarbinol, Virahol (IPA), THF, toluene, ethanol: water (preferred volume ratio is about 1:1), propyl carbinol, 2-butanols and Virahol: (preferred volume ratio is the about 10:1 of about 3:1-to water, for example about 3:1, about 5:1, approximately 7:1 or approximately 10:1).
The invention further relates to a kind of method that is used for optically enriched Lunesta free alkali, it comprises crystallization Lunesta free alkali from solvent, this solvent is selected from propyl carbinol, 2-butanols, isobutyl acetate, isopropylcarbinol, Virahol (IPA), toluene, acetone, Virahol: water (preferred volume ratio is the about 10:1 of about 3:1-), ethanol: water (preferred volume ratio is the about 1:27 of about 1:1-) and acetone: water (preferred volume ratio is about 1:1).
Another embodiment of the present invention provides the Lunesta free alkali, and it has the residual solvent (one or more) of low levels.
Another embodiment of the present invention provides the method for the Lunesta free alkali of the residual solvent (one or more) that a kind of preparation has low levels, it comprises crystallization Lunesta from solvent, this solvent is selected from toluene, isobutyl acetate, the Virahol of the about 10:1 of the about 3:1-of volume ratio: the ethanol of the about 95:5 of the about 1:1-of water and volume ratio: water.
Detailed Description Of The Invention
As used in this article, " Lunesta " refers to the Lunesta free alkali.
As used in this article, " Lunesta crystal form A " is the crystallization Lunesta, is characterised in that following main XRD peak: 5.1,10.1,11.3,12.6,16.1,18.1,19.1,20.2, and 21.4,25.7,27.7 ± 0.2 ° of 2 θ.
As used in this article, " envrionment temperature " refers to room temperature, and represents the temperature that about 18-is about 25 ℃, about 22 ℃ of for example about 20-.
As used in this article, " chemical pure basically " refers to greater than about 97%, for example about at least 99% pass through the measured chemical purity of HPLC.
As used in this article, be (the S)-enantiomer that has by about at least 97% measured Zopiclone of chirality HPLC in " optical purity basically " meaning that relates to Lunesta.
As used in this article, the Lunesta free alkali meaning with " low levels residual solvent (one or more) " is that this Lunesta comprises the isobutyl acetate that the content that calculates based on this Lunesta product weight is not more than about 5000ppm, Virahol or ethanol, and/or be not more than the residual solvent of the toluene of about 1400ppm, wherein this residual solvent is the solvent that is used for the crystallization Lunesta, and it is retained in the Lunesta product after crystallization.
As used in this article, the solution of Lunesta free alkali can for example prepare by the temperature that is heated to about 50 ℃-approximately backflow.In addition, mix other solvent and can help dissolving.The volume of used solvent can be determined based on the solvability of Lunesta in each specific solvent.
The invention provides a kind of method for preparing the Lunesta crystal form A, it comprises crystallization Lunesta free alkali from solvent, and this solvent is selected from Virahol (IPA), methyl iso-butyl ketone (MIBK) (MIBK), acetone, propyl carbinol, isopropylcarbinol, 2-butanols, tetrahydrofuran (THF) (THF), methylcarbonate, methyl alcohol, ethanol, ethyl lactate, dimethyl formamide (DMF), tetracol phenixin, toluene, isobutyl acetate and its mixture.Perhaps, the Lunesta free alkali can slurrying in being selected from above-mentioned solvent.
It is preferred stirring in Lunesta crystal form A crystallisation process.
Settling step can perhaps carry out to described solution or slurries by adding anti-solvent (anti-solvent) by described solution of cooling or slurries.
Preferably, before Lunesta crystal form A precipitation, heat.Preferred this heating is the temperature in from envrionment temperature to about reflow temperature range.
Typically, cooling is to about-10 ℃ temperature to the about ambient temperature range.
Anti-solvent is non-polar solvent such as ether preferably, aromatic hydrocarbons and aliphatic hydrocarbon.More preferably, this anti-solvent is selected from: normal hexane, normal heptane, methyl tertiary butyl ether (MTBE) and water.The volume that joins the anti-solvent in the Lunesta solution can be about 50 volumes of about 1-of this Lunesta solution.
The crystal formation Lunesta crystal form A that is obtained can further reclaim.The recovery of Lunesta crystal form A can be by any method known to those skilled in the art for example by filtering, clean and drying, for example in vacuum oven.
Preferably, the Lunesta crystal form A that is obtained is chemical pure basically.
Preferably, the Lunesta crystal form A that is obtained is optically pure basically.
The invention provides a kind of preparation method of chemical pure Lunesta basically, it comprises crystallization Lunesta free alkali from solvent, and this solvent is selected from methyl iso-butyl ketone (MIBK), isobutyl acetate, acetone, isopropylcarbinol, Virahol (IPA), THF, toluene, ethanol: water (preferred volume ratio is about 1:1), propyl carbinol, 2-BuOH and Virahol: (preferred volume ratio is the about 10:1 of about 3:1-to water, for example about 3:1,5:1,7:1 or 10:1).Perhaps, the Lunesta free alkali can the solvent on be selected from slurrying.
Machined parameters as mentioned above.Preferably, described solvent is selected from MIBK, Virahol, and THF, toluene, volume ratio is the ethanol/water of about 1:1, acetone, 2-butanols, the isopropanol of the about 3:1 of volume ratio, about 5:1, about 7:1 or about 10:1, and isobutyl acetate.
The Lunesta that is obtained is the Lunesta crystal form A preferably.
Preferably, by this method the chemical pure basically Lunesta of Huo Deing have with HPLC measured greater than about 98%, more preferably greater than about 99%, even more preferably greater than about 99.5% and most preferably about 99.9% or above chemical purity.
The invention further relates to a kind of method of optically enriched Lunesta free alkali, it comprises crystallization Lunesta free alkali from solvent, and this solvent is selected from propyl carbinol, 2-butanols, isobutyl acetate, isopropylcarbinol, Virahol (IPA), toluene, acetone, IPA/H
2O (preferred volume ratio is the about 10:1 of about 3:1-), ethanol: water (preferred volume ratio is the about 1:27 of about 1:1-) and acetone: water (preferred volume ratio is about 1:1).Perhaps, the Lunesta free alkali can slurrying in being selected from above-mentioned solvent.
Machined parameters as mentioned above.
Preferably, solvent is selected from toluene, Virahol, propyl carbinol, the isopropanol of the about 3:1 of volume ratio, about 5:1, about 7:1 or about 10:1, and isobutyl acetate.
More preferably, the volume ratio of Virahol and water is about 7:1-10:1.
Typically, the optically pure basically solid Lunesta that is obtained is the Lunesta crystal form A.
Preferably, compare with initial Lunesta, this Lunesta is 0.5% optically enriched, is more preferably 4% optically enrichedly, and most preferably is 7% optically enriched.For example the Lunesta 4% optically enriched meaning is the high by 4% compared with the optical purity of beginning Lunesta as passing through the determined optical purity of chirality HPLC of this Lunesta product.
The Lunesta that is obtained is optically pure basically.Basically the optically pure Lunesta of Huo Deing can have by chirality HPLC (determined) and is preferably greater than about 98% by this method, more preferably greater than about 99%, more preferably greater than about 99.5% and about at least 99.9% optical purity most preferably.
When the mixture of used Virahol and water has the volume ratio of about 5:1 or 10:1, residual solvent (one or more) in final Lunesta product is not more than about 5000ppm, preferably be not more than about 800ppm and more preferably no more than about 700ppm.This method is better than at United States Patent (USP) 6,339, disclosed method in 086, and wherein the residual solvent levels of Lunesta product is lower.
Preferably, described method comprises Lunesta is dissolved in the mixture of Virahol and water; Heating; Obtain throw out with cooling.Preferably, this heating is to the temperature from about envrionment temperature to about reflux temperature, more preferably arrives about reflux temperature.Preferably, this cooling is to the temperature of about 0 ℃-about room temperature range, more preferably arrives about 10 ℃ temperature.Preferably, after cooling, obtain a kind of slurries.Preferably, stir described slurries.Preferably, stir about 30 minutes-about 20 hours.
Preferably, the Lunesta that is obtained is the Lunesta crystal form A.
In some embodiments of described method, compare with initial Lunesta, the Lunesta that is obtained is optically enriched by chirality HPLC determined about at least 0.1%, and preferred about at least 4% is optically enriched and more preferably 4.5% optically enriched.For example, the Lunesta that is obtained can be about 0.1% or about 4% optically enriched.
Preferably, further reclaim the throw out of this Lunesta product.
Reclaiming Lunesta (preferred crystal form A) on any in the method can be undertaken by any known method in this area, for example by filtration, cleaning and vacuum-drying.Preferably, cleaning is to carry out with the identical solvent that uses in the described method.Preferably, when solvent used in the described method was IPA/ water, cleaning was carried out with IPA.Preferably, drying is at about 30 ℃-about 70 ℃, more preferably at about 50 ℃-about 60 ℃ and most preferably carry out in about 50 ℃ temperature.
Another embodiment of the present invention provides the Lunesta free alkali of the residual solvent (one or more) with low levels.
Another embodiment of the present invention provides the method for the Lunesta free alkali of the residual solvent (one or more) that a kind of preparation has low levels, it comprises crystallization Lunesta from solvent, this solvent is selected from toluene, isobutyl acetate, the Virahol of the about 10:1 of the about 3:1-of volume ratio: the ethanol of the about 95:5 of the about 1:1-of water and volume ratio: water.Perhaps, the mixture of these solvents can be used in the described method.
Lunesta free alkali with residual solvent (one or more) of low levels preferably comprises and is not more than about 1350ppm toluene (more preferably no more than about 890ppm toluene), is not more than about 600ppm isobutyl acetate or is not more than about 800ppm (more preferably no more than about 700ppm) Virahol.
Preferably, the solution that provides in a kind of Lunesta free alkali solvent below is provided described method: toluene, isobutyl acetate, the Virahol of the about 10:1 of the about 3:1-of volume ratio: water, ethanol with the about 95:5 of the about 1:1-of volume ratio: water, and precipitate this Lunesta.Lunesta can desolvate and precipitates from solution by cooling or via evaporating removing of for example vacuum-evaporation.
Preferably, described method comprises the Lunesta free alkali and is selected from following solvent and makes up: toluene, isobutyl acetate, the Virahol of the about 10:1 of the about 3:1-of volume ratio: the ethanol of the about 95:5 of the about 1:1-of water and volume ratio: water; Heating; And cooling.
Preferably, heating is to about 30 ℃-about 90 ℃ temperature, more preferably arrives about 60 ℃-about 80 ℃ temperature.Preferably, cooling is to the temperature that is lower than about envrionment temperature.
Preferably, Virahol: water volume ratio is about 7:1-10:1.
Preferably, ethanol: water volume ratio is the about 10:1 of about 3:1-, more preferably about 95:5.
Preferably, the Lunesta that is obtained is chemical pure basically.
Preferably, the Lunesta that is obtained is optically pure basically.
Preferably, the Lunesta that is obtained is the Lunesta crystal form A.
With Virahol: water and ethanol: the Lunesta solution that water is used for having the volume of water of qualification is favourable, and this is because it can use the organic solvent of low quantity.
The identification of the Lunesta crystal form A that obtains by the inventive method is confirmed by powder x-ray diffraction (XRD) figure, this figure is to use the Scintag x-ray powder diffraction instrument to obtain by methods known in the art, and this diffractometer has variable angle gauge, has (the Cu radiation of Cu target anodic X-ray tube
), solid-state detector and circular standard aluminum sample fixer.
Described the present invention with reference to some embodiment preferred, other embodiments will become apparent from this specification sheets to those skilled in the art.The present invention further describes with reference to the embodiment of following detailed preparation of compositions of the present invention and using method.It will be apparent to those skilled in the art that many changes (material and method the two) can carry out and do not depart from the scope of the present invention.
Embodiment
HPLC method (about optical purity)
Post and stopping composition: Chiralcel OD-H 4.6 * 250mm, 5 μ m CN 14325
Eluant: 0.1% DEA in ethanol
Stand-by time: 25min
Flow velocity: 0.7ml/min
Detector: 306nm
Volume injected: 20 μ l.
Thinner: ethanol
Column temperature: 25 ℃
Self-actuated sampler temperature: 10 ℃
Runtime: R-ZP:12.9min; S-ZP:18.4min
HPLC method (about chemical purity)
Post and stopping composition: Inertsil ODS 3V 250*4.6mm 5 μ C.N 5020-01802
Buffer formulations: the 0.01M SODIUM PHOSPHATE, MONOBASIC is adjusted into pH=7.0 with 1N NaOH
Eluant A:66% buffer reagent: 34% acetonitrile
Eluant B: acetonitrile
Eluant gradient: time (min) eluant A (%) eluant B (%)
0min 100 0
13min 100 0
23min 40 60
33min 40 60
Stand-by time: 33min
Starting time: 7min
Flow velocity: 1.0ml/min
Detector: 306nm.
Volume injected: 20 μ l.
Thinner: 50% acetonitrile: 50% buffer reagent
Column temperature: 25 ℃
Self-actuated sampler temperature: 5 ℃
Embodiment 1-prepares Lunesta crystal form A [Comparative Examples] from ethyl acetate
In Lunesta free alkali (1g), add ethyl acetate (AR level) (20ml), and these slurries are heated to backflow.When refluxing, add other 10ml ethyl acetate and come complete dissolved solids.The temperature that stops to heat and in 15 minutes, in ice-acetone bath, solution is cooled to approximately-10 ℃.Precipitation starts from 60 ℃.This mixture approximately-10 ℃ is being stirred 1h.Cross filter solid, and produce the Lunesta crystal form As 60 ℃ of dryings with 2ml EtOAc cleaning and in vacuum electric furnace.Productive rate 80%.
Embodiment 2-prepares the Lunesta crystal form A from MIBK
In Lunesta free alkali (1.5g), add MIBK (CP level) (6ml), and the slurries that obtained are heated to backflow.In heat-processed, add the MIBK of other 6ml.When refluxing, add other solvent (9ml) and bring out solid and dissolve fully.Stop the heating and with the solution cool to room temperature.Precipitation starts from 80 ℃.After this with mixture at 45min internal cooling to 26 ℃.And at stirring at room 2h.Cross filter solid, and with 2ml MIBK clean and in vacuum electric furnace 65 ℃ of dryings.Wet material is the Lunesta crystal form A.Productive rate 80%.(chemical pure that HPLC measures is 99.96%).
Embodiment 3-prepares the Lunesta crystal form A from propyl carbinol
In Lunesta free alkali (1.5g), add n-BuOH (CP level) (6ml), and the slurries that obtained are heated to backflow.Refluxing (114 ℃), the n-BuOH that adds other 4ml dissolves fully up to solid in slurries.Stop then the heating and with the solution cool to room temperature.Solid precipitation starts from 100 ℃.With mixture at about 40min internal cooling to 29 ℃.Stir 1h in room temperature (26 ℃-29 ℃) then.Cross filter solid, and with 3ml n-BuOH clean and in vacuum electric furnace 65 ℃ and 7mm Hg drying.Productive rate 90%.(chemical pure that HPLC measures is 100%).
Embodiment 4-prepares the Lunesta crystal form A from isopropylcarbinol
In Lunesta free alkali (1g), add i-BuOH (CP level) (6ml), and the slurries that obtained are heated to backflow.Refluxing (106 ℃), the i-BuOH that adds other 4ml dissolves fully up to solid in slurries.Stop then the heating and with the solution cool to room temperature.Solid precipitation starts from 97 ℃.With mixture at about 35min internal cooling to 24 ℃.Stir 2h in room temperature (～24 ℃) then.Cross filter solid, with 2ml i-BuOH clean and in vacuum electric furnace 60 ℃ and 7mm Hg drying.Productive rate 71%.(chemical pure that HPLC measures is 97.37%).
Embodiment 5-prepares the Lunesta crystal form A from Virahol
In Lunesta free alkali (1.5g), add IPA (HPLC level) (3ml), and the slurries that obtained are heated to backflow.In heat-processed, add the IPA of other 6ml.Refluxing (82 ℃), the IPA that adds other 62ml dissolves fully up to solid in slurries.Stop then the heating and with the solution cool to room temperature.Solid precipitation starts from 60 ℃.Mixture at about 40min internal cooling to 25 ℃, is stirred 2h in room temperature (about 26 ℃-29 ℃) then.Cross filter solid, spend weekend with 3ml IPA cleaning is also dry on the top of the shelf.Then at 60 ℃ of drying solids.Productive rate 80%.(chemical purity that HPLC measures is 99.94%).
Embodiment 6-prepares the Lunesta crystal form A from THF
In Lunesta free alkali (1.5g), add THF (dry in addition) (7.5ml), and the slurries that obtained are heated to backflow.Refluxing, add other 16ml THF and dissolve fully up to solid.Stop the heating and with the solution cool to room temperature.Precipitation starts from 45 ℃.With mixture at about 1h internal cooling to 27 ℃, then at stirring at room 2h.Cross filter solid, with 3ml THF clean and in vacuum electric furnace 60 ℃ of dryings.Productive rate 60%.(chemical purity that HPLC measures is 99.93%).
Embodiment 7-prepares the Lunesta crystal form A from toluene
In Lunesta free alkali (0.9g), add toluene (dry in addition) (4.5ml), and slurries are heated to backflow.Refluxing, add other toluene (4ml) and dissolve fully up to solid.Stop the heating and with the solution cool to room temperature.Precipitation starts from 70 ℃.With mixture at about 50min internal cooling to 26 ℃, then at stirring at room 2h.Cross filter solid, with 1.5ml toluene clean and in vacuum electric furnace 65 ℃ of dryings.Productive rate 70%.(chemical purity that HPLC measures is 99.72%).
Embodiment 8-is from EtOH/H2O (1:1) preparation Lunesta crystal form A
In Lunesta free alkali (1.5g), add EtOH/H based on volume 1:1
2O mixture (15ml), and slurries are heated to backflow.At 76 ℃, observe solid and dissolve fully.80 ℃ stop the heating and with the slurries cool to room temperature.Precipitation starts from 68 ℃.With mixture at about 50min internal cooling to 28 ℃, then at stirring at room 2h.Cross filter solid, with the 3ml solvent mixture clean and in vacuum electric furnace 60 ℃ of dryings.Productive rate 67%.(chemical purity that HPLC measures is 99.65%).
Embodiment 9-prepares the Lunesta crystal form A from i-BuOAc
In Lunesta free alkali (1.5g), add i-BuOAc (AR level) (7.5ml), and slurries are heated to backflow.Refluxing, the i-BuOAc that adds other 18ml dissolves fully up to solid.Stop the heating and with the solution cool to room temperature.Precipitation starts from 85 ℃.With mixture at about 50min internal cooling to 28 ℃.Then at stirring at room 2h.Cross filter solid, with 3mli-BuOAc clean and in vacuum electric furnace 50 ℃ of dryings.Productive rate 93%.(chemical purity that HPLC measures is 99.95%).
The summary sheet as a result of embodiment 2-9
Embodiment 10-20 prepares Lunesta from other solvents by the described method of embodiment 2-9
Crystal form A
The Lunesta crystal form A is to use other solvents shown in the following table equally, with what prepare corresponding to the described method of embodiment 2-9.
Embodiment 21 is from preparing a right assistant gram as the THF of solvent with as the MTBE of anti-solvent
Grand crystal form A
In Lunesta free alkali (0.8g), add other exsiccant THF (12.5ml), and the slurries that obtained are heated to backflow.Refluxing, dissolve described solid and obtain clear solution.In this solution, add MTBE (CP level) and begin precipitation up to solid.Along with MTBE adds, the temperature of solution reduces.After the MTBE of 8ml added, precipitation started from about 60 ℃ temperature, stopped heating and with the slurries cool to room temperature.Mixture at 25min internal cooling to 28 ℃, is stirred 2h at 28 ℃ then.Cross filter solid, with the MTBE of 1.5ml clean and in vacuum electric furnace 60 ℃ of dryings.Productive rate 75%.
Embodiment 22-26 is right by embodiment 21 described method preparations from other solvent/anti-solvent
The Zopiclone crystal form A
The Lunesta crystal form A is to use other solvent/anti-solvent shown in the following table equally, to prepare corresponding to embodiment 21 described methods.
Embodiment 27-31 prepares optically enriched Lunesta by the described method of embodiment 2-9
Crystal form A
| Embodiment | Solvent | The solvent volume ml of the initial Lunesta of every gram | The optical purity of initial Lunesta (HPLC) | The optical purity of crystallization Lunesta (HPLC) | Productive rate (%) |
| 27 | Toluene | 9.5 | 92.5％ | 99.9％ | 78％ |
| 28 | i-BuOAc | 17 | 92.5％ | 96.66％ | 88％ |
| 29 | Virahol | 47 | 92.5％ | 97.4％ | 88％ |
| 30 | Isopropylcarbinol | 10 | 92.5％ | 93.4％ | 86％ |
| 31 | Propyl carbinol | 10 | 92.5％ | 97.2％ | 90％ |
Embodiment 32-35 prepares the Lunesta crystal form A from IPA/ water
With Lunesta (2.0g, optical purity 95.5-98.5%) by being dissolved at reflux in the water-based Virahol (" IPA ").With following 1 hour internal cooling of this solution stirring to room temperature, and other 1 hour in stirring at room.Cross filter solid, the use Virahol cleans, and 50 ℃ of vacuum-drying a whole nights, obtains the Lunesta crystal form A, and productive rate is 85-95%.
Embodiment 36 prepares the Lunesta crystal form A from IPA/ water by being cooled to 10 ℃
With Lunesta (7g, optical purity 98.45%) by being dissolved at reflux among the water-based Virahol 10:1 (136.5ml).Following 1 hour internal cooling of this solution stirring is arrived about 10 ℃, and stirred other 2 hours in this temperature.Cross filter solid, the use Virahol cleans, and 50 ℃ of vacuum-drying a whole nights, obtains the Lunesta of crystal form A, and productive rate is 89.5%.(the HPLC optical purity: 99.91%, HPLC chemical purity: 99.4%).
Embodiment 37 repeats the embodiment 2 of United States Patent (USP) 6,339,086
With 40% water-based salt of wormwood (1.6g, 4.64mmol) stir and 30 ℃ under slowly join Lunesta malate (2.0g, 3.74mmol HPLC purity is 99.96%, the HPLC optical purity is 96%) in the mixture in water (4ml) and ethyl acetate (20ml).Then with this mixture 60 ℃ of heating, and organic phase separated and clean with 20ml water.Mixture is concentrated to 2/3 volume of organic solvent.Formed slurries are cooled to 5 ℃ and stirred 2 hours in addition in same temperature.Cross filter solid, clean with cold ethyl acetate, in 50 ℃ of vacuum-dryings a whole night (dry for the first time), produce the Lunesta of the residual ethyl acetate that contains 7534ppm (GC) content, it has 96.35% HPLC optical purity.This Lunesta produces the Lunesta of the residual ethyl acetate that contains 7360ppm (GC) content further at 75 ℃ of vacuum-dryings 18 hours (dry for the second time).
Embodiment 38 uses other organic solvents to be similar to United States Patent (USP) 6,339,086 enforcement
The process of the method in the example 2
With 40% water-based salt of wormwood (1.6g, 4.64mmol) stirring and slowly joining Lunesta malate (2.0g at 30 ℃, 3.74mmol HPLC purity is 99.96%, the HPLC optical purity is 96%) in the mixture of one of organic solvent shown in water (4ml) and the following table.Heat this mixture then, and clean with the organic phase separation with 20ml water.Mixture is concentrated.Formed slurries are cooled to 5 ℃ and stirred 2 hours in addition in same temperature.Cross filter solid, clean,, obtain to contain the Lunesta of residual solvent in 50 ℃ of vacuum-dryings a whole night (dry for the first time) with cold organic solvent (with used identical in front).This Lunesta obtains containing the Lunesta of residual solvent further at 75 ℃ of vacuum-dryings 18 hours (dry for the second time).
Embodiment 37 and result's (comprise by neutralization, organic solvent extraction and precipitation and prepare Lunesta from the Lunesta malate) of 38 are illustrated in the following table.
| Organic solvent | The organic solvent of the initial Lunesta of every gram | Heating temperature (in the extraction process) | Productive rate (%) | The rate of recovery *(％) | Chemical purity (%) | Optical purity (%) | Dried residual solvent for the first time | Dried residual solvent for the second time |
| Volume ml | (℃) | (ppm) | (ppm) | |||||
| Ethyl acetate | 20 | 60 | 80 | 96.35 | 7534 | 7360 | ||
| Butylacetate | 54 | 80 | 73 | Do not check | Do not analyze | 96.4 | 6733 | 6468 |
| Toluene | 25 | 80 | 75 | Do not check | 99.95 | 96.8 | 8025 | 7478 |
| Isobutyl acetate | 64 | 80 | 60 | 83 | 99.94 ** | 99.15 | 7799 | 7578 |
*" rate of recovery " relates to the total amount (with its solid form with in mother liquor) of Lunesta.
*The material balance of Lunesta: the productive rate of material is lower than 83% in solid in these tests and the mother liquor, and the purity that is dissolved in the material in the mother liquor is about 95%, and this has shown the decomposition of Lunesta.At aqueous phase, Lunesta does not exist.
Embodiment 39 is by neutralizing in water, filter and coming from right side assistant from the organic solvent crystallization
Clone's malate prepares Lunesta
Embodiment 39 is to use embodiment 38 described programs, uses different solvents to carry out.The result of this test is illustrated in the following table.
By the residual solvent in the prepared Lunesta of crystallization
| Solvent is with respect to the volume (ml/g) of initial Lunesta | Productive rate (%) | The chemical purity of Lunesta product (%) | The optical purity of initial Lunesta (%) | The optical purity of Lunesta product (%) | Residual solvent (ppm) |
| Toluene (9) | 90 | 99.97 | 98.85 | 99.96 | 1349 |
| Isobutyl acetate (27) | 80 | 99.95 | 98.85 | 99.97 | 568 |
| Isopropanol, volume ratio 5:1, (14) | 85 | 99.97 | 95.5 | 99.91 | 676 |
Claims (61)
1. method for preparing the Lunesta crystal form A, it comprises crystallization Lunesta free alkali from solvent, and this solvent is selected from Virahol, methyl iso-butyl ketone (MIBK), acetone, propyl carbinol, isopropylcarbinol, 2-butanols, tetrahydrofuran (THF), methylcarbonate, methyl alcohol, ethanol, ethyl lactate, dimethyl formamide, tetracol phenixin, toluene, isobutyl acetate and its mixture.
2. the method for claim 1, it further is included in this Lunesta free alkali of heating in the solvent.
3. the process of claim 1 wherein that this Lunesta crystal form A is sedimentary by cooling.
4. the method for claim 3, wherein this cooling is to approximately-10 ℃ and the temperature between the envrionment temperature.
5. the process of claim 1 wherein and stir the solution of this Lunesta free alkali in solvent.
6. the method for claim 1, it further comprises the slurrying in solvent of Lunesta free alkali.
7. the process of claim 1 wherein that the Lunesta crystal form A is to come sedimentary by adding at least a anti-solvent.
8. the method for claim 7, wherein this at least a anti-solvent is selected from non-polar organic solvent and water.
9. the method for claim 8, wherein this at least a anti-solvent is selected from ether, aromatic hydrocarbons, aliphatic hydrocarbon and water.
10. the method for claim 9, wherein this at least a anti-solvent is selected from methyl tertiary butyl ether, normal hexane, normal heptane and water.
11. the method for claim 7, wherein the volume of this at least a anti-solvent is about 1 volume-about 50 volumes, based on the volume of Lunesta free base solution.
12. the method for claim 7, it further comprises the slurrying in solvent and at least a anti-solvent of this Lunesta free alkali.
13. the process of claim 1 wherein that this solvent is selected from methyl iso-butyl ketone (MIBK), Virahol, tetrahydrofuran (THF), toluene, the ethanol/water that volume ratio is about 1: 1, acetone, the 2-butanols, volume ratio about 3: 1, about 5: 1, about 7: 1 or about 10: 1 isopropanol, and isobutyl acetate.
14. the process of claim 1 wherein this Lunesta crystal form A product have by HPLC measured greater than about 97% chemical purity.
15. the process of claim 1 wherein that this Lunesta crystal form A product has the about at least 97% measured optical purity by HPLC.
16. one kind prepares and has the measured method greater than the Lunesta of about 97% chemical purity by HPLC, it comprises crystallization Lunesta free alkali from solvent, and this solvent is selected from methyl iso-butyl ketone (MIBK), isobutyl acetate, acetone, isopropylcarbinol, Virahol, tetrahydrofuran (THF), toluene, ethanol: water, propyl carbinol, 2-butanols, Virahol: water and its mixture.
17. the method for claim 16, wherein ethanol: glassware for drinking water has about 1: 1 volume ratio, and Virahol: glassware for drinking water has about 3: the volume ratio that 1-is about 10: 1.
18. the method for claim 16, wherein this solvent is selected from methyl iso-butyl ketone (MIBK), Virahol, tetrahydrofuran (THF), toluene, the ethanol that volume ratio is about 1: 1: water, acetone, propyl carbinol, 2-butanols, volume ratio about 3: 1, about 5: 1, about 7: 1 or about 10: 1 Virahol: water, and isobutyl acetate.
19. the method for claim 18, wherein this solvent is selected from about 1: 1 ethanol of volume ratio: water, methyl iso-butyl ketone (MIBK), Virahol, tetrahydrofuran (THF), acetone, volume ratio about 3: 1, about 5: 1, about 7: 1 or about 10: 1 Virahol: water, toluene and isobutyl acetate.
20. the method for claim 18, wherein this solvent is selected from methyl iso-butyl ketone (MIBK), Virahol, tetrahydrofuran (THF), acetone, volume ratio about 3: 1, about 5: 1, about 7: 1 or about 10: 1 Virahol: water, toluene and isobutyl acetate.
21. the method for claim 16 wherein stirs the solution of this Lunesta free alkali in solvent.
22. the method for claim 16, it further comprises Lunesta free alkali and solvent is carried out slurrying.
23. the method for claim 16, wherein the Lunesta product has the chemical purity greater than about 99%.
24. the method for claim 23, wherein the Lunesta product has the chemical purity greater than about 99.5%.
25. the method for claim 24, wherein the Lunesta product has about at least 99.9% chemical purity.
26. the method for claim 16, wherein the Lunesta product is the Lunesta crystal form A.
27. method for preparing the Lunesta free alkali, this Lunesta free alkali has (the S)-enantiomer of about at least 97% the Zopiclone of measuring by HPLC, described method comprises crystallization Lunesta free alkali from solvent, and this solvent is selected from propyl carbinol, 2-butanols, isobutyl acetate, isopropylcarbinol, Virahol, toluene, acetone, Virahol: water, ethanol: water, acetone: water and its mixture.
28. the method for claim 27, wherein Virahol: water mixture has about 3: the volume ratio that 1-is about 10: 1, ethanol: water mixture has about 1: the volume ratio that 1-is about 1: 27, and acetone: water mixture has about 1: 1 volume ratio.
29. the method for claim 28, wherein solvent is selected from toluene, volume ratio about 3: 1, about 5: 1, about 7: 1 or about 10: 1 Virahol: water, and isobutyl acetate.
30. the method for claim 28, wherein solvent is to have about 5: the Virahol of the volume ratio that 1-is about 10: 1: water mixture.
31. the method for claim 30, wherein this solvent is to have about 7: the Virahol of about 10: 1 volume ratios of 1-: water mixture.
32. the method for claim 27 wherein stirs the solution of initial Lunesta free alkali in solvent.
33. the method for claim 27, it further comprises initial Lunesta free alkali and solvent is carried out slurrying.
34. the method for claim 27, the Lunesta free alkali product that is wherein obtained is the Lunesta crystal form A.
35. the method for claim 27 is wherein compared with initial Lunesta free alkali, the Lunesta free alkali product that is obtained is about at least 0.1% optically enriched.
36. the method for claim 35 is wherein compared with initial Lunesta free alkali, the Lunesta free alkali product that is obtained is about at least 4% optically enriched.
37. the method for claim 36 is wherein compared with initial Lunesta free alkali, the Lunesta free alkali product that is obtained is about 7% optically enriched.
38. the method for claim 27, the Lunesta free alkali product that is wherein obtained has the optical purity greater than about 99%.
39. the method for claim 38, the Lunesta free alkali product that is wherein obtained has the optical purity greater than about 99.5%.
40. the method for claim 39, the Lunesta free alkali product that is wherein obtained has about at least 99.9% optical purity.
41. the method for claim 27 wherein is dissolved in the Lunesta free alkali in the mixture of Virahol and water; Postheating, cooling obtains the throw out as Lunesta free alkali product then, and it has about at least 97% Lunesta.
42. the method for claim 41, wherein heating is to about reflux temperature, and cooling is the temperature to about 0 ℃-about room temperature range.
43. the method for claim 41, wherein cooling is to about 10 ℃.
44. the method for claim 41 wherein obtains slurries by cooling, and stirs this slurries.
45. the method for claim 44, wherein these slurries were stirred about 30 minutes-about 20 hours.
46. Lunesta, it has according to the weight of this Lunesta and calculates, and is not more than isobutyl acetate, Virahol or the ethanol of about 5000ppm and/or is not more than the toluene of about 1400ppm.
47. the Lunesta of claim 46, it has the isobutyl acetate that is not more than about 600ppm, is not more than the Virahol of about 800ppm and/or is not more than the toluene of about 1350ppm.
48. the Lunesta of claim 47, it has the toluene that is not more than about 890ppm.
49. method for preparing the Lunesta free alkali, this Lunesta free alkali have as one or more residual solvents, calculate according to this Lunesta weight, be not more than isobutyl acetate, Virahol or the ethanol of about 5000ppm, and/or be not more than the toluene of about 1400ppm, described method comprises crystallization Lunesta from solvent, this solvent is selected from toluene, isobutyl acetate, volume ratio about 3: the Virahol that 1-is about 10: 1: water, volume ratio about 1: the ethanol that 1-is about 95: 5: water and its mixture.
50. the method for claim 49, it further comprises the mixture of initial Lunesta of heating and solvent.
51. the method for claim 50, wherein heating is to backflow.
52. the method for claim 50, wherein heating is to about 30 ℃-about 90 ℃ temperature.
53. the method for claim 52, wherein heating is to about 60 ℃-about 80 ℃ temperature.
54. the method for claim 49, wherein the Lunesta product is sedimentary by the mixture that cools off initial Lunesta and solvent.
55. the method for claim 54, wherein cooling is to subambient temperature.
56. the method for claim 49, wherein solvent is a volume ratio about 7: the Virahol that 1-is about 10: 1: water.
57. the method for claim 49, wherein solvent is a volume ratio about 3: the ethanol that 1-is about 10: 1: water.
58. the method for claim 49, wherein solvent is about 95: 5 ethanol of volume ratio: water.
59. the method for claim 49, wherein the Lunesta that is obtained has the chemical purity greater than about 97%.
60. the method for claim 49, wherein the Lunesta that is obtained has about at least 97% optical purity.
61. the method for claim 49, wherein the Lunesta that is obtained is the Lunesta crystal form A.
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| US79330306P | 2006-04-20 | 2006-04-20 | |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103980278A (en) * | 2012-12-26 | 2014-08-13 | 上海中西制药有限公司 | Eszopiclone microcrystalline and preparation method thereof |
| CN112485351A (en) * | 2020-11-18 | 2021-03-12 | 天津华津制药有限公司 | Detection method of eszopiclone optical isomer |
-
2007
- 2007-04-20 CN CNA2007800139084A patent/CN101426794A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103980278A (en) * | 2012-12-26 | 2014-08-13 | 上海中西制药有限公司 | Eszopiclone microcrystalline and preparation method thereof |
| CN112485351A (en) * | 2020-11-18 | 2021-03-12 | 天津华津制药有限公司 | Detection method of eszopiclone optical isomer |
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