CN111072572A - Crystal form of bisulfate of Elagolix key intermediate and preparation and application thereof - Google Patents
Crystal form of bisulfate of Elagolix key intermediate and preparation and application thereof Download PDFInfo
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- CN111072572A CN111072572A CN201910214235.3A CN201910214235A CN111072572A CN 111072572 A CN111072572 A CN 111072572A CN 201910214235 A CN201910214235 A CN 201910214235A CN 111072572 A CN111072572 A CN 111072572A
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- 239000013078 crystal Substances 0.000 title claims abstract description 120
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- HEAUOKZIVMZVQL-VWLOTQADSA-N Elagolix Chemical compound COC1=CC=CC(C=2C(N(C[C@H](NCCCC(O)=O)C=3C=CC=CC=3)C(=O)N(CC=3C(=CC=CC=3F)C(F)(F)F)C=2C)=O)=C1F HEAUOKZIVMZVQL-VWLOTQADSA-N 0.000 title claims abstract description 14
- 229950004823 elagolix Drugs 0.000 title claims abstract description 14
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 79
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 66
- 238000002411 thermogravimetry Methods 0.000 claims description 31
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 27
- 239000003960 organic solvent Substances 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 24
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 23
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical group CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 22
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical group CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 claims description 15
- 238000001228 spectrum Methods 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 12
- 230000004580 weight loss Effects 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229910052739 hydrogen Inorganic materials 0.000 claims description 11
- 150000002576 ketones Chemical group 0.000 claims description 11
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical group CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 10
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 10
- 239000012296 anti-solvent Substances 0.000 claims description 9
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 9
- 229940011051 isopropyl acetate Drugs 0.000 claims description 9
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical group CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 9
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 8
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 150000002825 nitriles Chemical class 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 6
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 238000000746 purification Methods 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 8
- 239000007787 solid Substances 0.000 description 25
- 239000000243 solution Substances 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 10
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 10
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 6
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical class O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 150000003839 salts Chemical group 0.000 description 5
- 239000012453 solvate Substances 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 125000003158 alcohol group Chemical group 0.000 description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 4
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 4
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 4
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- SUSQOBVLVYHIEX-UHFFFAOYSA-N phenylacetonitrile Chemical compound N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 4
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 4
- -1 (R) -2-amino-2-phenyl-ethyl Chemical group 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 description 3
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 3
- 229940035893 uracil Drugs 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000003292 glue Substances 0.000 description 2
- 239000002474 gonadorelin antagonist Substances 0.000 description 2
- 229940121381 gonadotrophin releasing hormone (gnrh) antagonists Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- 238000001757 thermogravimetry curve Methods 0.000 description 2
- 201000009273 Endometriosis Diseases 0.000 description 1
- 102000006771 Gonadotropins Human genes 0.000 description 1
- 108010086677 Gonadotropins Proteins 0.000 description 1
- 102000008238 LHRH Receptors Human genes 0.000 description 1
- 108010021290 LHRH Receptors Proteins 0.000 description 1
- 206010046798 Uterine leiomyoma Diseases 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000002622 gonadotropin Substances 0.000 description 1
- 229940094892 gonadotropins Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a crystal form of hydrogen sulfate of an Elagolix key intermediate, and preparation and application thereof. Specifically, the invention discloses 4 crystal forms of a compound shown as a formula (I), wherein n and X are defined as the specification. The crystal forms have excellent purification effect.
Description
Technical Field
The invention relates to the field of medicines, in particular to a crystal form of bisulfate of an Elagolix key intermediate (uracil derivative) and preparation and application thereof.
Background
Elagolix is an oral GnRH antagonist developed by Abbvie in conjunction with Neurocrine Biosciences. It reduces the level of gonadotropins in blood circulation by inhibiting the pituitary gonadotropin-releasing hormone receptors. The Elagolix as a novel GnRH antagonist has better curative effect on hysteromyoma and endometriosis, and has great market prospect.
WO2005007165 first reports a synthetic method of Elagolix, the synthetic route is shown in scheme one:
route one
WO2009062087 discloses another method for synthesizing Elagolix, the synthetic route of which is shown in scheme two:
route two
The two synthesis methods both pass through a key intermediate compound shown as a formula (II), and the chemical name of the compound is 3- ((R) -2-amino-2-phenyl-ethyl) -5- (2-fluoro-3-methoxy-phenyl) -1- (2-fluoro-6-trifluoromethyl-benzyl) -6-methyl-1H-pyrimidine-2, 4-diketone.
The inventor synthesizes Elagolix according to the methods disclosed in WO2005007165 and WO2009062087, and finds that the compound shown in the formula (II) and the salt form thereof are difficult to crystallize, easy to form oil, gel or precipitate in an amorphous form, so that impurity enrichment and solvent wrapping are easy to cause, the purity of the product is poor, and the product is not beneficial to the next reaction. WO2009062087 discloses example 1 in which a seed crystal is added in the preparation of a solid of the compound of formula II, but no method for the preparation of the seed crystal is disclosed, nor is the solid form of the compound of formula II specifically described. The inventors obtained the compound of formula (ii) either as an oil or in amorphous form according to the method of WO2009062087, example 1, without seeding.
Therefore, there is a need to develop a novel crystal form of the compound of formula (ii) or its salt, which has an excellent and definite purification effect, and a preparation method of the novel crystal form, which is simple, convenient and easy to operate, has low cost, and is suitable for drug development and industrial production.
Disclosure of Invention
The invention aims to provide a novel crystal form of bisulfate of an Elagolix key intermediate (uracil derivative) with excellent purification effect, and preparation and application thereof.
In a first aspect of the invention, there is provided a compound of formula (I):
wherein X is an organic solvent or water, and n is all values between 0 and 3.
In another preferred embodiment, the organic solvent is selected from the group consisting of: alcohols, ketones, esters, ethers, nitriles.
In another preferred embodiment, the alcohols are selected from the group consisting of: methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, n-pentanol, cyclopentanol, cyclohexanol, isobutanol.
In another preferred embodiment, the ketones are selected from the group consisting of: methyl isobutyl ketone, 2-butanone, acetone and N-methylpyrrolidone.
In another preferred embodiment, the esters are selected from the group consisting of: isopropyl acetate, ethyl acetate, methyl acetate, n-propyl acetate, isobutyl acetate, ethyl formate.
In another preferred embodiment, the ethers are selected from the group consisting of: methyl tert-butyl ether, diethyl ether, anisole and isopropyl ether.
In another preferred embodiment, the nitriles are selected from the group consisting of: acetonitrile, phenylacetonitrile, benzonitrile.
In another preferred embodiment, n is all positive numbers between 0 and 3.
In another preferred embodiment, the compound is crystalline.
In another preferred embodiment, the compound is a crystalline form of the compound of formula (I) having an XRPD pattern comprising 3 or more 2 Θ values selected from the group consisting of: 5.5 degrees +/-0.2 degrees, 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees, 23.0 degrees +/-0.2 degrees and 26.1 degrees +/-0.2 degrees.
In another preferred embodiment, the XRPD pattern of the crystalline form comprises 6 or more than 62 Θ values selected from the group consisting of: 5.5 degrees +/-0.2 degrees, 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees, 23.0 degrees +/-0.2 degrees and 26.1 degrees +/-0.2 degrees.
In another preferred embodiment, the XRPD pattern of the crystalline form comprises 9 or more than 9 2 Θ values selected from the group consisting of: 5.5 degrees +/-0.2 degrees, 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 14.5 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees, 21.6 degrees +/-0.2 degrees, 23.0 degrees +/-0.2 degrees, 26.1 degrees +/-0.2 degrees and 26.7 degrees +/-0.2 degrees.
In another preferred embodiment, the compound is a crystalline form of the compound of formula (I), selected from the group consisting of: crystal form AZT-I, crystal form AZT-II, crystal form AZT-III and crystal form AZT-IV,
the crystalline form AZT-I has an XRPD pattern comprising 3 or more than 3 2 Θ values selected from the group consisting of: 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees, 23.0 degrees +/-0.2 degrees and 26.1 degrees +/-0.2 degrees;
the XRPD pattern of crystalline form AZT-II comprises 3 or more than 3 2 Θ values selected from the group consisting of: 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees, 23.0 degrees +/-0.2 degrees and 26.7 degrees +/-0.2 degrees;
the XRPD pattern of crystalline form AZT-III comprises 3 or more than 3 2 Θ values selected from the group consisting of: 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 14.5 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 17.9 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees, 21.6 degrees +/-0.2 degrees, 22.9 degrees +/-0.2 degrees and 26.7 degrees +/-0.2 degrees;
the crystalline form AZT-IV has an XRPD pattern comprising 3 or more than 3 2 Θ values selected from the group consisting of: 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 14.5 degrees +/-0.2 degrees, 15.9 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 17.9 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees, 21.2 degrees +/-0.2 degrees, 22.8 degrees +/-0.2 degrees and 26.7 degrees +/-0.2 degrees.
In another preferred embodiment, the crystalline form AZT-I has an XRPD pattern comprising 6 or more 2 Θ values selected from the group consisting of: 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees, 23.0 degrees +/-0.2 degrees and 26.1 degrees +/-0.2 degrees.
In another preferred embodiment, the XRPD pattern of crystalline form AZT-II comprises 6 or more 2 Θ values selected from the group consisting of: 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees, 23.0 degrees +/-0.2 degrees and 26.7 degrees +/-0.2 degrees.
In another preferred embodiment, the XRPD pattern of crystalline form AZT-III comprises 6 or more 2 Θ values selected from the group consisting of: 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 14.5 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 17.9 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees, 21.6 degrees +/-0.2 degrees, 22.9 degrees +/-0.2 degrees and 26.7 degrees +/-0.2 degrees.
In another preferred embodiment, the crystalline form AZT-IV has an XRPD pattern comprising 6 or more 2 Θ values selected from the group consisting of: 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 14.5 degrees +/-0.2 degrees, 15.9 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 17.9 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees, 21.2 degrees +/-0.2 degrees, 22.8 degrees +/-0.2 degrees and 26.7 degrees +/-0.2 degrees.
In another preferred embodiment, the XRPD pattern of said crystalline form exhibits a deviation in 2 θ of ± 0.5, preferably a deviation of ± 0.3, more preferably a deviation of ± 0.1.
In another preferred embodiment, the crystalline form AZT-I has an XRPD pattern substantially as shown in figure 1.
In another preferred embodiment, the crystalline form AZT-II has an XRPD pattern substantially as shown in figure 5.
In another preferred embodiment, the crystalline form AZT-III has an XRPD pattern substantially as shown in figure 7.
In another preferred embodiment, the crystalline form AZT-IV has an XRPD pattern substantially as shown in figure 11.
In another preferred embodiment, in the crystalline form AZT-I, X is n-pentanol;
in the crystal form AZT-II, X is isobutanol;
in the crystal form AZT-III, X is isopropyl acetate;
in the crystal form AZT-IV, X is methyl isobutyl ketone.
In another preferred embodiment, the crystalline form has one or more characteristics selected from the group consisting of:
1) hydrogen spectrum of the crystal form AZT-I (1H NMR) substantially as shown in figure 2;
2) the TGA graph of the crystal form AZT-I has a weight loss of about 11.0% at 25-150 ℃;
3) a thermogravimetric analysis (TGA) curve of said crystalline form AZT-I substantially as shown in figure 3;
4) a DSC chart of the crystal form AZT-I has an endothermic peak at 110-148 ℃;
5) the Differential Scanning Calorimetry (DSC) curve of the crystal form AZT-I is basically shown in figure 4;
6) hydrogen spectrum of the crystal form AZT-II (1H NMR) substantially as shown in figure 6;
7) hydrogen spectrum of the crystal form AZT-III (1H NMR) substantially as shown in figure 8;
8) the TGA graph of the crystal form AZT-III has a weight loss of about 6.4% at 25-150 ℃;
9) a thermogravimetric analysis (TGA) curve of said crystalline form AZT-III is substantially as shown in figure 9;
10) a DSC picture of the crystal form AZT-III has an endothermic peak at 121-145 ℃;
11) the Differential Scanning Calorimetry (DSC) curve of the AZT-III crystal form is basically shown in figure 10;
12) hydrogen spectrum of the crystalline form AZT-IV (1H NMR) substantially as shown in figure 12;
13) the TGA graph of the crystal form AZT-IV has a weight loss of about 7.1% at 25-150 ℃;
14) a thermogravimetric analysis (TGA) curve of said crystalline form AZT-IV is substantially as shown in figure 13;
15) a DSC picture of the crystal form AZT-IV has an endothermic peak at 108-144 ℃;
16) the Differential Scanning Calorimetry (DSC) curve of the AZT-IV crystal form is basically shown in figure 14.
In a second aspect of the present invention, there is provided a method for preparing a compound according to the first aspect of the present invention, comprising the steps of:
1) adding a compound shown in a formula (II) into a first organic solvent to obtain a first solution;
2) adding concentrated sulfuric acid into an anti-solvent to obtain a second solution;
3) adding the second solution to the first solution under stirring, and crystallizing to obtain the compound of the first aspect of the invention.
In another preferred embodiment, the first organic solvent is an alcohol solvent; and/or
The antisolvent is selected from the group consisting of: water, n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, or combinations thereof.
In another preferred embodiment, the alcoholic solvent is selected from the group consisting of: methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol, n-pentanol, cyclopentanol, cyclohexanol, isobutanol, or a combination thereof.
In another preferred embodiment, step 3) is carried out at 10-35 ℃, preferably 15-25 ℃.
In another preferred embodiment, the method further comprises the following step after the step 3): drying the product obtained in step 3) at a first temperature for a first time.
In another preferred embodiment, the first temperature is 25-70 ℃, preferably 35-60 ℃.
In another preferred embodiment, the first time is 1-20h, preferably 5-15 h.
In another preferred embodiment, the product obtained by the method is selected from the group consisting of: crystal form AZT-I and crystal form AZT-II.
In a third aspect of the present invention, there is provided a method for preparing the compound of the first aspect of the present invention, comprising the steps of:
i) suspending the crystal form AZT-I in a second organic solvent or water, and stirring to obtain the compound of the first aspect of the invention.
In another preferred embodiment, the second organic solvent is a ketone, ester, ether, or nitrile solvent.
In another preferred embodiment, the ketones are selected from the group consisting of: methyl isobutyl ketone, 2-butanone, acetone and N-methylpyrrolidone.
In another preferred embodiment, the ketone is methyl isobutyl ketone and a solvent selected from the group consisting of: 2-butanone, acetone and N-methylpyrrolidone.
In another preferred embodiment, the esters are selected from the group consisting of: isopropyl acetate, ethyl acetate, methyl acetate, n-propyl acetate, isobutyl acetate, ethyl formate.
In another preferred embodiment, the ethers are selected from the group consisting of: methyl tert-butyl ether, diethyl ether, anisole and isopropyl ether.
In another preferred embodiment, the nitriles are selected from the group consisting of: acetonitrile, phenylacetonitrile, benzonitrile.
In another preferred embodiment, in step i), the stirring is carried out at 0-15 ℃, preferably 2-10 ℃.
In another preferred embodiment, in step i), the stirring time for stirring is 0.1 to 10 days, preferably 0.3 to 8 days, more preferably 0.5 to 6 days.
In another preferred embodiment, the product obtained by the method is selected from the group consisting of: crystal form AZT-III and crystal form AZT-IV.
In a fourth aspect of the invention, there is provided the use of a compound according to the first aspect of the invention, characterized in that it is used for the preparation of Elagolix.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Drawings
FIG. 1 is an XRPD pattern for crystalline AZT-I obtained in example 1.
FIG. 2 shows the crystalline form AZT-I obtained in example 11H NMR spectrum.
FIG. 3 is a TGA trace of crystalline form AZT-I obtained in example 1.
FIG. 4 is a DSC of AZT-I crystalline form obtained in example 1.
FIG. 5 is an XRPD pattern of AZT-II crystalline form obtained in example 2.
FIG. 6 shows the crystalline form AZT-II obtained in example 21H NMR spectrum.
FIG. 7 is an XRPD pattern for crystalline AZT-III obtained in example 3.
FIG. 8 shows the crystalline form AZT-III obtained in example 31H NMR spectrum.
FIG. 9 is a TGA profile of crystalline form AZT-III obtained in example 3.
FIG. 10 is a DSC of AZT-III crystal form obtained in example 3.
FIG. 11 is an XRPD pattern for AZT-IV form obtained in example 4.
FIG. 12 shows the crystalline form AZT-IV obtained in example 41H NMR spectrum.
FIG. 13 is a TGA trace of AZT-IV form obtained in example 4.
FIG. 14 is a DSC of AZT-IV in crystalline form obtained in example 4.
FIG. 15 is an amorphous XRPD pattern of the bisulfate salt of the compound of formula (II) obtained in example 5.
Detailed Description
The present inventors have conducted extensive and intensive studies for a long time and have unexpectedly prepared 4 crystal forms of bisulfate salts of key intermediates (uracil derivatives) of Elagolix having excellent purification effects. On this basis, the inventors have completed the present invention.
Compounds of formula (I) and processes for their preparation
A compound of formula (I):
wherein X is an organic solvent or water and n is all numbers between 0 and 3.
Furthermore, the organic solvent is alcohols, ketones, esters, ethers or nitriles.
Further, the compound is present in a crystalline form.
Further, the XRPD pattern of said crystalline form comprises 3 or more than 3 2 Θ values selected from the group consisting of: 5.5 degrees +/-0.2 degrees, 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees and 17.0 degrees +/-0.2 degrees.
Further, the XRPD pattern of said crystalline form comprises 6 or more 2 Θ values selected from the group consisting of: 5.5 degrees +/-0.2 degrees, 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees and 23.0 degrees +/-0.2 degrees.
Further, the crystalline form AZT-I has an XRPD pattern comprising 6 or more than 62 Θ values selected from the group consisting of: 5.5 degrees +/-0.2 degrees, 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 14.5 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees, 21.6 degrees +/-0.2 degrees, 23.0 degrees +/-0.2 degrees, 26.1 degrees +/-0.2 degrees, 26.7 degrees +/-0.2 degrees
Further, the crystalline form has an XRPD pattern substantially as shown in figure 1;
further, the preparation method of the crystal form comprises the following steps:
1) adding a compound shown in a formula (II) into an organic solvent to obtain a solution of the compound shown in the formula (II);
2) adding concentrated sulfuric acid into an anti-solvent to obtain a diluted sulfuric acid solution;
3) adding the sulfuric acid solution into a solution of a compound shown in a formula (II) under stirring, and crystallizing to obtain the crystal form; wherein the organic solvent is an alcohol solvent, and the alcohol solvent is n-pentanol and a solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, cyclopentanol, cyclohexanol, or a combination thereof.
Further, the preparation method of the crystal form comprises the following steps: suspending the compound shown in the formula (I) in an organic solvent or water, and stirring to obtain the crystal form; wherein the organic solvent is ketone, ester, ether or nitrile solvent.
Further, the ketone solvent is methyl isobutyl ketone and a solvent selected from the group consisting of 2-butanone, acetone, N-methylpyrrolidone, or a combination thereof.
Further, the ester solvent is isopropyl acetate and a solvent selected from the group consisting of ethyl acetate, methyl acetate, n-propyl acetate, isobutyl acetate, ethyl formate, or a combination thereof.
Further, the ether solvent is methyl tert-butyl ether and a solvent selected from the group consisting of ethyl ether, anisole, isopropyl ether, and combinations thereof.
Further, the nitrile solvent is acetonitrile.
Crystal form AZT-I and preparation method thereof
The X of the compound of formula (I) provided by the invention is n-pentanol.
Furthermore, the compounds are in the form of crystalline AZT-I.
Furthermore, the X-ray powder diffraction pattern of the crystal form AZT-I has characteristic peaks at 2 theta values of 5.5 degrees +/-0.2 degrees, 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees and 17.0 degrees +/-0.2 degrees.
Furthermore, the X-ray powder diffraction pattern of the crystal form AZT-I has characteristic peaks at 2 theta values of 5.5 degrees +/-0.2 degrees, 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees and 23.0 degrees +/-0.2 degrees.
Furthermore, the X-ray powder diffraction pattern of the crystal form AZT-I has characteristic peaks at 2 theta values of 5.5 +/-0.2 degrees, 6.4 +/-0.2 degrees, 7.6 +/-0.2 degrees, 9.2 +/-0.2 degrees, 12.9 +/-0.2 degrees, 14.5 +/-0.2 degrees, 16.3 +/-0.2 degrees, 17.0 +/-0.2 degrees, 19.1 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.6 +/-0.2 degrees, 23.0 +/-0.2 degrees, 26.1 +/-0.2 degrees and 26.7 +/-0.2 degrees.
Furthermore, the crystalline form AZT-I has an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 1.
Furthermore, there is a variation of + -0.5, preferably a variation of + -0.3, more preferably a variation of + -0.1 in the XRPD pattern of said crystalline form AZT-I.
Furthermore, the hydrogen spectrum of the crystal form AZT-I (A)1H NMR) is substantially as shown in figure 2.
Furthermore, a thermogravimetric analysis (TGA) curve of the crystal form AZT-I is basically shown in figure 3, and the weight loss is about 11.0% at 25-150 ℃.
Furthermore, a Differential Scanning Calorimetry (DSC) curve of the crystal form AZT-I is basically shown in figure 4, and an endothermic peak is formed at 110-148 ℃.
In another aspect, the invention provides a preparation method of a crystal form AZT-I, which is characterized by comprising the following steps:
1) adding a compound shown in a formula (II) into an organic solvent to obtain a solution of the compound shown in the formula (II);
2) adding an anti-solvent into concentrated sulfuric acid to obtain a diluted sulfuric acid solution;
3) under the condition of stirring, dripping the sulfuric acid solution into a solution of a compound shown in a formula (II), and crystallizing to obtain the crystal form AZT-I; wherein the organic solvent is an alcohol solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol or a combination thereof.
Still further, the antisolvent is selected from the group consisting of: water, alkanes, or combinations thereof.
Further, the alkanes include, but are not limited to, the following: n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, or combinations thereof.
Furthermore, the molar ratio of the concentrated sulfuric acid to the compound of formula (II) is 1: 0.8-1: 1.2, preferably 1: 1.0-1: 1.1.
Further, the stirring is performed at 5 to 40 ℃, preferably 10 to 30 ℃, more preferably 15 to 28 ℃.
Furthermore, the stirring time is 1 to 7 days, preferably 1 day.
Crystal form AZT-II and preparation method thereof
The X of the compound of formula (I) provided by the invention is isobutanol.
Furthermore, the compound exists in a form of a crystal form AZT-II.
Furthermore, the X-ray powder diffraction pattern of the crystal form AZT-II has characteristic peaks at 2 theta values of 5.5 degrees +/-0.2 degrees, 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees and 17.0 degrees +/-0.2 degrees.
Furthermore, the X-ray powder diffraction pattern of the crystal form AZT-II has characteristic peaks at 2 theta values of 5.5 degrees +/-0.2 degrees, 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees and 23.0 degrees +/-0.2 degrees.
Furthermore, the X-ray powder diffraction pattern of the crystal form AZT-II has characteristic peaks at 2 theta values of 5.5 +/-0.2 degrees, 6.4 +/-0.2 degrees, 7.6 +/-0.2 degrees, 9.2 +/-0.2 degrees, 12.9 +/-0.2 degrees, 13.4 +/-0.2 degrees, 14.5 +/-0.2 degrees, 16.3 +/-0.2 degrees, 16.6 +/-0.2 degrees, 17.0 +/-0.2 degrees, 19.1 +/-0.2 degrees, 20.3 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.6 +/-0.2 degrees, 22.3 +/-0.2 degrees, 23.0 +/-0.2 degrees, 26.1 +/-0.2 degrees, 26.7 +/-0.2 degrees and 27.0 +/-0.2 degrees.
Furthermore, the crystalline form AZT-II has an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 5.
Furthermore, there is a deviation of ± 0.5, preferably a deviation of ± 0.3, more preferably a deviation of ± 0.1, in the XRPD pattern of said crystalline form AZT-ii.
Furthermore, the hydrogen spectrum of the crystal form AZT-II (1H NMR) is substantially as shown in figure 6.
In another aspect of the invention, a preparation method of the crystal form AZT-II is provided, which comprises the following steps:
1) dissolving a compound shown in a formula (II) in an organic solvent to obtain a solution of the compound shown in the formula (II);
2) adding concentrated sulfuric acid into an anti-solvent to obtain a diluted sulfuric acid solution;
3) adding the sulfuric acid solution into a solution of a compound shown in a formula (II) under the condition of stirring, and crystallizing to obtain the crystal form AZT-II; wherein the organic solvent is an alcohol solvent, and the alcohol solvent is isobutanol and a solvent selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, n-pentanol, cyclopentanol, cyclohexanol or a combination thereof.
Still further, the antisolvent is selected from the group consisting of: water, alkanes, or combinations thereof.
Further, the alkanes include, but are not limited to, the following: n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane.
Furthermore, the molar ratio of the concentrated sulfuric acid to the compound of formula (II) is 1: 0.8-1: 1.2, preferably 1: 1.0-1: 1.1.
Further, the stirring is carried out at 5-40 ℃, preferably 10-30 ℃, more preferably 15-28 ℃.
Further, the stirring time is 1 to 7 days, preferably 1 day.
Crystal form AZT-III and preparation method thereof
The X of the compound of formula (I) provided by the invention is isopropyl acetate.
Furthermore, the compound exists in a form of a crystal form AZT-III.
Furthermore, the X-ray powder diffraction pattern of the crystal form AZT-III has characteristic peaks at 2 theta values of 5.5 degrees +/-0.2 degrees, 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees and 17.0 degrees +/-0.2 degrees.
Furthermore, the crystal form AZT-III of the crystal form AZT-III has characteristic peaks in an X-ray powder diffraction pattern at 2 theta values of 5.5 degrees +/-0.2 degrees, 6.4 +/-0.2 degrees, 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 14.2 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 18.8 degrees +/-0.2 degrees, 21.2 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees and 23.0 degrees +/-0.2 degrees.
Furthermore, the X-ray powder diffraction pattern of the crystal form AZT-III has the characteristic that the peak at 2 theta values of 5.5 +/-0.2 degrees, 6.4 +/-0.2 degrees, 7.6 +/-0.2 degrees, 9.2 +/-0.2 degrees, 12.9 +/-0.2 degrees, 13.1 +/-0.2 degrees, 14.5 +/-0.2 degrees, 15.5 +/-0.2 degrees, 16.3 +/-0.2 degrees, 17.0 +/-0.2 degrees, 17.9 +/-0.2 degrees, 19.1 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.6 +/-0.2 degrees, 22.9 +/-0.2 degrees, 23.9 +/-0.2 degrees, 25.7 +/-0.2 degrees, 26.2 +/-0.2 degrees, 26.7 +/-0.2 degrees, 27.8 +/-0.2 degrees, 28.3 +/-0.2 degrees, 29.4 +/-0.2 degrees.
Furthermore, the crystalline form AZT-iii has an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 7.
Furthermore, there is a deviation of ± 0.5, preferably a deviation of ± 0.3, more preferably a deviation of ± 0.1, in the XRPD pattern of said crystalline form AZT-iii.
Furthermore, the crystal form AZHydrogen spectrum of T-III (1H NMR) is substantially as shown in figure 8.
Furthermore, a thermogravimetric analysis (TGA) curve of the crystal form AZT-III is basically shown in figure 9, and the weight loss is about 6.4% at 25-150 ℃.
Furthermore, a Differential Scanning Calorimetry (DSC) curve of the crystal form AZT-III is basically shown in figure 10, and an endothermic peak is formed at 121-145 ℃.
The invention also provides a preparation method of the crystal form AZT-III, which comprises the following steps: suspending crystal form AZT-I of a compound shown in a formula (I) in an organic solvent, and stirring to obtain crystal form AZT-III; wherein the organic solvent is an ester solvent; the ester solvent is isopropyl acetate and a solvent selected from the following group: ethyl acetate, n-propyl acetate, isobutyl acetate, or combinations thereof.
Furthermore, the stirring time is 1 to 7 days, preferably 4 days.
Further, the stirring is performed at 5 to 40 ℃, preferably 10 to 30 ℃, more preferably 15 to 28 ℃.
Crystal form AZT-IV and preparation method thereof
The X of the compound of formula (I) provided by the invention is methyl isobutyl ketone.
Furthermore, the compound exists in a form of AZT-IV crystal form.
Furthermore, the X-ray powder diffraction pattern of the crystal form AZT-IV has characteristic peaks at 2 theta values of 5.5 degrees +/-0.2 degrees, 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees and 9.2 degrees +/-0.2 degrees.
Furthermore, the X-ray powder diffraction pattern of the crystal form AZT-IV has characteristic peaks at 2 theta values of 5.5 degrees +/-0.2 degrees, 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 14.1 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees and 23.0 degrees +/-0.2 degrees.
Furthermore, the X-ray powder diffraction pattern of the crystal form AZT-IV has the characteristic that the peak angles of the 2 theta values are 5.5 +/-0.2 degrees, 6.4 +/-0.2 degrees, 7.6 +/-0.2 degrees, 9.2 +/-0.2 degrees, 12.9 +/-0.2 degrees, 14.5 +/-0.2 degrees, 15.5 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.3 +/-0.2 degrees, 17.0 +/-0.2 degrees, 17.9 +/-0.2 degrees, 19.1 +/-0.2 degrees, 19.7 +/-0.2 degrees, 20.6 +/-0.2 degrees, 21.2 +/-0.2 degrees, 22.8 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.7 +/-0.2 degrees, 25.6 +/-0.2 degrees, 26.1 +/-0.2 degrees, 26.7 +/-0.2 degrees, 27.8 +/-0.0.2 degrees, 23.0 degrees, 31.5 +/-2 degrees.
Further, the crystalline form AZT-iv has an X-ray powder diffraction (XRPD) pattern substantially as shown in figure 11.
Furthermore, there is a variation of ± 0.5, preferably a variation of ± 0.3, more preferably a variation of ± 0.1 in the XRPD pattern of crystalline form AZT-iv.
Furthermore, the hydrogen spectrum of the crystal form AZT-IV (1H NMR) is substantially as shown in figure 12.
Furthermore, a thermogravimetric analysis (TGA) curve of the crystal form AZT-IV is basically shown in figure 13, and the weight loss is about 7.1% at 25-150 ℃.
Furthermore, a Differential Scanning Calorimetry (DSC) curve of the crystal form AZT-IV is basically shown in figure 14, and an endothermic peak is formed at 108-144 ℃.
The invention also provides a preparation method of the crystal form AZT-IV, which comprises the following steps: suspending crystal form AZT-I of a compound shown in a formula (I) in an organic solvent, and stirring to obtain crystal form AZT-IV; wherein the organic solvent is a ketone solvent, and the ketone solvent is methyl isobutyl ketone and a solvent selected from the following group: acetone, 2-butanone, N-methylpyrrolidone, or a combination thereof.
Furthermore, the stirring time is 1 to 7 days, preferably 4 days.
Further, the stirring is performed at 5 to 40 ℃, preferably 10 to 30 ℃, more preferably 15 to 28 ℃.
Applications of
The compound of formula (I) provided by the invention can be used for preparing a compound of formula (II) or other salts, solvates and the like, and the preparation method can be according to a conventional method.
The compound of formula (I) provided by the invention can be used for preparing Elagolix or salts thereof, and the preparation method can be according to the conventional method.
The crystal form has excellent purification effect, can improve the phenomena of oil forming, glue forming and amorphous formation in the synthesis process, and improves the purity of the product.
Compared with the prior art, the invention has the following main advantages:
(1) the crystal form has excellent purification effect;
(2) the crystal form can improve the phenomena of oil forming, glue forming and amorphous formation in the synthesis process, reduce solvent wrapping, facilitate post-treatment such as drying and the like, and is beneficial to the next reaction;
(3) the preparation method of the crystal form is simple and easy to implement, mild in operation condition and low in cost, and is suitable for being applied to medicine research and development and industrial production. From the purification aspect, the method is more suitable for mass production than the purification method of column chromatography.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
The solvents used in the present invention were all analytically pure and had a water content of about 0.1%. The compound of formula (II) used as starting material in the examples was prepared according to patent WO2009062087 and was obtained by column chromatography purification, unless otherwise specified, the starting materials used in the examples were from different batches. All test methods of the invention are general methods, and the test parameters are as follows:
XRPD pattern determination method:
x-ray powder diffraction instrument: bruker D2Phaser X-ray powder diffractometer; radiation source Cu
Generator (Generator) kv: 30 kv; generator (Generator) mA: 10 mA; initial 2 θ: 2.000 °, scan range: 2.0000-35.000 degrees, a scanning step size of 0.02 degrees and a scanning speed of 0.1 s/step.
TGA profile determination method:
thermogravimetric analysis (TGA) instrument: TGA55 from TA USA; temperature range: 20-300 ℃; heating rate: 10 ℃/min; nitrogen flow rate: 40 mL/min.
DSC chart measurement method:
differential Scanning Calorimetry (DSC) instrument: TA Q2000 by TA, USA; temperature range: 25-300 ℃, heating rate: 10 ℃/min, nitrogen flow rate: 50 mL/min.
4. Chemical purity determination method (HPLC):
the instrument comprises the following steps: agilent 1260
A chromatographic column: inertsil ODS-3V 4.6MM 250MM, 5 μm
Mobile phase A: acetonitrile
Mobile phase B: phosphate buffer solution (1.36 g potassium dihydrogen phosphate is weighed and dissolved in 1L water, pH is adjusted to 3.0 with phosphoric acid)
Flow rate: 1.0mL/min
Detection wavelength: 210nm
Column temperature: 30 deg.C
Sample concentration: 0.5mg/mL
Diluent agent: acetonitrile-water (50:50)
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 20 | 80 |
| 20 | 70 | 30 |
| 40 | 70 | 30 |
| 41 | 20 | 80 |
| 50 | 20 | 80 |
Example 1: preparation of crystal form AZT-I
47.0mg of the compound of formula (II) are weighed out and dissolved in 0.4mL of n-pentanol. 0.2mL of cyclohexane was added to 5.0. mu.L of concentrated sulfuric acid (95-98%). The diluted sulfuric acid solution was slowly added dropwise to a solution of the compound of formula (II) in n-pentanol at 20 ℃ with stirring until a solid precipitated and dried at 50 ℃ for 12 h. The obtained solid is a crystal form AZT-I of the compound shown as the formula (I) and is an n-pentanol solvate.
The resulting solid was subjected to XRPD testing, the X-ray powder diffraction pattern of which is shown in figure 1; subjecting the obtained solid to1HNMR test, the spectrogram is shown in figure 2; TGA testing was performed on the resulting solid, the figure of which is shown in figure 3; the resulting solid was subjected to DSC measurement, and the chart is shown in FIG. 4.
As can be seen from fig. 1: the main diffraction peaks and relative intensities of the crystalline form AZT-I are shown in Table 1.
TABLE 1
| 2θ(°) | Relative Intensity |
| 5.5° | 4.6％ |
| 6.4° | 10.3％ |
| 7.6° | 100.0％ |
| 9.2° | 5.9％ |
| 12.9° | 8.2％ |
| 14.5° | 3.4％ |
| 15.3° | 4.7％ |
| 16.3° | 3.9％ |
| 17.0° | 5.3％ |
| 19.1° | 4.4％ |
| 20.6° | 5.0％ |
| 21.6° | 4.8％ |
| 22.0° | 3.4％ |
| 23.0° | 14.9％ |
| 26.1° | 7.3％ |
| 26.7° | 4.1％ |
As can be seen from FIG. 3, the crystal form AZT-I has a weight loss of about 11.0% at 25-150 ℃.
As can be seen from FIG. 4, the crystal form AZT-I has an endothermic peak at 110-148 ℃.
Example 2: preparation of crystal form AZT-II
49.0mg of the compound of formula (II) was weighed out and dissolved in 0.4mL of isobutanol. 0.2mL of cyclohexane was added to 5.0. mu.L of concentrated sulfuric acid (95-98%). Slowly dripping the diluted sulfuric acid solution into the isobutanol solution of the compound shown in the formula (II) at the temperature of 20 ℃, and stirring until solids are separated out. The obtained solid is a crystal form AZT-II of the compound shown as the formula (I) and is an isobutanol solvate.
The resulting solid was subjected to XRPD testing, and its X-ray powder diffraction pattern is shown in fig. 5; subjecting the obtained solid to1The HNMR test shows the spectrogram in FIG. 6.
As can be seen from fig. 5: the main diffraction peaks and relative intensities of the crystal form AZT-II are shown in Table 2.
TABLE 2
| 2θ(°) | Relative Intensity |
| 5.5° | 13.5％ |
| 6.4° | 8.4％ |
| 7.6° | 100.0％ |
| 9.2° | 16.1％ |
| 12.9 | 3.4％ |
| 13.4° | 9.4％ |
| 14.5° | 7.7％ |
| 16.3° | 15.4％ |
| 16.6° | 46.5％ |
| 17.0° | 31.9％ |
| 20.6° | 14.7％ |
| 21.6° | 12.5％ |
| 22.3° | 9.2％ |
| 23.0° | 22.8％ |
| 26.1° | 5.0％ |
| 26.7° | 18.8％ |
| 27.0° | 10.0％ |
Example 3: preparation of crystalline AZT-III
20.0mg of AZT-I crystalline form of the compound of formula (I) prepared in example 1 (prepared according to the preparation process of example 1) are weighed out and suspended in 0.5mL of isopropyl acetate. Stirred at 5 ℃ for 4 days. The obtained solid is a crystal form AZT-III of the compound shown as the formula (I) and is an isopropyl acetate solvate.
The resulting solid was subjected to XRPD testing, and its X-ray powder diffraction pattern is shown in fig. 7; subjecting the obtained solid to1HNMR test, the spectrogram is shown in figure 8; TGA testing was performed on the resulting solid, the figure of which is shown in figure 9; the resulting solid was subjected to DSC measurement, and the chart is shown in FIG. 10.
As can be seen from fig. 7: the main diffraction peaks and relative intensities of crystalline form AZT-III are shown in Table 3.
TABLE 3
As can be seen from FIG. 9, the crystal form AZT-III has a weight loss of about 6.4% at 25-150 ℃.
As can be seen from FIG. 10, the crystal form AZT-III has an endothermic peak at 121-145 ℃.
Example 4: preparation of crystal form AZT-IV
20.0mg of AZT-I crystalline form of the compound of formula (I) prepared in example 1 (prepared according to the preparation process of example 1) are weighed out and suspended in 0.5mL of methyl isobutyl ketone. Stirred at 5 ℃ for 4 days. The obtained solid is a crystal form AZT-IV of the compound shown as the formula (I), and is a methyl isobutyl ketone solvate.
The resulting solid was subjected to XRPD testing, and its X-ray powder diffraction pattern is shown in fig. 11; subjecting the obtained solid to1H NMR measurement, the spectrum of which is shown in fig. 12; TGA testing was performed on the resulting solid, the figure of which is shown in figure 13; the resulting solid was subjected to DSC measurement, and the chart is shown in FIG. 14.
As can be seen from fig. 11: the main diffraction peaks and relative intensities of the crystalline form AZT-IV are shown in Table 4.
TABLE 4
| 2θ(°) | Relative Intensity |
| 5.5° | 9.5％ |
| 6.4° | 6.2％ |
| 7.6° | 100.0％ |
| 9.2° | 20.8％ |
| 12.9° | 10.5％ |
| 14.5° | 27.2％ |
| 15.5° | 16.6％ |
| 15.9° | 36.0％ |
| 16.3° | 53.2％ |
| 17.0° | 65.1％ |
| 17.9° | 46.3％ |
| 19.1° | 44.2％ |
| 19.7° | 11.6％ |
| 20.6° | 6.5％ |
| 21.2° | 35.8％ |
| 22.8° | 22.3％ |
| 23.0° | 9.2％ |
| 23.7° | 6.6％ |
| 25.6° | 14.9％ |
| 26.1° | 11.4％ |
| 26.7° | 22.5％ |
| 27.8° | 11.6％ |
| 28.1° | 12.1％ |
| 31.5° | 9.4％ |
As can be seen from FIG. 13, the crystal form AZT-IV has a weight loss of about 7.1% at 25-150 ℃.
As can be seen from FIG. 14, the crystal form AZT-IV has an endothermic peak at 108-144 ℃.
Example 5: amorphous preparation of the bisulfate salt of the compound of formula (II)
25.0mg of the compound of formula (II) are weighed out and dissolved in 0.2mL of dimethyl sulfoxide. 2.5 mul of concentrated sulfuric acid (95-98%) is added to 0.2mL of dimethyl sulfoxide. The diluted sulfuric acid solution was slowly dropped into the dimethylsulfoxide solution of the compound of formula (II) at 20 ℃ and then 0.4mL of water was added thereto, followed by stirring until a solid precipitated. The solid obtained is amorphous form of the hydrosulphate salt of the compound of formula (II).
The resulting solid was subjected to XRPD testing and its X-ray powder diffraction pattern is shown in fig. 15.
Example 6: comparison of chemical purities of crystalline forms AZT-I, AZT-II, AZT-III, AZT-IV and amorphous forms
The samples were analyzed by HPLC for their chromatographic purity in crystalline form AZT-I, prepared according to the method of example 1, crystalline form AZT-II, prepared according to example 2, crystalline form AZT-III, prepared according to example 3, crystalline form AZT-IV, prepared according to example 4 and amorphous form prepared according to example 5, the results being shown in Table 5.
TABLE 5
| Compound (I) | Chemical purity of the starting Material | Chemical purity of the product | Percentage of increase |
| AZT-Ⅰ | 97.17％ | 99.27％ | 2.10 |
| AZT-Ⅰ | 75.00％ | 90.87％ | 15.87 |
| AZT-Ⅱ | 97.17％ | 98.34％ | 1.17 |
| AZT-Ⅲ | 84.00％ | 87.75％ | 3.75 |
| AZT-Ⅳ | 84.00％ | 93.07％ | 9.07 |
| Amorphous form | 97.17％ | 96.53％ | -0.64 |
Wherein "starting material chemical purity" refers to the purity of the starting material from which the compound is prepared, either crystalline or amorphous; by "product chemical purity" is meant the crystalline or amorphous purity obtained in the examples.
As shown in Table 5, compared with the amorphous form, the crystal forms AZT-I, AZT-II, AZT-III and AZT-IV have better impurity removal and purification effects.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. A compound of formula (I):
wherein X is an organic solvent or water, and n is all values between 0 and 3.
2. The compound of claim 1, wherein the compound is a crystalline form of the compound of formula (I) having an XRPD pattern comprising 3 or more 2 Θ values selected from the group consisting of: 5.5 degrees +/-0.2 degrees, 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees, 23.0 degrees +/-0.2 degrees and 26.1 degrees +/-0.2 degrees.
3. The compound of claim 1, wherein the compound is a crystalline form of the compound of formula (I) selected from the group consisting of: crystal form AZT-I, crystal form AZT-II, crystal form AZT-III and crystal form AZT-IV,
the crystalline form AZT-I has an XRPD pattern comprising 3 or more than 3 2 Θ values selected from the group consisting of: 6.4 degrees +/-0.2 degrees, 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 12.9 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees, 23.0 degrees +/-0.2 degrees and 26.1 degrees +/-0.2 degrees;
the XRPD pattern of crystalline form AZT-II comprises 3 or more than 3 2 Θ values selected from the group consisting of: 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 16.6 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 20.6 degrees +/-0.2 degrees, 23.0 degrees +/-0.2 degrees and 26.7 degrees +/-0.2 degrees;
the XRPD pattern of crystalline form AZT-III comprises 3 or more than 3 2 Θ values selected from the group consisting of: 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 14.5 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 17.9 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees, 21.6 degrees +/-0.2 degrees, 22.9 degrees +/-0.2 degrees and 26.7 degrees +/-0.2 degrees;
the crystalline form AZT-IV has an XRPD pattern comprising 3 or more than 3 2 Θ values selected from the group consisting of: 7.6 degrees +/-0.2 degrees, 9.2 degrees +/-0.2 degrees, 14.5 degrees +/-0.2 degrees, 15.9 degrees +/-0.2 degrees, 16.3 degrees +/-0.2 degrees, 17.0 degrees +/-0.2 degrees, 17.9 degrees +/-0.2 degrees, 19.1 degrees +/-0.2 degrees, 21.2 degrees +/-0.2 degrees, 22.8 degrees +/-0.2 degrees and 26.7 degrees +/-0.2 degrees.
4. A compound according to claim 3,
in the crystal form AZT-I, X is n-amyl alcohol;
in the crystal form AZT-II, X is isobutanol;
in the crystal form AZT-III, X is isopropyl acetate;
in the crystal form AZT-IV, X is methyl isobutyl ketone.
5. The compound of claim 3, wherein the crystalline form has one or more characteristics selected from the group consisting of:
1) hydrogen spectrum of the crystal form AZT-I (1H NMR) substantially as shown in figure 2;
2) the TGA graph of the crystal form AZT-I has a weight loss of about 11.0% at 25-150 ℃;
3) a thermogravimetric analysis (TGA) curve of said crystalline form AZT-I substantially as shown in figure 3;
4) a DSC chart of the crystal form AZT-I has an endothermic peak at 110-148 ℃;
5) the Differential Scanning Calorimetry (DSC) curve of the crystal form AZT-I is basically shown in figure 4;
6) hydrogen spectrum of the crystal form AZT-II (1H NMR) substantially as shown in figure 6;
7) hydrogen spectrum of the crystal form AZT-III (1H NMR) substantially as shown in figure 8;
8) the TGA graph of the crystal form AZT-III has a weight loss of about 6.4% at 25-150 ℃;
9) a thermogravimetric analysis (TGA) curve of said crystalline form AZT-III is substantially as shown in figure 9;
10) a DSC picture of the crystal form AZT-III has an endothermic peak at 121-145 ℃;
11) the Differential Scanning Calorimetry (DSC) curve of the AZT-III crystal form is basically shown in figure 10;
12) hydrogen spectrum of the crystalline form AZT-IV (1H NMR) substantially as shown in figure 12;
13) the TGA graph of the crystal form AZT-IV has a weight loss of about 7.1% at 25-150 ℃;
14) a thermogravimetric analysis (TGA) curve of said crystalline form AZT-IV is substantially as shown in figure 13;
15) a DSC picture of the crystal form AZT-IV has an endothermic peak at 108-144 ℃;
16) the Differential Scanning Calorimetry (DSC) curve of the AZT-IV crystal form is basically shown in figure 14.
6. A process for the preparation of a compound according to claim 1, comprising the steps of:
1) adding a compound shown in a formula (II) into a first organic solvent to obtain a first solution;
2) adding concentrated sulfuric acid into an anti-solvent to obtain a second solution;
3) adding the second solution to the first solution under stirring, and crystallizing to obtain the compound of claim 1.
7. The method of claim 6, wherein the first organic solvent is an alcoholic solvent; and/or
The antisolvent is selected from the group consisting of: water, n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, or combinations thereof.
8. A process for the preparation of a compound according to claim 1, comprising the steps of:
i) suspending form AZT-I in a second organic solvent or water and stirring to obtain the compound of claim 1.
9. The method of claim 8, wherein the second organic solvent is a ketone, ester, ether, or nitrile solvent.
10. Use of a compound according to claim 1 for the preparation of Elagolix.
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| CN111763176A (en) * | 2020-07-10 | 2020-10-13 | 常州制药厂有限公司 | GnRH receptor antagonist key intermediate and preparation method thereof |
| WO2021009034A1 (en) * | 2019-07-12 | 2021-01-21 | Moehs Iberica, S.L. | 3-[2(r)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1h-pyrimidine-2,4(1h,3h)-dione hydrochloride salt (i) in solid form, process for preparing same, and use thereof in the synthesis of elagolix |
| CN114835650A (en) * | 2021-02-01 | 2022-08-02 | 上海漠澳浩医药科技有限公司 | Salt and crystal of oxalagogri intermediate, and preparation method and application thereof |
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| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
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| WO2009062087A1 (en) * | 2007-11-07 | 2009-05-14 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021009034A1 (en) * | 2019-07-12 | 2021-01-21 | Moehs Iberica, S.L. | 3-[2(r)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-1h-pyrimidine-2,4(1h,3h)-dione hydrochloride salt (i) in solid form, process for preparing same, and use thereof in the synthesis of elagolix |
| CN111763176A (en) * | 2020-07-10 | 2020-10-13 | 常州制药厂有限公司 | GnRH receptor antagonist key intermediate and preparation method thereof |
| CN114835650A (en) * | 2021-02-01 | 2022-08-02 | 上海漠澳浩医药科技有限公司 | Salt and crystal of oxalagogri intermediate, and preparation method and application thereof |
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