CN113801065A - Crystalline forms of ethyl (R) -2-mercapto-1- (1-phenylethyl) -1H-imidazole-5-carboxylate - Google Patents
Crystalline forms of ethyl (R) -2-mercapto-1- (1-phenylethyl) -1H-imidazole-5-carboxylate Download PDFInfo
- Publication number
- CN113801065A CN113801065A CN202010551508.6A CN202010551508A CN113801065A CN 113801065 A CN113801065 A CN 113801065A CN 202010551508 A CN202010551508 A CN 202010551508A CN 113801065 A CN113801065 A CN 113801065A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- crystalline form
- type solvent
- solvent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- URUAOABMVSHWSB-UHFFFAOYSA-N ethyl 3-(1-phenylethyl)-2-sulfanylidene-1h-imidazole-4-carboxylate Chemical compound CCOC(=O)C1=CNC(=S)N1C(C)C1=CC=CC=C1 URUAOABMVSHWSB-UHFFFAOYSA-N 0.000 title abstract description 4
- 239000013078 crystal Substances 0.000 claims abstract description 56
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 30
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims abstract description 11
- 229960001690 etomidate Drugs 0.000 claims abstract description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 78
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 62
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 54
- 239000002904 solvent Substances 0.000 claims description 46
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical class 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 claims description 45
- 150000001875 compounds Chemical class 0.000 claims description 41
- 238000003756 stirring Methods 0.000 claims description 32
- 238000002425 crystallisation Methods 0.000 claims description 22
- 230000008025 crystallization Effects 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 15
- 238000000967 suction filtration Methods 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000002386 leaching Methods 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 238000004458 analytical method Methods 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000003158 alcohol group Chemical group 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 238000001757 thermogravimetry curve Methods 0.000 claims description 4
- 238000004321 preservation Methods 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 27
- 230000008569 process Effects 0.000 abstract description 18
- 239000007787 solid Substances 0.000 abstract description 9
- 230000002349 favourable effect Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000001228 spectrum Methods 0.000 abstract description 2
- 239000000523 sample Substances 0.000 description 27
- 238000000113 differential scanning calorimetry Methods 0.000 description 14
- 238000001816 cooling Methods 0.000 description 11
- 239000012071 phase Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 238000005303 weighing Methods 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 8
- 238000002411 thermogravimetry Methods 0.000 description 8
- 238000001291 vacuum drying Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000002441 X-ray diffraction Methods 0.000 description 2
- 230000037005 anaesthesia Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- -1 ethyl (R) -2-mercapto-1- (1-phenylethyl) -1H-imidazole-5-carboxylic Chemical compound 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000013094 purity test Methods 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- NPUKDXXFDDZOKR-UHFFFAOYSA-N 3-(1-phenylethyl)-4-imidazolecarboxylic acid ethyl ester Chemical compound CCOC(=O)C1=CN=CN1C(C)C1=CC=CC=C1 NPUKDXXFDDZOKR-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 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
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012468 concentrated sample Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000004455 differential thermal analysis Methods 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000002695 general anesthesia Methods 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000002245 particle 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
- 229910052697 platinum Inorganic materials 0.000 description 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 description 1
- 229940116357 potassium thiocyanate Drugs 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000010512 thermal transition Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile 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
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to crystalline forms of ethyl (R) -2-mercapto-1- (1-phenylethyl) -1H-imidazole-5-carboxylate. The XRPD spectrum of the crystal form expressed by the angle of 2 theta has diffraction peaks at least at 4.09 +/-0.2 degrees, 8.11 +/-0.2 degrees, 12.53 +/-0.2 degrees, 22.58 +/-0.2 degrees and 23.53 +/-0.2 degrees. The crystal form provided by the invention is a high-purity solid form, is favorable for improving the purity of a subsequent etomidate product, simplifies the post-treatment process and is favorable for industrial production of etomidate.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a crystal form of a compound ethyl (R) -2-mercapto-1- (1-phenylethyl) -1H-imidazole-5-carboxylic ester and a preparation method thereof.
Background
Etomidate is a non-barbiturate short-acting anesthetic capable of rapidly passing through blood-brain and spinal fluid barriers, and has strong hypnotic effectThe medicine has the advantages of quickness, high safety and the like, is one of common medicines for anesthesia induction, and is used for vein general anesthesia induction or anesthesia assistance. Etomidate belongs to imidazole derivatives, is hydroxylation salt of imidazole, has a chemical name of (+) -1- (1-phenethyl) -1H-imidazole-5-carboxylic acid ethyl ester and a molecular formula of C14H16N2O2The molecular weight is 244.29, and the structure formula of etomidate is shown as formula I:
the synthetic route of etomidate disclosed IN indian patent IN2011CH04309 is as follows:
through repeated research, the applicant finds that the compound of the formula II, namely ethyl (R) -2-mercapto-1- (1-phenylethyl) -1H-imidazole-5-carboxylic ester in the process route is easily presented in an oily substance form, is difficult to crystallize, is not beneficial to the purification of the compound of the formula II, and influences the purification and quality control of subsequent products. Therefore, there is an urgent need to develop a crystalline form of the compound of formula II and a method for preparing the same.
Disclosure of Invention
The invention provides a crystal form A of a compound shown in a formula II, wherein an X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following 2 theta angles: 4.09 ± 0.2 °, 8.11 ± 0.2 °, 12.53 ± 0.2 °, 22.58 ± 0.2 ° and 23.53 ± 0.2 °;
in some embodiments of the invention, the form a has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 Θ angles: 4.09 +/-0.2 degrees, 8.11 +/-0.2 degrees, 9.27 +/-0.2 degrees, 12.53 +/-0.2 degrees, 19.78 +/-0.2 degrees, 20.22 +/-0.2 degrees, 22.58 +/-0.2 degrees, 23.53 +/-0.2 degrees and 24.37 +/-0.2 degrees.
In some embodiments of the invention, the form a has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 Θ angles: 4.09 +/-0.2 degrees, 6.40 +/-0.2 degrees, 8.11 +/-0.2 degrees, 9.27 +/-0.2 degrees, 12.53 +/-0.2 degrees, 13.42 +/-0.2 degrees, 15.13 +/-0.2 degrees, 17.63 +/-0.2 degrees, 19.78 +/-0.2 degrees, 20.22 +/-0.2 degrees, 22.58 +/-0.2 degrees, 23.53 +/-0.2 degrees, 24.37 +/-0.2 degrees and 25.28 +/-0.2 degrees.
In some embodiments of the invention, the form a has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 Θ angles: 4.09 +/-0.2 degrees, 6.40 +/-0.2 degrees, 8.11 +/-0.2 degrees, 9.27 +/-0.2 degrees, 12.53 +/-0.2 degrees, 13.42 +/-0.2 degrees, 15.13 +/-0.2 degrees, 17.63 +/-0.2 degrees, 18.30 +/-0.2 degrees, 19.25 +/-0.2 degrees, 19.78 +/-0.2 degrees, 20.22 +/-0.2 degrees, 21.07 +/-0.2 degrees, 21.99 +/-0.2 degrees, 22.58 +/-0.2 degrees, 23.53 +/-0.2 degrees, 24.37 +/-0.2 degrees, 25.28 +/-0.2 degrees and 29.10 +/-0.2 degrees.
In some embodiments of the invention, the compound of formula II is in crystalline form a having X-ray powder diffraction pattern analysis data as shown in table 1:
TABLE 1X-ray powder diffraction Pattern analysis data for crystalline form A of the Compound of formula II
In some embodiments of the invention, form a of the compound of formula II has the XRPD pattern as shown in figure 1, i.e. has the characteristics represented by the XRPD pattern as shown in figure 1.
In some embodiments of the invention, the differential scanning calorimetry curve of form a of the compound of formula II has an endothermic peak at 77.65 ± 5 ℃; in some typical embodiments of the invention, the differential scanning calorimetry curve of form a of the compound of formula II has an endothermic peak at 77.65 ± 3 ℃.
In some embodiments of the present invention, form a of the compound of formula II has a DSC profile as shown in figure 2, i.e. has the characteristics represented by the DSC profile as shown in figure 2.
In some embodiments of the invention, the thermogravimetric analysis curve of form a of the compound of formula II has a weight loss of 1.072 ± 0.2% at 70 ± 3 ℃.
In some embodiments of the invention, form a of the compound of formula II has a TGA profile as shown in figure 3, i.e. has the characteristics represented by the TGA profile shown in figure 3.
In yet another aspect, the present invention also provides a process for preparing form a of the compound of formula II, comprising the steps of:
(1) adding a solvent A into the compound of the formula II to dissolve the compound;
(2) adding a B-type solvent into the mixed solution in the step (1);
(3) crystallizing;
(4) carrying out suction filtration, leaching the B-type solvent, and drying;
wherein the A solvent is selected from alcohol, ester, 1, 4-dioxane, tetrahydrofuran, toluene or dichloromethane, preferably isopropanol, ethyl acetate, 1, 4-dioxane, tetrahydrofuran, toluene or dichloromethane, more preferably dichloromethane; the solvent of class B is selected from water or organic alkane reagents, preferably water, n-hexane or n-heptane, more preferably n-heptane.
In some embodiments of the invention, the mass to volume ratio of the compound of formula II to the group A solvent is 0.25 to 4.0g/ml, preferably 0.5 to 2.0g/ml, more preferably 0.5 to 1.0 g/ml.
In some embodiments of the present invention, the volume ratio of the group A solvent to the group B solvent is 1:1 to 40, preferably 1:10 to 40; further preferably 1: 20-40; more preferably 1: 40.
In some embodiments of the invention, step (1) is performed by stirring the supernatant at room temperature;
in some embodiments of the invention, the group B solvent in step (2) is added in a manner of slowly dripping while stirring;
in some embodiments of the present invention, the crystallization mode in step (3) is thermal crystallization or cooling crystallization, wherein the cooling crystallization includes, but is not limited to, cooling or natural cooling; preferably, the crystallization mode of the step (3) is thermal insulation crystallization.
In some embodiments of the present invention, the crystallization time in step (3) is from 0.5 to 4 hours, preferably from 0.5 to 2 hours, more preferably from 1 to 2 hours, from the end of the dropwise addition.
In yet another aspect, the present invention also provides a process for preparing form a of the compound of formula II, comprising the steps of:
(a) adding a C-type solvent into the compound of the formula II for dissolving;
(b) adding a D-type solvent while stirring;
(c) adding seed crystal, and carrying out heat preservation and crystallization;
(d) carrying out suction filtration, leaching the D-type solvent and drying;
wherein the C-type solvent is selected from alcohol, ester, 1, 4-dioxane, tetrahydrofuran, toluene or dichloromethane, preferably isopropanol, ethyl acetate, 1, 4-dioxane, tetrahydrofuran, toluene or dichloromethane, and more preferably dichloromethane or toluene; the D-type solvent is selected from water or an organic alkane reagent, preferably water, n-hexane or n-heptane, and more preferably n-heptane.
In some embodiments of the present invention, the mass/volume ratio of the compound of formula II to the group C solvent is 0.1 to 1.0g/ml, preferably 0.2 to 0.5g/ml, and more preferably 0.4 to 0.5 g/ml.
In some embodiments of the present invention, the volume ratio of the group C solvent to the group D solvent is 1:1 to 5, preferably 1:2 to 5; more preferably 1:4.5 to 4.8.
In some embodiments of the invention, step (a) may be accomplished by dissolving the sample by stirring and raising the temperature;
in some embodiments of the invention, the D-type solvent in step (b) is added slowly while stirring, and after the dropwise addition, the temperature can be naturally reduced, and then step (c) is performed; in some embodiments of the present invention, the group D solvent of step (b) may be added in one portion or in multiple portions.
In some embodiments of the invention, the mass of the seed crystals added in step (c) is 0.25% to 1%, preferably 0.5% to 1%, more preferably 1% of the mass of the compound of formula II.
In some embodiments of the invention, the crystallization time in step (c) is maintained at 0.5 to 4 hours, preferably 0.5 to 2 hours, more preferably 1 to 2 hours, from the end of the dropwise addition.
In yet another aspect, the present invention also provides a crystalline composition, wherein the weight of form a of the compound of formula II is greater than 50% of the weight of the crystalline composition; preferably more than 80%; more preferably 90% or more; more preferably 95% or more.
In yet another aspect, the present invention also provides the use of form a of the compound of formula II or a crystalline form composition thereof in the preparation of etomidate.
As used herein, the following terms and phrases are intended to have the following meanings unless otherwise indicated. A particular phrase or term should not be considered as ambiguous or unclear without special definition, but rather construed in a generic sense.
In the present invention, the term "diffraction peak" when referring to a map and/or data in a map refers to a characteristic peak that one skilled in the art would not attribute to background noise.
Herein, "XRPD" refers to X-ray powder diffraction;
in the present invention, "DSC" refers to differential scanning calorimetry;
in the present invention, "TGA" refers to thermogravimetric analysis;
in the present invention, "h" means hour, "min" means minute, "ml" means milliliter, "μ l" means microliter;
in the present invention, "room temperature" means 25 ℃;
in the present invention, "suction filtration" refers to filtration under reduced pressure.
In the present invention, the X-ray diffraction (also called "X-ray powder diffraction", X-ray powder diffctometer, XRPD) is measured as follows:
the instrument model is as follows: d8 Advance
And (3) testing conditions are as follows:
an X-ray generator: the concentration of Cu, k alpha,
tube voltage: 40kV, tube current: 40mA.
Scattering slit: 0.6mm
Detector slit: 5mm
Backscatter slit: 0.6mm
Scanning range: 3-40deg
Step length: 0.02deg
Rate: 0.3S
It is noted that in X-ray powder diffraction spectroscopy (XRPD), the diffraction pattern obtained from a crystalline compound is often characteristic for a particular crystal, where the relative intensities of the bands (especially at low angles) may vary due to the dominant orientation effects resulting from differences in crystallization conditions, particle size, and other measurement conditions. Thus, the relative intensities of the diffraction peaks are not characteristic of the crystal in question, and it is judged whether, at the same time as the known crystalline phase, it is more important to note the relative positions of the peaks rather than their relative intensities. In addition, there may be slight errors in the position of the peaks for any given crystal, which are also well known in the crystallography art. For example, the position of the peak may shift due to a change in temperature when analyzing the sample, a movement of the sample, or a calibration of the instrument, etc., and the measurement error of the 2 θ value is sometimes about ± 0.5 °, preferably about ± 0.3 °, and more preferably about ± 0.2 °. Therefore, this error should be taken into account when determining each crystalline structure, and 2 θ values within the error are also within the scope of the present invention. The peak position is usually expressed in the XRPD pattern as 2 θ angle or crystal plane distance d, with a simple conversion between the two: d is λ/2sin θ, where d represents a surface distance (also called a "surface distance"), λ represents a wavelength of incident X-rays, and θ is a diffraction angle. For the same crystal of the same compound, the peak positions of the XRPD spectra have similarity as a whole, and the relative intensity error may be large. It should also be noted that in the identification of mixtures, the loss of part of the diffraction lines may be due to, for example, a reduction in the content, in which case it is not necessary to rely on all the bands observed in the high-purity sample, even one band may be characteristic for a given crystal.
The invention relates to a Differential thermal analysis (also called Differential Scanning calorimetry, DSC) method
The instrument model is as follows: DSC 25
The test method comprises the following steps: a sample (1-10 mg) is placed in a DSC aluminum pot for testing, and the method comprises the following steps: the initial temperature is 40 ℃ to 10 ℃/min.
DSC measures the transition temperature when a crystal absorbs or releases heat due to a change in its crystalline structure or melting of the crystal. For the same crystal of the same compound, the thermal transition temperature and melting point errors in successive analyses are typically within about 5 ℃, usually within about 3 ℃, which means ± 5 ℃ when we say that a compound has a given DSC peak or melting point. DSC provides an auxiliary method to distinguish different crystals. Different crystalline morphologies can be identified by their different transition temperature characteristics. It is noted that the DSC peak or melting point for the mixture may vary over a larger range. Furthermore, the melting temperature is related to the rate of temperature rise due to decomposition that accompanies the process of melting the substance.
The present invention is a Thermal Gravimetric Analysis (TGA) method
The instrument model is as follows: TGA550
And (3) testing conditions are as follows: a sample (1-10 mg) is placed in a TGA platinum pan for testing, and the method comprises the following steps: the initial temperature is 30 ℃ and the heating rate is 10 ℃/min.
The crystal form A of the compound shown in the formula II is a high-purity solid form, is favorable for improving the purity of a subsequent etomidate product, simplifies the post-treatment process and is favorable for industrial production of etomidate.
Drawings
FIG. 1 is an X-ray diffraction pattern (XPD pattern) of form A of the compound of formula II prepared in example 3.
Figure 2 is a Differential Scanning Calorimetry (DSC) plot of form a of the compound of formula II prepared in example 3.
Figure 3 is a thermogravimetric analysis (TGA) of form a of the compound of formula II prepared in example 3.
FIG. 4 is a high performance liquid chromatogram of the compound of formula II prepared in reference example 1.
FIG. 5 is a high performance liquid chromatogram of the crystals of the compound of formula II prepared in example 3.
Detailed Description
For a better understanding of the present invention, reference will now be made to the following examples which are set forth to illustrate, but are not to be construed as the limit of the invention.
The reagents and raw materials used in the invention are all commercial products.
Reference example 1: preparation method of compound (ethyl (R) -2-mercapto-1- (1-phenylethyl) -1H-imidazole-5-carboxylate) of formula II
Referring to a preparation method of the compound of formula II in an etomidate synthetic route disclosed in India patent 2011CH04309, the specific operation is as follows:
under the protection of nitrogen and at the temperature of 60-70 ℃, slowly dropwise adding 121.2g of ethyl chloroacetate into a mixed solution of 100g of the compound shown in the formula VI, 200ml of toluene and 100g of triethylamine, controlling the dropwise adding time to be 1h, and after the dropwise adding is finished, heating the reaction to 70 ℃ and continuously stirring for 7 h. Cooling to room temperature after the reaction is finished, then adding 200ml of water, stirring, separating the water phase, then adding 100ml of saturated sodium chloride solution into the organic phase, stirring for 15 minutes, separating the organic phase from the water phase, recovering the organic phase (toluene layer), and concentrating to dryness to obtain the compound shown in the formula V. Adding 58g of formic acid into a mixed solution of the compound shown in the formula V and 200ml of toluene, carrying out reflux stirring at 95-110 ℃ for 5h, naturally cooling a reaction solution to room temperature after the reaction is finished, adjusting the pH value to 7-8 by using a 10% sodium carbonate solution, carrying out liquid separation after stirring, adding 100ml of saturated saline solution into a collected toluene layer, carrying out stirring and layering, collecting an organic phase, namely the toluene layer, and concentrating to dryness. To the concentrated sample, 183.0g of ethyl formate was added under nitrogen protection and mixed well, and slowly added to 230ml of toluene containing 90.0g of sodium ethoxide at 25-30 ℃ and stirred under nitrogen protection for 4 hours. After the reaction is finished, cooling the reaction solution to 5-10 ℃, adding 300ml of water into the reaction solution, stirring for 15 minutes at 5-10 ℃, standing for layering, retaining the water phase, washing the organic phase with 200ml of purified water, and combining the water phases. Adding 96.0g of potassium thiocyanate into the aqueous solution, stirring for dissolving, absorbing heat of a system, cooling, and slowly adding 240ml of concentrated hydrochloric acid at the temperature of 5-10 ℃. Heating to 45 ℃, reacting for 5h, cooling to 20 ℃, adding 350ml of toluene into the reaction solution, extracting, separating a water phase, recovering an organic phase, adjusting the pH value of the water phase to 7.0-7.5 by using a saturated sodium carbonate aqueous solution, separating the water phase, and recovering the organic phase; the obtained organic phase was washed with 100ml of saturated brine, the aqueous phase was separated, the organic phase was recovered, and the title compound was obtained by concentration.
Example 1
The inventors tried to obtain a crystal sample of the compound of formula II by studying crystallization conditions, starting with the oil of the compound of formula II prepared in reference example 1. The inventors tried to investigate the effect of different solvent systems on crystallization in different ways.
Weighing 1g of the compound of the formula II prepared in reference example 1, adding the compound into a sample bottle, adding a proper amount of the A-type solvent, stirring and dissolving the mixture at room temperature, then slowly adding the B-type solvent while stirring, wherein the using amount of the B-type solvent is shown in Table 2, and after the dropwise addition, carrying out heat preservation and crystallization for 2 hours. If solid is separated out, suction filtration is carried out, a proper amount of B-type solvent is used for leaching, and vacuum drying is carried out.
The inventors investigated the effect of different solvent systems on crystallization using the method of example 1. The results are shown in Table 2. The analytical method of example 11 was used, and the results showed that the purity of the oil obtained after the treatment was not significantly changed from the purity of the compound of formula II obtained in reference example 1.
TABLE 2 crystallization Effect of different solvent systems on oils of formula II
Example 2
To the solvent systems listed in table 3, an excess of each of the compounds of formula II prepared in reference example 1 was added, sufficiently shaken at room temperature to dissolve as much of the sample as possible, the resulting suspension was filtered, and the filtrate was slowly volatilized at room temperature to try to obtain a solid sample.
The inventors investigated the effect of different solvent systems on crystallization using the method of example 2. The results are shown in Table 3. The analytical method of example 11 was used, and the results showed that the purity of the oil obtained after the treatment was not significantly changed from the purity of the compound of formula II obtained in reference example 1.
TABLE 3 crystallization Effect of different solvent systems on oils of formula II
Serial number | Solvent | Product traits | |
1 | Methanol | Oil-like substance | |
2 | Acetone (II) | Oil-like substance | |
3 | Acetonitrile | Oil-like substance | |
4 | Tetrahydrofuran (THF) | Oil-like substance | |
5 | Methylene dichloride | Oil-like substance | |
6 | Methyl tert-butyl ether | Oil-like substance | |
7 | Ethanol/water (9:1) | Oil- |
|
8 | Dichloromethane/n-heptane (4:1) | Oil-like substance |
Example 3: process for the preparation of crystalline form a of the compound of formula II
Weighing 1g of the compound of the formula II prepared in reference example 1, adding the compound into a sample bottle, adding 1ml of dichloromethane, stirring at room temperature to dissolve, slowly adding 40ml of n-heptane while stirring, separating out a solid sample in the dropwise adding process, keeping the temperature after dropwise adding is finished, crystallizing 1, performing suction filtration, leaching with 5ml of n-heptane, and drying a filter cake in vacuum to obtain crystals. The crystal is characterized by XRPD, DSC and TGA to obtain the patterns shown in figures 1, 2 and 3 respectively.
Example 4: process for the preparation of crystalline form a of the compound of formula II
Weighing 1g of the compound of the formula II prepared in reference example 1, adding the compound into a sample bottle, adding 4ml of dichloromethane, stirring at room temperature to dissolve, slowly adding 90ml of n-heptane while stirring, separating out a solid sample in the dropwise adding process, keeping the temperature for crystallization for 2 hours after dropwise adding, carrying out suction filtration, leaching with 5ml of n-heptane, and carrying out vacuum drying on a filter cake to obtain a crystal. The crystal is characterized by XRPD, and the crystal is a crystal form A.
Example 5: process for the preparation of crystalline form a of the compound of formula II
Weighing 1g of the compound of the formula II prepared in reference example 1, adding the compound into a sample bottle, adding 2ml of dichloromethane, stirring at room temperature to dissolve, slowly adding 40ml of n-heptane while stirring, separating out a solid sample in the dropwise adding process, keeping the temperature after dropwise adding is finished, crystallizing 1, performing suction filtration, leaching with 5ml of n-heptane, and drying a filter cake in vacuum to obtain crystals. The crystal is characterized by XRPD, and the crystal is a crystal form A.
Example 6: process for the preparation of crystalline form a of the compound of formula II
Weighing 1g of the compound of the formula II prepared in reference example 1, adding the compound into a sample bottle, adding 0.5ml of dichloromethane, stirring at room temperature to dissolve, slowly adding 5ml of n-heptane while stirring, separating out a solid sample in the dropwise adding process, keeping the temperature for crystallization for 1.5h after dropwise adding, performing suction filtration, leaching with 5ml of n-heptane, and performing vacuum drying on a filter cake to obtain crystals. The crystal is characterized by XRPD, and the crystal is a crystal form A.
Example 7: process for the preparation of crystalline form a of the compound of formula II
Weighing 1g of the compound of the formula II prepared in reference example 1, adding the compound into a sample bottle, adding 0.25ml of dichloromethane, stirring at room temperature to dissolve, slowly adding 2ml of n-heptane while stirring, separating out a solid sample in the dropwise adding process, keeping the temperature for crystallization for 1h after dropwise adding, carrying out suction filtration, eluting with 5ml of n-heptane, and carrying out vacuum drying on a filter cake to obtain a crystal. The crystal is characterized by XRPD, and the crystal is a crystal form A.
Example 8: process for the preparation of crystalline form a of the compound of formula II
Weighing 5g of the compound of the formula II prepared in reference example 1, adding the compound into a sample bottle, adding 12ml of dichloromethane, stirring, heating to 39 ℃, slowly dripping 55ml of n-heptane after the sample is dissolved, naturally cooling to 20 ℃, adding 1% of seed crystal (prepared in example 3), keeping the temperature, stirring, crystallizing for 1h, performing suction filtration, leaching with 25ml of n-heptane, and performing vacuum drying on a filter cake to obtain crystals. The crystal is characterized by XRPD, and the crystal is a crystal form A.
Example 9: process for the preparation of crystalline form a of the compound of formula II
Weighing 10g of the compound of the formula II prepared in reference example 1, adding the compound into a sample bottle, adding 20ml of dichloromethane at room temperature to dissolve a sample, slowly dropwise adding 40ml of n-heptane, adding 1% of seed crystal (prepared in example 3), keeping the temperature, stirring, crystallizing for 2 hours, performing suction filtration, leaching with 50ml of n-heptane, and performing vacuum drying on a filter cake to obtain crystals. The crystal is characterized by XRPD, and the crystal is a crystal form A.
Example 10: process for the preparation of crystalline form a of the compound of formula II
Weighing 10g of the compound of the formula II prepared in reference example 1, adding the compound into a sample bottle, adding 35ml of toluene, stirring, heating to 40 ℃ to dissolve a sample, naturally cooling to 20 ℃, slowly dropwise adding 40ml of n-heptane, adding 1% of seed crystal (prepared in example 3), keeping the temperature, stirring and crystallizing for 0.5-1 h; slowly dripping 65ml of n-heptane, keeping the temperature, stirring, crystallizing for 1.5h, carrying out suction filtration, leaching with 50ml of n-heptane, and carrying out vacuum drying on a filter cake to obtain crystals. The crystal is characterized by XRPD, and the crystal is a crystal form A.
The results of examples 8-10 show that crystallization of the compound of formula II can be achieved by seed induction, with a controlled process, suitable for scale-up production.
Example 11 purity test method and results
The inventors conducted purity tests using high performance liquid chromatography with respect to the oily matter of the compound of formula II prepared in reference example 1 and the crystals of the compound of formula II prepared in example 3.
A chromatographic column: kromasil 100-5-C18(250 mm. times.4.6 mm,5 μm);
column temperature: 30 ℃;
flow rate: 1 ml/min;
detection wavelength: 215 nm;
sample introduction volume: 10 mu l of the mixture;
mobile phase: mobile phase A: potassium dihydrogen phosphate (triethylamine adjusted to pH 6.5);
mobile phase B: acetonitrile;
operating time: 45 min;
detecting the compounds of formula II prepared in reference example 1 and example 3 by the above-mentioned high performance liquid chromatography detection method, wherein liquid chromatograms thereof are shown in FIGS. 4 and 5, respectively; the analysis results are shown in tables 4 and 5, respectively.
Table 4: chromatographic analysis results of Compound of formula II prepared in reference example 1
As can be seen from fig. 4 and table 4: the compound of formula II prepared in reference example 1 was 94.48% pure.
Table 5: chromatographic analysis results of Compound II prepared in example 3
As can be seen from fig. 5 and table 5: the compound of formula II prepared in example 3 was 98.28% pure.
Claims (10)
2. the crystalline form of claim 1, characterized by an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 Θ angles: 4.09 ± 0.2 °, 8.11 ± 0.2 °, 9.27 ± 0.2 °, 12.53 ± 0.2 °, 19.78 ± 0.2 °, 20.22 ± 0.2 °, 22.58 ± 0.2 °, 23.53 ± 0.2 ° and 24.37 ± 0.2 °; preferably, the crystalline form has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 4.09 + -0.2 °, 6.40 + -0.2 °, 8.11 + -0.2 °, 9.27 + -0.2 °, 12.53 + -0.2 °, 13.42 + -0.2 °, 15.13 + -0.2 °, 17.63 + -0.2 °, 19.78 + -0.2 °, 20.22 + -0.2 °, 22.58 + -0.2 °, 23.53 + -0.2 °, 24.37 + -0.2 ° and 25.28 + -0.2 °; further preferably, the crystalline form has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2 Θ angles: 4.09 +/-0.2 °, 6.40 +/-0.2 °, 8.11 +/-0.2 °, 9.27 +/-0.2 °, 12.53 +/-0.2 °, 13.42 +/-0.2 °, 15.13 +/-0.2 °, 17.63 +/-0.2 °, 18.30 +/-0.2 °, 19.25 +/-0.2 °, 19.78 +/-0.2 °, 20.22 +/-0.2 °, 21.07 +/-0.2 °, 21.99 +/-0.2 °, 22.58 +/-0.2 °, 23.53 +/-0.2 °, 24.37 +/-0.2 °, 25.28 +/-0.2 ° and 29.10 +/-0.2 °; still more preferably, the crystalline form has X-ray powder diffraction pattern analysis data as shown in table 1:
3. a crystalline form according to claim 1 characterized by a differential scanning calorimetry curve which has an endothermic peak at 77.65 ± 5 ℃; preferably, the differential scanning calorimetry curve of form a of the compound of formula II has an endothermic peak at 77.65 ± 3 ℃.
4. The crystalline form of claim 1, wherein the crystalline form has the characteristics represented by the XRPD pattern as depicted in figure 1; or has the characteristics represented by the DSC profile shown in figure 2; or have the characteristics represented by the TGA profile shown in figure 3.
6. use of the crystalline form of claim 1 or the crystalline form composition of claim 5 in the preparation of etomidate.
7. A process for preparing the crystalline form of claim 1, comprising the steps of:
(1) adding a solvent A into the compound of the formula II to dissolve the compound;
(2) adding a B-type solvent into the mixed solution in the step (1);
(3) crystallizing;
(4) carrying out suction filtration, leaching the B-type solvent, and drying;
wherein the A solvent is selected from alcohol, ester, 1, 4-dioxane, tetrahydrofuran, toluene or dichloromethane, preferably isopropanol, ethyl acetate, 1, 4-dioxane, tetrahydrofuran, toluene or dichloromethane, more preferably dichloromethane; the solvent of class B is selected from water or organic alkane reagents, preferably water, n-hexane or n-heptane, more preferably n-heptane.
8. The preparation method of claim 7, wherein the mass-to-volume ratio of the compound of formula II to the group A solvent is 0.25-4.0 g/ml, preferably 0.5-2.0 g/ml, and more preferably 0.5-1.0 g/ml; the volume ratio of the A-type solvent to the B-type solvent is 1: 1-40, preferably 1: 10-40; further preferably 1: 20-40; more preferably 1: 40.
9. A process for preparing the crystalline form of claim 1, comprising the steps of:
(a) adding a C-type solvent into the compound of the formula II for dissolving;
(b) adding a D-type solvent while stirring;
(c) adding seed crystal, and carrying out heat preservation and crystallization;
(d) carrying out suction filtration, leaching the D-type solvent and drying;
wherein the C-type solvent is selected from alcohol, ester, 1, 4-dioxane, tetrahydrofuran, toluene or dichloromethane, preferably isopropanol, ethyl acetate, 1, 4-dioxane, tetrahydrofuran, toluene or dichloromethane, and more preferably dichloromethane or toluene; the D-type solvent is selected from water or an organic alkane reagent, preferably water, n-hexane or n-heptane, and more preferably n-heptane.
10. The preparation method of claim 9, wherein the mass-to-volume ratio of the compound of formula II to the C-type solvent is 0.1-1.0 g/ml, preferably 0.2-0.5 g/ml, and more preferably 0.4-0.5 g/ml; the volume ratio of the C-type solvent to the D-type solvent is 1: 1-5, preferably 1: 2-5; further preferably 1: 4.5-4.8; the mass of the seed crystal added in the step (c) is 0.25 to 1 percent, preferably 0.5 to 1 percent, and more preferably 1 percent of the mass of the compound of the formula II.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010551508.6A CN113801065A (en) | 2020-06-17 | 2020-06-17 | Crystalline forms of ethyl (R) -2-mercapto-1- (1-phenylethyl) -1H-imidazole-5-carboxylate |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010551508.6A CN113801065A (en) | 2020-06-17 | 2020-06-17 | Crystalline forms of ethyl (R) -2-mercapto-1- (1-phenylethyl) -1H-imidazole-5-carboxylate |
Publications (1)
Publication Number | Publication Date |
---|---|
CN113801065A true CN113801065A (en) | 2021-12-17 |
Family
ID=78943160
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010551508.6A Pending CN113801065A (en) | 2020-06-17 | 2020-06-17 | Crystalline forms of ethyl (R) -2-mercapto-1- (1-phenylethyl) -1H-imidazole-5-carboxylate |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113801065A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114456118A (en) * | 2022-02-16 | 2022-05-10 | 汉瑞药业(荆门)有限公司 | Etomidate crystal form I and preparation method thereof |
-
2020
- 2020-06-17 CN CN202010551508.6A patent/CN113801065A/en active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114456118A (en) * | 2022-02-16 | 2022-05-10 | 汉瑞药业(荆门)有限公司 | Etomidate crystal form I and preparation method thereof |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3280408B1 (en) | Process for the preparation of dicycloplatin | |
CN101402655B (en) | Process for producing platinum | |
CN102070567A (en) | Method for preparing high-purity orlistat by using reverse phase high-performance liquid chromatogram | |
CN113801065A (en) | Crystalline forms of ethyl (R) -2-mercapto-1- (1-phenylethyl) -1H-imidazole-5-carboxylate | |
CN114249711A (en) | Method for preparing nicotine by resolution | |
CN110467580B (en) | Resolution method of Raxinard axis chiral enantiomer | |
CN111153775B (en) | Preparation method of triclosan methyl ester | |
CN111004179B (en) | Resolution method of 5' -methoxylapatin | |
WO2014102834A2 (en) | Process for lurasidone | |
CN107915687B (en) | High-efficiency preparation method of polysubstituted phenazine derivative and oxide thereof | |
EP2330107A2 (en) | Improved production method for adefovir dipivoxil | |
CN115403475A (en) | Preparation method and application of diagnostic reagent for specifically detecting copper ion concentration | |
CN108373488B (en) | Catalpol 6-caffeic acid ester derivative and preparation method and application thereof | |
CN110818676A (en) | Crystal form of cyclohexane derivative | |
CN112834643B (en) | Method for measuring 2, 6-dihydroxy-4-methylpyridine and 2, 6-dihydroxy-3-cyano-4-methylpyridine | |
CN113698353B (en) | Imidazolyl Schiff base fluorescence sensor for detecting copper (II) particles in aqueous solution and synthesis method thereof | |
CN108884119A (en) | A kind of preparation method of bis-dicarboxylic diamino platinum (II) derivative | |
CN115636742B (en) | Recrystallization method | |
CN116217436B (en) | Fluorescent probe for detecting mercury ions in traditional Chinese medicinal materials and preparation method thereof | |
WO2012085191A1 (en) | Crystalline form of pravastatine and process for the preparation thereof | |
CN110016032B (en) | Preparation method of 2-dimethylamino-6-benzoyl-7-phenylimidazotriazine compound | |
CN109265407B (en) | Synthesis method of bislinezolid | |
US6215000B1 (en) | Crystalline complexes of baccatin III with imidazole, 2-methylimidazole or isopropanol | |
CN114605357A (en) | Separation and purification method of paclitaxel-oleic acid micromolecules | |
CN104513189B (en) | A kind of oxiracetam intermediate and its preparation method and application |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20211217 |
|
WD01 | Invention patent application deemed withdrawn after publication |