CN105153012A - Novel preparation method for Mitiglinide calcium - Google Patents
Novel preparation method for Mitiglinide calcium Download PDFInfo
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- CN105153012A CN105153012A CN201510428259.0A CN201510428259A CN105153012A CN 105153012 A CN105153012 A CN 105153012A CN 201510428259 A CN201510428259 A CN 201510428259A CN 105153012 A CN105153012 A CN 105153012A
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- reaction
- mitiglinide
- weight ratio
- cis
- benzyl succinic
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- 229960003365 mitiglinide Drugs 0.000 title claims abstract description 38
- PMRVFZXOCRHXFE-FMEJWYFOSA-L Kad 1229 Chemical compound [Ca+2].C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1.C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)[O-])C1=CC=CC=C1 PMRVFZXOCRHXFE-FMEJWYFOSA-L 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 24
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims abstract description 13
- 239000001110 calcium chloride Substances 0.000 claims abstract description 13
- 229910001628 calcium chloride Inorganic materials 0.000 claims abstract description 13
- ODSNARDHJFFSRH-OCAPTIKFSA-N (3as,7ar)-2,3,3a,4,5,6,7,7a-octahydro-1h-isoindole Chemical compound C1CCC[C@@H]2CNC[C@@H]21 ODSNARDHJFFSRH-OCAPTIKFSA-N 0.000 claims abstract description 12
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229910000104 sodium hydride Inorganic materials 0.000 claims abstract description 10
- 239000012312 sodium hydride Substances 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 9
- -1 mitiglinide sodium salt Chemical class 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 abstract description 7
- WPGGHFDDFPHPOB-BBWFWOEESA-N mitiglinide Chemical compound C([C@@H](CC(=O)N1C[C@@H]2CCCC[C@@H]2C1)C(=O)O)C1=CC=CC=C1 WPGGHFDDFPHPOB-BBWFWOEESA-N 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract 2
- OOEHLTSDDZKTQB-VIFPVBQESA-N (3s)-3-benzyloxolane-2,5-dione Chemical compound O=C1OC(=O)C[C@@H]1CC1=CC=CC=C1 OOEHLTSDDZKTQB-VIFPVBQESA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000011734 sodium Substances 0.000 abstract 1
- 229910052708 sodium Inorganic materials 0.000 abstract 1
- 239000011780 sodium chloride Substances 0.000 abstract 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Inorganic materials [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000001953 recrystallisation Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- GTOFKXZQQDSVFH-VIFPVBQESA-N (r)-2-benzylsuccinate Chemical compound OC(=O)C[C@@H](C(O)=O)CC1=CC=CC=C1 GTOFKXZQQDSVFH-VIFPVBQESA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 229940059260 amidate Drugs 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- ARLZGEXVMUDUQZ-UHFFFAOYSA-N O.O.[Ca] Chemical compound O.O.[Ca] ARLZGEXVMUDUQZ-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention relates to a novel preparation method for Mitiglinide calcium. The method comprises the steps: enabling (S)-2-benzyl succinic anhydride, cis-octahydroisoindole and sodium hydride, which serve as raw materials, to be subjected to one-pot-method reaction, so as to produce Mitiglinide sodium; and enabling Mitiglinide sodium and calcium chloride to be subjected to reaction in an aqueous solution, thereby obtaining the Mitiglinide calcium product. The Mitiglinide calcium product can be further refined. The method has the characteristics of simple process, easiness and feasibility in operation, mild conditions and controllable isomers, and industrial production is easy to realize.
Description
Technical field
The present invention relates to a kind of novel preparation method of ofhypoglycemic medicine, a kind of is specifically the method that S 21403 prepared by raw material with (S)-2-benzyl Succinic anhydried.
Background technology
S 21403 (MitiglinideCalcium), chemistry two (2S)-2-benzyl-3-(cis-six hydrogen isoindoline-2-carbonyl)-propionic acid one calcium dihydrate by name, its structural formula is as follows:
S 21403 is a kind of type II diabetes medicine developed by the raw drugmaker of Japanese tachibana, within 2004, goes on the market first in Japan.It is continue repaglinide, nateglinide Hou Sange MAG row carbamide type medicine.Relative to traditional Remedies for diabetes, there is onset faster, the advantages such as the transformation period is short, and curative effect is stronger, be both conducive to the postprandial blood sugar reducing diabetic subject, and the hypoglycemia that lasting hypoglycemic causes can have been avoided again, have the laudatory title of " external pancreas ".
Bibliographical information be that the method that S 21403 prepared by raw material mainly can be divided into acid anhydrides method and active ester method two kinds by (S)-2-benzyl succinic acid.
Acid anhydrides method: patent CN1680321A, CN102101838A report the method for acid anhydrides method synthesis S 21403.
The method for raw material, with cis-hexahydroisoindoline generation amidate action, generates mitiglinide with the acid anhydrides of (S)-2-benzyl succinic acid dehydration generation; After mitiglinide and alkali reaction salify, react to obtain product S 21403 with calcium chloride.The method step is short, and unfortunately isomeric by-products content is high, purifying products difficulty.
Active ester method: Yamaguchi in 1998 etc., the little brightness of Cao in 2009 etc. report the method that active ester method prepares S 21403.
The method reacts the two-element active ester that generates for raw material with (S)-2-benzyl succinic acid and oxy-compound, with cis-hexahydroisoindoline generation selectivity amidate action, then is hydrolyzed in the basic conditions, reacts to obtain product S 21403 with calcium chloride.The method has good regioselectivity, but reactions steps is many, and operating process is loaded down with trivial details, and product yield is lower; Moreover will use more auxiliary material in synthesis, synthesis cost is high.Thus, this route is not suitable for suitability for industrialized production.
Summary of the invention
The object of the invention is to the deficiency overcoming above-mentioned existing S 21403 preparation method, provide a kind of technique simple and direct, the novel preparation method of S 21403 simple to operate.
The realization of the object of the invention, is mainly that starting raw material prepares S 21403 with (S)-2-benzyl Succinic anhydried, comprises the steps:
(1) (S)-2-benzyl Succinic anhydried, cis-hexahydroisoindoline, sodium hydride are raw material, generate mitiglinide sodium salt through the reaction of " one kettle way " method;
(2) mitiglinide sodium salt and calcium chloride react to obtain product S 21403 in aqueous, and products obtained therefrom can be refined further.
Temperature of reaction in described step (1) is-20 ~ 45 DEG C, cis-hexahydroisoindoline and (S)-2-benzyl Succinic anhydried molar weight ratio are 1.00 ~ 1.25, sodium hydride and (S)-2-benzyl Succinic anhydried molar weight ratio are 1.05 ~ 1.50, and the reaction times is 5 ~ 9h; In described step (2), temperature of reaction is-10 ~ 60 DEG C, and calcium chloride is 0.50 ~ 0.75 with the molar weight ratio of mitiglinide sodium salt, and the reaction times is 1 ~ 5h.
Preferably, in above-mentioned preparation process, temperature of reaction in described step (1) is-15 ~ 5 DEG C, cis-hexahydroisoindoline and (S)-2-benzyl Succinic anhydried molar weight ratio are 1.05 ~ 1.20, sodium hydride and (S)-2-benzyl Succinic anhydried molar weight ratio are 1.10 ~ 1.25, and the reaction times is 6 ~ 8h.
Preferably, in above-mentioned preparation process, the solvent in described step (1) is selected from the mixture of one or more solvents of the aprotic solvent such as benzene,toluene,xylene, ethylene dichloride, hexanaphthene, normal hexane, normal heptane, sherwood oil.
Preferably, in above-mentioned preparation process, in described step (2), temperature of reaction is-5 ~ 45 DEG C, and calcium chloride is 0.50 ~ 0.60 with the molar weight ratio of mitiglinide sodium salt, and the reaction times is 2 ~ 4h.
Preferably, in above-mentioned preparation process, in described step (2), drip calcium chloride water in mitiglinide sodium salt, rate of addition is wanted slowly, stirs and wants violent, remain in the product to prevent the S 21403 solid phase prod generated from wrapping up unreacted mitiglinide acid sodium-salt.
Preferably, in above-mentioned preparation process, in described step (2), refine further and mainly refer to recrystallization, recrystallization solvent is selected from the mixing solutions of a certain proportion of methyl alcohol or ethanol and water, preferably 95% ethanolic soln.
Beneficial effect: it is that starting raw material prepares S 21403 that method of the present invention is suitable for by (S)-2-benzyl Succinic anhydried, technical scheme has concise in technology, simple to operate, the feature that isomer is controlled.And easily realize suitability for industrialized production.
Embodiment
Below in conjunction with specific embodiment, exemplary illustration and understanding are further carried out to the application, but embodiment only provides as an example, is not considered as whole technical scheme of the present invention, is not limited overall technical solution.All have same or similar technical characteristic, simple change or to replace, and all belongs to scope.
Embodiment 1
By (S)-2-benzyl Succinic anhydried (19.00g, 0.10mol), sodium hydride (4.40g, 0.11mol), 100mL toluene adds in reaction flask, and cryosel is cooled to-15 ~-10 DEG C.The toluene solution of slow dropping cis-hexahydroisoindoline (13.75g, 0.11mol), stirring reaction 8h.Reaction is finished, and adds the 100mL aqueous solution in reaction system, stirs 2h, point water-yielding stratum.Organic layer divides three times, and at every turn with 30mL washing, combining water layer, slowly drips the aqueous solution of calcium chloride (6.67g, 0.06mol) wherein, vigorous stirring reaction 2h.Question response is complete, suction filtration, washing, dry thick product 35.03g.The thick product of gained 95% ethyl alcohol recrystallization obtains finished product 28.71g.
Embodiment 2
By (S)-2-benzyl Succinic anhydried (19.00g, 0.10mol), sodium hydride (4.40g, 0.11mol), 100mL toluene adds in reaction flask, and cryosel bath is cooled to-12 ~-6 DEG C.The toluene solution of slow dropping cis-hexahydroisoindoline (15.00g, 0.12mol), stirring reaction 7h.Reaction is finished, and adds the 100mL aqueous solution in reaction system, stirs 2h, point water-yielding stratum.Organic layer divides three times, and at every turn with 30mL washing, combining water layer, slowly drips the aqueous solution of calcium chloride (5.57g, 0.05mol) wherein, vigorous stirring reaction 4h.Question response is complete, suction filtration, washing, dry thick product 34.55g.The thick product of gained 95% ethyl alcohol recrystallization obtains finished product 29.03g.
Embodiment 3
By (S)-2-benzyl Succinic anhydried (19.00g, 0.10mol), sodium hydride (4.80g, 0.12mol), 100mL toluene adds in reaction flask, and cryosel bath is cooled to-13 ~-7 DEG C.The toluene solution of slow dropping cis-hexahydroisoindoline (15.00g, 0.12mol), stirring reaction 6h.Reaction is finished, and adds the 100mL aqueous solution in reaction system, stirs 2h, point water-yielding stratum.Organic layer divides three times, washes with 30mL at every turn.Combining water layer, slowly drips the aqueous solution of calcium chloride (6.64g, 0.06mol) wherein, vigorous stirring reaction 5h.Question response is complete, suction filtration, washing, dry thick product 34.34g.The thick product of gained 95% ethyl alcohol recrystallization obtains finished product 29.13g.
Claims (3)
1. a novel preparation method for S 21403, is characterized in that: the method comprises the steps:
(1) (S)-2-benzyl Succinic anhydried, cis-hexahydroisoindoline, sodium hydride are raw material, generate mitiglinide sodium salt through the reaction of " one kettle way " method;
(2) mitiglinide sodium salt and calcium chloride react to obtain product S 21403 in aqueous.
2. the preparation method of a kind of S 21403 according to claim 1, it is characterized in that: the temperature of reaction in described step (1) is-20 ~ 45 DEG C, cis-hexahydroisoindoline and (S)-2-benzyl Succinic anhydried molar weight ratio are 1.00 ~ 1.25, sodium hydride and (S)-2-benzyl Succinic anhydried molar weight ratio are 1.05 ~ 1.50, and the reaction times is 5 ~ 9h; In described step (2), temperature of reaction is-10 ~ 60 DEG C, and calcium chloride is 0.50 ~ 0.75 with the molar weight ratio of mitiglinide sodium salt, and the reaction times is 1 ~ 5h.
3. according to claim 1, the preparation method of a kind of S 21403 described in 2, is characterized in that: the temperature of reaction in described step (1) is-15 ~ 5 DEG C; Cis-hexahydroisoindoline and (S)-2-benzyl Succinic anhydried molar weight ratio are 1.05 ~ 1.20, and sodium hydride and (S)-2-benzyl Succinic anhydried molar weight ratio are 1.10 ~ 1.25; Reaction times is 6 ~ 8h; In described step (2), temperature of reaction is-5 ~ 45 DEG C; Calcium chloride is 0.50 ~ 0.60 with the molar weight ratio of mitiglinide sodium salt; Reaction times is 2 ~ 4h.
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|---|---|---|---|
| CN201510428259.0A CN105153012B (en) | 2015-07-20 | 2015-07-20 | A kind of preparation method of Mitiglinide Calcium |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510428259.0A CN105153012B (en) | 2015-07-20 | 2015-07-20 | A kind of preparation method of Mitiglinide Calcium |
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| CN105153012B CN105153012B (en) | 2018-01-02 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101973926A (en) * | 2010-11-05 | 2011-02-16 | 威海迪素制药有限公司 | Method for preparing R-mitiglinide calcium |
| CN102101838A (en) * | 2010-12-06 | 2011-06-22 | 张家港田由新材料科技有限公司 | Preparation method of mitiglinide calcium |
| CN102382033A (en) * | 2010-08-31 | 2012-03-21 | 凯瑞斯德生化(苏州)有限公司 | Preparation methods for optical activity mitiglinide ester and mitiglinide salt |
-
2015
- 2015-07-20 CN CN201510428259.0A patent/CN105153012B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102382033A (en) * | 2010-08-31 | 2012-03-21 | 凯瑞斯德生化(苏州)有限公司 | Preparation methods for optical activity mitiglinide ester and mitiglinide salt |
| CN101973926A (en) * | 2010-11-05 | 2011-02-16 | 威海迪素制药有限公司 | Method for preparing R-mitiglinide calcium |
| CN102101838A (en) * | 2010-12-06 | 2011-06-22 | 张家港田由新材料科技有限公司 | Preparation method of mitiglinide calcium |
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Effective date of registration: 20240123 Address after: 712000 Factory Building No. 5, South Zone 1, Hongshengxing Aviation Technology Industrial Park, Dunhua Road, Airport New City, Xixian New Area, Xi'an City, Shaanxi Province Patentee after: Xi'an Meinan Biotechnology Co.,Ltd. Country or region after: China Address before: Gehu Lake Road Wujin District 213164 Jiangsu city of Changzhou province No. 1 Patentee before: CHANGZHOU University Country or region before: China |