CN114573489B - Separation method of carboprost - Google Patents
Separation method of carboprost Download PDFInfo
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- CN114573489B CN114573489B CN202210233529.2A CN202210233529A CN114573489B CN 114573489 B CN114573489 B CN 114573489B CN 202210233529 A CN202210233529 A CN 202210233529A CN 114573489 B CN114573489 B CN 114573489B
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- carboprost
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- chiral amine
- extraction
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- DLJKPYFALUEJCK-MRVZPHNRSA-N carboprost Chemical compound CCCCC[C@](C)(O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C\CCCC(O)=O DLJKPYFALUEJCK-MRVZPHNRSA-N 0.000 title claims abstract description 51
- 229960003395 carboprost Drugs 0.000 title claims abstract description 50
- 238000000926 separation method Methods 0.000 title claims description 8
- 239000000047 product Substances 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 14
- -1 amine compound Chemical class 0.000 claims abstract description 10
- 239000012043 crude product Substances 0.000 claims abstract description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 20
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- GEJJWYZZKKKSEV-UONOGXRCSA-N (1r,2s)-2-amino-1,2-diphenylethanol Chemical compound C1([C@@H](O)[C@@H](N)C=2C=CC=CC=2)=CC=CC=C1 GEJJWYZZKKKSEV-UONOGXRCSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 230000020477 pH reduction Effects 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 3
- 230000008025 crystallization Effects 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 abstract description 7
- 230000003287 optical effect Effects 0.000 abstract description 2
- 150000003839 salts Chemical class 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 238000001514 detection method Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical group [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 208000036029 Uterine contractions during pregnancy Diseases 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 1
- 238000007239 Wittig reaction Methods 0.000 description 1
- BGABKEVTHIJBIW-XVKPBYJWSA-N [(1s,4r)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonyl chloride Chemical compound C1C[C@]2(CS(Cl)(=O)=O)C(=O)C[C@H]1C2(C)C BGABKEVTHIJBIW-XVKPBYJWSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 229940127293 prostanoid Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 230000033458 reproduction Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 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 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for separating carboprost, which comprises the steps of reacting a carboprost crude product with an amine compound with optical activity, splitting and purifying to obtain a carboprost pure product. According to the technical scheme, the crude product of the carboprost is reacted with chiral amine to obtain salt, and then post-treatment such as resolution is carried out, so that the carboprost is prepared with high purity and low cost, and the method is suitable for large-scale popularization and application.
Description
Technical Field
The invention belongs to the technical field of synthesis of small molecular medicines, and particularly relates to a separation method of carboprost.
Background
Prostaglandins (abbreviated as PG) are bioactive substances and have physiological effects on reproduction, cardiovascular, urinary and nervous systems, and carboprost belongs to prostanoid compounds, and has the effects of softening and dilating cervix, increasing uterine contraction frequency and contraction amplitude, and enhancing uterine contraction, and the structural formula is shown as follows:
in recent years, a great deal of research has been conducted on the synthesis of carboprost, but there is still a problem in that the optical activity of the product is not sufficiently satisfactory. The carboprost used for clinical treatment has a specific configuration, so that how to effectively obtain the active isomer of the carboprost has great significance for subsequent administration.
The patent application with the application number of CN201810119119.9 discloses a synthesis method of carboprost and tromethamine carboprost, wherein the method specifically discloses a method for preparing carboprost by introducing an alkyl silicon protecting group when a ketone carbonyl at the 15-position reacts with a Grignard reagent and removing the alkyl silicon protecting group after the reaction is finished, so as to realize the technical effects of reducing isomers and easily separating products, but the introduced alkyl silicon protecting group has a certain steric hindrance and can cause the follow-up reaction to be difficult to carry out, so that the yield and purity of the carboprost still have a larger promotion space, and the problems of complex reaction steps and long routes exist.
Patent application No. CN201911054580.1 discloses a method for separating a carboprost isomer, wherein the method specifically discloses a method for separating chiral hydroxyl in a carboprost intermediate compound (shown as the following) by using a resolution reagent, namely D-camphor-10-sulfonyl chloride, to separate the isomer in advance, and then carrying out hydrolysis and Wittig reaction to obtain a single configuration of the carboprost:
however, the method separates 15-bit isomer in advance, so that the possibility of 15-bit hydroxyl configuration conversion in subsequent reaction exists, and the stability of the method cannot be effectively ensured. And thus are not suitable for mass production.
In view of the foregoing, there is a need for a process for separating crude carboprost in high yield and purity to obtain carboprost.
Disclosure of Invention
Aiming at the problem that the yield and the product purity are unsatisfactory in the method for separating the crude product of the carboprost in the prior art, the invention provides a novel separation method, and the carboprost crude product is separated and purified after being reacted with a chiral amine compound to obtain the carboprost, so that the carboprost can be separated with excellent yield and purity, the production cost can be effectively reduced, and the mass production is facilitated.
In order to achieve the technical purpose, the invention provides the following technical scheme: a method for separating carboprost comprises the following specific steps:
the crude product of the carboprost reacts with chiral amine compounds in a solvent, and the pure product of the carboprost is obtained after resolution and purification.
Further, the chiral amine compound is an aryl-substituted compound having a chiral amine structure.
Further, the chiral amine compound is a compound with chiral amine structure and substituted by aryl and hydroxy.
Further, the chiral amine compound is (1R, 2S) - (-) -2-amino-1, 2-diphenylethanol.
Further, the resolution is particularly recrystallized.
Still further, the recrystallization is to cool to room temperature after heating to 30-50 ℃ and to stand for 1-48 hours.
Further, the purification specifically comprises acidification, extraction and crystallization.
Further, the acidification is to adjust the pH to 3-5 by using a hydrochloric acid aqueous solution with the mass fraction lower than 20%.
Still further, the pH is adjusted to 3-4.
Further, the extraction is to extract the solution obtained after acidification with an aprotic solvent, and the organic phases are combined.
Further, the crystallization is to dissolve the product obtained after extraction in a solvent, heat to 30-60 ℃, then reduce to 0-15 ℃ and stand for 1-48 hours.
Further, the solvent is a mixture of an alcohol having 1 to 4 carbon atoms and an ether having 1 to 6 carbon atoms.
Further, the alcohol with the carbon number of 1-4 comprises methanol, ethanol, n-propanol or isopropanol;
still further, ethanol or isopropanol;
further, the ether with the carbon number of 1-6 is diethyl ether, propyl ether or methyl tertiary butyl ether;
still further, methyl tertiary butyl ether.
Still further, the volume ratio of the alcohol having 1 to 4 carbon atoms to the ether having 1 to 6 carbon atoms is 1 to 5:5 to 20.
By adopting the technology, compared with the prior art, the invention has the remarkable advantages that:
1) The yield and purity of the carboprost prepared from the carboprost crude product can be obviously improved, the purity and activity of the medicament are not adversely affected, the recycling of the reagent can be realized, and the influence on the environment is reduced;
2) The chiral amine compound and the crude product of the carboprost are salified, split and post-treated, so that the carboprost can be separated in high yield and high purity, and the method has the advantages of low reagent cost and extremely high cost performance.
Detailed Description
In order to make the technical scheme and advantages of the present invention more apparent, the present invention will be further described in detail with reference to specific examples, but the scope of the present invention is not limited thereto.
Example 1
1) Reacting crude carboprost with chiral amine:
200mL of ethanol and 800mL of methyl tert-butyl ether are added into a four-necked flask at room temperature, 36.85g of crude carboprost product shown in a formula III is added, the mixture is stirred uniformly at room temperature, 10.66g of (1R, 2S) - (-) -2-amino-1, 2-diphenylethanol is added dropwise and heated to 35 ℃, the reaction is carried out for 10 minutes after heat preservation, the temperature is reduced to room temperature, the mixture is kept for 12 hours, the precipitated solid is filtered, a mixture of 100mL of ethanol and methyl tert-butyl ether (volume ratio of 1:4) is used for leaching, and then the mixture is dried, thus 29.09g of solid compound of the formula II is obtained, and the detection purity of High Performance Liquid Chromatography (HPLC) is 99.5%.
2) Preparation of pure carboprost:
adding the compound of the formula II obtained in the previous step and 200mL of pure water into a four-necked flask, adding dilute hydrochloric acid to adjust the pH to 3-4, stirring at room temperature for 20 minutes, extracting by using ethyl acetate (200 mL multiplied by 3), washing the organic phase by saturated saline after combining, heating the product to 30 ℃ while stirring after decompressing and desolventizing the product into a mixture of 200mL of ethanol and methyl tertiary butyl ether (volume ratio is 1:4), maintaining the temperature for 30 minutes, reducing the temperature to 10 ℃, standing for 12 hours, filtering to obtain a solid, washing and drying to obtain a pure product of the carboprost shown as the formula I, wherein the purity of 18.41g is 99.3 percent by HPLC detection, and the ee value is as shown in the formula I: 100%.
Example 2
1) Reacting crude carboprost with chiral amine:
200mL of methanol and 800mL of methyl tert-butyl ether are added into a four-necked flask at room temperature, 36.85g of crude carboprost product shown in a formula III is added, the mixture is stirred uniformly at room temperature, 10.66g of (1R, 2S) - (-) -2-amino-1, 2-diphenylethanol is added dropwise and heated to 35 ℃, the reaction is carried out for 10 minutes after heat preservation, the temperature is reduced to room temperature, the mixture is kept for 12 hours, the precipitated solid is filtered, a mixture of 100mL of methanol and methyl tert-butyl ether (volume ratio of 1:4) is used for leaching, and then the mixture is dried, so that 28.76g of solid compound of the formula II is obtained, and the detection purity of High Performance Liquid Chromatography (HPLC) is 98.9%.
2) Preparation of pure carboprost:
adding the compound of the formula II obtained in the previous step and 200mL of pure water into a four-necked flask, adding dilute hydrochloric acid to adjust the pH to 3-4, stirring at room temperature for 20 minutes, extracting by using ethyl acetate (200 mL multiplied by 3), washing the organic phase by saturated saline after combining, heating the product to 30 ℃ while stirring after decompressing and desolventizing the product into a mixture of 200mL of methanol and methyl tertiary butyl ether (volume ratio is 1:4), maintaining the temperature for 30 minutes, reducing the temperature to 10 ℃, standing for 12 hours, filtering to obtain a solid, washing and drying to obtain a pure product of the carboprost shown as the formula I, wherein the purity of 18.02g is 98.8 percent by HPLC detection, and the ee value is shown as the formula I: 99.97%.
Example 3
1) Reacting crude carboprost with chiral amine:
200mL of isopropanol and 800mL of methyl tert-butyl ether were added to a four-necked flask at room temperature, 36.85g of crude carboprost represented by formula III was added, the mixture was stirred uniformly at room temperature, 10.66g of (1R, 2S) - (-) -2-amino-1, 2-diphenylethanol was added dropwise and heated to 35℃to react for 10 minutes, the reaction was allowed to stand at room temperature for 12 hours, and the precipitated solid was filtered and eluted with 100mL of a mixture of isopropanol and methyl tert-butyl ether (volume ratio: 1:4) and dried to give 29.09g of a solid compound of formula II having a High Performance Liquid Chromatography (HPLC) detection purity of 99.8%.
2) Preparation of pure carboprost:
adding the compound of the formula II obtained in the previous step and 200mL of pure water into a four-necked flask, adding dilute hydrochloric acid to adjust the pH to 3-4, stirring at room temperature for 20 minutes, extracting by using ethyl acetate (200 mL multiplied by 3), washing the organic phase by saturated saline after combining, heating the product to 30 ℃ while stirring after decompressing and desolventizing the product into a mixture of 200mL of isopropanol and methyl tertiary butyl ether (volume ratio is 1:4), maintaining the temperature for 30 minutes, reducing the temperature to 15 ℃, standing for 10 hours, filtering to obtain a solid, washing and drying to obtain a pure product of the carboprost shown as the formula I, wherein the purity of 18.42g is 99.7 percent by HPLC (ee value): 100%.
Example 4
1) Reacting crude carboprost with chiral amine:
200mL of isopropyl alcohol and 800mL of diethyl ether are added into a four-necked flask at room temperature, 36.85g of crude carboprost product shown in a formula III is added, the mixture is stirred uniformly at room temperature, 10.66g of (1R, 2S) - (-) -2-amino-1, 2-diphenylethanol is added dropwise and heated to 35 ℃, the temperature is kept for 10 minutes, the reaction is cooled to room temperature, the reaction mixture is kept stand for 12 hours, the precipitated solid is filtered, and the solid is leached and dried by using a mixture of 100mL of isopropyl alcohol and diethyl ether (volume ratio is 1:4), so as to obtain 28.32g of solid compound shown in the formula II, and the detection purity of the solid is 0.981 percent by High Performance Liquid Chromatography (HPLC).
2) Preparation of pure carboprost:
adding the compound of the formula II obtained in the previous step and 200mL of pure water into a four-necked flask, adding dilute hydrochloric acid to adjust the pH to 3-4, stirring at room temperature for 20 minutes, extracting by using ethyl acetate (200 mL multiplied by 3), washing the organic phase by saturated saline after combining, heating the product to 30 ℃ while stirring after decompressing and desolventizing 200mL of a mixture of isopropanol and diethyl ether (volume ratio is 1:4), maintaining the temperature to 15 ℃ after 30 minutes, standing for 10 hours, filtering to obtain a solid, washing and drying to obtain 17.56g of a pure product of the carboprost shown in the formula I, and detecting the purity by HPLC to 97.7%, and ee value: 98.3%.
The above examples are only preferred embodiments of the present invention, and should not be construed as limiting the invention, and the scope of the present invention should be defined by the claims, including the equivalents of the technical features in the claims, and any person skilled in the art who is within the scope of the present invention shall be covered by the scope of the present invention.
Claims (5)
1. The method for separating the carboprost is characterized by comprising the following specific steps of: the crude product of the carboprost is reacted with a chiral amine compound in a solvent, and the chiral amine compound is (1R, 2S) - (-) -2-amino-1, 2-diphenylethanol, and the solvent is ethanol or a mixture of isopropanol and methyl tertiary butyl ether with the volume ratio of 1-5:5-20, so that the pure product of the carboprost is obtained.
2. The separation process according to claim 1, wherein the resolution is in particular recrystallisation.
3. The separation method according to claim 1, wherein the purification comprises acidification, extraction and crystallization.
4. A separation process according to claim 3, wherein the acidification is to adjust the pH to 3-5 using an aqueous hydrochloric acid solution with a mass fraction lower than 20%.
5. A separation process according to claim 3, wherein the extraction is extraction of the acidified solution with an aprotic solvent and combining the organic phases.
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| CN202210233529.2A CN114573489B (en) | 2022-03-10 | 2022-03-10 | Separation method of carboprost |
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| CN202210233529.2A CN114573489B (en) | 2022-03-10 | 2022-03-10 | Separation method of carboprost |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1639109A (en) * | 2000-09-29 | 2005-07-13 | 布里斯托尔-迈尔斯斯奎布公司 | Dynamic resolution of isomers and resolved isomers |
| WO2017093770A1 (en) * | 2015-12-01 | 2017-06-08 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | Process for the preparation of carboprost and its tromethamine salt |
| CN107759623A (en) * | 2016-08-23 | 2018-03-06 | 苏州旺山旺水生物医药有限公司 | Intermediate of JAK inhibitor and preparation method thereof |
| CN113548993A (en) * | 2021-09-01 | 2021-10-26 | 河北化工医药职业技术学院 | Preparation method of carboprost |
-
2022
- 2022-03-10 CN CN202210233529.2A patent/CN114573489B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1639109A (en) * | 2000-09-29 | 2005-07-13 | 布里斯托尔-迈尔斯斯奎布公司 | Dynamic resolution of isomers and resolved isomers |
| WO2017093770A1 (en) * | 2015-12-01 | 2017-06-08 | CHINOIN Gyógyszer és Vegyészeti Termékek Gyára Zrt. | Process for the preparation of carboprost and its tromethamine salt |
| CN107759623A (en) * | 2016-08-23 | 2018-03-06 | 苏州旺山旺水生物医药有限公司 | Intermediate of JAK inhibitor and preparation method thereof |
| CN113548993A (en) * | 2021-09-01 | 2021-10-26 | 河北化工医药职业技术学院 | Preparation method of carboprost |
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