CN112159398A - Preparation method of paroxetine hydrochloride - Google Patents
Preparation method of paroxetine hydrochloride Download PDFInfo
- Publication number
- CN112159398A CN112159398A CN202011083040.9A CN202011083040A CN112159398A CN 112159398 A CN112159398 A CN 112159398A CN 202011083040 A CN202011083040 A CN 202011083040A CN 112159398 A CN112159398 A CN 112159398A
- Authority
- CN
- China
- Prior art keywords
- paroxetine hydrochloride
- solvent
- acid
- stirring
- filtering
- 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
- AHOUBRCZNHFOSL-UHFFFAOYSA-N 3-(1,3-benzodioxol-5-yloxymethyl)-4-(4-fluorophenyl)piperidine Chemical compound C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 title claims abstract description 97
- 229960005183 paroxetine hydrochloride Drugs 0.000 title claims abstract description 47
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 22
- 238000003756 stirring Methods 0.000 claims abstract description 21
- 238000001816 cooling Methods 0.000 claims abstract description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 238000001035 drying Methods 0.000 claims abstract description 11
- 238000010438 heat treatment Methods 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 7
- 238000002425 crystallisation Methods 0.000 claims abstract description 4
- 230000008025 crystallization Effects 0.000 claims abstract description 4
- 238000004321 preservation Methods 0.000 claims abstract description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 238000007670 refining Methods 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000000843 powder Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 4
- 239000012452 mother liquor Substances 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 3
- 239000003651 drinking water Substances 0.000 description 3
- 235000020188 drinking water Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229960002296 paroxetine Drugs 0.000 description 3
- 230000003321 amplification Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 210000002569 neuron Anatomy 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 208000020401 Depressive disease Diseases 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 210000000748 cardiovascular system Anatomy 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 208000019906 panic disease Diseases 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 210000003568 synaptosome Anatomy 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- 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
Abstract
The invention relates to a preparation method of paroxetine hydrochloride, which comprises the steps of (a) adding a refined solvent and a small amount of acid into paroxetine hydrochloride, heating and stirring to dissolve the solution; (b) optionally adding a proper amount of activated carbon, and stirring for a certain time under heat preservation; (c) filtering, cooling and crystallizing; (d) and (5) after crystallization, filtering and drying to obtain pure paroxetine hydrochloride. The preparation method of paroxetine hydrochloride provided by the invention is simple to operate, cheap in raw materials and mild in conditions. The obtained pure paroxetine hydrochloride does not turn red.
Description
Technical Field
The invention relates to a preparation method of paroxetine hydrochloride, belonging to the field of pharmaceutical chemistry
Background
Paroxetine hydrochloride formula I was developed by Smith-kline Beecham and has been clinically approved for the treatment of depression, panic disorder, and obsessive-compulsive concepts and behaviors, and was first introduced in the United kingdom in 2 months 1991 and introduced in the United states in 10 months 1992. The paroxetine hydrochloride phenyl piperidine derivative can powerfully and selectively inhibit reuptake of 5-hydroxytryptamine of neuron synaptosomes, enables 5-hydroxytryptamine among neuron synapses to accumulate, promotes transmission of the 5-hydroxytryptamine, plays a role in resisting depression, has weak effect on other transmitters, has small influence on a physical nervous system and a cardiovascular system, and belongs to SSRIs medicaments.
Paroxetine hydrochloride presents a general technical problem-the production or storage of Paroxetine hydrochloride API may cause a color change (pinkish). Patent CN1516585 proposes that the impurity in paroxetine hydrochloride acts in changing colour to pink, the Relative Retention Time (RRT) of the impurity in High Pressure Liquid Chromatography (HPLC) being about 1.5, however at lower levels of the impurity, a colour change can still occur, revealing that other impurities may also act in changing colour.
The inventor finds that the existing paroxetine production process has certain probability to obtain a pink paroxetine product, but the pink paroxetine product is difficult to remove by the conventional purification method, and the pink product can be converted into a white product by refining for many times. Therefore, it is necessary to develop a process for stably preparing paroxetine hydrochloride in white.
Disclosure of Invention
The invention provides a method for preparing paroxetine hydrochloride, which comprises the following steps:
(a) adding a refined solvent and a small amount of acid into the paroxetine hydrochloride crude product, heating and stirring to dissolve the solution;
(b) optionally adding a proper amount of activated carbon, and stirring for a certain time under heat preservation;
(c) filtering, cooling and crystallizing;
(d) and (5) after crystallization, filtering and drying to obtain a finished product of paroxetine hydrochloride.
As a preferred embodiment of the present invention:
wherein the refined solvent in the step (a) is a single organic solvent or a mixed solution prepared from an organic solvent and water. Wherein the organic solvent is an organic solvent which can be mutually dissolved with water, and preferably methanol, ethanol and acetone.
The mass ratio of the volume dosage of the refined solvent to the paroxetine hydrochloride is 5-50 mL/g.
Wherein the acid in step (a) is an inorganic acid, such as hydrochloric acid, sulfuric acid, nitric acid, etc., preferably hydrochloric acid. The molar ratio of the acid dosage to the paroxetine hydrochloride dosage is 0.016-0.16, preferably 0.032.
The preparation method also comprises the steps of adding a proper amount of solvent after filtering in the step (c), and then cooling and crystallizing. The solvent is an organic solvent which can be mutually dissolved with water, such as methanol, ethanol, acetone and the like, and acetone is preferred. The mass ratio of the volume dosage of the solvent to the paroxetine hydrochloride is 5-50 mL/g.
In the method, when the activated carbon is added, the dosage of the activated carbon is 5-20% of the mass of the paroxetine hydrochloride.
The preparation method of paroxetine hydrochloride provided by the invention is simple to operate and mild in condition, and can stably obtain a white pure paroxetine hydrochloride.
Detailed Description
The present invention will be described in further detail with reference to the following examples, which should not be construed as limiting the scope of the present invention. In order to embody the purification effect of the invention, the raw materials adopted in the experimental process of the invention are all paroxetine hydrochloride in pink.
Example 1
Adding 12.5g of paroxetine hydrochloride pink, 62.5mL of acetone and 0.1mL of refined hydrochloric acid into a three-necked bottle in sequence, heating to 55-60 ℃, slowly dropwise adding purified water until the mixture is stirred and dissolved clearly (the amount of drinking water is about 4.4mL), filtering, adding 62.5mL of acetone into the filtrate, slowly cooling to-5-0 ℃, keeping the temperature and stirring for 2-4 hours, performing filter throwing and drying to obtain paroxetine hydrochloride. Yield: 85%, purity: 99.87 percent. Color: white crystalline powder.
Example 2
Adding 12.5g of paroxetine hydrochloride pink, 62.5mL of acetone and 0.5mL of refined hydrochloric acid into a three-necked bottle in sequence, heating to 55-60 ℃, slowly dropwise adding purified water until the mixture is stirred and dissolved clearly (the amount of drinking water is about 4.4mL), filtering, adding 62.5mL of acetone into the filtrate, slowly cooling to-5-0 ℃, keeping the temperature and stirring for 2-4 hours, performing filter throwing and drying to obtain paroxetine hydrochloride. Yield: 83%, purity: 99.89 percent. Color: white crystalline powder.
Example 3
Adding 12.5g of paroxetine hydrochloride pink, 62.5mL of methanol and 0.05mL of refined hydrochloric acid into a three-necked bottle in sequence, heating to 60-65 ℃, stirring to dissolve, filtering, slowly cooling to-5-0 ℃, keeping the temperature, stirring for 2-4 hours, filtering by throwing, and drying to obtain paroxetine hydrochloride. Yield: 80%, purity: 99.93 percent. Color: white crystalline powder.
Example 4
Adding 12.5g of paroxetine hydrochloride pink, 62.5mL of ethanol and 0.1mL of refined hydrochloric acid into a three-necked bottle in sequence, heating to 75-80 ℃, stirring to dissolve, filtering, slowly cooling to-5-0 ℃, keeping the temperature, stirring for 2-4 hours, filtering by throwing, and drying to obtain paroxetine hydrochloride. Yield: 82%, purity: 99.92 percent. Color: white crystalline powder.
Example 5
Adding 12.5g of paroxetine hydrochloride pink, 625mL of acetone and 0.1mL of refined hydrochloric acid into a three-necked bottle in sequence, heating to 55-60 ℃, filtering, slowly cooling to-5-0 ℃, keeping the temperature and stirring for 2-4 hours, filtering by throwing, and drying to obtain paroxetine hydrochloride. Yield: 75%, purity: 99.91 percent. Color: white crystalline powder.
Example 6
And (3) sequentially adding 500mL of paroxetine hydrochloride refined mother liquor (from the same proportion amplification in example 1) into a three-necked bottle, controlling the temperature to be 40-60 ℃, and concentrating under reduced pressure until the mother liquor is dry to obtain 10g of crude recovery. Adding 50mL of acetone and 0.1mL of refined hydrochloric acid, heating to 55-50 ℃, dropwise adding 2.6mL of purified water, and stirring to dissolve. Adding 1g of active carbon, keeping the temperature and stirring for 1 hour, and filtering to obtain filtrate. Adding 50mL of acetone into the filtrate, slowly cooling to 35 +/-5 ℃, cooling to-5-0 ℃, keeping the temperature and stirring for 1 hour, filtering, and drying the filter cake to obtain 8.1g (white crystalline powder) of the recovered paroxetine hydrochloride, wherein the recovery rate is 81% (yield/crude recovered matter is 100%), and the purity is 99.88%.
Example 7
And (3) sequentially adding 500mL of paroxetine hydrochloride refined mother liquor (from the same proportion amplification in example 1) into a three-necked bottle, controlling the temperature to be 40-60 ℃, and concentrating under reduced pressure until the mother liquor is dry to obtain 10g of crude recovery. Adding 50mL of acetone and 0.2mL of refined hydrochloric acid, heating to 55-50 ℃, dropwise adding 2.5mL of purified water, and stirring to dissolve. Adding 2g of active carbon, keeping the temperature and stirring for 1 hour, and filtering to obtain filtrate. Adding 50mL of acetone into the filtrate, slowly cooling to 35 +/-5 ℃, cooling to-5-0 ℃, stirring for 1 hour under the condition of heat preservation, filtering, and drying the filter cake to obtain 8.0g (white crystalline powder) of the recovered paroxetine hydrochloride, wherein the recovery rate is 80% (yield/crude recovered substance is 100%) and the purity is 99.84%. Comparative example 1:
adding 12.5g of paroxetine hydrochloride pink and 62.5mL of acetone into a three-necked bottle in sequence, heating to 55-60 ℃, slowly dropwise adding purified water until the mixture is dissolved clearly by stirring (the consumption of drinking water is about 4.4mL), filtering, adding 62.5mL of acetone into the filtrate, slowly cooling to-5-0 ℃, keeping the temperature and stirring for 2-4 hours, performing spin filtration, and drying to obtain paroxetine hydrochloride. Yield: 86%, purity: 99.8 percent. Color: pink crystalline powder.
Example 8:
and (3) stability investigation: the samples obtained in reference examples 1 to 7 remained white after being stored and observed at room temperature of 20 to 30 ℃ for 1 year.
Claims (10)
1. A process for the preparation of paroxetine hydrochloride which comprises the steps of:
(a) adding a refined solvent and a small amount of acid into paroxetine hydrochloride, heating, stirring and dissolving;
(b) optionally adding a proper amount of activated carbon, and stirring for a certain time under heat preservation;
(c) filtering, cooling and crystallizing;
(d) and (5) after crystallization, filtering and drying to obtain pure paroxetine hydrochloride.
2. The method according to claim 1, wherein (a) the refining solvent is a single organic solvent or a mixed solution of an organic solvent and water.
3. The method of claim 2, wherein the organic solvent is a water-miscible organic solvent, preferably methanol, ethanol, acetone.
4. The method according to claim 1 or 2, wherein the ratio of the volume dosage of the refining solvent to the mass of paroxetine hydrochloride is 5-50 mL/g.
5. The process according to claim 1, wherein (a) the acid is an inorganic acid, preferably hydrochloric acid, sulfuric acid, nitric acid.
6. The process according to claim 5, wherein the ratio of the amount of the acid to the moles of paroxetine hydrochloride is from 0.016 to 0.16, preferably 0.032.
7. The method according to claim 1, further comprising adding a proper amount of solvent after the filtration in step (c), and cooling for crystallization.
8. The process according to claim 7, the solvent is a water-miscible organic solvent, preferably methanol, ethanol, acetone.
9. The method according to claim 7, wherein the ratio of the volume dosage of the refining solvent to the mass of paroxetine hydrochloride is 5-50 mL/g.
10. The process according to claim 1, wherein the amount of activated carbon, when added, is 5-20% by mass of paroxetine hydrochloride.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011083040.9A CN112159398A (en) | 2020-10-12 | 2020-10-12 | Preparation method of paroxetine hydrochloride |
| CN202180066909.5A CN116348110A (en) | 2020-10-12 | 2021-10-12 | Paroxetine hydrochloride purification method |
| PCT/CN2021/123203 WO2022078312A1 (en) | 2020-10-12 | 2021-10-12 | Method for purifying paroxetine hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011083040.9A CN112159398A (en) | 2020-10-12 | 2020-10-12 | Preparation method of paroxetine hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112159398A true CN112159398A (en) | 2021-01-01 |
Family
ID=73868072
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011083040.9A Pending CN112159398A (en) | 2020-10-12 | 2020-10-12 | Preparation method of paroxetine hydrochloride |
| CN202180066909.5A Pending CN116348110A (en) | 2020-10-12 | 2021-10-12 | Paroxetine hydrochloride purification method |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202180066909.5A Pending CN116348110A (en) | 2020-10-12 | 2021-10-12 | Paroxetine hydrochloride purification method |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN112159398A (en) |
| WO (1) | WO2022078312A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022078312A1 (en) * | 2020-10-12 | 2022-04-21 | 浙江华海药业股份有限公司 | Method for purifying paroxetine hydrochloride |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1295572A (en) * | 1998-02-06 | 2001-05-16 | 史密丝克莱恩比彻姆有限公司 | Salt of paroxetine |
| IL159280A0 (en) * | 2001-06-14 | 2004-06-01 | Teva Pharma | A process for preparing paroxetine hcl which limits formation of pink colored compounds |
| CN102285973B (en) * | 2011-09-20 | 2013-03-06 | 海南美大制药有限公司 | Paroxetine hydrochloride compound and preparation method thereof |
| CN112159398A (en) * | 2020-10-12 | 2021-01-01 | 浙江华海药业股份有限公司 | Preparation method of paroxetine hydrochloride |
-
2020
- 2020-10-12 CN CN202011083040.9A patent/CN112159398A/en active Pending
-
2021
- 2021-10-12 WO PCT/CN2021/123203 patent/WO2022078312A1/en active Application Filing
- 2021-10-12 CN CN202180066909.5A patent/CN116348110A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022078312A1 (en) * | 2020-10-12 | 2022-04-21 | 浙江华海药业股份有限公司 | Method for purifying paroxetine hydrochloride |
Also Published As
| Publication number | Publication date |
|---|---|
| CN116348110A (en) | 2023-06-27 |
| WO2022078312A1 (en) | 2022-04-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2636939C2 (en) | Method for producing trihydroxyethyl rutoside | |
| EP1246831B1 (en) | Preparation method of azithromycin dihydrate | |
| CN112159398A (en) | Preparation method of paroxetine hydrochloride | |
| CN109485581B (en) | Method for refining levodopa | |
| CN106543025A (en) | A kind of preparation method of high-purity hydrochloric acid doxycycline | |
| CN109096129B (en) | Preparation method of L-carnitine tartrate | |
| CN101560188B (en) | Method for separating and purifying 2-methylimidazole crystal impurity | |
| CN113214333B (en) | Preparation method of high-purity pleocidin | |
| US1867274A (en) | Resolution of ephedrine and its homologues and of mandelic acid, and certain intermediates | |
| EP2341056B1 (en) | Crystallizing method of erythromycin | |
| KR20070024490A (en) | Process for the manufacture of lysergic acid | |
| DE69631608T2 (en) | PRODUCTION OF A CLAVULANIC ACID SALT | |
| MXPA06002938A (en) | Process for purifying mesotrione. | |
| CN106146403B (en) | A kind of purification process of the miscellaneous Shandong amine of grace | |
| CN113527338A (en) | Synthesis process of cefozopran hydrochloride | |
| CN110437248B (en) | Production method of milbemycins capable of shortening production cycle | |
| CN112661727B (en) | Purification method of 7- (2, 2-trichloroethyl oxycarbonyl) taxol | |
| US2978447A (en) | Preparation of p-aminobenzyl penicillin and derivatives thereof | |
| CN109422679B (en) | Purification of bedaquiline and preparation method of stable crystal form | |
| AU2008298402B2 (en) | Method for producing N-methacryloyl-4-cyano-3-trifluoromethylaniline | |
| CN112321582B (en) | Synthesis of tebipenem side chain and refining method of intermediate | |
| US11324771B2 (en) | Process for the preparation of hydroxocobalamin hydrochloride | |
| CN113121466B (en) | Recrystallizing solvent of acotiamide hydrochloride and refining method thereof | |
| CN109535179B (en) | Improved 6-APA extraction method | |
| CN111187255A (en) | Preparation method of dextro-ilaprazole potassium salt and preparation method of dextro-ilaprazole |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20210101 |