CN114702416A - Method for efficiently preparing montelukast sodium side chain intermediate - Google Patents
Method for efficiently preparing montelukast sodium side chain intermediate Download PDFInfo
- Publication number
- CN114702416A CN114702416A CN202210327100.XA CN202210327100A CN114702416A CN 114702416 A CN114702416 A CN 114702416A CN 202210327100 A CN202210327100 A CN 202210327100A CN 114702416 A CN114702416 A CN 114702416A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction
- reagent
- cyanide
- sodium
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/02—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of thiols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/16—Preparation of halogenated hydrocarbons by replacement by halogens of hydroxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
- C07C29/149—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof with hydrogen or hydrogen-containing gases
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C327/00—Thiocarboxylic acids
- C07C327/20—Esters of monothiocarboxylic acids
- C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Abstract
The invention discloses a method for efficiently preparing a montelukast sodium side chain intermediate, and belongs to the technical field of biological pharmacy. The method comprises the steps of taking 1, 1-cyclopropyl dicarboxylic acid as a raw material, mixing the raw material with hydrogen to react, then carrying out catalytic chlorination by using Lewis acid, then carrying out addition reaction with sodium cyanide, then carrying out reaction with a mercapto reagent, and finally carrying out alkaline hydrolysis to obtain the target compound. The preparation method has the advantages of short process route, simplified process steps, low cost, high yield, high product purity and good industrial application prospect.
Description
Technical Field
The invention relates to the technical field of biological pharmacy, in particular to a preparation process of a montelukast sodium side chain intermediate.
Background
Montelukast sodium, an antiasthmatic, anti-inflammatory and antiallergic agent, is used for the prevention and long-term treatment of asthma, including the prevention of daytime and nighttime asthmatic symptoms, the treatment of aspirin-sensitive asthmatics, and the prevention of exercise-induced bronchoconstriction. The chemical name is 1- [ [ [ (1R) -1- [3- [ (1E) -2- (7-chloro-2-quinoline) ethenyl ] phenyl ] -3- [2- (1-hydroxy-1-methylethyl) phenyl ] propyl ] thio ] methyl ] cyclopropane sodium acetate, the structural formula is as follows:
by analyzing the structural formula, 1- (mercaptomethyl) cyclopropyl acetic acid or a derivative thereof of a side chain part is a key intermediate for synthesizing montelukast sodium, and 1-hydroxymethyl cyclopropyl acetonitrile is a key intermediate for synthesizing the 1- (mercaptomethyl) cyclopropyl acetic acid.
At present, few reports on the synthesis of 1-mercaptomethylcyclopropylacetonitrile are reported, and WO2008058118A2 discloses a preparation process of 1-mercaptomethylcyclopropylacetonitrile: taking diethyl malonate as a starting material, preparing 1, 1-cyclopropyl dimethanol by cyclization and reduction, and synthesizing a target product by four-step reaction under the action of thionyl chloride, sodium cyanide, methane sulfonyl chloride and sodium methoxide in sequence. The specific route is as follows:
the method has long process route and complicated whole process.
The other method is to use 1-hydroxymethyl cyclopropyl acetonitrile as a raw material to respectively react with bromide, thiourea, alkali and metal to synthesize the 1-mercaptomethyl cyclopropyl acetic acid. The preparation method has long process route, and the preparation method needs to react for 12 hours at the temperature of 100 ℃, has high temperature and long time, is difficult to avoid side reaction and generates by-products, so that the purity of the 1-mercaptomethylcyclopropyl acetic acid product is low. As shown in scheme (1) (US patent US6512140B 1).
The preparation method in the prior art mostly adopts a traditional reaction kettle, the used time is as long as several hours or even tens of hours, the retention time of reactants is too long, and the generation of byproducts is caused.
Disclosure of Invention
The invention aims to solve the problems of high production cost, low yield, long route, long time and the like of the existing preparation process, and provides a preparation process of a montelukast sodium side chain intermediate so as to realize large-scale production of the montelukast sodium side chain intermediate.
The preparation process comprises the following specific scheme:
the invention provides a preparation method of a compound with a structure shown in formula 1, which comprises the following technical route:
specifically, the technical route and the operation steps are as follows:
step (1):
preparation of Material A: mixing water, methanol and 1, 1-cyclopropyl dicarboxylic acid;
preparing a material B: adding hydrogen to the methanol/water mixture;
conveying the materials A, B together into a fixed bed reactor, reacting for 10-150 s under the conditions of Ru-Sn-Pt/C catalyst or copper-chromium catalyst at 120-240 ℃ under 1-10MPa, wherein the heat exchange medium is ethylene glycol or a mixture of water and ethylene glycol;
and (3) decompressing and desolventizing the solvent of the material after the reaction is finished until the material is dry to obtain a compound 5.
Furthermore, the catalyst is a supported Ru catalyst added with Sn andor Pt, Re and the like, preferably a 6% Ru-5% Sn-3% Pt/C catalyst or a copper-chromium catalyst.
Further, the reaction temperature is 100 ℃ to 240 ℃, and can be, but is not limited to, 100 ℃, 120 ℃, 160 ℃, 200 ℃, 240 ℃, preferably 160 ℃.
Further, the reaction pressure is 1MPa to 10MPa, but not limited to 1MPa, 3MPa, 5MPa, 8MPa, 10MPa, preferably 6 MPa.
Step (2):
and (3) under the catalysis of Lewis acid, mixing the compound 5 with hydrogen chloride gas to obtain a compound 4.
Further, the feeding molar ratio of the 1, 1-cyclopropane dimethanol to the hydrogen chloride gas is 1:0.1 to 2.5, but not limited to 1:0.1, 1:0.2, 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.5, 1:1.7, 1:2, 1:2.3, 1:2.5, preferably 1: 2.2.
Further, the catalyst is a lewis acid, including but not limited to zinc chloride, aluminum trichloride, magnesium chloride.
And (3):
adding the compound 4 and sodium cyanide (potassium cyanide or other salts) solid or aqueous solution into an organic solvent, and stirring to react to obtain a compound 3.
Further, the feeding molar ratio of the compound 4 to the cyanide is 1: 0.1-2.5, preferably 1:1.2, and the solvent includes but is not limited to N, N-dimethylformamide, acetonitrile, methanol, and water; the cyaniding reagent is one of sodium cyanide, potassium cyanide and hydrocyanic acid, preferably sodium cyanide; the reaction temperature is 60-150 ℃, and preferably 90 ℃.
And (4):
adding the compound 3 and a sulfhydryl reagent into an organic solvent, and stirring for reaction to obtain a compound 2.
Further, the feeding molar ratio of the compound 3 to the thiol reagent is 1: 0.1-2.5, preferably 1:1.1, and the solvent includes but is not limited to N, N-dimethylformamide, acetonitrile, methanol; the mercapto reagent is one of thiourea, potassium thioacetate and methylsulfonyl chloride, and is preferably potassium thioacetate; the reaction temperature is 30-90 ℃, and preferably 45 ℃.
Further, the reaction temperature is 30-90 ℃, but not limited to 30 ℃, 45 ℃, 60 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, preferably 45 ℃.
And (5):
adding the compound 2 and alkali into a solvent, and stirring for reaction to obtain a compound 1.
Furthermore, the feeding molar ratio of the compound 2 to the alkali is 1: 0.1-2.5, preferably 1:1.1, the alkali reagent is one of sodium hydroxide and potassium hydroxide, preferably sodium hydroxide; the reaction temperature is 30-80 ℃, and preferably 45 ℃.
By adopting the technical scheme of the invention, the technical effects are as follows:
1. the first step of reaction of the invention adopts a continuous fixed bed reactor, the reaction time is shortened to hundreds of seconds, the safety is qualitatively improved compared with the traditional reaction kettle, the reaction time is greatly shortened, and the safety is increased;
2. the method has the advantages of short steps, few byproducts and environmental friendliness, and avoids using reagents with serious pollution, such as thionyl chloride, bromine and the like.
3. The preparation process route is short, the preparation process steps are simplified, and the preparation process route is 2-3 steps shorter than the traditional route;
4. the invention adopts the continuous fixed bed reactor to prepare the product, can realize continuous production, has high automation degree of the preparation method, is convenient to control, reduces the labor cost and has good industrial application prospect.
Detailed Description
For better understanding of the present invention, the following embodiments are provided to clearly and completely describe the technical solutions of the present invention, but the specific embodiments are not intended to limit the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Wherein the content of the first and second substances,
preparation of Material A: mixing methanol (15L), 1-cyclopropane dimethanol (100mol, 7.6kg) and water (15L), and stirring to dissolve;
preparing a material B: hydrogen gas;
respectively conveying A, B materials into a fixed bed reactor through a plunger pump, setting the flow rate of A, B materials through a counter pump, enabling the molar ratio of 1, 1-cyclopropane dimethanol to hydrogen to be 1:4, enabling the pressure to be 6MPa, and keeping the reaction at 160 ℃ for 10-150 s;
the reaction solution was desolventized under reduced pressure to dryness, and dried to obtain 5.94kg of compound 5 with a yield of 99.7%.
Example 2
59.4g of compound 5, 1.0g of zinc chloride, 46.7g of hydrogen chloride and 300ml of acetonitrile are uniformly mixed, reacted at 45 ℃ for 4 hours, and the solvent is evaporated under reduced pressure to obtain 80.4g of compound 4.
Example 3
Compound 4(80.4g, 582.6mmol), NaCN (31.4g, 640.9mmol) and EtOH (550mL) were added to a reaction flask, the temperature was slowly raised to 90 ℃ and the reaction was allowed to incubate for 20 hours. After the reaction is finished, the temperature is reduced to 45 ℃, ethanol is evaporated under reduced pressure, 200ml of toluene and 200ml of water are added into the system, liquid separation is carried out, and the toluene phase is evaporated to dryness to obtain a target product with the purity of 99.7%.
Example 4
Compound 3(23.6g, 182.6mmol), potassium thioacetate (25.0g, 219.1mmol) and ethanol (200mL) were added to a reaction flask, and the temperature was slowly raised to 45 ℃ and the reaction was maintained for 20 hours. After the reaction is finished, ethanol is evaporated under reduced pressure, 200ml of toluene and 200ml of water are added into the system, liquid separation is carried out, the toluene phase is evaporated to dryness, and the target product 2 is obtained, wherein the yield is 94.3%, and the purity is 98.7%.
Example 5
Compound 2(13.9g, 82.6mmol), sodium hydroxide (3.6g, 90.9mmol), and ethanol (200mL) were added to a reaction flask, and the temperature was slowly raised to 45 ℃ and the reaction was maintained for 20 hours. After the reaction, ethanol was distilled off under reduced pressure, and 100ml of toluene and 100ml of water were added to the system to separate the mixture. Adjusting the pH of the water phase to 3-4, adding 100ml of toluene into the water phase, and evaporating the toluene phase to dryness to obtain the target product 1, wherein the yield is 96.3 percent, and the purity is 98.5 percent.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention.
Claims (11)
1. The method for efficiently preparing the montelukast sodium side chain intermediate is characterized in that the intermediate has a structural formula
The technical route is as follows:
step (1), 1-cyclopropyl dicarboxylic acid is used as a raw material and is reduced by hydrogen to obtain a compound 5;
step (2), the compound 5 is subjected to Lewis acid catalytic chlorination to obtain a compound 4;
step (3), adding the compound 4 with sodium cyanide to obtain a compound 3;
reacting the compound 3 with a thiol reagent to obtain a compound 2;
step (5), the compound 2 is hydrolyzed by alkali to obtain a compound 1,
the structural formulas of the compound 1, the compound 2, the compound 3, the compound 4 and the compound 5 are respectively as follows:
2. the process according to claim 1, characterized in that step (1) is carried out in a continuous catalytic bed reactor.
3. The method of claim 1, wherein step (1) comprises:
preparation of material A: mixing water, methanol and 1, 1-cyclopropyl dicarboxylic acid;
preparing a material B: adding hydrogen to the methanol/water mixture;
conveying the preparation material A and the preparation material B together into a fixed bed reactor, wherein the catalyst is a supported Ru catalyst added with Sn and/or Pt and Re, preferably a 6% Ru-5% Sn-3% Pt/C catalyst or a copper-chromium catalyst, and reacts for 10-150 s under the conditions of 1-10MPa and 120-240 ℃, and the heat exchange medium is ethylene glycol or a mixture of water and ethylene glycol;
and (3) decompressing and desolventizing the solvent of the material after the reaction is finished until the material is dry to obtain the compound 5.
4. The method of claim 1, wherein step (2) comprises:
under the catalysis of the Lewis acid, the compound 4 is obtained by mixing the compound 5 with hydrogen chloride gas or other chlorinating agents including but not limited to thionyl chloride, phosphorus oxychloride and phosphorus trichloride.
5. The method according to claim 4, wherein the feeding molar ratio of the compound 5 to the hydrogen chloride in the step (2) is 1: 0.1-2.5, preferably 1: 2.2; the lewis acid includes but is not limited to zinc chloride, aluminum trichloride, magnesium chloride.
6. The method of claim 1, wherein step (3) comprises:
adding the compound 4 and sodium cyanide (potassium cyanide or other salts) solid or aqueous solution into an organic solvent, and stirring to react to obtain the compound 3.
7. The method according to claim 6, wherein the feeding molar ratio of the compound 4 to the cyanide in the step (3) is 1: 0.1-2.5, preferably 1:1.2, and the solvent includes but is not limited to N, N-dimethylformamide, acetonitrile, methanol, water; the cyaniding reagent is one of sodium cyanide, potassium cyanide and hydrocyanic acid, preferably sodium cyanide; the reaction temperature is 60-150 ℃, and preferably 90 ℃.
8. The method of claim 1, wherein the step (4) comprises:
and adding the compound 3 and a sulfhydryl reagent into an organic solvent, and stirring for reaction to obtain the compound 2.
9. The method according to claim 8, wherein the molar ratio of the compound 3 to the thiol reagent in step (4) is 1: 0.1-2.5, preferably 1:1.1, and the solvent includes but is not limited to N, N-dimethylformamide, acetonitrile, methanol; the sulfhydryl reagent is one of thiourea, potassium thioacetate and methylsulfonyl chloride, and preferably potassium thioacetate; the reaction temperature is 30-150 ℃, and preferably 45 ℃.
10. The method of claim 1, wherein step (5) comprises:
adding the compound 2 and alkali into a solvent, and stirring for reaction to obtain the compound 1.
11. The method according to claim 10, wherein the compound 2 and the base are fed in the step (5) at a molar ratio of 1: 0.1-2.5, preferably 1:1.1, and the base reagent is one of sodium hydroxide and potassium hydroxide, preferably sodium hydroxide; the reaction temperature is 30-80 ℃, and preferably 45 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210327100.XA CN114702416A (en) | 2022-03-30 | 2022-03-30 | Method for efficiently preparing montelukast sodium side chain intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210327100.XA CN114702416A (en) | 2022-03-30 | 2022-03-30 | Method for efficiently preparing montelukast sodium side chain intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114702416A true CN114702416A (en) | 2022-07-05 |
Family
ID=82170912
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210327100.XA Pending CN114702416A (en) | 2022-03-30 | 2022-03-30 | Method for efficiently preparing montelukast sodium side chain intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114702416A (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1143065A (en) * | 1995-02-21 | 1997-02-19 | 拜尔公司 | Method for preparing carboxymethyl cyclopropane |
| GB2312896A (en) * | 1996-05-10 | 1997-11-12 | Merck & Co Inc | Synthesis of 1,1-bis(hydroxymethyl)cyclopropane |
| US6495730B1 (en) * | 1999-09-21 | 2002-12-17 | Asahi Kasei Kabushiki Kaisha | Catalysts for hydrogenation of carboxylic acid |
| WO2008058118A2 (en) * | 2006-11-06 | 2008-05-15 | Dr. Reddy's Labortories, Ltd. | Preparation of montelukast and its salts |
| CN101200442A (en) * | 2007-12-06 | 2008-06-18 | 台耀化学股份有限公司 | Method for preparing [1-(mercapto methyl) cyclopropyl] acetate and derivatives thereof |
| CN112094212A (en) * | 2020-09-07 | 2020-12-18 | 宿迁盛基医药科技有限公司 | Preparation method of montelukast sodium side chain |
| CN114591140A (en) * | 2022-03-24 | 2022-06-07 | 江苏阿尔法药业股份有限公司 | Montelukast sodium intermediate, preparation method thereof and preparation method using intermediate |
-
2022
- 2022-03-30 CN CN202210327100.XA patent/CN114702416A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1143065A (en) * | 1995-02-21 | 1997-02-19 | 拜尔公司 | Method for preparing carboxymethyl cyclopropane |
| GB2312896A (en) * | 1996-05-10 | 1997-11-12 | Merck & Co Inc | Synthesis of 1,1-bis(hydroxymethyl)cyclopropane |
| US6495730B1 (en) * | 1999-09-21 | 2002-12-17 | Asahi Kasei Kabushiki Kaisha | Catalysts for hydrogenation of carboxylic acid |
| WO2008058118A2 (en) * | 2006-11-06 | 2008-05-15 | Dr. Reddy's Labortories, Ltd. | Preparation of montelukast and its salts |
| CN101200442A (en) * | 2007-12-06 | 2008-06-18 | 台耀化学股份有限公司 | Method for preparing [1-(mercapto methyl) cyclopropyl] acetate and derivatives thereof |
| CN112094212A (en) * | 2020-09-07 | 2020-12-18 | 宿迁盛基医药科技有限公司 | Preparation method of montelukast sodium side chain |
| CN114591140A (en) * | 2022-03-24 | 2022-06-07 | 江苏阿尔法药业股份有限公司 | Montelukast sodium intermediate, preparation method thereof and preparation method using intermediate |
Non-Patent Citations (2)
| Title |
|---|
| VIDONNE, ANNICK 等: "Integrating replication processes with mechanically interlocked molecular architectures", 《TETRAHEDRON》, pages 8464 - 8475 * |
| ZAKHARKIN, L. I. 等: "Synthesis of pentadecanedioic acid from cyclododecanone or dodecanedioic acid", 《ZHURNAL ORGANICHESKOI KHIMII》, pages 326 - 330 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN110862310B (en) | Synthesis method of cyclopropyl methyl ketone | |
| CN111704555A (en) | Method for synthesizing 4-methoxy-2-nitroaniline by adopting continuous flow reactor | |
| CN109369545B (en) | Synthesis process of 2-methyl-5-pyrazine formate | |
| CN103664923B (en) | The preparation method of Nifuratel | |
| CN110862323A (en) | Synthesis method of diaminodiphenylethane compound | |
| WO2015078235A1 (en) | Method for preparing medetomidine intermediate | |
| CN112979498A (en) | Preparation method of 3-fluoro-4-trifluoromethyl benzonitrile | |
| CN114702416A (en) | Method for efficiently preparing montelukast sodium side chain intermediate | |
| CN113698276B (en) | Synthesis method of 2, 6-dihydroxytoluene | |
| CN112321399B (en) | Preparation method of chemical intermediate | |
| CN103896858A (en) | Technology for preparing cytosine | |
| CN112358404A (en) | Preparation method of 2-chloro-6-methylaniline | |
| CN100463898C (en) | Preparation method of 3,3'-dimethyl-4,4'-diamino dibenzyl methane | |
| CN103755706B (en) | A kind of environment-friendly preparation method synthesizing folic acid | |
| CN108516942B (en) | Preparation method of levorotatory milnacipran hydrochloride | |
| CN109851551A (en) | A method of synthesis 3- bromine isonicotinic acid intermediate | |
| CN109627209B (en) | Preparation method of 2- (trifluoromethyl) pyridine-3-formaldehyde (I) | |
| CN102675310B (en) | Method for preparing pyrazol heteroaromatic compound | |
| CN114195638B (en) | Preparation method of phenyl o-hydroxybenzoate | |
| CN107652195A (en) | A kind of preparation method of 1 amino cyclopropanecarboxylic acid | |
| CN114805218B (en) | Preparation method of rosuvastatin calcium intermediate | |
| CN107586279A (en) | A kind of new synthetic method of Gefitinib | |
| CN113072471B (en) | Lifeiste intermediate and preparation method thereof | |
| CN107954981B (en) | Method for synthesizing alpha-ethyl azacycloheptane-2-ketone substituted pyridine compound | |
| CN114605283A (en) | Method for efficiently preparing montelukast sodium side chain intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20221014 Address after: 404002 Rooms 5-01, 5-02, 5-03, 5-04, 5-05, Building 4, Wanzhou Science and Technology Innovation Center, No. 1 Mengzi Middle Road, Gaofeng Town, Wanzhou District, Chongqing (Wanzhou Economic Development Zone) Applicant after: Chongqing Puyou Biomedical Co.,Ltd. Address before: Room 301, building 1, No. 19, Tianrong street, Daxing biomedical industry base, Zhongguancun Science Park, Daxing District, Beijing 102600 Applicant before: Famres medical technology (Beijing) Co.,Ltd. |