CN111960955B - Preparation method of terbutaline - Google Patents
Preparation method of terbutaline Download PDFInfo
- Publication number
- CN111960955B CN111960955B CN202010671179.9A CN202010671179A CN111960955B CN 111960955 B CN111960955 B CN 111960955B CN 202010671179 A CN202010671179 A CN 202010671179A CN 111960955 B CN111960955 B CN 111960955B
- Authority
- CN
- China
- Prior art keywords
- reaction
- terbutaline
- compound
- anhydride
- ethyl acetate
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/16—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by esterified hydroxyl radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of pharmacy, and particularly relates to a preparation method of terbutaline. The technical points are as follows: s1, adding a compound I and dichloromethane into a reaction kettle, stirring and dissolving, and then adding anhydride; s2, adding dilute alkaline water into the system after the reaction is finished, fully stirring and washing, collecting a dichloromethane phase, and carrying out reduced pressure distillation to obtain a yellow oily substance, namely a compound II; s3, adding a compound II, ethyl acetate, tert-butylamine, sodium hydroxide and an oxidation protective agent into a reaction kettle; s4, after the reaction in the step S3 is finished, adding purified water into the system to wash the reaction liquid in the step S3, collecting an ethyl acetate phase, and distilling the ethyl acetate phase under reduced pressure to obtain the terbutaline. The technical scheme provided by the invention reduces the treatment difficulty after the reaction, so that the intermediate compound is easy to separate from the reaction system, side reactions such as epoxy bond hydrolysis and the like are avoided, and the stability and yield of the final product terbutaline are increased.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a preparation method of terbutaline.
Background
Terbutaline is a short-acting beta 2-receptor agonist type COPD therapeutic drug developed by Aslicon, and is a clinical recommended drug for patients with mild or moderate COPD. Has lower dose-dependent side effects than other short-acting beta 2-receptor agonist terbutaline sulfate inhalants which are already on the market. Terbutaline is prepared by taking 3, 5-dibenzyloxy acetophenone as an initial raw material, brominating and condensing to obtain 2- (N-benzyl tert-butylamino) -1- (3, 5-dibenzyloxy phenyl) ethanone sulfate. Carrying out hydrogenation reduction and debenzylation to prepare terbutaline, adding water for dissolution, adjusting the pH value to 5.5 by alkali, evaporating water, and carrying out crystallization and purification on a large amount of methanol. The acid and alkali are used for adjusting pH to control the sulfate radical content, so that a large amount of salt is introduced, the methanol reflux purification solubility is low, and the methanol is used in a large amount. Meanwhile, water distillation is difficult, and oxidative degradation of products is easily caused. And then, sodium acetate is added into the terbutaline acetic acid solution, and the content of sulfate radicals is controlled by utilizing the solubility difference of sodium sulfate. In recent years, the prepared 2- (N-benzyl tertiary butylamino) -1- (3, 5-dibenzyloxyphenyl) ethanol is further hydrogenated and debenzylated to prepare terbutaline sulfate, the terbutaline sulfate is firstly hydrogenated and debenzylated, then is evaporated to dryness under pressure, distilled water is added, the pH value is adjusted by sulfuric acid and then is evaporated to dryness, and methanol is added for dissolution and crystallization. The most advanced method in the prior art is an industrial production method of high-purity terbutaline sulfate, which takes bambuterol hydrochloride as a starting material to prepare the terbutaline sulfate through alkaline hydrolysis and salification. The disadvantages are that the raw materials are high in the market price; the hydrolysis polyphenol is easy to be oxidized under the alkaline condition; the refining process has large solvent consumption, poor purification effect and excessive impurity content. Meanwhile, the generated terbutaline finished product is protected from being oxidized into the preparation difficulty in a reaction system. In the reported process, because the terbutaline sulfate has good water solubility, is easy to oxidize and has complicated post-treatment, the currently general process of evaporating a solvent to dryness is followed by methanol reflux and cooling crystallization, and the oxidation of terbutaline is easily caused under the high-temperature condition, so that the purity of the terbutaline is low. The problem of oxidation resistance is not well solved and the quality of the terbutaline final product is not significantly improved.
In view of the defects in the existing terbutaline preparation method, the inventor actively makes research and innovation based on practical experience and professional knowledge which are abundant for years in the design and manufacture of the product and by matching with the application of theory, so as to create a terbutaline preparation method, and an intermediate compound II of propionyl, butyryl or valeryl is formed by using reagents such as propionic anhydride, butyric anhydride or valeric anhydride, so that the polarity of the molecule is remarkably reduced, the selectivity of an organic phase-alkaline water extraction system is further improved, the intermediate compound II can be better separated from a reaction system, the difficulty of treatment after reaction is greatly reduced, and the stability and yield of the terbutaline are remarkably increased. After continuous research and design and repeated trial production and improvement, the invention with practical value is finally created.
Disclosure of Invention
The technical purpose of the invention is to provide a preparation method of terbutaline, the post-treatment operation of the method provided by the invention is simple, the purity of the obtained product is more than 99%, and the method has industrial value.
The technical purpose of the invention is realized by the following technical scheme:
the invention provides a method for preparing terbutaline, the reaction chemical equation is as follows:
wherein n is more than or equal to 1; the specific operation steps are as follows:
s1, adding a compound I and dichloromethane into a reaction kettle, stirring and dissolving, and then adding anhydride;
s2, adding dilute alkaline water into the system after the reaction is finished, fully stirring and washing, collecting a dichloromethane phase, and carrying out reduced pressure distillation to obtain a yellow oily substance, namely a compound II;
s3, adding the compound II, ethyl acetate, tert-butylamine, sodium hydroxide and an oxidation protective agent into a reaction kettle to react to obtain reaction liquid;
s4, after the reaction in the step S3 is finished, adding purified water into the system to wash the reaction liquid in the step S3, collecting an ethyl acetate phase, and distilling the ethyl acetate phase under reduced pressure to obtain the terbutaline.
Further, the acid anhydride in step S1 is any one of propionic anhydride, butyric anhydride or valeric anhydride. Propionic anhydride, butyric anhydride or valeric anhydride protects phenolic hydroxyl in the form of propionyl, butyryl or valeryl in the system, and because the polarity of the propionyl, butyryl or valeryl is small, the polarity of the molecules is obviously reduced, the selectivity of an organic phase-alkaline water extraction system is further improved, an intermediate compound II reaction system can be better separated out, and the yield and the purity of terbutaline are effectively improved.
Further, the dilute alkali solution in step S2 is a 10% to 40% aqueous solution of an acid anhydride selected from diisopropylethylamine, 1-methylpiperidine, 4-methylmorpholine, and 4-dimethylaminopyridine. The target product in the system can be extracted more selectively by using an aqueous solution of diisopropylethylamine, 1-methylpiperidine, 4-methylmorpholine or 4-dimethylaminopyridine.
Further, the oxidation protecting agent in step S3 is any one of sodium thiosulfate, antioxidant BHT or antioxidant BHA. By using the oxidation protective agent, the reaction can be effectively carried out in an alkaline environment, the oxidation of the polyphenol after the protection is removed can be avoided, and the higher purity of the finished product terbutaline is ensured.
Further, the oxidation protective agent in step S3 is any one of fullerene, polybenzimidazole two-dimensional conjugated organic porous material, or nitrogen-doped graphite carbon-coated iron nanomaterial. The three antioxidants are easy to separate, and do not generate side reaction with reactants, so that the purity and the yield of the product terbutaline are ensured; the nitrogen-doped graphitic carbon-coated iron nano material can generate a catalytic effect on deprotection reaction, and meanwhile, the ring opening of an epoxy group is promoted to be easy to realize, free radicals are obtained, and the subsequent reaction is catalyzed; due to the conjugated structure of the poly-benzimidazole two-dimensional conjugated organic porous material, electron cloud on a benzene ring in a compound II can be effectively balanced, an epoxy group is promoted to open a ring, the catalytic action on subsequent reaction is realized, and the generation of byproducts is inhibited, so that the purity and the yield of the product are improved.
Further, in step S2, MgSO is added to the yellow oil4Or stirring and filtering the 4A molecular sieve to obtain a compound II.
Furthermore, in the step S1, the feeding molar ratio of the compound I to the acid anhydride is 1: 1-1: 10.
Further, the reaction temperature of the step S1 is 10-40 ℃.
Furthermore, in the step S3, the feeding molar ratio of the compound II to the tert-butylamine is 1: 1-1: 20.
Furthermore, the feeding molar ratio of the compound II and the sodium hydroxide in the step S3 is 1: 1-1: 5.
Furthermore, the feeding molar ratio of the compound II to the oxidation protective agent in the step S3 is 1: 1-1: 8.
Further, the reaction temperature in the step S3 is 10-70 ℃.
Furthermore, the reaction time of the step S1 is 1-10 h.
Furthermore, the reaction time of the step S2 is 1-8 h.
In conclusion, the invention has the following beneficial effects:
1. the intermediate compound II of propionyl, butyryl or valeryl is formed by using reagents such as propionic anhydride, butyric anhydride or valeric anhydride and the like, so that the polarity of the molecule is obviously reduced, the selectivity of an organic phase-alkaline water extraction system is further improved, and the intermediate compound II can be better separated from a reaction system.
2. The invention effectively reacts in alkaline environment by using the oxidation protective agent, can avoid the oxidation of polyphenol after the removal of protection, and ensures the higher purity of the finished product terbutaline.
3. The method greatly reduces the difficulty of post-treatment of the reaction, obviously increases the stability of the terbutaline, can recycle reaction reagents and solvents, and greatly reduces the environmental protection pressure.
Detailed Description
To further illustrate the technical means and effects of the present invention adopted to achieve the predetermined objects, the detailed description of the preparation method of terbutaline according to the present invention, the specific implementation manner, the characteristics and the effects thereof are as follows.
Example 1: preparation method of terbutaline
The method comprises the following operation steps:
s1, adding 10kg of a compound I (65.72mol) and 30L of dichloromethane into a reaction kettle, stirring to dissolve, adding 8.55kg of propionic anhydride (65.72mol), and stirring to react for 10 hours at a reaction temperature of 10 ℃;
s2, adding 10% diisopropylethylamine aqueous solution into the system after the reaction is finished, fully stirring and washing, collecting a dichloromethane phase, and carrying out reduced pressure distillation to obtain 18.44kg (yield is 96%) of a yellow oily compound II;
s3, adding 18.44kg of compound II (63.08mol), 35L of ethyl acetate, 4.61kg of tert-butylamine (63.08mol), 2.52kg of sodium hydroxide (63.08mol) and sodium thiosulfate (63.08mol) into a reaction kettle, and stirring and reacting at 10 ℃ for 8 hours under the control of reaction temperature;
s4, after the reaction is finished, adding purified water into the system to wash the reaction solution, collecting an ethyl acetate phase, and carrying out reduced pressure distillation to obtain 13.36kg of a finished product of the terbutaline (yield is 94%).
Note: yield ═ WCompound I×MTerbutaline)/(MCompound I×WTerbutaline)×100％
Purity ═ aTerbutaline/ΣAAll chromatographic peaks)×100％
Example 2: preparation method of terbutaline
The method comprises the following operation steps:
s1, adding 10kg of a compound I (65.72mol) and 30L of dichloromethane into a reaction kettle, stirring to dissolve, adding 51.98kg of butyric anhydride (65.72mol), and stirring to react for 6 hours at 25 ℃;
s2, adding 20% of 1-methylpiperidine aqueous solution into the system after the reaction is finished, fully stirring and washing, collecting a dichloromethane phase, and carrying out reduced pressure distillation to obtain 18.64kg (yield is 97%) of a yellow oily compound II;
s3, adding 18.64kg of compound II (63.76mol), 35L of ethyl acetate, 46.64kg of tert-butylamine (637.6mol), 7.65kg of sodium hydroxide (191.28mol) and antioxidant BHT (255.04mol) into a reaction kettle, and stirring to react for 4.5 hours at the temperature of 40 ℃;
s4, after the reaction is finished, adding purified water into the system to wash the reaction solution, collecting the ethyl acetate phase, and carrying out reduced pressure distillation to obtain 13.07kg of the finished terbutaline product (yield is 91%).
Example 3: preparation method of terbutaline
S1, adding 10kg of a compound I (65.72mol) and 30L of dichloromethane into a reaction kettle, stirring to dissolve, adding 122.40kg of valeric anhydride (657.2mol), and stirring to react for 1h at the reaction temperature of 40 ℃;
s2, adding 30% of 4-methylmorpholine aqueous solution into the system after the reaction is finished, fully stirring and washing, collecting a dichloromethane phase, and carrying out reduced pressure distillation to obtain 17.67kg (yield is 92%) of a yellow oily compound II;
s3, adding 17.67kg of compound II (60.46mol), 35L of ethyl acetate, 88.44kg of tert-butylamine (1209.25mol), 12.09kg of sodium hydroxide (302.3mol) and antioxidant BHA (483.68mol) into a reaction kettle, and stirring and reacting for 1h at the temperature of 70 ℃;
s4, after the reaction is finished, adding purified water into the system to wash the reaction solution, collecting the ethyl acetate phase, and carrying out reduced pressure distillation to obtain 12.40kg of a finished product of the terbutaline (yield is 92%).
Example 4: preparation method of terbutaline
The method comprises the following operation steps:
s1, adding 10kg of a compound I (65.72mol) and 30L of dichloromethane into a reaction kettle, stirring to dissolve, adding 122.40kg of valeric anhydride (657.2mol), and stirring to react for 1h at the reaction temperature of 40 ℃;
s2, adding 40% of 4-dimethylaminopyridine aqueous solution into the system after the reaction is finished, fully stirring and washing, collecting a dichloromethane phase, adding a drying agent MgSO45g, stirred, filtered and distilled under reduced pressure to obtain 18.05kg of compound II as yellow oil (yield 94%);
s3, adding 18.05kg of compound II (60.46mol), 35L of ethyl acetate, 88.44kg of tert-butylamine (1209.25mol), 12.09kg of sodium hydroxide (302.3mol) and fullerene (483.68mol) into a reaction kettle, and controlling the reaction temperature to be stirred and react for 1h at 70 ℃;
s4, after the reaction is finished, adding purified water into the system to wash the reaction solution, collecting the ethyl acetate phase, and carrying out reduced pressure distillation to obtain 12.66kg of the finished terbutaline product (yield is 94%).
Example 5: preparation method of terbutaline
The method comprises the following operation steps:
s1, adding 10kg of a compound I (65.72mol) and 30L of dichloromethane into a reaction kettle, stirring to dissolve, adding 51.98kg of butyric anhydride (65.72mol), and stirring to react for 6 hours at 25 ℃;
s2, adding 15% of 4-dimethylaminopyridine aqueous solution into the system after the reaction is finished, fully stirring and washing, collecting a dichloromethane phase, adding 3g of a 4A molecular sieve, uniformly stirring, filtering, and carrying out reduced pressure distillation to obtain 18.64kg (yield is 97%) of a yellow oily compound II;
s3, adding 18.64kg of compound II (63.76mol), 35L of ethyl acetate, 46.64kg of tert-butylamine (637.6mol), 7.65kg of sodium hydroxide (191.28mol) and a polybenzimidazole two-dimensional conjugated organic porous material (255.04mol) into a reaction kettle, and controlling the reaction temperature to stir and react for 2.5 hours at 40 ℃;
s4, after the reaction is finished, adding purified water into the system to wash the reaction solution, collecting the ethyl acetate phase, and carrying out reduced pressure distillation to obtain 13.64kg of the finished terbutaline product (yield is 91%).
According to the yield and the purity of the embodiment 1-5, the preparation method of terbutaline provided by the invention can reduce the interference of byproducts and effectively improve the yield and the purity of the product; comparing example 3 with example 4, it can be seen that the yield of compound II can be improved by adding the drying agent, and a product with a higher yield can be obtained by adding fullerene as an antioxidant; it can be known from the comparison between example 2 and example 5 that the addition of the antioxidant polybenzimidazole two-dimensional conjugated organic porous material can generate a catalytic effect on the reaction of step S3, effectively shorten the reaction time, and improve the yield and purity of the product.
Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (6)
1. A process for the preparation of terbutaline, characterized by the following reaction equation:
wherein n is more than or equal to 1; the specific operation steps are as follows:
s1, adding the compound I and dichloromethane into the reaction kettle, stirring and dissolving, and then adding anhydride;
s2, adding dilute alkaline water into the system after the reaction is finished, fully stirring and washing, collecting a dichloromethane phase, and carrying out reduced pressure distillation to obtain a yellow oily substance, namely a compound II;
s3, adding the compound II, ethyl acetate, tert-butylamine, sodium hydroxide and an oxidation protective agent into the reaction kettle to react to obtain a reaction solution;
s4, adding purified water into the system after the reaction in the step S3 is finished to wash the reaction liquid in the step S3, collecting an ethyl acetate phase, and distilling the ethyl acetate phase under reduced pressure to obtain the terbutaline; the acid anhydride in the step S1 is any one of propionic anhydride, butyric anhydride or valeric anhydride; the dilute alkaline water in the step S2 is 10% -40% aqueous solution of diisopropylethylamine, 1-methylpiperidine, 4-methylmorpholine or 4-dimethylaminopyridine; the oxidation protective agent in the step S3 is any one of sodium thiosulfate, antioxidant BHT or antioxidant BHA; the oxidation protective agent in step S3 is a fullerene or polybenzobisimidazole two-dimensional conjugated organic porous material.
2. The method for preparing terbutaline according to claim 1, wherein the molar ratio of compound I to anhydride fed in step S1 is 1:1 to 1: 10.
3. The method for preparing terbutaline according to claim 1, wherein the molar ratio of compound II to tert-butylamine charged in step S3 is 1: 1-1: 20.
4. The method for preparing terbutaline according to claim 1, wherein the molar ratio of compound II to sodium hydroxide in step S3 is 1:1 to 1: 5.
5. The method for preparing terbutaline according to claim 1, wherein the charging molar ratio of compound II to oxidation protective agent in step S3 is 1: 1-1: 8.
6. The method for preparing terbutaline according to claim 1, wherein the reaction temperature in step S3 is 10-70 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010671179.9A CN111960955B (en) | 2020-07-13 | 2020-07-13 | Preparation method of terbutaline |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010671179.9A CN111960955B (en) | 2020-07-13 | 2020-07-13 | Preparation method of terbutaline |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111960955A CN111960955A (en) | 2020-11-20 |
| CN111960955B true CN111960955B (en) | 2022-05-13 |
Family
ID=73361529
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010671179.9A Active CN111960955B (en) | 2020-07-13 | 2020-07-13 | Preparation method of terbutaline |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111960955B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107513023A (en) * | 2017-08-30 | 2017-12-26 | 石家庄智时医药科技有限公司 | A kind of preparation method of bricalin |
| CN110835306A (en) * | 2019-11-05 | 2020-02-25 | 嘉实（湖南）医药科技有限公司 | Novel preparation method of terbutaline sulfate |
| CN110950765A (en) * | 2019-12-10 | 2020-04-03 | 浙江医药高等专科学校 | Preparation method of terbutaline sulfate |
| CN110981739A (en) * | 2019-09-12 | 2020-04-10 | 杭州百诚医药科技股份有限公司 | Preparation method of terbutaline sulfate |
-
2020
- 2020-07-13 CN CN202010671179.9A patent/CN111960955B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107513023A (en) * | 2017-08-30 | 2017-12-26 | 石家庄智时医药科技有限公司 | A kind of preparation method of bricalin |
| CN110981739A (en) * | 2019-09-12 | 2020-04-10 | 杭州百诚医药科技股份有限公司 | Preparation method of terbutaline sulfate |
| CN110835306A (en) * | 2019-11-05 | 2020-02-25 | 嘉实（湖南）医药科技有限公司 | Novel preparation method of terbutaline sulfate |
| CN110950765A (en) * | 2019-12-10 | 2020-04-03 | 浙江医药高等专科学校 | Preparation method of terbutaline sulfate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111960955A (en) | 2020-11-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113072434B (en) | Method for preparing cyclopropyl methyl ketone by one-step method | |
| EP1770084B1 (en) | Method for producing (z)-1-phenyl-1-diethylaminocarbonyl-2-aminomethyl cyclopropane hydrochloride | |
| CN108912062B (en) | Preparation method of triazolethione derivative | |
| CN111960955B (en) | Preparation method of terbutaline | |
| CN100560573C (en) | A kind of preparation method of high purity letrozole | |
| CN106431911B (en) | Preparation and purification method of 4-felbinac | |
| CN111170846B (en) | Method for preparing 3,3-dimethyl-2-oxo-butyric acid | |
| CN103360455A (en) | Industrial production method of 5 alpha-androst-2-ene-17-one | |
| EP3851429A1 (en) | A process for the purification of crisaborole | |
| CN112010793A (en) | Synthetic method of 2-methylsulfonyl-4-trifluoromethylbenzoic acid | |
| CN110698335A (en) | Synthesis method of terbutaline intermediate | |
| US20080207946A1 (en) | Process for preparation of highly pure isotretinoin | |
| CN112375120B (en) | Preparation method of 5 a-androst-2-ene-17-one | |
| CN111377850B (en) | Chiral N-substituted-3,3-difluoro-4-hydroxypiperidine derivative and preparation method thereof | |
| CN112250586A (en) | Preparation method of terbutaline sulfate and B crystal form thereof | |
| CN111018928A (en) | Synthetic method and application of gastrodin hemihydrate | |
| CN113861034A (en) | Preparation method of 2-fluoro-3-nitrobenzoic acid | |
| CN109879775A (en) | A kind of environment-friendly preparation method of 5-ALA hydrochloride intermediate | |
| CN113372235B (en) | Process for preparing 1-amino-2-phenylcyclopropanecarboxylic acids | |
| CN115322239B (en) | Method for recovering diketone from mandipropamid carbon loss ester mother liquor | |
| CN113444004B (en) | 3, 5-dibromo-o-amino benzaldehyde production process | |
| CN116813455A (en) | Preparation method of 2-adamantanone compound | |
| CN114436950B (en) | Method for the alkylation of ester groups using lithium arylalkylamides as sterically bulky bases | |
| CN109336820B (en) | Preparation method of 1H-imidazole-4-carbonitrile | |
| CN106957235A (en) | A kind of preparation method of TAM |
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 | ||
| CB02 | Change of applicant information | ||
| CB02 | Change of applicant information |
Address after: 210033 room 317, building F6, No.9, Weidi Road, Xianlin street, Qixia District, Nanjing City, Jiangsu Province Applicant after: Nanjing H&D Pharmaceutical Technology Co.,Ltd. Address before: 210033 room 317, building F6, No.9, Weidi Road, Xianlin street, Qixia District, Nanjing City, Jiangsu Province Applicant before: Nanjing H&D Pharmaceutical Technology Co.,Ltd. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP02 | Change in the address of a patent holder | ||
| CP02 | Change in the address of a patent holder |
Address after: Building D3, No. 9, Weidi Road, Xianlin Street, Qixia District, Nanjing, Jiangsu 210033 Patentee after: Nanjing H&D Pharmaceutical Technology Co.,Ltd. Address before: 210033 room 317, building F6, No.9, Weidi Road, Xianlin street, Qixia District, Nanjing City, Jiangsu Province Patentee before: Nanjing H&D Pharmaceutical Technology Co.,Ltd. |