CN111170886B - Preparation method of dezocine impurity - Google Patents
Preparation method of dezocine impurity Download PDFInfo
- Publication number
- CN111170886B CN111170886B CN202010005217.7A CN202010005217A CN111170886B CN 111170886 B CN111170886 B CN 111170886B CN 202010005217 A CN202010005217 A CN 202010005217A CN 111170886 B CN111170886 B CN 111170886B
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- reaction
- preparation
- dezocine
- 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
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/76—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members
- C07C2603/80—Ring systems containing bridged rings containing three rings containing at least one ring with more than six ring members containing eight-membered rings
Abstract
The invention discloses a preparation method of dezocine impurities, which adopts (5R,11S,13S) -3-methoxy-5-methyl-5, 6,7,8,9,10,11, 12-octahydro-5, 11-methylene benzocyclodecene-13-amine as a starting raw material to efficiently synthesize and prepare (5R,11S) -3-hydroxy-5-methyl-5, 6,7,8,9,10,11, 12-octahydro-5, 11-methylene benzocyclodecene-13-imine; the preparation method has the advantages of simple operation, easily obtained raw materials, mild reaction conditions, high product purity and high yield, and is suitable for large-scale preparation. The synthesized impurities can be used for qualitative and quantitative analysis of the impurities, so that the medication safety of dezocine can be improved.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of impurities generated in the preparation process of dezocine injection.
Background
Dezocine belongs to a powerful opioid analgesic, mainly acts on mu receptors and kappa receptors, and can relieve pain caused by postoperative and cancer. Clinical studies prove that the dezocine injection has the analgesic strength, the onset time and the action time equivalent to those of morphine, good tolerance and lower abuse tendency of drugs than that of morphine. Animal experiments show that the body dependence of dezocine generated by mice and rats is obviously lower than that of morphine hydrochloride in the aspects of promotion and natural withdrawal response, and the dezocine does not increase with the increase of dosage but decreases.
Dezocine, having the english name Dezocine, having the chemical name (-) - [5R- (5 α,11 α,13S) ] -13-amino-5, 6,7,8,9,10,11, 12-octahydro-5-methyl-5, 11-methylenebenzocyclodecen-3-ol, is represented by the following chemical structural formula i:
controlling the amount of degradation impurities is critical to the clinical safety of the formulation. As can be seen from the chemical structural formula of dezocine, the dezocine structure contains phenolic hydroxyl and primary amino, and is easy to be oxidized to generate other impurities. CN109206385A discloses a method for synthesizing impurity a generated by oxidizing phenolic hydroxyl group in dezocine structure, and also discloses a compound of formula 3, i.e. (5R,11S) -3-hydroxy-5-methyl-5, 6,7,8,9,10,11, 12-octahydro-5, 11-methylene benzocyclodecene-13-imine, the structural formula of which is shown below:
the dezocine impurity, namely the compound shown in the formula 3, is an oxidative degradation impurity generated in the production process of dezocine, and the structure contains a rare unsubstituted imine structure, so that the synthesis has high technical difficulty. Through literature search, no literature reports a synthetic method of the compound, and no standard product is sold in the market.
Disclosure of Invention
The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.
The invention provides a preparation method of a dezocine impurity compound shown in a formula 3. The method does not need harsh reaction conditions, has high product purity, and is suitable for large-scale preparation. The synthesized dezocine impurity can be used for qualitative and quantitative analysis of the impurity, and the medication safety of the dezocine can be improved.
US 39397666 discloses a synthesis of a compound of formula 2: the compound of the formula 4 is subjected to hydrogenation reduction under the catalysis of Raney nickel to obtain the compound of the formula 2. However, this process is not easy to control and the imine is easily further reduced to ammonia. And is a pressure hydrogenation reaction, which is not conducive to laboratory operations.
There are many methods for methoxy demethylation reported in the prior art, and most methods use strong lewis acids such as boron trifluoride to activate ether bonds, followed by hydrolytic cleavage. Because the imine structure existing in the structure of the compound of formula 2 is unstable, hydrolysis easily occurs under the condition of strong Lewis acid, imine is changed into ketone, and the yield is low.
The invention overcomes the defects of the prior method, and the compound shown in the formula 2 is obtained by oxidizing NXS (N-chlorosuccinimide, N-bromosuccinimide and N-iodosuccinimide) under an alkaline condition without generating other oxidation products such as hydroxylamine, nitrosamine and the like. Under the conditions of aluminum chloride and mercaptan, the product is not further hydrolyzed while demethylating, and the dezocine impurity compound shown in the formula 3 is efficiently synthesized.
In an embodiment of the invention, the compound of formula 1 has the structure:
the chemical name is as follows: (5R,11S,13S) -3-methoxy-5-methyl-5, 6,7,8,9,10,11, 12-octahydro-5, 11-methylenebenzocyclodecen-13-amine.
In an embodiment of the invention, the compound of formula 2 has the structure:
the chemical name is as follows: (5R,11S) -3-methoxy-5-methyl-5, 6,7,8,9,10,11, 12-octahydro-5, 11-methylenebenzocyclodecene-13-imine.
In an embodiment of the invention, the dezocine impurity compound of formula 3 has the structure:
the chemical name is as follows: (5R,11S) -3-hydroxy-5-methyl-5, 6,7,8,9,10,11, 12-octahydro-5, 11-methylenebenzocyclodecene-13-imine.
The invention provides a preparation method of dezocine impurities, wherein the dezocine impurities are shown as a formula 3, and the preparation method comprises the following steps:
carrying out oxidation reaction on a compound of a formula 1 in the presence of an oxidant to obtain a compound of a formula 2;
secondly, reacting the compound of the formula 2 obtained in the step I under the action of aluminum chloride to obtain the compound of the formula 3.
In some embodiments of the present invention, the present invention provides a method for preparing dezocine impurities, wherein in the step (i), the oxidizing agent is one or more of N-chlorosuccinimide, N-bromosuccinimide, and N-iodosuccinimide.
In some embodiments of the present invention, the molar ratio of the compound of formula 1 to the oxidant in step (i) is 1 (1-5), preferably 1 (1.2-1.7).
In some embodiments of the present invention, the oxidation reaction of step (i) further comprises performing under the addition of a base, wherein the base is one or more of pyridine, triethylamine, 4-Dimethylaminopyridine (DMAP) and 1, 8-diazabicyclo [5.4.0] -undec-7-ene (DBU), preferably DBU.
In some embodiments of the present invention, the reaction temperature of the oxidation reaction of the step (r) is optionally 45 to 60 ℃.
In an embodiment of the present invention, optionally, the compound of formula 2 obtained in said step (r) is used directly in the next reaction without column chromatography.
In some embodiments of the invention, the molar ratio of the aluminum chloride to the compound of formula 2 in the step (II) is 1 (1.5-3).
In some embodiments of the invention, the reaction of step (ii) is carried out in the presence of a mercaptan, the mercaptan being one or more of thiophenol, ethanethiol, and octanethiol; the molar ratio of the mercaptan to the compound of the formula 2 is 1 (1.5-3).
In some embodiments of the present invention, the reaction in step (ii) is carried out in the presence of an organic solvent, which is a mixed solvent of one or both of dichloromethane and 1, 2-dichloroethane.
In some embodiments of the present invention, the reaction temperature of the reaction of step (c) is from 30 ℃ to 40 ℃.
In some embodiments of the present invention, the reaction time of the reaction in the second step is 2 to 6 hours.
In the above embodiment, the preparation method comprises the steps of:
carrying out oxidation reaction on a compound of a formula 1 in the presence of an oxidant and alkali to obtain a compound of a formula 2;
② reacting the compound of formula 2 obtained in the step (I) in an organic solvent under the action of aluminum chloride and in the presence of mercaptan to obtain the compound of formula 3.
The invention has the beneficial effects that: the preparation method is simple, has low requirements on reaction conditions, high product purity and high yield, and is suitable for large-scale preparation. The synthesized impurities can be used for quantitative and qualitative analysis of the impurities, so that the safety of clinical medication of dezocine is improved.
Additional features and advantages of the invention will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objectives and other advantages of the invention may be realized and attained by the structure particularly pointed out in the written description.
Detailed Description
Hereinafter, embodiments of the present invention will be described in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.
Nuclear magnetic resonance spectroscopy (NMR) instrument model: BRUKER model AV-500 NMR spectrometer;
high resolution mass spectrometry (HRMS instruments model: Bruker Daltonics, Inc., APEX 7.0TESLA FTMS.
High performance liquid chromatography (Agilent 1260, Agilent technologies, Inc.).
The HPLC detection method disclosed by CN 106018584 is a method for detecting related substances of dezocine: reversed phase chromatography is adopted, octadecylsilane chemically bonded silica is used as a filler, the detection wavelength is 281nm, and the concentration is 1.4mg/ml by mobile phase research on the basis of triethylamine solution (1000 ml of water is added with 2.5ml of triethylamine, and diluted phosphoric acid (1-5) is used for adjusting the pH value to 3.2) -acetonitrile (80: 20).
Example 1
The compound of formula 1 (5.0g, 19.3mmol) and 60ml of 1, 2-dichloroethane were added to a 250ml reaction flask, N-chlorosuccinimide (3.8g, 28.95mmol) was slowly added dropwise at room temperature, and the reaction was stirred for 3 hours. Adding DBU (2mL), heating to 40-50 ℃, and reacting for 12h to finish the reaction. Water (75mL) was added to the reaction flask, filtered through a Buchner filter to remove solids, washed with saturated brine, and dried to give the crude compound of formula 2 (4.8g, as a pale yellow solid) which was used in the next reaction without further purification.
The compound of formula 2 (4.8g) was dissolved in dichloromethane (55mL), aluminum chloride (5.13g, 38.6mmol) was added slowly, thiophenol (4.24g, 38.6mmol) was added dropwise, after the addition was complete, the temperature was raised to 30-350 ℃ and the reaction was held for 6 h. Cooling the reaction system to about 0 ℃ in ice bath, slowly dropwise adding ammonia water to quench the reaction until the pH is more than 7, maintaining the temperature of the system to be not more than 10 ℃, adding water (100mL), extracting for 3 times by using dichloromethane, washing an organic phase by using saturated saline solution, drying, quickly filtering by using diatomite, and spin-drying the solution to obtain 4.0g of a crude compound. The crude compound obtained above was slurried with n-hexane to give the compound of formula 3 (3.0g, off-white solid) in a two-step reaction molar yield of 63.9% with an HPLC purity of 96.6%.
Example 2
The compound of formula 1 (5.0g, 19.3mmol) and 60ml of 1, 2-dichloroethane were charged into a 250ml reaction flask, N-bromosuccinimide (4.05g, 23.16mmol) was slowly added dropwise at room temperature, and the reaction was stirred for 2 hours. Adding triethylamine (2mL), heating to 50-60 ℃, and reacting for 18h to finish the reaction. Water (75mL) was added to the reaction flask, filtered through a Buchner filter to remove solids, washed with saturated brine, and dried to give the crude compound of formula 2 (4.9g, as a pale yellow solid) which was used in the next reaction without further purification.
The compound of formula 2 (4.9g) was dissolved in dichloromethane (55mL), aluminum chloride (7.7g, 57.9mmol) was added slowly, and ethanethiol (3.58g, 57.9mmol) was added. After the addition is finished, the temperature is raised to 30-35 ℃, and the reaction is carried out for 4 hours under the condition of heat preservation. Cooling the reaction system to about 0 ℃ in ice bath, slowly dropwise adding ammonia water to quench the reaction until the pH is more than 7, maintaining the temperature of the system to be not more than 10 ℃, adding water (100mL), extracting for 3 times by using dichloromethane, washing an organic phase by using saturated saline solution, drying, quickly filtering by using diatomite, and spin-drying the solution to obtain 4.5g of a crude compound. The crude compound obtained above was slurried with n-hexane to give the compound of formula 3 (3.4g, off-white solid) in a two-step reaction molar yield of 72.4%.
Example 3
The compound of formula 1 (5.0g, 19.3mmol) and 80ml of 1, 2-dichloroethane were added to a 250ml reaction flask, N-iodosuccinimide (7.3g, 32.81mmol) was slowly added dropwise at room temperature, and the reaction was stirred for 1.5 h. Adding pyridine (2mL), heating to 50-60 ℃, and reacting for 18h to finish the reaction. Water (100mL) was added to the reaction flask, filtered through a Buchner filter to remove solids, washed with saturated brine, and dried to give the crude compound of formula 2 (4.7g, pale yellow solid) which was used in the next reaction without further purification.
The compound of formula 2 (4.7g) was dissolved in 1, 2-dichloroethane (55mL), ethanethiol (3.58g, 57.9mmol) was added, and aluminum chloride (7.7g, 57.9mmol) was slowly added. After the addition is finished, the temperature is raised to 35-40 ℃, and the reaction is carried out for 2 hours under the condition of heat preservation. Cooling the reaction system to about 0 ℃ in ice bath, slowly dropwise adding ammonia water to quench the reaction until the pH is more than 7, maintaining the temperature of the system to be not more than 10 ℃, adding water (100mL), extracting for 3 times by using dichloromethane, washing an organic phase by using saturated saline solution, drying, quickly filtering by using diatomite, and spin-drying the solution to obtain 4.4g of a crude compound. The crude compound obtained above was slurried with n-hexane to give the compound of formula 3 (3.2g, off-white solid) in a two-step reaction molar yield of 68.2%.
Example 4
The compound of formula 1 (5.0g, 19.3mmol) and 80ml of 1, 2-dichloroethane were added to a 250ml reaction flask, N-bromosuccinimide (4.05g, 23.16mmol) was slowly added dropwise at room temperature, and the reaction was stirred for 1.5 h. Adding DBU (2mL), heating to 50-60 ℃, and reacting for 18h to finish the reaction. Water (100mL) was added to the reaction flask, filtered through a Buchner filter to remove solids, washed with saturated brine, and dried to give the crude compound of formula 2 (4.6g, pale yellow solid) which was used in the next reaction without further purification.
The compound of formula 2 (4.6g) was dissolved in 1, 2-dichloroethane (55mL), and aluminum chloride (2.57g, 19.3mmol) was added slowly followed by octyl mercaptan (2.8g, 19.3 mmol). After the addition is finished, the temperature is raised to 35-40 ℃, and the reaction is carried out for 4 hours under the condition of heat preservation. Cooling the reaction system to about 0 ℃ in ice bath, slowly dropwise adding ammonia water to quench the reaction until the pH is more than 7, maintaining the temperature of the system to be not more than 10 ℃, adding water (100mL), extracting for 3 times by using dichloromethane, washing an organic phase by using saturated saline solution, drying, quickly filtering by using diatomite, and spin-drying the solution to obtain 4.3g of a crude compound. The crude compound obtained above was slurried with n-hexane to give the compound of formula 3 (3.3g, off-white solid) in a two-step reaction molar yield of 70.3%.
Dezocine impurity compound of formula 3 spectrogram data obtained in inventive examples 1-4: NMR spectrum (500MHz, DMSO). sub.8.16 (s,1H, OH), 6.88(d,1H, ArH), 6.69(d,1H, ArH), 6.54-6.56(dd,1H, ArH), 5.98(m,1H, NH), 2.83-2.85(d,1H, CH), 2.65-2.68(m,1H, CH), 2.18-2.20(d,1H, CH), 1.65-1.67(m,2H, CH)2)，1.46-1.58(m,8H，CH2)，1.31(s,3H,CH3)；
Nuclear magnetic resonance carbon spectrum (125MHz, DMSO) 188.63, 155.85, 144.67, 129.59, 124.70, 113.01, 112.19, 47.11, 45.38, 43.32, 34.37, 29.11, 28.45, 25.58, 22.95, 21.33;
MS：(M+1)＝244.1695。
comparative example 1
The compound of formula 1 (5.54g, 21.4mmol) and 90ml of 1, 2-dichloroethane were charged into a 250ml reaction flask, N-bromosuccinimide (4.57g, 25.68mmol) was slowly added dropwise at room temperature, and the reaction was stirred for 1.5 h. DBU (2.1mL) is added, the temperature is raised to 50-60 ℃, and the reaction is finished after 18 h. Water (100mL) was added to the reaction flask, filtered through a Buchner filter to remove solids, washed with saturated brine, and dried to give the crude compound of formula 2 (5.1g, pale yellow solid) which was used in the next reaction without further purification.
The compound of formula 2 (5.1g) was dissolved in DCM (55mL) and cooled to-78 ℃. Slowly dropwise adding BBr3And (3) adding the solution (64.2mL, 64.2mmol and 1mol/L), and slowly raising the temperature of the system to room temperature after the dropwise adding is finished until the compound of the formula 2 completely reacts. Slowly dropwise adding water to quench and react, extracting with DCM for 3 times, washing an organic phase with water, drying, and spin-drying to obtain 4.1g of a crude compound. The crude compound obtained above was slurried with n-hexane to give the compound of formula 3 (2.8g, pale yellow solid) in a two-step reaction molar yield of 53.8% with an HPLC purity of 64.4%.
It can be seen that comparative example 1, using boron tribromide as the demethylating agent, gave a 2-step reaction yield of only 53.8%, a sample having an HPLC purity of only 64.4%, and a 24.9% impurity peak at retention time 54.380. In the embodiment of the invention, aluminum chloride is adopted, the reaction yield of 2 steps is 63.9%, the HPLC purity is 96.6%, and the use requirement of an impurity reference substance can be met. In conclusion, the embodiment of the invention can improve the yield of the target product, namely the compound shown in the formula 3, and has higher purity and obvious advantages.
Although the embodiments disclosed in the present application are described above, the descriptions are only for the convenience of understanding the present application, and are not intended to limit the present application. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the disclosure as defined by the appended claims.
Claims (13)
1. A preparation method of dezocine impurities is shown as a formula 3, and comprises the following steps:
carrying out oxidation reaction on a compound shown in a formula 1 in the presence of an oxidant to obtain a compound shown in a formula 2;
② reacting the compound of formula 2 obtained in the step I under the action of aluminum chloride to obtain a compound of formula 3,
wherein the oxidant in the step (i) is one or more of N-chlorosuccinimide, N-bromosuccinimide and N-iodosuccinimide.
2. The preparation method according to claim 1, wherein the molar ratio of the compound of formula 1 to the oxidant is 1 (1-5).
3. The preparation method according to claim 1, wherein the molar ratio of the compound of formula 1 to the oxidant is 1 (1.2-1.7).
4. The process according to claim 1, wherein the oxidation reaction of step (i) is further carried out with addition of a base, which is one or more of pyridine, triethylamine, 4-dimethylaminopyridine and 1, 8-diazabicyclo [5.4.0] -undec-7-ene.
5. The process according to claim 4, wherein the base is 1, 8-diazabicyclo [5.4.0] -undec-7-ene.
6. The process according to claim 1, wherein the reaction temperature of the oxidation reaction in the step (i) is 45 to 60 ℃.
7. The method according to claim 1, wherein the compound of formula 2 obtained in step (i) is used in the next reaction without column chromatography.
8. The preparation method according to any one of claims 1 to 7, wherein the molar ratio of the aluminum chloride to the compound of formula 2 in step (ii) is 1 (1.5-3).
9. The production method according to any one of claims 1 to 7, wherein the reaction of step (ii) is carried out in the presence of a mercaptan, which is one or more of thiophenol, ethanethiol, and octanethiol.
10. The preparation method according to claim 9, wherein the molar ratio of the thiol to the compound of formula 2 is 1 (1.5-3).
11. The production method according to any one of claims 1 to 7, wherein the reaction in step (ii) is carried out in the presence of an organic solvent which is a mixed solvent of one or both of dichloromethane and 1, 2-dichloroethane.
12. The production method according to any one of claims 1 to 7, wherein the reaction temperature in the step (ii) is 30 ℃ to 40 ℃.
13. The preparation method according to any one of claims 1 to 7, wherein the reaction time of the reaction in the step (II) is 2 to 6 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010005217.7A CN111170886B (en) | 2020-01-03 | 2020-01-03 | Preparation method of dezocine impurity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010005217.7A CN111170886B (en) | 2020-01-03 | 2020-01-03 | Preparation method of dezocine impurity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111170886A CN111170886A (en) | 2020-05-19 |
| CN111170886B true CN111170886B (en) | 2021-11-09 |
Family
ID=70618718
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010005217.7A Active CN111170886B (en) | 2020-01-03 | 2020-01-03 | Preparation method of dezocine impurity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111170886B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006103418A1 (en) * | 2005-03-28 | 2006-10-05 | Orexo Ab | New pharmaceutical compositions useful in the treatment of pain |
| CN106018584A (en) * | 2016-05-12 | 2016-10-12 | 华润双鹤利民药业（济南）有限公司 | Detection method for dezocine related substances |
| WO2017011738A1 (en) * | 2015-07-16 | 2017-01-19 | Saint Louis University | Antagonists of gpr160 for the treatment of pain |
| CN109206385A (en) * | 2017-07-03 | 2019-01-15 | 扬子江药业集团有限公司 | A kind of preparation method of dezocine impurity A and its homologue |
-
2020
- 2020-01-03 CN CN202010005217.7A patent/CN111170886B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006103418A1 (en) * | 2005-03-28 | 2006-10-05 | Orexo Ab | New pharmaceutical compositions useful in the treatment of pain |
| WO2017011738A1 (en) * | 2015-07-16 | 2017-01-19 | Saint Louis University | Antagonists of gpr160 for the treatment of pain |
| CN106018584A (en) * | 2016-05-12 | 2016-10-12 | 华润双鹤利民药业（济南）有限公司 | Detection method for dezocine related substances |
| CN109206385A (en) * | 2017-07-03 | 2019-01-15 | 扬子江药业集团有限公司 | A kind of preparation method of dezocine impurity A and its homologue |
Non-Patent Citations (2)
| Title |
|---|
| Effects of dezocine for the prevention of postoperative catheter-related bladder discomfort: a prospective randomized trial;Guang-Fen Zhang，等;《Drug Design, Development and Therapy》;20191231;第308-309页 * |
| 药物热浅析;段明辉，等;《临床误诊误治》;19991231;第1281-1288页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111170886A (en) | 2020-05-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Hajipour et al. | Benzyltriphenylphosphonium peroxymonosulfate: As a novel and efficient reagent for oxidation of alcohols under solvent-free conditions | |
| US20240018109A1 (en) | Method for synthesis of roxadustat and intermediate thereof, and intermediate thereof | |
| FR2680786A1 (en) | Process for the synthesis of glucuronides of 4,5-epoxymorphinans | |
| CN111170886B (en) | Preparation method of dezocine impurity | |
| CN102718768B (en) | Chiral five-membered bicyclic guanidine compound, preparation method and application thereof | |
| CN104892426B (en) | A kind of method using pyrrolidinone compounds ionic liquid as the nitroanthraquinone of catalyst preparation 1 | |
| CN113004300B (en) | Stable isotope labeled patulin and synthesis method thereof | |
| CN109796344B (en) | Preparation method of (E) -1, 3-diphenyl-4-nitro-1-butene | |
| CN112225769A (en) | Method for synthesizing and purifying tulathromycin impurity E | |
| CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
| CN107915747A (en) | The synthetic method of PA 824 | |
| CN110218195B (en) | Stable isotope labeled quinoxaline-2-carboxylic acid and synthesis method thereof | |
| CN108129269B (en) | Method for synthesizing 1, 3-diphenyl-1-propanol from 1, 3-diphenyl-1-propanol and nitromethane | |
| CN113214094A (en) | Synthetic method of voglibose | |
| CN111362795A (en) | Preparation method of substituted butyrate derivatives | |
| CN110734443B (en) | Preparation method of tadalafil-related substance I | |
| CN110078669B (en) | Green synthesis method of metronidazole and deuterated derivatives thereof | |
| CN114044762B (en) | Preparation method of chlormezanone intermediate | |
| CN109535211B (en) | Method for synthesizing and purifying tulathromycin impurity C | |
| CN110938015B (en) | Preparation method of azido-substituted salicylic acid derivative | |
| CN108976182A (en) | A method of preparing Dapagliflozin five-membered ring impurity | |
| CN111995508A (en) | Synthesis method of antitumor active compound Sanjoseolide | |
| CN115108965A (en) | Preparation method of anti-neocoronarism drug Parovidekey intermediate | |
| CN1721414A (en) | Process for synthesizing 2-p-trifluoro toluene-4-methyl-5-thiazolyl ethyl formate | |
| CN115703691A (en) | 13 Synthesis method of C-p-methoxybenzoic acid |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |