CN114716332A - Preparation method of ketamine - Google Patents
Preparation method of ketamine Download PDFInfo
- Publication number
- CN114716332A CN114716332A CN202210445584.8A CN202210445584A CN114716332A CN 114716332 A CN114716332 A CN 114716332A CN 202210445584 A CN202210445584 A CN 202210445584A CN 114716332 A CN114716332 A CN 114716332A
- Authority
- CN
- China
- Prior art keywords
- reaction
- ketamine
- chlorophenyl
- solvent
- compound
- 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.)
- Granted
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C247/00—Compounds containing azido groups
- C07C247/14—Compounds containing azido groups with azido groups bound to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02W—CLIMATE CHANGE MITIGATION TECHNOLOGIES RELATED TO WASTEWATER TREATMENT OR WASTE MANAGEMENT
- Y02W10/00—Technologies for wastewater treatment
- Y02W10/30—Wastewater or sewage treatment systems using renewable energies
- Y02W10/37—Wastewater or sewage treatment systems using renewable energies using solar energy
Abstract
The invention provides a preparation method of ketamine, which comprises the steps of dissolving 2-o-chlorophenyl-2-azido cyclohexanone and a reducing agent in a solvent 1, heating to 50-70 ℃ for reaction for 10-15h, cooling the reaction liquid to room temperature after the reaction is finished, adding water for reflux, carrying out reduced pressure distillation to remove tetrahydrofuran to obtain a crude product, extracting, washing, drying, and carrying out reduced pressure concentration to obtain 2-o-chlorophenyl-2-aminocyclohexanone; placing 2-o-chlorophenyl-2-aminocyclohexanone, a methylating agent, acetic acid and sodium cyanoborohydride in a reaction vessel, adding a solvent 2, reacting at room temperature for 10-15h, adding a saturated sodium carbonate solution after the reaction is finished, and performing extraction, washing, drying, filtering, reduced pressure distillation and recrystallization to obtain the ketamine. The ketamine prepared by the method has high industrialization degree, the product quality is greatly improved compared with the prior art, and no intermediate impurity exists; the process route is simple to operate, the cost is low, and the condition is mild.
Description
The mother case patent: 201911113780X
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to an intermediate compound for synthesizing ketamine and a preparation method thereof.
Background
Ketamine, chemical name 2-o-chlorophenyl-2-methylaminocyclohexanone, is a derivative of phencyclidine. The medicine is generally used as a vein general anesthetic in medical clinic; has bronchodilatory effect, and can be used for treating asthma and dilating cerebral vessels.
The current main synthesis method of ketamine is to prepare ketamine by rearrangement reaction of N-methyl imine hydrochloride of intermediate 1-hydroxy cyclopentyl o-chlorophenyl ketone. However, the rearrangement reaction generally occurs at a high temperature of 160 ℃ or higher, and sometimes microwave irradiation is required, which is not suitable for industrial production.
WO2017208031A1 discloses a method for preparing a compound shown as a formula (II), and the synthetic route is as follows:
the method has the advantages of long steps, long production period, more reaction steps, low total yield, severe corrosion to equipment due to the use of strong acid in the production process, and generation of chronic respiratory tract irritation symptoms and digestive dysfunction due to long-term contact of people. The produced waste acid water is easy to cause pollution and damage to the environment.
CN201610871662.5 discloses the synthesis route of ketamine as follows:
the oxidizing agent used in the route is easy to open the ring of the six-membered ring, and the oxidizing reaction has harsh conditions, is difficult to control and has difficult post-treatment operation; the used nitrating reagent is easy to explode, the used nitric acid can cause acute poisoning, shock or renal failure and the like, the nitrating reagent is needed to be carried out by taking great care in the using process, and simultaneously, the generated waste water is easy to pollute the environment; the used reducing agent is a metal reducing agent such as iron powder, and experimental research is repeatedly carried out according to the embodiment of the patent, so that the catalyst is particularly easy to be poisoned, the storage time is long, the catalytic reaction effect is poor, the total reaction of the nitro group is incomplete, and the reaction can not be completely carried out even if the reducing agent is supplemented; and the waste iron powder and acid water produced after the reaction are easy to pollute the environment. Therefore, the route and the process conditions are also extremely unsuitable for industrial production.
Disclosure of Invention
Aiming at the technical problems, the invention provides the intermediate compound for synthesizing ketamine and the preparation method thereof, so that the synthesis operation of ketamine is simpler, the cost is lower, the conditions are milder, and the method is suitable for industrial production. In order to solve the technical problems, the invention provides the following technical scheme:
an intermediate compound II for synthesizing ketamine, which has the chemical structural formula as follows:
dissolving the compound I in a solvent, adding an oxidant and an azide reagent at the temperature of-25 to-15 ℃ for reaction, heating the system temperature to room temperature after the reaction is carried out for 15 to 20 hours, washing the reaction liquid with water, extracting with ethyl acetate, combining organic phases, drying and concentrating the organic phases to obtain the compound II 2-o-chlorophenyl-2-azido cyclohexanone, wherein the synthesis method of the intermediate compound II comprises the following steps:
preferably, the oxidant used in the above reaction comprises one or more of iodosobenzene, iodobenzene acetate, bis (trifluoroacetoxy) iodobenzene or chromium trioxide.
Preferably, the azide reagent used in the above reaction is TMSN3、(1- (azido) -1, 2-phenyliodoacyl-3 (1H) -ones),
Hair brushIn a preferable embodiment, the oxidant is iodobenzene acetate, the oxidant and the azide compound form an azide complex at the temperature of between 25 ℃ below zero and 15 ℃ below zero, and particularly, the iodobenzene acetate and the azide compound form a complex C6H5I(OAc)2-(N3)nThereby realizing the double functionalization reaction of olefin to obtain the compound II, which is a key step of the method.
The mass ratio of the compound of the formula (I), the azide reagent and the oxidant is 1:1.3-1.6: 1.0-1.3.
As a preferable reaction condition, the mass ratio of the compound of the formula (I), the azide reagent and the oxidant is 1:1.5:1.2, the reaction temperature is-20 ℃, and the reaction time is 16 h.
The reaction solvent comprises dichloromethane and tetrahydrofuran.
The invention also provides a preparation method of ketamine, which comprises the following steps:
(2)Reacting with a methylating agent to obtain ketamineDissolving a compound II 2-o-chlorophenyl-2-azido cyclohexanone and a reducing agent in a solvent 1, heating to 50-70 ℃ for reaction for 10-15h, after the reaction is finished, cooling the reaction liquid to room temperature, adding water for reflux, carrying out reduced pressure distillation to remove tetrahydrofuran to obtain a crude product, extracting, washing, drying, and carrying out reduced pressure concentration to obtain a compound III 2-o-chlorophenyl-2-aminocyclohexanone;
(2) placing the compound III 2-o-chlorophenyl-2-aminocyclohexanone, a methylating agent, acetic acid and sodium cyanoborohydride in a reaction vessel, adding a solvent 2, reacting at room temperature for 10-15h, adding a saturated sodium carbonate solution after the reaction is finished, extracting, washing, drying, filtering, distilling under reduced pressure, and recrystallizing to obtain a compound IV.
The reducing agent is triarylphosphine or trialkylphosphine, such as triphenylphosphine and trimethylphosphine (in the method, the organophosphorus reagent is the reducing agent and reacts with the azide to generate iminophosphorane which is further reacted to obtain a compound III).
The methylating agent comprises any one of formaldehyde, dimethyl sulfate, methyl trifluoromethanesulfonate, methyl iodide and dimethyl carbonate. In a preferred embodiment, the methylating agent is formaldehyde.
Preferably, the first and second electrodes are formed of a metal,the methylation reaction takes formaldehyde as a methylation reagent under the action of acetic acid and sodium cyanoborohydride.
Compared with the method disclosed in WO2017208031A1, the preparation method of the compound II adopts a one-step method, has the advantages of shortened reaction steps, higher yield and shortened production period, and is more suitable for industrial production. In the method disclosed in WO2017208031A1, the total reaction steps for synthesizing the compound II from the compound I are four steps, and the reaction time reaches 29 hours. The method obviously reduces the used medicines and is beneficial to reducing the production cost of companies. More importantly, the yield of the one-step reaction is obviously increased to 71 percent relative to the yield of the four-step reaction. The method has obvious advantages compared with the method disclosed in WO2017208031A1 by combining 3 points, and has more application prospects.
Compared to the four-step reaction reported in WO2017208031A1, which takes 29 hours, the production cycle is longer if work-up and product purification and drying times are added.
The product quality of the compound (II) prepared by the method is greatly improved by utilizing patents
The compound (II) prepared in example 1 of WO2017208031A1 has a purity of 84.11% by HPLC detection, while the compound (II) prepared by the method of the present invention has a purity of 97% or more by HPLC detection. Meanwhile, the ketamine prepared by the method has high industrialization degree, the product quality is greatly improved compared with the prior art, and no intermediate impurity exists; the process route is simple to operate, the cost is low, and the condition is mild.
Drawings
FIG. 1 preparation of Compound II of example 11H NMR spectrum.
FIG. 2 preparation of Compound II of example 113C NMR spectrum.
FIG. 3 preparation of Compound III of example 41H NMR spectrum.
FIG. 4 preparation of Compound III of example 413C NMR spectrum.
FIG. 5 preparation of Compound IV of example 51H NMR spectrum.
FIG. 6 preparation of Compound IV of example 513C NMR spectrum.
FIG. 7 HPLC chromatogram of Compound IV of example 5.
FIG. 8 HPLC chromatogram of compound IV of this patent prepared in example 1 in CN 201610871662.5.
FIG. 9 HPLC chromatogram of Compound II of example 1.
FIG. 10 is an HPLC chromatogram of compound II of this patent prepared by the method disclosed in WO2017208031A 1.
The specific implementation mode is as follows:
the preferred embodiments of the present invention are described below, and the embodiments described herein are only for illustrating and explaining the present invention and are not intended to limit the present invention.
Example 1: intermediate compound II: synthesis of 2-o-chlorophenyl-2-azidocyclohexanone
1-o-chlorophenyl cyclohexene (1.92g) was dissolved in 30mL of dichloromethane and PhI (OAc) was added at-20 ℃)2(3.86g) and TMSN3(1.75g), and the reaction was carried out for 16 hours while maintaining-20 ℃. After the reaction is finished, the temperature of the system is raised to room temperature, the reaction liquid is washed by water and extracted by ethyl acetate, and organic phases are combined and are used as organic phasesWater Na2SO4After drying and concentration, column chromatography (petroleum ether: ethyl acetate: 20:1) was performed to obtain 2-o-chlorophenyl-2-azidocyclohexanone as a colorless oily liquid (1.78g, yield 71%).1H NMR(400MHz,CDCl3):δ=1.76-1.80(m,2H),1.81-1.93(m,2H),2.41-2.44(m,2H),3.01-3.05(m,2H),7.34-7.48(m,4H);13C NMR(100MHz,CDCl3):δ=17.18,23.10,24.87,41.87,119.48,127.07,128.76,130.59,130.74,131.85,139.22,202.45.
The compound (II) was tested according to the method recorded in the second edition of chinese pharmacopoeia 2015, and compared with the compound (II) prepared in example 1 of patent WO2017208031a1, the purity of the compound (II) obtained in the patent was only 84.11% by HPLC test, whereas the HPLC purity of the compound (II) prepared by the method of the present invention was 97%, and the results are shown in fig. 9 and 10.
Example 2: intermediate compound II: synthesis of 2-o-chlorophenyl-2-azidocyclohexanone
1-o-chlorophenyl cyclohexene (19.2g) was dissolved in 300mL of methylene chloride, followed by addition of iodosobenzene (26.4g) and 1- (azido) -1, 2-phenyliodosyl-3 (1H) -one (43.4g) at-22 ℃ for 17H reaction. After the reaction is finished, the temperature of the system is raised to room temperature, the reaction liquid is washed by water and extracted by ethyl acetate, organic phases are combined, and the organic phase is extracted by anhydrous Na2SO4After drying and concentration, column chromatography (petroleum ether: ethyl acetate: 20:1) was performed to obtain 2-o-chlorophenyl-2-azidocyclohexanone as a colorless oily liquid (20.4g, yield 82%).
Example 3: intermediate compound II: synthesis of 2-o-chlorophenyl-2-azidocyclohexanone
1-o-chlorophenyl cyclohexene (19.2g) was dissolved in 300mL of methylene chloride, followed by addition of bis (trifluoroacetoxy) iodobenzene (58g) and 1- (azido) -3, 3-bis trifluoromethyl-1, 3-dihydro-1, 2-benziodoxolane (45.4g) at-18 ℃ and reaction for 13h at-18 ℃. After the reaction was completed, the temperature of the system was raised to room temperature, the reaction solution was washed with water and extracted with ethyl acetate, and the organic phases were combined and extracted with anhydrous MgSO4Drying, concentrating, and performing column chromatography (petroleum ether: ethyl acetate: 20:1) to obtain colorless oily liquid 2-o-isomerChlorophenyl-2-azidocyclohexanone (21.6g, 87% yield).
Example 4: intermediate compound III: synthesis of 2-o-chlorophenyl-2-aminocyclohexanone
2-o-chlorophenyl-2-azidocyclohexanone (1.5g,6mmol) and triphenylphosphine (1.9g, 7.2mmol) were dissolved in 30mL tetrahydrofuran and heated to 65 ℃ for 12 h. After the reaction, the reaction mixture was cooled to room temperature, 3mL of water was added and refluxed for 3h, tetrahydrofuran was removed by distillation under reduced pressure to obtain a crude product, which was extracted with 30mL of dichloromethane, and the organic phase was washed with 1M hydrochloric acid (15mL), saturated sodium bicarbonate (15mL), and saturated sodium chloride (15mL) in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-o-chlorophenyl-2-aminocyclohexanone (1.28g, 95% yield).1H NMR(300MHz,DMSO):δ=7.87-7.84(m,1H),7.39-7.35(m,2H),7.32-7.27(m,1H),2.77(m,1H),2.42-2.35(m,2H),2.34-2.30(s,3H),1.91-1.63(m,4H);13C NMR(100MHz,DMSO):δ=209.3,143.9,132.1,130.5,129.0,129.0,127.3,64.9,38.9,37.7,25.5,21.2.
Example 5: compound IV: synthesis of ketamine
2-o-chlorophenyl-2-aminocyclohexanone (0.90g,4.0mmol), 37% formaldehyde (390. mu.L, 5.0mmol), acetic acid (27. mu.L, 4.0mmol), and sodium cyanoborohydride (0.4g,6.0mmol) were placed in a 50mL reaction flask, and 15mL of methanol was added and reacted at room temperature for 12 hours. After the reaction was completed, 10mL of saturated sodium carbonate solution was added, followed by extraction with 10mL of ether 3 times, and the organic phases were combined, washed with 10mL of saturated saline solution, dried over anhydrous sodium sulfate, filtered, distilled under reduced pressure, and recrystallized from acetone to give ketamine (0.86g, yield 90%) as a white solid. The HPLC assay results are shown in fig. 7, and the assay method was performed according to the method recorded in chinese pharmacopoeia 2015 edition two.
1H NMR(400MHz,CDCl3):δ=7.60-7.58(m,1H),7.43-7.34(m,2H),7.29-7.27(m,1H),2.57-2.48(m,2H),2.15(s,1H),2.14(s,3H),2.04-1.97(m,1H),1.93-1.82(m,1H),1.80-1.76(m,3H);13C NMR(100MHz,CDCl3):δ=133.82,131.26,129.40,128.69,126.63,77.23,70.18,39.57,38.68,29.16,28.13,21.90.
Example 6 preparation of ketamine in CN201610871662.5
The preparation was carried out according to the method of example 1 in patent CN201610871662.5 to obtain ketamine sample, and the HPLC detection result is shown in fig. 8, and the detection method was carried out according to the method recorded in second edition of chinese pharmacopoeia 2015, wherein RT (retention time) 10.385min is intermediate nitro compound impurity (2-amino-2- (2-chlorobenzene) cyclohexanone). As can be seen from the comparison of the results in fig. 7 and fig. 8, the quality of the ketamine prepared by the method of the present invention is much higher than that of the ketamine prepared by the method disclosed in patent CN201610871662.5, and the method of the present invention does not use a column chromatography method for product purification, so that the operation is simpler, the time cost is saved, and the pollution of a large amount of solvents for column chromatography to the environment is avoided.
Claims (10)
1. The preparation method of ketamine is characterized by comprising the following steps:
(1) dissolving 2-o-chlorophenyl-2-azido cyclohexanone and a reducing agent in a solvent 1, heating to 50-70 ℃ for reaction for 10-15h, cooling the reaction liquid to room temperature after the reaction is finished, adding water for reflux, carrying out reduced pressure distillation to remove tetrahydrofuran to obtain a crude product, extracting, washing, drying, and carrying out reduced pressure concentration to obtain 2-o-chlorophenyl-2-aminocyclohexanone;
(2) placing 2-o-chlorophenyl-2-aminocyclohexanone, a methylating agent, acetic acid and sodium cyanoborohydride in a reaction vessel, adding a solvent 2, reacting at room temperature for 10-15h, adding a saturated sodium carbonate solution after the reaction is finished, and performing extraction, washing, drying, filtering, reduced pressure distillation and recrystallization to obtain the ketamine.
2. The method for preparing ketamine according to claim 1, wherein the reducing agent in step (1) is triphenylphosphine or trimethylphosphine.
3. The method for producing ketamine according to claim 2, wherein the molar ratio of 2-o-chlorophenyl-2-azidocyclohexanone to reducing agent is 1: 1.0-1.5.
4. The method for preparing ketamine according to claim 1, wherein the methylating agent in step (2) comprises any one of formaldehyde, dimethyl sulfate, methyl trifluoromethanesulfonate, methyl iodide and dimethyl carbonate.
5. The method for preparing ketamine according to claim 4, wherein the molar ratio of 2-o-chlorophenyl-2-aminocyclohexanone, methylating agent, acetic acid, and sodium cyanoborohydride is 5-10:3-6:3-6: 5-8.
6. The method for producing ketamine according to claim 1, wherein said solvent 1 comprises tetrahydrofuran, dichloromethane; the solvent 2 comprises any one of methanol, ethanol and isopropanol.
7. The preparation method of ketamine as in claim 1, wherein the preparation method of 2-o-chlorophenyl-2-azido cyclohexanone comprises the steps of dissolving the compound I in a solvent, adding an oxidant and an azido reagent at-25 to-15 ℃ for reaction, heating the system to room temperature after 15-20h of reaction, washing the reaction solution with water, extracting with ethyl acetate, combining organic phases, drying and concentrating the organic phases to obtain the 2-o-chlorophenyl-2-azido cyclohexanone, and the process route is as follows:
8. the method for preparing ketamine according to claim 7, wherein the oxidant used comprises one or more of iodosobenzene, iodobenzene acetate, bis (trifluoroacetoxy) iodobenzene or chromium trioxide;
9. The method for preparing ketamine according to claim 1, wherein the mass ratio of the compound of formula (I), the azide reagent and the oxidant is 1:1.3-1.6: 1.0-1.3.
10. The method for producing ketamine according to claim 1, wherein the reaction solvent comprises dichloromethane or tetrahydrofuran.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210445584.8A CN114716332B (en) | 2019-11-14 | 2019-11-14 | Preparation method of ketamine |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201911113780.XA CN110818587B (en) | 2019-11-14 | 2019-11-14 | Preparation method of ketamine and synthesis method of intermediate compound |
CN202210445584.8A CN114716332B (en) | 2019-11-14 | 2019-11-14 | Preparation method of ketamine |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911113780.XA Division CN110818587B (en) | 2019-11-14 | 2019-11-14 | Preparation method of ketamine and synthesis method of intermediate compound |
Publications (2)
Publication Number | Publication Date |
---|---|
CN114716332A true CN114716332A (en) | 2022-07-08 |
CN114716332B CN114716332B (en) | 2023-06-02 |
Family
ID=69555342
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210445584.8A Active CN114716332B (en) | 2019-11-14 | 2019-11-14 | Preparation method of ketamine |
CN201911113780.XA Active CN110818587B (en) | 2019-11-14 | 2019-11-14 | Preparation method of ketamine and synthesis method of intermediate compound |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201911113780.XA Active CN110818587B (en) | 2019-11-14 | 2019-11-14 | Preparation method of ketamine and synthesis method of intermediate compound |
Country Status (1)
Country | Link |
---|---|
CN (2) | CN114716332B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112194602A (en) * | 2020-03-17 | 2021-01-08 | 国药集团工业有限公司 | Synthesis method of ketamine and its derivatives and intermediates |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106478367A (en) * | 2016-09-30 | 2017-03-08 | 兰州大学 | A kind of synthesis midbody compound of ketamine and the synthetic method of ketamine |
WO2017208031A1 (en) * | 2016-06-03 | 2017-12-07 | Small Pharma Ltd | Solid oral dosage forms of 2r,6r-hydroxynorketamine or derivatives thereof |
-
2019
- 2019-11-14 CN CN202210445584.8A patent/CN114716332B/en active Active
- 2019-11-14 CN CN201911113780.XA patent/CN110818587B/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017208031A1 (en) * | 2016-06-03 | 2017-12-07 | Small Pharma Ltd | Solid oral dosage forms of 2r,6r-hydroxynorketamine or derivatives thereof |
CN106478367A (en) * | 2016-09-30 | 2017-03-08 | 兰州大学 | A kind of synthesis midbody compound of ketamine and the synthetic method of ketamine |
Non-Patent Citations (1)
Title |
---|
YIXIN HAN等: "Simple Enantioselective Syntheses of (2R,6R)-Hydroxynorketamine and Related Potential Rapid-Onset Antidepressants" * |
Also Published As
Publication number | Publication date |
---|---|
CN114716332B (en) | 2023-06-02 |
CN110818587A (en) | 2020-02-21 |
CN110818587B (en) | 2022-06-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
DE2453648A1 (en) | PROCESS FOR PRODUCING HYDROXYCHOLESTEROLS | |
MAY et al. | Structures related to morphine. III. Synthesis of an analog of N-methylmorphinan | |
CN110818587B (en) | Preparation method of ketamine and synthesis method of intermediate compound | |
CN113651663B (en) | Preparation method of deuterated aromatic carbonyl compound | |
WO2005044805A1 (en) | A novel process for preparing donepezil and its derivatives | |
Fujii et al. | NAD (P)+-NAD (P) H models. 65. Photochemical reductive desulfonylation of. BETA.-keto sulfones with Hantzsch ester. | |
CN111320548A (en) | Synthesis method of anticancer drug intermediate 2-fluoro-3-methyl aminobenzoate | |
CN113621015B (en) | 7-dehydrocholesterol and preparation method thereof | |
CN113072514B (en) | Preparation method of Xuanjinning and intermediate thereof | |
CN110845512B (en) | Total synthesis method of triterpenoid natural product (+) -Arisugacins F/G | |
CN104876812B (en) | Process for preparing sertraline hydrochloride intermediates and impurities | |
CN107915610B (en) | Preparation method of cyclopentadecanone | |
CN103372461B (en) | Chiral emulsion catalyst as well as preparation method and application thereof | |
CN113683655B (en) | Preparation method of rocuronium bromide intermediate | |
CN111592491A (en) | Preparation method of levo-hydrochloric acid demethyl phencynonate | |
KR100641825B1 (en) | Preparation method of 4-biphenylacetic acid | |
JPWO2004000795A1 (en) | Process for producing vinyl perfluoroalkanesulfonic acid ester derivatives | |
CN112745256B (en) | Preparation method of 4- (2-bromoethyl) -1, 3-dihydro-2H-indol-2-one | |
CN115572263B (en) | Method for synthesizing pyrazoline by catalyzing ketazine cyclization with hydrazine salt | |
CN114685410B (en) | Preparation method of butylphthalide | |
RU2174126C1 (en) | Method of preparing allobetulin | |
De | Facile Beckmann rearrangement of ketoximes mediated by yttrium triflate | |
CN109134251B (en) | Preparation method of 3-oxo-2-pentyl-cyclopentenyl methyl acetate | |
US2933531A (en) | Substituted 1-(alpha-methylphenethyl)-2, 2-dimethylhydrazine | |
JP4851016B2 (en) | Method for producing 3-hydroxymethyltetrahydrofuran |
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 |