CN103387507A - Preparation method of 1-amide adamantane - Google Patents
Preparation method of 1-amide adamantane Download PDFInfo
- Publication number
- CN103387507A CN103387507A CN2012101401749A CN201210140174A CN103387507A CN 103387507 A CN103387507 A CN 103387507A CN 2012101401749 A CN2012101401749 A CN 2012101401749A CN 201210140174 A CN201210140174 A CN 201210140174A CN 103387507 A CN103387507 A CN 103387507A
- Authority
- CN
- China
- Prior art keywords
- reaction
- preparation
- temperature
- formula
- amide group
- 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
Abstract
The invention discloses a preparation method of 1-amide adamantine. The method comprises the steps that: 1, trifluoroacetic acid is adopted as a solvent, under the existence of oxygen, and under the effect of sodium nitrite, a compound represented by the formula I is subjected to an oxidation reaction, wherein a reaction temperature is 10-35 DEG C; 2, the reaction liquid obtained in the step 1 is mixed with RCN or RCONH2, and a reaction is carried out, such that a compound represented by the formula II is obtained, wherein a reaction temperature is 60-80 DEG C, and R is hydrogen, methyl, ethyl or C3-C5 cycloalkyl. The preparation method provided by the invention has the advantages of mild reaction condition, simple operation, less side product, simple post-treatment, and suitability for industrialized productions. With the method, high-yield and high-purity 1-amide adamantine can be prepared.
Description
Technical field
The present invention relates to the synthetic field of medicine, be specifically related to a kind of preparation method of 1-amide group diamantane.
Background technology
1-amide group diamantane is important intermediate synthetic antiviral, treatment parkinsonism medicine amantadine, and their molecular structure is as shown in the formula II compound and formula IV compound.Amantadine is the first antiviral drug of U.S.'s approval, and at first Davis found its antivirus action in 1964, and in succession was written into British Pharmacopoeia, American Pharmacopeia, Japanese Pharmacopoeia and Chinese Pharmacopoeia.Domestic in 1971, the beginning produces.In addition, folk prescription amantadine sheet is mainly used in treating Parkinson's disease.
1-amide group diamantane amantadine
Document Journal of Medicinal Chemistry 1963,6 (6), the synthetic method of 760-763 report amantadine, the first step of reaction need to use aluminum chloride and tertiary butyl chloride to prepare intermediate 1-chloro diamantane (formula IV) intermediate by diamantane (formula I), this reaction environment is seriously polluted, the aluminum chloride aftertreatment is loaded down with trivial details, and the method need to just can make 1-acetamido diamantane through two-step reaction.
Document Chemische Berichte 1959,92 (7), the synthetic method of 1629-1635 report 1-kharophen diamantane: 1-adamantanol (formula V) is as the synthetic 1-kharophen diamantane of raw material, the method need to first prepare the 1-adamantanol, need to use the strongly-acid system during preparation 1-kharophen diamantane, increase and pollute.Its reaction is as follows:
Document Synthesis 2000; (12); the synthetic method of 1709-1712 report N-chloracetyl diamantane-1-amine (formula VI): 1-adamantanol (formula V) obtains formula VI compound as raw material and chloromethyl cyanide reaction, and the latter and thiocarbamide reaction directly make adamantanamine hydrochloride (formula VII).This synthetic route has been used the higher chloromethyl cyanide of price, causes the increase of cost.
Summary of the invention
Technical problem to be solved by this invention is; in the existing method for preparing 1-amide group diamantane, step is many, productive rate is not high, aftertreatment is complicated in order to overcome; be unfavorable for the defect of suitability for industrialized production and environment protection, and a kind of preparation method of 1-amide group diamantane is provided.Preparation method's reaction conditions of the present invention is gentle, and easy and simple to handle, by product is less, and aftertreatment is simple, is suitable for suitability for industrialized production, and can make high yield, highly purified 1-amide group diamantane.
The invention provides a kind of preparation method of 1-amide group diamantane, it comprises the following steps:
Step 1:, take trifluoroacetic acid as solvent,, in the situation that oxygen exists, under the effect of Sodium Nitrite, formula I compound is carried out oxidizing reaction, temperature of reaction is 10 ℃~35 ℃;
Step 2: reaction solution and RCN or RCONH that step 1 is obtained
2Mix, react, obtain formula II compound, get final product, temperature of reaction is 60 ℃~80 ℃;
Wherein, R is hydrogen, methyl, ethyl or C
3~C
5Cycloalkyl.
The preparation method of described 1-amide group diamantane preferably includes the following step:
Step 1: in the situation that oxygen exists, with trifluoroacetic acid and formula I compound, the temperature while adding Sodium Nitrite is controlled at 10 ℃~20 ℃, controls the temperature of oxidizing reaction in 10 ℃~35 ℃, oxidizing reaction 2~10 hours;
Step 2: add RCN or RCONH in the reaction solution that step 1 obtains
2React, temperature of reaction is controlled at 60 ℃~80 ℃, gets final product.
The reaction method of step 1 and condition can be with reference to this type of reactions of this area, as Synlett 2006, and (15), 2415-2418.The present invention is following reaction conditions particularly preferably:
In step 1, preferred 15 ℃~35 ℃ of the temperature of described oxidizing reaction, more preferably 15 ℃~25 ℃, most preferably 20~25 ℃.Preferred 10 ℃~15 ℃ of described temperature while adding Sodium Nitrite, temperature herein refers to the envrionment temperature of reaction, and the envrionment temperature of described reaction can be controlled by ice-water bath.Preferred 2~8 hours of the time of described oxidizing reaction, more preferably 3~4 hours.The consumption of described Sodium Nitrite is preferably 0.2~1.0 times of formula I compound molar weight, more preferably 0.2~0.4 times.The process of described step 1 can be monitored by GC, when the formula I compound of generally using disappears as the terminal of step 1.
In the present invention, the reaction solution that described step 1 obtains can pass through simple aftertreatment, such as: concentrated etc.; Or can directly carry out the reaction of step 2 without aftertreatment.
The reaction method of step 2 and condition can be with reference to this type of reactions of this area, as Synthesis 1997, and (9), 1034-1040.The present invention is following reaction conditions particularly preferably:
In step 2, preferred 75 ℃~80 ℃ of the temperature of described reaction.Preferred 8~24 hours of the time of described reaction, more preferably 12~15 hours.The consumption of described RCN or RCONH2 is preferably 1.5~10 times of formula I compound molar weight, more preferably 2~4 times.
In the present invention, the preferred hydrogen of R, methyl or ethyl, more preferably hydrogen or methyl.
In the present invention, the consumption of described trifluoroacetic acid can be selected according to the ordinary method of this area under the prerequisite that the assurance reaction can be carried out, be preferably 15~25ml/g formula I compound, more preferably 15~20ml/g formula I compound, most preferably be 20ml/g formula I compound.
In the present invention, after step 2 reaction finishes, adoptable aftertreatment is further purified the formula II compound that obtains, the method of described aftertreatment can be the conventional post-treating method of this type of reaction, as reference Synthesis 1997, (9), 1034-1040 and document Chemische Berichte l 959,92 (7), 1629-1635 carries out aftertreatment.The method of described aftertreatment preferably includes the following step: reaction system fallen cooling, reaction solution is added dropwise in water, and with saturated aqueous common salt and saturated sodium bicarbonate aqueous solution washing, that organic phase is dry after extraction, boil off solvent and get final product.Wherein, describedly coolingly preferably be cooled to 10 ℃~15 ℃.The consumption of described water is preferably 25~35ml/g formula I compound.In the process of described dropping, the temperature of reaction system preferably is no more than 25 ℃.The preferred methylene dichloride of solvent that described extraction is used.Shown drying is preferably used anhydrous magnesium sulfate.Described drying also can comprise filtration later.
In the present invention, without prejudice to the field on the basis of common sense, but above-mentioned each optimum condition arbitrary combination obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material be commercially available obtaining all.
Positive progressive effect of the present invention is:
(1) utilize diamantane as starting raw material in the present invention, do not separate reaction intermediate and directly obtain formula 1-amido diamantane, simplified operating process, reduce costs, reaction conditions is gentle, and aftertreatment is easy, is conducive to industrial production and environment protection.
(2) reaction described in the present invention can obtain high yield, highly purified formula II compound.
(3) the formula II compound that is made by the present invention, can further be used for preparing amantadine, and productive rate and purity all can reach industrial requirement.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to ordinary method and condition, or select according to catalogue.
Embodiment 1 preparation 1-kharophen diamantane
add 120ml (184g in three mouthfuls of reaction flasks of the 250ml that agitator and thermometer are housed, 1.62mol) trifluoroacetic acid and 6g (0.0441mol) diamantane, reaction flask is placed under ice-water bath and stirs, make solution temperature be down to 10 ℃, add afterwards 1.2g (0.0174mol) Sodium Nitrite, be warming up to gradually 25 ℃ in 40min, reddish-brown gas appears in reaction system, solid dissolves gradually, continue to add 7.2g (0.176mol) acetonitrile in the backward reaction solution of reaction 4h in 25 ℃, be heated to 80 ℃ of backflows, react 12 hours it, be cooled to 25 ℃, reaction solution is added dropwise in the 500ml reaction flask that 360ml water is housed, use afterwards dichloromethane extraction three times (each 100ml), combining extraction liquid uses respectively saturated aqueous common salt and saturated sodium bicarbonate aqueous solution (each 100ml) to wash again, through the water dried over mgso, remove by filter anhydrous magnesium sulfate, solvent evaporated, obtain white solid 7.83g product, productive rate 92%, GC purity is more than 98%.
Embodiment 2 preparation 1-kharophen diamantane
add 60ml (92g in three mouthfuls of reaction flasks of the 100ml that agitator and thermometer are housed, 0.81mol) trifluoroacetic acid and 6g (0.0441mol) diamantane, reaction flask is placed under ice-water bath and stirs, make solution temperature be down to 10 ℃, add afterwards 1.2g (0.0174mol) Sodium Nitrite, be warming up to gradually 25 ℃ in 40min, reddish-brown gas appears in reaction system, solid dissolves gradually, continue to add 7.2g (0.176mol) acetonitrile in the backward reaction solution of reaction 4h in 25 ℃, be heated to 80 ℃ of backflows, react 12 hours it, be cooled to 25 ℃, reaction solution is added dropwise in the 250ml reaction flask that 180ml water is housed, use afterwards dichloromethane extraction three times (each 100ml), combining extraction liquid uses respectively saturated aqueous common salt and saturated sodium bicarbonate aqueous solution (each 100ml) to wash again, through anhydrous magnesium sulfate drying, remove by filter anhydrous magnesium sulfate, solvent evaporated, obtain white solid 6.9g product, productive rate 81%, GC purity 90%.
Embodiment 3 preparation 1-kharophen diamantane
add 120ml (184g in three mouthfuls of reaction flasks of the 250ml that agitator and thermometer are housed, 1.62mol) trifluoroacetic acid and 6g (0.0441mol) diamantane, reaction flask is placed under ice-water bath and stirs, make solution temperature be down to 10 ℃, add afterwards 1.2g (0.0174mol) Sodium Nitrite, be warming up to gradually 15 ℃ in 40min, reddish-brown gas appears in reaction system, solid dissolves gradually, continue to add 7.2g (0.176mol) acetonitrile in the backward reaction solution of reaction 4h in 15 ℃, be heated to 80 ℃ of backflows, react 12 hours it, be cooled to 25 ℃, reaction solution is added dropwise in the 500ml reaction flask that 360ml water is housed, use afterwards dichloromethane extraction three times (each 100ml), combining extraction liquid uses respectively saturated aqueous common salt and saturated sodium bicarbonate aqueous solution (each 100ml) to wash again, through the water dried over mgso, remove by filter anhydrous magnesium sulfate, solvent evaporated, obtain white solid 4.4g product, productive rate 51%, GC purity 92%.
Embodiment 4 preparation 1-kharophen diamantane
add 120ml (184g in three mouthfuls of reaction flasks of the 250ml that agitator and thermometer are housed, 1.62mol) trifluoroacetic acid and 6g (0.0441mol) diamantane, reaction flask is placed under ice-water bath and stirs, make solution temperature be down to 10 ℃, add afterwards 1.2g (0.0174mol) Sodium Nitrite, be warming up to gradually 35 ℃ in 40min, reddish-brown gas appears in reaction system, solid dissolves gradually, continue to add 7.2g (0.176mol) acetonitrile in the backward reaction solution of reaction 4h in 35 ℃, be heated to 80 ℃ of backflows, react 12 hours it, be cooled to 25 ℃, reaction solution is added dropwise in the 500ml reaction flask that 360ml water is housed, use afterwards dichloromethane extraction three times (each 100ml), combining extraction liquid uses respectively saturated aqueous common salt and saturated sodium bicarbonate aqueous solution (each 100ml) to wash again, through the water dried over mgso, remove by filter anhydrous magnesium sulfate, solvent evaporated, obtain white solid 4.9g product, productive rate 57%, GC purity 89%.MS (m/z): [M+H]
+194.15, [M+2H]
+195.17, [2M+H]
+387.10;
1HNMR (400MHz, CDCl
3) δ 5.28 (br, 1H); (2.05-1.98 m, 3H); (1.98-1.90 m, 6H); (1.88 s, 3H); (1.67-1.59 m, 6H) (
1H-NMR and mass-spectrometric data reference European Journal of Organic Chemistry 2007,2007 (9), 1474-1490).
Embodiment 5 preparation 1-formamido group diamantane
add 120ml (184g in three mouthfuls of reaction flasks of the 250ml that agitator and thermometer are housed, 1.62mol) trifluoroacetic acid and 6g (0.0441mol) diamantane, reaction flask is placed under ice-water bath and stirs, make solution temperature be down to 10 ℃, add afterwards 1.2g (0.0174mol) Sodium Nitrite, be warming up to gradually 25 ℃ in 40min, reddish-brown gas appears in reaction system, solid dissolves gradually, continue to add 6.7g (0.148mol) methane amide in the backward reaction solution of reaction 4h in 25 ℃, be heated to 80 ℃ of backflows, react 12 hours it, be cooled to 25 ℃, reaction solution is added dropwise in the 500ml reaction flask that 360ml water is housed, use afterwards dichloromethane extraction three times (each 100ml), combining extraction liquid uses respectively saturated aqueous common salt and saturated sodium bicarbonate aqueous solution (each 100ml) to wash again, through the water dried over mgso, remove by filter anhydrous magnesium sulfate, solvent evaporated, obtain white solid 7.83g product, productive rate 92%, GC purity 98%.
Embodiment 6 preparation 1-formamido group diamantane
add 60ml (92g in three mouthfuls of reaction flasks of the 100ml that agitator and thermometer are housed, 0.81mol) trifluoroacetic acid and 6g (0.0441mol) diamantane, reaction flask is placed under ice-water bath and stirs, make solution temperature be down to 10 ℃, add afterwards 1.2g (0.0174mol) Sodium Nitrite, be warming up to gradually 25 ℃ in 40min, reddish-brown gas appears in reaction system, solid dissolves gradually, continue to add 6.7g (0.148mol) methane amide in the backward reaction solution of reaction 4h in 25 ℃, be heated to 80 ℃ of backflows, react 12 hours it, be cooled to 25 ℃, reaction solution is added dropwise in the 250ml reaction flask that 180ml water is housed, use afterwards dichloromethane extraction three times (each 100ml), combining extraction liquid uses respectively saturated aqueous common salt and saturated sodium bicarbonate aqueous solution (each 100ml) to wash again, through the water dried over mgso, remove by filter anhydrous magnesium sulfate, solvent evaporated, obtain white solid 5.21g product, productive rate 65%, GC purity 91%.MS (m/z): [M+H]
+180.10, [M+2H]
+181.12, [2M+H]
+359.20;
1HNMR (400MHz, CDCl
3) δ 8.28 (d, J=12.8Hz) and 8.03 (d, J=1.9Hz, 1H, NHCHO, 2Isomers); (5.86 d, J=12.8Hz) and 5.04 (br.s, 1H, NHCHO, 2Isomers) 2.18-1.60 (m, 15H) (
1H-NMR and mass-spectrometric data reference European Journal of Organic Chemistry 2007,2007 (9), 1474-1490).
Claims (10)
1. the preparation method of a 1-amide group diamantane, is characterized in that, comprises the following steps:
Step 1:, take trifluoroacetic acid as solvent,, in the situation that oxygen exists, under the effect of Sodium Nitrite, formula I compound is carried out oxidizing reaction, temperature of reaction is 10 ℃~35 ℃;
Step 2: reaction solution and RCN or RCONH that step 1 is obtained
2Mix, react, obtain formula II compound, get final product, temperature of reaction is 60 ℃~80 ℃;
Wherein, R is hydrogen, methyl, ethyl or C
3~C
5Cycloalkyl.
2. the preparation method of 1-amide group diamantane as claimed in claim 1, is characterized in that, comprises the following steps:
Step 1: in the situation that oxygen exists, with trifluoroacetic acid and formula I compound, the temperature while adding Sodium Nitrite is controlled at 10 ℃~20 ℃, controls the temperature of oxidizing reaction in 10 ℃~35 ℃, oxidizing reaction 2~10 hours;
Step 2: add RCN or RCONH in the reaction solution that step 1 obtains
2, to react, temperature of reaction is controlled at 60 ℃~80 ℃, gets final product;
Wherein, R is hydrogen, methyl, ethyl or C
3~C
5Cycloalkyl.
3. the preparation method of 1-amide group diamantane as claimed in claim 1 or 2, is characterized in that,
In step 1, the temperature of described oxidizing reaction is 15 ℃~35 ℃; The time of described oxidizing reaction is 2~8 hours.
4. the preparation method of 1-amide group diamantane as claimed in claim 1 or 2, is characterized in that,
In step 1, described temperature while adding Sodium Nitrite is 10 ℃~15 ℃.
5. the preparation method of 1-amide group diamantane as claimed in claim 3, is characterized in that,
In step 1, the temperature of described oxidizing reaction is 15 ℃~25 ℃; The time of described oxidizing reaction is 3~4 hours.
6. the preparation method of 1-amide group diamantane as claimed in claim 5, is characterized in that,
In step 1, the temperature of described oxidizing reaction is 20~25 ℃.
7. the preparation method of 1-amide group diamantane as claimed in claim 1 or 2, is characterized in that,
In step 1, the consumption of described Sodium Nitrite is 0.2~1.0 times of formula I compound molar weight.
8. the preparation method of 1-amide group diamantane as claimed in claim 1 or 2, is characterized in that,
In step 2, the time of described reaction is 8~24 hours; Described RCN or RCONH
2Consumption be 1.5~10 times of formula I compound molar weight.
9. the preparation method of 1-amide group diamantane as claimed in claim 1 or 2, is characterized in that,
In step 2, described temperature of reaction is 75 ℃~80 ℃.
10. the preparation method of 1-amide group diamantane as claimed in claim 8, is characterized in that,
In step 2, the time of described reaction is 12~15 hours; Described RCN or RCONH
2Consumption be 2~4 times of formula I compound molar weight.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210140174.9A CN103387507B (en) | 2012-05-08 | 2012-05-08 | A kind of preparation method of 1-amide groups adamantane |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201210140174.9A CN103387507B (en) | 2012-05-08 | 2012-05-08 | A kind of preparation method of 1-amide groups adamantane |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103387507A true CN103387507A (en) | 2013-11-13 |
CN103387507B CN103387507B (en) | 2016-05-25 |
Family
ID=49531939
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201210140174.9A Expired - Fee Related CN103387507B (en) | 2012-05-08 | 2012-05-08 | A kind of preparation method of 1-amide groups adamantane |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103387507B (en) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1566075A (en) * | 2003-07-01 | 2005-01-19 | 北京德众万全药物技术开发有限公司 | Preparation method for substituted symmetrel compounds or salt thereof |
CN101993377A (en) * | 2009-08-07 | 2011-03-30 | 出光兴产株式会社 | Method for producing amine and quaternary ammonium salt having adamantane skeleton |
-
2012
- 2012-05-08 CN CN201210140174.9A patent/CN103387507B/en not_active Expired - Fee Related
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1566075A (en) * | 2003-07-01 | 2005-01-19 | 北京德众万全药物技术开发有限公司 | Preparation method for substituted symmetrel compounds or salt thereof |
CN101993377A (en) * | 2009-08-07 | 2011-03-30 | 出光兴产株式会社 | Method for producing amine and quaternary ammonium salt having adamantane skeleton |
Non-Patent Citations (5)
Title |
---|
ELVIRA SHOKOVA 等: "Adamantylation and Adamantylalkylation of Amides, Nitriles and Ureas in Trifluoroacetic Acid", 《SYNTHESIS》, no. 9, 31 December 1997 (1997-12-31) * |
GEORGE A.OLAH 等: "Synthetic Methods and Reactions. 86."Novel Synthesis of N-( 1-Adamanty1)amides from adamantane", 《J.ORG.CHEM.》, vol. 45, no. 17, 31 August 1980 (1980-08-31), pages 3532 - 3533, XP002168001, DOI: doi:10.1021/jo01305a041 * |
LI-QIAN CUI 等: "Effective oxidation of benzylic and alkane C–H bonds catalyzed by sodium o-iodobenzenesulfonate with Oxone as a terminal oxidant under phase-transfer conditions", 《ORG.BIOMOL.CHEM.》, vol. 9, 8 February 2011 (2011-02-08), pages 2258 - 2265 * |
ONOMURA,OSAMU 等: "Efficient Oxidation of Adamantanes by Sodium Nitrite with Molecular Oxygen in Trifluoroacetic Acid", 《SYNLETT》, vol. 15, 30 June 2006 (2006-06-30) * |
葛孝忠 等: "金刚烷类药物的研究进展", 《中国医药工业杂志》, vol. 34, no. 11, 20 November 2003 (2003-11-20), pages 583 - 586 * |
Also Published As
Publication number | Publication date |
---|---|
CN103387507B (en) | 2016-05-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106279074B (en) | A kind of compound and preparation method thereof and the purposes in Bu Waxitan is synthesized | |
WO2020147861A1 (en) | Electrochemical preparation method for β-trifluoromethylamide compound | |
ES2384368T3 (en) | Process for preparing derivatives of 1- (2-halobiphenyl-4-yl) -cyclopropanecarboxylic acid | |
CN106432030B (en) | A kind of preparation method of Bu Waxitan | |
CN103570580B (en) | Preparation method of high-purity iopromide | |
CN106365986B (en) | Compound and preparation method thereof and the purposes in synthesis Bu Waxitan | |
CN103897028A (en) | Synthesis method of bortezomib | |
CN106187857A (en) | A kind of method preparing Apremilast | |
CN105315184B (en) | A kind of fertile Preparation Method And Their Intermediate for Xi Ting | |
CN104529734A (en) | Preparation method and preparation intermediate of fingolimod hydrochloride | |
EP3088382B1 (en) | Method for producing nitro compound | |
CN108164423B (en) | Preparation method of naftifine hydrochloride | |
CN103387507A (en) | Preparation method of 1-amide adamantane | |
CN114790151B (en) | Composite catalytic preparation method of 2-cyano-2-methyl valproate | |
CN102807516A (en) | Intermediate in amisulpride and method for preparing amisulpride by using intermediate | |
CN101514167A (en) | Method for preparing chiral baclofen | |
CN101397247B (en) | Method for synthesizing raw medicine dihydroindene-1-carboxyl acid for clidabac | |
CN105418436B (en) | A kind of preparation method of melitracen hydrochloride | |
CN111116510B (en) | 2-substituted methylene dihydrobenzo [ d ] thiazole derivatives and synthesis method and application thereof | |
CN103694130A (en) | High-yield synthesis method of n-ethyl-p-menthane-3-carboxamide | |
CN104817476B (en) | Method for preparing unnatural amino acid | |
CN103965068A (en) | 1-amide adamantane preparation method | |
CN109928910A (en) | The preparation method of anti-migraine drug Almotriptan | |
CN104817511B (en) | Method for using maleic anhydride to prepare favipiravir key intermediate | |
CN103508906A (en) | Method for preparing (1R,3S)-3-aminomethyl-2,2-dimethyl cyclopropane methyl alcohol and salts thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20160525 Termination date: 20210508 |
|
CF01 | Termination of patent right due to non-payment of annual fee |