WO2012049688A1 - Procédé amélioré pour la préparation de 6,6-diméthyl-3-azabicyclo-[3.1.0]hexane racémique et de ses sels, une matière première clef pour l'inhibiteur de vhc - Google Patents

Procédé amélioré pour la préparation de 6,6-diméthyl-3-azabicyclo-[3.1.0]hexane racémique et de ses sels, une matière première clef pour l'inhibiteur de vhc Download PDF

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WO2012049688A1
WO2012049688A1 PCT/IN2011/000428 IN2011000428W WO2012049688A1 WO 2012049688 A1 WO2012049688 A1 WO 2012049688A1 IN 2011000428 W IN2011000428 W IN 2011000428W WO 2012049688 A1 WO2012049688 A1 WO 2012049688A1
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formula
compound
dimethyl
azabicyclo
hexane
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PCT/IN2011/000428
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WO2012049688A8 (fr
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Anant Dharma Shinde
Bapu Atmaram Chaudari
Ganesh Gurpur Pai
Arun Kanti Mandal
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Arch Pharmalabs Limited
Ranbhan, Kamlesh Jayantilal
Sonaane, Sachin Ulhas
Sarjekar, Pushpalata Bakrishna
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Publication of WO2012049688A8 publication Critical patent/WO2012049688A8/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered

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  • TITLE An improved process for the preparation of racemic 6, 6- dimethyl-3-azabicyclo-[3.1.0]-hexane and its salts, a key raw material for HCV inhibitor.
  • the present invention discloses an efficient and economical process for the preparation of racemic 6, 6-dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I and its salts.
  • the invention relates to the compounds of formulae I and II.
  • the compound of formula I is a key raw material for the preparation of a key intermediate (1R, 2S, 5S) - methyl 6,6-dimethyl -3-azabicyclo [3.1.0] hexane-2 carboxylic acid and ester and salts of formula III for a class of inhibitors of the protease of the formula PI.
  • compounds those inhibit HCV NS3/NS4a serine protease activity are preferred.
  • Rl is hydrogen ,aralkyl, substituted
  • Rl aralkyl or alkenyl prefereably Rl is
  • R is, for example alkyl, aryl,
  • Rl is H, OR8, NR9R10 or CHR9R10, wherein R8, R9 and RIO can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl- , aryl-, heteroalkyl-, hetroaryl-, cyclalkyl-, heterocyclyl-, aryl-, heteroalkyl, heteroaryl-, cycloalkyl-, heterocyclyl- arylalkyl- and heteroarylalkyl;
  • a and M can be the same or different, each being independently selected from R, OR, NHR, NRR',SR, SO2R and halo; or A and M are connected to each other such that the moiety:
  • E is C (H) or C(R);
  • L is C (H),C(R), CH2C(R) or C(R)CH2;
  • R3 can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl- , aryl-, heteroalkyl-, hetroaryl-, cycloalkyl-, heterocyclyl-, aryl-, heteroalkyl, heteroaryl-, (cycloalkyl) alkyl-, (heterocyclyl) alkyl- arylalkyl- and heteroarylalkyl; or alternately R and R' in NRR' are connected to each other such that NRR' forms a four to eight membered heterocyclyl
  • Y is selected from the following moieties:
  • G is NH or O; and R15, R16, R17, R17 and R18 can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkenyl-, alkynyl- , aryl-, heteroalkyl-, heteroalkenyl, cycloalkyl, , alkynyl, cyclalkyl, heterocyclyl, arylalkyl, heteroarylalkyl or alternately, (i) R15 and R16 ar connected to each other to form a four to eight membered cyclic structure , and (ii) likewise, independently R17 and R18 are connected to each other to form a three to eight membered cycloalkyl or heterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting hydroxy, alkoxy,
  • R15 and R16 are connected to each other to form a four to eight membered cyclic structure and (ii) likewise independently R17 and R18 are connected to form a three to eight membered cycloalkyl or heterocyclyl means the following possibilities: (i) R15 and R16 are connected to form a cyclic structure while R17 and R18 are not, (ii) rl7 and R18 are connected to form a cyclic structure while R15 and R16 are not and (iii) R15 and R16 are connected to form a cyclic structure and R17 and R 18 are also connected to form a cyclic structure . These possibilities can occur independent of one another.
  • preferred alkyl is made of one to ten carbon atoms
  • preferred alkenyl or alkynyl is made of two to ten carbon atoms
  • preferred heteroalkyl, heteroaryl or heterocyclalkyl has one to six oxygen, nitrogen, sulphur or phosphorus atoms.
  • the compounds represented by formula PI can be useful for treating diseases such as HCV, HIV and related disorders as well as for modulating the activity of hepatitis C virus (HCV) protease, preventing HCV or ameliorating one or more symptoms of hepatitis C.
  • HCV hepatitis C virus
  • the HCV protease may be NS3 or NS4a protease.
  • the invention discloses an improved and economical process for the preparation of racemic 6,6- dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I and its corresponding salts in high yield and good purity.
  • This compound is a key raw material for the preparation of (1R, 2S, and 5S) - methyl 6,6-dimethyl -3- azabicyclo [3.1.0] hexane-2 carboxylic acid and ester of formula III and salts thereof.
  • Esters of 6,6-dimethyl -3-azabicyclo [3.1.0] hexane-2 carboxylic acid are useful as intermediates in the synthesis of the compounds that have a utility, for example (1R, 2S, and 5S) - 6,6- dimethyl -3-azabicyclo [3.1.0] hexane-2 carboxylic acid methyl ester hydrochloride is a key intermediate used in the preparation of serine protease inhibitor of the general formula PI.
  • Compound of formula PI is useful for treating hepatitis C and related disorders, specifically, the HCV NS 3 /NS 4a serine protease.
  • esters of 6,6-dimethyl -3- azabicyclo [3.1.0] hexane-2 carboxylic acid of the formula III Various methods are known in the art to make esters of 6,6-dimethyl -3- azabicyclo [3.1.0] hexane-2 carboxylic acid of the formula III.
  • the general scheme for the preparation of esters of 6,6-dimethyl -3- azabicyclo [3.1.0] hexane-2 carboxylic acid of the formula III via racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane using caronic anhydride can be represented as follows: However there are very limited processes for the preparation of racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane and its corresponding salts of formula I a key raw material for the preparation of 6,6-dimethyl -3- azabicyclo [3.1.0] hexane-2 carboxylic acid esters.
  • the present invention discloses an efficient and economical process for the preparation of racemic 6, 6-dimethyl-3-azabicyclo-[3.1.0]-hexane of the formula I as shown below:
  • the efficient and economical process comprises the reduction of the compound of the formula II wherein Rl is hydrogen using alkali metal borohydride as a reducing agent in the presence of an acid yielding the compound of formula I.
  • Another aspect of the invention is the improved process for the conversion of the compound of the formula II into compound of formula I as shown below:
  • the efficient and economical process relates to the reduction of the compound of the formula II wherein Rl is benzyl group using alkali metal borohydride as a reducing agent in the presence of an acid yielding the compound of formula V followed by its debenzylation using palladium hydroxide replacing palladium/C(known in the prior art) or chloroformates like 1-chlorethylchloroformate yielding the compound of formula I.
  • WO2008082508 discloses the process for the preparation of the compound of formula I comprising two steps of reduction, first is to deoxygenate the compound of formula IV using lithium aluminium hydride to obtain the compound of formula V, second reduction is hydrogenation using palladium /charcoal yielding compound of formula I.
  • WO2007075790A1 discloses use of lithium aluminium hydride as reducing agent for the preparation of the compound of formula I. The yield reported is 88%, but there is no mention of the purity. The compound of formula was further converted into its hydrochloride by purging dry HC1 at -23°C to -20°C.
  • WO2009/73380A1 also discloses use of lithium aluminium hydride as reducing agent for the preparation of the compound of formula I. The yield reported is 88%, but there is no mention of the purity.
  • US7723531 (hereinafter referred as '531) discloses both the possible routes as shown below. It also discloses the use of reducing agent selected from the group consisting of lithium aluminium hydride, lithium borohydride, vitride chemically named as sodium bis(2- methoxyethoxy) aluminium hydride and borane. The inventors of '531 have broadened the scope of claim by also including so many other reducing agents such as boranes to convert the compound of formula II into compound of formula I.
  • inventive feature of the present invention for the preparation of racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I lies in the reaction of compound of formula II with alkali metal borohydride in combination with an Acid.
  • inventive feature can also be applied for the preparation of compound of formula I from compound of formula IV via compound of formula V.
  • Another key feature of the invention is the debenzylation of compound of formula V either by hydrogenation in presence of palladium hydroxide or by heating with 1-chloro-ethylchloroformate.
  • Formula I is 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane.
  • Formula II (Rl is H) is 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4- dione.
  • Formula III is esters of 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane carboxylic acid.
  • Formula IV is 3-benzyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4- dione.
  • Formula V is 3-benzyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane.
  • Formula VI is salt of 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane. presented by IA is 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane. represented by IB is 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane (1R, 2S, 5S) nitrile H °° 0H represented by IC is 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane (1R, 2S, 5S) carboxylic acid
  • C OOMe represented by III is Methyl 6,6-dimethyl-3-azabicyclo- [3.1.0]- hexane (1R, 2S, 5S) carboxylate
  • First aspect of the invention is to provide an efficient and economical process for the preparation of racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]- hexane of formula I from compound of formula II using alkali metal borohydride in combination with acid.
  • Second aspect of the invention is to provide a process for the preparation of corresponding salts of racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]- hexane of formula VI from compound of formula II using sodium borohydride in combination with an acid.
  • Fourth aspect of the invention is to provide a process for the preparation of racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I from caronic anhydride of formula ⁇ via compounds of formulae IV and V using alkali metal borohydride in combination with acid .
  • Fifth aspect of the invention is to provide a process for the preparation of racemic 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I from caronic anhydride of formula IF via compounds of formulae IV and V using alkali metal borohydride in combination with acid and its utility of the compound of formula I for the preparation of key intermediate of formula III via Enzymatic desymmetrization followed by cyanation, hydrolysis and esterification as shown in the scheme below.
  • Sixth aspect of the invention is to provide a novel process for the preparation of the compound of formula V from compound of formula IV.
  • Seventh aspect of the invention is to provide a novel process for the conversion of compound of formula V into compound of formula I by hydrogenation using palladium hydroxide or by heating in 1-chloro- ethylchloro formate.
  • the present invention discloses an efficient and economical process for the preparation of racemic 6, 6-dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I and its salts from compound of formula II comprising alkali metal borohydride in combination with acid.
  • the present invention also discloses an improved process for the preparation of racemic 6, 6-dimethyl-3-azabicyclo-[3.1.0]-hexane of formula I and its salts from compound of formula IV using alkali metal borohydride in combination with acid followed by debenzylation of the compound of formula V comprising palladium hydroxide or by heating in 1-chlro-ethylchloroformate yielding the compound of formula I.
  • Compound of formula I is commercially available or known in the art. Present invention relates to an improvement over the processes known in the art to overcome the shortcomings therein in the prior art.
  • compound of formula I is prepared by reacting compound of formula II with alkali metal borohydride in combination with acid in a single step with higher yield and high purity.
  • Scheme II of the present invention relates to an improved process for the preparation of compound of formula VI comprising reduction of compound of formula II using alkali metal borohydride in combination with acid and insitu converting into corresponding salts of formula VI with higher yield and good purity.
  • ⁇ X is anion like CI, Br, I, N03, HS04
  • Scheme III discloses an improved process which overcomes the shortcomings of processes reported in the prior art that comprises reduction followed by debenzylation.
  • reduction of the compound of formula IV is carried out using alkali metal borohydride in combination with acid yielding compound of formula V.
  • Compound of formula V is debenzylated by hydrogenation using palladium hydroxide or by heating in 1-chloro- ethylchloro formate resulting into compound of formula I.
  • Reduction of the compound of formulae II or IV yields compound of formula I.
  • Reducing agent is selected from the group of alkali metal borohydride consisting of lithium borohydride, sodium borohydride, potassium borohydride and the like.
  • Preferable reducing agent is sodium borohydride.
  • Acid is selected from mineral acid, lewis acid.
  • Mineral acid is selected from HC1, H 2 S0 4 and the like.
  • mineral acid is H 2 S0 4 .
  • Lewis acid is selected from magnesium bromide.BF3 etherate, BF 3 etherate, Ferric chloride, aluminium chloride and the like.
  • lewis acid is BF 3 etherate.
  • Solvent used for the reduction of the compound of formula II or IV is selected from tetrahydrofuran, 2-methyl tetrahydrofuran, tert-butyl methyl ether, 1,2-dimethoxyethane, toluene or mixtures of two or more thereof.
  • solvent is tetrahydrofuran.
  • the product is isolated by distillation of solvent. Reduction reaction to convert compound of formula II and IV to compound of formula I is carried out at a temperature from about -20°C to about 80°C.
  • Solvent for the hydrogenation for debenzylation of the compound of formula V is selected from aliphatic alcohols or substituted chloroformates.
  • aliphatic alcohol is selected from ethanol, methanol or the like. More preferably aliphatic alcohol is methanol.
  • Substituted chloroformates is selected from 2,2,2-trichloro ethyl formate , 1-chloro-ethylchloroformate and the like.
  • substituted chloroformates is 1-chloro-ethylchloroformate.
  • compound of formula I is converted into the corresponding salt (compound of formula VI) by reacting it with a suitable acid.
  • suitable acids comprise but not limited to mineral acids selected from HC1, HBr, HI, HN03, or H2S04 and the like.
  • suitable organic solvents it is preferred to use suitable organic solvents to provide a mineral acid solution for this treatment.
  • Compound of formula I may also be converted into esters of 6,6- dimethyl-3-azabicyclo-[3.1.0]-hexane carboxylic acid of formula ⁇ by the known procedures as given in US2010/0145069 or US7723531.
  • the compound of formula I made by the efficient and economical process disclosed herein can be further converted into the compound of formula III and thereby into compound of formula PI.
  • the compound of formula IB is then hydrolysed using methanolic HCL yielding 6,6-dimethyl-3-azabicyclo-[3.1.0]-hexane (1R, 2S, 5S) carboxylic acid followed by its ester formation using methanol and thionyl chloride resulting into methyl 6,6-dimethyl-3-azabicyclo-[3.1.0]- hexane (1R, 2S, 5S) carboxylate.
  • compound of formula I is prepared by reacting compound of formula II with sodium borohydride in combination with BF 3 etherate as an acid in THF as a solvent in a single step with higher yield 88-90 % and high purity of 98-99%.
  • compound of the formula I is prepared by reacting the caronic anhydride of the formula ⁇ with benzyl amine to obtain compound of formula IV followed by its reaction with sodium borohydride in combination with BF 3 etherate as an acid in THF as a solvent affording compound of formula V and further debenzylation using either the process of hydrogenation using palladium hydroxide or heating in chloroformates to obtain compound of formula I.
  • the compound of the formula I which itself is prepared by the reduction of the compounds of formula II or IV using sodium borohydride in combination with BF 3 etherate as an acid is converted into compound of the formula III via Enzymatic desymmetrization followed by cyanation as shown and described hereinabove in third aspect of the present invention).
  • X is anion like CI, Br, I, N03,
  • R is alkyl group
  • esters of 6,6- dimethyl-3-azabicyclo-[3.1.0]-hexane carboxylic acid of formula III is used as a key intermediate and are HCV inhibitors.
  • Example 1 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane: To a well- stirred suspension of 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4- dione of formula II, Rl is Hydrogen, (2.0 g, 14.38 mmol) in dry THF (20.0 mL) sodium borohydride (1.64 g, 43.16 mmol) was added at - 30 to -20 °C. BF 3 . Et 2 0 (43.16 mmol) was then added slowly at the same temperature. Reaction mixture was then stirred for 7-8 hrs at 40 to 50 °C temperature. THF was then distilled off followed by stripping of toluene to remove the THF.
  • Reaction mass was cooled and unreacted NaBH 4 was quenched with methanol (5.0 mL), diluted with water (100 mL), and extracted with toluene (3 x 25 mL). The combined toluene layers were washed with water and dried over anhydrous sodium sulfate. The solvent was removed under the reduced pressure keeping the temperature below 55°C to get 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane as a colorless liquid (1.3g) with GC purity of 96%.
  • Reaction mass was cooled and unreacted NaBH4 was quenched with methanol (5.0 mL), diluted with water (100 mL), and extracted with toluene (3 x 25 mL). The combined toluene layers were washed with water and dried over anhydrous sodium sulfate. HC1 gas was then purged at 5 - 10 °C to make 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane hydrochloride. Maintain the reaction mass at 10 °C for 30 min. Product was filtered off under inert condition then Dry compound under vacuum at 40 - 45 °C to get 1.7 g dry compound with GC purity of 95%.
  • Example 3 Preparation of 6,6-Dimethyl-3-aza-bicyclo[3.1.0]hexane- 2,4-dione (II): 560 (4moles) gm of Caronic anhydride and 280 gm urea (4.6 moles) was charged. Contents were heated at 160 - 170°C till the completion of the reaction. Reaction mass was brought at 55°C and 1125 ml MDC was added and stirring was continued for 15-20 minutes followed by the addition of 560 mL water and stirring continued. MDC layer was separated and dried over sodium sulphate. MDC was distilled off and residual MDC was removed by the stripping of toluene. Toluene was distilled off under reduced pressure. The reaction mixture was cooled to 0 to 10°C over a 5 hour period till the product was crystallized. The crystals were collected by filtration, washed, and dried to yield compound II as a white crystalline powder.
  • Example 4 3-benzyl-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2,4- dione
  • TBME benzyl-6,6-dimethyl-3-azabicyclo [3.1.0] hexane-2,4- dione
  • the solution was maintained between 170 and 180° C for approximately 3 to 5 hours to complete the cyclization.
  • the resulting solution was cooled to between 60 and 70° C, and 100 mL of a solution of 5% water in isopropanol was added and the mixture was cooled to room temperature. After cooling further to between 0 and 10° C, the product was isolated by filtration, rinsed with clean, cold isopropanol, and dried in a vacuum oven to afford 70.99 g of the benzyl imide of formula IV.
  • reaction mass was cooled and unreacted NaBH 4 was quenched with methanol (5.0 ml), diluted with water (100 mL), and extracted with toluene (3 x 25 mL).
  • methanol 5.0 ml
  • water 100 mL
  • toluene 3 x 25 mL
  • the combined toluene layers were washed with water and dried over anhydrous sodium sulfate.
  • Toluene layer was cooled and the HC1 gas was purged at 5 - 10°C to make 6, 6-dimethyl-3- azabicyclo [3.1.0] hexane hydrochloride. Maintain the reaction mass at 10°C for 30 min.
  • Product was filtered off under inert atmosphere.
  • the compound was dried under vacuum at 40 - 45°C to get 1.5 g dry compound.
  • hexane nitrile via corresponding hex-2-ene 100 gm of 6, 6- dimethyl-3-azabicyclo [3.1.0] hexane base was added into 452 mL DM water containing 126 gm of sodium bisulphite to get the BS solution.
  • enzymatic solution was prepared by adding 2gm enzyme CDX - 616, 2.1 gm of catalase and 0.3 gm of antifoam in 50 ml of freshly boiled DM water. This enzymatic solution was then added into the base solution mentioning the pH at 7.4 using 3M sodium hydroxide in about 30 hours.
  • hexane carboxylic acid Methanolic solution containing 81 gm (0.367 mol) 6, 6-dimethyl-3-(lR,2S,5S)-azabicyclo [3.1.0] hexane nitrile was charged into methanol saturated with hydrogen chloride at -5 to 5°C in a period of an hour. Temperature was gradually brought to 30-35°C and was maintained for 8-10 hours. Solid ammonium chloride was removed by filtration. Filtrate so collected was added with 400 mL water and contents were heated for another 10-15 hours at 45-50°C till the hydrolysis was complete. Methanol was distilled off under the reduced pressure and titled product was isolated as its hydrochloride.
  • Example 10 Preparation of Methyl 6, 6-dimethyl-3-(lR, 2S, 5S)- azabicyclo [3.1.0] hexane carboxylate: 100 gm (0.522mol) of 6, 6- dimethyl-3-(lR,2S,5S)-azabicyclo [3.1.0] hexane carboxylic acid was charged into 500mL methanol. The contents were cooled to 0°C and thionyl chloride was added dropwise maintain the temperature between 0-10°C. Temperature was gradually brought to 30-35°C and stirring was continued for 4 hours till the completion of the reaction. Thionyl chloride and methanol is distilled off under the reduced pressure. Apply the vacuum to the contents free from thionyl chloride and methanol. The titled product was precipitated from isopropanol and ethyl acetate. The product was filtered off and dried under vacuum. Yield obtained is 95gm.

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Abstract

La présente invention divulgue un procédé efficace et économique pour la préparation de 6,6-diméthyl-3-azabicyclo-[3.1.0]-hexane racémique de formule I et de ses sels. L'invention concerne des composés de formules I et II. Le composé de formule I est une matière première clef pour la préparation d'un intermédiaire clef de l'acide et de l'ester de (1R, 2S, 5S)-méthyle 6,6-diméthyl-3-azabicyclo[3.1.0]hexane-2-carboxylique et des sels de formule III pour une classe d'inhibiteurs de la protéase de formule PI. Parmi les composés fournis dans la présente, les composés qui inhibent l'activité de la VHC NS3/NS4a sérine protéase sont préférés.
PCT/IN2011/000428 2010-10-12 2011-06-28 Procédé amélioré pour la préparation de 6,6-diméthyl-3-azabicyclo-[3.1.0]hexane racémique et de ses sels, une matière première clef pour l'inhibiteur de vhc WO2012049688A1 (fr)

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CN115028570A (zh) * 2022-05-13 2022-09-09 浙江新和成股份有限公司 （1r，2s，5s）-6，6-二甲基-3-氮杂双环[3，1，0]己基-2-羧酸酯的制备方法
CN115322167A (zh) * 2022-08-15 2022-11-11 淄博矿业集团有限责任公司 一种抗病毒药物中间体的制备方法
WO2023206700A1 (fr) * 2022-04-27 2023-11-02 凯莱英医药集团（天津）股份有限公司 Procédé de réduction par hydrogénation en continu d'amide

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EP2899207A1 (fr) 2014-01-28 2015-07-29 Amikana.Biologics Nouveau procédé pour tester l'inhibition de la protéase du HCV
CN105330589A (zh) * 2015-11-16 2016-02-17 江苏大学 一种波普瑞韦中间体的制备方法
CN113999160A (zh) * 2021-10-21 2022-02-01 江苏省药物研究所有限公司 一种6,6-二甲基-3-氮杂双环[3．1．0]己烷的制备方法
CN113999160B (zh) * 2021-10-21 2022-12-27 江苏省药物研究所有限公司 一种6,6-二甲基-3-氮杂双环[3.1.0]己烷的制备方法
CN114133350A (zh) * 2021-12-16 2022-03-04 浙江乐普药业股份有限公司 一种抗新冠药物Paxlovid中间体的制备方法
CN114085181A (zh) * 2022-01-18 2022-02-25 南京桦冠生物技术有限公司 一种6,6-二甲基-3-氮杂双环[3.1.0]己烷的合成方法及其应用
CN114544801A (zh) * 2022-01-20 2022-05-27 汉瑞药业(荆门)有限公司 一种azabicyclo[3.1.0]hexane的GC-FID检测方法
CN114544801B (zh) * 2022-01-20 2023-02-28 汉瑞药业(荆门)有限公司 一种azabicyclo[3.1.0]hexane的GC-FID检测方法
CN114609290B (zh) * 2022-03-22 2024-02-09 武汉海特生物创新医药研究有限公司 一种帕罗维德中间体纯度的hplc-uv检测方法
CN114609290A (zh) * 2022-03-22 2022-06-10 汉瑞药业(荆门)有限公司 一种帕罗维德中间体纯度的hplc-uv检测方法
CN115010647A (zh) * 2022-04-19 2022-09-06 浙江天宇药业股份有限公司 一种双环内酰胺类化合物的制备方法
CN115010647B (zh) * 2022-04-19 2024-04-09 浙江天宇药业股份有限公司 一种双环内酰胺类化合物的制备方法
WO2023206700A1 (fr) * 2022-04-27 2023-11-02 凯莱英医药集团（天津）股份有限公司 Procédé de réduction par hydrogénation en continu d'amide
CN115028570A (zh) * 2022-05-13 2022-09-09 浙江新和成股份有限公司 （1r，2s，5s）-6，6-二甲基-3-氮杂双环[3，1，0]己基-2-羧酸酯的制备方法
CN114634441A (zh) * 2022-05-16 2022-06-17 南京海辰药业股份有限公司 一种合成6,6-二甲基-3-氮杂双环[3,1,0]己烷的新方法
CN114634441B (zh) * 2022-05-16 2022-07-26 南京海辰药业股份有限公司 一种合成6,6-二甲基-3-氮杂双环[3,1,0]己烷的方法
CN115322167A (zh) * 2022-08-15 2022-11-11 淄博矿业集团有限责任公司 一种抗病毒药物中间体的制备方法
CN115322167B (zh) * 2022-08-15 2023-06-30 淄博矿业集团有限责任公司 一种抗病毒药物中间体的制备方法

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