The content of the invention
The technical problems to be solved by the invention be in order to overcome in the prior art Wei Patawei (Velpatasvir or
GS5816 preparation method), chiral isomer control is difficult in course of reaction, and obtained product chiral purity is poor, does not reach original
Expect medicine standard, total recovery is low, and production cost is high, the defects of being not suitable for industrialized production, and provides GS5816 intermediates, system
Preparation Method and application.The preparation method reaction condition of the present invention is gentle, and step is short, high income, and obtained product purity is high, can
Reach bulk drug (API) standard, production cost is low, is suitable for industrialized production.
The invention provides the preparation method of compound 12, and it comprises the following steps:In organic solvent, existing for condensing agent
Under the conditions of, compound 13 and compound 9 are subjected to condensation reaction, compound 12 is made;
The preparation method of described compound 12 can be the conventional method of such condensation reaction in this area, in of the invention
Particularly preferred following reaction method and condition:
In the preparation method of described compound 12, described organic solvent preferred amide class solvent;Described acid amides
The preferred N,N-dimethylformamide of class solvent (DMF).
In the preparation method of described compound 12, the preferred 1- ethyls of described condensing agent-(3- dimethylaminos third
Base) phosphinylidyne diimmonium salt hydrochlorate (EDCI), 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters
(HATU), BTA-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HBTU), O- BTAs-N, N, N', N'-
Tetramethylurea tetrafluoro boric acid ester (TBTU), BTA -1- three (dimethylamino)-trifluoro phosphate (BOP), chloro tripyrrole alkane
Ji Phosphonium hexafluorophosphate (PyClOP), hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl (PyBOP), the ring of N, N'- bis-
Hexyl carbodiimide (DCC), (2- oximidos-cyan-acetic ester)-N, N- Dimethyl-morpholin base urea hexafluorophosphoric acid esters (COMU),
2- oximes ethyl cyanoacetate (Oxyma) and propylphosphonic anhydride (T3P the one or more in).Described propylphosphonic anhydride (T3P) can be with
For conventional commercial propylphosphonic anhydride (T3P) reagent, such as mass concentration are 50% propylphosphonic anhydride (T3P) N, N- dimethyl formyl
Amine (DMF) solution, it is molten that described mass concentration refers to that the quality of propylphosphonic anhydride accounts for propylphosphonic anhydride DMF
The percentage of liquid gross mass.
In the preparation method of described compound 12, described condensing agent and the molar ratio of described compound 13 are excellent
Select 1~3, further preferred 1~1.5, such as 1.1.
In the preparation method of described compound 12, the molar ratio of described compound 9 and described compound 13
It is preferred that 1~3, further preferred 1~1.5, such as 1.1.
In the preparation method of described compound 12, preferably 0 DEG C~40 DEG C of the temperature of described condensation reaction, further
It is preferred that 10 DEG C~30 DEG C, such as 20 DEG C~25 DEG C.
In the preparation method of described compound 12, the process of described condensation reaction can be using normal in this area
Rule detection method (such as HPLC, TLC or NMR) is monitored, described as the terminal of reaction when typically being disappeared using compound 13
Preferably 1 hour~10 hours time of condensation reaction, further preferred 2 hours~8 hours, such as 5 hours~6 hours.
The preparation method of described compound 12 preferably uses following steps:0-10 DEG C, by compound 13 and organic solvent
The mixture of formation, it is added drop-wise in the mixture that compound 9, condensing agent and organic solvent are formed, carries out condensation reaction and obtain institute
The compound 12 stated.
The preparation method of described compound 12 preferably uses following post-processing step:After reaction terminates, cool, be added dropwise
Water, stir, filtering, washing obtains described compound 12.Described cooling is preferably dropped to 5 DEG C~10 DEG C of temperature.It is described
Stirring preferably 2 hours~3 hours time.
The preparation method of described compound 12 preferably further includes the preparation method of compound 13, and it includes following step
Suddenly:In organic solvent, compound 14 is carried out to the reaction of deaminizating protection group with acid, described compound 13 is made;
Wherein, described P is amino protecting group, preferably tertbutyloxycarbonyl, benzyloxycarbonyl group or p-toluenesulfonyl.
The preparation method of described compound 13 can be the routine of the reaction of such removing amino protecting group in this area
Method, particularly preferred following reaction method and condition in of the invention:
In the preparation method of described compound 13, the preferred esters solvent of described organic solvent;Described esters are molten
The preferred isopropyl acetate of agent.
In the preparation method of described compound 13, described sour preferred inorganic acid;The preferred chlorination of described inorganic acid
Hydrogen.Described hydrogen chloride can in gaseous form or its solution form use, the preferred hydrogen chloride of described hydrogen chloride solution
Isopropyl acetate solution.
In the preparation method of described compound 13, the described sour molar ratio preferably 1 with described compound 14
~10, further preferred 4~6, such as 5.
In the preparation method of described compound 13, preferably 40 DEG C of the temperature of the reaction of described removing amino protecting group
~100 DEG C, further preferred 50 DEG C~70 DEG C, such as 60 DEG C~65 DEG C.
In the preparation method of described compound 13, the process of the reaction of described removing amino protecting group can use
Common detection methods (such as HPLC, TLC or NMR) in this area are monitored, as reaction when typically being disappeared using compound 14
Terminal, preferably 1 hour~10 hours time of the reaction of described removing amino protecting group, further preferred 2 hours~8 is small
When, such as 2 hours~6 hours.
The preparation method of described compound 12 preferably further includes the preparation method of compound 14, and it includes following step
Suddenly:Under protective gas protection, in organic solvent, under the conditions of alkali is existing, compound 25 and compound 24 are subjected to condensation reaction,
Obtain described compound 14;
P is as defined above described.
The preparation method of described compound 14 can be the conventional method of such condensation reaction in this area, in of the invention
Particularly preferred following reaction method and condition:
In the preparation method of described compound 14, the preferred nitrogen of described protective gas and/or argon gas.
In the preparation method of described compound 14, described organic solvent preferred amide class solvent;Described acid amides
The preferred DMF of class solvent (DMF).
In the preparation method of described compound 14, the preferred inorganic base of described alkali;The preferred carbonic acid of described inorganic base
Potassium.
In the preparation method of described compound 14, described alkali and the molar ratio preferably 1 of described compound 25
~3, further preferred 1.00~1.50, such as 1.05.
In the preparation method of described compound 14, the molar ratio of described compound 24 and described compound 25
It is preferred that 1~3, further preferred 1.00~1.50, such as 1.05.
In the preparation method of described compound 14, preferably 10 DEG C~50 DEG C of the temperature of described condensation reaction, enter one
Preferably 20 DEG C~40 DEG C of step.
In the preparation method of described compound 14, the process of described condensation reaction can be using normal in this area
Rule detection method (such as HPLC, TLC or NMR) is monitored, as the terminal of reaction when typically being disappeared using described compound 25,
Preferably 1 hour~5 hours time of described condensation reaction, further preferred 2 hours~4 hours, such as 3 hours.
Present invention also offers the preparation method of compound 8, and it comprises the following steps:Preparation method as described above
Described compound 12 and then in organic solvent is made, compound 12 and halogenating agent are subjected to substitution reaction and obtain institute
The compound 8 stated;
Wherein, L represents leaving group, such as p-toluenesulfonyl (Tos), mesyl (- OMs), trifyl
(-OSO2CF3), Br, Cl or I;Described halogenating agent is paratoluensulfonyl chloride, mesyl chloride, trifluoromethanesulfchloride chloride, tribromo pyrrole
Pyridine, trichloropyridine or three iodine pyridines.
The preparation method of described compound 8 can be the conventional method of such substitution reaction in this area, in of the invention
Particularly preferred following reaction condition:
In the preparation method of described compound 8, the preferred halogenated hydrocarbon solvent of described organic solvent;Described halo
The preferred chlorinated hydrocarbon solvent of varsol;The preferred dichloromethane of described chlorinated hydrocarbon solvent.
In the preparation method of described compound 8, described halogenating agent and the molar ratio of described compound 12
It is preferred that 1~3, further preferred 1.1~1.5, such as 1.1.
In the preparation method of described compound 8, when doing halogenating agent using pyridinium tribromide, described pyridinium tribromide
Can be conventional commercial pyridinium tribromide reagent in this area, such as pyridinium tribromide methanol solution.
In the preparation method 2 of described compound 8, preferably 0 DEG C~40 DEG C of the temperature of described substitution reaction, further
It is preferred that 10 DEG C~15 DEG C.
In the preparation method of described compound 8, the process of described substitution reaction can be using normal in this area
Rule detection method (such as HPLC, TLC or NMR) is monitored, and is typically disappeared with compound 12 for reaction end, described substitution
Preferably 1 hour~10 hours time of reaction, further preferred 2 hours~5 hours, such as 3 hours.
The preparation method of described compound 8, it is preferred to use following steps:0 DEG C~5 DEG C, by being added dropwise to of halogenating agent
In the mixed liquor that compound 12 is formed with organic solvent, carry out substitution reaction and obtain described compound 8.
The preparation method of described compound 8, it is preferred to use following post-processing step:After reaction terminates, filter, wash,
It is dried to obtain described compound 8.Described filtering, washing, drying can use the conventional method of the generic operation in this area.
Described washing preferably uses alcohols solvent, the preferred methanol of described alcohols solvent.
Present invention also offers the preparation method of compound 6, and it comprises the following steps:Preparation method as described above
Described compound 8 is made and then under protective gas protection, in organic solvent, under the conditions of alkali is existing, by compound 8
Nucleophilic substitution is carried out with compound 7, obtains described compound 6;
Wherein, P is as defined above described;L represent leaving group, such as p-toluenesulfonyl (Tos), mesyl (-
OMs), trifyl (- OSO2CF3), Br, Cl or I.
The preparation method of described compound 6 can be the conventional method of such nucleophilic substitution in this area, this hair
Bright particularly preferably following reaction method and condition:
In the preparation method of described compound 6, the preferred nitrogen of described protective gas and/or argon gas.
In the preparation method of described compound 6, described organic solvent preferred amide class solvent, nitrile solvents, ether
One or more in class solvent and halogenated hydrocarbon solvent.The preferred DMF of described amide solvent (DMF).
The preferred acetonitrile of described nitrile solvents.The preferred tetrahydrofuran of described ether solvent.The preferred chloro of described halogenated hydrocarbon solvent
Varsol;The preferred dichloromethane of described chlorinated hydrocarbon solvent.
In the preparation method of described compound 6, described alkali can be inorganic base or organic base;Described inorganic base
It is preferred that potassium carbonate and/or sodium carbonate.The preferred triethylamine of described organic base and/or N, N- diisopropyl ethyl amine.
In the preparation method of described compound 6, the molar ratio preferably 1 of described alkali and described compound 8~
3, further preferred 1.00~1.20, such as 1.05.
In the preparation method of described compound 6, the molar ratio of described compound 7 and described compound 8 is excellent
Select 1~3, further preferred 1.00~1.20, such as 1.05.
In the preparation method of described compound 6, preferably 10 DEG C~50 DEG C of the temperature of described nucleophilic substitution, enter
Preferably 15 DEG C~45 DEG C of one step, such as 20 DEG C~40 DEG C.
In the preparation method of described compound 6, the process of described nucleophilic substitution can be used in this area
Routine monitoring method (such as TLC, HPLC or NMR) be monitored, as the terminal of reaction, institute when typically being disappeared using compound 8
Preferably 5 hours~24 hours time for the nucleophilic substitution stated, further preferred 10 hours~20 hours, such as 16 hours.
The preparation method of described compound 6, following post-processing step can be used:Reaction terminate after, cooling, plus water,
Stir, filter, washing, being dried to obtain compound 6 after purification.Described cooling is preferably dropped to temperature as 5 DEG C~10 DEG C.
The time of described stirring can be 2 hours~3 hours.Described washing and drying can use the generic operation in this area
Conventional method.Described washing can use water.Described drying can use vacuum drying.
Present invention also offers the preparation method of compound 17, and it comprises the following steps:Preparation side as described above
Method is made described compound 12 and then under protective gas protection, and in organic solvent, compound 12 is contracted with ammonium salt
Close the compound 17 that reaction is made described;
The preparation method of described compound 17 can be the conventional method of such condensation reaction in this area, and the present invention is special
Not not preferably following reaction method and condition:
In the preparation method of described compound 17, the preferred nitrogen of described protective gas and/or argon gas.
In the preparation method of described compound 17, described organic solvent preferred aromatic hydrocarbons class solvent;Described aromatic hydrocarbons
The preferred toluene of class solvent.
In the preparation method of described compound 17, described ammonium salt is ammonia with acid reaction generation by ammonium ion and acid
The ionic compound that radical ion is formed.In the preferred ammonium acetate of described ammonium salt, ammonium chloride, ammonium nitrate, ammonium carbonate and ammonium sulfate
It is one or more.
In the preparation method of described compound 17, described ammonium salt and the molar ratio of described compound 12 are preferred
1~40, further preferred 15~25, such as 20.
In the preparation method of described compound 17, preferably 50 DEG C~120 DEG C of the temperature of described condensation reaction, such as
80 DEG C~100 DEG C.
In the preparation method of described compound 17, the process of described condensation reaction can be using normal in this area
Rule detection method (such as TLC, HPLC or NMR) is monitored, as the end of reaction when typically being disappeared using compound 12 and intermediate state
Point, preferably 5 hours~24 hours time of described condensation reaction, further preferred 15 hours~22 hours, such as 20 hours.
The preparation method of described compound 17, following post-processing step can be used:After reaction terminates, it is molten to add alcohols
Agent, washing, removing solvent obtain compound 17 after purification.The preferred n-butanol of described alcohols solvent.Described washing
The conventional method of the generic operation in this area can be used with solvent is removed.Described washing preferably uses water and/or saturation chlorine
Change sodium water solution washing.Described removing solvent is preferably by the way of being evaporated under reduced pressure.
Present invention also offers the preparation method of compound 16, and it comprises the following steps:Preparation side as described above
Described compound 17 and then in organic solvent is made in method, and compound 17 and halogenating agent are carried out into substitution reaction, are made
Described compound 16;
Wherein, L is as defined above described;Described halogenating agent is paratoluensulfonyl chloride, mesyl chloride, trifluoro methylsulfonyl
Chlorine, pyridinium tribromide, trichloropyridine or three iodine pyridines.
The preparation method of described compound 16 can be the conventional method of such substitution reaction in this area, in of the invention
Particularly preferred following reaction condition:
In the preparation method of described compound 16, the preferred halogenated hydrocarbon solvent of described organic solvent;Described halogen
For the preferred chlorinated hydrocarbon solvent of varsol;The preferred dichloromethane of described chlorinated hydrocarbon solvent.
In the preparation method of described compound 16, described halogenating agent and the molar ratio of described compound 17
It is preferred that 1~3, further preferred 1.1~1.5, such as 1.1.
In the preparation method of described compound 16, when doing halogenating agent using pyridinium tribromide, described tribromo pyrrole
Pyridine can be conventional commercial pyridinium tribromide reagent in this area, such as pyridinium tribromide methanol solution.
In the preparation method of described compound 16, preferably 0 DEG C~40 DEG C of the temperature of described substitution reaction, further
It is preferred that 10 DEG C~15 DEG C.
In the preparation method of described compound 16, the process of described substitution reaction can be using normal in this area
Rule detection method (such as HPLC, TLC or NMR) is monitored, and is typically disappeared with compound 17 for reaction end, described substitution
Preferably 1 hour~10 hours time of reaction, further preferred 2 hours~5 hours, such as 3 hours.
The preparation method of described compound 16, it is preferred to use following steps:0 DEG C~5 DEG C, by being added dropwise to of halogenating agent
In the mixed liquor that compound 17 is formed with organic solvent, carry out substitution reaction and obtain described compound 16.
In the preparation method of described compound 16, it is preferred to use following post-processing step:After reaction terminates, filter, wash
Wash, be dried to obtain described compound 16.Described filtering, washing, drying can use the routine of the generic operation in this area
Method.Described washing preferably uses alcohols solvent, the preferred methanol of described alcohols solvent.
Present invention also offers the preparation method of compound 15, and it comprises the following steps:Preparation side as described above
Method is made described compound 16 and then under protective gas protection, in organic solvent, under the conditions of alkali is existing, by chemical combination
Thing 16 carries out the obtained described compound 15 of nucleophilic substitution with compound 7;
Wherein, P is as defined above described;L represent leaving group, such as p-toluenesulfonyl (Tos), mesyl (-
OMs), trifyl (- OSO2CF3), Br, Cl or I.
The preparation method of described compound 15 can be the conventional method of such nucleophilic substitution in this area, this hair
Bright particularly preferably following reaction condition:
In the preparation method of described compound 15, the preferred nitrogen of described protective gas and/or argon gas.
In the preparation method of described compound 15, described organic solvent preferred amide class solvent, described acid amides
The preferred DMF of class solvent (DMF).
In the preparation method of described compound 15, the preferred inorganic base of described alkali, the preferred carbonic acid of described inorganic base
Potassium.
In the preparation method of described compound 15, described alkali and the molar ratio of described compound 16 are preferred
1.00~3.00, further preferred 1.00~1.50, such as 1.05.
In the preparation method of described compound 15, the molar ratio of described compound 7 and described compound 16
It is preferred that 1.00~3.00, further preferred 1.00~1.50, such as 1.05.
In the preparation method of described compound 15, preferably 10 DEG C~60 DEG C of the temperature of described nucleophilic substitution,
Further preferred 20 DEG C~40 DEG C.
In the preparation method of described compound 15, the process of described nucleophilic substitution can be used in this area
Routine monitoring method (such as HPLC, TLC or NMR) be monitored, typically disappeared with compound 16 for reaction end, it is described
Preferably 10 hours~30 hours time of nucleophilic substitution, further preferred 12 hours~20 hours, such as 16 hours.
In the preparation method of described compound 15, it is preferred to use following post-processing step:After reaction terminates, cooling,
Add water, stir, filtering, be dried to obtain compound 15.Described cooling is preferably dropped to -5 DEG C of temperature~10 DEG C, such as 5 DEG C~10
℃.Described plus water is preferably added dropwise, and the speed of dropwise addition is defined by system temperature no more than 10 DEG C.Described stirring, filtering, drying
The conventional method of the generic operation in this area can be used.
Present invention also offers the preparation method of compound 5, and it is method A or method B;
Method A it comprises the following steps:Preparation method as described above be made described compound 6 and then
Under protective gas protection, in organic solvent, compound 6 and ammonium salt are subjected to condensation reaction and obtain described compound 5;
P is defined as above described;
Method B comprises the following steps:Preparation method as described above is made described compound 15 and then protected
Protect under gas shield, in organic solvent, compound 15 and ammonium salt are subjected to condensation reaction and obtain described compound 5;
P is defined as above described.
The preparation method A of described compound 5 can be the conventional method of such condensation reaction in this area, and the present invention is special
Not not preferably following reaction method and condition:
In the preparation method A of described compound 5, the preferred nitrogen of described protective gas and/or argon gas.
In the preparation method A of described compound 5, described organic solvent preferred aromatic hydrocarbons class solvent;Described aromatic hydrocarbons
The preferred toluene of class solvent.
In the preparation method A of described compound 5, described ammonium salt is ammonia with acid reaction generation by ammonium ion and acid
The ionic compound that radical ion is formed.In the preferred ammonium acetate of described ammonium salt, ammonium chloride, ammonium nitrate, ammonium carbonate and ammonium sulfate
It is one or more.
In the preparation method A of described compound 5, described ammonium salt and the molar ratio preferably 1 of described compound 6
~40, further preferred 15~25, such as 20.
In the preparation method A of described compound 5, preferably 50 DEG C~120 DEG C of the temperature of described condensation reaction, enter one
Preferably 60 DEG C~110 DEG C of step, such as 80 DEG C~100 DEG C.
In the preparation method A of described compound 5, the process of described condensation reaction can be using normal in this area
Rule monitoring method (such as TLC, HPLC or NMR) is monitored, as the end of reaction when typically being disappeared using compound 6 and intermediate state
Point, preferably 5 hours~24 hours time of described condensation reaction, further preferred 15 hours~22 hours, such as 20 hours.
The preparation method A of described compound 5, it is preferred to use following post-processing step:After reaction terminates, it is molten to add alcohols
Agent, washing, removing solvent obtain compound 5 after purification.Described alcohols solvent can be n-butanol.Described washing
The conventional method of the generic operation in this area can be used with solvent is removed.Described washing preferably uses water and/or saturation chlorine
Change sodium water solution washing.Described removing solvent is preferably by the way of being evaporated under reduced pressure.
The preparation method B of described compound 5 can be the conventional method of such condensation reaction in this area, and the present invention is special
Not not preferably following reaction method and condition:
In the preparation method B of described compound 5, the preferred nitrogen of described protective gas and/or argon gas.
In the preparation method B of described compound 5, described organic solvent preferred aromatic hydrocarbons class solvent;Described aromatic hydrocarbons
The preferred toluene of class solvent.
In the preparation method B of described compound 5, described ammonium salt is ammonia with acid reaction generation by ammonium ion and acid
The ionic compound that radical ion is formed.In the preferred ammonium acetate of described ammonium salt, ammonium chloride, ammonium nitrate, ammonium carbonate and ammonium sulfate
It is one or more.
In the preparation method B of described compound 5, described ammonium salt and the molar ratio of described compound 15 are preferred
1~40, further preferred 15~25, such as 20.
In the preparation method B of described compound 5, preferably 50 DEG C~120 DEG C of the temperature of described condensation reaction, enter one
Preferably 60 DEG C~110 DEG C of step, such as 80 DEG C~100 DEG C.
In the preparation method B of described compound 5, the process of described condensation reaction can be using normal in this area
Rule monitoring method (such as TLC, HPLC or NMR) is monitored, as the end of reaction when typically being disappeared using compound 15 and intermediate state
Point, preferably 5 hours~24 hours time of described condensation reaction, further preferred 15 hours~22 hours, such as 20 hours.
The preparation method B of described compound 5, following post-processing step can be used:After reaction terminates, it is molten to add alcohols
Agent, washing, removing solvent obtain compound 5 after purification.The preferred n-butanol of described alcohols solvent.Described washing and
The conventional method of the generic operation in this area can be used by removing solvent.Described washing preferably uses water and/or saturation chlorination
Sodium water solution washs.Described removing solvent is preferably by the way of being evaporated under reduced pressure.
Present invention also offers the preparation method of compound 4, and it comprises the following steps:Preparation method as described above
Described compound 5 is made and then under protective gas protection, in organic solvent, compound 5 is aoxidized with oxidant
Reaction, obtain described compound 4;
P is defined as above described.
The preparation method of described compound 4 can be the conventional method of such oxidation reaction in this area, and the present invention is special
Not not preferably following reaction method and condition:
In the preparation method of described compound 4, the preferred nitrogen of described protective gas and/or argon gas.
In the preparation method of described compound 4, the preferred halogenated hydrocarbon solvent of described organic solvent;Described halo
The preferred chlorinated hydrocarbon solvent of varsol;The preferred dichloromethane of described chlorinated hydrocarbon solvent.
In the preparation method of described compound 4, the preferred manganese dioxide of described oxidant, DDQ
(DDQ), chloranil, N- chlorosuccinimides (NCS), N- bromo-succinimides (NBS) and Pd/Al2O3/O2In one kind or
It is a variety of.The activated manganese dioxide of the preferred now-making-now-using of described manganese dioxide.The preparation method of described manganese dioxide can adopt
With the customary preparation methods in this area.
In the preparation method of described compound 4, described oxidant and the molar ratio of described compound 5 are preferred
1~20, further preferred 5~15, such as 10.
In the preparation method of described compound 4, preferably 0 DEG C~40 DEG C of the temperature of described oxidation reaction, further
It is preferred that 1 DEG C~20 DEG C, such as 5 DEG C~10 DEG C.
In the preparation method of described compound 4, the process of described oxidation reaction can be using normal in this area
Rule detection method (such as TLC, HPLC or NMR) is monitored, described as the terminal of reaction when typically being disappeared using compound 5
Preferably 5 hours~24 hours time of oxidation reaction, such as 10 hours~15 hours.
The preparation method of described compound 4, it is preferred to use following post-processing step:After reaction terminates, add in reaction solution
Enter diatomite, stirring, filtering, remove solvent, then add ether solvent and inorganic base aqueous solution, flow back, filtering, remove part
Solvent, crystal seed is added, crystallization, obtains compound 4.Described stirring, filtering and removing solvent can be used in this area
The conventional method of the generic operation.Described ether solvent can be methyl tertiary butyl ether(MTBE).The preferred sodium hydroxide of described inorganic base
Or potassium hydroxide.The mass concentration of described inorganic base aqueous solution preferably 5%~40%, further preferred 5%~15%, example
Such as 10%, described mass concentration refers to that the quality of inorganic base accounts for the percentage of inorganic base aqueous solution gross mass.Described " removes
Partial solvent " refers to that the ratio of the solvent volume and filtrate solvent cumulative volume removed is 0.2~0.7.The temperature of described crystallization
It is preferred that 0 DEG C~20 DEG C.After described crystallization preferably removes partial solvent, not benign solvent crystallization is added;Described is not benign molten
The preferred alkane solvents of agent, the preferred normal heptane of described alkane solvents.
Present invention also offers the preparation method of compound 3, and it comprises the following steps:Preparation method as described above
Compound 4 described in being made and then the reaction by compound 4 and acid progress deaminizating protection group, obtain described compound 3
;
Wherein, P is amino protecting group, such as tertbutyloxycarbonyl (Boc), benzyloxycarbonyl group (CBz) or p-toluenesulfonyl
(Tosyl)。
The preparation method of described compound 3 can be the conventional method that such deaminizating protection group is reacted in this area,
Following reaction method specifically preferred according to the invention and condition:
The preparation method of described compound 3 can be carried out in a solvent or under the conditions of solvent-free;When entering in a solvent
During row, the one or more in the preferred alcohols solvent of described solvent, halogenated hydrocarbon solvent and ether solvent.Described alcohols is molten
The preferred methanol of agent.The preferred chlorinated hydrocarbon solvent of described halogenated hydrocarbon solvent;The preferred dichloromethane of described chlorinated hydrocarbon solvent.
The preferred tetrahydrofuran of described ether solvent.
In the preparation method of described compound 3, described acid can be organic acid or inorganic acid.Described organic acid
It is preferred that the one or more in trifluoromethanesulfonic acid, benzene sulfonic acid and methanesulfonic acid.The preferred hydrochloric acid of described inorganic acid and/or sulfuric acid.Institute
The hydrochloric acid stated can be conventional commercial hydrochloric acid reagent, and the mass concentration of described hydrochloric acid can be 20%~37%, described matter
Amount concentration refers to that the quality of hydrogen chloride accounts for the percentage of hydrochloric acid solution gross mass.
In the preparation method of described compound 3, the described sour and molar ratio preferably 1 of described compound 4~
20, further preferred 5~15, such as 10.
In the preparation method of described compound 3, preferably 40 DEG C of the temperature of the reaction of described deaminizating protection group~
70 DEG C, such as 60 DEG C~65 DEG C.
In the preparation method of described compound 3, the process of the reaction of described deaminizating protection group can use this
Common detection methods (such as TLC, HPLC or NMR) in field are monitored, as the end of reaction when typically being disappeared using compound 4
Point, preferably 1 hour~10 hours time of the reaction of described deaminizating protection group, such as 2 hours~6 hours.
The preparation method of described compound 3, it is preferred to use following post-processing step:After reaction terminates, solvent is added, is stirred
Mix, filter, it be 11-12 that solid, which is suspended in organic solvent and adjusts pH, and washing, removing solvent obtain compound 3 after purification i.e.
Can.The preferred ether solvent of described solvent, the preferred methyl tertiary butyl ether(MTBE) of described ether solvent.The preferred halogen of described organic solvent
For varsol;The preferred chlorinated hydrocarbon solvent of described halogenated hydrocarbon solvent;The preferred dichloromethane of described chlorinated hydrocarbon solvent.
Described regulation pH preferably uses organic base;The preferred ammoniacal liquor of described organic base.Described ammoniacal liquor can be conventional in this area
Commercially available ammoniacal liquor reagent, the mass concentration of described ammoniacal liquor can be 5%~25%, and described mass concentration refers to the quality of ammonia
Account for the percentage of ammonia spirit gross mass.Described washing and removing solvent can use the routine side of the generic operation in this area
Method.Described washing is preferably washed using water and/or saturated sodium-chloride water solution.Described removing solvent is preferably steamed using decompression
The mode evaporated.
Present invention also offers Wei Patawei 1 (GS5816) preparation method, and it comprises the following steps:As described above
Preparation method described compound 3 and then in organic solvent is made, under the conditions of alkali, catalyst and condensing agent are existing,
Compound 3 and MOC-L- valines are subjected to condensation reaction, obtain Wei Patawei 1;
Described Wei Patawei 1 preparation method can be the conventional method of such condensation reaction in this area, of the invention
Particularly preferred following reaction method and condition:
In described Wei Patawei 1 preparation method, the preferred polar organic solvent of described organic solvent;Described pole
One or more in the preferred nitrile solvents of property organic solvent, amide solvent and ether solvent.Described nitrile solvents are preferred
Acetonitrile.The preferred N,N-dimethylformamide of described amide solvent (DMF).The preferred tetrahydrofuran of described ether solvent
(THF)。
In described Wei Patawei 1 preparation method, the preferred I-hydroxybenzotriazole of described catalyst (HOBt).
In described Wei Patawei 1 preparation method, described catalyst and the molar ratio of described compound 3 are excellent
Select 1~5, further preferred 2~4, such as 2.6.
In described Wei Patawei 1 preparation method, the preferred 1- ethyls of described condensing agent-(3- dimethylaminos third
Base) phosphinylidyne diimmonium salt hydrochlorate (EDCI), 2- (7- azos BTA)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters
(HATU), BTA-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HBTU), O- BTAs-N, N, N', N'-
Tetramethylurea tetrafluoro boric acid ester (TBTU), BTA -1- three (dimethylamino)-trifluoro phosphate (BOP), chloro tripyrrole alkane
Ji Phosphonium hexafluorophosphate (PyClOP), hexafluorophosphoric acid BTA -1- bases-epoxide tripyrrole alkyl (PyBOP), the ring of N, N'- bis-
Hexyl carbodiimide (DCC), (2- oximidos-cyan-acetic ester)-N, N- Dimethyl-morpholin base urea hexafluorophosphoric acid esters (COMU),
2- oximes ethyl cyanoacetate (Oxyma) and propylphosphonic anhydride (T3P the one or more in).
In described Wei Patawei 1 preparation method, described condensing agent and the molar ratio of described compound 3 are excellent
Select 1~5, further preferred 2~4, such as 2.5.
In described Wei Patawei 1 preparation method, the preferred organic base of described alkali;Described organic base preferred N, N-
Diisopropylethylamine (DIPEA) and/or triethylamine.
In described Wei Patawei 1 preparation method, described alkali and the molar ratio preferably 1 of described compound 3
~5, further preferred 2~4, such as 3.5.
In described Wei Patawei 1 preparation method, preferably -5 DEG C~30 DEG C of the temperature of described condensation reaction, enter one
Preferably 0 DEG C~20 DEG C of step, such as 0 DEG C~15 DEG C.
In described Wei Patawei 1 preparation method, the process of described condensation reaction can be used in this area
Routine monitoring method (such as TLC, HPLC or NMR) is monitored, described as the terminal of reaction when typically being disappeared using compound 3
Condensation reaction preferably 5 hours~24 hours time, further preferred 10 hours~20 hours, such as 12 hours~16 is small
When.
Described Wei Patawei 1 preparation method, it is preferred to use following reactions steps:Compound 3 and alkali are sequentially added
In the mixture that MOC-L- valines, catalyst, condensing agent and organic solvent are formed, condensation reaction is carried out, obtains Wei Patawei 1
.
Described Wei Patawei 1 preparation method, following post-processing step can be used:After reaction terminates, extraction, mistake
Filter, washing, removing solvent obtain Wei Patawei 1 after purification.Described extraction, filtering, washing and remove solvent can be with
Using the conventional method of the generic operation in this area.The solvent that described extraction uses can be isopropyl acetate and water.It is described
Washing can use sodium hydrate aqueous solution, saturated sodium-chloride water solution and water washing successively.Described sodium hydroxide is water-soluble
The molar concentration of liquid can be 0.5mol/L (i.e. 0.5N);Described molar concentration refers to the mole and hydroxide of sodium hydroxide
The ratio of sodium water solution cumulative volume.Described removing solvent can be by the way of being evaporated under reduced pressure.
Described Wei Patawei 1 preparation method can use following route
Route 1:
Route 2:
Present invention also offers the and of midbody compound 3,4,5,6,8,12,13,14,15,16 for preparing Wei Patawei 1
17, its structural formula is as follows:
Present invention also offers the described midbody compound 3 for preparing Wei Patawei, 4,5,6,8,12,13,14,15,
16 and 17 preparation method, its reactions steps are same as above.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and it is each preferably to produce the present invention
Example.
Agents useful for same and raw material of the present invention are commercially available.
In the present invention, described room temperature refers to environment temperature, is 10 DEG C~35 DEG C.
The positive effect of the present invention is:The preparation method reaction condition of the present invention is gentle, safety simple to operate, nothing
Extraordinary purifier apparatus is needed, avoids operation, high income (reaching 67%), obtained dimension pa is used column chromatography in last handling process
His Wei Chundu is high, and (chemistry and optical purity are all higher than 99.50%, and all impurity are respectively less than 0.10%, can reach bulk drug mark
It is accurate), cost is low, is suitable for industrialized production.