CN107739319A - A kind of preparation method of Glecaprevir synthetic intermediates and its amine salt - Google Patents
A kind of preparation method of Glecaprevir synthetic intermediates and its amine salt Download PDFInfo
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- CN107739319A CN107739319A CN201711037958.8A CN201711037958A CN107739319A CN 107739319 A CN107739319 A CN 107739319A CN 201711037958 A CN201711037958 A CN 201711037958A CN 107739319 A CN107739319 A CN 107739319A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/02—Preparation of ethers from oxiranes
- C07C41/03—Preparation of ethers from oxiranes by reaction of oxirane rings with hydroxy groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
Abstract
The invention provides a kind of preparation method of Glecaprevir synthetic intermediates; using cyclopentane epoxide as original material; carry out the ring-opening reaction generation propenyloxy group pentamethylene of 2 hydroxyl 1; acetylation obtains the propenyloxy group pentamethylene of 2 acetoxyl group 1; activation and amino condensation are sequentially carried out after fractionation again, obtains Glecaprevir synthetic intermediates.Method reactions steps provided by the invention are few, and yield is higher, and total recovery is above 30%, and significantly larger than of the prior art 10%；Simultaneously cost is low, environment-friendly, reaction condition is gentle, it is easy to operate, suitable for industrialized production.Present invention also offers a kind of preparation method of Glecaprevir synthetic intermediates amine salt, equally with high income, reacts the characteristics of gentle, easy to operate.
Description
Technical field
The present invention relates to technical field of organic synthesis, more particularly to a kind of Glecaprevir synthetic intermediates and its amine salt
Preparation method.
Background technology
2017 Nian8Yue FDA (Food and Drug Adminstration)s (FDA) have approved the anti-hepatitis new drug Mavyret's of Ai Baiwei research and development
Application for quotation.Mavyret is a kind of compound medicine of general genotype, can treat the patients with chronic hepatitis C of all 6 kinds of hypotypes.
Mavyret is made up of two kinds of main components, and one of which is NS3/4A protease inhibitors Glecaprevir (100mg)；It is another
Kind is NS5A protease inhibitors Pibrentasvir (40mg).This new drug need to only be taken once daily, and need not be extra
Using Ribavirin (ribavirin), the hepatitis therapeutic effect with regard to general genotype can be played.Mavyret allows doctor to have with patient
Brand-new therapeutic scheme, it is highly effective, potential that most of hepatitis patient was cured within short 8 weeks, and without considering
The genotype of virus, greatly simplify the therapeutic scheme of hepatitis.The compound medicine is constantly subjected to extensive concern, once obtains the U.S.
The breakthrough sex therapy identification that FDA is issued, and qualification is preferentially evaluated, there is wide market expectations value.
Wherein, for NS3/4A protease inhibitors Glecaprevir structural formula as shown in formula I, its is complicated, by multiple
Chiral segment synthesizes to obtain.
And compound shown in formula II ((S) -2- (((((1R, 2R) -2- (allyloxy) cyclopentyloxy) carbonyl) amino) -3,
3- acid dimethyls)) it is the important intermediate for synthesizing Glecaprevir, the intermediate has three chiral centres, synthesizes difficulty
Greatly.
The method that US9220748 reports compound shown in a kind of synthesis type II：Using the ring pentanediol of racemization as raw material, warp
After acetylation, hydrolase splits to obtain hand-type intermediate, then obtains formula II by allylation reaction, hydrolysis and condensation reaction
Shown compound.However, this method reactions steps is more, yield is relatively low, and total recovery is about 10%.
The content of the invention
It is an object of the invention to provide a kind of preparation method of Glecaprevir synthetic intermediates in high yield.
In order to realize foregoing invention purpose, the present invention provides following technical scheme：
The invention provides a kind of preparation method of Glecaprevir synthetic intermediates, comprise the following steps：
(1) cyclopentane epoxide, propenyl, catalysts and solvents are mixed, ring-opening reaction is carried out, after addition triethylamine is quenched
Obtain 2- hydroxyl -1- propenyloxy group pentamethylene；
The catalyst is boron trifluoride etherate and/or three (pentafluorophenyl group) diethyl etherates；
(2) the 2- hydroxyls -1- propenyloxy groups pentamethylene, acetylation reagent, alkali and solvent mixing carry out acetylization reaction,
Obtain 2- acetoxyl group -1- propenyloxy group pentamethylene；
The acetylation reagent is acetic anhydride and/or chloroacetic chloride；
The alkali is the one or more in sodium acetate, potassium acetate, triethylamine, diisopropylethylamine and pyridine；
(3) the 2- acetoxyl groups -1- propenyloxy groups pentamethylene is hydrolyzed in the presence of biology enzyme and buffer solution
Split, obtain (-) -2- hydroxyl -1- propenyloxy group pentamethylene；
The biology enzyme is one kind in Lipase PS, Novozym 435, Acalase 2.4L and Acalase 2.5L
It is or several；
The buffer solution is phosphate solution；
(4) under inert atmosphere, (-) -2- hydroxyls -1- propenyloxy groups pentamethylene by described in mixes with activating reagent and solvent,
Generation priming reaction, add after frozen water is quenched and obtain reactive intermediate；
The activating reagent is N, the one or more in N'- carbonyl dimidazoles, phosgene and triphosgene；
(5) reactive intermediate is mixed with S-Leucine, 2 hydroxy pyrimidine oxynitrides and solvent, carries out ammonia
Base acid condensation reaction, obtains Glecaprevir synthetic intermediates.
Preferably, the temperature of the ring-opening reaction is -10~30 DEG C, and the time is 1~3h.
Preferably, solvent is dichloromethane, chloroform, tetrahydrofuran, 2- methyltetrahydrofurans and acetonitrile in the step (1)
In one or more；
The cyclopentane epoxide, propenyl, catalyst, the mass ratio of solvent and triethylamine are 1:(1.2~10):(0.1~
1):(5~10):(1.5~2.5).
Preferably, the temperature of the acetylization reaction is 0~30 DEG C, and the time is 12~18h.
Preferably, the solvent in the step (2) is dichloromethane, chloroform, tetrahydrofuran, methyl tertiary butyl ether(MTBE), acetonitrile
With the one or more in acetone；
2- hydroxyls -1- propenyloxy groups the pentamethylene, acetylation reagent, the mass ratio of alkali and solvent are 1:(1~2):
(1.2~5):(5~10).
Preferably, the temperature of the Hydrolysis Resolution is 0~40 DEG C, and the time is 12~72h.
Preferably, in the step (3) 2- acetoxyl group -1- propenyloxy groups pentamethylene, biology enzyme and buffer solution quality
Than for 1:(0.1~1):(5~20).
Preferably, the temperature of priming reaction is -10~30 DEG C in the step (4), and the time is 1~3h；
The solvent is one kind or several in dimethyl-tetrahydrofuran, tetrahydrofuran, dimethylformamide and dichloromethane
Kind；
(-) -2- hydroxyls -1- propenyloxy groups pentamethylene, activating reagent, the mass ratio of solvent and frozen water are 1:(1.5~
2):(8~12):(1~5).
Preferably, the temperature that amino acid condensation reacts in the step (5) is 20~100 DEG C, and the time is 12~16h；
The solvent is one kind or several in 1-METHYLPYRROLIDONE, tetrahydrofuran, dimethylformamide and dimethyl sulfoxide
Kind；
(-) -2- hydroxyls -1- propenyloxy groups pentamethylene, S-Leucine, the quality of 2 hydroxy pyrimidine oxynitrides
Than for 1:(0.8~2):(0.8~2)；
The mass ratio of the reactive intermediate and solvent is 1:(5~15).
Present invention also offers a kind of preparation method of Glecaprevir synthetic intermediates amine salt, comprise the following steps：
According to Glecaprevir synthetic mesophases are prepared in (1)~(5) the step of preparation method described in above-mentioned technical proposal
Body；
The Glecaprevir synthetic intermediates and amine are subjected to salt-forming reaction, obtain Glecaprevir synthetic intermediates
Amine salt.
The invention provides a kind of preparation method of Glecaprevir synthetic intermediates, using cyclopentane epoxide as original material
Material, carries out ring-opening reaction generation 2- hydroxyl -1- propenyloxy group pentamethylene, and acetylation obtains 2- acetoxyl group -1- propenyloxy group rings
Pentane, activation and amino condensation are sequentially carried out after fractionation again, obtains Glecaprevir synthetic intermediates.Side provided by the invention
Method reactions steps are few, and yield is higher, and total recovery is above 30%, and significantly larger than of the prior art 10%；While cost is low, ring
Border is friendly, reaction condition is gentle, it is easy to operate, suitable for industrialized production.Present invention also offers a kind of Glecaprevir synthesis
The preparation method of intermediate amine salt, equally with high income, react the characteristics of gentle, easy to operate.
Embodiment
The invention provides a kind of preparation method of Glecaprevir synthetic intermediates, comprise the following steps：
(1) cyclopentane epoxide, propenyl, catalysts and solvents are mixed, ring-opening reaction is carried out, after addition triethylamine is quenched
Obtain 2- hydroxyl -1- propenyloxy group pentamethylene；
The catalyst is boron trifluoride etherate and/or three (pentafluorophenyl group) diethyl etherates；
(2) the 2- hydroxyls -1- propenyloxy groups pentamethylene, acetylation reagent, alkali and solvent mixing carry out acetylization reaction,
Obtain 2- acetoxyl group -1- propenyloxy group pentamethylene；
The acetylation reagent is acetic anhydride and/or chloroacetic chloride；
The alkali is the one or more in sodium acetate, potassium acetate, triethylamine, diisopropylethylamine and pyridine；
(3) the 2- acetoxyl groups -1- propenyloxy groups pentamethylene is hydrolyzed in the presence of biology enzyme and buffer solution
Split, obtain (-) -2- hydroxyl -1- propenyloxy group pentamethylene；
The biology enzyme is one kind in Lipase PS, Novozym 435, Acalase 2.4L and Acalase 2.5L
It is or several；
The buffer solution is the phosphate solution that pH value is 5~8；
(4) under inert atmosphere, (-) -2- hydroxyls -1- propenyloxy groups pentamethylene by described in mixes with activating reagent and solvent,
Generation priming reaction, add after frozen water is quenched and obtain reactive intermediate；
The activating reagent is N, the one or more in N'- carbonyl dimidazoles, phosgene and triphosgene；
(5) reactive intermediate is mixed with S-Leucine, 2 hydroxy pyrimidine oxynitrides and solvent, carries out ammonia
Base acid condensation reaction, obtains Glecaprevir synthetic intermediates.
The present invention mixes cyclopentane epoxide, propenyl, catalysts and solvents, carries out ring-opening reaction.In the present invention, institute
It is preferably boron trifluoride etherate and/or three (pentafluorophenyl group) diethyl etherates to state catalyst；The solvent is preferably
One or more in dichloromethane, chloroform, tetrahydrofuran, 2- methyltetrahydrofurans and acetonitrile.The present invention is to the epoxide ring
Pentane, propenyl, the source of catalysts and solvents do not have any particular/special requirement, using city well-known to those skilled in the art
The above-mentioned substance sold.
The present invention preferably first mixes propenyl, catalysts and solvents, then adds cyclopentane epoxide；It is of the invention preferred
At a temperature of 0~20 DEG C to above-mentioned propenyl, catalysts and solvents mixture in be added dropwise cyclopentane epoxide, more preferably 5~
15 DEG C, most preferably 8~13 DEG C.System temperature can change during the dropwise addition, and the present invention is to being added dropwise the epoxide ring
The speed of pentane does not have any particular/special requirement, to control the temperature of reaction system to be maintained between 0~20 DEG C.
In the present invention, the temperature of the ring-opening reaction is preferably -10~30 DEG C, more preferably 0~20 DEG C, is most preferably
10~15 DEG C；The time of the ring-opening reaction is preferably 1~3h, more preferably 2h.In the present invention, as long as there is cyclopentane epoxide
It is added in the mixture of aforesaid propylene alcohol, catalysts and solvents, the ring-opening reaction begins to carry out, herein described open loop
The time of reaction is the timing since when the addition of all cyclopentane epoxides finishes.
After the ring-opening reaction time reaches, the present invention adds after reaction is quenched in triethylamine and obtains 2- hydroxyl -1- propenyloxy group rings
Pentane.In the present invention, the temperature for reaction being quenched after addition triethylamine is preferably -10~10 DEG C, more preferably -5~5 DEG C；When
Between be preferably 0.5~1h, more preferably 0.6~0.8h.
In the present invention, the mass ratio of the cyclopentane epoxide, propenyl, catalyst, solvent and triethylamine is preferably 1:
(1.2~10):(0.1~1):(5~10):(1.5~2.5), more preferably 1:(3~8):(0.2~0.8):(6~9):(1.8
~2.3), most preferably 1:(4~6):(0.4~0.6):(7~8):(2~2.1).
It is described end is quenched after, the product system that preferred pair of the present invention obtains carries out vacuum distillation processing, obtains pure
2- hydroxyl -1- propenyloxy group pentamethylene.In the present invention, the vacuum of the vacuum distillation is preferably 20mba, and temperature is preferably
75~80 DEG C.The present invention does not have particular/special requirement to the time of the vacuum distillation, can obtain pure target product.
The reaction that the present invention prepares 2- hydroxyl -1- propenyloxy group pentamethylene is substantially：
It is of the invention by the 2- hydroxyls -1- propenyloxy groups pentamethylene, second after obtaining 2- hydroxyl -1- propenyloxy group pentamethylene
Acylating reagent, alkali and solvent mixing carry out acetylization reaction, obtain 2- acetoxyl group -1- propenyloxy group pentamethylene.In the present invention
In, the acetylation reagent is acetic anhydride and/or chloroacetic chloride；The alkali is sodium acetate, potassium acetate, triethylamine, diisopropyl second
One or more in amine and pyridine；The solvent is preferably dichloromethane, chloroform, tetrahydrofuran, methyl tertiary butyl ether(MTBE), acetonitrile
With the one or more in acetone.The present invention does not have any particular/special requirement to the source of the acetylation reagent, alkali and solvent,
Using commercially available above-mentioned substance well-known to those skilled in the art.
The present invention preferably first mixes 2- hydroxyl -1- propenyloxy groups pentamethylene, alkali and solvent, then adds acetylation examination
Agent；It is of the invention preferred first by catalyst and 2- hydroxyl -1- propenyloxy groups pentamethylene, alkali, solvent mixing, then add second
Acylating reagent；Acetylation reagent is added dropwise into the above-mentioned mixture being mixed to get preferably at 0~10 DEG C in the present invention, more preferably
2~8 DEG C, most preferably 4~6 DEG C.The present invention does not have any particular/special requirement to the speed that the acetylation reagent is added dropwise, with control
The temperature of reaction system processed is maintained between 0~10 DEG C.In the present invention is bright, the catalyst is preferably 4- dimethylaminos
Pyridine (DMAP)
In the present invention, the temperature of the acetylization reaction is preferably 0~30 DEG C, more preferably 10~20 DEG C, most preferably
For 14~16 DEG C；Time is preferably 12~18h, more preferably 14~16h.In the present invention, as long as there is acetylation reagent addition
Into the mixture of above-mentioned 2- hydroxyls -1- propenyloxy groups pentamethylene, alkali and solvent, the acetylization reaction begins to carry out, this
The time for applying for the acetylization reaction is the timing since when the addition of all acetylation reagents finishes.
In the present invention, the mass ratio of the 2- hydroxyls -1- propenyloxy groups pentamethylene, acetylation reagent, alkali and solvent is excellent
Elect 1 as:(0.1~2):(0.2~5):(5~10), more preferably 1:(1.2~1.8):(2~4):(6~9), most preferably 1:
(1.4~1.6):(2.5~3):(7~8)；The mass ratio of the 2- hydroxyls -1- propenyloxy groups pentamethylene and catalyst is preferably
(10~11):1.
The reaction that the present invention prepares 2- acetoxyl group -1- propenyloxy group pentamethylene is substantially：
It is of the invention by the 2- acetoxyl groups -1- propenyloxy group rings after obtaining 2- acetoxyl group -1- propenyloxy group pentamethylene
Fractionation is hydrolyzed in pentane in the presence of biology enzyme and buffer solution, obtains (-) -2- hydroxyl -1- propenyloxy group pentamethylene.
In the present invention, the Hydrolysis Resolution process also includes solvent, the solvent be preferably acetone, dimethyl sulfoxide (DMSO) or
Tetrahydrofuran；The volume ratio of the solvent and buffer solution is preferably 1:(3~7), more preferably 1:5.
In the present invention, the biology enzyme is Lipase PS, Novozym 435, Acalase 2.4L and Acalase
One or more in 2.5L；The buffer solution is phosphate solution, and the phosphate is preferably potassium phosphate and/or sodium phosphate；
The concentration of the buffer solution is preferably 0.5~1.5M.More preferably 1M.The present invention does not have to the source of the biology enzyme and buffer solution
There is any particular/special requirement, using commercially available above-mentioned substance well-known to those skilled in the art.
In the present invention, the temperature of the Hydrolysis Resolution is preferably 0~40 DEG C, more preferably 10~30 DEG C, is most preferably
15~25 DEG C；Time is preferably 12~72h, more preferably 20~60h, most preferably 40~50h.
The present invention preferably adds 1.0N sodium hydroxide solution during the Hydrolysis Resolution into system, to maintain
The pH value of reaction system is 5~8, preferably 6.8~7.1.
In the present invention, 2- acetoxyl group -1- propenyloxy groups pentamethylene in the step (3), biology enzyme and buffer solution
Mass ratio is preferably 1:(0.1~1):(5~20), more preferably 1:(0.2~0.8):(10~15), most preferably 1:(0.4~
0.6):(12~13).
After the Hydrolysis Resolution terminates, the product system that preferred pair of the present invention obtains is filtered, the filter to being filtrated to get
Liquid adds ethyl acetate and extracted.After extraction, organic phase, which is concentrated under reduced pressure to give crude product, can carry out lower sequence step.The present invention is right
The embodiment being concentrated under reduced pressure does not have any particular/special requirement, subtracts using those skilled in the art institute is conventional use of
Concentration means are pressed to carry out.
The reaction of Hydrolysis Resolution process of the present invention is substantially：
After Hydrolysis Resolution, under an inert atmosphere, (-) -2- hydroxyls -1- propenyloxy groups pentamethylene is with activating by described in by the present invention
Reagent and solvent mixing, occur priming reaction.In the present invention, the inert atmosphere is preferably nitrogen atmosphere；The activation examination
Agent is preferably N, the one or more in N'- carbonyl dimidazoles (CDI), phosgene and triphosgene；The solvent is preferably 2- methyl
One or more in tetrahydrofuran, tetrahydrofuran, dimethylformamide and dichloromethane.The present invention to the activating reagent and
The source of solvent does not have any particular/special requirement, using commercially available above-mentioned substance well-known to those skilled in the art.
The present invention preferably first mixes activating reagent and partial solvent, then adds the mixed of resolved product and residual solvent
Compound.The present invention adds the mixture of resolved product and residual solvent preferably at 0~5 DEG C, caused by avoiding exothermic heat of reaction
Temperature drastically raises, more preferably 1~4 DEG C, most preferably 2~3 DEG C.
In the present invention, preferably -10~30 DEG C of the temperature of priming reaction in the step (4), more preferably 0~20
DEG C, most preferably 10~15 DEG C；Time is preferably 1~3h, more preferably 2h.In the present invention, as long as having resolved product with remaining
The mixture of remaining solvent is added in the mixture of above-mentioned activating reagent and partial solvent, and the priming reaction begins to carry out,
The time of herein described priming reaction is the timing since when the addition of the mixture of all resolved products and residual solvent finishes.
After the priming reaction time reaches, the present invention is added after frozen water is quenched into reaction system and obtained among activity
Body.In the present invention, the mass ratio of (-) -2- hydroxyls -1- propenyloxy groups pentamethylene, activating reagent, solvent and frozen water is preferred
For 1:(1.5~2):(8~12):(1~5), more preferably 1:(1.6~1.9):(9~11):(2~4), most preferably 1:
(1.7~1.8):10:3.
It is described end is quenched after, the present invention preferably adds n-hexane and extracts reactive intermediate to being quenched in system.At this
In invention, the mass ratio of the activating reagent and n-hexane is preferably (1.5~2):(5~10), more preferably (1.6~1.8):
(6~8).The present invention does not have any particular/special requirement to the embodiment of the extraction, is commonly used using those skilled in the art
Extracting process carry out.
After the extraction terminates, the organic phase that preferred pair of the present invention is obtained by extraction carries out being evaporated processing.The present invention is to described
Being evaporated the embodiment of processing does not have any particular/special requirement, and method is evaporated i.e. using what those skilled in the art commonly used
Can.
It is of the invention by the reactive intermediate and S-Leucine, 2 hydroxy pyrimidine nitrogen oxidation after obtaining reactive intermediate
Compound and solvent mixing, carry out amino acid condensation reaction, obtain Glecaprevir synthetic intermediates.In the present invention, it is described molten
Agent is preferably the one or more in 1-METHYLPYRROLIDONE, tetrahydrofuran, dimethylformamide and dimethyl sulfoxide.The present invention is right
The source of the S-Leucine, 2 hydroxy pyrimidine oxynitrides and solvent does not have any particular/special requirement, using this area
The above-mentioned substance of commercial source known to technical staff.
In the present invention, (-) -2- hydroxyls -1- propenyloxy groups pentamethylene, S-Leucine, 2 hydroxy pyrimidine nitrogen oxygen
The mass ratio of compound is preferably 1:(0.8~2):(0.8~2)；More preferably 1:(1~1.8):(1~1.8), it is most preferably
1:(1.2~1.5):(1.2~1.5)；The mass ratio of the reactive intermediate and solvent is preferably 1:(5~15), more preferably
1:(8~13), most preferably 1:(10~11).
In the present invention, the temperature that amino acid condensation reacts in the step (5) is preferably 20~100 DEG C, more preferably
40~80 DEG C, most preferably 50~60 DEG C；Time is preferably 12~16h, more preferably 13~15h.
After the amino acid condensation reaction terminates, the present invention preferably adds methyl tertiary butyl ether(MTBE) into product system
(MTBE), the O matter H amounts of the methyl tertiary butyl ether(MTBE) and S-Leucine are than being preferably (5~10):(1~1.8) O, more preferably
(6~9):(1.2~1.6), it is most preferably (7~8):(1.3~1.4).
After adding methyl tertiary butyl ether(MTBE), the present invention preferably sequentially carries out washing extraction, methyl tertbutyl to obtained system
Ether extracts and saturated aqueous common salt extraction, to obtain pure 4 Glecaprevir synthetic intermediates.
In the present invention, the Glecaprevir synthetic intermediates are specifically (S) -2- (((((1R, 2R) -2- (allyls
Epoxide) cyclopentyloxy) carbonyl) amino) -3,3- acid dimethyls), its structural formula is as shown in formula II：
Present invention also offers a kind of preparation method of Glecaprevir synthetic intermediates amine salt, comprise the following steps：
Glecaprevir synthetic intermediates are prepared according to (1) the step of above-mentioned preparation method~(5)；
The Glecaprevir synthetic intermediates and amine are subjected to salt-forming reaction, obtain Glecaprevir synthetic intermediates
Amine salt.
In the present invention, the amine is preferably tert-butylamine, dicyclohexyl amine, R- phenyl ethylamines and one kind or several in 2- butylamine
Kind.
In the present invention, the salt-forming reaction is carried out preferably in methyl tert-butyl ether solvent, the tertiary bright ammonia of amine and L-
The mass ratio of acid is preferably (1~1.5):1, more preferably (1.2~1.3):1；The quality and methyl tertiary butyl ether(MTBE) of the amine are molten
The volume ratio of agent is preferably (1~1.5) g:(10~15) mL, more preferably (1.2~1.3) g:(12~13) mL.
In the present invention, the salt-forming reaction includes the one-level holding stage and two level holding stage sequentially carried out, described
The temperature of one-level holding stage is preferably 40~50 DEG C, more preferably 42~48 DEG C, most preferably 45~46 DEG C；The one-level is protected
The time of thermophase is preferably 1~3h, more preferably 2h；The temperature of the two level holding stage is preferably 20~30 DEG C, more excellent
Elect 22~28 DEG C, most preferably 24~26 DEG C as；The time of the two level holding stage is preferably 5~6h, more preferably 5.5h.
After the salt-forming reaction terminates, the present invention preferably carries out filtration treatment to product system under an inert atmosphere, obtains
Solid product；Then the solid product is washed using methyl tertiary butyl ether(MTBE), the solid product after washing is done
It is dry, obtain pure Glecaprevir synthetic intermediate amine salt.In the present invention, the inert atmosphere is preferably nitrogen；It is described
Dry temperature is preferably 30~40 DEG C, more preferably 34~36 DEG C；The time of the drying is preferably 8~10h.
The preparation method of Glecaprevir synthetic intermediates provided by the invention and its amine salt is entered with reference to embodiment
Row detailed description, but they can not be interpreted as limiting the scope of the present invention.
Embodiment 1
1.4L propenyls are sequentially added into reaction bulb, 82mL boron trifluoride ether solutions, 15L dichloromethane, stirring is
It is even.10 DEG C are cooled to, 0.52L cyclopentane epoxide is added dropwise, maintains temperature at 10 DEG C.It is added dropwise to complete, maintains the temperature to stir 3h.
After GC tracks reaction completely, 1.4L triethylamines are added dropwise reaction is quenched, distilled after the concentrated solvent that pressurizes and obtain colorless oil
(6.17g, 75.8%).
Carrying out nuclear-magnetism test result to obtained colorless oil is：1H NMR(400MHz,CDCl3)δ6.06(m,
1H),5.42(m,1H),5.30(m,1H),4.20(m,1H),4.15(m,2H),3.78(m,1H),2.06(m,1H),1.73(m,
J=4H), 1.45 (m, 1H) testing results show, obtained colorless oil is target product 2- hydroxyl -1- propenyloxy group rings
Pentane.
2- hydroxyl -1- propenyloxy group the pentamethylene that 13.4g above-mentioned steps obtain, 11.6g second are sequentially added into reaction bulb
Sour sodium, 1.3gDMAP and 54mL dichloromethane, stirs.10 DEG C are cooled to, acetic anhydride 11.6g is added dropwise.After being added dropwise,
12h is stirred at 20 DEG C.After GC detection reactions terminate, filtering.Filtrate adds 20mL drinking water, layering, aqueous phase 30mL dichloromethanes
Alkane extracts once.Organic phase merges, and is concentrated under reduced pressure to give 2- acetoxyl group -1- propenyloxy groups pentamethylene (12g, 70%).
The nuclear-magnetism result of 2- acetoxyl group -1- propenyloxy group pentamethylene is：1H NMR(500MHz,CDCl3)δ6.06(m,
1H),5.42(m,1H)5.36(m,1H),5.09(m,1H),4.13(d,2H),4.04(m,1H),2.15(m,1H),2.02(s,
3H),1.90(m,1H),1.82–1.58(m,3H),1.45(m,1H).
PH=7.0 40L buffer solution of potassium phosphate, 8L acetone are once added into reaction bulb, 3.4kg above-mentioned steps obtain
2- acetoxyl group -1- propenyloxy group pentamethylene, 400g Lipase PS.Reaction system maintains 10 DEG C, stirring reaction 12h.GC
After the completion of detection reaction, filtering.Filtrate adds ethyl acetate (10L x 2) extraction.Merge organic phase, concentration organic phase obtains slightly
Product, crude product are directly used in (ee values in next step without purifying:99.0%).
A small amount of Product samples are taken to pass through silica gel purification, Testing and appraisal is product after fractionation, and nuclear-magnetism result is：1H NMR
(400MHz,CDCl3)δ6.06(m,1H),5.42(m,1H),5.30(m,1H),4.20(m,1H),4.15(m,2H),3.78(m,
1H), 2.06 (m, 1H), 1.73 (m, J=4H), 1.45 (m, 1H))
Under nitrogen protection, 3.0g CDI, 19mL 2- methyltetrahydrofurans are added into there-necked flask, after stirring.Cooling
To 0 DEG C, the 4mL 2- methyltetrahydrofuran solution for the resolved product that 2.0g above-mentioned steps obtain is added dropwise.Drop finishes, and is warming up to 25 DEG C
Stir 2h.After GC detection reactions completely, frozen water is added dropwise reaction is quenched.Add n-hexane 10mL extractions.After organic phase concentration is dry, add
Enter 13g 1-METHYLPYRROLIDONEs to dilute and be transferred in clean there-necked flask.Add 1.0g S-Leucines and 0.27g 2-
Pyridone oxynitrides.At 60 DEG C, stirring reaction 12h.After reaction terminates, methyl tertiary butyl ether(MTBE) (15mL x are added
2), extracted with water (10mL).Organic phase is washed twice, and saturated common salt is washed once, and organic phase is concentrated into 3V-5V, stops concentration,
Obtain Glecaprevir synthetic intermediates.
Embodiment 2
1.4L propenyls are sequentially added into reaction bulb, 82mL boron trifluoride ether solutions, 15L dichloromethane, stirring is
It is even.20 DEG C are cooled to, 0.52L cyclopentane epoxide is added dropwise, maintains temperature at 20 DEG C.It is added dropwise to complete, 3h is stirred at 30 DEG C.GC
After tracking reactions completely, 1.4L triethylamines are added dropwise and are quenched reaction, distilled after the concentrated solvent that pressurizes obtain colorless oil 2- hydroxyls-
1- propenyloxy group pentamethylene.
2- hydroxyl -1- propenyloxy group the pentamethylene that 13.4g above-mentioned steps obtain, 11.6g second are sequentially added into reaction bulb
Sour sodium, 1.3gDMAP and 54mL dichloromethane, stirs.0 DEG C is cooled to, acetic anhydride 11.6g is added dropwise.After being added dropwise,
18h is stirred at 10 DEG C.After GC detection reactions terminate, filtering.Filtrate adds 20mL drinking water, layering, aqueous phase 30mL dichloromethanes
Alkane extracts once.Organic phase merges, and is concentrated under reduced pressure to give 2- acetoxyl group -1- propenyloxy group pentamethylene.
PH=7.0 40m L buffer solution of potassium phosphate, 8m L acetone are once added into reaction bulb, 4g above-mentioned steps obtain
2- acetoxyl group -1- propenyloxy group the pentamethylene arrived, 400mg Novozym 435.Reaction system maintains 40 DEG C, stirring reaction
30h.After the completion of GC detection reactions, filtering.Filtrate adds ethyl acetate (20mLx 2) extraction.Merge organic phase, concentrate organic phase
Crude product is obtained, crude product is directly used in (ee values in next step without purifying:94.0%).Take a small amount of Product samples pure by silica gel
Change, Testing and appraisal is product after fractionation.
Under nitrogen protection, 3.0g CDI, 19mL 2- methyltetrahydrofurans are added into there-necked flask, after stirring.Cooling
To 5 DEG C, the 4mL 2- methyltetrahydrofuran solution for the resolved product that 2.0g above-mentioned steps obtain is added dropwise.Drop finishes, and is warming up to 10 DEG C
Stir 2h.After GC detection reactions completely, frozen water is added dropwise reaction is quenched.Add n-hexane 10mL extractions.After organic phase concentration is dry, add
Enter 13g 1-METHYLPYRROLIDONEs to dilute and be transferred in clean there-necked flask.Add 1.0g S-Leucines and 0.27g 2-
Pyridone oxynitrides.At 100 DEG C, stirring reaction 12h.After reaction terminates, methyl tertiary butyl ether(MTBE) (15mL x are added
2), extracted with water (10mL).Organic phase is washed twice, and saturated common salt is washed once, and organic phase is concentrated into 3V-5V, stops concentration,
Obtain Glecaprevir synthetic intermediates.
Embodiment 3
1.4L propenyls are sequentially added into reaction bulb, 82mL boron trifluoride ether solutions, 15L dichloromethane, stirring is
It is even.0 DEG C is cooled to, 0.52L cyclopentane epoxide is added dropwise, maintains temperature at 0 DEG C.It is added dropwise to complete, 3h is stirred at 10 DEG C.GC with
After track reaction completely, 1.4L triethylamines are added dropwise reaction is quenched, distilled after the concentrated solvent that pressurizes and obtain colorless oil 2- hydroxyls -1-
Propenyloxy group pentamethylene.
2- hydroxyl -1- propenyloxy group the pentamethylene that 13.4g above-mentioned steps obtain, 11.6g second are sequentially added into reaction bulb
Sour sodium, 1.3gDMAP and 54mL dichloromethane, stirs.5 DEG C are cooled to, acetic anhydride 11.6g is added dropwise.After being added dropwise,
14h is stirred at 30 DEG C.After GC detection reactions terminate, filtering.Filtrate adds 20mL drinking water, layering, aqueous phase 30mL dichloromethanes
Alkane extracts once.Organic phase merges, and is concentrated under reduced pressure to give 2- acetoxyl group -1- propenyloxy group pentamethylene.
PH=8.0 400mL buffer solution of sodium phosphate, 80mL acetone are once added into reaction bulb, 40g above-mentioned steps obtain
2- acetoxyl group -1- propenyloxy group the pentamethylene arrived, 40mLAcalase 2.4L.Reaction system maintains 30 DEG C, stirring reaction
72h.After the completion of GC detection reactions, filtering.Filtrate adds ethyl acetate (100mL x 2) extraction.Merge organic phase, concentration is organic
Crude product is mutually obtained, crude product is directly used in (ee values in next step without purifying:95.0%).Take a small amount of Product samples pure by silica gel
Change, Testing and appraisal is product after fractionation.
Under nitrogen protection, 3.0g CDI, 19mL 2- methyltetrahydrofurans are added into there-necked flask, after stirring.Cooling
To 0 DEG C, the 4mL 2- methyltetrahydrofuran solution for the resolved product that 2.0g above-mentioned steps obtain is added dropwise.Drop finishes, and is warming up to 0 DEG C and stirs
Mix 2h.After GC detection reactions completely, frozen water is added dropwise reaction is quenched.Add n-hexane 10mL extractions.After organic phase concentration is dry, add
13g 1-METHYLPYRROLIDONEs dilute and are transferred in clean there-necked flask.Add 1.0g S-Leucines and 0.27g 2- hydroxyls
Yl pyridines oxynitrides.At 20 DEG C, stirring reaction 12h.After reaction terminates, methyl tertiary butyl ether(MTBE) (15mL x 2) is added,
Extracted with water (10mL).Organic phase is washed twice, and saturated common salt is washed once, and organic phase is concentrated into 3V-5V, is stopped concentration, is obtained
To Glecaprevir synthetic intermediates.
Embodiment 4
Using the gained Glecaprevir synthetic intermediates of embodiment 1 as raw material, methyl tertiary butyl ether(MTBE) is added to 10V, organic phase
It is transferred in 100mL reaction bulbs.45 DEG C are warming up to, the methyl tertiary butyl ether(MTBE) (12mL) that the tert-butylamine (1.2g) prepared is added dropwise is molten
Liquid.After completion of dropwise addition, 45 DEG C of insulation reaction 2h.Slow cooling is to 25 DEG C and stirs 5h.After insulation terminates, under nitrogen protection,
Filtering, filter cake are washed with 2.0g methyl tertiary butyl ether(MTBE)s.Filter cake is dried under reduced pressure 9h at 35 DEG C, obtains 4.5g Glecaprevir conjunctions
It is white solid into the tert-butylamine salt of intermediate, yield 85%.
MS calcd for C15H25NO5(M+H)+300.0,found 300.0.
1H NMR(400MHz,CDCl3) δ 5.88 (ddd, J=22.6,10.6,5.4Hz, 1H), 5.41 (d, J=9.0Hz,
1H), 5.25 (dd, J=17.2,1.6Hz, 1H), 5.18-5.12 (m, 1H), 4.92 (d, J=5.9Hz, 1H), 4.02 (m, 2H),
3.80 (t, J=7.0Hz, 2H), 2.31-1.83 (m, 2H), 1.64 (m, 4H), 1.32 (s, 9H), 0.98 (s, 9H)
It is computed understanding, the yield that the embodiment of the present application 1~3 prepares Glecaprevir synthetic intermediates is above 50%,
Significantly larger than 30% level in the prior art.
As seen from the above embodiment, the invention provides a kind of preparation method of Glecaprevir synthetic intermediates, with ring
Oxygen pentamethylene is original material, carries out ring-opening reaction generation 2- hydroxyl -1- propenyloxy group pentamethylene, and acetylation obtains 2- acetyl oxygen
Base -1- propenyloxy group pentamethylene, activation and amino condensation are sequentially carried out after fractionation again, obtains Glecaprevir synthetic intermediates.
Method reactions steps provided by the invention are few, and yield is higher, and total recovery is above 30%, significantly larger than of the prior art
10%；Simultaneously cost is low, environment-friendly, reaction condition is gentle, it is easy to operate, suitable for industrialized production.Present invention also offers
A kind of preparation method of Glecaprevir synthetic intermediates amine salt, it is equally gentle, special easily to operate with high income, reaction
Point.
Described above is only the preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of preparation method of Glecaprevir synthetic intermediates, is comprised the following steps：
(1) cyclopentane epoxide, propenyl, catalysts and solvents are mixed, carries out ring-opening reaction, added after triethylamine is quenched and obtain
2- hydroxyl -1- propenyloxy group pentamethylene；
The catalyst is boron trifluoride etherate and/or three (pentafluorophenyl group) diethyl etherates；
(2) the 2- hydroxyls -1- propenyloxy groups pentamethylene, acetylation reagent, alkali and solvent mixing carry out acetylization reaction, obtain
2- acetoxyl group -1- propenyloxy group pentamethylene；
The acetylation reagent is acetic anhydride and/or chloroacetic chloride；
The alkali is the one or more in sodium acetate, potassium acetate, triethylamine, diisopropylethylamine and pyridine；
(3) fractionation is hydrolyzed in the 2- acetoxyl groups -1- propenyloxy groups pentamethylene in the presence of biology enzyme and buffer solution,
Obtain (-) -2- hydroxyl -1- propenyloxy group pentamethylene；
The biology enzyme is one kind or several in Lipase PS, Novozym 435, Acalase 2.4L and Acalase 2.5L
Kind；
The buffer solution is phosphate solution；
(4) under inert atmosphere, (-) -2- hydroxyls -1- propenyloxy groups pentamethylene by described in mixes with activating reagent and solvent, occurs
Priming reaction, add after frozen water is quenched and obtain reactive intermediate；
The activating reagent is N, the one or more in N'- carbonyl dimidazoles, phosgene and triphosgene；
(5) reactive intermediate is mixed with S-Leucine, 2 hydroxy pyrimidine oxynitrides and solvent, carries out amino acid
Condensation reaction, obtain Glecaprevir synthetic intermediates.
2. preparation method according to claim 1, it is characterised in that the temperature of the ring-opening reaction is -10~30 DEG C, when
Between be 1~3h.
3. preparation method according to claim 1 or 2, it is characterised in that in the step (1) solvent be dichloromethane,
One or more in chloroform, tetrahydrofuran, 2- methyltetrahydrofurans and acetonitrile；
The cyclopentane epoxide, propenyl, catalyst, the mass ratio of solvent and triethylamine are 1:(1.2~10):(0.1~1):
(5~10):(1.5~2.5).
4. preparation method according to claim 1, it is characterised in that the temperature of the acetylization reaction is 0~30 DEG C, when
Between be 12~18h.
5. the preparation method according to claim 1 or 4, it is characterised in that the solvent in the step (2) is dichloromethane
One or more in alkane, chloroform, tetrahydrofuran, methyl tertiary butyl ether(MTBE), acetonitrile and acetone；
2- hydroxyls -1- propenyloxy groups the pentamethylene, acetylation reagent, the mass ratio of alkali and solvent are 1:(1~2):(1.2~
5):(5~10).
6. preparation method according to claim 1, it is characterised in that the temperature of the Hydrolysis Resolution is 0~40 DEG C, the time
For 12~72h.
7. the preparation method according to claim 1 or 6, it is characterised in that 2- acetoxyl groups -1- third in the step (3)
The mass ratio of alkenyloxy group pentamethylene, biology enzyme and buffer solution is 1:(0.1~1):(5~20).
8. preparation method according to claim 1, it is characterised in that the temperature of priming reaction is -10 in the step (4)
~30 DEG C, the time is 1~3h；
The solvent is the one or more in 2- methyltetrahydrofurans, tetrahydrofuran, dimethylformamide and dichloromethane；
(-) -2- hydroxyls -1- propenyloxy groups pentamethylene, activating reagent, the mass ratio of solvent and frozen water are 1:(1.5~2):
(8~12):(1~5).
9. the preparation method according to claim 1 or 8, it is characterised in that amino acid condensation reacts in the step (5)
Temperature is 20~100 DEG C, and the time is 12~16h；
The solvent is the one or more in 1-METHYLPYRROLIDONE, tetrahydrofuran, dimethylformamide and dimethyl sulfoxide；
(-) -2- hydroxyls -1- propenyloxy groups pentamethylene, S-Leucine, the mass ratio of 2 hydroxy pyrimidine oxynitrides are
1:(0.8~2):(0.8~2)；
The mass ratio of the reactive intermediate and solvent is 1:(5~15).
10. a kind of preparation method of Glecaprevir synthetic intermediates amine salt, is comprised the following steps：
According to Glecaprevir synthesis is prepared in (1)~(5) the step of preparation method described in claim 1~9 any one
Intermediate；
The Glecaprevir synthetic intermediates and amine are subjected to salt-forming reaction, obtain Glecaprevir synthetic intermediate amine
Salt.
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