CN108329332A - A method of preparing Glecaprevir - Google Patents
A method of preparing Glecaprevir Download PDFInfo
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- CN108329332A CN108329332A CN201810218686.XA CN201810218686A CN108329332A CN 108329332 A CN108329332 A CN 108329332A CN 201810218686 A CN201810218686 A CN 201810218686A CN 108329332 A CN108329332 A CN 108329332A
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Abstract
The present invention relates to the field of chemical synthesis, more particularly to a kind of method preparing Glecaprevir.With compound shown in Formula IX nucleophilic substitution occurs for compound shown in this method modus ponens II, and compound shown in Formula V is made；Through deprotection, compound shown in Formula IV is obtained；Under the action of condensing agent, organic base, condensation reaction occurs with compound shown in Formula XI and obtains compound shown in Formula VII；In the presence of alkali, saponification occurs and obtains compound shown in Formula X；Under the conditions of existing for solvent and additive, the catalytic action through ruthenium catalyst occurs intramolecular metathesis reaction, obtains compound shown in Formula VIII；Condensation reaction occurs under the action of organic base and condensing agent, then with compound shown in Formula XII, obtains compound I.This method is easy to operate, and using raw material and catalyst cheap and easy to get, intermediate is easy to polishing purification, and technology is suitable for industrialization large-scale production.
Description
Technical field
The present invention relates to the field of chemical synthesis, more particularly to a kind of method preparing Glecaprevir.
Background technology
The Mavyret developed by Ai Baiwei drugmakers of the U.S. is a kind of compound medicine of general genotype, in August, 2017
U.S. FDA approval is obtained, for treating hepatitis C caused by full genome type hepatitis c virus infection.Mavyret is main by two kinds
Active constituent forms, containing a kind of NS3/4A protease inhibitors Glecaprevir (Formulas I), a kind of NS5A protease inhibition
Agent Pibrentasvir.This new drug need to only take the hepatitis C that can once treat the infection of full genome type daily.
Mavyret provides completely new therapeutic scheme for doctor and patient.This compound medicine good effect, and it is potential short by 8
Most of hepatitis patient is cured within week, and without considering the genotype of virus, greatly simplify the therapeutic scheme of hepatitis.Cause
This, which is constantly subjected to extensive concern, once obtains the breakthrough sex therapy identification that U.S. FDA is issued, and preferentially evaluate qualification,
Industry analyst assesses it and has a vast market foreground one after another.
NS3/4A protease inhibitors Glecaprevir (Formulas I) is complicated, containing multiple chiral segments, has in synthesis
There is very big challenge.Currently, only document report preparation method of Glecaprevir.This method is with compound II
It is raw material, nucleo philic substitution reaction, esterification, deprotection reaction, condensation reaction, metathesis reaction, soap with compound III
Change reaction and condensation reaction, Glecaprevir (shown in formula I) is prepared in totally seven steps reaction.
This method is not suitable for being applied to industrialized production there are shortcomings.Major defect has：
1) esterification of compound IV needs to use costliness, and raw material susceptible to hydrolysis-trimethyl silicane diazomethane
(TMSCHN2)。
2) compound VII is thick glassy state liquid, can not carry out polishing purification by recrystallization method.It is obtained
Compound VII is of low quality, has seriously affected subsequent metathesis reaction.
3) metathesis reaction of compound VII is catalyzed with Zhan Shi catalyst.Catalyst is very expensive, reaction control oxygen
Condition is extremely harsh, and reaction selectivity is low, causes reaction yield low, and manufacturing cost is high.
Invention content
In view of this, the present invention provides a kind of new method for preparing Glecaprevir (shown in formula I).This method
Easy to operate, using raw material and catalyst cheap and easy to get, intermediate is easy to polishing purification, and it is big that technology is suitable for industrialization
Large-scale production.
In order to achieve the above-mentioned object of the invention, the present invention provides following technical scheme：
The present invention provides a kind of preparation methods of Glecaprevir, include the following steps：
Step 1：With compound shown in Formula IX nucleophilic substitution occurs for compound shown in Formula II, and chemical combination shown in Formula V is made
Object；
Step 2：Compound shown in the Formula V is deprotected, and obtains compound shown in Formula IV；
Step 3：Compound shown in the Formula IV occurs under the action of condensing agent, organic base with compound shown in Formula XI
Condensation reaction obtains compound shown in Formula VII；
Step 4：Compound shown in the Formula VII in the presence of alkali, occurs saponification and obtains compound shown in Formula X；
Step 5：Under the conditions of existing for solvent and additive, the catalytic action through ruthenium catalyst, the hair of compound shown in Formula X
Raw intramolecular metathesis reaction, obtains compound shown in Formula VIII；
The additive is selected from potassium iodide, tetrabutylammonium iodide, tetraisopropyl titanate, sodium borohydride or lithium bromide；
Step 6：Under the action of organic base and condensing agent, compound shown in Formula VIII occurs with compound shown in Formula XII
Condensation reaction obtains compound I.
In some specific embodiments of the present invention, the solvent of nucleophilic substitution described in step 1 is selected from N, N- bis-
Methylformamide, N, N- dimethylacetylamide, acetonitrile or acetone；The alkali of the nucleophilic substitution be selected from cesium carbonate, potassium carbonate,
Sodium carbonate, sodium bicarbonate or sodium tert-butoxide.
In some specific embodiments of the present invention, the molar ratio of compound shown in Formula II and compound shown in Formula IX is
1.0:(1.0~1.5).
In some specific embodiments of the present invention, the solvent that use is deprotected described in step 2 is selected from acetic acid isopropyl
Ester, ethyl acetate, dioxane or methanol；The acid that the deprotection uses is selected from hydrogen chloride gas, hydrochloric acid, sulfuric acid, trifluoro vinegar
Acid；The temperature of the deprotection is 0~50 DEG C；It is preferred that 20~30 DEG C.
In some specific embodiments of the present invention, condensing agent described in step 3 is selected from 2- (three nitrogen of 7- azos benzo
Azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU), 1- (3- dimethylamino-propyls) -3- ethyl carbodiimide hydrochlorides
Salt (EDCI.HCl) and/or the chloro- 4,6- dimethoxys -1,3,5- triazines (CDMT) of I-hydroxybenzotriazole (HOBt), 2-, (1-
Cyano -2- ethyoxyl -2- oxo ethyleneiminos oxygroup) dimethylaminomorpholine is for carbon hexafluorophosphate (COMU)；It is described
Organic base is selected from diisopropylethylamine, triethylamine, pyridine or N-methylmorpholine；The solvent of the condensation reaction is selected from dichloromethane
Alkane, acetonitrile or N, dinethylformamide；The temperature of the condensation reaction is -10~50 DEG C.It is preferred that 10~20 DEG C.
In some specific embodiments of the present invention, the molar ratio of compound shown in Formula IV and compound shown in Formula XI is
1.0:(1.0~1.5).
In some specific embodiments of the present invention, alkali described in step 4 is selected from potassium hydroxide, sodium hydroxide, hydrogen-oxygen
Change lithium；The solvent of the saponification is selected from methanol, ethyl alcohol, isopropanol, tetrahydrofuran or 2- methyltetrahydrofurans；The saponification
The temperature of reaction is -20~30 DEG C.It is preferred that 0~10 DEG C.
In some specific embodiments of the present invention, solvent described in step 5 is selected from toluene or dichloroethanes；The ruthenium
Catalyst is selected from bis- (2,4,6- trimethylphenyls) -2- (imidazolidine subunit) (dichloro benzylidene) (tricyclohexyl phosphine) rutheniums of 1,3-
(bis- generations of Grubbs catalyst), dichloro (adjacent isopropoxy benzene methylene) (tricyclohexyl phosphine) ruthenium or (1,3- is bis--(2,4,6-
Trimethylphenyl) -2- imidazolidines subunit) dichloro (adjacent isopropoxy benzylidene) conjunction ruthenium (bis- generations of H-G catalyst)；The ruthenium is urged
The dosage of agent is 0.3~20%mol.It is preferred that 0.3~10%mol, more preferable 0.3~4%mol.Specifically, the ruthenium catalysis
The dosage of agent is compound molal quantity 0.3~20%, preferably 0.3~10%mol shown in Formula X, more preferable 0.3~4%mol.
In some specific embodiments of the present invention, organic base described in step 6 is selected from diisopropylethylamine, three second
Amine, pyridine or N-methylmorpholine；The condensing agent is selected from 2- (7- azos benzotriazole)-N, N, N', N'- tetramethylurea hexafluoros
Phosphate (HATU), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides (EDCI.HCl)/I-hydroxybenzotriazole
(HOBt), the chloro- 4,6- dimethoxys -1,3,5- triazines (CDMT) of 2-, (1- cyano -2- ethyoxyl -2- oxo ethyleneimino oxygen
Base) dimethylaminomorpholine is for carbon hexafluorophosphate (COMU)；The solvent of the condensation reaction be selected from dichloromethane, acetonitrile or
N, dinethylformamide；The temperature of the condensation reaction is -10~50 DEG C.It is preferred that 10~20 DEG C.
In some specific embodiments of the present invention, the quality of compound shown in Formula VIII and compound shown in Formula XII
Than or molar ratio be 1.0:(1.0~1.4).
The present invention provides a kind of new methods for preparing Glecaprevir (Formulas I).This method comprises the following steps：Formula
With compound shown in Formula IX nucleophilic substitution occurs for compound shown in II, and compound shown in Formula V is made；Formula V shownization
Object deprotection is closed, compound shown in Formula IV is obtained；Compound shown in the Formula IV is under the action of condensing agent, organic base, with formula
Compound shown in XI occurs condensation reaction and obtains compound shown in Formula VII；Compound shown in the Formula VII in the presence of alkali,
Saponification occurs and obtains compound shown in Formula X；Under the conditions of existing for solvent and additive, the catalysis through ruthenium catalyst is made
With intramolecular metathesis reaction occurs for compound shown in Formula X, obtains compound shown in Formula VIII；The additive is selected from iodate
Potassium, tetrabutylammonium iodide, tetraisopropyl titanate, sodium borohydride or lithium bromide；Under the action of organic base and condensing agent, Formula VIII
With compound shown in Formula XII condensation reaction occurs for shown compound, obtains compound I.This method is easy to operate, using cheap
The raw material and catalyst being easy to get, intermediate are easy to polishing purification, and technology is suitable for industrialization large-scale production.
Description of the drawings
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technology description to be briefly described.
Fig. 1 shows existing preparation method in background technology；
Fig. 2 shows preparation method provided by the invention.
Specific implementation mode
The invention discloses a kind of new methods for preparing Glecaprevir (shown in formula I), and those skilled in the art can
To use for reference present disclosure, it is suitably modified technological parameter realization.In particular, it should be pointed out that all similar substitutions and modifications are to this
It is it will be apparent that they are considered as being included in the present invention for field technology personnel.The method of the present invention and application are
Be described by preferred embodiment, related personnel obviously can not depart from the content of present invention, in spirit and scope to herein
The methods and applications are modified or suitably change and combine, to realize and apply the technology of the present invention.
The present invention provides a kind of methods (as shown in Figure 2) of prepare compound Glecaprevir (Formulas I), have following
Feature.
1) in a suitable solvent, under the action of appropriate base, it is anti-that compound II directly carries out nucleophilic displacement of fluorine with compound IX
It answers, compound V can be obtained with a step.The suitable alkali:Cesium carbonate, potassium carbonate, sodium carbonate, sodium bicarbonate or the tert-butyl alcohol
Sodium；The suitable solvent：N, dinethylformamide, N, N- dimethylacetylamide, acetonitrile or acetone.
2) in a suitable solvent, compound V sloughs Boc protecting groups, obtains compound under the action of suitable acid
VI.The suitable solvent is：Isopropyl acetate, ethyl acetate, dioxane or methanol；The suitable acid is：Chlorination
Hydrogen, hydrochloric acid, sulfuric acid or trifluoracetic acid.Reaction temperature：0-50℃；It is preferred that 20-30 DEG C.
3) in a suitable solvent, compound VI is under condensing agent, organic base effect, with (S) -2- (((((1R, 2R) -2-
(allyloxy) cyclopenta) oxo) carbonyl) amino) -3,3- acid dimethyls (Formula XI) occur condensation reaction obtain compound
VII；The suitable solvent：Dichloromethane, acetonitrile, N, dinethylformamide；The suitable condensing agent:(7- is even by 2-
Nitrogen benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU), 1- (3- dimethylamino-propyls) -3- ethyl carbon
Diimmonium salt hydrochlorate (EDCI.HCl) and/or the chloro- 4,6- dimethoxys -1,3,5- triazines of I-hydroxybenzotriazole (HOBt), 2-
(CDMT), (1- cyano -2- ethyoxyl -2- oxo ethyleneiminos oxygroup) dimethylaminomorpholine is for carbon hexafluorophosphate
(COMU)；The suitable organic base：Diisopropylethylamine, triethylamine, pyridine or N-methylmorpholine；Reaction temperature：- 10~50
DEG C, preferably 10-20 DEG C.
4) compound VII in the presence of alkali, occurs saponification and obtains compound X.X carries out essence by suitable method
System purifying can obtain the sterling that purity is higher than 99%.The appropriate base：Potassium hydroxide, sodium hydroxide, lithium hydroxide；Institute
The suitable solvent stated：Methanol, ethyl alcohol, isopropanol, tetrahydrofuran or 2- methyltetrahydrofurans；Reaction temperature：It is -20~30 DEG C, excellent
Select 0~10 DEG C.
5) in a suitable solvent, under the action of ruthenium catalyst cheap and easy to get, intramolecular double decomposition occurs for compound X
Reaction.Under low catalyst load, reaction smoothly obtains compound VIII.The suitable solvent：Toluene, dichloroethanes；Institute
The suitable ruthenium catalyst stated：Bis- (2,4,6- trimethylphenyls) -2- (imidazolidine subunit) (dichloro benzylidene) (three hexamethylenes of 1,3-
Base phosphine) ruthenium (bis- generations of Grubbs catalyst), dichloro (adjacent isopropoxy benzene methylene) (tricyclohexyl phosphine) ruthenium or (1,3- is bis--
(2,4,6- trimethylphenyls) -2- imidazolidines subunit) dichloro (adjacent isopropoxy benzylidene) conjunction ruthenium (bis- generations of H-G catalyst)；
Catalyst amount：0.3-20%mol, preferably 0.3-10%mol, more preferable 0.3-4%mol.
6) in above-mentioned metathesis reaction, suitable additive is added, effectively increases reaction rate, catalyst is reduced and uses
Amount, improves reaction yield.The suitable additive:Potassium iodide, tetrabutylammonium iodide, tetraisopropyl titanate, sodium borohydride
Or lithium bromide.
7) under condensing agent effect, compound VIII and (1R, 2R) -1- amino -2- (difluoromethyl)-N- ((1- methyl rings
Propyl) sulfuryl) cyclopropane -1- carboxamide hydrochlorides (Formula XII) occur condensation reaction obtain it is suitable molten described in compound I.
Agent：Dichloromethane, acetonitrile, N, dinethylformamide；The suitable condensing agent：2- (7- azos benzotriazole)-N, N,
N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides
(EDCI.HCl) the chloro- 4,6- dimethoxys -1,3,5- triazines (CDMT) of/I-hydroxybenzotriazole (HOBt), 2-, (1- cyano -2-
Ethyoxyl -2- oxo ethyleneiminos oxygroup) dimethylaminomorpholine is for carbon hexafluorophosphate (COMU)；Described properly has
Machine alkali：Diisopropylethylamine, triethylamine, pyridine or N-methylmorpholine；Reaction temperature：- 10~50 DEG C, preferably 10-20 DEG C.
The invention discloses a kind of methods preparing Glecaprevir (Formulas I), for inexpensive, environmental-friendly, suitable
The process route synthesis compound Glecaprevir of industrialized production.
Raw materials used, auxiliary material and reagent in the method provided by the invention for preparing Glecaprevir (shown in formula I)
It is bought by market.
It is further as raw material using compound II with reference to embodiment based on the synthetic route of the present invention as shown in Figure 2
Illustrate the synthesis of other each compounds in the present invention.
The synthesis of 1 compound V of embodiment：
1.1 in N2Under protection, sequentially added into reaction bulb 39g compounds IX, 304mL N, dinethylformamide and
64g cesium carbonates.After stirring 30min, 38g compound II are added, insulation reaction is for 24 hours at 40-45 DEG C.Sampling, send HPLC to detect
To the reaction was complete.After reaction, reaction solution is filtered, 100mL drinking water and 150mL methyl tertiary butyl ether(MTBE)s is added in filtrate.Point
Liquid, organic phase 500mL drinking water, 250mL saturated common salt water washings successively.Organic phase is concentrated under reduced pressure into dripless and drips, and is added
380mL normal heptanes are crystallized with 38mL methyl tertiary butyl ether(MTBE)s, obtain 60g compound V (yields：84.5%, HPLC purity:96%).
1H NMR (400MHz, CDCl3) δ 8.11 (dd, J=7.9,4.5Hz, 1H), 7.86 (t, J=9.9Hz, 1H),
7.76 (dd, J=12.7,6.3Hz, 1H), 7.64 (t, J=7.6Hz, 1H), 6.37 (dq, J=17.5,11.0Hz, 1H),
6.00-5.77 (m, 2H), 5.61 (dd, J=11.0,4.8Hz, 1H), 5.36 (m, 1H), 4.68-4.22 (m, 1H), 3.75 (s,
3H),2.84–2.59(m,1H),2.55–2.15(m,1H),1.57–1.35(s,10H).MS-ESI m/z 450(M+H)+
1.2 in N2Under protection, sequentially added into reaction bulb 4.9g compounds IX, 50mL N, dinethylformamide and
8.6g potassium carbonate.After stirring 30min, 4.8g compound II are added, insulation reaction is for 24 hours at 40-45 DEG C.Sampling, send HPLC to examine
It surveys to the reaction was complete.After reaction, reaction solution is filtered, 50mL drinking water and 50mL methyl tertiary butyl ether(MTBE)s is added in filtrate.Point
Liquid, organic phase use 20mL drinking water, 10ml saturated common salt water washings successively.Organic phase is concentrated under reduced pressure into dripless and drips, and is added
90mL normal heptanes are crystallized with 9mL methyl tertiary butyl ether(MTBE)s, obtain 8.5g compound V (yields：94.8%, HPLC purity:96.1%).
1.3 in N2Under protection, sequentially added into reaction bulb 5.9g compounds IX, 50mL N, dinethylformamide and
8.6g potassium carbonate.After stirring 30min, 4.8g compound II are added, insulation reaction is for 24 hours at 40-45 DEG C.Sampling, send HPLC to examine
It surveys to the reaction was complete.After reaction, reaction solution is filtered, 50mL drinking water and 50mL methyl tertiary butyl ether(MTBE)s is added in filtrate.Point
Liquid, organic phase use 20mL drinking water, 10ml saturated common salt water washings successively.Organic phase is concentrated under reduced pressure into dripless and drips, and is added
90mL normal heptanes are crystallized with 9mL methyl tertiary butyl ether(MTBE)s, obtain 8.78g compound V (yields：98.0%, HPLC purity:
96.1%).
1.4 in N2Under protection, sequentially added into reaction bulb 7.35g compounds IX, 50mL N, dinethylformamide and
8.6g potassium carbonate.After stirring 30min, 4.8g compound II are added, insulation reaction is for 24 hours at 40-45 DEG C.Sampling, send HPLC to examine
It surveys to the reaction was complete.After reaction, reaction solution is filtered, 50mL drinking water and 50mL methyl tertiary butyl ether(MTBE)s is added in filtrate.Point
Liquid, organic phase use 20mL drinking water, 10ml saturated common salt water washings successively.Organic phase is concentrated under reduced pressure into dripless and drips, and is added
90mL normal heptanes are crystallized with 9mL methyl tertiary butyl ether(MTBE)s, obtain 8.73g compound V (yields：97.4%, HPLC purity:
96.1%).
1.5 in N2Under protection, 5g compounds IX, 50mL acetonitrile and 8.6g potassium carbonate are sequentially added into reaction bulb.Stirring
After 30min, 4.8g compound II are added, insulation reaction is for 24 hours at 40-45 DEG C.Sampling, send HPLC to detect to the reaction was complete.Instead
After answering, reaction solution is filtered, 50mL drinking water and 50mL methyl tertiary butyl ether(MTBE)s is added in filtrate.Liquid separation, organic phase are used successively
20mL drinking water, 10ml saturated common salt water washings.Organic phase is concentrated under reduced pressure into dripless and drips, and 90mL normal heptanes and 9mL is added
Methyl tertiary butyl ether(MTBE) crystallizes, and obtains 8.1g compound V (yields：90.4%, HPLC purity:96.1%).2 compound VI of embodiment
Synthesis：
2.1 in N2Under protection, 9.1g compound V and 32mL isopropyl acetates are sequentially added into reaction bulb.Stir 30min
The isopropyl acetate solution (4N) of the hydrogen chloride of 23mL is added in dissolved clarification.At 20-30 DEG C, insulated and stirred reacts 12h.Sampling, send
HPLC is detected to the reaction was complete.After reaction, reaction solution is filtered, filter cake is washed with 20mL isopropyl acetates, at 40-50 DEG C
Lower vacuum drying 8h obtains 7.2g compound VI (yields：92.3%, HPLC purity:98.4%).
1H NMR (400MHz, DMSO) δ 10.19 (br, 1H), 8.13 (d, J=8.1Hz, 1H), 7.92 (tt, J=8.4,
4.0Hz, 2H), 7.78 (ddd, J=8.4,6.4,2.0Hz, 1H), 6.63 (m, 1H), 5.85 (m, 2H), 5.71 (d, J=
11.1Hz, 1H), 4.54 (dd, J=11.0,7.3Hz, 1H), 3.90 (dd, J=13.3,5.4Hz, 1H), 3.8 (s, 3H) 2.76-
2.53(m,2H).MS-ESI m/z 350(M+H)+
2.2 in N2Under protection, 2.0g compound V and 10mL ethyl acetate is sequentially added into reaction bulb.It is molten to stir 30min
Clearly, the ethyl acetate solution (4N) of the hydrogen chloride of 10mL is added.At 20-30 DEG C, insulation reaction stirs 12h.Sampling, send HPLC
Detection is to the reaction was complete.After reaction, reaction solution is filtered, filter cake is washed with 5.0mL ethyl acetate, true at 40-50 DEG C
The dry 8h of sky obtains 1.4 compound VI (yields：90%, HPLC purity:98%)
2.3 in N2Under protection, 2.0g compound V and 10mL isopropyl acetates are sequentially added into reaction bulb.Stir 30min
The isopropyl acetate solution (4N) of the hydrogen chloride of 10mL is added in dissolved clarification.At 0 DEG C, insulation reaction stirs for 24 hours.Sampling, send HPLC
Detection is to the reaction was complete.After reaction, reaction solution is filtered, filter cake is washed with 5.0mL isopropyl acetates, at 40-50 DEG C
Vacuum drying 8h obtains 1.4 compound VI (yields：93%, HPLC purity:98%)
2.4 in N2Under protection, 2.0g compound V and 10mL isopropyl acetates are sequentially added into reaction bulb.Stir 30min
The isopropyl acetate solution (4N) of the hydrogen chloride of 10mL is added in dissolved clarification.At 50 DEG C, insulation reaction stirs 6h.Sampling, send HPLC
Detection is to the reaction was complete.After reaction, reaction solution is filtered, filter cake is washed with 5.0mL isopropyl acetates, at 40-50 DEG C
Vacuum drying 8h obtains 1.3 compound VI (yields：83%, HPLC purity:96%)
2.5 in N2Under protection, 2.0g compound V and 10mL dichloromethane is sequentially added into reaction bulb.It is molten to stir 30min
Clearly, the trifluoracetic acid of 3mL is added.At 20 DEG C, insulation reaction stirs 6h.Sampling, send HPLC to detect to the reaction was complete.Reaction knot
Reaction solution is concentrated to give 1.46 compound VI (yields by Shu Hou：94.2%, HPLC purity:96%)
The synthesis of 3 compound VII of embodiment：
3.1 in N2Under protection, 100g compounds VI, 1000mL dichloromethane, 128.4g are sequentially added into reaction bulb
(S) -2- (((((1R, 2R) -2- (allyloxy) cyclopenta) oxo) carbonyl) amino) -3,3- acid dimethyls (Formula XI), 82g
EDCI.HCl and 43g HOBt.30min is stirred, is cooled to 5-10 DEG C, 110g diisopropylethylamine is added dropwise, 10-20 DEG C is maintained and stirs
Mix reaction 12h.Sampling, send HPLC to detect to the reaction was complete.After reaction, 400mL water quenchings are added to go out reaction.Liquid separation, it is organic
300mL saturated sodium carbonate solutions, 400ml saturated common salt water washings are mutually used successively.Liquid separation, organic phase are concentrated under reduced pressure into dripless drop
Under, it obtains 163g compounds VII and is directly used in reaction (HPLC purity in next step:93%).
1H NMR (400MHz, CDCl3) δ 8.12 (d, J=7.9Hz, 1H), 7.86 (d, J=7.7Hz, 1H), 7.76 (t, J
=7.1Hz, 1H), 7.65 (t, J=7.0Hz, 1H), 6.35 (m, 1H), 5.93 (m, 1H), 5.91-5.68 (m, 2H), 5.56 (d,
J=11.0Hz, 1H), 5.35 (d, J=9.8Hz, 1H), 5.22 (dd, J=17.2,1.6Hz, 1H), 5.15-5.02 (m, 1H),
4.91-4.77 (m, 1H), 4.70 (t, J=8.5Hz, 1H), 4.25 (dd, J=21.3,10.7Hz, 2H), 4.17-4.05 (m,
1H), 4.00 (dd, J=12.8,5.3Hz, 1H), 3.90 (dd, J=12.9,5.6Hz, 1H), 3.79 (s, 3H), 2.70 (m,
1H),2.35(m,1H),2.00–1.78(m,2H),1.78–1.43(m,4H),1.05(s,9H).MS-ESI m/z 631(M+H
)+
3.2 in N2Under protection, 14g compounds VI, 100mL dichloromethane, 18g (S) -2- are sequentially added into reaction bulb
(((((1R, 2R) -2- (allyloxy) cyclopenta) oxo) carbonyl) amino) -3,3- acid dimethyls (Formula XI), 18g HATU.
30min is stirred, is cooled to 5-10 DEG C, 16g diisopropylethylamine is added dropwise, maintains 10 DEG C or less.After being added dropwise to complete, it is warming up to 25-
30 DEG C, it is stirred to react 8h.Sampling, send HPLC to detect to the reaction was complete.After reaction, 70mL dilute hydrochloric acid is added and reaction is quenched.
Liquid separation, water phase are extracted with dichloromethane.Merge organic phase, 50mL saturated sodium carbonate solutions, 40ml saturated common salts is used to wash successively
It washs.Liquid separation, organic phase are concentrated under reduced pressure into dripless and drip, and obtain 22.7g compounds VII and are directly used in reaction (HPLC in next step
It is pure:95.2%).
3.3 in N2Under protection, 10g compounds VI, 100mL dichloromethane, 12.7g (S) -2- are sequentially added into reaction bulb
(((((1R, 2R) -2- (allyloxy) cyclopenta) oxo) carbonyl) amino) -3,3- acid dimethyls (Formula XI), 8.2g
EDCI.HCl and 4.3g HOBt.30min is stirred, is cooled to 5-10 DEG C, 110g diisopropylethylamine is added dropwise, maintains subzero 10 DEG C
It is stirred to react 30h.Sampling, send HPLC to detect to the reaction was complete.After reaction, 40mL water quenchings are added to go out reaction.Liquid separation, it is organic
30mL saturated sodium carbonate solutions, 40ml saturated common salt water washings are mutually used successively.Liquid separation, organic phase are concentrated under reduced pressure into dripless drop
Under, obtain 14.5g compounds VII be directly used in next step reaction (HPLC is pure:95.5%).
3.4 in N2Under protection, 10g compounds VI, 100mL dichloromethane, 12.7g (S) -2- are sequentially added into reaction bulb
(((((1R, 2R) -2- (allyloxy) cyclopenta) oxo) carbonyl) amino) -3,3- acid dimethyls (Formula XI), 8.2g
EDCI.HCl and 4.3g HOBt.30min is stirred, is cooled to 5-10 DEG C, 110g diisopropylethylamine is added dropwise, maintains 50 DEG C of stirrings
React 6h.Sampling, send HPLC to detect to the reaction was complete.After reaction, 40mL water quenchings are added to go out reaction.Liquid separation, organic phase according to
Secondary 30mL saturated sodium carbonate solutions, 40ml saturated common salt water washings.Liquid separation, organic phase are concentrated under reduced pressure into dripless and drip, and obtain
Being directly used in reaction in next step to 12.7g compounds VII, (HPLC is pure:86.4%).
3.5 in N2Under protection, 14g compounds VI, 100mL dichloromethane, 12g (S) -2- are sequentially added into reaction bulb
(((((1R, 2R) -2- (allyloxy) cyclopenta) oxo) carbonyl) amino) -3,3- acid dimethyls (Formula XI), 18g HATU.
30min is stirred, is cooled to 5-10 DEG C, 16g diisopropylethylamine is added dropwise, maintains 10 DEG C or less.After being added dropwise to complete, it is warming up to 25-
30 DEG C, it is stirred to react 8h.Sampling, send HPLC to detect to the reaction was complete.After reaction, 70mL dilute hydrochloric acid is added and reaction is quenched.
Liquid separation, water phase are extracted with dichloromethane.Merge organic phase, 50mL saturated sodium carbonate solutions, 40ml saturated common salts is used to wash successively
It washs.Liquid separation, organic phase are concentrated under reduced pressure into dripless and drip, and obtain 19.7g compounds VII and are directly used in reaction (HPLC in next step
It is pure:95.2%).
3.6 in N2Under protection, 14g compounds VI, 100mL dichloromethane, 15g (S) -2- are sequentially added into reaction bulb
(((((1R, 2R) -2- (allyloxy) cyclopenta) oxo) carbonyl) amino) -3,3- acid dimethyls (Formula XI), 18g HATU.
30min is stirred, is cooled to 5-10 DEG C, 16g diisopropylethylamine is added dropwise, maintains 10 DEG C or less.After being added dropwise to complete, it is warming up to 25-
30 DEG C, it is stirred to react 8h.Sampling, send HPLC to detect to the reaction was complete.After reaction, 70mL dilute hydrochloric acid is added and reaction is quenched.
Liquid separation, water phase are extracted with dichloromethane.Merge organic phase, 50mL saturated sodium carbonate solutions, 40ml saturated common salts is used to wash successively
It washs.Liquid separation, organic phase are concentrated under reduced pressure into dripless and drip, and obtain 21.5g compounds VII and are directly used in reaction (HPLC in next step
It is pure:95.2%).
The synthesis of 4 compound X of embodiment：
4.1 5.0g compound VII and 35mL isopropanols are added into 250mL single port bottles.Stirring and dissolving is cooled to 0-5 DEG C,
15mL potassium hydroxide aqueous solutions (3N) are added dropwise.It maintains at 0-10 DEG C, is stirred to react 3h.Sampling, send HPLC to detect to the reaction was complete.
After reaction, 1.0N hydrochloric acid solutions are added and adjust pH=1-2.4.3g product X (yields are obtained after filtration drying：86%, HPLC
Purity:98.4%).
1H NMR (400MHz, CDCl3) δ 8.12 (d, J=7.9Hz, 1H), 7.86 (d, J=7.7Hz, 1H), 7.76 (t, J
=7.1Hz, 1H), 7.65 (t, J=7.0Hz, 1H), 6.35 (m, 1H), 5.93 (m, 1H), 5.91-5.68 (m, 2H), 5.56 (d,
J=11.0Hz, 1H), 5.35 (d, J=9.8Hz, 1H), 5.22 (dd, J=17.2,1.6Hz, 1H), 5.15-5.02 (m, 1H),
4.91-4.77 (m, 1H), 4.70 (t, J=8.5Hz, 1H), 4.25 (dd, J=21.3,10.7Hz, 2H), 4.17-4.05 (m,
1H), 4.00 (dd, J=12.8,5.3Hz, 1H), 3.90 (dd, J=12.9,5.6Hz, 1H), 2.70 (m, 1H), 2.35 (m,
1H),2.00–1.78(m,2H),1.78–1.43(m,4H),1.05(s,9H).MS-ESI m/z 617(M+H)+
4.2 5.0g compound VII and 35mL isopropanols are added into 250mL single port bottles.Stirring and dissolving is cooled to subzero 20
DEG C, 15mL potassium hydroxide aqueous solutions (3N) are added dropwise.Subzero 20 DEG C are maintained, is stirred to react for 24 hours.Sampling, send HPLC to detect to reaction
Completely.After reaction, 1.0N hydrochloric acid solutions are added and adjust pH=1-2.4.4g product X (yields are obtained after filtration drying：
88%, HPLC purity:97.6%).
4.3 5.0g compound VII and 35mL isopropanols are added into 250mL single port bottles.Stirring and dissolving is cooled to 0-5 DEG C,
15mL potassium hydroxide aqueous solutions (3N) are added dropwise.It maintains at 30 DEG C, is stirred to react 1h.Sampling, send HPLC to detect to the reaction was complete.Instead
After answering, 1.0N hydrochloric acid solutions are added and adjust pH=1-2.3.8g product X (yields are obtained after filtration drying：76%, HPLC are pure
Degree:92.4%).
4.4 5.0g compounds VII, 10mL methanol and 20mL tetrahydrofurans are added into 250ml single port bottles.Stirring and dissolving,
It is cooled to 0-5 DEG C, the lithium hydroxide aqueous solution (1N) of 5mL is added dropwise.It maintains at 0-10 DEG C, is stirred to react 3h.Sampling, send HPLC to examine
It surveys to the reaction was complete.After reaction, 1.0N hydrochloric acid solutions are added and adjust pH=1-2.The extraction of 30ml ethyl acetate is added, point
Liquid, water phase discard.Organic phase 10mL saturated common salt water washings, water phase discard.Organic phase is concentrated under reduced pressure into nothing at 40-50 DEG C
Drop drips to obtain 4.5g compound X (yields：94%, HPLC purity:98.4%).
The synthesis of 5 compound VIII of embodiment：
5.1 in N2Under protection, 5.5g compound X and 220mL dichloroethanes is sequentially added into reaction bulb.Stir 30min
Afterwards, it is warming up to 60-65 DEG C.Advertise N2One hour, it is molten that the dichloroethanes that 10mL contains 660mg Grubbs bis- generations catalyst is added dropwise
Liquid.It maintains at 60-65 DEG C, is stirred to react 3h.Sampling, send HPLC to detect to the reaction was complete.Organic phase is concentrated into dripless and drips
Crude product is obtained, 2.63g compound VIII (yields are obtained by acetone and water crystallization：45%, HPLC purity:99.5%)
1H NMR (400MHz, DMSO) δ 12.56 (s, 1H), 8.10 (dd, J=17.7,7.8Hz, 1H), 8.00-7.83
(m, 2H), 7.83-7.67 (m, 1H), 7.44 (d, J=9.0Hz, 1H), 6.41 (dd, J=25.1,9.5Hz, 1H), 6.33-
6.17 (m, 1H), 6.09 (s, 1H), 4.86 (dd, J=12.6,6.2Hz, 1H), 4.57-4.15 (m, 4H), 4.11-3.89 (m,
2H), 3.70 (d, J=31.6Hz, 1H), 2.34-2.09 (m, 1H), 1.92 (dd, J=15.4,8.5Hz, 2H), 1.78-1.59
(m, 3H), 1.47 (dd, J=13.2,4.2Hz, 1H), 1.20 (t, J=15.3Hz, 2H), 1.02 (s, 9H) .MS-ESI m/z
589(M+H)+
5.2 in N2Under protection, 45g compound X and 1800mL toluene is sequentially added into reaction bulb.After stirring 30min, rise
Temperature is to 100-110 DEG C.Advertise N2One hour, the toluene solution that 50ml contains 5.4g Grubbs bis- generations catalyst is added dropwise.It maintains
At 100-110 DEG C, it is stirred to react 3h.Sampling, send HPLC to detect to the reaction was complete.Organic phase is concentrated into dripless and drips to obtain slightly
Product obtain 22.4g compound VIII (yields by acetone and water crystallization：52.3%, HPLC purity:99.0%).
5.3 in N2Under protection, 20g compounds X, 800mL dichloroethanes and 4.0g potassium iodide are sequentially added into reaction bulb.
After stirring 30min, it is warming up to 60-65 DEG C.Advertise N2One hour, 20mL is added dropwise and contains the two of 1.4g Grubbs bis- generations catalyst
Chloroethanes solution.It maintains to be stirred to react 3h at 60-65 DEG C.Sampling, send HPLC to detect to the reaction was complete.Organic phase is concentrated into aneroid
It drips to obtain crude product, 11.5g compound VIII (yields is obtained by acetone and water crystallization：60.2%, HPLC purity:
99.7%).
5.4 in N2Under protection, 26g compounds X, 1000mL dichloroethanes and 0.2g hydroborations are sequentially added into reaction bulb
Sodium.After stirring 30min, it is warming up to 60-65 DEG C.Advertise N21h is added dropwise 30mL and contains the two of 2.0g Grubbs bis- generations catalyst
Chloroethanes and solution.It maintains to be stirred to react 3h at 60-65 DEG C.Sampling, send HPLC to detect to the reaction was complete.Organic phase is concentrated into nothing
Drop drips to obtain crude product, and 17.4g compound VIII (yields are obtained by acetone and water crystallization：72.9%, HPLC purity:
98.9%).
5.5 in N2Under protection, 5.5g compound X and 220mL dichloroethanes is sequentially added into reaction bulb.Stir 30min
Afterwards, it is warming up to 60-65 DEG C.Advertise N2One hour, be added dropwise 10mL contain 558mg (1,3- is bis--(2,4,6- trimethylphenyls) -2-
Imidazolidine subunit) dichloro (adjacent isopropoxy benzylidene) conjunction ruthenium
The dichloroethane solution of (bis- generations of H-G catalyst).It maintains at 60-65 DEG C, is stirred to react 3h.Sampling, send HPLC to examine
It surveys to the reaction was complete.Organic phase is concentrated into dripless and drips to obtain crude product, and 2.73g compounds are obtained by acetone and water crystallization
VIII (yields：52%, HPLC purity:99.5%)
5.6 in N2Under protection, 20g compounds X, 800mL dichloroethanes and 4.0g potassium iodide are sequentially added into reaction bulb.
After stirring 30min, it is warming up to 60-65 DEG C.Advertise N2One hour, 20mL is added dropwise and contains the two of 826mg Grubbs bis- generations catalyst
Chloroethanes solution.It maintains to be stirred to react 3h at 60-65 DEG C.Sampling, send HPLC to detect to the reaction was complete.Organic phase is concentrated into aneroid
It drips to obtain crude product, 8.6g compound VIII (yields is obtained by acetone and water crystallization：45%, HPLC purity:99.7%).
5.7 in N2Under protection, 20g compounds X, 800mL dichloroethanes and 4.0g potassium iodide are sequentially added into reaction bulb.
After stirring 30min, it is warming up to 60-65 DEG C.Advertise N2One hour, 20mL is added dropwise and contains the two of 5.8g Grubbs bis- generations catalyst
Chloroethanes solution.It maintains to be stirred to react 3h at 60-65 DEG C.Sampling, send HPLC to detect to the reaction was complete.Organic phase is concentrated into aneroid
It drips to obtain crude product, 10.8g compound VIII (yields is obtained by acetone and water crystallization：56.5%, HPLC purity:
99.7%).
The synthesis of 6 compound I of embodiment：
6.1 in N2Under protection, 10.8g compounds VIII, 70mL dichloromethane is sequentially added into reaction bulb, 6.3g (1R,
2R) -1- amino -2- (difluoromethyl)-N- ((1- methylcyclopropyl groups) sulfuryl) cyclopropane -1- carboxamide hydrochlorides (Formula XII institute
Show) and 8.3g HATU.After stirring 30min, it is cooled to 5-10 DEG C, 7.1g diisopropylethylamine is added dropwise.It maintains to stir at 5-10 DEG C
React 2h.Sampling, send HPLC to detect to the reaction was complete.After reaction, 50mL water quenchings are added to go out reaction.Liquid separation, organic phase according to
Secondary 10mL saturated sodium carbonate solutions, 10ml saturated common salt water washings.Liquid separation, organic phase are concentrated into dripless and drip to obtain 14g
Compound I (yields：93.3%, HPLC purity:99.3%).
1HNMR (400MHz, dmso) δ 10.54 (br, 2H), 8.92 (br, 2H), 8.11 (d, J=7.6Hz, 1H), 7.91
(d, J=15.7Hz, 1H), 7.75 (s, 1H), 7.41 (d, J=8.1Hz, 1H), 6.57-6.36 (m, 1H), 6.29 (m, 1H),
6.05 (m, 1H), 5.81 (m, 1H), 4.86 (s, 1H), 4.46 (d, J=11.9Hz, 1H), 4.39-4.11 (m, 3H), 4.03 (d,
J=11.7Hz, 2H), 3.67 (m, 1H), 2.17 (m, 1H), 1.83 (m, 7H), 1.41 (m, 6H), 1.23 (m, 2H), 1.12-
0.81(m,10H).MS-ESI m/z839(M+H)+。
6.2 in N2Under protection, 3.45g compounds VIII, 25mL CH are sequentially added into reaction bulb3CN and 2.0g (1R,
2R) -1- amino -2- (difluoromethyl)-N- ((1- methylcyclopropyl groups) sulfuryl) cyclopropane -1- carboxamide hydrochlorides (Formula XII institute
Show).6.39g pyridines are added dropwise into mixed liquor.After stirring 30min, it is cooled to 5-10 DEG C, 1.23g EDC.HCl are added.It maintains
It is stirred to react 8h at 15-25 DEG C.Sampling, send HPLC to detect to the reaction was complete.After reaction, 50mL water quenchings are added to go out reaction.
Liquid separation, organic phase use 10mL saturated sodium carbonate solutions, 10mL saturated common salt water washings successively.Liquid separation, organic phase are concentrated into aneroid
It drips to obtain 5.0g compound I (yields：99%, HPLC purity:97.8%).
The synthesis of 1 compound V of comparative example
Under nitrogen protection, the trans--N-Boc-4- hydroxy-prolines of 2.4g and 14mL DMF are added into 250mL there-necked flasks
With 50mL THF.Dissolved clarification is stirred, 0 DEG C is cooled to, 3.0g sodium tert-butoxides is added portionwise.Reaction system is warmed to room temperature, and is stirred to react
1.0h.It is cooled to 0 DEG C, 2.45g compound II are added, is warmed to room temperature, is stirred to react 4.0h.Dilute hydrochloric acid is added, reaction, water is quenched
Mutually it is extracted with ethyl acetate.Organic phase water, salt water washing, are concentrated to dryness.By concentrate solution 50mL dichloromethane, and
It is transferred in reaction bulb, 10mL methanol is added.Under stiring, 10.4mL trimethyl silicanes diazomethane (TMSCHN2) is being added just
Hexane solution.It is stirred to react 30 minutes, is then concentrated to dryness.Concentrate is detached with rapid column chromatography, obtains 3.41g compound V,
Yield 73%.
The synthesis of 2 compound VII of comparative example
3.0g compound V and 20mL dichloromethane is added into 100mL reaction bulbs.20mL hydrogen chloride is added in stirring and dissolving
Dioxane solution.It is stirred to react 2 hours, is concentrated to dryness.Concentrate is dissolved in 50mL DMF, and is transferred in reaction bulb.
Under nitrogen protection, 1.85g (S) -2- (((((1R, 2R) -2- (allyloxy) cyclopenta) oxo) carbonyl) amino) -3 is added,
3- acid dimethyls (Formula XI), 3.32g HATU and 2.33mL diisopropylethylamine.At room temperature, it is stirred to react 5 hours.It depressurizes dense
It is reduced to dry, concentrate solution ethyl acetate, with dilute hydrochloric acid and salt water washing, concentration.Gained concentrate is detached with rapid column chromatography,
Obtain 2.48g compound VII, yield 59%.
The synthesis of 3 compound VIII of comparative example
Under nitrogen protection, 1.38g compound VII and 50mL toluene is added into 100mL reaction bulbs.Zhan 128mg is added
Family name's 1B catalyst is heated to 110 DEG C and reacts 36 hours.Period adds catalyst twice, each 70mg.After the completion of reaction, decompression
Concentration.Gained concentrate is detached with rapid column chromatography, obtains 0.55g compound VIII, yield 41.7%.
Comparative example 4
In N2Under protection, 210mg compounds VIII, 15mL dichloromethane is sequentially added into reaction bulb, 130mg (1R,
2R) -1- amino -2- (difluoromethyl)-N- ((1- methylcyclopropyl groups) sulfuryl) cyclopropane -1- carboxamide hydrochlorides (Formula XII institute
Show) and 17.6mg HATU.After stirring 30min, 124 microlitres of diisopropylethylamine are added dropwise, are stirred to react 3h.50mL dichloros are added
Methane, organic phase use dilute hydrochloric acid, tap water and saturated common salt water washing successively.It is pure with silica gel column chromatography after organic phase concentration
Change obtains 233mg compound I (yields：78.1%, HPLC purity:96.5%).
Embodiment 7
Comparison result is shown in Table 1, table 2.
Table 1
Note：*Show has significant difference (P ＜ 0.05) compared with comparative example；#Show has pole significant difference compared with comparative example
(P ＜ 0.01)
The preparation of 2 compound I of table is compared
| Group | Yield (%) | Purity (%) |
| Embodiment 6 | 93.3~99# | 97.8~99.3 |
| Comparative example 4 | 78.1 | 96.5 |
Note：*Show has significant difference (P ＜ 0.05) compared with comparative example；#Show has pole significant difference compared with comparative example
(P ＜ 0.01)
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (10)
1. a kind of preparation method of Glecaprevir, which is characterized in that include the following steps：
Step 1：With compound shown in Formula IX nucleophilic substitution occurs for compound shown in Formula II, and compound shown in Formula V is made；
Step 2：Compound shown in the Formula V is deprotected, and obtains compound shown in Formula IV；
Step 3：Compound shown in the Formula IV is condensed under the action of condensing agent, organic base with compound shown in Formula XI
Compound shown in Formula VII is obtained by the reaction；
Step 4：Compound shown in the Formula VII in the presence of alkali, occurs saponification and obtains compound shown in Formula X；
Step 5：Under the conditions of existing for solvent and additive, the catalytic action through ruthenium catalyst, compound shown in Formula X occurs to divide
Metathesis reaction in son obtains compound shown in Formula VIII；
The additive is selected from potassium iodide, tetrabutylammonium iodide, tetraisopropyl titanate, sodium borohydride or lithium bromide；
Step 6：Under the action of organic base and condensing agent, compound shown in Formula VIII is condensed with compound shown in Formula XII
Reaction, obtains compound I.
2. preparation method according to claim 1, which is characterized in that the solvent of nucleophilic substitution described in step 1 selects
From N, dinethylformamide, N, N- dimethylacetylamide, acetonitrile or acetone；The alkali of the nucleophilic substitution is selected from carbonic acid
Caesium, potassium carbonate, sodium carbonate, sodium bicarbonate or sodium tert-butoxide.
3. preparation method according to claim 1 or 2, which is characterized in that compound shown in Formula II and chemical combination shown in Formula IX
The molar ratio of object is 1.0:(1.0~1.5).
4. preparation method according to any one of claims 1 to 3, which is characterized in that deprotection described in step 2 uses
Solvent is selected from isopropyl acetate, ethyl acetate, dioxane, methanol or dichloromethane；The acid that the deprotection uses is selected from chlorine
Change hydrogen, hydrochloric acid, sulfuric acid, trifluoracetic acid；The temperature of the deprotection is 0~50 DEG C.
5. preparation method according to any one of claims 1 to 4, which is characterized in that condensing agent described in step 3 is selected from 2-
(7- azos benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid esters (HATU), 1- (3- dimethylamino-propyls) -3- second
Base carbodiimide hydrochloride (EDCI.HCl) and/or the chloro- 4,6- dimethoxys -1,3,5- of I-hydroxybenzotriazole (HOBt), 2-
Triazine (CDMT), (1- cyano -2- ethyoxyl -2- oxo ethyleneiminos oxygroup) dimethylaminomorpholine are for carbon hexafluorophosphoric acid
Salt (COMU)；The organic base is selected from diisopropylethylamine, triethylamine, pyridine or N-methylmorpholine；The condensation reaction it is molten
Agent is selected from dichloromethane, acetonitrile or N, dinethylformamide；The temperature of the condensation reaction is -10~50 DEG C.
6. preparation method according to any one of claims 1 to 5, which is characterized in that compound shown in Formula IV and Formula XI institute
Show that the molar ratio of compound is 1.0:(1.0~1.5).
7. preparation method according to any one of claims 1 to 6, which is characterized in that alkali described in step 4 is selected from hydroxide
Potassium, sodium hydroxide, lithium hydroxide；The solvent of the saponification is selected from methanol, ethyl alcohol, isopropanol, tetrahydrofuran or 2- methyl
Tetrahydrofuran；The temperature of the saponification is -20~30 DEG C.
8. preparation method according to any one of claims 1 to 7, which is characterized in that solvent described in step 5 is selected from toluene
Or dichloroethanes；The ruthenium catalyst is selected from bis- (2,4,6- trimethylphenyls) -2- (imidazolidine subunit) (the dichloro-benzenes methylenes of 1,3-
Base) (tricyclohexyl phosphine) ruthenium (bis- generations of Grubbs catalyst), dichloro (adjacent isopropoxy benzene methylene) (tricyclohexyl phosphine) ruthenium
Or (1,3- bis--(2,4,6- trimethylphenyls) -2- imidazolidines subunit) dichloro (adjacent isopropoxy benzylidene) closes ruthenium (H-G bis-
For catalyst)；The dosage of the ruthenium catalyst is 0.3~20%mol.
9. according to claim 1 to 8 any one of them preparation method, which is characterized in that organic base described in step 6 is selected from two
Wopropyl ethyl amine, triethylamine, pyridine or N-methylmorpholine；The condensing agent is selected from 2- (7- azos benzotriazole)-N, N, N',
N'- tetramethylurea hexafluorophosphoric acid esters (HATU), 1- (3- dimethylamino-propyls) -3- ethyl-carbodiimide hydrochlorides
(EDCI.HCl) the chloro- 4,6- dimethoxys -1,3,5- triazines (CDMT) of/I-hydroxybenzotriazole (HOBt), 2-, (1- cyano -2-
Ethyoxyl -2- oxo ethyleneiminos oxygroup) dimethylaminomorpholine is for carbon hexafluorophosphate (COMU)；The condensation reaction
Solvent be selected from dichloromethane, acetonitrile or N, dinethylformamide；The temperature of the condensation reaction is -10~50 DEG C.
10. according to claim 1 to 9 any one of them preparation method, which is characterized in that compound and formula shown in Formula VIII
The molar ratio of compound shown in XII is 1.0:(1.0~1.4).
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| CN115010639A (en) * | 2021-12-14 | 2022-09-06 | 上海艾洋化学科技有限公司 | Intermediate compound and preparation method and application thereof |
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