CN106565707B - Pa Boxini novel synthesis - Google Patents
Pa Boxini novel synthesis Download PDFInfo
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- CN106565707B CN106565707B CN201610953376.3A CN201610953376A CN106565707B CN 106565707 B CN106565707 B CN 106565707B CN 201610953376 A CN201610953376 A CN 201610953376A CN 106565707 B CN106565707 B CN 106565707B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The present invention provides the novel synthesis of Pa Boxini a kind of, includes the following steps: 1) under the action of alkali and solvent, and intermediate V and intermediate B 1 are carried out condensation reaction and obtain compound VI；2) it reacts to obtain compound VII with acylating reagent after compound VI is exchanged with Grignard Reagent, when X is acetyl group, compound VI is compound VII；3) compound VII deprotection reaction under isethionic acid effect obtains finished product Pa Boxini X at salt again.Simple, low in cost, the suitable industrialized production of the synthetic method craft route.Synthetic route are as follows:
Description
Technical field
The invention belongs to field of medicine and chemical technology, it is related to being used to prepare the novel synthesis of Pa Boxini.
Background technique
Pa Boxini (Palbocicib, trade name Ibrance) is the new and effective oral anticancer developed by Pfizer
Medicine.It is the CDK4/6 kinase inhibitor of the first listing in the whole world, being capable of selective depression cell cycle protein dependent kinase 4
It is significant for treating breast cancer late effect with 6.Global breast cancer medicines market can achieve multi-billion dollar, Pa Bo every year
Western Buddhist nun has a vast market foreground.
Pa Boxini chemical name: 6- acetyl group -8- cyclopenta -5- methyl -2- (5- piperazine -1- base-pyridine -2- base ammonia
Base) -8H- pyrido [2,3-d] pyrimidin-7-ones isethionate, molecular structure is as follows:
In current synthetic method reported in the literature, the molecular structure skeleton of product is generally by backbone molecule A and side chain molecule B
Dock, core reaction be how rapid synthesis key molecule A female ring structure and how Y substituent group efficiently to be turned
Turn to acetyl group.
Patent WO2003062236A, WO2010039997A and WO2012068381A etc. are open to report Pa Boxini's
The preparation method is as follows:
This route steps is long, and has used lithium aluminium hydride in experiment, and technological operation danger coefficient is big.Segment A1 and segment
The yield highest of B1 docking only has 40% or so, and whole route yield is extremely low.In addition, noble metal catalyst and tin have also been used in reaction
Reagent, process costs are high, are not suitable for technique amplification.
Patent WO2008032157A and WO2014128588A improves 1 synthetic method of route, it was recently reported that as follows
Route:
The route steps are still longer, and the heck of preparation female ring molecule A2 is coupled, cyclization reaction and two step of subsequent bromo are anti-
The yield answered is all relatively low, in addition needs to use multistep coupling reaction in route, needs stringent oxygen free condition, to process equipment,
Technological operation requires height, and has used the noble metal catalyst of larger dose, high process cost, and technique zoom comparison is difficult.
China Patent Publication No. CN105111205A reports following route:
The technique obtains the skeleton point of product with 2- acetoxybutanoic acid methyl esters, malononitrile and guanidine derivatives one kettle way cyclization
Son, it is secondary anti-in cyclization involved in route, diazotising, alkylation of amide and oxidation reaction although shortening reaction step
It should compare more, not only be enlarged that difficulty is big, and reaction yield is low, and purifying products are difficult, are unfavorable for technique amplification, so still
Need to find simpler, efficiently, inexpensive novel synthesis.
Summary of the invention
In view of the deficiencies of the prior art, the object of the present invention is to provide the novel synthesis of Pa Boxini a kind of, the synthesis
Simple, low in cost, the suitable industrialized production of method and process route.
The synthetic method of Pa Boxini product, includes the following steps:
1) under the action of alkali and solvent, intermediate V and intermediate B 1 is subjected to condensation reaction and obtain compound VI；
2) it reacts to obtain compound VII with acylating reagent after compound VI is exchanged with Grignard Reagent, when X is acetyl group,
Compound VI is compound VII；
3) compound VII deprotection reaction under isethionic acid effect obtains finished product Pa Boxini X at salt again；
Preferably, alkali is selected from organic base and inorganic base in condensation reaction in the step 1), inorganic base is selected from carbonic acid
Potassium, cesium carbonate, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, hexamethyl silicon amine lithium, hexamethyl silicon amine sodium etc., have
Machine alkali is selected from diisopropylethylamine, triethylamine, 11 carbon -7- alkene (DBU) of 1,8- diazabicylo [5.4.0] or triethylene two
Amine；Solvent is selected from dimethylformamide, dimethyl acetamide, methylene chloride, tetrahydrofuran, 1,4- dioxane, acetonitrile or third
Ketone；Reaction temperature is -20~80 DEG C.
Preferably, the grignard reagent of the grignard exchange reaction of the step 2 is selected from isopropylmagnesium chloride, isopropyl chloride
Change magnesium chlorination lithium complex, cyclohexyl magnesium chloride or n-butylmagnesium chloride magnesium；Acylating agent is selected from DMAC N,N' dimethyl acetamide, N- first
Base-N- methoxyl acetamide, chloroacetic chloride, aceticanhydride, N- methyl-N-methoxy -2- chloroacetamide or N- methyl-N-methoxy -2-
Acetbromamide；Reaction dissolvent is tetrahydrofuran, toluene, 2- methyltetrahydrofuran, methylene chloride.Reaction temperature generally -75~
80℃。
Preferably, the solvent for needing to use in the step 3) is selected from ethyl alcohol, tetrahydrofuran, toluene, 2- methyl tetrahydro
Furans or methylene chloride；Reaction temperature is generally at -15~80 DEG C.
The present invention, which opens, discloses the synthetic method of Pa Boxini key intermediate V, takes the following technical solution:
The synthetic method of Pa Boxini key intermediate V, includes the following steps:
1) in the presence of the effect of alkali and organic solvent, 2,6- dichloro pyrimidine I carry out coupling reaction with cyclopenta amine and obtain
To compound II；
2) in the presence of the solvent, that compound II is anti-with acylating reagent completion friedel-crafts acylation under lewis acid effect
It should obtain compound III；
3) in the presence of solvent, phosphonate reagent IV is reacted with after alkali effect with compound III, one kettle way completes Wittig-
Horner and ring closure reaction obtain intermediate V；
Preferably, alkali is selected from triethylamine, diisopropylethylamine, triethylene diamine in the coupling reaction of the step 1)
(DABCO) or 11 carbon -7- alkene (DBU) of 1,8- diazabicylo [5.4.0]；Organic solvent is selected from dimethylformamide, diformazan
Yl acetamide, dimethyl sulfoxide, ethyl acetate, methylene chloride, tetrahydrofuran, 1,4- dioxane, acetonitrile or toluene；Reaction temperature
Degree is 0~120 DEG C.
Preferably, in the friedel-crafts acylation of the step 2 acylating reagent be selected from aceticanhydride, chloroacetic chloride, acetamide or
Acetonitrile；Lewis acid is selected from alchlor, zinc dichloride, ferric trichloride, titanium tetrachloride or boron chloride etc.；Solvent be selected from benzene,
Toluene, methylene chloride, 1,2- dichloroethanes, tetrahydrofuran or 1,4- dioxane；Reaction temperature is -10~120 DEG C.
Preferably, in the Wittig-Horner and ring closure reaction of the step 3) alkali be selected from sodium hydride, sodium tert-butoxide,
Potassium tert-butoxide, hexamethyl silicon amine lithium, butyl lithium or lithium diisopropylamine, solvent are selected from tetrahydrofuran, toluene, dichloromethane
Alkane, 1,4- dioxane, dimethylformamide or dimethyl acetamide；Reaction temperature is -10~80 DEG C.
More specifically, the synthetic method of Pa Boxini product, includes the following steps:
1) in the presence of the effect of alkali and organic solvent, 2,6- dichloro pyrimidine I carry out coupling reaction with cyclopenta amine and obtain
To compound II；
2) in the presence of the solvent, that compound II is anti-with acylating reagent completion friedel-crafts acylation under lewis acid effect
It should obtain compound III
3) in the presence of solvent, phosphonate reagent IV is reacted with after alkali effect with compound III, one kettle way completes Wittig-
Horner and ring closure reaction obtain intermediate V；
4) under the action of alkali and solvent, intermediate V and intermediate B 1 is subjected to condensation reaction and obtain compound VI；
5) it reacts to obtain compound VII with acylating reagent after compound VI is exchanged with Grignard Reagent, when X is acetyl group,
Compound VI is compound VII；
6) compound VII deprotection reaction under isethionic acid effect obtains finished product Pa Boxini X at salt again；
The route of Pa Boxini provided by the invention is starting material by 2,6- dichloro pyrimidine, is passed through after docking with cyclopenta amine
Cross friedel-crafts acylation, then reacted with substituted phosphine acyl acetic acid three ethyl and cyclization obtains female ring molecule A3, then with segment B1
Final products are obtained at simple reactions such as salt using grignard reaction, acidification after docking.This route is easy to operate, shortens reaction
Step, not only yield is higher, avoids the coupling reaction using precious metal catalyst, and obtained product purity is also higher, drops significantly
Low cost is suitble to amplification production.
Specific embodiment:
It elaborates below to the embodiment of the present invention, the present embodiment carries out under the premise of the technical scheme of the present invention
Implement, the detailed implementation method and specific operation process are given, but protection scope of the present invention is not limited to following implementation
Example.
Embodiment 1
It is added in three-necked flask 2,4- dichloro pyrimidine (14.90g, 100mmol), triethylamine (2.24g, 20mmol) and dichloro
Methane (149mL), is cooled to 0~5 DEG C after mixing evenly, is slowly dropped into cyclopenta amine (8.51g), and it is anti-to be warming up to room temperature after adding
It answers 6-8 hours, reaction terminates plus water 277mL quenching reaction, and water phase is extracted 3 times with methylene chloride (75mL), and it is full to merge organic phase
It is washed 1 time with saline solution (75mL), sodium sulphate is dry, must be changed after concentration with ethyl acetate methylene chloride mixed solvent column chromatography for separation
It closes object II (15.22g, 77%).ESI m/z=198.1(M+1).
Triethylamine in embodiment 1 can be replaced with diisopropylethylamine, DABCO, DBU etc.；Methylene chloride can use two
Methylformamide, dimethyl acetamide, dimethyl sulfoxide, ethyl acetate, tetrahydrofuran, 1,4- dioxane, acetonitrile or toluene
To replace.
Embodiment 2
The chloro- 4- of 2- (clopentylamino) pyrimidine II (19.77g, 100mmol), 1,2- dichloroethanes are added in three-necked flask
(99mL) is cooled to 0~5 DEG C after mixing evenly, the dichloromethane solution (60mL, 120mmol) of 2mol/L boron chloride is added,
It adds rear insulated and stirred 30 minutes, is added dropwise acetonitrile (4.93g, 120mmol), back flow reaction is warming up to after adding 20-24 hours, instead
It should terminate cooling plus 4mol/L hydrochloric acid (75mL, 300mmol) quenching reaction, stirring separates organic phase after twenty minutes, and water phase is used again
Methylene chloride (100mL) extracts 2 times, merges organic phase saturated sodium bicarbonate (100mL) solution and washes once, saturated common salt washing 2
Secondary (100mL), sodium sulphate is dry, obtains compound III with ethyl acetate methylene chloride mixed solvent column chromatography for separation after concentration
(21.09g,88%)。ESI m/z=240.2(M+1)。
Acylating reagent acetonitrile can be replaced with aceticanhydride, chloroacetic chloride or acetamide in embodiment 2, and lewis acid boron chloride is available
Alchlor, zinc dichloride, ferric trichloride or titanium tetrachloride replace；Solvent 1,2- dichloroethanes can use benzene, toluene, dichloromethane
Alkane, tetrahydrofuran or 1,4- dioxane replace.
Embodiment 3
Phosphonate reagent 4 (33.34g, 110mmol) and dimethylformamide (96mL) are added in three-necked flask, after stirring and dissolving
Be added potassium tert-butoxide (22.44g, 200mmol), add rear insulation reaction 30 minutes, then instill intermediate III (23.97g,
Dimethylformamide (48mL) solution 100mmol), is warmed to room temperature reaction 3~4 hours after dripping off.Reaction terminates plus water 240mL
Quenching reaction, water phase are extracted 3 times with ethyl acetate (120mL), are merged organic phase saturated common salt and are washed 2 times (120mL), sodium sulphate
It is dry, compound 5 (27.41g, 80%) is obtained with petroleum ether ethyl acetate mixed solvent column chromatography for separation after concentration.ESI m/z=
342.0,344.1(M+1)。
Potassium tert-butoxide can use sodium hydride, sodium tert-butoxide, hexamethyl silicon amine lithium, butyl lithium or diisopropyl in embodiment 3
Lithium amide replaces；Solvent dimethylformamide can use tetrahydrofuran, toluene, methylene chloride, 1,4- dioxane or dimethyl second
Amide replaces.
Embodiment 4
Phosphonate reagent 6 (38.51g, 110mmol) and dimethylformamide (96mL) are added in three-necked flask, after stirring and dissolving
Be added potassium tert-butoxide (22.44g, 200mmol), add rear insulation reaction 30 minutes, then instill intermediate III (23.97g,
Dimethylformamide (48mL) solution 100mmol), is warmed to room temperature reaction 3~4 hours after dripping off.Reaction terminates plus water 240mL
Quenching reaction, water phase are extracted 3 times with ethyl acetate (120mL), are merged organic phase saturated common salt and are washed 2 times (120mL), sodium sulphate
It is dry, compound 7 (28.40g, 73%) is obtained with petroleum ether ethyl acetate mixed solvent column chromatography for separation after concentration.ESI m/z=
390.2(M+1)。
Potassium tert-butoxide can use sodium hydride, sodium tert-butoxide, hexamethyl silicon amine lithium, butyl lithium or diisopropyl in embodiment 4
Lithium amide replaces；Solvent dimethylformamide can use tetrahydrofuran, toluene, methylene chloride, 1,4- dioxane or dimethyl second
Amide replaces.
Embodiment 5
Phosphonate reagent 8 (29.29g, 110mmol) and dimethylformamide (96mL) are added in three-necked flask, after stirring and dissolving
Be added potassium tert-butoxide (22.44g, 200mmol), add rear insulation reaction 30 minutes, then instill intermediate III (23.97g,
Dimethylformamide (48mL) solution 100mmol), is warmed to room temperature reaction 3~4 hours after dripping off.Reaction terminates plus water 240mL
Quenching reaction, water phase are extracted 3 times with ethyl acetate (120mL), are merged organic phase saturated common salt and are washed 2 times (120mL), sodium sulphate
It is dry, compound 9 (21.71g, 71%) is obtained with petroleum ether ethyl acetate mixed solvent column chromatography for separation after concentration.ESI m/z=
306.3(M+1)。
Potassium tert-butoxide can use sodium hydride, sodium tert-butoxide, hexamethyl silicon amine lithium, butyl lithium or diisopropyl in embodiment 5
Lithium amide replaces；Solvent dimethylformamide can use tetrahydrofuran, toluene, methylene chloride, 1,4- dioxane or dimethyl second
Amide replaces.
Embodiment 6
B1 (30.62g, 110mmol) and n,N-Dimethylformamide (170mL) are added in three-necked flask, after mixing evenly
It is cooled to 0~5 DEG C, is added hexamethyl silicon amine lithium tetrahydrofuran solution (1.0M, 120mL, 120mmol), low temperature stirs 20~30 points
Compound 5 (34.26g, 100mmol) is added dropwise after clock, 20~25 DEG C are warmed to room temperature after adding and is reacted 6~8 hours.Reaction terminates to add
Enter water, extracted 3 times with ethyl acetate (170mL), merges organic phase saturated common salt and wash 1 time (170mL), anhydrous sodium sulfate is dry
It is dry, compound 10 (53.81g, 92%) is obtained with ethyl acetate methylene chloride mixed solvent column chromatography for separation after concentration.ESI m/z=
584.2,586.1(M+1)。
Solvent N,N-dimethylformamide can use dimethyl acetamide, methylene chloride, tetrahydrofuran, 1,4- in embodiment 6
Dioxane, acetonitrile or acetone replace；Alkali hexamethyl silicon amine lithium can use potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, uncle
Butanol potassium, sodium tert-butoxide, hexamethyl silicon amine sodium, diisopropylethylamine, triethylamine, 11 carbon of 1,8- diazabicylo [5.4.0]-
7- alkene (DBU) or triethylene diamine etc. replace.
Embodiment 7
B1 (30.62g, 110mmol) and n,N-Dimethylformamide (190mL) are added in three-necked flask, after mixing evenly
It is cooled to 0~5 DEG C, is added hexamethyl silicon amine lithium tetrahydrofuran solution (1.0M, 120mL, 120mmol), low temperature stirs 20~30 points
Compound 1 (38.90g, 100mmol) is added dropwise after clock, 20~25 DEG C are warmed to room temperature after adding and is reacted 6~8 hours.Reaction terminates to add
Enter water, extracted 3 times with ethyl acetate (170mL), merges organic phase saturated common salt and wash 1 time (190mL), anhydrous sodium sulfate is dry
It is dry, compound 8 (54.94g, 87%) is obtained with ethyl acetate methylene chloride mixed solvent column chromatography for separation after concentration.ESI m/z=
632.3(M+1)。
Solvent N,N-dimethylformamide can use dimethyl acetamide, methylene chloride, tetrahydrofuran, 1,4- in embodiment 7
Dioxane, acetonitrile or acetone replace；Alkali hexamethyl silicon amine lithium can use potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, uncle
Butanol potassium, sodium tert-butoxide, hexamethyl silicon amine sodium, diisopropylethylamine, triethylamine, 11 carbon of 1,8- diazabicylo [5.4.0]-
7- alkene (DBU) or triethylene diamine etc. replace.
Embodiment 8
B1 (30.62g, 110mmol) and n,N-Dimethylformamide (150mL) are added in three-necked flask, after mixing evenly
It is cooled to 0~5 DEG C, is added hexamethyl silicon amine lithium tetrahydrofuran solution (1.0M, 120mL, 120mmol), low temperature stirs 20~30 points
Compound 9 (30.58g, 100mmol) is added dropwise after clock, 20~25 DEG C are warmed to room temperature after adding and is reacted 6~8 hours.Reaction terminates to add
Enter water, extracted 3 times with ethyl acetate (150mL), merges organic phase saturated common salt and wash 1 time (150mL), anhydrous sodium sulfate is dry
It is dry, compound 12 (46.21g, 79%) is obtained with ethyl acetate methylene chloride mixed solvent column chromatography for separation after concentration.ESI m/z=
548.2(M+1)。
Solvent N,N-dimethylformamide can use dimethyl acetamide, methylene chloride, tetrahydrofuran, 1,4- in embodiment 8
Dioxane, acetonitrile or acetone replace；Alkali hexamethyl silicon amine lithium can use potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, uncle
Butanol potassium, sodium tert-butoxide, hexamethyl silicon amine sodium, diisopropylethylamine, triethylamine, 11 carbon of 1,8- diazabicylo [5.4.0]-
7- alkene (DBU) or triethylene diamine etc. replace.
Embodiment 9
10 (58.45g, 100mmol) and tetrahydrofuran (300mL) are added in three-necked flask, it is cooled to -10 after mixing evenly~
0 DEG C, the tetrahydrofuran solution (2.0M, 110mL, 220mmol) of isopropylmagnesium chloride chlorination lithium complex, low temperature stirring 20 is added
Stirring is warmed to room temperature after~30 minutes 3~4 hours.It is cooled to 0~5 DEG C of dropwise addition N- methyl-N-methoxy -2- chloroethene after basic conversion
Amide (22.69g, 220mmol) is warmed to room temperature 20~30 DEG C and reacts 4~6 hours after adding.Reaction terminates that dilute hydrochloric acid is added
(2mol/L, 150mmol) quenching reaction is extracted 3 times with ethyl acetate (150mL), is merged organic phase saturated common salt and is washed 2 times
(150mL), anhydrous sodium sulfate is dry, obtains compound 12 with petroleum ether ethyl acetate mixed solvent column chromatography for separation after concentration
(42.72g,78%)。
In embodiment 9, grignard reagent isopropylmagnesium chloride chlorination lithium complex can use isopropylmagnesium chloride, cyclohexyl chlorination
Magnesium or n-butylmagnesium chloride magnesium replace；Acylating agent N- methyl-N-methoxy -2- chloroacetamide can use DMAC N,N' dimethyl acetamide, N-
Methyl-N-methoxy acetamide, chloroacetic chloride, aceticanhydride or N- methyl-N-methoxy -2- acetbromamide replace；Solvents tetrahydrofurane
It can be replaced with toluene, 2- methyltetrahydrofuran or methylene chloride.
Embodiment 10
11 (63.15g, 100mmol) and tetrahydrofuran (300mL) are added in three-necked flask, it is cooled to -10 after mixing evenly~
0 DEG C, the tetrahydrofuran solution (2.0M, 110mL, 220mmol) of isopropylmagnesium chloride chlorination lithium complex, low temperature stirring 20 is added
Stirring is warmed to room temperature after~30 minutes 3~4 hours.It is cooled to 0~5 DEG C of dropwise addition N- methyl-N-methoxy -2- chloroethene after basic conversion
Amide (22.69g, 220mmol) is warmed to room temperature 20~30 DEG C and reacts 4~6 hours after adding.Reaction terminates that dilute hydrochloric acid is added
(2mol/L, 150mmol) quenching reaction is extracted 3 times with ethyl acetate (150mL), is merged organic phase saturated common salt and is washed 2 times
(150mL), anhydrous sodium sulfate is dry, obtains compound 12 with petroleum ether ethyl acetate mixed solvent column chromatography for separation after concentration
(47.10g,86%)。
Grignard reagent isopropylmagnesium chloride chlorination lithium complex can use isopropylmagnesium chloride, cyclohexyl chlorination in embodiment 10
Magnesium or n-butylmagnesium chloride magnesium replace；Acylating agent N- methyl-N-methoxy -2- chloroacetamide can use DMAC N,N' dimethyl acetamide, N-
Methyl-N-methoxy acetamide, chloroacetic chloride, aceticanhydride or N- methyl-N-methoxy -2- acetbromamide replace；Solvents tetrahydrofurane
It can be replaced with toluene, 2- methyltetrahydrofuran or methylene chloride.
Embodiment 11
Compound 12 (54.76g, 100mmol) is added in three-necked flask, is added dehydrated alcohol (274mL), after stirring and dissolving
It is added isethionic acid (18.92g, 150mmol), 45~55 DEG C is heated to after adding and is reacted 2~4 hours.Reaction terminates
After a small amount of product crystal seed can be added and be slowly cooled to room temperature, filter, solid wash with ethyl alcohol (55mL), is dried, is obtained Rui Bo
Western Buddhist nun's product X about 51.06g (89%).ESI m/z=448.4(M+1).
Etoh solvent can be replaced with tetrahydrofuran, toluene, 2- methyltetrahydrofuran, methylene chloride in embodiment 11.
Claims (8)
1. the synthetic method of Pa Boxini product, it is characterised in that include the following steps:
1) under the action of alkali and solvent, intermediate V and intermediate B 1 is subjected to condensation reaction and obtain compound VI；
2) it reacts to obtain compound VII with acylating reagent after compound VI is exchanged with Grignard Reagent；
3) compound VII deprotection reaction under isethionic acid effect obtains finished product Pa Boxini X at salt again；
2. the synthetic method of Pa Boxini product according to claim 1, it is characterised in that the condensation in the step 1)
Alkali is selected from organic base and inorganic base in reaction, and inorganic base is selected from potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, organic base choosing
From potassium tert-butoxide, sodium tert-butoxide, hexamethyl silicon amine lithium, hexamethyl silicon amine sodium, diisopropylethylamine, triethylamine, 1,8- diaza
Two rings [5.4.0], 11 carbon -7- alkene (DBU) or triethylene diamine；Solvent is selected from dimethylformamide, dimethyl acetamide, two
Chloromethanes, tetrahydrofuran, 1,4- dioxane, acetonitrile or acetone；Reaction temperature is -20~80 DEG C.
3. the synthetic method of Pa Boxini product according to claim 1, it is characterised in that the grignard of the step 2) is handed over
The grignard reagent for changing reaction is selected from isopropylmagnesium chloride, isopropylmagnesium chloride chlorination lithium complex, cyclohexyl magnesium chloride or positive fourth
Base magnesium chloride；Acylating agent is selected from DMAC N,N' dimethyl acetamide, N- methyl-N-methoxy acetamide, chloroacetic chloride, aceticanhydride, N- methyl-
N- methoxyl group -2- chloroacetamide or N- methyl-N-methoxy -2- acetbromamide；Reaction dissolvent is tetrahydrofuran, toluene, 2- first
Base tetrahydrofuran, methylene chloride；Reaction temperature is -75~80 DEG C.
4. the synthetic method of Pa Boxini product according to claim 1, it is characterised in that need to use in the step 3)
The solvent arrived is selected from ethyl alcohol, tetrahydrofuran, toluene, 2- methyltetrahydrofuran or methylene chloride；Reaction temperature is -15~80 DEG C.
5. the synthetic method of Pa Boxini product according to claim 1, it is characterised in that Pa Boxini key intermediate V
Synthetic method, include the following steps:
1) in the presence of the effect of alkali and organic solvent, 2,6- dichloro pyrimidine I carry out coupling reaction with cyclopenta amine
Close object II；
2) compound II in the presence of the solvent, is completed friedel-crafts acylation with acylating reagent under lewis acid effect to obtain
To compound III
3) in the presence of solvent, phosphonate reagent IV is reacted with after alkali effect with compound III, one kettle way completes Wittig-
Horner and ring closure reaction obtain intermediate V；
6. the synthetic method of Pa Boxini product according to claim 5, it is characterised in that Pa Boxini key intermediate V
Synthetic method step 1) coupling reaction in alkali be selected from triethylamine, diisopropylethylamine, triethylene diamine (DABCO) or 1,8-
11 carbon -7- alkene (DBU) of diazabicylo [5.4.0]；Organic solvent is selected from dimethylformamide, dimethyl acetamide, diformazan
Base sulfoxide, ethyl acetate, methylene chloride, tetrahydrofuran, 1,4- dioxane, acetonitrile or toluene；Reaction temperature is 0~120 DEG C.
7. the synthetic method of Pa Boxini product according to claim 5, it is characterised in that Pa Boxini key intermediate V
Synthetic method step 2) friedel-crafts acylation in acylating reagent be selected from aceticanhydride, chloroacetic chloride, acetamide or acetonitrile；Louis
Acid is selected from alchlor, zinc dichloride, ferric trichloride, titanium tetrachloride or boron chloride；Solvent be selected from benzene, toluene, methylene chloride,
1,2- dichloroethanes, tetrahydrofuran or 1,4- dioxane；Reaction temperature is -10~120 DEG C.
8. the synthetic method of Pa Boxini product according to claim 5, it is characterised in that Pa Boxini key intermediate V
Synthetic method step 3) Wittig-Horner and ring closure reaction in alkali be selected from sodium hydride, sodium tert-butoxide, potassium tert-butoxide, six
Methyl silicon amine lithium, butyl lithium or lithium diisopropylamine, solvent are selected from tetrahydrofuran, toluene, methylene chloride, Isosorbide-5-Nitrae-dioxy six
Ring, dimethylformamide or dimethyl acetamide；Reaction temperature is -10~80 DEG C.
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