CN109988108A - A kind of rich preparation method for Buddhist nun of card - Google Patents

A kind of rich preparation method for Buddhist nun of card Download PDF

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Publication number
CN109988108A
CN109988108A CN201711475428.1A CN201711475428A CN109988108A CN 109988108 A CN109988108 A CN 109988108A CN 201711475428 A CN201711475428 A CN 201711475428A CN 109988108 A CN109988108 A CN 109988108A
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compound
buddhist nun
preparation
formula
card according
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CN109988108B (en
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葛广存
张长华
张景乐
刘普根
袁恒立
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
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Jiangsu Hansoh Pharmaceutical Group Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention belongs to field of medicinal chemistry, are related to a kind of rich preparation method for Buddhist nun of card.Method of the invention reacts preparation formula III compound with 4-aminophenol by 4 halogenated -6,7- dimethoxy-quinolines, and cyclopropane -1,1- dicarboxylic acids/ester reacts preparation formula V compound with para-fluoroaniline, and then condensation reaction preparation card is rich replaces Buddhist nun's compound.The advantages that preparation method of the present invention has easy to operate, yield height, at low cost, and industrial prospect is wide.

Description

A kind of rich preparation method for Buddhist nun of card
Technical field
The invention belongs to pharmaceutical chemistry and organic chemistry filed, and in particular to cyclopropane -1,1- dioctyl phthalate [4- (6,7- bis- Methoxy quinoline -4- base oxygroup)-phenyl]-amide (4- fluorophenyl)-amide (Cabozantinib) and its intermediate synthesis.
Background technique
Card is rich to replace Buddhist nun (Cabozantinib), entitled cyclopropane -1,1- dioctyl phthalate [4- (6, the 7- dimethoxy-quinolines-of chemistry 4- base oxygroup)-phenyl]-amide (4- fluorophenyl)-amide, structure is shown in formula I.
It is a kind of polyceptor tyrosine kinase inhibitor (tyrosine developed by Exelixis company that card, which is won for Buddhist nun, Kinases inhibitor), target RET, MET, VEGFR-1, -2, -3, KIT, TRKB, FLT-3, AXL, TIE-2 etc..Junket ammonia Acid kinase plays very important effect in the generation, development process of tumour, carries out drug as target spot using tyrosine kinase and grinds Hair has become the hot spot of anti-tumor drug research in the world.Tyrosinase inhibitor by inhibit tumour cell injury repair, So that cell division is arrested in G1 phase, induction and the multipaths such as Apoptosis, anti-angiogenesis is maintained to realize antitumous effect； Its anticancer spectrum is wide, has become the fiest-tire medication for treating various Cancerous diseases.
By patent searching document, the card reported at present it is rich for Buddhist nun's synthetic method mainly include the following types:
1) patent WO2005030140 is the compound patent of Yuan Yan company, wherein the rich synthetic method for Buddhist nun of report card is such as Under:
This method is that point two lines 3 and 5 are made respectively then prepare that card is rich to replace Buddhist nun by being condensed.A wherein route It is to be condensed, replaced to prepare 3 for raw material with cyclopropane -1,1- dicarboxylic acids.Another route is with 1- (3,4- dimethoxy Phenyl) ethyl ketone be raw material prepare 5 through nitrification, reduction, cyclization, substitution.This method energy consumption is high, uses genotoxicity reagen, behaviour It is lower to make cumbersome and yield.
2) patent CN103459373A is the preparation method patent of Yuan Yan company, and route is as follows:
This method is that point two lines 3 and 6 are made respectively then prepare that card is rich to replace Buddhist nun by being condensed.A wherein route It is 4- hydroxyl -6,7- dimethoxy-quinoline to prepare 3 through chloro, substitution for raw material.Another route be with cyclopropane -1, 1- dicarboxylic acids is that raw material prepares 5 through condensation, chlorination, and then the obtained card of condensation is rich replaces Buddhist nun.After this method is using thionyl chloride Manage cumbersome, industrial production efficiency is low.
Summary of the invention
The purpose of the present invention is to solve the above problem, provides a kind of rich preparation method for Buddhist nun of new card, the method Including following synthesis step:
It is rich for Buddhist nun's compound to obtain compound of formula I card for formula III compound and Formula V compound condensation:
Wherein, R1For C1~C10Alkyl, preferably methyl, ethyl, propyl and isopropyl, R2For C1~C10Alkyl or H, preferably H, methyl, ethyl, propyl and isopropyl.
Preferably, formula III compound and Formula V compound molar ratio are 1:0.5~5, preferably 1:0.5~2, more preferably 1:1.2~2.
Preferably, reaction temperature is -20~80 DEG C, preferably -10~30 DEG C, more preferable 20~30 DEG C.
Preferably, the dosage of alkali and formula III compound molar ratio be 1~20:1, preferably 5~10:1, more preferable 5~ 8:1.
The rich method for Buddhist nun of card according to the present invention, formula IV compound and para-fluoroaniline are prepared under the action of alkali or condensing agent Formula V compound,
Wherein condensing agent optional EDCHCl or DCC；Alkali optional t-BuONa, t-BuOK, LHMDS, NaHMDS, KHMDS or Grignard Reagent, preferably NaHMDS, KHMDS or Grignard Reagent.
Preferably, formula IV compound and para-fluoroaniline molar ratio are 1:0.5~5, preferably 1:0.5~2, more preferable 1: 1.2~2.
Preferably, reaction temperature is -20~80 DEG C, preferably -10 DEG C~30 DEG C, more preferable 20 DEG C~30 DEG C.
Preferably, condensing agent dosage and the molar ratio of formula IV compound are 1~10:1, preferably 1.2~5:1.
Preferably, base amount and the molar ratio of formula IV compound are 1~20:1, preferably 5~20:1, more preferable 5~10:1.
The rich method for Buddhist nun of card, Formula II compound react preparation formula with 4-aminophenol in the presence of alkali according to the present invention III compound,
Wherein, X is selected from F, Cl, Br or I.
Preferably, alkali is selected from sodium tert-butoxide or potassium tert-butoxide..
Preferably, reaction temperature is 90~120 DEG C.
Preferably, the molar ratio of alkali and Formula II compound is 1~8:1.
The rich new preparation method for replacing Buddhist nun and its intermediate of card provided by the invention, preparation method is simple, and reaction cost is low, It is easy to operate, it avoids having used toxic agent, and the product yield high, the purity that prepare are good, are suitble to industrialized production.
Specific embodiment
Following specific embodiment, its object is to so that those skilled in the art is more clearly understood that and implement this hair It is bright.They should not be construed as limiting the scope of the present invention, and only exemplary illustration and Typical Representative of the invention.This Solvent, reagent used in invention and raw material etc. are commercial product.
The preparation of 1 4- of embodiment ((6,7- dimethoxy-4 '-yl) oxygroup) aniline
By the chloro- 6,7- dimethoxy-quinoline (10g, 0.045mol, 1.0eq.) of 4-, 4-aminophenol (6.9g, 0.063mol, 1.4eq.) it is added in 50mL n,N-dimethylacetamide, it is cooled to 0 DEG C, is slowly added to sodium tert-butoxide The suspension of (6.1g, 0.063mol, 1.4eq.) and 50mL n,N-dimethylacetamide, finish, and are warming up to 100 DEG C, reaction 5 Hour, reaction solution is cooled to 0 DEG C, purified water 400mL, 15~16h of stirring and crystallizing is added.Stop stirring, filtering, filter cake purifying Water 20mL washing, obtains 4- ((6,7- dimethoxy-4 's-yl) oxygroup) aniline 11.2g, yield 84.5%, purity 99.1%.
MS (ESI): m/z 297.20 [M+H]+.
1H NMR(DMSO-d6, 400MHz): δ 3.94 (s, 6H), 5.19 (s, 2H), 6.38 (d, J=2.8Hz, 1H), 6.68 (d, J=8.4Hz, 2H), 6.93 (d, J=8.8Hz, 2H), 7.37 (s, 1H), 7.51 (s, 1H), 8.43 (d, J=5.2Hz, 1H).
The preparation of 2 4- of embodiment ((6,7- dimethoxy-4 '-yl) oxygroup) aniline
By the chloro- 6,7- dimethoxy-quinoline (10g, 0.045mol, 1.0eq.) of 4-, 4-aminophenol (6.9g, 0.063mol, 1.4eq.) it is added in 50mL n,N-dimethylacetamide, it is cooled to 0 DEG C, is slowly added to sodium tert-butoxide The suspension of (6.1g, 0.063mol, 1.4eq.) and 50mL n,N-dimethylacetamide, finish, and are warming up to 110 DEG C, reaction 4 Hour, reaction solution is cooled to 0 DEG C, purified water 400mL, 15~16h of stirring and crystallizing is added.Stop stirring, filtering, filter cake purifying Water 20mL washing, obtains 4- ((6,7- dimethoxy-4 's-yl) oxygroup) aniline 11.8g, yield 89.1%, purity 99.1%.
Mass spectrum and hydrogen modal data and embodiment 1 are almost the same.
The preparation of 3 4- of embodiment ((6,7- dimethoxy-4 '-yl) oxygroup) aniline
By the chloro- 6,7- dimethoxy-quinoline (10g, 0.045mol, 1.0eq.) of 4-, 4-aminophenol (6.9g, 0.063mol, 1.4eq.) it is added in 50mL n,N-dimethylacetamide, it is cooled to 0 DEG C, is slowly added to potassium tert-butoxide The suspension of (7.1g, 0.063mol, 1.4eq.) and 50mL n,N-dimethylacetamide, finish, and are warming up to 100 DEG C, reaction 5 Hour, reaction solution is cooled to 0 DEG C, purified water 400mL, 15~16h of stirring and crystallizing is added.Stop stirring, filtering, filter cake purifying Water 20mL washing, obtains 4- ((6,7- dimethoxy-4 's-yl) oxygroup) aniline 11.1g, yield 83.8%, purity 99.2%.
Mass spectrum and hydrogen modal data and embodiment 1 are almost the same.
The preparation of 4 1- of embodiment ((4- fluorophenyl) carbamoyl) cyclopropanecarboxylate
By 1,1- cyclopropyl mono methyl dicarboxylate (10g, 0.069mol, 1.0eq.), para-fluoroaniline (11.6g,
0.104mol, 1.5eq.) it is added in 150mL methylene chloride, it is added with stirring 1- ethyl-(3- dimethylamino Propyl) phosphinylidyne diimmonium salt hydrochlorate (20g, 0.104mol, 1.5eq.), reaction 2h is stirred at room temperature.Concentration removes methylene chloride, to Methanol 30mL is added in concentrate, stirs dissolved clarification, purified water 150mL stirring and crystallizing, filtering is added, filter cake purifies 20mL washing It washs, obtains 1- ((4- fluorophenyl) carbamoyl) cyclopropanecarboxylate 14.5g, yield 96.7%, purity 99.8%.
MS (ESI): m/z 238.27 [M+H]+,260.17[M+Na]+.
1H NMR(DMSO-d6, 400MHz): δ 1.37~1.44 (m, 4H), 3.68 (s, 3H), 7.12~7.18 (m, 2H), 7.61~7.66 (m, 2H), 10.35 (s, 1H)
The preparation of 5 1- of embodiment ((4- fluorophenyl) carbamoyl) cyclopropanecarboxylate
By 1,1- cyclopropyl dimethyl dicarboxylate (10.9g, 0.069mol, 1.0eq.), para-fluoroaniline (11.6g, 0.104mol, 1.5eq.) it is added in tetrahydrofuran 100mL, it is cooled to 0 DEG C, is added with stirring bis- (trimethyl silicon substrate) ammonia of 2M Reaction 2h is stirred at room temperature in base sodium (NaHMDS)/tetrahydrofuran (207mL, 0.414mol, 6.0eq.).Reaction terminates that purifying is added Water 1.8L 5~6h of stirring and crystallizing, filtering, filter cake purified water 20mL washing obtain 1- ((4- fluorophenyl) carbamoyl) cyclopropyl Alkane methyl formate 13.7g, yield 91.3%, purity 99.7%.
Mass spectrum and hydrogen modal data and embodiment 4 are almost the same.
The rich preparation for Buddhist nun's compound of the card of embodiment 6
By 4- ((6,7- dimethoxy-4 '-yl) oxygroup) aniline (10g, 0.034mol, 1.0eq.), 1- ((4- fluorophenyl) Carbamoyl) cyclopropanecarboxylate (11.3g, 0.048mol, 1.4eq.) is added in tetrahydrofuran 100mL, it is cooled to 0 DEG C, it is slowly added to the NaHMDS tetrahydrofuran solution (102mL, 0.204mol, 6.0eq.) of 2M, is finished, 4h is reacted at room temperature, it will be anti- It answers liquid to be cooled to 0 DEG C, is slowly added to purified water 1200mL, 5~6h of stirring and crystallizing, filter, purified water 20mL washing, get Ka Bo is replaced Buddhist nun solid 16g, yield 94.6%, purity 99.6%.
MS (ESI): m/z 502.48 [M+H]+,524.37[M+Na]+.
1H NMR(DMSO-d6, 400MHz): δ 1.49 (s, 4H), 3.94 (s, 3H), 3.95 (s, 3H), 6.43 (d, J= 5.2Hz, 1H), 7.13~7.19 (m, 2H), 7.24 (d, J=9.2Hz, 2H), 7.40 (s, 1H), 7.51 (s, 1H), 7.64~ 7.67 (m, 2H), 7.78 (d, J=8.8Hz, 2H), 8.47 (d, J=5.2Hz, 1H), 10.08 (s, 1H), 10.20 (s, 1H)
The rich preparation for Buddhist nun's compound of the card of embodiment 7
By 4- ((6,7- dimethoxy-4 '-yl) oxygroup) aniline (10g, 0.034mol, 1.0eq.), 1- ((4- fluorophenyl) Carbamoyl) cyclopropanecarboxylate (11.3g, 0.048mol, 1.4eq.) is added in tetrahydrofuran 100mL, it is cooled to 0 DEG C, it is slowly added to the KHMDS tetrahydrofuran solution (102mL, 0.204mol, 6.0eq.) of 2M, is finished, 4h is reacted at room temperature, it will be anti- It answers liquid to be cooled to 0 DEG C, is slowly added to purified water 1200mL, 5~6h of stirring and crystallizing, filter, purified water 20mL washing, get Ka Bo is replaced Buddhist nun solid 15.7g, yield 92.8%, purity 99.7%.
Mass spectrum and hydrogen modal data and embodiment 6 are almost the same.
The rich preparation for Buddhist nun's compound of the card of embodiment 8
By 4- ((6,7- dimethoxy-4 '-yl) oxygroup) aniline (10g, 0.034mol, 1.0eq.), 1- ((4- fluorophenyl) Carbamoyl) cyclopropanecarboxylate (11.3g, 0.048mol, 1.4eq.) is added in tetrahydrofuran 100mL, it is cooled to 0 DEG C, it is slowly added to the isopropylmagnesium chloride tetrahydrofuran solution (102mL, 0.204mol, 6.0eq.) of 2M, is finished, is reacted at room temperature Reaction solution is cooled to 0 DEG C by 4h, is slowly added to purified water 1200mL, 5~6h of stirring and crystallizing, filtering, purified water 20mL washing, Get Ka Bo replaces Buddhist nun's solid 15.5g, yield 91.6%, purity 99.6%.
Mass spectrum and hydrogen modal data and embodiment 6 are almost the same.
The rich preparation for Buddhist nun's compound of the card of embodiment 9
By 4- ((6,7- dimethoxy-4 '-yl) oxygroup) aniline (10g, 0.034mol, 1.0eq.), 1- ((4- fluorophenyl) Carbamoyl) cyclopropanecarboxylate (11.3g, 0.048mol, 1.4eq.) is added in tetrahydrofuran 100mL, under room temperature It is slowly added to the LHMDS tetrahydrofuran solution (102mL, 0.204mol, 6.0eq.) of 2M, is finished, 4h is reacted at room temperature, to reaction solution In be slowly added to purified water 1200mL, 5~6h of stirring and crystallizing, filter, purified water 20mL washing, get Ka Bo replace Buddhist nun's solid 15g, receive Rate 88.9%, purity 99.8%.
Mass spectrum and hydrogen modal data and embodiment 6 are almost the same.

Claims (12)

1. a kind of rich preparation method for Buddhist nun's compound of card, comprising: formula III compound and Formula V compound contract in alkaline conditions It closes, obtains compound of formula I card and win for Buddhist nun's compound,
Wherein, R1Selected from C1~C10Alkyl, preferably methyl, ethyl, propyl and isopropyl.
2. the rich preparation method for Buddhist nun's compound of card according to claim 1, which is characterized in that the alkali is selected from t- BuONa, t-BuOK, LHMDS, NaHMDS, KHMDS or Grignard Reagent.
3. the rich preparation method for Buddhist nun's compound of card according to claim 1, which is characterized in that formula III compound and Formula V Compound molar ratio is 1:0.5~5, preferably 1:0.5~2, more preferable 1:1.2~2.
4. the rich preparation method for Buddhist nun's compound of card according to claim 1, which is characterized in that the dosage and formula III of alkali Compound molar ratio is 1~20:1, preferably 5~10:1, more preferable 5~8:1.
5. the rich preparation method for Buddhist nun's compound of card according to claim 1, which is characterized in that formula IV compound with to fluorine Aniline preparation formula V compound under the action of alkali or condensing agent,
Wherein, R2Selected from C1~C10Alkyl or H, preferably H, methyl, ethyl, propyl and isopropyl.
6. the rich preparation method for Buddhist nun's compound of card according to claim 5, which is characterized in that the optional EDC of condensing agent HCl or DCC；Alkali optional t-BuONa, t-BuOK, LHMDS, NaHMDS, KHMDS or Grignard Reagent, preferably NaHMDS, KHMDS or Grignard Reagent.
7. the rich preparation method for Buddhist nun's compound of card according to claim 5, which is characterized in that reaction temperature is -20~ 80 DEG C, preferably -10 DEG C~30 DEG C, more preferable 20 DEG C~30 DEG C.
8. the rich preparation method for Buddhist nun's compound of card according to claim 5, which is characterized in that condensing agent dosage and formula IV The molar ratio of compound is 1~10:1, preferably 1.2~5:1.
9. the rich preparation method for Buddhist nun's compound of card according to claim 5, which is characterized in that base amount and formula IV chemical combination The molar ratio of object is 1~20:1, preferably 5~10:1.
10. the rich preparation method for Buddhist nun's compound of card according to claim 1, which is characterized in that Formula II compound and 4- Amino-phenol reacts preparation formula III compound in the presence of alkali,
Wherein, X is selected from F, Cl, Br or I.
11. the rich preparation method for Buddhist nun's compound of card according to claim 10, which is characterized in that alkali is selected from sodium tert-butoxide Or potassium tert-butoxide.
12. the rich preparation method for Buddhist nun's compound of card according to claim 10, which is characterized in that reaction temperature is 90~ 120℃。
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110903240A (en) * 2019-12-12 2020-03-24 上海玉函化工有限公司 Preparation method of broad-spectrum anticancer drug cabozantinib
CN111217745A (en) * 2020-02-25 2020-06-02 漯河医学高等专科学校 Preparation method of cabozantinib

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103068384A (en) * 2010-04-29 2013-04-24 德西费拉制药有限责任公司 Cyclopropyl dicarboxamides and analogs exhibiting anti-cancer and anti-proliferative activites
WO2014000713A1 (en) * 2012-06-29 2014-01-03 Zhejiang Beta Pharma Incorporation NOVEL FUSED PYRIDINE DERIVATIVES USEFUL AS c-MET TYROSINE KINASE INHIBITORS
WO2017029362A1 (en) * 2015-08-19 2017-02-23 Sandoz Ag Asymmetric bisamidation of malonic ester derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103068384A (en) * 2010-04-29 2013-04-24 德西费拉制药有限责任公司 Cyclopropyl dicarboxamides and analogs exhibiting anti-cancer and anti-proliferative activites
WO2014000713A1 (en) * 2012-06-29 2014-01-03 Zhejiang Beta Pharma Incorporation NOVEL FUSED PYRIDINE DERIVATIVES USEFUL AS c-MET TYROSINE KINASE INHIBITORS
WO2017029362A1 (en) * 2015-08-19 2017-02-23 Sandoz Ag Asymmetric bisamidation of malonic ester derivatives

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110903240A (en) * 2019-12-12 2020-03-24 上海玉函化工有限公司 Preparation method of broad-spectrum anticancer drug cabozantinib
CN111217745A (en) * 2020-02-25 2020-06-02 漯河医学高等专科学校 Preparation method of cabozantinib
CN111217745B (en) * 2020-02-25 2021-05-11 漯河医学高等专科学校 Preparation method of cabozantinib

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