CN109836382A - The rich preparation method for replacing Buddhist nun and its intermediate of malic acid card - Google Patents
The rich preparation method for replacing Buddhist nun and its intermediate of malic acid card Download PDFInfo
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- CN109836382A CN109836382A CN201711225990.9A CN201711225990A CN109836382A CN 109836382 A CN109836382 A CN 109836382A CN 201711225990 A CN201711225990 A CN 201711225990A CN 109836382 A CN109836382 A CN 109836382A
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Abstract
The present invention relates to a kind of rich preparation methods for replacing Buddhist nun and its intermediate of malic acid card, with 4- chloro- 6,7- dimethoxy-quinoline (I) is that starting material A is substituted, is condensed, obtaining N- (4- { [6 at salt, bis- (methoxyl group) quinolyl-4s of 7-] oxygroup } phenyl)-N- (4- fluorophenyl) cyclopropane -1,1- diacid amide malate (malic acid card is rich to replace Buddhist nun).The present invention is compared with other malic acid cards are rich for Buddhist nun's synthetic method, and raw material is cheap and easily obtains, and reaction condition is mild, and overall yield is high, and product purity is high, avoids high temperature production, reduces risk, simplifies operation, is more advantageous to industrialized production.
Description
Technical field
The present invention relates to pharmaceutical synthesis fields, and in particular to a kind of rich synthesis side for replacing Buddhist nun and its intermediate of malic acid card
Method.
Background technique
Malic acid card is rich to replace Buddhist nun (Cabozantinib (S)-malate), chemical name: N- (4- { [6,7- bis- (methoxyl group) quinolines
Quinoline -4- base] oxygroup } phenyl)-N1(4- fluorophenyl) cyclopropane -1,1- diacid amide malate is a kind of polyceptor junket ammonia
Acid kinase inhibitor (tyrosine kinases inhibitor), target RET, MET, VEGFR-1, -2, -3, KIT, TRKB,
FLT-3, AXL, TIE-2 etc..Tyrosine kinase plays very important effect in the generation, development process of tumour, with junket ammonia
Acid kinase is the hot spot that target spot carries out that medicament research and development has become anti-tumor drug research in the world.Tyrosinase inhibitor passes through suppression
The injury repair of tumour cell processed makes cell division be arrested in G1 phase, induction and maintains Apoptosis, anti-angiogenesis etc.
Multipath realizes antitumous effect；Its anticancer spectrum is wide, has become the fiest-tire medication for treating various Cancerous diseases.
Malic acid card is rich to replace Buddhist nun without chiral centre, structural formula are as follows:
The rich synthetic method for Buddhist nun of malic acid card reported in the literature has very much, can according to the difference of last condensation intermediate
It is summarized as three classes:
Malic acid card is rich to replace Buddhist nun's synthetic method statistical form
Synthetic route one[1]:
Patent WO2005030140[1]It is the compound patent synthetic method of Yuan Yan company report.This method is the road Fen Liangtiao
3 and 5 are made respectively and then prepares card by being condensed and wins for Buddhist nun for line.Wherein a route is to be with cyclopropane -1,1- dicarboxylic acids
Raw material is condensed, is replaced to prepare 3.Another route is to be nitrified using 1- (3,4- Dimethoxyphenyl) ethyl ketone as raw material, also
Original, cyclization, substitution prepare 5.
This method setting-up point is high, and yield is lower, is not suitable for industrialized production.
Synthetic route two[2]:
Patent CN103459373A[2]It is the preparation patent of Yuan Yan company.This method is that point two lines are made 3 and 6 respectively
Then it is rich for Buddhist nun that card is prepared by being condensed.Wherein a route is 4- hydroxyl -6,7- dimethoxy-quinoline with for raw material, through chlorine
In generation, replaces to prepare 3.It is that raw material prepares 5 through condensation, chlorination that another route, which is with cyclopropane -1,1- dicarboxylic acids, is then contracted
It closes to be made to block to win and replaces Buddhist nun.
Route two is compared with route one, though low, high income, simple operation and other advantages with reaction temperature, it is being made
It needs to react > 12 hours at 110 DEG C when standby 3, and when preparing 6, has been applied to the dichloro with penetrating odor
Sulfoxide, these are unfavorable for industrialized production.
Synthetic route three[3]:
Patent CN103664776A[3]The synthetic method of middle report is very close with the synthetic route of route one, this method be with
Cyclopropane -1,1- ethyl dicarboxylate is raw material, through hydrolysis, condensation, hydrolysis, condensation and etc. to prepare, card is rich to replace Buddhist nun.
The features such as route three equally has reaction temperature high compared with route one, and yield is low, complicated for operation, therefore equally not
It is suitble to industrialized production.
Therefore, the generally existing reaction temperature of the rich preparation process for Buddhist nun of malic acid card is high in the prior art, and the time is long, and receives
The lower disadvantage of rate, or a large amount of deficiencies using unsuitable industrialized productions such as irritation reagents find an efficient, letter
Just, the preparation process of environmental protection and suitable industrialized production is technical problem urgently to be solved.
Summary of the invention
The present invention is directed to overcome the above malic acid card rich for some unsuitable industrialized productions present in Buddhist nun's synthetic method
The shortcomings that, a kind of rich method for replacing Buddhist nun and its intermediate of easy and high-purity synthesizing apple acid card is provided.
One of the objects of the present invention is to provide the rich preparation methods for Buddhist nun's intermediate of card shown in a kind of formula (II), including with
Lower step:
Formula (I) compound replace with 4-aminophenol under alkali A effect is prepared formula (II) compound；
The alkali A can be selected from sodium tert-butoxide, triethylamine, diisopropylethylamine, potassium carbonate, potassium hydroxide, sodium hydroxide, carbon
One of sour sodium, potassium tert-butoxide, sodium hydride and bis- (trimethyl silicon substrate) sodium amides are a variety of, preferably sodium tert-butoxide or the tert-butyl alcohol
Potassium.
The reaction dissolvent of the method can be selected from DMAC N,N' dimethyl acetamide, N,N-dimethylformamide, tetrahydrofuran, two
Six ring of oxygen, dimethyl sulfoxide and acetonitrile, preferably n,N-dimethylacetamide or n,N-Dimethylformamide.
The molar ratio of formula (I) compound and 4-aminophenol can be 1:1-1:3, preferably 1:1-1:1.5, more preferable 1:
1.4。
The w/v of formula (I) compound and reaction dissolvent can be 150:1g/L-50:1g/L, preferably 100:1g/
L。
The molar ratio of formula (I) compound and alkali A can be 1:1-1:3, preferably 1:2.
The reaction temperature of the method can be 80 DEG C~120 DEG C, preferably 100 DEG C~110 DEG C.
The object of the invention is also to provide the rich methods for Buddhist nun of card shown in a kind of formula (III), including by formula (II) chemical combination
Object and formula (VII) compound are condensed to yield formula (III) compound under alkali B effect；
R is selected from the substituted or unsubstituted C of phenyl1-8Alkyl and C0-8Alkyl-substituted phenyl, preferably methyl, ethyl, positive third
Base, isopropyl, butyl, phenyl, benzyl or phenethyl.
The alkali B can be selected from bis- (trimethyl silicon substrate) sodium amides (NaHMDS), triethylamine, diisopropylethylamine, potassium carbonate,
One of potassium hydroxide, sodium hydroxide, sodium carbonate and sodium hydride are a variety of, preferably bis- (trimethyl silicon substrate) sodium amides.
The reaction dissolvent of the method can be selected from DMAC N,N' dimethyl acetamide, N,N-dimethylformamide, tetrahydrofuran, two
Six ring of oxygen, dimethyl sulfoxide and acetonitrile, preferably tetrahydrofuran.
The w/v of formula (II) compound and reaction dissolvent can be 100:1g/L-20:1g/L, preferably 60:1g/
L-40:1g/L, more preferable 50:1g/L.
The molar ratio of formula (II) compound and formula (VII) compound can be 1:1-1:2, preferably 1:1-1:1.5, more excellent
Select 1:1.4.
The molar ratio of formula (II) compound and alkali B can be 1:2~10, preferably 1:6~10.
The reaction temperature of the method can be -20 DEG C~10 DEG C, preferably -5 DEG C~5 DEG C.
The rich method for replacing Buddhist nun of card shown in above-mentioned formula (III) can further comprise also following step: formula (I) compound is in alkali
A effect is lower to be carried out replacing formula (II) compound described in being prepared with 4-aminophenol；
The alkali A can be selected from sodium tert-butoxide, triethylamine, diisopropylethylamine, potassium carbonate, potassium hydroxide, sodium hydroxide, carbon
One of sour sodium, potassium tert-butoxide, sodium hydride and bis- (trimethyl silicon substrate) sodium amides are a variety of, preferably sodium tert-butoxide or the tert-butyl alcohol
Potassium.
The reaction dissolvent of the method can be selected from DMAC N,N' dimethyl acetamide, N,N-dimethylformamide, tetrahydrofuran, two
Six ring of oxygen, dimethyl sulfoxide and acetonitrile, preferably n,N-dimethylacetamide or n,N-Dimethylformamide.
The molar ratio of formula (I) compound and 4-aminophenol can be 1:1-1:3, preferably 1:1-1:1.5, more preferable 1:
1.4。
The w/v of formula (I) compound and reaction dissolvent can be 150:1g/L-50:1g/L, preferably 100:1g/
L。
The molar ratio of formula (I) compound and alkali A can be 1:1-1:3, preferably 1:2.
The reaction temperature of the method can be 80 DEG C~120 DEG C, preferably 100 DEG C~110 DEG C.
The object of the invention is also to provide a kind of rich preparation methods for Buddhist nun of malic acid card, comprising the following steps:
N- (4- { [bis- (methoxyl group) quinolyl-4s of 6,7-] oxygroup } benzene is obtained under formula (III) compound and malic acid effect
Base)-N1(4- fluorophenyl) cyclopropane -1,1- diacid amide malate (IV)；
The reaction dissolvent can be selected from DMAC N,N' dimethyl acetamide, N,N-dimethylformamide, tetrahydrofuran, dioxy six
Ring, dimethyl sulfoxide, methanol, ethyl alcohol, isopropanol and acetonitrile, preferably tetrahydrofuran.
Rich above-mentioned malic acid card for the preparation method of Buddhist nun can further comprise also following step: by formula (II) compound with
Formula (VII) compound is condensed to yield described formula (III) compound under alkali B effect；
R is selected from the substituted or unsubstituted C of phenyl1-8Alkyl and C0-8Alkyl-substituted phenyl, preferably methyl, ethyl, positive third
Base, isopropyl, butyl, phenyl, benzyl or phenethyl.
The alkali B can be selected from bis- (trimethyl silicon substrate) sodium amides (NaHMDS), triethylamine, diisopropylethylamine, potassium carbonate,
One of potassium hydroxide, sodium hydroxide, sodium carbonate and sodium hydride are a variety of, preferably bis- (trimethyl silicon substrate) sodium amides.
The reaction dissolvent of the method can be selected from DMAC N,N' dimethyl acetamide, N,N-dimethylformamide, tetrahydrofuran, two
Six ring of oxygen, dimethyl sulfoxide and acetonitrile, preferably tetrahydrofuran.
The w/v of formula (II) compound and reaction dissolvent can be 100:1g/L-20:1g/L, preferably 60:1g/
L-40:1g/L, more preferable 50:1g/L.
The molar ratio of formula (II) compound and formula (VII) compound can be 1:1-1:2, preferably 1:1-1:1.5, more excellent
Select 1:1.4.
The molar ratio of formula (II) compound and alkali B can be 1:2~10, preferably 1:6~10.
The reaction temperature of the method can be -20 DEG C~10 DEG C, preferably -5 DEG C~5 DEG C.
The rich preparation method for replacing Buddhist nun of above-mentioned malic acid card can further comprise also following step: formula (I) compound is in alkali A
Effect is lower to be carried out replacing formula (II) compound described in being prepared with 4-aminophenol；
The alkali A can be selected from sodium tert-butoxide, triethylamine, diisopropylethylamine, potassium carbonate, potassium hydroxide, sodium hydroxide, carbon
One of sour sodium, potassium tert-butoxide, sodium hydride and bis- (trimethyl silicon substrate) sodium amides are a variety of, preferably sodium tert-butoxide or the tert-butyl alcohol
Potassium.
The reaction dissolvent of the method can be selected from DMAC N,N' dimethyl acetamide, N,N-dimethylformamide, tetrahydrofuran, two
Six ring of oxygen, dimethyl sulfoxide and acetonitrile, preferably n,N-dimethylacetamide or n,N-Dimethylformamide.
The molar ratio of formula (I) compound and 4-aminophenol can be 1:1-1:3, preferably 1:1-1:1.5, more preferable 1:
1.4。
The w/v of formula (I) compound and reaction dissolvent can be 150:1g/L-50:1g/L, preferably 100:1g/
L。
The molar ratio of formula (I) compound and alkali A can be 1:1-1:3, preferably 1:2.
The reaction temperature of the method can be 80 DEG C~120 DEG C, preferably 100 DEG C~110 DEG C.
For this method compared with other existing methods, raw material is cheap and easily-available, reacts milder, easy to operate, reduces reaction
Temperature shortens the reaction time, avoids reducing the wind in industrial production using the thionyl chloride reagent with penetrating odor
Danger, is more advantageous to industrialized production.
Specific embodiment
To embody technical solution of the present invention and its acquired effect, the present invention is done below in conjunction with specific embodiment
It further illustrates, but protection scope of the present invention is not limited to specific embodiment.
The preparation of embodiment one, compound (II)
Compound (I) (500g, 2.23mol), 4-aminophenol (345g, 3.16mol) are added in reaction flask, are added
DMA (3L), is cooled to 0 DEG C~5 DEG C, and DMA (2L) suspension of sodium tert-butoxide (430g) is added dropwise, and drop finishes, be warming up to 100 DEG C~
110 DEG C, insulation reaction 4~5 hours.(TLC monitors fully reacting, Rf value 0.4 (methylene chloride: methanol=20:1)).Be cooled to-
It 5 DEG C~0 DEG C, is added ice water (10L), stirring and crystallizing 15~16 hours.Filtering, filter cake are washed with a small amount, dry in 50 DEG C of air blast
Obtain light yellow solid 595g, yield 90%, HPLC purity 99.7% within dry 15~16 hours.
The preparation of embodiment two, compound (II)
Compound (I) (500g, 2.23mol), 4-aminophenol (345g, 3.16mol) are added in reaction flask, are added
DMA (3L) is cooled to 0 DEG C~5 DEG C, and DMA (2L) drop that potassium tert-butoxide (450g) is added dropwise finishes, and is warming up to 100 DEG C~110 DEG C, protects
Temperature reaction 4~5 hours.(TLC monitors fully reacting, Rf value 0.4 (methylene chloride: methanol=20:1)).It is cooled to -5 DEG C~0
DEG C, it is added ice water (1L), stirring and crystallizing 15~16 hours.Filtering, filter cake is washed with a small amount, in 50 DEG C of forced air dryings 15~16
Hour obtains light yellow solid 590g, yield 89%, HPLC purity 99.3%.
The synthesis of embodiment three, compound (VII)
Compound (V) (200g, 1.39mol), THF (2L) are added in reaction flask, under ice bath, are slowly added to thionyl chloride
(50ml), finishes, and after being stirred at room temperature 2 hours, is added compound (VI) (154g), reacts at room temperature 2 hours, and TLC monitoring has been reacted
Finish, add water, be extracted with dichloromethane, organic phase anhydrous sodium sulfate dries, filters, and is evaporated under reduced pressure to off-white powder 280g, receives
Rate 85%.
The synthesis of example IV, compound (III)
Reaction is added in compound (II) (200g, 0.67mol), compound (VII) (220g, 0.93mol), THF (2L)
In bottle, -5 DEG C~5 DEG C are cooled to, THF (2mol/L) 2L solution of NaHMDS is added dropwise, drop finishes, and is stirred to react 1 in -5 DEG C~5 DEG C
~2 hours.(TLC monitors fully reacting, Rf value 0.5 (methylene chloride: methanol=20:1)).Add water (16L) into reaction solution, stirs
It mixes crystallization 1~2 hour, filters, filter cake is dried in vacuo 23~24 hours to obtain off-white powder 312g, yield in 40 DEG C~50 DEG C
92.9%, HPLC purity 99.5%.
1H NMR (400MHz, d6- DMSO): δ 10.2 (s, 1H), 10.08 (s, 1H), 8.4 (s, 1H), 7.8 (m, 2H),
7.65 (m, 2H), 7.5 (s, 1H), 7.4 (s, 1H), 7.24 (m, 2H), 7.15 (m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5
(s, 4H).MS (ESI): m/z 502 [M+H]+.
The synthesis of embodiment five, compound (III)
Reaction is added in compound (II) (200g, 0.67mol), compound (VII) (285g, 0.95mol), THF (2L)
In bottle, -5 DEG C~5 DEG C are cooled to, THF (2mol/L) 2L solution of NaHMDS is added dropwise, drop finishes, and is stirred to react 1 in -5 DEG C~5 DEG C
~2 hours.(TLC monitors fully reacting, Rf value 0.5 (methylene chloride: methanol=20:1)).Add water (1.6L) into reaction solution,
Stirring and crystallizing 1~2 hour, filtering, filter cake was dried in vacuo 23~24 hours to obtain off-white powder 310g, quality in 40 DEG C~50 DEG C
Yield 92.2%, HPLC purity 99.3%, the substantially same example IV of nuclear magnetic data.
The synthesis of embodiment six, compound (IV)
It is spare after the THF dissolved clarification that L MALIC ACID (76.8g) is applied to 1440ml.Compound (III) (240g) is used
After the THF dissolved clarification of 1440ml, filtering, gained filtrate is added in reaction flask, and under stirring, the THF solution of L MALIC ACID is added dropwise.Drop
Finish, 20 DEG C~30 DEG C are stirred 1~1.5 hour.After being slowly added to acetonitrile (3L), 20 DEG C~30 DEG C are stirred 15~16 hours.Filtering,
It is off-white powder that filter cake, which is dried in vacuo in 40~50 DEG C and obtains within 23~24 hours formula (IV) compound L-malic acid card and win for Buddhist nun,
245g, yield 80%, HPLC purity 99.9%.
1H NMR (400MHz, d6- DMSO): δ 10.2 (s, 1H), 10.08 (s, 1H), 8.5 (s, 1H), 7.8 (m, 2H),
7.68 (m, 2H), 7.5 (s, 1H), 7.4 (s, 1H), 7.25 (m, 2H), 7.18 (m, 2H), 6.5 (d, 1H), 4.3 (m, 1H), 4.0
(d, 6H), 2.6 (m, 1H), 2.5 (m, 1H), 1.5 (s, 4H).MS:M+H=502.
Claims (13)
1. the rich preparation method for Buddhist nun of card, comprising the following steps:
It is rich for Buddhist nun that formula (II) compound and formula (VII) compound are condensed to yield card under alkali B effect；
Wherein, R is selected from the substituted or unsubstituted C of phenyl1-8Alkyl and C0-8Alkyl-substituted phenyl, preferably methyl, ethyl, positive third
Base, isopropyl, butyl, phenyl, benzyl or phenethyl.
2. preparation method according to claim 1, which is characterized in that alkali B is selected from bis- (trimethyl silicon substrate) sodium amides, three second
One of amine, diisopropylethylamine, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium carbonate and sodium hydride are a variety of, preferably double
(trimethyl silicon substrate) sodium amide.
3. preparation method according to claim 1, which is characterized in that the reaction dissolvent of the method is selected from N, N- dimethyl
Acetamide, n,N-Dimethylformamide, tetrahydrofuran, dioxane, dimethyl sulfoxide and acetonitrile, preferably tetrahydrofuran.
4. preparation method according to claim 3, which is characterized in that the weight of formula (II) compound and reaction dissolvent
Volume ratio is 100:1g/L-20:1g/L, preferably 60:1g/L-40:1g/L, more preferable 50:1g/L.
5. preparation method according to claim 1, which is characterized in that formula (II) compound and formula (VII) compound
Molar ratio be 1:1-1:2, preferably 1:1-1:1.5, more preferable 1:1.4.
6. preparation method according to claim 1, which is characterized in that the molar ratio of formula (II) compound and alkali B is
1:2~10, preferably 1:6~10.
7. preparation method according to claim 1, which is characterized in that the reaction temperature of the method is -20 DEG C~10 DEG C,
It is preferred that -5 DEG C~5 DEG C.
8. preparation method described in -7 any one according to claim 1, which is characterized in that still further comprise and change formula (I)
Conjunction object replace with 4-aminophenol under alkali A effect is prepared formula (II) compound；
9. preparation method according to claim 8, which is characterized in that the alkali A is selected from sodium tert-butoxide, triethylamine, two different
Propylethylamine, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium tert-butoxide, sodium hydride and bis- (trimethyl silicon substrate) ammonifications
One of sodium is a variety of.
10. preparation method according to claim 8, which is characterized in that the reaction dissolvent of the substitution reaction is selected from N, N-
Dimethyl acetamide, n,N-Dimethylformamide, tetrahydrofuran, dioxane, dimethyl sulfoxide and acetonitrile, preferably N, N- diformazan
Yl acetamide or N,N-dimethylformamide.
11. the rich preparation method for Buddhist nun of malic acid card, which is characterized in that the step described in any one of claim 1~10
On the basis of, still further comprise the following steps:
N- (4- { [bis- (methoxyl group) quinolyl-4s of 6,7-] oxygroup } phenyl)-is obtained under formula (III) compound and malic acid effect
N1(4- fluorophenyl) cyclopropane -1,1- diacid amide malate；
12. according to the method for claim 11, which is characterized in that reaction dissolvent is selected from n,N-dimethylacetamide, N, N-
Dimethylformamide, tetrahydrofuran, dioxane, dimethyl sulfoxide, methanol, ethyl alcohol, isopropanol and acetonitrile, preferably tetrahydro furan
It mutters.
Formula 13. (VII) compound
Wherein R is selected from the substituted or unsubstituted C of phenyl1-8Alkyl and C0-8Alkyl-substituted phenyl, preferably methyl, ethyl, positive third
Base, isopropyl, butyl, phenyl, benzyl or phenethyl.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN112979544A (en) * | 2019-12-17 | 2021-06-18 | 江苏先声药业有限公司 | Preparation method of cabozantinib or salt thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| 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 |
| CN112979544A (en) * | 2019-12-17 | 2021-06-18 | 江苏先声药业有限公司 | Preparation method of cabozantinib or salt thereof |
| 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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| CN109836382B (en) | 2021-11-05 |
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