CN109053727A - A kind of preparation method of ABT-199 intermediate - Google Patents
A kind of preparation method of ABT-199 intermediate Download PDFInfo
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- CN109053727A CN109053727A CN201811150333.7A CN201811150333A CN109053727A CN 109053727 A CN109053727 A CN 109053727A CN 201811150333 A CN201811150333 A CN 201811150333A CN 109053727 A CN109053727 A CN 109053727A
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- 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
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Abstract
The invention discloses a kind of preparation methods of ABT-199 intermediate, the i.e. preparation method of 5- bromo-7-azaindole.Specifically, 5- bromo-7-azaindole is finally synthesized by three steps of initial feed point of 2- amino -3- methyl -5- bromopyridine.The preparation method reaction condition is mild, easily operated, does not need anhydrous and oxygen-free operation, highly-safe without high temperature and pressure；The high income of reaction step；Raw material is easy to get, at low cost；Catalysis reaction is carried out without heavy metal；Production technology may be implemented to industrialize, and can carry out hundred feather weight productions.
Description
Technical field
The present invention relates to pharmaceutical technology field more particularly to a kind of preparation methods of ABT-199 intermediate.
Background technique
Ai Baiwei is announced within 2015, the new drug venetoclax (ABT- of the treatment chronic lymphocytic leukemia of exploitation
199) the breakthrough drug certification of FDA is obtained.The drug is a kind of experimental B cell lymphoma factor -2 (BCL-2) inhibitor.
ABT-199/venetoclax shows high reactivity in intractable/recurrent CLL as single medicine.Especially in intractable/recurrence
Property CLL in show high CR rate (as single medicine 29%, 39%) with Rituximab combination.So ABT-199 can be used as effectively
Single medicine tends to the broad spectral pattern new drug of hematological malignancy disease with other drugs combination.5- bromo-7-azaindole is synthesis new drug
The key intermediate of venetoclax (ABT-199).
In the prior art, such as WO2004/78757,2004, A2；CN106045995,2016,A；US2011/28511,
Just described in 2011, A1 venetoclax (ABT-199) about and its intermediate preparation method.But the bromo- 7- azepine of 5-
It is oxidation reaction that indole preparation method, which mainly usually has 3 kinds: 1., by bromo- 2,3- dihydro -1H- pyrrole radicals [2,3-B] the pyridine oxygen of 5-
It is melted into 5- bromo-7-azaindole, this method oxidation reaction period is long, it usually needs 5-7 days, and be easy reaction and be not thorough, it leads
Cause yield low, and oxidation process generates a large amount of waste water, brings very big pressure to environmental protection；2. being with the bromo- 7- aza-titanium oxide Yin of 5-
Diindyl reduction synthesis, reduction reaction need to use the reducing agents such as borine or metal hydride, and reaction is not easily controlled, and are not suitable for
It is used in industrialized production；3. being that pyridine alkynyl compounds carries out intramolecular cyclization, firstly, the synthesis of pyridine alkynyl compounds
Using being metal catalysed reaction, there is heavy metal pollution, secondly, cyclization generallys use autoclave pressurization to promote product to produce, it is high
Pressure reaction and relevant operation risk are high, are unfavorable for industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of ABT-199 intermediate, that is, 5- bromo-7-azaindole it is simple, safely, be easy to
Amplify the preparation method of production.
The preparation method of ABT-199 intermediate provided by the invention, the ABT-199 intermediate are the bromo- 7- azepine Yin of 5-
Diindyl comprising following steps:
(1) synthesis of (E)-N- (the bromo- 3- picoline -2- base of 5-) formic acid imine ethyl ester, reaction equation are as follows:
(2) synthesis of (E)-N'- (the bromo- 3- picoline -2- base of 5-)-N- methyl-N- formic acid imines phenyl ester, reaction equation is such as
Under:
(3) synthesis of 5- bromo-7-azaindole, reaction equation are as follows:
Optionally, ABT-199 intermediate preparation method the following steps are included:
(1) 2- amino -3- methyl -5- bromopyridine, trimethyl orthoformate, acidic catalyst and the first solvent are added and are reacted
In kettle, heating stirring is reacted 16 hours to flowing back, and raw material end of reaction adds water and stirs, liquid separation, and organic phase is dry, is evaporated off organic
Solvent obtains (E)-N- (the bromo- 3- picoline -2- base of 5-) formic acid imine ethyl ester；
(2) (E)-N- (the bromo- 3- picoline -2- base of 5-) formic acid imine ethyl ester, methylphenylamine and second solvent is added
Enter in reaction kettle, heat up 60 degrees Celsius, stir 16 hours, raw material end of reaction adds water and stirs, liquid separation, and organic phase is dry, is evaporated off
Organic solvent obtains (E)-N'- (the bromo- 3- picoline -2- base of 5-)-N- methyl-N- formic acid imines phenyl ester；
(3) (E)-N'- (the bromo- 3- picoline -2- base of 5-)-N- methyl-N- formic acid imines phenyl ester and third solvent are added
Enter in reaction kettle, be cooled to 10 degrees Celsius, highly basic is added in stirring, and control temperature is no more than 15 degrees Celsius, finishes, and stirring 16 is small
When, raw material end of reaction adds water and stirs, liquid separation, and organic phase is dry, and organic solvent is evaporated off, recrystallizes to obtain the bromo- 7- azepine Yin of 5-
Diindyl；
Wherein, the acidic catalyst is p-methyl benzenesulfonic acid, acetic acid, sulfuric acid or phosphoric acid；First solvent is 1,2- bis-
Chloromethanes, dioxane, tetrahydrofuran or acetonitrile；Second solvent is toluene, dimethylbenzene or chlorobenzene；The third solvent is
Glycol dimethyl ether, dioxane or tetrahydrofuran；The highly basic is Sodamide, sodium hydride, sodium tert-butoxide or potassium tert-butoxide.
Optionally, in step (1), the 2- amino -3- methyl -5- bromopyridine, trimethyl orthoformate and acidic catalyst
Molar ratio be 1:(0.001-0.003): (2-4).
Optionally, in step (2), (E)-N- (the bromo- 3- picoline -2- base of 5-) the formic acid imine ethyl ester and N- methyl
The molar ratio of aniline is 1:(1-2).
Optionally, in step (3), (E)-N'- (the bromo- 3- picoline -2- base of the 5-)-N- methyl-N- formic acid imines
The molar ratio of phenyl ester and highly basic is 1:(1-1.2).
Optionally, ABT-199 intermediate preparation method the following steps are included:
(1) by 1000mol 2- amino -3- methyl -5- bromopyridine, 2mol p-methyl benzenesulfonic acid, 3000mol orthoformic acid front three
Ester and 950L 1,2- methylene chloride are added in reaction kettle, and heating stirring is reacted 16 hours, raw material end of reaction adds water to flowing back
Stirring, liquid separation, organic phase is dry, and organic solvent is evaporated off, obtains (E)-N- (the bromo- 3- picoline -2- base of 5-) formic acid imine ethyl ester；
(2) 500mol (E)-N- (the bromo- 3- picoline -2- base of 5-) formic acid imine ethyl ester, 750mol methylphenylamine and
750L toluene is added in reaction kettle, heats up 60 degrees Celsius, stirs 16 hours, raw material end of reaction adds water and stirs, and liquid separation is organic
It is mutually dry, organic solvent is evaporated off, obtains (E)-N'- (the bromo- 3- picoline -2- base of 5-)-N- methyl-N- formic acid imines phenyl ester；
(3) by 100mol (E)-N'- (the bromo- 3- picoline -2- base of 5-)-N- methyl-N- formic acid imines phenyl ester and 300L
Glycol dimethyl ether is added in reaction kettle, is cooled to 10 degrees Celsius, and 110mol Sodamide is added in stirring, and control temperature is no more than 15
Degree Celsius, it finishes, stirs 16 hours, raw material end of reaction adds water and stirs, liquid separation, and organic phase is dry, organic solvent is evaporated off, weight
Crystallize to obtain 5- bromo-7-azaindole.
The invention has the following advantages:
(1) reaction condition of the present invention is mild, easily operated, does not need anhydrous and oxygen-free operation, without high temperature and pressure, safety
Property it is high；
(2) high income of reaction step of the invention；
(3) reaction raw materials of the present invention are easy to get, at low cost；
(4) present invention reaction carries out catalysis reaction without heavy metal；
(5) production technology of the present invention may be implemented to industrialize, and can carry out hundred feather weight productions.
It should be understood that above general description and following detailed description be only it is exemplary and explanatory, not
It can the limitation present invention.
Specific embodiment
The following is a clear and complete description of the technical scheme in the embodiments of the invention, it is clear that described embodiment
Only a part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, the common skill in this field
Art personnel every other embodiment obtained without making creative work belongs to the model that the present invention protects
It encloses.
The synthetic route of ABT-199 intermediate, that is, 5- bromo-7-azaindole provided by the invention is as follows
Embodiment 1
(1) synthesis of (E)-N- (the bromo- 3- picoline -2- base of 5-) formic acid imine ethyl ester
By 2- amino -3- methyl -5- bromopyridine (185kg, 1000mol), p-methyl benzenesulfonic acid (3.44kg, 2mol), primitive nail
Sour trimethyl (318kg, 3000mol), 1,2- methylene chloride (950L) are added in reaction kettle, heating stirring to reflux, reaction 16
Hour, raw material end of reaction adds water and stirs, liquid separation, and organic phase is dry, and organic solvent is evaporated off, obtains (E)-N- (bromo- 3- methyl of 5-
Pyridine -2- base) formic acid imine ethyl ester (205.4kg, 84.4mol), yield 84.4%.
(2) synthesis of (E)-N'- (the bromo- 3- picoline -2- base of 5-)-N- methyl-N- formic acid imines phenyl ester
By (E)-N- (the bromo- 3- picoline -2- base of 5-) formic acid imine ethyl ester (121kg, 500mol), methylphenylamine
(160.5kg, 750mol), toluene (750L) are added in reaction kettle, heat up 60 degrees Celsius, stir 16 hours, raw material end of reaction,
It adds water and stirs, liquid separation, organic phase is dry, and organic solvent is evaporated off, obtains (E)-N'- (the bromo- 3- picoline -2- base of 5-)-N- methyl -
N- formic acid imines phenyl ester (1331.5kg, 438mol), yield 87.6%.
(3) synthesis of 5- bromo-7-azaindole
By (E)-N'- (the bromo- 3- picoline -2- base of 5-)-N- methyl-N- formic acid imines phenyl ester (30.4kg, 100mol),
Glycol dimethyl ether (300L) is added in reaction kettle, is cooled to 10 degrees Celsius, and Sodamide (4.29kg, 110mol) is added in stirring,
It controlling temperature and is no more than 15 degrees Celsius, finish, stir 16 hours, raw material end of reaction adds water and stirs, liquid separation, and organic phase is dry,
Organic solvent is evaporated off, recrystallizes to obtain 5- bromo-7-azaindole (16.5kg, 83.7mol), yield 87.6%.
1H NMR (CDCl3,400MHz) δ 6.46 (d, J=3.2Hz, 1H), 7.37 (d, J=3.2Hz, 1H), 8.09 (s,
1H),8.34(s,1H),10.85(bs,1H).
13C NMR(CDCl3,100MHz)δ100.5,111.4,122.3,126.8,131.4,142.3,146.3.IR
(KBr,cm-1)3132,2862,1558,1282,884,740.
In addition to the implementation, acidic catalyst can also be acetic acid, sulfuric acid or phosphoric acid other than p-methyl benzenesulfonic acid.The
One solvent can also be dioxane, tetrahydrofuran or acetonitrile outside 1,2- methylene chloride.Second solvent other than toluene,
It can also be dimethylbenzene or chlorobenzene.Third solvent can also be dioxane or tetrahydrofuran other than glycol dimethyl ether.By force
Alkali can also be sodium hydride, sodium tert-butoxide or potassium tert-butoxide other than Sodamide, for pulling out cyclization after hydrogen.
In addition, in step (1), mole of 2- amino -3- methyl -5- bromopyridine, trimethyl orthoformate and acidic catalyst
Than for 1:(0.001-0.003): (2-4).In step (2), (E)-N- (the bromo- 3- picoline -2- base of 5-) formic acid imine ethyl ester
Molar ratio with methylphenylamine is 1:(1-2).In step (3), (E)-N'- (the bromo- 3- picoline -2- base of 5-)-N- methyl -
The molar ratio of N- formic acid imines phenyl ester and highly basic is 1:(1-1.2).
Under above-mentioned condition, ABT-199 intermediate i.e. 5- bromo-7-azaindole can be prepared, and yield is higher than 80%.
Since above-mentioned preparation method reaction step is few, easily operated, the high income of reaction step；Reaction condition is mild, no
Anhydrous and oxygen-free is needed to operate, highly-safe without high temperature and pressure, production technology of the present invention may be implemented to industrialize, Ke Yijin
The production of hundred feather weight of row, and guarantee higher product yield.
Invention described above embodiment is not intended to limit the scope of the present invention..
Those skilled in the art will readily occur to of the invention its after considering specification and the disclosure invented here of practice
Its embodiment.The present invention is directed to cover any variations, uses, or adaptations of the invention, these modifications, purposes or
Person's adaptive change follows general principle of the invention and including the undocumented common knowledge in the art of the present invention
Or conventional techniques.The description and examples are only to be considered as illustrative, and true scope and spirit of the invention are by following
Claim is pointed out.
Claims (6)
1. a kind of preparation method of ABT-199 intermediate, which is characterized in that the ABT-199 intermediate is the bromo- 7- azepine Yin of 5-
Diindyl comprising following steps:
(1) synthesis of (E)-N- (the bromo- 3- picoline -2- base of 5-) formic acid imine ethyl ester, reaction equation are as follows:
(2) synthesis of (E)-N'- (the bromo- 3- picoline -2- base of 5-)-N- methyl-N- formic acid imines phenyl ester, reaction equation are as follows:
(3) synthesis of 5- bromo-7-azaindole, reaction equation are as follows:
2. the preparation method of ABT-199 intermediate according to claim 1, which comprises the following steps:
(1) reaction kettle is added in 2- amino -3- methyl -5- bromopyridine, trimethyl orthoformate, acidic catalyst and the first solvent
In, heating stirring is reacted 16 hours to flowing back, and raw material end of reaction adds water and stirs, liquid separation, and organic phase is dry, is evaporated off organic molten
Agent obtains (E)-N- (the bromo- 3- picoline -2- base of 5-) formic acid imine ethyl ester；
(2) (E)-N- (the bromo- 3- picoline -2- base of 5-) formic acid imine ethyl ester, methylphenylamine and the second solvent are added anti-
It answers in kettle, heats up 60 degrees Celsius, stir 16 hours, raw material end of reaction adds water and stirs, liquid separation, and organic phase is dry, is evaporated off organic
Solvent obtains (E)-N'- (the bromo- 3- picoline -2- base of 5-)-N- methyl-N- formic acid imines phenyl ester；
(3) (E)-N'- (the bromo- 3- picoline -2- base of 5-)-N- methyl-N- formic acid imines phenyl ester and third solvent are added anti-
It answers in kettle, is cooled to 10 degrees Celsius, highly basic is added in stirring, and control temperature is no more than 15 degrees Celsius, finishes, stirs 16 hours, former
Expect end of reaction, add water and stir, liquid separation, organic phase is dry, and organic solvent is evaporated off, recrystallizes to obtain 5- bromo-7-azaindole；
Wherein, the acidic catalyst is p-methyl benzenesulfonic acid, acetic acid, sulfuric acid or phosphoric acid；First solvent is 1,2- dichloromethane
Alkane, dioxane, tetrahydrofuran or acetonitrile；Second solvent is toluene, dimethylbenzene or chlorobenzene；The third solvent is second two
Diethylene glycol dimethyl ether, dioxane or tetrahydrofuran；The highly basic is Sodamide, sodium hydride, sodium tert-butoxide or potassium tert-butoxide.
3. the preparation method of ABT-199 intermediate according to claim 2, which is characterized in that in step (1), the 2-
The molar ratio of amino -3- methyl -5- bromopyridine, trimethyl orthoformate and acidic catalyst is 1:(0.001-0.003): (2-4).
4. the preparation method of ABT-199 intermediate according to claim 2, which is characterized in that described in step (2)
(E)-N- (the bromo- 3- picoline -2- base of 5-) formic acid imine ethyl ester and the molar ratio of methylphenylamine are 1:(1-2).
5. the preparation method of ABT-199 intermediate according to claim 2, which is characterized in that described in step (3)
(E) molar ratio of-N'- (the bromo- 3- picoline -2- base of 5-)-N- methyl-N- formic acid imines phenyl ester and highly basic is 1:(1-1.2).
6. the preparation method of ABT-199 intermediate according to claim 2, which comprises the following steps:
(1) by 1000mol 2- amino -3- methyl -5- bromopyridine, 2mol p-methyl benzenesulfonic acid, 3000mol trimethyl orthoformate and
950L 1,2- methylene chloride are added in reaction kettle, and heating stirring is reacted 16 hours, raw material end of reaction adds water to stir to flowing back
It mixes, liquid separation, organic phase is dry, and organic solvent is evaporated off, obtains (E)-N- (the bromo- 3- picoline -2- base of 5-) formic acid imine ethyl ester；
(2) 500mol (E)-N- (the bromo- 3- picoline -2- base of 5-) formic acid imine ethyl ester, 750mol methylphenylamine and 750L
Toluene is added in reaction kettle, heats up 60 degrees Celsius, stirs 16 hours, and raw material end of reaction adds water and stirs, liquid separation, organic relevant
It is dry, organic solvent is evaporated off, obtains (E)-N'- (the bromo- 3- picoline -2- base of 5-)-N- methyl-N- formic acid imines phenyl ester；
(3) by 100mol (E)-N'- (the bromo- 3- picoline -2- base of 5-)-N- methyl-N- formic acid imines phenyl ester and 300L second two
Diethylene glycol dimethyl ether is added in reaction kettle, is cooled to 10 degrees Celsius, 110mol Sodamide is added in stirring, and it is Celsius that control temperature is no more than 15
Degree, finishes, and stirs 16 hours, and raw material end of reaction adds water and stirs, liquid separation, and organic phase is dry, and organic solvent is evaporated off, and recrystallizes
Obtain 5- bromo-7-azaindole.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011110479A1 (en) * | 2010-03-09 | 2011-09-15 | F. Hoffmann-La Roche Ag | Process for the manufacture of 5-halogenated-7-azaindoles |
| CN106045995A (en) * | 2016-06-13 | 2016-10-26 | 菏泽学院 | Synthesizing method of 5-bromine-1H-pyrrolo[2,3-b]pyridine |
| CN108752341A (en) * | 2018-08-03 | 2018-11-06 | 南京杰运医药科技有限公司 | A kind of preparation method of bromo- 7 azaindoles of 5- |
-
2018
- 2018-09-29 CN CN201811150333.7A patent/CN109053727B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011110479A1 (en) * | 2010-03-09 | 2011-09-15 | F. Hoffmann-La Roche Ag | Process for the manufacture of 5-halogenated-7-azaindoles |
| WO2011109932A1 (en) * | 2010-03-09 | 2011-09-15 | F.Hoffmann-La Roche Ag | Novel process for the manufacture of 5-halogenated-7-azaindoles |
| CN106045995A (en) * | 2016-06-13 | 2016-10-26 | 菏泽学院 | Synthesizing method of 5-bromine-1H-pyrrolo[2,3-b]pyridine |
| CN108752341A (en) * | 2018-08-03 | 2018-11-06 | 南京杰运医药科技有限公司 | A kind of preparation method of bromo- 7 azaindoles of 5- |
Non-Patent Citations (1)
| Title |
|---|
| R. R. LORENZ等: "A New Indole Synthesis", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
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