CN109053727B - Preparation method of ABT-199 intermediate - Google Patents
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- CN109053727B CN109053727B CN201811150333.7A CN201811150333A CN109053727B CN 109053727 B CN109053727 B CN 109053727B CN 201811150333 A CN201811150333 A CN 201811150333A CN 109053727 B CN109053727 B CN 109053727B
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- LQBVNQSMGBZMKD-UHFFFAOYSA-N venetoclax Chemical compound C=1C=C(Cl)C=CC=1C=1CC(C)(C)CCC=1CN(CC1)CCN1C(C=C1OC=2C=C3C=CNC3=NC=2)=CC=C1C(=O)NS(=O)(=O)C(C=C1[N+]([O-])=O)=CC=C1NCC1CCOCC1 LQBVNQSMGBZMKD-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229960001183 venetoclax Drugs 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- LPTVWZSQAIDCEB-UHFFFAOYSA-N 5-bromo-1h-pyrrolo[2,3-b]pyridine Chemical compound BrC1=CN=C2NC=CC2=C1 LPTVWZSQAIDCEB-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 14
- KBLGGRWUEVCNPY-UHFFFAOYSA-N 5-bromo-3-methylpyridin-2-amine Chemical compound CC1=CC(Br)=CN=C1N KBLGGRWUEVCNPY-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims description 28
- -1 5-bromo-3-methylpyridin-2-yl Chemical group 0.000 claims description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 14
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 claims description 12
- 238000001035 drying Methods 0.000 claims description 12
- 238000001704 evaporation Methods 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 11
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 5
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 5
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 9
- 238000006555 catalytic reaction Methods 0.000 abstract description 3
- 229910001385 heavy metal Inorganic materials 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 description 11
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 10
- 239000002904 solvent Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000002378 acidificating effect Effects 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- DHPKTHROZFIEJK-UHFFFAOYSA-N 5-bromo-1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound BrC1=CN=C2NC(=O)CC2=C1 DHPKTHROZFIEJK-UHFFFAOYSA-N 0.000 description 1
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 1
- 208000003950 B-cell lymphoma Diseases 0.000 description 1
- 208000002250 Hematologic Neoplasms Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 125000005489 p-toluenesulfonic acid group Chemical group 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pyridine Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a preparation method of an ABT-199 intermediate, namely a preparation method of 5-bromo-7-azaindole. Specifically, 2-amino-3-methyl-5-bromopyridine is used as an initial raw material to finally synthesize the 5-bromo-7-azaindole in three steps. The preparation method has mild reaction conditions, is easy to operate, does not need anhydrous and anaerobic operation, does not need high temperature and high pressure, and has high safety; the yield of the reaction steps is high; the raw materials are easy to obtain, and the cost is low; the catalytic reaction is carried out without adopting heavy metal; the production process can realize industrialization and can carry out hundred-kilogram production.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a preparation method of an ABT-199 intermediate.
Background
Ebervix announced in 2015 that a new drug developed for treating chronic lymphocytic leukemia, venetocalax (ABT-199), obtained breakthrough drug certification by FDA. The drug is an experimental B cell lymphoma factor-2 (BCL-2) inhibitor. ABT-199/venetocalax showed high response rates as single drug in refractory/relapsed CLL. In particular, high CR rates were shown in refractory/relapsed CLL (29% as single agent combined with rituximab 39%). ABT-199 is therefore prone to a broad spectrum of new hematological malignancies either as an effective single agent or in combination with other drugs. 5-bromo-7-azaindole is a key intermediate for synthesizing a novel drug venetoclax (ABT-199).
In the prior art, e.g. WO2004/78757,2004, A2; CN106045995,2016, a; U.S. Pat. No. 5,2011, 28511,2011,A1 describes processes for the preparation of venetocalax (ABT-199) and intermediates thereof. However, there are generally 3 main processes for the preparation of 5-bromo-7-azaindole: 1. the method is an oxidation reaction, and 5-bromo-2, 3-dihydro-1H-pyrrolyl [2,3-B ] pyridine is oxidized into 5-bromo-7-azaindole, so that the method has the advantages of long oxidation reaction period, generally 5-7 days, easiness in incomplete reaction, low yield, large amount of wastewater generated in the oxidation process and great pressure on environmental protection; 2. the 5-bromo-7-azaoxindole is used for reduction synthesis, a reducing agent such as borane or metal hydride is needed in the reduction reaction, the reaction is not easy to control, and the method is not suitable for industrial production; 3. the pyridine alkynyl compound is subjected to intramolecular ring closure, firstly, the synthesis of the pyridine alkynyl compound adopts metal catalytic reaction and has heavy metal pollution, secondly, the ring closure usually adopts high-pressure autoclave pressurization to promote the production of products, and the high-pressure reaction and related operation have high risk and are not beneficial to industrial production.
Disclosure of Invention
The invention aims to provide a simple, safe and easily-amplified preparation method of an ABT-199 intermediate, namely 5-bromo-7-azaindole.
The invention provides a preparation method of an ABT-199 intermediate, wherein the ABT-199 intermediate is 5-bromo-7-azaindole, and the preparation method comprises the following steps:
(1) synthesis of ethyl (E) -N- (5-bromo-3-methylpyridin-2-yl) carboxylate, the reaction scheme is as follows:
(2) synthesis of (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-formimino phenyl ester, reaction formula:
(3) the synthesis of 5-bromo-7-azaindole has the following reaction formula:
alternatively, the process for preparing the ABT-199 intermediate comprises the steps of:
(1) adding 2-amino-3-methyl-5-bromopyridine, trimethyl orthoformate, an acidic catalyst and a first solvent into a reaction kettle, heating and stirring until reflux, reacting for 16 hours, adding water and stirring after the raw materials react, separating liquid, drying an organic phase, and evaporating to remove the organic solvent to obtain (E) -N- (5-bromo-3-methylpyridin-2-yl) ethyl formiate;
(2) adding (E) -N- (5-bromo-3-methylpyridin-2-yl) ethyl formiate, N-methylaniline and a second solvent into a reaction kettle, heating to 60 ℃, stirring for 16 hours, adding water for stirring after the raw materials react, separating liquid, drying an organic phase, and evaporating to remove the organic solvent to obtain (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-ethyl formiate phenyl ester;
(3) adding (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-phenylformiate and a third solvent into a reaction kettle, cooling to 10 ℃, stirring, adding a strong base, controlling the temperature to be not more than 15 ℃, stirring for 16 hours after the addition is finished, adding water and stirring after the reaction of the raw materials is finished, separating liquid, drying an organic phase, evaporating the organic solvent, and recrystallizing to obtain 5-bromo-7-azaindole;
wherein the acidic catalyst is p-toluenesulfonic acid, acetic acid, sulfuric acid or phosphoric acid; the first solvent is 1, 2-dichloromethane, dioxane, tetrahydrofuran or acetonitrile; the second solvent is toluene, xylene or chlorobenzene; the third solvent is ethylene glycol dimethyl ether, dioxane or tetrahydrofuran; the strong base is sodium amide, sodium hydride, sodium tert-butoxide or potassium tert-butoxide.
Alternatively, in step (1), the molar ratio of the 2-amino-3-methyl-5-bromopyridine to the trimethyl orthoformate to the acidic catalyst is 1: (0.001-0.003): (2-4).
Alternatively, in step (2), the molar ratio of the (E) -ethyl N- (5-bromo-3-methylpyridin-2-yl) carboxylate to N-methylaniline is 1: (1-2).
Alternatively, in step (3), the molar ratio of the phenyl (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-carboxylate to the strong base is 1: (1-1.2).
Alternatively, the process for preparing the ABT-199 intermediate comprises the steps of:
(1) adding 1000mol of 2-amino-3-methyl-5-bromopyridine, 2mol of p-toluenesulfonic acid, 3000mol of trimethyl orthoformate and 950L of 1, 2-dichloromethane into a reaction kettle, heating and stirring until reflux, reacting for 16 hours, adding water and stirring after the raw materials react, separating liquid, drying an organic phase, and evaporating to remove an organic solvent to obtain (E) -N- (5-bromo-3-methylpyridin-2-yl) ethyl formate;
(2) adding 500mol (E) -ethyl N- (5-bromo-3-methylpyridin-2-yl) formate imine, 750mol N-methylaniline and 750L toluene into a reaction kettle, heating to 60 ℃, stirring for 16 hours, adding water and stirring after the raw materials react, separating liquid, drying an organic phase, and evaporating to remove an organic solvent to obtain (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-phenylformate imine;
(3) adding 100mol of (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-phenylimino formate and 300L of ethylene glycol dimethyl ether into a reaction kettle, cooling to 10 ℃, stirring, adding 110mol of sodium amide, controlling the temperature to be not more than 15 ℃, stirring for 16 hours after the addition is finished, adding water and stirring after the reaction of the raw materials is finished, separating liquid, drying an organic phase, evaporating to remove the organic solvent, and recrystallizing to obtain the 5-bromo-7-azaindole.
The invention has the following beneficial effects:
(1) the method has mild reaction conditions, is easy to operate, does not need anhydrous and anaerobic operation, does not need high temperature and high pressure, and has high safety;
(2) the yield of the reaction steps is high;
(3) the invention has the advantages of easily obtained reaction raw materials and low cost;
(4) the reaction of the invention does not need to adopt heavy metal to carry out catalytic reaction;
(5) the production process can realize industrialization and can carry out hundred-kilogram production.
It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The synthetic route of the ABT-199 intermediate, namely 5-bromo-7-azaindole provided by the invention is as follows
Example 1
(1) Synthesis of ethyl (E) -N- (5-bromo-3-methylpyridin-2-yl) carboxylate
Adding 2-amino-3-methyl-5-bromopyridine (185kg, 1000mol), p-toluenesulfonic acid (3.44kg, 2mol), trimethyl orthoformate (318kg, 3000mol) and 1, 2-dichloromethane (950L) into a reaction kettle, heating and stirring until refluxing are carried out, reacting for 16 hours, adding water and stirring after the raw materials are reacted, separating liquid, drying an organic phase, and evaporating to remove an organic solvent to obtain (E) -N- (5-bromo-3-methylpyridin-2-yl) ethyl formiate (205.4kg, 84.4mol) with the yield of 84.4%.
(2) Synthesis of (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-formimino phenyl ester
Adding (E) -ethyl N- (5-bromo-3-methylpyridin-2-yl) formiminium formate (121kg, 500mol), N-methylaniline (160.5kg, 750mol) and toluene (750L) into a reaction kettle, heating to 60 ℃, stirring for 16 hours, adding water and stirring after the raw materials react, separating liquid, drying an organic phase, and evaporating to remove an organic solvent to obtain (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-formiminium phenyl ester (1331.5kg, 438mol) with the yield of 87.6%.
(3) Synthesis of 5-bromo-7-azaindole
Adding (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-phenylimino formate (30.4kg, 100mol) and ethylene glycol dimethyl ether (300L) into a reaction kettle, cooling to 10 ℃, stirring, adding sodium amide (4.29kg, 110mol), controlling the temperature to be not more than 15 ℃, stirring for 16 hours after the addition is finished, adding water, stirring, separating, drying an organic phase, evaporating an organic solvent, and recrystallizing to obtain the 5-bromo-7-azaindole (16.5kg, 83.7mol) with the yield of 87.6%.
1H NMR(CDCl3,400MHz)δ6.46(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 above examples, the acidic catalyst may be acetic acid, sulfuric acid or phosphoric acid in addition to p-toluenesulfonic acid. The first solvent may be dioxane, tetrahydrofuran or acetonitrile in addition to 1, 2-dichloromethane. The second solvent may be xylene or chlorobenzene, in addition to toluene. The third solvent may be dioxane or tetrahydrofuran in addition to ethylene glycol dimethyl ether. The strong base can be sodium hydride, sodium tert-butoxide or potassium tert-butoxide besides sodium amide, and is used for ring closure after hydrogen is removed.
In addition, in the step (1), the molar ratio of the 2-amino-3-methyl-5-bromopyridine to the trimethyl orthoformate to the acidic catalyst is 1: (0.001-0.003): (2-4). In the step (2), the molar ratio of (E) -N- (5-bromo-3-methylpyridin-2-yl) ethyl iminecarboxylate to N-methylaniline is 1: (1-2). In the step (3), the molar ratio of (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-phenylformiate to strong base is 1: (1-1.2).
Under the conditions, the ABT-199 intermediate, namely 5-bromo-7-azaindole can be prepared, and the yield is higher than 80%.
The preparation method has the advantages of few reaction steps, easy operation and high yield of the reaction steps; the reaction condition is mild, no anhydrous and anaerobic operation is needed, high temperature and high pressure are not needed, the safety is high, the production process can realize industrialization, hundred-kilogram-level production can be carried out, and higher product yield is ensured.
The above-described embodiments of the present invention should not be construed as limiting the scope of the present invention.
Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the disclosure herein. This invention is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.
Claims (1)
1. A preparation method of an ABT-199 intermediate is characterized by comprising the following steps:
(1) adding 1000mol of 2-amino-3-methyl-5-bromopyridine, 2mol of p-toluenesulfonic acid, 3000mol of triethyl orthoformate and 950L of 1, 2-dichloromethane into a reaction kettle, heating and stirring until reflux, reacting for 16 hours, adding water and stirring after the raw materials react, separating liquid, drying an organic phase, and evaporating to remove an organic solvent to obtain (E) -N- (5-bromo-3-methylpyridin-2-yl) ethyl formate;
(2) adding 500mol (E) -ethyl N- (5-bromo-3-methylpyridin-2-yl) formate imine, 750mol N-methylaniline and 750L toluene into a reaction kettle, heating to 60 ℃, stirring for 16 hours, adding water and stirring after the raw materials react, separating liquid, drying an organic phase, and evaporating to remove an organic solvent to obtain (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-phenylformate imine;
(3) adding 100mol of (E) -N' - (5-bromo-3-methylpyridin-2-yl) -N-methyl-N-phenylimino formate and 300L of ethylene glycol dimethyl ether into a reaction kettle, cooling to 10 ℃, stirring, adding 110mol of sodium amide, controlling the temperature to be not more than 15 ℃, stirring for 16 hours after the addition is finished, adding water and stirring after the reaction of the raw materials is finished, separating liquid, drying an organic phase, evaporating to remove the organic solvent, and recrystallizing to obtain the 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- |
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