CN109232583A - A kind of preparation method of bromo- 3H- pyrrolo- [2,1-f] [1,2,4] triazine -4- ketone of 6- - Google Patents
A kind of preparation method of bromo- 3H- pyrrolo- [2,1-f] [1,2,4] triazine -4- ketone of 6- Download PDFInfo
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- CN109232583A CN109232583A CN201811439262.2A CN201811439262A CN109232583A CN 109232583 A CN109232583 A CN 109232583A CN 201811439262 A CN201811439262 A CN 201811439262A CN 109232583 A CN109232583 A CN 109232583A
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- compound
- bromo
- pyrrolo
- triazine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
The invention belongs to pharmaceutical technology fields, and in particular to a kind of bromo- 3H- pyrrolo- [2,1-f] [1 of 6-, 2,4] preparation method of triazine -4- ketone (I), described method includes following steps: 2,5- dimethoxy-tetrahydrofurans and tertbutyloxycarbonyl hydrazine reaction obtain compound IV；It reacts to obtain compound V with trichloro-acetic chloride again；Compound VI is obtained through bromination；Compound VII is obtained through esterification；Finally cyclisation obtains bromo- 3H- pyrrolo- [2,1-f] [1,2,4] triazine -4- ketone of 6-.Compared with prior art, the present invention substantially increases the yield and purity of bromo- 3H- pyrrolo- [2,1-f] [1,2, the 4] triazine -4- ketone of 6-, reduces production cost, has good application value.
Description
Technical field:
The invention belongs to pharmaceutical technology fields, and in particular to bromo- 3H- pyrrolo- [2,1-f] [1,2, the 4] triazine -4- ketone of 6-
Preparation method.
Background technique:
Avapritinib (BLU-285) is a kind of oral small molecule medicine, is U.S. Blueprint Medicines public affairs
Highly selective 17 inhibitor of PDGFR α D842V and Kit Exon of the one kind researched and developed is taken charge of, the drug research is just located at present
In three phase of clinical research.
In June, 2017, Avapritinib obtain FDA and break through sex therapy identification, have PDGFR α D842V for treating
Mutation can not cut off or metastatic gastrointestinal stromal tumor (GIST) patient.Before this, FDA has authorized Avapritinib Orphan drug
Qualification, for treating gastrointestinal stromal tumor (GIST) and systemic mastocytosis (SM).
United States Patent (USP) US2018134728 disclose Avapritinib for treat relevant to KIT and PDGFR illness,
In addition the compound treats and prevents mastocytosis, gastrointestinal stromal tumor etc. by adjusting KIT activity.
Disclosed in United States Patent (USP) US20160031892 and US2017204104 the bromo- 3H- pyrrolo- [2,1-f] of 6- [1,2,
4] triazine -4- ketone is the raw material for synthesizing Avapritinib, bromo- 3H- pyrrolo- [2,1-f] [1,2, the 4] triazine -4- ketone of 6-, CAS
Number: 888721-83-3, molecular formula: C6H4BrN3O, molecular weight: 214.0, structural formula such as Formulas I.
United States Patent (USP) US 20160031892 and US2017204104 also disclose the bromo- 3H- pyrrolo- [2,1-f] of 6- [1,
2,4] preparation method of triazine -4- ketone, route is as shown in Scheme 1.
This method is obtained using the bromo- 1H- pyrroles -2- methyl formate of 4-, O- (two phenenyl phosphinyl)-azanol and formamide as raw material
To bromo- 3H- pyrrolo- [2,1-f] [1,2,4] triazine -4- ketone of 6-.The bromo- 1H- pyrroles -2- methyl formate price of starting material 4- is high
Expensive, synthesis cost is high, using a large amount of NaH, severe reaction conditions, and column chromatography is needed to be purified, total recovery is low.
Summary of the invention:
In order to overcome drawbacks described above present in the prior art, the invention discloses a kind of bromo- 3H- pyrrolo-es [2,1- of 6-
F] [1,2,4] triazine -4- ketone preparation method.
Concrete technology route is as follows:
For achieving the above object, The technical solution adopted by the invention is as follows:
Step a): compound II reacts to obtain compound IV with compound III；
Step b): compound IV reacts to obtain compound V with trichloro-acetic chloride；
Step c): compound V obtains compound VI through bromination；
Step d): compound VI obtains compound VII through esterification, and wherein R is Me, Et, i-Pr；
Step e): compound VII is cyclized to obtain compound I；
Further, step a) is to carry out in acid condition, and the acid is dilute hydrochloric acid.
Further, the organic solvent that step b) is used is selected from methyl tertiary butyl ether(MTBE), tetrahydrofuran, isopropyl ether, preferably
Methyl tertiary butyl ether(MTBE).
Further, the bromide reagent that bromination reaction described in step c) is selected is bromine, NBS, preferably bromine.
Further, esterification described in step d) be compound VI to sodium methoxide, sodium ethoxide, sodium isopropylate corresponding
Alcoholic solvent in reacted, preferably sodium methoxide.
Further, step d) is described that esterification carries out in corresponding alcoholic solvent, and the alcoholic solvent is methanol, second
Alcohol, isopropanol.
Further, cyclization described in step e) is that compound VII is reacted with formamidine acetate.
Further, cyclization described in step e) carries out under the high temperature conditions, and preferably 150~180 DEG C.
The invention has the advantages that:
Compared with prior art, the technology path that the present invention uses, low in cost, reaction condition is mild, avoids using strong
The biggish reagent of the danger coefficients such as alkali, environmentally protective, yield is higher, is suitble to industrialized production.
Detailed description of the invention
Fig. 1 compound IV's1HNMR figure
Fig. 2 compound V's1HNMR figure
Fig. 3 compound VI's1HNMR figure
Fig. 4 compound VII's1HNMR schemes (R=Me)
Fig. 5 compound I's1HNMR figure
Specific embodiment
Technology contents of the invention are further elaborated combined with specific embodiments below, its purpose is to better
Understand the contents of the present invention, but the scope of the present invention is not limited thereto.
The preparation of 1 compound IV of embodiment
Compound II (4.0g, 30.3mmol) and compound III (8.0g, 60.6mmol) is dissolved in 16mL NMP, then
1.5mL 2mmol/L HCl is slowly added thereto, 70 DEG C of reaction 20h are heated to.Reaction terminates, and cools the temperature to 20 DEG C, analysis
Clear yellow viscous solid out is stirred for loose, filtering.25mL MTBE is added into filter cake, stirs dissolved clarification, stratification, through nothing
Water magnesium sulfate dries organic phase, filters and is evaporated under reduced pressure to obtain crude product and is dried in vacuo for 24 hours, obtains compound IV 4.74g,
Yield is 85.9%.
The preparation of 2 compound V of embodiment
By compound IV (5g, 27.4mmol), sodium carbonate (4.35g, 41mmol) is added to molten in 50mL methyl tertiary butyl ether(MTBE)
Solution, 10 DEG C of reactions, then trichloro-acetic chloride (14.97g, 82.3mmol) is slowly added dropwise to wherein, room temperature reaction 28h terminates, mistake
Filter, extraction, is dried over anhydrous sodium sulfate organic phase, filters and is evaporated under reduced pressure to obtain brownish black oily and is directly used in next step.
The preparation of 3 compound VI of embodiment
The compound V (2g, 6.1mmol) that Example 2 obtains is dissolved in 20mL methylene chloride, is cooled to -10 DEG C, then
The bromine (1.33g, 8.32mmol) for being dissolved in DCM is added dropwise to and wherein reacts 0.5h, be quenched with 10% aqueous sodium carbonate and is incited somebody to action
PH is adjusted to 8, there is black solid precipitation, filters, and extraction is dried over anhydrous sodium sulfate organic phase, filters and be evaporated under reduced pressure to obtain
1.28g black solid product, yield 68.7%.
The preparation of 4 compound VII of embodiment
Compound VI (6.5g, 21.4mmol) is added in 65mL methanol and stirs dissolved clarification, at room temperature by 30% sodium methoxide
Solution (3.9g, 21.4mmol), which is added dropwise to wherein reaction 1h, to be terminated, and reaction solution is evaporated under reduced pressure to obtain dark oil object, is directly used
In feeding intake in next step.
The preparation of 5 compound VII of embodiment
Compound VI (6.5g, 21.4mmol) is added in 65mL ethyl alcohol and stirs dissolved clarification, ethyl alcohol will be dissolved at room temperature
Sodium ethoxide (2.9g, 42.8mmol), which is added dropwise to wherein reaction 1h, to be terminated, and reaction solution is evaporated under reduced pressure to obtain dark oil object, directly
For feeding intake in next step.
The preparation of 6 compound VII of embodiment
Compound VI (6.5g, 21.4mmol) is added in 65mL isopropanol and stirs dissolved clarification, isopropyl will be dissolved at room temperature
The sodium isopropylate (3.5g, 42.8mmol) of alcohol, which is added dropwise to wherein reaction 1h, to be terminated, and reaction solution is evaporated under reduced pressure to obtain dark oil
Object is directly used in and feeds intake in next step.
The preparation of 7 compound I of embodiment
Compound VII (4.5g, 0.02mol) obtained in embodiment 4 and formamidine acetate (11.2g, 0.11mol) are added
Into 250mL there-necked flask, 150 DEG C of reaction 1h are heated to, room temperature is cooled the temperature to after reaction, is then added to reaction solution
0.5h is stirred in 200mL ethyl acetate, is filtered, and extraction, vacuum distillation obtains 3.1g yellow solid, yield 69.9%.
The preparation of 8 compound I of embodiment
The compound VII (4.64g, 0.02mol) and formamidine acetate (11.2g, 0.11mol) that embodiment 5 is obtained are added
To 250mL there-necked flask；180 DEG C of reaction 1h are heated to, then cool the temperature to room temperature, reaction solution is then added to 200mL acetic acid second
0.5h is stirred in ester, is filtered, and extraction, vacuum distillation obtains 2.8g yellow solid, yield 65.7%.
Claims (8)
1. a kind of preparation method of bromo- 3H- pyrrolo- [2,1-f] [1,2, the 4] triazine -4- ketone (I) of compound 6-, feature exist
In described method includes following steps:
Step a): compound II reacts to obtain compound IV with compound III；
Step b): compound IV reacts to obtain compound V with trichloro-acetic chloride；
Step c): compound V obtains compound VI through bromination；
Step d): compound VI obtains compound VII through esterification, wherein R be Me, Et,i-Pr；
Step e): compound VII obtains compound I through cyclisation,
Specific route is as follows:
。
2. the method as described in claim 1, it is characterised in that: step a) is to carry out in acid condition, and the acid is dilute salt
Acid.
3. the method as described in claim 1, it is characterised in that: step b) is to react in organic solvent, and the solvent is selected from
Methyl tertiary butyl ether(MTBE), tetrahydrofuran, isopropyl ether.
4. the method as described in claim 1, it is characterised in that: bromination reaction described in step c) select bromine, NBS into
Row bromination.
5. the method as described in claim 1, it is characterised in that: esterification described in step d) is compound VI and first
Sodium alkoxide, sodium ethoxide, sodium isopropylate react in corresponding alcoholic solvent.
6. the method as described in claim 5, it is characterised in that: corresponding alcoholic solvent described in step d) be selected from methanol,
Ethyl alcohol, isopropanol.
7. the method as described in claim 1, it is characterised in that: cyclization described in step e) is compound VII and vinegar
Sour carbonamidine cyclization.
8. the method as described in claim 1, it is characterised in that: cyclization described in step e) is at 150 ~ 180 DEG C
It carries out.
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| CN201811439262.2A CN109232583A (en) | 2018-11-29 | 2018-11-29 | A kind of preparation method of bromo- 3H- pyrrolo- [2,1-f] [1,2,4] triazine -4- ketone of 6- |
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| CN201811439262.2A CN109232583A (en) | 2018-11-29 | 2018-11-29 | A kind of preparation method of bromo- 3H- pyrrolo- [2,1-f] [1,2,4] triazine -4- ketone of 6- |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1871215A (en) * | 2003-08-21 | 2006-11-29 | 布里斯托尔-迈尔斯·斯奎布公司 | Cyclic derivatives as modulators of chemokine receptor activity |
| CN101365454A (en) * | 2005-12-02 | 2009-02-11 | 拜尔健康护理有限责任公司 | Substituted 4-amino-pyrrolotriazine derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
| CN105658652A (en) * | 2013-10-17 | 2016-06-08 | 蓝图药品公司 | Compositions useful for treating disorders related to kit |
-
2018
- 2018-11-29 CN CN201811439262.2A patent/CN109232583A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1871215A (en) * | 2003-08-21 | 2006-11-29 | 布里斯托尔-迈尔斯·斯奎布公司 | Cyclic derivatives as modulators of chemokine receptor activity |
| CN101365454A (en) * | 2005-12-02 | 2009-02-11 | 拜尔健康护理有限责任公司 | Substituted 4-amino-pyrrolotriazine derivatives useful for treating hyper-proliferative disorders and diseases associated with angiogenesis |
| CN105658652A (en) * | 2013-10-17 | 2016-06-08 | 蓝图药品公司 | Compositions useful for treating disorders related to kit |
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