CN112028834B - Synthesis method of Abelide intermediate - Google Patents
Synthesis method of Abelide intermediate Download PDFInfo
- Publication number
- CN112028834B CN112028834B CN202010951939.1A CN202010951939A CN112028834B CN 112028834 B CN112028834 B CN 112028834B CN 202010951939 A CN202010951939 A CN 202010951939A CN 112028834 B CN112028834 B CN 112028834B
- Authority
- CN
- China
- Prior art keywords
- abelide
- synthesizing
- reaction
- abeli
- condensation reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
Abstract
The invention discloses a synthesis method of Abeli intermediate, which takes 5-bromo-3-fluoro-1, 2-phenylenediamine as initial raw material to carry out condensation reaction with acetic acid to obtain intermediate 1, and the intermediate 1 and acetone are used as reducing agentReacting at 0-80 ℃ to obtain 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D]Imidazole, an abbeli intermediate; the reaction route is shown as the following formula:
Description
Technical Field
The invention belongs to the field of drug synthesis, relates to a synthesis method of a drug intermediate, and particularly relates to a synthesis method of an Abeli intermediate.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
In recent years, breast cancer drugs that inhibit cyclin dependent kinases 4 and 6(CDK4/6) have received various attention and have become the field of great competitive development of various medicines, including palbociclib, Ribociclib (LEE011) and Abemaciclib (LY2835219), which are new drugs represented by three companies, namely, pyroxene, Nowa and Gift.
LY2835219 (Chinese name is Abelide, Bomacini, Aboxib, CAS number 1231929-97-7) is a potent, CDK4 and CDK6 selective inhibitor, is an orally potent cyclin-dependent kinase (CDK) inhibitor, targets CDK4(cyclin D1) and CDK6(cyclin D3) cell cycle pathways, and has potential antitumor activity. The incidence and mortality of breast cancer dominates worldwide female malignancies. In recent years, surgery, chemoradiotherapy, endocrine therapy and targeted therapy have made great progress in the treatment of breast cancer, but the mortality rate is still high. Therefore, exploring new therapeutic targets and developing new targeted drugs are the main research directions for individualized treatment of breast cancer. Cell cycle regulation plays a critical role in the development of breast cancer, and deregulation is one of the important mechanisms of tumor production and growth. The CDK4/6 inhibitor is the latest hotspot of the research of the current breast cancer targeted therapy drugs, Abeli is a new CDK4/6 inhibitor developed by the Li Lai company, the early-stage clinical experimental result of the drug is better, and the traditional Chinese medicine effect is obvious particularly on ER positive patients, so that the synthetic Abeli becomes the hotspot of various large medicine enterprises at present.
6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole is an intermediate for the synthesis of Abelide, and has the chemical formula:
patent document US20100160340 discloses that 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole is prepared by a three-step reaction using 4-bromo-2, 6-difluoroaniline and isopropylamine as starting materials, respectively:
the inventor researches and discovers that the two methods for preparing N-isopropylacetamide (s-1) related to the patent have complex operation and long reaction time, the reaction needs to be carried out overnight after the reaction is carried out at room temperature in the later period, the reaction is stirred overnight in the post-treatment, two solvents with low boiling points, namely dichloromethane and diethyl ether are used, the diethyl ether is easy to volatilize and self-ignite in summer, the solvent is not easy to recover, great potential safety hazard is caused, the yield is not high, and the method is not suitable for industrial scale-up production. In the process of preparing N-isopropyl acetamide from acetyl chloride and isopropylamine, the acetyl chloride is extremely unstable in air, can smoke, is inflammable, is difficult to avoid the processes of transferring and pumping in production, and has large using amount and large storage capacity, thereby causing potential safety hazards and bringing environmental protection pressure.
Meanwhile, the inventor also finds that S-1 related to the patent forms a chloroimine intermediate under the action of phosphorus oxychloride, receives nucleophilic attack of S-2 to obtain a compound S-3, extracts protons of the compound S-3 under the basic condition of potassium tert-butoxide/sodium, and obtains a benzimidazole compound S-4 through nucleophilic aromatic substitution reaction, the used solvents are various and need to be filtered frequently, particularly in the preparation process from S-3 to S-4, because of the affinity of potassium/sodium tert-butoxide, 4-position fluorine on the benzene ring is substituted, and a byproduct of the substitution of 4-position fluorine by tert-butoxy is generated, if the dosage of the potassium/sodium tert-butoxide is adjusted, the raw materials can not react completely, and the used solvent can not be recovered, so the method has high cost and complex operation and is not suitable for industrial scale-up production.
Patent CN201911210835.9 discloses that S-3 is extracted from free hydrogen protons on imine under the action of strong alkali and sodium hydride, intramolecular affinity substitution cyclization is carried out to synthesize S-4, and the obtained crude product is pulped with petroleum ether and filtered to obtain the finished product. The inventor researches and discovers that the patent relates to the use of sodium hydride, has high risk degree, causes great potential safety hazard due to spontaneous combustion explosion when meeting water, and is not suitable for industrial scale-up production.
Patent WO2019/102492A1 discloses that s-1 and s-2 are added with phosphorus oxychloride and triethylamine in a toluene solvent, the mixture is refluxed for 2-3h, water is added for adjusting pH in post-treatment, an organic phase is separated out, the organic phase is directly used for the next reaction after being concentrated, potassium hydroxide and dimethyl sulfoxide are added, the reflux is carried out, and water generated in the reaction needs to be continuously separated and removed. However, the inventor finds that the waste water COD and ammonia nitrogen of the dimethyl sulfoxide generated by the method are high, the waste water amount is large, certain pressure is brought to environmental protection, and the dimethyl sulfoxide cannot be recovered in the production, so that the cost is high.
Patent CN106467517A discloses a reaction from s-3 to s-4, which comprises adding potassium tert-butoxide by using anhydrous DMF as a solvent, heating to 110 ℃, reacting for 4h, and adding ethyl acetate and water for layering after the post-treatment. However, the inventors have found that this process has a large wastewater volume, high COD and ammonia nitrogen, low yield, and carries by-product impurities that are difficult to remove.
Disclosure of Invention
In order to solve the defects of the prior art, the invention aims to provide a synthesis method of an Abeli intermediate, which has the advantages of simpler operation, less three wastes and better guaranteed yield and product quality and is more suitable for industrial scale-up production.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a synthesis method of an Abeli intermediate comprises the steps of carrying out a condensation reaction on 5-bromo-3-fluoro-1, 2-phenylenediamine serving as an initial raw material and acetic acid to obtain an intermediate 1, and reacting the intermediate 1 with acetone at 0-80 ℃ under the action of a reducing agent to obtain 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole, namely the Abeli intermediate; the reaction route is shown as the following formula:
the invention takes 5-bromine-3-fluorine-1, 2-phenylenediamine as an initial raw material, firstly carries out condensation with acetic acid, then carries out reaction in acetone, obtains Abeli intermediate in two steps, and has short reaction route and high yield.
The invention has the beneficial effects that:
the raw materials adopted by the invention are conventional chemical raw materials, are low in price and easy to obtain, have less three wastes and high yield, and the total yield of the invention can reach more than 80% through experiments.
The method has simple purification process, and can obtain the Abeli intermediate with higher purity which can reach 99% only by washing and recrystallizing.
Detailed Description
It is to be understood that the following detailed description is exemplary and is intended to provide further explanation of the invention as claimed. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
In view of the defects of high cost of raw materials or reagents, long reaction route and the like of the existing method for preparing the Abeli intermediate, the invention provides a synthetic method of the Abeli intermediate.
The invention provides a typical embodiment of a synthesis method of an Abeli intermediate, which comprises the steps of carrying out condensation reaction on 5-bromo-3-fluoro-1, 2-phenylenediamine serving as a starting raw material and acetic acid to obtain an intermediate 1, and reacting the intermediate 1 with acetone at 0-80 ℃ under the action of a reducing agent to obtain 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole, namely the Abeli intermediate; the reaction route is shown as the following formula:
the invention takes 5-bromine-3-fluorine-1, 2-phenylenediamine as an initial raw material, firstly carries out condensation with acetic acid, then carries out reaction in acetone, obtains Abeli intermediate in two steps, and has short reaction route and high yield.
In some examples of this embodiment, the condensation reaction is at a temperature of 0 to 120 ℃. When the temperature of the condensation reaction is 90-110 ℃, the reaction speed is high, and the byproducts are less.
In some examples of this embodiment, the solvent for the condensation reaction is tetrahydrofuran, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO), toluene. The condensation reaction has better reaction effect at the temperature of 90-110 ℃, and when the solvent is toluene, the boiling point is higher, and the operation is simpler.
In some examples of this embodiment, intermediate 1 is prepared as an Abelide intermediate at a reaction temperature of 45-55 ℃. The reaction effect is better.
In some examples of this embodiment, the reducing agent for intermediate 1 to prepare an abbeli intermediate is potassium borohydride, sodium borohydride, potassium borohydride acetate, sodium borohydride acetate, or the like. When the reducing agent is sodium borohydride acetate, the effect is better.
In some examples of this embodiment, the material after the condensation reaction is washed with an aqueous solution of sodium carbonate and then a reducing agent is added to the washed organic phase to produce an abbe intermediate.
In one or more embodiments, the concentration of the aqueous sodium carbonate solution is 3-7%. % is mass percent.
In some examples of this embodiment, the purification steps in the preparation of the abbeli intermediate from intermediate 1 are: and (3) washing the reacted materials with water, and concentrating, recrystallizing and filtering the organic phase after washing with water.
In one or more embodiments, the organic solvent for recrystallization is an alkane, which is hexane, heptane, or petroleum ether, or a mixed solvent of an alkane and an alcohol. When the organic solvent for recrystallization is n-heptane, the purity of the obtained Abeli intermediate is better.
In one or more embodiments, the solvent of the organic phase after washing is removed, n-heptane is added for recrystallization, and the temperature is reduced to 5-10 ℃ for crystallization and filtration.
In one or more embodiments, the crystallization time is 1.5 to 2.5 hours.
In order to make the technical solutions of the present invention more clearly understood by those skilled in the art, the technical solutions of the present invention will be described in detail below with reference to specific embodiments.
Example 1
(1) Adding 300g (1.46mol) of 5-bromo-3-fluoro-1, 2-phenylenediamine serving as a raw material into a 2L clean four-neck bottle provided with a stirring device, a thermometer and a condensing tube, adding 600g of toluene, starting stirring until the materials are uniformly stirred, adding 105g (1.75mol) of acetic acid, heating in an oil bath until the materials are refluxed, the reflux temperature is 110 ℃, reacting for 2 hours, and monitoring the reaction by TLC (dichloromethane: methanol ═ 20: 1), cooling to 25 ℃ after the reaction is finished, adding 100g of 5% sodium carbonate aqueous solution, continuously stirring for 10 minutes, pouring into a separating funnel, standing for layering, adding 100g of 5% sodium carbonate aqueous solution after the water in the lower layer is separated out, shaking uniformly, standing for layering, and separating out an organic phase for later use. The product in the organic phase was analyzed by mass spectrometry as 6-bromo-4-fluoro-2-methyl-1H-benzo [ D ]]Imidazole. MS (ES)+)：M/Z＝292(M+H)+。
(2) Pouring the separated organic phase into a 2L clean four-mouth bottle with a stirrer, a thermometer and a condenser, adding 110g (1.90mol) of acetone, starting stirring, stirring uniformly, adding 340g (1.61mol) of sodium borohydride acetate in batches, heating to 50 ℃ in an oil bath, carrying out heat preservation reaction for 4h, monitoring the reaction by TLC, adding a developing agent (dichloromethane: methanol is 20: 1), cooling to room temperature after the reaction is finished, pouring into a separating funnel, separating water generated by the reaction, washing twice by 200g of water, concentrating the upper organic phase until the organic phase is dry to obtain a yellow solid which is a crude product, adding n-heptane with twice of the mass ratio to recrystallize, cooling to 5 ℃ for two hours of crystallization, and filtering to obtain 318g of a light yellow to white-like product, wherein the total yield is 80% and the purity of the liquid phase is 99%. MS (ES)+):M/Z＝272(M+H)+。
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A synthesis method of an Abeli intermediate is characterized in that 5-bromo-3-fluoro-1, 2-phenylenediamine is used as an initial raw material and is subjected to condensation reaction with acetic acid to obtain an intermediate 1, and the intermediate 1 and acetone are subjected to reaction at 0-80 ℃ under the action of a reducing agent to obtain 6-bromo-4-fluoro-1-isopropyl-2-methyl-1H-benzo [ D ] imidazole, namely the Abeli intermediate; the reaction route is shown as the following formula:
the reducing agent for preparing the Abelix intermediate from the intermediate 1 is potassium borohydride, sodium borohydride, potassium acetate borohydride or sodium acetate borohydride.
2. The method for synthesizing an Abelide intermediate as claimed in claim 1, wherein the condensation reaction temperature is 0 to 120 ℃.
3. The method for synthesizing an Abelide intermediate according to claim 1, wherein the solvent for the condensation reaction is tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide or toluene.
4. The method for synthesizing an Abelide intermediate as claimed in claim 1, wherein the reaction temperature for preparing the Abelide intermediate from the intermediate 1 is 45-55 ℃.
5. The method for synthesizing an Abeli intermediate according to claim 1, wherein the material after the condensation reaction is washed with an aqueous solution of sodium carbonate, and then a reducing agent is added to the washed organic phase to prepare the Abeli intermediate.
6. The method for synthesizing an Abelide intermediate as claimed in claim 5, wherein the concentration of the aqueous solution of sodium carbonate is 3 to 7%.
7. The method for synthesizing an abbeli intermediate as claimed in claim 1, wherein the purification step of the process for preparing the abbeli intermediate from the intermediate 1 comprises: and (3) washing the reacted materials with water, and concentrating, recrystallizing and filtering the organic phase after washing with water.
8. The method for synthesizing an Abelide intermediate according to claim 7, wherein the organic solvent for recrystallization is an alkane or a mixed solvent of an alkane and an alcohol, and the alkane is hexane, heptane or petroleum ether.
9. The method for synthesizing an Abelide intermediate as claimed in claim 7, wherein the solvent of the organic phase after water washing is removed, n-heptane is added, and the temperature is reduced to 5 to 10 ℃ for crystallization and filtration.
10. The method for synthesizing an Abelide intermediate as claimed in claim 9, wherein the crystallization time is 1.5 to 2.5 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010951939.1A CN112028834B (en) | 2020-09-11 | 2020-09-11 | Synthesis method of Abelide intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010951939.1A CN112028834B (en) | 2020-09-11 | 2020-09-11 | Synthesis method of Abelide intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112028834A CN112028834A (en) | 2020-12-04 |
| CN112028834B true CN112028834B (en) | 2022-03-29 |
Family
ID=73588579
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010951939.1A Active CN112028834B (en) | 2020-09-11 | 2020-09-11 | Synthesis method of Abelide intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112028834B (en) |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JO2885B1 (en) * | 2008-12-22 | 2015-03-15 | ايلي ليلي اند كومباني | Protein kinase inhibitors |
| JP5114610B1 (en) * | 2009-11-10 | 2013-01-09 | ファイザー・インク | N1-pyrazolospiroketone acetyl-CoA carboxylase inhibitor |
| JP2013510191A (en) * | 2009-11-10 | 2013-03-21 | ファイザー・インク | N-2 pyrazolospiroketone acetyl-CoA carboxylase inhibitor |
| MA52360A (en) * | 2018-04-26 | 2021-03-03 | Pfizer | 2-AMINO-PYRIDINE OR 2-AMINO-PYRIMIDINE DERIVATIVES USED AS CYCLINE-DEPENDENT KINASE INHIBITORS |
-
2020
- 2020-09-11 CN CN202010951939.1A patent/CN112028834B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN112028834A (en) | 2020-12-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108892669B (en) | Method for preparing 2-amino-6-chloropurine | |
| CN111470983B (en) | Preparation method of bromhexine hydrochloride | |
| CN103360410B (en) | Ofloxacine USP 23 preparation method | |
| CN111087394A (en) | Synthetic method of 2, 9-substituted 4-halo-1, 10-phenanthroline | |
| CN1679586A (en) | Novel synthesis and crystallization of piperazine ring-containing compounds | |
| CN112028834B (en) | Synthesis method of Abelide intermediate | |
| CN110903264B (en) | Method for preparing diazoxide | |
| CN106674084A (en) | Preparation method of 2-isopropoxy-5-methyl-4-(piperidine-4-yl) aniline dihydrochloride | |
| AU2016426847B2 (en) | Method for preparing deuterated imidazole diketone compound | |
| CN109761914B (en) | Method for preparing 5-trifluoromethyl uracil | |
| CN110698381A (en) | Method for synthesizing N- (benzyloxycarbonyl) succinimide by one-pot two-phase method | |
| CN113372336A (en) | Preparation method and application of brexpiprazole | |
| EP1619190B1 (en) | Salts of (2s,3s)-3- [[(1s)-1-isobutoxymethyl-3-methylbutyl]carbamoyl] oxirane-2-carboxylic acid | |
| CN111675710B (en) | Preparation method of duloxetine | |
| CN111747879A (en) | Large-process synthesis method of erexib | |
| CN111747874B (en) | Ericoxib intermediate and preparation method and application thereof | |
| EP1201656A1 (en) | Processes for the preparation of ipidacrine or ipidacrine hydrochloride hydrate | |
| JP4587529B2 (en) | Method for producing ipidacrine and ipidacrine hydrochloride hydrate | |
| CN112920114B (en) | Synthetic method of hydroxychloroquine sulfate | |
| EP2540717B1 (en) | Lamivudine oxalate and preparation method thereof | |
| CN111423437B (en) | Preparation method of palbociclib intermediate | |
| CN111747873B (en) | Ericoxib intermediate and preparation method and application thereof | |
| CN101555248A (en) | Method for preparing poly-substituted 1, 5-naphthyridine compound | |
| TWI685485B (en) | Processes to produce acalabrutinib | |
| CN117402163A (en) | Preparation method of reed-keatinib phosphate impurity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |