CN111362854B - Preparation method of ralotinib intermediate - Google Patents
Preparation method of ralotinib intermediate Download PDFInfo
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- CN111362854B CN111362854B CN202010365061.3A CN202010365061A CN111362854B CN 111362854 B CN111362854 B CN 111362854B CN 202010365061 A CN202010365061 A CN 202010365061A CN 111362854 B CN111362854 B CN 111362854B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Abstract
The invention discloses a preparation method of a ralotinib intermediate, belonging to the field of drug synthesis, wherein 4-chloro-1- (2, 5-difluorophenyl) butan-1-one (I) is used as a raw material to obtain 4-amino-1- (2, 5-difluorophenyl) butan-1-one hydrochloride (II) through a Delbin reaction, and intramolecular cyclization is performed under an alkaline condition to obtain 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (III). The method has mild reaction conditions and simple operation, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of drug synthesis, and relates to a synthesis method of an antitumor drug Lalotinib intermediate 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (III).
Background
Larotrectinib (LOXO-101) is sold as Vitrakvi, and Chinese translation name is: erlotinib or erlotinib, which is an ATP-competitive, orally selective inhibitor, has a nanomolar 50% inhibitory concentration for three subtypes (TRKA, B and C) of tropomyosin-associated kinase (TRK) family of receptors. 11/27 of 2018, FDA accelerated approval for the co-developed pan-cancer-targeted drug vitrakvi (larotretinib) by Bayer and Loxo Oncology for marketing in adult and pediatric patients with locally advanced or metastatic solid tumors carrying NTRK gene fusion.
The action mechanism is as follows: is a Tropomyosin Receptor Kinase (TRK) inhibitor, can highly specifically inhibit three proteins of TRKA, TRKB and TRKC, and has an effect on tumor patients with TRK fusion variation.
Dosage form and specification: capsules, 25 and 100 mg.
Adverse reactions: fatigue, nausea, dizziness, vomiting, elevated AST, cough, elevated ALT, constipation and diarrhea.
Ralotinib formula: c21H22F2N6O2Molecular weight: 428.4, CAS: 1223403-58-4, chemical name: (3S) -N- [5- [ (2R) -2- (2, 5-difluorophenyl) -1-pyrrolidineBase of]Pyrazolo [1,5-A]Pyrimidin-3-yl]-3-hydroxy-1-pyrrolidinecarboxamide, having the following chemical formula:
wherein 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (III) is an important intermediate for synthesizing the ralotinib, and the chemical structural formula is shown as follows:
patent WO2009140128A2 relates to a synthesis method of 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (III), and a specific synthetic route is shown as follows:
the process is a simple and feasible route, but the reaction of the first step needs to be carried out at ultralow temperature of-78 ℃, the reaction conditions are harsh, and the price of the N-Boc-2-pyrrolidone is high, so that the route has high production cost and large industrial implementation difficulty.
Chinese patent CN108794370A reports a synthesis process of obtaining 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (III) from 4-chloro-1- (2, 5-difluorophenyl) butan-1-one (I) through an azidation reaction and a staudinger reaction, and the specific synthetic route is as follows:
the method is a brand new synthesis route, but virulent sodium azide is used in the azidation reaction, and meanwhile, the sodium azide is explosive, triphenylphosphine is used in the Staudinger reaction, and a byproduct triphenylphosphine oxide is difficult to remove, so that great difficulty is caused in the purification of a product.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a synthetic method of a synthetic ralotinib intermediate 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (III).
The invention takes 4-chloro-1- (2, 5-difluorophenyl) butan-1-one (I) as a raw material to obtain 4-amino-1- (2, 5-difluorophenyl) butan-1-one hydrochloride (II) through a Delbin reaction, and the 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (III) is obtained through intramolecular cyclization under an alkaline condition, wherein the specific synthetic route is as follows:
s1: adding the compound I, urotropine and a catalyst into a three-necked flask, adding a solvent, reacting for 4 hours at 35-55 ℃, cooling to room temperature of 20-25 ℃ after TLC (thin layer chromatography) controlled reaction is finished, generating a large amount of solid, dropwise adding concentrated hydrochloric acid, continuing stirring for reacting for 2-3 hours after the dropwise adding is finished, clarifying the system, stirring overnight, precipitating a large amount of solid, filtering, and drying to obtain a white solid, namely 4-amino-1- (2, 5-difluorophenyl) butan-1-one hydrochloride (II).
S2: adding 4-amino-1- (2, 5-difluorophenyl) butan-1-one hydrochloride (II) into a three-necked bottle, adding a mixed solvent, adding alkali in batches under the stirring state, raising the temperature to a certain temperature for reacting for 3-4 hours, controlling the reaction in TLC, concentrating the solvent, adding ethyl acetate and water, layering, drying, and concentrating an organic phase to obtain a colorless or pale yellow oily substance, namely 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (III).
In step S1, the solvent is one or more of methanol, ethanol, isopropanol, and tert-butanol, preferably the solvent is ethanol; the solvent amount is 3-5 times, preferably 4 times of the mass of the compound I; the catalyst is one of potassium iodide and sodium iodide, and the dosage of the catalyst is 5-10% of the mass of the compound I; the molar ratio of the compound I to the urotropine is 1:1.0-1.3, and the preferable molar ratio is 1: 1.2.
In step S2, the alkali is one or more of potassium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide, preferably potassium carbonate; the molar ratio of the compound (II) to the base is 1: 2-2.5; the mixed solvent is a mixture of water and an organic solvent, wherein the volume ratio of the water to the organic solvent is 1:4, the organic solvent is one of methanol, ethanol, tetrahydrofuran, 1, 4-dioxane and acetonitrile, and the mixed solvent is preferably tetrahydrofuran/water; the reaction temperature is 50-60 ℃.
The invention has the beneficial effects that:
the method comprises the steps of taking 4-chloro-1- (2, 5-difluorophenyl) butan-1-one (I) as a raw material, carrying out a Delbin reaction to obtain 4-amino-1- (2, 5-difluorophenyl) butan-1-one hydrochloride (II), and carrying out intramolecular cyclization under an alkaline condition to obtain 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (III). The invention discloses a synthesis method of a ralotinib intermediate, which has the advantages of mild reaction conditions, simplicity in operation, high safety, reduction in production cost and suitability for industrial production.
Detailed Description
Example 1:
preparation of 4-amino-1- (2, 5-difluorophenyl) butan-1-one hydrochloride (II):
adding 50g of 4-chloro-1- (2, 5-difluorophenyl) butan-1-one (1eq) (purchased from Shanghai Haohnhong biomedical science and technology Co., Ltd.), 35g of urotropine (1.1eq), 5g of potassium iodide (10%), adding 300mL of ethanol, reacting at 50 ℃ for 4 hours, after TLC (thin layer chromatography) is finished, cooling to room temperature of 20-25 ℃, generating a large amount of solid, slowly adding 95mL of concentrated hydrochloric acid (5eq, 12M), after finishing adding, continuously stirring and reacting for 2-3 hours, the system becomes clear, is stirred overnight, a large amount of solid is separated out, filtered and dried to obtain 50g of white solid, i.e. 4-amino-1- (2, 5-difluorophenyl) butan-1-one hydrochloride (II), was directly put into the next reaction without further purification.
Preparation of 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (III):
50g (1eq) of 4-amino-1- (2, 5-difluorophenyl) butan-1-one hydrochloride (II) is added into a 500mL three-necked flask, 200mL of a mixed solvent of tetrahydrofuran/water (volume ratio 4:1) is added, 32g (2.5eq) of potassium carbonate is added in portions under stirring, the temperature is raised to 55 ℃, the reaction is carried out for 3-4 hours, the TLC is used for controlling the reaction to be finished, the solvent is concentrated, ethyl acetate and water are added, the layers are separated, dried and the organic phase is concentrated to obtain 38g of colorless or light yellow oily matter, namely 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (III), and the total yield of the two steps is 91%.
Example 2:
preparation of 4-amino-1- (2, 5-difluorophenyl) butan-1-one hydrochloride (II):
adding 200g of 4-chloro-1- (2, 5-difluorophenyl) butan-1-one (1eq) (purchased from Shanghai Haohnhong biomedical science and technology Co., Ltd.), 128g of urotropine (1eq) and 10g of potassium iodide (5%), adding 1.2L of ethanol, reacting at 50 ℃ for 4h, after TLC is performed, cooling to room temperature of 25 ℃ and a large amount of solid is generated, slowly adding 380mL (5eq) of concentrated hydrochloric acid (12M), stirring for 2h after the dropwise addition is completed, clarifying the system, stirring overnight, precipitating a large amount of solid, filtering, drying to obtain 190g of white solid, namely 4-amino-1- (2, 5-difluorophenyl) butan-1-one hydrochloride (II), and directly putting the mixture into the next reaction without further purification.
Preparation of 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (III):
190g (1eq) of 4-amino-1- (2, 5-difluorophenyl) butan-1-one hydrochloride (II) is added into a 2L three-necked flask, 800mL of a mixed solvent of tetrahydrofuran/water (volume ratio 4:1) is added, 97g (2eq) of potassium carbonate is added in portions under stirring, the temperature is raised to 60 ℃, the reaction is carried out for 4 hours, the TLC is controlled to be finished, the solvent is concentrated, ethyl acetate and water are added, layers are separated, the organic phase is dried and concentrated, 147g of colorless or pale yellow oily matter is obtained, namely 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (III), and the total yield of the two steps is 88%.
Example 3:
preparation of 4-amino-1- (2, 5-difluorophenyl) butan-1-one hydrochloride (II):
50g of 4-chloro-1- (2, 5-difluorophenyl) butan-1-one (1eq) (available from Haohnhong, Shanghai, Bio-medicine technology Co., Ltd.) and 35g of urotropin (1.1eq) were added to a 500mL three-necked flask, without catalyst, 300mL of ethanol was added, the reaction was carried out at 50 ℃ for 10 hours, and the unreacted reaction was controlled by TLC.
Preparation of 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (III):
adding 50g (1eq) of 4-amino-1- (2, 5-difluorophenyl) butan-1-one hydrochloride (II) into a 500mL three-necked bottle, adding 200mL of a mixed solvent of tetrahydrofuran and water (volume ratio is 1:1), adding 19.2g (1.5eq) of potassium carbonate in batches under stirring, reacting for 4 hours at room temperature of 25 ℃, controlling the residual 55% of raw materials in a liquid phase, prolonging the reaction time to 10 hours, controlling the residual 50% of raw materials in the liquid phase, and continuing to prolong the time without change.
Although the present invention has been described with reference to the specific embodiments, it should be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention.
Claims (1)
1. A preparation method of a ralotinib intermediate 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (III) comprises the following steps:
s1, reacting 4-chloro-1- (2, 5-difluorophenyl) butan-1-one (I) under the action of a catalyst to obtain 4-amino-1- (2, 5-difluorophenyl) butan-1-one hydrochloride (II), wherein the solvent in the step S1 is one or more of methanol, ethanol, isopropanol and tert-butanol, the amount of the solvent is 3-5 times of the mass of the compound I, and the catalyst is one of potassium iodide and sodium iodide, and the using amount of the catalyst is 5% -10% of the mass of the compound I;
s2, carrying out intramolecular ring closure reaction on 4-amino-1- (2, 5-difluorophenyl) butan-1-one hydrochloride (II) to obtain 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (III); the alkali adopted in the step S2 is one or more of potassium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide, the molar ratio of the compound (II) to the alkali is 1:2-2.5, the mixed solvent is a mixture of water and an organic solvent, and the volume ratio of the water to the organic solvent is 1: 4;
the compound (II) in the step S1 is obtained by carrying out a Delbin reaction on the compound (I) and urotropine;
the mixed solvent in the step S2 is tetrahydrofuran/water.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018165520A1 (en) * | 2017-03-10 | 2018-09-13 | Vps-3, Inc. | Metalloenzyme inhibitor compounds |
| CN109310694A (en) * | 2016-04-04 | 2019-02-05 | 洛克索肿瘤学股份有限公司 | The method for treating Paediatric cancer |
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| KR20120034644A (en) * | 2009-05-12 | 2012-04-12 | 알바니 몰레큘라 리써치, 인크. | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109310694A (en) * | 2016-04-04 | 2019-02-05 | 洛克索肿瘤学股份有限公司 | The method for treating Paediatric cancer |
| WO2018165520A1 (en) * | 2017-03-10 | 2018-09-13 | Vps-3, Inc. | Metalloenzyme inhibitor compounds |
Non-Patent Citations (1)
| Title |
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| Cellular Localisation of Antitumoral 6-Alkyl Thymoquinones Revealed by an Alkyne–Azide Click Reaction and the Streptavidin–Biotin System;Katharina Effenberger-Neidnicht et al.;《ChemBioChem》;20110415;第12卷(第8期);第1237-1241页 * |
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