KR101934096B1 - Method for preparing idelalisib - Google Patents
Method for preparing idelalisib Download PDFInfo
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- KR101934096B1 KR101934096B1 KR1020177007729A KR20177007729A KR101934096B1 KR 101934096 B1 KR101934096 B1 KR 101934096B1 KR 1020177007729 A KR1020177007729 A KR 1020177007729A KR 20177007729 A KR20177007729 A KR 20177007729A KR 101934096 B1 KR101934096 B1 KR 101934096B1
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- amino
- reaction
- purin
- substitution reaction
- sodium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
Abstract
The present invention relates to a process for the preparation of Idelalisib I wherein R-2-hydroxybutyrate (II) and 6-amino-9H-purine (6- amino-9H-purine) is reacted with an intermediate S-2- (N-9H-purin-6-yl) amino butyrate (S-2- (III) and 2-formic acid-3-fluoroaniline are converted to S-2- (N-aminobutyrate (III) 6-yl) amino-N- (2-formyl-3-fluorophenyl) butyramide (IV) (I) is obtained by proceeding a cyclization reaction with acetic anhydride, followed by a substitution reaction with phenylamine, to produce 2-formic acid-3-fluorophenyl butyramide (IV) The manufacturing method of the present invention is characterized in that it is easy to obtain the raw material, the process is simple and economical, Not only environmental, but also suitable for mass production.
Description
The present invention relates to the field of organic synthesis pathway design and its raw materials and intermediates production technology, and more particularly, to a method for the preparation of this drug, a drug for the treatment of chronic lymphocytic leukemia.
Idelalisib is a phosphoinositide 3-kinase (PI3K) inhibitor developed by Icos Corporation, Gilead Sciences, USA. The drug was approved by the US Food and Drug Administration in July 2014 and was approved for use in patients with chronic lymphocytic leukemia (CLL) recurred by combination therapy with Rituximab, a type 3 B cell leukemia, It is used to treat non-Hodgkin's lymphoma (FL) and recurrent small lymphocytic lymphoma (SLL), the trade name is Zydelig. Since the drug has not yet been standardized in the Chinese translation designation, the applicant here uses it to translate it into " This deliriousness ".
The chemical name of Idelalisib is 5-fluoro-3-phenyl-2 - [(1S) -1- (9H-purin-6-ylamine) propyl] -4- (3H) -quinazolinone (I) (5-Fluoro-3-phenyl-2 - [(1S) -1- (1H-purin-6-ylamino) propyl] -4 (3H) -quinazolinone).
Methods for the preparation of this delalisy have already been investigated and disclosed, in particular, the method of synthesizing delalissis and analogues thereof, PCT application WO2005113554 of the United States of America. This method first synthesizes a quinazolinone ring to obtain an intermediate and a bromine purine bond, followed by preparation of the edelarylate (I).
As can be seen from the above, the above-mentioned preparation method is a method for synthesizing the delalisy, which is synthesized first and identifies the compound. However, there are some process combinations or weaknesses in the process. For example, it is difficult to obtain a raw material such as 6-bromine-purine, and amino in S-2-aminobutyric acid must be protected and deprotected, and acylation reaction of thionyl chloride with S- The bromination reaction of 6-bromine-purine pollutes the environment because it produces wastewater containing chlorine and bromine. In addition, since the process studies on the delaligy so far are very few, it is possible to promote the mass production of the above-mentioned raw materials by economically, economically, eco-friendly, There is a need to improve social utility.
An object of the present invention is to propose a manufacturing method of an edulary slurry which is easy to obtain a raw material, is simple in process, economical and environmentally friendly, and is suitable for mass production.
In order to achieve the above object, the present invention adopts the following main technical scheme. In the method of manufacturing the delalith (I)
R-2-hydroxybutyrate (II) and 6-amino-9H-purine were subjected to nucleophilic substitution reaction under the action of a releasing agent and an acid binding agent. (S-2- (N-9H-purin-6-yl) aminobutyrate (III)) as an intermediate S- 2- (N-9H-purin-6-yl) aminobutyrate (III) and 2-formic acid-3-fluoroaniline are reacted with an intermediate S- (N-9H-purin-6-yl) amino-N- (2-formic acid-3-fluorophenyl) butyramide (IV) (N-9H-purin-6-yl) amino-N- (2-formic acid-3-fluorophenyl) butyramide (IV) Phenyl) butyramide (IV) undergoes a cyclization reaction in acetic anhydride, followed by a substitution reaction with phenylamine to obtain the indolyl group (I).
The present invention further proposes the following additional technical measures,
The ester group (R 1 ) in the raw material R-2-hydroxybutyrate (II) is an aliphatic hydrocarbon group of 1 to 10 carbon atoms, a phenyl group or a benzyl group, preferably a methyl group or an ethyl group.
The raw material introduction molar ratio of the nucleophilic substitution reaction raw material R-2-hydroxybutyrate (II) and 6-amino-9H-purine is 1: 0.5 to 1.5, preferably 1: 0.8 to 1.2, Is 1: 1.
The release agent for the nucleophilic substitution reaction may be selected from the group consisting of methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride and trifluoromethanesulfonyl chloride. , Preferably methanesulfonyl chloride or p-toluenesulfonyl chloride.
The acid binding agent of the nucleophilic substitution reaction may be triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine or 4-dimethylaminopyridine. ), Preferably triethylamine or diisopropylethylamine.
The solvent for the nucleophilic substitution reaction is dichloromethane, 1,2-dichloromethane, chloroform, tetrahydrofuran or N, N-dimethylformamide, preferably dichloromethane Or N, N-dimethylformamide.
The temperature of the nucleophilic substitution reaction is 0 to 60 캜, preferably 10 to 30 캜.
The catalyst for the amidation reaction may be selected from the group consisting of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium amide, sodium amide, n-butyllithium, trimethylaluminium, ethylmagnesium bromide or sodium bis (trimethylsilyl) amide, preferably trimethylsilylamide, Aluminum or n-butyllithium.
The solvent for the amidation reaction may be hexane, tetrahydrofuran, toluene, dichloromethane, 1,2-dichloroethane or N, N-dimethylformamide N, N-dimethylformamide), preferably hexane or dichloromethane.
The temperature of the amidation reaction is 0 to 100 캜, preferably 40 to 60 캜.
The temperature of the cyclization reaction is 100 to 150 캜, preferably 120 to 130 캜.
The solvent of the substitution reaction is methanol, ethanol, acetonitrile, benzene, toluene or acetic acid, preferably toluene or acetic acid, more preferably acetic acid.
Compared with the prior art, the preparation method of the present invention (I) mentioned in the present invention is characterized by being easy to obtain a raw material, simple in process, economical and environmentally friendly. Therefore, mass production of the raw material can be facilitated, contributing to promoting the economic development of the related art.
Hereinafter, the technical solution of the present invention will be described in more detail by way of example and some comparatively preferred embodiments, and it does not limit the scope of protection of the present invention.
Example 1:
To the reaction vessel was added R-2-hydroxybutyrate (II) (6.6 g, 50 mmol), methanesulfonyl chloride (6.3 g, 55 mol) and 100 mL of dichloromethane, After stirring for 1 hour, triethylamine (5.6 g, 55 mol) was added dropwise, and the temperature was raised to room temperature, followed by stirring for 8 to 10 hours to complete the TLC detection reaction. The reaction solution was washed sequentially with 10% acetic acid solution, saturated sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oil was dissolved in 50 mL of N, N-dimethylformamide , 6.8 g (50 mmol) of 6-amino-9H-purine was added, the temperature was raised to 120 ° C and pyridine (4.0 g, 50 mmol) The reaction solution was poured into ice water and extracted three times with dichloromethane. The solution was combined with the organic phase, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure. The residue was dissolved in hexane Recrystallization was carried out using dichloromethane (1: 1, V / V) and vacuum drying was conducted to obtain 10.2 g of light yellow solid S-2- (N-9H-purin-6-yl) aminoethyl butyrate (III) , Yield 82.0%, EI-MS m / z 250 (M + H).
Example 2:
To the reaction vessel was added R-2-hydroxybutanoic acid benzyl ester (II) (1.9 g, 10 mmol), methanesulfonyl chloride (2.1 g, 11 mol) and 25 mL of dichloromethane, , And diisopropylethylamine (1.4 g, 11 mol) was added dropwise thereto. The mixture was reacted for 1 hour while maintaining the above temperature, and then the temperature was raised to room temperature and stirred for 6 to 8 hours to complete the TLC detection reaction. The reaction solution was washed sequentially with 10% acetic acid solution, saturated sodium hydrogencarbonate solution and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained oil was dissolved in 20 mL of N, N-dimethylformamide, 6-Amino-9H-purine (1.4 g, 10 mmol) was added, the temperature was raised to 120 ° C and pyridine (8.0 g, 10 mmol) was slowly added dropwise and the temperature was then maintained at 120-130 ° C The mixture was stirred for 3 hours and then cooled to room temperature. The reaction mixture was poured into ice water and extracted three times with dichloromethane. The mixture was combined with the organic phase, dried over anhydrous sodium sulfate, and the solvent was recovered under reduced pressure. The residue was dissolved in hexane and dichloromethane Recrystallization was carried out using methane (1: 1, V / V) and vacuum drying was conducted to obtain 2.46 g of pale yellow solid S-2- (N-9H- purin-6-yl) aminobenzyl butyrate (III) Yield was 79.1%, EI-MS m / z 312 (M + H).
Example 3:
S-2- (N-9H-purin-6-yl) aminoethyl butyrate (III) (5.0 g, 20 mmol) and 50 mL of dichloromethane were added to a reaction vessel under nitrogen atmosphere. Was added dropwise, the temperature was slowly raised to room temperature, 15 mL of dichloromethane solution of 2-formic acid-3-fluoroaniline (3.1 g, 20 mmol) was added dropwise, After the temperature is raised, the reaction is carried out for 5 to 6 hours to complete the TLC detection reaction. After cooling, the reaction mixture is poured into a 15% sodium hydroxide solution, extracted three times with dichloromethane, and then combined with the organic phase and dried over anhydrous magnesium sulfate. After concentration, the residue was recrystallized using methanol to obtain an off-white solid S-2- (N-9H-purin-6-yl) amino-N- (2-formic acid-3-fluorophenyl) butyramide ), And the yield was 92.2%, EI-MS m / z 359 (M + H).
Example 4:
S-2- (N-9H-purin-6-yl) aminobenzyl butyrate (III) (3.1 g, 10 mmol) and 25 mL of dichloromethane were added to a reaction vessel under a nitrogen atmosphere. 15 mL of a hexane solution of butyllithium was added dropwise, the temperature was slowly raised to room temperature, a 10 mL dichloromethane solution of 2-formic acid-3-fluoroaniline (1.6 g, 10 mmol) was added dropwise, After raising the temperature to reflux, the reaction is carried out for 5 to 6 hours to complete the TLC detection reaction. After cooling, the reaction mixture is poured into a 15% sodium hydroxide solution, extracted three times with dichloromethane, and then combined with the organic phase and dried over anhydrous magnesium sulfate. After concentration, the residue was recrystallized using methanol to obtain an off-white solid S-2- (N-9H-purin-6-yl) amino-N- (2-formic acid-3-fluorophenyl) butyramide ), And the yield was 86.6%, EI-MS m / z 359 (M + H).
Example 5:
The reaction vessel was charged with S-2- (N-9H-purin-6-yl) amino-N- (2-formate-3-fluorophenyl) butyramide (IV) (1.8 g, And the mixture was reacted at 120 to 130 ° C for 6 hours. The residue was dissolved in 25 mL of toluene, phenylamine (0.5 g, 5 mmol) was added thereto, the temperature was raised, and the toluene refluxing reaction was maintained for 3 to 5 hours to carry out a TLC detection reaction Complete. After concentrating under reduced pressure, the residue was recrystallized using ethanol to give 1.3 g of delarris (I) as a pale yellow solid. The yield was 62.8%, 1 H NMR (DMSO-d 6)? 0.77 (t, (m, 2H), 3.82 (brs, IH), 4.75 (m, IH), 7.30 (s, 1H), EI-MS m / z 416 (M + H).
Example 6:
The reaction vessel was charged with S-2- (N-9H-purin-6-yl) amino-N- (2-formate-3-fluorophenyl) butyramide (IV) (1.8 g, And the mixture was reacted at 120 to 130 ° C for 6 hours. The residue was dissolved in 25 mL of acetic acid, phenylamine (0.5 g, 5 mmol) was added thereto, the temperature was raised, and the acetic acid reflux reaction was maintained for 3 to 5 hours to perform TLC detection reaction . After concentration under reduced pressure, the mixture is allowed to stand overnight. After filtration, the filter cake was recrystallized using ethanol to obtain 1.5 g of a pale yellow solid delariship (I), and the yield was 72.5%, 1 H NMR (DMSO-d 6)? 0.77 (t, 3H), 1.99 (m, 2H), 3.82 (brs, IH), 4.75 (m, IH), 7.30 s, 1 H), EI-MS m / z 416 (M + H).
It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. . All changes and modifications that fall within the spirit and scope of the present invention are within the scope of the present invention.
Claims (8)
R-2-hydroxybutyrate (II) and 6-amino-9H-purine were subjected to nucleophilic substitution reaction under the action of a releasing agent and an acid binding agent. (S-2- (N-9H-purin-6-yl) aminobutyrate (III)) as an intermediate S- 2- (N-9H-purin-6-yl) aminobutyrate (III) and 2-formic acid-3-fluoroaniline are reacted with an intermediate S- (N-9H-purin-6-yl) amino-N (2-formyl-3-fluorophenyl) butyramide (N-9H-purin-6-yl) amino-N- (2-formic acid-3-fluorophenyl) butyramide) (I), characterized in that the amide is subjected to a cyclization reaction in acetic anhydride, followed by a substitution reaction with phenylamine to obtain the delaleri (I).
(I), wherein the ester group in the raw material R-2-hydroxybutyrate (II) is an aliphatic hydrocarbon group of 1 to 10 carbon atoms, a phenyl group or a benzyl group.
Wherein the starting molar ratio of the nucleophilic substitution reaction raw material R-2-hydroxybutyrate (II) to 6-amino-9H-purine is 1: 0.5 to 1.5.
The release agent for the nucleophilic substitution reaction may be selected from the group consisting of methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride and trifluoromethanesulfonyl chloride. (I). ≪ / RTI >
The acid binding agent of the nucleophilic substitution reaction may be triethylamine, pyridine, N-methylmorpholine, diisopropylethylamine or 4-dimethylaminopyridine. (I). ≪ / RTI >
The catalyst for the amidation reaction may be selected from the group consisting of sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium amide, (trimethylsilyl) amide, sodium amide, n-butyllithium, trimethylaluminium, ethylmagnesium bromide or sodium bis (trimethylsilyl) amide. (I).
Wherein the cyclization reaction is carried out at a temperature of 100 to 150 占 폚.
Wherein the solvent for the substitution reaction is methanol, ethanol, acetonitrile, benzene, toluene or acetic acid.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410416005.2A CN104262344B (en) | 2014-08-22 | 2014-08-22 | The preparation method of Chinese mugwort Dana Delany |
| CN201410416005.2 | 2014-08-22 | ||
| PCT/CN2015/085706 WO2016026380A1 (en) | 2014-08-22 | 2015-07-31 | Method for preparing idelalisib |
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| KR20170075713A KR20170075713A (en) | 2017-07-03 |
| KR101934096B1 true KR101934096B1 (en) | 2019-01-02 |
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| KR (1) | KR101934096B1 (en) |
| CN (1) | CN104262344B (en) |
| WO (1) | WO2016026380A1 (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3083623A1 (en) | 2013-12-20 | 2016-10-26 | Gilead Calistoga LLC | Polymorphic forms of a hydrochloride salt of (s) -2-(9h-purin-6-ylamino) propyl) -5-fluoro-3-phenylquinazolin-4 (3h) -one |
| NZ720867A (en) | 2013-12-20 | 2018-01-26 | Gilead Calistoga Llc | Process methods for phosphatidylinositol 3-kinase inhibitors |
| CN104262344B (en) * | 2014-08-22 | 2015-11-04 | 苏州明锐医药科技有限公司 | The preparation method of Chinese mugwort Dana Delany |
| CN106146500A (en) * | 2015-03-26 | 2016-11-23 | 江苏豪森药业集团有限公司 | 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purine-6-base amino) propyl group]-4 (3H)-quinazolinone crystal formations and preparation method thereof |
| CN106146501A (en) * | 2015-03-26 | 2016-11-23 | 江苏豪森药业集团有限公司 | A kind of preparation method of unformed inhibitors of kinases |
| CN104892612B (en) * | 2015-04-15 | 2017-12-19 | 上海方楠生物科技有限公司 | A kind of Ai Delibu amorphous article and preparation method thereof |
| CN106146352A (en) * | 2015-04-16 | 2016-11-23 | 上海医药工业研究院 | Idelalisib intermediate and preparation method thereof |
| CN106146503A (en) * | 2015-04-16 | 2016-11-23 | 上海医药工业研究院 | A kind of preparation method of Idelalisib |
| CZ2015347A3 (en) * | 2015-05-22 | 2016-11-30 | Zentiva, K.S. | Solid forms of 5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]quinazolin-4-one and their preparation |
| HU231016B1 (en) * | 2015-11-30 | 2019-11-28 | Egis Gyógyszergyár Zrt. | New polymorph and solvate of idelalisib |
| US20190040066A1 (en) | 2016-02-03 | 2019-02-07 | Lupin Limited | Process for the preparation of phosphatidylinositol 3-kinase inhibitor |
| WO2017191608A1 (en) * | 2016-05-05 | 2017-11-09 | Laurus Labs Limited | Novel process for preparation of idelalisib |
| CN106074430A (en) * | 2016-06-13 | 2016-11-09 | 佛山市腾瑞医药科技有限公司 | A kind of Ai Dailalisi effervescent tablet and preparation method thereof |
| CN105943510A (en) * | 2016-06-13 | 2016-09-21 | 佛山市腾瑞医药科技有限公司 | Idelalisib preparation and application thereof |
| WO2017221272A1 (en) * | 2016-06-23 | 2017-12-28 | Sun Pharmaceutical Industries Limited | Process for the preparation of idelalisib |
| CN106632337B (en) * | 2016-10-18 | 2018-11-20 | 湖北生物医药产业技术研究院有限公司 | It ends for this crystal form, pharmaceutical composition, preparation method and purposes of Larry |
| CN108409740B (en) * | 2018-03-14 | 2020-05-08 | 盐城师范学院 | Preparation method of Aidallas |
| WO2019178596A1 (en) | 2018-03-16 | 2019-09-19 | Johnson Matthey Public Limited Company | Pyridine or n,n-dimethyl acetamide solvated solid state forms of solvated idelalisib, their use and preparation |
| CN111471001B (en) * | 2020-05-20 | 2023-05-26 | 上海鲲博玖瑞医药科技发展有限公司 | Preparation method of 4- [ (1R) -1-amino-2-hydroxyethyl ] -3-fluoro-benzonitrile |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005113554A2 (en) | 2004-05-13 | 2005-12-01 | Icos Corporation | Method of preparing 3-phenyl-2-[9h-purin-6-ylamino)-methyl]-3h-quinazolin-4-one and substituted and related compounds |
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| WO2013116562A1 (en) * | 2012-02-03 | 2013-08-08 | Gilead Calistoga Llc | Compositions and methods of treating a disease with (s)-4 amino-6-((1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethyl)amino)pyrimidine-5-carbonitrile |
| CN104262344B (en) * | 2014-08-22 | 2015-11-04 | 苏州明锐医药科技有限公司 | The preparation method of Chinese mugwort Dana Delany |
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2014
- 2014-08-22 CN CN201410416005.2A patent/CN104262344B/en active Active
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- 2015-07-31 KR KR1020177007729A patent/KR101934096B1/en active IP Right Grant
- 2015-07-31 WO PCT/CN2015/085706 patent/WO2016026380A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005113554A2 (en) | 2004-05-13 | 2005-12-01 | Icos Corporation | Method of preparing 3-phenyl-2-[9h-purin-6-ylamino)-methyl]-3h-quinazolin-4-one and substituted and related compounds |
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| Publication number | Publication date |
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| CN104262344A (en) | 2015-01-07 |
| KR20170075713A (en) | 2017-07-03 |
| CN104262344B (en) | 2015-11-04 |
| WO2016026380A1 (en) | 2016-02-25 |
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