CN106146352A - Idelalisib intermediate and preparation method thereof - Google Patents
Idelalisib intermediate and preparation method thereof Download PDFInfo
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- CN106146352A CN106146352A CN201510180925.3A CN201510180925A CN106146352A CN 106146352 A CN106146352 A CN 106146352A CN 201510180925 A CN201510180925 A CN 201510180925A CN 106146352 A CN106146352 A CN 106146352A
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Abstract
The invention discloses a kind of Idelalisib new intermediate compound (V) (S)-2-{ [the fluoro-2-of 3-[(phenyl amino) carbonyl] phenyl] amino-1-ethyl }-isobutyl carbamate.Utilizing this intermediate to prepare Idelalisib, compared with existing open method, not only stable reaction, yield are high, and reaction condition is gentle, overcomes the defect that prior art exists, and is very suitable for the big production of industry, and yield is higher than existing method.
Description
Technical field
The present invention relates to Idelalisib intermediate and preparation method thereof technical field.
Background technology
Idelalisib is PI3K inhibitor to be administered orally by the first selectivity of lucky Leadd B.V research and development, compared with α, β, γ subunit, its can high selectivity act on δ subunit, retardance PI3K δ-Akt signal path also promotes apoptosis, U.S. FDA approval listing is obtained, for recurring the treatment of chronic lymphocytic leukemia, follicular lymphoma and small lymphocytic lymphoma in July, 2014.Chemistry entitled (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-base amino) propyl group]-3H-quinazoline-4-one.
Its synthetic route of synthetic method that international monopoly WO2005113556A1 discloses a kind of Idelalisib is as follows:
The method is with 2-fluoride-6-nitrobenzoic acid as raw material; elder generation and aniline condensation; react with N-Boc-L-2-aminobutyric acid after obtaining intermediate with thionyl chloride reaction again and obtain bisamide product; obtaining (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one after reduction cyclization, deprotection again, last and 6-bromine purine obtains (S)-5-fluoro-3-phenyl-2-[1-(9H-purine-6-base amino) propyl group]-3H-quinazoline-4-one (i.e. Idelalisib) through nucleophilic displacement of fluorine.
But the defect of said method is that compound 6 is as the important source material preparing Idelalisib, the most commercially do not have cheap finished industrial product can buy, and in prior art disclosed in international monopoly WO2005113556A1, this step yield preparing compound 4 is relatively low, and need to be obtained by column chromatography, prepare this step of compound 5 also needs to be obtained by column chromatography simultaneously, and obtains being foaming solid, purity is bad, is unfavorable for subsequent operation and industrialized production.
It is thus desirable to a kind of raw material of exploitation is easy to get, safety, the method that what yield was high prepare Idelalisib key intermediate.
Summary of the invention
The purpose of the present invention solves existing technical problem exactly, it is provided that a kind of new intermediate preparing Idelalisib, uses this intermediate synthesis Idelalisib to overcome the drawbacks described above of prior art, is very suitable for the big production of industry, and yield is higher than existing method.
It is a further object to provide the preparation method of above-mentioned intermediate.
For reaching above-mentioned purpose, the technical scheme that the present invention takes is as follows:
The compound (V) of following formula:
The preparation method of formula (V) compound, the method be the activated carboxylic of formula IV compound is become anhydride after again with formula III compound reaction obtain:
The activator of above-mentioned activation formula IV BOC-L-2-aminobutyric acid carboxyl can be chloro-formate class such as isobutyl chlorocarbonate etc., alkali used is organic base such as N-methylmorpholine and triethylamine etc., the anhydride obtained after activation and formula III compound react in former reaction system, i.e. one cooking-pot type reaction.
Further, above-mentioned formula III compound is formula II compound reduction reaction to be obtained:
This reduction reaction can be Pd/C be that catalyst carries out hydro-reduction, it is also possible under the conditions of Zn/ ammonium chloride reduce.
Further, above-mentioned formula II compound be formula I compound is first become amide after obtain with aniline reaction the most in the basic conditions:
Acylating agent used by the reaction of this step can be oxalyl chloride, thionyl chloride etc., and solvent used during reaction is oneself alkyl chloride hydro carbons such as dichloromethane etc. of knowing of those skilled in the art, afterwards with aniline reaction selected by solvent can be cyclic ethers class such as Isosorbide-5-Nitrae-dioxane etc..Reaction temperature can select optimal temperature range according to solvent used, those skilled in the art.The alkali that can use includes such as sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate.
Beneficial effects of the present invention: present inventor has been found surprisingly that a kind of suitable new intermediate compound (S)-2-{ [the fluoro-2-of 3-[(phenyl amino) carbonyl] phenyl] amino-1-ethyl when studying the preparation method of Idelalisib }-isobutyl carbamate, utilize this intermediate to prepare Idelalisib, compared with existing open method, not only stable reaction, yield height, and reaction condition is gentle, overcome the defect that prior art exists, it is very suitable for the big production of industry, and yield is higher than existing method.
Detailed description of the invention
The preparation of embodiment 1-2:2-fluoro-6-nitro-N-phenyl-Benzoylamide formula II
By 2-fluoride-6-nitrobenzoic acid (18.5g), DMF (1ml) and dichloromethane (100ml) mix and blend, the dropping dichloromethane solution (60ml) containing oxalyl chloride (19g), reaction 2 hour is stirred at room temperature, is concentrated to give orange solids serosity.Above-mentioned serosity is dissolved in containing in anhydrous dioxanes (16ml), and it is slowly dropped at 6 DEG C containing aniline (9ml) and sodium bicarbonate (16.8g) in the mixing suspension of dioxanes (40) and water (40), after finishing, half an hour is stirred at room temperature, adds water (250ml), have solid to produce, solid is collected by filtration, wash with water, obtain title compound 2-fluoro-6-nitro-N-phenyl-Benzoylamide 25.6g, yield 98.4%.1H NMR(400MHz,CDCl3) δ 8.01 (d, J=8.2Hz, 1H), 7.70-7.60 (m, 4H), 7.41 (t, J=7.8Hz, 2H), 7.23 (t, J=7.4Hz, 1H) .ESI-MS (m/z): 261 [M+H]+
By 2-fluoride-6-nitrobenzoic acid (18.5g), DMF (1ml) and dichloromethane (100ml) mix and blend, the dropping dichloromethane solution (60ml) containing oxalyl chloride (19g), reaction 2 hour is stirred at room temperature, is concentrated to give orange solids serosity.Above-mentioned serosity is dissolved in containing in anhydrous THF (16ml), and it is slowly dropped at 6 DEG C containing aniline (9ml) and sodium bicarbonate (16.8g) in the mixing suspension of THF (40ml) and water (40ml), after finishing, half an hour is stirred at room temperature, adds water (250ml), have solid to produce, solid is collected by filtration, wash with water, obtain title compound 2-fluoro-6-nitro-N-phenyl-Benzoylamide 24.6g, yield 94.6%.
The preparation of embodiment 3-4:2-amino-6-fluoro-N-phenyl-benzamide formula III
2-amino-6-fluoro-N-phenyl-benzamide (13g), Pd/C (1g) and ethyl acetate (100ml) are blended in 50 DEG C of hydrogenations four hours, filter, it is concentrated to dryness and obtains title compound 2-amino-6-fluoro-N-phenyl-benzamide 11.1g, yield 96.5%.1H NMR(400MHz,CDCl3) δ 8.33 (d, J=15.5Hz, 1H), 7.61 (d, J=7.6Hz, 2H), 7.43 7.35 (m, 2H), 7.21 7.12 (m, 2H), 6.51 (d, J=8.3Hz, 1H), 6.43 (ddd, J=13.0,8.1,1.0Hz, 1H), 5.97 (s, 2H) .ESI-MS (m/z): 231 [M+H]+
2-amino-6-fluoro-N-phenyl-benzamide (13g), Pd/C (0.8g) and ethyl acetate (100ml) are blended in 50 DEG C of hydrogenations six hours, filter, it is concentrated to dryness and obtains title compound 2-amino-6-fluoro-N-phenyl-benzamide 10.5g, yield 91.3%.
Embodiment 5-6:(S)-2-{ [the fluoro-2-of 3-[(phenyl amino) carbonyl] phenyl] amino-1-ethyl } preparation of-isobutyl carbamate formula (V)
nullBy BOC-L-2-aminobutyric acid (20.3g)、N-methylmorpholine (11.2g) is dissolved in anhydrous THF (120ml)，The dropping anhydrous THF (40ml) solution containing isobutyl chlorocarbonate (13.7g) at-15 DEG C，Drip and finish，Stir 1 hour under the conditions of-15 DEG C，Anhydrous THF (40ml) solution of dropping fluoro-N-phenyl-benzamide Han 2-amino-6-(11.5g) again，Drip and finish，React half an hour at this temperature，It is slowly increased to room temperature，React 1 hour，Filter out solid，Filtrate is warming up to back flow reaction 3.5 hours，Concentration of reaction solution，Add ethyl acetate (150ml) and water (200ml)，Separatory，Aqueous layer with ethyl acetate (100ml × 2) extracts，Merge organic layer，Washing，Saturated common salt is washed，It is dried，Filter，It is concentrated to give crude product 19.2g，It is recrystallized to give title compound (S)-2-{ [the fluoro-2-of 3-[(phenyl amino) carbonyl] phenyl] amino-1-ethyl with isopropanol (70ml) }-isobutyl carbamate 17.1g，Yield 82.4%.1H NMR(400MHz,CDCl3) δ 11.72 (s, 1H), 8.55 (d, J=8.5Hz, 1H), 8.37 (d, J=14.5Hz, 1H), 7.64 (d, J=7.8Hz, 2H), 7.51 7.45 (m, 1H), 7.41 (t, J=7.9Hz, 2H), 7.23 (t, J=7.4Hz, 1H), 6.93 (dd, J=12.3,8.4Hz, 1H), 5.11 (s, 1H), 4.28 (s, 1H), 2.07 1.97 (m, 1H), 1.83 1.73 (m, 1H), 1.45 (s, 9H), 1.03 (t, J=7.4Hz, 3H) .ESI-MS (m/z): 416 [M+H]+
nullBy BOC-L-2-aminobutyric acid (20.3g)、N-methylmorpholine (11.2g) is dissolved in anhydrous THF (120ml)，The dropping anhydrous THF (40ml) solution containing isobutyl chlorocarbonate (13.7g) at-15 DEG C，Drip and finish，Stir 1 hour under the conditions of-15 DEG C，Anhydrous THF (40ml) solution of dropping fluoro-N-phenyl-benzamide Han 2-amino-6-(11.5g) again，Drip and finish，React half an hour at this temperature，It is slowly increased to room temperature，React 1 hour，Filtrate is warming up to back flow reaction 3.5 hours，Concentration of reaction solution，Add ethyl acetate (150ml) and water (200ml)，Separatory，Aqueous layer with ethyl acetate (100ml × 2) extracts，Merge organic layer，Washing，Saturated common salt is washed，It is dried，Filter，It is concentrated to give crude product 19.2g，It is recrystallized to give title compound (S)-2-{ [the fluoro-2-of 3-[(phenyl amino) carbonyl] phenyl] amino-1-ethyl with isopropanol (70ml) }-isobutyl carbamate 14.9g，Yield 71.8%.
Embodiment 7-8:(S) preparation of [1-(5-fluorin-4-oxygen generation-3-phenyl-3,4-dihydro-quinazolin-2-yl)-propyl group]-isobutyl carbamate
By (S) [1-(5-fluorin-4-oxygen generation-3-phenyl-3, 4-dihydro-quinazolin-2-yl)-propyl group]-isobutyl carbamate (8.3g), trim,ethylchlorosilane (40ml), triethylamine (150ml) is blended in acetonitrile (500ml) vexed tank under nitrogen-sealed and reacts 48 hours, filter, it is concentrated to dryness, add ethyl acetate (500ml), successively with saturated sodium carbonate solution (150ml), water (150ml), saturated aqueous common salt (150ml) is washed, it is dried, filter, it is concentrated to give title compound (S) [1-(5-fluorin-4-oxygen generation-3-phenyl-3, 4-dihydro-quinazolin-2-yl)-propyl group]-isobutyl carbamate 7.2g, yield 90.6%.1H NMR(400MHz,CDCl3) δ 7.71 (td, J=8.2,5.4Hz, 1H), 7.65 7.49 (m, 4H), 7.38 (d, J=6.5Hz, 1H), 7.29 (d, J=7.6Hz, 1H), 7.13 (dd, J=10.4,8.2Hz, 1H), 5.43 (s, 1H), 4.43 (s, 1H), 1.67 1.49 (m, 2H), 1.44 (s, 9H), 0.79 (t, J=7.4Hz, 3H) .ESI-MS (m/z): 398 [M+H]+
By (S) [1-(5-fluorin-4-oxygen generation-3-phenyl-3,4-dihydro-quinazolin-2-yl)-propyl group]-isobutyl carbamate (8.3g), trim,ethylchlorosilane (40ml), triethylamine (150ml) be blended in nitrogen in acetonitrile (500ml) and react 48 hours, and thin layer chromatography is displayed without reaction.
Embodiment 9:(S) preparation of-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one
By (S) [1-(5-fluorin-4-oxygen generation-3-phenyl-3, 4-dihydro-quinazolin-2-yl)-propyl group]-isobutyl carbamate (7.94g) is dissolved in dichloromethane (40ml) and trifluoroacetic acid (40ml), it is stirred at room temperature 2 hours, it is concentrated to dryness, dichloromethane (100ml) and 10% potassium carbonate (100ml) solution distribute, separatory, water layer extracts with dichloromethane (50ml × 2) again, merge organic layer, washing, saturated common salt is washed, it is dried, filter, it is concentrated to give title compound (S)-2-(1-amino-propyl)-5-fluoro-3-phenyl-3H-quinazoline-4-one 5.1g, yield 85.8%.1H NMR(400MHz,CDCl3) δ 7.70 (td, J=8.2,5.4Hz, 1H), 7.63 7.50 (m, 4H), 7.29 (dd, J=12.9,5.9Hz, 2H), 7.12 (dd, J=10.2,8.4Hz, 1H), 3.55 3.41 (m, 1H), 1.88 1.76 (m, 1H), 1.60 1.47 (m, 1H), 0.81 (t, J=9.6Hz, 3H) .ESI-MS (m/z): 298 [M+H]+ 。
Claims (8)
1. the compound (V) of following formula:
2. the preparation method of formula (V) compound, the method be the activated carboxylic of formula IV compound is become anhydride after again with formula III compound reaction obtain:
3. the preparation method of formula (V) compound as claimed in claim 2, it is characterised in that: formula III compound is formula II compound reduction reaction to be obtained:
4. the preparation method of formula (V) compound as claimed in claim 3, it is characterised in that: formula II compound be formula I compound is first become amide after obtain with aniline reaction the most in the basic conditions:
5. the preparation method of formula (V) compound as described in claim 2-4 is arbitrary, it is characterised in that: the activator of activated b OC-L-2-aminobutyric acid carboxyl is chloro-carbonic acid esters.
6. the preparation method of formula (V) compound as described in claim 2-4 is arbitrary, it is characterised in that: the anhydride obtained after BOC-L-2-aminobutyric acid activated carboxylic and formula III compound react in former reaction system.
7. the preparation method of formula (V) compound as described in claim 2-4 is arbitrary, it is characterised in that: the reduction of formula II compound carries out hydro-reduction with Pd/C for catalyst or reduces under the conditions of Zn/ ammonium chloride.
8. the preparation method of formula (V) compound as described in claim 2-4 is arbitrary, it is characterised in that: the acylating agent used by amide reaction is oxalyl chloride, thionyl chloride.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109503430A (en) * | 2018-12-29 | 2019-03-22 | 浙江东亚药业股份有限公司 | A kind of neighbour's fluorine neighbour's imido grpup benzoic acid Intermediate compound and its preparation method and application |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101472930A (en) * | 2006-04-26 | 2009-07-01 | 霍夫曼-拉罗奇有限公司 | Thieno [3, 2-d] pyrimidine derivative useful as pi3K inhibitor |
| CN102229609A (en) * | 2004-05-13 | 2011-11-02 | 艾科斯有限公司 | Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta |
| CN104130261A (en) * | 2014-08-04 | 2014-11-05 | 山东康美乐医药科技有限公司 | Idelalisib synthetic method |
| CN104262344A (en) * | 2014-08-22 | 2015-01-07 | 苏州明锐医药科技有限公司 | A preparing method of Idelalisib |
| WO2015018522A1 (en) * | 2013-08-06 | 2015-02-12 | Oncoethix Sa | Bet-bromodomain inhibitor shows synergism with several anti-cancer agents in pre-clinical models of diffuse large b-cell lymphoma (dlbcl) |
| WO2015042077A1 (en) * | 2013-09-22 | 2015-03-26 | Calitor Sciences, Llc | Substituted aminopyrimidine compounds and methods of use |
-
2015
- 2015-04-16 CN CN201510180925.3A patent/CN106146352A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102229609A (en) * | 2004-05-13 | 2011-11-02 | 艾科斯有限公司 | Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta |
| CN101472930A (en) * | 2006-04-26 | 2009-07-01 | 霍夫曼-拉罗奇有限公司 | Thieno [3, 2-d] pyrimidine derivative useful as pi3K inhibitor |
| WO2015018522A1 (en) * | 2013-08-06 | 2015-02-12 | Oncoethix Sa | Bet-bromodomain inhibitor shows synergism with several anti-cancer agents in pre-clinical models of diffuse large b-cell lymphoma (dlbcl) |
| WO2015042077A1 (en) * | 2013-09-22 | 2015-03-26 | Calitor Sciences, Llc | Substituted aminopyrimidine compounds and methods of use |
| CN104130261A (en) * | 2014-08-04 | 2014-11-05 | 山东康美乐医药科技有限公司 | Idelalisib synthetic method |
| CN104262344A (en) * | 2014-08-22 | 2015-01-07 | 苏州明锐医药科技有限公司 | A preparing method of Idelalisib |
Non-Patent Citations (2)
| Title |
|---|
| 卢新生等主编: "《现代有机合成反应技术与应用研究》", 30 October 2014 * |
| 陆国元: "《有机反应与有机合成》", 30 June 2009 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109503430A (en) * | 2018-12-29 | 2019-03-22 | 浙江东亚药业股份有限公司 | A kind of neighbour's fluorine neighbour's imido grpup benzoic acid Intermediate compound and its preparation method and application |
| CN109503430B (en) * | 2018-12-29 | 2021-01-29 | 浙江东亚药业股份有限公司 | O-fluoro-o-imine benzoic acid intermediate compound and preparation method and application thereof |
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