WO2017130221A1 - Improved process for the preparation of idelalisib - Google Patents

Improved process for the preparation of idelalisib Download PDF

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Publication number
WO2017130221A1
WO2017130221A1 PCT/IN2017/050038 IN2017050038W WO2017130221A1 WO 2017130221 A1 WO2017130221 A1 WO 2017130221A1 IN 2017050038 W IN2017050038 W IN 2017050038W WO 2017130221 A1 WO2017130221 A1 WO 2017130221A1
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WIPO (PCT)
Prior art keywords
formula
compound
reaction
idelalisib
protecting group
Prior art date
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PCT/IN2017/050038
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French (fr)
Inventor
Rajamannar Thennati
Shriprakash Dhar DWIVEDI
Kanaksinh Jesingbhai Jadav
Vimeshkumar Maganlal Patel
Krunalkumar Chetanbhai JOSHI
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Sun Pharmaceutical Industries Limited
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Publication of WO2017130221A1 publication Critical patent/WO2017130221A1/en

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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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • solvent in step a) of above process, may be selected from any suitable solvent for the reaction such as acetonitrile, dimethyl sulfoxide, dimethylacetamide or mixtures thereof.
  • suitable solvent for the reaction such as acetonitrile, dimethyl sulfoxide, dimethylacetamide or mixtures thereof.
  • the most preferred solvent is acetonitrile.
  • Example 1 (5)-[l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl)-propyl]- carbamic acid tert-butyl ester

Abstract

The present invention provides an improved process for the preparation of compound of formula III by cyclizing compound of formula II in presence of hexamethyldisilazane and a base in a solvent. The compound of formula III is further converted to Idelalisib. Wherein X is an amino protecting group.

Description

IMPROVED PROCESS FOR THE PREPARATION OF IDELALISIB
RELATED APPLICATIONS This application claims the benefit of Indian Patent Application no. IN 201621003350 filed on January 29, 2016 and IN 201621013517 filed on April 18, 2016; which is hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention provides an improved process for the preparation of Idelalisib.
BACKGROUND OF THE INVENTION Idelalisib is an inhibitor of phosphatidylinositol 3-kinase, PI3K<5; chemically known as 5- fluoro-3-phenyl-2-[(15)-l-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one. The chemical structure of Idelalisib is as shown below, represented by a compound of formula I:
Figure imgf000002_0001
formula I
Idelalisib is marketed in the United States under the brand name Zydelig as oral tablets and indicated for the treatment of patients with:
• Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.
• Relapsed follicular B-cell non-Hodgkin lymphoma (FL) in patients who have received at least two prior systemic therapies.
Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies. The United States patent No. USRE44638 (the '638 patent) discloses Idelalisib and process for its preparation, but the preparation method is relatively cumbersome, the yield is low, in particular for synthesis of interme la Ilia.
Figure imgf000003_0001
formula Ilia
The '638 patent discloses the preparation of intermediate compound of formula Ilia, wherein it is isolated by purification with silica gel column chromatography in low yield.
The WIPO patent application WO2013116562A1 discloses preparation of related chloro analogue of intermediate compound of formula Ilia, as shown below:
Figure imgf000003_0002
by cyclizing (S)-teri-butyl l-(3-chloro-2-(phenylcarbamoyl)phenylamino)-l-oxopropan-2- ylcarbamate using chlorotrimethylsilane, but the reaction being carried out in a sealed condition and for longer reaction time, makes it not suitable for industrial scale.
The WIPO patent application WO2015042077A1 discloses preparation of intermediate compound of formula Ilia, by cyclizing (5)-teri-butyl(l-((3-fluoro-2- (phenylcarbamoyl)phenyl)amino)-l-oxobutan-2-yl)carbamate using expensive N,0- bis(trimethylsilyl)acetamide reagent. In addition it required purification by silica gel column chromatography and the yield is low.
Various processes for the preparation of Idelalisib and its intermediates are disclosed in CN104130261A, CN104876931A, WO2015095601A1. The processes reported for the preparation of Idelalisib, in particular to synthesis of intermediate compound of formula Ilia or its analogues, suffer from one or more drawbacks such as involving use of expensive reagents like N,0-bis(trimethylsilyl)acetamide; fuming reagents like chlorotrimethylsilane, harsh reaction conditions such as reaction in sealed condition, longer reaction time, low yield and often required purification by column chromatography which makes it difficult to prepare intermediate compound of formula Ilia on commercial scale. There is therefore a need for a simple and efficient process for the preparation of Idelalisib.
The present invention provides a simple, scalable and economical process for the preparation of Idelalisib with desired chiral purity. SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of Idelalisib, a compound of formula I
Figure imgf000004_0001
formula I
comprising:
(a) cyclizing a compound of formula II,
Figure imgf000005_0001
formula II
wherein X is an amino protecting group,
in presence of hexamethyldisilazane (HMDS) and a base in a solvent to obtain a compound of formula III,
Figure imgf000005_0002
wherein X is an amino protecting group,
(b) deprotecting the compound of formula III, to obtain a compound of formula IV
Figure imgf000005_0003
formula IV
and,
(c) reacting the compound of formula IV either with 6-halopurine to obtain the compound of Formula I or with a compound of formula V
halo
Figure imgf000005_0004
formula V wherein R is an amino protecting group and halo is halogen, to obtain a compound of formula VI
Figure imgf000006_0001
formula VI
wherein R is an amino protecting group, followed by deprotecting the compound of VI to obtain the compound of formula I. DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present invention provides a process for the preparation of Idelalisib, a compound of formula I
Figure imgf000006_0002
formula I
comprising:
(a) cyclizing a compound of formula
Figure imgf000006_0003
formula II
wherein X is an amino protecting group, in presence of hexamethyldisilazane (HMDS) and a base in a solvent to obtain a compound of formula III,
Figure imgf000007_0001
wherein X is an amino protecting group,
(b) deprotecting the compound of formula III to obtain a compound of formula IV
Figure imgf000007_0002
formula IV
and,
(c) reacting the compound of formula IV either with 6-halopurine to obtain the compound of Formula I or with a compound of
Figure imgf000007_0003
formula V wherein R is an amino protecting group and halo is halogen, to obtain a compound of formula VI
Figure imgf000007_0004
wherein R is an amino protecting group, followed by deprotecting the compound of VI to obtain the compound of formula I.
In one embodiment, in step a) of above process, base may be selected from any organic or inorganic bases suitable for the reaction. Organic bases may be selected from but should not be restricted to triethylamine, trimethylamine, di-isopropylamine, N,N- diisopropylethylamine, pyridine, imidazole, l,4-diazabicyclo[2.2.2]octane (DABCO), 1,8- diazabicycloundec-7-ene (DBU), 4-dimethylaminopyridine. The most preferred base is triethylamine. The base may be used in a molar equivalent of about 1 to 50 with respect to compound of formula II, preferably about 10 to 30 equivalent, more preferably about 15 to 20 equivalent.
In another embodiment, in step a) of above process, solvent may be selected from any suitable solvent for the reaction such as acetonitrile, dimethyl sulfoxide, dimethylacetamide or mixtures thereof. The most preferred solvent is acetonitrile.
In another embodiment, in step a) of above process, hexamethyldisilazane (HMDS) may be used in molar equivalent of about 1 to 20 with respect to compound of formula II. Preferably, HMDS may be used in molar equivalent of about 5 to 10; more preferably in molar equivalent of about 5 to 7.5.
In another embodiment, in step a) of above process, X in the compound of formula II and compound of formula III is an amino protecting group such as teri-butyloxycarbonyl (Boc), carbobenzyloxy (Cbz), benzyl, p-methoxybenzyl, 9-fluorenylmethyloxycarbonyl (Fmoc) and the like. The preferred amino protecting group is Boc.
In another embodiment, step a) of above process, may be carried out at a temperature ranging from room temperature to reflux temperature of solvent; preferably reaction may be carried out at reflux temperature of solvent; more preferably at a temperature of 70 °C to 80 °C. Reaction may be carried out for a period of 10 to 30 hours; more preferably for 10-12 hours.
The present inventors found that when the cyclization of compound of formula II (wherein X is Boc) was carried out using chlorotrimethylsilane to yield compound of formula III, a dark brown color reaction mass was obtained, which made the work up procedure more tedious due to difficulties like in organic/aqueous layer separation and requirement of number of water washes. Moreover, the product was isolated as brown oil which was found to be only 80 % pure. The yield of the product was less than 75 %. The failure of chlorotrimethylsilane led the inventors to search for the alternatives. Inventors surprisingly found that use of HMDS afforded a clean reaction and the crude product isolated from it was found to be having more than 95 % purity by JH NMR. The yield of the reaction also improved substantially to more than 99 %. Moreover, the obtained product of compound of formula III was found to have 99.9 % chiral purity. The compound of formula III may be isolated or directly subjected to deprotection without isolation as per step (b). The compound of formula III may be isolated by any process known to a person skilled in the art, for instance by concentrating the reaction mass or by extracting with a suitable solvent & concentrating under reduced pressure to obtain the compound of Formula III.
The step a) of the present invention provides compound of formula III in greater than 99 % chiral purity. In one embodiment, the chiral purity of obtained compound of formula III is greater than 99 %. In another embodiment, the chiral purity of obtained compound of formula III is greater than 99.5 %. In a preferred embodiment, the chiral purity of obtained compound of formula III is greater than 99.9 %.
Step b) of above process involves deprotection of compound of formula III to obtain a compound of formula IV. Deprotection of compound of formula III may be carried out by any process known for deprotection of amino protecting group, such as by using acids or by hydrogenolysis. For example, Boc-deprotection may be carried out by using reagents such as hydrochloric acid, trifluoroacetic acid, and the like.
In another embodiment, in step c) of above process, the compound of formula IV is reacted with 6-halopurine to obtain Idelalisib. The 6-halopurine may be selected from 6- bromopurine, 6-chloropurine or 6-iodopurine; more preferably 6-chloropurine. The compound of formula IV may be reacted with 6-halopurine in presence or absence of base in a suitable solvent. For example, compound of formula IV may be reacted with 6-halopurine as disclosed in the United States patent No. USRE44638. In another embodiment, in step c) of above process, the compound of formula IV is reacted with a compound of formula V (N-protected 6-halopurine)
halo
Figure imgf000010_0001
formula V wherein R is an amino protecting group and halo is halogen, to obtain a compound of formula VI
Figure imgf000010_0002
formula VI
wherein R is an amino protecting group; and the compound of formula VI is deprotected to obtain the compound of formula I.
In an embodiment, R in the compound of formula V and compound of formula VI is an amino protecting group selected from a group consisting of (Ci-C4)alkoxymethyl, benzyloxymethyl and pivaloyloxymethyl. In a preferred embodiment, R in the compound of formula V and compound of formula VI is methoxymethyl (MOM). In another embodiment, halo in the compound of formula V is selected from chloro, bromo or iodo; preferably chloro.
The term "(Ci-C4)alkoxymethyl" refers to an alkyl group straight or branched having 1-4 carbon atoms, attached to methyl group via an oxygen atom. Non limiting examples of (Ci - C4)alkoxymethyl includes methoxymethyl, ethoxymethyl and the like.
The reaction of compound of formula IV with the compound of formula V is carried out in presence of a base in a suitable solvent to obtain the compound of formula VI. A suitable base for the reaction may be selected from organic bases such as triethylamine, trimethylamine, di-isoropylamine, N,N-diisopropylethylamine, pyridine, piperidine, imidazole, l ,4-diazabicyclo[2.2.2]octane (DABCO), l ,8-diazabicycloundec-7-ene (DBU), 4- dimethylaminopyridine or a mixture thereof; or inorganic bases such as potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide or a mixture thereof. The most preferred base is triethylamine. A suitable solvent for the reaction may be selected from a group consisting of water, ethanol, methanol, n-butanol, teri-butanol, isopropyl alcohol, N,N- dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidine, acetonitrile, acetone, methylisobutyl ketone or a mixture thereof. The most preferred solvent is a mixture of ethanol and water. Reaction may be carried out at a temperature ranging from room temperature to reflux temperature of the solvent; more preferably at a temperature of 70 °C to 80 °C and for a time suitable for the completion of reaction.
The compound of formula VI may be isolated or directly subjected to deprotection without isolation. The compound of formula VI may be isolated by any process known to a person skilled in the art, for instance by concentrating the reaction mass or by extracting with a suitable solvent & concentrating under reduced pressure to obtain the compound of Formula VI.
The deprotection of compound of formula VI may be carried out by treating the compound of formula VI with any reagent used for the deprotection of an amino protecting group such as acids or by catalytic hydrogenolysis. For instance, the methoxymethyl (MOM) deprotection can be carried out by using hydrochloric acid. The hydrochloric acid can be generated in-situ. For example, acetyl chloride and ethanol can be used in generating hydrochloric acid in-situ.
The compound of formula II used in step a) of above process, may be prepared as disclosed in prior art such as WO2015042077A1.
The process of the present invention can be depicted as in following scheme:
Figure imgf000012_0001
formula VI
The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention.
EXAMPLES:
Example 1 : (5)-[l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl)-propyl]- carbamic acid tert-butyl ester
To a solution of (5)-teri-butyl-l-[3-fluoro-2-(phenylcabamoyl)phenylamino]-l-oxobutan-2- ylcarbamate (10 g, 1 equivalent) in acetonitrile (300 mL) was added triethyl amine (114.1 g, 47 equivalent), followed by the drop wise addition of hexamethyldisilazane (58.1 g, 15 equivalent). The reaction mixture was stirred at reflux temperature for 10-12 hours. After completion of reaction, the reaction mass was concentrated under reduced pressure. Dichloromethane (200 mL) was added to the residue and washed with water followed by brine wash. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield off-white solid of title compound (9.5 g, yield: 99.6 %; Purity > 95 %). Example 2: (5)-[l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydro-quinazolin-2-yl)-propyl]- carbamic acid tert-butyl ester
To a solution of (5)-teri-butyl-l-[3-fluoro-2-(phenylcabamoyl)phenylamino]-l-oxobutan-2- ylcarbamate (100 g, 1 equivalent) in acetonitrile (2000 mL) was added triethyl amine (377.52 g, 15.5 equivalent), followed by the drop wise addition of hexamethyldisilazane (194.24 g, 5 equivalent). The reaction mixture was stirred at reflux temperature for 24 hours. After completion of reaction, the reaction mass was concentrated under reduced pressure. Dichloromethane (1000 mL) was added to the residue and washed with water followed by brine wash. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product which was further purified by slurrying with cyclohexane. Yield: 80 g, 84 %; Chiral Purity: 99.9%.
Example 3: 2-[(15)-l-Aminopropyl]-5-fluoro-3-phenyl-quinazoline-4-one
A mixture of teri-butyl N-[(15)-l-(5-fluoro-4-oxo-3-phenyl-quinazoline-2- yl)propyl]carbamate (100 g, 0.251 moles) was dissolved in acetonitrile (600 mL) and treated with concentrated hydrochloric acid (125 mL) at 25-30 °C. The reaction mixture was stirred for 5-6 hours at 25-30 °C. After completion of reaction, the reaction mass was concentrated under reduced pressure and washed with toluene. The aqueous layer was basified with liquor ammonia and filtered to provide the title product as an off white solid (71.06 g).
Example 4: 6-Chloro-9-(methoxymethyl)-9H-purine
A mixture of 6-chloro-9H-purine (50 g, 0.323 moles) and triethylamine (98.20 g, 0.97 moles) in dry tetrahydrofuran (600 mL) was stirred at 0-5 °C. Chloromethoxymethane (52.1 g, 0.646 moles) was added drop wise into the reaction mixture by maintaining 0-5 °C temperature. Then the reaction mass was allowed to attain 25-30 °C temperature and stirred for 2 hours. After 2 hours, triethylamine hydrochloride salt was filtered out and washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure and the crude product was crystallized in tetrahydrofuran to obtain the title product (50g, 77.8 %).
Example 5: 5-Fluoro-2-[(15)-l-[[9-(methoxymethyl)purin-6-yl]amino] propyl]-3-phenyl- quinazolin-4-one
A mixture of 2-[(15)-aminopropyl]-5-fluoro-3-phenyl-quinazoli-4-one (30 g, 0.100 moles), 6- chloro-9-(methoxymethyl)-9H-purine (22.02 g, 0.11 moles) and triethyl amine (15.3 g, 0.15 moles) in ethanol (150 mL) and water (75 mL) was stirred together at 75-80 °C until completion of reaction. After completion of reaction, the reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was again washed with water and concentrated under reduced pressure to provide crude solid title compound (46.2 g).
Example 6: Idelalisib
A mixture of crude product from above example 5 in ethanol (400 mL) was stirred at 25-30 °C. Acetyl chloride (18.30 g, 0.233 moles) was slowly added into the reaction mass and the reaction mass was stirred at 40 °C until completion of reaction. After completion of reaction, the reaction mass was concentrated and water was added to it. Aqueous layer was washed with di-isoproyl ether. Aqueous layer was basified with aqueous ammonia and filtered to provide the title product (25 g). Example 7: Idelalisib
A mixture of 5-fluoro-2-[(15)-l-[[9-(methoxymethyl)purin-6-yl]amino] propyl] -3 -phenyl- quinazolin-4-one (100 g, 0.217 moles) in methanol (1000 mL) was stirred at 25-30 °C. Acetyl chloride (68.33 g, 0.8705 moles) was slowly added into the reaction mass and the reaction mass was stirred at 40 °C for 5 hours. After completion of reaction, the reaction mass was concentrated to afford the crude residue which was crystallized in ethanol to afford HC1 salt of Idelalisib. The HC1 salt of Idelalisib was basified with aqueous ammonia and filtered to afford Idelalisib. Yield: 72 g, 80 %, Purity: 99.84 % by HPLC, Chiral Purity: 99.92 %.
Example 8: 5-Fluoro-2-[(15)-l-[[9-(methoxymethyl)purin-6-yl]amino]propyl]-3-phenyl- quinazolin-4-one
A mixture of hydrochloride salt of 2-[(15)-aminopropyl]-5-fluoro-3-phenyl-quinazoli-4-one (30g, 0.0901 moles), 6-chloro-9-(methoxymethyl)-9H-purine (19.68 g, 0.0991 moles) and triethyl amine (22.8 g, 0.225 moles) in ethanol (150 mL) and water (75 mL) was stirred together at 75-80 °C until completion of reaction. After completion of reaction, reaction mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was again washed with water and concentrated under reduced pressure to provide crude solid product (41.2 g).
Example 9: Idelalisib A mixture of hydrochloride salt of 2-[(15)-aminopropyl]-5-fluoro-3-phenyl-quinazoli-4-one (30 g, 0.0901 moles), 6-chloro-9-(methoxymethyl)-9H-purine (19.68 g, 0.0991 moles) and triethyl amine (22.8 g, 0.225 moles) in ethanol (150 mL) and water (75 mL) were stirred together at 75-80 °C until completion of reaction. After completion of reaction, the reaction mixture was concentrated. The concentrated mass was dissolved in ethanol (300 mL). Acetyl chloride (18.30 g, 0.233 moles) was slowly added into the reaction mass and stirred at 40 °C for 6-8 hours. After completion of reaction, the reaction mixture was concentrated and stirred in acetone (100 mL). The solid was filtered off to provide HCl salt of Idelalisib (29.87 g, 80 %). HCl salt of Idelalisib was converted into free base by treating it with aqueous ammonia followed by filtration.

Claims

Claims:
1. A process for the preparation of Idelalisib a compound of formula I
Figure imgf000016_0001
formula I
comprising:
(a) cyclizing a compound of formula II
Figure imgf000016_0002
formula II wherein X is an amino protecting group,
in presence of hexamethyldisilazane and a base in a solvent to obtain a compound of formula III,
Figure imgf000016_0003
formula III
wherein X is an amino protecting group,
(b) deprotecting the compound of formula III, to obtain a compound of formula IV
Figure imgf000017_0001
formula IV
and,
(c) reacting the compound of formula IV either with 6-halopurine to obtain the compound of Formula I or with a compound of formula V
halo
VXS
R
formula V wherein R is an amino protecting group and halo is halogen, to obtain a compound of formula VI
Figure imgf000017_0002
formula VI
wherein R is an amino protecting group, followed by deprotecting the compound of VI to obtain the compound of formula I.
2. The process as in claim 1, wherein in step a, X in the compound of formula II and compound of formula III is teri-butyloxycarbonyl (Boc).
3. The process as in claim 1, wherein in step a, the base is selected from a group consisting of triethylamine, trimethylamine, di-isoropylamine, N,N-diisopropylethylamine, pyridine, imidazole, l,4-diazabicyclo[2.2.2]octane (DABCO), l,8-Diazabicycloundec-7-ene (DBU) and 4-dimethylaminopyridine.
4. The process as in claim 3, wherein the base is triethylamine.
5. The process as in claim 1, wherein in step a, the solvent is selected from a group consisting of acetonitrile, dimethyl sulfoxide, dimethylacetamide or mixtures thereof.
6. The process as in claim 5, wherein the solvent is acetonitrile.
7. The process as in claim 1, wherein R in the compound of formula V and compound of formula VI is methoxymethyl.
8. The process as in claim 1, wherein halo in the compound of formula V is chloro.
9. The process as in claim 1, wherein in step c, the 6-halopurine is 6-chloropurine.
PCT/IN2017/050038 2016-01-29 2017-01-25 Improved process for the preparation of idelalisib WO2017130221A1 (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11358966B2 (en) 2018-03-16 2022-06-14 Johnson Matthey Public Limited Company Pyridine or N,N-dimethyl acetamide solvated solid state forms of solvated idelalisib, their use and preparation

Citations (2)

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Publication number Priority date Publication date Assignee Title
USRE44638E1 (en) * 2004-05-13 2013-12-10 Icos Corporation Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta
WO2015042077A1 (en) * 2013-09-22 2015-03-26 Calitor Sciences, Llc Substituted aminopyrimidine compounds and methods of use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE44638E1 (en) * 2004-05-13 2013-12-10 Icos Corporation Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta
WO2015042077A1 (en) * 2013-09-22 2015-03-26 Calitor Sciences, Llc Substituted aminopyrimidine compounds and methods of use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
UA KSHIRSAGAR ET AL.: "Hexamethyldisilazane-iodine induced intramolecular dehydrative cyclization of diamides: a general access to natural and unnatural quinazolinones", TETRAHEDRON LETTERS, vol. 48, pages 3243 - 3246, XP022021575, Retrieved from the Internet <URL:10.1016/j.tetlet.2007.03.032> [retrieved on 20070312], DOI: doi:10.1016/j.tetlet.2007.03.032 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11358966B2 (en) 2018-03-16 2022-06-14 Johnson Matthey Public Limited Company Pyridine or N,N-dimethyl acetamide solvated solid state forms of solvated idelalisib, their use and preparation

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