WO2017009333A1 - Method for purifying idelalisib - Google Patents

Method for purifying idelalisib Download PDF

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Publication number
WO2017009333A1
WO2017009333A1 PCT/EP2016/066532 EP2016066532W WO2017009333A1 WO 2017009333 A1 WO2017009333 A1 WO 2017009333A1 EP 2016066532 W EP2016066532 W EP 2016066532W WO 2017009333 A1 WO2017009333 A1 WO 2017009333A1
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Prior art keywords
idelalisib
acid addition
addition salt
salt
process according
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Application number
PCT/EP2016/066532
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French (fr)
Inventor
Libor Vyklicky
Miroslav Zabadal
Original Assignee
Synthon B.V.
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Publication date
Application filed by Synthon B.V. filed Critical Synthon B.V.
Priority to EP16738171.4A priority Critical patent/EP3322708A1/en
Publication of WO2017009333A1 publication Critical patent/WO2017009333A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to the preparation of pharmaceuticals.
  • it relates to a stable acid addition salt of idelalisib (1) and its use as intermediate in a purification process for idelalisib.
  • Idelalisib (WO2005113556) is a ⁇ 3 ⁇ inhibitor of structure (1) and is used for the treatment of patients with follicular lymphoma, relapsed small lymphocytic lymphoma and relapsed chronic lymphocytic leukaemia.
  • WO2005113556 describes the preparation of idelalisib as depicted below,
  • WO2013134288 describes polymorphic forms of idelalisib.
  • One of the examples for preparing polymorphic form I of idelalisib uses the hydrochloride salt of idelalisib as intermediate.
  • the hydrochloride salt is however not isolated, nor is it used as a means to purify idelalisib.
  • the hydrochloride salt is prepared by treating idelalisib with 12N hydrochloric acid in an ethanol/water mixture. The resulting salt is described as a suspension and is not isolated, but treated with aqueous base to convert the salt back into idelalisib free base and further processed to prepare polymorphic form I crystals of idelalisib as a free base.
  • the present invention relates to a process for purifying idelalisib of formula (1),
  • the salt is a salt of idelalisib with hydrochloric or nitric acid. Most preferred is the salt with nitric acid.
  • the first object of the invention is a process for purifying idelalisib comprising the step of isolating an acid addition salt of idelalisib.
  • idelalisib does not form solid acid addition salts easily, we found that precipitation or crystallisation of idelalisib in salt form, if formed, is an effective method to reduce the impurity level.
  • the method is more convenient and economic on an industrial scale than the chromatography process of WO2005113556.
  • hydrochloride and nitrate were particularly isolable in good yields.
  • the hydrochloric or nitric acid addition salts of idelalisib are the preferred salts to be used in the purification process of this invention. Most preferred is the nitrate salt.
  • Idelalisib nitrate has surprisingly low hygroscopicity when compared to the other acid addition salts which may take on water when exposed to moisture.
  • the preferred solvents for preparing the acid addition salts of idelalisib are solvents or solvent mixtures comprising an ether and/or a halogen containing solvent.
  • ethers are: diethyl ether, THF, 2-Me-THF and dioxanes.
  • Typical examples of halogen containing solvents are dichloromethane, chloroform and dichloroethane. More preferred are solvents or solvent mixtures comprising ethers and/or halogen containing solvents with a boiling point above 50°C. Most preferred are solvents or solvent mixtures comprising 1 ,4-dioxane and/or chloroform.
  • the salts of idelalisib can be prepared by adding a sufficient amount of acid to idelalisib.
  • the acid can be added to a reaction mixture comprising idelalisib after workup of a reaction mixture comprising idelalisib, or it can be added after isolation of raw idelalisib.
  • Precipitation or crystallisation of the nitric acid salt of idelalisib can start spontaneously or may be induced by methods common in the art. Typical examples of such methods to induce precipitation or crystallisation are: allowing a warm solution to cool down, addition of anti solvent to the solution, concentration of a solution, addition of seed crystals, and combinations of these methods.
  • idelalisib Treatment of idelalisib, with an assay of 88%, with 1 equivalent of nitric acid leads to formation of a nitrate salt of idelalisib with 97.8 % purity. If the precipitation/crystallisation of the idelalisib salt does not immediately lead to the desired purity level, the material may be recrystallised, or treated with base to repeat the process leading to precipitation or crystallisation of the idelalisib salt to increase the purity level.
  • the material can be treated with base to liberate idelalisib free base with an increased purity level.
  • Procedures and materials to use for liberating idelalisib from its acid addition salt are generally known to the skilled artisan.
  • Idelalisib hydrochloride is a hygroscopic compound and needs to be protected from moisture if stored for a longer period of time. Other salts have also showed hygroscopicity. Hygroscopic compounds are less attractive for use as active ingredients in pharmaceutical dosage forms. They are difficult to handle since costly and burdensome measures must be taken to prevent exposure to moisture during formulation since water may affect stability and decrease bioavailability.
  • idelalisib nitrate is not hygroscopic and stable in storage, which additionally makes it a viable alternative active ingredient to use in pharmaceutical dosage forms.
  • the solubility of idelalisib nitrate is higher compared to idelalisib as a free base and may allow preparation of pharmaceutical dosage forms with improved aqueous dissolution properties and higher bioavailability levels that are not realisable with the less soluble free base of idelalisib.
  • Purity levels in the examples are levels as determined by uncalibrated HPLC with UV detection.
  • idelalisib hydrochloride 0.036g was mixed with 3 ml of 1,4-dioxane and 0.015 ml of hydrochloric acid (35%). The mixture was heated to 90°C and allowed to cool to 20°C. The precipitate was isolated to yield 0.030 g (77%) of idelalisib hydrochloride.
  • idelalisib hydrochloride 0.036g was mixed with 3 ml of 1,4-dioxane and 7.57 ⁇ of hydrochloric acid (35%). The mixture was heated to 90°C and allowed to cool to 20°C. The precipitate was isolated and dried in a vacuum oven (100 torr, 25°C) to yield 0.035 g (85%) of idelalisib hydrochloride.
  • idelalisib 0.036g was mixed with 3 ml of 1,4-dioxane and 5.94 ⁇ of nitric acid (65%). The mixture was heated to 90°C and allowed to cool to 20°C. The precipitate was isolated to yield 0.025 g (60.9%) of idelalisib nitrate.
  • Example 4 Preparation of idelalisib nitrate
  • idelalisib 0.138g was mixed with 3 ml of chloroform and 0.023 ml of nitric acid (65%). The mixture was heated to 55°C and cooled to 0°C. The precipitate was isolated to yield 0.160 g (100%) of idelalisib nitrate.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a new purification process of idelalisib (1). The process includes the steps of creating an acid addition salt of idelalisib and precipitation or crystallisation of such a salt..

Description

METHOD FOR PURIFYING IDELALISIB
BACKGROUND OF THE PRESENT INVENTION
This invention relates to the preparation of pharmaceuticals. In particular it relates to a stable acid addition salt of idelalisib (1) and its use as intermediate in a purification process for idelalisib.
Idelalisib (WO2005113556) is a ΡΙ3Κδ inhibitor of structure (1) and is used for the treatment of patients with follicular lymphoma, relapsed small lymphocytic lymphoma and relapsed chronic lymphocytic leukaemia. WO2005113556 describes the preparation of idelalisib as depicted below,
Figure imgf000003_0001
The process for preparing idelalisib as described in WO2005113556 requires chromatographic purification steps for intermediates (4) and (3), and for idelalisib (1). Chromatographic purification steps are tedious and expensive process steps on an industrial scale. Therefore, there is a need for alternative methods which reduce the number of chromatographic purification steps in the preparation of idelalisib.
WO2013134288 describes polymorphic forms of idelalisib. One of the examples for preparing polymorphic form I of idelalisib uses the hydrochloride salt of idelalisib as intermediate. The hydrochloride salt is however not isolated, nor is it used as a means to purify idelalisib. The hydrochloride salt is prepared by treating idelalisib with 12N hydrochloric acid in an ethanol/water mixture. The resulting salt is described as a suspension and is not isolated, but treated with aqueous base to convert the salt back into idelalisib free base and further processed to prepare polymorphic form I crystals of idelalisib as a free base. No other acid addition salts of idelalisib are known. The experiments in WO2013134288 do not present any evidence that the crystallisation of idelalisib (as a free base) in any of the polymorphic forms increases the purity of the material.
BRIEF DESCRIPTION OF THE PRESENT INVENTION
The present invention relates to a process for purifying idelalisib of formula (1),
Figure imgf000004_0001
comprising the step of isolating an acid addition salt of idelalisib. Preferably the salt is a salt of idelalisib with hydrochloric or nitric acid. Most preferred is the salt with nitric acid.
DETAILED DESCRIPTION OF THE INVENTION
The first object of the invention is a process for purifying idelalisib comprising the step of isolating an acid addition salt of idelalisib. Although idelalisib does not form solid acid addition salts easily, we found that precipitation or crystallisation of idelalisib in salt form, if formed, is an effective method to reduce the impurity level. The method is more convenient and economic on an industrial scale than the chromatography process of WO2005113556.
From the known pharmaceutically acceptable salts, hydrochloride and nitrate were particularly isolable in good yields. The hydrochloric or nitric acid addition salts of idelalisib are the preferred salts to be used in the purification process of this invention. Most preferred is the nitrate salt.
Idelalisib nitrate has surprisingly low hygroscopicity when compared to the other acid addition salts which may take on water when exposed to moisture. The preferred solvents for preparing the acid addition salts of idelalisib are solvents or solvent mixtures comprising an ether and/or a halogen containing solvent. Typical examples of ethers are: diethyl ether, THF, 2-Me-THF and dioxanes. Typical examples of halogen containing solvents are dichloromethane, chloroform and dichloroethane. More preferred are solvents or solvent mixtures comprising ethers and/or halogen containing solvents with a boiling point above 50°C. Most preferred are solvents or solvent mixtures comprising 1 ,4-dioxane and/or chloroform.
The salts of idelalisib can be prepared by adding a sufficient amount of acid to idelalisib. The acid can be added to a reaction mixture comprising idelalisib after workup of a reaction mixture comprising idelalisib, or it can be added after isolation of raw idelalisib.
Precipitation or crystallisation of the nitric acid salt of idelalisib can start spontaneously or may be induced by methods common in the art. Typical examples of such methods to induce precipitation or crystallisation are: allowing a warm solution to cool down, addition of anti solvent to the solution, concentration of a solution, addition of seed crystals, and combinations of these methods.
Treatment of idelalisib, with an assay of 88%, with 1 equivalent of nitric acid leads to formation of a nitrate salt of idelalisib with 97.8 % purity. If the precipitation/crystallisation of the idelalisib salt does not immediately lead to the desired purity level, the material may be recrystallised, or treated with base to repeat the process leading to precipitation or crystallisation of the idelalisib salt to increase the purity level.
After isolation of the precipitate/crystals, the material can be treated with base to liberate idelalisib free base with an increased purity level. Procedures and materials to use for liberating idelalisib from its acid addition salt are generally known to the skilled artisan.
Idelalisib hydrochloride is a hygroscopic compound and needs to be protected from moisture if stored for a longer period of time. Other salts have also showed hygroscopicity. Hygroscopic compounds are less attractive for use as active ingredients in pharmaceutical dosage forms. They are difficult to handle since costly and burdensome measures must be taken to prevent exposure to moisture during formulation since water may affect stability and decrease bioavailability.
Surprisingly idelalisib nitrate is not hygroscopic and stable in storage, which additionally makes it a viable alternative active ingredient to use in pharmaceutical dosage forms. The solubility of idelalisib nitrate is higher compared to idelalisib as a free base and may allow preparation of pharmaceutical dosage forms with improved aqueous dissolution properties and higher bioavailability levels that are not realisable with the less soluble free base of idelalisib.
The invention will be further illustrated by the following, non-limiting, examples.
EXAMPLES
Purity levels in the examples are levels as determined by uncalibrated HPLC with UV detection.
Example 1. Preparation of idelalisib hydrochloride
0.036g of idelalisib was mixed with 3 ml of 1,4-dioxane and 0.015 ml of hydrochloric acid (35%). The mixture was heated to 90°C and allowed to cool to 20°C. The precipitate was isolated to yield 0.030 g (77%) of idelalisib hydrochloride.
Example 2. Preparation of idelalisib hydrochloride
0.036g of idelalisib was mixed with 3 ml of 1,4-dioxane and 7.57 μΐ of hydrochloric acid (35%). The mixture was heated to 90°C and allowed to cool to 20°C. The precipitate was isolated and dried in a vacuum oven (100 torr, 25°C) to yield 0.035 g (85%) of idelalisib hydrochloride.
Example 3. Preparation of idelalisib nitrate
0.036g of idelalisib was mixed with 3 ml of 1,4-dioxane and 5.94 μΐ of nitric acid (65%). The mixture was heated to 90°C and allowed to cool to 20°C. The precipitate was isolated to yield 0.025 g (60.9%) of idelalisib nitrate. Example 4. Preparation of idelalisib nitrate
0.138g of idelalisib was mixed with 3 ml of chloroform and 0.023 ml of nitric acid (65%). The mixture was heated to 55°C and cooled to 0°C. The precipitate was isolated to yield 0.160 g (100%) of idelalisib nitrate.
Example 5. Preparation of idelalisib nitrate starting from raw idelalisib
Crude idelalisib (0.680 g, 1.277 mmol) with an assay of 88% was dissolved in Chloroform (12 ml) and Nitric acid (0.088 ml, 65%, 1.277 mmol) was added during 1 minute. The mixture was stirred under argon at room temperature (22 - 25 °C) for 0.5 r. No precipitate was formed in the yellow solution. The solution was concentrated on a rotary evaporator (100 mbar; 35°C) to approximately 7 ml. A yellow precipitate formed and was isolated by filtration. Yield: 0.576g (82%) of yellow crystals with a purity of 97.80%.

Claims

1. A process for purifying idelalisib of formula (1) comprising the step of isolating an acid addition salt of idelalisib,
Figure imgf000008_0001
2. The process of claim 1 wherein the acid addition salt of idelalisib is a salt of idelalisib with hydrochloric acid or nitric acid.
3. A process according to claim 1 or 2, comprising the steps of:
(a) Mixing idelalisib free base with an acid; and
(b) Isolating the acid addition salt of idelalisib.
4. A process according to claims 1-3 wherein the acid addition salt of idelalisib is
prepared in a solvent or solvent mixture comprising an ether and/or a halogenated solvent.
5. A process according to claims 1-4 wherein the ether and/or a halogenated solvents are ether and/or a halogenated solvents with a boiling point above 50°C.
6. A process according to claims 1-5 wherein the ether and/or a halogenated solvents are 1,4-dioxane and/or chloroform.
7. A process according to claims 1-6 wherein the solvent is 1,4-dioxane.
8. A process according to claims 1-6 wherein the solvent is chloroform.
9. A process according to claims 1-8 comprising precipitating or crystallising the acid addition salt of idelalisib.
10. A process for preparing idelalisib according to claims 1-9, further comprising the step of treating a nitric acid addition salt of idelalisib with a base to prepare idelalisib free base.
11. A nitric acid addition salt of idelalisib of formula (1).
12. The nitric acid addition salt of idelalisib of claim 7 in hydrate or solvate form.
13. A pharmaceutical composition comprising a nitric acid addition salt of idelalisib.
PCT/EP2016/066532 2015-07-13 2016-07-12 Method for purifying idelalisib WO2017009333A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013134288A1 (en) * 2012-03-05 2013-09-12 Gilead Calistoga Llc Polymorphic forms of (s)-2-(1-(9h-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3h)-one
US20150175606A1 (en) * 2013-12-20 2015-06-25 Gilead Calistoga Llc Polymorphic forms of a hydrochloride salt of (s)-2-(1-(9h-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3h)-one
EP3031808A1 (en) * 2014-12-09 2016-06-15 ratiopharm GmbH Salt of idelalisib
WO2016108206A2 (en) * 2014-12-31 2016-07-07 Dr. Reddy’S Laboratories Limited Processes for preparation of idelalisib and intermediates thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013134288A1 (en) * 2012-03-05 2013-09-12 Gilead Calistoga Llc Polymorphic forms of (s)-2-(1-(9h-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3h)-one
US20150175606A1 (en) * 2013-12-20 2015-06-25 Gilead Calistoga Llc Polymorphic forms of a hydrochloride salt of (s)-2-(1-(9h-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3h)-one
EP3031808A1 (en) * 2014-12-09 2016-06-15 ratiopharm GmbH Salt of idelalisib
WO2016108206A2 (en) * 2014-12-31 2016-07-07 Dr. Reddy’S Laboratories Limited Processes for preparation of idelalisib and intermediates thereof

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