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Title:
PROCESS FOR THE PREPARATION OF AN INTERMEDIATE PRODUCT OF IVOSIDENIB
Document Type and Number:
WIPO Patent Application WO/2020/127887
Kind Code:
A1
Abstract:
The application relates to a process for preparing (3,3-difluorocyclobutyl)isonitrile of formula (2) comprising the steps of mixing N-(3,3-difluorocyclobutyl)formamide with an aprotic solvent and reacting the N-(3,3-difluorocyclobutyl)formamide with propylphosphonic acid anhydride in the presence of a tertiary amine base. The intermediate of formula (2) is used for the preparation of ivosidenib of formula (4).

Inventors:
NERDINGER SVEN (AT)
SZARMACH MIROSLAW (PL)
MANIKOWSKI ANDRZEJ (PL)
Application Number:
EP2019/086549
Publication Date:
June 25, 2020
Filing Date:
December 20, 2019
Export Citation:
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Assignee:
SANDOZ AG (CH)
International Classes:
C07C291/10; C07D401/12; C07D401/14
Domestic Patent References:
WO2013107291A12013-07-25
WO2013107405A12013-07-25
WO2005070879A12005-08-04
WO2013107291A12013-07-25
Foreign References:
Other References:
JANETA POPOVICI-MULLER ET AL: "Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers", ACS MEDICINAL CHEMISTRY LETTERS, vol. 9, no. 4, 19 January 2018 (2018-01-19), pages 300 - 305, XP055543764, ISSN: 1948-5875, DOI: 10.1021/acsmedchemlett.7b00421
Attorney, Agent or Firm:
TER MEER STEINMEISTER & PARTNER PATENTANWÄLTE MBB (DE)
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Claims:
Claims

1. Process for preparing (3,3-difluorocyclobutyl)isonitrile according to formula (2)

comprising the steps:

(a) mixing A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de according to formula (1)

with an aprotic solvent (I) and

(b) reacting the A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de according to formula (1) with propylphosphonic acid anhydride (III) in the presence of a tertiary amine base (II).

2. The process of claim 1, wherein step (b) comprises the steps of

(bl) adding the tertiary amine base (II) to the A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de according to formula (1) in an aprotic solvent (I) and subsequently

(b2) adding the propylphosphonic acid anhydride (III).

3. The process of claim 1 or 2, wherein the tertiary amine base (II) is selected from the group consisting of triethylamine, di -/.vo-propy 1 ethyl am i ne, DBU, DABCO, quinuclidine and mixtures thereof.

4. The process of any one of claims 1 to 3, wherein the aprotic solvent (I) is selected from the group consisting of EtOAc, THF, acetonitrile, 1,4-dioxane, DMF, DMA and mixtures thereof.

5. The process of any one of claims 1 to 4, wherein step (b) further comprises:

adding the at least one tertiary amine base and/or the propylphosphonic acid anhydride (III) to the A -(3 , 3 -di fl uorocy cl ob uty 1 )form a i de according to formula (1) at a temperature Ti selected from -78°C to 30°C and subsequently heating the mixture to T2 selected from above 30°C to 77°C.

6. The process of any one of claims 1 to 5 comprising the steps:

(a) mixing A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de according to formula (1) with

EtOAc,

(bl) adding triethylamine (II) to the A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de according to formula (1) in EtOAc at a temperature Tia selected from 0°C to 30°C,

(b2) adding the propylphosphonic acid anhydride (III) at a temperature Tib selected from 0°C to 30 °C and subsequently

(b3) heating the mixture to T2 selected from above 30°C to 77°C.

7. Use of propylphosphonic acid anhydride (III) for preparing (3,3-difluorocyclo- butyl)isonitrile according to formula (2), A - J 1 -(2-chl orophenyl )-2-[(3 , 3 -di fl uorocy cl o- butyl)amino]-2-oxo-ethyl}-N-(5-fluoro-3-pyridyl)-(S)-5-oxo-pyrrolidine-2-carboxamide according to formula

and/or ivosidenib according to formula (4)

8. Process for preparing the compound of formula (3) comprising the steps

(i) preparing (3,3-difluorocyclobutyl)isonitrile according to formula (2) by the process according to any one of claims 1 to 6 and

(ii) reacting the (3,3-difluorocyclobutyl)isonitrile according to formula (2) with 2-chlorobenzaldehyde, 3 -amino-5 -fluoropyri dine and L-pyroglutamic acid to obtain the compound according to formula (3).

9. Process for preparing ivosidenib according to formula (4) comprising the step:

(i) preparing (3,3-difluorocyclobutyl)isonitrile according to formula (2) by the process according to any one of claims 1 to 6,

(ii) reacting the (3,3-difluorocyclobutyl)isonitrile according to formula (2) with 2-chlorobenzaldehyde, 3 -amino-5 -fluoropyri dine, and L-pyroglutamic acid to obtain the compound according to formula (3), and

(iii) reacting the compound according to formula (3) with a compound selected from 2-bromo-4-cyano-pyridine, 4-cyano-2-fluoro-pyridine, 4-cyano-2-iodo-pyridine, and (4-cyano-2-pyridinyl)-trifluoromethanesulfonate and purifying to obtain ivosidenib according to formula (4).

10. The process according to claim 8 or claim 9, wherein the (3,3-difluorocyclo- butyl)isonitrile according to formula (2) prepared in step (i) is reacted in-situ in step (ii) to obtain the ivosidenib according to formula (4) in a one-pot process.

Description:
Process for the preparation of an intermediate product of ivosidenib

Field of the invention The present invention is directed to a process for the preparation of (3,3-difluorocyclo- butyl)isonitrile, an intermediate product in the synthesis of ivosidenib.

Background of the invention The preparation of ivosidenib, IUPAC name /V-[(lri)-l-(2-chlorophenyl)-2-[(3,3-di- fluorocyclobutyl)amino]-2-oxoethyl]-l-(4-cyanopyridin-2-yl)- /V-(5-fluoropyridin-3-yl)- 5-oxo-L-prolinamide, is known from WO 2013/107291. According to WO 2013/107291, the intermediate product (3,3-difluorocyclobutyl)isonitrile is prepared from A -(3 , 3 -di fl uorocy cl ob uty 1 )form a i de in dichloromethane using PPh3 and CCU and TEA (triethylamine) and is subsequently purified by filtration and column chromatography.

The chemical formulae (1), (2), (3), and (4) of A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de, (3,3-difluorocyclobutyl)isonitrile, A - J 1 -(2-chl orophenyl )-2-[(3 , 3 -di fl uorocy cl o- butyl )amino]-2-oxo-ethyl J-A f -(5-fluoro-3-pyridyl)-(S)-5-oxo-pyrrolidine-2-carboxam ide and ivosidenib, respectively, are shown below as well as the process for preparing ivosidenib, as described in WO 2013/107291.

This process for preparing (3,3-difluorocyclobutyl)isonitrile has several disadvantages. Several byproducts are formed so that the (3,3-difluorocyclobutyl)isonitrile needs to be purified by filtration and column chromatography. However, purification by column chromatography is expensive, cumbersome, and not suitable for the purification of an intermediate product in large scale production. Furthermore, PPh3 and CCU are not environmentally friendly and their use causes significant regulatory burden. Furthermore, the use of PPI13 poses several problems. First, PPI13 needs to be added as a solid under N2 atmosphere. Second, PPh3 byproducts are difficult to remove during the purification process.

Therefore, it was an object of the present invention to provide an improved process for preparing (3,3-difluorocyclobutyl)isonitrile that is more cost efficient, requires fewer starting materials, has a higher yield and does not require an additional purification step by filtration and column chromatography.

Summary of the invention

These objects have surprisingly been solved by the process according to the present invention for preparing (3,3-difluorocyclobutyl)isonitrile according to formula (2)

NC

(2)

comprising the steps:

(a) mixing A -(3 , 3 -di fl uorocy cl ob uty 1 )form a i de according to formula (1)

with an aprotic organic solvent (I), and (b) reacting the A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de according to formula (1) with propylphosphonic acid anhydride (III) in the presence of a tertiary amine base (II).

It has surprisingly been found that the use of propylphosphonic acid anhydride (III) in the presence of a tertiary amine base (II) overcomes the problems associated with the prior art process for preparing (3,3-difluorocyclobutyl)isonitrile. In particular, this new process omits the necessity for an additional purification step after the reaction is completed and the (3,3-difluorocyclobutyl)isonitrile can be used directly in the subsequent step of the synthesis of ivosidenib without purification or isolation. Additionally, the two-component system of solid PPh3 and liquid CCU is replaced by one component, making the process more facile to handle. Even further, the process of the present invention results in improved yields over the prior art process.

In another embodiment, the present invention relates to the use of propylphosphonic acid anhydride (III) for preparing a compound according to formulae (2), (3) and/or (4).

In another embodiment, the present invention relates to a process for preparing the compound of formula (3) comprising the steps

(i) preparing (3,3-difluorocyclobutyl)isonitrile according to formula (2) by the process according to the present invention and

(ii) reacting the (3,3-difluorocyclobutyl)isonitrile according to formula (2) with 2- chlorobenzaldehyde, 3-amino-5-fluoropyridine, and L-pyroglutamic acid to obtain the compound according to formula (3).

In yet another embodiment, the present invention relates to a process for preparing ivosidenib according to formula (4) comprising the step

(i) preparing (3,3-difluorocyclobutyl)isonitrile according to formula (2) by the process according to the present invention.

Detailed description

The following definitions are relevant in connection with the embodiments of the present invention.

Aprotic solvents are usually solvents that do not readily donate H + ions under reaction conditions in the presence of the tertiary amine base, i.e. the pK a of the solvent is at least 20. Preferably, aprotic solvents comprise aliphatic, aromatic, ether, amide and ester solvents. Non-limiting examples of aprotic solvents comprise pentane, hexane, benzene, toluene, chloroform, DCM (di chi orom ethane), diethyl ether, 1,2-dimethoxy ether, MTBE (methyl -/t V-butyl ether), 1,4-dioxane, THF (tetrahydrofuran), MTHF (methyl- tetrahydrofuran), EtOAc (ethyl acetate), acetonitrile, DMF (A) A-di methyl form amide), DMA (A) A -di m ethyl acetam i de), DMSO (dimethylsulfoxide), and mixtures thereof.

Tertiary amine bases usually are hindered amines that contain three substituents independently selected from alkyl and aryl substituents. For the present invention, the term“tertiary amine” also refers to secondary cyclic amines and alkali metal acetate. These hindered amines act as a base, but do not act as nucleophiles due to steric hindrance. Non-limiting examples of tertiary amines comprise triethylamine, tributyl- amine, DIPEA ( N , A -di -/.vo-propy 1 ethyl am i ne), DBU (l,8-diazabicyclo[5.4.0]undec-7- ene), TBD (l,5,7-triazabicyclo(4.4.0)dec-5-ene), MTBD (7-methyl-l,5,7-triazabi- cyclo(4.4.0)dec-5-ene), DBN (l,5-diazabicyclo[4.3.0]non-5-ene), TMP (2,2,6,6-tetra- methylpiperidine), DABCO (l,4-diazabicyclo[2.2.2]octane), quinuclidine, and mixtures thereof.

Propylphosphonic acid anhydride, also called //-propylphosphonic anhydride, is usually supplied as 50 vol-% solution in various aprotic solvents under the trade mark T3P ® .

Preferred embodiments according to the invention are defined hereinafter. The preferred embodiments are preferred alone or in combination. Further, it is to be understood that the following preferred embodiments refer to all aspects of the present invention, i.e. the process for preparing the compounds of formula (2), (3) or (4) and the use of propylphosphonic acid anhydride (III), if not specified otherwise.

In an embodiment, step (b) comprises the steps of

(bl) adding the tertiary amine base (II) to the A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de according to formula (1) in an aprotic solvent (I) and subsequently

(b2) adding the propylphosphonic acid anhydride (III).

In another embodiment, step (b) comprises the steps of (bT) adding the propylphosphonic acid anhydride (III) to the A -(3 , 3 -di fl uorocy cl o- butyl)formamide according to formula (1) in an aprotic solvent (I) and subsequently,

(b2’) adding the tertiary amine base (II).

The propylphosphonic acid anhydride (III) and the tertiary amine base (II) may be added in pure, undiluted form or as solution in a suitable aprotic solvent.

In an embodiment, the tertiary amine base (II) is selected from triethylamine, DIPEA, DBU, DABCO, quinuclidine and mixtures thereof. In a preferred embodiment, the tertiary amine base (II) is selected from triethylamine, DIPEA and mixtures thereof.

In an embodiment, the aprotic solvent (I) is a polar solvent. In an embodiment, the aprotic solvent (I) is selected from EtOAc, THF, acetonitrile, 1,4-dioxane, DMF, DMA and mixtures thereof. In a preferred embodiment, the aprotic solvent is EtOAc.

The process may be performed at room temperature. The term room temperature or ambient temperature is to be understood to encompass temperatures from 15°C to 30°C.

In an embodiment, step (b) further comprises: adding the at least one tertiary amine base (II) and/or the propylphosphonic acid anhydride (III) to the A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de according to formula (1) at a temperature Ti selected from -78°C to 30°C and subsequently heating the mixture to T2 selected from above 30°C to 77°C.

In an embodiment, step (b) further comprises: adding the at least one tertiary amine base (II) and/or the propylphosphonic acid anhydride (III) to the A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de according to formula (1) at a temperature Ti selected from 0°C to 30°C and subsequently heating the mixture to T2 selected from above 30°C to 77°C. In an embodiment, step (b) further comprises: adding the at least one tertiary amine base (II) and/or the propylphosphonic acid anhydride (III) to the A -(3 , 3 -di fl uorocy cl ob uty 1 )form a i de according to formula (1) at a temperature Ti selected from 0°C to 30°C and subsequently heating the mixture to the boiling temperature of the aprotic solvent (I).

In an embodiment, temperature Ti is independently selected for the respective addition of the tertiary amine base (Ti a ) and the addition of the propylphosphonic acid anhydride (Tib).

The skilled person will know how to select an appropriate temperature T2 for the heating so that the reaction is run to completion. If the heating temperature T2 is above the boiling temperature of the respective solvent, the reaction is performed under pressure. It is, however, preferred that the process is performed at ambient pressure.

In a more preferred embodiment, the process for preparing (3,3-difluorocyclo- butyl)isonitrile according to formula (2) comprising the steps:

(a) mixing A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de according to formula (1) with

EtOAc,

(bl) adding triethylamine to the A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de according to formula (1) in EtOAc

(b2) adding the propylphosphonic acid anhydride (III).

In an even more preferred embodiment, the process for preparing (3,3-difluorocyclo- butyl)isonitrile according to formula (2) comprises the steps:

(a) mixing A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de according to formula (1) with

EtOAc,

(bl) adding triethylamine (II) to the A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de according to formula (1) in EtOAc at a temperature Ti a selected from 0°C to 30°C, (b2) adding the propylphosphonic acid anhydride (III) at a temperature Ti b selected from 0°C to 30 °C and subsequently

(b3) heating the mixture to T2 selected from above 30°C to 77°C.

In an embodiment, the process for preparing ivosidenib according to formula (4) comprises the steps

(i) preparing (3,3-difluorocyclobutyl)isonitrile according to formula (2) by the process according to any one of claims 1 to 5,

(ii) reacting the (3,3-difluorocyclobutyl)isonitrile according to formula (2) with 2-chlorobenzaldehyde, 3 -amino-5 -fluoropyri dine, and L-pyroglutamic acid to obtain the compound according to formula (3), and

(iii) reacting the compound according to formula (3) with a compound selected from 2-bromo-4-cyano-pyridine, 4-cyano-2-fluoro-pyridine, 4-cyano-2-iodo-pyridine, and (4-cyano-2-pyridinyl)-trifluoromethanesulfonate, and purifying to obtain ivosidenib according to formula (4).

This reaction can be referred to as a Ugi one-pot reaction. This reaction is a four component reaction (U-4CR), wherein the components comprise an aldehyde/ketone (2- chlorobenzaldehyde), an amine (3-amino-5-fluoropyridine), a carboxylic acid (L-pyro glutamic acid) and an isonitrile functional group ((3,3-difluorocyclobutyl)isonitrile).

The purification in step (iii) comprises separating the diastereomers to obtain ivosidenib. The skilled person will know suitable techniques, such as high-performance liquid column chromatography (HPLC) or recrystallization from suitable solvents, to obtain ivosidenib as the desired diastereomer.

The reaction in step (ii) with a compound selected from 2-bromo-4-cyano-pyridine, 4- cyano-2-fluoro-pyridine, 4-cyano-2-iodo-pyridine, and (4-cyano-2-pyridinyl)-trifluoro- methanesulfonate, is a metal-catalyzed cross coupling reaction, e.g. a Buchwald- Hartwig coupling. Suitable reaction conditions, base, ligand and metal catalyst are known to the person skilled in the art. It is preferred that the metal catalyst is a palladium catalyst and that the ligand is a sterically hindered phosphine ligand, preferably a dialkylbiaryl phosphine, dppf (l, l'-bis(diphenylphosphino)ferrocene) or XantPhos ligand (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene). It is even more preferred that the metal catalyst is Pd 2 (dba) 3 and the ligand is XantPhos.

In a preferred embodiment, the process for preparing the compound of formula (3) and the process for preparing ivosidenib according to formula (4) comprises the steps

(i) preparing (3,3-difluorocyclobutyl)isonitrile according to formula (2) by the process of the present invention and reacting the 3,3-difluorocyclobutyl)isonitrile according to formula (2) prepared in step (i) in-situ in step (ii) to obtain the compound of formula (3) in a one-pot process.

It is to be understood that in-situ and one-pot refer to a process wherein either both step (i) and step (ii) are performed in the same reaction vessel and only the additional reactants needed in step (ii) are further added to the reaction vessel or the 3,3-difluorocyclobutyl)isonitrile prepared in step (i) is obtained as a crude product by routine work-up and directly used in step (ii) without further purification by e.g. filtration or column chromatography.

Example

A -(3 , 3 -di fl uorocy cl ob uty 1 )form am i de was dissolved in EtOAc and TEA was added at 5°C. Propylphosphonic acid anhydride (III) (solution in EtOAc, 50 vol.-%) was added dropwise. After complete addition, the reaction was heated to reflux (77°C) until no amide was detected. The solution was transferred to a separating funnel and water was added. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic solvents were removed in vacuo to obtain the product as an oil. This material was used for the next step without further purification.