PROCESS AND INTERMEDIATES FOR THE PRODUCTION OF FORMULA (I)

A process and intermediates for making the compound of Formula (I).

The present specification relates to a process and intermediates for the production of the compound of Formula (I):

or a pharmaceutically acceptable salt or co-crystal thereof.

International patent application WO2017/080979 A1 describes the compound of Formula (I) (Example 18 therein) as an inhibitor of ERK, and that it is useful in the treatment of cancer. WO2017/080979 A1 further describes the adipic acid co-crystal of the compound of Formula (I) (Example 34 therein). The compound of Formula (I) is also known by its chemical name: (R)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-2-(5-methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin-4-yl)-6,7-dihydroimidazo [1,2-a] pyrazin-8(5H)-one.

WO2017/080979 A1 further describes a method for the production of the compound of Formula (I), with the method summarised in Scheme 1 below. The following abbreviations are used in Scheme 1: SEM=2-(trimethylsilyl)ethoxymethyl; NBS=N-Bromosuccinimide; pin=pinacolato; Ac=acyl, TFA=trifluoroacetic acid; 18-crown-6=1,4,7,10,13,16-hexaoxacyclooctadecane; and Boc=tert-butyloxycarbonyl.

Although the synthetic route described in the prior art provides a reliable method for producing the compound of Formula (I) on a laboratory scale, the route has a number of drawbacks. These include:(i) The synthetic route is relatively long, with 10 isolated intermediates in the longest linear sequence;(ii) The route depends on the compound of Formula (A), otherwise known by the chemical name tert-butyl (4S)-4-(methoxymethyl)-2,2-dioxo-oxathiazolidine-3-carboxylate, which is of high cost and limited chemical stability at room temperature; and(iii) The compound of Formula (I) formed by this method required purification by chromatography, which is expensive on large scale.

Thus, whilst the synthetic route shown in Scheme 1 is adequate to make the compound of Formula (I) on a laboratory scale, there is a need for a process suitable for the large-scale production of the compound of Formula (I).

We have now found an improved synthetic process which substantially overcomes the drawbacks described above. The improved process is summarised in Scheme 2 below.

In Scheme 2 the following further abbreviations are used: Piv=pivaloyl; RuPhos Pd G3=(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl-crysta)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate; CDMT=2-chloro-4,6,-dimethoxy-1,3,5-triazine; DIPEA=N,N-diisopropylethylamine; mCPBA=meta-chloroperoxybenzoic acid; and LHNDS=lithium bis(trimethylsilyl)amide. Square brackets indicate that it was not necessary to isolate the compound during the synthetic sequence.

The improved process of Scheme 2 was shown to be suitable for manufacture of the compound of Formula (I) on a multikilogram scale. In particular:(i) It is not necessary to isolate the compounds Formula (V) or Formula (III), so only 6 intermediates require isolation;(ii) The improved process avoids the need for the compound of Formula (A), reducing the cost of goods; and(iii) The compound of Formula (I) is formed in sufficient purity that it can be isolated by crystallisation with adipic acid to form the adipic acid co-crystal of the compound of Formula (I), avoiding the need for chromatography.

In the first aspect, this specification provides a process for the production of the compound of Formula (I):

comprising a reaction of a compound of Formula (II), (6R)-7-[(3,4-difluorophenyl)methyl]-6-(methoxymethyl)-2-(5-methyl-2-methylsulfonyl-pyrimidin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-8-one:

In the next aspect, this specification provides a compound of Formula (II), (6R)-7-[(3,4-difluorophenyl)methyl]-6-(methoxymethyl)-2-(5-methyl-2-methylsulfonyl-pyrimidin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-8-one:

In the next aspect, this specification provides a compound of Formula (III), (6R)-7-[(3,4-difluorophenyl)methyl]-6-(methoxymethyl)-2-(5-methyl-2-methylsulfanyl-pyrimidin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-8-one:

In the next aspect, this specification provides a compound of Formula (IV), (6R)-7-[(3,4-difluorophenyl)methyl]-6-(hydroxymethyl)-2-(5-methyl-2-methylsulfanyl-pyrimidin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-8-one:

In the next aspect, this specification provides a compound of Formula (V), N-[(3,4-difluorophenyl)methyl]-4-(5-methyl-2-methylsulfanyl-pyrimidin-4-yl)-1-[[(2R)-oxiran-2-yl]methyl]imidazole-2-carboxamide:

In the next aspect, this specification provides a compound of Formula (VI), N-[(3,4-difluorophenyl)methyl]-4-(5-methyl-2-methylsulfanyl-pyrimidin-4-yl)-1H-imidazole-2-carboxamide:

In the next aspect, this specification provides a compound of Formula (VII), 4-(5-methyl-2-methylsulfanyl-pyrimidin-4-yl)-1H-imidazole-2-carboxylic acid:

As set forth above, there is provided a process for the production of a compound of Formula (I):

comprising the step of (i) the reaction of a compound of Formula (II), (6R)-7-[(3,4-difluorophenyl)methyl]-6-(methoxymethyl)-2-(5-methyl-2-methylsulfonyl-pyrimidin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-8-one:

In an embodiment, the reaction is conducted in the presence of a base, such as lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, potassium tert-butoxide or sodium hydride. In a further embodiment, the base is lithium bis(trimethylsilyl)amide.

In embodiments, the process comprises the further step of (ii) making the compound of Formula (II) from the reaction of a compound of Formula (I), (6R)-7-[(3,4-difluorophenyl)methyl]-6-(methoxymethyl)-2-(5-methyl-2-methylsulfanyl-pyrimidin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-8-one:

and an oxidising agent. In embodiments, the oxidising agent is hydrogen peroxide, oxone or mCPBA. In further embodiments, the oxidising agent is mCPBA.

In embodiments, the process comprises the further step of (iii) making the compound of Formula (III) from the reaction of a compound of Formula (IV), (6R)-7-[(3,4-difluorophenyl)methyl]-6-(hydroxymethyl)-2-(5-methyl-2-methylsulfanyl-pyrimidin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-8-one:

and a methylating agent, such as methyl iodide, dimethyl sulfate or methyl triflate. In further embodiments, the methylating agent is methyl iodide. In further embodiments, the reaction is conducted in the presence of a base, such as sodium hydride, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide or potassium tert-butoxide. In further embodiments, the base is sodium hydride.

In embodiments, the process comprises the further step of (iv) making the compound of Formula (IV) from the reaction of a compound of Formula (V), N-[(3,4-difluorophenyl)methyl]-4-(5-methyl-2-methylsulfanyl-pyrimidin-4-yl)-1-[[(2R)-oxiran-2-yl]methyl]imidazole-2-carboxamide:

and lithium bromide.

In embodiments, the process comprises the further step of (v) making the compound of Formula (V) from the reaction of a compound of Formula (VI), N-[(3,4-difluorophenyl)methyl]-4-(5-methyl-2-methylsulfanyl-pyrimidin-4-yl)-1H-imidazole-2-carboxamide:

In embodiments, the reaction is conducted in the presence of 4-dimethylaminopyridine. In further embodiments, the reaction is conducted in the presence of a base, such as DIPEA, triethylamine or tributylamine. In further embodiments, the base is DIPEA.

In embodiments, the process comprises the further step of (vi) making the compound of Formula (VI) from the reaction of a compound of Formula (VII), 4-(5-methyl-2-methylsulfanyl-pyrimidin-4-yl)-1H-imidazole-2-carboxylic acid:

In further embodiments, the reaction is conducted in the presence of a peptide coupling agent, such as 2-chloro-4,6-dimethoxy-1,3,5-triazine in combination with 4-methylmorpholine, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in combination with hydroxybenzotriazole, benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate, propanephosphonic acid anhydride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 1,1′-carbonyldiimidazole, an acid halide forming reagent or an acid anhydride forming reagent. In further embodiments, the peptide coupling agent is 2-chloro-4,6-dimethoxy-1,3,5-triazine in combination with 4-methylmorpholine.

In an embodiment, there is provided a compound of Formula (II), (6R)-7-[(3,4-difluorophenyl)methyl]-6-(methoxymethyl)-2-(5-methyl-2-methylsulfonyl-pyrimidin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-8-one:

In a further embodiment, the compound of Formula (I) is in an enantiomeric excess (% ee) of ≥95%, ≥98% or ≥99%. In a further embodiment, the compound of Formula (II) is in an enantiomeric excess (% ee) of ≥99%.

In an embodiment, there is provided a compound of Formula (II), (6R)-7-[(3,4-difluorophenyl)methyl]-6-(methoxymethyl)-2-(5-methyl-2-methylsulfanyl-pyrimidin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-8-one:

In a further embodiment, the compound of Formula (III) is in an enantiomeric excess (% ee) of ≥95%, ≥98% or ≥99%. In a further embodiment, the compound of Formula (II) is in an enantiomeric excess (% ee) of ≥99%.

In an embodiment, there is provided a compound of Formula (IV), (6R)-7-[(3,4-difluorophenyl)methyl]-6-(hydroxymethyl)-2-(5-methyl-2-methylsulfanyl-pyrimidin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-8-one:

In a further embodiment, the compound of Formula (IV) is in an enantiomeric excess (% ee) of ≥95%, ≥98% or ≥99%. In a further embodiment, the compound of Formula (IV) is in an enantiomeric excess (% ee) of ≥99%.

In an embodiment, there is provided a compound of Formula (V), N-[(3,4-difluorophenyl)methyl]-4-(5-methyl-2-methylsulfanyl-pyrimidin-4-yl)-1-[[(2R)-oxiran-2-yl]methyl]imidazole-2-carboxamide:

In a further embodiment, the compound of Formula (V) is in an enantiomeric excess (% ee) of ≥95%, ≥98% or ≥99%. In a further embodiment, the compound of Formula (V) is in an enantiomeric excess (% ee) of ≥99%.

In an embodiment, there is provided a compound of Formula (VI), N-[(3,4-difluorophenyl)methyl]-4-(5-methyl-2-methylsulfanyl-pyrimidin-4-yl)-1H-imidazole-2-carboxamide:

In an embodiment, there is provided a compound of Formula (VII), 4-(5-methyl-2-methylsulfanyl-pyrimidin-4-yl)-1H-imidazole-2-carboxylic acid:

Compounds described in this specification may form acid addition salts or base addition salts.

In general, an acid addition salt can be prepared using various inorganic or organic acids. Such salts can typically be formed by, for example, mixing the compound with an acid (e.g., a stoichiometric amount of acid) using various methods known in the art. This mixing may occur in water, an organic solvent (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile), or an aqueous/organic mixture. An acid addition salt may for example be formed using an inorganic acid selected from the group consisting of hydrochloric acid.

For compounds that may form base addition salts, it may be possible to make, for example, an alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as a calcium) salt by treating a compound with an alkali metal or alkaline earth metal hydroxide or alkoxide (e.g., an ethoxide or methoxide) or a suitably basic organic amine (e.g., a choline or meglumine) in an aqueous medium.

The general principles and techniques of preparing salts can be found in Berge et al., J. Pharm. Sci., 66, 1-19 (1977).

Compounds described in this specification may exist in solvated forms and unsolvated forms. For example, a solvated form may be a hydrated form, such as a hemi-hydrate, a mono-hydrate, a di-hydrate, a tri-hydrate or an alternative quantity thereof. This specification encompasses all such solvated and unsolvated forms.

Atoms of the compounds and salts described in this specification may exist as their isotopes. This specification encompasses all such compounds where an atom is replaced by one or more of its isotopes (for example a compound where one or more carbon atom is an11C or13C carbon isotope, or where one or more hydrogen atoms is a2H or3H isotope).

The compound of Formula (I), prepared by the processes described herein, may be used to provide formulations, such as tablets, for use as medicaments for the treatment of cancer. Suitable formulations and therapeutic uses of the medicaments so prepared are described in WO2017/080979 A1, the contents of which are hereby incorporated by reference.

The various embodiments are illustrated by the following Examples. The disclosure is not to be interpreted as being limited to the Examples. During the preparation of the Examples, generally:

i. Operations were carried out at ambient temperature, i.e. in the range of about 17 to 30° C. and under an atmosphere of an inert gas such as nitrogen unless otherwise stated;

ii. Yields, where present, are not necessarily the maximum attainable;

iv. Compounds were also characterised by high resolution mass spectrometry following liquid chromatography (LC-MS). LC-MS was carried out using a Waters H-Class Bio UPLC connected to a Waters Synapt G2-Si ESI mass spectrometer operating in positive electrospray mode and an Acquity BEH RP18 column (2.1×100 mm, 1.7 mm) at a flow rate of 0.6 mL/min using a solvent system of 90/5/5 A/B/C to 5/90/5 A/B/C over 12 minutes followed by a hold at 5/90/5 A/B/C for 1.2 minutes, where A=water, B=acetonitrile and C=250 mM ammonium acetate in water;

v. IUPAC names were generated using BIOVIA™ Draw, version 16.1.

vii. (6R)-7-[(3,4-Difluorophenyl)methyl]-6-(methoxymethyl)-2-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5,6-dihydroimidazo[1,2-a]pyrazin-8-one adipic acid co-crystal seed corresponds to Example 34 of WO2017/080979 A1 (page 180 therein) and can be prepared according to the method disclosed therein.

(6R)-7-[(3,4-difluorophenyl)methyl]-6-(methoxymethyl)-2-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5,6-dihydroimidazo[1,2-a]pyrazin-8-one, and the adipic acid co-crystal thereof

A mixture of (6R)-7-[(3,4-difluorophenyl)methyl]-6-(methoxymethyl)-2-(5-methyl-2-methylsulfonyl-pyrimidin-4-yl)-5,6-dihydroimidazo[1,2-a]pyrazin-8-one (35.0 g, 73.3 mmol) and 2-methylpyrazol-3-amine (21.4 g, 220 mmol) in THF (875 mL) was stirred at 20° C. The mixture was then concentrated by distillation at atmospheric pressure. Further THF (175 mL) was added to the mixture, and the mixture was again concentrated by distillation at atmospheric pressure. A Karl-Fisher analysis confirmed that the water content of the mixture was below 400 ppm. The mixture was then cooled to −10° C. and treated with a pre-formed mixture of LHMDS (1 M in THF) and THF (220 mL) over 30 minutes at −10° C. THF (17.5 mL) was added to the mixture as a line wash. The mixture was stirred for 45 minutes at −10° C. before being treated with a solution of phosphoric acid (366 mmol, 85 mass %, 42.3 g) in water (131 mL) over 15 minutes. The mixture was stirred for a further 10 minutes at 15° C., and then the aqueous layer was removed. The organic layer was treated with a solution of sodium chloride (427 mmol, 25.0 g) and phosphoric acid (366 mmol, 85 mass %, 42.3 g) in water (150 mL) at 15° C. The mixture was stirred for 10 minutes at 15° C. and the aqueous layer removed. The organic layer was treated with a solution of sodium chloride (427 mmol, 25.0 g) in water (150 mL) and stirred for 10 minutes at minutes at 15° C. The aqueous layer was removed, and the organic layer treated with a solution of sodium bicarbonate (12.0 g) in water (169 mL) over 15 minutes at 15° C. The mixture was stirred for a further 10 minutes at 15° C. and the aqueous layer removed. The organic layer was concentrated by atmospheric distillation. The residue was treated with ethanol (599 mL) and the resulting mixture concentrated by atmospheric distillation to give crude product (6R)-7-[(3,4-difluorophenyl)methyl]-6-(methoxymethyl)-2-[5-methyl-2-[(2-methylpyrazol-3-yl)amino]pyrimidin-4-yl]-5,6-dihydroimidazo[1,2-a]pyrazin-8-one.