Pharmaceutical process and intermediates

Abstract

To provide intermediates for safe, cost-effective, efficient and ecological production of a compound 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (hereafter referred to as a compound of formula (I)).SOLUTION: The invention provides, e.g., a compound of formula (II) (where LG1 is a leaving group), which is an intermediate in production of a compound of formula (I), by reacting a compound of formula (III) with an oxidative enzyme.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present disclosure relates to the large-scale manufacture of pharmaceutical compounds and novel intermediates for use in the manufacture thereof. [Background technology]

[0002] International Patent Application WO 2005 / 023633 discloses morpholinopyrimidines useful for treating cancer, their preparation methods, and pharmaceutical compositions thereof. In particular, WO 2005 / 023633 discloses the compound 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-((R)-S-methylsulfonimidoyl)cyclopropyl]pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine (hereinafter referred to as compound of formula (I)) as experimental example 2.02 on page 60. The structure of compound of formula (I) is shown below. [ka]

[0003] The synthetic route for compounds of formula (I) is described on pages 51-57, 66 and 67 of WO 2005 / 023391 and is summarized in Scheme 1 below. [ka] [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2011154737 Brochure Summary of the Invention [Problem to be solved by the invention]

[0005] There are several potential disadvantages to the route to compounds of formula (I) shown in Scheme 1. For example, out of a total of 15 steps in Scheme 1 (the starting compound (R)-3-methylmorpholine is commercially available, but there are five synthetic steps to obtain this compound), the longest linear sequence is made up of 14 steps, which is non-convergent and may not be desirable on an industrial scale. In addition, the cyclopropanation step is extremely challenging, requiring a continuous stirred tank process with difficult workup, only moderate yields, and many impurities formed. The introduction of reactive sulfoximines early in the scheme also poses significant problems for subsequent cyclopropanation and Suzuki coupling. The scheme also requires the early introduction of expensive chiral morpholines. In addition, the use of rhodium in the sulfoximine formation step can be expensive. Taken together or individually, these potential disadvantages may make the route shown in Scheme 1 less attractive for use on an industrial scale at reasonable cost.

[0006] The compound of formula (I) is being developed as an active pharmaceutical compound for treating cancer. Therefore, suitable methods for the safe, cost-effective, efficient and environmentally friendly manufacture of the compound of formula (I) are desirable. In view of the potential disadvantages highlighted above, it is desirable to develop a more efficient, economical and shorter route, i.e., one with fewer steps. [Means for solving the problem]

[0007] Applicants have now discovered a route to synthesize the cyclopropyl key intermediate of formula (II), depicted in Scheme 2 below, where LG1 is a leaving group. [ka] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0008] Thus, in a first aspect of the present disclosure, there is provided a method for preparing a compound of formula (II), wherein LG1 is a leaving group, comprising asymmetric sulfur oxidation by reacting a compound of formula (III) with an oxidase (Scheme 2). [ka]

[0009] As used herein, the LG group is selected from chlorine, bromine, and triflate (also known as trifluoromethanesulfonate). In one embodiment, LG is chlorine. In one embodiment, LG is bromine or triflate.

[0010] The reaction can be carried out using a suitable oxidase, such as a mono-oxygenase enzyme, such as a Baeyer-Villiger mono-oxygenase (BVMO) or cyclohexanone mono-oxygenase (CHMO) enzyme. CHMO enzymes are considered in the art to be a subset of BVMO enzymes. In one embodiment, the oxidase is cyclohexanone mono-oxygenase. The reaction is carried out in the presence of oxygen.

[0011] An enzyme cofactor, such as nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP), can also be used in this reaction. In one embodiment, the enzyme cofactor is nicotinamide adenine dinucleotide phosphate.

[0012] Coenzymes can be used to recycle cofactors, such as ketoreductases, which are well known to those skilled in the art.

[0013] The reaction can be carried out in water and a water-miscible organic solvent. Suitable water-miscible organic solvents include isopropyl alcohol or tetrahydrofuran. In one embodiment, the solvent comprises isopropyl alcohol and water.

[0014] The reaction can be carried out at a temperature range, for example, from 10° C. to 50° C. In one embodiment, the reaction is carried out between 25° C. and 35° C. The reaction can be carried out at a pH range, such as from pH 7 to pH 10. In a further embodiment, the reaction is carried out at pH 8 using a potassium phosphate buffer, for example potassium dihydrogen phosphate.

[0015] In another aspect of the present disclosure, there is provided a process for preparing a compound of formula (III), comprising reacting a compound of formula (IV) with (R)-3-methylmorpholine or a salt thereof in the presence of a base and a suitable solvent (Scheme 3). [ka]

[0016] The LG1 and LG2 groups are independently selected from chlorine, bromine, and triflate. In one embodiment, LG1 and LG2 are both chlorine.

[0017] (R)-3-methylmorpholine can be used as either a salt or the free base. In one embodiment, (R)-3-methylmorpholine hydrochloride is used.

[0018] The reaction can be carried out in a variety of organic solvents, such as acetonitrile, dimethylsulfoxide, N,N-dimethylformamide, tetrahydrofuran, and toluene, etc. In one embodiment, the solvent comprises dimethylsulfoxide.

[0019] The reaction can be carried out using a variety of bases, such as potassium carbonate, triethylamine, N,N-diispropylethlamine, or combinations thereof. In one embodiment, the base comprises a mixture of potassium carbonate and triethylamine.

[0020] The reaction can be carried out at a temperature range of, for example, 0° C. to 100° C. In one embodiment, the reaction is carried out between 15° C. and 25° C.

[0021] In another aspect of the disclosure, there is provided a method for preparing a compound of formula (IV), comprising reacting a compound of formula (V) with a suitable activating reagent in the presence of a base (Scheme 4). [ka]

[0022] The LG1 and LG2 groups are independently selected from chlorine, bromine, and triflate. In one embodiment, LG1 and LG2 are both chlorine.

[0023] The reaction can be carried out using a variety of bases, such as N,N-diethylaniline, N,N-diisopropylethylamine, and triethylamine. In one embodiment, the base is N,N-diethylaniline.

[0024] The activating reagent used for the substitution will depend on the groups selected for LG1 and LG2. Those skilled in the art will be able to select a suitable activating reagent depending on the identity of LG1 and LG2. For example, when LG1 and LG2 are both chlorine, the activating reagent will be a chlorinating agent. Suitable chlorinating agents include phosphoryl chloride, phosphonic dichloride, and phosphorous pentachloride, which are used in excess. In one embodiment, when LG1 and LG2 are both chlorine, the chlorinating agent is phosphoryl chloride.

[0025] The reaction can be carried out using a variety of co-solvents, such as toluene, acetonitrile, and chlorobenzene. Alternatively, the reaction can be carried out in the neat chlorinating reagent in the presence of a base.

[0026] The reaction can be carried out at a temperature ranging from, for example, 50° C. to 140° C. In one embodiment, the reaction is carried out between 90° C. and 110° C.

[0027] During work-up, any unreacted activating agent, such as phosphoryl chloride, can be quenched by addition to the aqueous solution. The pH can be adjusted, for example, by simultaneous addition of sodium hydroxide in aqueous sodium acetate to quench the reaction. Maintaining the pH within the range of 5-7 has the advantage of reducing decomposition of the product of formula (IV).

[0028] In another embodiment of the present disclosure, a method for preparing a compound of formula (V) from a compound of formula (VI) is provided (Scheme 5). [ka]

[0029] The reaction can be carried out using a variety of reagents. Reagents suitable for converting thiopyrimidones to pyrimidones, such as chloroacetic acid, iodosobenzene or oxone, are well known to those skilled in the art. In one embodiment, the reagent is chloroacetic acid.

[0030] The reaction can be carried out in a variety of solvents, such as methanol, ethanol, water, 1,4-dioxane, and tetrahydrofuran. In one embodiment, the solvent is water. Additional acids, such as hydrochloric acid or acetic acid, can be used for this transformation.

[0031] The reaction can be carried out, for example, at a temperature range of 20° C. to 120° C. In one embodiment, the reaction is carried out between 90° C. and 100° C.

[0032] In another aspect of the disclosure, there is provided a method of preparing a compound of formula (VI), comprising reacting a compound of formula (VII) with thiourea (Scheme 6). [ka]

[0033] The reaction with thiourea can be carried out in the presence of a base. The base can be an inorganic base, such as sodium hydroxide or a metal alkoxide, such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium salts thereof. In one embodiment, the base comprises sodium ethoxide. In another embodiment, the base comprises potassium tert-butoxide. In yet another embodiment, thiourea is replaced by urea. In at least one embodiment, thiourea is used.

[0034] The reaction can be carried out in a variety of organic solvents, such as methanol, ethanol, isopropanol, tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile, etc. In one embodiment, the solvent comprises ethanol.

[0035] The reaction can be carried out at a temperature ranging from, for example, 50° C. to 120° C. In one embodiment, the reaction is carried out at a temperature between 70° C. and 85° C., for example, 75° C. to 80° C.

[0036] In another aspect of the present disclosure, there is provided a method for preparing a compound of formula (VII) comprising the steps of acylation of a malonate derivative with an activated form of a compound of formula (VIII) followed by decarboxylation (Scheme 7). [ka]

[0037] The reaction can be carried out in a variety of organic solvents, such as ethyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, and acetonitrile, hi one embodiment, the solvent comprises 2-methyltetrahydrofuran.

[0038] Suitable coupling reagents for generating the activated species are well known to those skilled in the art and include carbonyldiimidazole, thionyl chloride, oxalyl chloride, or isobutyl chloroformate. In one embodiment, carbonyldiimidazole is used as the coupling reagent.

[0039] Suitable reagents for making beta-ketoesters are well known to those skilled in the art and include potassium ethyl malonate or Meldrum's acid. In one embodiment, the reagent is potassium ethyl malonate.

[0040] The reaction can be carried out using a variety of bases, such as triethylamine, N,N-diisopropylethylamine, potassium carbonate, or potassium hydroxide. In one embodiment, the base is triethylamine.

[0041] The reaction can be carried out using a salt additive to enhance the decarboxylation reaction, in one embodiment the additive is magnesium chloride.

[0042] The reaction can be carried out, for example, at a temperature range of 0° C. to 80° C. In one embodiment, the reaction is carried out at a temperature between 10° C. and 40° C.

[0043] In another aspect of the present disclosure, there is provided a process for preparing a compound of formula (VIII) comprising the steps of thiomethylation and base-induced cyclization of a compound of formula (IX) followed by hydrolysis (Scheme 8). [ka]

[0044] The reaction can be carried out in a variety of organic solvents, such as methanol, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and acetonitrile or mixtures of solvents, hi one embodiment, the solvent comprises a mixture of 2-methyltetrahydrofuran and methanol.

[0045] The first step of this reaction requires the nucleophilic displacement of bromine with thiomethoxide. This reaction can be carried out using a variety of thiomethoxide salts. In one embodiment, the thiomethoxide salt is sodium thiomethoxide.

[0046] The reaction can be carried out using a variety of bases, such as sodium hydroxide or metal alkoxides, such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, or potassium salts thereof. In one embodiment, the base is sodium methoxide.

[0047] The hydrolysis step can be carried out by methods well known to those skilled in the art. A variety of aqueous bases or acids can be used, such as sodium hydroxide, potassium hydroxide, or hydrochloric acid. In one embodiment, the base for hydrolysis is sodium hydroxide.

[0048] The reaction can be carried out at a temperature range of, for example, 0° C. to 80° C. In one embodiment, the reaction is carried out between 10° C. and 25° C.

[0049] The product may be crystallized or telescoped to the next stage as a solution in an organic solvent, hi one embodiment, the product is telescoped as a solution in 2-methyltetrahydrofuran.

[0050] In addition to the above synthetic routes, the applicants have found an alternative route for the synthesis of compounds of formula (IV) from compounds of formula (VIII), which reduces the above four-step process (Schemes 4-7) to two steps, as shown in Schemes 9 and 10 below. Incorporating this alternative route into the production of compounds of formula (I) means that the overall length is reduced to eight steps, with the longest linear sequence being only seven steps. This shortened production route further improves the efficiency and cost-effective production of compounds of formula (I), and is more environmentally sustainable due to reduced resources and waste volumes.

[0051] Thus, in an alternative aspect of the present disclosure, there is provided a method for preparing a compound of formula (IV), comprising reacting a compound of formula (XIII) with a 2,4-difunctionalized pyrimidine in the presence of light and a photocatalyst (Scheme 9). [ka]

[0052] The LG1 and LG2 groups are each independently selected from chlorine, bromine, and triflate. In one embodiment, LG1 and LG2 are both chlorine.

[0053] The R1 group is a group suitable for fragmentation and decarboxylation under photoredox conditions. Suitable groups are known to those skilled in the art and include phthalimide and tetrachlorophthalimide. In one embodiment, R1 is phthalimide, and thus the compound of formula (XIII) can be represented as the compound of formula (XIIIa). [ka]

[0054] In one embodiment, the functionalized pyrimidine is selected from 2,4-dichloropyrimidine, 2,4-dibromopyrimidine, and 2,4-pyrimidinediylbis(trifluoromethanesulfonate). In one embodiment, the 2,4-difunctionalized pyrimidine is 2,4-dichloropyrimidine.

[0055] The reaction can be carried out using a variety of photocatalysts, such as 4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridinyl)phenyl]iridium(III) hexafluorophosphate, bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridyl]iridium hexafluorophosphate, 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile, 2,4,6-tris(di-4-biphenylylamino)-3,5-difluorobenzonitrile, 2,3,4,5,6-pentakis(3,6-diphenylcarbazol-9-yl)benzonitrile and 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile. In one embodiment, the photocatalyst is selected from (4,4'-di-tert-butyl-2,2'-bipyridine)bis[(2-pyridinyl)phenyl]iridium(III)hexafluorophosphate, bis[2-(2,4-difluorophenyl)-5-trifluoromethylpyridine][2-2'-bipyridyl]iridium hexafluorophosphate, and 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile. In one embodiment, the catalyst is 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN).

[0056] In one embodiment, the catalyst is a benzonitrile or isophthalonitrile organic photocatalyst, such as 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile, 2,4,6-tris(di-4-biphenylylamino)-3,5-difluorobenzonitrile, 2,3,4,5,6-pentakis(3,6-diphenylcarbazol-9-yl)benzonitrile or 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile.

[0057] In one embodiment, the catalyst is a benzonitrile photocatalyst selected from 2,4,6-tris(di-4-biphenylylamino)-3,5-difluorobenzonitrile, 2,3,4,5,6-pentakis(3,6-diphenylcarbazol-9-yl)benzonitrile, and 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile. These benzonitrile catalysts have certain advantages over other photocatalysts. For example, they can improve the throughput and improve the overall yield of the continuous flow process described herein by enabling faster reaction rates. Furthermore, the benzonitrile catalysts described herein do not require the use of N,N-diisopropylethylamine (DIPEA) as an additive to improve reaction rates. The advantages of not using DIPEA in the photoredox reaction are known to those skilled in the art and include significantly reduced light extinction and allowing for more efficient scale-up of the photoredox reaction.

[0058] In one embodiment, the catalyst is 2,4,6-tris(di-4-biphenylylamino)-3,5-difluorobenzonitrile. In another embodiment, the catalyst is 2,3,4,5,6-pentakis(3,6-diphenylcarbazol-9-yl)benzonitrile. In another embodiment, the catalyst is 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile.

[0059] Applicants have identified a novel compound useful as a photocatalyst. Accordingly, in one aspect of the present invention, there is provided the compound 2,4,6-tris(di-4-biphenylylamino)-3,5-difluorobenzonitrile. [ka]

[0060] Applicants have further discovered that the compound 2,3,4,5,6-pentakis(3,6-diphenylcarbazol-9-yl)benzonitrile, previously believed to only be described for use in LED display screen applications (e.g., WO2016202251), is useful as a photocatalyst. Thus, in a further aspect of the present invention, there is provided the use of the compound 2,3,4,5,6-pentakis(3,6-diphenylcarbazol-9-yl)benzonitrile as a catalyst in photoredox reactions.

[0061] Additionally, 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile, a known photocatalyst but not believed to have been previously disclosed as catalyzing the Minisci reaction, has been found to be useful in the reaction shown in Scheme 9.

[0062] A light source, such as a blue light-emitting diode (LED), that provides light of a wavelength suitable for photocatalysis is required for this reaction (reaction depicted in Scheme 9).

[0063] The reaction can be carried out in a variety of solvents, such as N,N-dimethylformamide, dimethylsulfoxide, or toluene. In one embodiment, the solvent is dimethylsulfoxide.

[0064] The reaction can be carried out using a variety of additives, such as acids, Lewis acids, amine bases, or other radical donors. Examples of additives include trifluoroacetic acid, malonic acid, indium triflate, or N,N-diisopropylethylamine. In one embodiment, the additive is N,N-diisopropylethylamine.

[0065] The reaction can be carried out at a temperature range of, for example, 0° C. to 100° C. In one embodiment, the reaction is carried out between 25° C. and 50° C.

[0066] The reaction can be carried out in the presence of light as a batch or continuous flow process, hi one embodiment, the reaction is carried out in a continuous flow reactor with a blue LED light source.

[0067] In another embodiment of the present disclosure, there is a process for preparing a compound of formula (XIII) from a compound of formula (VIII) in the presence of an activating reagent and a base (Scheme 10). [ka]

[0068] R1 is a group suitable for fragmentation and decarboxylation under photoredox conditions. Suitable groups are known to those skilled in the art and include phthalimide and tetrachlorophthalimide. In one embodiment, R1-OH is N-hydroxyphthalimide or N-hydroxytetrachlorophthalimide. In one embodiment, R1 is a phthalimide group or a tetrachlorophthalimide group. When R1-OH is N-hydroxyphthalimide, R1 is a phthalimide group, and thus the compound of formula (XIII) is represented as the compound of formula (XIIIa).

[0069] The reaction can be carried out in a variety of organic solvents, such as dichloromethane, tetrahydrofuran, and 2-methyltetrahydrofuran, hi one embodiment, the reaction is carried out in dichloromethane.

[0070] The reaction can be carried out using various activating reagents, such as thionyl chloride or oxalyl chloride, to form acid chlorides. In one embodiment, oxalyl chloride is used in the presence of catalytic N,N-dimethylformamide. Alternatively, activating reagents can be used to form active esters, such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, or carbonyldiimidazole.

[0071] The reaction can be carried out using a variety of bases, such as triethylamine, pyridine, or potassium carbonate, hi one embodiment, the base is triethylamine.

[0072] The reaction can be carried out at a temperature range of, for example, 0° C. to 80° C. In one embodiment, the reaction is carried out between 5° C. and 25° C.

[0073] The cyclopropyl intermediate of formula (II), or a salt thereof, synthesized by the methods described herein, is a key intermediate in the synthesis of a compound of formula (I). [ka] wherein LG1 is a leaving group selected from chlorine, bromine, and triflate. In one embodiment, LG1 is a leaving group selected from bromine and triflate.

[0074] In certain embodiments, the compound (3R)-4-(2-chloro-6-{1-[(R)-methylsulfinyl]cyclopropyl}-4-pyrimidinyl)-3-methylmorpholine, or a salt thereof, is provided. In further embodiments, the compound (3R)-4-(2-chloro-6-{1-[(R)-methylsulfinyl]cyclopropyl}-4-pyrimidinyl)-3-methylmorpholine is provided in free base form.

[0075] In a further aspect of the disclosure there is provided a compound of formula (III) or a salt thereof: [ka] wherein LG1 is a leaving group selected from chlorine, bromine and triflate.

[0076] In a further embodiment, the compound (3R)-4-{2-chloro-6-[1-(methylsulfanyl)cyclopropyl]-4-pyrimidinyl}-3-methylmorpholine, or a salt thereof, is provided. In a further embodiment, the compound (3R)-4-{2-chloro-6-[1-(methylsulfanyl)cyclopropyl]-4-pyrimidinyl}-3-methylmorpholine is provided in free base form.

[0077] In a further aspect of the disclosure, there is provided a compound of formula (IV): [ka] wherein LG1 and LG2 are each independently selected from chlorine, bromine and triflate.

[0078] In a further embodiment, the compound 2,4-dichloro-6-[1-(methylsulfanyl)cyclopropyl]pyrimidine is provided.

[0079] In a further aspect of the disclosure there is provided a compound of formula (V) or a salt thereof: [ka]

[0080] In a further embodiment, the compound 6-[1-(methylsulfanyl)cyclopropyl]-2,4(1H,3H)-pyrimidinedione, or a salt thereof, is provided. In a further embodiment, the compound 6-[1-(methylsulfanyl)cyclopropyl]-2,4(1H,3H)-pyrimidinedione is provided in free base form.

[0081] In a further aspect of the disclosure there is provided a compound of formula (VI) or a salt thereof: [ka]

[0082] In a further embodiment, the compound 6-[1-(methylsulfanyl)cyclopropyl]-2-sulfanylidene-2,3-dihydro-4(1H)-pyrimidinone, or a salt thereof, is provided. In a further embodiment, the compound 6-[1-(methylsulfanyl)cyclopropyl]-2-sulfanylidene-2,3-dihydro-4(1H)-pyrimidinone is provided in free base form.

[0083] In a further aspect of the disclosure there is provided a compound of formula (VII) or a salt thereof: [ka]

[0084] In a further embodiment, the compound ethyl 3-[1-(methylsulfanyl)cyclopropyl]-3-oxopropanoate, or a salt thereof, is provided. In a further embodiment, the compound 3-[1-(methylsulfanyl)cyclopropyl]-3-oxopropanoate is provided in free base form.

[0085] The compounds described herein may form acid addition salts or base addition salts. In general, acid addition salts can be prepared using various inorganic or organic acids. Such salts can usually be formed, for example, by mixing the compound with an acid (e.g., a stoichiometric amount of an acid) using various methods known in the art. This mixing can be carried out in water, an organic solvent (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile), or an aqueous / organic mixture. Acid addition salts can be formed, for example, using an inorganic acid selected from the group consisting of hydrochloric acid.

[0086] For compounds capable of forming base addition salts, it may be possible to make alkali metal (such as sodium, potassium or lithium) or alkaline earth metal (such as calcium) salts, for example, by treating the compound with an alkali metal or alkaline earth metal hydroxide or alkoxide (e.g., ethoxide or methoxide), or a suitably basic organic amine (e.g., choline or meglumine) in an aqueous medium.

[0087] General principles and techniques for preparing salts can be found in Berge et al., J. Pharm. Sci., 66, 1-19 (1977).

[0088] In one embodiment, there is provided a compound of formula (I) or a salt thereof, which is a single optical isomer with an enantiomeric excess (% ee) of ≧95%, ≧98% or ≧99%. In one embodiment, the single optical isomer is present in an enantiomeric excess (% ee) of ≧99%.

[0089] In one embodiment, there is provided a compound of formula (II) or a salt thereof, which is a single optical isomer with an enantiomeric excess (% ee) of ≧95%, ≧98% or ≧99%. In one embodiment, the single optical isomer is present with an enantiomeric excess (% ee) of ≧99%.

[0090] In one embodiment, there is provided a compound of formula (III) or a salt thereof, which is a single optical isomer with an enantiomeric excess (% ee) of ≧95%, ≧98% or ≧99%. In one embodiment, the single optical isomer is present with an enantiomeric excess (% ee) of ≧99%.

[0091] In one embodiment, there is provided a compound of formula (X) or a salt thereof, which is a single optical isomer with an enantiomeric excess (% ee) of ≧95%, ≧98% or ≧99%. In one embodiment, the single optical isomer is present in an enantiomeric excess (% ee) of ≧99%.

[0092] In yet another aspect, there is provided the use of a compound of formula (II), (III), (IV), (V), (VI), (VII), (VIII), (IV) or (XIII), or any of their salts, where applicable, as an intermediate in the preparation of a compound of formula (I). [ka]

[0093] The methods described herein provide an alternative route to compounds of formula (I) that may overcome several problems of previously disclosed routes, such as reducing the total number of steps, improving cyclopropanation in part by introducing the sulfoximine later in the scheme, and eliminating the need for rhodium in the sulfoximine formation step.

[0094] A general synthetic route to compounds of formula (I) starting from compounds of formula (II) is presented below in Scheme 11, where LG1 is a leaving group selected from chlorine, bromine and triflate. In one embodiment, LG1 is a leaving group selected from bromine and triflate. [ka]

[0095] Thus, in a further aspect of the disclosure, there is provided a method of preparing a compound of formula (I), the method comprising: (a) reacting a compound of formula (II) with a nitrogen source and iodobenzene diacetate; forming a compound of formula (X), (b) reacting a compound of formula (XI) with reacting with a boron reagent in the presence of a palladium catalyst or after lithium-halogen exchange, and optionally adding diethanolamine, to form a compound of formula (XII); (c) cross-coupling a compound of formula (X) with a compound of formula (XII), forming a compound of formula (I), Including, In the compounds of formula (II) and formula (X), LG1 is a leaving group selected from chlorine, bromine and triflate, and BG is a boronic acid ester, for example, BPin, a B(OR)2 group, where R is hydrogen or C1-4 alkyl, or a diethanolamine boronate ester (B(DEA)). A process for preparing a compound of formula (I) is provided.

[0096] In a further embodiment, LG1 in the compound of formula (II) and formula (X) represents chlorine. In one embodiment, LG1 in the compound of formula (II) and formula (X) represents bromine or triflate. In a further embodiment, BG in the compound of formula (XII) is BPin. In a further embodiment, BG in the compound of formula (XII) is B(DEA).

[0097] A general synthetic route to compounds of formula (I) starting from compounds of formula (III) is set out in Scheme 12 below, where LG1 is a leaving group selected from chlorine, bromine and triflate. [ka]

[0098] In a further aspect of the disclosure, there is provided a method for preparing a compound of formula (I), the method comprising: (a) reacting a compound of formula (II) with a nitrogen source and iodobenzene diacetate to form a compound of formula (X); (b) reacting a compound of formula (XI) with a boron reagent in the presence of a palladium catalyst or after lithium-halogen exchange, and optionally adding diethanolamine, to form a compound of formula (XII); and (c) cross-coupling a compound of formula (X) with a compound of formula (XII) to form a compound of formula (I); Including, Step (a) is preceded by a step of reacting a compound of formula (III) with an oxidase to form a compound of formula (II), In the compounds of formula (III), (II) and (X), LG1 is a leaving group selected from chlorine, bromine and triflate, and BG is a boronic acid ester, for example, BPin, a B(OR)2 group, where R is hydrogen or C1-4 alkyl, or a diethanolamine boronate ester (B(DEA)); A process for preparing a compound of formula (I) is provided.

[0099] In a further embodiment, LG1 represents chlorine. In a further embodiment, BG of the compound of formula (XII) is BPin. In a further embodiment, BG of the compound of formula (XII) is B(DEA).

[0100] As used herein, the term "C1-4 alkyl" is straight or branched. Examples of C1-4 alkyl include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl, for example, methyl, ethyl, i-propyl or t-butyl.

[0101] The following embodiments are described with respect to aspects related to Schemes 11 and 12 above.

[0102] In one embodiment, step (a) can be carried out using various nitrogen sources, such as ammonia, ammonium carbamate and ammonium acetate. In one embodiment, the nitrogen source of step (a) is ammonium carbamate. In a further embodiment, the reaction of step (a) can be carried out in an organic solvent, such as methanol, ethanol, acetonitrile or toluene, or a combination thereof. In one embodiment, the organic solvent comprises methanol and toluene. In another further aspect, the reaction of step (a) is carried out between 0° C. and 50° C., such as between 0° C. and 10° C. In yet another aspect, the compound of formula (X) is isolated as either the free base or the hydrochloride salt. An alternative to step (a), known to those skilled in the art, is to carry out the reaction using transition metal catalysis by transfer of trifluoroacetamide, sulfonamide, carbamate or amide, followed by hydrolysis. A particular advantage of step (a) is that it avoids the need for expensive rhodium metal.

[0103] In a further embodiment, step (b) can be carried out using various palladium catalysts, such as tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetonyl)bis-palladium, bis(triphenylphosphine)palladium(II) dichloride, or palladium acetate, together with triphenylphosphine. In one embodiment, the palladium catalyst is tetrakis(triphenylphosphine)palladium(0) or tris(dibenzylideneacetonyl)bis-palladium. Other suitable catalysts are known to those skilled in the art. In one embodiment, the palladium catalyst is tetrakis(triphenylphosphine)palladium(0). In another embodiment, the palladium catalyst is bis(triphenylphosphine)palladium(II) dichloride. In one embodiment, the boron reagent is selected from bis-boronic acid esters, such as bis(pinacolato)diboron (B2Pin2), or B2(OR)4 groups, where R is hydrogen or C1-4 alkyl. In one embodiment, the boron reagent is B2Pin2. In a further embodiment, the reaction is carried out in an organic solvent, such as 1,4-dioxane, 1,2-dimethoxyethane, or isopropyl acetate. In one embodiment, the reaction is carried out in an organic solvent, such as 1,4-dioxane or 1,2-dimethoxyethane. In one embodiment, the organic solvent is 1,4-dioxane. In another embodiment, the organic solvent is isopropyl acetate. In yet another embodiment, the reaction of step (b) can be carried out in the presence of a base, such as potassium carbonate or potassium acetate. In one embodiment, the base is potassium acetate. In yet another embodiment, the reaction of step (b) is carried out at between 90° C. and 100° C.

[0104] As mentioned above, in an optional further embodiment, step (b) further comprises the addition of diethanolamine after the reaction with the boron reagent in the presence of a palladium catalyst. The addition of diethanolamine leads to a substitution or transesterification reaction of the ester of formula (XII), which can be carried out in two different ways. First, in one embodiment, diethanolamine is added to a compound of formula (XII) where BG is BPin. In one embodiment, the reaction step requiring the addition of diethanolamine is carried out in the presence of an organic solvent, such as isopropanol or THF, or a combination thereof. In one embodiment, the reaction is carried out at room temperature. Second, in an alternative embodiment, step (b) is carried out as a telescoping synthesis starting from a compound of formula (XI). In this second embodiment, diethanolamine is added to the reaction product after the addition of the boron reagent and the palladium catalyst. In one embodiment, the addition of diethanolamine is carried out at a temperature between 20°C and 80°C, for example at 75°C. In one embodiment, when diethanolamine is added as part of the telescoping synthesis, the palladium catalyst is palladium acetate.

[0105] When step (b) comprises the additional step of adding diethanolamine, the compound of formula (XII) is the boronic ester of diethanolamine, i.e., BG is B(DEA). In one embodiment, the compound of formula (XII) is a compound of formula (XIIb). [ka]

[0106] In a further aspect, step (c) can be carried out using various palladium catalysts, such as tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, or [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). In one embodiment, the palladium catalyst is [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). In a further embodiment, the reaction is carried out in an organic solvent, such as ethanol, 1-butanol, and 2-methyltetrahydrofuran. In one embodiment, the solvent is ethanol. In another further embodiment, the reaction of step (c) can be carried out in the presence of a base, such as potassium carbonate, triethylamine, or potassium phosphate. In one embodiment, the base is potassium carbonate. In a further embodiment, the reaction of step (c) is carried out at a temperature between 50°C and 100°C.

[0107] As described with respect to Scheme 12, in one embodiment, step (a) is preceded by a step of reacting a compound of formula (III) with an oxidase to form a compound of formula (II).

[0108] The reaction can be carried out using a suitable oxidase, such as a mono-oxygenase enzyme, such as a Baeyer-Villiger mono-oxygenase (BVMO) or cyclohexanone mono-oxygenase (CHMO) enzyme. In one embodiment, the oxidase is cyclohexanone mono-oxygenase. The reaction is carried out in the presence of oxygen.

[0109] An enzyme cofactor, such as nicotinamide adenine dinucleotide (NAD) or nicotinamide adenine dinucleotide phosphate (NADP), can also be used in this reaction. In one embodiment, the enzyme cofactor is nicotinamide adenine dinucleotide phosphate.

[0110] Coenzymes can be used to recycle cofactors, such as ketoreductases, which are well known to those skilled in the art.

[0111] The reaction can be carried out in water and a water-miscible organic solvent. Suitable water-miscible organic solvents include isopropyl alcohol or tetrahydrofuran. In one embodiment, the solvent comprises isopropyl alcohol and water.

[0112] The reaction can be carried out at a temperature range, for example, from 10° C. to 50° C. In one embodiment, the reaction is carried out between 25° C. and 35° C. The reaction can be carried out at a pH range, such as from pH 7 to pH 10. In a further embodiment, the reaction is carried out at pH 8 using a potassium phosphate buffer, for example potassium dihydrogen phosphate.

[0113] In a further aspect of the present disclosure, there is provided a method for preparing a compound of formula (I), comprising reacting a compound of formula (XI) with a boron reagent in the presence of a palladium catalyst, followed by addition of diethanolamine to form a compound of formula (XIIb).

[0114] Thus, in a further aspect of the disclosure, there is provided a method of preparing a compound of formula (I), the method comprising: (a) cyclopropanation of a compound of formula (IX) followed by hydrolysis to form a compound of formula (VIII); (b) reacting the activated form of the compound of formula (VIII) with a malonate derivative, followed by decarboxylation to form a compound of formula (VII); (c) reacting a compound of formula (VII) with urea or thiourea to form a compound of formula (VI); (d) reacting the compound of formula (VI) with a suitable reagent to form a compound of formula (V); (e) reacting a compound of formula (V) with a chlorinating or other activating reagent to form a compound of formula (IV); (f) coupling the compound of formula (IV) with (R)-3-methylmorpholine or a salt thereof to form a compound of formula (III); (g) reacting the compound of formula (III) with an oxidase to form a compound of formula (II); (h) reacting the compound of formula (II) with a nitrogen source and then with iodobenzene diacetate to form a compound of formula (X) or a salt thereof; (i) reacting a compound of formula (XI) with a boron reagent in the presence of a palladium catalyst or reacting with a boron reagent after lithium-halogen exchange to form a compound of formula (XII); (j) reacting a compound of formula (X) or a salt thereof with a compound of formula (XII) to form a compound of formula (I); Including, LG1 and LG2 each independently represent chlorine, bromine or triflate; A process for preparing a compound of formula (I) is provided.

[0115] In one embodiment, LG1 and LG2 both represent chlorine.

[0116] In one embodiment, LG1 and LG2 each independently represent bromine or triflate.

[0117] In an alternative embodiment of the present disclosure, there is provided a method of preparing a compound of formula (I), the method comprising: (a) cyclopropanation of a compound of formula (IX) followed by hydrolysis to form a compound of formula (VIII); (b) reacting a compound of formula (VIII) with R1-OH, where R1 is a phthalimide group or a tetrachlorophthalimide group, to form a compound of formula (XIII); (c) reacting the compound of formula (XIII) with a 2,4-difunctionalized pyrimidine in the presence of light and a photocatalyst to form a compound of formula (IV); (d) coupling the compound of formula (IV) with (R)-3-methylmorpholine or a salt thereof to form a compound of formula (III); (e) reacting the compound of formula (III) with an oxidase to form a compound of formula (II); (f) reacting the compound of formula (II) with a nitrogen source and then with iodobenzene diacetate to form a compound of formula (X) or a salt thereof; (g) reacting the compound of formula (XI) with a boron reagent in the presence of a palladium catalyst or reacting with a boron reagent after lithium-halogen exchange to form a compound of formula (XII); (h) reacting a compound of formula (X) or a salt thereof with a compound of formula (XII) to form a compound of formula (I); Including, LG1 and LG2 represent chlorine, bromine or triflate; A process for preparing a compound of formula (I) is provided.

[0118] In one embodiment, LG1 and LG2 both represent chlorine.

[0119] In one embodiment, LG1 and LG2 represent bromine or triflate.

[0120] In one embodiment, a method of preparing a compound of formula (I) according to Scheme 13 is provided. [ka]

[0121] In another embodiment, an alternative method for preparing compounds of formula (I) according to Scheme 14 is provided. [ka]

[0122] In an alternative embodiment, for the step of forming a compound of formula (XIIa) in Schemes 13 and 14, this step further comprises the addition of diethanolamine, such that the compound of formula (XIIa) becomes instead a compound of formula (XIIb).

[0123] In an alternative embodiment, a method of preparing a compound of formula (I) according to Scheme 15 is provided. [ka]

[0124] In another embodiment, an alternative method for preparing compounds of formula (I) according to Scheme 16 is provided. [ka]

[0125] In an alternative embodiment, for the step of forming a compound of formula (XIIa) in Scheme 15 or Scheme 16, this step further comprises the addition of diethanolamine, such that the compound of formula (XIIa) instead becomes a compound of formula (XIIb).

[0126] Abbreviation BPin 4,4,5,5-Tetramethyl-1,3,2-dioxaborolane CDI Carbonyldiimidazole CHMO Cyclohexanone monooxygenase DCM Methylene dichloride DMF Dimethylformamide DMSO Dimethyl sulfoxide DIPEA N,N-Diisopropylethylamine Et2N Triethylamine Et2NPh N,N-Diethylaniline EtOH Ethanol IPA Isopropyl Alcohol IPrOAc Isopropyl acetate KBP Potassium dihydrogen phosphate K2CO3 Potassium carbonate KOAc Potassium Acetate KRED Ketoreductase LiBH4 Lithium borohydride mCPBA meta-chloroperbenzoic acid MeOH Methanol 2-MeTHF 2-Methyltetrahydrofuran MgCl2 Magnesium chloride MgO Magnesium oxide MsCl Methanesulfonyl chloride NADP Nicotinamide adenine dinucleotide phosphate NaOEt Sodium ethoxide NaOH Sodium hydroxide NaSMe Sodium thiomethoxide NaOMe Sodium methoxide Pd(dppf)Cl2 1,1'-Bis(diphenylphosphino)ferrocene Pd(PPh3)4 Tetrakis(triphenylphosphine)palladium(0) Pd(PPh3)2Cl2 Bis(triphenylphosphine)palladium(II) dichloride Pd(OAc)2 Palladium acetate PhI(OAc)2 Phenyl iodide diacetate POCl3 Phosphoryl chloride PPh3 Triphenylphosphine Rh(OAc)2 Rhodium(II) acetate dimer tert-BuOK Potassium tert-butoxide THF Tetrahydrofuran

[0127] General method Unless otherwise stated, starting materials were commercially available. All solvents and commercially available reagents were of laboratory grade and used as received. Unless otherwise stated, all operations were carried out at ambient temperature, i.e., in the range of 17-28°C, and, where necessary, under an inert gas atmosphere such as nitrogen.

[0128] Large scale reactions were carried out in stainless steel or glass-lined steel reactors equipped with heat transfer jackets and appropriate auxiliary equipment.

[0129] Photo-flow reactions were carried out in a commercially available Vapourtec UV-150® flow reactor using a blue LED.

[0130] Where 1H NMR spectra are given, they were recorded on a Bruker DRX500 (500 MHz), Bruker 400 (400 MHz). Either the central peak of chloroform-d (CDCl3; δH 7.27 ppm) or dimethylsulfoxide-d6 (d6-DMSO; δH 2.50 ppm), or the internal standard of tetramethylsilane (TMS; δH 0.00 ppm) was used as a reference. To distance exchangeable proton signals (e.g. from maleic acid) from the analyte resonance, the sample solution may also contain an internal standard for the assay measurements (e.g. maleic acid or 2,3,5,6-tetrachloronitrobenzene) and / or added trifluoroacetic acid. Spectral data are reported as a list of chemical shifts (δ, in ppm) with a description of each signal using standard abbreviations (s=singlet, d=doublet, m=multiplet, t=triplet, q=quartet, br=broad line, etc.). It is well known in the art that chemical shifts and J-coupling constants can vary slightly as a result of differences in sample preparation, such as the concentration of the analyte and whether or not additives (e.g., NMR assay standards or trifluoroacetic acid) are included.

[0131] In general, compounds were named using “Structure to Name,” part of Biovia Draw 2016. EXAMPLES

[0132] Example 1: Preparation of 1-(methylsulfanyl)cyclopropanecarboxylic acid [ka] Methyl 2,4-dibromobutyrate (221 kg, 851 mol, 1.0 equiv) and 2-methyltetrahydrofuran (758 kg) were charged to the vessel at 10-15° C. A solution of sodium thiomethoxide (59.7 kg, 851 mol, 1.0 equiv) in methanol (184 kg) was charged to the vessel at 10-20° C. The vessel contents were stirred at 15-25° C. for 4 hours. A solution of sodium methoxide (53.1 kg, 1.15 equiv) in methanol (160 kg) was charged to the vessel at 15-25° C. The vessel contents were stirred at 15-25° C. for 2 hours. An aqueous solution of sodium hydroxide (2 M, 510.6 L, 1.2 equiv) was charged to the vessel at 15-25° C. The vessel contents were stirred at about 20° C. for 10 hours. The vessel contents were concentrated by distillation under reduced pressure to a volume of about 5 relative volumes. 2-Methyltetrahydrofuran (1512 kg) was charged to the vessel. The mixture was acidified with 4 molar aqueous hydrochloric acid to a pH of 1-2. The biphasic mixture was stirred for 1 hour and then the batch was allowed to settle. The aqueous layer was removed. The organic solution was washed with aqueous sodium chloride (445 kg) and the aqueous layer was removed. The organic solution was washed with aqueous sodium chloride (439 kg) and the aqueous layer was removed. The organic solution was concentrated under reduced pressure to about 2 relative volumes. 2-Methyltetrahydrofuran (562 kg) was charged to the vessel. The organic solution was concentrated under reduced pressure to about 2 relative volumes. 2-Methyltetrahydrofuran (560 kg) was charged to the vessel. The organic solution was concentrated under reduced pressure to about 2 relative volumes. 2-Methyltetrahydrofuran (570 kg) was charged to the vessel. The organic solution is concentrated under reduced pressure to approximately 2 relative volumes to give 1-(methylsulfanyl)cyclopropanecarboxylic acid as a solution in dry 2-methyltetrahydrofuran (883 kg, 10.73% w / w, 84% yield). 1H NMR (400 MHz, DMSO) 1.12 (2H, q), 1.43 (2H, q), 2.15 (3H, s).

[0133] Example 2: Preparation of ethyl 3-[1-(methylsulfanyl)cyclopropyl]-3-oxopropanoate [ka] A solution of 1-(methylsulfanyl)cyclopropanecarboxylic acid (94.4 kg, 714.2 mol) in 2-methyltetrahydrofuran (788 kg) was charged to a solution of carbonyldiimidazole (124.4 kg, 752.3 mol) in 2-methyltetrahydrofuran (488 kg) in vessel 1. The contents of vessel 1 were stirred at about 20° C. for 4.5 hours. 2-Methyltetrahydrofuran (1206 kg) was charged to vessel 2 and then stirring was started. Potassium ethyl malonate (184.1 kg, 1074.4 mol) and magnesium chloride (103 kg, 1074.7 mol) were charged to vessel 2 at 15-25° C. Triethylamine (124.2 kg, 1218 mol) was charged to vessel 2 at 15-25° C. The contents of vessel 2 were stirred at about 20° C. for 1 hour. The contents of vessel 1 were transferred to vessel 2 at 15-25° C. The contents of vessel 2 were stirred at about 40-45°C for 15 hours. The mixture was cooled to about 20°C. Aqueous hydrochloric acid (4M, 1210 kg) was charged to vessel 2. The contents of vessel 2 were stirred for 1 hour, then stirring was stopped and the aqueous layer was removed. Water (474 ​​L) was charged to vessel 2. The contents of vessel 2 were stirred for 10 minutes, then stirring was stopped and the aqueous layer was removed. Aqueous sodium bicarbonate solution (8% wt / wt, 542 kg) was charged to vessel 2. The contents of vessel 2 were stirred for 1 hour, then stirring was stopped and the aqueous layer was removed. Aqueous sodium bicarbonate solution (8% wt / wt, 510 kg) was charged to vessel 2. The contents of vessel 2 were stirred for 1 hour, then stirring was stopped and the aqueous layer was removed. A solution of sodium chloride (118 kg) in water (477 kg) was charged to vessel 2. The contents of vessel 2 were stirred for 1 hour, then stirring was stopped and the aqueous layer was removed. The organic solution was concentrated by vacuum distillation to 2-3 relative volumes. Ethanol (155 kg) was charged to vessel 2. The organic solution was concentrated by vacuum distillation to 2-3 relative volumes. Ethanol (153 kg) was charged to vessel 2. The organic solution was concentrated by vacuum distillation to 3-4 relative volumes to give ethyl 3-[1-(methylsulfanyl)cyclopropyl]-3-oxopropanoate as a solution in ethanol (473.8 kg, 23.8% w / w, 558 mol, 78% yield).1H NMR(400MHz,DMSO)1.19(3H,t),1.23-1.32(2H,m),1.45 -1.60(2H,m),2.14(3H,s),3.90(2H,s),4.10(2H,q).

[0134] Example 3: Preparation of 6-[1-(methylsulfanyl)cyclopropyl]-2-sulfanylidene-2,3-dihydro-4(1H)-pyrimidinone [ka] A solution of sodium ethoxide in ethanol (20% w / t, 454.5 kg, 1394 mol) was charged to a stirred solution of thiourea (60.2 kg, 781 mol) in ethanol (90 kg). The vessel contents were heated to about 78°C. A solution of ethyl 3-[1-(methylsulfanyl)cyclopropyl]-3-oxopropanoate (112.7 kg, 557.7 mol) in ethanol (361 kg) was charged to the vessel. The vessel contents were stirred at about 78°C for 15 hours. The vessel contents were distilled under reduced pressure to a volume of about 5 relative volumes. Aqueous hydrochloric acid (2M, 1090 kg) was added slowly at 15-25°C. The vessel contents were stirred for 1 hour. The resulting solid was collected by filtration. The filter cake was washed with a mixture of ethanol (178 kg) and 2-methyltetrahydrofuran (48 kg) and then dried to give 6-[1-(methylsulfanyl)cyclopropyl]-2-sulfanylidene-2,3-dihydro-4(1H)-pyrimidinone (77.6 kg, 96.4% w / w, 349.1 mol, 63% yield) as a solid. 1H NMR (500 MHz, DMSO, 27°C) 0.97-1.14 (2H,m), 1.22-1.31 (2H,m), 2.06 (3H,s), 5.72 (1H,s), 12.34 (1H,s), 12.52 (1H,s). MS: (M+H)+ 215.

[0135] 6-[1-(methylsulfanyl)cyclopropyl]-2-sulfanylidene-2,3-dihydro-4(1H)-pyrimidinone can also be prepared as follows: [ka] Potassium tert-butoxide (108.6 kg) was charged to tetrahydrofuran (451.2 kg) with stirring. Ethanol (788.2 kg) was added and the resulting solution was concentrated to about 6 relative volumes by vacuum distillation. Ethanol (394.1 kg) was charged to the solution and the resulting solution was then concentrated to about 6 relative volumes by vacuum distillation. Ethanol (394.1 kg) was charged to the solution and the resulting solution was then concentrated to about 6 relative volumes by vacuum distillation. Thiourea (74.9 kg, 984.0 mol) was charged to the stirred solution and the resulting mixture was heated to about 78° C. A solution of ethyl 3-[1-(methylsulfanyl)cyclopropyl]-3-oxopropanoate (166.5 kg, 824.0 mol) in ethanol (169 kg) was charged to the vessel. The contents of the vessel were stirred at about 78° C. for 10 hours. The mixture was cooled to about 20°C and then water (666 kg) was charged. Concentrated hydrochloric acid solution (143.2 kg) was added slowly at 15-25°C. The vessel contents were stirred for 2 hours. The resulting solid was collected by filtration. The filter cake was washed with a mixture of ethanol (262.7 kg) and water (166.5 kg) and then dried to give 6-[1-(methylsulfanyl)cyclopropyl]-2-sulfanylidene-2,3-dihydro-4(1H)-pyrimidinone (138.4 kg, 95.0% w / w, 614.3 mol, 75% yield) as a solid. 1H NMR(500MHz,DMSO,27℃)0.97-1.14(2H,m),1.22-1.31(2H,m),2.06(3H,s),5.72(1H,s),12.34(1H,s),12.52(1H,s).MS:(M+H)+ 215.

[0136] Example 4: Preparation of 6-[1-(methylsulfanyl)cyclopropyl]-2,4(1H,3H)-pyrimidinedione [ka] 6-[1-(methylsulfanyl)cyclopropyl]-2-sulfanylidene-2,3-dihydro-4(1H)-pyrimidinone (76.8 kg, 345 mol) and water (607 kg) were charged to a vessel. Agitation was started. Chloroacetic acid (162.5 kg, 1719 mol) was charged to the vessel. The vessel contents were stirred at about 95° C. for 9 hours and then cooled to about 5° C. The resulting solid was collected by filtration. The filter cake was washed with aqueous hydrochloric acid (4 moles, 238 kg). The resulting solid was dried at about 40° C. to provide 6-[1-(methylsulfanyl)cyclopropyl]-2,4(1H,3H)-pyrimidinedione (52.7 kg, 97.4% w / w, 259 mol, 75% yield) as a solid. 1H NMR(400MHz,DMSO,27℃)0.95-1.13(2H,m),1.19-1.32(2H,m),2.08(3H,s),5.41(1H,t),10.94(2H,s).MS:(M+H)+ 199.

[0137] Example 5: Preparation of 2,4-dichloro-6-[1-(methylsulfanyl)cyclopropyl]pyrimidine [ka] Phosphoryl chloride (335 kg) was charged to vessel 1. Agitation was commenced. 6-[1-(methylsulfanyl)cyclopropyl]-2-sulfanylidene-2,3-dihydro-4(1H)-pyrimidinone (52.2 kg, 254 mol) was charged to vessel 1. N,N-Diethylaniline (96 kg, 636 mol, 2.5) was charged to vessel 1 at 15-25°C. Water (1.85 kg) was slowly charged to vessel 1 while maintaining the temperature below 50°C. The contents of vessel 1 were heated at 90-100°C for 7 hours. The contents of vessel 1 were cooled to 15-25°C. A solution of sodium acetate (10.1 kg) in water (306 kg) was charged to vessel 2. The contents of vessel 1 and an aqueous solution of sodium hydroxide (25% w / w, 1157 kg) were added simultaneously to vessel 2, maintaining the internal temperature in the range of 15-30°C and the pH in the range of 5-8. The resulting mixture was stirred at 0-10°C for a further 2 hours. A solution of hydrochloric acid (4M) was added to adjust the pH to pH 4. The solid was collected by filtration. The filter cake was washed with water (407 kg) and then dried at 30-40°C to give 2,4-dichloro-6-[1-(methylsulfanyl)cyclopropyl]pyrimidine (51.4 kg, 92% w / w, 201 mol, 79% yield) as a solid. 1H NMR(500MHz,DMSO,27℃)1.42-1.55(2H,m),1.61-1.77(2H,m),2.14(3H,s),8.03(1H,s).MS:(M+H)+ 235.

[0138] Example 6: Preparation of (3R)-4-{2-chloro-6-[1-(methylsulfanyl)cyclopropyl]-4-pyrimidinyl}-3-methylmorpholine [ka] Dimethylsulfoxide (261 kg) was charged to vessel 1. Agitation was started. 2,4-Dichloro-6-[1-(methylsulfanyl)cyclopropyl]pyrimidine (51.0 kg, 200 mol) was charged to vessel 1. Potassium carbonate (72.5 kg) was charged to vessel 1. (R)-3-Methylmorpholine hydrochloride (33.9 kg, 230 mol) was charged to vessel 1. Triethylamine (52.5 kg) was charged to vessel 1. The contents of vessel 1 were stirred at about 20° C. for 15 hours. Heptane (324 kg) and water (335 kg) were charged to vessel 1. The contents of vessel 1 were stirred for 30 minutes, then a small amount of solids were removed by filtration and the layers were separated. The organic layer was charged to vessel 2 and washed with water (189 kg). The aqueous layer was removed. Aqueous hydrochloric acid (4M, 940 kg) was charged to vessel 2. The contents of vessel 2 were stirred for 30 minutes and then the layers were allowed to settle. The aqueous layer was removed and transferred to vessel 3. Aqueous hydrochloric acid (4M, 141 L) was charged to vessel 2. The contents of vessel 2 were stirred for 30 minutes and then the layers were allowed to settle. The aqueous layer was removed and transferred to vessel 3. tert-Butyl methyl ether (350 kg) was charged to the stirred contents of vessel 3. Aqueous NaOH (50% w / w, 353 kg) was slowly charged to vessel 3 until the contents were adjusted to pH 14. The stirring was stopped and the layers were allowed to settle. The layers were separated and then the aqueous layer was recharged to vessel 3. tert-Butyl methyl ether (104 kg) was charged to vessel 3. This mixture was stirred for 20 minutes and then the stirring was stopped and the layers were allowed to settle. The aqueous layer was removed and then both tert-butyl methyl ether solutions were combined in vessel 3. The contents of vessel 3 were concentrated by vacuum distillation to a volume of about 3 relative volumes. Isopropyl alcohol (150 kg) was charged to vessel 3 and the contents of vessel 3 were then concentrated by distillation to a volume of about 3 relative volumes. Isopropyl alcohol (150 kg) was charged to vessel 3 and the contents of vessel 3 were then concentrated by distillation to a volume of about 3 relative volumes.The solid was collected by filtration to give (3R)-4-{2-chloro-6-[1-(methylsulfanyl)cyclopropyl]-4-pyrimidinyl}-3-methylmorpholine (27.6 kg, 96.7% w / w, 89.1 mol, 44% yield) as a solid and (3R)-4-{2-chloro-6-[1-(methylsulfanyl)cyclopropyl]-4-pyrimidinyl}-3-methylmorpholine as an isopropyl alcohol solution (106 kg, 11.13% w / w, 39.6 mol, 20% yield), total yield 64%. 1H NMR(500MHz,DMSO,27℃)1.21(3H,d),1.28(2H,d),1.44-1.64(2H,m),2.12(3H,s),3.20(1H,td), 3.45(1H,td),3.59(1H,dd),3.72(1H,d),3.86-4.12(2H,m),4.36(1H,s),7.10(1H,s).MS(M+H)+ 300.

[0139] Example 7: Preparation of (3R)-4-(2-chloro-6-{1-[(R)-methylsulfinyl]cyclopropyl}-4-pyrimidinyl)-3-methylmorpholine [ka] Dipotassium hydrogen phosphate trihydrate (39.1 kg) and water (1712 kg) were charged to the vessel. Agitation was started and then concentrated hydrochloric acid (2.1 kg) was added. A solution of (3R)-4-{2-chloro-6-[1-(methylsulfanyl)cyclopropyl]-4-pyrimidinyl}-3-methylmorpholine (35.36 kg, 117.9 mol) in isopropyl alcohol (109 kg) was charged to the vessel. Nicotinamide adenine dinucleotide phosphate (0.68 kg) was charged to the vessel. Cyclohexanone mono-oxygenase Rhodococcus Ruber (Accession No. AAL14233.1, crude cell lysate, 277.3 kg, 8% w / w) was charged to the vessel. Ketoreductase (Asymchem 6511, 69.5 kg) was charged to the vessel. A mixture of air and nitrogen (1:2) was blown through the reaction mixture using a sparger and the contents of the vessel were stirred at about 30°C for 10 hours. The contents of the vessel were adjusted to pH 3 using 10% aqueous hydrochloric acid (40.6 kg). Sodium chloride (520 kg) was charged to the vessel. The resulting mixture was stirred for 2 hours. The solids were removed by centrifugation and the filter cake was washed with ethyl acetate (3 x 310 kg). The combined filtrate was charged to a clean vessel and then water (505 kg) was added. The mixture was stirred for 1 hour and then the aqueous layer was removed. The organic layer was concentrated to a total volume of 1000 L by distillation under reduced pressure. The mixture was filtered. A solution of sodium hydroxide (68.7 kg) in water (276.3 kg) was added at 15-30°C. The resulting mixture was extracted with ethyl acetate (3 x 636 kg). The combined organic phase was washed with water (689 kg). The resulting organic solution was concentrated by vacuum distillation to a total volume of about 150 L. Heptane (235 kg) was charged to the vessel and the contents of the vessel were then concentrated by vacuum distillation to a total volume of about 150 L. Heptane (235 kg) was charged to the vessel and the contents of the vessel were then concentrated by vacuum distillation to a total volume of about 150 L. The contents of the vessel were stirred at 80° C. for 2 hours, then cooled to about 10° C. and stirred for an additional 4 hours. The solids were collected by filtration.The filter cake was washed with heptane (185 kg) and dried to give (3R)-4-(2-chloro-6-{1-[(R)-methylsulfinyl]cyclopropyl}-4-pyrimidinyl)-3-methylmorpholine (28.5 kg, 95.2% w / w, 86.07 mol, 73% yield) as a solid. 1H NMR(400MHz,DMSO,27℃)1.20(3H,d),1.26-1.34(2H,m),1.40-1.52(2H,m),2.52(3H,s),3.17(1H,td),3.42 (1H,td),3.57(1H,dd),3.71(1H,d),3.92(1H,dd),4.01(1H,d),4.36-4.40(1H,m),6.66(1H,s).MS:(M+H)+ 316.

[0140] Example 8: Preparation of (3R)-4-{2-chloro-6-[1-(S-methylsulfonimidoyl)cyclopropyl]-4-pyrimidinyl}-3-methylmorpholine hydrochloride [ka] Toluene (258 kg) and methanol (47.4 kg) were charged to the vessel. Agitation was commenced and the contents were cooled to 0-10° C. (3R)-4-(2-chloro-6-{1-[(R)-methylsulfinyl]cyclopropyl}-4-pyrimidinyl)-3-methylmorpholine (31.7 kg, 94.26 mol) and (diacetoxyiodo)benzene (65.0 kg, 197.9 mol) were charged to the vessel at 0-10° C. Ammonium carbamate (30 kg, 377.0 mol) was charged to the vessel at 0-10° C. and the contents of the vessel were then stirred at 0-10° C. for 20 hours. Aqueous citric acid (30% w / w) was charged to the vessel until the pH was adjusted to pH 2-3. The mixture was stirred for 30 minutes. Agitation was stopped and the aqueous layer was removed. Agitation was resumed and then aqueous citric acid (30% w / w) was charged to the vessel until the pH was adjusted to pH 2. Agitation was stopped and the layers were split. The aqueous phases were combined and agitation was started. Aqueous sodium hydroxide (30% w / w) was charged until the pH was adjusted to pH 8-9. Sodium chloride (96 kg) was charged. Ethyl acetate (101 kg) and tetrahydrofuran (33 kg) were charged and the resulting mixture was stirred for 30 minutes. Agitation was stopped and the layers were split. The aqueous layer was recharged to the vessel and agitation was started. Ethyl acetate (89.1 L) and tetrahydrofuran (29.7 L) were charged and the resulting mixture was stirred for 30 minutes. Agitation was stopped and the layers were split. The aqueous layer was recharged to the vessel and agitation was started. Ethyl acetate (101 kg) and tetrahydrofuran (33 kgL) were charged and the resulting mixture was stirred for 30 minutes. Agitation was stopped and the layers were split. The aqueous layer was recharged to the vessel and agitation was started. Ethyl acetate (101 kg) and tetrahydrofuran (33 kgL) were charged and the resulting mixture was stirred for 30 minutes. Agitation was stopped and the layers were split. The aqueous layer was recharged to the vessel and agitation was started. Ethyl acetate (101 kg) and tetrahydrofuran (33 kgL) were charged and the resulting mixture was stirred for 30 minutes. Stirring was stopped and the layers were split. The organic phases were combined in a vessel and then concentrated by distillation to approximately 59 L. Isopropyl alcohol (48 kg) was charged and the solution was then concentrated by distillation to approximately 59 L. Isopropyl alcohol (48 kg) was charged and the solution was then concentrated by distillation to approximately 59 L. The resulting solution was cooled to 0-5° C. and then a solution of hydrogen chloride in isopropyl alcohol (6M, 21.7 kg) was charged to the vessel.The resulting mixture was stirred at 0-5°C for approximately 2 hours. Methyl tert-butyl ether (135 kg) was charged to the vessel and the contents were stirred for an additional 2 hours. The solids were collected by filtration and washed with methyl tert-butyl ether (45 kg). The solids were recharged to the vessel and then methanol (54 kg) was added. The slurry was stirred at 35-40°C for 1 hour and then cooled to 20-25°C. Methyl tert-butyl ether (103 kg) was charged to the vessel and the mixture was stirred for 1 hour. The solids were collected by filtration and then the filter cake was washed with methyl tert-butyl ether (59 L) and dried to provide (3R)-4-{2-chloro-6-[1-(S-methylsulfonimidoyl)cyclopropyl]-4-pyrimidinyl}-3-methylmorpholine hydrochloride (30.2 kg, 78.2 mol, 83% yield) as a solid. 1H NMR(500MHz,DMSO,27℃)1.23(3H,d),1.65-1.70(1H,m),1.85-1.89(3H,m),3.18-3.24(1H,m),3.42(1H,td),3.58(1 H,dd),3.73(3H,s),3.80-3.87(1H,m),3.95(1H,dd),4.05-4.15(1H,m),4.34-4.46(1H,m),7.12(1H,s).MS:(M+H)+ 331.

[0141] Example 9: Preparation of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine [ka] 1,4-Dioxane (938 kg) was charged to the vessel. The vessel was inerted with nitrogen and stirring was started. 4-Bromo-7-azaindole (62.6 kg, 304.5 mol) was charged to the vessel. Potassium acetate (62.3 kg, 615 mol) was charged to the vessel. Bis(pinacolato)diboron (105.5 kg, 397.2 mol) was charged to the vessel. Tetrakis(triphenylphosphine)palladium(0) (3.67 kg, 3.05 mol) was charged to the vessel. The contents of the vessel were heated at 90-100° C. for 12 hours. The mixture was cooled to 25-35° C. and the solids were removed by filtration. The filter cake was washed with 1,4-dioxane (105 kg) and then the combined filtrate was charged to the vessel. The filtrate was concentrated by distillation under reduced pressure to a volume of approximately 125 L. The contents of the vessel were heated to 40° C. and then water (189 kg) was charged to the vessel. The contents of the vessel were stirred at about 20° C. for 12 hours and then the solids were collected by filtration. The filter cake was washed with water (2×63 kg). The solids and methyl tert-butyl ether (237 kg) were charged to the vessel and the mixture was stirred at about 35° C. for 30 minutes. The mixture was cooled to about 15° C. and stirred for an additional 4 hours. The solids were collected by filtration. The filter cake was washed with methyl tert-butyl ether (46 kg) and then dried at about 40° C. to provide 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (57.5 kg, 96% w / w, 222.3 mol, 73% yield) as a solid. 1H NMR(500MHz,DMSO)1.35(12H,s),6.67(1H,dd),7.30(1H,d),7.44-7.57(1H,m),8.23(1H,d),11.65(1H,s).

[0142] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine can also be prepared as follows: [ka] Isopropyl acetate (387 kg) was charged to the vessel. The vessel was inerted with nitrogen and stirring was started. 4-Bromo-7-azaindole (41.5 kg, 211 mol) was charged to the vessel. Potassium acetate (43.1 kg, 439 mol) was charged to the vessel. Bis(pinacolato)diboron (54.7 kg, 215.4 mol) was charged to the vessel. Bis(triphenylphosphine)palladium(II) dichloride (2.9 kg, 4.13 mol) was charged to the vessel. The contents of the vessel were heated at 85-90°C for 22 hours. The mixture was cooled to 50°C and then washed with water (4 x 218 kg). Mercaptosilica (27.8 kg) was added to the organic phase and the mixture was heated at 50°C for 8 hours. The solids were removed by filtration and the filter cake was washed with isopropyl acetate (98 kg). The combined filtrate was concentrated by vacuum distillation to a volume of about 240 L. The mixture was cooled to about 27° C. and then methyl tert-butyl ether (200 kg) was added. The mixture was cooled to about 3° C. and stirred for an additional 7 hours. The solid was collected by filtration. The filter cake was washed with methyl tert-butyl ether (40 kg) and then dried at about 40° C. to give 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (39.7 kg, 98.9% w / w, 161.0 mol, 76% yield) as a solid. 1H NMR(500MHz,DMSO)1.35(12H,s),6.67(1H,dd),7.30(1H,d),7.44-7.57(1H,m),8.23(1H,d),11.65(1H,s).

[0143] Example 9a: Preparation of 4-(1,3,6,2-dioxazaborocan-2-yl)-1H-pyrrolo[2,3-b]pyridine from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine [ka] A solution of diethanolamine (1.420 g, 13.51 mmol) in isopropanol (1.4 mL) and tetrahydrofuran (1.4 mL) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (3.354 g, 13.47 mmol) in tetrahydrofuran (13.5 mL) with stirring. After 20 minutes, the solid was collected by filtration. The solid was washed twice with a mixture of isopropanol (0.7 mL) and tetrahydrofuran (6.8 mL) and then dried in a vacuum oven at 40° C. for 21 hours to give 4-(1,3,6,2-dioxazaborocan-2-yl)-1H-pyrrolo[2,3-b]pyridine (2.494 g, 77%) as a solid. 1H NMR(400MHz,DMSO,27℃)2.89(2H,ddt),3.15(2H,ddt),3.83-3.99(4H,m),6.56(1H,dd), 6.97-7.04(1H,m),7.08(1H,d),7.22-7.26(1H,m),8.02(1H,d),11.11(1H,s).MS:(M+H)+ 232.

[0144] Example 9b: Preparation of 4-(1,3,6,2-dioxazaborocan-2-yl)-1H-pyrrolo[2,3-b]pyridine from 4-bromo-7-azaindole [ka] A mixture of 4-bromo-1H-pyrrolo[2,3-b]pyridine (8.00 g, 40.0 mmol), potassium acetate (7.91 g, 80.6 mmol), bis(pinacolato)diboron (13.25 g, 52.18 mmol), palladium acetate (182 mg, 0.811 mmol) and triphenylphosphine (421 mg, 1.61 mmol) in isopropyl acetate (80 mL) was stirred at 90° C. for 21 h. The mixture was washed with aqueous brine solution (80 mL). The organic layer was diluted with isopropyl acetate (80 mL) and washed with aqueous brine solution (80 mL). The organic layer was concentrated by distillation to a volume of about 40 mL. Isopropyl acetate (60 mL) was added to the remaining solution and then the organic layer was concentrated by distillation to a volume of about 40 mL. Isopropyl acetate (60 mL) was added to the remaining solution, and the organic layer was then concentrated by distillation to a volume of about 40 mL. The stirred solution was seeded with 4-(1,3,6,2-dioxazaborocan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.08 g), for example obtained from Example 9a above. A solution of diethanolamine (8.48 g, 80.7 mmol) in isopropanol (30 mL, 186 mmol) was added dropwise at 75° C. The mixture was stirred at 75° C. for an additional 13 hours. The solid was collected by filtration. The solid slurry was washed twice with a mixture of isopropanol (2 mL) and 2-methyltetrahydrofuran (20 mL) and then dried in a vacuum oven at 40° C. for 21 h to give 4-(1,3,6,2-dioxazaborocan-2-yl)-1H-pyrrolo[2,3-b]pyridine (6.653 g, 69%) as a solid. 1H NMR (400 MHz, DMSO, 27° C.) 2.89 (2H, ddt), 3.15 (2H, ddt), 3.83-3.99 (4H, m), 6.56 (1H, dd), 6.97-7.04 (1H, m), 7.08 (1H, d), 7.22-7.26 (1H, m), 8.02 (1H, d), 11.11 (1H, s). MS: (M+H)+ 232.

[0145] Example 10: Preparation of 4-{4-[(3R)-3-methyl-4-morpholinyl]-6-[1-(S-methylsulfonimidoyl)cyclopropyl]-2-pyrimidinyl}-1H-pyrrolo[2,3-b]pyridine

change

[0146] Examples 11 and 12 describe an alternative method for the synthesis of 2,4-dichloro-6-[1-(methylsulfanyl)cyclopropyl]pyrimidine from 1-(methylsulfanyl)cyclopropanecarboxylic acid by a photoredox reaction.

[0147] Example 11: Preparation of (1,3-dioxoisoindolin-2-yl) 1-methylsulfanyl cyclopropanecarboxylate [ka] Oxalyl chloride (7.56 g, 59.0 mmol)) was added to a stirred solution of 1-(methylsulfanyl)cyclopropanecarboxylic acid (7.08 g, 53.6 mmol) in dichloromethane (142 mL) at about 20° C. Dimethylformamide (0.196 g, 2.68 mmol) was added to the solution. The resulting solution was warmed to 25° C. and then stirred for an additional 2 hours. The solution was concentrated and then redissolved in DCM (142 mL). The resulting solution was cooled to about 5° C. and then N-hydroxyphthalimide (9.92 g, 59.0 mol) was added slowly with stirring. Triethylamine (6.03 g, 59.0 mmol) was added and then the resulting mixture was warmed to about 20° C. and stirred for 22 hours. Water (142 mL) was charged to the mixture and then the layers were split. The organic layer was concentrated and the residue was dissolved in ethyl acetate (53 mL). The solution was warmed to about 45° C. with stirring. Heptane (71 mL) was added to the stirred solution and the mixture was then cooled slowly to 20° C. The resulting solid was isolated by filtration and the filter cake was washed with heptane (21 mL) to give (1,3-dioxoisoindolin-2-yl) 1-methylsulfanyl cyclopropanecarboxylate (8.15 g, 99% w / w, 29.2 mmol, 55% yield). 1H NMR (500 MHz, DMSO, 27° C.) 1.46-1.65 (2H,m), 1.67-1.86 (2H,m), 2.32 (3H,s), 7.87-8.06 (4H,m). MS: (M+H)+ 278.

[0148] Example 12: Preparation of 2,4-dichloro-6-[1-(methylsulfanyl)cyclopropyl]pyrimidine by photoreduction [ka] (1,3-Dioxoisoindolin-2-yl)1-methylsulfanylcyclopropanecarboxylate (3.00 g, 10.4 mmol), 2,4-dichloropyrimidine (4.76 g, 31.3 mmol) and 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (250 mg, 0.314 mmol) were dissolved in dimethylsulfoxide (120 mL). The solution was degassed by sparging with nitrogen for 10 minutes and then N,N-diisopropylethylamine (0.370 mL, 2.12 mmol) was added to the solution. The resulting solution was pumped through a flow cell (heated to 50° C.) which was illuminated with blue visible light. When the reaction mechanism reached steady state, a sample (68.5 g) of the crude reaction mixture was collected. The resulting solution was added dropwise to a mixture of water (50 mL) and heptane (50 mL), then a further portion of heptane (50 mL) was added and the mixture was stirred at about 20° C. for 30 min. The resulting precipitate was removed by filtration. The biphasic filtrate was transferred to a separatory funnel and the organic layer was separated and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using increasingly polar mixtures of ethyl acetate in heptane as eluents. The fractions containing the desired product were then concentrated under reduced pressure to give 2,4-dichloro-6-(1-methylsulfanylcyclopropyl)pyrimidine as a white solid (470 mg, 97% w / w, 1.98 mmol, 39% yield). 1H NMR(500MHz,DMSO,27℃)1.42-1.55(2H,m),1.61-1.77(2H,m),2.14(3H,s),8.03(1H,s).MS:(M+H)+ 235.

[0149] An alternative synthetic route using the photocatalyst 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (3DPA2FBN) is described below. [ka] (1,3-Dioxoisoindolin-2-yl) 1-methylsulfanyl cyclopropanecarboxylate (250 g, 1.0 equiv.), 2,4-dichloropyrimidine (336.12 g, 2.50 equiv.) and 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (3DPA2FBN) (5.77 g, 0.01 equiv.) were dissolved in DMSO (6.25 L). The solution was degassed by sparging with nitrogen for 10 min. The resulting solution was pumped through a plug-flow cell (FEP tubing, 8 mm inner diameter, heated to 50° C.) which was irradiated with blue light (450 nm). The exiting solution was added dropwise to a stirred mixture of water (3.12 L) and heptane (6.25 L). The layers were partitioned and the organic layer was then washed three times with a mixture of water (3.75 L) and DMSO (5.625 L). The organic layer was concentrated to give 2,4-dichloro-6-[1-(methylsulfanyl)cyclopropyl]pyrimidine (118 g, 44% yield). Assay 79% w / w. 1H NMR (500 MHz, DMSO, 27° C.) 1.42-1.55 (2H,m), 1.61-1.77 (2H,m), 2.14 (3H,s), 8.03 (1H,s). MS: (M+H)+ 235.

[0150] Alternative benzonitrile, isophthalonitrile or other photocatalysts can be used in place of the above 3DPA2FBN catalyst, and those skilled in the art can adapt the photoredox reaction accordingly. The 3DPA2FBN photocatalyst in the above photoredox reaction can be replaced with 2,3,4,5,6-pentakis(3,6-diphenylcarbazol-9-yl)benzonitrile photocatalyst or 2,4,6-tris(di-4-biphenylylamino)-3,5-difluorobenzonitrile photocatalyst. The synthesis of these photocatalysts is described below.

[0151] Example 13a: Preparation of the photocatalyst 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (3DPA2FBN) [ka] Sodium hydride (60% dispersion in mineral oil, 2.46 g) was added portionwise to a stirred solution of diphenylamine (6.57 g. 38.5 mmol) in tetrahydrofuran (80 mL) at about 20° C. The resulting mixture was heated to 50° C. for 1 h. Pentafluorobenzonitrile (2.00 g, 10.3 mmol) was added and the resulting mixture was heated at about 55° C. for 20 h. The mixture was cooled to about 25° C. and then water (2 mL) was added dropwise. Dichloromethane (200 mL) and water (150 mL) were added and then the layers were partitioned. The organic layer was washed with water (150 mL) and then concentrated. The residue was purified by flash chromatography (eluent isohexane / DCM). The product was slurried in methanol, then collected by filtration and dried to give 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile (3.89 g, 6.01 mmol, 59%) as a yellow solid. 1H NMR (500 MHz, DMSO, 27° C.) 6.88-7.17 (18H, m), 7.20-7.37 (12H, m). MS: (M+H)+ 641.

[0152] Example 13b: Preparation of the photocatalyst 2,3,4,5,6-pentakis(3,6-diphenylcarbazol-9-yl)benzonitrile [ka] Sodium hydride (60% dispersion in mineral oil, 0.400 g) was added portionwise to a stirred solution of 3,6-diphenyl-9H-carbazole (2.15 g, 6.73 mmol) in tetrahydrofuran (20 mL) at about 20° C. The resulting mixture was stirred at 20° C. for 1 h. Pentafluorobenzonitrile (0.200 g, 1.05 mmol) was added and the resulting mixture was stirred at about 55° C. for 3 days. Water (20 mL) and dichloromethane (100 mL) were added and the layers were then partitioned. The organic layer was washed with brine (20 mL) and then concentrated. The residue was purified by flash chromatography using heptane / DCM as eluent to give e2,3,4,5,6-pentakis(3,6-diphenylcarbazol-9-yl)benzonitrile (350 mg, 0.2071 mmol, 20%) as a solid. 1H NMR(500MHz,DMSO,27℃)7.04-7.11(6H,m),7.22-7.44(42H,m),7.54-7.57(4H,m),7.64-7.68(8 H,m),7.82-7.52(6H,m),7.90-7.94(4H,m),7.96-7.99(2H,m),8.07-8.11(4H,m),8.34(4H,m).

[0153] Example 13c: Preparation of the photocatalyst 2,4,6-tris(di-4-biphenylylamino)-3,5-difluorobenzonitrile [ka] Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 6.15 mL) was added to a solution of bis(4-biphenylyl)amine (1.77 g, 5.38 mmol) in tetrahydrofuran (9.00 mL) at 20° C. After stirring for 10 min at 20° C., pentafluorobenzonitrile (0.300 g, 1.54 mmol) was added. The resulting mixture was stirred at 60° C. for 20 h. The mixture was cooled to 20° C., then water (1.5 mL) was added, and then the mixture was concentrated. The residue was chromatographed using dichloromethane / heptane as eluent. The resulting product was slurried in ethyl acetate / heptane, isolated by filtration, and then dried to give 2,4,6-tris(di-4-biphenylylamino)-3,5-difluorobenzonitrile (0.303 g, 0.276 mmol, 18%) as a solid. 1H NMR (500 MHz, DMSO, 27° C.) 7.24-7.46 (30H, m), 7.55-7.72 (24H, m). MS: (M+H)+ 1098.

Claims

1. Formula (II): 【Chemistry 1】 16. A method for preparing a compound of formula (I), comprising the steps of: Formula (III): 【Chemistry 2】 reacting the compound of formula (I) with an oxidase; and optionally thereafter forming a salt thereof, wherein LG1 is selected from chlorine, bromine, or triflate; A process for preparing a compound of formula (II).

2. The compound of formula (III) may be represented by formula (IV): 【Chemistry 3】 with (R)-3-methylmorpholine or a salt thereof, LG1 and LG2 are independently selected from chlorine, bromine or triflate; The method of claim 1.

3. The compound of formula (IV) may be represented by the formula (V): 【Chemistry 4】 with an activating agent, Optionally, a salt thereof is then formed. The method of claim 2.

4. The compound of formula (V) may be represented by formula (VI): 【Chemistry 5】 is prepared from a compound of Optionally, a salt thereof is then formed. The method according to claim 3.

5. The compound of formula (VI) may be represented by the formula (VII): 【Chemistry 6】 5. The method of claim 4, wherein the compound is prepared by reacting the compound of formula (I) with thiourea.

6. The compound of formula (VII) may be reacted with a malonate derivative of formula (VIII): 【Chemistry 7】 6. The method of claim 5, wherein the compound is prepared by acylation of the compound in its activated form with the compound of formula (I) followed by decarboxylation.

7. The compound of formula (VIII) may be represented by formula (IX): 【Chemistry 8】 7. The method of claim 6, wherein the compound of formula (I) is prepared by thiomethylation and base induced cyclization followed by hydrolysis.

8. The compound of formula (IV) is represented by formula (XIII): 【Chemistry 9】 with a 2,4-difunctionalized pyrimidine in the presence of light and a photocatalyst, R1 is a phthalimido group or a tetrachlorophthalimido group; The method of claim 2.

9. 9. The method of claim 8, wherein the compound of formula (XIII) is prepared by reacting the compound of formula (VIII) with OH-R1, wherein R1 is a phthalimido group or a tetrachlorophthalimido group.

10. Formula (II): 【Chemistry 10】 or a salt thereof, wherein LG1 is selected from bromine or triflate.

11. Formula (III): 【Chemistry 11】 or a salt thereof, wherein LG1 is selected from chlorine, bromine or triflate.

12. Formula (IV): 【Chemistry 12】 wherein LG1 and LG2 are independently selected from chlorine, bromine or triflate.

13. Formula (V): 【Chemistry 13】 or a salt thereof.

14. Formula (VI): 【Chemistry 14】 or a salt thereof.

15. Formula (VII): 【Chemistry 15】 or a salt thereof.

16. Formula (XIIb): 【Chemistry 16】 Compound.

17. 13. A compound according to claim 11 or claim 12, wherein LG1 is chlorine and LG2, if present, is chlorine.

18. Use of the compound according to any one of claims 10 to 17, or a salt thereof, as a pharmaceutical intermediate.

19. The compound according to any one of claims 10 to 17, or a salt thereof, of formula (I): 【Chemistry 17】 as an intermediate in the manufacture of the compound of

20. Formula (I) 【Chemistry 18】 16. A method for preparing a compound of formula (I), comprising the steps of: (g) reacting the compound of formula (III) according to claim 11 with an oxidase to obtain a compound of formula (II) 【Chemistry 19】 forming a compound of (h) reacting the compound of formula (II) with a nitrogen source and then with iodobenzene diacetate to produce a compound of formula (X): 【Chemistry 20】 or a salt thereof; (i) Formula (XI) 【Chemistry 21】 with a boron reagent in the presence of a palladium catalyst to give a compound of formula (XII) 【Chemical 22】 forming a compound of the formula: (j) reacting a compound of formula (X) or a salt thereof with a compound of formula (XII) to form a compound of formula (I); Including, LG1 of formula (II) and formula (X) is selected from chlorine, bromine and triflate; A process for preparing a compound of formula (I).

21. 21. The process for preparing a compound of formula (I) according to claim 20, wherein step (i) further comprises the addition of diethanolamine after the reaction with the boron reagent in the presence of a palladium catalyst.

22. The compound of formula (XII) has the formula (XIIb): 【Chemistry 23】 22. A process for preparing a compound of formula (I) according to claim 21, which is a compound of the formula:

23. Formula (I): 【Chemistry 24】 A method for preparing a compound of the formula: (i) reacting a compound of formula (XI) with a boron reagent in the presence of a palladium catalyst, followed by addition of diethanolamine to form a compound of formula (XIIb); A process for preparing a compound of formula (I).

24. A process for preparing a compound of formula (I) according to any one of claims 20 to 22, comprising the steps of: (a) cyclopropanation of a compound of formula (IX) followed by hydrolysis to form a compound of formula (VIII); (b) reacting a compound of formula (VIII) with an acylating agent to form a compound of formula (VII); (c) reacting a compound of formula (VII) with urea or thiourea to form a compound of formula (VI); (d) reacting the compound of formula (VI) with a suitable reagent to form a compound of formula (V); (e) reacting the compound of formula (V) with an activating reagent to form a compound of formula (IV); (f) coupling the compound of formula (IV) with (R)-3-methylmorpholine or a salt thereof to form a compound of formula (III); Further comprising: LG1 and LG2 each independently represent chlorine, bromine or triflate; A process for preparing a compound of formula (I).

25. A process for preparing a compound of formula (I) according to any one of claims 20 to 22, comprising the steps of: (a) cyclopropanation of a compound of formula (IX) followed by hydrolysis to form a compound of formula (VIII); (b) reacting a compound of formula (VIII) with R1-OH, where R1 is a phthalimido group or a tetrachlorophthalimido group, to form a compound of formula (XIII); (c) reacting the compound of formula (XIII) with a 2,4-difunctionalized pyrimidine in the presence of light and a photocatalyst to form a compound of formula (IV); (d) coupling the compound of formula (IV) with (R)-3-methylmorpholine or a salt thereof to form a compound of formula (III); Further comprising: LG1 and LG2 represent chlorine, bromine or triflate; A process for preparing a compound of formula (I).

26. 26. A process for preparing a compound of formula (I) according to claim 24 or claim 25, wherein LG1 and LG2 both represent chlorine.

27. A compound of formula (I) prepared according to the method of any one of claims 1 to 9 or any one of claims 20 to 26: 【Chemistry 25】 Compound.

28. The compound 2,4,6-tris(di-4-biphenylylamino)-3,5-difluorobenzonitrile. 【Chemistry 26】

29. Use of the compound 2,3,4,5,6-pentakis(3,6-diphenylcarbazol-9-yl)benzonitrile as a photocatalyst.

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