Process for the preparation of substituted pyrrolopyrimidines and intermediates

Abstract

A new and improved synthetic route is provided for the synthesis of the compound 1-{2-[(1R)-1-aminoethyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (Formula (I)) that is readily scalable for commercial production. (I) Key intermediate compounds formed in the new and improved synthetic route for the synthesis of the compound of Formula (I) are also provided. [Formula 1] JPEG2025526982000037.jpg46128

Description

[Technical Field]

[0001] (Related Applications) This application claims the benefit of priority to U.S. Patent Application No. 63 / 400,445, filed August 24, 2022, which is incorporated herein by reference in its entirety.

[0002] International Patent Application No. 2016 / 087338 discloses thioxopyrrolopyrimidone derivatives useful as myeloperoxidase (MPO) inhibitors. Specifically, it discloses 1-{2-[(1R)-1-aminoethyl]-4-chlorobenzyl}-2-thioxo-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (hereinafter referred to as compound of formula (I)). The structure of compound of formula (I) is shown below.

[0003] [ka]

[0004] The compound of formula (I) is being developed as an active pharmaceutical compound for the treatment of respiratory diseases. Therefore, suitable methods for the safe, cost-effective, efficient and environmentally friendly production of the compound of formula (I) may be desirable.

[0005] A previous enantioselective synthesis of the compound of formula (I) is described in Example 3 of International Patent Application No. 2016 / 087338.

[0006] One previous synthesis involved 10 steps (a-j) in an overall yield of 22%, providing 633 g of compound. The yield obtained for step (i) of this synthesis was sub-gram scale; dioxane protection / deprotection of the acetophenone was required.

[0007] Another earlier synthesis (Alternative Example 3) involved at least 8 steps in 47% yield, providing 16 g of compound (note that a reductive amination and cyclization step is implicitly performed between (e) and (f)). BOC protection / deprotection of the amine was required.

[0008] Both previous syntheses rely on dichloromethane, a less environmentally friendly and carcinogenic solvent. Both previous syntheses required the use of toxic carbon monoxide gas (also using flammable hydrogen gas) and superatmospheric pressure to introduce the formyl group. Such reaction conditions do not scale well. Both previous syntheses also first perform enantioselective amine formation, which requires stoichiometric amounts of expensive chiral sulfinamides. Therefore, material loss in subsequent steps of these syntheses is less cost-effective than if enantioselective amine formation were performed later in the synthesis. Summary of the Invention

[0009] The present invention relates to a new and improved synthetic route for the synthesis of compounds of formula (I), which is easily scalable for commercial production and is depicted in Scheme 1 below. The square brackets indicate compounds that can be telescoped to the next step in their crude form (i.e., without isolation and / or purification). Compound (Ia1) is depicted as the hydrochloride salt, although the corresponding free base or a different salt thereof may also be used.

[0010] [ka]

[0011] In a first aspect, there is provided a process for preparing a compound of formula (I), comprising at least one of steps (i) to (viii).

[0012] The new improved process involves only 8 steps with an overall yield of 46% and is commercially scalable to provide at least 82 kg of compound (over 130 times more by weight than the largest previous synthesis). If the two telescope procedures described herein are performed, it may even be the case that only 6 steps are considered.

[0013] No chlorinated solvents are used. The need for a protection step in the main reaction sequence is eliminated, as the only protecting group is introduced as part of the acetophenone formation and removed after the cyclization step. Unlike both previous syntheses, the enantioselective amine formation is the final structural transformation, thus maximizing the conservation of the resulting valuable product for cost-effectiveness. Furthermore, the formylation step is avoided, as commercially available starting materials already contain the formyl group required for reductive amination.

[0014] In one embodiment, the process for preparing a compound of formula (I) comprises at least two, three, four, five, six, seven, or all of steps (i) through (viii).

[0015] In one embodiment, the process for preparing a compound of formula (I) comprises the steps of: (i) reacting a compound of formula (I) with at least two of steps (i) to (viii), optionally reacting (i) and (ii), (i) and (iii), (i) and (iv), (i) and (v), (i) and (vi), (i) and (vii), (i) and (viii), (ii) and (iii), (ii) and (iv), (ii) and (v), (ii) and (vi), (ii) and (vii), (ii) and (viii), (iii) and (iv), (iii) and (v), (iii) and (vi), (iii) and (vii), (iii) and (viii), (iv) and (v), (iv) and (vi), (iv) and (vii), (iv) and (viii), (v) and (vi), (v) and (vii), (v) and (viii), (vi) and (vii), (vi) and (viii), or (vii) and (viii).

[0016] In one embodiment, the process for preparing a compound of formula (I) comprises steps (i) to (viii), optionally comprising at least three of steps (i), (ii), and (iii), (i), (ii), and (iv), (i), (ii), and (v), (i), (ii), and (vi), (i), (ii), and (vii), (i), (ii), and (viii), (i), (iii), and (iv), (i), (iii), and (v), (i), (iii), and (vi), (i), (iii), and (vii), (i), (iii), and (viii), (i ), (iv), and (v), (i), (iv), and (vi), (i), (iv), and (vii), (i), (iv), and (viii), (i), (v), and (vi), (i), (v), and (vii), (i), (v), and (viii), (i), (vi), and (vii), (i), (vi), and (viii), (i), (vii), and (viii), (ii), (iii), and (iv), (ii), (iii), and (v), (ii), (iii), and (vi), (ii), (iii), and (vii), (ii), (iii), and and (viii), (ii), (iv), and (v), (ii), (iv), and (vi), (ii), (iv), and (vii), (ii), (iv), and (viii), (ii), (v), and (vi), (ii), (v), and (vii), (ii), (v), and (viii), (ii), (vi), and (vii), (ii), (vi), and (viii), (ii), (vii), and (viii), (ii), (vii), and (viii), (iii), (iv), and (v), (iii), (iv), and (vi), (iii), (iv), and (vii), (iii), (iv), and (vii), (iii), (iv) ), and (viii), (iii), (v), and (vi), (iii), (v), and (vii), (iii), (v), and (viii), (iii), (vi), and (vii), (iii), (vi), and (viii), (iii), (vii), and (viii), (iv), (v), and (vi), (iv), (v), and (vii), (iv), (v), and (viii), (iv), (vi), and (vii), (iv), (vi), and (vii), (iv), (vi), and (viii), (iv), (vii), and (viii), (iv), (vii), and (viii), (iv), (vii), and (viii), (v), (vii), and (viii), (v), (vii), and (vii),(v), (vi), and (viii), (v), (vii), and (viii), or (vi), (vii), and (viii).

[0017] In one embodiment, the process for preparing a compound of formula (I) comprises at least four of steps (i) to (viii), optionally including (i), (ii), (iii), and (iv), (i), (ii), (iii), and (v), (i), (ii), (iii), and (vi), (i), (ii), (iii), and (vii), (i), (ii), (iii), and (viii), (i), (ii), (iv), and (v), (i), (ii), (iv), and (vi), (i), (ii), (iv), and (vi), (i), (ii), (iv), and (vii), (i), (ii), (iv). ), and (viii), (i), (ii), (v), and (vi), (i), (ii), (v), and (vii), (i), (ii), (v), and (viii), (i), (ii), (vi), and (vii), (i), (ii), (vi), and (viii), (i), (ii), (vii), and (viii), (i), (iii), (iv), and (v), (i), (iii), (iv), and (vi), (i), (iii), (iv), and (vii), (i), (iii), (iv), and (viii), (i), (iii), (v), and (vi), (i), (iii), (v), and (vii), (i), (iii), (v), and (viii), (i), (iii), (vi), and (vii), (i), (iii), (vi), and (viii), (i), (iii), (vii), and (viii), (i), (iv), (v), and (vi), (i), (iv), (v), and (vii), (i), (iv), (v), and (viii), (i), (iv), (vi), and (vii), (i), (iv), (vi), and (vii), (i), (iv), (vi), and (viii), (i), (iv), (vi), and (vii), (i), (iv), (vi), and (viii), (i), (iv), (vii), and (v iii), (i), (v), (vi), and (vii), (i), (v), (vi), and (viii), (i), (v), (vii), and (viii), (i), (vi), (vii), and (viii), (ii), (iii), (iv), and (v), (ii), (iii), (iv), and (vi), (ii), (iii), (iv), and (vii), (ii), (iii), (iv), and (viii), (ii), (iii), (v), and (vi), (ii), (iii), (v), and (vi), (ii), (iii), (v), and (vi), (ii), (iii), (v), and (vii), (ii), (iii), (v),and (viii), (ii), (iii), (vi), and (vii), (ii), (iii), (vi), and (viii), (ii), (iii), (vii), and (viii), (ii), (iv), (v), and (vi), (ii), (iv), (v), and (vii), (ii), (iv), (v), and (viii), (ii), (iv), (vi), and (vii), (ii), (iv), (v), and (viii), (ii), (iv), (vi), and (vii) i), (ii), (iv), (vi), and (viii), (ii), (iv), (vii), and (viii), (ii), (v), (vi), and (vii), (ii), (v), (vi), and (viii), (ii), (v), (vii), and (viii), (ii), (vi), (vii), and (viii), (ii), (vi), (vii), and (viii), (iii), (iv), (v), and (vi), (i ii), (iv), (v), and (vii), (iii), (iv), (v), and (viii), (iii), (iv), (vi), and (vii), (iii), (iv), (vi), and (viii), (iii), (iv), (vii), and (viii), (iii), (v), (vi), and (vii), (iii), (v), (vi), and (vii), (iii), (v), (vi), and (viii), (ii i), (v), (vii), and (viii), (iii), (vi), (vii), and (viii), (iv), (v), (vi), and (vii), (iv), (v), (vi), and (viii), (iv), (v), (vii), and (viii), (iv), (vi), (vii), and (viii), or (v), (vi), (vii), and (viii).

[0018] In one embodiment, the process for preparing a compound of formula (I) comprises at least five of steps (i) through (viii), optionally including (i), (ii), (iii), (iv), and (v), (i), (ii), (iii), (iv), and (vi), (i), (ii), (iii), (iv), and (vii), (i), (ii), (iii), (iv), and (viii), (i), (ii), (iii), (v), and (vi), (i), (ii), (iii), (v), and (vii), (i), (ii), (iii), (v), and (vii). ii), (i), (ii), (iii), (vi), and (vii), (i), (ii), (iii), (vi), and (viii), (i), (ii), (iii), (vii), and (viii), (i), (ii), (iv), (v), and (vi), (i), (ii), (iv), (v), and (vii), (i), (ii), (iv), (v), and (viii), (i), (ii), (iv), (vi), and (vii), (i), (ii), (iv), (vi), and (viii), (i), (ii), (iv), (vi), and (vii), (i), (ii), (iv), (vi), and (viii), (i), (ii), (iv), (vii), and (vii), (i), (ii), (iv), (vi), and (viii), (i), (ii), (iv), (vii), and (vii) ii), (i), (ii), (v), (vi), and (vii), (i), (ii), (v), (vi), and (viii), (i), (ii), (v), (vii), and (viii), (i), (ii), (vi), (vii), and (viii), (i), (iii), (iv), (v), and (vi), (i), (iii), (iv), (v), and (vii), (i), (iii), (iv), (v), and (viii), (i), (iii), (iv), (vi), and (vii), (i), (iii), (iv), (v), and (viii), (i), (iii), (iv), (vi), and (vii), (i), (iii), (iv), (vi), and (vii), (i), (iii), (iv), (vi), and (vii), (i), (iii), (iv), (vi), and (vii), (i), (iii), (iv), (vi), and (vii), (i), (iii), (iv), (vi), and (vi ii), (i), (iii), (iv), (vii), and (viii), (i), (iii), (v), (vi), and (vii), (i), (iii), (v), (vi), and (viii), (i), (iii), (v), (vii), and (viii), (i), (iii), (vi), (vii), and (viii), (i), (iv), (v), (vi), and (vii), (i), (iv), (v), (vi), and (viii), (i), (iv), (v), (vi), and (viii), (i), (iv), (v), (vi), and (viii), (i), (iv), (v), (vii), and (viii), (i), (iv), (v), (vii), and (viii), (i), (iv), (vi), (vii), and (viii), (i), (iv), (vi), (vii),and (viii), (i), (v), (vi), (vii), and (viii), (ii), (iii), (iv), (v), and (vi), (ii), (iii), (iv), (v), and (vii), (ii), (iii), (iv), (v), and (viii), (ii), (iii), (iv), (vi), and (vii), (ii), (iii), (iv), (v), and (viii), (ii), (iii), (iv), (vi), and (vii), (ii), (iii), (i v), (vi), and (viii), (ii), (iii), (iv), (vii), and (viii), (ii), (iii), (v), (vi), and (vii), (ii), ( iii), (v), (vi), and (viii), (ii), (iii), (v), (vii), and (viii), (ii), (iii), (vi), (vii), and (viii) ), (ii), (iv), (v), (vi), and (vii), (ii), (iv), (v), (vi), and (viii), (ii), (iv), (v), (vii), and (v iii), (ii), (iv), (vi), (vii), and (viii), (ii), (v), (vi), (vii), and (viii), (iii), (iv), (v), (vi ), and (vii), (iii), (iv), (v), (vi), and (viii), (iii), (iv), (v), (vii), and (viii), (iii), (iv), (vi), (vii), and (viii), (iii), (v), (vi), (vii), and (viii), or (iv), (v), (vi), (vii), and (viii).

[0019] In one embodiment, the process for preparing a compound of formula (I) comprises at least six of steps (i) to (viii), optionally including (i), (ii), (iii), (iv), (v), and (vi), (i), (ii), (iii), (iv), (v), and (vii), (i), (ii), (iii), (iv), (v), and (viii), (i), (ii), (iii), (iv), (vi), and (vii), (i), (ii), (iii), (iv), (vi), and (viii), (i), (ii), (iii), (iv), (vi), and (viii), (i), (ii), (iii), (iv), (vi) and (viii), (i), (ii), (iii), (iv), (vii ), and (viii), (i), (ii), (iii), (v), (vi), and (vii), (i), (ii), (iii), (v), (vi), and (viii), (i), (ii), (iii), (v), (vii), and (viii), (i), (ii), (iii), (vi), (vii), and (viii), (i), (ii), (iv), (v), (vi), and (vii), (i), (ii), (iv), (v), (vi), and (viii), (i), (ii), (iv), (v), (vi), and (viii), (i), (ii), (iv), (v), (vii), and (viii), (i), (ii), (iv), (v), (vi), and (viii), (i), (ii), (iv), (v), (vii), and (viii), (i), (ii), (iv), (v), (vii), and (viii), (i), (ii), (ii ), (iv), (vi), (vii), and (viii), (i), (ii), (v), (vi), (vii), and (viii), (i), (iii), (iv), (v), (vi), and (vii), (i), (iii), (iv), (v), (vi), and (viii) , (i), (iii), (iv), (v), (vii), and (viii), (i), (iii), (iv), (vi), (vii), and (viii), (i), (iii), (v), (vi), (vii), and (viii), (i), (iv), (v), (vi), (v ii), and (viii), (ii), (iii), (iv), (v), (vi), and (vii), (ii), (iii), (iv), (v), (vi), and (viii), (ii), (iii), (iv), (v), (vii), and (viii), (ii), (iii) ), (iv), (vi), (vii), and (viii), (ii), (iii), (v), (vi), (vii), and (viii), (ii), (iv), (v), (vi), (vii), and (viii), or (iii), (iv), (v), (vi), (vii),and (viii).

[0020] In one embodiment, the process for preparing a compound of formula (I) comprises at least seven of steps (i) to (viii), optionally including (i), (ii), (iii), (iv), (v), (vi), and (vii), (i), (ii), (iii), (iv), (v), (vi), and (viii), (i), (ii), (iii), (iv), (v), (vii), and (viii), (i), (ii), (iii), (iv), (v), (vii), and (viii), (i), (ii), (iii), ), (iv), (vi), (vii), and (viii), (i), (ii), (iii), (v), (vi), (vii), and (viii), (i), (ii), (iv), (v), (vi), (vii), and (viii), (i), (iii), (iv), (v), (vi), (vii), and (viii), or (ii), (iii), (iv), (v), (vi), (vii), and (viii).

[0021] In one embodiment, compound (Ib) is telescoped to the next step in its crude form (i.e., without isolation and / or purification). In another embodiment, compound (If) is telescoped to the next step in its crude form (i.e., without isolation and / or purification).

[0022] More specifically, the synthetic route for the synthesis of compounds of formula (I) is set forth in Scheme 2 below. The brackets indicate compounds that can be telescoped to the next step in their crude form (i.e., without isolation and / or purification). Compound (Ia1) is depicted as the hydrochloride salt, but the corresponding free base or a different salt thereof may also be used.

[0023] [ka]

[0024] In one embodiment, step (i) comprises at least the following steps:

[0025] [ka] (ia) decomposing the hydrochloride salt of the compound of formula (Ia1) or the corresponding free base or a different salt thereof in the presence of an inorganic base, optionally wherein the inorganic base is sodium carbonate;

[0026] [ka] (ib) reacting the resulting compound of step (ia) with a compound of formula (Ia2) under acidic conditions, optionally wherein the acid is acetic acid; (ic) reducing the resulting imine compound of step (ib) by reacting it with a reducing agent, optionally wherein the reducing agent is sodium triacetoxyborohydride; (id) crystallizing the compound of formula (Ia) obtained from step (c) as the hydrochloride salt.

[0027] In one embodiment, (ii) comprises reacting at least (ii-a) the compound of Formula (Ia) with 4-(vinyloxy)butan-1-ol in the presence of a palladium catalyst, optionally where the palladium catalyst is palladium acetate, and optionally also in the presence of a phosphine ligand, preferably where the phosphine ligand is one of 1,3-bis(diphenylphosphino)propane (DPPP), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (X-Phos), or 1,3-bis(diphenylphosphino)benzene.

[0028] In one embodiment, step (iii) comprises reacting at least (iii-a) a compound of formula (Ib) with benzoyl isothiocyanate.

[0029] In one embodiment, step (iv) comprises reacting at least (iv-a) a compound of formula (Ic) with an inorganic acid, optionally wherein the inorganic acid is hydrochloric acid or sulfuric acid.

[0030] In one embodiment, step (v) comprises reacting at least (va) a compound of formula (Id) with a chiral sulfinamide reagent in the presence of a dehydrating reagent, optionally wherein the dehydrating reagent is titanium ethoxide.

[0031] In one embodiment, step (vi) comprises reacting at least (vi-a) the compound of formula (Ie) with a reducing agent, optionally wherein the reducing agent is lithium tri-tert-butoxyaluminum hydride.

[0032] In one embodiment, step (vii) comprises reacting at least (vii-a) a compound of formula (If) with a chiral resolving agent, optionally wherein the compound of formula (If) is provided from the preceding step (vi) in an organic solvent without purification.

[0033] In one embodiment, step (viii) comprises at least (viii-a) reacting a compound of formula (Ig) with an inorganic base to provide a compound of formula (I).

[0034] In one embodiment, the base is an inorganic base selected from a hydroxide, a carbonate, or a bicarbonate. In one embodiment, the base is an inorganic base that is a non-metal hydroxide. In one embodiment, the base is ammonium hydroxide.

[0035] In a second aspect,

[0036] [ka] A compound selected from the group consisting of:

[0037] In a third aspect, the structure:

[0038] [ka] Compounds having the formula: DETAILED DESCRIPTION OF THE INVENTION

[0039] Stage 1 / Step (i): Reductive amination

[0040] [ka]

[0041] The salt decomposition step can be carried out in a mixture of water and various organic solvents such as dichloromethane, 2-methyltetrahydrofuran, isopropyl acetate, or toluene. In one embodiment, the salt decomposition was carried out in water and toluene. The salt decomposition can be carried out using various bases such as sodium carbonate, potassium carbonate, or cesium carbonate. In one embodiment, sodium carbonate was used as the base.

[0042] The reaction can be carried out in a variety of organic solvents, such as dichloromethane, ethanol, methanol, tetrahydrofuran, isopropyl alcohol, dioxane, and toluene. In one aspect, the reaction was carried out in toluene. Various acids can be used, such as trifluoroacetic acid, hydrochloric acid, toluenesulfonic acid, or acetic acid. Alternatively, the reaction can be carried out in the absence of acid. In one aspect, acetic acid was used as the acid. The reduction stage can be carried out by methods that would be familiar to those skilled in the art. Various reducing agents can be used, such as lithium aluminum hydride, sodium cyanoborohydride, sodium borohydride, palladium on carbon, or sodium triacetoxyborohydride. In one aspect, sodium triacetoxyborohydride was used in the reduction step.

[0043] The reaction can be carried out over a range of temperatures, e.g., from -40°C to 30°C. In one aspect, the reaction was carried out at from -10°C to 10°C. In one aspect, the ranges disclosed herein are inclusive of the recited endpoints (e.g., the range of from -10°C to 10°C includes both -10°C and 10°C).

[0044] The product can be crystallized as the HCl salt by addition of hydrochloric acid in methanol, ethanol, or isopropyl alcohol. In one embodiment, hydrochloric acid in ethanol was used.

[0045] Stage 2A / Step (ii): Mizoroki-Heck coupling

[0046] [ka]

[0047] The reaction can be carried out in a variety of solvents or mixtures of solvents, including water, dioxane, methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, and isopropyl alcohol. In one embodiment, a mixture of polar solvents is preferred. In another embodiment, a mixture of a polar aprotic solvent and a polar protic solvent is preferred. In one embodiment, the solvent comprises a mixture of tetrahydrofuran and water. The reaction can be carried out using a variety of bases, such as potassium carbonate, sodium carbonate, triethylamine, or sodium hydroxide. In one embodiment, potassium carbonate was used as the base. The reaction can be carried out using a variety of palladium catalysts, such as tetrakis(triphenylphosphine)palladium(0), palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, or dichlorobis(triphenylphosphine)palladium(II), or any other catalyst that would be familiar to one skilled in the art. In one embodiment, palladium acetate was used as the catalyst. A range of ligands may also be used, such as 1,3-bis(diphenylphosphino)propane (DPPP), X-Phos, or 1,3-bis(diphenylphosphino)benzene. In one embodiment, 1,3-bis(diphenylphosphino)propane was used as the ligand.

[0048] The reaction can be carried out over a range of temperatures, for example, from 40°C to 150°C. In one embodiment, the reaction was carried out at 70°C to 85°C.

[0049] Stage 2B / Step (iii): Cyclization

[0050] [ka]

[0051] The reaction can be carried out in a variety of organic solvents, such as toluene, methanol, ethanol, ethyl acetate, or tetrahydrofuran. In one aspect, polar solvents are preferred. In another aspect, polar protic solvents are preferred. In one aspect, the reaction was carried out in methanol. The cyclization step can be carried out using a variety of bases, such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, or sodium methoxide. In one aspect, an inorganic base is preferred. In another aspect, a carbonate, hydroxide, or alkoxide is preferred. In one aspect, potassium carbonate was used as the base.

[0052] The reaction can be carried out at a range of temperatures, for example, from 0° C. to 70° C. In one aspect, the first step of the reaction was carried out at 0° C. to 10° C., and the cyclization step at 40° C. to 60° C.

[0053] Stage 3 / Step (iv): Enol ether cleavage

[0054] [ka]

[0055] The reaction can be carried out in a variety of solvents, including water, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, dimethyl sulfoxide, or a mixture of solvents. In one aspect, polar solvents are preferred. In another aspect, polar aprotic solvents are preferred. In one aspect, tetrahydrofuran was used. Many acids can be used, such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, or methylsulfonic acid. In one aspect, inorganic acids are preferred. In one aspect, hydrochloric acid was used. In one aspect, sulfuric acid was used.

[0056] The reaction can be carried out at a range of temperatures, for example, from 0°C to 50°C. In one embodiment, the reaction was carried out at 10°C to 30°C.

[0057] Stage 4 / Step (v): Sulfinimine formation

[0058] [ka]

[0059] The reaction can be carried out in a variety of organic solvents, such as tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, isopropyl alcohol, or ethyl acetate. In one embodiment, polar solvents are preferred. In another embodiment, polar aprotic solvents are preferred. In one embodiment, 2-methyltetrahydrofuran was used as the reaction solvent. The reaction can be carried out using a variety of dehydrating agents that will be familiar to those skilled in the art, such as titanium ethoxide, titanium isopropoxide, or titanium chloride. In one embodiment, titanium ethoxide is used in this reaction. In another embodiment, (R)- or (S)-tert-butanesulfinamide, preferably (R)-tert-butanesulfinamide, can be used. The reaction can be carried out at a range of temperatures, for example, from 40°C to 100°C. In one embodiment, the reaction was carried out at 70°C to 90°C.

[0060] Stage 5 / Step (vi): Stereoselective reduction

[0061] [ka]

[0062] The reaction can be carried out in a variety of organic solvents, such as tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, toluene, or a mixture of solvents. In one embodiment, polar solvents are preferred. In another embodiment, a mixture of polar aprotic solvents is preferred. In one embodiment, a mixture of 2-methyltetrahydrofuran and tetrahydrofuran was used in the reaction. The reaction can be carried out using a variety of reducing agents that will be familiar to those skilled in the art, such as L-Selectride®, diisobutylaluminum hydride, lithium aluminum hydride, sodium borohydride, or lithium tri-tert-butoxyylaluminum hydride (LTBA). In one embodiment, lithium tri-tert-butoxyylaluminum hydride (LTBA) was used as the reducing agent with (R)—N-[(1E)-1-[5-chloro-2-[(4-oxo-2-sulfanylidene-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethylidene]-2-methylpropane-2-sulfinamide. In one embodiment, L-Selectride® was used as the reducing agent with (S)—N-[(1E)-1-[5-chloro-2-[(4-oxo-2-sulfanylidene-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethylidene]-2-methylpropane-2-sulfinamide. The reaction can be carried out over a range of temperatures, for example, from -40°C to 50°C. In one embodiment, the reaction was carried out at 0°C to 20°C. The product can be crystallized or telescoped to the next stage as a solution in an organic solvent. In one embodiment, the product was crystallized from methanol. In one embodiment, the product can then be telescoped to the next stage as a solution in DMSO.

[0063] Stage 6 / Step (vii): Sulfinyl group cleavage

[0064] [ka]

[0065] The reaction can be carried out in a range of organic solvents, such as water, ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, or a mixture of solvents. In one embodiment, polar solvents are preferred. In another embodiment, a mixture of a polar aprotic solvent and a polar protic solvent is preferred. In one embodiment, the reaction was carried out in a mixture of dimethyl sulfoxide and water. In another embodiment, (R)- or (S)-camphorsulfonic acid, preferably having the same configuration as the chiral amine, can be used. The reaction can be carried out at a range of temperatures, for example, from 20°C to 80°C. In one embodiment, the reaction was carried out at 40°C to 70°C.

[0066] Stage 7 / Step (viii): Free base formation

[0067] [ka]

[0068] The reaction can be carried out in a range of solvents, such as water, ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, or a mixture of solvents. In one aspect, a mixture of polar solvents is preferred. In another aspect, a mixture of a polar aprotic solvent and a polar protic solvent is preferred. In one aspect, the reaction was carried out in dimethyl sulfoxide and water. The reaction can be carried out using a variety of bases, such as ammonium hydroxide, triethylamine, and diisopropylamine. In one aspect, ammonium hydroxide was used as the base.

[0069] The reaction can be carried out over a range of temperatures, for example, from 10° C. to 60° C. In one embodiment, the reaction was carried out at 15° C. to 45° C. [Example]

[0070] General method Unless otherwise noted, starting materials were commercially available. All solvents and commercially available reagents were laboratory grade and used as received. Unless otherwise noted, all operations were carried out at ambient temperature, i.e., in the range of 17-28 °C, and under an atmosphere of inert gas, such as nitrogen, where appropriate.

[0071] Large scale reactions were carried out in stainless steel or glass-lined steel reactors equipped with heat transfer jackets and appropriate auxiliary equipment.

[0072] When obtained, 1 H NMR spectra were recorded on a Bruker A500 (500 MHz) and a Bruker A400 (400 MHz). Either the central peak of chloroform-d (CDCl3, δ 7.27 ppm) or dimethyl sulfoxide-d6 (d6-DMSO, δ 2.50 ppm) or an internal standard of tetramethylsilane (TMS, δ 0.00 ppm) were used as references. Sample solutions may also contain an internal standard (e.g., maleic acid or 2,3,5,6-tetrachloronitrobenzene) for assay determination. 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, 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 analyte concentration and whether or not additives (e.g., NMR assay standards) are included.

[0073] It should be understood that each of the reaction parameters (e.g., temperature, time, reagent ratios and / or amounts, workup, purification) in all examples disclosed herein are also disclosed individually and generally.

[0074] Stage 1 / Step (i): Reductive amination Ethyl 3-[[(2-bromo-4-chlorophenyl)methyl]amino]-1H-pyrrole-2-carboxylate hydrochloride

[0075] [ka]

[0076] Ethyl 3-amino-1H-pyrrole-2-carboxylate hydrochloride (110 kg, 577 mol, 1.0 equiv.) and toluene (2200 L, 20 vol.) were charged to a vessel at 25°C. Water (550 L, 5 vol.) and sodium carbonate (61.6 kg, 577 mol, 1.0 equiv.) were charged, and the contents of the vessel were stirred for 10 minutes until a biphasic solution formed. The batch was allowed to settle for 30 minutes, after which the aqueous phase was removed. Sodium chloride (55 kg, 50% w / w) was charged to the aqueous phase, which was back-extracted with toluene (550 L, 5 vol.). The combined organic phases were cooled to 0°C, and acetic acid (86.9 kg, 1442 mol, 2.5 equiv.) and 2-bromo-4-chlorobenzaldehyde (151.8 kg, 692 mol, 1.2 equiv.) were charged. The mixture was held at 0°C for 20 minutes. Sodium triacetoxyborohydride (183.7 kg, 865 mol, 1.5 eq) was charged while maintaining the temperature below 5°C, and the mixture was held at 0°C for 20 minutes. Aqueous ammonia solution (242 L of 25-28% ammonia solution in 770 L of water) was charged to the vessel at 15°C. The mixture was held for 1 hour. The batch was allowed to settle, and the aqueous phase was removed. The aqueous phase was back-extracted with toluene (110 L, 1 vol), and the combined organic phases were washed twice with water (2 x 550 L, 5 vol). A solution of anhydrous HCl in ethanol (89.1 kg, 807 mol, 1.4 eq) was charged at 20°C, and the mixture was held for 30 minutes. The resulting solid was collected by filtration. The filter cake was washed with toluene (220 L, 2 volumes) and dried at 55° C. to give ethyl 3-[[(2-bromo-4-chlorophenyl)methyl]amino]-1H-pyrrole-2-carboxylate hydrochloride (205.7 kg, 86.5% w / w free base assay, 519 mol, 90% yield) as a solid.

[0077] 1H NMR (400MHz, DMSO, 27℃) 1.28 (3H, t), 4.21 (2H, q), 4.32 (2H, d), 5.96 (1H, s), 6.71 (1H, t), 7.32-7.45 (2H, m), 7.47-7.78 (2H, m), 10.81 (1H, s).

[0078] Stage 2A / Step (ii): Mizoroki-Heck coupling Ethyl 3-[([4-chloro-2-[1-(4-hydroxybutoxy)ethenyl]phenyl]methyl)amino]-1H-pyrrole-2-carboxylate

[0079] [ka]

[0080] Ethyl 3-[[(2-bromo-4-chlorophenyl)methyl]amino]-1H-pyrrole-2-carboxylate hydrochloride (205 kg, 520 mol, 1.0 equiv.), tetrahydrofuran (472 L, 2.3 vol.), water (1578 L, 7.7 vol.), and potassium carbonate (215.3 kg, 1560 mol, 3.0 equiv.) were charged to a vessel. 4-(Vinyloxy)butan-1-ol (180.4 kg, 1560 mol, 3.0 equiv.), 1,3-bis(diphenylphosphino)propane (6.56 kg, 15.6 mol, 0.03 equiv.), and palladium(II) acetate (1.74 kg, 7.8 mol, 0.015 equiv.) were added. The solution was degassed using nitrogen, and the reaction mixture was heated to 75°C for 20 hours. The mixture was cooled to approximately 25°C and ethyl acetate (1025 L, 5 volumes) was charged. Acetylcysteine (127.1 kg, 780 mol, 1.5 equivalents) was charged, and the resulting biphasic solution was stirred at 25°C for 3 hours. The batch was settled and the aqueous phase was removed. The aqueous phase was back-extracted with ethyl acetate (1025 L, 5 volumes), and the combined organic phases were washed twice with aqueous sodium chloride solution (2 x 1025 L, 5 volumes). The resulting organic phase was distilled under reduced pressure to approximately 2.5 volumes. Methanol (1025 L, 5 volumes) was charged, and the batch was distilled under reduced pressure to approximately 2.5 volumes to provide ethyl 3-[([4-chloro-2-[1-(4-hydroxybutoxy)ethenyl]phenyl]methyl)amino]-1H-pyrrole-2-carboxylate (705.3 kg, 29.5% w / w assay, quantitative yield).

[0081] 1 H NMR (400MHz, CDCl3, 27℃) 1.32 (3H, t), 1.65-1.70 (3H, m), 1.77-1.86 (2H, m), 3.66 (2H, t), 3.87 (2H, t), 4.17- 4.32(3H, m), 4.33-4.40(3H, m), 5.63(1H, t), 6.67(1H, s), 7.18-7.29(1H, m), 7.3-7.42(2H, m), 7.73(2H, s).

[0082] Stage 2B / Step (iii): Cyclization 1-([4-chloro-2-[1-(4-hydroxybutoxy)ethenyl]phenyl]methyl)-2-sulfanylidene-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0083] [ka]

[0084] A solution of ethyl 3-[([4-chloro-2-[1-(4-hydroxybutoxy)ethenyl]phenyl]methyl)amino]-1H-pyrrole-2-carboxylate (705 kg, 29.5% w / w assay, 496 mol, 1.0 eq) in methanol was charged to a vessel. Methanol (585 L, 3 volumes) was charged and the resulting solution was cooled to 5° C. Benzoyl isothiocyanate (93.6 kg, 571 mol, 1.15 eq) was charged dropwise while maintaining the batch temperature below 10° C. The reaction was held for 1 hour. Potassium carbonate (150.2 kg, 1092 mol, 2.2 eq) was charged and the mixture was heated to 45° C. and held for 8 hours. The reaction was cooled to 25° C. and acetic acid (134.6 kg, 2233 mol, 4.5 eq) was charged dropwise over 1.5 hours. The mixture was held for 30 minutes. Ethyl acetate (1560 L, 8 volumes) and water (975 L, 5 volumes) were charged and the biphasic mixture was held for 15 minutes. The batch was allowed to settle and the aqueous phase removed. The aqueous phase was back extracted twice with ethyl acetate (585 L, 3 volumes, then 390 L, 2 volumes). The combined organic phases were distilled under reduced pressure to approximately 5 volumes. Ethyl acetate (975 L, 5 volumes) was charged and the batch was distilled to approximately 5 volumes. Ethyl acetate (975 L, 5 volumes) was charged and the batch was distilled to approximately 5 volumes. The resulting slurry was cooled to 5°C and held for 5 minutes. The solids were collected by filtration and the filter cake was washed with ethyl acetate (780 L, 4 volumes) cooled to 0°C. The solid was dried at 50° C. to give 1-([4-chloro-2-[1-(4-hydroxybutoxy)ethenyl]phenyl]methyl)-2-sulfanylidene-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (195 kg, 95.7% w / w, 76% yield) as a solid.

[0085] 1 H NMR (500 MHz, DMSO, 27 °C): 1.50-1.59 (2H, m), 1.70-1.80 (2H, m), 3.43 (2H, t), 3.89 (2H, t), 4.43 (1H, d), 4.56 (1H, d), 5.64-5.68 (2H, m), 5.77 (1H, d), 6.88 (1H, d), 7.23 (1H, d), 7.31 (1H, dd), 7.38 (1H, d). No exchangeable protons were observed.

[0086] Stage 3 / Step (iv): Enol ether cleavage 1-[(2-acetyl-4-chlorophenyl)methyl]-2-sulfanylidene-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0087] [ka]

[0088] Method a: 1-([4-chloro-2-[1-(4-hydroxybutoxy)ethenyl]phenyl]methyl)-2-sulfanylidene-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (236 kg, 560 mol, 1.0 equiv) and tetrahydrofuran (1888 L, 8 volumes) were charged to a vessel. Concentrated hydrochloric acid (59 kg, 560 mol, 1.0 equiv) was charged dropwise while maintaining the batch temperature at 25° C. The reaction was held for 1 hour. The resulting slurry was cooled to 10° C. and water (2832 L, 12 volumes) was charged dropwise. The batch was cooled to 5° C. and held for 1 hour, after which the solid was isolated by filtration. The filter cake was washed twice with water (2×472 L, 2 volumes) and dried at 60° C. to give 1-[(2-acetyl-4-chlorophenyl)methyl]-2-sulfanylidene-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (237 kg, 543 mol, 97% yield) as a solid.

[0089] 1H NMR (500MHz, DMSO, 27°C) 2.71 (3H, s), 5.81 (2H, s), 6.09 (1H, d), 6.86 (1H, d), 7.31 (1H, d), 7.51 (1H, dd), 8.07 (1H, d), 12.36 (1H, s), 12.49 (1H, s).

[0090] Alternative Method b: 1-([4-chloro-2-[1-(4-hydroxybutoxy)ethenyl]phenyl]methyl)-2-sulfanylidene-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (76 kg, 187 mol, 1.0 equiv) and dimethyl sulfoxide (577.6, 7.6 vol) were charged to a vessel. The mixture was stirred at 25° C. for 30 minutes and screened. Concentrated sulfuric acid (14.4 kg, 0.75 equiv) in water (47.9 L, 0.63 vol) was charged. The mixture was heated to 40° C. and held for 2 hours. Methanol (152 L, 2 vol) was added over 1.5 hours. 1-(2-Acetyl-4-chlorobenzyl)-2-sulfanylidene-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one seeds (0.76 kg, 0.01 wt) were added over 3 hours, followed by a 3:2 mixture of aqueous methanol (380 L, 5 vol). The mixture was held at 40°C for 4 hours, and water (152 L, 2 vol) was added over 1 hour. The mixture was cooled to 20°C over 5 hours and held at 20°C for 1 hour, after which the solid was isolated by filtration. The filter cake was washed twice with water (2 × 304 L, 4 volumes) and dried at 50 °C to give 1-[(2-acetyl-4-chlorophenyl)methyl]-2-sulfanylidene-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (61.04 kg, 98.6% w / w, 96% yield) as a solid. Seeding in Stage 3 was done to ensure that the solid was more easily isolable by large-scale filtration and to improve manufacturability. In an alternative method, the steps were identical but no seeds were used, which did not affect the overall yield. The seeds used in the above method were made using Method a in Stage 3 on a 0.4 kg scale.

[0091] Stage 4 / Step (v): Sulfinimine formation (R)-N-[(1E)-1-[5-chloro-2-[(4-oxo-2-sulfanylidene-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethylidene]-2-methylpropane-2-sulfinamide

[0092] [ka]

[0093] 1-[(2-acetyl-4-chlorophenyl)methyl]-2-sulfanylidene-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (115 kg, 344 mol, 1.0 equiv.), 2-methyltetrahydrofuran (575 L, 5 vol.), (R)-(+)-2-methyl-2-propanesulfinamide (62 kg, 502 mol, 1.5 equiv.), and titanium ethoxide (236 kg, 1004 mol, 3.0 equiv.) were charged to a vessel. The resulting slurry was heated to 80°C and held for 20 hours. The batch was cooled to 25°C and charged with 2-methyltetrahydrofuran (1725 L, 15 vol.). Aqueous potassium glycolate solution (5 M, 15 vol.) and tetrahydrofuran (690 L, 6 vol.) were charged, and the resulting biphasic solution was held for 1 hour. The batch was allowed to settle and the aqueous phase removed. The aqueous phase was back extracted with 2-methyltetrahydrofuran (575 L, 5 volumes) and the combined organic phases were washed with 5% aqueous sodium bicarbonate solution (575 L, 5 volumes) followed by 15% aqueous sodium chloride solution (575 L, 5 volumes). The vessel contents were distilled under reduced pressure to 3.5 volumes. Methanol (575 L, 5 volumes) was charged. The vessel contents were distilled under reduced pressure to 3.5 volumes and additional methanol (345 L, 3 volumes) was charged. The resulting slurry was cooled to 0°C and held for 30 minutes. The solids were collected by filtration and washed with pre-chilled methanol (230 L, 2 volumes). The product was dried at 50°C to give (R)-N-[(1E)-1-[5-chloro-2-[(4-oxo-2-sulfanylidene-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethylidene]-2-methylpropane-2-sulfinamide (115 kg, 98% w / w assay, 90.5% yield) as a solid.

[0094] 1 H NMR (400MHz, DMSO) 1.22 (9H, s), 2.80 (3H, s), 5.62-5.91 (2H, m), 6.09 (1H, d ), 6.85(1H, d), 7.31-7.41(2H, m), 7.76(1H, d), 12.37(1H, s), 12.49(1H, s).

[0095] Stage 5 / Step (vi): Stereoselective reduction (R)-N-[(1R)-1-[5-chloro-2-[(4-oxo-2-sulfanylidene-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethyl]-2-methylpropane-2-sulfinamide

[0096] [ka]

[0097] (R)—N-[(1E)-1-[5-chloro-2-[(4-oxo-2-sulfanylidene-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethylidene]-2-methylpropane-2-sulfinamide (127 kg, 292 mol, 1.0 equiv.) and 2-methyltetrahydrofuran (1274 L, 10 vol.) were charged to a vessel and cooled to 10° C. Lithium tri-tert-butoxyaluminum hydride (496 L, 1 M solution in tetrahydrofuran, 496 mol, 1.7 equiv.) was charged dropwise, and the resulting mixture was held at 10° C. for 3 hours. A solution of approximately 19% aqueous sodium bisulfate (1274 L, 10 vol.) was charged dropwise, and the batch was warmed to 25° C. The batch was allowed to separate, and the aqueous phase was removed. The organic phase was washed with aqueous sodium chloride solution (637 L, 5 volumes), followed by 1 M pH 7.5 phosphate buffer solution (1274 L, 10 volumes). 2-Methyltetrahydrofuran (1274 L, 10 volumes) was charged and the vessel contents were distilled under reduced pressure to 8 volumes. 2-Methyltetrahydrofuran (1274 L, 10 volumes) was charged and the vessel contents were distilled under reduced pressure to 8 volumes. The batch was cooled to 25°C and seeded with (R)-N-[(1R)-1-[5-chloro-2-[(4-oxo-2-sulfanylidene-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethyl]-2-methylpropane-2-sulfinamide (0.64 kg, 0.5% w / w). The seed was maintained for 1 hour. Heptane (255 L, 2 vol) was charged over 1 hour and the batch was held for 2 hours. Heptane (382 L, 3 vol) was charged over 1 hour and the batch was held for 2 hours. Heptane (382 L, 3 vol) was charged over 1 hour and the batch was held for 2 hours. Heptane (892 L, 7 vol) was charged over 1 hour and the batch was held for 8 hours. The slurry was filtered and the filter cake was washed twice with heptane (2 x 64 L, 0.5 vol).The product was dried at 50°C to give (R)-N-[(1R)-1-[5-chloro-2-[(4-oxo-2-sulfanylidene-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethyl]-2-methylpropane-2-sulfinamide (143 kg, 82.8% assay, 92% yield) as a solid. Seeding in Stage 5 was to ensure that the solid was more easily isolable by large-scale filtration and to improve manufacturability. In an alternative method followed, the steps were identical but no seeds were used, which did not affect the overall yield. The seeds used in the above method were made using an alternative method on a 0.05 kg scale.

[0098] 1 H NMR (500MHz, DMSO, 27℃) 1.14 (9H, s), 1.47 (3H, d), 4.70-4.78 (1H, m), 5.65 (1H, d), 5.81 (1H, d), 5. 83(1H, d), 6.03(1H, d), 6.61(1H, d), 7.16(1H, dd), 7.31(1H, d), 7.60(1H, d), 12.07-12.79(2H, br m).

[0099] Stage 6 / Step (vii): Sulfinyl group cleavage and chiral resolution [(1R)-1-[5-chloro-2-[(4-oxo-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethyl]ammonium (7,7-dimethyl-2-oxo-1-bicyclo[2.2.1]heptanyl)methanesulfonate

[0100] [ka]

[0101] Method a: (R)-N-[(1R)-1-[5-chloro-2-[(4-oxo-2-sulfanylidene-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethyl]-2-methylpropane-2-sulfinamide (140 kg, 82.8% w / w, 264 mol, 1.0 equiv), dimethyl sulfoxide (556 L, 4.8 vol), and water (140 L, 1.2 vol) were charged to a vessel, the contents of which were set to 25° C., and (R)(R)-(−)-10-camphorsulfonic acid (123 kg, 528 mol, 2.0 equiv) was charged, and the resulting solution was heated to 55° C. for 20 hours. The batch was heated to 60° C., and water (70 L, 0.6 vol) was charged over 30 minutes. [(1R)-1-[5-chloro-2-[(4-oxo-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethyl]ammonium (7,7-dimethyl-2-oxo-1-bicyclo[2.2.1]heptanyl) methanesulfonate seeds (0.58 kg, 0.5% w / w) were charged and the batch was held for 30 minutes to allow the seed bed to grow. Water (163 L, 1.4 vol) was charged dropwise at 60°C and the slurry was held for 1 hour. The slurry was cooled to 50°C, held for 1 hour, cooled to 40°C, held for 1 hour, cooled to 20°C over 4 hours, and held at 20°C for 18 hours. The solid was isolated by filtration, and the filter cake was washed with 3:2 DMSO:water (232 L, 2 volumes) and ethanol (58 L, 0.5 volumes), then dried at 50 °C to give [(1R)-1-[5-chloro-2-[(4-oxo-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethyl]ammonium (7,7-dimethyl-2-oxo-1-bicyclo[2.2.1]heptanyl) methanesulfonate (142.9 kg, 59% free base assay, 95% yield) as a solid. Seeding in Stage 6, Method a, was performed to ensure that the solid was more easily isolable by large-scale filtration and to improve manufacturability. In an alternative method followed, the steps were identical, but no seeds were used, which did not affect the overall yield. The seeds used in the above method were produced using Alternative Method a on a 0.2 kg scale.

[0102] 1 H NMR(500MHz、DMSO、27℃)0.72(3H、s)、1.02(3H、s)、1.21-1.31(2H、m)、1.54(3H、d)、1.77(1H、d)、1.79-1.87(1H、m)、1.92(1H、t)、2.22(1H、dt)、2.39(1H、d)、2.59-2.67(1H、d)、2.88(1H、d)、4.82(1H、q)、5.65(1H、d)、5.79(1H、d)、6.06(1H、d)、6.70(1H、d)、7.29(1H、dd)、7.34(1H、dd)、7.70(1H、d)、8.42(3H、br s)、11.00-12.97(2H、br m)。

[0103] Alternative Method b: (R)—N-[(1E)-1-[5-chloro-2-[(4-oxo-2-sulfanylidene-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethylidene]-2-methylpropane-2-sulfinamide (773.4 g, 1.77 mol, 1.0 eq) and 2-methyltetrahydrofuran (3867 mL, 5 vol) were charged to a vessel and cooled to 5° C. Lithium tri-tert-butoxyaluminum hydride (3009 mL, 1 M solution in tetrahydrofuran, 3.01 mol, 1.7 eq) was charged dropwise and the resulting mixture was held at 10° C. for 3 hours. The mixture was quenched with 28.8% w / w aqueous sodium bisulfate (6190 mL, 8 vol) and the batch was warmed to 20° C. The batch was partitioned and the aqueous phase removed. The organic phase was washed with aqueous sodium chloride solution (2320 mL, 3 volumes), followed by 3 M pH 7.2 phosphate buffer solution (1934 mL, 2.5 volumes). Dimethyl sulfoxide (3713 mL, 4.8 volumes) was charged and the mixture was screened. The contents of the vessel were distilled under reduced pressure to approximately 7.5 volumes. Water (365 g, 0.5 volumes) was added, followed by (R)-(-)-10-camphorsulfonic acid (838.7 g, 3.54 mol, 2.0 equiv.), and the resulting solution was heated to 55°C for approximately 16 hours. The batch was heated to 60°C and water (464.1 g, 0.6 volumes) was charged over 30 minutes. [(1R)-1-[5-chloro-2-[(4-oxo-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethyl]ammonium (7,7-dimethyl-2-oxo-1-bicyclo[2.2.1]heptanyl) methanesulfonate seeds (4.7 g, 0.6 wt%) were charged and the batch was held for 30 minutes to allow the seed bed to grow. Water (1856 g, 2.4 vol) was charged dropwise over 1.5 hours at 60°C, and the slurry was held for 1 hour. The slurry was cooled to 20°C over 2.5 hours and held at 20°C for 15 hours.The solid was isolated by filtration and the filter cake was washed with 1.1:0.9 DMSO:water (1547 mL, 2 vol), water (773 mL, 1 vol), and ethanol (2×773 mL (2×2 vol) and then dried at 50° C. to give [(1R)-1-[5-chloro-2-[(4-oxo-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethyl]ammonium (7,7-dimethyl-2-oxo-1-bicyclo[2.2.1]hepta[2,3-diyl]methyl]phenyl]ethyl]ammonium (7,7-dimethyl-2-oxo-1-bicyclo[2.2.1]hepta[2,3-diyl]methyl]phenyl]ethyl). (Nyl) methanesulfonate (908 g, 59% free base assay, 90% yield) was obtained as a solid. Seeding in Alternative Method B in Stage 6 was done to ensure that the solid was more easily isolable by large-scale filtration, improving manufacturability. In the alternative method performed, the steps were identical, but no seeds were used, which did not affect the overall yield. The seeds used in the above method were made using Alternative Method B on a 0.2 kg scale.

[0104] Stage 7 / Step (viii): Free base formation 1-[[2-[(1R)-1-aminoethyl]-4-chloro-phenyl]methyl]-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-4-one

[0105] [ka]

[0106] [(1R)-1-[5-chloro-2-[(4-oxo-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethyl]ammonium (7,7-dimethyl-2-oxo-1-bicyclo[2.2.1]heptanyl) methanesulfonate (137 kg, 238 mol, 1.0 equiv.) and dimethyl sulfoxide (822 L, 6 vol.) were charged to a vessel, and the temperature was adjusted to 22.5°C. The resulting solution was passed through a screening filter. A solution of aqueous ammonium hydroxide (34.3 kg, approximately 25% w / w, 511 mol, 2.15 equiv.) in water (118 kg, 0.86 vol.) was charged dropwise. The batch was warmed to 40°C and 1-[[2-[(1R)-1-aminoethyl]-4-chloro-phenyl]methyl]-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-4-one seeds (3.97 kg, 5% w / w based on free base) were charged. The resulting slurry was held for 1 hour. Water (129 L, 0.94 vol) was charged over 3.5 hours and the slurry was held for 2 hours. Water (548 L, 4 vol) was charged over 7 hours. The slurry was held for 1 hour before being cooled to 22.5°C over 1 hour. The batch was held for 8 hours and then isolated by filtration. The filter cake was washed with 1:1 dimethyl sulfoxide:water (274 L, 2 vol) followed by three washes with ethanol (3 x 274 L, 2 vol). The product was dried at 50°C to give 1-[[2-[(1R)-1-aminoethyl]-4-chloro-phenyl]methyl]-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-4-one (82 kg, 99% w / w, 97% yield) as a solid. Seeding in Stage 7 was to ensure that the solid was more easily isolable by large-scale filtration and to improve manufacturability. In an alternative method followed, the steps were identical but no seeds were used, which did not affect the overall yield. The seeds used in the above method were made using an alternative method on a 0.2 kg scale.

[0107] 1H NMR (500 MHz, DMSO, 27 °C): 1.31 (3H, d), 3.37 (2H, br s), 4.36 (1H, q), 5.65 (1H, d), 5.81 (1H, d), 6.03 (1H, d), 6.58 (1H, d), 7.10 (1H, dd), 7.2 (1H, d), 7.64 (1H, d). No exchangeable protons were observed.

[0108] All references cited herein, including patents, patent applications, articles, textbooks, etc., and the references cited therein, to the extent they are not already cited, are incorporated herein by reference in their entirety for all purposes.

Claims

1. A process for preparing a compound of formula (I), comprising steps (i) to (viii): 【Chemical 1】 (i) forming a compound according to formula (Ia) from a compound according to formula (Ia1), or the corresponding free base or a different salt thereof, and a compound according to formula (Ia2); 【Chemistry 2】 (ii) forming a compound of formula (Ib) from a compound of formula (Ia); 【Chemistry 3】 (iii) forming a compound of formula (Ic) from a compound of formula (Ib); 【Chemistry 4】 (iv) forming a compound of formula (Id) from a compound of formula (Ic); 【Chemistry 5】 (v) forming a compound of formula (Ie) from a compound of formula (Id); 【Chemistry 6】 (vi) forming a compound of formula (If) from a compound of formula (Ie); 【Chemistry 7】 (vii) forming a compound of formula (Ig) from a compound of formula (If), and 【Chemistry 8】 (viii) a process for preparing a compound of formula (I), comprising at least one of the steps of forming a compound of formula (I) from a compound of formula (Ig).

2. The method includes at least step (i), wherein step (i) comprises at least the following steps: 【Chemistry 9】 (ia) decomposing the compound of formula (Ia1) or the corresponding free base or a different salt thereof in the presence of an inorganic base, optionally wherein said inorganic base is sodium carbonate; 【Chemistry 10】 (ib) reacting the resulting compound of step (ia) with a compound of formula (Ia2) under acidic conditions, optionally wherein the acid is acetic acid; (ic) reducing the resulting imine compound of step (ib) by reacting it with a reducing agent, optionally wherein the reducing agent is sodium triacetoxyborohydride; (id) crystallizing the compound of formula (Ia) obtained from step (c) as a hydrochloride salt.

3. The method includes at least step (ii), wherein step (ii) comprises at least (ii-a) A process for preparing a compound of formula (I) according to claim 1 or 2, comprising reacting a compound of formula (Ia) with 4-(vinyloxy)butan-1-ol in the presence of a palladium catalyst, optionally wherein the palladium catalyst is palladium acetate, and optionally also in the presence of a phosphine ligand, preferably wherein the phosphine ligand is one of 1,3-bis(diphenylphosphino)propane (DPPP), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (X-Phos), or 1,3-bis(diphenylphosphino)benzene.

4. The method includes at least step (iii), wherein step (iii) comprises at least (iii-a) A process for preparing a compound of formula (I) according to any one of claims 1 to 3, comprising reacting a compound of formula (Ib) with benzoyl isothiocyanate.

5. The method includes at least step (iv), wherein step (iv) comprises at least (iv-a) A process for preparing a compound of formula (I) according to any one of claims 1 to 4, comprising reacting a compound of formula (Ic) with an inorganic acid, optionally wherein said inorganic acid is hydrochloric acid or sulfuric acid.

6. The method includes at least step (v), wherein step (v) comprises at least (va) a process for preparing a compound of formula (I) according to any one of claims 1 to 5, comprising reacting a compound of formula (Id) with a chiral sulfinamide reagent in the presence of a dehydrating reagent, optionally wherein said dehydrating reagent is titanium ethoxide.

7. The method includes at least step (vi), wherein step (vi) comprises at least (vi-a) a process for preparing a compound of formula (I) according to any one of claims 1 to 6, comprising reacting a compound of formula (Ie) with a reducing reagent, optionally wherein said reducing reagent is lithium tri-tert-butoxyaluminum hydride.

8. At least step (vii), wherein step (vii) comprises at least (vii-a) A process for preparing a compound of formula (I) according to any one of claims 1 to 7, comprising reacting a compound of formula (If), optionally said compound of formula (If) is provided from the preceding step (vi) in an organic solvent without purification, with a chiral resolving agent.

9. The method includes at least step (viii), wherein step (viii) comprises at least (viii-a) a process for preparing a compound of formula (I) according to any one of claims 1 to 8, comprising reacting a compound of formula (Ig) with an inorganic base, optionally wherein the inorganic base is ammonium hydroxide, to provide a compound of formula (I).

10. A process for preparing a compound of formula (I) according to any one of claims 1 to 9, comprising at least step (i).

11. A process for preparing a compound of formula (I) according to any one of claims 1 to 10, comprising at least steps (v) and (vi).

12. A process for preparing a compound of formula (I) according to any one of claims 1 to 11, comprising at least steps (vii) and (viii).

13. 13. A process for preparing a compound of formula (I) according to any one of claims 1 to 12, comprising all of steps (i) to (viii), optionally wherein compound (Ib) and / or compound (If) are telescoped to the next step without isolation and / or purification.

14. 【Catalog 11】 A compound selected from the group consisting of:

15. structure: 【Chemistry 12】 A compound having the formula:

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