Process for preparation of substituted pyrrolopyrimidines and intermediates

Abstract

The present invention provides a novel and improved synthesis route for the synthesis of the compound 1-{2-[(1R)-1-aminoethyl]-4-chlorobenzyl}-2-thio-1, 2, 3, 5-tetrahydro-4H-pyrrolo [3, 2-d] pyrimidin-4-one (Formula (I)), which can be readily scaled up for commercial production. (I) also provides important intermediate compounds formed in new and improved synthetic routes for the synthesis of compounds of Formula (I). # imgabs0 #

Description

[0001] Related Applications

[0002] This application claims the benefit of priority to U.S. Application No. 63 / 400,445, filed on August 24, 2022, which is incorporated herein by reference in its entirety.

[0003] International patent application WO2016 / 087338 discloses thiopyrrolopyrimidinone derivatives that can be used as myeloperoxidase (MPO) inhibitors. Specifically, 1-{2-[(1R)-1-aminoethyl]-4-chlorobenzyl}-2-thio-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (hereinafter referred to as the compound of formula (I)) is disclosed. The structure of the compound of formula (I) is shown below.

[0004]

[0005] Compounds of formula (I) are being developed as active pharmaceutical compounds for the treatment of respiratory diseases. Therefore, suitable methods for the safe, cost-effective, efficient and environmentally sensitive manufacture of compounds of formula (I) may be needed.

[0006] A previous enantioselective synthesis of compounds of formula (I) is described in Example 3 of WO2016 / 087338.

[0007] A previous synthesis involved 10 steps (aj) with an overall yield of 22% and provided 633 g of the compound. Step (i) of the synthesis gave a sub-gram yield. Dioxane protection / deprotection of the acetophenone was required.

[0008] Another previous synthesis (Alternative Example 3) involved at least 8 steps, gave a 47% yield, and provided 16 g of the compound (note that the reductive amination and cyclization steps were implicitly performed between (e) and (f)). BOC protection / deprotection of the amine was required.

[0009] Both previous syntheses rely on dichloromethane, a less environmentally friendly and carcinogenic solvent. Both previous syntheses require the use of toxic carbon monoxide gas (combustible hydrogen is also used) and pressures above atmospheric pressure to introduce the formyl group. Such reaction conditions cannot be scaled up well. Both previous syntheses also first perform enantioselective amine formation, which requires expensive stoichiometric amounts of chiral sulfenamide. Therefore, in the subsequent steps of these syntheses, the loss of material is less cost-effective than performing enantioselective amine formation at the later stage of the synthesis. Summary of the invention

[0010] The present invention relates to a novel and improved synthetic route for synthesizing compounds of formula (I) which can be easily scaled up for commercial production and is described in Scheme 1 below. Square brackets indicate compounds that can be taken to the next step in their crude form (i.e. without isolation and / or purification). Compound (Ia1) is shown as a hydrochloride salt, but its corresponding free base or a different salt may be used.

[0011]

[0012] In a first aspect, a method for preparing a compound of formula (I) is provided, the method comprising at least one of steps (i) to (viii).

[0013] The new and improved method involves only 8 steps, has an overall yield of 46%, and can be commercially scaled up to provide at least 82 kg of compound (more than 130 times more by weight than the previous largest synthesis). Even only 6 steps can be considered if the two shortened procedures described herein are implemented.

[0014] No chlorinated solvents are used. No protection step is required in the main reaction sequence, since the only protecting group is introduced as part of the acetophenone formation and is removed after the cyclization step. Unlike the two previous syntheses, the enantioselective amine formation is the last structural transformation, so the resulting valuable product is maximally conserved in terms of cost efficiency. In addition, a formylation step is avoided, since the commercially available starting materials already contain the formyl group required for the reductive amination.

[0015] In one embodiment, the method for preparing the compound of formula (I) comprises at least two steps, three steps, four steps, five steps, six steps, seven steps or all steps of steps (i) to (viii).

[0016] In one embodiment, the process for preparing a compound of formula (I) comprises at least two of steps (i) to (viii), optionally (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 (vii); (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).

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

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

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

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

[0021] In one embodiment, the method for preparing a compound of formula (I) comprises at least seven of steps (i) to (viii); optionally (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), (vi), (vii) and (viii); (i), (ii), (iii), (v), (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).

[0022] In one embodiment, compound (Ib) is shortened to the next step in its crude form (i.e. without separation and / or purification). In another embodiment, compound (If) is shortened to the next step in its crude form (i.e. without separation and / or purification).

[0023] More specifically, the synthetic route to the compound of formula (I) is described in Scheme 2 below. Square brackets indicate compounds that can be taken to the next step in their crude form (i.e. without isolation and / or purification). Compound (Ia1) is shown as a hydrochloride salt, but its corresponding free base or a different salt may be used.

[0024]

[0025] In one embodiment, step (i) comprises at least the following steps:

[0026]

[0027] (ia) in the presence of an inorganic base, reacting the hydrochloride of the compound of formula (Ia1) or its corresponding free base

[0028] or different salt cleavage, optionally wherein the inorganic base is sodium carbonate;

[0029]

[0030] (ib) reacting the resulting compound of step (ia) with a compound of formula (Ia2) under acidic conditions, optionally wherein the acid is acetic acid;

[0031] (ic) reducing the imine compound obtained in step (ib) by reaction with a reducing agent, optionally wherein the reducing agent is sodium triacetoxyborohydride; and

[0032] (id) The compound of formula (Ia) obtained in step (c) is crystallized as a hydrochloride salt.

[0033] In one embodiment, (ii) comprises at least (ii-a) reacting a compound of formula (Ia) with 4-(vinyloxy)butan-1-ol in the presence of a palladium catalyst, optionally also in the presence of a phosphine ligand, optionally wherein the palladium catalyst is palladium acetate, preferably wherein the phosphine ligand is one of 1,3-bis(diphenylphosphino)propane (DPPP), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-Phos) or 1,3-bis(diphenylphosphino)benzene.

[0034] In one embodiment, step (iii) comprises at least (iii-a) reacting a compound of formula (Ib) with benzoyl isothiocyanate.

[0035] In one embodiment, step (iv) comprises at least (iv-a) reacting a compound of formula (Ic) with an inorganic acid, optionally wherein the inorganic acid is hydrochloric acid or sulfuric acid.

[0036] In one embodiment, step (v) comprises at least (va) reacting a compound of formula (Id) with a chiral sulfenamide reagent in the presence of a dehydrating agent, optionally wherein the dehydrating agent is titanium ethoxide.

[0037] In one embodiment, step (vi) comprises at least (vi-a) reacting a compound of formula (Ie) with a reducing agent, optionally wherein the reducing agent is lithium tri-tert-butoxyaluminum hydride.

[0038] In one embodiment, step (vii) comprises at least (vii-a) reacting a compound of formula (If) with a chiral resolving agent, optionally wherein the compound of formula (If) is provided by the preceding step (vi) in an organic solvent without purification.

[0039] 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).

[0040] 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 which is a non-metallic hydroxide. In one embodiment, the base is ammonium hydroxide.

[0041] In a second aspect, there is provided a A compound selected from the group consisting of:

[0042]

[0043] In a third aspect, a compound is provided, the compound having the following structure:

[0044] DETAILED DESCRIPTION

[0045] Stage 1 / Step (i): Reductive amination

[0046]

[0047] The salt cleavage step can be performed in a mixture of water and various organic solvents such as dichloromethane, 2-methyltetrahydrofuran, isopropyl acetate or toluene. In one aspect, the salt cleavage is performed in water and toluene. The salt cleavage can be performed using various bases such as sodium carbonate, potassium carbonate or cesium carbonate. In one aspect, sodium carbonate is used as the base.

[0048] The reaction can be carried out in various organic solvents (such as dichloromethane, ethanol, methanol, tetrahydrofuran, isopropanol, dioxane and toluene). On the one hand, the reaction is carried out in toluene. Various acids such as trifluoroacetic acid, hydrochloric acid, toluenesulfonic acid or acetic acid can be used. Alternatively, the reaction can be carried out in the absence of acid. In one aspect, acetic acid is used as acid. The reduction stage can be carried out by methods 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 is used for the reduction step.

[0049] The reaction can be carried out, for example, at a temperature range of -40°C to 30°C. In one aspect, the reaction is carried out between -10°C and 10°C. In one aspect, the ranges disclosed herein include the endpoints (e.g., the range between -10°C and 10°C includes -10°C and 10°C).

[0050] The product can be crystallized as the HCl salt by adding hydrochloric acid in methanol, ethanol or isopropanol. In one aspect, hydrochloric acid in ethanol is used.

[0051] Phase 2A / Step (ii): Mizoroki–Heck Coupling

[0052]

[0053] The reaction can be carried out in various solvents or solvent mixtures, including water, dioxane, methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, toluene and isopropanol. In one aspect, a mixture of polar solvents is preferred. In another aspect, a mixture of polar aprotic solvents and polar protic solvents is preferred. In one aspect, the solvent includes a mixture of tetrahydrofuran and water. The reaction can be carried out using various bases (such as potassium carbonate, sodium carbonate, triethylamine or sodium hydroxide). In one aspect, potassium carbonate is used as a base. The reaction can be carried out using various palladium catalysts (such as tetrakis (triphenylphosphine) palladium (0), palladium acetate, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) or dichlorobis (triphenylphosphine) palladium (II), or any other catalyst familiar to those skilled in the art). In one aspect, palladium acetate is used as a catalyst. A series of ligands can also be used, such as 1,3-bis (diphenylphosphino) propane (DPPP), X-Phos or 1,3-bis (diphenylphosphino) benzene. In one aspect, 1,3-bis(diphenylphosphino)propane is used as the ligand.

[0054] The reaction can be carried out at a temperature range of, for example, 40°C to 150°C. In one aspect, the reaction is carried out between 70°C and 85°C.

[0055] Stage 2B / Step (iii): Cyclization

[0056]

[0057] The reaction can be carried out in various 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 is carried out in methanol. The cyclization step can be carried out using various bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide or sodium methoxide. In one aspect, inorganic bases are preferred. In another aspect, carbonates, hydroxides or alkoxides are preferred. In one aspect, potassium carbonate is used as a base.

[0058] The reaction can be carried out at a temperature range of, for example, 0°C to 70°C. In one aspect, the first step of the reaction is carried out between 0°C and 10°C, and the cyclization step is carried out between 40°C and 60°C.

[0059] Stage 3 / Step (iv): Enol ether cleavage

[0060]

[0061] The reaction can be carried out in various solvents including water, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, dimethyl sulfoxide or solvent mixtures. In one aspect, polar solvents are preferred. In another aspect, polar aprotic solvents are preferred. In one aspect, tetrahydrofuran is used. A variety of acids can be used, such as hydrochloric acid, sulfuric acid, trifluoroacetic acid or methanesulfonic acid. In one aspect, inorganic acids are preferred. In one aspect, hydrochloric acid is used. In one aspect, sulfuric acid is used.

[0062] The reaction can be carried out, for example, at a temperature ranging from 0°C to 50°C. In one aspect, the reaction is carried out between 10°C and 30°C.

[0063] Stage 4 / Step (v): Sulfenyl imine formation

[0064]

[0065] The reaction can be carried out in various organic solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, acetonitrile, isopropanol or ethyl acetate. In one aspect, polar solvents are preferred. In another aspect, polar aprotic solvents are preferred. In one aspect, 2-methyltetrahydrofuran is used as a reaction solvent. The reaction can be carried out using various dehydrating agents familiar to those skilled in the art such as titanium ethoxide, titanium isopropoxide or titanium chloride. In one aspect, titanium ethoxide is used for the reaction. In another aspect, (R)- or (S)-tert-butanesulfenamide, preferably (R)-tert-butanesulfenamide, can be used. The reaction can be carried out in a temperature range of, for example, 40°C to 100°C. In one aspect, the reaction is carried out between 70°C and 90°C.

[0066] Stage 5 / Step (vi): Stereoselective reduction

[0067]

[0068] The reaction can be carried out in various organic solvents such as tetrahydrofuran, 2-methyltetrahydrofuran, tert-butyl methyl ether, toluene or solvent mixtures. In one aspect, polar solvents are preferred. In another aspect, mixtures of polar aprotic solvents are preferred. In one aspect, a mixture of 2-methyltetrahydrofuran and tetrahydrofuran is used for the reaction. The reaction can be carried out using various reducing agents familiar to those skilled in the art such as In one aspect, for (R)-N-[(1E)-1-[5-chloro-2-[(4-oxo-2-sulfaneylidene-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethylidene]-2-methylpropane-2-sulfenamide, tri-tert-butoxyaluminum hydride (LTBA) is used as a reducing agent. In one aspect, for (S)-N-[(1E)-1-[5-chloro-2-[(4-oxo-2-sulfaneylidene-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethylidene]-2-methylpropane-2-sulfenamide, tri-tert-butoxyaluminum hydride (LTBA) is used as a reducing agent. As a reducing agent. The reaction can be carried out in a temperature range of, for example, -40°C to 50°C. In one aspect, the reaction is carried out between 0°C and 20°C. The product can be crystallized as a solution in an organic solvent or shortened to the next stage. In one aspect, the product is crystallized from methanol. In one aspect, the product is then shortened to the next stage as a solution in DMSO.

[0069] Stage 6 / step (vii): sulfinyl cleavage

[0070]

[0071] The reaction can be carried out in a series of organic solvents (such as water, ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide or solvent mixtures). In one aspect, polar solvents are preferred. In another aspect, a mixture of polar aprotic solvents and polar protic solvents is preferred. In one aspect, the reaction is carried out in a mixture of dimethyl sulfoxide and water. In another aspect, (R)- or (S)-camphorsulfonic acid can be used, preferably with the same stereo configuration as the chiral amine. The reaction can be carried out in a temperature range of, for example, 20°C to 80°C. In one aspect, the reaction is carried out between 40°C and 70°C.

[0072] Stage 7 / Step (viii): Free Base Formation

[0073]

[0074] The reaction can be carried out in a range of solvents (such as water, ethanol, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide or solvent mixtures). In one aspect, a mixture of polar solvents is preferred. In another aspect, a mixture of polar aprotic solvents and polar protic solvents is preferred. In one aspect, the reaction is carried out in dimethyl sulfoxide and water. The reaction can be carried out using various alkalis (such as ammonium hydroxide, triethylamine and diisopropylamine). In one aspect, ammonium hydroxide is used as a base.

[0075] The reaction can be carried out, for example, at a temperature ranging from 10°C to 60°C. In one aspect, the reaction is carried out between 15°C and 45°C.

[0076] Example

[0077] General approach

[0078] Unless otherwise stated, starting materials are commercially available. All solvents and commercial reagents are laboratory grade and used as is. Unless otherwise stated, all operations are carried out at ambient temperature, i.e. in the range of 17° C. to 28° C. and under an atmosphere of an inert gas (such as nitrogen) if appropriate.

[0079] Large scale reactions are carried out in stainless steel or glass-lined steel reactors equipped with heat transfer jackets and appropriate ancillary equipment.

[0080] When given, 1 H NMR spectra were recorded on Bruker A500 (500 MHz) and Bruker A400 (400 MHz). The central peak of chloroform-d (CDCl 3 ; δH 7.27ppm) or the central peak of dimethyl sulfoxide-d6 (d6-DMSO; δH 2.50ppm) or an internal standard of tetramethylsilane (TMS; δH (0.00ppm) was used as a reference. The sample solution may also contain an internal standard (e.g., maleic acid or 2,3,5,6-tetrachloronitrobenzene) for determination. Spectral data are reported as a list of chemical shifts (δ, in ppm) using standard abbreviations (s=singlet, d=doublet, m=multiplet, t=triplet, q=quartet, br=broad, etc.) with each signal described. It is well known in the art that chemical shifts and J-coupling constants may vary slightly due to sample preparation differences, such as analyte concentration and whether additives (e.g., NMR assay standards) are included.

[0081] It is to be understood that each of the reaction parameters (eg, temperature, time, reagent ratios and / or amounts, work-up, purification) in all of the examples disclosed herein is also disclosed individually and generically.

[0082] Stage 1 / Step (i): Reductive amination

[0083] 3-[[(2-Bromo-4-chlorophenyl)methyl]amino]-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride

[0084]

[0085] 3-amino-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (110kg, 577mol, 1.0eq.) and toluene (2200L, 20 volumes) were charged to a container at 25°C. Water (550L, 5 volumes) and sodium carbonate (61.6kg, 577mol, 1.0eq.) were charged and the contents of the container were stirred for 10 minutes until a two-phase solution was formed. The batch was allowed to settle for 30 minutes and then the aqueous phase was removed. Sodium chloride (55kg, 50% w / w) was charged to the aqueous phase and stripped with toluene (550L, 5 volumes). The combined organic phase was cooled to 0°C and acetic acid (86.9kg, 1442mol, 2.5eq.) and 2-bromo-4-chlorobenzaldehyde (151.8kg, 692mol, 1.2eq.) were charged. The mixture was kept at 0°C for 20 minutes. Sodium triacetoxyborohydride (183.7 kg, 865 mol, 1.5 eq.) was charged, the temperature was maintained below 5°C, and the mixture was held at 0°C for 20 minutes. An aqueous ammonia solution (242 L of a 25% to 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 stripped with toluene (110 L, 1 volume) and the combined organic phases were washed twice with water (2 x 550 L, 5 volumes). Anhydrous HCl in methanol (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.

[0086] 1 H NMR (400MHz, DMSO, 27°C) 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).

[0087] Phase 2A / Step (ii): Mizoroki-Heck coupling

[0088] 3-[([4-chloro-2-[1-(4-hydroxybutoxy)vinyl]phenyl]methyl)amino]-1H-pyrrole-2-carboxylic acid ethyl ester

[0089]

[0090] 3-[[(2-bromo-4-chlorophenyl)methyl]amino]-1H-pyrrole-2-carboxylic acid ethyl ester hydrochloride (205 kg, 520 mol, 1.0 eq), tetrahydrofuran (472 L, 2.3 volumes), water (1578 L, 7.7 volumes) and potassium carbonate (215.3 kg, 1560 mol, 3.0 eq.) were charged into a vessel. 4-(vinyloxy)butan-1-ol (180.4 kg, 1560 mol, 3.0 eq), 1,3-bis(diphenylphosphino)propane (6.56 kg, 15.6 mol, 0.03 eq) and palladium(II) acetate (1.74 kg, 7.8 mol, 0.015 eq) were charged, the solution was degassed using nitrogen and the reaction mixture was heated to 75° C. for 20 hours. The mixture was cooled to about 25° C. and ethyl acetate (1025 L, 5 volumes) was charged. Acetylcysteine ​​(127.1 kg, 780 mol, 1.5 eq) was charged and the resulting biphasic solution was stirred at 25° C. for 3 hours. The batch was allowed to settle and the aqueous phase was removed. The aqueous phase was stripped with ethyl acetate (1025 L, 5 volumes) and the combined organic phases were washed twice with aqueous sodium chloride (2×1025 L, 5 volumes). The resulting organic phase was distilled to approximately 2.5 volumes under reduced pressure. Methanol (1025 L, 5 volumes) was charged and the batch was distilled to approximately 2.5 volumes under reduced pressure to give ethyl 3-[([4-chloro-2-[1-(4-hydroxybutoxy)vinyl]phenyl]methyl)amino]-1H-pyrrole-2-carboxylate (705.3 kg, 29.5% w / w assay, quantitative yield).

[0091] 1 H NMR (400 MHz, CDCl 3 , 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).

[0092] Stage 2B / Step (iii): Cyclization

[0093] 1-([4-chloro-2-[1-(4-hydroxybutoxy)vinyl]phenyl]methyl)-2-sulfanylidene-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0094]

[0095] A solution of ethyl 3-[([4-chloro-2-[1-(4-hydroxybutoxy)vinyl]phenyl]methyl)amino]-1H-pyrrole-2-carboxylate in methanol (705 kg, 29.5% w / w assay, 496 mol, 1.0 eq) 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, keeping 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 (1560L, 8 volumes) and water (975L, 5 volumes) were loaded and the two-phase mixture was kept for 15 minutes. The batch was allowed to settle and the aqueous phase was removed. The aqueous phase was stripped twice with ethyl acetate (585L, 3 volumes, then 390L, 2 volumes). The combined organic phase was distilled to about 5 volumes under reduced pressure. Ethyl acetate (975L, 5 volumes) was loaded and the batch was distilled to about 5 volumes. Ethyl acetate (975L, 5 volumes) was loaded and the batch was distilled to about 5 volumes. The resulting slurry was cooled to 5°C and kept for 5 minutes. The solid was collected by filtration and the filter cake was washed with ethyl acetate (780L, 4 volumes) cooled to 0°C. The solid was dried at 50 °C to give 1-([4-chloro-2-[1-(4-hydroxybutoxy)vinyl]phenyl]methyl)-2-sulfanylidene-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one as a solid (195 kg, 95.7% w / w, 76% yield).

[0096] 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.

[0097] Stage 3 / Step (iv): Enol ether cleavage

[0098] 1-[(2-acetyl-4-chlorophenyl)methyl]-2-sulfanediyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one

[0099]

[0100] Method a: 1-([4-chloro-2-[1-(4-hydroxybutoxy)vinyl]phenyl]methyl)-2-sulfanediyl-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (236 kg, 560 mol, 1.0 eq.) and tetrahydrofuran (1888 L, 8 volumes) were charged to a vessel. Concentrated hydrochloric acid (59 kg, 560 mol, 1.0 eq) was charged dropwise, maintaining the temperature of the batch 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, then the solid was isolated by filtration. The filter cake was washed twice with water (2 x 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.

[0101] 1 H 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).

[0102] Alternative method b: 1-([4-chloro-2-[1-(4-hydroxybutoxy)vinyl]phenyl]methyl)-2-sulfanylidene-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one (76 kg, 187 mol, 1.0 eq.) and dimethyl sulfoxide (577.6, 7.6 volumes) were charged to a vessel. The mixture was stirred at 25°C for 30 minutes and sieved. Concentrated sulfuric acid (14.4 kg, 0.75 eq) in water (47.9 L, 0.63 volumes) was charged. The mixture was heated to 40°C and maintained for 2 hours. Methanol (152 L, 2 volumes) was added over 1.5 hours. 1-(2-acetyl-4-chlorobenzyl)-2-sulfaneylidene-1,2,3,5-tetrahydro-4H-pyrrolo[3,2-d]pyrimidin-4-one seed (0.76 kg, 0.01 wt) was added, followed by a 3:2 aqueous methanol mixture (380 L, 5 volumes) over 3 hours. The mixture was maintained at 40°C for 4 hours, and water (152 L, 2 volumes) was added over 1 hour. The mixture was cooled to 20°C over 5 hours and maintained at 20°C for 1 hour, and 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-sulfaneylidene-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 is to ensure that the solid is more easily separated by large-scale filtration and to improve manufacturability. In the alternative method performed, the steps are the same, but no seeds are used, and this does not affect the overall yield. The seeds used in the above method are made using stage 3 method a at a scale of 0.4 kg.

[0103] Stage 4 / Step (v): Sulfenyl imine formation

[0104] (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-sulfenamide

[0105]

[0106] 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 eq), 2-methyltetrahydrofuran (575 L, 5 volumes), (R)-(+)-2-methyl-2-propanesulfenamide (62 kg, 502 mol, 1.5 eq) and titanium ethoxide (236 kg, 1004 mol, 3.0 eq) 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 volumes). Aqueous potassium glycolate solution (5 M, 15 volumes) and tetrahydrofuran (690 L, 6 volumes) were charged and the resulting two-phase solution was held for 1 hour. The batch was allowed to settle and the aqueous phase was removed. The aqueous phase was stripped with 2-methyltetrahydrofuran (575 L, 5 volumes), and the combined organic phase was washed with 5% sodium bicarbonate aqueous solution (575 L, 5 volumes), followed by 15% sodium chloride aqueous solution (575 L, 5 volumes). The contents of the container were distilled to 3.5 volumes under reduced pressure. Methanol (575 L, 5 volumes) was loaded. The contents of the container were distilled to 3.5 volumes under reduced pressure, and methanol (345 L, 3 volumes) was further loaded. The resulting slurry was cooled to 0 ° C and maintained for 30 minutes. The solid was collected by filtration and washed with pre-cooled 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-sulfenamide as a solid (115 kg, 98% w / w, 90.5% yield).

[0107] 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).

[0108] Stage 5 / Step (vi): Stereoselective reduction

[0109] (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-sulfenamide

[0110]

[0111] (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-sulfenamide (127 kg, 292 mol, 1.0 eq.) and 2-methyltetrahydrofuran (1274 L, 10 volumes) were charged to a vessel and cooled to 10° C. Lithium tri-tert-butoxyaluminum hydride (496 L, 1M solution in tetrahydrofuran, 496 mol, 1.7 eq.) was charged dropwise and the resulting mixture was maintained at 10° C. for 3 hours. Approximately 19% aqueous sodium bisulfate solution (1274 L, 10 volumes) was charged dropwise and the batch was warmed to 25° C. The batch was separated and the aqueous phase removed. The organic phase was washed with aqueous sodium chloride (637 L, 5 volumes) and then with 1 M pH 7.5 phosphate buffer (1274 L, 10 volumes). 2-Methyltetrahydrofuran (1274 L, 10 volumes) was charged and the contents of the vessel were distilled to 8 volumes under reduced pressure. 2-Methyltetrahydrofuran (1274 L, 10 volumes) was charged and the contents of the vessel were distilled to 8 volumes under reduced pressure. The batch was cooled to 25°C and seeded with (R)-N-[(1R)-1-[5-chloro-2-[(4-oxo-2-sulfaneylidene-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethyl]-2-methylpropane-2-sulfenamide (0.64 kg, 0.5% w / w). The seed was maintained for 1 hour. Heptane (255 L, 2 volumes) was charged within 1 hour and the batch was held for 2 hours. Heptane (382 L, 3 volumes) was charged within 1 hour and the batch was held for 2 hours. Heptane (382 L, 3 volumes) was charged within 1 hour and the batch was held for 2 hours. Heptane (892 L, 7 volumes) was charged within 1 hour and the batch was held for 8 hours. The slurry was filtered and the filter cake was washed twice with heptane (2×64 L, 0.5 volumes). The product was dried at 50° C. to give a solid (R)-N-[(1R)-1-[5-chloro-2-[(4-oxo-2-sulfanediyl-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). Seeding in stage 5 is to ensure that the solid is more easily separated by large-scale filtration and to improve manufacturability. In the alternative method performed, the steps are the same, but no seeds are used, and this does not affect the overall yield. The seeds used in the above method are made using the alternative method at a scale of 0.05 kg.

[0112] 1H 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).

[0113] Stage 6 / Step (vii): Sulfinyl cleavage and chiral resolution

[0114] [(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]heptyl)methanesulfonate

[0115]

[0116] Method a: -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 eq), dimethyl sulfoxide (556 L, 4.8 vols) and water (140 L, 1.2 vols) were charged to a vessel and the contents were set to 25° C. (R)-(-)-10-camphorsulfonic acid (123 kg, 528 mol, 2.0 eq) 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 vols) was charged over 30 minutes. [(lR)-l-[5-chloro-2-[(4-oxo-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-l-yl)methyl]phenyl]ethyl]ammonium (7,7-dimethyl-2-oxo-l-bicyclo[2.2.1]heptyl)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 develop. Water (163 L, 1.4 volumes) was charged dropwise at 60°C and the slurry was held for 1 hour. The slurry was cooled to 50°C and held for 1 hour, cooled to 40°C and held for 1 hour, cooled to 20°C over 4 hours and held at 20°C for 18 hours. The solids were isolated by filtration and the filter cake was washed with 3:2 DMSO:water (232 L, 2 vols) and ethanol (58 L, 0.5 vols) and then dried at 50 °C to give (7,7-dimethyl-2-oxo-1-bicyclo[2.2.1]heptyl)methanesulfonic acid [(1R)-1-[5-chloro-2-[(4-oxo-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-1-yl)methyl]phenyl]ethyl]ammonium (142.9 kg, 59% free base assay, 95% yield) as a solid. Seeding in Stage 6 Method a is to ensure that the solids are more easily isolated by large-scale filtration and to improve manufacturability. In the alternative method performed, the steps are the same, but no seeds are used, and this does not affect the overall yield. The seeds used in the above method are made using the alternative method at a scale of 0.2 kg.

[0117] 1H NMR (500MHz, DMSO, 27℃) 0.72 (3H, s), 1.02 (3H, s), 1.21-1.31 (2H, m), 1.54 (3 H, 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).

[0118] Alternative method b: -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-sulfenamide (773.4 g, 1.77 mol, 1.0 eq.) and 2-methyltetrahydrofuran (3867 mL, 5 vols) 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 added dropwise and the resulting mixture was maintained at 10°C for 3 hours. The mixture was quenched with 28.8% w / w aqueous sodium bisulfate solution (6190 mL, 8 vols) and the batch was warmed to 20°C. The batch was separated and the aqueous phase removed. The organic phase was washed with aqueous sodium chloride (2320 mL, 3 volumes) and then with 3M pH 7.2 phosphate buffer (1934 mL, 2.5 volumes). Dimethyl sulfoxide (3713 mL, 4.8 volumes) was added and the mixture was sieved. The contents of the vessel were distilled to about 7.5 volumes under reduced pressure. Water (365 g, 0.5 volume) was added followed by (R)-(-)-10-camphorsulfonic acid (838.7 g, 3.54 mol, 2.0 eq.) and the resulting solution was heated to 55° C. for about 16 hours. The batch was heated to 60° C. and water (464.1 g, 0.6 volume) was added 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]heptyl)methanesulfonate seeds (4.7 g, 0.6 wt%) were charged and the batch was held for 30 minutes to allow the seed bed to develop. Water (1856 g, 2.4 volumes) was added dropwise at 60°C over 1.5 hours 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 vols), water (773 mL, 1 vol) and ethanol (2 x 773 mL (2 x 2 vols) 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]heptyl)methanesulfonate as a solid (908 g, 59% free base assay, 90% yield). Seeding in Stage 6 Alternative Method b was to ensure that the solid was more easily isolated by large scale filtration and to improve manufacturability. In the alternative method performed, the steps were the same, but no seeds were used and this did not affect the overall yield. The seeds used in the above method were made using Alternative Method b at a 0.2 kg scale.

[0119] Stage 7 / Step (viii): Free Base Formation

[0120] 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-4-one

[0121]

[0122] [(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]heptyl)methanesulfonate (137 kg, 238 mol, 1.0 eq) and dimethyl sulfoxide (822 L, 6 volumes) were charged to a vessel and the temperature was adjusted to 22.5° C. The resulting solution was passed through a screen filter. An aqueous solution of ammonium hydroxide (34.3 kg, about 25% w / w, 511 mol, 2.15 eq.) in water (118 kg, 0.86 volumes) was added dropwise. The batch was warmed to 40 °C and seeded with 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-thioxo-5H-pyrrolo[3,2-d]pyrimidin-4-one (3.97 kg, 5% w / w based on free base). 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 and then 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) and then washed three times with ethanol (3×274 L, 2 vol). The product was dried at 50 °C to give 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]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 is to ensure that the solid is more easily separated by large-scale filtration and to improve manufacturability. In the alternative method performed, the steps are the same, but no seeds are used, and this does not affect the overall yield. The seeds used in the above method are made using the alternative method at a scale of 0.2 kg.

[0123] 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.

[0124] All references cited herein, including patents, patent applications, articles, textbooks, etc., and references cited therein, as well as those not cited therein, are incorporated herein by reference in their entirety for all purposes.

Claims

1. A method for preparing a compound of formula (I), the method comprising at least one of steps (i) to (viii); (i) forming a compound according to formula (Ia) from a compound according to formula (Ia1) or its corresponding free base or different salts and a compound according to formula (Ia2); (ii) forming a compound of formula (Ib) from a compound of formula (Ia); (iii) forming a compound of formula (Ic) from a compound of formula (Ib); (iv) forming a compound of formula (Id) from a compound of formula (Ic); (v) forming a compound of formula (Ie) from a compound of formula (Id); (vi) forming a compound of formula (If) from a compound of formula (Ie); (vii) forming a compound of formula (Ig) from a compound of formula (If); and (viii) forming a compound of formula (I) from a compound of formula (Ig).

2. The method for preparing a compound of formula (I) according to claim 1, comprising at least step (i), wherein step (i) comprises at least the following steps: (ia) cleaving a salt of a compound of formula (Ia1) or its corresponding free base or a different salt thereof in the presence of an inorganic base, optionally wherein the inorganic base is sodium carbonate; (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 reaction with a reducing agent, optionally wherein the reducing agent is sodium triacetoxyborohydride; and (id) The compound of formula (Ia) obtained in step (c) is crystallized as a hydrochloride salt.

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

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

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

6. A process for preparing a compound of formula (I) according to any one of the preceding claims, comprising at least step (v), wherein step (v) comprises at least: (va) reacting a compound of formula (Id) with a chiral sulfenamide reagent in the presence of a dehydrating agent, optionally wherein the dehydrating agent is titanium ethoxide.

7. A method for preparing a compound of formula (I) according to any one of the preceding claims, comprising at least step (vi), wherein step (vi) comprises at least: (vi-a) reacting a compound of formula (Ie) with a reducing agent, optionally wherein the reducing agent is lithium tri-tert-butoxyaluminium hydride.

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

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

10. A process for the preparation of a compound of formula (I) according to any one of the preceding claims, comprising at least step (i).

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

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

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

14. A compound selected from the group consisting of:

15. A compound having the following structure:

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