Process Development of an N-Benzylated Chloropurine at the Kilogram Scale

Abstract

A two-step pharmaceutical manufacturing process was developed for the large-scale preparation of 6-chloro-9-((4methoxy-3,5-dimethylpyridin-2-yl)methyl)-9H-purin-2-amine methanesulfonic acid salt (4) from commercially available starting materials. In the first step, the benzylpurine free base (3) was prepared by benzylation of 6-chloro-9H-purin-2-amine (1) with 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine hydrochloride (2). The benzylpurine free base was then directly converted into the methanesulfonic acid salt. It was necessary to charge the pyridine hydrochloride 2 in portions into the mixture of K 2 CO 3 (−325 mesh) and the chloropurine compound 1 in dimethylacetamide (DMA). The major regioisomeric impurity (6), formed by N 7 benzylation, and inorganic salts were removed by filtration. Treatment of the DMA filtrate with MsOH afforded the target salt with negligible degradation. In the second step, recrystallization of the crude salt from DMSO−EtOAc with seeding gave crystalline API in high yield and purity despite the hydrolytic instability of the product in solution.

Impurity Occurrence and Removal in Crystalline Products from Process Reactions

“…The use of methyl acetate as the antisolvent gave material containing 0.45% of the N 7 alkylated impurity 73 , while the use of ethyl acetate as antisolvent gave 0.28% of the same impurity. In the final developed process, the methylate salt 72 was dissolved in DMSO at 22 °C; ethyl acetate antisolvent was added with seeding and cooling to 0 °C to give the required product with both impurities under 0.06% …”

“…In the final developed process, the methylate salt 72 was dissolved in DMSO at 22 °C; ethyl acetate antisolvent was added with seeding and cooling to 0 °C to give the required product with both impurities under 0.06%. 57 Three polymorphs of an unidentified "API X" 75 (Figure 5) were known, designated forms A, B, and C, of which the crystal structures and supramolecular packing motifs of these forms were fully characterized. A dimer 76 involving H•••F hydrogen bonds was one of the motifs found in forms A and B.…”

Determination of composition distributions of multi-particle crystalline samples by sequential dissolution with concomitant particle sizing and solution analysis

“…The motivation for this work arises from the common occurrence of molecular impurities in pharmaceutical and fine chemical manufacturing and the use of crystallisation as the principle method of product isolation and purification. [4][5][6][7][8] In some instances, crystallisations are not sufficient to adequately remove impurities without an accompanying phase transformation or optimisation of the process chemistry, [9][10][11][12][13][14][15][16][17][18] in which cases the question of the location of impurities in crystalline batches arises. This is particularly the case when the impurity does not form a physically distinct phase which can be observed by XRD, thermal analysis or microscopy.…”

“…9 In cases where a crystallisation does not acceptably reduce the level of a particular impurity, successful purification may occur in conjunction with a phase transformation giving a different crystal form which better rejects the impurity. 10,11,12 In some cases, the process chemistry may need to be further refined so as to reduce the quantity of impurity formed in advance of purification by crystallisation. [13][14][15][16][17][18] The efficiency of washing during isolation and filtration of the crystalline mass is also important in achieving purity specification.…”

Targeted Protein Degradation Induced by HEMTACs Based on HSP90

“…1 4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-9Hpurin-2-amine (37, BIIB021). 40,48 A mixture of compound 36 (1.0 g, 5.9 mmol, 1.0 equiv), compound 4 (1.57 g, 7.08 mmol, 1.2 equiv), K 2 CO 3 (978.02 mg, 7.08 mmol, 1.2 equiv), and anhydrous DMSO (25 mL) was stirred at 40 °C for 12 h. The reaction mixture was added into a mixture solution of H 2 O (15 mL) and IPA (15 mL) in portions. The solid was collected by filtration, and the crude product was purified by silica gel chromatography eluted with PE and EtOAc (PE/EtOAc = 1:1) to give title compound 37 as a white solid.…”