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Process for preparing (2R,5R)-1,6-diphenylhexane-2,5-diamine

IP.com Disclosure Number: IPCOM000238071D
Publication Date: 2014-Jul-31
Document File: 4 page(s) / 52K

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Process for preparing (2R,5R)-1,6-diphenylhexane-2,5-diamine

    Provided herein is a process for preparing (2R,5R)-1,6-diphenylhexane-2,5-diamine hydrochloride salt, referred herein as Compound I. The process is described in Example 1. The isolated samples were analyzed by X-ray powder diffraction ("XRPD"), which indicated a formation of a crystalline form of Compound I. Figure 1 depicts the XRPD of the obtained crystalline form.

    Compound I may be used for preparing 1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2-[(methyl{[2- (propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6- diphenylhexan-2-yl]carbamate.

Figure 1: XRPD of a crystalline form of Compound I

     According to Figure 1, the crystalline form of Compound I is characterized by XRPD peaks at:
10.2, 11.4, 16.7, 17.0, 17.9, 19.0, 19.2, 20.4, 20.6, 21.2, 22.9, 24.0, 26.1, 26.9, 28.5, 28.9, 29.9, 32.5, 32.9,
33.5, 37.5, 38.6 and 39.4 ± 0.2 degrees 2-theta.

XRPD method:

The analysis was performed on Bruker D8 powder X-Ray diffractometer model D8 Advance equipped with a solid state detector. Copper radiation of 1.5418 Å was used. Scanning parameters: range: 2-40 degrees two-theta; scan mode: continuous scan; step size: 0.05°.; and a rate of 3 deg/min.

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Example 1: Preparation of (2R,5R)-1,6-diphenylhexane-2,5-diamine hydrochloride salt

Step 1: Preparation of (S)-2-chloro-3-phenylpropanoic acid

    To a stirred suspension of L-phenylalanine (82.6 g) in 5N HCl (650 mL) at -10°C to - 15°C, a solution of sodium nitrite (55.2 g) in water (200 mL) was added drop-wise, carefully maintaining the temperature < -10°C. The reaction mixture was allowed to warm to RT after addition and stirred for 2h at RT, then ethylacetate (250 mL) was added. After separation of the organic phase, the aqueous phase was extracted with ethyl acetateThe combined organic layers were washed with water until pH ~3 was achieved. The organic layer was dried (Na2SO4), and concentrated under vacuum to give the titled compound as a viscous oil.

Step 2: Preparation of (S)-2-chloro-3-phenylpropan-1-ol

    To a stirred solution of NaBH4 (18 g) in THF (160 mL) at 0°C was added BF3.Et2O (66 mL) dropwise. The reaction was warmed to RT and cooled to 0°C. (S)-2-chloro-3- phenylpropanoic acid (80g) was added drop-wise and the reaction mixture was stirred overnight at 0°C. The reaction mixture was quenched by addition of acetone (80 mL) followed by the addition of Acetic acid/water (125 mL/250 mL). The reaction mixture was warmed to RT and then extracted with MTBE . The combined organic layers were dried and concentrated under vacuum to give the titled compound as a viscous oil.

Step 3: Preparation of (R)-2-benzyloxirane

    To a stirred suspension of (S)-2-chloro-3-phenylpropan-1-ol (51 g, 0.3 mol) in DMSO/H2O (1/3) (500 mL) was added KOH (25 g) in water (100 mL) at RT. The reaction mixture became cloudy and was stirred for 45 min. The desired compound was extracted with MTBE , dried and...