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Process for the preparation of (2S)-2-((tert-butoxycarbonyl) amino)-2-(3-hydroxyadamantan-1-yl) acetic acid

IP.com Disclosure Number: IPCOM000241212D
Publication Date: 2015-Apr-06
Document File: 4 page(s) / 148K

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Page 01 of 4

Process for the preparation of (2S)-2-((tert-butoxycarbonyl) amino)-2-(3- hydroxyadamantan-1-yl) acetic acid

     (2S)-2-((tert-butoxycarbonyl) amino)-2-(3-hydroxyadamantan-1-yl) acetic acid (referred to herein as Compound A) is an intermediate in the synthesis of (1S,3S,5S)-2-[2(S)-2-Amino-2-(3- hydroxyadamant-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile.

     Enclosed herein is process for preparation of compound A, as well as intermediates in this synthesis.

Procedure

1. Preparation of 1-Adamantane methanol (referred to as Compound-2)

Process-A

     Sodium borohydride (23.0 gms) was added to tetrahydrofuran (300 ml) and cooled to -10 to -5ºC.Added Borontrifluoride(87 ml) etherate to it at -10 to -5ºC.Sitrred for 30-40 minutes and added a solution of 1-Adamantane Carboxylic acid (100.0 gms) dissolved in 300 ml tetrahydrofuran at -10 to 0ºC. Stirred at 0ºC and monitored the reaction Quenched the reaction by adding it to a mixture of acetic acid (48 ml) and water (800 ml). Stirred at 20-25ºC followed by addition of sodium hydroxide solution (40.0 gms dissolved in 200 ml water) and stirred for 2 hours. Concentrated the mass under reduced pressure to remove tetrahydrofuran and added 200 ml water. Stirred and filtered product under vacuum and washed with water. Dried under vacuum at 45ºC.Yield obtained is > 95% with purity by GC >99.0% .

Process-B

     To tetrahydrofuran (100 ml) added 1-Adamantane carboxylic acid (10 gms) and cooled to 0-5ºC. Added sodium borohydride (7.36 gms) and stirred for 1 hour. Added trifluoroacetic acid
(22.12 gms ) in 1 hour at 0-5ºC. Raise the temperature to 20-25ºC and stirred for 12 hours. Added sodium hydroxide solution (9.0 gms dissolved in 40 ml water) and concentrated the mass under vacuum at 50ºC to isolate solid. Added water( 100 ml) stirred for 2 hours at 50ºC. Cooled to 25 ºC and filtered under vacuum. Washed with water( 20 ml) and dried at 50ºC under vacuum for 6 hours. Dry weight of product is 9.10 gms with GC purity >99.0% and yield more than 95.0%.


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2. Preparation of 1-Adamantane carboxaldehyde (referred to as Compound -3)

Process A

Added 1-Adamantane methanol (compound 2) (92.0 gms) to dichloromethane (740 ml) and water (184 ml). Added potassium bromide (13.19 gms). Added 2,2,6,6-Tetramethyl-1- piperidinyloxy ( 0.43 gm) and cooled to -10ºC. Added sodium hypochlorite solution (7.50%) (516 ml) drop wise at -5 to 0 ºC Stir at 0ºC and monitor reaction. Separate the layers after completion of reaction. Purity of Compound-3 is >95.0%. Product is carried forward for next step as solution in dichloromethane.

Process B

     Added 1-Adamantane methanol (compound 2) (10.0 gms) to dichloromethane (100 ml) and water (20 ml). Added potassium bromide (1.44 gms). Added sodium bicarbonate (7.0 gms) and 2,2,6,6-Tetramethyl-1-piperidinyloxy ( 0.10 gm) and cooled to -5ºC. Added sodium hypochlorite solution (7.20%) (57 ml) drop wise at -5 to 0 ºC Stir at 0ºC and monitor reaction. Separate the laye...