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Generated: January 18, 2018

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Title: Process for the preparation of a substituted diaminodiol
Abstract:A process is disclosed for the preparation of a substituted diaminodiol.
Inventor(s): Sowin; Thomas J. (Grayslake, IL), Hannick; Steven M. (Highland Park, IL), Doherty; Elizabeth M. (New Haven, CT), Sato; Takahiro (Tokyo, JP), Suzuki; Takayuki (Kanagawa, JP)
Assignee: Abbott Laboratories (Abbott Park, IL)
Filing Date:Apr 23, 1993
Application Number:08/048,921
Claims:1. A process for the preparation of the (3R,4S)-diol of the formula: ##STR5## wherein at each occurrence R.sub.3 is independently selected from hydrogen and an N-protecting group comprising

(a) reaction of the (3R,4R)-diol of the formula: ##STR6## wherein R.sub.3 is R*OC(O)-- wherein R* is loweralkyl or benzyl with a compound of the formula R.sub.7 C(OR.sub.8).sub.3 wherein R.sub.7 is hydrogen, loweralkyl, phenyl or benzyl and R.sub.8 is loweralkyl to provide a compound of the formula: ##STR7## (b) reaction of the product of step a with R**SO.sub.2 Cl or (R**SO.sub.2).sub.2 O wherein R** is methyl, trifluoromethyl or 4-methylphenyl to provide the sulfonate derivative of the product of step a;

(c) heating the product of step b in an inert solvent to provide a compound of the formula: ##STR8## (d) reaction of the product of step c with a strong base.

2. The process of claim 1 wherein R.sub.3 is carbonylbenzyloxy and R.sub.7 is CH.sub.3.

3. A process for the preparation of the (3R,4S)-diol of the formula: ##STR9## wherein at each occurrence R.sub.3 is independently selected from hydrogen and an N-protecting group comprising

(a) reaction of the (3R,4R)-diol of the formula: ##STR10## wherein R.sub.3 is carbonylbenzyloxy with CH.sub.3 C (OCH.sub.2 CH.sub.3).sub.3 to provide a compound of the formula: ##STR11## wherein R.sub.3 is carbonylbenzyloxy and R.sub.7 is CH.sub.3 ; (b) reaction of the product of step a with methanesulfonylchloride to provide the methansulfonate-derivative of the product of step a;

(c) heating the product of step b in an inert solvent to provide a compound of the formula: ##STR12## (d) reaction of the product of step c with a strong base.

4. A process for the preparation of the (3R,4S)-diol of the formula: ##STR13## wherein R.sub.3 is hydrogen comprising (a) reaction of the (3R,4R)-diol of the formula: ##STR14## wherein R.sub.3 is carbonylbenzyloxy with CH.sub.3 C (OCH.sub.2 CH.sub.3).sub.3 to provide a compound of the formula: ##STR15## wherein R.sub.3 is carbonylbenzyloxy and R.sub.7 is CH.sub.3 ; (b) reaction of the product of step a with methanesulfonylchloride to provide the methansulfonate-derivative of the product of step a;

(c) heating the product of step b in dimethylformamide in the presence of aqueous ammonium chloride to provide a compound of the formula: ##STR16## wherein R.sub.3 is carbonylbenzyloxy and R.sub.7 is CH.sub.3 ; and (d) reaction of the product of step c with a strong base.

5. A process for the preparation of the (3R,4R)-diol of the formula: ##STR17## wherein R.sub.3 is hydrogen or an N-protecting group comprising (a) reaction of N-protected L-phenylalaninal with a mixture of VCI.sub.3 (THF).sub.3 and zinc dust to produce a mixture of the (3R,4R)-, (3R,4S)- and (3S,4S)-diols of the formula: ##STR18## (b) reaction of the mixture of diols from step a with acetone and sulfuric acid to produce a mixture of the acetonides resulting from the (3R,4R)-, (3R,4S)- and (3S,4S)-diols;

(c) separation by selective crystallization of the acetonide resulting from the (3S,4S)-diol from the acetonides resulting from the (3R,4R)-diol and the (3R,4S)-diol;

(d) reaction of the mixture of acetonides resulting from the (3R,4R)- and (3R,4S)-diols with hydrochloric acid to selectively cleave the acetonide resulting from the (3R,4R)-diol, producing a mixture of the (3R,4R)-diol and the acetonide resulting from the (3R,4S)-diol; and

(e) separation by selective crystallization of the (3R,4R)-diol.

6. The process of claim 5 wherein R.sub.3 is carbonylbenzyloxy.

7. A process for the preparation of the (3R,4R)-diol of the formula: ##STR19## wherein R.sub.3 is hydrogen or an N-protecting group comprising (a) reaction of N-protected L-phenylalaninal with a mixture of VCI.sub.3 (THF).sub.3 and zinc dust to produce a mixture of the (3R,4R)-, (3R,4S)- and (3S,4S)-diols of the formula: ##STR20## (b) reaction of the mixture of diols from step a with acetone and sulfuric acid to produce a mixture of the acetonides resulting from the (3R,4R)-, (3R,4S)- and (3S,4S)-diols;

(c) separation by selective crystallization of the acetonide resulting from the (3S,4S)-diol from the acetone/H.sub.2 SO.sub.4 solution of the mixture of acetonides resulting from the (3R,4R)-diol and the (3R,4S)-diol;

(d) addition of water to the acetone/H.sub.2 SO.sub.4 solution of the mixture of acetonides of the (3R,4R)-diol and the (3R,4S)-diol resulting from step c, followed by heating; and

(e) separation by selective crystallization of the (3R,4R)-diol.

8. The process of claim 7 wherein R.sub.3 is carbonylbenzyloxy.

9. A process for the preparation of the (3R,4R)-diol of the formula: ##STR21## where R.sub.3 is carbonylbenzyloxy comprising (a) reaction of N-carbonylbenzyloxy-L-phenylalaninal with a mixture of VCI.sub.3 (THF).sub.3 and zinc dust to produce a mixture of the (3R,4R)-, (3R,4S)- and (3S,4S)-diols of the formula: ##STR22## wherein R.sub.3 is carbonylbenzyloxy; (b) reaction of the mixture of diols from step a with acetone and sulfuric acid to produce a mixture of the acetonides resulting from the (3R,4R)-, (3R,4S)- and (3S,4S)-diols;

(c) separation by selective crystallization of the acetonide resulting from the (3S,4S)-diol from the acetonides resulting from the (3R,4R)-diol and the (3R,4S)-diol;

(d) reaction of the mixture of acetonides resulting from the (3R,4R)- and (3R,4S)-diols with hydrochloric acid to selectively cleave the acetonide resulting from the (3R,4R)-diol, producing a mixture of the (3R,4R)-diol and the acetonide resulting from the (3R,4S)-diol; and

(e) separation by selective crystallization of the (3R,4R)-diol.

10. A process for the preparation of the (3R,4R)-diol of the formula: ##STR23## wherein R.sub.3 is carbonylbenzyloxy comprising (a) reaction of N-carbonylbenzyloxy-L-phenylalaninal with a mixture of VCI.sub.3 (THF).sub.3 and zinc dust to produce a mixture of the (3R,4R)-, (3R,4S)- and (3S,4S)-diols of the formula: ##STR24## wherein R.sub.3 is carbonylbenzyloxy; (b) reaction of the mixture of diols from step a with acetone and sulfuric acid to produce a mixture of the acetonides resulting from the (3R,4R)-, (3R,4S)- and (3S,4S)-diols;

(c) separation by selective crystallization of the acetonide resulting from the (3S,4S)-diol from the acetone/H.sub.2 SO.sub.4 solution of the mixture of acetonides resulting from the (3R,4R)-diol and the (3R,4S)-diol;

(d) addition of water to the acetone/H.sub.2 SO.sub.4 solution of the mixture of acetonides of the (3R,4R)-diol and the (3R,4S)-diol resulting from step c, followed by heating; and

(e) separation by selective crystallization of the (3R,4R)-diol.
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