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Preparation of (5R,6R)-6-((R)-1-((tert-butyldimethylsilyl)oxy)allyl)-2,2,3,3,12,12,13,13-octamethyl-5-(prop-2-yn-1-yl)-4,7,11-trioxa-3,12-disilatetradecane

IP.com Disclosure Number: IPCOM000236283D
Publication Date: 2014-Apr-17
Document File: 6 page(s) / 31K

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The IP.com Prior Art Database

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    Disclosed herein after is a process for the preparation of (5R,6R)-6-((R)-1- ((tert-butyldimethylsilyl)oxy)allyl)-2,2,3,3,12,12,13,13-octamethyl-5-(prop-2-yn-1- yl)-4,7,11-trioxa-3,12-disilatetradecane from (1S,2R)-1-((R)-2,2-dimethyl-1,3- dioxolan-4-yl)but-3-ene-1,2-diol, which can be an intermediate in the synthesis of (1R,2R,3R,Z)-5-(2-((1R,7aR,E)-1-((R)-6-hydroxy-6-methylheptan-2-yl)-7a- methyloctahydro-4H-inden-4-ylidene)ethylidene)-2-(3-hydroxypropoxy)-4- methylenecyclohexane-1,3-diol((1R,2R,3R,5Z,7E)-2-(3-Hydroxypropyloxy)-9,10- secocholesta-5,7,10(19)-triene-1,3,25-triol).

    The preparation of the starting material, (1S,2R)-1-((R)-2,2-dimethyl-1,3- dioxolan-4-yl)but-3-ene-1,2-diol, can be done by methods known in the art. For example, (1S,2R)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)but-3-ene-1,2-diol can be prepared from D-Mannitol as described in previous publications IPCOM000225941D and IPCOM0002322556D). This compound was then purified by column chromatography on silica gel. It could also be purified by crystallization with/or without chromatography on silica gel.

Preparation of (1S,2R)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-(3-((4-

methoxybenzyl)oxy)propoxy)but-3-en-2-ol, (1S,2R)-1-((R)-2,2-dimethyl-1,3-

dioxolan-4-yl)-2-(3-((4-methoxybenzyl)oxy)propoxy)but-3-en-1-ol or (R)-4-

((7S,8R)-1,14-bis(4-methoxyphenyl)-8-vinyl-2,6,9,13-tetraoxatetradecan-7-yl)-

2,2-dimethyl-1,3-dioxolane.

    Sodium hydride (0.78 g) was added to a solution of (1S,2R)-1-((R)-2,2- dimethyl-1,3-dioxolan-4-yl)but-3-ene-1,2-diol (4.1 g) in DMF (25 mL) at 0-5 °C.

3-((4-methoxybenzyl)oxy)propyl methanesulfonate (3.5 g) was added to the mixture at 0-5 °C, the resulting mixture was heated to 20 °C and stirred at 20 °C. The mixture was cooled to 0-5 °C, neutralized with 10 % solution of citric acid and extracted with MTBE. The organic layer was evaporated to obtain an oily residue (6.3 g). The oil was purified on silica gel (EtOAc/Toluene) to separate (R)-4-((7S,8R)-1,14-bis(4-

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Preparation of (5R,6R)-6-((R)-1-((tert-butyldimethylsilyl)oxy)allyl)-

2,2,3,3,12,12,13,13-octamethyl-5-(prop-2-yn-1-yl)-4,7,11-trioxa-3,12-

disilatetradecane



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methoxyphenyl)-8-vinyl-2,6,9,13-tetraoxatetradecan-7-yl)-2,2-dimethyl-1,3- dioxolane (MS-confirmed: [M+NH4]+=562) and to isolate a mixture of (1S,2R)-1-
((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-(3-((4-methoxybenzyl)oxy)propoxy)but-3-en- 2-ol and (1S,2R)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(3-((4- methoxybenzyl)oxy)propoxy)but-3-en-1-ol ( 1.6 g) in a ratio of about 4:1 (MS- confirmed: [M+H]+=367). (1S,2R)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-(3-((4- methoxybenzyl)oxy)propoxy)but-3-en-2-ol could be isolated from the mixture by preparative chromatography.

The following steps of the synthetic scheme could be performed using pure (1S,2R)- 1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-(3-((4-methoxybenzyl)oxy)propoxy)but-3- en-2-ol or a mixture of (1S,2R)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-1-(3-((4- methoxy...