US 6,683,219 B2Granted

Synthesis of A-ring synthon of 19-nor-1α,25-dihydroxyvitamin D3 from (D)-glucose

AssigneeWisconsin Alumni Research Foundation

InventorsHector F. DeLuca, Masato Shimizu, Sachiko Yamada

Life of this patent

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Abstract

The present invention provides a method for the synthesis of an A-ring synthon phosphine oxide used in the preparation of 19-nor vitamin D compounds, and to novel synthetic intermediates formed during the synthesis. The new method prepares the phosphine oxide from (D)-glucose.

Claims18

Dependent claims

A method of making a phosphine oxide having the structure

where R3, R4 and R5 are each independently a hydroxy-protecting group comprising the steps of:
(a) converting D-glucose having the structure
to a 2-deoxy-glucose derivative having the structure
where R1 is an alkyl group and Bn represents a benzyl group;
(b) iodinating the 2-deoxy-glucose derivative to form a 5-iodinated derivative having the structure
(c) eliminating the iodine substituent of said 5-iodinated derivative to form a 1-ether derivative having the structure
(d) reducing the 1-ether derivative to form a 1-alcohol derivative having the structure
(e) converting the 1-alcohol derivative to a 1-protected derivative having the structure
where R2 is a hydroxy protecting group;
(f) reducing the 1-protected derivative with a metal hydride to form a 5-alcohol derivative having the structure
(g) benzylating the 5-alcohol derivative to form a benzylated derivative having the structure
(h) hydrolyzing the benzyl derivative to form a 1-hydroxyl derivative having the structure
(i) oxidizing the 1-hydroxyl derivative to form a 1-ketone derivative having the structure
(j) converting the 1-ketone derivative to a 3,4,5-protected derivative having the structure
where R3, R4 and R5 are each independently a hydroxy-protecting group;
(k) condensing the 3,4,5-protected derivative to an ester derivative having the structure
where R6 is an alkyl group;
(l) reducing the ester derivative with a metal hydride to form a 3,4,5-protected-1-alcohol derivative having the structure
(m) and converting the 3,4,5-protected-1-alcohol to a phosphine oxide having the structure

16 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/205,453Filed 25 Jul 2002 · us provisional application
Priority: 30 Jul 2001
Published: US 2003/0069212 A110 Apr 2003
Granted: 27 Jan 2004
Term ends: Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07H 9/04
The hetero ring containing only oxygen as ring hetero atoms: cyclic acetals
C07C 43/196
Having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring: containing hydroxy or O-metal groups
C07C 45/29
By oxidation: of hydroxy groups
C07C 45/60
With oxygen as the only heteroatom: in six-membered rings

Family

Application60/308,716Us provisional application · filed 30 Jul 2001
US 2003/0069212 A1Pre-grant publication · published 10 Apr 2003
US 6,683,219 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Facts

Application

10/205,453Filed 25 Jul 2002 · us provisional application

Priority

30 Jul 2001

Published

US 2003/0069212 A110 Apr 2003

Granted

27 Jan 2004

Term ends

Not estimatedThe source records don’t support an estimate.

Classification11 codes

C07H 9/04
The hetero ring containing only oxygen as ring hetero atoms: cyclic acetals
C07C 43/196
Having an ether-oxygen atom bound to a carbon atom of a ring other than a six-membered aromatic ring: containing hydroxy or O-metal groups
C07C 45/29
By oxidation: of hydroxy groups
C07C 45/60
With oxygen as the only heteroatom: in six-membered rings