.

Pharmaceutical Business Intelligence

  • Anticipate P&T budget requirements
  • Evaluate market entry opportunities
  • Find generic sources and suppliers
  • Predict branded drug patent expiration

► Plans and Pricing

Upgrade to enjoy subscriber-only features like email alerts and data export. See the Plans and Pricing

DrugPatentWatch Database Preview

Details for Patent: 6,175,008

« Back to Dashboard

Details for Patent: 6,175,008

Title: Processes for preparing substituted 1,3-oxathiolanes with antiviral properties
Abstract:Disclosed are processes for preparing compounds of the formula (I) and pharmaceutically acceptable salts or esters thereof: ##STR1## wherein R.sub.2 is a purine or pyrimidine base or an analogue or derivative thereof; and Z is S, S.dbd.O or SO.sub.2. The invention also relates to intermediates of use in the preparation of these compounds.
Inventor(s): Belleau; Bernard (late of Westmount, CA), Mansour; Tarek (Montreal, CA), Tse; Allan (Ville St-Laurent, CA), Evans; Colleen A. (Montreal, CA), Jin; Haolun (Pierrefonds, CA), Zacharie; Boulos (Laval des Rapides, CA), Nguyen-Ba; Nghe (La Prairie, CA)
Assignee: BioChem Pharma Inc. (Laval, CA)
Filing Date:Jun 06, 1995
Application Number:08/466,329
Claims:1. A process comprising:

reacting mercaptoacetaldehyde with a compound of formula R.sub.y OOCCHO, wherein R.sub.y is C.sub.1-12 alkyl or C.sub.6-20 aryl to obtain a compound of formula (XV) ##STR43##

wherein said mercaptoacetaldehyde is the monomer of 1,4-dithiane-2,5 diol.

2. The process according to claim 1, wherein the mercaptoacetaldehyde monomer is obtained from 1,4-dithianc-2,5-diol dissolved in an inert solvent.

3. The process according to claim 2, wherein said inert solvent is selected from group consisting of: pyridine, toluene and DMSO.

4. A process according to claim 1, wherein said compound of formula R.sub.y OOCCHO is ethyl gloxylate.

5. The process according to claim 1, further comprising converting the hydroxyl of the compound of formula (XV) to a leaving group L to obtain a compound of formula (XVI): ##STR44##

6. The process according to claim 5, wherein L is OR.sub.z, wherein R.sub.z is selected from the group consisting of; a saturated or unsaturated C.sub.1-6 alkyl group, an aliphatic or aromatic C.sub.1-6 acyl group, a saturated or unsaturated alkoxycarbonyl group, a sulphonyl imidazolide, a carbonyl imidazolide, a aliphatic or aromatic amino carbonyl group, a alkyl imidate group, a saturated or unsaturated phosphinoyl, and a aliphatic or aromatic sulphonyl group.

7. The process according to claim 5 further comprising reacting the compound of formula (XVI) with a silylated --R.sub.2 compound in the presence of a Lewis acid, whereby said leaving group is displaced, to produce a compound of formula (XVII): ##STR45##

wherein

Z is S,

R.sub.2 is selected from the group consisting of: ##STR46## ##STR47##

R.sub.11 is in each case independently selected from hydrogen, acetyl, and C.sub.1-6 alkyl;

R.sub.12 and R.sub.13 are each independently selected from hydrogen, hydroxymethyl, trifluoromethyl, C.sub.1-6 alkyl or alkenyl, bromine, chlorine, fluorine, and iodine; and

W is in each case independently selected from hydrogen, bromine, chlorine, fluorine, iodine, amino, and hydroxyl.

8. The process according to claim 5 or 6, further comprising:

(a) converting the group R.sub.y O.sub.2 C of the compound of formula (XVI) to hydroxymethyl (HOCH.sub.2); and (b) protecting the resulting hydroxymethyl with a protecting function R.sub.1 to obtain a compound of formula (XXII): ##STR48##

wherein R.sub.1 is selected from the group consisting of C.sub.1-16 acyl, t-butyldimethylsilyl, and t-butyldiphenylsily.

9. The process according to claim 8, further comprising:

reacting the compound of formula (XXII) with a silylated --R.sub.2 compound, in the presence of a Lewis acid, whereby said leaving group is displaced, to obtain a compound of formula (XXIII): ##STR49##

wherein

R.sub.2 is selected from the group consisting of ##STR50##

wherein:

X is oxygen or sulfur; Y is oxygen or sulfur;

R.sub.3 and R.sub.4 are independently selected from the group consisting of hydrogen, hydroxyl, amino, C.sub.1-6 alkyl, alkenyl, C.sub.2-6 alkynyl, and C.sub.1-10 acyl or aracyl;

R.sub.5 and R.sub.6 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, carboxy, carbamoyl, alkoxycarbonyl, hydroxymethyl, trifluoromethyl, thioaryl, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-10 acyloxy;

R.sub.7 and R.sub.8 are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, thiol, thioalkyl, amino, halogen, cyano, carboxy, alkoxycarbonyl, carbamoyl, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-10 acyloxy; and

R.sub.9 is selected from the group consisting of hydrogen, hydroxy, alkoxy, amino, halogen, azido, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-10 acylo and

Z is S; and

optionally further comprising oxidizing Z of said compound of formula (XXIII) to obtain a compound of formula (XXIII) wherein Z is S.dbd.O or SO.sub.2.

10. The process according to claim 9, further comprising converting R.sub.1 OCH.sub.2 from compound (XXIII) to hydroxymethyl (HOCH.sub.2) to obtain a compound of formula (I): ##STR51##

11. The process according to claim 9, wherein the Lewis acid is selected from the group consisting of: TMSOTf, TMSI, TiCl.sub.4 and SnCl.sub.4.

12. The process according to claim 5, further comprising:

(a) reacting the compound of formula (XVI) with a halogen-containing Lewis acid to obtain a compound of formula (XXVI): ##STR52##

wherein Hal is a halogen and

(b) coupling the compound of formula (XXVI) with a purine compound, under basic condition, whereby said halogen is displaced to obtain a compound of formula (XVII): ##STR53##

wherein

R.sub.2 is selected from the group consisting of: ##STR54##

wherein:

X is oxygen or sulfur;

Y is oxygen or sulfur;

R.sub.3 and R.sub.4 are independently selected from the group consisting of hydrogen, hydroxyl, amino, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-10 acyl or aracyl;

R.sub.5 and R.sub.6 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, carboxy, carbamoyl, alkoxycarbonyl. hydroxymethyl, trifluoromethyl, thioaryl, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-10 acyloxy;

R.sub.7 and R.sub.8 are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, thiol, thioalkyl, amino, halogen, cyano, carboxy, alkoxycarbonyl, carbamoyl, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-10 acyloxy; and

R.sub.9 is selected from the group consisting of hydrogen, hydroxy, alkoxy, amino, halogen, azido, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-10 acyloxy; and Z is S.

13. The process according to claim 12, wherein said halogen is iodine.

14. The process according to claim 12, wherein said Lewis acid is trimethylsilyl iodide.

15. The process according to claim 13 or 14, wherein the purine compound is 6-chloropurine.

16. The process according to claim 5, further comprising reacting the compound of formula (XVI) with a silylated R.sub.2 -compound in the presence of a Lewis acid, whereby said leaving group is displaced, to produce a compound of formula (XVII): ##STR55##

wherein

Z is S;

R.sub.2 is selected from the group consisting of: ##STR56##

X is oxygen or sulfur;

Y is oxygen or sulfur;

R.sub.3 and R.sub.4 are independently selected from the group consisting of hydrogen, hydroxyl, amino, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-10 acyl or aracyl;

R.sub.5 and R.sub.6 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, amino, cyano, carboxy, carbamoyl, alkoxycarbonyl, hydroxymethyl, trifluoromethyl, thioaryl, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-10 acyloxy;

R.sub.7 and R.sub.8 are independently selected from the group consisting of hydrogen, hydroxy, alkoxy, thiol, thioalkyl, amino, halogen, cyano, carboxy, alkoxycarbonyl, carbamoyl, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-10 acyloxy; and

R.sub.9 is selected from the group consisting of hydrogen, hydroxy, alkoxy, amino, halogen, azido, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, and C.sub.1-10 acyloxy.

17. The process according to claim 16, further comprising

oxidizing Z of the compound of formula (XVII) to give a compound of formula (XVII) wherein Z is S.dbd.O or SO.sub.2.

18. The process according to claim 16, wherein the Lewis acid is selected from the group consisting of: TMSOTf, TMSI, TiCl.sub.4 and SnCl.sub.4.

19. The process according to claim 16, further comprising

optionally oxidizing Z of the compound of formula (XVII) to give a compound of formula XVII wherein Z is S.dbd.O or SO.sub.2 and

reducing the R.sub.y O.sub.2 C group of the compound of formula (XVII) to obtain a compound of formula (I): ##STR57##

wherein:

Z is selected from the group consisting of S, S.dbd.O and SO.sub.2.

20. The process according to claim 19, wherein R.sub.2 is uracil and further comprising the steps of:

(a) protecting the hydroxyl group of the compound of formula (I) with a protecting function R.sub.1 to obtain a compound of formula (XIX): ##STR58##

wherein R.sub.1 is selected from the group consisting of C.sub.1-16 acyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl;

(b) interconverting the uracil group R.sub.2 of formula (XIX) to a cytosine group, designated as R.sub.2a, to obtain a compound of formula (XX): ##STR59##

and (c) removing the protecting function R.sub.1 of the compound of formula (XX) to obtain a compound of formula (I'): ##STR60##

21. A process comprising:

combining 1,4-dithiane-2,5-diol, in a solvent, with a compound of formula R.sub.y OOCCHO, wherein R.sub.y is C.sub.1-12 alkyl or C.sub.6-20 aryl to obtain a compound of formula (XV) ##STR61##

22. A process according to claim 21, wherein said compound of formula R.sub.y OOCCHO is ethyl gloxylate.
« Back to Dashboard

For more information try a trial or see the database preview and plans and pricing

How are People Using DrugPatentWatch?

Drugs may be covered by multiple patents or regulatory protections. All trademarks and applicant names are the property of their respective owners or licensors. Although great care is taken in the proper and correct provision of this service, thinkBiotech LLC does not accept any responsibility for possible consequences of errors or omissions in the provided data. The data presented herein is for information purposes only. There is no warranty that the data contained herein is error free. thinkBiotech performs no independent verifification of facts as provided by public sources nor are attempts made to provide legal or investing advice. Any reliance on data provided herein is done solely at the discretion of the user. Users of this service are advised to seek professional advice and independent confirmation before considering acting on any of the provided information. thinkBiotech LLC reserves the right to amend, extend or withdraw any part or all of the offered service without notice.

`abc