WO1995034536B1 - Production of hydroxythioacetamides and use thereof in the synthesis of benzothiophenes - Google Patents
Production of hydroxythioacetamides and use thereof in the synthesis of benzothiophenesInfo
- Publication number
- WO1995034536B1 WO1995034536B1 PCT/US1995/007399 US9507399W WO9534536B1 WO 1995034536 B1 WO1995034536 B1 WO 1995034536B1 US 9507399 W US9507399 W US 9507399W WO 9534536 B1 WO9534536 B1 WO 9534536B1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pages
- formula
- process according
- page
- benzo
- Prior art date
Links
- QTNWIBQLURUPJO-UHFFFAOYSA-N 2-hydroxyethanethioamide Chemical class NC(=S)CO QTNWIBQLURUPJO-UHFFFAOYSA-N 0.000 title claims 4
- FCEHBMOGCRZNNI-UHFFFAOYSA-N Benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title claims 4
- 238000004519 manufacturing process Methods 0.000 title claims 3
- 230000015572 biosynthetic process Effects 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- 230000002194 synthesizing Effects 0.000 title 1
- -1 dialkylamino thioformamide Chemical compound 0.000 claims abstract 5
- 125000005605 benzo group Chemical group 0.000 claims abstract 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims 6
- 125000000217 alkyl group Chemical group 0.000 claims 3
- 150000007970 thio esters Chemical class 0.000 claims 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 150000003464 sulfur compounds Chemical class 0.000 claims 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N Ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 125000005265 dialkylamine group Chemical group 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 150000001450 anions Chemical class 0.000 abstract 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract 1
- 230000005494 condensation Effects 0.000 abstract 1
- 238000009833 condensation Methods 0.000 abstract 1
- 238000010511 deprotection reaction Methods 0.000 abstract 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 abstract 1
- 230000001404 mediated Effects 0.000 abstract 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 abstract 1
- 150000003577 thiophenes Chemical class 0.000 abstract 1
Abstract
A group of 2-amino-3-aroyl-benzo[β]thiophenes are prepared by preparing an α-hydroxy thioacetamide by silyl mediated condensation of an aldehyde with an anion of dialkylamino thioformamide, cyclizing the α-hydroxy thioamide, and subsequently acylating the benzo[β]thiophene to yield the 2-amino-3-aryl derivative. These compounds may be treated with suitable phenyl Grignard reagents, and after deprotection, yield 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[β]thiophene.
Claims
1. A process for preparing an α-hydroxythioacetamide of the formula:
OH
wherein R, Rβ and Rg independently represent C^-Cg alkyl; comprising: (a) reacting an alkyl imidate of the formula:
OH
where R' ' ' is C-^-Cg alkyl, with a sulfur compound to yield a thioester of the formula:
R.„
(b) reacting the thioester with a dialkylamine of the formula NRgRg to yield the α-hydroxythioacetamide; said steps being conducted without isolation or purification of the thioester.
2. A process according to Claim 1, wherein R is methyl.
3. A process according to Claim 1, wherein R8 and R9 are methyl.
4. A process according to Claim 1 , wherein R' ' ' is ethyl.
5. A process according to Claim 1, wherein the protic acid is HC1.
6. A process according to Claim 1, wherein the sulfur compound is ethanethiol.
7. The process as claimed in Claim 1 further comprising cyclizing the α-hydroxythioacetamide to form a 2- amino benzo[β]thiophene; acylating the benzothiophene at the 3-position; reacting the resulting 3-acylated benzothiophene to produce a 2-(4-protected hydroxyphenyl) 3-acylated benzothiophene; and deprotecting to provide a compound of the formula:
wherein R" is piperidinoethoxy, pyrrolidinoethoxy, or methyl-pyrrolidino ethoxy.
35
STATEMENT UNDER ARTICLE 19
The International Search Report for the captioned application was mailed 12 October 1995. In accordance with Article 19 of the Patent Cooperation Treaty, applicant submits herewith four replacement sheets (pages 30-33) for pages 30-32 of the International Application as originally filed. New claim 7 has been added and is directed to a method for producing a 6-hydroxy-2-(4-hydroxyphenyl)-3-benzoyl)benzo[/3]thiophene compound. Support for new claim 7 is found throughout the application and in particular on page 6, lines 26-29, Scheme I on page 9, page 15, lines 12-18, and Example 11 on page 29.
Applicant submits herewith replacement sheets (pages 30-33) for pages 30-32 of the International Application as originally filed. The abstract is unchanged except for the page number.
Priority Applications (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BR9507968A BR9507968A (en) | 1994-06-10 | 1995-06-07 | Production of hydroxyacetamides and their use in the synthesis of benzothiophenes |
| MX9606177A MX9606177A (en) | 1995-06-07 | 1995-06-07 | Production of hydroxythioacetamides and use thereof in the synthesis of benzothiophenes. |
| DK95923804T DK0764150T3 (en) | 1994-06-10 | 1995-06-07 | Preparation of hydroxythioacetamides and their use in the synthesis of benzothiophenes |
| DE69513022T DE69513022T2 (en) | 1994-06-10 | 1995-06-07 | METHOD FOR PRODUCING HYDROXYTHIOACETAMIDES AND THE USE THEREOF FOR SYNTHESIS OF BENZOTHIOPHENES |
| AU28236/95A AU2823695A (en) | 1994-06-10 | 1995-06-07 | Production of hydroxythioacetamides and use thereof in the synthesis of benzothiophenes |
| SI9530337T SI0764150T1 (en) | 1994-06-10 | 1995-06-07 | Production of hydroxythioacetamides and use thereof in the synthesis of benzothiophenes |
| EP95923804A EP0764150B1 (en) | 1994-06-10 | 1995-06-07 | Production of hydroxythioacetamides and use thereof in the synthesis of benzothiophenes |
| JP8502366A JPH10503175A (en) | 1994-06-10 | 1995-06-07 | Preparation of hydroxythioacetamide and its use in the synthesis of benzothiophene |
| FI964854A FI964854A (en) | 1994-06-10 | 1996-12-04 | Preparation of hydroxythioacetamides and their use in the synthesis of benzothiophenes |
| GR20000400106T GR3032409T3 (en) | 1994-06-10 | 2000-01-19 | Production of hydroxythioacetamides and use thereof in the synthesis of benzothiophenes |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/258,641 | 1994-06-10 | ||
| US08/258,641 US5420349A (en) | 1994-06-10 | 1994-06-10 | 2-amino-3-aroyl-benzo[β]thiophenes and methods for preparing and using same to produce 6-hydroxy-2-(4-hydroxyphenyl)-3-]benzo[4-(2-aminoethoxy)-benzoyl[β]thiophenes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1995034536A1 WO1995034536A1 (en) | 1995-12-21 |
| WO1995034536B1 true WO1995034536B1 (en) | 1996-01-11 |
Family
ID=22981480
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US1995/007399 WO1995034536A1 (en) | 1994-06-10 | 1995-06-07 | Production of hydroxythioacetamides and use thereof in the synthesis of benzothiophenes |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US5420349A (en) |
| EP (1) | EP0764150B1 (en) |
| JP (1) | JPH10503175A (en) |
| AT (1) | ATE186050T1 (en) |
| AU (1) | AU2823695A (en) |
| BR (1) | BR9507968A (en) |
| CA (1) | CA2192096A1 (en) |
| DE (1) | DE69513022T2 (en) |
| DK (1) | DK0764150T3 (en) |
| ES (1) | ES2139222T3 (en) |
| FI (1) | FI964854A (en) |
| GR (1) | GR3032409T3 (en) |
| HU (3) | HU217822B (en) |
| WO (1) | WO1995034536A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5466810A (en) * | 1994-06-10 | 1995-11-14 | Eli Lilly And Company | 2-amino-3-aroyl-benzo[β]thiophenes and methods for preparing and using same to produce 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-aminoethoxy)-benzoyl]benzo[β]thiophenes |
| CA2214196A1 (en) * | 1996-09-26 | 1998-03-26 | Eli Lilly And Company | Benzo[b]indeno[2,1-d]thiophene compounds, intermediates, processes, compositions and methods |
| CA2287920A1 (en) * | 1997-04-30 | 1998-11-05 | Eli Lilly And Company | Intermediates and a process for preparing benzo¬b|thiophenes |
| CA2499819A1 (en) | 2002-09-30 | 2004-04-08 | A/S Gea Farmaceutisk Fabrik | Novel raloxifene acid addition salts and/or solvates thereof, improved method for purification of said raloxifene acid addition salts and/or solvates thereof and pharmaceutical compositions comprising these |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4133814A (en) * | 1975-10-28 | 1979-01-09 | Eli Lilly And Company | 2-Phenyl-3-aroylbenzothiophenes useful as antifertility agents |
| US4418068A (en) * | 1981-04-03 | 1983-11-29 | Eli Lilly And Company | Antiestrogenic and antiandrugenic benzothiophenes |
| US4380635A (en) * | 1981-04-03 | 1983-04-19 | Eli Lilly And Company | Synthesis of acylated benzothiophenes |
-
1994
- 1994-06-10 US US08/258,641 patent/US5420349A/en not_active Expired - Lifetime
-
1995
- 1995-06-07 AU AU28236/95A patent/AU2823695A/en not_active Abandoned
- 1995-06-07 EP EP95923804A patent/EP0764150B1/en not_active Expired - Lifetime
- 1995-06-07 DE DE69513022T patent/DE69513022T2/en not_active Expired - Fee Related
- 1995-06-07 CA CA002192096A patent/CA2192096A1/en not_active Abandoned
- 1995-06-07 ES ES95923804T patent/ES2139222T3/en not_active Expired - Lifetime
- 1995-06-07 HU HU9802648A patent/HU217822B/en not_active IP Right Cessation
- 1995-06-07 WO PCT/US1995/007399 patent/WO1995034536A1/en active IP Right Grant
- 1995-06-07 JP JP8502366A patent/JPH10503175A/en not_active Ceased
- 1995-06-07 BR BR9507968A patent/BR9507968A/en not_active Application Discontinuation
- 1995-06-07 HU HU9603404A patent/HU213834B/en not_active IP Right Cessation
- 1995-06-07 AT AT95923804T patent/ATE186050T1/en not_active IP Right Cessation
- 1995-06-07 DK DK95923804T patent/DK0764150T3/en active
- 1995-06-07 HU HU9603403A patent/HU216272B/en not_active IP Right Cessation
-
1996
- 1996-12-04 FI FI964854A patent/FI964854A/en unknown
-
2000
- 2000-01-19 GR GR20000400106T patent/GR3032409T3/en not_active IP Right Cessation
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