EP1001919A1 - Efficient synthesis of cyclopropylacetylene - Google Patents
Efficient synthesis of cyclopropylacetyleneInfo
- Publication number
- EP1001919A1 EP1001919A1 EP98937309A EP98937309A EP1001919A1 EP 1001919 A1 EP1001919 A1 EP 1001919A1 EP 98937309 A EP98937309 A EP 98937309A EP 98937309 A EP98937309 A EP 98937309A EP 1001919 A1 EP1001919 A1 EP 1001919A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- compound
- represented
- alkyl
- base
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
- C07C13/02—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
- C07C13/04—Monocyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with a three-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
Definitions
- a key step in the synthesis of the reverse transcriptase inhibitor, (-)-6-chloro-4-cyclopropylenthynyl-4-triflouromethyl- 1 ,4- dihydro-2H-3,l-benzoxazin-2-one, also known as DMP-266, is the chiral addition to the 2-flouromethylcarbonyl-4-choloroanaline using cyclopropyl acetylene as a nucleophile, a chiral additive, a non-chiral additive, and an organic.
- the instant invention discloses a more efficient process for the synthesis of this important substrate.
- the present invention relates to a process for the preparation of cyclopropyl acetylene (CPA), represented by formula I:
- X is H, halo, CF 3 , or C-_ 6 alkyl
- each R is independently a C,_ 6 alkyl and X is described above;
- the instant invention relates to a process for the preparation of cyclopropyl acetylene (CPA), represented by formula I:
- X is H, halo, CF 3 , or C-_ 6 alkyl
- the base employed is an alkyl lithium such as phenyl lithium, Butyl lithium (BuLi) or a potassium alkyl such potassium methyl and the like , preferably BuLi and the silylating agent employed is selected from the group consisting of trialkylsilylchlorides, triakylsilyliodides and triflates such as trimethylsilylchloride, triethylsilylchloride, t-butyldimethylsilyl chloride, t-butyldiphenylsilylchloride, trimethylsilyltriflate, t- butyldimethylsilyltriflate, triethylsilyltriflate, triethylsilyliodide and the like, preferably trimethylsilylchloride (TMSC1).
- TMSC1 trimethylsilylchloride
- the solution of thioanisole consisting of thioanisole and a protic solvent such as tetrahydrofuran (THF), is cooled to a temperature of about -100°C to about -60°C, preferably - 95°C to about -70°C before contact with the strong base.
- the solution is warmed to a temperature of about -5°C to about 5°C, preferably about -2°C to about 1°C for approximately 10 minutes to about one hour and then cooled to a temperature of about -100°C to about -60°C preferably - 95°C to about -70°C before contact with the silylating agent.
- the mixture is warmed to a temperature of about - 5°C to about 5°C, preferably about -2°C to about 1°C for approximately 10 minutes to about one hour.
- the base employed is an alkyl lithium such as phenyl lithium, Butyl lithium (BuLi) or a potassium alkyl such potassium methyl and the like , preferably BuLi.
- the solution of Compound III is cooled to a temperature of about - 100°C to about -60°C, preferably - 95°C to about -70°C before contact with compound IV.
- Compound V and VI are then reacted in the presence of potassium diaminopropane (KAPA) to yield the desired product, cyclopropyl acetylene (CPA).
- KAPA potassium diaminopropane
- alkyl relates to lower alkyls such as methyl, ethyl, isopropyl, butyl, propyl and the like.
- halo relates to fluoro, chloro, iodo and bromo.
- CPA can be isolated, after aqueous quench of the reaction, by extraction into an organic solvent, such a s hexane or toluene.
- CPA can be isolated and purified by distillation.
- KAPA may be generated from KH and diamino propane by methods known in the art.
- Compound IV is cyclopropyl carboxaldehyde.
- the present invention is embodied by the following non- limiting example.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
Claims
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US5486097P | 1997-08-06 | 1997-08-06 | |
US54860P | 1997-08-06 | ||
GB9800464 | 1998-01-09 | ||
GBGB9800464.1A GB9800464D0 (en) | 1998-01-09 | 1998-01-09 | Efficient synthesis of cycloproplacetylene |
PCT/US1998/015957 WO1999007657A1 (en) | 1997-08-06 | 1998-08-03 | Efficient synthesis of cyclopropylacetylene |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1001919A1 true EP1001919A1 (en) | 2000-05-24 |
EP1001919A4 EP1001919A4 (en) | 2000-10-11 |
Family
ID=26312923
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP98937309A Ceased EP1001919A4 (en) | 1997-08-06 | 1998-08-03 | Efficient synthesis of cyclopropylacetylene |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1001919A4 (en) |
JP (1) | JP2001513518A (en) |
AU (1) | AU738790B2 (en) |
CA (1) | CA2298835A1 (en) |
WO (1) | WO1999007657A1 (en) |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5519021A (en) * | 1992-08-07 | 1996-05-21 | Merck & Co., Inc. | Benzoxazinones as inhibitors of HIV reverse transcriptase |
US5663467A (en) * | 1995-01-23 | 1997-09-02 | Merck & Co., Inc. | Synthesis of cyclopropylacetylene |
US5633405A (en) * | 1995-05-25 | 1997-05-27 | Merck & Co., Inc. | Asymmetric synthesis of (-)-6-chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxanzin-2-one |
-
1998
- 1998-08-03 CA CA002298835A patent/CA2298835A1/en not_active Abandoned
- 1998-08-03 AU AU86049/98A patent/AU738790B2/en not_active Ceased
- 1998-08-03 EP EP98937309A patent/EP1001919A4/en not_active Ceased
- 1998-08-03 JP JP2000507195A patent/JP2001513518A/en active Pending
- 1998-08-03 WO PCT/US1998/015957 patent/WO1999007657A1/en not_active Application Discontinuation
Non-Patent Citations (2)
Title |
---|
No further relevant documents disclosed * |
See also references of WO9907657A1 * |
Also Published As
Publication number | Publication date |
---|---|
EP1001919A4 (en) | 2000-10-11 |
CA2298835A1 (en) | 1999-02-18 |
AU8604998A (en) | 1999-03-01 |
AU738790B2 (en) | 2001-09-27 |
WO1999007657A1 (en) | 1999-02-18 |
JP2001513518A (en) | 2001-09-04 |
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Legal Events
Date | Code | Title | Description |
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PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
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17P | Request for examination filed |
Effective date: 20000306 |
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RIC1 | Information provided on ipc code assigned before grant |
Free format text: 7C 07C 13/04 A, 7C 07C 1/32 B, 7C 07C 4/00 - |
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17Q | First examination report despatched |
Effective date: 20010618 |
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Free format text: ORIGINAL CODE: EPIDOS AGRA |
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STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN REFUSED |
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18R | Application refused |
Effective date: 20030418 |