WO1999051573A2 - Process for the preparation of a 2-oxopyrrolidine compound - Google Patents
Process for the preparation of a 2-oxopyrrolidine compound Download PDFInfo
- Publication number
- WO1999051573A2 WO1999051573A2 PCT/US1999/004292 US9904292W WO9951573A2 WO 1999051573 A2 WO1999051573 A2 WO 1999051573A2 US 9904292 W US9904292 W US 9904292W WO 9951573 A2 WO9951573 A2 WO 9951573A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- formula
- acetonitrile
- solution
- mole
- Prior art date
Links
- KWZUPJYTFLDYSH-JTQLQIEISA-N N[C@@H](CCN1c(cc2)ccc2C#N)C1=O Chemical compound N[C@@H](CCN1c(cc2)ccc2C#N)C1=O KWZUPJYTFLDYSH-JTQLQIEISA-N 0.000 description 2
- XYVHYQRCFGWXLF-UHFFFAOYSA-N CC(C(CCBr)Br)=O Chemical compound CC(C(CCBr)Br)=O XYVHYQRCFGWXLF-UHFFFAOYSA-N 0.000 description 1
- WPIZASJVDDJWKA-UHFFFAOYSA-N N#Cc(cc1)ccc1N(CCC1Br)C1=O Chemical compound N#Cc(cc1)ccc1N(CCC1Br)C1=O WPIZASJVDDJWKA-UHFFFAOYSA-N 0.000 description 1
- WMFAHRZMHCTIFC-UHFFFAOYSA-N N#Cc(cc1)ccc1NC(C(CCBr)Br)=O Chemical compound N#Cc(cc1)ccc1NC(C(CCBr)Br)=O WMFAHRZMHCTIFC-UHFFFAOYSA-N 0.000 description 1
- ZZSRGROJYJYZJA-ABLWVSNPSA-N N[C@@H](CCC1CCc(cc2)ccc2C#N)C1=O Chemical compound N[C@@H](CCC1CCc(cc2)ccc2C#N)C1=O ZZSRGROJYJYZJA-ABLWVSNPSA-N 0.000 description 1
- YBAZINRZQSAIAY-UHFFFAOYSA-N Nc(cc1)ccc1C#N Chemical compound Nc(cc1)ccc1C#N YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 1
- LTJVIGPJZUWMNN-UHFFFAOYSA-N O=C(C(CCCl)Br)Br Chemical compound O=C(C(CCCl)Br)Br LTJVIGPJZUWMNN-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-SSDOTTSWSA-N O[C@@H](C(O)=O)c1ccccc1 Chemical compound O[C@@H](C(O)=O)c1ccccc1 IWYDHOAUDWTVEP-SSDOTTSWSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
Definitions
- the present invention is directed to a process for the preparation of (3S)-3-amino-1-(4-cyanophenyl)-2-oxopyrrolidine hydrochloride which is useful as an intermediate in the preparation of a GP llb/llla antagonist compound.
- This compound is useful in the preparation of the platelet aggregation inhibitor, GP lib/Ill antagonist, orbofiban.
- Orbofiban is an antiplatelet pharmaceutical agent of the formula
- R is a protecting group such as t-butoxycarbonyl (BOC) or carbobenzyloxy (CBZ) and Z is H, -CN, -CONH 2 or C0 2 alkyl from a methionine analog of the formula
- Ri is hydrogen, alkyl, aryl, arylalkyl, a heterocyclyl radical containing 1 to 3 heteroatoms or a heterocyclylalkyl and R 6 is selected from alkyl, aryl, arylalkyl or acyloxymethyl.
- the process disclosed herein provides an efficient, scalable and cost effective synthesis of the intermediate (3S)-3-amino-1 -(4-cyanophenyl)-2- oxopyrrolidine hydrochloride.
- the present process is advantageous over the process disclosed in U.S. 5,484,946 in that the process disclosed in U.S. 5,484,946 involved the coupling and acylization of a methionine residue which generated a great amount of dimethylsulfide.
- the cost associated with the waste handling of this by-product made the process unsuitable on a manufacturing scale.
- the presently disclosed process was designed to overcome this problem.
- SUMMARY OF THE INVENTION The present invention is directed to producing a lactam of the formula
- X is Cl and Y is Br or X is Br and Y is Br with 4-aminobenzonitrile in THF or ACN, in the presence of propylene oxide or cyclohexene oxide or in the presence of a base selected from the group consisting of Na 2 HP0 4 , Na 3 P0 4 , K 2 C0 3 , Na 2 C0 3 and NEt 3 to produce a compound of the formula
- the invention herein relates to the process set forth above. More specifically the invention relates to the detailed Scheme set forth hereafter and the description and examples which follow.
- Solvents such as methanol, ethanol or isopropanol (IPA) at their respective reflux temperature are suitable for achieving this type of transformation.
- IPA isopropanol
- the preferred results were found with IPA as the solvent, which gave the shortest reaction time and highest ee and salicylaldehyde, as it is easier to handle and more economic than 3,5- dichlorosalicylaldehyde.
- An excess of MA and a small amount of water results in shorter reaction time and higher optical purity of the isolated salt 4.
- the dynamic resolution which follows was found to be ineffective if a small amount of water was not included in the reaction.
- the preferred conditions (IPA at reflux temperature 3.25% H 2 0, 7.75% excess MA); resulted in a high yield (78%) and high ee (>96%).
- HPLC high performance liquid chromatography
- IPA isopropanol
- Na 2 HPO 4 disodium phosphate
- Na 3 PO 4 sodium phosphate
- HP-1 column crosslinked methyl siloxane
- length 10 m
- ID 0.53 mm
- film thickness 2.65 micron
- phase ratio 50, initial time: 2 minutes, initial temperature: 50°C, injector temperature: 180°C, detector temperature: 250°C, rate: 15°C/minute, final temperature: 170°C, final time: 0 minutes, run time: 10 minutes
- injector volume 1 mL.
- Preparation of methyl 2-bromo-4-chlorobutyrate BCBB 100g, 0.37mole
- MeOH 100 mL
- 2,4-Dibromobutyryl bromide (BBBB, 12.13 g, 0.039 mole) was added via an addition funnel to a cold (5°C), well stirred slurry of 4-aminobenzonitrile (4-ABN, 4.0 g, 0.034 mole), Na 3 PO 4 (3.05 g, 0.019 mole) and acetonitrile (42 mL) while maintaining a temperature below 30°C during the addition.
- the addition funnel was rinsed with acetonitrile (2 mL).
- K 2 CO 3 (9.36 g, 0.069 mole) was added via an addition funnel while maintaining the reaction temperature below 30°C.
- the mixture was held at 22°C and stirred for 2 hours at this temperature to form a homogeneous solution.
- the THF was removed under reduced pressure and toluene (250 mL) was added. After precipitation, the mixture was cooled to 5°C and stirred for 16 hours at this temperature, filtered in a pressure filter, washed with toluene (50 mL) and dried under a flow of nitrogen and vacuum in the filter for 3 hours to afford the desired material (49.3 g).
- the mother liquor was concentrated to dryness (oily solid), taken up in toluene (125 mL) and THF (20 mL), recrystallized by heating to 50°C (homogeneous solution ) and cooled slowly to 2°C. The solution was filtered and the cake washed with toluene to afford additional material (15.09 g, total yield 72%).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pyrrole Compounds (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99916116A EP1068183A2 (en) | 1998-04-08 | 1999-04-06 | Process for the preparation of a 2-oxopyrrolidine compound |
AU34496/99A AU3449699A (en) | 1998-04-08 | 1999-04-06 | Process for the preparation of a 2-oxopyrrolidine compound |
JP2000542294A JP2002510674A (en) | 1998-04-08 | 1999-04-06 | Method for producing 2-oxopyrrolidine compound |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US8107598P | 1998-04-08 | 1998-04-08 | |
US60/081,075 | 1998-04-08 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1999051573A2 true WO1999051573A2 (en) | 1999-10-14 |
WO1999051573A3 WO1999051573A3 (en) | 1999-12-02 |
Family
ID=22161945
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/004292 WO1999051573A2 (en) | 1998-04-08 | 1999-04-06 | Process for the preparation of a 2-oxopyrrolidine compound |
Country Status (5)
Country | Link |
---|---|
US (1) | US5986107A (en) |
EP (1) | EP1068183A2 (en) |
JP (1) | JP2002510674A (en) |
AU (1) | AU3449699A (en) |
WO (1) | WO1999051573A2 (en) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994022820A1 (en) * | 1993-03-31 | 1994-10-13 | G.D. Searle & Co. | 1-amidinophenyl-pyrrolidones piperidinones azetinones as platelet aggregation inhibitors |
WO1996017827A1 (en) * | 1994-12-05 | 1996-06-13 | G.D. Searle & Co. | PROCESS FOR THE PREPARATION OF AMIDINO PHENYL PYRROLIDINE β-ALANINE UREA ANALOGS |
WO1996037466A1 (en) * | 1995-05-26 | 1996-11-28 | Zeneca Limited | Process for the preparation of (thio-)carbonic/carbamic acid 2-pyrrolidonyl-3-esters, thio esters and amides |
-
1999
- 1999-03-02 US US09/261,303 patent/US5986107A/en not_active Expired - Fee Related
- 1999-04-06 JP JP2000542294A patent/JP2002510674A/en active Pending
- 1999-04-06 EP EP99916116A patent/EP1068183A2/en not_active Withdrawn
- 1999-04-06 AU AU34496/99A patent/AU3449699A/en not_active Abandoned
- 1999-04-06 WO PCT/US1999/004292 patent/WO1999051573A2/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994022820A1 (en) * | 1993-03-31 | 1994-10-13 | G.D. Searle & Co. | 1-amidinophenyl-pyrrolidones piperidinones azetinones as platelet aggregation inhibitors |
WO1996017827A1 (en) * | 1994-12-05 | 1996-06-13 | G.D. Searle & Co. | PROCESS FOR THE PREPARATION OF AMIDINO PHENYL PYRROLIDINE β-ALANINE UREA ANALOGS |
WO1996037466A1 (en) * | 1995-05-26 | 1996-11-28 | Zeneca Limited | Process for the preparation of (thio-)carbonic/carbamic acid 2-pyrrolidonyl-3-esters, thio esters and amides |
Non-Patent Citations (1)
Title |
---|
P.-J. COLSON ET AL.: TETRAHEDRON: ASYMMETRY, vol. 9, 1998, pages 2587-2593, XP002117116 OXFORD GB * |
Also Published As
Publication number | Publication date |
---|---|
AU3449699A (en) | 1999-10-25 |
JP2002510674A (en) | 2002-04-09 |
EP1068183A2 (en) | 2001-01-17 |
US5986107A (en) | 1999-11-16 |
WO1999051573A3 (en) | 1999-12-02 |
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