WO1997021700A1 - Process for the preparation of an endothelin antagonist - Google Patents
Process for the preparation of an endothelin antagonist Download PDFInfo
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- WO1997021700A1 WO1997021700A1 PCT/US1996/019545 US9619545W WO9721700A1 WO 1997021700 A1 WO1997021700 A1 WO 1997021700A1 US 9619545 W US9619545 W US 9619545W WO 9721700 A1 WO9721700 A1 WO 9721700A1
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- 0 CCCc(cc(*)cc1)c1OC(C(NC)=O)c(cc1)cc2c1OCO2 Chemical compound CCCc(cc(*)cc1)c1OC(C(NC)=O)c(cc1)cc2c1OCO2 0.000 description 4
- FTNJQNQLEGKTGD-UHFFFAOYSA-N C1Oc(cccc2)c2O1 Chemical compound C1Oc(cccc2)c2O1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 description 1
- FWUWIQGHMCDOPH-UHFFFAOYSA-N CC(C(N1CCCC1)=O)OC Chemical compound CC(C(N1CCCC1)=O)OC FWUWIQGHMCDOPH-UHFFFAOYSA-N 0.000 description 1
- YAADWXYUBQRRJJ-UHFFFAOYSA-N CC(C)(COC1=O)C1OC Chemical compound CC(C)(COC1=O)C1OC YAADWXYUBQRRJJ-UHFFFAOYSA-N 0.000 description 1
- RSRQCLOLDFXSEQ-UHFFFAOYSA-N CC(C)c(cc1)ccc1S(=O)=O Chemical compound CC(C)c(cc1)ccc1S(=O)=O RSRQCLOLDFXSEQ-UHFFFAOYSA-N 0.000 description 1
- OWZFULPEVHKEKS-UHFFFAOYSA-N CCOC(C(Cl)=O)=O Chemical compound CCOC(C(Cl)=O)=O OWZFULPEVHKEKS-UHFFFAOYSA-N 0.000 description 1
- ZYJHZYNSHIMYJQ-UHFFFAOYSA-N CCOC(C(c(cc1)cc2c1OCO2)=O)=O Chemical compound CCOC(C(c(cc1)cc2c1OCO2)=O)=O ZYJHZYNSHIMYJQ-UHFFFAOYSA-N 0.000 description 1
- VIIPQXJHKXQJKY-UHFFFAOYSA-N OC(C(c(cc1)cc2c1OCO2)=O)=O Chemical compound OC(C(c(cc1)cc2c1OCO2)=O)=O VIIPQXJHKXQJKY-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- Endothelin is a 21 -amino acid peptide produced by endothelial cells.
- the peptide is secreted not only by endothelial cells but also by tracheal epithelial cells or from kidney cells.
- Endothelin (ET-1 ) has a potent vasoconstrictor effect. The vasoconstricting effect is caused by the binding of endothelin to its receptor on the vascular smooth muscle cells. [Nature, 332, 41 1 -415 ( 1988); FEBS Letters, 231 , 440-444 (1988); Biochem. Biophys. Res. Commun. 154, 868-875 (1988).]
- Endothelin- 1 is one of three recently identified potent vasoconstricting peptides which also includes endothelin-2 (ET-2) and endothelin-3 (ET-3) whose sequences differ from ET- 1 by two and six amino acids, respectively. [TiPS, 13, 103- 108, March 1992.1
- Endothelin was also found to control the release of many physiological substances such as renin, atrial natriuretic peptide, endothelium-derived relaxing factor (EDRF), thromboxane A2, prostacyclin, norepinephrine, angiotensin II and substance P.
- renin atrial natriuretic peptide
- EDRF endothelium-derived relaxing factor
- thromboxane A2 thromboxane A2
- prostacyclin norepinephrine
- angiotensin II angiotensin II and substance P.
- Endothelin receptors are present in high concentration in the peripheral tissues and also in the central nervous system, and cerebral administration of endothelin has been shown to induce behavioral changes in animals, suggesting that endothelin may play an important role in controlling neural functions. [Neuroscience Letters, 97, 276-279 (1989).]
- Endotoxin has been shown to promote the release of endothelin. This finding has suggested that endothelin is an important mediator for endotoxin-induced diseases. [ Biochem. Biophys. Res. Commun. 161, 1220-1227 (1989); and Acta. Physiol. Scand., L37, 317- 318 ( 1989).]
- Endothelin is an endogenous substance which directly or indirectly (through the controlled release of various other endogenous substances) induces sustained contraction of vascular or non-vascular smooth muscles. Its excess production or excess secretion is believed to be one of the factors responsible for hypertension, pulmonary hypertension, Raynaud's disease, bronchial asthma, acute renal failure, myocardial infarction, angina pectoris, arteriosclerosis, cerebral vasospasm and cerebral infarction. See A. M. Doherty, Endothelin: A New Challenge. J. Med. Chem., 35, 1493- 1508 ( 1992).
- Substances which specifically inhibit the binding of endothelin to its receptor are believed to block the physiological effects of endothelin and are useful in treating patients with endothelin related disorders.
- the present invention relates to a stereoselective synthesis of the compound
- This inventions relates to the stereoselective synthesis of
- the synthesis involves the use of a chiral auxiliary to enhance the stereoselectivity of the alkylation step.
- the enantiomeric may be enhanced by recrystallization of a diastereomeric purity of salt.
- This invention relates to a process for the stereoselective synthesis of
- the instant invention relates to a process for the preparation of a compound of the structural formula 1:
- M+ is Na + , K+, or Li + ;
- R a is (Ci -C6)-alkyl, phenyl, or cyclohexyl
- R l 3 is (Cl -C6)-alkyl, phenyl or cyclohexyl;
- R 14 and R 1 - ⁇ are independently: (Cl -Ci ⁇ )-alkyl, or R 14 and R 15 can join together to form a 5- or 6- membered heterocyclic ring selected from the group consisting of: piperadinyl or pyrrolidinyl;
- X is Br, Cl, or I
- step a is selected from the group consisting of sodium, potassium, or lithium carbonate, sodium, potassium, or lithium t-butoxide, sodium, potassium, or lithium t-amylate, sodium, potassium, or lithium hydroxide, or sodium, potassium, or lithium hydride; and the aprotic solvent in step a is selected from the group consisting of: tetrahydrofuran, toluene and dimethylformamide.
- the Lewis acid in the acylating step b is selected from the group consisting of: AICI3, FeCl3, TiCl4, and BF3-etherate; and the organic solvent in the acylating step b is selected from the group consisting of dichloromethane and dichlorobenzenes.
- the base in the hydrolysis step c is selected from the group consisting of: NaOH, KOH, NaOCH3, KOCH3, KOCH2CH3, NaOCH2CH3, KOt-butyl and NaOt- butyl; and the solvent in the hydrolysis step c is selected from the group consisting of: tetrahydrofuran. methanol, ethanoi, t-butanol, dimethylformamide and dimethylsulfoxide.
- step d wherein the chlorinating agent in step d is selected from the group consisting of: oxalyl chloride, SO2CI2, POCI3, PCI3 and PCI5; and the solvent in step d is selected from the group consisting of: tetrahydrofuran, toluene and dimethylformamide.
- the chiral auxiliary in step e is selected from the group consisting of:
- step e is selected from the group consisting of: triethylamine, pyridine and diisopropylethylamine.
- step f is selected from the group consisting of: NaBH4, NaCNBH3 and Na(OAc)3BH; and the solvent in step f is selected from the group consisting of: tetrahydrofuran -water, ethanoi, methanol, dimethylformamide and dimethylsulfoxide.
- halogenating agent in the halogenation step g is selected from the group consisting of: PBr3, CBr4-P(C6H5)3, NBS-DMF, PCI3, CCl4-P(C6H5)3 and NCS- DMF; and the organic solvent in the halogenating step is selected from the group consisting of tetrahydrofuran, dichloromethane and toluene.
- step h wherein the organic solvent in step h is selected from the group consisting of: tetrahydrofuran, toluene and dimethylformamide.
- the inorganic base in the chiral auxiliary hydrolysis step i is selected from the group consisting of: LiOH-H2 ⁇ 2, LiOH, KOH or NaOH; and the aqueous organic solvent mixture in the chiral auxiliary hydrolysis step i is selected from the group consisting of: tetrahydrofuran, toluene-water. dimethylformamide, methanol, ethanoi and t-butanol.
- the chlorinating agent in the acyl chloride formation step j is selected from the group consisting of: oxalyl chloride, SO2CI2, POCI3, PCI3 and PCI5; and the solvent in step j is selected from the group consisting of: tetrahydrofuran, toluene and dimethylformamide.
- the source of ammonia in step k is selected from the group consisting of: NH3(g), aqueous ammonium hydroxide, ammonium chloride-Na2C03 and ammonium chloride-K2C03.
- step 1 wherein the base in step 1 is selected from the group consisting of: NaOt-amyl, KOt-amyl, NaOt- butyl, KOt-butyl, NaH, and KH; and the solvent in step 1 is selected from the group consisting of tetrahydrofuran and toluene.
- step m is selected from the group consisting of: NaOH, KOH and LiOH; and the solvent in step m is selected from the group consisting of: tetrahydrofuran- water.
- step n is selected from HCI, H2SO4 and HNO3.
- organic solvent in step 0 is selected from the group consisting of ethyl acetate, isopropyl acetate, methanol, ethanoi and t-butanol.
- step q is selected from the group consisting of: KOH, KOCH3, KOCH2CH3 and KOt-butyl; and the solvent in step q is selected from the group consisting of: methanol, ethanoi, t-butanol, water, and mixtures therefrom.
- the stereogenic center represented in the instant invention using an asterik is optically enriched in two steps in the instant methodology: 1) the alkylation step using a chiral auxiliary; and 2) a diastereoselective recrystallization.
- the examples are believed to have the stereochemistry indicated.
- the chiral auxiliary and the amine salt used will dictate the isomer which will predominate in the alkylation step and the diastereoisomer which will crystallize out.
- a chiral auxiliary is defined as an easily removable group chiral group which is attached at a position near the site of alkylation and is capable of influencing the direction of nucleophilic attack.
- R a is (Cl -C6)-alkyl, phenyl, or cyclohexyl
- R l 3 is (Ci -C6)-alkyl, phenyl or cyclohexyl; and R ! 4 and R 1 are independently: (C] -Ci ⁇ )-alkyl, or R l 4 and R 1 - ⁇ can join together to form a 5- or 6-membered heterocyclic ring selected from the group consisting of: piperadinyl or pyrrolidinyl.
- alkyl substituents recited above denote straight and branched chain hydrocarbons of the length specified such as methyl, ethyl, isopropyl, isobutyl, neopentyl, isopentyl, etc.
- alkenyl-substituents denote alkyl groups as described above which are modified so that each contains a carbon to carbon double bond such as vinyl, allyl and 2-butenyl.
- Cycloalkyi denotes rings composed of 3 to 8 methylene groups, each of which may be substituted or unsubstituted with other hydrocarbon substituents, and include for example cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl.
- the alkoxy substituent represents an alkyl group as described above attached through an oxygen bridge.
- the heteroaryl is defined as carbazolyl, furyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, purinyl or quinolinyl.
- the synthesis begins with the allylation of readily available methyl-4-hydroxybenzoate (Scheme 1 ).
- the allylated phenol is then thermally rearranged in dichlorobenzene and subsequently hydrogenated to provide the desired Methyl-4-hydroxy-3-n- propylbenzoate in good overall yield.
- the coupling reaction of the sodium salt of methyl-4- hydroxy-3-n-propylbenzoate with the bromide 7 is conducted in THF at -35°C. Under these conditions the reaction requires ⁇ 1 h to go to completion and the product is obtained in 80% yield with a diastereomeric ratio of approximately 90: 10. Running the reaction at higher temperatures accelerates the rate, however, the diastereoselectivity is lower.
- the crude coupling product was treated with lithium hydroperoxide in order to hydrolyze the lactate auxiliary (Scheme 4). Under these conditions, little or no racemization of the chiral center was observed. Saponification using a stronger base such as lithium hyroxide leads to some racemization.
- Diacid 14 is crystallized from methanol and water to provide pure (>99A%, >99% ee) material. Formation of the dipotassium salt of 14 to generate compound I is complicated by the fact that the product forms a variety of different solvates and hydrates. Ultimately, it was found that the MeOH solvate of Compound I crystallized nicely and could be converted to the desired dihydrate through exposure to an atmosphere of moist air. SCHEME 5
- ketoester 3 182 g, 0.82 mole
- methanol 800 ml
- 5N sodium hydroxide 300 ml
- water 300 ml
- the batch was aged for 20 min. during which time a precipitate formed.
- Methylene chloride 500 ml was added and the mixture was acidified to pH 3.0 using concentrated HCI.
- the layers were separated and the organic phase was concentrated in vacua to 100 ml.
- Toluene (300 ml) was added and concentration was continued to a final volume of 300 ml.
- the resulting slurry was aged for l h and filtered.
- the wet cake was washed with hexane and air dried to provide 120 g of ketoacid as a tan solid.
- ketoacid 80 g, 0.41 moles
- methylene chloride 800 ml
- DMF 3 ml
- NMR assay of a small sample indicated ⁇ 5% ketoacid remaining.
- the mixture was aged for lh. The batch was quenched into water (500 ml) and the layers separated. The organic layer was washed with water (500 ml) and then with sat'd sodium bicarbonate (2x300 ml). Concentration in vacuo provided 100 g of product as an oil. The material is used in the next step without purification.
- the mixture was aged for 20 min and then added via a cannula to a solution of the bromide (55.0 g, 0.15 mole) in THF (400 ml) at -35 °C.
- the reaction was aged at -35 °C for 20 h.
- the mixture was poured into a mixture of brine (200 ml), water (200 ml), and ethyl acetate (400 ml). The layers were cut and the organic layer was concentrated in vacua to yield 69.0 g of product as an oil.
- HPLC assay Column: Zorbax Rx-C8 4.6mm x 25cm; solvent: CH3CN:H2 ⁇ (0.1 % H3PO4) 60:40; flow rate: I ml/min; wavelength: 220 nm; column temperature: 25 °C; retention time: major isomer, 20.2 min.; minor isomer 18.8 min.; and bromide, 7.8 min.
- reaction mixture was aged for 30 min, cooled to 0-5 °C and quenched with sat'd aqueous sodium bisulfite (6 1).
- HPLC assay of the product indicated an 88: 12 mixture of diastereomers.
- HPLC assay Column: Zorbax Rx-C8 4.6mm x 25cm; solvent: CH3CN:H2 ⁇ (0.1 % H3PO4) 60:40; flow rate: 1 ml/min; wavelength: 220 nm; column temperature: 25 Q C; retention time: product. 5.6 min.; statring material, 6.9 min.
- the diamine salt (800 g) was dissolved in methanol (7 1) and water (6 1) was added over 30 min. Methanol ( 1.5 1) was removed by vacuum distillation at 20-30 °C and water (5 1) was added to the resulting slurry over 30 min. The slurry was aged for 30 min and filtered. The product was dried under a nitrogen sweep for 18 h to provide 430 g of product as a off- white solid. HPLC assay under the same conditions indicated >99%ee.
- HPLC assay indicated the material to be >99 A% pure.
- Chiral HPLC assay indicated the material to be > 99% ee.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP96944270A EP0873334A1 (en) | 1995-12-12 | 1996-12-09 | Process for the preparation of an endothelin antagonist |
JP9522139A JP2000502998A (en) | 1995-12-12 | 1996-12-09 | Method for producing endothelin antagonist |
AU14122/97A AU703486B2 (en) | 1995-12-12 | 1996-12-09 | Process for the preparation of an endothelin antagonist |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US875695P | 1995-12-12 | 1995-12-12 | |
US60/008,756 | 1995-12-12 | ||
GBGB9603243.8A GB9603243D0 (en) | 1996-02-16 | 1996-02-16 | Process for the preparation of an endothelin antagonist |
GB9603243.8 | 1996-02-16 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997021700A1 true WO1997021700A1 (en) | 1997-06-19 |
Family
ID=26308722
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/019545 WO1997021700A1 (en) | 1995-12-12 | 1996-12-09 | Process for the preparation of an endothelin antagonist |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0873334A1 (en) |
JP (1) | JP2000502998A (en) |
AU (1) | AU703486B2 (en) |
CA (1) | CA2238976A1 (en) |
WO (1) | WO1997021700A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1229031A1 (en) * | 1999-10-13 | 2002-08-07 | Ube Industries, Ltd. | Process for the preparation of 3,4-methylenedioxy-mandelic acid |
US7091230B2 (en) | 2001-02-09 | 2006-08-15 | Merck & Co., Inc. | 2-aryloxy-2-arylalkanoic acids for diabetes and lipid disorders |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0617001A1 (en) * | 1993-03-19 | 1994-09-28 | Merck & Co. Inc. | Phenoxyphenylacetic acid derivatives |
WO1996004905A1 (en) * | 1994-08-08 | 1996-02-22 | Merck & Co., Inc. | Phenoxyphenylacetic acid derivatives |
WO1996008486A1 (en) * | 1994-09-14 | 1996-03-21 | Merck & Co., Inc. | Endothelin antagonists bearing 5-membered heterocyclic amides |
-
1996
- 1996-12-09 JP JP9522139A patent/JP2000502998A/en active Pending
- 1996-12-09 EP EP96944270A patent/EP0873334A1/en not_active Ceased
- 1996-12-09 WO PCT/US1996/019545 patent/WO1997021700A1/en not_active Application Discontinuation
- 1996-12-09 AU AU14122/97A patent/AU703486B2/en not_active Ceased
- 1996-12-09 CA CA 2238976 patent/CA2238976A1/en not_active Abandoned
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0617001A1 (en) * | 1993-03-19 | 1994-09-28 | Merck & Co. Inc. | Phenoxyphenylacetic acid derivatives |
WO1996004905A1 (en) * | 1994-08-08 | 1996-02-22 | Merck & Co., Inc. | Phenoxyphenylacetic acid derivatives |
WO1996008486A1 (en) * | 1994-09-14 | 1996-03-21 | Merck & Co., Inc. | Endothelin antagonists bearing 5-membered heterocyclic amides |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1229031A1 (en) * | 1999-10-13 | 2002-08-07 | Ube Industries, Ltd. | Process for the preparation of 3,4-methylenedioxy-mandelic acid |
EP1229031A4 (en) * | 1999-10-13 | 2003-04-16 | Ube Industries | Process for the preparation of 3,4-methylenedioxy-mandelic acid |
KR100721598B1 (en) * | 1999-10-13 | 2007-05-25 | 우베 고산 가부시키가이샤 | Process for the preparation of 3,4-methylenedioxy-mandelic acid |
US7091230B2 (en) | 2001-02-09 | 2006-08-15 | Merck & Co., Inc. | 2-aryloxy-2-arylalkanoic acids for diabetes and lipid disorders |
US7495020B2 (en) | 2001-02-09 | 2009-02-24 | Merck & Co., Inc. | 2-aryloxy-2-arylalkanoic acids for diabetes and lipid disorders |
Also Published As
Publication number | Publication date |
---|---|
CA2238976A1 (en) | 1997-06-19 |
AU1412297A (en) | 1997-07-03 |
AU703486B2 (en) | 1999-03-25 |
EP0873334A1 (en) | 1998-10-28 |
JP2000502998A (en) | 2000-03-14 |
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