AU728441B2

AU728441B2 - Endothelin intermediates by asymmetric conjugate addition reaction using a chiral additive

Info

Publication number: AU728441B2
Application number: AU59089/98A
Authority: AU
Inventors: Richard D Tillyer; David M Tschaen; Feng Xu
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1997-01-14
Filing date: 1998-01-09
Publication date: 2001-01-11
Anticipated expiration: 2018-01-09
Also published as: TW432028B; WO1998030543A1; CN1243509A; PL334318A1; HRP980001A2; BR9806875A; AU5908998A; EA199900661A1; EA002056B1; NZ336220A; CA2277161A1; EP0973742A1; YU30499A; JP2000507969A; SK93499A3; KR20000070085A

Description

WO 98/30543 PCT/US98/00263 1 -1- ENDOTHELIN INTERMEDIATES BY ASYMMETRIC CONJUGATE ADDITION REACTION USING A CHIRAL

ADDITIVE

BACKGROUND OF THE INVENTION The present invention relates to novel key intermediates in the synthesis of an endothelin antagonist and the method for preparing these key intermediates of formula

I.

The compound possessing a high affinity for at least one of two receptor subtypes, are responsible for the dilation of smooth muscle, such as blood vessels or in the trachea. The endothelin antagonist compounds provide a potentially new therapeutic target, particularly for the treatment of hypertension, pulmonary hypertension, Raynaud's disease, acute renal failure, myocardial infarction, angina pectoris, cerebral infarction, cerebral vasospasm, arteriosclerosis.

asthma, gastric ulcer, diabetes, restenosis, prostatauxe endotoxin shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation, and/or cyclosporin-induced renal failure or hypertension.

Endothelin is a polypeptide composed of amino acids, and it is produced by vascular endothelial cells of human or pig. Endothelin has a potent vasoconstrictor effect and a sustained and potent pressor action (Nature, 332, 411-415 (1988)).

Three endothelin isopeptides (endothelin-1, endothelin-2 and endothelin-3), which resemble one another in structure, exist in the bodies of animals including human, and these peptides have vasoconstriction and pressor effects (Proc. Natl. Acad, Sci, USA, 86 2863-2867 (1989)).

As reported, the endothelin levels are clearly elevated in the blood of patients with essential hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's disease, diabetes or atherosclerosis, or in the washing fluids of the respiratory tract or the blood of patients with asthmaticus as compared with normal levels (Japan, J. Hypertension, 12, 79, (1989), J. Vascular medicine Biology, 2, 207 (1990), Diabetologia, 33, 306-310 (1990), J. Am. Med.

SUBSTITUTE SHEET rule 26) WO 98/30543 PCT/US98/00263 -2- Association, 264, 2868 (1990), and The Lancet, ii, 747-748 (1989) and ii, 1144-1147 (1990)).

Further, an increased sensitivity of the cerebral blood vessel to endothelin in an experimental model of cerebral vasospasm (Japan. Soc. Cereb. Blood Flow Metabol., 1, 73 (1989)), an improved renal function by the endothelin antibody in an acute renal failure model Clin, invest., 83, 1762-1767 (1989), and inhibition of gastric ulcer development with an endothelin antibody in a gastric ulcer model (Extract of Japanese Society of Experimental Gastric Ulcer. (1991)) have been reported. Therefore, endothelin is assumed to be one of the mediators causing acute renal failure or cerebral vasospasm following subarachnoid hemorrhage.

Further, endothelin is secreted not only by endothelial cells but also by tracheal epithelial cells or by kidney cells (FEBS Letters, 255, 129-132 (1989), and FEBS Letters, 249, 42-46 (1989)).

Endothelin was also found to control the release of physiologically active endogenous substances such as renin, atrial natriuretic peptide, endothelium-derived relaxing factor (EDRF), thromboxane A2, prostacyclin, noradrenaline, angiotensin II and substance P (Biochem. Biophys, Res. Commun., 157, 1164-1168 (1988); Biochem. Biophys, Res. Commun., 155, 20 167-172 (1989); Proc. Natl. Acad. Sci. USA, 85 1 9797-9800 (1989); J. Cardiovasc.

Pharmacol., 13, S89-S92 (1989); Japan. J. Hypertension, 12, 76 (1989) and Neuroscience Letters, 102, 179-184 (1989)). Further, endothelin causes contraction of the smooth muscle of gastrointestinal tract and the uterine smooth muscle (FEBS Letters, 247, 337-340 (1989); Eur. J.

Pharmacol., 154, 227-228 (1988); and Biochem. Biophys Res.

Commun., 159, 317-323 (1989)). Further, endothelin was found to promote proliferation of rat vascular smooth muscle cells, suggesting a possible relevance to the arterial hypertrophy (Atherosclerosis, 78, 225- 228 (1989)). Furthermore, since the endothelin receptors are present in a high density not only in the peripheral tissues but also in the central nervous system, and the cerebral administration of endothelin induces a behavioral change in animals, endothelin is likely to play an important SUBSTITUTE SHEET rule 26) WO 98/30543 PCT/US98/00263 -3role for controlling nervous functions (Neuroscience Letters, 97, 276- 279 (1989)). Particularly, endothelin is suggested to be one of mediators for pain (Life Sciences, 49, PL61-PL65 (1991)).

Internal hyperplastic response was induced by rat carotid artery balloon endothelial denudation. Endothelin causes a significant worsening of the internal hyperplasia Cardiovasc. Pharmacol., 9, 355 359 371 373(1993)). These data support a role of endothelin in the phathogenesis of vascular restenosis. Recently, it has been reported that both ETA and ETB receptors exist in the human prostate and endothelin produces a potent contraction of it. These results suggest the possibility that endothelin is involved in the pathophysiology of benign prostatic hyperplasia Urology, 151, 763 766(1994), Molecular Pharmocol., 45, 306 311(1994)).

On the other hand, endotoxin is one of potential candidates to promote the release of endothelin. Remarkable elevation of the endothelin levels in the blood or in the culture supernatant of endothelial cells was observed when endotoxin was exogenously administered to animals or added to the culture endothelial cells, respectively. These findings suggest that endothelin is an important mediator for endotoxininduced diseases (Biochem. Biophys. Commun., 161, 1220-1227 (1989); and Acta Physiol. Scand., 137, 317-318 (1989)).

Further, it was reported that cyclosporin remarkably increased endothelin secretion in the renal cell culture (LLC-PKL cells) (Eur. J. Pharmacol., 180, 191-192 (1990)). Further, dosing of cyclosporin to rats reduced the glomerular filtration rate and increased the blood pressure in association with a remarkable increase in the circulating endothelin level. This cyclosporin-inducea renal failure can be suppressed by the administration of endothelin antibody (Kidne Int., 37, 1487-1491 (1990)). Thus, it is assumed that endothelin is significantly involved in the pathogenesis of the cyclosporin-induced diseases.

Such various effects of endothelin are caused by the binding of endothelin to endothelin receptors widely distributed in many tissues (Am. J. Physiol., 256, R856-R866 (1989)).

SUBSTITUTE SHEET rule 26 WO 98/30543 PCT/US98/00263 -4- It is known that vasoconstriction by the endothelins is caused via at least two subtypes of endothelin receptors Cardiovasc.

Pharmacol., 7 (Suppl.7, S119-SI21 (1991)). One of the endothelin receptors is ETA receptor Selective to ET-1 rather than ET-3, and the other is ETB receptor equally active to ET-1 and ET-3. These receptor proteins are reported to be different from each other (Nature, 348, 730- 735 (1990)).

These two subtypes of endothelin receptors are differently distributed in tissues. It is known that the ETA receptor is present mainly in cardiovascular tissues, whereas the ETB receptor is widely distributed in various tissues such as brain, kidney, lung, heart and vascular tissues.

Substances which specifically inhibit the binding of endothelin to the endothelin receptors are believed to antagonize various pharmacological activities of endothelin and to be useful as a drug in a wide field. Since the action of the endothelins is caused via not only the ETA receptor but also the ETB receptor, novel non-peptidic substances with ET receptor antagonistic activity to either receptor subtype are desired to block activities of the endothelins effectively in various diseases.

Endothelin is an endogenous substance which directly or indirectly (by controlling liberation of various endogenous substances) induces sustained contraction or relaxation of vascular or non-vascular smooth muscles, and its excess production or excess secretion is believed to be one of pathogeneses for hypertension, pulmonary hypertension, Raynaud's disease, bronchial asthma, gastric ulcer, diabetes, arteriosclerosis, restenosis, acute renal failure, myocardial infarction, angina pectoris, cerebral vasospasm and cerebral infarction. Further, it is suggested that endothelin serves as an important mediator involved in diseases such as restenosis, prostatauxe, endotoxin shock, endotoxininduced multiple organ failure or disseminated intravascular coagulation, and cyclosporin-induced renal failure or hypertension.

Two endothelin receptors ETA and ETB are known so far and antagonists of these receptors have been shown to be potential drug SUBSTITUTE SHEET rule 26 WO 98/30543 PCT/US98/00263 targets. EP 0526708 Al and WO 93/08799 Al are representative examples of patent applications disclosing non-peptidic compounds with alleged activity as endothelin receptor antagonists.

The present invention discloses an asymmetric conjugate addition for preparing the compound of Formula

I,

a key intermediate in the synthesis of endothelin antagonists of the following structure:

R

3 b wherein represents: 5- or 6-membered heterocyclyl, 5- or 6membered carbocyclyl, and aryl; R1 is: C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, aryl, or heteroaryl;

R

2 is OR 4 and N(R 5 2

R

3 b is aryl, or heteroaryl;

R

4 is C1-C8 alkyl; and

R

5 is: Cl-C8 alkyl, or aryl.

SUBSTITUTE SHEET rule 26) Summary of the Invention The instant invention relates to a process for the preparation of a compound of formula I:

R

3

R

2

A

O

-R1

R

I

wherein Aj represents: a) 5- or 6-membered heterocyclyl containing one, two or three double bonds, but at least one double bond and 1, 2 or 3 heteroatoms selected from O, N and S, the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C0 2

R

4 Br, Cl, F, I, CF 3

N(R

5 2 Ci-C 8 alkoxy, C 1 -Cs alkyl, C 2

-C

8 alkenyl, C 2

-C

8 alkynyl, or C 3

-C

8 cycloalkyl, CO(CH 2 )nCH 3 and

CO(CH

2 )nCH 2

N(R

5 2 and S 15 b) aryl, wherein aryl is as defined below, 0 [R\LIBAA]08336.doc:kww WO 98/30543 PCTIUS98/00263 -7- C l-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R 4 Br, Cl, F, I, CF3,

N(R

5 Cl-C8 alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH 3 and CO(CH2)nCH2N(R5) 2 aryl is defined as phenyl or naphthyl which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R 4 Br, Cl, F, I, CF3, N(R5)2, CI-C8 alkoxy, CI-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R5) 2 and when two substituents are located on adjacent carbons they can join to form a 5- or 6membered ring with one, two or three heteroatoms selected from O, N, and S, which is unsubstituted or substituted with with one, two or three substituents selected from the group consisting of: H, OH, C02R 6 Br, Cl, F, I, CF3,

N(R

7 )2, C1-C8 alkoxy, Cl-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5) 2 Ri is: a) C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, b) aryl, or c) heteroaryl; heteroaryl is defined as a 5- or 6 -membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R 4 Br, Cl, F, I, CF3, N(R 5 Cl-C8 alkoxy, CI-C8 SUBSTITUTE SHEET( rule 26) -8alkyl, C2-C8 ailkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5) 2 R is: OR 4 or (52 R3is: a)

H,

b) C I-C8 alkyl, c) C I -C8 alkenyl, C I-C8 alkynyl, e) C I-C8 alkoxyl, f) C3-C7 cycloalkyl, g) Br, Cl, F, 1, aryl, D) heteroaryl, k)

N(RS)

2 1) NE-2, CR0, n) -CO-C

I-C

8 alkyl, 0 -CO-aryl, P) -CO-heteroaryl, q) -C02R 4 or r) protected aldehyde; n is: 0 to *9 30 t is:O0"lor 2;

R

4 is: C I-C8 alkyl; WO 98/30543 PCT/US98/00263 -9-

R

5 is: C1-C8 alkyl, or aryl;

R

6 is: H, C -C8 alkyl, or aryl;

R

7 is: H, C1-C8 alkyl, aryl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R 4 Br, Cl, F, I, CF3, N(R 5 2 C1- C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R5)2; or when two R 7 substutients are on the same nitrogen they can join to form a ring of 3 to 6 atom; comprising reacting a a,3P-unsaturated ester or amide R 3 A -A R

R

2 0 O with an organolithium compound, RILi, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78 C to about 0OC.

DETAILED DESCRIPTION OF THE INVENTION The instant invention relates to a process for the preparation of a compound of formula

I:

R

3

A

R

1

O

wherein wherein SUBSTITUTE SHEET rule 26 AjI represents: a) 5- or 6-membered heterocyclyl containing one, two or three double bonds, but at least one double bond and 1, 2 or 3 heteroatoms selected from 0, N and S, the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C0 2

R

4 Br, Cl, F, 1, CF 3

NCR

5 2

CI-C

8 alkoxy, C 1

-C

8 alkyl, C 2

-C

8 alkenyl, C 2

-C

8 alkynyl, or C 3

-C

8 cycloalkyl, CO(CH 2

)"CH

3 and

CO(CH

2

),CH

2

N(R

5 2 and b) aryl, wherein aryl is as defined below,

CI-C

8 alkoxy, C 1

-C

8 alkyl, C 2

-C

8 alkenyl, C 2

-C

8 alkynyl, or C 3

-C

8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C0 2

R

4 Br, Cl, F, 1, C17 3

N(R

5 2

CI-C

8 alkoxy, C 3

-C

8 cycloalkyl,

CO(CH

2 )nCH 3 and CO(CH 2 )nCH 2

N(R

5 2 aryl is defin.ed as phenyl or naphthyl, which is unsubstituted or substituted with one, two of three substituents selected from the group consisting of:. OH, C0 2

R

4 Br, Cl, F, I,

CF

3

N(R

5 2

C

1 -Cg alkoxy, C 1

-C

8 alkyl, C 2

-C

8 alkenyl, C 2

-C

8 alkynyl, or 3C cycloalkyl, CO(CH 2 )nCH 3 and CO(CH 2 )nCH 2 N(R 5)2, and when two substituents are [R:'LIBAA]08336.doc:kww WO 98/30543 PCTIUS98/00263 located on adjacent carbons they can join to form a 5- or 6membered ring with one, two or three heteroatoms selected from 0, N, and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: H, OH, C02R 6 Br, Cl, F, 1, CF3,

N(R

7 2 C1I-C8 alikoxy, C I-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5) 2 RI is: a) CLI-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, b) aryl, or C) heteroaryl; heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from 0, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of:- OH, C02R 4 Br, Cl, F, 1, CF3, N(R 5 C1I-C8 alkoxy, C1I-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5) 2

R

2 is OR 4 or N(R 5 )2;

R

3 is a)

H,

b) C1I-C8 alkyl, C) C1-C8 alkenyl, d) C1-C8 alkynyl, e) C I-C8 alkoxyl, f) C3-C7 cycloalkyl, g) h) Br, Cl, F, 1, SUBSTITUTE SHEET rule 26) WO 98/30543 PCTIUS98/00263 12 i) aryl, j) heteroaryl, k)

N(R

5 )2, 1) NH-2, m)

CHO,

n) -CO-C Il-C8 alkyl, o) -CO-aryl, P) -CO-heteroaryl, q) -C02R 4 or r) protected aldehyde; X and Y are independently: 0, S, or NR 5 n is: 0 to t is: 0, 1 or 2;

R

4 is C1I-C8 alkyl;

R

5 is: C I-C8 alkyl, or aryl; and

R

6 is: H, C1I-C8 alkyl, and aryl; and R7are independently: H, C I-C8 alkyl, and aryl, when there are two R 7 substituents on a nitrogen they can join to form a 3through 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R 4 ,BCFIF3

N(R

5 Cl-C8 alkoxy, Cl.-C8 alkyl, C?-C8 alkenyl, C2-C8 ailkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R5) 2 comprising reacting a (x,-unsaturated ester or amide SUBSTITUTE SHEET rule 26) WO 98/30543 PCT/US98/00263 13 A 3 R2

^R

2 O 0 with an organolithium compound, RILi, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78 0 C to about 0OC.

The process as recited above, wherein the number of equivalents of the organolithium compound, RILi, is 1 to about 4. and preferably about 1.5 to about The process as recited above, wherein the chiral additive is a chiral compound capable of coordinating with chiral additives, such as a) (-)-sparteine, b) N,N,N',N'-tetra(C 1-C6)-alkyltrans- 1,2-diaminocyclohexane, or

R

8

RO

1 R9 c)

N(R

7 2 wherein

R

8 and R 9 are independently:

H,

Cl-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R 8 and R9 cannot simultaneously be H; and R 1 0 is C1-C6 alkvl or aryl, are useful in this process. It is understood that the amino alcohol represented by the above noted structure has at least one, and potentially two chiral centers.

The process as recited above, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane, and dioxane, or a mixture of said solvents. The process as recited above, wherein the preferred aprotic solvent is toluene.

The solvent mixtures useful in this process are: hexane and toluene with a catalytic amount of tetrahydrofuran, and pentane and SUBSTITUTE SHEET rule 26 14 toluene with a catalytic amount of tetrahydrofuran, preferably hexane and toluene with a catalytic amount of tetrahydrofuran.

The process as recited above, wherein the temperature range is about -78 0 C to about 0 C, and preferably about -78 0 C to about -50 0

C.

An embodiment of this invention is the process for the preparation of a compound of formula I: R3 A2

I

wherein

A

D represents: a) 5- or 6-membered heterocyclyl containing one, two or three double bonds, but S* at least one double bond and 1, 2 or 3 heteroatoms selected from 0, N and S, the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected 15 from the group consisting of: OH, C0 2

R

4 Br, Cl, F, I, CF 3

N(R

5 2

C

1

-C

8 alkoxy, Ci-Cs

**C

alkyl, C 2

-C

8 alkenyl, C 2

-C

8 alkynyl, or C 3

-C

8 cycloalkyl, CO(CH 2 )nCH 3 and

SCO(CH

2 )nCH 2

N(R

5 2 and b) aryl, wherein aryl is as defined below, Ci-C 8 alkoxy, Ci-Cs alkyl, C 2

-C

8 alkenyl, C 2

-C

8 alkynyl, or C 3

-C

8 cycloalkyl, are 20 unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C0 2

R

4 Br, Cl, F, I, CF 3

N(R

5 2

C

1

-C

8 alkoxy, C 3 -Cs cycloalkyl,

CO(CH

2 )nCH 3 and CO(CH 2 )nCH 2

N(R

5 2 aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C0 2

R

4 Br, Cl, F, I,

CF

3

N(R

5 2

C

1

-C

8 alkoxy, Ci-C 8 alkyl, C 2

-C

8 alkenyl, C 2

-C

8 alkynyl, or C 3

-C

8 cycloalkyl, CO(CH 2 )nCH 3 and CO(CH 2 )nCH 2

N(R

5 2 and when two substituents are located on adjacent carbons they can join to form a 5- or 6-membered ring with one, two or three heteroatoms selected from O, N, and S, which is unsubstituted or substituted with foone, two or three substituents selected from the group consisting of: H, OH, CO 2

R

6 Br, [R\LIBAA]08336.doc:kww Cl, F, I, CF 3

N(R

7 CI-Cg alkoxy, CI-C 8 alkyl, C 2

-C

8 aikenyl, C 2

-C

8 alkynyl, or 3C cycloalkyl, CO(CH 2

),,CH

3 and CO(CH 2 )nCH 2 N(R 5 2

R

1 is: a) CI-C 8 alkyl, C 2

-C

8 alkenyl, C 2

-C

8 alkynyl, or C 3

-C

8 cycloalkyl, b) aryl, or c) heteroaryl; heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from 0, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, [R).L[BAA]08336.doc:kww WO 98/30543 PCTIUS98/00263 16- C02R 4 Br, Cl. F, 1, CF3, N(R 5 C I-C8 alkoxy, C 1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2) 11

CH

3 and CO(CH2)ncH2N(R5) 2

R

2 is OR 4 or N(R5) 2 R3is a)

CHO,

b) CH(0R 4 2 n is: 0 to t Is: 0, 1 or 2; X and Y are independently: 0, S, or NR 5

R

4 is C I-C8 alkyl;

R

5 is: C I-C8 alkyl, or aryl;

R

6 is: H, C I-C8 alkyl, and aryl; R7are independently: H, C I-C8 alkyl, and aryl, when there are two R 7 substituents on a nitrogen they can join to form a 3through 6 -membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R 4 Br, Cl, F, 1, CF3,

N(R

5 C I-C8 alkoxy, C1I-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH 3 CO(CH2)nCH2N(R5) 2 comprising the steps of: 1) reacting an P- unsaturated ester or amide SUBSTITUTE SHEET rule 26) WO 98/30543 PCT/US98/00263 -17- R R A R 0 where

R

3 is CH(OR4)2; with an organolithium compound, RILi, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78 0 C to about 0°C to give the conjugate adduct; and 2) removing the aldehyde protecting group with an acid to give the compound of Formula I, where

R

3 is CHO.

The process as recited above, wherein the number of equivalents of the organolithium compound, R ILi, is 1 to about 4. and preferably about 1.5 to about The process as recited above, wherein the chiral additive is a chiral compound capable of coordinating with chiral additives, such as a) (-)-sparteine, b) N,N,N',N'-tetra(C 1 -C6)-alkyltrans-1, 2 -diaminocyclohexane, or

R

8

R

10 R9 c)

N(R

7 2 wherein

R

8 and R 9 are independently:

H,

C1-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R 8 and 20R9 cannot simultaneously be H; and R 10 is C1-C6 alkyl or aryl, are useful in this process.

The process as recited above, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane, and dioxane. or a mixture of said solvents. The process as recited above, wherein the preferred aprotic solvent is toluene.

SUBSTITUTE SHEET rule 26 18 The solvent mixtures useful in this process are: hexane and toluene with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, preferably hexane and toluene with a catalytic amount of tetrahydrofuran.

The solvent mixtures useful in this process are: hexane and toluene with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, preferably hexane and toluene with a catalytic amount of tetrahydrofuran.

The process as recited above, wherein the temperature range is about -78 0 C to about -20 0 C, and preferably about -78 0 C to about An embodiment of this invention is the process for the preparation of the protected aldehyde

OR

4 a

OR

4 a N CO 2 But

OTBS

Me OMe wherein R 4 a is defined as Ci-C 8 alkyl or taken together represent a 2- or 3-carbon S1is methylene chain of a 5- or 6-membered ring, the process comprising reacting an a,p-unsaturated ester or amide

OR

4a

R

SOR4a 'OBut 0 with an organolithium compound with an organolithium compound [R:\LIBAA]08336.doc:kww WO 98/30543 PCT/US98/00263 19- Li e OTBS SMe MeO in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78 0 C to about -20 0

C.

The process as recited above, wherein the number of equivalents of the organolithium compound, RI Li is 1 to about 4. and preferably about 1.5 to about The process as recited above, wherein the chiral additive is a chiral compound capable of coordinating with chiral additives, such as a) (-)-sparteine, b) N,N,N',N'-tetra(C 1-C6)-alkyltrans- 1,2-diaminocyclohexane, or

R

8

R

10 0

R

9 c)

N(R

7 2 wherein

R

8 and R 9 are independently:

H,

C1-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R 8 and R9 cannot simultaneously be H; and R 10 is C1-C6 alkvl or aryl, are useful in this process.

The process as recited above, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane, and dioxane, or a mixture of said solvents. The process as recited above, wherein the preferred aprotic solvent is tetrahydorfuran.

The solvent mixtures useful in this process are: hexane and toluene with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, preferrably hexane and toluene with a catalytic amount of tetrahydrofuran.

SUBSTITUTE SHEET rule 26 WO 98/30543 PCT/US98/00263 The process as recited above, wherein the temperature range is about -78 0 C to about -20 0 C, preferably about -78 0 C to about and most preferably about -78 0 C to about It is further understood that the substituents recited above would include the definitions recited below.

The alkyl substituents recited above denote straight and branched chain hydrocarbons of the length specified such as methyl, ethyl, isopropyl, isobutyl, tert-butyl, neopentyl, isopentyl, etc.

The 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.

Cycloalkyl 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 substituent represents an carbazolyl, furanyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, purinyl.

The heterocyclyl substituent represents a pyridyl, pyrimidyl, thienyl, furanyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, imidazolyl, imidazoldinyl, thiazolidilnyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrrolidinyl.

The protected aldehyde represents an acetal, such as 0 0 D or CH(OCl-C 8 alkyl)2, O o0 The a,p-unsaturated ester or amide SUBSTITUTE SHEET rule 26 WO 98 30543 PCT/US98/00263 -21can generally be prepared in two steps: 1) a coupling reaction at the one position of Ring A 2 R 3 A Ry2 1 Z 0 wherein

R

3 is CHO, Z is a leaving group, such as Br. Cl, I OTriflyl, OTosyl or OMesyl and R 2 is OR 4 or N(R5)2; and 2) the conversion of the aldehyde

(R

3 is CHO) to the desired protected aldehyde

(R

3 is CH(OR 4 )2 and R 4 is C1-C8 alkyl).

Commercially available pyridone 1 is alkylated via its dianion with propyl bromide, and the product is then converted into the bromopyridine 3a using a brominating agent such as PBr3. The nitrile 3a is then reduced to the aldehyde 3 using diisobutyl aluminum hydride (DIBAL). The aldehyde then undergoes a Heck reaction with t-butyl acrylate using NaOAc, (allyl)2PdC12, tri-o-tolylphosphine, toluene.

reflux to provide the unsaturated ester 4a in high yield. The unsaturated ester 4a is then treated with an alcohol

(R

4 0H) and aqueous acid to give the acetal-acceptor SUBSTITUTE SHEET rule 26 WO 98/30543 PCTIUS98/00263 22 Scheme 1

-CN

LDA

C

3

H

7 Br Bu'

OCN

PBr 3 ~CN

CHO

I DIBAL

IH

2

C=CHC

2 But Bu- Br BuN- Br

CHO

BiN7) OBut R 4 OH, H+ OR 4 OR 4 Bu -N OBut 5a 0 Comnmericially available acid 10 is reduced with BH3*SMe 2 to the alcohol 11, which is then converted into the bromnidel3, via the mesylate 12 using mesyl chloride. triethylamnine followed by the addition of NaBr and dimethylacetamide

(DMAC).

SUB STITUTE SHEET rule 26) WO 98/30543 PCTIUS98/00263 -23 Scheme 2

OH

OMe OMe 11 Br Br OMe OMe 12 Commercial available 1, 2 -amino indanol is acylated (propionyl choride, K2CO3) to give amide 8, which is then converted into the acetonide 9 2 -methoxypropene, pyridinium p-toluene-sulfonate (PPTS)). Acetonide 9 is then alkylated with the bromide 13, (LiHMDS) to give 14, which is then hydrolyzed MeOH) to give a mixture of acid and methyl ester 15. Reduction (LAH) of the ester/acid mixture provided the alcohol 16 in high yield and optical purity. Protection of the alcohol 16 (TBSC1, imidazole) provided bromide 17, the precursor to organolithium 17a.

SUBSTITUTE SHEET rule 26) WO 98/30543 PCTIUS98/o0263 -24- Scheme 3 0=

NH

-OH

8 OMe OBr 0 13, LiHMDS THF, MeOH Br OH/Me

LAH

OMe OMe 16 99.5 %ee Li

OTBS

'OTBS

OMe 17 OMe 17a SUB3STITUTE SHEET rule 26) WO 98/30543 PCT/US98/00263 Compound 17a and a chiral additive, such as sparteine, are added to the ca,P-unsaturated ester 5a at -780 to -50 0 C. Work up with water affords compounds 6a and 6b. Mixtures of compounds 6a and 6b are treated with TBAF or aqueous acid to deprotect the silylated alcohol or acetal and silylated alcohol.

SUBSTITUTE SHEET rule 26 WO 98/30543 PCT(US98/00263 26 Scheme 4

OTBS

OR 4 a

OR

4 OMe 1 O'Bu 1 Bu N (-)-sparteine 0 OR 4 OR 4 .OtBu Bu' .OtBu

TBAF

H3 0 OR 4 OtBu .OtBu OMe 6c16d 6e/6f SUBSTITUTE SHEET rule 26 WO 98/30543 PCT/US98/00263 -27- The instant invention can be understood further by the following examples, which do not constitute a limitation of the invention.

EXAMPLE 1

CN

Me N 0

H

1 Preparation of 1 Compound 1 is a commericially available starting material, for example, see Aldrich Chemical Company, Milwaukee, WI, USA 53201.

EXAMPLE 2 ON

ON

Me N 0 Bu

N

H

1 2 Preparation of 2 Diisopropyl amine (MW 101.19, d 0.772, 2.1 equ, 20.54 mL) in 200 mL THF. Cool to -50°C and add n-BuLi (1.6 M in hexanes, 2.05 equ, 96 mL), allowing solution to warm to -20 0 C. Age 0-3 0 C for min, then cool to -30 0 C and add 1 (MW 134.14, 75 mmol, 10.0 g).

Age 0°C to 43 0 C for 2 h. Cool to -50'C and add bromopropane

(MW

123.00, d 1.354, 1.0 equ, 6.8 mL). Warm to 25 0 C over 30 min, and age min. Add NH4C1 and CH2C12. Dry organic (magnesium sulfate) then evaporate in vacuo to afford 61% of 2.

SUBSTITUTE SHEET rule 26 WO 98/30543 PCTIUS98/00263 -28- EXAMPLE 3

CHO

Bu N Br Preparation of 3 Mix 2 (MW 176.22, 46 mmol) and PBr3 (MW 270.70, d 2.880, 2.5 equ, 10.8 mL) and age at 160 0 C. After 2 h, cool to 25 0 C and add some CH2C12. Slowly quench by adding water. Separate layers and wash aqueous two times with CH2C12. Combine organic layers and dry (magnesium sulfate). Concentrate and isolate solid by silica gel chromatography (90:10 hexanes:ethyl acetate) in 60% yield (MW 239.12, 6.60 g).

Dissolve product of bromination reaction (MW 239.12, 27.6 mmol, 6.60 g) in 66 mL toluene and cool to -42°C. Slowly add DIBAL (1.5 M in toluene, 2 equ, 37 mL) and age 1 h at -42 0 C. Add HC1 (2 N, 10 equ, 134 mL) and stir vigorously for 30 min. Dilute with ethyl acetate, separate layers, and wash aqueous with ethyl acetate.

Combine organic layers, dry (magnesium sulfate), and concentrate in vacuo to afford 90% (MW 242.11, 6.01 g) of 3.

EXAMPLE 4a SCHO

CHO

Bu N Br Bu N O Bu 3 4a 0 SUBSTITUTE SHEET rule 26 WO 98/30543 PCT/US98/00263 -29- Preparation of 4a Dissolve 3 (MW 242.11, 24.8 mmol, 6.01 g) in 75 mL toluene. Add sodium acetate (MW 82, 3 equ, 6.13 t-butyl acrylate (MW 128.17, d 0.875, 2.5 equ, 9.08 mL), P(o-tolyl)3 (MW 304.38, mol 755 mg) and allyl palladium chloride dimer (MW 365.85, 5 mol 455 mg). Age at reflux for 24 h. Cool, filter and evaporate in vacuo. Isolate 4a (MW 289.37) by silica gel chromatography (92:8 hexanes:ethyl acetate) in 80% yield (5.74 g).

EXAMPLE 4b CHO CHO B N.N(Me) 2 Bu N Br Bu NN(Me) 3 4b 0 Preparation of 4b Dissolve 3 (MW 242.11, 24.8 mmol, 6.01 g) in 75 mL toluene. Add sodium acetate (MW 82, 3 equ, 6.13 g), dimethylacrylamide (MW 99.13, d 0.962, 1 equ, 2.55 mL), PPh3 (MW 262.29, 10 mol 653 mg) and allyl palladium chloride dimer (MW 365.85, 5 mol 455 mg). Age at 140°C in sealed tube for 24 h. Cool, filter and evaporate in vacuo. Isolate 4b (MW 260.34) by silica gel chromatography (80:20 hexanes:ethyl acetate) in 70% yield (4.52 g).

EXAMPLE OMe CHO OMe OMe Bu N OtBuu OtBu Bu N Bu N 4a O

O

aSTITUTE SHEET SUBSTITUTE SHEET rule 26 WO 98/30543 PCT/US98/00263 Preparation of A solution of 16.0 g (55.36 mmol) of aldehyde 4a and 1.4 g (5.54 mmol) of PPTS in 280 mL of MeOH was heated at reflux for 2.5 h. After cooling to room temperature, the solvents were evaporated in vacuo. The residue was dissolved into EtOAc and washed with satd. sodium bicarbonate solution. Concentration of the organic layer gave 18.2 g of the desired product 5a. 98% yield.

H NMR

(CDCL

3 6: 7.95 1 7.80 1 7.12 1 7.04 (d, 1 5.09 (1 3.45 6 2.80 2 1.73 2 1.54 9 1.40 2 0.95 3 H) ppm.

SUBSTITUTE SHEET rule 26 WO 98/30543 PCTIUS98/00263 -31 EXAMPLE 6 Br

OTBS

OMe I OMe 0 OMe 1 (-)-sparteine OMe OMe DMe 6a OMe 6b STBAF

$H

3 0' OAe

CHO

OtBu

C

y BU Noa 0 H0 OMe 6c6OMe 6e/6f Step A: (1.37 mL, Preparation of 6n and 6b To a solution of 17 (2.23 g, 5.97 rnmol), (-)-sparteine 5.97 mmol), and THF (73 [tL, 0.896 mmol) in 20 mL of SUBSTITUTE SHEET rule 26) WO 98/30543 PCT/US98/00263 -32toluene at -78 oC was added t-BuLi (1.7 M in Hexane, 7.0 mL, 11.94 mmol) dropwise. The solution was aged for 30 min. at -78 oC. A solution of the unsaturated t-butyl ester 5a (1.0 g, 2.98 mmol) in 5 mL of toluene was added dropwise over 10 min. at -78 oC. After 20 min at 78 C, the reaction was quenched with water. The organic phase was separated and dried over anhydrous sodium sulfate. Purification of the crude product by silica gel chromatography (EtOAc/Hex, 2:98) gave 1.52 g of the desired products 6a and 6b. 81% yield.

For major diasteromer 6b: 'H NMR (CDCL 3 6: 7.24 (dd, 1 7.00 1 6.84 1 6.70 1 6.55 (dd, 1 5.74 1 5.02 1 3.72 3 3.55 4 3.22 3 2.92 3 2.80 2 2.50 2 2.12 1 1.75 2 1.40 2 H), 1.28 9 0.95 6 0.90 9 0.09 3 0.08 3 H) ppm.

In order to determine the ratio of the two diasteroisomers 6a and 6b, the above compounds were further deprotected by treatment with TBAF in THF or with either HCI or pTSA in aqueous acetone.

Step B: Preparation of 6c and 6d (Method

A)

A solution of 500 mg (0.8 mmol) of above products 6a and 6b and 0.96 mL of TBAF (1.0 M in THF) in 6 mL of THF was allowed to stir for 4 h. at room temperature. The reaction solution was then washed with water and dried over sodium sulfate. The product was analyzed by H' NMR. Integration of the singlet peaks at 5.42 ppm (major diasteromer) and 5.38 ppm (minor diasteromoer) was used to determine the ratio of the two diasteromers.

Step C: Preparation of 6e and 6f Method

B)

A solution of 100 mg (0.16 mmol) of above products 6a and 6b in 3 mL of acetone and 1 mL of 5% HCI or 45 mg pTSA in 3 mL of acetone and 1 mL of water was allowed to stir for 5 h. at room temperature. The solvents were evaporated in vacuo. The residue was dissolved in EtOAc and washed with 10% sodium carbonate. The product was concentrated and analyzed by H' NMR. Integration of the SUBSTITUTE SHEET rule 26 WO 98/30543 PCT/US98/00263 -33singlet peaks at 10.35 ppm (major diasteromer) and 10.20 ppm (minor diasteromoer) was used to determine the ratio of the two diasteromers.

EXAMPLE 7

NH

2

OH

7 Preparation of 7 Compound 7 is a commericially available starting material, for example, see DSM Andeno, Grubbenvorsterweg 8, P.O. Box 81, 5900 AB Venlo,The Netherlands.

EXAMPLE 8 0

NH

2 HN OH-

OH

7 8 Preparation of 8 Na2CO3 (MW 105.99, 1.5 equ, 8.8 g) dissolved in 82 mL water. Add a solution of (1R,2S) amino indanol 7 (MW 149.19, 55.0 mmol, 8.2 g) in 160 mL CH2C12. Cool to -5 0 C and add propionyl chloride (MW 92.53, d 1.065, 1.3 equ, 6.2 mL). Warm to 25 0 C and age 1 h. Separate layers and dry organic (magnesium sulfate). Concentrate in vacuo to afford 8 (MW 205.26, 10 g) in 89% isolated yield.

SUBSTITUTE SHEET rule 26) WO 98/30543 PCT/US98/00263 34 EXAMPLE 9

O

HN

8 Preparation of 9 To a solution of 8 (MW 205.26, 49.3 mmol, 10 g) in 200 mL THF, add pyridinium p-toluenesulfonate (PPTS) (MW 251.31, 0.16 equ, 2g) then methoxypropene (MW 72.11, d 0.753, 2.2 equ, 10.4 mL).

Age 2 h at 38 0 C, then add aqueous sodium bicarbonate and ethyl acetate.

The organic layer was dried (magnesium sulfate). After concentration in vacuo, 9 (MW 245.32, 12.09 g) was formed in quantitative yield.

EXAMPLE OMe Preparation of Compound 10 is a commericially available starting material, for example, see Lancaster Synthesis, P.O. Box 1000, Windham, NH 03087-9977 or Ryan Scientific, Inc., P.O. Box 845, Isle of Palms, SC 29451-0845.

SUBSTITUTE SHEET rule 26 WO 98/30543 PCTIUS98/00263 EXAMPLE 11 OMe OMe 11 Preparation of 1 1 (MW 231.05, 130 mmol, 30.0 g) in 300 mL CH2C12 at 0OC. Add BH3-SMe2 (3 equ, 25.2 mL) and age for 2 h at Quench into aqueous 2 N HC1 and separate layers. Dry organic (magnesium sulfate) and concentrate in vacuo to obtain 94% yield of 11 (MW 217.06, 25.5 g).

EXAMPLE 12 OMs OMe 11 OMe 12 Preparation of 12 Dissolve 11 (MW 217.06, 47.2 mmol, 10.24 g) in 55 mL CH2C12 and cool to -20 0 C. Add DIEA (MW 129.25, d 0.742, 1.3 equ, 10.69 mL) then methane sulfonyl chloride (MsCI) (MW 114.55, d 1.480, 1.2 equ, 4.38 mL). Age -5°C to 0 C for 1 h then quench into mL water. Extract with CH2C12 then wash with IN H2S04 (40 mL), then brine. Dry organic layers (magnesium sulfate) and concentrate in vacuo to afford 12 (MW 295.15, 13.23 g) in 95% yield.

SUBSTITUTE SHEET rule 26) WO 98/30543 PCTIUS98/00263 -36- EXAMPLE 13 OMs OMe 12 OMe 13 Preparation of 13 12 (MW 295.15, 44.8 mmol, 13.23 g) in 44 mL dimethylacetamide (DMAC). Add NaBr (MW 102.90, 2 equ, 9.22 g) and age Ih. Add 88 mL water and collect solid by filtration. Wash cake with water and dry by suction. Quantitative yield of 13 (MW 279.96, 12.54 g) is obtained.

EXAMPLE 14 0

^N

13 Preparation of 14 9 (MW 245.32, 1.1 equ, 89.1 g) in 1 L THF, cooled to 0 C. Add LiHMDS (1.0 M in THF, 1.5 equ, 545 mL) and age 1.5 h, warming to -30 0 C. Add 13 (MW 279.96, 327 mmol, 91.3 g) in 300 mL THF, and age -35 0 C for 1 h. Warm to -10°C over 1 h, then quench into SUBSTITUTE SHEET rule 26 WO 98/30543 PCT/US98/00263 -37aqueous NH4C1. Separate layers and extract with ethyl acetate. Dry organic and concentrate in vacuo to afford crude 14 (MW 444.37).

EXAMPLE Br 0 Br 0 rY N p AOH/Me OMe Preparation of 14 in 1 L MeOH and cooled to 10 0 C. Bubble in HCI gas for 1 h until reaction is complete. 2 L H20 added and the product was filtered. The cake was washed with H20 and dried to give the product hydroxyamide, which was then dissolved in 1 L MeOH and 1.5 L 6N HCI and refluxed overnight. The mixture was cooled to 25°C and extracted with CH2C12 to give, after concentration, compounds 15 g, 64% from bromide 13).

EXAMPLE 16 OH/Me OMe OMe SUBSTITUTE SHEET rule 26 WO 98/30543 PCT/US98/00263 -38- Preparation of 16 (mixture of acid and ester, 26.88 mmol) in 150 mL THF at -78 0 C. Add lithium aluminum hydride (LiA1H4) (1 M in THF, 2 equ, 53.76 mL) over 30 min. Warm to 25 0 C over 1 h, then quench into aqueous NH4CI. Add ethyl acetate, extract ethyl acetate. Wash organics with brine, dry (magnesium sulfate), and concentrate in vacuo to afford 95% yield of 16 (MW 259.14, 6.62 g).

EXAMPLE 17 Br Br OH

OTBS

OMe 16 OMe 17 Preparation of 17 16 (MW 259.14, 25.54 mmol, 6.62 g) in 35 mL CH2C12 and cool to 0°C. Add imidazole (MW 68.08, 2.5 equ, 4.35 g) and then tert-butyldimethylsilyl chloride (TBSC1) (MW 150.73, 1 equ, 3.85 g).

Age 1 h at 25 0 C then quench with aqueous NaHCO3 and add ethyl acetate. Extract with ethyl acetate, then dry organic layer (magnesium sulfate) and concentrate in vacuo to afford a quantitative yield of 17 (MW 373.41, 9.54 g).

1 H NMR (CDC13) 7.41 J=8.74, 1H), 6.77 J=3.04, 1H), 6.63 (dd, J=8.73, 3.06, 1H), 3.78 3 3.50 J=5.75, 2 2.89 (dd, J=13.31, 6.15, 1 2.45 (dd, J=13.30, 8.26, 1 2.03 1 0.94 9 0.92 J=5.01, 3 0.07 6 H).

13C NMR (CDC13) 159.1, 141.6, 133.2, 117.0, 115.4, 113.2, 67.4, 55.4, 39.7, 36.3, 26.0 18.4, 16.5, -5.3 (2C).

SUBSTITUTE SHEET rule 26 WO 98/3054.3 PCTIUS98/00263 39 EXAMPLE 18-22 Following the procedure described in Example 6 the listed chiral additive resulted in the indicated diastereomeric ratios of compounds 6a to 6b.

Example No.

Chiral Additive Diastereomeric Ratio 6a:6b) (-)sparteine N-methyl ephedrine 1:1 P Me 2.7:1 MeO NMe 2 PhPh 1:1.3 MeO OMe PhMe 3.7:1 MeO

N::

Q ~NMe 2 2.2:1 "NMe 2 SUBSTITUTE SHEET rule 26)

Claims

1. A process for the preparation of a compound of formula I: 3 wherein Al represents: a) 5- or 6-membered heterocyclyl containing one, two or three double bonds, but at least one double bond and 1, 2 or 3 heteroatoms selected from 0, N and S, the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C0

2 R 4 Br, Cl, F, 1, C17

3 N(R 5 2 CI-C 8 alkoxy, C 1 -C 8 alkyl, C 2 -C 8 atkenyl, C 2 -C 8 alkynyl, or C 3 -C 8 cycloalkyl, CO(CH 2 )"CH 3 and 0, CO(CH 2 ),CH 2 N(R 5 2 and b) aryl, wherein aryl is as defined below, 15 CI-C 8 alkoxy, CI-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C 3 -C 8 cycloalkyl, are unsubstituted or substituted with one, RALBAA]08336.doc: k- WO 98/30543 PCT1US98/00263 -41- two or three substituents selected from the group Consisting, of: H, 02R, Br, CI, F, 1, CF3, N(R 5 C1-C8 alkoxy, C3-Cg cycloallcyl, CO(CH2)flCH3, and CO(CH2)nCH2N(R5) 2 aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R

4 Br, Cl, F, 1, CF3, N(R

5 C1I-C8 alkoxy, C I-C8 ailkyl, C2-C8 alcenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH-)N(R5) 2 and when two substituents are located on adjacent carbons they can join to form a or 6- membered ring with one, two or three heteroatoms selected from 0, N, and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: H, OH, C02R 6 Br, CI, F, 1, CF3, N(R 7 )2, ClI-C8 ailcoxy, C1I-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5) 2 RI is: a) C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, b) aryl, or c) heteroaryl; heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from 0, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R 4 Br, Cl, F, I, CF3, N(R 5 C1I-C8 alkoxy, ClI-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5) 2 SUBSTITUTE SHEET rule 26 -42 R 2 is OR 4 or (52 R3is a) H, b) C I-C8 alkyl, c) C I -C8 alkenyl, d) Cl-C8 alkynyl, e) C1I-C8 alkoxyl, f) C3-C7 cycloalkyl, g) S(O)tR 5 h) Br, Cl, Fl It i) aryl, j) heteroaryl, k) N(R 5 )2, 1) NH2, m) CHO, -CO-C1I-C8 alkyl, 00 o) -CO-aryl, 4 *5 0.006P) -CO-heteroaryl, 20 q) -C02R 4 or r) protected aldehyde; 25 n is:O0to S t is: 0, 1 or 2; R4isC-C lkI SR6 is:H C-C8 alkyl n ry;ad WO 98/30543 PCT/US98/00263 -43- R7 are independently: H, Cl-C8 alkyl, and aryl, when there are two R 7 substituents on a nitrogen they can join to form a 3- through

6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R 4 Br, Cl, F, I, CF3, N(R 5 Cl-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R5) 2 comprising reacting a ca, 3 -unsaturated ester or amide R 3 A j A R2 0 O with an organolithium compound, RILi, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78 0 C to about 0°C. 2. The process as recited in Claim 1, wherein the number of equivalents of the organolithium compound, R Li, is 1 to about 4. 3. The process as recited in Claim 2, wherein the chiral additive is selected from the group consisting of: a) (-)-sparteine, b) N,N,N',N'-tetra(C -C6)-alkyltrans- 1, 2 -diamino- cyclohexane, or SUBSTITUTE SHEET rule 26 WO 98/30543 PCT/US98/00263 -44- R 8 RoOj R9 c) N(R 7 2 wherein R 8 and R 9 are independently: H, C1-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R 8 and R9 cannot simultaneously be H; and R 10 is H, C1-C6 alkyl or aryl. 4. The process as recited in Claim 3, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, methyl t-butyl ether, benzene, toluene, hexane, pentane, and dioxane, or a mixture of said solvents. range temperature The process as recited in Claim 4, is about -78°C to about -20 0 C. wherein the 6. A process for the preparation of a compound of formula I: wherein represents: a) 5- or 6 -membered heterocyclyl containing one, two or three double bonds, but at least one double bond and 1, 2 or 3 heteroatoms selected from O, N and S, the heterocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, SUBSTITUTE SHEET rule 26 CO 2 R 4 Br, Cl, F, 1, CF 3 N(R 5 2 CI-C 8 alkoxy, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -Cg alkynyl, or C 3 -C 8 cycloalkyl, CO(CHA)CH 3 and CO(CH 2 ),CH 2 N(R 5 2 and b) aryl, wherein aryl is as defined below, CI-C 8 alkoxy, CI-C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C 3 -C 8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C0 2 R 4 Br, Cl, F, 1, CF 3 N(R 5 2 CI-C 8 alkoxy, C 3 -C 8 cycloalkyl, CO(CH 2 ).CH 3 and CO(CH 2 )nCH 2 N(R 5 2 aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C0 2 R 4 Br, Cl, F, 1, CF 3 N(R 5 2 C 1 -C 8 alkoxy, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C 3 -C 8 cycloatkyl, CO(CH 2 ),,CH 3 and CO(CH 2 )nCH 2 N(R 5 2 and when two substituents are located on adjacent carbons they can join to form a 5- or 6-membered ring with one, two or three heteroatoms selected from 0, N, and S, which is unsubstituted or substituted with 6 one, two or three substituents selected from the group consisting of:- H, OH, C0 2 R Br, Cl, F, 1, CF 3 N(R 7 2 CI-C 8 alkoxy, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or 3C cycloalkyl, CO(CH 2 )nCH 3 and CO(CH 2 )nCH 2 N(R) 2 .9 sees 0*00 *0 a ,fee* [R-ALIBAA]O8336.doc:kww -46- RI is: a) C I-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 8 cycloalkyl, b) aryl, or C) heteroaryl; heteroaryl is defined as a 5- or 6 -membered aromatic ring containing 1, 2 or 3 heteroatoms selected from 0,'N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of:- OH, C02R 4 Br, Cl, F, L, CF3, N(R5)2, Cl-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloallcyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5) 2 R 2 is OR 4 or N(R 5 )2; R3is CHO, CH(0R4) 2 n0s t is ,1 r2 seat R5 2 is:0CItCo akyorarl R6~ is: 0, 1 or 2; ly, n rl R7 a ei d p n enl H 6C ak l n r lw e h r r tw R7 sb tt e t nanto enteSa ont o m a3 WO 98/30543 PCT/US98/00263 -47- through 6 -membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R 4 Br, Cl, F, I, CF3, N(R 5 Cl-C8 alkoxy, Cl-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R5) 2 comprising the steps of: 1) reacting an a.,-unsaturated ester or amide A0 O where R 3 is CH(OR 4 2 with an organolithium compound, RILi, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78 0 C to about 0°C to give the conjugate adduct; and 2) removing the protecting group with an acid to give the compound of Formula I, where R 3 is CHO.

7. The process as recited in Claim 6, wherein the number of equivalents of the organolithium compound, RILi, is 1 to about 4.

8. The process as recited in Claim 7, wherein the chiral additive is selected from the group consisting of: a) (-)-sparteine, b) N,N,N' ,N'-tetra(C 1 -C6)-alkyltrans- 1,2-diamino- cyclohexane, or SUBSTITUTE SHEET rule 26 48 R 8 R 10 0 R 7 c) N(R)2, wherein R 8 and R 9 are independently: H, Ci-C 6 alkyl, C 3 -C 7 cycloalkyl or aryl, except that R 8 and R 9 cannot simultaneously by H; and R' 1 is H, Ci-C 6 alkyl or aryl.

9. The process as recited in claim 8, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, methyl t-butyl ether, benzene, toluene, hexane, pentane, and dioxane, or a mixture of said solvents.

The process as recited in claim 9, wherein the temperature range is about 78 0 C to about -20 0 C.

11. A process for the preparation of OR 4 a OR 4 a N CO 2 But OTBS Me OMe wherein R 4 a is defined as C 1 -C 8 alkyl or taken together represent a 2- or 3-carbon methylene chain of a 5- or 6-membered ring, the process comprising reacting an ca,-unsaturated ester or amide OR 4 OR 4 a 11 OBu' 0. O with an organolithium compound [R:ULBAA]08336.doc:kw 49 in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78 0 C to about

12. The process as recited in claim 11, wherein the number of equivalents of the organolithium compound, R'Li, is 1 to about 4. s

13. The process as recited in claim 11, wherein the chiral additive is selected from the group consisting of: a) (-)-sparteine, b) N,N,N',N'-tetra(Ci-C 6 )-alkyltrans-1,2-diamino-cyclohexane, or R 8 R 10 R9 N(R )2 c) wherein R 7 is H, Ci-C 8 alkyl, aryl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C0 2 R 4 Br, Cl, F, I, CF 3 N(R 5 2 C 1 -C 8 alkoxy, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C 3 -C 8 cycloalkyl, CO(CH 2 )nCH 3 and CO(CH 2 ),CH 2 NR 5 2 or when two R 7 substituents are on the same nitrogen they can join to form a ring of 3 to 6 atom; S8 8 15 R and R 9 are independently: H, CI-C 6 alkyl, C 3 -C 7 cycloalkyl or aryl, except that R and *9 R 9 cannot simultaneously be H; and R 1 0 is C 1 -C 6 alkyl or aryl.

14. The process as recited in claim 13, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, methyl t-butyl ether, benzene, 20 toluene, pentane, hexane, and dioxane, or a mixture of said solvents.

15. The process as recited in claim 14, wherein the temperature range is about 0 C to about

16. The process as recited in claim 15, wherein the number of equivalents of the organolithium compound, R'Li, is 1.5 to about 25

17. The process as recited in claim 16, wherein the aprotic solvent is toluene- hexane-(catalytic) tetrahydrofuran mixture.

18. The process as recited in claim 17, wherein the temperature range is about -78°C to about -70 0 C.

19. A process for the preparation of an endothelin intermediate, said process being substantially as hereinbefore described with reference to any one of the examples. [R\LIBAA]8336.dockw An endothelin intermediate prepared by the process of any one of claims 1 to 19. Dated 16 October, 2000 Merck Co., Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [RAL1BAA]08336.doc:kww