MXPA99006544A - Endothelin intermediates by asymmetric conjugate addition reaction using a chiral additive - Google Patents
Endothelin intermediates by asymmetric conjugate addition reaction using a chiral additiveInfo
- Publication number
- MXPA99006544A MXPA99006544A MXPA/A/1999/006544A MX9906544A MXPA99006544A MX PA99006544 A MXPA99006544 A MX PA99006544A MX 9906544 A MX9906544 A MX 9906544A MX PA99006544 A MXPA99006544 A MX PA99006544A
- Authority
- MX
- Mexico
- Prior art keywords
- alkyl
- aryl
- cycloalkyl
- group
- alkoxy
- Prior art date
Links
- 239000000654 additive Substances 0.000 title claims abstract description 22
- 230000000996 additive Effects 0.000 title claims abstract description 19
- 102000002045 Endothelin Human genes 0.000 title description 33
- 108050009340 Endothelin Proteins 0.000 title description 33
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N Endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 title description 32
- 239000000543 intermediate Substances 0.000 title description 4
- 238000007259 addition reaction Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 38
- 238000002360 preparation method Methods 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims description 69
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 55
- 125000003118 aryl group Chemical group 0.000 claims description 52
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 47
- 125000001424 substituent group Chemical group 0.000 claims description 46
- 125000003545 alkoxy group Chemical group 0.000 claims description 39
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 35
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims description 35
- 229910052757 nitrogen Inorganic materials 0.000 claims description 35
- 125000004649 C2-C8 alkynyl group Chemical group 0.000 claims description 34
- 125000000217 alkyl group Chemical group 0.000 claims description 34
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 26
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 229910052717 sulfur Inorganic materials 0.000 claims description 18
- 239000000010 aprotic solvent Substances 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 17
- 239000008079 hexane Substances 0.000 claims description 17
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- -1 N (R5) 2 Chemical group 0.000 claims description 14
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- 125000004452 carbocyclyl group Chemical group 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 230000003197 catalytic Effects 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
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- 125000005038 alkynylalkyl group Chemical group 0.000 claims 1
- RBBOWEDMXHTEPA-UHFFFAOYSA-N hexane;toluene Chemical compound CCCCCC.CC1=CC=CC=C1 RBBOWEDMXHTEPA-UHFFFAOYSA-N 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
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Abstract
This invention relates to a process for the preparation of a key intermediate in the synthesis of an endothelin antagonist, having formula (I) by using a chiral additive to effect an asymmetric conjugate addition.
Description
ENDOTHELINE INTERMEDIARIES OBTAINED THROUGH REACTION OF ASYMMETRIC CONJUGATE ADDITION USING A QUIRAL ADDITIVE
BACKGROUND OF THE INVENTION
The present invention relates to novel key intermediates in the synthesis of an endothelin antagonist, and to the method for preparing these key intermediates of formula I. Compounds having a high affinity for at least one of two receptor subtypes, are responsible for Dilation of the smooth muscle, as in blood vessels or in the trachea. Endothelin antagonist compounds constitute a potentially novel 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, shock of prostatauxia by endotoxin, multiple organ failure induced by endotoxin or disseminated intravascular coagulation, and / or hypertension or renal insufficiency induced by ciclosporin. Endothelin is a polypeptide formed from amino acids, and 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, 41 1-415 (1988)).
Three endothelin isopeptides (endothelin-1, endothelin-2 and endothelin-3), which resemble each other in structure, exist in the body of animals that include humans, and these peptides have vasoconstrictor and pressor effects (Proc. Nati. , Sci, USA, 86, 2863-2867 (1989)). As reported, 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 purifying fluids of the respiratory tract or the blood of patients with asthmatic levels comparatively with normal levels (Japan, J. Hypertension, 12, 79 (1989), J. Vascular Medicine Biology, 2, 207 (1990), Diabetology, 33, 306-310 (1990), J. Am. Med. Association, 264, 2868 (1990) and The Lancet, ii, 747-748 (1989) and ii, 1144-1147 (1990)). In addition, an increased sensitivity of cerebral blood vessels to endothelin has been reported in an experimental model of cerebral vasospasm (Japan, Soc. Cereb. Blood Flow &Metabol., 1, 73 (1989)), improved renal function by the endothelin antibody in a model of acute renal failure (J. Clin. Invest., 83, 1762-1767 (1989)), and inhibition of the development of gastric ulcer with an endothelin antibody in a gastric ulcer model ( the Japanese Society of Experimental Gastric Ulcer, 50 (1991)). Therefore, it is thought that endothelin is one of the mediators that cause acute renal failure or cerebral vasospasm secondary to subarachnoid hemorrhage.
In addition, endothelin is secreted not only by endothelial cells, but also by epithelial cells of the trachea or by renal cells (FEBS Letters, 255, 129-132 (1989) and FEBS Letters, 249, 42-46 (1989)). It was also found that endothelin controls the release of physiologically active endogenous substances such as renin, atrial natriuretic peptide, endothelium-derived relaxation factor (EDRF), thromboxane A2, prostacyclin, noradrenaline, angiotensin II and substance P (Biochem. Biophys, Res. Commun., 157, 1 164-1 168 (1988); Biochem. Biophys, Res. Commun., 155, 20 167-172 (1989); Proc. Nati. 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)). In addition, endothelin causes contraction of smooth muscle of the gastrointestinal tract and uterine smooth muscle (FEBS Letters, 247, 337-340 (1989), Eur. J. Pharmacol., 154, 227-228 (1988), and Biochem. Res. Commun., 159, 317-323 (1989)., endothelin was found to promote the proliferation of vascular smooth muscle cells of the rat, suggesting a possible relevance for arterial hypertrophy (Atherosclerosis, 78, 225-228 (1989)). Furthermore, since endothelin receptors are present at a high density not only in peripheral tissues, but also in the central nervous system, and brain administration of endothelium induces a change in the behavior of animals, endothelin probably plays a role important in the control of nerve functions (Neuroscience Letters, 97, 276-279 (1989)). Particularly, it is suggested that endothelin is one of the mediators for pain (Life Sciences, 49, PL61-PL65 (1991)). Internal hyperplastic response was induced by endothelial denudation with balloon of carotid artery of rats. Endothelin causes a significant worsening of internal hyperplasia (J. Cardiovasc Pharmacol., 22, 355-359 &; 371-373 (1993)). These data support the role of endothelin in the pathogenesis of vascular restenosis. Recently, it has been reported that there are ETA and ETB receptors in the human prostate, and that endothelin produces a powerful contraction of them. These results suggest the possibility that endothelin may intervene in the pathophysiology of benign prostatic hyperplasia (J. Urology, 151, 763-766 (1994), Molecular Pharmacol., 45, 306-311 (1994)). On the other hand, endotoxin is one of the potential candidates that promotes the release of endothelin. A remarkable increase in endothelin levels in the blood or in the endothelial cell culture supernatant was observed when exogenous endotoxin was administered to animals, or was added to endothelial cells in culture, respectively. These findings suggest that endothelin is an important mediator in endotoxin-induced diseases (Biochem, Biophys, Commun., 161, 1220-1227 (1989), and Acta Physiol. Scand., 137, 317-318 (1989)). In addition, cyclosporin was reported to markedly increase endothelin secretion in the kidney cell culture (LLC-PKL cells) (Eur. J. Pharmacol., 180, 191-192 (1990)). In addition, the dosage of ciclosporin to rats reduced the glomerular filtration rate and increased blood pressure in association with a marked increase in the level of circulating endothelin. This renal failure induced by cyclosporine can be suppressed by the administration of endothelin antibody (Kidney Int., 37, 1487-1491 (1990)). Thus, it is thought that endotheiin intervenes significantly in the pathogenesis of diseases induced by cyclosporine. Such diverse effects of endothelin are caused by the binding of endothelin to receptors thereof widely distributed in many tissues (Am. J. Physiol., 256, R856-R866 (1989)). It is known that vasoconstriction by endothelin is caused by at least two subtypes of endothelin receptors (J. Cardiovasc Pharmacol., 17 (Suppl 7), S1 19-SI 21 (1991)). One of the endoteiin receptors is the selective ETA receptor for ET-1, rather than ET-3, and the other is the ETB receptor equally active for ET-1 and ET-3. It is reported that these receptor proteins are different from each other (Nature, 348, 730-735 (1990)). These two subtypes of endothelin receptors are distributed differently in tissues. It is known that the ETA receptor is present mainly in cardiovascular tissues, while the ETB receptor is widely distributed in various tissues such as cerebral, renal, pulmonary, cardiac and vascular tissues. It is thought that substances that specifically inhibit the binding of endothelin to endothelin receptors antagonize several pharmacological activities of endothelin, and that they are useful as a drug in a broad field. Since the action of endothelin is caused not only by the ETA receptor, but also by the ETB receptor, it is desirable that novel non-peptide substances with ET receptor antagonist activity to any receptor subtype, effectively block the activities of endothelin in several diseases. Endothelin is an endogenous substance that directly or indirectly induces (controlling the release of various endogenous substances) the sustained contraction or relaxation of vascular or non-vascular smooth muscles, and it is thought that its excess production or excess secretion is one of the pathogenesis 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. Furthermore, it is suggested that endothelin functions as an important mediator involved in diseases such as restenosis, prostatauxia, endotoxin shock, multiple organ failure induced by endotoxin or disseminated intravascular coagulation, and hypertension or cyclosporin-induced renal failure. Up to now, two endothelin receptors, ETA and ETB, have been known and antagonists of these receptors have been shown to be potential drug targets. EP 0526708 A1 and WO 93/08799 A1 are representative examples of patent applications describing non-peptidic compounds with proposed activity as endothelin receptor antagonists.
The present invention describes the addition of an asymmetric conjugate to prepare the compound of formula I:
a key intermediate in the synthesis of endothein antagonists of the following structure:
where
represents: 5 or 6 membered heterocyclyl, 5 or 6 membered carbocyclyl, and aryl; R1 is C-i-C-s alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, aryl, or heteroaryl;
R2 is OR4 and N (R5) 2; R3b is aryl, or heteroaryl; R4 is CrC8 alkyl; and R5 is CrC8 alkyl, or aryl.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of a compound of formula I:
R3
where
represents: a) 5- or 6-membered heterocyclyl containing 1, 2 or 3 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 1, 2 or 3 substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, C8 alkoxy, C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, b) 5-membered 6-membered carbocyclyl containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, C8 alkoxy, alkyl of C C8, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, c) aryl, wherein aryl is as defined later, alkoxy
C? -C8, C-? -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, C02R4, Br, Cl, F, I, CF3, N (R5) 2, d-C8 alkoxy, C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N (R5) 2, alkoxy Cs, 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 in adjacent carbons, may be joined 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 one, two or three substituents selected from the group consisting of of: H, OH, C02R6, Br, Cl, F, I, CF3, N (R7) 2, alkenyl alkoxy of C2-C8, C2-C8 aikinyl, or C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, R1 is: a) CT-CS alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, b) aryl, c) heteroaryl; heteroaryl is defined as a five or six membered aromatic ring containing one, two or three 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 , C02R4, Br, Cl, F, I, CF3) N (R5) 2, C? -C8 alkoxy, C? -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-cycloalkyl C8, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, R2 is: OR4 or N (R5) 2; R3 is: a) H, b) C? -C8 alkyl, c) C? -C8 alkenyl, d) C8 C alkynyl, e) C? -C8 alkoxy, f) C3-C cycloalkyl, ) S (O) tR5, h) Br, Cl, F, I, i) aryl, j) heteroaryl,
k) N (R5) 2, NH2, m) CHO, n) -CO- C-C8 alkyl, or) -CO-aryl,
P) -CO- heteroaryl, q) -CO2R4, or
r) protected aldehyde; X and Y are independently: 0, S or NR5; n is: from 0 to 5; t is: 0, 1 or 2; R4 is: C -? - C8 alkyl; R5 is: CrC8 alkyl, or aryl; R6 is: H, C8 alkyl, or aryl; R7 is: H, C? -C8 alkyl, aryl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R 5) 2, C 8 alkoxy, C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C 3 -C 8 cycloalkyl, CO (CH 2) n CH 3,
CO (CH2) nCH2N (R5) 2; or when two substituents of R7 are in the same nitrogen, they can be joined to form a ring of 3 to 6 atoms;
which comprises reacting an α, β-unsaturated amide or ester
with an organolithium compound, R1Li, in the presence of a chiral additive and an aprotic solvent at a temperature temperature of about -78 ° C to about 0 ° C.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of a compound of formula I:
where
? represents: a) 5- or 6-membered heterocyclyl containing 1, 2 or 3 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 1, 2 or 3 substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, C8 alkoxy, C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, b) 5- or 6-membered carbocyclyl containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, C8 alkoxy, alkyl of C C8, C2-C8 alkenyl, C2-C8 alkynyl, or C-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, c) aryl, wherein aryl is as defined hereinafter, C -? - C8 alkoxy, C? -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or cycloalkyl
C3-C8, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, C8 alkoxy, cycloalkyl C3-C8, CO (CH2) nCH3 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 , CO 2 R 4, Br, Cl, F, I, CF 3) N (R 5) 2, C 8 alkoxy, C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or C 3 -C 8 cycloalkyl, CO ( CH2) nCH3, CO (CH2) nCH2N (R5) 2, and when two substituents are located on adjacent carbons, they can be joined 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 one, two or three substituents selected from the group consisting of: H, OH, C02R6, Br, Cl, F, I, CF3, N (R7) 2, C8 alkoxy, Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO (CH2) nCH 3 and CO (CH2) nCH2N (R5) 2, R1 is: a) C -? - C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, b) aryl, c) heteroaryl; heteroaryl is defined as a five or six member aromatic ring containing one, two or three 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 , CO2R4, Br, Cl, F, I, CF3, N (R5) 2, CrC8 alkoxy, C? -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, R2 is: OR4 or N (R5) 2; R 3 is: a) H, b) C 8 alkyl, c) C 8 alkenyl, d) C 8 -C 8 alkyny, e) C 1 Cs alkoxy, f) C 3 -C 7 cycloalkyl, g) S (0) ), R5, h) Br, Cl, F, I, ¡) aryl, j) heteroaryl, k) N (R5) 2, i) NH2, m) CHO, n) -CO- C8 alkyl, o) -CO-aryio, P) -CO- heteroaryl, q) -C02R4, or) protected aldehyde; X and Y are independently: O, S or NR5; n is: from 0 to 5; t is: 0, 1 or 2; R4 is: C -? - C8 alkyl; R5 is: C ^ Cs alkyl, or aryl; R6 is: H, C -? - C8 alkyl, and aryl; and R7 is independently: H, C? -C8 alkyl, and aryI, when there are two substituents of R7 in a nitrogen, can be joined to form a 3 to 6 membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, C? -C8 alkoxy, C8 alkyl, C2-C8 alkenyl, alkynyl of C2-C8, or C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, which comprises reacting a rx, β-unsaturated amide or ester
with an organolithium compound, R1Li, in the presence of a chiral additive and an aprotic solvent at a temperature scale of about -78 ° C to about 0 ° C. The process is as described above, wherein the number of equivalents of the organolithium compound, R1Li, is from 1 to about 4, and preferably from about 1.5 to about 2.5. The process is as described above, wherein the chiral additive is a chiral compound capable of coordinating with chiral additives, such as a) (-) - aspartin, b) NNN'.N'-tetraalkyl C6-transcarboxylic acid 1,2-diaminocyclohexane, or
wherein R 8 and R 9 are independently: H, C 1 -C 6 alkyl, aryl or C 3 -C 7 cycloalkyl, except that R 8 and R 9 can not be simultaneously H; and R 0 is aryl or C 1 -C 6 alkyl, are useful in this process. It is understood that the amino alcohol represented by the structure described above has at least one, and potentially two, chiral centers. The process is as described above, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, MTBE (t-butyl methyl ether), toluene, benzene, hexane, pentane and dioxane, or a mixture of said solvents. The process is as described 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 toluene with a catalytic amount of tetrahydrofuran, preferably hexane and toluene with a catalytic amount of tetrahydrofuran. The process is as described above, wherein the temperature scale is from about -78 ° C to about -20 ° C, and preferably from about -78 ° C to about -50 ° C. One embodiment of this invention is the process for the preparation of a compound of formula I: wherein
represents: a) 5- or 6-membered heterocyclyl containing 1, 2 or 3 double bonds, but at least one double bond and 1, 2 cf 3 heteroatoms selected from O, N and S, the heterocyclyl is unsubstituted or substituted with 1, 2 or '3 substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, C? -C8 alkoxy, C? Cs alkyl, alkenyl C2-C8, C2-C8 alkynyl) or C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, b) 5-6 membered carbocyclyl containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, akoxy of d-Cs, Ct-Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, c) arium, where aryl is as defined below, alkoxy
C1-C5, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, or cycloalkyl
C3-C8, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R) 2, C8 alkoxy, cycloalkyl C3-C8, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, ary is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH , C02R4, Br, C, F, I, CF3, N (R5) 2, d-Cs alkoxy, C8 alkyl, C2-C8 alkenyl, C2-C8 aikinyl, or C3-C8 cycloalkyl, CO (CH2) nCH3, CO (CH2) nCH2N (R5) 2, and when two substituents are located on adjacent carbons, they can be joined 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 one, two or three substituents selected from the group consisting of: H, OH, CO2R6, Br, Cl, F, I, CF3, N (R7) 2, C alkoxy C8, Cs alkyl, C2-C8 alkenyl) C2-C8 alkynyl, or C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH 2) nCH 2 N (R 5) 2, R 1 is: a) C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 8 cycloalkyl, b) aryl, or c) heteroaryl; heteroaryl is defined as a five or six membered aromatic ring containing one, two or three 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 , C02R4, Br, Cl, F, I, CF3, N (R5) 2, Ci-Cs alkoxy, C?-C8 alkyl, C2-C8 alkenyl, C2-C8 aikinyl, or C3-C8 cycloalkyl , CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, R2 is: OR4 or N (R5) 2; R3 is a) CHO, b) CH (OR4) 2; n is: from 0 to 5, t is: 0, 1 or 2; X and Y are independently: O, S or NR5; R 4 is C 1 -C 8 alkyl; R5 is: C ^ Cs alkyl, or aryl; R6 is: H, C? -C8 alkyl, and aryl; R7 is independently: H, C-C8 alkyl, and aryl, when there are two substituents of R7 on a nitrogen, can be joined to form a 3 to 6 membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, C-? - C8 alkoxy, C ^ Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO (CH2) pCH3 and CO (CH2) nCH2N (R5) 2, which comprises the steps of: 1) reacting an α, β-unsaturated amide or ester
wherein R3 is CH (OR4) 2; with an organolithium compound, R1Li, in the presence of a chiral additive and an aprotic solvent at a temperature scale of about -78 ° 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, wherein R3 is CHO. The process is as described above, wherein the number of equivalents of the organolithium compound, R1Li, is from 1 to about 4, and preferably from about 1.5 to about 2.5. The procedure is as described above, wherein the chiral additive is a chiral compound capable of coordinating with chiral additives, such as a) (-) - aspartein, b) N, N, N ', N'-tetraalkium of C? -C6-trans-1, 2-diamino-cyclohexane, oc)
wherein R 8 and R 9 are independently: H, C 1 -C 7 alkyl, aryl or C 3 -C 7 cycloalkyl, except that R 8 and R 9 can not be simultaneously H; and R10 is aryl or C-Cß alkyl, are useful in this process. The process is as described above, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, MTBE (t-butyl methyl ether), toluene, benzene, hexane, pentane and dioxane, or a mixture of said solvents. The process is as described 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 toluene with a catalytic amount of tetrahydrofuran, preferably hexane and toluene with a catalytic amount of tetrahydrofuran. The process is as described above, wherein the temperature scale is from about -78 ° C to about -20 ° C, and preferably from about -78 ° C to about -50 ° C. One modality of this invention is the procedure for the preparation of the protected aldehyde:
which comprises reacting an α, β-unsaturated amide or ester
with an organolithium compound
in the presence of a chiral additive and an aprotic solvent at a temperature scale of about -78 ° C to about -20 ° C. The process is as described above, wherein the number of equivalents of the organolithium compound, R1Li, is from 1 to about 4, and preferably from about 1.5 to about 2.5. The procedure is as described above, wherein the chiral additive is a chiral compound capable of coordinating with chiral additives, such as a) (-) - aspartein, b) N, N, N ', N'-tetraalkyl of C? -C6-trans-1, 2-diamino-cyclohexane, or
wherein R8 and R9 are independently: H, CrC6 alkyl, aryl or C3-C7 cycloalkyl, except that R8 and R9 can not be simultaneously H; and R10 is aryl or C6 alkyl, are useful in this process. The process is as described above, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, MTBE (t-butyl methyl ether), toluene, benzene, hexane, pentane and dioxane, or a mixture of said solvents. The process is as described above, wherein the preferred aprotic solvent is 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 is as described above, wherein the temperature rise is from about -78 ° C to about -20 ° C, preferably from about -78 ° C to about -50 ° C, and more preferably from about -78 ° C to about -70 ° C. It is further understood that the aforementioned substituents would include the definitions given below.
The alkyl substituents described above denote straight and branched chain hydrocarbons of the specified length, such as methyl, ethyl, isopropium, isobutyl, tert-butyl, neopentyl, isopentyl, etc. The alkenyl substitutes denote alkyl gs as described above, which are modified, so that each contains a carbon carbon double bond, such as vinyl, allyl and 2-butenyl. Cycloalkyl denotes rings composed of 3 to 8 methylene gs, each of which can be substituted or unsubstituted with other hydrocarbon substituents, and include for example cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl. The alkoxy substituent represents an alkyl g as described above linked thh an oxygen bridge. The heteroaryl substituent represents a carbazolyl, furanyl, thienyl, pyrrolyl, isothiazolyl, midazolyl, isoxazoyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl and purinyl. The heterocyclyl substituent represents a pyridyl, pyrimidium, thienium, furanyl, oxazolidinyl, oxazoylyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl or pyrrolidinyl. The protected aldehyde represents an acetal, such as -CH (0 C? -C8 alkyl) 2 >;
The α, β-unsaturated amide or ester
it can be prepared generally in two steps: 1) a coupling reaction at position one of ring A
wherein R is CHO, Z is a residual group, such as Br, Cl, I, O triflyl, O tosyl or O mesyl and R2 is OR4 or N (R5) 2; and 2) the conversion of the aldehyde (R3 is CHO) to the desired protected aldehyde (R3 is CH (OR4) 2 and R4 is C8 alkyl). The commercially available pyridone 1 is alkylated by its dianion with propyl bromide, and the product is then converted to the bromopyridine 3a using a brominating agent such as PBr3. The nitrile 3a is then reduced to the aldehyde 3 using diisobutylaluminum hydride (DIBAL). The aldehyde then undergoes a Heck reaction with t-butyl acrylate using NaOAc, (alii) 2PdCl2, tri-o-tolyl-phosphine, toluene, at reflux to provide the unsaturated 4a ester in high yield. The unsaturated ester 4a is then treated with an alcohol (R4OH) and aqueous acid to give the 5a acceptor of acetal.
SCHEME 1
H
The commercially available acid is reduced with BH3 »SMe2 to alcohol 11, which is then converted to bromide 13, by mesylate 12 using mesyl chloride, triethylamine followed by the addition of NaBr and dimethylacetamide (DMAC).
SCHEME 2
12 13
The commercially available 1, 2-aminoindanol is acylated (propionyl chloride, K2CO3) to give amide 8, which is then converted to acetonide 9 (2-methoxypropene, pyridinium p-toluene sulfonate (PPTS)). The acetonide 9 is then alkylated with bromide 13 (LiHMDS) to give compound 14, which is then hydrolyzed (H +, MeOH) to give a mixture of acid and methyl ester 15. The reduction (LAH) of the ester mixture / acid provides alcohol 16 with high yield and optical purity. Alcohol protection 16 (TBSCI, midazole) provides bromide 17, the precursor of organolithium 17a.
SCHEME 3
14
95%, 99.5% e.e. Compound 17a and a chiral additive, such as aspartin, are added to α, β-unsaturated ester 5a from -78 to -50 ° C. The preparation with water produces compounds 6a and 6b. The mixtures of the compounds 6a and 6b are treated with TBAF or aqueous acid to deprotect the silylated alcohol or acetal and the silylated alcohol.
SCHEME 4
6c / 6d 6e / 6f The present invention can be better understood by the following examples, which do not constitute a limitation thereof.
EXAMPLE 1
Preparation of compound 1 Compound 1 is a commercially available starting material, for example, see Aldrich Chemical Company, Milwaukee, WI, USA 53201.
EXAMPLE 2
1 Preparation of compound 2 Düsopropyiamine (MW 101 .19, d 0.772, 2.1 eq., 20.54 ml) in 200 ml of THF. Cool to -50 ° C and add n-BuLi (1.6 M in hexanes, 2.05 eq., 96 mL), allowing the solution to warm to -20 ° C. Aging from 0 to 3 ° C for 15 minutes, then cool to -30 ° C and add compound 1 (MW 134.14, 75 mmol, 10.0 g). Aging from 0 ° C to 43 ° C for 2 hours. Cool to -50 ° C and add bromopropane (MW 123.00, d 1354, 1.0q eq., 6.8 ml). Heat at 25 ° C for 30 minutes, and age for 30 minutes. Add NH4CI and CH2CI2. Dry the organic layers (magnesium sulfate), and then evaporate in vacuo to yield 61% of compound 2.
EXAMPLE 3
2
Preparation of compound 3 Mix compound 2 (MW 176.22, 46 mmole) and PBr3 (MW 270.70, d 2.880, 2.5 eq., 10.8 ml) and age at 160 ° C. After 2 hours, cool to 25 ° C and add a certain amount of CH2Cl2. Temper slowly by adding water. Separate the layers and wash the aqueous solution 2 times with CH2Cl2. Combine the organic layers and dry (magnesium sulfate). Concentrate and isolate the solids by silica gel chromatography (90:10 ratio of hexanes: ethyl acetate) with 60% yield (MW 239.12, 6.60 g). Dissolve the product of the bromination reaction (MW 239.12, 27.6 mmoles, 6.60 g) in 66 ml of toluene, and cool to -42 ° C. Slowly add DIBAL (1.5 M in toluene, 2 eq., 37 ml) and age 1 hour at -42 ° C. Add HCl (2 N, 10 eq., 134 ml) and stir vigorously for 30 minutes. Dilute with ethyl acetate, separate the layers, and wash the aqueous solution with ethyl acetate. Combine the organic layers, dry (magnesium sulfate), and concentrate in vacuo to yield 90% (MW 242.1 1, 6.01 g) of compound 3.
EXAMPLE 4a
Preparation of compound 4a Dissolve compound 3 (MW 242.1 1, 24.8 mmol, 6.01 g) in 75 ml of toluene. Add sodium acetate (MW 82, 3 eq., 6.13 g), t-butyl acrylate (MW 128.17, d 0.875, 2.5 eq., 9.08 ml), P (o-tolyl) 3 (MW 304.38, 10 mol% , 755 mg) and allyl-palladium chloride dimer (MW 365.85, 5 mol%, 455 mg). Aging at reflux for 24 hours. Cool, filter and evaporate in vacuum. Isolate compound 4a (MW 289.37) by silica gel chromatography (ratio 92: 8 hexanes: ethyl acetate) in 80% yield (5.74 g).
EXAMPLE 4b
Preparation of compound 4b Dissolve compound 3 (MW 242.11, 24.8 mmol, 6.01 g) in 75 ml of toluene. Add sodium acetate (MW 82, 3 eq., 6.13 g), dimethylacrylamide (MW 99.13, d 0.962, 1 eq., 2.55 ml), PPh3 (MW 262.29, 10 mol%, 653 mg) and allyl chloride dimer of palladium (MW 365.85, 5 mol%, 455 mg). Aging at 140 ° C in a sealed tube for 24 hours. Cool, filter and evaporate in vacuum. Isolate compound 4b (MW 260.34) by silica gel chromatography (ratio 80:20 hexanes: ethyl acetate) in 70% yield (4.52 g).
EXAMPLE 5a
Preparation of compound 5a A solution of 16.0 g (55.36 mmoles) of aldehyde 4a was heated and
1. 4 g (5.54 mmoles) of PPTS in 280 ml of MeOH at reflux for 2.5 hours. After cooling to room temperature, the solvents were evaporated in vacuo. The residue was dissolved in EtOAc and washed with saturated sodium bicarbonate solution. The concentration of the organic layer gave 18.2 g of the desired product 5a in 98% yield. 1 H NMR (CDCl 3) d: 7.95 (d, 1 H), 7.80 (d, 1 H), 7.12 (d, 1 H), 7.04 (d, 1 H), 5.09 (1 H), 3.45 (s, 6 H) ), 2.80 (t, 2H), 1.73 (m, 2H), 1.54 (s, 9H), 1.40 (m, 2H), 0.95 (t, 3H) ppm.
EXAMPLE 6 Step A: Preparation of Compounds 6a and 6b To a solution of compound 17 (2.23 g, 5.97 mmol), (-) aspartein (1.37 mL, 5.97 mmol) and THF (73 μL, 0.896 mmol) in 20 ml of toluene at -78 ° C was added dropwise t-BuLi (1.7 M in hexane, 7.0 ml, 1.94 mmole). The solution was aged for 30 minutes at -78 ° C. A solution of the 5-unsaturated t-butyl ester (1.0 g, 2.98 mmol) in 5 ml of toluene was added dropwise over 10 minutes at -78 ° C. After 20 minutes at -78 ° C, the reaction was warmed 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 in 81% yield. For the main diastereomer 6b: 1 H NMR (CDCl 3) d: 7.24 (dd,
1 H), 7.00 (d, 1 H), 6.84 (d, 1 H), 6.70 (d, 1 H), 6.55 (dd, 1 H), 5.74 (s, 1 H). 5.02 (m,
1 H), 3.72 (s, 3 H), 3.55 (m, 4 H), 3.22 (s, 3 H), 2.92 (s, 3 H). 2.80 (t, 2H), 2.50 (m, 2H), 2.12 (m, 1 H), 1.75 (m, 2H), 1.40 (m, 2H), 1.28 (s, 9H), 0.95 (m, 6H) ), 0.90 (s,
9H), 0.09 (s, 3H), 0.08 (s, 3H) ppm. To determine the ratio of the two diastereomers 6a and 6b, the above compounds were further deprotected by treatment with TBAF in THF or with HCl or pTSA in aqueous acetone.
Step B: Preparation of compounds 6c and 6d (method A) A solution of 500 mg (0.8 mmol) of the above products 6a and 6b and 0.96 ml of TBAF (1.0 M in THF) was allowed to stir for 4 hours at room temperature. in 6 ml of THF. The reaction solution was then washed with water and dried over sodium sulfate. The product was analyzed by 1 H NMR. The integration of the individual band peaks at 5.42 ppm (major diastereomer) and 5.38 ppm (minor diastereomer) was used to determine the ratio of the two diastereomers.
Step C: Preparation of Compounds 6e and 6f (Method B) A solution of 100 mg (0.16 mmol) of the above products 6a and 6b in 3 mL of acetone and 1 mL of HCl was allowed to stir for 5 hours at room temperature. 5% or 45 mg of pTSA in 3 ml of acetone and 1 ml of water. 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 1 H NMR. The integration of the individual band peaks at 10.35 ppm (major diastereomer) and 10.20 ppm (minor diastereomer) was used to determine the ratio of the two diastereomers.
EXAMPLE 7
Preparation of compound 7 Compound 7 is a commercially available starting material, for example, see DSM Andeno, Grubbepvorsterweg 8, P.O. Box 81. 5900 AB Venlo, Holland.
EXAMPLE 8
8
Preparation of compound 8 Na2CO3 (MW 105.99, 1.5 eq., 8.8 g) dissolved in 82 ml of water.
Add a solution of aminoindanol 7 (1 R, 2S) (MW 149.19, 55.0 mmole, 8.2 g) in 160 ml of CH2Cl2. Cool to -5 ° C and add propionyl chloride (MW 92.53, d 1.065, 1.3 eq., 6.2 ml). Heat at 25 ° C and age for 1 hour. Separate and dry the organic layers (magnesium sulfate). Concentrate in vacuo to yield compound 8 (MW 205.26, 10 g) with 89% isolated yield.
EXAMPLE 9
8
Preparation of compound 9 To a solution of compound 8 (MW 205.26, 49.3 mmol, 10 g) in
200 ml of THF, add pyridinium p-toiuensulfonate (PPTS) (MW 251 .31, 0.16 eq., 2 g) and then methoxypropene (MW 72.1 1, d 0.753, 2.2 eq., 10.4 ml). Aging for 2 hours at 38 ° C, and then adding aqueous sodium bicarbonate and ethyl acetate. Dry the organic layer (magnesium sulfate). After concentrating in vacuo, compound 9 (MW 245.32, 12.09 g) is formed in quantitative yield.
EXAMPLE 10
Preparation of compound 10 Compound 10 is a commercially 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.
EXAMPLE 11
Preparation of compound 11 Compound 10 (MW 231.05, 130 mmol, 30.0 g) in 300 ml of CH 2 Cl 2 at 0 ° C. Add BH3-SMe2 (3 eq., 25.2 ml) and age for 2 hours at 25 ° C. Temperate in aqueous HCl at 2 N, and separate the layers. Dry the organic layers (magnesium sulfate) and concentrate in vacuo to obtain 94% yield of compound 11 (MW 217.06, 25.5 g).
EXAMPLE 12
Preparation of compound 12 Dissolve compound 11 (MW 217.06, 47.2 mmol, 10.24 g) in 55 ml of CH 2 Cl 2, and cool to -20 ° C. Add DIEA (MW 129.25, d 0.742, 1.3 eq., 10.69 ml), and then methanesulfonyl chloride (MsCl) (MW 114.55, d 1.480, 1.2 eq., 4.38 ml). Aging from -5 ° C to 0 ° C for 1 hour and then tempering in 55 ml of water. Extract with CH2Cl2, and then wash with H2SO4 at 1 N (40 mL), and then with brine. Dry the organic layers (magnesium sulfate) and concentrate in vacuo to yield compound 12 (MW 295.15, 13.23 g) in 95% yield.
EXAMPLE 13
Preparation of compound 13 Compound 12 (MW 295.15, 44.8 mmol, 13.23 g) in 44 ml of dimethylacetamide (DMAC). Add NaBr (MW 102.90, 2 eq., 9.22 g), and age for 1 hour. Add 88 ml of water and collect the solids by filtration.
Wash the cake with water and dry by suction. The quantitative yield of compound 13 is obtained (MW 279.96, 12.54 g).
Preparation of compound 14 Compound 9 (MW 245.32, 1.1 eq., 89.1 g) in 1 L of THF, cooled to -50 ° C. Add LiHMDS (1.0 M in THF, 1.5 eq., 545 ml) and age for 1.5 hours, heating to -30 ° C. Add compound 13 (MW 279.96, 327 mmol, 91.3 g) in 300 ml of THF, and age at -35 ° C for 1 hour. Heat at -10 ° C for 1 hour, and then quench in aqueous NH CI. Separate the layers and extract with ethyl acetate. Dry the organic layers and concentrate in vacuo to yield the crude product 14 (MW 444.37).
EXAMPLE 15
Preparation of compound 15 Compound 14 in one liter of MeOH and cooled to 10 ° C. Bubble in gaseous HCl for 1 hour until the reaction is complete. Add 2 liters of H20 and filter the product. Wash the cake with H20 and dry to obtain the hydroxyamide product, which is then dissolved in 1 liter of MeOH and 1.5 l of HCl at 6N and refluxed overnight. Cool the mixture to 25 ° C and extract with CH2C2 to give, after concentration, compound 15 (60 g, 64% of bromide 13).
EXAMPLE 16
Preparation of compound 16 Compound 15 (mixture of acid and ester, 26.88 mmol) in 150 ml of THF at -78 ° C. Add lithium aluminum hydride (UAIH4) (1 M in THF, 2 eq., 53.76 mi) for 30 minutes. Heat at 25 ° C for 1 hour, and then quench in aqueous NH 4 Cl. Add ethyl acetate and extract the same. Wash the organic layers with brine, dry (magnesium sulfate) and concentrate in vacuo to yield 95% yield of compound 16 (MW 259.14, 6.62 g).
EXAMPLE 17
Preparation of compound 7 Compound 16 (MW 259.14, 25.54 mmol, 6.62 g) in 35 ml of CH2Cl2 and cooled to 0 ° C. Add imidazole (MW 68.08, 2.5 eq., 4.35 g) and then tert-butyldimethylsilyl chloride (TBSCI) (MW 150.73, 1 eq., 3.85 g). Aging for 1 hour at 25 ° C, then quenching with aqueous NaHCO 3 and adding ethyl acetate. Extract with ethyl acetate, then dry the organic layer (magnesium sulfate) and concentrate in vacuo to yield a quantitative yield of compound 17 (MW 373.41, 9.54 g). 1 H NMR (CDCl 3: 7.41 (d, J = 8.74, 1 H), 6.77 (d, J = 3.04, 1 H), 6.63 (dd, J = 8.73, 3.06, 1 H), 3.78 (s, 3 H) , 3.50 (d, J = 5.75, 2H), 2.89 (dd, J = 13.31, 6.15, 1 H), 2.45 (dd, J = 13.30, 8.26, 1 H), 2.03 (m, 1 H), 0.94 ( s, 9 H), 0.92 (d, J = 5.01, 3H), 0.07 (s, 6H).
13 C NMR (CDCl 3): 159.1, 141.6, 133.2, 117.0, 115.4, 113.2, 67.4, 55.4, 39.7, 36.3, 26.0 (3C), 18.4, 16.5, -5.3 (2C).
EXAMPLES 18 TO 22
Following the procedure described in Example 6, the aforementioned chiral additive resulted in the indicated diastereomeric ratios of compounds 6a and 6b.
Example No. Chiral additive Diastereomeric ratio (6a: 6b)
6 (-) aspartein 1: 5 18 N-methyl ephedrine 1: 1
Ph Me 21 3.7: 1 MeO N
22 2.2: 1 ME-
Claims (18)
1. - A process for the preparation of a compound of formula I: where represents: a) 5- or 6-membered heterocyclyl containing 1, 2 d 3 double bonds, but at least one double bond and 1, 2 d 3 heteroatoms selected from O, N and S, the heterocyclyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, C8 alkoxy, C8 alkyl, C2-C8 alkenyl > C2-C8 alkynyl, or C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, b) 5- or 6-membered carbocyclyl containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, C-Cβ alkoxy, alkyl of C C8, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO (CH2) nCH3 and C0 (CH2) nCH2N (R5) 2, c) aryl, wherein aryl is as defined below, C8-C-alkoxy, C-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 consists of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, C ^ Cs alkoxy, C3-C8 cycloalkyl, CO (CH2) nCH3 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 with system of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, CrC8 alkoxy, C? -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3 cycloalicylic acid -C8, CO (CH2) nCH3, CO (CH2) nCH2N (R5) 2 > and when two substituents are located on adjacent carbons, they can be joined 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 one, two or three substituents selected from the group consisting of: H, OH, C02R6, Br, Cl, F, 1, CF3, N (R7) 2, C? -C8 alkoxy, C? -C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2l R1 is: a) C?-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, b) aryl, c) heteroaryl; heteroaryl is defined as a five or six membered aromatic ring containing one, two or three 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 , C02R4, Br, Cl, F, I, CF3, N (R5) 2, CrC8 alkoxy, C8 alkyl, C2-C8 alkenylene, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO (CH2) ) nCH3 and CO (CH2) nCH2N (R5) 2, R2 is: OR4 or N (R5) 2; R3 is: H, C? -C8 alkyl, d-Cs alkenyl, C8 alkynyl, d-C8 alkoxy, C3-C7 cycloalkyl, S (O) tR5, Br, Cl, F, I, aryl , heteroaryl, N (R5) 2, NH2, CHO, -CO- C8 alkyl, -CO-aryl, -CO-heteroaryl, -C02R4, or protected aldehyde; X and Y are independently: O, S or NR5; n is: from 0 to 5; t is: 0, 1 or 2; R4 is: C? -C8 alkyl; R5 is: C? -C8 alkyl, or aryl; R6 is: H, C-r C8 alkyl, or aryl; R7 is independently: H, C? -C8 alkyl, and aryl, when there are two substituents of R7 in a nitrogen, can be joined to form a 3 to 6 membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, CrC8 alkoxy, CrC8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or cycloalicyue of C3-C8, CO (CH2) nCH3, CO (CH2) nCH2N (R5) 2; which comprises reacting an amide or ester, β-unsaturated with an organolithium compound, R1Li, in the presence of a chiral additive and an aprotic solvent at a temperature scale of about -78 ° C to about 0 ° C.
2. - The process according to claim 1, further characterized in that the number of equivalents of the organolithium compound, R1 Li, is from 1 to about 4.
3. The process according to claim 2, further characterized in that the chiral additive is selected from the group consisting of: (-) - asparteine, N, N, N ', N' -tetraalkyl of C -? - C6-trans 1,2-diamino-cyclohexane, or wherein R 8 and R 9 are independently: H, C 1 -C 6 alkyl) aryl or C 3 -C 7 cycloalkyl, except that R 8 and R 9 can not be simultaneously H; and R10 is aryl or C6-C6 alkyl.
4. The process according to claim 3, further characterized in that the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, t-butyl methyl ether, benzene, toluene, hexane, pentane and dioxane, or a mixture of said solvents.
5. - The method according to claim 4, further characterized in that the temperature scale is from about -78 ° C to about -20 ° C.
6. - A process for the preparation of a compound of formula I: where represents: a) 5- or 6-membered heterocyclyl containing 1, 2 or 3 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 1, 2 or 3 substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, C? -C8 alkoxy, C? -C8 alkyl, C2 alkenyl -C8, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, b) 5- or 6-membered carbocyclyl containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubstituted or substituted with 1, 2 or 3 substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, C akoxy C8, C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, c) aryl, wherein aryl is as defined below, d-Cs alkoxy, C?-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or cycloalkyl C3-C8, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, C8 alkoxy, C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted by one, two or three substituents selected from the group consisting of : OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, C? -C8 alkoxy, C? -C8 alkyl, C-C8 alkenyl, C-C8 alkynyl, or cycloalkyl C3-C8, CO (CH2) nCH3, CO (CH2) nCH2N (R5) 2l and when two substituents are located on adjacent carbons, they can be joined 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 one, two or three substituents selected from the group consisting of: H, OH, C02R6, Br, Cl, F, 1, CF3, N (R7) 2, C? -C8 alkoxy, CrC8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloaicil, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, R1 is: a) C -? - C8 alkyl, C2 - C8 alkenyl, C2 - C8 - aikinyl, C3 - C8 - cycloalkyl, b) aryl, c) heteroaryl; heteroaryl is defined as a five or six membered aromatic ring containing one, two or three 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 , C02R4, Br, Cl, F, I, CF3, N (R5) 2, C? -C8 alkoxy, Cs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, R2 is: OR4 or N (R5) 2; R3 is CHO, CH (OR4) 2; n is: from 0 to 5, t is: 0, 1 or 2; X and Y are independently: O, S or NR5; R4 is CrC8 alkyl; R5 is: C -? - C8 alkyl, or aryl; R6 is: H, alkyl of d-Cs, and aryl; R7 is independently: H, d-C8 alkyl, and aryl, when there are two substituents of R7 on a nitrogen, they can be joined to form a 3 to 6 membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, C02R4, Br, Cl, F, I, CF3, N (R5) 2, d-C8 alkoxy, d-C8 alkyl, C2-C8 alkenylene, C2 alkynyl -C8, or C3-C8 cycloalkyl, CO (CH2) nCH3 and CO (CH2) nCH2N (R5) 2, which comprises the steps of: 1) reacting an α, β-unsaturated amide or ester wherein R3 is CH (OR4) 2; with an organolithium compound, R1Li, in the presence of a chiral additive and an aprotic solvent at a temperature scale of about -78 ° 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, wherein R3 is CHO.
7. - The method according to claim 6, further characterized in that the number of equivalents of the organolithium compound, R1 Li, is from 1 to about 4.
8. - The method according to claim 7, further characterized in that the chiral additive is selected from the group consisting of: (-) - asparteine, N, N, N ', N'-tetraalkyl of C -? - C6-trans- 1, 2-diamino-cyclohexane, or wherein R8 and R9 are independently: H, d-C6 alkyl, aryl or C3-C7 cycloalkyl, except that R8 and R9 can not simultaneously be H; and R10 is aryl or C6 alkyl.
9. The process according to claim 8, further characterized in that the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, t-butyl methyl ether, benzene, toluene, hexane, pentane and dioxane, or a mixture of said solvents.
10. - The method according to claim 9, further characterized in that the temperature scale is from about -78 ° C to about -20 ° C.
11. - A procedure for the preparation of which comprises reacting an α, β-unsaturated amide or ester with an organolithium compound in the presence of a chiral additive and an aprotic solvent at a temperature scale of about -78 ° C to about -20 ° C.
12. - The process according to claim 11, further characterized in that the number of equivalents of the organolithium compound, R1 Li, is from 1 to about 4.
13. - The method according to claim 1, further characterized in that the chiral additive is selected from the group consisting of: (-) - aspartein, N, N, N ', N'-tetraalkyl of CrC6-trans-1, 2 -diamino-cyclohexane, or R1 wherein R8 and R9 are independently: H, d-C6 alkyl, aryl or C3-C7 cycloalkyl) except that R8 and R9 can not simultaneously be H; and R10 is aryl or d-C6 alkyl.
14. - The process according to claim 13, further characterized in that the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, t-butyl methyl ether, benzene, toluene, hexane, pentane and dioxane, or a mixture of said solvents.
15. - The method according to claim 14, further characterized in that the temperature scale is from about -78 ° C to about -50 ° C.
16. - The process according to claim 15, further characterized in that the number of equivalents of the organolithium compound, R1 Li, is from 1.5 to about 2.5.
17. The process according to claim 16, further characterized in that the aprotic solvent is toluene or a mixture of toluene-hexane (catalytic) -tetrahydrofuran.
18. - The method according to claim 17, further characterized in that the temperature drop is from about -78 ° C to about -70 ° C.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US035462 | 1993-03-23 | ||
US60/035462 | 1997-01-14 | ||
GB9705858.0 | 1997-03-21 |
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MXPA99006544A true MXPA99006544A (en) | 2000-01-21 |
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