HRP980001A2 - Asymmetric conjugate addition reaction using a chiral additive - Google Patents

Description

State of the art

This invention relates to new key intermediates in the synthesis of endothelin antagonists and the method of preparation of the subject intermediates from Formula I.

Compounds that have a pronounced affinity for at least one of the two receptor subgroups are responsible for the dilation of smooth muscles, such as blood vessels or those in nitrogen. Endothelin antagonistic compounds provide a potential new therapeutic effect, especially in the treatment of high blood pressure, pulmonary hypertension, Raynaud's disease, acute kidney failure, myocardial infarction, angina pectoris, stroke, cerebral vasospasm, arteriosclerosis, asthma, gastric ulcer, diabetes, restenosis, prostatitis endotoxin shock, endotoxin-induced multiple organ failure and disseminated intravascular coagulation, as well as ciclosporin-induced kidney failure or high blood pressure.

Endothelin is a polypeptide composed of amino acids, and it is produced by the endothelial cells of human and pig blood vessels. Endothelin has a strong vasoconstrictor effect, as well as a strong and long-lasting effect on blood pressure (Nature, 332, 411-415, (1988)).

In the body of animals, including humans, there are 3 endothelin isopeptides (endothelin-1, endothelin-2 and endothelin-3), which are similar in structure to each other, and act on blood vessel constriction and blood pressure. (Proc. Natl. Acad. Sci, USA, 86, 2863-2867 (1989)).

As known in the literature, the level of endothelin is undoubtedly elevated in the blood of patients with essential hypertension, Paynaud's disease, diabetes or arteriosclerosis, and in the weeping fluids of the respiratory tract or blood of patients with asthma compared to normal levels (Japan, J. Hypertension, 12 , 79, (1989), J. Vascular medicine Biology, 2, 207 (1990), Diabetologia, 33, 306-310 (1990), J. Am. Med.

Association, 264, 2868 (1990), and Lancet, ii, 747-748 (1989) and ii, 1144-1147 (1990).

Also determined and published: increased sensitivity of cerebral blood vessels to endothelin in an experimental model of cerebral vasospasm (Japan. Soc. Cereb. Blood Flow & Metabol., 1, 73 (1989)), improvement of kidney function using endothelin antibody in a model of acute kidney failure (J. Clin. invest., 83, 1762 -1767 (1989), as well as the inhibition of gastric ulcer development by endothelin antibody in a gastric ulcer model (Extract of Japanese Society of Experimental Gastric Ulcer, 50 (1991). Therefore, endothelin is considered one of the mediators that cause acute renal failure or cerebral vasospasm after subarachnoid hemorrhage.

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

It was also established that endothelin controls the secretion of physiologically active endogenous substances such as renin, atrial natriuretic peptide, EDRF (endothelium-derived relaxing factor), 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 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 gastrointestinal smooth muscle and 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)). Endothelin has also been found to enhance the growth of smooth muscle cells in rats, suggesting a possible association with arterial hypertrophy (Atherosclerosis, 78, 225-228 (1989)). As endothelin receptors are densely present not only in peripheral tissues but also in the central nervous system, and cerebral application causes behavioral changes in animals, it seems that endothelin plays an important role in the control of nerve functions (Neuroscience Letters, 97, 276 - 279 (1989)) . The role of endothelin as a mediator of pain is considered particularly important (Life Sciences, 49, PL61 - PL65 (1991)).

In one experiment on rats, an internal hyperplastic reaction was provoked by exposing the endothelium in the carotid artery with a balloon. Endothelin causes a significant worsening of intimal hyperplasia (J. Cardiovasc. Pharmacol., 22, 355-359 & 371-373 (1993)). These data confirm the role of endothelin in the pathogenesis of vascular restenosis. It has recently been reported that both ETA and ETB receptors exist in the human prostate, and that endothelin causes strong prostate contractions, and such results suggest that endothelin is associated with 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 possible candidates that stimulate the secretion of endothelin. A significant increase in the level of endothelin in the blood or in the liquid part of the endothelial cell culture was observed after endotoxin was externally administered to the animals, i.e. after addition to the endothelial cell culture. The aforementioned findings indicate that endothelin is an important mediator in diseases caused by endotoxin (Biochem. Biophy. Commun., 161, 1220-1227 (1989); and Acta Physiol. Scand., 137, 317-318 (1989)).

Cyclosporine has also been found to significantly increase endothelin secretion in kidney cell culture (LLC - PKL) cells (Eur. J. Pharmacol., 180, 191-192 (1990)). Administration of cyclosporine to rats decreased glomerular filtration rate and increased blood pressure, with a simultaneous significant increase in circulating endothelin levels. Cyclosporine-induced renal failure can be reversed by administration of an endothelin antibody (Kidney Int., 37, 1487-1491 (1990)). Therefore, endothelin is thought to be significantly related to the pathogenesis of cyclosporine-induced diseases.

The aforementioned various actions of endothelin are caused by the binding of endothelin to endothelin receptors, which are widespread in many tissues (Am. J. Physiol., 256, R856-R866 (1989)).

Endothelins are known to cause vasoconstriction via at least two endothelin receptor subtypes (J. Cardiovasc. Pharmacol., 17 (suppl.7), S119-S121 (1991)). One of the endothelin receptors is the ETA receptor, which is more sensitive to ET-1 than to ET-3, and the other is the ETB receptor, which is equally active on ET-1 and ET-3. These two receptor proteins were found to be distinct from each other (Nature, 348, 730-735 (1990)).

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

It is believed that substances that specifically prevent the binding of endothelin to endothelin receptors antagonize various pharmacological actions of endothelin, and that they are useful as drugs in a wide field of application. As the action of endothelin is achieved not only through the ETA receptor, but also through the ETB receptor, new non-peptide substances with antagonistic ET action on both types of receptors are needed to effectively block the action of endothelin in various diseases.

Endothelin is an endogenous substance that directly or indirectly (by controlling the release of various endogenous substances) causes longer-term contraction or relaxation of vascular or non-vascular smooth muscles, and excessive production or secretion of endothelin is considered one of the pathotenesis of high blood pressure, pulmonary hypertension, Raynaud's disease, bronchial asthma , stomach ulcer, diabetes, arteriosclerosis, restenosis, acute kidney failure, myocardial infarction, angina pectoris, cerebral vasospasm and cerebral infarction. In addition, endothelin is thought to serve as an important mediator in diseases such as restenosis, prostatosis, endotoxin shock, endotoxin-induced multiorgan failure or disseminated intravascular coagulation, as well as cyclosporine-induced renal failure or hypertension.

Two endothelin receptors, ETA and ETB, have been discovered so far, 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 that disclose non-peptide compounds with the stated activity of endothelin receptor antagonists.

This invention discloses an asymmetric conjugate addition for the preparation of compounds of formula I,

[image]

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

[image]

whereby

[image]

represents: 5- or 6-membered heterocyclo, 5- or 6-membered carbocyclyl, and aryl;

R 1 is: C 1 - C 8 alkyl, C 2 - C 8 alkenyl, C 2 - C 8 alkynyl, C 3 - C 8 cycloalkyl, aryl or heteroaryl;

R 2 is: OR 4 and N(R 5 ) 2 ;

R3b is aryl or heteroaryl;

R 4 is C 1 - C 8 alkyl; And

R5 is C1-C8 alkyl or aryl.

Presentation of the essence of the invention

The immediate discovery relates to the process of obtaining the compound of formula I:

[image]

whereby

[image]

presents:

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; heterocyclyl is substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-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, carbocyclyl is substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5) 2;

c) aryl, when defined as below, C1-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 groups consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2 ;

aryl is defined as phenyl or naphthyl, which is substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2; when two substituents are located on two adjacent carbon atoms they can be joined to form a 5- or 6-membered ring with one, two or three heteroatoms selected from O, N and S atoms substituted or unsubstituted by one, two or three substituents selected from the group consisting of: H, OH, CO2R6, Br, Cl, F, I, CF3, N(R7)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3- C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2;

R1 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 are substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br , Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-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 ;

R3 is:

a) H,

b) C1-C8 alkyl,

c) C1-C8 alkenyl,

d) C1-C8 alkynyl,

e) C1-C8 alkoxyl,

f) C3-C7 cycloalkyl,

g) S(O)tR5,

h) Br, Cl, F, I,

i) aryl,

j) heteroaryl,

k) N(R5)2,

l) NH2,

m) CHO,

n) -CO-C1-C8 alkyl,

o) -CO-aryl,

p) -CO-heteroaryl,

q) -CO2R4, or

r) protected aldehyde;

X and Y are, independently: O, S or NR 5 ;

n is 0 to 5;

t is 0, 1 or 2;

R 4 is C 1 - C 8 alkyl;

R 5 is C 1 - C 8 alkyl or aryl;

R 6 is H, C 1 -C 8 alkyl or aryl;

R7 is H, C1 - C8 alkyl, aryl which is substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2; when two R7 substituents are on the same nitrogen atom, they can be linked to form a ring of 3 to 6 atoms;

and includes the reaction of an α, β - unsaturated ester or amide

[image]

with an organolithium compound, R1Li, in the presence of a chiral additive and an aprotic solvent in the temperature range from approx. - 78°C to approx. 0°C.

Detailed description of the invention

The immediate disclosure relates to the process of compounds of formula I:

[image]

whereby

[image]

presents

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; heterocyclyl is substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-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, carbocyclyl is substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5) 2;

c) aryl, when defined as below, C1-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 groups consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2 ;

aryl is defined as phenyl or naphthyl, which is substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2; when two substituents are located on two adjacent carbon atoms they can be joined to form a 5- or 6-membered ring with one, two or three heteroatoms selected from O, N and S atoms substituted or unsubstituted by one, two or three substituents selected from the group consisting of: H, OH, CO2R6, Br, Cl, F, I, CF3, N(R7)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3- C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2;

R1 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 are substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br , Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-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 ;

R3 is:

a) H,

b) C1-C8 alkyl,

c) C1-C8 alkenyl,

d) C1-C8 alkynyl,

e) C1-C8 alkoxyl,

f) C3-C7 cycloalkyl,

g) S(O)tR5,

h) Br, Cl, F, I,

i) aryl,

j) heteroaryl,

k) N(R5)2,

l) NH2,

m) CHO,

n) -CO-C1-C8 alkyl,

o) -CO-aryl,

p) -CO-heteroaryl,

q) -CO2R4, or

r) protected aldehyde;

X and Y are, independently: O, S or NR 5 ;

n is 0 to 5;

t is 0, 1 or 2;

R 4 is C 1 -C 8 alkyl;

R 5 is C 1 -C 8 alkyl or aryl; And

R 6 is H, C 1 -C 8 alkyl or aryl;

R7 is H, C1-C8 alkyl, and aryl, and when there are two R7 substituents on the nitrogen atom 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, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C8 cycloalkyl, CO( CH2)nCH3, and CO(CH2)nCH2N(R5)2;

and includes the reaction of an α, β - unsaturated ester or amide

[image]

with an organolithium compound, R1Li, in the presence of a chiral additive and an aprotic solvent in the temperature range of about -78°C to about 0°C.

The process is the same as above, wherein the number of equivalents of the organolithium compound R1Li is in the range of 1 to about 4, and preferably in the range of 1.5 to about 2.5.

The process is the same as above, where the chiral additive is a chiral compound that can coordinate with chiral additives such as:

a) (-)-sparteine,

b) N,N,N',N'-tetra(C1-C6)-alkyltrans-1,2-diamino-cyclohexane, or

[image]

wherein R 8 and R 9 are independently H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or aryl, except that R 8 and R 9 cannot simultaneously be H; and R 10 is C 1 -C 6 alkyl or aryl;

and can be used in this process. It is understood that the amino alcohol represented by the above notation has at least one, and potentially two, chiral centers.

The process is identical to the above, where 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 the mentioned solvents. The process is the same as above, with the best aprotic solvent being toluene.

Solvent mixtures that can be used in this process are: hexane and toluene, with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, and preferably hexane and toluene, with a catalytic amount of tetrahydrofuran.

The process is the same as above, with the temperature range being from about -78°C to about -20°C, preferably from about -78°C to about -50°C.

The embodiment of this invention is a process for the preparation of the compound of formula I:

[image]

whereby

[image]

presents:

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; heterocyclyl is substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-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; carbocyclyl is substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2;

c) aryl, when defined as below, C1-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 groups consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2 ;

aryl is defined as phenyl or naphthyl, which is substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2; when two substituents are located on two adjacent carbon atoms they can be joined to form a 5- or 6-membered ring with one, two or three heteroatoms selected from O, N and S atoms substituted or unsubstituted by one, two or three substituents selected from the group consisting of: H, OH, CO2R6, Br, Cl, F, I, CF3, N(R7)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3- C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2;

R1 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 are substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br , Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-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 ;

R3 is:

a) CHO,

b) CH(OR4)2;

n is 0 to 5;

t is 0, 1 or 2;

X and Y are, independently: O, S or NR 5 ;

R 4 is C 1 -C 8 alkyl;

R 5 is C 1 -C 8 alkyl or aryl;

R 6 is H, C 1 -C 8 alkyl or aryl;

R7 are independently: H, C1-C8 alkyl, and aryl, and when there are two R7 substituents on the nitrogen atom 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, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2;

and includes the following stages:

1) reaction of α, β - unsaturated ester or amide

[image]

where R 3 is CH(OR 4 ) 2 ;

with an organolithium compound, R1Li, in the presence of a chiral additive and an aprotic solvent in the temperature range from about -78°C to about 0°C to obtain a conjugated addition compound, and

2) removal of the aldehyde protecting group with acid to give a compound of Formula I, wherein R 3 is CHO.

The process is the same as above, wherein the number of equivalents of the organolithium compound R1Li is in the range of 1 to about 4, and preferably in the range of 1.5 to about 2.5.

The process is the same as above, where the chiral additive is a chiral compound that can coordinate with chiral additives such as:

a) (-)-sparteine,

b) N,N,N',N'-tetra(C1-C6)-alkyltrans-1,2-diamino-cyclohexane, or

[image]

wherein R 8 and R 9 are independently: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or aryl, except that R 8 and R 9 cannot simultaneously be H; and R 10 is C 1 -C 6 alkyl or aryl;

and can be used in this process.

The process is identical to the above, where 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 the mentioned solvents. The process is the same as above, with the best aprotic solvent being toluene.

Solvent mixtures that can be used in this process are: hexane and toluene, with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, and preferably hexane and toluene, with a catalytic amount of tetrahydrofuran.

The process is the same as above, with the temperature range being from about -78°C to about -20°C, preferably from about -78°C to about -50°C.

An embodiment of the present invention is a process for the preparation of a protected aldehyde

[image]

which involves the reaction of an α, β - unsaturated ester or amide

[image]

with an organolithium compound,

[image]

in the presence of a chiral additive and an aprotic solvent in the temperature range from about -78°C to about 0°C.

The process is the same as above, wherein the number of equivalents of the organolithium compound R1Li is in the range of 1 to about 4, and preferably in the range of 1.5 to about 2.5.

The process is the same as above, where the chiral additive is a chiral compound that can coordinate with chiral additives such as:

a) (-)-sparteine,

b) N,N,N',N'-tetra(C1-C6)-alkyltrans-1,2-diamino-cyclohexane, or

[image]

wherein R 8 and R 9 are independently: H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or aryl, except that R 8 and R 9 cannot simultaneously be H; and R 10 is C 1 -C 6 alkyl or aryl;

and can be used in this process.

The process is identical to the above, where 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 the mentioned solvents. The process is the same as above, with the best aprotic solvent being toluene.

Solvent mixtures that can be used in this process are: hexane and toluene, with a catalytic amount of tetrahydrofuran, and pentane and toluene with a catalytic amount of tetrahydrofuran, and preferably hexane and toluene, with a catalytic amount of tetrahydrofuran.

The process is the same as above, with the temperature range being from about -78°C to about -20°C, more preferably from about -78°C to about -50°C, and best from -78°C to about -70 °C.

It is also understood that the above substituents will include the definitions that follow in the further text of the application.

The above substituents denote straight and branched chain hydrocarbons of certain lengths such as methyl, ethyl, isopropyl, isobutyl, tert-butyl neopentyl, isopentyl, etc.

Alkenyl substituents denote alkyl groups such as those described above which are modified so that each contains a double bond of two carbon atoms, such as vinyl, allyl and 2-butylene.

Cycloalkyl refers to rings composed of 3 to 8 methylene groups, each of which may or may not be substituted with other hydrocarbon substituents, and includes, for example, cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl.

Alkoxy substituent represents an alkyl group, as described above, linked by an oxygen bridge.

The heteroaryl substituent represents carbazolyl, furanyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, priazolyl, pyrazinyl, pyridyl, pyrimidyl, purinyl.

Heterocyclic substituent represents pyridyl, pyrimidyl, thienyl, furanyl, oxazolinidyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, thiazdiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl or pyridylidinyl.

A protected aldehyde is an acetal, such as -CH(OC1-C8 alkyl)2,

[image]

α, β -unsaturated ester or amide

[image]

can generally be prepared in two stages:

1) by coupling reaction at one point of Ring A

[image]

wherein R 3 is SHO, Z is a leaving group, such as Br, Cl, I, Otrifil, Otozil or Omezil, and R 2 is OR 4 or (N(R 5 ); and

2) by converting the aldehyde (R3 is DHO) to the desired protected aldehyde (R3 is CH(OR4)2 and R4 is C1-C8 alkyl).

Commercial pyridone 1 is alkylated via its dianion with propyl bromide, and the resulting product is then converted to bromopyridine 3a using a brominating agent such as Pbr3. Nitrile 3a is then reduced to aldehyde 3 using diisobutyl aluminum hydride (DIBAL). The aldehyde is then subjected to a Heck reaction with t-butyl acrylate using: NaOAc, (allyl2PdCl2, tri-o-tolylphosphine, toluene, under reflux to give the unsaturated ester 4a in high yield. The unsaturated ester 4a is then treated with alcohol (R4OH) and with an aqueous acid solution to obtain the acetyl acceptor 5a.

Scheme 1

[image]

Commercially available acid 10 is reduced by BH3.SMe2 to alcohol 11, which is then converted to bromide 13, via mesylate 12 using mesyl chloride and triethylamine, followed by addition of NaBr and dimethylacetamide (DMAC).

Scheme 2

[image]

Commercially available 1,2-amino indanol is acylated (propionyl chloride, K2CO3) to give amide 8, which is then converted to acetonide 9 (2-methoxypropene, pyridinium p-toluenesulfonate (PPTS)). The acetonide 9 is then alkylated with bromide 13 (LiHMDS) to give 14, which is then hydrolyzed (H+, MeOH) to give an acid/methyl ester mixture 15. Reduction (LAH) of the ester/acid mixture gave alcohol 16 in high yield and optical purity. Protection of alcohol 16 (TBSCI, imidazole) afforded bromide 17, precursor of organolithium 17a.

Scheme 3

[image]

Compound 17a and a chiral additive, such as sparteine, are added to the α,β-unsaturated ester 5a at a temperature of -78°C to -50°C. Workup with water gives compounds 6a and 6b. A mixture of compounds 6a and 6b is treated with TBAF or an aqueous acid solution to deprotect the silylated alcohol or acetal and silylated alcohol.

Scheme 4

[image]

The immediate novelty of the invention can be further clarified by the following examples, which, however, do not limit the novelty of this invention.

Example 1

[image]

Preparation 1

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

Example 2

[image]

Preparation 2

Diisopropyl amine (MW 101.19; d 0.772; 2.1 eq; 20.54 mL) in 200 mL THF. It was cooled to -50°C and n-BuLi (1.6 M in hexane, 2.05 eq; 96 mL) was added, and the solution was allowed to warm to -20°C. It is kept for 15 minutes at a temperature of 0 - 3°C, then it is cooled to -30°C and 1 (MW 134.14; 75 mmol; 10.0 g) is added. The mixture is then slowly heated at a temperature of 0 to 43°C for 2 hours. It was then cooled to -50°C and bromopropane (MW 123.00; d 1.354; 1.0 eq; 6.8 mL) was added. It is heated to 25°C for a period of 30 minutes, and kept for 30 minutes. NH4Cl and CH3CL2 are added. The organic part was dried (magnesium sulfate) and then evaporated in vacuo to give 61% of compound 2.

Example 3

[image]

Preparation 3

Mix 2 (MW 176.22; 46 mmol) and PBr3 (MW 270.70; d 2.880; 2.5 eq; 10.8 mL) and keep at 160°C. After 2 hours, cool to 25°C and add a little CH2Cl. Quench slowly by adding water. Separate the layers and wash the sediments twice with CH2Cl2. Combine the organic layers and dry (magnesium sulfate). Concentrate and isolate the solid part by silica gel chromatography (90:10 hexane:ethyl acetate) in 60% yield (MW 239.12; 6.60 g).

Dissolve the product of the bromination reaction (MW 239.12; 27.6 mmol); 6.60 g) in 66 mL of toluene and cool to -42°C. Slowly add DIBL (1.5 M in toluene, 2 eq; 37 mL) and keep at -42°C for 1 hour. Add HCl (2N; 10 eq; 134 mL) and stir vigorously for 30 min. Dilute with ethyl acetate, separate the layers, and wash the sediments with ethyl acetate. Combine the organic layers, dry (magnesium sulfate) and concentrate in vacuo to obtain a 90% yield (MW 242.11; 6.01 g) of compound 3.

Example 4a

[image]

Preparation 4a

Dissolve 3a (MW 242.22; 24.8 mmol 6.01 g) in 75 mL 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). Keep under reflux for 24 hours. Cool, filter and evaporate in vacuo. Isolate 4a (MW 289.37) by silica gel chromatography (92:8 hexane:ethyl acetate) in 80% yield (5.74 g).

Example 4b

[image]

Preparation 4b

Dissolve 3 (MW 242.11; 24.8 mmol 6.01 g) in 75 mL toluene. Add sodium acetate (MW 82; 3 eq; 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). Keep at 140°C in a hermetically sealed tube for 24 hours. Cool, filter and evaporate in vacuo. Isolate 4b (MW 260.34) by silica gel chromatography (80:20 hexane:ethyl acetate) in 70% yield (4.52 g).

Example 5a

[image]

Preparation 5a

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 refluxed for 2.5 h. After cooling to room temperature, the solvents were evaporated in vacuo. The residue was dissolved in EtOAc and washed with saturated sodium bicarbonate solution. Concentration of the organic layer gave 18.2 g of the desired product 5a. 98% yield.

1 H NMR (CDCl 3 ) δ : 7.95 (d, 1 H); 7.80 (d, 1H); 7.12 (d, 1H); 7.04 (d, 1H); 5.09 (1H); 3.45 (s, 6H); 2.80 (t, 2H); 1.73 (m, 2H); 1.54 (s, 9H); 1.40 (m, 2H); 0.95 (t, 3 H) ppm.

Example 6

[image]

Phase A: Preparation of 6a and 6b

To a solution of compound 17 (2.23 g; 5.97 mmol), (-)-sparteine (1.37 mL; 5.97 mmol), and THF (73 µL; 0.896 mmol) in 20 mL of toluene at -78° t-BuLi (1.7 M in Hexane; 7.0 mL; 11.94 mmol) was added dropwise. The solution is kept for 30 minutes at -78°C. A solution of unsaturated t-butyl ester 5a (1.0 g; 2.98 mmol) in 5 mL of toluene was added dropwise over 10 min at -78°C. After 20 min. at -78°C the reaction is quenched with water. The organic phase is 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 the major diastereomer 6b: 1H NMR (CDCl3) δ : 7.24 (dd, 1 H); 7.00 (d, 1H); 6.84 (d, 1H); 6.70 (d, 1H); 6.55 (dd, 1 H); 5.74 (s, 1H); 5.02 (m, 1H); 3.72 (s, 3H); 3.55 (m, 4H); 3.22 (s, 3H); 2.92 (s, 3H); 2.80 (t, 2 H); 2.50 (m, 2 H); 2.12 (m, 1 H); 1.75 (m, 2 H); 1.40 (m, 2H); 1.28 (s, 9H); 0.95 (m, 6 H); 0.90 (s, 9H); 0.09 (s, 3H); 0.08 (s, 3 H) ppm.

To determine the ratio between the two diastereoisomers 6a and 6b , the above compounds were deprotected by further treatment with TBAF in THF, or alternatively with Hcl or pTSA in dilute acetone.

Phase B: Preparation of 6c and 6d (Method A)

A solution of 500 mg (0.08 mmol) of the above products 6a and 6b and 0.96 mL of TBAF (1.0 M in THF) in 6 mL of THF was stirred for 4 h at room temperature. The resulting reaction solution is then washed with water and dried over sodium sulfate. The product is then analyzed by H1 NMR. By integrating the peak value of singlets of 5.42 ppm (for the main diastereomer) and 5.38 ppm (for the minor diastereomer), the ratio of the two diastereomers was determined.

Phase C: Preparation of 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 5% HCl or 45 mM pTSA in 3 mL of acetone and 1 mL of water was stirred for 4 h at room temperature. The solvent was washed in vacuo. The residue was dissolved in EtOAc and washed with 10% sodium carbonate. The product is concentrated and analyzed by H1 NMR. By integrating the peak value of one-electron bonds of 10.35 ppm (for the main diastereomer) and 10.20 ppm (for the minor diastereomer), the ratio of the two diastereomers was determined.

Example 7

[image]

Preparation 7

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

Example 8

[image]

Preparation 8

Na2CO3 (MW 105.99; 1.5 eq; 8.8 g) is dissolved in water. A solution of (1R, 2S) amino indanol 7 (MW 149.19; 55.0 mmol; 8.2 g) in 160 mL of CH2Cl2 was added. It was then cooled to -5°C and propionyl chloride (MW 92.53; d 1.065; 1.3 eq; 6.2 mL) was added. It is heated to 25°C and kept / matured for 1 hour. Separate the layers and dry the organic part (magnesium sulfate). Concentrate in vacuo to give compound 8 (MW 205.26; 10 g) in 89% isolated yield.

Example 9

[image]

Preparation 9

To a mixture of compound 8 (MW 205.26; 49.3 mmol; 10 g) in 200 mL THF was added pyridinium p-toluenesulfonate (PPTS) (MW 251.31; 0.16 eq; 2 g) and then methoxypropene (MW 72 .11; d 0.753; 2.2 eq; 10.4 mL). It is kept for 2 h at 38°C, then sodium bicarbonate in water and ethyl acetate are added. The organic layer is dried (magnesium sulfate). After concentration in vacuo, compound 9 (MW 245.32; 12.09 g) is formed in quantitative yield.

Example 10

[image]

Preparation 10

Compound 10 is a commercially available starting material, see for example 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

[image]

Preparation 11

Compound 10 (MW 231.05; 130 mmol; 30.0 g) in 300 mL CH2Cl2 at 0°C. BH3-SMe2 (3 eq; 25.2 mL) was added and kept for 2 h at 25°C. It is quenched in 2 N HCl in water, and the layers are separated. The organic portion was dried (magnesium sulfate) and concentrated in vacuo to give a 94% yield of compound 11 (MW 217.06; 25.5 g).

Example 12

[image]

Preparation 12

Dissolve 11 (MW 217.06; 47.2 mmol; 10.24 g) in 55 mL of CH2Cl2 and cool to -20°C. DIEA (MW 129.25; d 0.742; 1.3 eq; 10.69 mL) and methane sulfonyl chloride (MsCl) (MW 114.55; d 1.480; 1.2 eq; 4.38 mL) were added. It is kept for 1 h at -5°C to 0°C and then extinguished in 55 mL of water. Extract with CH2Cl2 and wash with 1H H2SO4 (40 mL) and then with brine. The organic layers were dried (magnesium sulfate) and concentrated in vacuo to give compound 12 (MW 295.15; 13.23 g) in 95% yield.

Example 13

[image]

Preparation 13

Compound 12 (MW 295.15; 44.8 mmol, 13.23 g) in 44 mL of dimethylacetamide (DMC). NaBr (MW 102.90; 2equ; 9.22 g) was added and kept for 1 h. 88 mL of water is added and the solid parts are collected by filtration. The resulting cake is washed with water and dried by suction. A quantitative yield of compound 13 was obtained (MW 279.96; 12.54 g).

Example 14

[image]

Preparation 14

Compound 9 (MW 245.32; 1.1 eq; 89.1 g) in 1 L THF, cooled to -50°C. LiHMDS (1.0 M in THF; 1.5 eq; 545 mL) was added and kept for 1.5 h with warming to -30°C. Add compound 13 (MW 279.96; 327 mmol); 91.3 g) in 300 mL of THF, and then kept for 1 h at -35°C. It is heated to -10°C for a period of 1 h, and then extinguished in an aqueous solution of NH4Cl. The layers are separated and extracted with ethyl acetate. The organic was dried and concentrated in vacuo to give crude compound 14 (MW 444.37).

Example 15

[image]

Preparation 15

Compound 14 in 1 L MeOH was cooled to 10°C. Hcl gas is pushed through the solution for 1 h until the reaction is complete. 2 L H2O is added and then the product is separated by filtration. The cake is washed with H2O and dried to obtain the hydroxyamide as a product, which is then dissolved in 1 L MeOH and 1.5 L 6N Hcl and refluxed overnight. The mixture was then cooled to 25V and extracted with CH2Cl2 to give, after concentration, compound 15 (60 g, 64% from bromide 13).

Example 16

[image]

Preparation 16

Compound 15 (mixture of acid and ester, 16.88 mmol) in 150 mL THF at -78°C. Lithium aluminum hydride (LiAlH4) (1 M in THF; 2 eq; 53.76 mL) was added over a period of 30 min. It is heated to 25°C for 1 h, then quenched in an aqueous solution of NH4Cl. Ethyl acetate is added, ethyl acetate is extracted. The organic portion was washed with brine, dried (magnesium sulfate) and concentrated in vacuo to give a 95% yield of compound 16 (MW 259.14; 6.62 g).

Example 17

[image]

Preparation 17

Compound 16 (MW 259.14; 25.54 mmol); 6.62 g) in 35 mL of CH2Cl2 is cooled to 0°C. Imidazole (MW 68.08; 2.5 eq; 4.35 g) was added followed by tert-butyldimethylsilyl chloride (TBSCl) (MW 150.73; 1 eq; 3.85 g). It is kept for 1 h at 25°C, quenched with an aqueous solution of NaHCO3 and then ethyl acetate is added. It is extracted with ethyl acetate, then the organic layer is dried (magnesium sulfate) and concentrated in vacuo to obtain 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; 1H); 6.63 (dd, J=8.73; 3.06, 1H); (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,=3 (m, 1 H); 0.94 (s, 9H); (s, 9 H); 0.92 (d, J=5.01; 3 h); 0.07 (s, 6 H).

13C NMR (CDCl3): 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).

Example 18 - 22

As a result of the procedure described in Example 6, the following chiral additive was obtained in the indicated diastereomeric ratios of compounds 6a to 6b.

Example no. Chiral additive Diastereomeric

ratio (6a : 6b)

[image]

Claims (18)

1. The process of preparing the compound from formula I: [image] indicated by that [image] presents 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; heterocyclyl is substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-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, carbocyclyl is substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5) 2; c) aryl, when defined as below, C1-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 groups consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2 ; aryl is defined as phenyl or naphthyl, which is substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2; when two substituents are located on two adjacent carbon atoms they can be joined to form a 5- or 6-membered ring with one, two or three heteroatoms selected from O, N and S atoms substituted or unsubstituted by one, two or three substituents selected from the group consisting of: H, OH, CO2R6, Br, Cl, F, I, CF3, N(R7)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3- C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2; R1 is: C1 - C8 alkyl, C2 - C8 alkenyl, C2 - C8 alkynyl, C3 - C8 cycloalkyl, aryl, or 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 are substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br , Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-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 ; R3 is: a) H, b) C1-C8 alkyl, c) C1-C8 alkenyl, d) C1-C8 alkynyl, e) C1-C8 alkoxyl, f) C3-C7 cycloalkyl, g) S(O)tR5, h) Br, Cl, F, I, i) aryl, j) heteroaryl, k) N(R5)2, l) NH2, m) CHO, n) -CO-C1-C8 alkyl, o) -CO-aryl, p) -CO-heteroaryl, q) -CO2R4, or r) protected aldehyde; X and Y are, independently: O, S or NR 5 ; n is: 0 to 5; t is: 0, 1 or 2; R 4 is C 1 -C 8 alkyl; R5 is: C1-C8 alkyl or aryl; R6 is: H, C1-C8 alkyl or aryl; R7 are independently: H, C1-C8 alkyl, and aryl; when there are two R7 substituents on the nitrogen atom, they can be joined to form a 3- to 6-membered ring, which is substituted or not substituted by one two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5) 2; indicated that α, β - unsaturated ester or amide [image] reacts with the organolithium compound R1Li, in the presence of a chiral additive and an aprotic solvent in the temperature range from about -78°C to about 0°C. 2. A process identical to the process of Claim 1, characterized in that the number of equivalents of the organolithium compound, R1Li, is in the range of 1 to about 4. 3. The same process as in Claim 2, characterized by the fact that the chiral additive is selected from the group consisting of: a) (-)-sparteine, b) N,N,N',N'-tetra(C1-C6)-alkyltrans-1,2-diamino-cyclohexane, or [image] characterized in that R 8 and R 9 are independently H, C 1 - C 6 alkyl, C 3 - C 7 cycloalkyl or aryl, except that R 8 and R 9 cannot simultaneously be H; and R 10 is C 1 - C 6 alkyl or aryl; 4. A process identical to the process from Claim 3, characterized in that the aprotic solvent is selected from the group consisting of: tetrahydrofuran, diethyl ether, methyl t-butyl ether, toluene, benzene, hexane, pentane, and dioxane, or a mixture of the mentioned solvents. 5. A process identical to the process of Claim 4, characterized in that the temperature range is from about -78°C to about -20°C. 6. Process for the preparation of the compound of formula I. [image] indicated that [image] presents: 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; heterocyclyl is substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-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; carbocyclyl is substituted or unsubstituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2; c) aryl, when defined as below, C1-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 groups consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1 - C8 alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2 ; aryl is defined as phenyl or naphthyl, which is substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2; when two substituents are located on two adjacent carbon atoms they can be joined to form a 5- or 6-membered ring with one, two or three heteroatoms selected from O, N and S atoms substituted or unsubstituted by one, two or three substituents selected from the group consisting of: H, OH, CO2R6, Br, Cl, F, I, CF3, N(R7)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3- C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2; R1 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 are substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-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 ; R3 is: a) CHO, b) CH(OR4)2; n is: 0 to 5; t is: 0, 1 or 2; X and Y are, independently: O, S or NR 5 ; R 4 is C 1 -C 8 alkyl; R5 is: C1-C8 alkyl or aryl; R6 is: H, C1-C8 alkyl or aryl; R7 are, independently: H, C1-C8 alkyl, and aryl when there are two R7 substituents on the nitrogen atom they can be joined to form a 3- to 6-membered ring which is substituted or unsubstituted by one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl or C3-C8 cycloalkyl, CO( CH2)nCH3, and CO(CH2)nCH2N(R5)2;; indicated by the following stages: 1) reaction of α, β - unsaturated ester or amide [image] where R 3 is CH(OR 4 ) 2 ; with the organic compound R1Li, in the presence of a chiral additive and an aprotic solvent in the temperature range from about -78°C to about 0°C to obtain a conjugate addition compound, and 2) removal of the aldehyde protecting group with acid to give a compound of Formula I, wherein R 3 is CHO. 7. A process identical to the process of Claim 6, characterized in that the number of equivalents of the organolithium compound, R1Li, is in the range from 1 to about 4. 8. A process identical to the process from Claim 7, characterized by the fact that the chiral additive is selected from the group consisting of: a) (-)-sparteine, b) N,N,N',N'-tetra(C1-C6)-alkyltrans-1,2-diamino-cyclohexane, or [image] characterized in that R8 and R9 are independently H, C1-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R8 and R9 cannot simultaneously be H; and R 10 is C 1 -C 6 alkyl or aryl; 9. Process identical to the process from Claim 8, characterized in that the aprotic solvent is selected from the group consisting of: tetrahydrofuran, diethyl, ether, methyl t-butyl ether, toluene, benzene, hexane, pentane, and dioxane, or a mixture of said solvents. 10. A process identical to the process of Claim 9, characterized in that the temperature range is from about -78°C to about -20°C. 11. Preparation process [image] indicated that α, β - unsaturated ester or amide [image] reacts with an organolithium compound [image] in the presence of a chiral additive and an aprotic solvent in the temperature range of approximately -78°C to approximately -20°C 12. A process identical to the process of Claim 11, characterized in that the number of equivalents of the organolithium compound, R1Li, is in the range of approximately 4. 13. A process identical to the process from Claim 11, characterized in that the chiral additive is selected from the group consisting of: a) (-)-sparteine, b) N,N,N',N'-tetra(C1-C6)-alkyltrans-1,2-diamino-cyclohexane, or [image] characterized in that R8 and R9 are independently H, C1-C6 alkyl, C3-C7 cycloalkyl or aryl, except that R8 and R9 cannot simultaneously be H; and R 10 is C 1 -C 6 alkyl or aryl; 14. A process identical to the process from Claim 13, characterized in that the aprotic solvent is selected from the group consisting of; tetrahydrofuran, diethyl ether, methyl t-butyl ether, benzene, toluene, pentane, hexane and dioxane, or a mixture of the mentioned solvents. 15. A process identical to the process of Claim 14, characterized in that the temperature range is from about -78°C to about -50°C. 16. A process identical to the process of Claim 15, characterized in that the number of equivalents of the organolithium compound R1Li is in the range of 1.5 to approximately 2.5. 17. A process identical to the process from Claim 16, characterized in that the aprotic solvent is toluene or a mixture of toluene-hexane-(catalytic)tetrahydrofuran. 18. A process identical to the process of Claim 17, characterized in that the temperature range is from about -78°C to about -70°C.