CN101374816A - Stereoselective preparation of alcohols from α,β-unsaturated compounds - Google Patents

Abstract

The invention relates to a method that takes a compound of formula (V) as a compound of intermediate synthesis formula (I).

Description

Stereoselective preparation of alcohols from α,β-unsaturated compounds

The present invention relates to a stereoselective process for the preparation of (R or S)-2-alkyl-3-heterocyclyl-1-propanols and novel intermediates obtained in the process stage.

WO 2005/090305 A1 discloses delta-amino-gamma-hydroxy-omega-(heterocyclyl)alkanecarboxamides which exhibit renin-inhibiting properties and are useful as antihypertensive agents in pharmaceutical compositions. The preparation disclosed therein proceeds via the coupling of heterocyclyl-metal entities to aldehydes as a key step, which is not suitable for industrial processes, especially in view of the unsatisfactory yields in some cases.

In a new method, the starting material is 2,7-dialkyl-8-heterocyclyl-4-octenamide, whose double bond is simultaneously halogenated at the 5-position and hydrogenated at the 4-position by lactonization , the halogen is then replaced by the azide, the lactone is amidated, and the azide is then converted to an amine group. The desired alkanecarboximides are obtained in this new process in significantly higher overall yields. Halolactonization, azidation and azide reduction were carried out as described by P. Herold in Journal of Organic Chemistry, Vol. 54 (1989), pp. 1178-1185.

2,7-Dialkyl-8-heterocyclyl-4-octenamide may for example correspond to formula A,

wherein Het represents an unsaturated bicyclic heterocyclic group connected to the remaining molecule via a carbon atom, the ring not directly bonded to the remaining molecule is replaced by _R'1 and _R'2 , and _R'1 and _R'2 independently represent H, C ₁ -C ₈ -alkyl, halogen, polyhalo-C ₁ -C ₈ -alkoxy, polyhalo-C ₁ -C ₈ -alkyl, C ₁ -C ₈ -alkoxy, C ₁ -C ₈ -alkoxy-C ₁ -C ₈ -alkyl or C ₁ -C ₈ -alkoxy-C ₁ -C ₈ -alkoxy, R' ₁ and R' ₂ do not represent H at the same time , R' ₃ represents C ₁ -C ₈ -alkyl, R' ₄ is C ₁ -C ₈ -alkyl, R' ₅ represents C ₁ -C ₈ -alkyl or C ₁ -C ₈ -alkoxy, R' ₆ represents C ₁ -C ₈ -alkyl or R' ₅ and R' ₆ together form tetramethylene, pentamethylene, 3-oxa-1,5-pentylene or -CH ₂ CH ₂ OC(O)-, which is optionally substituted by C ₁ -C ₄ -alkyl, phenyl or benzyl, and wherein the carbon atom to which the R _' group is bonded exhibits the (R) or (S) configuration , the (R) configuration is preferred.

Compounds of formula A can be obtained by reacting compounds of formula B with compounds of formula C in the presence of alkali metals or alkaline earth metals

wherein Het, _R'1 to _R'4 , _R'5 and _R'6 have the meanings given above, Y represents Cl, Br or I and Z represents Cl, Br or I, and wherein with _R'3 group Bonded carbon atoms exhibit the (R) or (S) configuration, the (R) configuration being preferred. Y and Z preferably represent Br or Cl, particularly preferably Cl.

Compounds of formula C can be prepared by amidation of the corresponding carboxylic acid esters, carboxylic acid amides or carboxylic acid halides. S.M.Weinreb in Organic Syntheses, 59, pp. 49-53 (1980) describes the synthesis of carboxylates and Amines form carboxamides. The carboxylate can be obtained by reaction of trans-1,3-dihalopropene (such as trans-1,3-dichloropropene) with a suitable carboxylate in the presence of a strong base, such as an alkali metal amide .

The stereoselective preparation of compounds of formula B is unknown. It has been found that, surprisingly, 2-alkyl-3-heterocyclyl-1-propanols (compounds of formula B in which Y has the meaning of OH; subsequently described as compounds of formula I) can be obtained in only four or Stereospecifically prepared in high yields in five process stages; if analogously to the process disclosed in WO 02/02487 A1, condensation of appropriately substituted unsaturated heterocyclic aldehydes with carboxylates gives 2-alkane The diastereomeric products were obtained in high yields. It has been found that, surprisingly, in the case of 2-alkyl-3-hydroxy-3-(heterocyclyl)carboxylates, the resulting diastereomers advantageously do not separate because after converting the hydroxyl group to the leaving The group is then base-initiated scavenged to form (E)-3-heterocyclyl-2-alkylacrylates with high stereoselectivity. The (E)-3-heterocyclyl-2-alkylacrylate is an important intermediate in the process. Starting from these (E)-3-heterocyclyl-2-alkyl acrylates, 2-alkyl-3-heterocyclyl-1-propanols can be obtained in three process variants:

1) From crude 3-heterocyclyl-2-alkylacrylic acid, (E)-3-heterocyclyl-2-alkylacrylic acid is obtained exclusively in high yield after saponification and crystallization. This (E)-3-heterocyclyl-2-alkylacrylic acid can be hydrogenated in the presence of specific catalysts to produce almost enantiomerically pure 2-alkyl-3-heterocyclyl-1-propionic acid, which can be obtained by Reductive conversion to 2-alkyl-3-heterocyclyl-1-propanol of formula I.

2) From crude 3-heterocyclyl-2-alkylacrylic acid, after saponification and crystallization, (E)-3-heterocyclyl-2-alkylacrylic acid is exclusively obtained in high yield. This (E)-3-heterocyclyl-2-alkylacrylic acid can be reduced to give allyl alcohol; the resulting allyl alcohol is in turn hydrogenated in the presence of a specific catalyst to give almost enantiomerically pure 2-alkyl of formula I -3-Heterocyclyl-1-propanol.

3) (E)-3-heterocyclyl-2-alkylacrylate can be reduced to produce allyl alcohol. The resulting allyl alcohols are in turn hydrogenated in the presence of specific catalysts to yield almost enantiomerically pure 2-alkyl-3-heterocyclyl-1-propanols of formula I.

In process variants 1) and 2), all process steps up to (E)-3-heterocyclyl-2-alkylacrylic acid are advantageously carried out without purification of intermediates, which is necessary for industrial-scale preparation language constitutes a significant advantage (for example, cost savings). Process variant 3) has one less process stage, which likewise facilitates production on an industrial scale.

The 2-alkyl-3-heterocyclyl-1-propanols of the formula I thus obtained can subsequently be obtained in a manner known per se, for example according to J. Maibaum in Tetrahedron Letters, Vol. 41 (2000), No. 10085 - Conversion to compounds of formula B by halogenation, as described on page 10089.

The subject of the invention is a process for the preparation of compounds of formula I

wherein Het represents an unsaturated bicyclic heterocyclic group connected to the remaining molecule via a carbon atom, the ring not directly bonded to the remaining molecule is replaced by _R'1 and _R'2 , and _R'1 and _R'2 independently represent H, C ₁ -C ₈ -alkyl, halogen, polyhalo-C ₁ -C ₈ -alkoxy, polyhalo-C ₁ -C ₈ -alkyl, C ₁ -C ₈ -alkoxy, C ₁ -C ₈ -alkoxy-C ₁ -C ₈ -alkyl or C ₁ -C ₈ -alkoxy-C ₁ -C ₈ -alkoxy, R' ₁ and R' ₂ do not represent H at the same time , R' ₃ represents a C ₁ -C ₈ -alkyl group, and wherein the carbon atom bonded to the R' ₃ group exhibits (R) or (S) configuration, (R) configuration is preferred, characterized by lies in

a) make the compound of formula II

wherein Het, _R'1 and _R'2 have the meanings given above,

react with a compound of formula III,

wherein R' has the meaning given _above ,

thus yielding a diastereomeric mixture of formula IV,

wherein _R'7 is C ₁ -C ₁₂ -alkyl, C ₃ -C ₈ -cycloalkyl, phenyl or benzyl,

b) converting the OH group of the diastereomeric mixture of formula IV into a leaving group and scavenging the leaving group in the presence of a strong base to give the acrylate of formula V,

Method variant 1

This method variant is characterized by

1c) converting an acrylate of formula V by saponification to produce a compound of formula VI,

1d) hydrogenation of the acid of the formula VI in the presence of hydrogen and a catalytic amount of a metal complex comprising ruthenium, rhodium and iridium bonded to a chiral bidentate ligand as an asymmetric hydrogenation catalyst metals to produce compounds of formula VII,

且

and

1e) Reduction of an acid of formula VII to yield a compound of formula I.

Method variant 2

This method variant is characterized by

2c) converting an acrylate of formula V by saponification to produce a compound of formula VI,

2d) reduction of an acid of formula VI to produce a compound of formula VIII

且

and

2e) hydrogenation of an alcohol of the formula VIII in the presence of hydrogen and a catalytic amount of a metal complex as an asymmetric hydrogenation catalyst comprising a compound selected from the group consisting of ruthenium, rhodium and iridium bonded to a chiral bidentate ligand metals to produce compounds of formula I.

Method variant 3

This method variant is characterized by

3c) reduction of acrylates of formula V to yield compounds of formula VIII

and

3d) hydrogenation of the alcohol of the formula VIII in the presence of hydrogen and a catalytic amount of a metal complex comprising ruthenium, rhodium and iridium bonded to a chiral bidentate ligand as an asymmetric hydrogenation catalyst metals to produce compounds of formula I.

R' ₁ and R' ₂ , as C ₁ -C ₈ -alkyl, can be straight-chain or branched and preferably contain 1 to 4 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl.

R' ₁ and R' ₂ , as polyhalo-C ₁ -C ₈ -alkyl, can be straight-chain or branched and preferably contain 1 to 4, particularly preferably 1 or 2, carbon atoms. Examples are fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2-chloroethyl and 2,2,2-trifluoroethyl.

R' ₁ and R' ₂ , as polyhalo-C ₁ -C ₈ -alkoxy, can be straight-chain or branched and preferably contain 1 to 4, particularly preferably 1 or 2, carbon atoms. Examples are fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, 2-chloroethoxy and 2,2,2-tris Fluoroethoxy.

_R'1 and _R'2 , as halogen, may include halo in polyhalo-C ₁ -C ₈ -alkyl and polyhalo-C ₁ -C ₈ -alkoxy, representing F, Cl or Br , F and Cl are preferred.

R' ₁ , R' ₂ and R' ₅ , as C ₁ -C ₈ -alkoxy, can be straight-chain or branched and preferably contain 1 to 4 carbon atoms. Examples are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy, pentyloxy and hexyloxy.

R' ₁ and R' ₂ , as C ₁ -C ₈ -alkoxy-C ₁ -C ₈ -alkyl, can be straight-chain or branched. Alkoxy preferably contains 1 to 4, especially 1 or 2, carbon atoms, and alkyl preferably contains 1 to 4 carbon atoms. Examples are methoxymethyl, 1-methoxyeth-2-yl, 1-methoxyprop-3-yl, 1-methoxybut-4-yl, methoxypentyl, methoxy Hexyl, ethoxymethyl, 1-ethoxyeth-2-yl, 1-ethoxyprop-3-yl, 1-ethoxybut-4-yl, ethoxypentyl, ethoxy Hexyl, propoxymethyl, butoxymethyl, 1-propoxyeth-2-yl and 1-butoxyeth-2-yl.

R' ₁ and R' ₂ , as C ₁ -C ₈ -alkoxy-C ₁ -C ₈ -alkoxy, can be straight-chain or branched. One alkoxy group preferably contains 1 to 4, especially 1 or 2 carbon atoms, the other alkoxy group preferably contains 1 to 4 carbon atoms. Examples are methoxymethoxy, 2-methoxyethoxy, 3-methoxypropoxy, 4-methoxybutoxy, methoxypentyloxy, methoxyhexyloxy, Ethoxymethoxy, 2-ethoxyethoxy, 3-ethoxypropoxy, 4-ethoxybutoxy, ethoxypentyloxy, ethoxyhexyloxy, propoxy methoxy, butoxymethoxy, 2-propoxyethoxy and 2-butoxyethoxy.

In a preferred embodiment, _R'1 represents methoxy- or ethoxy- _C1 - _C4 -alkyl, and _R'2 preferably represents methyl, ethyl, methoxy or ethoxy. Very particular preference is given to compounds of the formula I in which _R'1 represents 3-methoxypropyl or 4-methoxybutyl and _R'2 represents methyl or methoxy.

R' ₃ , R' ₄ , R' ₅ and R' ₆ , as C ₁ -C ₈ -alkyl, can be straight-chain or branched and preferably contain 1 to 4 carbon atoms. Examples are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl and hexyl. In a preferred embodiment, in the compound of formula I, _R'3 represents isopropyl and the carbon atom to which the _R'3 group is bonded exhibits the (R) configuration.

Het, as an unsaturated bicyclic heterocyclic group attached to the remainder of the molecule via a carbon atom, comprises an unsaturated bicyclic heterocyclic group having 1 to 4 nitrogen atoms and/or 1 or 2 sulfur or oxygen atoms, having one or Groups with two nitrogen atoms are preferred. Preferred bicyclic rings consist in each case of 5- and/or 6-membered rings. Examples of Het are benzothiazolyl, quinazolinyl, quinolinyl, quinoxalinyl, isoquinolyl, benzo[b]thienyl, isobenzofuryl, benzimidazolyl, indolyl , Dihydrobenzofuryl, tetrahydroquinoxalinyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, 1H-pyrrolizinyl, phthalazinyl, dihydro -2H-Benzo[1,4]thiazinyl, 1H-pyrrolo[2,3-b]pyridyl, imidazo[1,5-a]pyridyl, benzoxazolyl, 2,3- Indolinyl, indazolyl or benzofuryl. Het particularly preferably represents 1H-indol-6-yl or 1H-indazol-6-yl.

Particularly preferred compounds of formula I are those wherein Het substituted by _R'1 and _R'2 represents 1-(3-methoxypropyl)-3-methyl-1H-indol-6-yl, 3- (3-methoxypropyl)-1-methylimidazo[1,5-a]pyridin-6-yl or 1-(3-methoxypropyl)-3-methyl-1H-indazole -6-yl and _R'3 represents isopropyl.

R' ₇ , as C ₃ -C ₈ -cycloalkyl, can represent cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

R' ₇ preferably represents C ₁ -C ₆ -alkyl, particularly preferably C ₁ -C ₄ -alkyl; some examples are methyl, ethyl, n-propyl and n-butyl.

The starting compounds of the formulas II and III used in process stage a) are known or can be prepared analogously to known methods. Compounds of the formula II are prepared in a manner known per se from the unsaturated bicyclic heterocyclylbromides disclosed in WO 2005/090305 A1 via halogen/metal exchange and subsequent reaction with N,N-dimethylformamide. The reaction of process stage a) is advantageously carried out at low temperatures, for example from -40 to 0° C., in the presence of at least one equivalent of a strong base. The reaction can also be carried out in a solvent, ethers such as diethyl ether, tetrahydrofuran and dioxane are particularly suitable. Suitable strong bases are especially alkali metal alkoxides and alkali metal secondary amides, for example lithium diisopropylamide.

A mixture of the two diastereomers of formula IV was obtained in almost quantitative yield. The diastereomeric mixture is advantageously used in the next process stage without purification.

The conversion of OH groups into leaving groups in process stage b) is known per se. Reaction with carboxylic or sulfonic acids or acid chlorides or anhydrides thereof (acylation) is particularly suitable. Some examples of carboxylic or sulfonic acids are formic acid, acetic acid, propionic acid, benzoic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid and trifluoromethanesulfonic acid. The use of acetic anhydride in the presence of a catalytic amount of 4-dimethylaminopyridine has proven to be particularly suitable. This scavenging can be carried out in the presence of a strong base, alkali metal alkoxides such as potassium tert-butoxide being particularly suitable. The presence of solvents such as ethers is desirable. The reaction is advantageously carried out at low temperature, for example from 0°C to 40°C. The scavenging reaction is advantageously carried out directly in the reaction mixture of process stage a). This scavenging is surprisingly selective to the desired E isomer of the acrylate of formula V.

The saponification of the acrylates of the formula V in process stages 1c) and 2c) is advantageously after reaching complete clearance (process stage b)) and after concentration of the solvent by adding, for example, potassium hydroxide solution and at a temperature of 80° C. to 100° C. Stirring down to proceed directly. The resulting acids of the formula VI are highly crystalline and can accordingly be isolated in a simple manner by extraction and crystallization without substantial losses. The yield is higher than 60%. Surprisingly, only the desired E isomer was obtained.

Analogously to process stage 1d) for α,β-unsaturated carboxylic acids of formula VI and process stages 2e) and 3d) for α,β-unsaturated alcohols of formula VIII, the asymmetric hydrogenation catalyst using a homogeneous Hydrogenation is known per se and as described by J.M. Brown in E. Jacobsen, A. Pfaltz and H. Yamamoto (Eds.), Comprehensive Asymmetric Catalysis, I to III, Springer Verlag, 1999, pp. 121-182, and X. Zhang In Chemical Reviews, Vol. 103 (2003), pp. 3029-3069. Ruthenium, rhodium and iridium catalysts are particularly effective.

The asymmetric hydrogenation of α, β-unsaturated carboxylic acids of formula VI can usually be preferably used as J.M.Brown in E.Jacobsen, A.Pfaltz and H.Yamamoto (Eds.), ComprehensiveAsymmetric Catalysis, I to III, Springer Verlag, 1999 , pp. 163-166, W. Weissensteiner and F. Spindler in Advanced Synthesis and Catalysis, Vol.345 (2003), pp. 160-164 and T. Yamagishi in Journal of the Chemical Society, Perkin Transactions 1, (1997), Ruthenium or rhodium catalysts described on pages 1869-1873.

As ligands for rhodium and ruthenium, chiral ditertiary bispohsphine is generally used. Such chiral di-tertiary bisphosphines are described, for example, by X. Zhang in Chemical Reviews, Vol. 103 (2003), pp. 3029-3069.

Ligands with a ferrocenyl backbone are generally particularly suitable for the asymmetric hydrogenation of α,β-unsaturated carboxylic acids. An example of this is described by F. Spindler in Tetrahedron: Asymmetry, Vol. 15 (2004), pp. 2299-2306. For example, Walphos, Josiphos, Mandyphos and Taniaphos-like ligands. For example, X. Zhang in Chemical Reviews, Vol. 103 (2003), pp. 3029-3069, and P. Knochel in Chemistry, a European Journal, Vol. 8 (2002), pp. 843-852, H.-U. Blaser in These types of ligands are described in Topics in Catalysis, Vol. 19 (2002), pp. 3-16 and F. Spindler in Tetrahedron: Asymmetry, Vol. 15 (2004), pp. 2299-2306.

It has surprisingly been found that rhodium metal complexes, whose ligands belong to the class of chiral di-tertiary bisphosphines with a ferrocenyl backbone, are particularly suitable for the α,β-unsaturated carboxylic acids of the formula VI Asymmetric hydrogenation.

Using the abovementioned ferrocenyl ligands in the metal complexes of the formulas IX and IXa described below, a high enantiomeric purity can be obtained, which constitutes a considerable advantage (eg cost saving) for industrial-scale preparation.

[LMYZ](IX), [LMY] ⁺ E ^- (IXa),

in

M stands for rhodium;

Y is two alkenes or dienes;

Z represents Cl, Br or I;

E ^- represents the anion of an oxyacid or complex acid; and

L is a chiral ligand selected from di-tertiary bisphosphines.

When Y is an alkene, it may be a C ₂ -C ₁₂ -alkene, preferably a C ₂ -C ₆ -alkene, particularly preferably a C ₂ -C ₄ -alkene. Examples are propylene, butene, especially ethylene. The dienes may contain 5 to 12, preferably 5 to 8, carbon atoms and may be open-chain, cyclic or polycyclic dienes. The two alkene groups of the diene are preferably linked by one or two _CH2 groups. Examples are 1,3-pentadiene, cyclopentadiene, 1,5-hexadiene, 1,4-cyclohexadiene, 1,4- or 1,5-heptadiene, 1,4- or 1,5-Cycloheptadiene, 1,4- or 1,5-octadiene, 1,4- or 1,5-cyclooctadiene and norbornadiene. Preferably, Y represents two ethylenes or 1,5-hexadiene, 1,5-cyclooctadiene or norbornadiene.

In formula IX, Z preferably represents Cl or Br. Examples of E ^- are ClO ₄ ^- , CF ₃ SO ₃ ^- , CH ₃ SO ₃ ^- , HSO ₄ ^- , BF ₄ ^- , B(phenyl) ₄ ^- , BARF(B(3,5-bis(trifluoromethyl yl)phenyl) ₄ ^- ), PF ₆ ^- , SbCl ₆ ^- , AsF ₆ ^- or SbF ₆ ^- .

In process stage 1d), starting from the α,β-unsaturated carboxylic acids of the formula VI, correspondingly in particular the metal complexes of the formulas IX and IXa can be used, the ligands of which belong to chiral compounds with a ferrocenyl backbone. Sexual di-tertiary bisphosphines. Such ligands preferably correspond to the formula X or Xa,

in

R ¹ can be C ₃ -C ₈ -cycloalkyl or aryl, and

R ² can be C ₃ -C ₈ -cycloalkyl or aryl.

Examples of R ¹ within the meaning of C ₃ -C ₈ -cycloalkyl are cyclohexyl and 2-norbornyl.

Examples of R ¹ within the meaning of aryl are phenyl optionally substituted by 1 or 2 methyl, methoxy or trifluoromethyl.

An example of R ² within the meaning of C ₃ -C ₈ -cycloalkyl is cyclohexyl.

Examples of ^R2 within the meaning of aryl are phenyl optionally substituted by 1, 2 or 3 methyl, methoxy or trifluoromethyl.

Particular preference is given to ligands of the formulas X and Xa in which R ¹ represents aryl and R ² represents aryl, and ligands of formulas X and Xa in which R ¹ represents aryl and R ² represents C ₃ -C ₈ -cycloalkyl body.

Very particular preference is given to ^R representing 3,5-bis(trifluoromethyl)phenyl and R representing cyclohexyl or ^R representing 3,5- ^bis (trifluoromethyl)phenyl and ^R representing phenyl or ligands of formulas X and Xa wherein R ¹ represents 3,5-bis(trifluoromethyl)phenyl and R ² represents 4-methoxy-3,5-dimethylphenyl.

Furthermore, it has been found that iridium metal complexes, whose ligands belong to the class of chiral di-tertiary bisphosphines with a ferrocenyl backbone, are surprisingly also suitable for the α,β-unsaturated carboxyl Asymmetric hydrogenation of acids.

Using the above-mentioned ferrocenyl ligands in the metal complexes of the following formulas XI and XIa, a remarkably high enantiomeric purity can be obtained, and the use of iridium instead of rhodium constitutes a significant advantage (e.g. saving cost).

[LM'YZ](XI), [LM'Y] ⁺ E ^- (XIa),

in

M' stands for iridium;

Y is two alkenes or dienes;

Z represents Cl, Br or I;

E ^- represents the anion of an oxyacid or complex acid; and

L is a chiral ligand selected from di-tertiary bisphosphines.

When Y is an alkene, it may be a C ₂ -C ₁₂ -alkene, preferably a C ₂ -C ₆ -alkene, particularly preferably a C ₂ -C ₄ -alkene. Examples are propylene, butene, especially ethylene. The dienes may contain 5 to 12, preferably 5 to 8, carbon atoms and may be open-chain, cyclic or polycyclic dienes. The two alkene groups of the diene are preferably linked by one or two _CH2 groups. Examples are 1,3-pentadiene, cyclopentadiene, 1,5-hexadiene, 1,4-cyclohexadiene, 1,4- or 1,5-heptadiene, 1,4- or 1,5-Cycloheptadiene, 1,4- or 1,5-octadiene, 1,4- or 1,5-cyclooctadiene and norbornadiene. Preferably, Y represents two ethylenes or 1,5-hexadiene, 1,5-cyclooctadiene or norbornadiene.

In formula IX, Z preferably represents Cl or Br. Examples of E ^- are ClO ₄ ^- , CF ₃ SO ₃ ^- , CH ₃ SO ₃ ^- , HSO ₄ ^- , BF ₄ ^- , B(phenyl) ₄ ^- , BARF(B(3,5-bis(trifluoromethyl yl)phenyl) ₄ ^- ), PF ₆ ^- , SbCl ₆ ^- , AsF ₆ ^- or SbF ₆ ^- .

In process stage 1d), starting from α,β-unsaturated carboxylic acids of the formula VI, correspondingly, for example, metal complexes of the formulas XI and XIa can be used, the ligands of which belong to chiral compounds with a ferrocenyl backbone. Sexual di-tertiary bisphosphines.

Such ligands preferably correspond to the formula X or Xa,

in

R ¹ and R ² have the meanings given above.

Particular preference is given to ligands of the formulas X and Xa in which R ¹ represents aryl and R ² represents aryl, and ligands of formulas X and Xa in which R ¹ represents aryl and R ² represents C ₃ -C ₈ -cycloalkyl body.

Very particular preference is given to ligands of the formulas X and Xa in which ^R represents 3,5-bis(trifluoromethyl)phenyl and ^R represents cyclohexyl;

or corresponding to formula XII or XIIa,

in

R ³ is dimethylamino,

R ⁴ can be C ₃ -C ₈ -cycloalkyl or aryl,

R ⁵ can be C ₃ -C ₈ -cycloalkyl or aryl.

An example of R ⁴ and R ⁵ within the meaning of C ₃ -C ₈ -cycloalkyl is cyclohexyl.

Examples of ^R4 and ^R5 within the meaning of aryl are phenyl optionally substituted by 1, 2 or 3 methyl, methoxy or trifluoromethyl.

Particular preference is given to ligands of the formulas XII and ^XIIa in which R ^and R represent phenyl;

or corresponding to formula XIII or XIIIa,

in

R ⁶ is dimethylamino,

R ⁷ can be C ₃ -C ₈ -cycloalkyl or aryl,

R ⁸ can be C ₃ -C ₈ -cycloalkyl or aryl.

An example of R ⁷ and R ⁸ within the meaning of C ₃ -C ₈ -cycloalkyl is cyclohexyl.

Examples of R ⁷ and R ⁸ within the meaning of aryl are phenyl optionally substituted by 1, 2 or 3 methyl, methoxy or trifluoromethyl.

Particular preference is given to ligands of formulas XIII and XIIIa in which R ⁷ and R ⁸ represent aryl.

Very particular preference is given to ligands of the formulas XIII and XIIIa in which R ⁷ and R ⁸ represent 4-methoxy-3,5-dimethylphenyl.

和T.Troxler在Tetrahedron:Asymmetry，卷14(2003)，第3469-3477页、R.Gilbertson在Tetrahedron Letters，卷44(2003)，第953-955页、P.G.Andersson在the Journal of the AmericanChemical Society，卷126(2004)，第14308-14309页、A.Pfaltz在Organic Letters，卷6(2004)，第2023-2026页和F.Spindler在Tetrahedron:Asymmetry，卷15(2004)，第2299-2306页中所述的钌、铱和铑催化剂进行。The asymmetric hydrogenation of α,β-unsaturated alcohols of formula VIII in process stage 2e) or 3d) can preferably be used as M.

and T. Troxler in Tetrahedron: Asymmetry, Vol. 14 (2003), pp. 3469-3477, R. Gilbertson in Tetrahedron Letters, Vol. 44 (2003), pp. 953-955, PG Andersson in the Journal of the American Chemical Society, Vol. 126 (2004), pp. 14308-14309, A. Pfaltz in Organic Letters, Vol. 6 (2004), pp. 2023-2026 and F. Spindler in Tetrahedron: Asymmetry, Vol. 15 (2004), pp. 2299-2306 The ruthenium, iridium and rhodium catalysts are used.

As ligands for rhodium and ruthenium, chiral di-tertiary bisphosphines are generally used. Such chiral di-tertiary bisphosphines are described, for example, by X. Zhang in Chemical Reviews, Vol. 103 (2003), pp. 3029-3069.

As ligands for iridium, chiral phosphine-oxazoline ligands or phosphinite-oxazoline ligands are generally used. Such chiral phosphine-oxazoline ligands or phosphinate-oxazoline ligands are described, for example, by A. Pfaltz in Advanced Synthesis and Catalysis, Vol. 345 (2003), pp. 33-43.

It has surprisingly been found that rhodium metal complexes, the ligands of which belong to the class of chiral di-tertiary bisphosphines, are particularly suitable for the asymmetric hydrogenation of α,β-unsaturated alcohols of the formula VIII.

Using the above-mentioned chiral di-tertiary bisphosphines in the metal complexes of the formulas IX and IXa described below, high enantiomeric purity can be achieved, which constitutes a significant advantage (eg cost saving) for industrial scale preparation.

[LMYZ](IX), [LMY] ⁺ E ^- (IXa),

in

M, Y, Z, ^E- and L have the meanings and preferences given above.

In process stages 2e) and 3d), starting from the α,β-unsaturated alcohols of the formula VIII, correspondingly it is possible, for example, to use metal complexes of the formulas IX and IXa, the ligands of which belong to the group having a ferrocenyl backbone Chiral di-tertiary bisphosphines. Such ligands preferably correspond to formula XIV or XIVa,

in

R ⁹ may be C ₁ -C ₈ -alkyl, C ₃ -C ₈ -cycloalkyl or aryl, and

R ¹⁰ may be C ₁ -C ₈ -alkyl, C ₃ -C ₈ -cycloalkyl or aryl.

An example of R ⁹ within the meaning of C ₁ -C ₈ -alkyl is tert-butyl.

An example of R ⁹ within the meaning of C ₃ -C ₈ -cycloalkyl is cyclohexyl.

Examples of R ⁹ within the meaning of aryl are phenyl optionally substituted by 1 or 2 methyl groups.

Examples of R ¹⁰ within the meaning of C ₁ -C ₈ -alkyl are ethyl and tert-butyl.

An example of R ¹⁰ within the meaning of C ₃ -C ₈ -cycloalkyl is cyclohexyl.

Examples of R ¹⁰ within the meaning of aryl are phenyl optionally substituted by 1, 2 or 3 methyl, methoxy or trifluoromethyl, and also 2-furyl and 1-naphthyl.

Particular preference is given to ligands of the formulas XIV and XIVa in which R ⁹ represents C ₁ -C ₈ -alkyl and R ¹⁰ represents aryl and in formula XIV in which R ⁹ represents aryl and R ¹⁰ represents C ₁ -C ₈ -alkyl and XIVa ligands.

Very particular preference is given to ligands of the formulas XIV and XIVa in which R ⁹ represents phenyl and R ¹⁰ represents tert-butyl;

or corresponding to formula XV, XVI or XVII

in

m and p are in each case independently of each other 0 or an integer of 1 to 4 (XV) or 0 or an integer of 1 or 2 (XVI), and R ¹¹ and R ¹² represent hydrogen or are selected from C ₁ -C ₄ - identical or different substituents of alkyl and C ₁ -C ₄ -alkoxy; and X ₃ and X ₄ independently of each other represent a secondary phosphino group.

For ligand XV, the substituent is preferably bonded at the 6-position or the 6,6' position.

R ¹¹ and R ¹² , as alkyl groups, preferably contain 1 or 2 carbon atoms. Straight chain alkyl groups are preferred. Examples of R ¹⁰ and R ¹¹ within the meaning of alkyl are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and tert-butyl. Methyl and ethyl are preferred, methyl is particularly preferred.

R ¹¹ and R ¹² , as alkoxy, preferably contain 1 or 2 carbon atoms. Straight chain alkoxy groups are preferred. Examples of R ¹¹ and R ¹² within the meaning of alkoxy are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Methoxy and ethoxy are preferred, methoxy is particularly preferred.

The X ₃ and X ₄ groups can be different, or are preferably the same, and correspond to the formula PR ¹³ R ¹⁴ , wherein R ¹³ and R ¹⁴ are the same or different and are branched C ₃ -C ₈ -alkyl, C ₃ -C ₈ - cycloalkyl, unsubstituted phenyl or phenyl substituted by 1 to 3 C ₁ -C ₄ -alkyl, C ₁ -C ₄ -alkoxy or -CF ₃ groups.

Particular preference is given to ligands of formula XV in which X ₃ and X ₄ represent PR ¹³ R ¹⁴ groups, wherein R ¹³ and R ¹⁴ each represent cyclobutyl, cyclopentyl, cyclohexyl, phenyl or are replaced by 1 or 2 Methyl, methoxy, or phenyl substituted with a _CF3 group.

Also particularly preferred are ligands of the formulas XV, XVI and XVII in which X ₃ and X ₄ represent a PR ¹³ R ¹⁴ group and wherein R ¹³ and R ¹⁴ represent a phenyl group.

Very particular preference is given to ligands of the formula XV in which R ¹¹ and R ¹² represent methoxy and m and p represent 3.

Also very particularly preferred are ligands of the formula XVI in which R ¹¹ and R ¹² represent methyl and m and p represent 2.

It has now also surprisingly been found that iridium metal complexes, whose ligands belong to the class of chiral di-tertiary bisphosphines, are particularly suitable for the asymmetric hydrogenation of α,β-unsaturated alcohols.

The use of these ferrocenyl ligands in the metal complexes of the formulas XI and XIa described below makes it possible to obtain high enantiomeric purity, which constitutes a significant factor for industrial-scale preparations compared to the usual standard use of rhodium. Significant advantages (eg, cost savings).

[LM'YZ](XI), [LM'Y] ⁺ E ^- (XIa),

in

M', Y, Z, ^E- and L have the meanings given above.

In process stages 2e) and 3d), starting from the α,β-unsaturated alcohols of the formula VIII, correspondingly, it is possible, for example, to use metal complexes of the formulas XI and XIa whose ligands belong to the group having a ferrocenyl backbone Chiral di-tertiary bisphosphines. Such ligands preferably correspond to formula XIV or XIVa,

in

R ⁹ and R ¹⁰ have the meanings and preferences given above;

or corresponding to formula XV

Wherein R ¹¹ and R ¹² and X ₃ and X ₄ have the meanings and preferences given above;

Ligands of the formula XV in which R ¹¹ and R ¹² represent methoxy and m and p represent 1 and the R ¹¹ and R ¹² substituents are in the 6,6' position are likewise very particularly preferred.

The metal complexes used as catalysts in process stages 1d), 2e) and 3d) can be added as isolated compounds produced separately or can also be formed in situ before the reaction and then mixed with the substrate to be hydrogenated. Advantageously, ligand is additionally added in reactions using isolated metal complexes, or excess ligand is used in in situ preparations. This excess may, for example, be up to 10 moles, and preferably 0.001 to 5 moles, based on the metal compound used for the preparation.

Process stages 1d), 2e) and 3d) can be carried out at standard pressure or preferably at overpressure. The pressure may be, for example, 10 ⁵ to 2×10 ⁷ Pa (Pascal).

The catalysts used for the hydrogenation in process stages 1d), 2e) and 3d) are preferably used in amounts of 0.0001 to 10 mol %, particularly preferably 0.001 to 10 mol %, especially preferably 0.01 to 5 mol %, of the compound to be hydrogenated.

The preparation of the catalyst as well as process stages 1d), 2e) and 3d) and further process stages can be carried out in the absence or presence of inert solvents, solvents or solvent mixtures can be used. Suitable solvents are, for example, aliphatic, cycloaliphatic and aromatic hydrocarbons (pentane, hexane, petroleum ether, cyclohexane, methylcyclohexane, benzene, toluene, xylene), aliphatic halogenated hydrocarbons ( Dichloromethane, chloroform, dichloroethane and tetrachloroethane), nitriles (acetonitrile, propionitrile, benzonitrile), ethers (diethyl ether, dibutyl, tert-butyl methyl ether, ethylene glycol dimethyl ether, ethyl Glycol diethyl ether, diethylene glycol dimethyl ether, tetrahydrofuran, dioxane, diethylene glycol monomethyl ether or monoethyl ether), ketones (acetone, methyl isobutyl ketone), carboxylic acid esters and Lactone (ethyl acetate, methyl acetate, valerolactone), N-substituted lactam (N-methylpyrrolidone), carboxamide (dimethylformamide), acrylate urea (dimethylimidazoline), substituent Sulfones and sulfones (dimethyl sulfoxide, dimethyl sulfone, tetramethylene sulfoxide, tetramethylene sulfone), alcohols (methanol, ethanol, propanol, butanol, ethylene glycol monomethyl ether, ethylene glycol mono diethyl ether, diethylene glycol monomethyl ether) and water. The solvents can be used alone, or in a mixture of at least two solvents.

The reactions of process stages 1d), 2e) and 3d) can be carried out in the presence of cocatalysts, such as quaternary ammonium halides (tetrabutylammonium iodide), and/or can be carried out in the presence of protic acids, such as mineral acids.

The processes of stages 1e) and 2d) are preferably carried out at low temperatures, for example from -40°C to 0°C, advantageously in solvents. Suitable solvents are, for example, ethers (tetrahydrofuran or dioxane). At least equimolar amounts of metal hydrides are suitable for this reduction, for example BH ₃ ·S(CH ₃ ) ₂ , LiAlH ₄ , NaBH ₄ +TiCl ₄ , NaBH ₄ +AlCl ₃ , NaBH ₄ +BF ₃ ·Et ₂ O, LiAlH (OMe) ₃ or AlH ₃ , and alkyl metal hydrides such as diisobutylaluminum hydride.

Process stage 3c) is preferably carried out at low temperatures, for example from -40° C. to 0° C., advantageously in a solvent. Suitable solvents are, for example, hydrocarbons (pentane, cyclohexane, methylcyclohexane, benzene, toluene and xylene). At least equimolar amounts of metal hydrides are suitable for this reduction, such as NaBH ₄ , LiAlH ₄ or AlH ₃ , as well as alkyl metal hydrides, such as diisobutylaluminum hydride and tributyltin hydride.

Thanks to the regiospecific or regioselective and enantioselective process of the present invention, intermediates for the preparation of compounds of formula (B) can be prepared in high yields through all process stages. The high overall yield makes this method suitable for industrial use.

Another subject of the invention are compounds (intermediates) of the formula

Formula V

Formula VI,

Formula VII,

和

and

Formula VIII,

wherein Het, _R'1 , _R'2 , _R'3 and _R'7 have the meanings given above, and wherein for formula VII the carbon atom bonded to the _R'3 group exhibits (R) or ( The S) configuration, the (R) configuration is preferred.

Another subject of the invention is a compound (intermediate) of formula IV,

wherein Het, _R'1 , _R'2 , _R'3 and _R'7 have the meanings given above.

The above embodiments and preferences apply to Het, R' ₁ , R' ₂ , R' ₃ and R' ₇ .

The following examples illustrate the invention in more detail.

HPLC gradient on Hypersil BDS C-18 (5 μm); column: 4 × 125 mm

(I) 90% water*/10% acetonitrile* to 0% water*/100% acetonitrile* within 5 min + 2.5 min (1.5 ml/min)

(II) 95% water*/5% acetonitrile* to 0% water*/100% acetonitrile* within 40 minutes (0.8 ml/min)

HPLC gradient on Synergi Polar-RP 80A (Phenomenex) (4 μm); column: 4.60 × 100 mm

(III) 90% water*/10% acetonitrile* to 0% water*/100% acetonitrile* within 5 min+2.5 min (1.5 ml/min)

(IV) 95% water*/5% acetonitrile* to 0% water*/100% acetonitrile* within 40 minutes (0.8 ml/min)

*Contains 0.1% trifluoroacetic acid

Example A)

Preparation of (R)-2-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-ylmethyl]-3-methylbutan-1-ol (A6) method

Embodiment A1 :

Preparation of 1-(3-methoxypropyl)-3-methyl-1H-indazole-6-carbaldehyde

A solution of 10.0 g of 6-bromo-1-(3-methoxypropyl)-3-methyl-1H-indazole (WO 2005/090305 A1) in 70 ml of tetrahydrofuran was cooled to -78°C and washed with 3.76 ml N-methylmorpholine treatment. Recool to -78°C and add 23 mL of n-butyllithium (1.6M in hexane) dropwise so that the internal temperature does not rise above -70°C. Stir for an additional 2 minutes at -70°C. Subsequently, 5.18 ml of N,N-dimethyl-formamide was added dropwise so that the internal temperature did not rise above -70°C. Stir for an additional 5 minutes at -70°C. To the reaction mixture was added 70 mL of 1M aqueous ammonium chloride and the reaction mixture was warmed to ambient temperature. The reaction mixture was diluted with 50 mL of water and extracted with tert-butyl methyl ether (2 x 100 mL). The organic phase was washed with brine solution (1 x 100 mL). The combined organic phases were dried over sodium sulfate, filtered and evaporated on a rotary evaporator. The crude title compound Al was obtained from the residue as a yellow oil. Content (NMR): 90% (contains 10% 1-(3-methoxypropyl)-3-methyl-1H-indazole). (7.80 g, 90.4%). Rf = 0.27 ( acetic ester /heptane 1:1); Rt = 3.67 (gradient I).

Embodiment A2 :

Preparation of ethyl 2-{hydroxy[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]methyl}-3-methylbutanoate

A solution of 2.628 mL of diisopropylamine and 20 mL of tetrahydrofuran was cooled to -20°C and 11.508 mL of n-butyllithium (1.6M in hexane) was added dropwise over 7 minutes. Stir for an additional 10 minutes at -20°C. A solution of 2.62 ml of ethyl isovalerate in 15 ml of tetrahydrofuran was then added dropwise over 10 minutes at -20°C. After another 5 minutes, a solution of 3.60 g of 1-(3-methoxypropyl)-3-methyl-1H-indazole-6-carbaldehyde (Al) in 15 mL of tetrahydrofuran was added dropwise and heated at -20 Stir for an additional 30 minutes at °C. Then 30 mL of saturated aqueous ammonium chloride were added dropwise and extraction was then carried out with tetrabutylmethyl ether (2 x 100 mL). The organic phase was washed sequentially with 0.5N hydrochloric acid (1 x 100 mL) and brine solution (1 x 50 mL). The combined organic phases were dried over sodium sulfate, filtered and evaporated on a rotary evaporator. The crude title compound A2 (4.98 g, 89.6%, syn:anti=67:33) was obtained from the residue as a white solid. Rf = 0.08 (acetate/heptane 1:2); Rt = 15.96, 16.75 (gradient II).

Embodiment A3 :

2-[1-[1-(3-Methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3-methylbutanoic acid ethyl ester preparation of

2.80 grams of ethyl 2-{hydroxy[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]methyl}-3-methylbutanoate (A2) and A solution of 47 mg of 4-dimethylaminopyridine in 20 ml of tetrahydrofuran was cooled to 0°C. 0.79 mL of acetic anhydride was added dropwise over 2 minutes and the reaction mixture was stirred at 0 °C for 1 hour. A solution of 2.63 g of potassium tert-butoxide in 20 ml of tetrahydrofuran was then added dropwise over 1 hour at 0°C, followed by stirring at 0°C for 1 hour. The reaction mixture was poured on 100 mL of ice-cold water and extracted with tert-butyl methyl ether (2 x 80 mL). The organic phase was washed successively with 80 ml of water and 80 ml of brine solution, dried over sodium sulfate, filtered and evaporated on a rotary evaporator. The pure title compound A3 (1.83 g, 70%) was obtained from the residue by flash chromatography ( _SiO2 60F, acetate/hexane 1:6) as a pale yellow oil. Rf = 0.28 (acetate/heptane 1:2); Rt = 22.42 (gradient II).

Embodiment A4 :

Preparation of 2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3-methylbutanoic acid

2.80 grams of ethyl 2-{hydroxy[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]methyl}-3-methylbutanoate (A2) and A solution of 47 mg of 4-dimethylaminopyridine in 20 ml of tetrahydrofuran was cooled to 0°C. 0.79 mL of acetic anhydride was added dropwise over 2 minutes and the reaction mixture was stirred at 0 °C for 1 hour. A solution of 2.63 g of potassium tert-butoxide in 20 ml of tetrahydrofuran was then added dropwise over 1 hour at 0°C, followed by stirring at 0°C for 1 hour. 10 mL of ice-cold water was added dropwise to the reaction mixture over 1 min and the tetrahydrofuran was evaporated on a rotary evaporator. The aqueous emulsion was treated with 28 mL of ethanol and 3.8 mL of 2M aqueous potassium hydroxide and heated at reflux for 13.5 hours. Ethanol was evaporated from the reaction mixture on a rotary evaporator (35°C). The resulting aqueous solution was washed with tert-butyl methyl ether (2 x 15 mL). The aqueous phase was acidified with 10 mL of 2M aqueous hydrochloric acid and extracted with tert-butyl methyl ether (2 x 30 mL). The organic phase was washed successively with 15 ml of water and 15 ml of brine solution, dried over sodium sulfate, filtered and evaporated on a rotary evaporator. The pure title compound A4 (1.44 g, 60.1%) was obtained from the residue as white crystals by crystallization from a hot acetate/heptane mixture. Rf = 0.27 ( acetate /heptane 3:1); Rt = 16.41 (gradient II).

Embodiment A5 :

(R)-2-[1-(3-Methoxypropyl)-3-methyl-1H-indazol-6-ylmethyl]-3-methylbutanoic acid

Through 2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3-methylbutanoic acid ( Catalytic asymmetric hydrogenation of A4) and flash chromatography ( _SiO2 60F, acetate) purification of the residue afford the title compound in the form of white crystals. Rf = 0.32 (acetate/heptane 2:1); Rt = 4.03 (gradient I).

2-[1-[1-(3-Methoxypropyl)-3-methyl-1H-indazol-6-yl]methyl-(E)- Asymmetric hydrogenation of the subunit]-3-methylbutanoic acid (A4).

The reaction mixture was investigated for conversion and enantiomeric excess using the HPLC method described below. For this, 80 μl of this reaction solution were dissolved in 1000 μl of ethanol. The following results are obtained:

Condition: 41.66 micromole 2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3-methano 500 microliters of solvent; 1.2 equivalents of ligand per equivalent of metal; p(H ₂ ): 20 bar; T: ambient temperature; Reaction time: 16 hours

^* Under otherwise identical conditions, enantiomeric ligands give products with the (R) configuration.

HPLC conditions:

Instruments SFC Berger Instruments

Column CHIRALPAK-AD (250mm ^* 0.46cm)

modifier ethanol

Outlet pressure 100 bar

Gradient 15% EtOH 8', 60%/min 40%, 2' 40%, 60%/min 15%, 15% 6', total 17'

Flow rate 1.5ml/min.

Detection UV(210nm)

Temperature 40℃

Sample concentration 2 mg product in 1.0 mL MeOH

Injection volume 5.0 μl loop

Running time 12 minutes

Dwell time:

-(S)-(A5) 4.7 minutes

-(R)-(A5) 5.8 minutes

-(A4) 8.5 minutes

Embodiment A6 :

(R)-2-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-ylmethyl]-3-methylbutan-1-ol

a) Starting from (R)-2-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-ylmethyl]-3-methylbutanoic acid (A5) preparation

8.55 grams of (R)-2-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-ylmethyl]-3-methylbutyric acid (A5) at 85 The solution in mL THF was cooled to 0°C and treated with 81.4 mL of borane-THF complex (1M in THF). The reaction mixture was stirred at ambient temperature for 17 hours. The reaction mixture was cooled to 0°C and then treated slowly with 100 mL of methanol. The mixture was evaporated on a rotary evaporator and dried under high vacuum. The pure title compound A6 (SiO ₂ 60F, acetate/hexane 2:1 ) was obtained from the residue by flash chromatography (8.05 g, 98%) as a colorless oil. Rf = 0.28 (acetate/heptane 2:1); Rt = 4.13 (gradient I).

Embodiment A6 :

(R)-2-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-ylmethyl]-3-methylbutan-1-ol

b) from 2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3-methylbutyl -1-alcohol (A7) as raw material preparation

Through 2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3-methylbutan-1 - Catalytic asymmetric hydrogenation of the alcohol (A7) and purification of the residue by flash chromatography ( _SiO2 60F, acetate) affords the title compound as a light pink oil. Rf = 0.32 (acetate/heptane 2:1); Rt = 4.13 (gradient I).

2-[1-[1-(3-Methoxypropyl)-3-methyl-1H-indazol-6-yl]methyl-(E)- Asymmetric hydrogenation of the subunit]-3-methylbutan-1-ol (A7).

Conditions: 41.66 micromoles of substrate; 500 microliters of solvent; 1.2 equivalents of ligand per equivalent of metal. The reaction mixture was investigated for conversion and enantiomeric excess using the HPLC method described below. For this, 80 μl of this reaction solution were dissolved in 1000 μl of ethanol. The following results are obtained:

Condition: 41.66 micromole 2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3-methano 500 μl of solvent; 1.2 equivalents of ligand per equivalent of metal; p(H ₂ ): 80 bar; T: 40° C.; Reaction time: 14 hours

^* Under otherwise identical conditions, enantiomeric ligands give products with the (R) configuration.

HPLC conditions:

Instruments SFC Berger Instruments

Column CHIRALPAK-AD(250mm*0.46cm)

Modifier Ethanol

Outlet pressure 100 bar

Gradient 15% EtOH 8', 60%/min 40%, 2' 40%, 60%/min 15%, 15% 6', total 17'

Flow rate 1.5ml/min.

Detection UV(210nm)

Temperature 40℃

Sample concentration 2 mg product in 1.0 mL MeOH

Injection volume 5.0 microliter loop

Running time 12 minutes

Dwell time:

-(S)-(A6) 6.1 minutes

-(R)-(A6) 7.5 minutes

-(A7) 8.2 minutes

A representative description of the reaction performed on a larger scale:

In a Schlenk tube prepare 1.65 mmoles of 2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]- A solution of 3-methylbutan-1-ol (A7) in 4 mL of degassed anhydrous solvent was stirred at ambient temperature for 10 minutes. A solution of the appropriate amount of ligand and metal precursor (1.05 equivalents of ligand per equivalent of metal) in 4 mL of degassed anhydrous solvent was prepared in a second Schlenk tube under an argon atmosphere, and the mixture was stirred at ambient temperature for 10 min . These two solutions were transferred via hollow needles into a 50 ml autoclave made of special stainless steel, which had been placed under an argon atmosphere in advance. The autoclave was closed and purged with argon (apply 10-12 bar pressure and release to 1 bar each, 4 times). Subsequently, the argon was replaced by hydrogen and purged with hydrogen (10-12 bar pressure applied and released to 1 bar each, 4 times). The autoclave was then put under a pressure of 80 bar with hydrogen and heated to 40°C. After 20 hours, cool to ambient temperature and remove the pressure.

The reaction mixture was investigated for conversion and enantiomeric excess using the HPLC method described above. For this, 80 μl of this reaction solution were dissolved in 1000 μl of ethanol. The following results are obtained:

Condition: 3.306 mmol 2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3-methano Butan-1-ol (A7); 10 ml solvent; p(H ₂ ): 80 bar; T: 40° C.; Reaction time: 17 hours

^* Under otherwise identical conditions, enantiomeric ligands give products with the (R) configuration.

Condition: 1.65 mmol 2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3-methano Butan-1-ol (A7); 10 ml solvent; p(H ₂ ): 80 bar; T: 40° C.; Reaction time: 17 hours

^* Under otherwise identical conditions, enantiomeric ligands give products with the (R) configuration.

Alternatively, 2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3-methyl 2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3 -Methylbutan-l-ol (A7) and subsequent catalytic asymmetric hydrogenation affords the title compound (A6).

Embodiment A7 :

2-[1-[1-(3-Methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3-methylbutan-1- alcohol

a) from 2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]methyl-(E)-ylidene]-3-methylbutyl Acid (A4) is prepared as raw material

470 mg of (2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3-methyl A solution of butyric acid (A4) in 2 mL of THF was cooled to 0° C. and treated with a solution of 56.4 mg of lithium aluminum hydride in 2.5 mL of THF. The reaction mixture was stirred at ambient temperature for 19 hours. Subsequently 50.0 mg of Lithium aluminum hydride was solid and the reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was treated slowly with 3 ml of glacial acetic acid. The mixture was washed with potassium sodium tartrate solution, the aqueous phase was extracted with tert-butyl methyl ether and the combined The organic phase was dried over sodium sulfate, filtered and evaporated on a rotary evaporator, the residue was dried under high vacuum. A yellow color was obtained from the residue by flash chromatography ( _SiO2 60F, acetate/hexane 2:1) Pure title compound A7 (252.7 mg, 56%) as a solid. Rf = 0.29 (acetate/heptane 2:1); Rt = 3.96 (gradient I).

Alternatively, 2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3-methyl Catalytic reduction of ethyl butyrate (A3) to 2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene ]-3-Methylbutan-1-ol (A7) and subsequent catalytic asymmetric hydrogenation to prepare the title compound (A6).

Embodiment A7 :

2-[1-[1-(3-Methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3-methylbutan-1- alcohol

b) from 2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3-methylbutyl Acetate ethyl ester (A3) is raw material preparation

19.68 grams of 2-[1-[1-(3-methoxypropyl)-3-methyl-1H-indazol-6-yl]meth-(E)-ylidene]-3-methylbutyl A solution of ethyl acetate (A3) in 433 ml of toluene was cooled to -20°C and treated with 115.2 ml of diisobutyllithium hydride solution (1.7M in toluene), keeping the temperature at -20°C. The reaction mixture was then warmed to ambient temperature and stirred at ambient temperature for 1 hour. Subsequently, the reaction mixture was slowly treated with 1 liter of 1M HCl, keeping the temperature below 30°C. The phases were separated and the aqueous phase was extracted with diethyl ether (1 x 1 L, 2 x 300 mL). The combined organic phases were washed successively with 1 liter each of water, saturated aqueous sodium carbonate solution and brine solution, dried over sodium sulfate, filtered and evaporated on a rotary evaporator, and the residue was dried under high vacuum. The pure title compound A7 (14.24 g, 82%) was obtained from the residue by flash chromatography ( _SiO2 60F, dichloromethane/methanol/concentrated ammonia 200:5:1) as a yellow oil. Rf = 0.29 (dichloromethane/ Methanol/concentrated ammonia 200:5:1); Rt=3.96 (gradient I).

The following compounds can be prepared analogously according to the method described in Example A:

B) (R)-2-[3-(3-methoxy-propyl)-1-methyl-imidazo[1,5-a]pyridin-6- ylmethyl ]-3-methyl- Butan-1-ol

Claims (10)

1. the method that is used for preparation I compound

Wherein Het representative is connected to unsaturated bicyclic heterocyclic radical on the residue molecule through carbon atom, is not bonded directly to ring on the residue molecule by R ' ₁And R ' ₂Replace R ' ₁And R ' ₂Represent H, C independently of one another ₁-C ₈-alkyl, halogen, many halo-C ₁-C ₈-alkoxyl group, many halo-C ₁-C ₈-alkyl, C ₁-C ₈-alkoxyl group, C ₁-C ₈-alkoxy-C ₁-C ₈-alkyl or C ₁-C ₈-alkoxy-C ₁-C ₈-alkoxyl group, R ' ₁And R ' ₂Different times table H, R ' ₃Represent C ₁-C ₈-alkyl, and wherein with R ' ₃The carbon atom of group bonding shows (R) or (S) configuration, and (R) configuration is preferred, it is characterized in that

A) make the compound of formula II

Wherein Het, R ' ₁And R ' ₂Have the implication that above provides,

With the compound reaction of formula III,

R ' wherein ₃Have the implication that above provides,

Thereby the non-enantiomer mixture of production IV,

R ' wherein ₇Be C ₁-C ₁₂-alkyl, C ₃-C ₈-cycloalkyl, phenyl or benzyl,

B) the OH groups converted with the non-enantiomer mixture of formula IV becomes leavings group, and removes the acrylate of this leavings group with production V in the presence of highly basic,

Subsequently, according to method variant 1

1c) by the compound of saponification with the acrylate conversion production VI of formula V,

1d) with the acid of formula VI hydrogen and catalytic amount as the metal complex of asymmetric hydrogenation catalyzer in the presence of hydrogenation, this metal complex comprises the metal that is selected from ruthenium, rhodium and iridium with chirality bidentate ligand bonding, with the compound of production VII,

And

1e) with the compound of the acid of formula VII reduction with production I;

Or according to method variant 2

2c) by the compound of saponification with the acrylate conversion production VI of formula V,

2d) with the compound of the acid of formula VI reduction with production VIII

And

2e) with the alcohol of formula VIII hydrogen and catalytic amount as the metal complex of asymmetric hydrogenation catalyzer in the presence of hydrogenation, this metal complex comprises the metal that is selected from ruthenium, rhodium and iridium with chirality bidentate ligand bonding, with the compound of production I;

Or according to method variant 3

3c) with the compound of the acrylate of formula V reduction production VIII

And

3d) with the alcohol of formula VIII hydrogen and catalytic amount as the metal complex of asymmetric hydrogenation catalyzer in the presence of hydrogenation, this metal complex comprises the metal that is selected from ruthenium, rhodium and iridium with chirality bidentate ligand bonding, with the compound of production I.

2. according to the method that is used for preparation I compound of claim 1, R ' ₁Representation methoxy-or oxyethyl group-C ₁-C ₄-alkyl, and R ' ₂Represent methylidene, ethyl, methoxy or ethoxy.

3. according to the method that is used for preparation I compound of one of claim 1 and 2, the Het representative has the unsaturated bicyclic heterocyclic group of 1 to 4 nitrogen-atoms and/or 1 or 2 sulphur or Sauerstoffatom, and it is made of 5 yuan and/or 6 yuan of rings in each case.

4. according to the method that is used for preparation I compound of one of claim 1 to 3, by R ' ₁And R ' ₂The Het that replaces represents 1-(3-methoxy-propyl)-3-Methyl-1H-indole-6-base or 1-(3-methoxy-propyl)-3-methyl isophthalic acid H-indazole-6-base and R ' ₃Represent sec.-propyl.

5. the compound of formula V

Wherein Het representative is connected to unsaturated bicyclic heterocyclic radical on the residue molecule through carbon atom, is not bonded directly to ring on the residue molecule by R ' ₁And R ' ₂Replace R ' ₁And R ' ₂Represent H, C independently of one another ₁-C ₈-alkyl, halogen, many halo-C ₁-C ₈-alkoxyl group, many halo-C ₁-C ₈-alkyl, C ₁-C ₈-alkoxyl group, C ₁-C ₈-alkoxy-C ₁-C ₈-alkyl or C ₁-C ₈-alkoxy-C ₁-C ₈-alkoxyl group, R ' ₁And R ' ₂Different times table H, R ' ₃Represent C ₁-C ₈-alkyl, and R ' ₇Be C ₁-C ₁₂-alkyl, C ₃-C ₈-cycloalkyl, phenyl or benzyl.

6. the compound of formula VI,

Wherein Het representative is connected to unsaturated bicyclic heterocyclic radical on the residue molecule through carbon atom, is not bonded directly to ring on the residue molecule by R ' ₁And R ' ₂Replace R ' ₁And R ' ₂Represent H, C independently of one another ₁-C ₈-alkyl, halogen, many halo-C ₁-C ₈-alkoxyl group, many halo-C ₁-C ₈-alkyl, C ₁-C ₈-alkoxyl group, C ₁-C ₈-alkoxy-C ₁-C ₈-alkyl or C ₁-C ₈-alkoxy-C ₁-C ₈-alkoxyl group, R ' ₁And R ' ₂Different times table H, and R ' ₃Represent C ₁-C ₈-alkyl.

7. the compound of formula VII

Wherein Het representative is connected to unsaturated bicyclic heterocyclic radical on the residue molecule through carbon atom, is not bonded directly to ring on the residue molecule by R ' ₁And R ' ₂Replace R ' ₁And R ' ₂Represent H, C independently of one another ₁-C ₈-alkyl, halogen, many halo-C ₁-C ₈-alkoxyl group, many halo-C ₁-C ₈-alkyl, C ₁-C ₈-alkoxyl group, C ₁-C ₈-alkoxy-C ₁-C ₈-alkyl or C ₁-C ₈-alkoxy-C ₁-C ₈-alkoxyl group, R ' ₁And R ' ₂Different times table H, R ' ₃Represent C ₁-C ₈-alkyl, and wherein with R ' ₃The carbon atom of group bonding shows (R) or (S) configuration, and (R) configuration is preferred.

8. the compound of formula VIII

Wherein Het representative is connected to unsaturated bicyclic heterocyclic radical on the residue molecule through carbon atom, is not bonded directly to ring on the residue molecule by R ' ₁And R ' ₂Replace R ' ₁And R ' ₂Represent H, C independently of one another ₁-C ₈-alkyl, halogen, many halo-C ₁-C ₈-alkoxyl group, many halo-C ₁-C ₈-alkyl, C ₁-C ₈-alkoxyl group, C ₁-C ₈-alkoxy-C ₁-C ₈-alkyl or C ₁-C ₈-alkoxy-C ₁-C ₈-alkoxyl group, R ' ₁And R ' ₂Different times table H, and R ' ₃Represent C ₁-C ₈-alkyl.

9. the compound of formula IV,

Wherein Het representative is connected to unsaturated bicyclic heterocyclic radical on the residue molecule through carbon atom, is not bonded directly to ring on the residue molecule by R ' ₁And R ' ₂Replace R ' ₁And R ' ₂Represent H, C independently of one another ₁-C ₈-alkyl, halogen, many halo-C ₁-C ₈-alkoxyl group, many halo-C ₁-C ₈-alkyl, C ₁-C ₈-alkoxyl group, C ₁-C ₈-alkoxy-C ₁-C ₈-alkyl or C ₁-C ₈-alkoxy-C ₁-C ₈-alkoxyl group, R ' ₁And R ' ₂Different times table H, R ' ₃Represent C ₁-C ₈-alkyl, and R ' ₇Be C ₁-C ₁₂-alkyl, C ₃-C ₈-cycloalkyl, phenyl or benzyl.

10. the method that is used for preparation formula A compound

Wherein Het representative is connected to unsaturated bicyclic heterocyclic radical on the residue molecule through carbon atom, is not bonded directly to ring on the residue molecule by R ' ₁And R ' ₂Replace R ' ₁And R ' ₂Represent H, C independently of one another ₁-C ₈-alkyl, halogen, many halo-C ₁-C ₈-alkoxyl group, many halo-C ₁-C ₈-alkyl, C ₁-C ₈-alkoxyl group, C ₁-C ₈-alkoxy-C ₁-C ₈-alkyl or C ₁-C ₈-alkoxy-C ₁-C ₈-alkoxyl group, R ' ₁And R ' ₂Different times table H, R ' ₃Represent C ₁-C ₈-alkyl, R ' ₄Be C ₁-C ₈-alkyl, R ' ₅Represent C ₁-C ₈-alkyl or C ₁-C ₈-alkoxyl group, R ' ₆Represent C ₁-C ₈-alkyl or R ' ₅And R ' ₆Constitute together tetramethylene, pentamethylene, 3-oxa--pentamethylene or-CH ₂CH ₂O-C (O)-, it is optional by C ₁-C ₄-alkyl, phenyl or benzyl replace, and wherein with R ' ₃The carbon atom of group bonding shows (R) or (S) configuration, and (R) configuration is preferred, it is characterized in that making the compound of formula B and the compound of formula C to react in the presence of basic metal or alkaline-earth metal

Wherein Het and R ' ₁To R ' ₆Have the implication that as above provides, on behalf of Cl, Br or I and Z, Y represent Cl, Br or I, and wherein with R ' ₃The carbon atom of group bonding shows (R) or (S) configuration, and (R) configuration is preferred,

The compound of formula B is by the halogenation preparation of the compound of the formula I that makes according to claim 1.