WO2000063173A1

WO2000063173A1 - Process for the preparation of substituted piperidines

Info

Publication number: WO2000063173A1
Application number: PCT/EP2000/003118
Authority: WO
Inventors: Bruno Lohri; Eric Vieira
Original assignee: F. Hoffmann-La Roche Ag
Priority date: 1999-04-14
Filing date: 2000-04-07
Publication date: 2000-10-26
Also published as: AU3818900A

Abstract

The present invention concerns a process for the preparation of a compound of formula (1) or salts thereof, comprising the reaction of a compound of formula (2) in the presence of an oxidant and a chiral osmium complex, wherein the hydroxy groups attached to the carbon atoms 3 and 4 of the piperidine cycle of formula (1) are in cis position and A, R?1 and R2¿ are as defined in the description and claims.

Description

Process for the preparation of substituted piperidines

The invention relates to a novel process for the preparation of substituted piperidines. More particularly the invention relates to the preparation of compounds of the formula 1

R'

1 or salts thereof, wherein the hydroxy groups attached to the carbon atoms 3 and 4 of the piperidine cycle are in cis position and

A is arylene;

R¹ is alkyl, aryl, aralkyl, diarylalkyl, alkoxycarbonyl, halogenated alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, allyloxycarbonyl, alkylcarbonyl, halogenated alkylcarbonyl, arylsulfonyl, alkylsulfonyl or alkylsilyl and

R" is alkoxy, cycloalkoxy, aryloxy, aralkoxy, aralkoxyalkoxy, hydroxy, alkylsulfonyloxy, arylsulfonyloxy, trifluoromethylsulfonyloxy, chlorine, bromine or iodine.

The compounds of formula 1 can be used as chiral building blocks in the preparation of renin inhibitors, especially disubstituted and trisubstituted renin inhibitors as e.g. disclosed in WO 97/09311. Examples for these compounds are 1- [2- [7-[(3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy] -phenyl] -piperidin-3- yloxymethyl] -naphthalen-2-yloxy] -ethyl] -4-methyl-piperazine and (3R,4S,5S)-4- [4-(3- benzyloxy-propoxy)-phenyl]-5-ethoxy-3-(naphthalen-2-ylmethoxy)-piperidine. The preparation of optically active renin inhibitors via conventional resolution of racemates as disclosed in the prior art results in a considerable loss of product. The present invention provides a process avoiding the disadvantages of the above process.

According to the present invention the compounds of formula 1 or salts thereof can be prepared by a process comprising the reaction of a compound of the formula 2

2

in the presence of an oxidant and a chiral osmium complex, wherein R¹, R² and A are defined as above.

The term "alkyl" means alone or in combination a branched or unbranched alkyl group containing 1 to 8 carbon atoms, preferred 1 to 6 carbon atoms. Examples for branched or unbranched -C₈ alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls, the isomeric octyls and preferred ethyl, n-propyl, and isopropyl and particularly preferred methyl.

The term "cycloalkyl" means alone or in combination a cycloalkyl cycle with 3 to 8 carbon atoms and preferred a cycloalkyl cycle with 3 to 6 carbon atoms. Examples for C₃-C₈ cycloalkyl are cyclopropyl, methyl-cyclopropyl, dimethyl- cyclopropyl, cyclobutyl, methyl-cyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, methyl- cyclohexyl, dimethyl-cyclohexyl and cycloheptyl.

The term "aryl" means alone or in combination a phenyl or a naphthyl group which can be substituted by one or several, preferably one to three substituents chosen from alkyl, cycloalkyl, alkoxy, halogen, carboxy, alkoxycarbonyl, hydroxy, amino, nitro, trifluoromethyl or aryl means 9-fluorenyl. Examples of aryl substituents are phenyl, tolyl, methoxyphenyl, fluorophenyl, chlorophenyl, hydroxyphenyl, trifluoromethylphenyl, 1-naphthyl, 2-naphthyl and 9-fluorenyl.

The term "arylene" means alone or in combination a phenylene or a naphthylene group which can be additionally substituted by one or several, preferably one to three substituents chosen from alkyl, halogen, nitro, cycloalkyl, alkoxy, hydroxy, amino, preferably alkyl, halogen and nitro. Examples for arylene are ortho-phenylene, meta- phenylene, para-phenylene, the tolylenes, methoxyphenylenes, fluorophenylenes, chlorophenylenes and naphthylenes. Preferred are phenylene, wherein the substituents of the phenylene which are defined by formula 1 are placed ortho, meta or preferred para to one another and wherein one to four additional substituents chosen from alkyl, halogen and nitro can be present at the arylene cycle. Especially preferred substituents are methyl, chloro and nitro. Particularly preferred is unsubstituted phenylene and especially unsubstituted para-phenylene.

The term "alkoxy" means alone or in combination the group alkyl-O-, wherein alkyl is defined as before. Examples are ethoxy, n-propyloxy, and iso-propyloxy. Preferred is methoxy.

The term "cycloalkoxy" means alone or in combination the group cycloalkyl-O- , wherein cycloalkyl is defined as before. Preferred examples are cyclopropyloxy, cyclopentyloxy and cyclohexyloxy.

The term "aryloxy" means alone or in combination the group aryl-O-, wherein aryl is defined as before. Examples are methoxyphenoxy and trifluoromethylphenoxy. Preferred is phenoxy.

The term "alkoxyalkyl" means alone or in combination an alkyl group, wherein a hydrogen is substituted by an alkoxy group. Examples are methoxymethyl, ethoxymethyl and 2-methoxyethyl. Particularly preferred is methoxymethyl.

The term "aralkyl" means alone or in combination an alkyl group, wherein a hydrogen is substituted by an aryl group. A preferred example is benzyl.

The term "diarylalkyl" means alone or in combination an alkyl group, wherein two hydrogens are substituted by aryl groups. Examples are phenyl(para- methoxyphenyl)methyl and preferably diphenylmethyl and di(para- rhethoxyphenyl ) methyl . The term "aralkoxy" means alone or in combination the group aralkyl-O- , wherein aralkyl is defined as before. Examples are benzyloxy, phenylethyloxy and para- methoxybenzyloxy. Preferred examples are benzyloxy and para-methoxybenzyloxy.

The term "aralkoxyalkyl" means alone or in combination an alkyl group, wherein a hydrogen is substituted by an alkoxy group in which a hydrogen is substituted by an aryl group. A preferred example for aralkoxyalkyl is 3-(2-methoxy-benzyloxy)-propyl.

The term "alkoxycarbonyl" means alone or in combination a group of the formula alkoxy-C(O)- wherein alkoxy is defined as before. Examples are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, iso-propoxycarbonyl and the isomeric butoxycarbonyls. Preferred examples are tert.-butoxycarbonyl and ethoxycarbonyl.

The term "halogenated alkoxycarbonyl" means alone or in combination an alkoxycarbonyl group, wherein one or several, preferably one to three hydrogens of the alkoxy group are substituted by halogen, preferably fluorine or chlorine. A preferred example is trichloroethoxycarbonyl.

The term "aryloxycarbonyl" means alone or in combination a group of the formula aryloxy-C(O)-, wherein aryloxy is defined as before e.g. para-tolyloxycarbonyl and preferably phenoxycarbonyl.

The term "aralkoxycarbonyl" means alone or in combination a group of the formula aralkoxy-C(O)-, wherein aralkoxy is defined as before e.g. 9-fiuorenylmethoxycarbonyl and more preferably benzyloxycarbonyl.

The term "aralkoxyalkoxy" means alone or in combination an alkoxy group, wherein a hydrogen is substituted by an aralkoxy group, wherein alkoxy and aralkoxy are defined as above. Examples are benzyloxymethoxy, benzyloxyethoxy and preferably 3-(2-methoxy-benzyloxy)-propoxy.

The term "alkylcarbonyl" means alone or in combination the group alkyl-C(O)-, wherein alkyl is defined as before, e.g. methylcarbonyl and ethylcarbonyl.

The term "halogenated alkylcarbonyl" means alone or in combination the group alkylcarbonyl, wherein one or several, preferably one to three hydrogens are substituted by halogen, preferably fluorine or chlorine, e.g. trichloromethylcarbonyl.

The term "allyloxycarbonyl" means preferably the group

CH₂=CH-CH₂-O-CO-. The term "alkylsulfonyl" means alone or in combination the group alkyl-S(O)₂-, wherein alkyl is defined as before, e.g. methylsulfonyl.

The term "arylsulfonyl" means alone or in combination the group aryl-S(O)₂-, wherein aryl is defined as before, e.g. tosylsulfonyl.

The term "alkylsulfonyloxy" means alone or in combination the group alkyl-S(O)₂O-, wherein alkyl is defined as before, e.g. methylsulfonyloxy.

The term "arylsulfonyloxy" means alone or in combination the group aryl-S(O)₂O-, wherein aryl is defined as before, e.g. tosylsulfonyloxy.

The term "alkylsilyl" means alone or in combination a silyl group which is substituted by one to three alkyl groups, e.g. t-butyl-dimethylsilyl or preferably dimethyl-(2,3-dimethyl-2-butyl)-silyl.

The term "halogen" means fluorine, chlorine, bromine, iodine and preferably chlorine and bromine and more preferably chlorine.

The term "salts" means compounds which are formed by reaction of compounds of formula 1 with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, para-toluenesulfonic acid, salicylic acid, and the like. The term salts includes solvates and particularly hydrates of such salts.

The term "Boc" means tert-butoxycarbonyl

The term "anion" means an atom, a group of atoms or a molecule with negative charge. This charge can be a single or a multiple charge. Examples of anions are the halogen anions, SO^, PO₄ ^3", preferably Cl^".

The term "cis position" of the hydroxy groups of the piperidine cycle means the configuration, wherein the hydroxy groups attached to the carbons 3 and 4 of the piperidine cycle are on the same side of the piperidine cycle. Examples of compounds according to formula 1, wherein the hydroxy groups attached to the carbons 3 and 4 of the piperidine cycle are in cis position are compounds of formula la and lb:

According to the Cahn-Ingold-Prelog-Convention the two carbon atoms 3 and 4 of the piperidine cycle are of R configuration in formula la and of S-configuration in formula lb.

The term "-O-" in groups such as alkyl-O- or cycloalkyl-O- means an oxygen with a free valence. For example alkyl-O- means alkoxy and cycloalkyl-O- means cycloalkoxy.

The "oxidation number" of a metal atom is indicated by a Roman numeral in parentheses after the name of the corresponding metal atom and is defined according to the IUPAC rules.

The term "stereoselective dihydroxylation" means the transformation of a carbon- carbon double bond to a vicinal diol, preferably to a vicinal cis-diol.

The term " chiral osmium complex" means an osmium metal complex with at least one chiral ligand, preferably one non-racemic chiral ligand. Preferred examples comprise a chiral ligand which contains dihydroquinine or dihydroquinidine derivatives. Particularly preferred ligands for the above chiral osmium complex are hydroquinidine 1,4-phthalazinediyl diether or hydroquinine 1,4-phthalazinediyl diether.

In a preferred aspect, the invention is concerned with the above process, wherein a compound of formula 1 has the stereochemistry according to formula la or lb, wherein R¹, R² and A are defined as before.

In a preferred embodiment the invention relates to a process, wherein a compound of formula la or a compound of formula lb is formed preferably.

Another preferred aspect of the present invention is a process, wherein the chiral osmium complex is obtainable by a reaction of an osmium compound in the presence of a chiral ligand, preferably a non-racemic chiral ligand and an oxidant. Preferred osmium compounds comprise osmium having an oxidation number between III and VIII. Non- racemic chiral ligand means a ligand which is optically active and which is not present in the form of its racemate. Examples for preferred osmium compounds are osmium trichloride or osmium tetrachloride, preferably alkali- or ammonium osmate and particularly preferred potassium osmate. The term osmium compound includes solvates and particularly hydrates. Such hydrates comprise one or several water of crystallization. Most preferred is potassium osmate dihydrate.

A more preferred embodiment of the present invention is the above process, wherein the chiral ligand comprises a hydroquinidine or hydroquinine substructure i.e. the chiral ligand is a derivative of dihydroquinine or dihydroquinidine. Preferred examples for such derivatives are hydroquinine 4-chlorobenzoate, hydroquinine 2,5-diphenyl-4,6- pyrimidinediyl diether, hydroquinine 4-methyl-2-quinolyl ether, hydroquinine 9- phenanthryl ether, 3,6-bis(9-O-dihydroquininyl)pyridazine, hydroquinidine 4- chlorobenzoate, hydroquinidine 2,5-diphenyl-4,6-pyrimidinediyl diether, hydroquinidine 4-methyl-2-quinolyl ether, hydroquinidine 9-phenanthryl ether and 3,6-bis(9-O- dihydroquinidinyl)pyridazine. Very preferred is the above process, wherein the chiral ligand is hydroquinidine 1,4-phthalazinediyl diether or hydroquinine 1,4-phthalazinediyl diether.

In addition, the reaction mixture may containe N-methyl-morpholine-N-oxide or preferably a ferricyanide. Particularly preferred is the above process, comprising potassium ferricyanide.

Beside that, the reaction mixture may contain a persulfate salt, particularly potassium persulfate. In a preferred embodiment the persulfate salt may be used in combination with a potassium ferricyanide e.g. potassium persulfate in combination with potassium ferricyanide.

An additional embodiment of the present invention relates to the regeneration of the oxidant at an anode.

In addition, the invention relates to a process, wherein the reaction mixture comprises a nucleophilic compound, preferably methanesulfonamide.

The reaction mixture may also contain a base, e.g. alkali carbonate bases, such as potassium carbonate. A particularly preferred embodiment of the present invention is the above process, wherein alkali ferricyanide, alkali persulfate, alkali osmate (VI), methanesulfonamide and alkali carbonate are present in the reaction mixture. An even more preferred embodiment of the present invention is a reaction mixture, wherein potassium ferricyanide, potassium persulfate, potassium osmate (VI), methanesulfonamide and potassium carbonate are present.

The preferred definitions of the substituents are as follows: A is substituted or unsubstituted ortho, meta or para phenylene, wherein the substituents of the phenylene which are defined by formula 1 are placed ortho, meta or para to one another. The para position is preferred. The substituted phenylene has one to four additional substituents, preferably one, independently selected from alkyl, halogene or nitro. Particularly preferred is the above process, wherein A is unsubstituted phenylene and especially unsubstituted para-phenylene.

Preferably, R¹ is a nitrogen protecting group for example an aralkyl or alkoxycarbonyl group, e.g. benzyl, tert-butoxycarbonyl and phenylethyl, especially ( 1R)- phenylethyl.

Also preferred is the above process, wherein R" is alkoxy or aralkoxy. Particularly preferred is methoxy or benzyloxy.

Another preferred aspect of the present invention is the process, wherein a compound of formula 2 is prepared by a process which comprises reacting a compound of formula 3

3

with a compound of formula R'-NH*^*. or a salt thereof, preferably in the presence of formaldehyde or a chemical equivalent thereof, wherein R¹ is alkyl, aryl or benzyl, R is alkoxy, cycloalkoxy, aryloxy, aralkoxy, aralkoxyalkoxy, alkylsulfonyloxy, arylsulfonyloxy, trifluoromethylsulfonyloxy, chlorine, bromine or iodine and A is defined as before. A further aspect of the present invention relates to the above process comprising in an additional step the transformation of a compound of formula 1 into a compound of formula 4

4

in the presence of a reducing agent such as hydrogen or preferably Raney nickel.

Another preferred aspect of the present invention comprises the transformation of a compound of formula 1 into a compound of formula 5

in the presence of an acid, such as Lewis acids, sulfuric acid, arylsulfonic acids or phosphorus oxychloride, preferably toluenesulfonic acid and more preferably para- toluenesulfonic acid.

Another aspect of the present invention is the transformation of (S,S)-3,4- dihydroxy-4-(4-methoxy-phenyl)-piperidine-l -carboxylic acid tert-butyl ester to l-[2- [7-[(3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3- yloxymethyl]-naphthalen-2-yloxy] -ethyl] -4-methyl-piperazine characterised in that

a) (S,S)-3,4-dihydroxy-4-(4-methoxy-phenyl)-piperidine-l-carboxylic acid tert- butyl ester is reduced with Raney nickel to yield (3R,4R)-3-hydroxy-4-(4-methoxy- phenyl) -piperidine- 1 -carboxylic acid tert-butyl ester; followed by b) cleavage of the methoxy group and the tert-butoxycarbonyl group in the presence of boron tribromide and subsequent reaction with di-tert-butyl dicarbonate in the presence of a base to form (3R,4R)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-l- carboxylic acid-tert-butylester;

c) reaction of the product of step b) with l-(3-chloro-propoxymethyl)-2- methoxy-benzene and potassium carbonate to yield (3R,4R)-3-hydroxy-4-[4-[3-(2- methoxy-benzyloxy)-propoxy] -phenyl] -piperidine- 1 -carboxylic acid tert-butylester;

d) reaction of the product of step c) with 2-chloromethyl-7-(2-trimethylsilanyl- ethoxymethoxy)-naphthalene and sodium hydride to yield (3R,4R)-4-[4-[3-(2- methoxy-benzyloxy)-propoxy] -phenyl] -3- [7-(2-trimethylsilanyl-ethoxymethoxy)- naphthalen-2-ylmethoxy] -piperidine- 1-carboxylic acid tert-butylester; followed by

e) reaction of the product of step d) with hydrochloric acid to yield (3R,4R)-3-(7- hydroxy-naphthalen-2-yloxymethyl)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]- phenyl] -piperidine- 1-carboxylic acid tert-butylester;

f) reaction of the product of step e) with l-(2-hydroxy-ethyl)-4-methyl-piperazine and triphenylphosphine to yield (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]- phenyl]-3-[7-[2-(4-methyl-piperazin-l-yl)-ethoxy]-naphthalen-2-ylmethoxy]- piperidine- 1-carboxylic acid tert-butylester; followed by

g) reaction of the product of step f) with hydrogen chloride.

In addition, the present invention relates to the transformation of (3R,4R)-4-(4- benzyloxy-pheny])-l- [(R)-l-phenyl-ethyl]-piperidine-3,4-diol in (3R,4S,5S)-4-[4-(3- benzyloxy-propoxy)-phenyl]-5-ethoxy-3-(naphthalen-2-ylmethoxy)-piperidine characterised in that

a) (3R,4R)-4-(4-benzyloxy-phenyl)-l-[(R)- l-phenyl-ethyl] -piperidine-3,4-diol is transformed into (3S)-4-(4-benzyloxy-phenyl)-l-[(lR)-phenyl-ethyl]- 1,2,3,6- tetrahydro-pyridin-3-ol by dehydration with toluenesulfonic acid; followed by

b) reaction of the product of step a) with sodium hydride and ethyl iodide to yield (3S)-4-(4-benzyloxy-phenyl)-3-ethoxy-l- [( lR)-phenyl-ethyl]-l,2,3,6-tetrahydro- pyridine; c) hydroboration of the product of step b) with sodium borohydride and boron trifluoride etherate followed by reaction with potassium hydroxide and hydrogen peroxide to yield (3R,4R,5S)-(4-benzyloxy-phenyl)-5-ethoxy-l-[(lR)-phenyl-ethyl]- piperidin-3-ol);

d) hydrogenolysis of the product of step c) to yield (3R,4R,5S)-5-ethoxy-4-(4- hydroxy-phenyl)-piperidin-3-ol;

e) reaction of the product of step d) with di-tert-butyldicarbonate and sodium hydrogenocarbonate followed by addition of NaOH to yield (3R,4R,5S)-5-ethoxy-3- hydroxy-4-(4-hydroxy-phenyl) -piperidine- 1-carboxylic acid tert-butylester;

f) treatment of the product of step e) with 3-bromo-propoxymethyl-benzene and potassium carbonate to yield (3R,4R,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5- ethoxy-3-hydroxy-piperidine- 1-carboxylic acid tert-butylester;

g) reaction of the product of step f) with 2-bromomethyl-naphthalene and sodium hydride to yield (3R,4S,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3- (naphthalen-2-ylmethoxy)-piperidine- 1-carboxylic acid tert-butylester;

h) reaction of the product of step g) with hydrochloric acid to yield (3R,4S,5S)-4- [4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-(naphthalen-2-ylmethoxy)-piperidine.

Compounds of formula 1 and their salts are new and also part of the present invention, wherein R" is alkoxy, cycloalkoxy, aryloxy, aralkoxy, aralkoxyalkoxy, hydroxy, alkylsulfonyloxy, arylsulfonyloxy, trifluoromethylsulfonyloxy, bromine or iodine and R¹ and A are defined as above.

Particularly preferred compounds of formula 1 are:

(S,S)-3,4-dihydroxy-4-(4-methoxy-phenyl)-piperidine- 1-carboxylic acid tert-butyl ester;

(3R,4R)-4-(4-benzyloxy-phenyl)-l-benzyl-piperidine-3,4-diol;

(3R,4R)-4-(4-benzyloxy-phenyl)-3,4-dihydroxy-piperidine- 1-carboxylic acid tert-butyl ester;

C3S,4S)-4-(4-benzyloxy-phenyl)-3,4-dihydroxy-piperidine- 1-carboxylic acid tert-butyl ester; (3R,4R)-4-(4-benzyloxy-phenyl)-l-[(R)-l-phenyl-ethyl]-piperidine-3,4-diol;

(3S,4S)-4-(4-benzyloxy-phenyl)-l-[(R)-l-phenyl-ethyl]-piperidine-3,4-diol.

The invention also relates to the use of the above compounds according to formula 1 in the preparation of renin inhibitors, such as for example l-[2-[7-[(3R,4R)- 4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl]- naphthalen-2-yloxy] -ethyl] -4-methyl-piperazine and (3R,4S,5S)-4-[4-(3-benzyloxy- propoxy)-phenyl]-5-ethoxy-3-(naphthalen-2-ylmethoxy)-piperidine, wherein R¹, R", and A in formula 1 are defined as described before.

Furthermore, the invention also relates to compounds as obtained by the above process.

In more detail, the process of the invention may be described as follows:

The following scheme shows the stereoselective dihydroxylation of a compound of formula 2:

5a 5b

wherein R , R and A are defined as before.

A compound of the formula 2 can be reacted in the presence of compounds which are known for their use in stereoselective dihydroxylations, especially in Sharpless dihydroxylations (H.C. Kolb, M.S. Van Nieuwenhze, K.B. Sharpless, Chem. Rev. 1994, 94, 2483). For example compounds of formula 2 can be reacted in the presence of a chiral transition metal complex and an oxidant. Examples of chiral transition metal complexes are chiral osmium complexes and preferably chiral osmium complexes comprising hydroquinidine 1,4-phthalazinediyl diether or hydroquinine 1,4- phthalazinediyl diether.

Examples for the above mentioned oxidant are N-methyl-morpholine-N-oxide and preferably a ferricyanide salt. More preferred is potassium ferricyanide, particularly in combination with a persulfate, preferably potassium persulfate. The ferricyanide salt may be used in catalytic quantity if the ferricyanide salt is regenerated by a persulfate.

The process is preferably carried out in the presence of a nucleophile e.g. methansulfonylamide and a base e.g. alkali carbonate, preferably potassium carbonate.

The chiral osmium complex may be obtained by the reaction of an osmium compound such as an osmium salt, particularly hydrate, in the presence a chiral ligand and, particularly in the presence of an oxidant. In a preferred embodiment an osmium compound is used, wherein the osmium has an oxidation number between III and VIII. Examples of such osmium compounds are OsCl₃ or OsO , preferably alkali- or ammonium osmate (VI) and particularly preferred potassium osmate (VI) and most preferred potassium osmate (VΙ)dihydrate.

In a further preferred embodiment of the present invention the reaction mixture in the above process comprises hydroquinidine 1,4-phthalazinediyl diether or hydroquinine 1,4-phthalazinediyl diether together with potassium ferricyanide, potassium persulfate, potassium osmate (VΙ)dihydrate, methanesulfonamide and potassium carbonate.

Inert solvents, preferably in combination with water can be used, especially those which are known for their utilisation in stereoselective dihydroxylation reactions and especially in reactions which are known as Sharpless dihydroxylations. Examples of such solvents are alcohols, toluene, acetone, acetonitrile and ethers, preferably in combination with water. Also included are mixtures of any of these solvents. Preferred is a mixture of alcohol with water and particularly a mixture of tert-butanol with water. More preferred is a mixture of tert-butanol with water in a ratio of about 1 to 1 (50 Vol.% : 50 Vol.%).

A temperature range of about -40°C to about 50°C is suitable for the reaction of the present invention. The preferred temperature range is between about -10°C and 30°C. Particularly preferred is a temperature range of from about 0°C to about 25°C. Especially preferred are the above temperature ranges, wherein the reaction compounds are mixed at a lower temperature and then stirred at a higher temperature.

The obtained compound of the formula 1, especially the desired stereoisomer, can be reacted with Raney nickel especially in the presence of a Lewis acid such as aluminium isopropoxide. Preferred solvents for this reaction are for example alcohols, especially secondary alcohols alone or in combination. Particularly preferred is isopropanol. The temperature range for this reaction is preferably between 40°C and the boiling point of the solvent. Particularly preferred is a temperature of about 60°C. If appropriate, the group R² can be transformed into a hydroxy group by e.g. catalytic hydrogenolysis in for example an alcohol in the presence of palladium on carbon and a base, preferably triethylamine. A preferred solvent for this reaction is methanol. This transformation can also be effected by a cleavage reaction using e.g. borontribromide in dichloromethane.

Compounds of formula 1 maybe used in the preparation of renin inhibitors as disclosed in WO 97/09311. In general, this preparation can be performed as follows: After conversion of compounds of formula 1 into compounds of formula 4, wherein R¹ being a protecting group, e.g. a Boc-group and R" being an hydroxy group, the selective functionalization of the phenolic function can be performed with alkylation reactions using aliphatic or benzylic chlorides, bromides, iodides, tosylates or mesylates in the presence of a base like potassium carbonate in solvents such as an ether like tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetone, methyl-ethyl-ketone, or pyridine at temperatures between 0°C and 140°C. The alkylating agents used can either contain the whole chain desired or optionally suitably protected functional groups which allow further structural modifications at a later stage of the synthesis. Functionalization at the secondary hydroxy function of the piperidine ring can then be performed in solvents as ethers like tetrahydrofuran or 1,2-dimethoxyethane, or in dimethylformamide or dimethylsulfoxide in the presence of a base like sodium hydride or potassium tert-butoxide and a suitable alkylating agent, preferentially benzylic chloride, bromide, mesylate or tosylate at temperatures between 0°C and 40°C. The alkylating agents used can either contain the whole substituent desired or optionally suitably protected functional groups which allow further structural modifications at a later stage of the synthesis. Further structural variations can comprise removal of protective functions followed by functionalizations of the liberated functional groups, e.g. etherifϊcation of a phenolic moiety. But also reduction of e.g. a quinoline unit to a tetrahydroquinoline unit by e.g. sodium borohydride, nickel chloride in solvents like methanol or ethanol. Final removal of the Boc-protective group can be performed in the presence of acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic acid in a variety of solvents such as alcohols and alcohol/water mixtures, ethers and chlorinated hydrocarbons. The Boc-protective group can also be removed with anhydrous zinc bromide in inert solvents such as dichloromethane. For the preparation of further renin inhibitors the following pathway maybe used: Dehydration of a compound of formula 1 by using an acid, preferably toluenesulfonic acid leading to a compound of the formula 5 followed by alkylation of the 3-hydroxy function of for example (3S)-4-(4-benzyloxy-phenyl)-l-[(lR)-phenyl-ethyl]-l,2,3,6- tetrahydro-pyridin-3-ol which can be performed in solvents as ethers like tetrahydrofuran and 1,2-dimethoxyethane, dimethylformamide or dimethylsulfoxide with aliphatic chlorides, bromides, iodides, tosylates or mesylates in the presence of a base like sodium hydride or potassium tert-butoxide. The alkylating agents used can either contain the whole substituent desired or optionally suitably protected functional groups which allow further structural modifications at a later stage of the synthesis. This substituent is represented by R' in formula 6 and 7.

Hydroboration of the ether compounds followed by subsequent basic oxidative work-up produces compounds of the general formula 6 with high diastereoselectivity. The hydroboration can be effected according to methods known per se, for example in a solvent which is inert under the reaction conditions, such as an ether, e.g. 1,2- dimethoxyethane, at a temperature between about 0°C and 70°C, and with a diborane- containing or diborane-liberating reagent such as e.g. borane in tetrahydrofuran or a mixture of sodium borohydride and boron trifluoride diethyl etherate. The carbo- boranes which are formed as intermediates can be converted for example into the secondary alcohols of general formula 6 by reaction with bases, e.g. potassium hydroxide, and an oxidizing agent, e.g. hydrogen peroxide, at a temperature between about room temperature and 120°C. Reorganization of protective groups, removal of the R¹ and elaboration of the R functions and re-introduction of a N-protective group by well established procedures as e.g.: Hydrogenolysis with hydrogen in the presence of a palladium catalyst followed by introduction of the Boc group with di-tert- butyldicarbonate in dioxane / water converts compounds of the general formula 6 into a compound of the following formula 7 bearing a phenolic and an aliphatic OH-function which can be functionalized selectively.

6

Selective functionalization of the phenolic function in compounds of the general formula 7 can be performed with alkylation reactions using aliphatic or benzylic chlorides, bromides, iodides, tosylates or mesylates in the presence of a base like potassium carbonate in solvents such as an ether like tetrahydrofuran, or in dimethylformamide, dimethylsulfoxide, acetone, methyl-ethyl-ketone, or pyridine at temperatures between 0°C and 140°C. The alkylating agents used can either contain the whole chain desired or optionally suitably protected functional groups which allow further structural modifications at a later stage of the synthesis. Functionalization at the secondary hydroxy function of the piperidine ring can then be performed in solvents as ethers like tetrahydrofuran or 1,2-dimethoxyethane, or in dimethylformamide or dimethylsulfoxide in the presence of a base like sodium hydride or potassium tert- butoxide and a suitable alkylating agent, preferentially an aryl methyl chloride, bromide, mesylate or tosylate at temperatures between 0°C and 40°C. The alkylating agents used can either contain the whole substituent desired or optionally suitably protected functional groups which allow further structural modifications at a later stage of the synthesis. Further structural variations may comprise removal of protective functions followed by functionalizations of the liberated functional groups, e.g. etherification of a phenolic moiety. Final removal of the Boc-protective group may be performed in the presence of acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic acid in a variety of solvents such as alcohols and alcohol/water mixtures, ethers and chlorinated hydrocarbons. The Boc-protective group can also be removed with anhydrous zinc bromide in inert solvents such as dichloromethane.

The starting compounds of formula 2 may be obtained by the following methods a, b, c, d, e and f: a) The preparation of a compound of formula 2 can be represented by the following scheme:

A compound of formula 2 can be obtained by the reaction of compound 11 with an acid, e.g. oxalic acid in an inert solvent, wherein compounds 11 are formed by reacting a compound of the formula 9 in an inert solvent with butyllithium or a Grignard reagent to form an organometallic intermediate which is reacted with a compound of the formula 10. The preparation of compound 9 can be performed by reacting a compound of the formula 8 with a compound of the formula R⁶-Hal in the presence of a base and preferably a catalyst such as Nal in an inert solvent. R¹ is alkyl, aryl, aralkyl or diarylalkyl, R is alkyl, cycloalkyl, aryl, aralkyl or aralkoxyalkyl and A is arylene. Compound 10 is obtainable for example by the reaction of R'-NH₂ with 1 -ethyl- 1- methyl-4-oxo-piperidinium iodide in the present of a base. l-Ethyl-l-methyl-4-oxo- piperidinium iodide is obtainable by the reaction of l-ethyl-4-piperidone with methyl iodide in an inert solvent.

b) Alternatively, a compound of formula 2 can be obtained by the reaction of an ammonium salt R'-NH₃ ⁺X^" with formaldehyde and compound 12 which can be obtained e.g. by a Wittig reaction of the appropriate phosphorane with compound 13 in an inert solvent. R² is alkoxy, cycloalkoxy, aryloxy, aralkoxy, aralkoxyalkoxy, alkylsulfonyloxy, arylsulfonyloxy, trifluoromethylsulfonyloxy, chlorine, bromine or iodine, A is arylene and R¹ is alkyl, aryl, aralkyl or diarylalkyl.

12

' Wittig reaction ^^*\

A * A 2 I

R R²

13 12

Further, a compound 2 may be prepared by the reaction of an ammonium salt of the formula R'-NH₃ ⁺X^" with formaldehyde and with a compound of the formula 3, wherein R² is alkoxy, cycloalkoxy, aryloxy, aralkoxy, aralkoxyalkoxy, alkylsulfonyloxy, arylsulfonyloxy, trifluoromethylsulfonyloxy, chlorine, bromine or iodine, A is arylene and R¹ is alkyl, aryl, diarylalkyl or aralkyl.

The compound of the formula 3 is formed by the reaction of an organometallic compound containing a methyl group attached to the metal as in methylmagnesium bromide or methyllithium with compound 13, while compound 3, wherein R² means chlorine, bromine or iodine maybe prepared via oxidation of a halocumene (e.g. described in US 3954876 or DE 2302751).

d) In addition compounds of formula 2 are obtainable by a reaction of a compound of formula 16 in the presence of formaldehyde and a salt of the formula R'-N^X, wherein R'-NH₃X is preferably generated in the reaction mixture using the appropriate amount of a suitable acid HX and the corresponding amine.

14 15 16

Furthermore, compound 16 can be obtained by the reaction of compound 15 with an adequate organometallic compound. Moreover, compound 15 is formed by the reaction of compound 14 with R -X in the presence of a base in an inert solvent. R¹ is defined as alkyl, aryl, aralkyl or diarylalkyl and R⁶ is alkyl, cycloalkyl, aralkyl or aralkoxyalkyl.

e) In the case, wherein R¹ is alkoxycarbonyl, halogenated alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, halogenated alkylcarbonyl, arylsulfonyl, alkylsulfonyl, alkylsilyl or allyloxycarbonyl and R² is alkoxy, cycloalkoxy, aryloxy, aralkoxy, aralkoxyalkoxy, alkylsulfonyloxy, arylsulfonyloxy, trifluoromethylsulfonyloxy, chlorine, bromine or iodine and A is arylene compounds of formula 2 can be obtained according to the reactions b, c and/or d, wherein an ammonium salt such as ammonium chloride is used instead of R^!-NH₃X. The obtained compound of formula 17

17

is reacted in the presence of a corresponding electrophile and a base in order to obtain compound 2.

f) Additionally, compounds according to formula 2, wherein R² is hydroxy can be obtained by reacting the corresponding compounds, wherein R² is benzyloxy under acid conditions in methanol. The compounds of formula 2, wherein R" is benzyloxy are obtainable as described before.

The following preparations and examples illustrate preferred embodiments of the present invention but are not intended to limit the scope of the invention.

Example 1

Preparation of (S,S)-3,4-dihydroxy-4-(4-methoxy-phenyl -piperidine-l-carboxylic acid tert-butyl ester

The reaction flask was charged under argon with 1.7 g of potassium ferricyanide

(5.2 mmol), 5.45 g of (DHQ)₂-PHAL (hydroquinine 1,4-phthalazinediyl diether) (7.0mmol), 0.515 g of potassium osmate (VI) dihydrate (1.4 mmol), 48.3 g of potassium carbonate (349.5mmol), and 52.0 g of potassium persulfate ( 192.3mmol). A mixture of 350 mL of water and 350 mL of tert butanol was added. The contents were stirred 20 min at room temperature, then 4.16 g of methanesulfonamide (43.7 mmol) was added to the yellow mixture, which was cooled to 0°C. At this temperature, 50.6 g of 4- (4- methoxy-phenyl)-3,6-dihydro-2H-pyridine-l-carboxylic acid tert- butyl ester (174.9 mmol) was added as a solid at once. The cooling bath was removed and the temperature slowly rose to 22-25°C where it was kept with a bath of cool water. Stirring was continued. After 5 h reaction time, 99.8% conversion of the starting material was reached. During the reaction the colour of the mixture had turned from yellow via off- white to light brown. The reaction was stopped by addition of 2.5 g of sodium sulfite which caused the temperature to rise by approx. 1°C. A test with an acidified potassium iodide/ starch paper revealed complete decomposition of all oxidants 5 min after the addition of the reductant.

The reaction mixture was transferred into a separation funnel. 500 mL of dichloromethane and 500 mL of water were added. After extraction, the organic phase was separated and washed successively with 250 mL of 2.5 % aqueous sodium bicarbonate, 250 mL of 5 % aqueous potassium hydrogensulfate, and 150 mL of diluted aqueous sodium chloride. Each aqueous phase was extracted with two fresh portions of 250 mL, i.e. a total of 500 mL of dichloromethane. The organic phases were combined, dried (MgSO ) and evaporated to dryness under reduced pressure to give 60 g of a yellow-brown solid product (ee: 98.7%). Example 2

Preparation of (3R,4R)-3-hydroxy-4-(4-methoxy-phenyl^')-piperidine-l-carboxyIic acid tert-butyl ester

The reaction flask was charged under argon with 300 g of wet Raney nickel. The water was decanted and 200 mL of isopropanol was added. The suspension was swirled for a few seconds and, after deposition of the nickel, the supernatant liquid was carefully decanted. This procedure was repeated another three times using 3 x 200 mL, i.e. a total of 600 mL of isopropanol. After the last portion of isopropanol had been decanted, a solution of 30 g of (S,S)-3,4-dihydroxy-4-(4-methoxy-phenyl)-piperidine-l-carboxylic acid tert-butyl ester (87 mmol) in 300 mL of isopropanol was added, followed by 1.78 g of aluminum isopropoxide (8.7 mmol). The black suspension was stirred at 60°C. After 22 h the reaction was stopped. Approximative 2% of starting material had not reacted.

Under an argon atmosphere, the supernatant liquid was carefully decanted from the deposited Raney nickel and filtered through a pad of filter aid (speedex). For the filtration, partial vacuum was applied in such a way that the filter cake always remained covered with liquid. 200 mL of isopropanol was added to the residual Raney nickel in the flask, and the suspension was stirred. After deposition of the nickel, the supernatant liquid was again decanted and filtered. This procedure was repeated for another five times using 5 x 200 mL, i.e. a total of 1 L of isopropanol. The combined filtrates were concentrated in vacuo. Yield: 20.5 g of crude (3R,4R)-3-hydroxy-4-(4-methoxy-phenyl)- piperidine- 1-carboxylic acid tert-butyl ester as a light yellow oil.

After repetition of the above reaction 41.4 g of crude (3R,4R)-3-hydroxy-4-(4-methoxy- phenyl)-piperidine- 1-carboxylic acid tert-butyl ester was dissolved in 200 mL of diethyl ether to give a slightly turbid solution. The solution was treated with 1 g of charcoal Darco KB-B, filtered through speedex and concentrated to give a colourless oil which was dissolved in ca. 20 mL of diethyl ether. The solution was concentrated to half of the volume, and 50 mL of hexane was slowly added. Crystals started to separate, and the suspension was stirred magnetically overnight at room temperature and for additional 3h at 0°C. The product was collected, washed with hexane and dried in vacuo. Yield: 28.3 g (3R,4R)-3-hydroxy-4-(4-methoxy-phenyl)-piperidine-l-carboxylic acid tert-butyl ester was obtained as white crystals (m.p.: 104.6-105.7°C) (> 97.2 % ee).

After repetition of the above reaction 54.3 g of (3R,4R)-3-hydroxy-4-(4-methoxy- phenyl) -piperidine- 1-carboxylic acid tert-butyl ester (first purification) was dissolved in a minimum amount of dichloromethane and concentrated under reduced pressure (bath 45°C, 15mbar) to a weight of 57 g. The residue was dissolved in 50 mL of diethyl ether by means of heat and ultrasound. The solution was magnetically stirred at room temperature and crystals started to separate. 50 mL of hexane was slowly added, and stirring was continued overnight. 25 mL of hexane was added, and the suspension was stirred lh at 0°C. Then, the product was collected, washed with cold hexane/ ether 9:1 and dried in vacuo. Yield: 50.5 g (3R,4R)-3-hydroxy-4-(4-methoxy-phenyl)-piperidine- 1-carboxylic acid tert-butyl ester was obtained as white crystals m.p.: 107.5-108.4°C (99.8 % ee).

Example 3

Preparation of (3R,4R)-4-(4-benzyloxy-phenyl)-l-benzyl-piperidine-3,4-dioI

The reaction flask was charged under argon with 0.89 g of potassium ferricyanide (2.7 mmol), 2.8 g of (DHQD)₂-PHAL (hydroquinidine 1,4-phthalazinediyl diether) (3.6 mmol), 0.265 g of potassium osmate (VI) dihydrate (0.72 mmol), 24.8 g of potassium carbonate (179.4 mmol), and 26.8 g of potassium persulfate (99.1 mmol). A mixture of 180mL of water and 270 mL of tert-butanol was added. The mixture was stirred 20 min at r.t., then 2.1 g of methanesulfonamide (22.5 mmol), followed by 32.0 g of l-benzyl-4- (4-benzyloxy-phenyl)-l,2,3,6-tetrahydro-pyridine (90 mmol) was added to the greenish-yellow mixture. The temperature of the slightly exothermal reaction was kept at 22-25°C using a bath of cool water. The mixture was stirred for 20 h and then quenched by addition of 0.3 g of sodium sulfite. A test with an acidified potassium iodide/starch paper revealed complete decomposition of all oxidants 10 min after the addition of the reductant.

The reaction mixture was transferred into a separation funnel. 600 mL of dichloromethane and 500 mL of water were added. After extraction, the organic phase was separated and washed with 500 mL of 10 % aqueous sodium chloride. The aqueous phases were extracted with 600 mL of dichloromethane. The organic phases were combined, dried (Na₂SO ) and treated with 10 g of charcoal. Filtration and evaporation of the filtrate to dryness under reduced pressure gave 40.8 g of a brownish oil.

The crude product was dissolved in 100 mL of dichloromethane at 40°C. 180mL of isopropanol was added and the dichloromethane as well as a small part of the isopropanol was distilled off at the rotary evaporator (500 mbar, bath 50°C). Crystallisation started when the solution was stirred at r.t. for 2 h. The suspension was stirred another 2 h at 0°C. The crystals were collected on a filter funnel and washed with two portions of 80 mL, i.e. a total of 160 mL of isopropanol-pentane 1:1 and with two portions of 50 mL, i.e. a total of 100 mL of pentane. The product was then dried for lh at 16 mbar/50°C. Yield: 30.8 g (88 %) of (3R,4R)-4-(4-benzyloxy-phenyl)-l-benzyl- piperidine-3,4-diol was obtained as white crystals, m.p. 108°C. Enantiomeric purity: 100 % ee.

After repetition of the the above reaction 66.0 g of crystallised product was dissolved in 800 mL of diethyl ether. 4 g of charcoal was added. Then, the suspension was stirred 30 min at r.t. and filtered, and the charcoal was washed with 3 portions of 50 mL, i.e. a total of 150 mL of diethyl ether. The filtrate was concentrated and the residue (72 g) was dissolved in 200 mL of dichloromethane. 400 mL of isopropanol was added and the dichloromethane as well as a small part of the isopropanol was distilled off at the rotary evaporator. Crystals started to separate. lOOmL of pentane was added and the suspension was stirred 2 h at 0°C. The crystals were collected on a filter funnel and washed with two portions of 60mL, i.e. a total of 120 mL of cold (0°C) isopropanol and with two portions of 60 mL, i.e. a total of 120 mL of pentane. The product was then dried 2h at 16mbar/50°C, 16 h at 0.2 mbar/r.t. and 20 h at 0.2 mbar/45°C. Yield: 56.6 g (81 %) of (3R,4R)-4-(4-benzyloxy-phenyl)-l-benzyl-piperidine-3,4-diol as white crystals, m.p. 112-113 °C. Enantiomeric purity:100 % ee.

Example 4

Preparation of (3R,4R)-4-(4-benzyloxy-phenyl)-3,4-dihydroxy-piperidine- 1-carboxylic acid tert-butyl ester

The reaction flask was charged under argon with 0.567 g of potassium ferricyanide

(1.7 mmol), 1.56 g of (DHQD)₂-PHAL (hydroquinidine 1,4-phthalazinediyl diether) (2.0 mmol), 0.160 g of potassium osmate (VI) dihydrate (0.43 mmol), 11.04 g of potassium carbonate (79.9 mmol), and 11.88 g of potassium persulfate (43.9 mmol). A mixture of lOOmL of water and 100 mL of tert-butanol was added. The contents were stirred 20 min at r.t. and then cooled to 0°C. 0.94 g of methanesulfonamide (9.9 mmol), followed by 14.62 g of 4-(4-benzyloxy-phenyl)-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester (40 mmol) was added to the mixture. The cooling bath was removed and the temperature slowly rose to 22-25°C where it was kept using a bath of cool water. Stirring was continued for 4 h. The mixture was quenched by addition of 0.7 g of sodium sulfite. A test with an acidified potassium iodide/starch paper revealed complete decomposition of all oxidants 30 min after the addition of the reductant.

The reaction mixture was transferred into a separation funnel. 250 mL of dichloromethane and 100 mL of water were added. After extraction, the organic phase was separated and washed with 200 mL of saturated aqueous sodium bicarbonate, 200 mL of 10 % aqueous sodium hydrogensulfate, and 200 mL of water. The aqueous phases were extracted with 200 mL of dichloromethane. The organic phases were combined, dried (Na₂SO ) and concentrated under reduced pressure to give 19.7 g of a brownish oil. Enantiomeric purity: 99.3 % ee.

The crude product was dissolved in 60 mL of diethyl ether at 35-38°C. During cooling to r.t. crystals started to separate. 20 mL of pentane was added dropwise and the suspension was stirred 3 h at r.t. and 2 h at 0°C. The crystals were collected on a filter funnel, washed with pentane and dried 1 h at 16 mbar/40°C and 2 h at 0.2 mbar/22°C. Yield: 14.75 g (92%) of (3R,4R)-4-(4-benzyloxy-phenyl)-3,4-dihydroxy-piperidine-l- carboxylic acid tert-butyl ester was obtained as white crystals, m.p. 136.5 °C. Enantiomeric purity: 99.3 % ee.

Example 5

Preparation of (3S,4S)-4-(4-Benzyloxy-phenyl)-3,4-dihydroxy-piperidine- 1-carboxylic acid tert-butyl ester

The reaction flask was charged under argon with 2.8 g AD-mix-α (Aldrich 39275- 8, contains chiral ligand (DHQ)₂PHAL, K₃Fe(CN)₆₎ K₂OsO₂(OH)₄ and K₂CO₃) in a mixture of t-BuOH (lOmL) and H₂O (lOmL) and stirred 20 min at r.t. and then cooled to 0°C. 190 mg (2 mmol) methanesulfonamide and 731 mg (2mmol) of 4-(4-benzyloxy- phenyl)-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester were added. The cooling bath was removed and the mixture was stirred for 24h. The oxidants were reduced by addition of 600 mg of Na₂SO₃. Extractive work-up and crystallisation of the crude product from Et₂O / pentane afforded 710 mg (89%) (3S,4S)-4-(4-benzyloxy- phenyl)-3,4-dihydroxy-piperidine- 1-carboxylic acid tert-butyl ester as white crystals, m.p. 135°C, 97.2 % ee HPLC, [α]_D = -9.3° (c=l, MeOH, 20°C). Example 6

Preparation of (3R,4R)-4-(4-Benzyloxy-phenyl)-l-[(R)-l-phenyl-ethyl]-piperidine-3,4- diol

A mixture of 30 mg (0.09 mmol) K₃Fe(CN)₆₎ 93.5 mg (0.12 mmol) (DHQD)₂- PHAL (hydroquinidine 1,4-phthalazinediyl diether), 8.8 mg (0.024 mmol)

K₂OsO₂(OH)₄₎ 828 mg (6 mmol) K₂CO₃ and 936 mg (3.46 mmol) K₂S₂O₈ was dissolved in t-BuOH (8 mL) and H₂O (6 mL). The solution was stirred for 20 min, then 71.2 mg (0.75 mmol) methanesulfonamide and 1.17 g (3.17 mmol) of (R)-4-(4-benzyloxy- phenyl)-l-(l-phenyl-ethyl)-l,2,3,6-tetrahydro-pyridine were added. After a reaction time of 27 h at r.t., HPLC showed 94% conversion of starting material. The oxidants were reduced by addition of Na₂SO₃. Extractive work-up, chromatography of the crude product on a silica gel column (150 g) using toluene / EtOAc 2:1 and toluene / EtOAc / MeOH 200:100:5 as the eluents, and subsequent crystallisation from i-PrOH / pentane afforded 725 mg (57%) (3R,4R)-4-(4-benzyloxy-phenyl)-l-[(R)-l-phenyl-ethyl]- piperidine-3,4-diol as white crystals, m.p. 117°C. The signals of the NMR spectrum were consistent with the expected values.

Example 7

Preparation of (3S,4S)-4-(4-Benzyloxy-phenyl)-l-[(R)-l-phenyl-ethyl]-piperidine-3,4- diol

A mixture of 30 mg (0.09 mmol) K₃Fe(CN)₆, 93.5 mg (0.12 mmol) (DHQ)₂-PHAL (hydroquinine 1,4-phthalazinediyl diether), 8.8 mg (0.024 mmol) K₂OsO₂(OH)₄, 828 mg (6 mmol) K₂CO₃ and 936 mg (3.46 mmol) K₂S₂O₈ was dissolved in t-BuOH (8 mL) and H₂O (6 mL). The solution was stirred for 20 min, then 71.2 mg (0.75 mmol) methanesulfonamide and 1.17 g (3.17 mmol) of (R)-4-(4-benzyloxy-phenyl)-l-(l- phenyl-ethyl)-l,2,3,6-tetrahydro-pyridine were added. After a reaction time of 20 h at r.t., HPLC showed 88 % conversion of starting material. The oxidants were reduced by addition of Na₂SO₃. Extractive work-up and chromatography of the crude product on a silica gel column using toluene / EtOAc 23:10 as the eluent afforded 1.16 g (90 %) (3S,4S)-4-(4-benzyloxy-phenyl)-l-[(R)-l-phenyl-ethyl]-piperidine-3,4-diol as white crystals, m.p. 131-132°C. The signals of the NMR, IR and MS spectra were consistent with the expected values. Example 8

Preparation of (S^')-l-Benzyl-4-(4-benzyloxy-phenyl)- 1,2,3, 6-tetrahydro-pyridin-3-ol

10 g of (3R,4R)-l-Benzyl-4-(4-benzyloxy-phenyl)-piperidine-3,4-diol (25.7 mmol) in 100 mL of toluene was stirred in the presence of 6.3 g of para-toluenesulfonic acid monohydrate (33.4 mmol) at 100°C for 3 h. The reaction mixture was cooled to room temperature and poured onto 200 mL of ice/water containing 20 mL of aqueous ammonia. Extraction with 300 mL of ethyl acetate, drying (Na2SO4) and concentration in vacuo afforded 10.8 g of crude product which was chromatographed on 280 g of silica gel with dichloromethane / ethyl acetate 9:1 as the eluent. 5.2 g (54 %) (S)-l-Benzyl-4- (4-benzyloxy-phenyl)-l,2,3,6-tetrahydro-pyridin-3-ol was obtained.

Example 9

Preparation of (3S)-4-(4-benzyloxy-phenyl)-l-((R)-l-phenyl-ethyl)-l,2,3,6-tetrahvdro- pyridin-3-ol

The allylic alcohol (3S)-4-(4-benzyloxy-phenyl)-l-((R)-l-phenyl-ethyl)-l,2,3,6- tetrahydro-pyridin-3-ol was obtained in 99.5 % diastereomeric purity by dehydration of (3R,4R)-4-(4-benzyloxy-phenyl)-l-[(R)-l-phenyl-ethyl]-piperidine-3,4-diol using 1.3 eq. of para-TsOH at 100°C for 2 h in toluene and subsequent extractive work-up followed by chromatography on a silica gel column with toluene /EtOAc 4 : 1 as the eluent.

Example 10

Preparation of (R)-4-(4-benzyloxy-phenyl)-l-((R)-l-phenyl-ethyl)-l,2,3,6-tetrahvdro- pyridin-3-ol

The allylic alcohol (R)-4-(4-benzyloxy-phenyl)-l-((R)-l-phenyl-ethyl)-l,2,3,6- tetrahydro-pyridin-3-ol was obtained diastereomerically pure by dehydration of (3S,4S)-4-(4-benzyloxy-phenyl)-l-[(R)-l-phenyl-ethyl]-piperidine-3,4-diol using para- TsOH (1.3 eq., toluene, 105°C, 2 h) and extractive work- up followed by chromatography on a silica gel column with toluene / EtOAc 9 : 1 as the eluent. Example 11

(Preparation of starting material)

Preparation of 4-(4-methoxy-phenyl)-3,6-dihydro-2H-pyridine- 1-carboxylic acid tert- butyl ester

a) A solution of 21.3 g (107 mmol) l-(tert-butoxycarbonyl)-4-piperidone in 100 mL THF was added within 40 min to a Grignard reagent made from 2.60 g (107 mmol) of magnesium and 25.0 g (134 mmol) of 4-bromoanisole in 120 mL THF. The reaction mixture was refluxed for 2 h, cooled to room temperature and then poured onto a mixture of 200 mL ice/water containing 20 g of ammonium chloride. Common work-up comprising extraction with ethyl acetate gave the crude product (38 g) which was recrystallized from isopropyl ether / pentane to afford 23.7 g (72 %) of 4-hydroxy-4-(4- methoxy-phenyl)-piperidine- 1-carboxylic acid tert-butyl ester as white crystals, m.p. 110-111 °C.

b) 23.1 g (75 mmol) of 4-hydroxy-4-(4-methoxy-phenyl)-piperidine-l-carboxylic acid tert-butyl ester prepared as described above was dissolved in 72 mL of pyridine. 115 g (0.75 mol) of phosphorus oxychloride was added dropwise within 0.5 h while the reaction mixture was stirred. The reaction mixture was heated 1 h at 60°C and then cooled to room temperature. 250 mL of diethyl ether was added and the mixture was cautiously poured onto a mixture of ice, water and sodium bicarbonate under stirring. Common work-up comprising extraction with diethyl ether gave the crude product (18 g) which was recrystallized from hexane to afford 15.0 g (69 %) of 4-(4-methoxy- phenyl)-3,6-dihydro-2H-pyridine-l-carboxylic acid tert-butyl ester. Further purification of the product included treatment with charcoal in isopropyl ether, recrystallisation from isopropyl ether / pentane, and filtration through silica gel using ethyl acetate / hexane as the eluent. Example 12

(Preparation of starting material)

Preparation of l-Benzyl-4-(4-benzyloxy-phenyl)-l,2,3,6-tetrahydro-pyridine

a) A solution of 44.4 g (235 mmol) l-benzyl-4-piperidone in 100 mL THF was added at room temperature within 1 h to a Grignard reagent made at 65°C from 6.7 g

(275 mmol) of magnesium and 65.8 g (250 mmol) of 4-benzyloxybromobenzene in 225 mL THF. The reaction mixture was stirred for an additional 30 min and then poured onto a mixture of 300 mL 10 percent aqueous sodium bicarbonate and 200 g of ice. Common work-up comprising extraction with ethyl acetate gave the crude product (87 g) which was recrystallized using dichloromethane, isopropanol and pentane to afford 43.0 g (49 %) of l-benzyl-4-(4-benzyloxy-phenyl)-piperidin-4-ol as off-white crystals, m.p. 105 °C.

b) 20.0 g (53.5 mmol) of l-benzyl-4-(4-benzyloxy-phenyl)-piperidin-4-ol prepared as described above was heated in 250 mL glacial acetic acid for 5 h at 100°C. The reaction mixture was concentrated to a volume of approx. 80 mL and then ice and dilute aqueous sodium hydroxide was added. Common work-up comprising extraction with dichloromethane afforded the crude product which was recrystallized from isopropanol / pentane to afford 15.4 g (81 %) l-benzyl-4-(4-benzyloxy-phenyl)-l,2,3,6-tetrahydro- pyridine, m.p. 126°C.

Example 13

(Preparation of starting material)

a) Preparation of 4-(4-benzyloxy-phenyl)-4-hydroxy-piperidine-l-carboxylic acid tert- butyl ester

The reaction flask was charged with 31.55 g of 4-benzyloxy-bromobenzene (120 mmol) in 265 mL of tetrahydrofuran. The solution was cooled to -75 °C, then 75 mL of 1.6 M n-butyllithium in hexane (120 mmol) was added during 1 h. The suspension was stirred for another 1 h at -75°C. Then, 20 g of 4-oxo-piperidine- 1-carboxylic acid tert-butyl ester (100 mmol) in 75 mL of tetrahydrofuran was added during 1 h. Stirring at -75°C was continued for 3 h. After warming up to 0°C, the reaction mixture was poured onto a mixture of 200 g of ice, 100 mL of saturated aqueous sodium chloride and 500 mL of ethyl acetate. The aqueous phase was separated and extracted with 400 mL of ethyl acetate, the organic phases were washed with half- saturated aqueous sodium chloride, combined, dried over sodium sulfate and concentrated in vacuo. The residue (45 g) was taken up in 120 mL of dichloromethane and treated with 5 g of charcoal. The charcoal was filtered off and the filtrate was concentrated to a volume of approx. 40 mL. 60 mL of hexane was slowly added in order to induce crystallization. The suspension was stirred for 2 h at room temperature. Then, the crystalline product was collected and washed with two portions of 50 mL, i.e. a total of 100 mL of hexane. The product was dried to afford 32 g (83 %) of 4-(4-benzyloxy-phenyl)-4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester as white crystals, m.p. 117-118°C.

b) Preparation of 4-(4-Benzyloxy-phenyl)-3,6-dihydro-2H-pyridine- 1-carboxylic acid tert-butyl ester

32 g of 4-(4-benzyloxy-phenyl)-4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester (83 mmol) was dissolved in 192 mL of pyridine. A solution of 30 mL of phosphorus oxychloride (322 mmol) in 64 mL of pyridine was added at room temperature and the mixture was stirred at 62 °C for 4.5 h. After cooling to room temperature the reaction mixture was concentrated to a volume of approx. 100 mL and then cooled to 0°C. 150 g of ice was added to the residue and the product was extracted with ethyl acetate (2x250 mL). The organic phases were combined, dried over sodium sulfate and concentrated in vacuo. The residue (33 g) was taken up in a mixture of 40 mL of dichloromethane and 60 mL of isopropanol. The dichloromethane was removed in vacuo (500 mbar, bath 55°C). Crystals started to separate and the suspension was slowly cooled to room temperature. 20 mL of isopropanol was added and the suspension was stirred for 1 h at room temperature. Then, the crystalline product was collected and washed with two portions of 50 mL, i.e. a total of 100 mL of isopropanol and two portions of 30 mL, i.e. a total of 60 mL of pentane. The product was dried to afford 20.5 g (67 %) of 4- (4- benzyloxy-phenyl)-3,6-dihydro-2H-pyridine- 1-carboxylic acid tert-butyl ester as white crystals, m.p. 96°C. Example 14

(Preparation of starting material) a) Preparation of4-benzyloxybrombenzene

200 g (1.16 mol) of 4-bromophenol was dissolved in acetone under argon. Then 320 g (2.31 mol) K₂CO₃ and 3.465 g (23.1 mmol) Nal were added. The mixture was stirred at room temperature and 292.7 g (2.31 mol) of benzyl chloride was added during 1 h. Then the mixture was boiled during 48 h. The acetone (ca. 500 mL) was partially removed in vacuo. 1.2 L 10 % aq. Na₂CO₃ was added to the residue. After extraction with ethyl acetate (lxl L + 2x500 mL) the organic phase was washed with 1 L of a half-saturated NaCl solution. After drying over Na SO and concentrating, the main part of the benzyl chloride was removed. 400 mL of pentane was added to the residue. The crystallisation began during stirring at 0°C. The crystals were separated and washed with 2x150 mL pentane and dried during 2 h at 15 mbar (40C° bath temperature) and 2 h under high vacuum at room temperature. 230 g (75 %) 4-benzyloxybromobenzene was obtained.

b) Preparation of l-ethyl-l-methyl-4-oxo-piperidinium-iodide

To a solution of 93 g (730 mmol) l-ethyl-4-piperidone (Aldrich 27950-1) in 730 mL acetone 124 g (876 mmol) methyl iodide (Acros 12237) was added during 30 min. The temperature was kept at 25-30°C. The product began to precipitate after addition of 1/5 of the methyl iodide. The mixture was stirred for 5 h at 22°C and 30 min at 0 °C. The cold suspension was filtered and the product was washed with acetone. 188 g (95 %) 1- ethyl-l-methyl-4-oxo-piperidinium iodide was obtained.

c) Preparation of (R)-l-(l-phenyl-ethyl)-piperidin-4-one

a) Under argon 84.6 g (698 mmol) (R)-(+)-l-phenylethylamine (Merck no. 807031) and 1.4 L ethanol were mixed. A solution of 203 g (1.47 mol) K₂CO₃ in water was added. The mixture was heated at 80°C under stirring and a solution of 188 g (698 mmol) 1- ethyl-l-methyl-4-oxo-piperidinium iodide in 700 mL water was added during 1 h. The mixture was heated again for 105 min under stirring and then ethanol was removed in vacuo.

The residue was extracted with dichloromethane (1x1.5 L + lxl L). The organic phases were washed with half-saturated NaCl solution (2x800 mL) and dried with Na₂SO . After evaporation of the solvent 144 g crude (R)-l-(l-phenyl-ethyl)-piperidin-4-one was obtained. 70 mL 37 % HCl were added at 5°C to 300 mL of isopropanol during 30 min. The mixture was added during 2 h under stirring at 15-20°C to a solution of 144 g crude (R)-l-(l-phenyl-ethyl)-piperidin-4-one in 100 mL ethylacetate. Crystallisation began after addition of 1/3 of the above mixture. The suspension was stirred overnight at room temperature and then for 3 h at 0°C. After adding 80 mL of pentane the mixture was stirred again for 3 h at 0°C. The product was separated and washed with isopropanol (3x70 mL). After drying the hydrochloride (188 g) was suspended in 1 L dichloromethane and 700 mL of 10 % Na CO₃ was added. The organic phase was separated and washed with half- saturated NaCl ( lxl L). After drying over MgSO₄ the organic phase was concentrated. The residue was dried during 2 h in high vacuum. 113 g (R)-l-(l-phenyl-ethyl)-piperidin-4-one was obtained.

d) Preparation of (R)-4-(4-benzyloxy-phenyl)-l-(l-phenyl-ethyl)-piperidin-4-ol

Under argon 175.2 g (666 mmol) 4-benzyloxybromobenzene was dissolved in 1.4 L dry THF (MS 4 A). The solution was cooled to -75°C and a solution of 416 mL 1.6 M butyllithium (666 mmol) in hexane was added during 40 min. After stirring for 1 h a solution of 113 g (555 mmol) (R)-l-(l-phenyl-ethyl)-piperidin-4-one in 400 mL dry THF was added during 1 h at -75°C. The mixture was stirred for another 1 h and, after heating to room temperature, poured into 1.5 L of ice water. The mixture was extracted with 1 L ethyl acetate. The organic phase was washed with 1 L of a half-saturated NaCl solution, dried over Na₂SO and concentrated. 262 g of crude (R)-4-(4-benzyloxy- phenyl)-l-(l-phenyl-ethyl)-piperidin-4-ol was obtained.

e) Preparation of (R)-4-(4-Benzyloxy-phenyl)-l-(l-phenyl-ethyl)- 1,2,3,6 tetrahydropyridine

121.7 g crude (R)-4-(4-benzyloxy-phenyl)-l-(l-phenyl-ethyl)-piperidin-4-ol was dissolved at 40°C in 1.21 L dichloromethane. 59.4 g (471 mmol) oxalic acid (Merck 492) was added. The mixture was boiled for 3 h, while 20 mL of water was separated. The reaction mixture was washed at room temperature with 1.2 L 10 % Na₂CO₃. The precipitate (52 g) was separated and added to a mixture of 250 mL 2 N NaOH and 300 mL dichloromethane. The residue was dissolved after stirring for 30 min at 30-35°C. The organic phase was separated and washed with a half-saturated NaCl solution. The obtained precipitate was separated and dissolved in 200 mL dichloromethane and 60 mL methanol. The combined organic phases were concentrated after drying over Na₂SO . 80 mL ethyl acetate was added to the residue and stirred for 2 h. The crystals were separated, washed with pentane, and dried. 36.5 g of (R)-4-(4-benzyloxy-phenyl)-l-(l- phenyl-ethyl)-l,2,3,6-tetrahydropyridine was obtained. The organic phase of the above-mentioned filtrate was washed with 1.5 L of a half- saturated NaCl solution. After drying the organic phase was concentrated. 80 mL ethyl acetate and 30 mL ether were added to the residue. After stirring for 3 h at 0°C the crystals were separated and then washed with ethylacetate (2x20 mL) and pentane (50 mL) and dried. 33.0 g of (R)-4-(4-benzyloxy-phenyl)-l-(l-phenyl-ethyl)-l,2,3,6- tetrahydropyridine was obtained.

In total: 33.0 g + 36.5 g = 69.5 g (R)-4-(4-benzyloxy-phenyl)-l-(l-phenyl-ethyl)-l,2,3,6- tetrahydropyridine (73 % based on (R)-l-(l-phenyl-ethyl)-piperidin-4-one) was obtained.

Example 15

(Preparation of renin inhibitor)

Preparation of 1- [2- [7- f (3R,4R)-4- [4- [3- (2-methoxy-benzyloxy)-propoxyl -phenyl! - piperidin-3-yloxymethyl] -naphthaIen-2-yloxyl -ethyl] -4-methyl-piperazine

a) 12.8 g (41.6 mmol) (3R,4R)-3-Hydroxy-4-(4-methoxy-phenyl)-piperidine-l- carboxylic acid tert-butylester were dissolved in 320 ml of dichloromethane and treated while stirring at 5° C to 8° C with 90.7 ml of an 1 molar solution of borontribromide in dichloromethane. Stirring was then continued at room temperature for additional 16 hours. The reaction mixture was again cooled to 0° C, then treated with 12.6 g (91.6 mmol) of potassium carbonate dissolved in 160 ml of H₂O. The two phases were separated, the dichloromethane phase evaporated and the resulting residue transferred back to the water phase with the aid of 200 ml of dioxane. The reaction mixture containing crude (3R,4R)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine was then treated with 10 g (45.8 mmol) of di-tert.-butyl-dicarbonate and stirred at room temperature for 1 hour. Then, the major part of the dioxane present was evaporated with the aid of a rotary evaporator and the aqueous phase was extracted twice with 100 ml of ethylacetate. The combined organic phases were dried over magnesium sulphate and concentrated. Then diethylether was added and the product started to crystallize. After adding pentane, the mixture was placed in the refrigerator. The next day the crystals were separated, washed with pentane and dried in vacuo. 11.2 g of (3R,4R)-3-hydroxy- 4-(4-hydroxy-phenyl)-piperidin-l-carboxylic-acid-tert-butylester was obtained as white crystals; MS : 237 (M-C₄H₈)⁺ . b) A solution of 16.50 g (56.24 mmol) of (3R,4R)-3-hydroxy-4-(4-hydroxy-phenyl)- piperidine- 1-carboxylic acid tert-butylester in 40 ml of dimethylformamide was treated in succession with 12.68 g (59.06 mmol) of l-(3-chloro-propoxymethyl)-2-methoxy- benzene (WO 97/09311) and 12.44 g (89.99 mmol) of potassium carbonate. This mixture was stirred at 120°C for 26 hours. Subsequently, it was filtered, concentrated to a few millilitres, poured into 300 ml of an ice/water mixture and extracted three times with 100 ml of dichloromethane each time. The combined organic phases were washed once with a small amount of water, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product (31.64 g) was separated on silica gel using a 99:1 mixture of dichloromethane and methanol as the eluent and yielded 25.4 g (95.8 % of theory) (3R,4R)-3-hydroxy-4-[4-[3-(2- methoxy-benzyloxy)-propoxy] -phenyl] -piperidine- 1-carboxylic acid tert-butylester as a slightly yellow oil; MS: 489 (M+NH₄ ⁺).

c) 25.4 g (53.86 mmol) of (3R,4R)-3-hydroxy-4-[4-[3-(2-methoxy-benzyloxy)- propoxy] -phenyl] -piperidine- 1-carboxylic acid tert-butylester and 17.78g (55.06 mmol) of 2-chloromethyl-7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalene (WO 97/09311) were dissolved in 180 ml of dimethylformamide under argon and then 2.49 g (57.09 mmol) of sodium hydride dispersion (55 % in mineral oil) was added. Subsequently, the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured onto ice-water, the product was extracted 3 times with dichloromethane, the organic phases were washed twice with distilled water, then dried over magnesium sulphate, filtered and concentrated under reduced pressure. The thus-obtained crude product was chromatographed on silica gel with dichloromethane and methanol. There were thus obtained 36.43 g (89.2 % of theory) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)- propoxy] -phenyl] -3- [7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy] - piperidine- 1-carboxylic acid tert-butylester as a yellowish oil; MS: 759 (M+H) ⁺.

d) 36.43 g (48.06 mmol) of (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]- phenyl]-3-[7-(2-trimethylsilanyl-ethoxymethoxy)-naphthalen-2-ylmethoxy]- piperidine- 1-carboxylic acid tert-butylester was placed in 700 ml of abs. methanol at 0°C, then 48 ml (96.1 mmol) of hydrochloric acid in methanol (2.0 molar) was added dropwise at 5°C max. and thereafter the mixture was warmed to room temperature. After 120 min the reaction mixture was poured into ice-cold sodium hydrogen carbonate solution and the product was extracted three times with methylene chloride. The organic phases were washed once with distilled water, then dried over magnesium sulphate, filtered and concentrated under reduced pressure. The thus-obtained crude product was chromatographed on silica gel with methylene chloride and methanol. There were thus obtained 28.06 g (93 % of theory) (3R,4R)-3-(7-hydroxy-naphthalen-2- yloxymethyl)-4- [4- [ 3- (2-methoxy-benzyloxy) -propoxy] -phenyl] -piperidine- 1- carboxylic acid tert-butylester as a light yellow amorphous solid; MS: 645 (M+NH-j.^"*^").

e) A mixture of 10.15 g (16.17 mmol) of (3R,4R)-3-(7-hydroxy-naphthalen-2- yloxymethyl)-4- [4- [3-(2-methoxy-benzyloxy)-propoxy] -phenyl] -piperidine- 1- carboxylic acid tert-butylester, 2.80 g (19.42 mmol) of l-(2-hydroxy-ethyl)-4-methyl- piperazine [J. Pharm. Sci. (1968), 57(3), 384-9] and 5.51 g (21.01 mmol) of triphenylphosphine were dissolved in 450 ml of tetrahydrofuran. Then, a solution of 4.75 g (20.22mmol) of di-tert-butyl azodicarboxylate in 50 ml of tetrahydrofuran was slowly added to the reaction mixture at 0°C and stirring continued for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The thus- obtained crude product was chromatographed on silica gel with dichloromethane and methanol. There was thus obtained 9.18 g (75.3 % of theory) of (3R,4R)-4-[4-[3-(2- methoxy-benzyloxy)-propoxy]-phenyl]-3-[7-[2-(4-methyl-piperazin-l-yl)-ethoxy]- naphthalen-2-ylmethoxy] -piperidine- 1-carboxylic acid tert-butylester as a colourless oil;

MS: 754 (M+H)+.

f) A solution of 9.15 g ( 12.14 mmol) (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)- propoxy] -phenyl] -3- [7- [2- (4-methyl-piperazin- l-yl)-ethoxy] -naphthalen-2- ylmethoxy] -piperidine- 1-carboxylic acid tert-butylester in 250 ml of methanol was treated at room temperature with 36.41 ml of a 2.0 M solution of hydrogen chloride in methanol and the mixture was stirred at 50°C for 4 hours. Subsequently, the solution was evaporated under reduced pressure and the residue was partitioned between 200 ml of saturated sodium carbonate solution and 150 ml of dichloromethane. The aqueous phase was again extracted twice with 100 ml of dichloromethane; thereafter the organic phases were combined, dried over sodium sulphate and evaporated under reduced pressure. For purification, the crude product was chromatographed on silica gel using a 90:10 mixture of dichloromethane and methanol as the eluent. There were obtained 5.25 g (66 % of theory) of l-[2-[7-[(3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]- phenyl] -piperidin-3-yloxymethyl] -naphthalen-2-yloxy] -ethyl] -4-methyl-piperazine as an amorphous, colourless solid; MS: 654 (M+H)⁺. Example 16

(Preparation of renin inhibitor)

Preparation of (3R,4S,5S)-4-f4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3- (naphthalen-2-ylmethoxy)-piperidine

a) 49.3 g (128mmol) of (3S)-4-(4-benzyloxy-phenyl)-l-[(lR)-phenyl-ethyl]-l,2,3,6- tetrahydro-pyridin-3-ol were dissolved in 250 ml of N,N-dimethylformamide, treated portionwise with 25 g (about 600mmol) of sodium hydride dispersion in mineral oil (55-65 %) and the reaction mixture was heated to 50°C under argon for 1 hour. After cooling to 5°C the mixture was treated slowly with 23 ml (285 mmol) of ethyl iodide and stirred without cooling for one hour. Thereupon, the reaction mixture was poured into 2 litres of ice-water and extracted three times with 1 litre of ethyl acetate. The combined ethyl acetate phases were subsequently washed with water, dried over magnesium sulfate and evaporated on a rotary evaporator at a maximum 40°C. The residue which was thereby obtained was chromatographed on silica gel with hexane/ ethyl acetate. There were thus obtained (3S)-4-(4-benzyloxy-phenyl)-3-ethoxy-l-[(lR)-phenyl-ethyl]- 1,2,3,6-tetrahydro-pyridine as a colourless oil.

b) 35 g (84.6 mmol) of (3S)-4-(4-benzyloxy-phenyl)-3-ethoxy-l-[(lR)-phenyl- ethyl]-l,2,3,6-tetrahydro-pyridine were dissolved in 500 ml of 1,2-dimethoxyethane, treated with 9.91 g (262 mmol) of sodium borohydride and then treated while cooling at a maximum 28°C with a solution of 44.3 ml (353 mmol) of boron trifluoride diethyetherate in 44.3 ml of 1,2-dimethoxyethane and the reaction mixture was stirred at room temperature for 2 hours. Subsequently, while cooling at a maximum of 35°C, 169 ml of 4.1 N potassium hydroxide solution followed by 33.9 ml of 30% hydrogen peroxide solution were added dropwise and the reaction mixture was heated under reflux for 3 hours. After cooling to room temperature the reaction solution was poured into 2 liters of water and extracted twice with 1 litre of dichloromethane each time. The combined dichloromethane phases were washed with water, dried over magnesium sulphate and evaporated on a rotary evaporator at a maximum 40°C. The residue which was thereby obtained was chromatographed on silica gel with hexane/ ethyl acetate. There were thus obtained (3R,4R,5S)-(4-benzyloxy-phenyl)-5-ethoxy-l-[(lR)-phenyl- ethyl]-piperidin-3-ol) as a colourless oil.

c) 20 g (46.3 mmol) (3R,4R,5S)-(4-benzyloxy-phenyl)-5-ethoxy-l-[(lR)-phenyl- ethyl]-piperidin-3-ol dissolved in 500 ml methanol were hydrogenated in the presence of 3.5 g of palladium catalyst (10% on charcoal) for 7 hours. The reaction mixture was then filtered and evaporated yielding crude (3R,4R,5S)-5-ethoxy-4-(4-hydroxy-phenyl)- piperidin-3-ol MS: 237(M⁺).

d) 11 g (46.3 mmol) crude (3R,4R,5S)-5-ethoxy-4-(4-hydroxy-phenyl)-piperidin-3- ol were dissolved in 100 ml dioxane/50 ml water and treated with 11 g (50 mmol) di- tert-butyldicarbonate and 8.4 g (100 mmol) sodium hydrogencarbonate. The reaction mixture was then stirred for 2 hours. 100 ml 2 N NaOH were then added and the mixture again stirred for an additional hour. It was then acidified with solid citric acid. Then, the product was extracted 3 times with dichloromethane, the organic phases were washed twice with distilled water, then dried over magnesium sulphate, filtered and concentrated under reduced pressure. The thus-obtained crude product was chromatographed on silica gel with dichloromethane/ ethyl acetate. There were thus obtained (3R,4R,5S)-5-ethoxy-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-l- carboxylic acid tert-butylester as colourless oil; MS: 338 (M+H⁺).

e) A solution of 11.8 g (35.0 mmol) of (3R,4R,5S)-5-ethoxy-3-hydroxy-4-(4- hydroxy-phenyl)-piperidine-l-carboxylic acid tert-butylester in 40 ml of dimethylformamide was treated in succession with 10.3 g (45.0 mmol) of 3-bromo- propoxymethyl-benzene and 8.29 g (60.0 mmol) of potassium carbonate. This mixture was stirred at 120°C for 26 hours. Subsequently, it was filtered, concentrated to a few millilitres, poured into 300 ml of an ice/water mixture and extracted three times with 100 ml of dichloromethane each time. The combined organic phases were washed once with a small amount of water, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The thus-obtained crude product was separated on silica gel using a mixture of dichloromethane and methanol as the eluent and yielded (3R,4R,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-hydroxy- piperidine- 1-carboxylic acid tert-butylester as colourless oil; MS: 486 (M+H⁺); 508 (M+Na⁺).

f) 14.6 g (30.0 mmol) of (3R,4R,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy- 3-hydroxy-piperidine- 1-carboxylic acid tert-butylester and 7.74 g (35.0 mmol) of 2- bromomethyl-naphthalene were dissolved in 110 ml of dimethylformamide under argon and then 1.77 g (40.0 mmol) of sodium hydride dispersion (55% in mineral oil) was added. Subsequently, the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured onto ice- water, the product was extracted 3 times with dichloromethane, the organic phases were washed twice with distilled water, then dried over magnesium sulfate, filtered and concentrated under reduced pressure. The thus- obtained crude product was chromatographed on silica gel with dichloromethane and methanol. (3R,4S,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-(naphthalen-2- ylmethoxy) -piperidine- 1-carboxylic acid tert-butylester was obtained as colourless oil; MS: 626.5(M+H⁺).

g) 14.4 g (23.0 mmol) of (3R,4S,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy- 3-(naphthalen-2-ylmethoxy)-piperidine-l-carboxylic acid tert-butylester were placed in 350 ml of abs. methanol at 0°C, then 24 ml (48 mmol) of hydrochloric acid in methanol (2.0 molar) were added dropwise at 5°C max. and thereafter the mixture was warmed to room temperature. After 120 min the reaction mixture was poured into ice-cold sodium hydrogen carbonate solution and the product was extracted three times with dichloromethane, the organic phases were washed once with distilled water, then dried over magnesium sulphate, filtered and concentrated under reduced pressure. The thus- obtained crude product was chromatographed on silica gel with dichloromethane and methanol. There were thus obtained (3R,4S,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5- ethoxy-3-(naphthalen-2-ylmethoxy)-piperidine as colourless oil; MS: 526 (M+H⁺).

Claims

1. A process for the preparation of a compound of formula

1 or salts thereof, wherein the hydroxy groups attached to the carbon atoms 3 and 4 of the piperidine cycle are in cis position, comprising the reaction of a compound of the formula

R¹ I

A R 2 in the presence of an oxidant and a chiral osmium complex, wherein

A is arylene; R is alkyl, aryl, aralkyl, diarylalkyl, alkoxycarbonyl, halogenated alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, allyloxycarbonyl, alkylcarbonyl, halogenated alkylcarbonyl, arylsulfonyl, alkylsulfonyl or alkylsilyl and

R is alkoxy, cycloalkoxy, aryloxy, aralkoxy, aralkoxyalkoxy, hydroxy, alkylsulfonyloxy, arylsulfonyloxy, trifluoromethylsulfonyloxy, chlorine, bromine or iodine.

2. The process of claim 1, wherein a compound of formula 1 has the stereochemistry according to formula la or lb:

3. The process according to claim 1 or 2, wherein the chiral osmium complex is obtainable by a reaction of an osmium compound in the presence of a chiral ligand and an oxidant.

4. The process according to any of claims 1 to 3, wherein the chiral ligand comprises a hydroquinidine or hydroquinine substructure.

5. The process according to any of claims 1 to 4, wherein the chiral ligand is hydroquinidine 1,4-phthalazinediyl diether or hydroquinine 1,4-phthalazinediyl diether.

6. The process according to any of claims 1 to 5, wherein the reaction is performed in the presence of a ferricyanide salt.

7. The process according to any of claims 1 to 6, comprising a persulfate salt.

8. The process according to any of claims 1 to 7, comprising a nucleophilic compound.

9. The process according to claim 8, wherein the nucleophilic compound is methanesulfonylamide.

10. The process according to claim 1 to 9, comprising a base.

11. The process according to any of claims 1 to 10, wherein A is phenylene, optionally substituted by one to four additional substituents independently selected from alkyl, halogen or nitro.

12. The process according to any of claims 1 to 11, wherein R¹ is aralkyl or alkoxycarbonyl.

13. The process according to any of claims 1 to 12, wherein R^" is alkoxy or aralkoxy.

14. The process according to any of claims 1 to 13, wherein a compound of formula 2 is prepared by a process which comprises reacting a compound of formula 3

OH

R 3

with a compound of formula R'-NH₂ or a salt thereof and, wherein R¹ is alkyl, aryl or benzyl, R² is alkoxy, cycloalkoxy, aryloxy, aralkoxy, aralkoxyalkoxy, alkylsulfonyloxy, arylsulfonyloxy, trifluoromethylsulfonyloxy, chlorine, bromine or iodine and A is defined as before.

15. The process according to any of claims 1 to 13, comprising the transformation of a compound of formula 1 into a compound of formula 4

4

in the presence of a reducing agent.

16. The process according to claim 15, wherein the reducing agent is Raney nickel or hydrogen.

17. The process according to any of claims 1 to 13, comprising the transformation of a compound of formula 1 into a compound of formula

in the presence of an acid.

18. The process according to claim 17, wherein the acid is toluenesulfonic acid.

19. The process according to any of claims 1 to 13, 15 and 16, wherein a compound of formula 1 is converted to l-[2-[7-[(3R,4R)-4-[4-[3-(2-methoxy- benzyloxy) -propoxy] -phenyl] -piperidin-3-yloxymethyl]-naphthalen-2-yloxy] -ethyl] -4- methyl-piperazine characterised in that

a) (S,S)-3,4-dihydroxy-4-(4-methoxy-phenyl)-piperidine- 1-carboxylic acid tert- butyl ester is reduced with Raney nickel to yield (3R, 4R)-3-hydroxy-4-(4-methoxy- phenyl) -piperidin- 1-carboxylic acid tert-butyl ester; followed by

b) cleavage of the methoxy group and the tert-butoxycarbonyl group in the presence of boron tribromide and subsequent reaction with di-tert-butyl dicarbonate in the presence of a base to form (3R,4R)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidin-l- carboxylic acid-tert-butylester;

c) reaction of the product of step b) with l-(3-chloro-propoxymethyl)-2- methoxy-benzene and potassium carbonate to yield (3R,4R)-3-hydroxy-4-[4-[3-(2- methoxy-benzyloxy)-propoxy] -phenyl] -piperidine- 1-carboxylic acid tert-butylester;

d) reaction of the product of step c) with 2-chloromethyl-7-(2-trimethylsilanyl- ethoxymethoxy)-naphthalene and sodium hydride to yield (3R,4R)-4-[4-[3-(2- methoxy-benzyloxy)-propoxy] -phenyl] -3- [ 7-(2-trimethylsilanyl-ethoxymethoxy)- naphthalen-2-ylmethoxy] -piperidine- 1-carboxylic acid tert-butylester; followed by

e) reaction of the product of step d) with hydrochloric acid to yield (3R,4R)-3-(7- hydroxy-naphthalen-2-yloxymethyl)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]- phenyl] -piperidine- 1-carboxylic acid tert-butylester; f) reaction of the product of step e) with l-(2-hydroxy-ethyl)-4-methyl-piperazine and triphenylphospine to yield (3R,4R)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]- phenyl]-3- [7- [2-(4-methyl-piperazin-l-yl)-ethoxy]-naphthalen-2-ylmethoxy]- piperidine- 1-carboxylic acid tert-butylester; followed by

g) reaction of the product of step f) with hydrogen chloride.

20. The process according to any of claims 1 to 13, 17 and 18, wherein a compound of formula 1 or a salt thereof is converted to (3R,4S,5S)-4-[4-(3-benzyloxy- propoxy)-phenyl]-5-ethoxy-3-(naphthalen-2-ylmethoxy)-piperidine characterised in that

a) (3R,4R)-4-(4-benzyloxy-phenyl)-l- [(R)- l-phenyl-ethyl] -piperidine-3,4-diol is transformed into (3S)-4-(4-benzyloxy-phenyl)-l-[(lR)-phenyl-ethyl]- 1,2,3,6- tetrahydro-pyridin-3-ol by dehydration with toluenesulfonic acid; followed by

b) reaction of the product of step a) with sodium hydride and ethyl iodide to yield (3S)-4-(4-benzyloxy-phenyl)-3-ethoxy-l-[( lR)-phenyl-ethyl] -l,2,3,6-tetrahydro- pyridine;

c) hydroboration of the product of step b) with sodium borohydride and boron trifluoride etherate followed by reaction with potassium hydroxide and hydrogen peroxide to yield (3R,4R,5S)-(4-benzyloxy-phenyl)-5-ethoxy-l-[( lR)-phenyl-ethyl] - piperidin-3-ol);

e) reaction of the product of step d) with di-tert-butyldicarbonate and sodium hydrogencarbonate followed by addition of NaOH to yield (3R,4R,5S)-5-ethoxy-3- hydroxy-4-(4-hydroxy-phenyl)-piperidine- 1-carboxylic acid tert-butylester;

g) reaction of the product of step f) with 2-bromomethyl-naphthalene and sodium hydride to yield (3R,4S,5S)-4-[4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3- (naphthalen-2-ylmethoxy)-piperidine- 1-carboxylic acid tert-butylester; h) reaction of the product of step g) with hydrochloric acid to yield (3R,4S,5S)-4- [4-(3-benzyloxy-propoxy)-phenyl]-5-ethoxy-3-(naphthalen-2-ylmethoxy)-piperidine.

21. A compound of formula 1 or a salt thereof, wherein R² is alkoxy, cycloalkoxy, aryloxy, aralkoxy, aralkoxyalkoxy, hydroxy, alkylsulfonyloxy, arylsulfonyloxy, trifluoromethylsulfonyloxy, bromine or iodine and R¹ and A are defined as in any of claims 1 and 11 to 13.

22. A compound according to claim 21 selected from:

(S,S)-3,4 dihydroxy-4-(4-methoxy-phenyl)-piperidine- 1-carboxylic acid tert-butyl ester;

(3R,4R)-4-(4-benzyloxy-phenyl)-l-benzyl-piperidine-3,4-diol;

(3R,4R)-4-(4-benzyloxy-phenyl)-3,4-dihydroxy-piperidine-l-carboxylic acid tert-butyl ester;

(3S,4S)-4-(4-Benzyloxy-phenyl)-3,4-dihydroxy-piperidine- 1-carboxylic acid tert-butyl ester;

(3R,4R)-4-(4-Benzyloxy-phenyl)-l-[(R)-l-phenyl-ethyl]-piperidine-3,4-diol;

(3S,4S)-4-(4-Benzyloxy-phenyl)-l-[(R)-l-phenyl-ethyl]-piperidine-3,4-diol.

23. The use of a compound as defined in claim 21 in the preparation of renin inhibitors.

24. A compound as obtained by the process according to any of claims 1 to 18.

25. The invention as described before.