ZA200300018B

ZA200300018B - Process for the preparation of substituted octanoyl amides.

Info

Publication number: ZA200300018B
Application number: ZA200300018A
Authority: ZA
Inventors: Peter Herold; Stefan Stutz; Felix Spindler
Original assignee: Speedel Pharma Ag
Priority date: 2000-07-05
Filing date: 2003-01-02
Publication date: 2004-04-08
Also published as: CN100526304C; CN1817872A

Description

Process for the preparation of substituted octanoyl amides

The invention relates to a process for the preparation of 2(5),4(8),5(8),7(8)-2, 7-dialkyl-4-hydroxy-5-amino-8-aryl- octanoyl amides and their physiologically acceptable salts; 5S and the new compounds used as intermediates in the multistage process.

In EP-A-0 678 503, J-amino-y-hydroxy-w-aryl-alkanecarbox- amides are described, which exhibit renin-inhibiting properties and could be used as antihypertensive agents in pharmaceutical preparations. The manufacturing procedures described are unsatisfactory in terms of the number of process steps and yields and are not suitable for "an industrial process. A disadvantage of these processes is also that the total yields of pure diastereomers that are obtainable are too small.

It has now been surprisingly found that these alkane- carboxamides can be prepared both in high total yields and in a high degree of purity, and that selectively pure dia- stereomers are obtainable, if the double bond of 2,7- dialkyl-8-aryl-4-octenic acid or 2,7-dialkyl-8-aryl-4~ octenic acid ester is simultaneously halogenated in the 5 position and hydroxylated in the 4 position under lactonization, the halolactone is converted to a hydroxylactone and then the hydroxy group is converted to a leaving group, the leaving group substituted with azide, the lactone amidated and then the azide converted to the amine group. Apart from the high yields and stereoselectivities in the individual process steps, particular attention is drawn ’ to the fact that substantially fewer by-products are formed in the azidation step.

A primary object of the invention is a process for the preparation of compounds of formula I,

OH R,

R, N—R,

R NH o

A R; 3 2 (1), wherein

Ry; and R; are, independently of one another, H, C;-Cealkyl,

C,-C¢halogenalkyl, Ci-Csalkoxy, Ci-Csalkoxy-C;—-Cealkyl, or

Ci-Csalkoxy-Cy-Cealkyloxy, Rs 1s C;-Cealkyl, Rs is C;-Cgsalkyl, and Rs 1s C;-Cealkyl, C;-Céhydroxyalkyl, C;-Csalkoxy-Ci~Ce- alkyl, Ci-Cealkanoyloxy—-C;-Cealkyl, Ci—Csaminoalkyl, Cqi~

Cealkylamino-Ci,-Ce~alkyl, Ci-Ce—dialkylamino-C,-Cg~alkyl, C,;-Ce- alkanoylamido-C;-Ce-alkyl, HO (0) C-C,-Cs~alkyl, Ci1-Cealkyl-0- (0)C-C1~-Csalkyl, H,N-C (0) -C;-Cealkyl, C1~Cealkyl-HN-C {0} -C,-

Cealkyl or (C;-Cealkyl) N-C(0)-C;-Ce-alkyl, comprising a) the reaction of a compound of formula II, 0 lo)

R, ,, .

R,

R N

R, 3 3 (II), with an amine of formula Rs-NH, to form a compound of formula

IIT,

OH R,

R N 0 . R; 3 3 (III), and b) reduction of the azide group of the compound of formula

III to the amine group and isolation of the compounds of

- 3 = formula I, if necessary with the addition of a salt-forming acid, comprising the preparation of compounds of formula II ’ by reacting cl) a compound of formula IV, . 5

R,

R, R, lo] (IV), wherein Re is C;-Cyalkyl, Cs-Cipcycloalkyl, Cs-Cicycloalkyl-

Ci—Csalkyl, Cs—Croaryl or Ce—Cio—aryl-C,-Csalkyl, with a halogenation agent to form a compound of formula VI, or c2) a carboxylic acid of formula V, or a salt of this carboxylic acid, -

Ry

R, o

R, (Vv), with a halogenation agent to form a compound of formula VI, lo) 0

Ry

R, X

R, (VI), wherein X is Cl, Br or I, ) d) reaction of the compound of formula VI in the presence of an alkali metal or alkaline earth metal hydroxide or an ) alcohol to form a compound of formula VII,

H O H R,

Rq *%, oM

R, o

R;

El (VII), wherein M is an alkali metal, an equivalent alkaline earth metal or the residue of an alcohol minus a hydroxyl group, e) hydrolysis of the compound of formula VII in the presence of an acid to form a compound of formula VIII, oO jo)

Ry “tr,

H R

R, OH

R; (VIII), f) substitution of the hydrogen atom of the hydroxyl group in the compound of formula VIII and conversion thereof to a leaving group AO to form compounds of formula IX, 0 o)

R, tay, : Rs

R, OA

R, (IX), g) and then reaction of the compound of formula IX with an azidation agent to form a compound of formula II, or h) reaction if the compound of formula VIII directly with a zinc azide/-bis-pyridine complex in the presence of a : 20 tertiary phosphine and an azodicarboxylate, if necessary in an organic solvent, to form a compound of formula II.

As an alkyl, R; and R; may be linear or branched and preferably comprise 1 to 4 C atoms. Examples are methyl,

ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl.

As a halogenalkyl, R; and R; may be linear or branched and ! 5 preferably comprise 1 to 4 C atoms, especially 1 or 2 C atoms. Examples are fluoromethyl, difluoromethyl, trifluoro- methyl, chloromethyl, dichloromethyl, trichloromethyl, 2~chloroethyl and 2,2,2-trifluoroethyl.

As an alkoxy, R, and R; may be linear or branched and preferably comprise 1 to 4 C atoms. Examples are methoxy, ethoxy, n- and i-propyloxy, n-, i- and t-butyloxy, pentyloxy and hexyloxy.

As an alkoxyalkyl, R; and R; may be linear or branched. The alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyl group preferably comprises 1 to 4 C atoms. Examples are methoxymethyl, l-methoxyeth-2-y1, l-methoxyprop-3-yl, l-methoxybut-4-yl, methoxypentyl, methoxyhexyl, ethoxymethyl, 1l-ethoxyeth-2-yl, l-ethoxyprop- 3-vl, l-ethoxybut-4-yl, ethoxypentyl, ethoxyhexyl, propyloxymethyl, butyloxymethyl, l-propyloxyeth-2-y1 and i1-butyloxyeth-2-yl.

As a C(;-Cealkoxy-C;—Csalkyloxy, R; and R; may be linear or branched. The alkoxy group preferably comprises 1 to 4 and especially 1 or 2 C atoms, and the alkyoxy group preferably comprises 1 to 4 C atoms. Examples are methoxymethyloxy, 1- methoxyeth-2-yloxy, l1-methoxyprop-3-yloxy, I-methoxybut-4- yloxy, methoxypentyloxy, methoxyhexyloxy, ethoxymethyloxy, l1-ethoxyeth-2-yloxy, l-ethoxyprop-3-yloxy, l-ethoxybut-4- : yloxy, ethoxypentyloxy, ethoxyhexyloxy, propyloxymethyloxy, butyloxymethyloxy, 1l-propyloxyeth-2-yloxy and l-butyloxyeth- . 2-yloxy.

In a preferred embodiment, R; is methoxy- or ethoxy-Ci-

Cialkyloxy, and Rp is preferably methoxy or ethoxy. ’ Particularly preferred are compounds of formula I, wherein R; is l-methoxyprop-3-yloxy and R, is methoxy. ‘ 5

As an alkyl, Rs and Ry may be linear or branched and preferably comprise 1 to 4 C atoms. Examples are methyl, ethyl, n- and i-propyl, n-, i- and t-butyl, pentyl and hexyl. In a preferred embodiment, Rs; and Rs, in compounds of formula I are in each case isopropyl.

As an alkyl, Rs may be linear or branched in the form of alkyl and preferably comprise 1 to 4 C atoms. Examples of alkyl are listed hereinabove. Methyl, ethyl, n- and i- propyl, n-, i- and t-butyl are preferred.

As a Cy-Cghydroxyalkyl, Rs may be linear or branched and preferably comprise 2 to 6 C atoms. Some examples are 2-hydroxyethy-1-yl, 2-hydroxyprop-1l-yl, 3-hydroxyprop-l-vyl, 2-, 3- or 4-hydroxybut-1-yl, hydroxypentyl and hydroxyhexyl.

As a Ci-Cgalkoxy-C;-Cgalkyl, Rs may be linear or branched. The alkoxy group preferably comprises 1 to 4 C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are 2-methoxyethy-1-yl, 2-methoxyprop-l-yl, 3-methoxyprop-1-vyi, 2-, 3- or 4-methoxybut-1-yl, 2-ethoxyethy-1l-vyi, 2- ethoxyprop-1-v1, 3-ethoxyprop-1-y1, and 2-, 3- or 4- ethoxybut-1-yi.

As a Cy-Cealkanoyloxy-C;-Cealkyl, Rs may be linear or branched. The alkanoyloxy group preferably comprises 1 to 4 * C atoms and the alkyl group preferably 2 to 4 C atoms. Some examples are formyloxymethyl, formyloxyethyl, acetyloxy- ~ ethyl, propionyloxyethyl and butyroyloxyethyl.

As a C;-Csaminoalkyl, Rs; may be linear or branched and preferably comprise 2 to 4 C atoms. Some examples are 2- ’ aminoethyl, 2- or 3-aminoprop-l-yl and 2-, 3- or 4-aminobut- 1-vyl. ’ 5

As Ci-Csalkylamino—~C,;~-Csalkyl and C1-Cedialkylamino-Ci~Ce¢— alkyl, Rs may be linear or branched. The alkylamino group preferably comprises C;-Csalkyl groups and the alkyl group preferably 2 to 4 C atoms. Some examples are 2- methylaminoeth-1-yl, 2-dimethylaminoeth-1-yl, 2-ethylamino- eth-1-yl, 2-ethylaminoeth-1-yl, 3-methylaminoprop-l-yl, 3- dimethylaminoprop-1-yl, 4-methylaminobut-1-y1 and 4-dimethylaminobut-1-yl.

As a C(C;-Cealkanoylamido-C;-Cealkyl, Rs may be linear or branched. The alkanoyl group preferably comprises 1 to 4 C atoms and the alkyl group preferably 1 to 4 C atoms. Some examples are 2-formamidoeth-1-yl, 2-acetamidoeth-1-yl, 3- propionylamidoeth-1-yl and 4-butyroylamidoeth-1-yl.

As a HO(0O)C-C;-Cgalkyl, Rs may be linear or branched and the alkyl group preferably comprises 2 to 4 C atoms. Some examples are carboxymethyl, carboxyethyl, carboxypropyl and carboxybutyl.

As a (C;-Cealkyl-0-(0)C-Cy-Cealkyl, Rs may be linear or branched, and the alkyl groups preferably comprise independently of one another 1 to 4 C atoms. Some examples are methoxycarbonylmethyl, 2-methoxycarbonyleth-1-yl, 3- methoxycarbonylprop-l~yl, 4-methoxycarbonylbut-1-yl, ethoxy- carbonylmethyl, 2-ethoxycarbonyleth-1-yl, 3-ethoxycarbonyl- . prop-1-yl, and 4-ethoxycarbonylbut-1-yl. - As a Hp,N-C(0)-C,-Csalkyl, Rs may be linear or branched, and the alkyl group preferably comprises 2 to 6 C atoms. Some examples are carbamidomethyl, 2-carbamidoeth-1-y1,

2~carbamido-2,2-dimethyleth-1-yl, 2- or 3-carbamidoprop-1- yl, 2-, 3- or 4-carbamidobut-1l-yl, 3-carbamido-2-methylprop- 1-y1, 3-carbamido-1, 2-dimethylprop-1-yl, 3-carbamido-3- methylprop-1-yl, 3-carbamido-2,2-dimethylprop-1-yl, 2-, 3-, ’ 5 4- or 5~carbamidopent-1-y1, 4-carbamido-3, 3- or =2,2- dimethylbut-1-yl.

As a C;-Csalkyl-HN-C(O)-C;-Ce¢—alkyl or (C,-Cealkyl),N-C(0O)-Ci-

Csalkyl, Rs may be linear or branched, and the NH-alkyl group preferably comprises 1 to 4 C atoms and the alkyl group preferably 2 to 6 C atoms. Examples are the carbamidoalkyl groups defined hereinabove, whose N atom is substituted with one or two methyl, ethyl, propyl or butyl.

A preferred subgroup of compounds of formula I is that in which R; is C;~-Csalkoxy or C;-Csalkoxy-C;-Csalkyloxy, R, is C;-

Cialkoxy, Rs; is Cy-Chalkyl, R4 is C;-Csalkyl and Rs is HNC (0) -

C:—Csalkyl which if necessary is N-monosubstituted or N-di-C;-

Csalkyl substituted.

A more preferred subgroup of compounds of formula I is that in which R; is methoxy-C,-C,-alkyloxy, R, is methoxy or ethoxy, Rs is C;-Csalkyl, Rs; is C,-Csalkyl and Rs is H,NC(0)-C;-

Cealkyl.

An especially preferred compound of formula I is that in which R; is 3-methoxy-prop-3-yloxy, R. is methoxy, Rs: and R, are l-methyleth-1-yl, and Rs is H,NC(O)-[C(CHs),]~CH,-.

As an alkyl, Rs may be linear or branched and comprise preferably 1 to 12 C atoms, 1 to 8 C atoms being especially : preferred. Re is particularly preferred as a linear (,-

Csalkyl. Some examples are methyl, ethyl and the isomers of . propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octacyl and eicosyl. Especially preferred are methyl and ethyl.

As a cycloalkyl, Re may preferably comprise 4 to 8 ring- carbon atoms, 5 or 6 being especially preferred. Some examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohe- ’ 5 xyl, cyclooctyl and cyclododecyl.

As a cycloalkyl-alkyl, R¢ may comprise preferably 4 to 8 ring-carbon atoms, 5 or 6 being especially preferred, and preferably 1 to 4 C atoms in the alkyl group, 1 or 2 C atoms being especially preferred. Some examples are cyclopropyl methyl, cyclobutyl methyl, cyclopentyl methyl or cyclopentyl ethyl, and cyclohexyl methyl or cyclohexyl ethyl.

As an aryl, Rg is preferably phenyl or naphthyl.

As an aralkyl, R¢ is preferably benzyl or phenyl ethyl.

In formula VII, M may be an alkaline earth metal, for example Mg, Ca or Sr. Equivalent in the context of the invention means the charge equalization of cation and anion.

M is preferably an alkali metal, for example Li, Na or K.

Particular preference is for M as Li. If M is the residue of an alcohol minus a hydroxyl group, it may be the Re group, including the embodiments and preferences described hereinbefore, in particular alkyl and cycloalkyl.

Residue A in the leaving group AO is preferably the residue of an organic acid, for example C;-Cgacyl, particular preference being for C,-Cssulfonyl. The acyl residue may be a carboxylic acid, such as formic acid, acetic acid, propionic acid, butyric acid and benzoic acid substituted if necessary " with C;-Csalkyl, C,-Cjalkoxy or halogen. The sulfonyl residue

A may correspond for example to formula R,-S0,~, wherein R, is * Ci-Cgalkyl, C;-Cghalogenalkyl, C3;-Cscycloalkyl, or phenyl or benzyl either unsubstituted or substituted with C;-C,alkyl,

Ci-Csalkoxy, Ci;-Cshakogenalkyl or halogen. Some examples of sulfonyl residues are methyl, ethyl, phenyl, methylphenyl, dimethyl phenyl, trimethyl phenyl, trifluoromethyl phenyl, chlorophenyl, dichlorophenyl, bromophenyl, dibromophenyl and trifluoromethyl sulfonyl. : 5

The individual process steps may be carried out in the presence of solvent. Suitable solvents are water and organic solvents, especially polar organic solvents, which can also be used as mixtures of at least two solvents. Examples of solvents are hydrocarbons (petroleum ether, pentane, hexane, cyclohexane, methylcyclohexane, benzene, toluene, xylene), halogenated hydrocarbon (dichloromethane, chloroform, tetrachloroethane, chlorobenzene) : ether (diethyl ether, dibutyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl or diethyl ether); carbonic esters and lactones (methyl acetate, ethyl acetate, methyl propionate, valerolactone); N,N-substituted carboxamides and lactams (dimethylformamide, dimethylacetamide, N-methylpyrrolidone); ketones (acetone, methylisobutylketone, cyclohexanone) ; sulfoxides and sulfones (dimethylsulfoxide, dimethylsulfone, tetramethylene sulfone); alcohols (methanol, ethanol, n- or i-propanol, n-, i- or t-butanol, pentanol, hexanol, cyclohexanol, cyclohexanediol, hydroxymethyl or dihydroxymethyl cyclohexane, benzyl alcohol, ethylene glycol, diethylene glycol, propanediol, butanediol, ethylene glycol monomethyl or monoethyl ether, and diethylene glycol monomethyl or monoethyl ether; nitriles (acetonitrile, propionitrile); tertiary amines (trimethylamine, triethylamine, tripropylamine and tributylamine, pyridine,

N-methylpyrrolidine, N-methylpiperazine, N-methylmorpholine) and organic acids (acetic acid, formic acid).

Process step a) . The reaction of compounds of formula II to form compounds of formula ITI with a compound RsNH, by opening of the lactone ring can be carried out with or without solvent. The reaction is expediently carried out in the presence of alcohols or amines, which can form activated carbonic esters ‘ or carboxamides. Such compounds are well-known. These may be 2-hydroxypyridine, N-hydroxycarboxamides and imides, and ) 5 carboximides (N-hydroxysuccinimide). Organic solvents are used as solvent, tertiary amines being of advantage, for example trimethylamine or triethylamine. The reaction temperature may range for example from approximately 40°C to 150°C and preferably from 50°C to 120°C.

Process step b)

Reduction of the azide group to the amine group in the compounds of formula III takes place in a manner known per se (see Chemical Reviews, Vol. 88 (1988), pages 298 to 317), for example using metal hydrides or more expediently using a catalytic method with hydrogen in the presence of homogeneous (Wilkinson catalyst) or heterogeneous catalysts, for example Raney nickel or precious metal catalysts such as platinum or palladium, if necessary on substrates such as carbon. The hydrogenation can also be carried out if necessary catalytically under phase transfer conditions, for example with ammonium formate as hydrogen donor. It is of advantage to use organic solvents. The reaction temperature may range for example from approximately 0°C to 200°C and preferably from 10°C to 100°C. Hydrogenation may be carried out at normal pressure or increased pressure up to 100 bar, for example, and preferably up to 50 bar.

The compounds of formula I may be converted to addition salts in a manner known per se by treatment with monobasic or polybasic, inorganic or organic acids. Hemifumarates are : preferred. - Process step cl)

Suitable chlorination, bromination and iodination agents are elemental bromine and iodine, in particular N-chlorine,

N-bromine and N-iodocarboxamides and dicarboximides.

Preferred are N-chloro, N-bromo and N-iodophthalimide and ' especially chloro, N-bromo and N-iodosuccinimide, as well as tertiary butyl hypochlorite and N-halogenated sulfonamides : 5 and sulfonimides, for example chloramine T. The reaction is advantageously carried out in organic solvents miscible with water, such as tetrahydrofuran or dioxane in the presence of at least an equivalent volume of water. The reaction takes place first at low temperatures, for example -20 to 10°C, and then at elevated temperatures, for example 30 to 100°C.

The presence of inorganic or organic acids may be advantageous. Suitable acids are for example formic acid, acetic acid, methanesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, toluenesulfonic acid, H,SO.,

HiPO4, hydrogen halides, acid ion exchange resins, and acids immobilized on solid carriers. The halclactone may be isolated for example by extraction with organic solvents.

Process step c2)

Suitable chlorination, bromination and iodination agents are elemental bromine and iodine, in particular N-chloro, N- bromo and N-iodocarboxamides and dicarboximides. Preferred are N-chloro, N-bromo and N-iodophthalimide and especially chloro, N-bromo and N-iodosuccinimide, as well as tertiary butyl hypochlorite and N-halogenated sulfonamides and sulfonimides, for example chloramine T. The reaction is advantageously carried out in organic solvents, such as halogenated hydrocarbons (chloroform, dichloromethane). The reaction temperature may range for example from approximately -70°C to ambient temperature and preferably from -30°C to 10°C. The halolactone may be isolated for : example by extraction with organic solvents. - Suitable salts of carboxylic acids of formula V are for example alkali metal or alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, as well as ammonium salts. The ammonium salts may derive from ammonia, primary, secondary or tertiary amines, or they may ‘ be quaternary ammonium salts. The amines may be acyclic or cyclic and comprise heteroatoms from the 0 and S group. The : 5 amines may comprise 1 to 18 C atoms, 1 to 12 being preferred and 1 to 8 especially preferred. Quaternary ammonium salts may comprise 4 to 18 C atoms, 4 to 12 being preferred and 4 to 8 especially preferred. Some examples of amines are methylamine, dimethylamine, triethylamine, ethylamine, diethylamine, triethylamine, propylamine, dipropylamine,

Tripropylamine, isopropylamine, butylamine, dibutylamine, tributylamine, phenylamine, methylethylamine, methyldiethylamine, phenylmethylamine, benzylamine, cyclo- pentylamine, cyclohexylamine, piperidine, N-methyl- piperidine, morpholine, pyrrolidine, and 2-phenylethylamine.

Salt formation allows a more efficient purification of the carboxylic acids of formula V with regard to their optical and chemical purity, especially when crystalline salts are formed with the selection of amines. The salts may be converted before the reaction to the carboxylic acids of formula V. However, the salts may also be used directly for halolactonization. In this case, the addition of acids, for example trifluoroacetic acid or other strong acids, is recommended, as described under process step cl).

The halolactonization 1s surprisingly stereoselective, and the desired cis-halolactones are formed in yields of up to 90% or more. . 30° Process step d)

The reaction of a compound of formula VI with at least ) equimolar quantities of alkali or alkaline earth metal hydroxides is expediently carried out in a polar organic solvent, for example alcohols such as isopropanol, and at low temperatures of, for example, -20 to 30°C. Aqueous solutions of hydroxides are preferably used, lithium hydroxide being especially preferred. The compound of formula VII does not need to be isolated, but the reaction mixture can be used directly in process step e). The desired ’ 5 stereoisomer is also formed in this step at high yields of up to 90% or more.

The reaction of a compound of formula VI with at least equimolar quantities of an alcohol, especially a C;-Cgalkanol and in particular methanol or ethanol, is expediently carried out in a polar organic solvent, for example ethers or the alkanols used for esterification, and at low temperatures of, for example -20 to 30°C. Bases are preferably used as well, for example alkali metal hydrogencarbonates or alkali metal carbonates, potassium hydrogencarbonate being especially preferred. The compound of formula VII does not need to be isolated, but the reaction mixture can be used directly in process step e).

The desired stereoisomer is also formed in this reaction at high yields of up to 90% or more.

Process step e)

Lactonization of the compounds of formula VII to form compounds of formula VIII is expediently carried out at a temperature of -20 to 50°C and in the presence of a preferably polar solvent, such as an alcohol (isopropanol) or ether (tetrahydrofuran, dioxane). It is advantageous to use inorganic acids, especially mineral acids such as hydrochloric acid, hydrobromic acid or sulfuric acid. The hydroxylactone of formula VII may be isolated for example by extraction with organic solvents. The desired stereoisomer ' is also formed in this step at high yields of up to 90% or more.

Process step f)

Conversion of the hydroxy group to a leaving group may be carried out in organic solvents, preferably polar organic solvents, and at temperatures of -20 to 50°C. Acid ) S halogenides, such as acid chlorides and acid bromides, are preferably used as reagents. Sulfonyl chlorides or bromides are especially preferred. The reaction is advantageously carried out in the presence of equivalent quantities of a base for bonding of the acid. Suitable bases are in particular tertiary amines, such as trimethylamine or triethylamine and dimethylaminopyridine. The hydroxylactone of a compound of formula VII may be isolated for example by extraction with organic solvents. The yields are up to 90% or more.

Process step 9g)

Suitable azidation agents are for example metal azides, especially alkaline earth metal azides and alkali metal azides, as well as silyl azides. Especially preferred azidation agents are lithium azide, sodium azide and potassium azide. The reaction may be carried out in organic solvents, such as 1,3-dinethyl-3,4,5, 6-tetrahydro-2 (1H) - pyrimidinone (DMPU) , dimethylacetamide (DMA) , N- methylpyrrolidone (NMP), dimethylformamide {DMF) , 1, 3- dimethylimidazolidinone (DMI), toluene or methylcyclohexane.

The reaction temperature may range for example from approximately 20°C to 150°C and preferably from 50°C to 120°C. It may be expedient to include the use of phase transfer catalysts. The preparation and synthetic use of azides are described for example by E. F. V. Scriven in

Chemical Reviews, Vol. 88 (1988), pages 298 to 317 The : yield amounts to an outstanding 70% or more. i} In one variant, the introduction of the leaving group in process step f) and the azidation in process step g) may be carried out simultaneously in one reaction vessel.

Process step h)

In one variant, the azidation may also be carried out directly with the hydroxyl compound of formula VIII. This ' 5 reaction has been described by David. IL. Hughes in Organic

Preparations and Procedures Int. (1996), 28 (2), pp. 127-164 and by M. C. Viaud et al. in Synthesis (1990), pp. 130 to 131. The azidation is carried out with at least equimolar quantities of zinc azide/bis-pyridine in the presence of, for example, triphenylphosphine in guantities of 2 equivalents or more, and approximately equal quantities of an azodicarboxylate such as azodiisopropylcarboxylate. The reaction is carried out in an organic solvent, especially an aromatic hydrocarbon, such as benzene, toluene or xylene.

The reaction temperature may be -20 to 80°C.

Some intermediates prepared using the process according to the invention are new and represent further objects of the invention.

A further object of the invention is thus a compound of formula X, 0] 0

R, OR,

R, (X), wherein k R; and R:; are, independently of one another, H, Ci1-Cealkyl,

Ci-Cé¢halogenalkyl, C;-Cgalkoxy, C;-Cealkoxy-Ci-Cealkyl, or Ci-

Cealkoxy-C;-Cealkyloxy, Rs is C;-Cealkyl, Ry; is C1-Cealkyl, and

Rs 1s Ci-Cealkyl, C;-Céhydroxyalkyl, Ci-Cealkoxy-Ci=Cs-alkyl,

Ci-Cealkanoyloxy-C;-Cealkyl, C;-Ceaminoalkyl, C;-Cesalkylamino-

C,-C¢~alkyl, Ci-Ce¢—dialkylamino-C;-C¢-alkyl, Ci-Cs—alkanoyl-

amido-C;~Ce-alkyl, HO (0) C-C;-Cs~alkyl, C1-Csalkyl-0~ (0) C~-Cyi—

Cealkyl, HN-C(0O)-Ci-Cealkyl, C;-Csalkyl-HN-C(0O)-C;-Csalkyl or (C1~Csalkyl) N-C (0) -C1-Cs~alkyl, and

Rg is hydrogen or RgO is a leaving group. : 5

For residues R;, R;, R;, and Ry; in compounds of formula X, the embodiments and preferences described hereinbefore apply.

A further object of the invention is a compound of formula

X11,

R X

R, ° (XI), wherein

X is halogen and Ry is a residue of formula lo}

Fo! “e, and

R; and R;, are, independently of one another, H, Ci~-Cealkyl,

C;-Céhalogenalkyl, Ci -Cealkoxy, C;-Cealkoxy-C,-Cealkyl, or C;-

Cealkoxy-C,-Cealkyloxy, Rs is C;-Cealkyl, R; is C,-Cealkyl, and

Rs is Ci—-Csalkyl ’ C.1-Cshydroxyal kyl ’ C1-Cesalkoxy-C,-Cs—al kyl ’

Ci-Csalkanoyloxy-Ci-Csalkyl, C;~Ceaminoalkyl, C;-Cealkylamino-

Cy-C¢~alkyl, Ci—-Ce¢—dialkylamino-C;~-Cs-alkyl, Ci-Ce—-alkanoyl- amido-C;-Ce¢—alkyl, HG (0) C~Cy-Ce~alkyl, Ci-Cealkyl-0-(0)C-C;~ . Csalkyl, H,N-C (0) -Cy~-Csalkyl, C;-Cealkyl-HN-C (0) -C;-Csalkyl or (C1—-Csalkyl) 2N-C (0) ~Ci—Ce—alkyl .

For ‘residues Ri, R;, Rs, and Ry, as well as for X, in compounds of formula XI, the embodiments and preferences described hereinbefore apply.

Claims

What is claimed is:

] 1. Process for preparation of compounds of formula I, OH R, R, H—r, rR, R, NH, lo! (I), wherein R: and R: are, independently of one another, H, C;-Cg¢alkyl, Ci—-Céhalogenalkyl, C;—-Cesalkoxy, Ci—-Cealkoxy-C,;-Cealkyl, or C;— Cealkoxy-Ci~Cgsalkyloxy, Rs is C;-Cealkyl, Rs is C;-Csalkyl, and Rs is Ci-Cealkyl, C;-Céhydroxyalkyl, C;-Csalkoxy-Ci-Ce—alkyl, Ci-Cesalkanoyloxy-C,—Cgalkyl, C,-Ceaminoalkyl, C;-Cealkylamino- C1-Ce—~alkyl, Ci-Ce¢-dialkylamino-C,-Ce—alkyl, C1—Ce— alkanoylamido~C;-Cs-alkyl, HO (0) C-C,-Cg—alkyl, C1-Cealkyl-0- {0)C-Ci-Csalkyl, H,N-C (0) ~C;-Cealkyl, C1~Cgalkyl-HN-C (QO) -Cq- Cealkyl or (C;-Cealkyl): N-C(0)-Ci-Ce-alkyl, a) by reacting a compound of formula II, lo) o) R oy, 1 "R, R, N, R, (IT), with an amine of formula Rs-NH, to form a compound of formula 111, OH R, H R, N—R; ry R, (III),

and b) by reducing the azide group of the compound of formula ’ III to the amine group and isolating the compounds of formula I, if necessary with the addition of a salt-forming acid, comprising the preparation of compounds of formula II by cl) reacting a compound of formula IV, Ry R, lo] R; (IV),

wherein Re is C;-Cpoalkyl, Cs-Ciscycloalkyl, Cs—Ci.cycloalkyl- Ci—-Cgalkyl, Ce—Cioaryl or Ce~Cro—aryl-C;~Csalkyil, with a halogenation agent to form a compound of formula VI, or c2) reacting a carboxylic acid of formula V, or a salt of this carboxylic acid, R, Ry lo] R, (Vv), with a halogenation agent to form a compound of formula VI,

o o R, $ , R, N R, (VI), ) wherein X is Cl, Br or I,

d) reacting the compound of formula VI in the presence of an alkali metal or alkaline earth metal hydroxide or an alcohol to form a compound of formula VII, H © H R, R, 3 oM R, lo} R, (VII), wherein M is an alkali metal, an equivalent alkaline earth metal or the residue of an alcohol minus a hydroxyl group, e) hydrolysing the compound of formula VII in the presence of an acid to form a compound of formula VIII, lo] 0 R, ‘a, H Rs R, OH R; (VIII), f) substituting the hydrogen atom of the hydroxyl group in the compound of formula VIII and converting it to a leaving group AO to form compounds of formula IX, o 0 R, “uy, : Ry R, OA R, (IX), : 20 g) and then reacting the compound of formula IX with an azidation agent to form a compound of formula II, or : h) reacting the compound of formula VIII directly with a zinc azide/-bis-pyridine complex in the presence of a

J 42 J tertiary phosphine and an azodicarboxylate, if necessary in an organic solvent, to form a compound of formula II.
2. A process according to claim 1 comprising an embodiment ‘ 5 wherein R; is C;-Cjalkoxy or C;-Csalkoxy-Ci-Csalkyloxy, R, is C;-Cqalkoxy, Rs 1s C;-Csalkyl, Ry 1s C;-Csalkyl and Rs is HNC (0) -C1-Csalkyl which if necessary is N-monosubstituted or N-di-C;-C,alkyl substituted.
3. A process according to claim 2 comprising an embodiment wherein R; is l-methoxyprop-3-yloxy and R; is methoxy.
4. A process according to claim 2 comprising an embodiment wherein Rs and Ry are in each case isopropyl.
5. A process according to claim 2 comprising an embodiment wherein Rs is H,NC(0)-C;-Csalkyl.
6. A process according to claim 1 comprising -an embodiment wherein R; is methoxy-C.~Csalkyloxy, R; is methoxy or ethoxy, R3 is C;—-Cjyalkyl, Rs is C»-Csalkyl and Rs is H,NC(0)-C;-Cealkyl.
7. A process according to claim 1 comprising an embodiment wherein R; is 3-methoxy-prop-3-yloxy, R; is methoxy, Rs and R, are each l-methyleth-1-yl, and Rs is H,NC(O)-[C(CHs),]-CH,—.
8. Compounds of formula X, o 0 R "vy, 1 x ‘R, R, OR, R, (X), ’ 30 wherein

R; and R; are, independently of one another, H, C;-Csalkyl, Ci-Céhalogenalkyl, Ci-Csalkoxy, C;-Cealkoxy-C;-Cgalkyl, or Ci- Cesalkoxy-Ci—-Csalkyloxy, Rs 1s C;-Ceéalkyl, Ry, is C;-Cealkyl, and Rs is Ci;-Cealkyl, C;-Cshydroxyalkyl, Ci-Cesalkoxy-Ci-Cs-alkyl, ) 5 Ci-Cealkanoyloxy-Ci-Cealkyl, C,-Cgaminoalkyl, C,-Cgalkylamino- C1-Ce—alkyl, Ci-Ce¢-dialkylamino-C;-Ce¢—alkyl, C1-Ce— alkanoylamido-C;-Ce-alkyl, HO (0) C-Cy-Cs~alkyl, C,-Csalkyl—-0O~ (0) C-C1-Cgalkyl, H,N-C (0) -C,-Cgalkyl, Ci1—Cealkyl—-HN-C (0) -Ci~ Cealkyl or (C;~Csalkyl),N-C(0)-C;—Ce-alkyl, and Rg is hydrogen or RsO is a leaving group.
9. Compounds of formula XI, R, Rg Trry R, (XI), wherein X is halogen and Ry is a residue of formula 0} 0 and R; and R; are, independently of one another, H, C:-Ceéalkyl, Ci-Céhalogenalkyl, C;-Csalkoxy, C;-Cesalkoxy-C;-Csalkyl, or C,;- Cealkoxy-Ci~Csalkyloxy, Rs is C;-Cealkyl, Ry is C;-Cgalkyl, and Rs is C;-Csalkyl, C;-Cghydroxyalkyl, Ci-Cealkoxy-C;-Cs-alkyl, Ci-Cesalkanoyloxy-C;-Cgalkyl, C;-Ceaminoalkyl, C;-Cgsalkylamino- , Ci-Ces—alkyl, Cy-Cs-dialkylamino-C,~Ce~alkyl, Ci1~Cg~ alkanoylamido-C;-Cs—alkyl, HO (0) C-C;-Ce~alkyl, Ci-Cealkyl-0- . (0O)C-C;-Csalkyl, H,N-C (0) -C;-Cealkyl, C1-Cealkyl-HN-C (0) -C,- Csalkyl or (Ci-Csalkyl),N-C(0)-C;-Ce¢—alkyl.
43/A
11. A process according to claim 1, substantially as herein described and exemplified.
12. Compounds according to any one of claims 8 — 10, substantially as herein described and exemplified. AMENDED SHEET