NO177566B - New 1,3-dioxane derivatives - Google Patents

Description

The present invention relates to hitherto unknown intermediates for use in the method according to divisional patent application no. 94.1725.

US Patent No. 4,647,576, the contents of which are considered to form part of the present disclosure, deals with certain trans-6-[2-(substituted-pyrrol-1-yl)alkyl]-pyran-2-ones.

US Patent No. 4,681,893, the contents of which are considered to form part of the present disclosure, relates to certain trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4- hydroxy-pyran-2-ones.

The compounds described in the above-mentioned US patents are useful as inhibitors of the enzyme 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase) and are thus useful hypolipidemic and hypocholesterolemic agents. Particularly valuable as hypolipidemic and hypocholesterolemic agents are trans(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo -2H-pyran-2-yl)-ethyl]-1H-pyrrole-3-carboxamide and (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1 -[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide. The above compounds have been prepared by a linear synthetic route, which made use of two reactions carried out at low temperatures (-78°C) under carefully controlled conditions. The two reactions involved addition of the dianion of ethyl acetoacetate to an aldehyde and reduction of the hydroxyketone produced by this reaction with sodium borohydride and a trialkylborane. Although these reactions provide the desired target compounds in high diastereomeric excess, they are difficult to perform on a large scale, and they use expensive reagents that are difficult to handle. They also do not produce enantiomerically pure products. The materials produced by the previous methods can be separated into enantiomerically pure products, but the process is very expensive and time-consuming, and it results in the loss of more than 50% of the starting material.

It has unexpectedly been found that the particularly valuable hypolipidemic and hypocholesterolemic agents trans(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy -6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide and (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4- diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide can be prepared from a hitherto unknown intermediate by means of fewer steps and with higher yields than with the previous methods. In addition, the method according to application 94.1725 is based on cheap starting materials and is applicable for synthesis on a large scale.

Accordingly, a first aspect of application 94,1725 is an improved method for preparing a compound with

formula I

and a dihydroxy acid and pharmaceutically acceptable salts thereof corresponding to the open lactone ring of a compound of formula I,

where R1 is

1- naphthyl,

2- naphthyl,

phenyl, or

phenyl substituted with

fluoride,

chlorine, or

bromine,

R2 or R3 are independent of each other

hydrogen,

phenyl, or

-CONhV where R6 is fenv1'

R4 is alkyl of one to six carbon atoms,

which method includes that one:

(a) reacts 1,6-heptadien-4-ol with

(1) alkyl lithium

(2) followed by iodine and carbon dioxide and (3) treating the resulting iodocarbonate intermediate in situ with a base in an aqueous alcohol at ca. 0°C to approx. 40°C to obtain a compound of formula IX,

(b) treating the compound of formula IX with (1) an alkali metal cyanide at ca. 0°C to approx. 40°C and

(2) reacting the resulting diol intermediate in situ with a ketal-forming reagent in the presence of an acid to obtain a compound of formula

VIII

where R? and Rg independently of each other are hydrogen, alkyl of one to three carbon atoms, phenyl or <R>_ and <R>_ together form -(CH_) -, lo 2 n where n is 4 or 5, (c) treating the compound with formula VIII with (1) ozone in an inert solvent and (2) reacting the resulting intermediate in situ with oxygen and triphenylphosphine at ca. -20°C to approx. -78°C to obtain a compound of formula VII

where R? and RQ is defined as above,

(d) treating the compound of formula VII with an oxidizing reagent at ca. 0°C to obtain a compound of formula VI

where R7 and Rg are as defined above,

(e) treating the compound of formula VI with a compound of formula

Hal-R9a

wherein Hal is halogen and RQa is alkyl of one to eight carbon atoms or a three- to six-membered cycloalkyl group, in the presence of a base to obtain a

connection with formula

where R_, RQ and Rn are as defined above,

7 8 9a

or treating the compound of formula VI with a compound of formula

wherein Rgb is tertiary butyl, tertiary amyl or α,α-dimethylbenzyl, in the presence of an activating agent, a catalytic amount of a base and an inert solvent to obtain a compound of formula V, b

where R?, Rg and Rgb are as defined above,

(f) treating the compound of formula V 3. with hydrogen in the presence of a catalyst and an acid at approx. 0°C to approx. 70°C to obtain a compound of formula IVa

where R?, Rg and Rga are as defined above,

or treating the compound of formula V.b with hydrogen in the presence of a catalyst and an acid or a catalyst and a base at approx. 0°C to approx. 70°C to obtain a compound of formula IV^

where R7, Rg and Rgfa are as defined above,

(g) treating the compound of formula IV with a compound of formula III

where R 1 , R 2 , R 3 and R 4 are as defined above in an inert solvent to obtain a compound of formula II

cl

where Rlf R2, <R>3,<R>4, R?, <R>8 and Rga are as defined above,

or treating the compound of formula IV, b with a compound of formula III in an inert solvent to obtain a compound of formula II,

b

where R1, R2, R3, R4, R?, Rg and Rgfa are as defined above,

(h) and finally treating a compound of formula IIa with (1) an acid in the presence of an inert solvent

(2) followed by hydrolysis with a base

(3) followed by neutralization with an acid and (4) dissolving and/or heating in an inert solvent with simultaneous removal of water to obtain a compound of formula I, or treating a compound of formula II with (1) an acid in presence of an inert solvent

(2) followed by the addition of a base

(3) followed by neutralization with an acid and (4) dissolution and/or heating in an inert solvent with simultaneous removal of

water to obtain a compound of formula I, (i) and, if desired, converts the resulting compound of formula I into a dihydroxy acid corresponding to the opened lactone ring of structural formula I by means of conventional hydrolysis and further, if desired, converts the dihydroxy acid into a corresponding pharmaceutical ceutically acceptable salt in a conventional manner, and if desired converts the pharmaceutically acceptable salt into a dihydroxy acid in a conventional manner and if desired converts the dihydroxy acid into a compound.

with formula I by heating in an inert solvent.

Another aspect of application 94.1725 is a hitherto unknown intermediate of formula II

where Rg is alkyl with one to eight carbon atoms, a three- to six-membered cycloalkyl group or α,α-dimethylbenzyl, and R2, R3, R4, R7 and Rg are as defined above, which is useful in the preparation of cholesterol biosynthesis inhibitors of formula I. A first aspect of the present invention is a hitherto unknown intermediate of formula IV

where R7, Rg and Rg are as defined above, which is useful in the preparation of a compound of formula II, which in turn is useful in the preparation of

cholesterol biosynthesis inhibitors of formula I.

Another aspect of the present invention is a hitherto unknown intermediate of formula V

where R_, RQ and RQ are as defined above, which is useful in the preparation of a compound of formula IV, which in turn is useful in the preparation of a compound of formula II, which in turn is useful in the preparation of cholesterol biosynthesis inhibitors of formula IN.

A third aspect of the present invention is a hitherto unknown intermediate of formula VI

where R7 and Rg are as defined above, which is useful in the preparation of a compound of formula V, which in turn is useful in the preparation of a compound of formula IV, which in turn is useful in the preparation of a compound of formula II , which in turn is useful in the preparation of cholesterol biosynthesis inhibitors of formula I. A fourth aspect of the present invention is a hitherto unknown intermediate of formula VII

where R7 and Rg are as defined above, which is useful in the preparation of a compound of formula VI, which in turn is useful in the preparation of a compound of formula V, which in turn is useful in the preparation of a compound of formula IV , which in turn is useful in the preparation of a compound of formula II, which in turn is useful in the preparation of cholesterol biosynthesis inhibitors of formula I.

A fifth aspect of the present invention is a hitherto unknown intermediate of formula VIII wherein R? and Rg is as defined above, which is useful in the preparation of a compound of formula VII, which in turn is useful in the preparation of a compound of formula VI, which in turn is useful in the preparation of a compound of formula V, which in turn is useful in the preparation of a compound of formula IV, which in turn is useful in the preparation of a compound of formula II, which in turn is useful in the preparation of

cholesterol biosynthesis inhibitors of formula I.

In the present invention, the term "alkyl" means a straight-chain or branched hydrocarbon group, having from one to eight carbon atoms, and which includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary-butyl, n- pentyl, tertiary-amyl, n-hexyl, n-heptyl, n-octyl and the like.

"Cycloalkyl" refers to a three- or six-membered saturated hydrocarbon ring and includes, for example, cyclobutyl, cyclopentyl, cyclohexyl and the like.

"Alkoxy" is O-alkyl, where alkyl is as defined above.

"Alkanoyloxy" is an alkyl group as defined above, attached to a carbonyl group and thence through an oxygen atom to the molecular parent residue.

"Carboalkoxy" is an alkyl group as defined above, bound to an oxygen atom and from there through a carbonyl group to the molecular parent residue.

"Norbornenyl" is a group derived by the removal of a hydrogen atom (but not from a bridgehead carbon atom) from bicyclo-[2.2.1]hept-2-ene.

"Halogen" is iodine, bromine and chlorine.

"Alkalimeta11" is a metal in group IA of the periodic table

system and includes, for example, lithium, sodium, potassium and the like.

"Alkaline earth metal" is a metal in group IIA in the periodic table and includes, for example, calcium, barium, strontium and the like.

"Precious metal" is platinum, palladium, rhodium, ruthenium and the like.

Particularly preferred compounds of formula I prepared by means of the improved process according to application 94.1725 are the following: trans-6-[2-[2-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrrol-1-yl]ethyl ]tetrahydro-4-hydroxy-2H-pyran-2-one,

trans-6[2-[2-(4-fluorophenyl)-5-methyl-1H-pyrrol-1-y1]ethyl]-tetrahydro-4-hydroxy-2H-pyran-2-one,

trans-6-[2-[2-(4-fluorophenyl)-5-(1-methylethyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one,

trans-6-[2-[2-cyclopropyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one,

trans-6-[2-[2-(1,1-dimethylethyl)-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]tetrahydro-4-hydroxy-2H-pyran-2-one,

trans-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxyphenyl)-5-methyl-1H-pyrrol-1-yl]ethyl]-2H-2-one,

trans-tetrahydro-4-hydroxy-6-[2-[2-(2-methoxyphenyl)-5-(1-methylethyl)-1H-pyrro1-1-yl]ethyl]-2H-pyran-2-one,

trans-tetrahydro-4-hydroxy-6-[2-[2-methyl-5-(1-naphthaleny1)-1H-pyrro1-1-y1]ethy1]-2H-pyran-2-one,

trans-6-[2-(2-bicyclo[2,2,1]hept-5-en-2-yl-5-methyl-1H-pyrrol-1-yl)ethyl]tetrahydro-4-hydroxy-2H- pyran-2-one,

trans(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl1-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl )ethyl]-1H-pyrrole-3-carboxamide,

(2R)-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2 -yl)ethyl]-1H-pyrrole-3-carboxamide,

trans-2-(4-fluorophenyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-5-trifluoromethyl-1H-pyrrole -3-carboxamide,

trans-5-(4-fluorophenyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-2-trifluoromethyl-1H-pyrrole -3-carboxamide and

a dihydroxy acid and pharmaceutically acceptable salts thereof corresponding to the open lactone ring of compounds of structural formula I.

As described above, the compounds of formula I are useful as inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG CoA reductase) and are thus useful as hypolipidemic or hypocholesterolemic agents.

The process of application 94.1725 is, in its first aspect, a new, improved, economically and commercially feasible process for the preparation of HMG CoA reductase inhibitors of formula I. The process of application 94.1725, in its first aspect, is outlined in Scheme I:

A compound of formula IX is prepared from the known 1,6-heptadien-4-ol (XI) using the method described by Bongini, A., et al, Journal of Organic Chemistry. 47, pp. 4626-4633 (1982) and Majewski, M., et al, Tetrahedron Letters, 25, pp. 2101-2104 (1984). thus the homoallylic alcohol (XI) is reacted with an alkyllithium such as n-butyllithium followed by iodine and carbon dioxide to obtain iodocarbonate (X) at -35°C to -20°C, which is not isolated but treated in situ with a base, such as an alkali or alkaline earth metal hydroxide or carbonate, for example sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate and the like in an aqueous alcohol with one to three carbon atoms such as methanol, ethanol, isopropanol and the like at approx. 0°C to approx. 40°C to obtain the epoxide of formula IX. The reaction is preferably carried out with potassium carbonate in aqueous methanol at approx. 0°C to approx. 40°C, preferably 0°C. The epoxy ring of formula IX is opened with either potassium or sodium cyanide in an aqueous alcohol, such as methanol, ethanol, tertiary butanol, isopropanol and the like at approx. 0°C to approx. 40°C. The reaction is preferably carried out with potassium cyanide in aqueous isopropanol at approx. 25°C. The resulting diol intermediate is not isolated, but is treated in situ with a ketal-forming reagent such as acetone, dimethoxypropane, 2-methoxypropene, benzaldehyde, cyclopentane, cyclohexanone, 1,1-dimethoxycyclopentane, 1,1-dimethoxycyclohexane and the like in the presence of an acid which for example camphorsulfonic acid, para-toluenesulfonic acid and the like in the presence of an excess of reagent or in an inert solvent such as dichloromethane and the like at approx. 0°C to the reflux temperature of the reagent or solvent to obtain a compound of formula VIII, wherein R_ and R_ are independently hydrogen, alkyl of one to three carbon atoms,

phenyl or R_ and R_ together are -(CH_) -, where n is 4 or 5.

/ o zn

A compound of formula VIII is treated with ozone in an inert solvent such as dichloromethane and the like, and the resulting intermediate ozonide, which is not isolated, is flushed in situ with oxygen to remove the ozone and then treated with triphenylphosphine or dimethyl sulfide at about -20°C to approx. -78°C, preferably approx. -78°C to obtain a compound of formula VII, where R_ / and Ro_ are as defined above. A compound of formula VII is treated with an oxidizing agent such as chromium trioxide-sulfuric acid-water and the like at approx. 0°C to obtain a compound of formula VI, where R7 and RQ are as defined above. A compound of formula VI is treated with a compound of formula

where Hal is halogen such as iodine, chlorine, bromine, and R9 _cl is alkyl with one to eight carbon atoms or a three- to six-membered cycloalkyl group, preferably isopropyl, isobutyl and the like in the presence of a base such as 1,8-diazabi -cyclo[5.4.0]undec-7-ene (DBU) and the like to obtain a compound of formula V , where R_, R_ and R_ are as above

a lo ya

defined. Furthermore, the compound of formula VI is treated with a compound of formula

where Rgk is tertiary butyl, tertiary amyl or a,ce-dimethylbenzyl in the presence of an activating agent such as dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole and the like in the presence of a base such as 4-dimethylaminopyridine and the like in an inert solvent such as for example dichloromethane, tetrahydrofuran and the like to obtain a compound of formula Vfa, where R 7 , R 8 and R 1 are as defined above. A compound of formula V is treated with hydrogen in the presence of a catalyst such as a noble metal, for example platinum, palladium, rhodium, ruthenium, derivatives thereof and the like, or Raney nickel, preferably platinum dioxide, and an acid such as acetic acid, by about. 0°C to approx. 70°C and a pressure of approx. 14 to 100 pounds per square inch to obtain a compound of formula IV, where R?/Rg and RQa are as above defined. Further, a compound of formula V^ is treated with hydrogen in the presence of a catalyst such as a noble metal, for example platinum, palladium, rhodium, ruthenium, derivatives thereof and the like, and an acid such as for example acetic acid, propanoic acid and the like or a catalyst which for example Raney nickel, Raney cobalt and the like in an inert solvent such as methanol, ethanol, isopropanol, tetrahydrofuran and the like, saturated with anhydrous ammonia or saturated with aqueous ammonium hydroxide or aqueous sodium hydroxide, preferably the reaction is carried out with Raney nickel in methanol saturated with anhydrous ammonia at approx. 0°C to approx. 70°C and a pressure of approx. 14 to approx. 100 pounds per square inch to obtain a compound of formula IV^, where R?, Rg and Rgb are as defined above. Raney nickel and Raney cobalt as described above are finely divided forms of nickel and cobalt. A compound of formula XXI is prepared by treating a compound of formula VI where R7 and Rg are as defined above, with hydrogen in the presence of a catalyst such as Raney nickel, Raney cobalt and the like in finely divided form in an inert solvent such as methanol, ethanol, isopropanol, tetrahydrofuran and the like, saturated with anhydrous ammonia or saturated with aqueous ammonium hydroxide solution or a catalyst such as platinum, palladium or the like in an inert solvent such as methanol, ethanol, isopropanol, tetrahydrofuran and the like in the presence of an acid such as acetic acid, propanoic acid and the like at approx. . 0°C to approx. 70°C and a pressure of approx. 14 to approx. 100 pounds per square inch to obtain a compound of formula XXI. A compound of formula XXIII is prepared from a for bond of formula XXV where R7 and Rg are as defined above, using the previously described method for preparing a compound of formula XXI from a compound of formula VI. A compound of formula XXV is prepared by treating a compound of formula VI

where R_ and RQ are as defined above, and tertiary butyl alcohol with a coupling reagent such as

dicyclohexylcarbodiimide and the like in the presence of a base such as 4-dimethylaminopyridine and the like in an inert solvent such as dichloromethane and the like to obtain a compound of formula XXV.

An optically active (R) compound of formula XXIII a is prepared as outlined in Scheme II. The starting material (R)-4-cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butanoic acid of formula XXIX is synthesized starting from isoascorbic acid using syntheses that are well known to those skilled in the art. This chemistry is identical to that described in U.S. Patent No. 4,611,067 (Merck & Co. Inc.), which is considered part of the present specification, using ascorbic acid to produce (S)-4 -cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-butanoic acid.

"'"US Patent No. 4,611,067 obviously incorrectly added the configuration R to the product of this reaction sequence starting with ascorbic acid.

Thus, the optically active compounds are prepared from the known isoascorbic acid using the method described by Volante R.P. et al, in US Patent No. 4,611,067, but in that case by starting with ascorbic acid. They establish this in formula XXV a and formula XXIIIa, as R desired optically active centers. Thus (R)-4-cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butanoic acid of formula XXIX is treated with carbonyldiimidazole in tetrahydrofuran at 0°C to -40°C, preferably -20°C, heated to 25°C, and the activated acid derivative is not isolated, but the solution is added to a suspension of a salt of 1,1-dimethylethylmalonic acid such as the potassium salt of 1,1-dimethylethylmalonic acid (half ester, half salt), anhydrous magnesium chloride and an amine such as, for example, diisopropylethylamine in acetonitrile at -10°C to 20<?>C, preferably at 5°C. The mixture is poured into a mixture of 1N hydrochloric acid and ethyl acetate to obtain (R)-1,1-dimethylethyl-6-cyano-5-[(1,1-dimethylethyl)dimethylsilyl]oxy-3-oxohexanoate of formula XXVIII. The ketone of formula XXVIII is treated with fluoride ion at 0°C to 65°C, preferably 25°C to obtain the (R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate of formula XXVII. The ketone of formula XXVII is treated with triethylborane and air (or methoxydiethylborane without air) followed by sodium borohydride and methanol in tetrahydrofuran at -78°C to -110°C, preferably -100°C to obtain [R-(R*,R* )]-1,1-dimethylethyl-6-cyano-3,5-hydroxyhexanoate of formula XXVI. The diol of formula XXVI is treated with a ketal-forming reagent such as acetone, dimethoxypropane, 2-methoxypropene, benzaldehyde, cyclopentanone, cyclohexanone, 1,1-dimethoxycyclopentane, 1,1-dimethoxycyclohexane and the like in the presence of an acid such as camphorsulfonic acid, para -toluenesulfonic acid and the like in the presence of an excess of reagent or in an inert solvent such as dichloromethane and the like at 0°C to the reflux temperature of the reagent or the solvent to obtain a compound of formula XXVa, where R_ / and R8_ are independently hydrogen, alkyl of one to three carbon atoms,

phenyl or R_ and RQ taken together as -(CH_) -, where n is 4

lol zn

or 5.

A compound of formula XXVa is treated with hydrogen gas in an alcohol such as methanol saturated with anhydrous ammonia or aqueous ammonium hydroxide in the presence of a catalyst such as Raney nickel or Raney cobalt or with a noble metal catalyst such as platinum oxide in the presence of an alkanoic acid such as acetic acid to obtain a compound of formula XXIII cl , where R_ / and Ro_ are as defined above.

Furthermore, an optically active compound of formula IV or formula IV can be prepared starting from the optically active epoxide of formula IX. The preparation of the optically active epoxide of formula IX is described by Kocienski, P.J., et al, Journal of the Chemical Society Perkin Transaction I. pages 2183-2187 (1987).

The procedure for the preparation of a compound of formula I is outlined in Scheme III:

A compound of formula IV or formula IV is reacted

a b

with a compound of formula III,

where is

1- naphthyl,

2- naphthyl,

phenyl, or

phenyl substituted with

fluoride,

chlorine, or

bromine,

P*2 or R3 independently of each other is

hydrogen,

phenyl, or

-CONH where Q is phenyl

OE OE

R4 is alkyl of one to six carbon atoms,

in an inert solvent such as toluene and the like at the reflux cooling temperature of the solvent to obtain a compound of formula II or formula II, ,

ab where Rx, R2, R3, R4, R?, <R>g, <Rg>a and Rgb are as defined above. Finally, a compound of formula II is treated with an acid such as aqueous hydrochloric acid and the like in an inert solvent such as tetrahydrofuran followed by hydrolysis with a base such as sodium hydroxide. The reaction is neutralized with an acid such as aqueous hydrochloric acid and dissolved and/or heated in an inert solvent such as toluene and the like with simultaneous removal of water to obtain a compound of formula I, where R 2 , R 2 , R 3 and R 4 are as above defined.

Furthermore, a compound of formula II is treated. b with an acid such as, for example, aqueous hydrochloric acid and the like in et

inert solvent such as, for example, tetrahydrofuran and the like in approx. 15 hours followed by the addition of a base such as for example sodium hydroxide and the like and stirred for approx. 30 hours. The reaction is made acidic again with an acid such as for example aqueous hydrochloric acid and dissolved and/or heated in an inert solvent such as for example toluene and the like with simultaneous removal of water to obtain a compound of formula I, where R^, R^ , R 1 and R 4 are defined as above.

In the ring-opened dihydroxy acid form, the compounds of application 94.1725 react to form salts with pharmaceutically acceptable metal and amine cations formed from organic and inorganic bases. The term "pharmaceutically acceptable metal salt" covers salts formed with sodium, potassium, calcium, magnesium, aluminum, iron and zinc ions. The term "pharmaceutically acceptable amine salt" covers salts with ammonia and organic nitrogenous bases strong enough to form salts with carboxylic acids. Bases useful in the formation of pharmaceutically acceptable non-toxic base addition salts of the compound of the present invention constitute a class, the limits of which are readily understood by those skilled in the art.

The free dihydroxy acid form of the compounds of application 94,1725 can be regenerated from the salt form, if desired, by contacting the salt with a dilute aqueous solution of an acid such as hydrochloric acid.

The ring-closed lactone form of the compounds according to application 94.1725 can be regenerated by dissolving the dihydroxy acid form of the compounds according to application 94.1725 in an inert solvent such as, for example, toluene, benzene, ethyl acetate and the like at approx. 0°C to approx. the boiling point of the solvent, usually, but not necessarily, with simultaneous removal of the resulting water and usually, but not necessarily, with a strong acid catalyst such as concentrated hydrochloric acid and the like.

The base addition salts may differ from the free acid forms of the compounds according to application 94.1725 in such physical characteristics as solubility and melting point, but are otherwise considered equivalent to the free acid form, as far as the purpose of the present invention is concerned.

The compounds according to application 94.1725 can exist in solvate or non-solvate form, and such forms are equivalent to the non-solvate forms, as far as the purposes of the present invention are concerned.

The compounds of structural formula I, above, have two asymmetric carbon centers, one at the 4-hydroxy position of the pyran-2-one ring, and the other at the 6-position of the pyran-2-one ring, where the alkylpyrrole group is attached. This asymmetry gives rise to four possible isomers, two of which are the 4R,6S and 4S,6R isomers, and the other two of which are the 4R,6R and 4S,6S isomers. The preferred isomer according to the present invention is the 4R,6R isomer of the compounds of formula I, I and XII above,

a

The following examples illustrate the preferred method for preparing the compounds according to the present application 94,1725.

EXAMPLE 1

Trans- 6- r 2- f 2- ethyl- 5- f 4- fluorophenyl)- 1H- pyrrole- 1- yl- etvll - tetrahvdrQ- 4- hvdroxy- 2H- pyran- 2- one

Step A: Preparation of ( R*. R*)- g- 2- propenyloxyranethanol

n-Butyllithium, 129 ml (200 mmol) is added dropwise to a 0°C solution of 1,6-heptadien-4-ol, 22.4 g (0.2 mol), in 200 ml anhydrous tetrahydrofuran, until the triphenylmethane indicator turns red . Carbon dioxide is then added while bubbling through for 30 minutes ("lecture" flask carbon dioxide passed through desiccant), and the pale yellow solution is stirred for 30 minutes under a balloon with carbon dioxide. To this solution is added iodine, 101.4 g (0.4 mol), dissolved in "200 ml of anhydrous tetrahydrofuran during 60 minutes. The mixture is allowed to warm to room temperature overnight, diluted with ethyl acetate, washed with 10% sodium bisulfite solution, saturated solution of sodium bicarbonate, brine and dried (magnesium sulfate). The crude product is dissolved in 200 ml of methanol and 20 ml of water, cooled to 0°C, and 0.5 g of solid potassium carbonate is added. The mixture is stirred vigorously for six hours,

filtered, concentrated and partitioned between ethyl acetate and brine. After extraction of the aqueous layer 2x with ethyl acetate, the combined organic phases are washed with salt water and dried (magnesium sulfate). Flash chromatography (4:1 hexane-ethyl acetate) gives, after concentration in vacuum, 18 g of (R*,R*)-α-2-propenyloxyranethanol.

200 MHZ NMR (CDCl 3 ) S 1.5-1.65 (m, 1H), 1.90 (dt, 1H, J = 15, 4 Hz), 2.2 (m, 3H), 2.53 (m , 1H), 2.79 (m, 1H), 3.12 (m, 1H), 3.94 (m, 1H), 5.19 (m, 2H), 5.80 (m, 1H).

IR (film) 3400, 3077, 2980, 2925, 1643, 1412, 1260, 918, 827 cm 1.

Step B: Preparation of (±)-cis-2,2-dimethyl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile.

Potassium cyanide, 1.3 g (20 mmol) is added to a solution of (R*R*)-cr-2-propeny 1 oxyranethano 1, 2.56 g (20 mmol), in 25 ml 4:1 isopropanol-water at room temperature. The solution is stirred for 20 hours at ambient temperature, concentrated and layered between ethyl acetate and salt water. The aqueous layer is extracted twice with ethyl acetate, and the combined ethyl acetate extracts are washed with brine and dried (magnesium sulfate). The crude product is dissolved in 20 ml of 2,2-dimethoxypropane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography give 1.30 g of (±)-cis-2,2-dimethyl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile.

200 MHZ NMR (CDCl 3 ) S 1.35 (m, 1H), 1.40 (s, 3H), 1.45 (s, 3H), 1.67 (m, 1H), 2.20 (m, 1H ), 2.33 (m, 1H), 2.50 (m, 2H), 3.89 (m, 1H), 4.10 (m, 1H), 5.10 (m, 2H), 5.7 -5.9 (m, 1H).

IR (film) 2995, 2944, 2255, 1644, 1334 cm"<1>.

Step C: Preparation of f±)-cis-6-(2-oxoethyl)-2,2-dimethyl-1,3-dioxane-4-acetonitrile.

A solution of (±)-cis-2,2-dimethyl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile, 3 g (15.36 mmol), in 100 ml of dichloromethane is cooled to -78 °C under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage = 90V) is then passed through a fritted gas inlet tube into the solution, until the blue color of ozone appears. The current is turned off, and oxygen is bubbled through until the blue color is removed. Triphenylphosphine, 4.2 g (16 mmol), is added and the colorless solution is allowed to warm to room temperature. lightning

chromatography gives, after concentration in vacuo, 2.5 g of pure (±)-cis-6-(2-oxoethyl)-2,2-dimethyl-1,3-dioxane-4-acetonitrile.

200 MHZ NMR (CDCl 3 ) S 1.30 (m, 1H), 1.39 (s, 3H), 1.48 (s, 3H), 1.78 (m, 1H), 2.46-2.75 (m, 4H), 4.2 (m, 1H), 4.40 (m, 1H), 9.79 (t, 1H, J = 1.6 Hz).

IR (film) 2250, 1720 cm"<1>.

Step D: Preparation of (±)-cis-6-(cyanomethyl)-2.2-dimethyl-1.3-dioxane-4-acetic acid.

Jones reagent (chromium trioxide-sulfuric acid-water), 3.8 ml (7.6 mmol), is added dropwise to a 0°C solution of (±)-cis-6-(2-oxoethyl)-2,2-dimethyl- 1,3-dioxane-4-acetonitrile, 1.50 g (7.6 mmol), dissolved in 50 ml of acetone, until the orange color is not emitted. After stirring for a further 15 minutes, the mixture is poured into 300 ml of diethyl ether and washed with salt water, until the wash water is colourless. The diethyl ether layer is dried (magnesium sulphate), filtered and concentrated to obtain 1.2 g of the acid which solidifies on standing. Trituration with isopropyl ether gives (±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid as a colorless solid,

m.p. 92-95°C.

A further trituration/recrystallization from isopropyl ether gives material with m.p. 98-103°C.

200 MHZ NMR (CDCl 3 ) S 1.35 (m, 1H), 1.42 (s, 3H), 1.49 (s, 3H), 1.82 (m, 1H), 2.4-2.7 (m, 4H), 4.18 (m, 1H), 4.35 (m, 1H).

<13>C-NMR(d6-acetone, 50 MHz) <S 19.95, 24.91, 30.17, 35.88, 41.34, 65.79, 66.35, 99.70, 117, 77, 171.83.

IR (KBr) broad OH 3500-2400, 2254, 1711, 940 cm"<1>.

Step E: Preparation of (±)-cis-1-methylethyl-6-(cyanomethyl)-2.2-dimethyl-1.3-dioxane-4-acetate.

To a solution of (±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid, 0.6 g (3 mmol), in acetonitrile, 2 ml, is added l, 8-diazabicyclo[5.4.0]-undec-7-ene (DBU), 0.45 mL (3 mmol) and 2-iodopropane, 0.33 mL (3.3 mmol). The solution is stirred overnight at room temperature, diluted with diethyl ether, washed with salt water and dried (magnesium sulfate). Flash chromatography gives 0.55 g of (±)-cis-1-methylethyl-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate. 90 MHZ NMR (CDCl 2 ) S 1.22 (d, 6H, J = 7 Hz), 1.3 (m, 1H), 1.35 (S, 3H), 1.40 (s, 3H), 1, 75 (m, 1H), 2.2-2.7 (m, 4H), 3.9-4.4 (m, 2H), 4.95 (sept, 1H, J = 7 Hz).

Step F: Preparation of (±)-cis-1-methylethyl-6-(2-aminoethyl)-2.2-dimethyl-1.3-dioxane-4-acetate.

A mixture of (±)-cis-1-methylethyl-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate, 0.55 g, in glacial acetic acid is hydrogenated with platinum dioxide at 50 pounds per square inch (PSI). Concentration, dilution with ethyl acetate and washing with bicarbonate followed by washing with brine and drying give 250 mg of (±)-cis-1-methylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4 -acetate. MS 260.1, 244.1

200 MHZ NMR (CDCl 2 ) S 1.25 (d, 6H, J = 7 Hz), 1.32 (m, 1H), 1.36 (s, 3H), 1.45 (s, 3H), 1, 60 (m, 1H), 2.33 (dd, 1H, J = 15, 6 HZ), 2.49 (dd, 1H, J = 15, 6 Hz), 2.85 (br t, 2H, J = 6

Hz), 3.40 (br s, 2H), 4.00 (m, 1H), 4.29 (m, 1H), 12.03 (sept, 1H, J = 7 Hz).

IR (film) 1734, 1387 cm"<1>.

Step G; Preparation of (±)-cis-1-methylethyl-6-f2-T2-ethyl-5-(4-fluorophenyl)-1H-pyrrole-1-v1-ethyl]-2.2-dimethyl-1.3- dioxane-4-acetate.

A solution of (±)-cis-1-methylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate, 0.15 g (0.58 mmol), and l -(4-Fluorophenyl)-1,4-hexanedione (Example A), 0.125 g (0.6 mmol), in 5 ml of toluene is stirred and heated under reflux overnight. The cooled solution is concentrated, and the highly UV-active pyrrole is separated from the starting material by preparative thin-layer chromatography, eluting 2x with 4:1 hexane-ethyl acetate. This gives 130 mg of pure (±)-cis-1-methylethyl-6-[2-[2-ethyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl- 1,3-dioxane-4-acetate.

200 MHz NMR (CDCl 3 ) δ 1.51 (m, 1H), 1.23 (d, 6H, J = 6 Hz), 1.33 (m, 9H), 1.5-1.6 (m, 3H ), 2.27 (dd, 1H, J = 15.3, 6 Hz), 2.44 (dd, 1H, J = 15.3, 6 Hz), 2.66 (q, 2H, J = 7, 5 Hz), 3.62 (m, 1H), 3.8-4.2 (m, 3H), 5.03 (sept, 1H, J = 6 Hz), 5.97 (d, 1H, J = 3.5 HZ), 6.11 (d, 1H, J = 3.5 Hz), 7.0-7.4 (m, 4H).

A solution of (±)-cis-1-methylethyl-6-[2-[2-ethyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]-2,2-dimethyl-1, 3-dioxane-4-acetate, 0.13 g (0.3 mmol), in 12 ml of 1:2 2M hydrochloric acid-tetrahydrofuran is stirred overnight at room temperature. To this is added sufficient 2M sodium hydroxide to bring the pH to 10. Stirring is continued for 30 minutes, water, 30 ml, is added and the mixture is extracted with diethyl ether. The aqueous layer is acidified with ice-cold 6N hydrochloric acid and extracted with ethyl acetate (2x). The organic phase is washed with salt water and dried (magnesium sulfate). The residue after filtration and concentration is dissolved in toluene (50 ml) and heated at reflux with azeotropic removal of water (6 hours). The cooled solution is concentrated and flash chromatographed to obtain 60 mg of trans-6-[2-[2-ethyl-5-(4-fluorophenyl)-1H-pyrrol-1-yl]ethyl]-tetrahydro-4-hydroxy-2H- pyran-2-one (elution with 2:1 hexane-ethyl acetate). 90 MHZ NMR (CDCl 3 ) S 1.25 (d, 6H, J = 7 Hz) 1.3-1.8 (m, 4H), 2.3 (br s, 1H, -0H), 2.55 ( m, 2H), 2.65 (q, 2H, J = 7Hz), 3.9-4.5 (m, 4H), 5.90 (d, 1H, J = 3.5 Hz), 6.05 (d, 1H, J = 3.5 Hz), 6.9-7.4 (m, 4H).

EXAMPLE 2

Trans-( ±)- 5-( 4- fluorophenyl)- 2-( 1- methylethyl)- N^- diphenyl- l-^-^ etrahydro^- hydroxy- e- oxo^ H- pyran^- vl) ethyl-1H-pyrrole-3-carboxamide.

METHOD OF PROCEDURE A

Step A: Preparation of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide.

A suspension of 100 kg of 4-methyl-3-oxo-N-phenylpentanamide (example B) in 660 kg of hexane is treated with shaking under nitrogen with 8 kg of β-alanine, 47 kg of benzaldehyde and 13 kg of glacial acetic acid. The resulting suspension is heated to reflux with removal of water for 20 hours, an additional 396 kg of hexane and 3 kg of glacial acetic acid are added, and reflux is continued with removal of water for one hour. The reaction mixture is cooled to 20-25°C, and the product is isolated by filtration. The product is purified by suspension in hexane at 50-60°C, cooling and filtration. The product is slurried twice with water at 20-25°C, filtered and dried in vacuum to obtain 110 kg of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide,

m.p. 143.7-154.4°C.

Vapor phase chromatography (VPC): 30 meter DB 5 capillary column 50-270°C at 15°C/min. 19.33 min, 99.7% (range).

Gas Chromatography/Mass Spectrometry (GC/MC): M/Z 293 [M]<+>.

Nuclear Magnetic Resonance (NMR): (CDCl 3 ) S 1.16 (6H, d) , 3.30 (1H, kin.), 7.09 (1H, m), 7.28 (5H, m), 7, 49 (5H, m), 8.01 (1H, brs).

Step B: Preparation of (±) 4-fluoro-a-f2-methyl-l-oxopropyl]-t-oxo-N.1f-diphenylbenzenebutanamide mixture of TR-(R*.R*) 1 . fR-( R*. S* n. rs-( R*, R* n and rS-( R*. S* n isomers).

A solution of 17.5 kg of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide in 300 1 of anhydrous ethanol is concentrated by distillation of 275 1 of ethanol. Under an argon atmosphere, 100 kg (340 mol) of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide, 47.5 1 (340 mol) of triethylamine and 40 1 (375 mol) of 4-fluorobenzaldehyde are added. The resulting solution is stirred and heated at 75-80°C for 23 hours. The product begins to form as a solid after approx. 1.5 hours, but approx. 24 hours are required for an essentially complete turnover. The slurry is dissolved in 600 1 isopropanol at 80°C. The resulting solution is cooled slowly, and the (±)4-fluoro-α-[2-methyl-1-oxopropyl]-r-oxo-N,Ø-diphenyl-benzenebutanamide mixture of [R-(R*,R<* >)], [R-(R*,S*)], [S-(R*,R*)] and [S-(R*,S<*>)] isomers are isolated by filtration. Washing the precipitate with isopropanol and drying in vacuo gave 99 kg of (±)4-fluoro-α-[2-methyl-1-oxopropyl]-T-oxo-N,/J-diphenylbenzenebutanamide mixture of [R-(R* ,R*) ], [R-(R*,S*)], [S-(R*,R*)] and [S-(R<*>,S<*>)] isomers;

m.p. 206.8-207.6°C.

NMR: (CDCl 3 ) S 1.03 (3H, d), 1.22 (3H, d), 2.98 (1H, kin.), 4.91 (1H, d, J = 11 HZ), 5, 51 (1H, d, J = 11 Hz), 6.98-7.43 (12H, m), 8.17 (2H, dd), 9.41 (1H, brs).

High Performance Liquid Chromatography (HPLC): (acetonitrile:tetrahydrofuran:water) (40:25:55) Econosil C._5m 25 cm 1.0 ml/min. 254 nm

laughed

16.77 min. 99.2% (range).

Step C: Preparation of 1-(3,3-diethoxypropyl)-5-(4-fluorophenyl)-2-1-methylethyl)-N,4-diphenyl-1H-pyrro1-3-carboxamide.

To a nitrogen-purged flask equipped with a mechanical stirrer is added 130 kg (311 mol) (±)4-fluoro-α-[2-methyl-1-oxopropyl]-T-oxo-N,0-diphenylbenzenebutanamide mixture of [R- (R*,R*)], [R-(R<*>,S<*>)], [S-(R*,R*)] and [S-(R<*>,S*)] isomers, 540 L of heptane and 60 L of toluene, 59 kg (400 mol) of 3-amino-1,1-diethoxypropane and 22.3 kg (218 mol) of pivalic acid. The mixture is stirred and heated to reflux while removing water with a Dean-Stark trap. The mixture is refluxed for 32 hours and cooled slowly to 60-65°C, diluted with 500 1 2-propanol-water (3:2), inoculated and cooled to 20-25°C. The product is isolated by filtration, washed with 300 l of 2-propanol and dried in vacuum to obtain 133.5 kg of 1-(3,3-diethoxy-propyl)-5-(4-fluorophenyl)-2-(1-methylethyl) -N,4-diphenyl-1H-pyrrole-3-carboxamide,

m.p. 125.1-127.7°C after recrystallization from ethanol.

HPLC: (acetonitrile:tetrahydrofuran:water) (40:25:55) 1.5 ml/min 254 nm Econosil Clg 5/x 25 cm R.T. = 37.70 min 99.4% (range)

NMR: ((CD3)2CO) S 1.04 (6H, m, t), 1.47 (6H, d), 1.82 (2H, m), 3.40 (5H, m), 3.99 (2H, m), 4.43 (1H, brt), 6.90-7.50 (14H, m), 8.26 (1H, brs)

By a procedure analogous to step C using suitable starting materials, the following compounds of formula XVI are prepared: 1-(3.3-dimethoxypropyl)-5-(4-fluorophenyl)-2-(1-methylethyl)-N.4- diphenyl-1H-pyrrole-3-carboxamide.

m.p. 167-168.2°C.

5- f 4- fluorophenyl)- 1- r 2-( 4- metvl- 1, 3- dioxolane- 2- vl)-ethyl11- 2-( 1- methy1etv1)- N. 4- dipheny1- 1H- pvrro1- 3 - carboxamide.

kp. 141.5-145.9°C.

Step D: Preparation of 5- (4-fluorophenyl)- 2-( 1 -

methylethyl)- 1- (3- oxopropyl)- N. 4- diphenyl-1H- pyrro1- 3- carboxamide.

To a nitrogen-flushed flask equipped with an "overhead" stirrer, a thermometer and a condenser is added 20 kg (37.8 mol) 1-(3,3-diethoxypropyl)-5-(4-fluorophenyl)-2-(1- methylethyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide together with 200 1 of acetone. The solution is stirred, and 100 1 2N hydrochloric acid solution is added. The mixture is heated to reflux for four hours, then cooled to 50°C ± 5°C, seeded and cooled to 0°C ± 5°C. The product is collected by filtration, washed with 100 1 2-propanol-water (1:1) and dried in vacuum at 50°C for 64 hours to obtain 16.2 kg of 5-(4-fluorophenyl)-2-(1- methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide as an off-white solid.

Step E: Preparation<g> of 2-(4-fluorophenyl)-6-hydroxy-5-(1-methylethyl)-flo-oxo-3-phenyl-4-f(phenylamino)carbonyl1-1H-pyrrole-1- heptanoic acid. metflester.

A 22 L three-necked flask equipped with an overhead stirrer, a low-temperature thermometer, and a 2 L calibrated separatory funnel is dried under a nitrogen purge, and 78 g (1.95 mol) of 60% sodium hydride in mineral oil is added followed by 248 ml (1.76 mol ) diisopropylamine and 8 1 tetrahydrofuran. The reaction is cooled to -10° to 0°C, a significant nitrogen purge of the flask is performed, and 212 mL (1.92 moles) of methyl acetoacetate is added via a slow stream over a period of 10 to 30 minutes. Stirring is continued at -10° to 10°C for an additional 10 to 30 minutes. After cooling to -15 to -5°C, 2.2 1 1.6 M n-butyllithium in hexane is added over a 30 to 60 minute period, while maintaining the temperature below 0°C. Stirring is continued for a further 1 to 1.5 hours at

-15° to 0°C and the mixture is cooled to -35° to -15°C.

In a separate 5 L flask, dissolve 0.7 kg (1.54 mol) of 5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole -3-carboxamide with 2.0 L of dry tetrahydrofuran, cooled to 0° to -5°C and added to the anion solution over a 30 to 45 minute period. The reaction is stirred at -20° to -15°C i

30 to 45 minutes, then stopped by the addition of 4 L of aqueous 2 N hydrochloric acid solution over 5 to 15 seconds with rapid stirring. After cessation of shaking, the lower layer is separated, and the remaining organic layer is washed with 4 1 of saturated aqueous sodium chloride. Step F: Preparation of cis-(4-fluorophenyl)-B. 6 - dihydroxyz-5-(1-methylethyl)-3-phenyl-4-f(phenylamino)-carbonyl-1-1H-pyrrole-1-heptanoic acid methyl ester. The reaction solution obtained from step E, which is stored in a 50 1 glass still equipped with a heating jacket, is concentrated by vacuum distillation to a thick oil, then dissolved with 19 1 tetrahydrofuran and cooled to 0°C under an atmosphere of air. Triethylborane, a 1 molar solution in hexane, (3.20 L, 1.4 equivalents based on step E) is added over a 10 minute period, the atmosphere in the flask is replaced with nitrogen, and the flask is cooled to -105^0 over 3 .5 hours. During this period, two liters of methanol are added, when the temperature reaches -67°C. Powdered sodium borohydride (184 g, 4.8 mol) is added in 20 to 50 g portions over 1.5 hours, and the reaction is maintained between -95° and -106°C for 13 hours, then between -60° pg -100°C for 10 hours. Unreacted sodium borohydride is neutralized by the addition of 750 ml (12.7 mol) of acetic acid in 50 ml portions over a 45 minute period while releasing gas in significant quantities and with a temperature rise from -60° to -40°C. Further neutralization is completed by adding a solution of 1.0 L of 30% hydrogen peroxide (9.7 mol), 3.0 L of water and 100 g of sodium dihydrogen phosphate over a 15 minute period, which is accompanied by a rise in temperature from -40° to 0° C. The reaction mixture is allowed to heat up to

room temperature overnight, after which the lower layer is separated, and the upper layer is washed with 4.0 1 of saturated aqueous sodium chloride solution.

Variation of stage F:

Preparation of cis-2-(4-fluorophenyl)-lf. 6-Dihydroxy-5-(1-methylethyl)-3-phenyl-4-(phenylamino)carbonyl-1H-pyrrole-1-heptanoic acid methyl ester.

The reaction solution obtained from step E is concentrated under vacuum to a volume of 5 to 8 1, then dissolved in 20 1 of tetrahydrofuran and 4 1 of methanol under a nitrogen atmosphere. This solution is cooled to -85°C, and 2.1 1 of a 15% solution of methoxydiethylborane in tetrahydrofuran (2.1 mol, 1.0 equivalent based on step E) is added. The reaction is cooled to -97°C over one hour and 144 g (3.78 moles) of sodium borohydride is added in 20 to 50 g portions over 1.5 hours. The reaction is kept between -93° and -97°C for 13 hours and is allowed to warm to room temperature and is left for 60 hours below

nitrogen atmosphere.

The reaction is stopped by the addition of 460 ml (7.9 mol) of acetic acid and concentrated by vacuum distillation to an oil. The residue is dissolved with 8 1 methanol, concentrated by vacuum distillation, dissolved again with 8 1 methanol and concentrated again by vacuum distillation to a volume of 6 1. The solution is diluted with 8 1 tetrahydrofuran, 4 1 hexane and brought to the next step.

Step G: Preparation of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N.4-diphenyl-1-f 2-(tetrahydro-4-hydroxy-6- oxo-2H-pyran-2-yl)ethyl1-1H-pyrro1-3-carboxamide.

The crude reaction mixture from step F is cooled to 8°C, 8.0 1 2.0 N aqueous sodium hydroxide is added, and the reaction is stirred for 2 hours at 15° to 18°C. The reaction is diluted with 12 1 of water, and the upper layer is removed. The remaining aqueous layer is washed with 8 1 of hexane, then 8 1 of ethyl acetate is added, followed by 1 1 of concentrated aqueous hydrochloric acid solution. The well-stirred mixture is allowed to separate, the lower layer is discarded, and the upper layer is washed four times with each 4 1 2 N aqueous hydrochloric acid solution.

The ethyl acetate layer is concentrated to a foaming syrup by vacuum distillation, and the residue is dissolved in 8 1 toluene. The toluene is concentrated by vacuum distillation to a volume of 6 1 and then left at room temperature for 16 hours. The resulting thick slurry is filtered through a Buchner funnel, washed with 1 L of cold toluene and 2 L of hexane and dried in a vacuum oven for 24 h at room temperature to obtain 686 g of trans-(±)-5-(4-fluorophenyl)-2- (1-Methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide. The filtrates are washed with 2 N aqueous hydrochloric acid solution and concentrated in vacuo to a volume of 2 1 and then left at room temperature for three days. The resulting solid is filtered, washed and dried as before, yielding 157 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-( tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide. HPLC of the solids shows 95% trans with 1.3% cis lactone for the first yield and 95% trans with 2.3% cis lactone for the second yield. The two yields of solid are dissolved in 8 1 of ethyl acetate by heating to 50 to 60°C and then filtered through a Buchner funnel together with 8 1 of hexane which has been heated to 50°C. The solution is allowed to cool to room temperature over 16 hours, the resulting slurry is filtered through a Buchner funnel, and the solid is washed with 2 L of hexane. The resulting solid is dried in a vacuum oven for 24 hours at room temperature, yielding 720 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2- (tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide with a 98%:0.9% trans:cis HPLC analysis. The other yield achieved by concentration as before is approx. 100 g.

PROCEDURE B

Step A: Preparation of (±)-cis-6-(2-aminoethyl)-2.2-dimethyl-1.3-dioxane-4-acetic acid.

A solution of 1.04 g (4.88 mmol) (±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid in 100 ml of methanol saturated with anhydrous ammonia is added to a Parr shaker bottle containing 0.53 g of water-braided Raney nickel #30. The solution is heated at 45°C and 50 psig hydrogen pressure for 17 hours. The suspension is cooled and filtered through filter aid to remove Raney nickel, and the precipitate is washed with methanol. The filtrate is concentrated under reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing activated carbon, filtered through filter aid and evaporated to obtain 0.56 g of (±)-cis-6-(2-aminoethyl)-2,2-dimethyl1-1,3 -dioxane-4-acetic acid,

m.p. 165° with decomposition at 169°C.

Fourier Transform Infrared (FTIR) (KBr): 1201.1, 1399.2, 1561.2, 2924.4, 3569.9 cm"<1>.

<1>H-NMR (D20, 200 MHz) S 0.84 (m, 1H), 0.96 (s, 3H), 1.11 (s, 3H),

1.2-1.5 (m, 3H), 1.84 (dd, 1H, J = 14.0 Hz, J = 6.6 Hz), 1.99 (dd,

1H, J = 14.0 Hz, J = 6.8 Hz), 2.68 (t, 2H, J = 7.2 Hz), 3.6-3.85

(m, 1H), 3.85-4.15 (m, 1H).

<13>C-NMR (D20, 50 MHZ) S 19.64, 29.32, 32.94, 35.86, 36.95, 44.73,

68.16, 68.25, 100.18, 178.56.

Mass spectrum (GC/MS), m/z 202, 198, 173, 142, 138, 120, 97, 82,

59, 43.

Step B: Preparation of trans-( ±)- 5-( 4- fluorophenyl)- 2-( 1-methylethyl)- N. 4- diphenyl- 1- r 2-( tetrahydro- 4- hydroxy-6- oxo- 2H-pvran-2-yl)ethyl-1H-pvrrol-3-carboxamide.

A solution of 0.26 g (1.21 mmol) of (±)-cis-6-(2-aminoethyl)2,2-dimethyl-1,3-dioxane-4-acetic acid and 0.504 g (1.20 mmol) (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-r-oxo-N,B-diphenylbenzenebutanamide mixture of [R-(R*,R<*>)], [R-(R< *>,S<*>)], [S-(R<*>,R<*>)] and [S-(R*,S*)]isomers in 5 ml of dimethylsulfoxide are heated at 105°C for 15 hours . The solution is cooled and poured into 100 ml of diethyl ether and 50 ml of saturated ammonium chloride in water. The layers are separated and the organic layer is washed with water (2 x 50 ml) and 5% sodium hydroxide solution (2 x 100 ml to extract the intermediate from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution and extracted with 30 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution, and it stands for 18 hours. The solution is concentrated in vacuo, and the concentrate is redissolved in 30 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 6 ml of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes out and is isolated by filtration. A total of 0.16 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo -2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two yields.

PROCEDURE C

Step A: Preparation of either (±)-( 2a . 46 . 60)- or ( ±)-( 2a . 4a . 60 )- 2- phenyl- 6-( 2- propenyl)- 1 . 3- dioxane- 4 -acetonitrile.

Potassium cyanide 1.3 g (20 mmol) is added to a solution at room temperature of (R*,R*)-α-2-propenyloxyranethanol, 2.56 g (20 mmol), in 25 ml of 4:1 isopropanol:water. The solution is stirred for 20 hours at ambient temperature, concentrated and layered between ethyl acetate and salt water. The aqueous layer is extracted twice with ethyl acetate, and the combined ethyl acetate extracts are washed with salt water and dried (magnesium sulfate). The crude product is dissolved in 20 ml of benzaldehyde dimethyl acetal, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography after concentration in vacuum gives 1.30 g of either (±) - (2a, 4/3,60) - or (±)-(2a,4a,60)-2-phenyl-6-(2- propenyl)-1,3-dioxane-4-acetonitrile.

200 MHZ NMR (CDCl 3 ) S 1.48 (m, 1H), 1.71 (m, 1H), 2.41 (m, 2H), 2.58

(m, 2H), 3.87 (m, 1H), 4.03 (m, 1H), 5.1 5.2 (m, 2H), 5.53 (s, 1H) , 5.87 (m , 1H), 7.3-7.6 (m, 5H)

<13>C-NMR (CDC13, 50 MHZ) S 24.23, 35.07, 39.79, 71.57, 75.48, 100.44, 116.37, 117.53, 125.89, 127 .91, 128.61, 133.05, 137.71.

GC/MS m/e 243 (M<+>), 242, 203, 202, 120, 107, 105, 79, 75, 41.

FTIR (pure) 699.6, 758.7, 920.8, 1028.8, 1051.9, 1121.4, 1345.2, 1383.7, 1401.7, 2253.1, 2916.6 cm"" <1>.

Step B: Preparation of either ( ±)-( 2a. 4a. 6a)- or f±)-( 2a. 40. 6/ 3) - 6-( 2- oxoethyl) - 2- phenyl- 1. 3- dioxane-4-acetonitrile.

A solution of either (±)-(2a,40,60)- or (±)-(2a,4a,6a)-2-phenyl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile , 4.11 g (16.89 mmol), in 100 ml of dichloromethane is cooled to -78°C under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage = 90V) is then passed through a fritted gas inlet tube into the solution, until the blue color of ozone appears. The current is turned off, and oxygen is bubbled through until the blue color is removed. Triphenylphosphine, 4.87 g (18.58 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography gives, after concentration in vacuum, 3.75 g of pure either (±)-(2a,4a,6a)-or (±)-(2a,4/3,60)-6-(2-oxoethyl)-2-phenyl -1,3-dioxane-4-acetonitrile.

GC/MS m/e 245 (M<+>), 244, 123, 105, 95, 94, 77, 51, 41.

Step C: Preparation of either (±)-(2a,4a.6a)- or (±)-(2a.40.60)-6-(cyanomethyl)-2-phenyl-1.3-dioxane-4-acetic acid .

Jones reagent (chromic trioxide-sulfuric acid-water), 3.8 ml (97.6 mmol), is added dropwise to a 0°C solution of either (±)-(2a,4a,6a)- or (±)-(2a) , 40, 60)-6-(2-oxoethyl)-2-phenyl-1,3-dioxane-4-acetonitrile, 1.86 g (7.6 mmol), dissolved in 50 ml of acetone, until the orange color remains . After stirring for a further 15 minutes, the mixture is poured into 300 ml of diethyl ether and washed with salt water, until the aqueous rinses are colourless. The diethyl ether layer is dried (magnesium sulfate), filtered and concentrated to obtain 1.84 g of either (±)-(2a,4a,6a)- or (±)-(2a-(2a,40,60)-6-(cyanomethyl )-2-phenyl-1,3-dioxane-4-acetic acid as a yellow gum.

200 MHZ NMR (CDCl 3 ) S 1.61 (m, 1H), 2.04 (m, 1H), 2.6 - 2.8 (m, 3H) 2.82 (dd, 1H, J = 15.9 Hz, J = 7.1 Hz), 4.20 (m, 1H), 4.40 (m, 1H), 5.60 (S, 1H), 7.2 - 7.5 (m, 5H).

Step D: Preparation of either ( ±)-( 2a. 4a . 6a)- or (±) -

( 2a . 40 . 60 )- 6- f 2- aminoethyl)- 2- phenyl- 1. 3- dioxane- 4-acetic acid.

A solution of 0.16 g (0.61 mmol) of either (±)-(2a,4a,6a)- or (±)-(2a,40,60)-6-(cyanomethyl)-2-phenyl- 1,3-dioxane-4-acetic acid in 50 ml of methanol saturated with anhydrous ammonia is added to a Parr shake flask containing 0.2 g of water-moistened Raney nickel #30. The solution is heated at 40°C and 50 pounds per square inch (psig) of hydrogen pressure for 6 hours. The suspension is cooled and filtered to remove Raney nickel through filter aid, and the precipitate is washed with methanol. The filtrate is concentrated under reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing activated carbon, filtered through filter aid and evaporated to obtain 0.11 g of either (±)-(2a,4a,6a) or (±)-(2a, 40, 6/3) -6-(2-aminoethyl 1)-2-phenyl 1-1,3-dioxane-4-acetic acid,

m.p. 215.9 -217.9°C with decomposition.

200 MHz NMR (D 2 O) S 1.4 - 1.9 (m, 4H), 2.39 (dd, 1H, J = 14.8 HZ, J = 6.7 Hz), 2.55 (dd, 1H , J = 14.8 Hz, J = 7.4 Hz), 2.73 (t, 2H, J = 7.2 HZ) 4.11 (m, 1H), 4.33 (m, 1H), 5 .70 (s, 1H), 7.4 - 7.6 (m, 5H).

<13>C-NMR (D20, 50 MHz) S 39.20, 39.78, 40.83, 47.11, 78.34, 78.73, 104.06, 129.15, 131.56, 132 .38, 140.51, 181.89.

Step E: Preparation of trans-( ±)- 5-( 4- fluorophenyl)- 2-( 1-methylethyl)- N. 4- diphenyl- 1- f2-( tetrahydro- 4-hydroxy- 6- oxo- 2H- pyran-2-yl)ethyl]-1H-pyrro1-3-carboxamide.

A solution of 0.31 g (1.21 mmol) of either (±)-(2a,4a,6a)- or (±)-(2a,40,60)-6-(2-aminoethyl)-2- phenyl-1,3-dioxane-4-acetic acid and 0.504 g (1.20 mmol) (±)-4-fluoro-a-[2-methyl-1-oxopropyl]-T-oxo-N,/3-diphenylbenzenebutanamide mixture of [R-(R*,R<*>)], [R-(R<*>,S<*>)], [S-(R<*>,R*)] and [S-(R *,S*)] isomers in 5 ml of dimethylsulfoxide are heated at 105°C for 15 hours. The solution is cooled and poured into 100 ml of diethyl ether and 50 ml of saturated ammonium chloride in water. The layers are separated and the organic layer is washed with water (2 x 50 mL) and 5% sodium hydroxide solution (2 x 100 mL to extract the intermediate from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid, stirred for three hours and extracted with 30 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution, the solution is stirred and left for 18 hours. The solution is concentrated in vacuo, and the concentrate is redissolved in 30 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 6 ml of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-dipheny1-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes out and is isolated by filtration. A total of 0.16 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo -2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two yields.

PROCEDURE D

Step A: Preparation of (±)-cis-9-(2-propenyl)-6.10-dioxaspiro[4.5"|decane-7-acetonitrile.

Potassium cyanide, 1.3 g (20 mmol), is added to a solution at room temperature of (R*,R*)-α-2-propenyloxyranethanol, 2.56 g (20 mmol), in 25 ml of 4:1 isopropanol:water . The solution is stirred for 20 hours at ambient temperature, concentrated and layered between ethyl acetate and salt water. The aqueous layer is extracted twice with ethyl acetate, and the combined ethyl acetate extracts are washed with salt water and dried (magnesium sulfate). The crude product is dissolved in 20 ml of 1,1-dimethoxycyclopentane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography after concentration in vacuum gives 1.40 g of (±)-cis-9-(2-propenyl)-6,10-dioxaspiro[4.5]decane-7-acetonitrile.

Step B: Preparation of (±)-cis-9-(2-oxoethyl)-6.10-dioxaspiro[4.51decane-7-acetonitrile.

A solution of (±)-cis-9-(2-propenyl)-6,10-dioxa-spiro[4.5]decane-7-acetonitrile, 3.4 g (15.36 mmol), in 100 ml of dichloromethane is cooled to -78°C under nitrogen. Ozone

(Welsbach generator, flow rate 0.1, voltage = 90V)

is then passed through a fritted gas inlet tube into the solution, until the blue color of ozone appears. The current is switched off, and oxygen is bubbled through until the blue color is removed. Triphenylphosphine, 4.2 g (16 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography gives, after concentration in vacuum, 2.5 g of pure (±)-cis-9-(2-oxoethyl)-6,10-dioxa-spiro[4.5]decane-7-acetonitrile.

Step C: Preparation of (±)-cis-9-(cyanomethyl)-6.10-dioxaspiro f4.5]decane-7-acetic acid.

Jones reagent (chromium trioxide-sulfuric acid-water), 3.8 ml (97.6 mmol), is added dropwise to a 0°C solution of (±)-cis-9-(2-oxoethyl)-6,10-dioxaspiro[ 4.5]decane-2-acetonitrile 1.70 g (7.6 mmol), dissolved in 50 ml of acetone, until the orange color does not disappear. After stirring for a further 15 minutes, the mixture is poured into 300 ml of diethyl ether and washed with salt water, until the aqueous rinses are colourless. The diethyl ether layer is dried (magnesium sulfate), filtered and concentrated to obtain 1.20 g of (±)-cis-9-(cyanomethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid as a colorless solid.

Step D: Preparation<g> of (±)-cis-9-(2-aminoethyl)-6. 10- dioxaspiro [ 4. 5") decane- 7- acetic acid.

A solution of 1.17 g (4.88 mmol) (±)-cis-9-(cyanomethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid in 100 ml of methanol saturated with anhydrous ammonia is added to a Parr shake flask containing 0.53 g of water-moistened Raney nickel #30. The solution is heated at 45°C and 50 pounds per square inch (psig) of hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove Raney nickel through filter aid, and the precipitate is washed with methanol. The filtrate is concentrated under reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing activated carbon, filtered through filter aid and evaporated to obtain 0.56 g of (±)-cis-9-(2-aminoethyl)-6,10-dioxaspiro-[4.5] decane-7-acetic acid.

Step E: Preparation of trans-( ±)- 5-( 4-fluorophenyl)-2- fluorophenyl)- N. 4- diphenyl- 1- r 2-( tetrahydro- 4- hydroxy- 6- oxo- 2H- pvran-2-yl)ethyl-1H-pvrrol-3-carboxamide.

A solution of 0.295 g (1.21 mmol) (±)-cis-9-(2-aminoethyl)-6,10-dioxaspiro[4.5]decane-7-acetic acid and 0.504 g (1.20 mmol) (±) -4-fluoro-α-[2-methyl-1-oxopropyl]-T-oxo-N,/3-diphenyl-benzenebutanamide mixture of [R-(R*,R*)], [R-(R*, S<*>)], [S-(R<*>,R<*>)] and [S-(R*,S*)] isomers in 5 ml of dimethylsulfoxide are heated at 105°C for 15 hours. The solution is cooled and poured into 100 ml of diethyl ether and 50 ml of saturated ammonium chloride in water. The layers are separated and the organic layer is washed with water (2 x 50 ml) and 5% sodium hydroxide solution (2 x 100 ml - to extract the intermediate protected acid from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 30 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution which stands for 18 hours. The solution is concentrated in vacuo, and the concentrate is redissolved in 30 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 6 ml of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- γ1)ethyl1]-1H-pyrro1-3-carboxamide crystallizes out and is isolated by filtration. A total of 0.16 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo -2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two yields.

PROCEDURE E

Step A: Preparation of (±)-cis-4-(2-propenyl)-1.5-dioxaspiro f 5.51undecane-2-acetonitrile.

Potassium cyanide, 1.3 g (20 mmol) is added to a solution at room temperature of (R*,R*)-α-2-propenyloxyranethanol, 2.56 g (20 mmol), in 25 ml of 4:1 isopropanol:water. The solution is stirred for 20 hours at ambient temperature, concentrated and layered between ethyl acetate and salt water. The aqueous layer is extracted twice with ethyl acetate and the combined ethyl acetate extracts are washed with salt water and dried (magnesium sulfate). The crude product is dissolved in 20 ml of 2,2-dimethoxycyclohexane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography after concentration in vacuum gives 1.50 g of (±)-cis-4-(2-propenyl)-1,5-dioxaspiro[5.5]undecane-2-acetonitrile.

200 MHZ NMR (CDCl 3 ) S 1.26 (m, 1H), 1.4 - 1.7 (m, 8H), 1.87 (m, 2H),

2.1 - 2.3 (m, 2H), 2.51 (d, 2H, J = 6.05 Hz), 3.95 (m, 1H), 4.15 (m, 1H), 5.0 - 5.2 (m, 2H), 5.83 (m, 1H).

<13>C-NMR (CDC13, 50 MHz) S 22.16, 24.71, 25.42, 28.20, 35.47, 38.33, 40.30, 64.08, 66.87, 98 .84, 116.53, 116.83, 113.46.

GC/MS m/e 235 (m<+>), 206, 192, 120, 99, 93, 79, 69, 55, 41.

FTIR (film) 964.5, 1121.4, 1160.0, 2253.1, 2937.2 cm"<1>.

Step B: Preparation of (±)-cis-4-(2-oxoethyl)-1.5-dioxaspiro[5.51undecane-2-acetonitrile.

A solution of (±)-cis-4-(2-propenyl)-1,5-dioxaspiro-[5.5]undecane-2-acetonitrile 4.26 g (19.42 mmol), in 100 ml of dichloromethane is cooled to -78 °C under nitrogen. Ozone

(Welsbach generator, flow rate 0.1, voltage = 90V)

is then passed through a fritted gas inlet tube into the solution, until the blue color of ozone appears.

The current is turned off, and oxygen is bubbled through until the blue color has disappeared. Triphenylphosphine, 5.6 g (21.36 mmol) is added and the colorless solution is allowed to warm to room temperature. Flash chromatography gives, after concentration in vacuum, 4.04 g of pure (±)-cis-4-(2-oxoethyl)-1,5-dioxa-spiro[5.5]undecane-2-acetonitrile.

200 MHZ NMR (CDCl 3 ) S 1.3 - 2.0 (m, 12H), 2.5 - 2.7 (m, 4H), 4.20 (m, 1H), 4.36 (m, 1H) , 9.81 (t, 1H, J = 1.74 Hz).

<13>C-NMR (CDC13, 50 MHz) S 22.39, 22.44, 24.97, 25.59, 28.44, 35.82, 38.48, 49.54, 63.25, 64 .17, 99.66, 116.57, 199.82.

GC/MS m/e 237 (m<+>), 208, 194, 122, 94, 81, 55, 42, 41.

FTIR (film) 969.6, 1069.9, 1126.5, 1160.0, 1368.3, 1386.3, 1728.4, 2934.6 cm"<1>.

Step C: Preparation of (±)-cis-4-(cyanomethyl)-1.5-dioxaspirof 5.5"|undecane-2-acetic acid.

Jones reagent (chromic trioxide-sulfuric acid-water), 4.4 ml (8.85 mmol), is added dropwise to a 0°C solution of (±)-cis-4-(2-oxoethyl)-1,5-dioxaspiro[ 5.5]undecane-2-acetonitrile, 3.62 g (12.6 mmol) dissolved in 30 ml of acetone, until the orange color does not disappear. After stirring for a further 15 minutes, the mixture is poured into 300 ml of diethyl ether and washed with salt water, until the aqueous rinses are colourless. The diethyl ether layer is dried (magnesium sulfate), filtered and concentrated to obtain 3.65 g of (±)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid as a yellow solid.

200 MHz NMR (Pyridine) S 1.2 - 2.0 (m, 12H), 2.5 - 2.9 (m, 4H), 4.19 (m, 1H), 4.50 (m, 1H) .

Step D: Preparation of (±)-cis-4-(2-aminoethyl)-1.5-dioxaspiro\5.51undecane-2-acetic acid.

A solution of 0.13 g of (±)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid in 20 ml of methanol saturated with anhydrous ammonia is added to a Parr shaking flask containing 0.2 g water-wet Raney nickel #30. The solution is heated at 40°C and 50 pounds per square inch (psig) of hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove Raney nickel through filter aid, and the precipitate is washed with methanol. The filtrate is concentrated under reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing activated carbon, filtered through filter aid and evaporated to obtain 0.13 g of (±)-cis-4-(2-aminoethyl)-1,5-dioxaspiro-[5.5] undecane-2-acetic acid.

200 MHz NMR (D2O) S 1.1 - 1.7 (m, 10H), 1.75 - 2.1 (m, 4H), 2.19 (dd, 1H, J = 14.6 Hz, J = 6.7 Hz), 2.31 (dd, 1H, J = 14.6 Hz, J = 7.3 Hz), 2.69 (t, 2H, J = 7.1 Hz), 4.09 (m , 1H), 4.34 (m, 1H).

<13>C-NMR (D20, 50 MHZ) S 24.50, 24.73, 27.55, 30.80, 38.91, 39.39, 39.63, 40.48, 47.03, 69 .37, 69.54, 102.74, 181.33.

Step E: Preparation of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N.4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H - pyran-2-yl)ethyl]-1H-pyrrol-3-carboxamide.

A solution of 0.31 g (1.21 mmol) (±)-cis-4-(2-aminoethyl)-1,5-dioxaspiro[5.5]undecane-2-acetic acid and 0.504 g (1.20 mmol) ( ±) -4-fluoro-α-[2-methyl-1-oxopropyl]-r-oxo-N,/3-diphenylbenzenebutanamide mixture of [R-(R*,R*)], [R-(R*,S *)], [S-(R*,R*)] and [S-(R*,S*)] isomers in 5 ml of dimethylsulfoxide are heated at 105°C for 15 hours. The solution is cooled and poured into 100 ml of diethyl ether and 50 ml of saturated ammonium chloride in water. The layers are separated and the organic layer is washed with water (2 x 50 ml) and 5% sodium hydroxide solution (2 x 100 ml - to extract the intermediate acid from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 30 ml of ethyl acetate to remove the protecting group before lactonization. The extract is concentrated and dissolved in 30 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution, and it stands for 18 hours. The solution is concentrated in vacuo, and the concentrate is redissolved in 30 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 6 ml of toluene. Trans-(±)-5-(4-fluoro-phenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran- 2-yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes out and is isolated by filtration. A total of 0.155 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-dipheny1-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H -pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two yields.

PROCEDURE F

Step A: Preparation of (±)-cis-6-(2-propenyl)-1.3-dioxane-4-acetonitrile

Potassium cyanide, 1.3 g (20 mmol), is added to a solution at room temperature of (R*,R*)-α-2-propenyloxyranethanol, 2.56 g (20 mmol), in 25 ml of 4:1 isopropanol:water . The solution is stirred for 20 hours at ambient temperature, concentrated and layered between ethyl acetate and salt water. The aqueous layer is extracted twice with ethyl acetate, and the combined ethyl acetate extracts are washed with salt water and dried (magnesium sulfate). The crude product is dissolved in 20 ml of dimethoxymethane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography after concentration in vacuum give 1.20 g of (±)-cis-6-(2-propenyl)-1,3-dioxane-4-acetonitrile.

Step B: Preparation of (±)-cis-6-(2-oxoethyl)-1.3-dioxane-4-acetonitrile.

A solution of (±)-cis-6-(2-propenyl)-1,3-dioxane-4-acetonitrile, 2.57 g (15.36 mmol), in 100 ml of dichloromethane is cooled to -78°C under nitrogen . Ozone (Welsbach generator, flow rate 0.1, voltage = 90V) is then passed through a fritted gas inlet tube into the solution, until the blue color of ozone appears. The current is turned off, and oxygen is bubbled through until the blue color has disappeared. Triphenylphosphine, 4.87 g (28.58 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography gives, after concentration in vacuum, 2.3 g of pure (±)-cis-6-(2-oxoethyl)-1,3-dioxane-4-acetonitrile.

Step C: Preparation of (±)-cis-6-(cyanomethyl)-1.3-dioxane-4-acetic acid.

Jones reagent (chromium trioxide-sulfuric acid-water), 3.8 ml (97.6 mmol), is added dropwise to a 0°C solution of (±)-cis-6-(2-oxoethyl)-1,3-dioxane- 4-acetonitrile, 1.29 g (7.6 mmol) dissolved in 50 ml of acetone, until the orange color does not disappear. After stirring for a further 15 minutes, the mixture is poured into 300 ml of diethyl ether and washed with salt water, until the aqueous rinses are colourless. The diethyl ether layer is dried (magnesium sulfate), filtered and concentrated to obtain 1.2 g of (±)-cis-6-(cyanomethyl)-1,3-dioxane-4-acetic acid as a colorless solid.

Step D; Preparation of (±)-cis-6-(2-aminoethyl)-1.3-dioxan-4-acetic acid.

A solution of 1.04 g (4.88 mmol) (±)-cis-6-(cyanomethyl)-1,3-dioxane-4-acetic acid in 100 ml of methanol saturated with anhydrous ammonia is added to a Parr shaking flask containing 0, 53 g of water-wetted Raney nickel #30. The solution is heated at 45°C and 50 pounds per square inch (psig) of hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove Raney nickel through filter aid, and the precipitate is washed with methanol. The filtrate is concentrated under reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with decolorizing activated carbon, filtered through filter aid and evaporated to obtain 0.56 g of (±)-cis-6-(2-aminoethyl)-1,3-dioxane-4- acetic acid.

Step E: Preparation of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N.4-diphenyl-1-r2-(tetrahydro-4-hydroxy-6-oxo-2H- pyran-2-yl)ethyl]-1H-pyrrol-3-carboxamide.

A solution of 0.26 g (1.21 mmol) of (±)-cis-6-(2-aminoethyl)-1,3-dioxane-4-acetic acid and 0.504 g (1.20 mmol) of 4-fluoro-a -[2-methyl-1-oxopropyl]-T-oxo-N,B-diphenylbenzenebutanamide in 5 ml of dimethylsulfoxide is heated at 105°C for 15 hours. The solution is cooled and poured into 100 ml of diethyl ether and 50 ml of saturated ammonium chloride in water. The layers are separated, and the organic layer is washed with water (2 x 50 ml) and 5% sodium hydroxide solution (2 x 100 ml - to extract the intermediate acid from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution and extracted with 30 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution, and it stands for 18 hours. The solution is concentrated in vacuo, and the concentrate is dissolved in 30 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 6 ml of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes out and is isolated by filtration. A total of 0.15 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo -2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two yields.

PROCEDURE G

Step A: Preparation of either ( ±)-( 2a. 4fl. 6fl)- or ( ±)-( 2a. 4a. 6a)- 2- methyl- 6-( 2- propenyl)- 1. 3-dioxane- 4 - acetonitrile.

Potassium cyanide, 1.3 g (20 mmol), is added to a solution

at room temperature of (R*,R*)-α-2-propenyloxyranethanol, 2.56 g (20 mmol), in 25 ml of 4:1 isopropanol:water. The solution is stirred for 20 hours at ambient temperature, concentrated and layered between ethyl acetate and salt water. The aqueous layer is extracted 2x

with ethyl acetate, and the combined ethyl acetate extracts are washed with salt water and dried (magnesium sulfate). The crude product is dissolved in 20 ml of 1,1-dimethoxyethane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography after concentration in vacuum gives 1.30 g of either (±)-(2a, 40,6/3) - or (±)-(2a,4a,6a)-2-methyl-6-(2-propeny1) )-1,3-dioxane-4-acetonitrile1.

Step B: Preparation of either ( ±)-( 2a. 4a. 6a)- or ( ±)-( 2a. 4fl. 6fl)- 2- metvl- 6- t2- oxoethvl)- 1. 3-dibxane- 4- acetonitrile.

A solution of either (±)-(2a,40, 60)- or

(2a,4a,6a)-2-methyl-6-(2-propenyl)-1,3-dioxane-4-acetonitrile, 2.78 g (15.36 mmol), in 100 ml dichloromethane cooled to -78° C under nitrogen. Ozone (Welsbach generator, flow rate 0.1, voltage = 90V) is then passed through a fritted gas inlet tube into the solution, until the blue color of ozone appears. The current is switched off, and oxygen is bubbled through until the blue color has disappeared. Triphenylphosphine, 4.2 g (16 mmol), is added and the colorless solution is allowed to warm to room temperature. Flash chromatography gives after concentration in vacuum 2.5 g pure either (±)-(2a,4a,6a)- or (±)-(2a,4/3,60)-2-methyl-6-(2-oxo) -ethyl) -1,3-dioxane-4-acetonitrile.

Step C: Preparation of either ( ±)-( 2a . 4a . 6a )- or ( ± )-( 2a . 40 . 60 )- 6-( cyanomethyl)-2-methyl-1. 3- dioxane- 4- acetic acid.

Jones reagent (chromium trioxide-sulfuric acid-water), 3.8 ml (7.6 mmol), is added dropwise to a 0°C solution of either (±)-(2a,4a,6a)- or (±)-(2a , 40, 6/3) -2-methyl-6-(2-oxoethyl)-1, 3-dioxane-4-acetonitrile, 1.40 g (7.6 mmol) dissolved in 50 ml of acetone, until the orange color does not disappear. After stirring for a further 15 minutes, the mixture is poured into 300 ml of diethyl ether and washed with salt water, until the aqueous rinses are colourless. The diethyl ether layer is dried (magnesium sulfate), filtered and concentrated to obtain 1.01 g of either (±)-

(2a,4a,6a)- or (±)-(2a,4/3,6/3)-6-(cyanomethyl)-2-methyl-1,3-dioxane-4-acetic acid as a colorless solid.

Step D: Preparation of either (±)-(2a.4a.6a)- or (±)-(2a.4)3.6B)-6-(2-aminoethyl)-2-methyl-1. 3- dioxane- 4- acetic acid.

A solution of 0.97 g (4.88 mmol) of either (±)-(2a,4a,6a)-or (±)-(2a,4/3,65)-6-(cyanomethyl)-2-methyl -1,3-dioxane-4-acetic acid in 100 ml of methanol saturated with anhydrous ammonia is added to a Parr shake flask containing 0.53 g of water-moistened Raney nickel #30. The solution is heated at 45°C and 50 psig hydrogen pressure for 17 hours. The suspension is cooled and filtered to remove Raney nickel through filter aid, and the precipitate is washed with methanol. The filtrate is concentrated under reduced pressure. The residue is dissolved in methanol saturated with anhydrous ammonia, treated with color-removing activated carbon, filtered through filter aid and evaporated to obtain 0.50 g of either (±)-(2a,4a,6a)- or (+)-(2a,4/ 3,6/3)-6-(2-aminoethyl)-2-methyl-1,3-dioxane-4-acetic acid.

Step E; Preparation of trans-( ±)- 5-( 4- fluorophenyl)-2- f1- methylethyl)- N. 4- diphenyl- 1- r 2- ftetra-hydro- 4- hydroxy- 6- oxo- 2H- pyran- 2-yl)ethyl]-1H-pyrrole-3-carboxamide.

A solution of 0.31 g of either (±)-(2a,4a,6a)- or (±)-(2a,4/3,6B)-6-(2-aminoethyl)-2-methyl-1,3 -dioxane-4-acetic acid and 0.504 g (1.20 mmol) (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-r-oxo-N,/3-diphenylbenzenebutanamide in 5 ml of dimethylsulfoxide are heated at 105°C for 15 hours. The solution is cooled and poured into 100 ml of diethyl ether and 50 ml of saturated ammonium chloride in water. The layers are separated, and the organic layer is washed with water (2 x 50 ml) and 5% sodium hydroxide solution (2 x 100 ml - to extract the intermediate acid from unreacted diketone). The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 30 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution, and it stands for 18 hours. The solution is concentrated in vacuo, and the concentrate is redissolved in 30 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 6 ml of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- yl)ethyl]-1H-pyrrole-3-carboxamide crystallizes out and is isolated by filtration. A total of 0.14 g of trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-dipheny1-1-[2-(tetrahydro-4-hydroxy-6-oxo -2H-pyran-2-yl)-ethyl]-1H-pyrrole-3-carboxamide is isolated in two yields.

PROCEDURE H

Step A: Preparation of (±)- cis- 1. 1- dimethylethyl- 6-( cyanomethyl)- 2. 2- dimethyl- 1. 3- dioxane- 4- acetate.

(±)-cis-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetic acid (3.72 g, 17.44 mmol) is dissolved in 20 ml of dichloromethane, cooled to 0°C, and 0.2 g of 4-dimethylaminopyridine (DMAP) is added followed by t-butyl alcohol and followed by 4.32 g of dicyclohexylcarbodiimide (DCC). This solution is allowed to slowly warm to room temperature over a 76.5 hour period. Thin layer chromatography (TLC) shows mainly product and some weak lower Rf by-products. The mixture is stirred for one hour, and 50 ml of dichloromethane is added, and stirring is continued for five hours, another 100 ml of diethyl ether is added, and the mixture is filtered. The precipitate is washed with diethyl ether. The filtrate is concentrated to an oil. The crude product is chromatographed on silica gel eluting with 4:1 hexane:ethyl acetate. The eluate is concentrated to obtain (±)-cis-1,1-dimethylethyl-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate.

200 MHZ NMR (CDCl 3 ) S 1.36 (m, 1H), 1.42 (s, 3H), 1.49 (S, 9H), 1.50

(s, 3H), 1.79 (dt, 1H, J = 2.5 Hz, J = 12.1 Hz), 2.40 (dd, 1H, J = 6.2 Hz, J = 15.4 HZ ), 2.5 - 2.7 (m, 1H), 2.55 (d, 2H, J = 6.1 HZ) 4.18 (m, 1H), 4.32 (m, 1H).

<13>C-NMR (CDC13, 50 MHz) 6 19.80, 25.16, 28.30, 29.94, 35.66,,42.56, 65.27, 65.87, 80.96, 99.57, 116.72, 169.83.

GCMS w/e 254, 199, 198, 154, 138, 59, 57, 43, 41.

FTIR (neat) 954.2, 987.6, 1152.3, 1201.1, 1257.7, 1316.9, 1368.3, 1383.7, 1728.4, 2253.1, 2942.4, 2983, 5 cm"<*1>.

Step B: Preparation of ( ±)- cis- 1. 1- dimethylethyl-6-( 2- aminoethyl)- 2. 2- dimethyl- 1. 3- dioxane- 4- acetate.

A solution of 6.75 g of (±)-cis-1,1-dimethylethyl-6-(cyanomethyl)-2,2-dimethyl-1,3-dioxane-4-acetate in 80 ml of methanol saturated with gaseous ammonia is treated with 0.7 g of Raney nickel #30 and hydrogen gas in a shaking flask at 50 pounds per square inch (psig) and 40°C. After 10 hours, thin-layer chromatography shows no presence of starting nitrile. The suspension is cooled, filtered through filter aid and concentrated to an oil. This crude oil is purified by flash chromatography on silica gel with 30:20:1 (ethyl acetate:methanol:ammonium hydroxide) as eluent to obtain 5.48 g of (±)-cis-1,1-dimethylethyl-6-(2-aminoethyl)- 2,2-dimethyl-1,3-dioxane-4-acetate (98.2 area %) as a clear oil which solidifies after some time.

200 MHz NMR (CDCl 3 ) S 1.0 - 1.2 (m, 1H), 1.22 (s, 3H), 1.31 (s, 12H), 1.35 - 1.45 (m, 1H) , 1.77 (brS, 2H), 2.15 (dd, 1H, J = 15.1 HZ, J = 6.2 Hz), 2.29 (dd, 1H, J = 15.1 Hz, J = 7.0 Hz), 2.66 (t, 2H, J = 6.6 Hz), 3.82 (m, 1H), 4.12 (m, 1H).

<13>C-NMR (CDC13, 50 MHz) S 19.56, 27.92, 29.96, 36.43, 38.18, 39.65, 42.55, 66.03, 67.16, 80 .19, 98.32, 169.80.

GC/MS m/e 258, 216, 215, 202, 200, 142, 113, 100, 99, 72, 57, 43.

FTIR (neat) 951.6, 1157.4, 1201.1, 1260.3, 1314.3, 1368.3, 1381.2, 1728.4, 2361.1, 2939.8, 2980.9 cm"< 1>.

Step C: Preparation of trans-(±)-5-(4-fluorophenyl)-2-[1-methylethyl]-N. 4- diphenyl- 1- r 2- ftetra-hydro- 4- hydroxy- 6- oxo- 2H- pyran- 2- yl) ethyl]- 1H- pyrrole- 3- carboxamide.

A solution of 0.79 g (2.89 mmol) of (±)-cis-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate and 1 .00 g (2.41 mmol) (±)-4-fluoro-α-[2-methyl-1-oxopropyl]-t-oxo-N,/8-diphenylbenzenebutanamide mixture of [R-(R*,R*) ], [R-(R*,S*)], [S-(R<*>,R<*>)] and [S-(R<*>,S*)] isomers in 15 ml of heptane:toluene (9:1) is heated by reflux cooling for 24 hours. The solution is cooled and poured into 100 ml of tetrahydrofuran and 50 ml of saturated ammonium chloride in water. The layers are separated, and the organic layer is washed with salt water. 5 ml of 10% hydrochloric acid solution is added to the organic layer, and the solution is stirred for 15 hours. 1.2 g of sodium hydroxide is added to this solution, and the mixture is stirred for 30 hours. The reaction is stopped by adding 50 ml of water, 30 ml of hexane and separating the layers. The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 50 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution, and the solution stands for 18 hours. The solution is concentrated in vacuo, and the concentrate is redissolved in 50 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 10 ml of toluene. Trans-(±)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- yl)ethyl]-1H-pyrrole-3-carboxamide is isolated in two yields.

PROCEDURE I

Step A: Preparation of either ( ± )-( 2a . 4a . 6a )- or ( ± )-( 2a . 4f . 6B )- 1. 1- dimethylethyl 6-( 2 - cyanomethyl) - 2- phenyl- 1 3-dioxane-4-acetate.

Either (±)-(2a,4a,6a) or (±)-(2a,4/3,6/3)-6-(cyanomethyl)-2-phenyl-1,3-dioxane-4-acetic acid (3 .07 g, 11.75 mmol) is dissolved in 15 ml of dichloromethane, cooled to 0°C, and 0.1 g of 4-dimethylaminopyridine (DMAP) is added followed by t-butyl alcohol, followed by 2.91 g of dicyclohexylcarbodiimide (DCC). This solution is allowed to slowly warm to room temperature and is stirred over a 16.5 hour period. Thin layer chromatography (TLC) shows mainly product and some weak lower Rf by-products. The mixture is stirred for one hour, and 50 ml of dichloromethane is added, and stirring is continued for five hours. A further 100 ml of diethyl ether is added and then filtered. The precipitate is washed with diethyl ether. The filtrate is concentrated to an oil. The crude product is chromatographed on silica gel eluting with hexane:ethyl acetate 4:1. The eluate is concentrated to obtain either (±)-(2a,4a,6a)- or (±)-(2a,40,60)-1,1-dimethylethyl-6-(2-cyanomethyl)-2-phenyl- 1,3-dioxane-4-acetate.

GC/MS m/e 260, 244, 202, 138, 107, 105, 77, 57, 41.

Step B: Preparation of either ( ±)-( 2a. 4a. 6a)- or

( ± )-( 2a . 40 . 60 )- 1 . 1- dimethylmethyl- 6-( 2-aminoethyl)- 2- phenyl- 1. 3- dioxane- 4- acetate.

A solution of 1.72 g of either (±)-(2a,4a,6a) or (±)-(2a,40,60)-1,1-dimethylethyl-6-(cyanomethyl)-2-phenyl-1 ,3-dioxane-4-acetate in 30 ml of methanol saturated with gaseous ammonia is treated with 0.3 g of Raney nickel #30 and hydrogen gas in a shaking flask at 50 pounds per square inch (psig) and 40°C. After 10 hours, thin-layer chromatography shows no presence of starting nitrile. The suspension is cooled, filtered through filter aid and concentrated to an oil. This crude oil is purified by flash chromatography on silica gel with 30:20:1 (ethyl acetate:methanol:ammonium hydroxide) as eluent to obtain 1.56 g of either (±)-(2a,4a,6a)-or (±)-( 2α,40,60)-1,1-dimethylethyl-6-(2-aminoethyl)-2-phenyl-1,3-dioxane-4-acetate (98.2 area %) as a clear oil which solidifies after a time .

200 MHz NMR (CDCl 3 ) S 1.2 - 1.9 (m, 4H) 1.44 (s, 9H), 2.03, (br.s, 2H), 2.42 (dd, 1H, J = 15.3 Hz, J = 6.3 Hz), 2.63 (dd,

1H, J = 15.3 HZ, J = 7.0 HZ), 2.89 (t, 2H, J = 6.8 Hz), 3.97 (m, 1H), 4.26 (m, 1H) , 5.56 (s, 1H), 7.3 - 7.4 (m, 3H), 7.4 - 7.5 (m, 2H).

<13>C NMR (CDC13, 50 MHz) S 28.07, 36.57, 38.23, 39.25, 42.17, 73.47, 74.87, 80.60, 100.36, 125, 82, 127.88, 128.34, 138.45, 169.73.

GC/MS, m/e 321, 320, 248, 215, 174, 142, 105, 57.

FTIR (film) 699.6, 756.2, 1026.2, 1116.2, 1149.7, 1368.3, 1394.0, 1718.1, 1733.5, 2872.9, 2932.1 cm"< 1.>

Step C: Preparation of trans-( ±)- 5-( 4- fluorophenyl)-2- 1- methylmethyl)- N. 4- diphenyl- 1- 2-( tetrahydro- 4- hydroxy- 6- oxo- 2H- pyran - 2-yl)ethyl]-1H-pyrrole-3-carboxamide.

In a method analogous to method H, the title compound is obtained by using (±)-(2a,4a,6a)- or (±)-(2a,40,6)8)-1,1-dimethylethyl-6-(2- aminoethyl)-2-phenyl-1,3-dioxane-4-acetate instead of (±)-cis-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3- dioxane-4-acetate.

PROCEDURE J

Step A: Preparation of ( ± )- cis- 1. 1- dimethylethyl- 4-( cyanomethyl)- 1. 5- dioxaspiro f 5. 51undecane- 2- acetate.

(±)-cis-4-(cyanomethyl)-1,5-dioxaspiro[5,5]-undecane-2-acetic acid 3.32 g (13.12 mmol) are dissolved in 15 ml of dichloromethane, cooled to 0°C, and 0.1 g of 4-dimethylaminopyridine (DMAP) is added followed by t-butyl alcohol and followed by 3.25 g of dicyclohexylcarbodiimide (DCC). This solution is stirred and allowed to slowly warm to room temperature over a 16.5 hour period. TLG mainly shows product and some faint lower Rf by-products. The mixture is stirred for one hour, and 50 ml of dichloromethane is added, and stirring is continued for four hours. 100 ml of diethyl ether are added and then filtered.

The filtrate is concentrated under reduced pressure. This crude concentrate is chromatographed on silica gel eluting with 4:1 hexane:ethyl acetate to obtain (±)-cis-1,1-dimethylethyl-4-(cyanomethyl)-1,5-dioxaspiro[5,5]undecane-2- acetate.

200 MHz NMR (CDCl 3 ) S 1.1 2.0 (m, 12H) 1.43 (s, 9H), 2.36 (m, 2H), 2.48 (m, 2H), 4.1 - 4 .4 (m, 2H).

<13>C-NMR (CDC13, 50 MHz) 22.37, 22.45, 25.08, 28.15, 28.55, 35.80, 38.57, 42.59, 64.31, 64, 92, 80.76, 99.56, 116.65, 169.82.

GC/MS m/e 309 (m<+>), 266, 224, 210, 138, 120, 99, 57, 55.

FTIR (KBr) 964.5, 1149.7, 1157.4, 1332.3, 1368.3, 1712.9, 2939.8 cm"<1>.

Step B: Preparation<g> of ( ±)- cis- 1. 1- dimethylethyl-4-( 2- aminoethyl)- 1. 5- dioxaspiro[ 5. 51- undecane- 2-acetate.

A solution of 1.19 g of (±)-cis-1,1-dimethylethyl-4-(cyanomethyl)-1,5-dioxaspiro[5,5]undecane-2-acetate in 30 ml of methanol saturated with gaseous ammonia is treated with 0.3 g of Raney nickel #30 and hydrogen gas in a shaking flask at 50 pounds per square inch (psig) and 40°C. After 22 hours, a thin-layer chromatograph shows no presence of starting nitrile. The suspension is cooled, filtered through filter aid and concentrated to an oil. This crude oil is purified by silica gel flash chromatography (30:20:1; ethyl acetate:methanol:ammonium hydroxide) to obtain 1.18 g of (±)-cis-1,1-dimethylethyl-4-(2-aminoethyl)-1,5 -dioxaspiro[5,5]undecane-2-acetate as a clear oil which becomes a solid on standing.

200 MHZ NMR (CDCl 3 ) S 1.2 - 2.0 (m, 12H), 1.43 (s, 9H), 2.34, (m, 2H), 2.50 (br.s, 2H), 2.84 (t, 2H, J = 6.7 Hz), 3.99 (m, 1H), 4.28 (m, 1H).

GC/MS, m/e 313, 270, 214, 185, 144, 142, 99.

FTIR (film) 961.9, 1098.2, 1154.8, 1368.3, 1725.8, 2934.6 cm"<1>.

Step C: Preparation of trans-( ±)- 5-( 4- fluorophenyl)-2- fl- methylethyl)- N. 4- diphenyl- 1- r2- ftetra-hydro- 4- hydroxy- 6- oxo- 2H- pyran-2-yl)ethyl]-1H-pyrrol-3-carboxamide.

In a method analogous to method H, the title compound is obtained by using (±)-cis-1,1-dimethylethyl-4-(2-aminoethyl)-1,5-dioxaspiro[5,5]undecane-2-acetate instead of (±)-cis-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate.

EXAMPLE 3

f2R- trans)- 5- f4- fluorophenyl)- 2- f1- metvletv11- N. 4- diphenvl- 1- r2-( tetrahydro- 4- hydroxyv- 6- oxo- 2H- pyran- 2- yl) ethyl- 1H - pvrrol-3-carboxamide.

METHOD OF PROCEDURE A

Step A: Preparation of (R)-1.1-dimethylethyl-6-cyano-5-f f (1.1-dimethylethyl)dimethylsilyl-)oxyl-3-oxohexanoate.

(R)-4-cyano-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]butanoic acid, 32 g (0.132 mol), is dissolved in 300 ml of tetrahydrofuran. The solution is cooled to -20°C and carbonyldiimidazole, 27 g (0.165 mol), is added. The solution is stirred and allowed to warm to 25°C over two hours. The solution is added to a slurry of potassium 1,1-dimethylethyl malonate (half ester, half salt), 60 g (0.3 mol), anhydrous magnesium chloride, 27.2 g (0.246 mol), diisopropylethylamine, 53 ml (0.3 mol) in 700 ml of dry acetonitrile. The mixture is stirred at 5°C for 18 hours and at 15°C for 108 hours. The mixture is poured into a mixture of 1 1 IN hydrochloric acid and 1 1 ethyl acetate, and the resulting two-phase system is stirred for 15 minutes. The teams are separated. The

organic layers are washed with 500 ml saturated saline and concentrated to obtain an oil. The oil consists of (R)-1,1-dimethylethyl-6-cyano-5-[[(1,1-dimethylethyl)-dimethylsilyl]oxy]-3-oxohexanoate and some 1,1-dimethylethyl malonate (half ester, half acid ) which is used directly in step B. The oil has acceptable NMR spectra after deduction of the rnalonate spectra obtained.

Step B; Preparation of (R)-1.1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate.

A solution of crude (R)-1,1-dimethylethyl-6-cyano-5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-oxohexanoate, 43 g (0.126 mol) in 350 ml of tetrahydrofuran is treated with 213 ml tetrabutyl ammonium fluoride solution (1.0 M in hexane). The resulting mixture is stirred for five hours at 25°C. The mixture is treated with 500 ml of water, 300 ml of diethyl ether is added, and the layers are separated. The organic layer is dried (magnesium sulfate) and then filtered through a plug of silica gel using anhydrous diethyl ether. The solvent is removed under vacuum to obtain 21 g of crude (R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxohexanoate with acceptable NMR, MS and IR spectra.

200 MHZ NMR (CDCl 3 ) S 1.48 (s, 9H), 2.62 (m, 2H), 2.89 (d, 2H, J = 6.1), 3.43 (s, 2H), 4 .41 (pentet, 2H, J = 6.1 Hz)

<13>C-NMR (CDC13, 50 MHz) S 25.05, 27.86, 48.03, 50.81, 63.39, 82.43, 117.03, 165.84, 202.03.

MS (Chemical ionization) m/e 228, 200, 172, 154.

FTIR (KBr) 1144.5, 1327.2, 1370.9, 1715.5, 1733.5, 2253.1, 2934.6, 2980.9, 3459.3 cm"<1>.

Step C: Preparation of fR-(R*.R*) 1-1.1-dimethylethyl-6-cyano-3,5-dihydroxyhexanoate.

Crude (R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxohexanoate, 21 g (0.0924 mol), is dissolved in 940 ml of tetrahydrofuran and 190 ml of methanol under a nitrogen atmosphere. This solution is cooled to -85°C, and 95 ml of a 15% solution of methoxydiethylborane in tetrahydrofuran is added. The reaction is cooled to -97°C and 6.5 g (0.172 mol) sodium borohydride is added in 0.5 g portions over 1.5 hours. The reaction is kept between -93°C and -97°C for 13 hours and is allowed to warm to room temperature and is left under a nitrogen atmosphere for 60 hours. The reaction is stopped by the addition of 25 ml (0.395 mol) of acetic acid and concentrated by vacuum distillation to an oil. The residue is dissolved with 500 ml of methanol, concentrated by vacuum distillation, redissolved with 500 ml of methanol and concentrated again by vacuum distillation to obtain a dark, brown oil. This oil is taken up in 500 ml of ethyl acetate and filtered through a plug of silica gel using 250 ml of ethyl acetate. The solution is evaporated to obtain 15 g of crude [R-(R*,R*)]-1,1-dimethylethyl-6-cyano-3,5-dihydroxyhexanoate which is used without further purification.

Step D: Preparation<g> of ( 4R- cis )- 1. 1- dimethylethyl- 6-cyanomethyl- 2. 2- dimethyl- 1. 3- dioxane- 4- acetate.

Crude o [R-(R * ,R *)]-1,1-dimethylethyl-6-cyano-3,5-dihydroxy-hexanoate, 15 g (61 mol), dissolve in 150 ml 2,2-dimethoxypropane, camphorsulfonic acid is added, and the solution is stirred for 18 hours at room temperature. Concentration and flash chromatography after concentration in vacuo gives 11.8 g of (4R-cis)-1,1-dimethylethyl-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate as an off-white solid ,

m.p. 64.7-68°C with acceptable IR, NMR, C-NMR and analysis.

200 MHZ NMR (CDCl 3 ) S 1.36 (m, 1H), 1.42 (s, 3H), 1.49 (s, 9H), 1.50 (S, 3H), 1.79 (dt, 1H , J = 2.5 Hz, J = 12.1 Hz), 2.40 (dd, 1H, J = 6.2 Hz, J = 15.4 Hz), 2.5 - 2.7 (m, 1H ), 2.55 (d, 2H, J = 6.1 Hz), 4.18 (m, 1H), 4.32 (m, 1H).

<13>C-NMR (CDC13, 50 MHz) S 19.74, 25.09, 28.24, 29.88, 35.58, 42.50, 65.20, 65.81, 80.87, 99 .48, 116.68, 169.75.

GC/MS m/e 254, 198, 154, 138, 120, 59, 57, 43, 41.

FTIR (KBr) 941.4, 1116.2, 1154.8, 1188.3, 1257.7, 1293.7, 1309.1, 1368.3, 1725.8, 2361.1, 2983.5, 2996.4 cm "<1.>

Step E: Preparation of (4R-cis)-1.1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1.3-dioxane-4-acetate.

A solution of (4R-cis)-1,1-dimethylethyl-6-cyanomethyl-2,2-dimethyl-1,3-dioxane-4-acetate, 5.63 g (0.048 mol), in 100 ml of methanol saturated with gaseous ammonia is treated with 0.5 g Raney nickel #30 and hydrogen gas in a shake flask at 50 psi and 40°C. After 16 hours, thin-layer chromatography shows no presence of starting nitrile. The suspension is cooled, filtered through filter aid and concentrated to an oil. This crude oil is purified by flash chromatography on silica gel with 30:20:1 (ethyl acetate:methanol:ammonium hydroxide) as eluent to obtain 4.93 g of (4R-cis)-1,1-dimethylethyl-6-(2-aminoethyl)- 2,2-dimethyl-1,3-dioxane-4-acetate (98.2 area %) as a clear oil with acceptable IR, NMR, C-NMR and MS spectra.

200 MHZ NMR (CDCl 3 ) 1.0 - 1.2 (m, 1H), 1.22 (s, 3H), 1.31 (s, 12H), 1.35 - 1.45 (m, 3H) , 2.15 (dd, 1H, J = 15.1 Hz, J = 6.2 Hz), 2.29 (dd, 1H, J = 15.1 Hz, J = 7.0 Hz), 2.66 (t, 2H, J = 6.6 HZ), 3.82 (m, 1H), 4.12 (m, 1H).

<13>C-NMR (CDC13, 50 MHz) S 19.60, 27.96, 30.00, 36.50, 38.25, 39.79, 42.61, 66.08, 67.18, 80 .21, 98.35, 169.82.

GC/MS w/e 202, 200, 173, 158, 142, 140, 114, 113, 100, 99, 97, 72, 57.

FTIR (neat) 951.6, 1159.9, 1201.1, 1260.3, 1314.3, 1368.3, 1381.2, 1731.0, 2870.3, 2939.8, 2980.9, 3382.2 cm "<1>.

Step F: Preparation of (4R-cis)-1,1-dimethylethyl-6-f2f2-f4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl - 1H-pyrrole-1-yl]ethyl]-2.2-dimethyl-1.3-dioxane-4-acetate»

A solution of (4R-cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate, 1.36 g (4.97 mol), and (±)-4-fluoro-α-[2-methyl-1-oxopropyl]—r-oxo-N,Æ-diphenylbenzenebutanamide mixture of [R-(R<*>,R*)], [R-(R *,S*)], [S-(R<*>,R*)] and [S-(R<*>,S<*>)] isomers, 1.60 g (3.83 mol), i 50 ml of heptane:toluene (9:1) is heated under reflux for 24 hours. The solution is cooled slightly, and 15 ml of 2-propanol is added. The mixture is allowed to cool to 25°C and filtered to obtain 1.86 g of (4R-cis)-1,1-dimethylethyl-6-[2[2-(4-fluorophenyl)-5-(1-methylethyl)- 3-Phenyl-4-[(phenylamino)carbonyl]-1H-pyrroi-1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate as a yellow solid with acceptable PNMR & C- NMR spectra.

1 H-NMR (CDCl 3 , 200 MHz) S1- 1.7 (m, 5H), 1.30 (s, 3H), 1.36 (s, 3H), 1.43 (s, 9H), 1, 53 (d, 6H, J = 7.1 Hz), 2.23 (dd, 1H, J = 15.3 Hz, J = 6.3 Hz), 2.39 (dd, 1H, J = 15.3 Hz, J = 6.3 Hz), 3.5 - 3.9 (m, 3H), 4.0 - 4.2 (m, 2H), 6.8 - 7.3 (m, 14H).

<13>C-NMR (CDC13, 50 MHz) 5 19.69, 21.60, 21.74, 26.12, 27.04, 28.12, 29.95, 36.05, 38.10, 40 .89, 42.54, 65.92, 66.46, 80.59, 98.61, 115.00, 115.34, 115.42, 119.52, 121.78, 123.36, 126.44 , 128.21, 128.31, 128.52, 128.75, 130.43, 133.01, 133.17, 134.69, 138.38, 141.47, 159.72, 164.64, 169 ,96.

Step G: Preparation of (2R-trans)-5-(4-fluorophenyl)-

2-(1-methylethyl)-N.4-diphenyl-1-r2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide.

(4R-cis)-1,1-dimethylethyl-6-[2[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)-carbonyl]-1H-pyrrole -1-yl]ethyl]-2,2-dimethyl-1,3-dioxane-4-acetate, 4.37 g (6.68 mol),

is dissolved in 200 ml of tetrahydrofuran, and 15 ml of 10% hydrochloric acid solution is added, and the solution is stirred for 15 hours. Sodium hydroxide (3.6 g) is added to this solution, and the mixture is stirred for 30 hours. The reaction is stopped by adding 150 ml of water, 90 ml of hexane, and the layers are separated. The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 150 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution, and the solution stands for 18 hours. The solution is concentrated in vacuo, and the concentrate is redissolved in 50 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 3.0 ml of toluene. (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- yl)ethyl]-1H-pyrrole-3-carboxamide (3.01 g) is isolated in two yields.

PROCEDURE B

A solution of (4R-cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate, 2.56 g (9.36 mol), and (±)-4-fluoro-α-[2-methyl-1-oxopropyl]—r-oxo-N,/J-diphenylbenzenebutanamide mixture of [R-(R<*>,R<*>)], [R -(R<*>,S<*>)], [S-(R*,R*)] and [S-(R*,S*)] isomers, 3.00 g (7.20 mol) , in 60 ml of heptane:toluene (9:1) is heated under reflux for 24 hours. The solution is cooled and poured into 300 ml of tetrahydrofuran and 150 ml of saturated ammonium chloride in water. The layers are separated, and the organic layer is added to 15 ml of 10% hydrochloric acid solution, and the solution is stirred for 15 hours. Sodium hydroxide (3.6 g) is added to this solution, and the mixture is stirred for 30 hours. The reaction is stopped by adding 150 ml of water, 90 ml of hexane, and the layers are separated. The aqueous layer is acidified with dilute hydrochloric acid solution, stirred for three hours and extracted with 150 ml of ethyl acetate. A drop of concentrated hydrochloric acid is added to the ethyl acetate solution, and the solution stands for 18 hours. The solution is concentrated in vacuo, and the concentrate is redissolved in 50 ml of ethyl acetate and treated with one drop of concentrated hydrochloric acid. The solution is stirred for two hours, concentrated in vacuo and dissolved in 3.0 ml of toluene. (2R-trans)-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- yl)-ethyl]-1H-pyrrole-3-carboxamide (2.92 g) is isolated in two yields.

MANUFACTURE OF STARTING MATERIALS

EXAMPLE A

1-(4-fluorophenyl)-1,4-hexanedione.

A mixture of 36.61 g (295 mmol) 4-fluorobenzaldehyde, 25 g (297.2 mmol) ethyl vinyl ketone, 29 ml (206.9 mmol) triethylamine and 11.94 g (44.25 mmol) 3-benzyl-5 -(2-hydroxyethyl)-4-methylthiazolium chloride is stirred and heated at 70°C for six hours. The cooled solution is diluted with 2 liters of diethyl ether and washed with 2 x 300 ml water, 2 x 100 ml 2M hydrochloric acid, 100 ml water, 200 ml saturated solution of sodium bicarbonate and saline. The organic layer is separated, dried (magnesium sulfate), filtered and concentrated to obtain 55 g of 1-(4-fluorophenyl)-1,4-hexanedione after recrystallization from methanol,

m.p. 56-57°C.

EXAMPLE B

4- methyl- 3- oxo- N- phenylpentanamide

Into a three-necked, 12 L round-bottomed flask equipped with a mechanical stirrer, a thermometer and installation for distillation are charged 2.6 L of toluene, 1.73 kg (12 mol) of methyl 4-methyl-3-oxopentanoate and 72 g (1, 18 mol) ethylenediamine. The mixture is heated to 80°C, and 0.49 kg of aniline is added. The mixture is refluxed and distillation is started. After 40 minutes, a further 0.245 kg of aniline is added, and at 40 minute intervals two further portions of aniline (0.245 and 0.25 kg) are added. Distillation is continued for another one to five hours, until a total of 985 ml of solvent is removed. The solution is stirred at room temperature for 16 hours, and an additional 550 ml of solvent is removed by distillation in vacuo (using about 85 mm Hg). The mixture is cooled, and 2 1 of water is added to obtain an oil. The mixture is heated to 40°C, and a further 1.0 1 of water is added. Seven hundred milliliters of toluene-water mixture is removed by distillation in vacuum (approx. 20 mm Hg). Two liters of water are added, and the mixture stands for 10 days. The product is isolated by filtration and washed with three portions of hexane. Drying in vacuum gives 1.7 kg of 4-methyl-3-oxo-

N-phenylpentanamide as a hydrate,

m.p. 46.5-58.8°C.

HPLC: 98.8% - retention time 3.56 min. 65/35 acetonitrile/water on a dry basis.

VPC: 87.6% - retention time 12.43 min. also 10.8% aniline (dec.).

Claims (10)

1. Connection, characterized by formula IV where R? and Rg independently of each other are hydrogen, alkyl of one to three carbon atoms, phenyl, or R_ / and RoQ together are -(CH £ ) n -, where n is 4 or 5, and Ry_ is alkyl of one to eight carbon atoms, a three- to six-membered cycloalkyl group or α,α-dimethylbenzyl. 2. A compound according to claim 1, characterized in that a) Rg is b) R? and Rg is methyl, and Rg is isopropyl, or c) R? and Rg is methyl, and Rg is tertiary butyl, or d) it is (4R-cis)-1,1-dimethylethyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4- acetate. 3. Connection, characterized by formula V where R7 and Rg independently of each other are hydrogen, alkyl with one to three carbon atoms, phenyl, or R_ / and RoQ together are - (CH2)n~, where n is 4 or 5, and Rg is alkyl with one to eight carbon atoms, a three- to six-membered cycloalkyl group or α,α-dimethylbenzyl. 4. Connection according to claim 3, characterized in that a) R7 and Rg are methyl, and Rg is isopropyl, or b) R7 and Rg are methyl, Rg is tertiary butyl, and the two optically active centers are R. 5. Connection, characterized by formula VI where R_ / and R o independently of each other are hydrogen, alkyl with one to three carbon atoms, phenyl, or R_ / and R o together are - (CH2)n~, where n is 4 or 5. 6. Connection according to claim 5, characterized in that R_ and R_ are methyl, and the two optically active centers are R. 7. Connection, characterized by formula VII where R7 and Rg independently of each other are hydrogen, alkyl with one to three carbon atoms, phenyl, or R„ / and Ro0 together are - (CH2)n~, where n is 4 or 5. 8 . Connection according to claim 7, characterized in that R„ and R are methyl, and the two optically active centers are R. 9 . Connection, characterized by formula VIII where R-, and R_ independently of each other are hydrogen, alkyl with one to three carbon atoms, phenyl, or R? and Rg together are - (CH2)n-, where n is 4 or 5. 10. Connection according to claim 9, characterized in that R_ / and R o are methyl, and the two optically active centers are R.