Process for the preparation of oxetanones

Process for the preparation of oxetanones for

The present invention relates to a novel process for the preparation of oxetanones of general formula.

<img file="PT96857B_D0001.tif" />

(I) in which

R 2 and R 2 each represent an alkyl group having a chain of up to 17 carbon atoms optionally interrupted by an oxygen atom at any position other than the 4 'or 4' positions; or benzyl optionally having from 1 to 3 substituents selected from C1-6 alkyl or alkoxy groups

X represents a hydrogen atom or a group of formula (RgR4) NCH (R4) (C1-4) -CO- wherein Rg represents a hydrogen atom or an alkyl or alkanoyl group R4 represents a hydrogen atom or a C1 -C4 alkyl group R4 represents a hydrogen atom or an Ar or Ar-alkyl group

-2C₁_₃ or C1-4 alkyl₇ optionally interrupted by a radical represented by Y and optionally having as substituent a radical represented by Z, Ar representing a phenyl group optionally having 1 to 3 substituents selected from groups of formula Rg or 0R_g wherein Rg represents a hydrogen atom or a C1-4 alkyl group₃; Y represents an oxygen or sulfur atom or a group of the formula N (Rg), C (O) N (Rg) or N (Rg) C (O) wherein Rg represents a hydrogen atom or a C1-4 alkyl group - ^ _₃; Z represents a group of formula - (0 or S) -R_?, -N- (R_?, R₈), -C (O) N (R)₇, R_g) or -N (R₇) C (O) Rg wherein R4 and Rg each represent a hydrogen atom or a C1-4 alkyl group₁_₃; en represents zero or the integer 1 with the proviso that Rg represents a hydrogen atom when n represents the integer 1; or R ^ and Rg form, together with the nitrogen atom to which they are attached, form a tetragonal, pentagonal or hexagonal saturated nucleus, and the salts of the oxetanones of formula I wherein X is not a hydrogen atom of acids weak.

The present invention further relates to novel intermediate compounds occurring in said process.

The compounds of formula I are known from European Patent No. 185,359A2. They possess valuable pharmacological properties. In particular, they inhibit pancreatic lipase and can therefore be used to control or prevent disease, especially obesity, hyperlipemia, even rosclerosis and arteriosclerosis.

The process according to the present invention consists of:

a) etherify an Î ± -hydroxy-lactone of formula tf

<img file="PT96857B_D0002.tif" />

II

b) open the resulting ether of general formula

<img file="PT96857B_D0003.tif" />

III in which

T represents a removable facuying group by means of a base,

c) reacting the resulting salt of formula

R₂-CHOHCH₂CH (0-T) CH (R) COO-M IV in which

M represents an alkaline or alkaline earth metal in an optional sequence with an arylmethyl halide and a base; and

(d) selectively cleaving the resulting diester of general formula

R₂-CH (OCH₂-Ar) CH₂CH (0-T) CH (^) COO-M (V) by the action of an acid,

e) subjecting to a resulting ο β-hydroxy acid cyclization reaction of the general formula

R₂-CH (OCH₂-Ar) CH₂CHOHCH (4) COOH (VI) optionally after resolution in the respective enantiomers;

f) cleaving the resulting β-lactonic ether of general formula

<img file="PT96857B_D0004.tif" />

(VII) and

(g) optionally esterifying the resulting lactone alcohol of formula I, wherein X represents a hydrogen atom, with an agent capable of introducing a group represented by X, and

h) optionally isolating the ester obtained as a salt of a weak acid.

Alkyl groups are straight or branched chain hydrocarbon residues, such as methyl, ethyl, propyl, isopropyl, butyl iso-

<img file="PT96857B_D0005.tif" />

/ butyl, pentyl, hexyl, undecyl, hexadecyl and heptadecyl.

Phenyl, tolyl and xylyl are examples of aryl groups. Pyrrolidinyl and pyridinyl are examples of tetragonal to hexagonal saturated nuclei.

Examples of weak acids which may form salts with the compounds of formula I, β-toluenesulfonic acid, methanesulfonic acid, oxalic acid, ascorbic acid, fumaric acid, maleic acid, malic acid, citric acid and phosphoric acid.

Examples of easily removable ether groups are tetrahydro-2H-pyran-2-yl ethers (THP), 1-ethoxyethyl and the like. such as trialkyl or mono - (aryl (C 1-4) alkyl} dia (C 1-4) alkylsilyl, for example t-butyl dimethylsilyl.

tetrahydro-2H-pyran-2-yl ether (THP) of formula III may be prepared by reacting a 2-hydroxy-lactam of formula II with 3,4-dihydro-2H- pyran at a temperature of about 50 ° C in a solvent such as methyl t-butyl ether (TBME), tetrahydrofuran (THF) or toluene in the presence of catalytic amounts of acid such as pyridinium toluenesulphonate or p -toluenesulphonic acid. 0 THP ether of general formula III may then be opened using sodium hydroxide or potassium hydroxide.

A silyl ether of formula III may be prepared by reacting one-hydroxy-lactone of formula II with a silyl halide such as t-butyldimethylsilyl chloride in the presence of a base such as ethyldiisopropylamine in a solvent such as dimethylformamide (DMF) under heating at a temperature

50 ° and 100 ° C. The silyl ether III may be opened with an alkali metal or alkaline earth metal base such as potassium hydroxide in a solvent such as dioxane.

An alkali metal hydride such as sodium hydride or preferably an alkali metal t-butylate, conveniently sodium t-butylate may be used as the basis for the etherification of the alkali metal salt or of alkaline earth metal of formula IV to diester of formula V. This esterification may be effected by treating the IV salt with, for example, benzyl bromide and sodium hydride or with sodium t-butylate in a solvent such as THF or TBME.

A diester of formula V may be selectively cleaved with an acid such as hydrochloric acid in the case of THP ether or with acetic acid in the case of a silyl ether at a temperature of up to 60 ° C. ° C.

Eventually the resolution of a racemic -hydroxy acid of formula VI may be carried out using a chiral amide such as (R) - (+) - or (S) - (-) -0 (-methylbenzylamine). of a solvent, such as an ester, for example methyl acetate or ethyl acetate.

A β-hydroxy acid of formula VI may be cyclized with an arylsulfonyl halide such as, for example benzenesulfonyl chloride in a solvent such as pyridine, with cooling to -10 ° C.

The cleavage of a 3-lactonic ether of formula VII may be carried out by hydrogenation in a solvent, such as, for example, a hydrocarbon or a halogen hydrocarbon.

hexane or methylene chloride, or with an ester or ether, for example ethyl acetate or tetrahydrofuran, with a catalyst, such as palladium on carbon (Pd / C), at a temperature up to about 40 ° C. Ç.

The optional esterification of a β-lactone alcohol of formula I wherein X represents a hydrogen atom with an acid of formula (R₃, R₄) NCH (R₅) '(CH₂)_no-COOH may be carried out in the presence of triphenylphosphine and diethyl azodicarboxylate in a solvent, such as an ether, for example tetrahydrofuran, at a temperature up to about -15 ° C.

An α-hydroxy acid of formula VI, cited above, may also be prepared by;

a) esterifying a salt of formula IV above with a halide of formula R1 -Hal in which Κ_1θ represents a C1-4 alkyl group₄ or arylalkyl ^Ç1-4 '

b) etherification of the resulting ester of general formula

R₂-CHOHCH₂CH (0-T) CH (R) COO-R₁₀ (IVa) and

(c) a possible saponification and scission sequence at position p of the resulting diester of formula R₂-CH (OCH₂-Ar) CH₂CH (0-T) CH (R) COO-R_1Q (GO)

Esterification of a salt of formula IV with a halide of formula R 1 -Hal, for example with benzyl bromide, may be carried out in a solvent such as tetrahydrofuran.

Etherification of the alcohol ester of general formula

-8IV-A may be carried out with a chloride of formula Ar-CH₂OC (NH) CCl 4, for example with benzyl 2,2,2-trichloroacetimidate, in the presence of an acid such as trifluoromethanesulfonic acid in a solvent such as cyclohexane, hexane or methylene chloride.

A diester of formula VA may first be treated with an acid such as, for example, aqueous acetic acid in the case of a silyl ether, or hydrochloric acid in the case of THP ether in a solvent such as such as dioxane at a temperature up to the reflux temperature of the reaction mixture and subsequent saponification in a solvent, such as an alkanol, for example methanol, using a strong base, such as an alkali metal or alkaline earth metal hydroxide, for example potassium hydroxide, at a temperature up to about 70 ° C.

It is also possible to prepare o-hydroxy acid of general formula VI by:

a) esterification of a ^ 5-hydroxy-lactone of formula II

b) opening of the resulting ester of general formula

<img file="PT96857B_D0006.tif" />

in which

Representa 'represents an aroyl group by acid catalysis in the presence of an alcohol of formula Ηΐθ-ΟΗ to give an ester of formula

-9*

R₂-CHOHCH₂CH (Q-τ ') CH (R) COOR₁₀ (IV-B)

c) etherification of the. ester of formula IV-B and

d) double saponification of the ether diester resulting from the general formula

R₂-CH (OCH₂-Ar) CH₂CH (O-T ') CH (R ^) COO-Ε ^ θ (VB)

Esterification of the β-hydroxy-lactone of formula II may be carried out, for example, with a functional derivative of an acid of formula Ar-COOH, for example an acid halide or an acid anhydride such as such as benzoic anhydride, and a strong acid such as perchloric acid or a base such as dimethylaminopyridine as a catalyst in a solvent such as toluene and subsequent opening of the ester of formula III.¹ carried out by acid catalysis, for example in the presence of an acid such as sulfuric acid or hydrochloric acid, with an alcohol of formula R R-OH, for example a lower alkanol, such as methanol, optionally in a solvent such as toluene at a temperature up to 60 ° C.

Etherification of the alcohol ester of general formula

IV-B may be carried out analogously to the etherification of the alcohol ester of formula IV-A described above.

Saponification of an ether diester of general formula

V-B may be carried out in a solvent, such as an alkanol, for example methanol, using a strong base such as an alkali metal hydroxide or an alkaline earth metal hydroxide, namely potassium hydroxide. at a temperature up to about 70 C.

-10ζ

X, • ΛΜ »

The β-hydroxy-lactones of general formula are stopped by:

II may need

a) saponification of an α-hydroxyester of formula r₂-chohch₂coo-r (VIII) in which

R represents an alkyl group

b) reaction of the 4-hydroxy acid imidazolyl resulting from general formula r₂-chohch₂cooh (IX) with a magnesium salt of a malonic acid ester derivative of general formula

HOCOCH (R) COO-R (X)

c) cyclization of the resulting Q-hydroxy-ketoester of general formula

R₂-CHOHCH₂COCH (R) COO-R (XI) and

d) catalytic hydrogenation of the resulting β-keto-lactone of formula

<img file="PT96857B_D0007.tif" />

(XII)

7-11i

Saponification of the 4-hydroxyester of general formula

VIII may be carried out in a solvent, such as dioxane, with a base such as sodium hydroxide in a solvent such as methanol.

The magnesium salt of the malonic acid ester derivative of formula X may be prepared by reacting the malonic acid diester CH₂(COOR)₂ with a solution of sodium methylate in methanol and a halide of formula I-Hal, for example a bromide, at a temperature up to the refluxing temperature of the solvent. The resulting diester derivative of the malonic acid of formula R 1 -CH (COOR)₂ It is then hydrolyzed with an alkali metal hydroxide, for example with potassium hydroxide, in a lower alkanol of the formula R-OH, such as methanol, to obtain a monoester of the formula Xe, subsequently converted to this in the desired magnesium salt with magnesium chloride in tetrahydrofuran in the presence of triethylamine at 0 ° C.

The 4-hydroxy acid imidazolide of formula IX may be prepared by reacting it with tetrahydrofuran with 1,1'-carbonyl diimidazole.

The magnesium salt of the monoester X may be reacted at room temperature with the hydroxide imidazolide of the general formula IX to give the Î ± -hydroxy-β-ketoester of the general formula XI.

This latter compound may be cyclized in a solvent, such as ethyl acetate, with an acid, such as hydrochloric acid, or with a base, such as sodium hydroxide, to give a β-keto-β. -lactone of general formula

XII.

<img file="PT96857B_D0008.tif" />

Catalytic hydrogenation of this lactone to give the Î ± -hydroxy-β-lactone of formula II may be carried out in a solvent, such as, for example, ethyl acetate or an ether such as tetrahydrofuran. in the presence of Raney nickel.

The 4-hydroxy lactones of formula II may further be prepared by:

a) reaction of a β-ketoester of general formula

CH2 COCH (R4) COO-R (XIII) with an ester of general formula

R₂-COO-R (XIV)

b) cyclization of the resulting diketide of formula r₂-coch₂coch₂ (Rj) COO-R (XV) and

c) catalytic hydrogenation of the resulting pyrone of general formula

<img file="PT96857B_D0009.tif" />

R,

OH

XVI

An α-ketoester of formula XIII may be prepared by alkylation of the corresponding α-ketoester of formula CH ^COC COCOOR with a halide of the formula R ^ -Hal, for example a bromide, in a methanolic solution of a methylate. sodium chloride at a temperature to the reflux temperature of the reaction mixture.

(«Ρ

The reaction of an α-ketoester of formula XIXI with an ester of formula XIV may be carried out in the presence of sodium hydride in a solvent, such as tetrahydrofuran, in the presence of butyl ester. lithium in hexane, with cooling, for example at -10 ° C.

Cyclization to form a pyrone of formula XVI may be carried out in a solvent, such as toluene, in the presence of 1,8-diazabicyclo-2f 5,4,0 ^ undec-7-ene (1, 5.5) (DBU).

Pyrone of formula XVI may be hydrogenated to form a -hydroxy lactone of formula II in the same manner as described above for catalytic hydrogenation of beta-keto-lactone of formula XII.

The β-keto - / - lactone of formula XII may also be prepared by:

a) reaction of an α-ketoester of general formula

CH.jCOCHdtjP COO-R (XIII) with an aldehyde of formula r₂-cho (XVII) and

b) cyclization of the resulting 4-hydroxy-ketoester of formula XI.

The reaction of the β-ketoester of formula XIII with the aldehyde of formula XVII may be carried out in the same manner as the reaction with an ester of formula XIV described above.

The cyclization of the β-hydroxy- / 3-ketoester of formula

XI to form a β-keto lactone of formula XII may be carried out in the presence of water, advantageously at room temperature.

In addition, the keto-lactones of formula XII may be prepared by:

a) etherification of a 4-hydroxyester of formula r₂-chohch₂coo-r (VIII)

b) saponification of the resulting ether of general formula

R₂-CH (OCH₂-Ar) CH₂COO-R (XVIII)

c) halogenation of the resulting ether acid of general formula

R₂-CH (OCH₂-Ar) CH₂COOH (XIX)

d) reaction of the resulting acid halide with Meldrum acid,

e) hydrogenolysis of the resulting compound of general formula

<img file="PT96857B_D0010.tif" />

and cyclization to form a β-keto lactone of general formula

<img file="PT96857B_D0011.tif" />

f) reacting the previously mentioned keto-lactone of formula XXI with an aldehyde capable of introducing a group represented by R4 or a group of formula having the formula

R - ^ - CHO (XXII) in which

Ru. together with the methylene group represents the group represented by the symbol R ^ to obtain the β-keto-L-lactone of formula XII, cited above.

Etherification of the α-hydroxy ester of formula VIII to an ester of formula XVIII may be carried out in a solvent such as cyclohexane, for example with benzyl trichloroacetimidate in the presence of trifluoromethanesulfonic acid at temperature up to 30 ° C.

Saponification of the ester of formula XVIII to an ether of acid of formula XIX may be carried out with an alkali metal hydroxide such as potassium hydroxide in a solvent such as methanol.

The ether of acid of formula XIX may be halogenated with oxalyl chloride in a solvent such as methylene chloride at a temperature up to approximately 25 ° C.

The reaction of the resulting acid halide with Meldrum acid may be carried out in a solvent such as methylene chloride in the presence of a base such as pyridine with cooling to -10 ° C.

Hydrogenolysis and cyclization of the compound of formula XX to give the β-keto-lactone of formula XXI may be carried out in a solvent such as ethyl acetate using a catalyst. , such as palladium on charcoal.

The reaction of the β-keto-lactone of formula XXI with the aldehyde of the formula R ^ -CHO to give a β-keto-lactone of formula XII is carried out, for example, with one with borane amine plexus, such as borane triethylamine, borane trimethyl amine or borane morpholine, in a solvent such as methanol, at a temperature of up to 50 ° C.

The β-keto lactone of formula XXI may also be prepared as follows:

a) reacting the 4-hydroxy acid imidazolide of formula R₂-chohch₂cited above, with the magnesium salt of a lower alkyl malonate, and

b) subjecting to a cyclization reaction the resulting S-hydroxy-ketoester ester of general formula

R₂CHOHCH₂COCH₂COO-R (XXIII) to obtain the lactide keto-ketone of formula XXI, cited above.

The preparation of the magnesium salt of a lower alkyl mononate malonate, the reaction of this salt with the Î ± -hydroxy acid imidazolide of formula IX to obtain a β-hydroxy keto ester of formula XXIII and its cyclization to give the β-keto-lactone of formula XXI can be carried out as described above for the preparation of the β-hydroxy-lactones of formula II via the hydroxy acid imidazolide of

-ηV χ

general formula IX and magnesium salt of the. ester of malonic acid of formula X.

A preferred aspect of the process of the present invention is to react a β-ketoester of formula XIII with an aldehyde of formula XVII, to cyclize the resulting β-hydroxy-tetraester of formula XI to give the β-keto Lactone of formula XII, catalytically hydrogenate this compound and converting the resulting β-hydroxy-lactone of formula II to an ester of formula I by the compounds of formula III to VII according to the procedure described above. .

The preparation of the ester of formula I wherein R 4 represents an n-hexyl group and represents an undecyl group is especially preferred.

The following β-hydroxy-β-lactones, β-keto- β-lactones and pyrones which are covered by the general formulas II, XII and XVI, as appropriate, are novel and as such are the subject of this invention:

rac- (2RS, 3RS, 5SR) -2-hexyl-3-hydroxy-5-undecyl-6-valeriolactone, rac- (2RS, 3RS, 5SR) -2-ethyl-5-heptadecyl-3-hydroxy- (2S, 3S, 5R) -2-Ethyl-5-heptadecyl-3-hydroxy-β-valeriolactone and rac- (2RS, 3RS, 5SR) -2-hexyl-3-hydroxy-5-pentyl-1-yl valeriolactone;

rac-5,6-dihydro-3-hexyl-4-hydroxy-6-undecyl-2H-pyran-2-one,

-18- / (R) -3-ethyl-5,6-dihydro-6-heptadecyl-4-hydroxy-2H-pyran-2-one and rac-5,6-dihydro-3-hexyl -4-hydroxy-6-pentyl-2H-pyran-2-one;

3-hexyl-4-hydroxy-6-undecyl-2H-pyran-2-one,

3-ethyl-6-heptadecyl-4-hydroxy-2H-pyran-2-one and

3-hexyl-4-hydroxy-6-pentyl-2H-pyran-2-one.

The α-keto-β-lactones of general formula XXI, wherein R 1 has the meaning defined above, but wherein the number of carbon atoms in the alkyl group represented by ® is greater than 9, especially as follows:

(R) -5,6-dihydro-6-undecyl-2H-pyran-2,4 (3H) -dione and (R) -5,6-dihydro-6-heptadecyl-2H-pyran-2 4,4 (3H) -dione are new and are the subject of the present invention;

Example 1

(a) 465 g of methyl acetoacetate were added dropwise under nitrogen with stirring to 720 g of a 30% sodium methylate solution in 1200 ml of methanol. Then 727 g of 1-bromohexane was added and the reaction mixture was refluxed for 20 hours. Most of the methanol was distilled off and the residue was poured into ice / water. The mixture was extracted with n-hexane and then water. The organic phases were combined and dried with sodium sulfate. The solvent was evaporated and the crude ester was distilled off. 499.4 g of methyl 2-acetyloctanoate were obtained. PE 124 ° -128 ° C / 15 Torr.

b) 200.3 g of methyl 2-acetyloctanoate was added to a suspension of 26.4 g of sodium hydride in 1250 ml of tetrahydrofuran. After stirring at 0 ° to 5 ° C for 1 hour, the mixture was cooled to -10 ° C. 675 ml of a 1.56 M butyl lithium solution in hexane were added at the same temperature. After stirring at -10 ° C for 30 minutes, 107.2 g of methyl laurate was added dropwise. The mixture was stirred at -10 ° C for a further 1 hour. The reaction solution under argon was added to 250 ml of 37% hydrochloric acid and 300 g of ice. The mixture was extracted with hexane and water. The organic phases were combined, dried, filtered and evaporated.

The residue (290.5 g) was dissolved in 1250 ml of toluene, treated with 76.1 g of DBU and refluxed under atmos. argon beast for 30 minutes. The reaction solution was extracted with toluene with 3N hydrochloric acid and water. The toluene phases were combined and evaporated at 40 ° C. The product was dissolved in hexane and cooled to room temperature with stirring. After stirring at -10 ° C for 17 hours the crystallized substance was filtered under suction, washed with hexane and dried. 123.9 g (yield 70.7%) of 3-hexyl-4-hydroxy-6-undecyl-2H-pyran-2-one were obtained. MP: 83 ° -84 ° C.

c) 100 g of Raney nickel and 2000 ml of ethyl acetate were added to 100 g of pyrone from step b). After hydrogenation for 17 hours with stirring at 30 ° C, the catalyst was removed by suction filtration and washed with ethyl acetate. The filtrate was concentrated and stirred overnight at -10 ° C. The crystallized was filtered off under

-^2θAfter suction, it was washed with ethyl acetate and then dried. 90.7 g (89.7% yield) of rac- (2RS, 3RS, 5SR) -2-hexyl-3-hydroxy-5-undecyl-β-valerolactone mp 98 ° -99 ° C.

d) 177.3 g of the β-lactone from step

c) in 1250 ml of toluene under stirring. After addition of 138.6% benzoic anhydride, the mixture was stirred for 10 minutes. Then 2.5 ml of perchloric acid was added, the mixture was stirred for a further 2.5 hours. The reaction solution was extracted with toluene with 1 N sodium hydroxide solution and then with water. The toluene phases were combined, dried, the drying agent was removed by suction filtration and washed with toluene. Evaporation of the solvent gave 237.2 g (103.4% yield) of rac- (2RS, 3RS, 5SR) -3-benzoyloxy-2-hexyl-5-undecyl-valerolactone which was used in the next step. without further purification.

e) 236 g of benzoate from step d) was treated in 1250 ml of methanol under argon and with stirring with

2.5 ml of concentrated sulfuric acid and stirring was continued for an additional 18 hours. Thereafter, the pH of the reaction solution was adjusted to 9 with triethylamine and the methanol was evaporated. The residue was taken up in hexane, washed with water and the aqueous phase extracted with hexane. After drying, the combined hexane phases were filtered. The filtrate contained no hexane. 253-g (105.5% yield) of methyl rac- (2RS, 3RS, 5SR) -3-benzoyloxy-2-hexyl-5-hydroxyhexadecanoate was used for the next step without purification. .

(f) 258 g of the hydroxy ester from step e) was treated in 1250 ml of hexane under argon with stirring with

<img file="PT96857B_D0012.tif" />

152 g of benzyl 2,2,2-trichloroacetomidate. Then 3.2 ml of trifluoromethanesulfonic acid were added. After stirring for 17 hours the precipitate was filtered off under suction and washed with hexane. The filtrate was extracted with 5% sodium hydrogen carbonate solution and then with water. The hexane phase was dried, filtered and evaporated to give 320 g (110% yield) of rac- (2RS, 3RS, 5SR) -3-benzoyloxy-5-benzyloxy-2-hexyl methyl hexadecanoate.

g) 319 g of the benzyl ether from step f) was treated in 1125 ml of methanol under argon with a solution of 140 g of potassium hydroxide in 125 ml of water. The reaction mixture was stirred at 40 ° C for 17 hours and then concentrated. The suspension was extracted with n-hexane with 10% sodium chloride solution and then with 1N hydrochloric acid. The organic phases were combined, dried over sodium sulfate, the drying agent removed by suction filtration and washed with hexane. The filtrate was concentrated to 1000 ml and kept at -20 ° C for day. The crystallize was filtered off under suction, washed with n-hexane and discarded. Evaporation of the filtrate gave 169 g (73% yield) of rac- (2RS, 3RS, 5SR) -5-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid.

h) 39.4 g of (S) - (-) - /) (- methylbenzylamine were added dropwise under argon and with stirring) to 169 g of β-hydroxy acid from step g) in 1250 ml of methyl acetate. The solution was seeded with phenethylamine salt and then cooled to -10 ° C. After 17 hours at this temperature, the crystalline slurry was filtered under suction, washed with

Methyl acetate was aspirated and dried. After two further crystallizations with methyl acetate, 56.5g (19.4% yield) of the (2S, 3S, 5R) -5-benzyloxy-2-hexyl-3-hydroxyphenic acid phenethylamine salt were obtained. hexadecanoic. Mp 104 ° -105 ° C.

(i) 56.5g of the phenethylamine salt from step h) was treated with 565 ml of hexane and 120 ml of 1N hydrochloric acid with stirring. The organic phase was washed with water, dried and concentrated. 44.2g (98.8% yield; 19.1% based on (β-lactone from step c)) of (2S, 3S, 5R) -5-benzyloxy-2-hexyl-3 acid hydroxyhexadecanoic acid.

j) 231.5g of the 4-hydroxy acid from

of step i) in 2500 ml of pyridine with stirring and cooling to 0 ° C. Then, 176.6g of benzenesulfonyl chloride was added dropwise. The solution was stirred at 0 ° C for a further 20 hours. Water was then added to the mixture and stirred at room temperature for 30 minutes. Pyridine was evaporated. The crystalline paste was extracted with hexane successively with 2N hydrochloric acid, 5% sodium hydrogen carbonate solution and 10% sodium chloride solution. The hexane phases were combined and concentrated. After drying, activated carbon was added and the mixture was stirred for 1 hour, filtered by suction, washed with hexane and evaporated. 222.1 g (99.9% yield) of (35.45) -4- /^- (R) -2-Benzyloxytridecyl] -3-hexyl-2-oxetanone, which was used in the next step without purification.

K) 222g of the β-lactone from step

j) in 2500 ml of tetrahydrofuran and hydrogenated with 11g of 10% palladium on charcoal for 18 hours. The solution was filtered and washed with tetrahydrofuran. The filtrate was evaporated. Crystals were obtained which dissolved in hexane. After stirring at 5 ° C for 18 hours, the crystallize was filtered off under suction, washed with hexane and dried. 150.5g (84.9% yield) of (3S, 4S) -3-hexyl-4- [(R) -2-hydroxytridecyl] -2-oxetanone was obtained. MP: 61 ° -62 ° C.

Example 2

<img file="PT96857B_D0013.tif" />

Tetrahydrofuran (1000 ml) was stirred with stirring (88.6 g of hydroxy-lactone from Example 1K), 51.7 g of N-formyl (S) -leucine and 98.4 g of triphenylphosphine. A solution of diethyl azodicarboxylate (72.6 g) in tetrahydrofuran (250 ml) was added dropwise with cooling to -10 ° C. The reaction solution was stirred at this temperature for 15 hours and subsequently the solvent was evaporated. The crystalline slurry was partitioned several times between hexane and a 70% methanol / water mixture with stirring. The hexane phases were combined, dried over sodium sulfate, the drying agent removed by suction filtration and washed with hexane. After distillation of hexane, the crude product was dissolved in hexane and slowly cooled to 5 ° C. The crystallize was filtered off under suction, washed with hexane and dried. 98.0 g of N-formyl-L-leucine (S) -1H [2 '(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] -dodecyl ester were obtained. MP: 44 ° -45 ° C.

Example 3

The)

A suspension of methyl (R) -3-hydroxyite-24 tradecanoate (206.7 g) in cyclohexane (1000 ml) was stirred under nitrogen under stirring with benzyl trichloroacetimidate (214.2 g) and dissolved. At 20 ° C, 10 ml of trifluoromethanesulfonic acid were added dropwise with ice / water cooling and thus the temperature maintained at 20 ° to 23 ° C. The resulting suspension was stirred at 25 to 30 ° C. The precipitate was filtered off and the filter cake was washed with cyclohexane, and the filtrates were extracted with saturated sodium hydrogen carbonate solution, water and saturated sodium chloride solution. The organic phase was dried with magnesium sulfate, filtered and the filter cake was washed with cyclohexane and the filtrate was evaporated. 314.5g of methyl (R) -3- (benzyloxy) tetradecanoate were obtained.

b) 314.0 g of the methyl ester from step a) was added to a solution of 89.8 g of potassium hydroxide in 680 ml of methanol. After stirring at room temperature for

18.5 hours, the resulting suspension was poured into 680g of ice and the pH was adjusted to 1 with 200 ml of 25% aqueous hydrochloric acid solution, with cooling to between 0 ° and 7 °. Ç. The resulting emulsion was extracted with methylene chloride, the organic phase was dried over magnesium sulfate, filtered, the filter cake was washed with methylene chloride and the filtrate was evaporated. 277.3g of (R) -3-benzyloxytetradecanoic acid was obtained.

c) 82.5 ml of oxalyl chloride was added dropwise to a solution of 276.5g of acid from step b) in 1400 ml of methylene chloride. After stirring for 3.5 hours, the (R) -3-benzyloxytetra chloride solution was concentrated.

-25./ decanoyl to 450 ml.

d) 164 ml of pyridine was added dropwise to a

At -6 to 0 ° C to a solution of Meldrum acid 122.28 in methylene chloride (900 ml). After stirring at -3 to -1 ° C for 10 minutes, the acid chloride solution from step c) was added dropwise. The resulting suspension was stirred at 0 ° C for 3 hours, then poured into a mixture of 400g ice and 1300ml hydrochloric acid, stirred for 10 minutes and the extracted organic phase separated. with 300 ml of 3N hydrochloric acid. The acidic aqueous phases were extracted with methylene chloride (500 ml), the organic phases were combined and dried with magnesium sulfate, filtered and the filter cake was washed with methylene chloride and concentrated. the filtrates. The solution was treated with silica gel and stirred. The silica gel was filtered off and washed with methylene chloride. The filtrates were concentrated to give 382.2g of 5- [(R) -3-benzyloxy-1-hydroxytetradecylidene] -2,2-dimethyl-m-dioxane-4,6-dione.

e) 33.1 g of 5% palladium on carbon were added to a solution of 381.5 g of the product obtained in step d) in 2500 ml of ethyl acetate. The mixture was hydrogenated for 3.5 hours, the suspension was filtered, the filter cake was washed with ethyl acetate and the filtrates concentrated. The obtained solution was boiled at 79-80 ° C, cooled to room temperature, evaporated and dried. The product was suspended in n-hexane, filtered and the filter cake was washed with n-hexane and the crystals dried. The mother liquor was concentrated, dissolved in n-hexane and left to stand.

-26&amp;

s

K is only at 4 ° C for 72 hours. The precipitated crystals were filtered off, washed with n-hexane and dried. The two crystallized were combined, suspended in water, stirred, filtered, the filter cake was washed with water and the crystals dried. 62.1 g of (R) -5,6-dihydro-6-undecyl-2H-pyran-2,4 (3H) -dione were obtained. MP: 82 ° -85 ° C.

f) Under nitrogen atmosphere, 100.65g of the pandione obtained in step e) was added to a solution of 43.14g of the borane-triethylamine complex in 1000 ml of methanol. The mixture was heated to 40 ° C. To the solution was added dropwise 75.12 g of capronaldehyde and stirred at 41 ° C for 70 minutes, then cooled to room temperature and poured into a water / ice mixture. The suspension was treated with 120 ml of 3N hydrochloric acid with stirring and stirring was continued for 30 minutes. The crystals were removed by suction filtration, washed with water and then dried. The product was suspended in n-hexane, stirred for 30 minutes, filtered under suction, washed with n-hexane and dried. 112.5 g (85% yield) of (R) -5,6-dihydro-3-hexyl-4-hydroxy-6-undecyl-2H-pyran-2-one were obtained. Mp: 106 ° -108 ° C, = -45.6 ° (c = 1% in dioxane).

g) 30.0g of the pyranone obtained in step f) was dissolved in 750 ml of ethyl acetate and, after addition of 30g of Raney nickel, was hydrogenated at room temperature for 24.5 hours. The catalyst was filtered off, washed with ethyl acetate and the filtrate concentrated. The product was dissolved in ethyl acetate at 45 ° C, cooled to 20 ° C in 2 hours and then to -10 ° C in 3 hours and stirred at this temperature for 16 hours, after which it was filtered. The crystals were washed with ethyl acetate and then dried. 25.5 g (85% yield) of (2S, 3S, 5R) -2-hexyl-3-hydroxy-5-undecyl-β-valerolactone were obtained. Mp: 103 ° -104.5 ° C, β (δ).^Ο= + 47.4 ° (c = 1% in chloroform).

(h) A solution of 12.0 g of lactone from step g) in 70 ml of dimethylformamide was treated with 6.77 g of ethyl diisopropylamine and, after addition of 7.64 g of t-butyldimethylsilyl chloride, at 80 ° C for 13 hours with stirring. The reaction mixture was concentrated, taken up with 120 mL of hexane, filtered and the filter cake was washed with 50 mL of hexane. The filtrates were combined and extracted with 3N hydrochloric acid and the organic phase was dried. After filtration and concentration, 15.7 g of (2S, 3S, 5R) -3-t-butyldimethylsiloxy-2-hexyl-5-undecyl-β-valerolactone was obtained.

(i) A solution of 42,2 g of lactone from step h) in 570 ml of dioxane was stirred for 5,5 hours after the addition of 90 ml of 1 N potassium hydroxide solution. The reaction mixture was concentrated and azeotropically dried by addition of toluene and distillation. The residue was dissolved in tetrahydrofuran (250 ml) and, after addition of 23.1 g of benzyl bromide and 4.75 g of 18-crown-6 ether, was stirred for 4 hours. The reaction mixture was concentrated, treated with n-hexane and extracted with 3N hydrochloric acid. The organic phase was dried, filtered and concentrated, whereby 61.7g of benzyl (2S, 3S, 5R) -3-t-butyldimethylsiloxy-2-hexyl-5-hydroxyhexadecanoate was obtained.

(j) A solution of 60,6g of the product obtained in step (i) was treated with 130 ml of methylene chloride and 260 ml of cyclohexane.

With 33.5 g of benzyl trichloro acetimidate and, after addition of 0.53 ml of trifluoromethanesulfonic acid, was stirred for 5 hours. The suspension was filtered, the filter cake was washed with hexane, the filtrates were combined and washed sequentially with 3N hydrochloric acid, 3N sodium hydroxide solution, 3N hydrochloric acid and water. The organic phase was dried, filtered and concentrated, whereby 74.8 g of benzyl (2S, 3S, 5R) -5-benzyloxy-3-t-butyldimethylsiloxy-2-hexylhexadecanoate were obtained. .

(k) A mixture of

20 g of the ester from step j), 48 ml of glacial acetic acid, 16 ml of water and 16 ml of dioxane, and then the acetic acid was removed by azeotropic distillation with the addition of 120 ml of dioxane. and concentrated. The residue was dissolved in hexane and stored at -25 ° C for 14 hours. The crystals formed were filtered, the filtrate concentrated for 24 hours and the residue, dissolved in methanol, was intimately mixed with an aqueous potassium hydroxide solution. The reaction solution was evaporated, the residue was taken up in hexane, washed with 1N hydrochloric acid, 10% sodium chloride solution and concentrated. The residue was dissolved in methyl acetate.

and treated with 2.6g of benzylamine. 6.0g of (2S, 3S, 5R) -5-benzyloxy-3-hydroxy-2-hexylhexadecanoic acid (the product of Example 1h) was crystallized as a benzylamine salt with a m.p. : 57 ° -60 ° C and then a further 1.4 g with a MP: 61 ° -64 ° C.

Example 4

a) A solution of 129.2g of methyl (R) -3-hydroxy-tetrade-29 canoate, 1033 ml of dioxane and 122.9 g was added dropwise under stirring under nitrogen. of a 28% sodium hydroxide solution. To the solution was added 77.5 ml of methanol dropwise and, after stirring for 1.5 hours, the resulting suspension was filtered, the filter cake was washed with 1000 ml of dioxane and separated by filtration. The pH of the filter cake was adjusted to pH 0 by the addition of 650 ml of 1.5N hydrochloric acid. The suspension was stirred, filtered and the filter cake was washed with 3000 ml of water and the crystals dried. 119.64 g (98% yield) of (R) -3-hydroxytetradecanoic acid was obtained.

MP: 70.6 ° -71.4 ° C.

(b) 5.11 g of magnesium chloride was suspended in 50 ml of tetrahydrofuran under a nitrogen atmosphere and cooled to 0 ° C. A solution of 11.33 g of monomethyl malonate in 70 ml of tetrahydrofuran was added and then 10.7 g of triethylamine was added dropwise. The suspension was stirred at 0 ° C.

I

c) 6.81 g of 1,1-carbonyldiimidazole was added under nitrogen and with stirring to a solution of 7.33 g of (R) -3-hydroxytetradecanoic acid.

d) The reaction solution obtained in step c) was added to a previously prepared suspension in step b) and stirred for 5 hours. The suspension was concentrated. The resin obtained was taken up in 200 ml of ethyl acetate. It was extracted with 3N hydrochloric acid. The ethyl acetate phase was treated with 3N sodium hydroxide solution and, after addition of ice / water, the aqueous phase was separated. The ethyl acetate phase was again mixed intimately with 3N sodium hydroxide solution, diluted with ice / water and extracted. The aqueous phases were combined, cooled to 0 ° C and adjusted to pH 25 with hydrochloric acid to 1. The resulting suspension was extracted with ethyl acetate. The organic phases were combined, dried and filtered. The filter cake was washed with ethyl acetate. The filtrates were combined and concentrated. The product was suspended in ice / water, stirred and filtered. The filter cake was washed with water and the crystals dried. 4.63 g (57.6% yield) of (R) -5,6-dihydro-6-undecyl-2H-pyran-2,4 (3H) -dione were obtained, PP: 84.1 -84.8 ° C, which is the product of Example 3 e).

Example 5

a) 350.1 g of a 30% solution of sodium methylate in methanol was diluted with 550 ml of methanol under nitrogen and with stirring. 264.2 g of dimethyl mayinate were added dropwise. After heating to 40 ° C 321.0 g of 1-bromohexane was added dropwise to the suspension. After stirring at that temperature for 1 hour under reflux for 2 hours at 65 ° to 69 ° C for 2.5 hours and cooling the suspension to room temperature, water was added and the mixture was stirred at room temperature. mixture. The organic phase was separated. The aqueous phase was extracted with methylene chloride, the organic extracts were combined, dried and filtered, the filter cake was washed with methylene chloride and the combined filtrates were concentrated. After distillation of the product 329.3 g (yield 78.3%) of dimethyl n-hexylmalonate were obtained.

b) A solution of 40.1 g of potassium hydroxide in 150 ml of methanol was added dropwise under nitrogen with stirring to 129.78 g of the ester obtained in a). The reaction mixture was stirred for 2 hours and then poured into ice / water and extracted with methylene chloride. Phase pH adjusted

-31 aqueous to 2 by the addition of. 3N hydrochloric acid and extracted with methylene chloride. The organic phases were dried and filtered, the filter residue was washed with methylene chloride, the filtrates were combined and concentrated. There were obtained 113.9 g (94% yield) of methylsomethyl n-hexylmalonate.

c) A solution of 21.57 g of the ester obtained in b) in 70 ml of tetrahydrofuran and then 10.7 g of triethylamine was added dropwise under a stirring atmosphere under nitrogen. a suspension of 5.11 g of magnesium chloride in 50 ml of tetrahydrofuran at 0 ° C while stirring the resulting suspension of the monomethyl n-hexylmalonate magnesium salt at 0 ° C for 75 minutes .

I

d) 6.81 g of 1,1-carbonyldiimidazole, under nitrogen and with stirring, was added to a solution of 7.33 g of (R) -3-hydroxytetradecanoic acid (Example 4 a) in 60 ml of tetrahydrofuran. After stirring, the reaction solution was added to the suspension of the monomethyl n-hexylmalonate magnesium salt and the mixture was stirred at room temperature for 22 hours. The suspension was concentrated, leaving 60.35 g of resin as residue. This was taken up in 200 ml of ethyl acetate, extracted with 200 ml of 3N hydrochloric acid and 600 ml of 5% sodium hydrogen carbonate solution. The ethyl acetate phase was separated and treated with 100 ml 25% hydrochloric acid with stirring at 10 ° to 15 ° C. The mixture was stirred at 25 ° C for 1.5 hours and the resulting homogeneous phase was allowed to stand at room temperature for 16 hours. The suspension was stored at -20 ° C for 4 hours, filtered, the filter cake was washed with water and the crystals dried. 3.63 g (34.3% yield) of (R) -5,6-dihydro-3-hexyl-4-hydroxy-6-undecyl-2H-pyran-2-one were obtained. 1.8-106.2 ° C, which is the product of Example 3 (f).

Example 6

a) 465 g of methyl acetoacetate and then 458 g of ethyl bromide under nitrogen were added to 720 g of a solution of 30% sodium methylate in 1200 ml of methanol. Thereafter, the reaction mixture was boiled under reflux. After methanol distillation, the residue was poured into ice / water and then extracted with n-hexane and water. The organic phases were combined and dried. After evaporation of the solvent and distillation, 328 g (56.9% yield) of methyl 2-acetylbutyrate, PE 77 ° -79 ° / 15 Torr.

(b) 144.17 g of the methyl ester obtained from

(a) under an argon atmosphere at a temperature of 0 to 5 ° C to a suspension of 26,4 g of sodium hydride in 1250 ml of tetrahydrofuran. After stirring at 0 ° to 5 ° C for 1.5 hours, the mixture was cooled to -10 ° C. At this temperature 675 ml of 1.56 M butyl lithium in hexane was added. After stirring at this temperature for 30 minutes, a solution of 149.3 g of methyl stearate in 250 ml was added dropwise. of THF was added dropwise. After stirring at -10 ° C for 1.5 hours, the reaction solution was added under argon to 250 ml of 37% hydrochloric acid and 300 g of ice. The mixture was extracted

<img file="PT96857B_D0014.tif" />

with hexane and water. The combined organic phases were dried, filtered and evaporated.

The residue was dissolved in tetrahydrofuran (2500 mL), treated with DBU (76.1 g) and refluxed under argon. The cooled reaction solution was extracted with 37% hydrochloric acid and then with saturated sodium chloride solution. The organic phases were combined, dried and evaporated. The product was dissolved in ethyl acetate. The solution was cooled to room temperature and stirred. at 25 ° C overnight. The crystallization was removed by suction filtration, washed with ethyl acetate and dried. 122.5 g (64.7% yield) of 3-ethyl-6-heptadecyl-4-hydroxy-2H-pyran-2-one were obtained. Mp: 101-102 ° C.

c) 100 g Raney nickel and 2000 ml tetrahydrofuran were added to 100 g pyrone obtained in b). After hydrogenation at 25 ° C for 3 days, the catalyst was removed by suction filtration and washed with tetrahydrofuran. The filtrate was evaporated to dryness. The residue was dissolved in ethyl acetate and stirred at 10 ° C for 17 hours. The crystallize was filtered off by suction, washed with cooled ethyl acetate to -10 ° C and dried at 40 ° C for 17 hours. 90.54 g (89.6% yield) of rac- (2RS, 3RS, 5SR) -2-ethyl-5-heptadecyl-3-hydroxy-valerolactone were obtained. Mp 101 ° -102 ° C.

d) 138.5 g of benzoic anhydride and then 2.5 ml of 70% perchloric acid were added to a suspension of 191.3 g of the β-lactone obtained in c) in 1250 ml of toluene. After stirring for 2.5 hours, the reaction mixture was extracted into toluene.

-Μ · / f

3 · 3 * 1 with 1 N sodium hydroxide solution in 20% sodium chloride solution and then with a saturated sodium chloride solution. The organic phases were combined, dried and evaporated. 243.4 g (100.0% yield) of rac- (2RS, 3RS, 5SR) -3-benzoyloxy-2-ethyl-5-heptadecyl-β-valerolactone, PP 64.5 ° - 66 ° C.

e) 243 g of the benzoate obtained in d) was dissolved in 450 ml of toluene under argon at 40 ° C. 1000 ml of methanol and then 2.5 ml of concentrated sulfuric acid were added to the reaction mixture which was stirred at 25 ° C for 20 hours. After neutralization of the sulfuric acid with triethylamine, the solvent was evaporated. The residue was dissolved in t-butyl methyl ether and washed with water. The aqueous phase was extracted with t-butyl methyl ether and the organic phases were combined, dried with sodium sulfate, the drying agent removed by suction filtration, and washed with t-butyl methyl ether and then evaporated. 257 g (99.1% yield) of methyl rac- (2RS, 3RS, 5SR) -3-benzoyloxy-2-ethyl-5-hydroxydocosanoate were obtained.

f) 257 g of the hydroxy ester obtained in e) were treated in 1250 ml of n-hexane under argon with 152 g of benzyl 2,2,2-trichloroacetimidate. Then 3.2 ml of trifluoromethanesulfonic acid were added and, after stirring at room temperature for 18 hours, the precipitate was filtered off with suction and washed with n-hexane. The filtrate was extracted with 5% sodium hydrogen carbonate solution and water. The hexane phases were combined, dried, filtered and concentrated.

After stirring at -20 ° C for 20 hours, filtered

<img file="PT96857B_D0015.tif" />

The crystallize was sucked off, washed with n-hexane and separated. The filtrate was evaporated. 239.6 g (yield 78.7%) of methyl rac- (2RS, 3RS, 5SR) -3-benzoyloxy-5-benzyloxy-2-ethyl docosanoate were obtained, which was used in the next step without purification.

g) 239.6 g of the benzyl ether obtained in f) were treated under argon with a solution of 140 g of potassium hydroxide in 1250 ml of a 95% (v / v) methanol / water mixture and stirred at 40 ° C for 17 hours. The mixture was then concentrated at that temperature, the suspension was taken up in t-butyl methyl ether and washed sequentially with 10% sodium chloride solution, 1N hydrochloric acid and again with 10% sodium chloride. The organic phase was dried with sodium sulfate and the drying agent was removed by suction filtration and washed with t-butyl methyl ether. The filtrate was evaporated to give 182.1 g (74.2% yield) of rac- (2RS, 3RS, 5SR) -5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid.

(h) 33.3 g of (S) - (-) - (N-methylbenzylamine) was added dropwise to a solution of 182.1 g of the 4-hydroxy acid obtained in step g) in 1250. ml of methyl acetate. The solution was seeded with 50 mg of (2S, 3S, 5R) -5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid phenethylamine salt and allowed to stand for 20 hours. The crystallize was filtered off by suction, washed with cooled methyl acetate at -20Â ° C and then dried. The first crystallized was dissolved in hot methyl acetate, cooled to 45 ° C and seeded with 50 mg of (2S, 3S, 5R) -5- benzyloxy-2-ethyl-3-hydroxydocosanoic. The solution was allowed to stand at room temperature for 20 hours. The crystallize was filtered off under suction, washed with cooled methyl acetate at -20 ° C and dried. For the second crystallized the procedure described for the first crystallized was repeated. 39.4 g (12.9% yield) of (2S, 3S, 5R) -5-benzyl x1-2-ethyl-3-hydroxydocosanoic acid phenethylamine salt were obtained, mp: 92 ° -95 ° C .

(i) 39.4 g of the phenethylamine salt obtained in h) was treated with 400 ml of t-butyl methyl ether and 80 ml of 1N hydrochloric acid and dissolved with stirring. The organic phase was washed with water, dried, filtered and concentrated. Obtained

31.4 g (99.4% yield; 12.8% based on β-lactone from c) of (2S, 3S, 5R) -5-benzyloxy-2-ethyl-3-hydroxydocosanoic acid Mp 62-63.5 ° C.

(j) Benzenesulfonyl chloride (17.6g), under argon atmosphere, was added dropwise to a solution of 24.5g of the β-hydroxy acid from step (i) in pyridine (250 ml) at 0 ° C. . After stirring at this temperature for 20 hours, 5 ml of water was added dropwise to this solution. The mixture was stirred at room temperature for 1 hour, the pyridine was evaporated and the crystalline slurry taken up with t-butyl methyl ether and washed successively with 2N hydrochloric acid, 5% sodium hydrogen carbonate solution and with 10% sodium chloride solution. The organic phase was dried with sodium sulfate and then triturated with activated charcoal. The drying agent and charcoal were removed by suction filtration and the filtrate was evaporated. 23.4g (99% yield) of (3S, 43) -4- (R) -2-benzyloxynonadecyl-3-ethyl-2-oxetanone was obtained.

(k) A solution of 23.4 g of oxetanone from step j) in 250 ml of tetrahydrofuran was treated with 2.3 g of 10% palladium on charcoal. After hydrogenation for 5 hours, the hydrogenation solution was suction filtered, washed with tetrahydrofuran, the filtrate evaporated, the residue dissolved in n-hexane and seeded with (3S, 4S) -. 3-ethyl-4 / (R) -2-hydroxynonadecenyl-7'-2-oxetanone. After 18 hours, the crystallized Christian was filtered under suction, washed with hexane and dried. 16.1 g (84.1% yield) of (3S, 4S) -3-ethyl-4- [(R) -2-hydroxy nonadecyl] -2-oxetanone, mp: 66.5 °. -68 ° C.

Example7

19.13g of hydroxy-β-lactone from Example 6k), 10.34g of N-formyl- (S) -leucine and 19.70g of triphenylphosphine were dissolved in 400ml of tetrahydrofuran under argon and with agitation. The mixture was cooled to 0 ° C and a solution of diethyl azodicarboxylate (14.5 g) in tetrahydrofuran (50 ml) was added dropwise. The reaction solution was stirred at 0 ° C for 4 hours and then the solvent was evaporated. The crystalline slurry was partitioned several times between hexane and 70% methanol / water. The hexane phases were combined, dried over sodium sulfate and the drying agent removed by suction filtration and washed with hexane. After hexane distillation, the product was dissolved in hexane and after 20 hours the crystallized was filtered off under suction, washed with hexane and dried. There were 20.74g (79.2% yield) '. N-Formyl-L-leucine (S) -1- [(2S, 3S) -3-Ethyl-4-oxo-2-oxetanyl] 7-methyl-octadecyl ester, mp 61 ° -62 ° C.

Example 8

a) To a suspension of 177.3g of (2S, 3S, 5R) -2-hexyl-3-hydroxy-5-undecyl-4-valerolactone in 1250 ml of toluene was added under argon atmosphere 135.7g of benzoic anhydride and, after stirring at room temperature for 10 minutes, 2.5 ml of 70% perchloric acid. After stirring for 4 hours, the reaction solution in toluene was extracted with 1 N sodium hydroxide solution and water. The toluene phases were combined, dried over sodium sulfate, the drying agent removed by suction filtration and washed with toluene. Evaporation of the solvent gave 249.9g (109% yield) of (2S, 3S, 5R) -3-benzoyloxy-2-hexyl-5-undecyl-4-valeriolactone, which was used in the next step without purification. .

(b) 249.8g of benzoate from step (a) was treated in 1250 ml of methanol with stirring under argon with

2.5 ml of concentrated sulfuric acid and stirred at 35 ° C. for 18 hours. The pH of the reaction solution was then adjusted to 9 with triethylamine and the methanol was evaporated. The residue was taken up in hexane, washed with water and the aqueous phase extracted with hexane. After drying the combined hexane phases, it was filtered to give a hexane free filtrate. 246.5g (100.5% yield) of methyl (2S, 3S, 5R) -3-benzoyloxy-2-hexyl-5-hydroxyhexanedecanoate was obtained, which was used in the next step without purification.

<img file="PT96857B_D0016.tif" />

<img file="PT96857B_D0017.tif" />

c) 246.5g of the hydroxy ester from step b) was treated with 1250 ml of hexane under argon and stirring with 152g of benzyl 2,2,2-trichloroacetimidate. Then 3.2 ml of trifluoromethanesulfonic acid were added. After stirring at room temperature for 17 hours, the precipitate was filtered off under suction and washed with hexane. The filtrate was extracted with 5% sodium hydrogen carbonate solution and then with water. The hexane phases were combined, dried, filtered and evaporated. 308g (yield 106.2%) of methyl (2S, 3S, 5R) -3-benzoyloxy-5-benzyloxy-2-hexylhexadecate were used for the next step without purification.

d) 308.5 g of the benzyl ether from step c) was treated with 1125 ml of methanol under argon with a solution of 140 g of potassium hydroxide in 125 ml of water. The reaction mixture was stirred at 40 ° C for 17 hours and then concentrated. The suspension was taken up in hexane and washed sequentially with 10% sodium chloride solution, 1N hydrochloric acid and 10% sodium chloride solution. The organic phase was dried with sodium sulfate, the drying agent was removed by suction filtration and washed with hexane. The filtrate was concentrated to 1000 ml and stirred at -20 ° C. The crystallize was filtered off under suction, washed with hexane and discarded. After evaporation of the solvent, the filtrate gave a product which was dissolved in methyl acetate and treated with benzylamine with stirring. The solution was seeded with (2S, 3S, 5R) -5-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid benzylamine salt and then cooled to -5 ° C. Subsequently, it crystallized

<img file="PT96857B_D0018.tif" />

temperature at -10 ° C for 17 hours. The crystallize was filtered off with suction, washed with methyl acetate and then dried. 116.7g (41% yield based on the starting valerolactone from step a) of (2S, 3S, 5R) -5-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid benzylamine salt were obtained, mp: 66 ° -68 ° C.

e) 116.7g of the benzylamine salt from step d) was treated with 1000 ml hexane and 250 ml 1N hydrochloric acid with stirring. The organic phase was washed with water, dried and evaporated. 95.4g (100.6% yield; 41.2% based on initial valerolactone from step a)) (2S, 3S, 5R) -5-benzyloxy-2-hexyl-3-acid hydroxyhexadecanoic acid, which is the product of Example 1 i).

Example 9

(a) 110.2g of methyl 2-acetyloctanoate (the product of Example 1a)) was added dropwise under an argon atmosphere and stirred at 0 ° to 5 ° C to a suspension of 14.4 g of 97% sodium hydride in 750 ml of tetrahydrofuran. The mixture was stirred at room temperature for 1 hour and then cooled to -12 ° C. 370 ml of 1.56 M butyl lithium in hexane was added over 1 hour at -12 ° to -10 ° C. The mixture was stirred at -12 ° C for 1 hour and then 92.2 g of lauricaldehyde was added dropwise at -10 ° C to the previously obtained solution. The mixture was stirred at this temperature for a further 1 hour. The reaction solution was added to 600 ml of water for 5 minutes with agi.

<img file="PT96857B_D0019.tif" />

<img file="PT96857B_D0020.tif" />

tation. The mixture was stirred at room temperature for a further 1 hour and then neutralized with 100 ml of 37% hydrochloric acid. After separation of the aqueous phase, the organic phase was washed with 300 ml of a saturated sodium chloride solution, dried over sodium sulfate and the drying agent filtered off under suction. After evaporation of the solvent the product was triturated with hexane. The crystallize was filtered off under suction, washed with hexane and dried. 130.6 g (74.1% yield) of rac-5,6-dihydro-3-hexyl-4-hydroxy-6-undecyl-2H-pyran-2-one, mp 121.5 ° C. -122.5 ° C.

b) Ethyl acetate (1000 ml) and Raney nickel (12.5 g) were added with stirring to the dihydropyrone (50 g) from step a). After hydrogenation for 17 hours while stirring at 30 ° C, the catalyst was filtered off under suction and washed with ethyl acetate. The filtrate was concentrated and stirred at -10 ° C. The crystallize was filtered off under suction, washed with ethyl acetate and dried. 45.4g (90.3% yield) of rac- (2RS, 3RS, 5SR) -2-hexyl-3-hydroxy-5-undecyl-6-valerolactone, m.p.

98.5 ° -99.5 ° C, which is the product of Example 1c).

Example 10

(a) To a solution of 117 g of Meldrum acid and 131 ml of pyridine in 1,5 liters of methylene chloride was added 270 ml of stearic acid chloride dropwise at a maximum temperature of 15 ° C. After stirring, the reaction mixture was washed with 4N hydrochloric acid, the aqueous phase extracted with methylene chloride, the methylene chloride phase dried and concentrated. The residue was taken up in methanol and stirred under¹ · * Reflux. After cooling the crystalline precipitate was filtered, dissolved in methylene chloride, chromatographed on silica gel with methylene chloride to give 175 g of methyl 3-oxoeicosanoate, mp: 52 ° -54 ° C. .

(b) to a solution of 9,1 mg (R) -2,2'1 diacetate

bis (diphenylphosphine) -6,6-dimethylbiphenyltruthenium in 20 ml of methylene chloride, 1.84 mg of acetyl chloride in 1.84 ml of methanol was added. The obtained solution was hydrogenated at 60 ° C under a pressure of 35 bar hydrogen along with 39.8 mg of the ketoester from step a) and 170 ml of methanol. After the addition of methylene chloride, the mixture was evaporated to dryness. Chromatography on silica gel with diethyl ether and recrystallization from n-hexane gave 35.7 g of methyl (R) -3-hydroxyeicosanoate, mp 64 ° -64.5 ° C.

c) Analogously to Example 4, from (R) -3-hydroxyeicosanoic acid from methyl (R) -3-hydroxyeicosanoate of mp 89 ° C, (R) -5,6-dihydroxydehyde Mp 6-heptadecyl-2H-pyran-2,4 (3H) -dione 97 ° C.

Analogous to Example 3f) and g) ', the previously obtained pirandione was converted with acetaldehyde via (R) -3-ethyl-5,6-dihydro-6-heptadecyl-4-hydroxy-2H-pyran-2-one mp 110.5 ° -112.5 ° C in (2S, 3S, 5R) -2-ethyl-5-heptadecyl-3-hydroxy-valerolactone, / -39.8 ° (c = 1 in chloroform ).

Similarly to Example 2h) to K), the previous pyre was converted via (3S, 4S, 6R) -4- (t-butyldimethylsiloxy) -3-ethyl-3,4,5,6-tetrahydro-6 -heptadecyl-2H-pyran-2-one,

<img file="PT96857B_D0021.tif" />

(2S, 3S, 5R) -3- (t-Butyldimethylsiloxy) -2-ethyl-5-hydroxydocosanoate; (2S, 3S, 5R) -5-benzyloxy-3- (t-butyldimethylsilyloxy) -2-ethyldocosanoate of benzyl (2S, 3S, 5R) -5-benzyloxy-3-hydroxy-2-acid ethyldocosanoic acid (the product of Example 6H)) as the benzylamine salt.

Example 11

a) Similarly to Example 1b), methyl 2-acetyl octanoate (Example 1a)) was converted to methyl hexanoate in 3-hexyl-4-hydroxy-6-pentyl-2H-pyran-2-one, mp 110 ° C. 1.8 -111.7 ° &lt;2.

b) Analogously to Example 9a), by hexanol, methyl 2-acetyloctanoate was converted to rac-5,6-dihydro-3-hexyl-4-hydroxy-6-pentyl-2H-pyran-2 -one, mp 137-139 ° C.

(c) hydrogenation of pyrone from steps (a) and

b), analogously to the procedure described in Example 1c) or 9c) led to the formation of rac (2RS, 3RS, 5SR) -2-hexyl-3-hydroxy-5-pentyl-valerolactone, mp: 117 ° - 118 ° C.

d) Analogously to Example 1d) to k), the lactone obtained in Example 11c) converted via rac- (2RS, 3RS, 5SR) -3-benzoyloxy-2-hexyl-5-pentyl-β-valerolactone, Methyl (2RS, 3RS, 5SR) -3-Benzoyloxy-2-hexyl-5-hydroxydecanoate, rac- (2RS, 3RS, 5SR) -3-Benzoyloxy-5-benzyloxy-2-hexyldecanoate, rac- ( Methyl 2RS, 3RS, 5SR) -5-benzyloxy-2-hexyl-3-hydroxydecanoate,

<img file="PT96857B_D0022.tif" />

(2), 3S, 5R) -5-Benzyloxy-2-hexyl-3-hydroxydecanoic acid (S) -O-methylbenzylamine salt, mp 116^O-117 ° C, (2S, 3S, 5R) -5-benzyloxy-2-hexyl-3-hydroxydecanoic acid, δ (= -31 _z5 ° (c = 0.635 in chloroform), and (3S, 4S) -4- (R) -2-benzyloxyheptyl-3-hexyl-2-oxetanone, / ((2⁰= 63.1 ° (c = 1 in chloroform), in (3S, 4S) -3-hexyl-4- / (R) -2-hydroxyheptyl J7-2-oxetanone, / * * 4 ° = -51 9 ° (c = 1 in chloroform).

e) The latter was esterified by a process analogous to that of Example 2 on (S) -1- [1 '(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl / methyl / hexyl ester. of N-formyl-L-valine (valylactone), mp 57.0 ° -57.3 ° C, or in the (S) -1- [1 '(2S, 3S) -3-hexyl-4-oxo ester N-formyl-L-leucine -2-oxetanyl-methylhexyl, mp 50-50.5 ° C.

Example 12

a) 3.55 g of rac (2RS, 3RS, 5SR) -2-hexyl-3-hydroxy-5-undecyl-α-valerolactone was stirred at 50 ° C for 20 hours (Example 1c) , 30 ml TBME, 12.6 mg pyridinium p-toluenesulfonate and 2.66 g 95% 3,4-dihydro-2H-pyran. The solution was washed with aqueous sodium chloride solution and then dried. Evaporation of solvent and drying gave

4.41 g (100.5% yield) of (2RS, 3RS, 5SR) -2-hexyl-3- (tetrahydro-2H-pyran-2-yloxy) -5-undecyl-4-valerio-lactone Mp 39-41 ° C.

(b) A solution of 4.41 g of the ether obtained in step (a) in 30 ml of t-butyl methyl ether was treated with 10 ml of a 2N sodium hydroxide solution and stirred for 20 hours. After separation of the aqueous phase, the organic phase was washed with 10 ml of 10% aqueous sodium chloride solution and evaporated at 55 ° C. The residue was dissolved in 30 ml of TBME and the solvent was evaporated again. A solution of the residue was first evaporated in 30 ml of tetrahydrofuran and then dried. 4.81 g (100.5% yield) of the sodium salt of (2RS, 3RS, 5SR) -2-hexyl-5-hydroxy-3- (tetrahydro-2H-pyran-2-acid) was obtained. yloxy) hexadecanoic.

(c) 4.60 g of the sodium salt from step b) was treated under argon with 50 ml of tetrahydrofuran, 2.57 g of benzyl bromide and 0.495 g of sodium hydride and Stirred at 50 ° C for 24 hours. The suspension was hydrolyzed to pH 0 with 10 ml 2N hydrochloric acid, stirred at 50 ° C for 2 hours and then the aqueous phase was stopped. After washing with an aqueous sodium chloride solution, the organic phase was evaporated. Obtained

5.42 g of rac- (2RS, 3RS, 5SR) -5-benzyloxy-2-hexyl-3-hydroxyhexadecanoic acid, the product of Example 1g), which was resolved into its antipodes according to the procedure described in Example 1h).

Example 13

(a) 177.3 mg of rac (2RS, 3RS, 5SR) -2-hexyl-3-hydroxy-5-undecyl-α-valerolactone was stirred at 50 ° C under argon for 20 hours (Example 1c), 750 ml TBME, 86.7 g 97% 3,4-dihydro-2H-pyran and 0.314 g pyridinium p-toluenesulfonate. To the reaction solution was added 500 ml of 2N sodium hydroxide and, after stirring at 50 ° C for 2.5 hours, the aqueous phase was separated and the organic phase was washed with 500 ml. of a 10% sodium chloride solution.

(b) After boiling in a water separator for 24 hours the sodium salt slurry was cooled, treated under argon with successively 152.7 g of benzyl bromide and

99.1 g of sodium t-butylate was stirred at room temperature for 24 hours. After addition of 750 ml of 2N hydrochloric acid and stirring at 50 ° C for 22 hours, the mixture was cooled, the aqueous phase separated and the organic phase was washed with a sodium chloride solution, dried. was filtered off. After evaporation of the solvent, 349.8 g of rac- (2RS, 3RS, 5SR) -5-benzyloxy-2-hexyl-3-hydroxydecanoic acid (the product of Examples 1g) and 12c)) were obtained.

c) In a variant of step b), the product of step a) was boiled in a water separator for 17 hours. Then the solvent was distilled off. After drying 253.4 g of (2RS, 3RS, 5SR) -2-hexyl-5-hydroxy-3- (tetrahydro-2H-pyran-2-yloxy) -hexadecanoic acid sodium salt were obtained.

d) A solution of the product from step c) in 2 liters of tetrahydrofuran was added to a suspension of 24.7 g of 97% sodium hydride in 500 ml of tetrahydrofuran and 131 g of benzyl bromide. at 50 ° C with stirring. After stirring for 22 hours, 500 ml of 2N hydrochloric acid was added. After cooling the aqueous phase was separated and washed with sodium chloride solution. The resultant racemic (2RS, 3RS, 5SR) -47-5-benzyloxy-2-hex-1-3-hydroxycecanoic acid racemic hydroxide solution (Example 13b) was used to separate the racemate (Example 1h) ).