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Title:
PROCESS FOR THE PREPARATION OF AN ORLISTAT DERIVATIVE USEFUL AS REFERENCE STANDARD IN THE DETERMINATION OF THE PURITY OF ORLISTAT AND PROCESS FOR THE PREPARATION OF ORLISTAT
Document Type and Number:
WIPO Patent Application WO/2006/035296
Kind Code:
A1
Abstract:
The invention relates to a leucine derivative, N-2[(S)-2-N-formylamino-4-methyl pentanoic acid (S)-1-[[3(S)-hydroxy-5-oxo-4-hexyl methyl]dodecyl ester] amino-4-methyl pentanoic acid (S)-1-[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl]methyl dodecyl ester of Formula (I), and process for isolating it. More particularly, it relates to the preparation of pure orlistat, which is (S)-2-Formylamino-4-methyl pentanoic acid (S)-1-[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester. The invention also relates to the use of the Compound of Formula (I) as reference standard or reference marker for checking the purity of orlistat.

Inventors:
Kanwar, Seema (House No. 2349, Sector - 22C, Chandigarh 2, 16002, IN)
Patel, Killol (202 Navjeevan Apartment, Vardhamannagar Dhandhusar Roa, Junagadh 1 Gujarat, 36200, IN)
Nayyar, Kaushal (House No. 1345, Sector - 17C Gurgaon, Haryana 1, 12200, IN)
Deo, Keshav (# M-11, First Floor South City - I, Unitec, Gurgaon Haryana 1, 12200, IN)
Prasad, Mohan (House No. P-3/3, Phase - II DLF Qutab Enclav, Gurgaon 1 Haryana, 12200, IN)
Kumar, Yatendra (U-26/5, Phase-III DLF Qutab Enclav, Gurgaon 1 Haryana, 12200, IN)
Application Number:
PCT/IB2005/002864
Publication Date:
April 06, 2006
Filing Date:
September 27, 2005
Export Citation:
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Assignee:
RANBAXY LABORATORIES LIMITED (Plot No. 90, Sector - 32 Gurgaon, Haryana 1, 122 00, IN)
Kanwar, Seema (House No. 2349, Sector - 22C, Chandigarh 2, 16002, IN)
Patel, Killol (202 Navjeevan Apartment, Vardhamannagar Dhandhusar Roa, Junagadh 1 Gujarat, 36200, IN)
Nayyar, Kaushal (House No. 1345, Sector - 17C Gurgaon, Haryana 1, 12200, IN)
Deo, Keshav (# M-11, First Floor South City - I, Unitec, Gurgaon Haryana 1, 12200, IN)
Prasad, Mohan (House No. P-3/3, Phase - II DLF Qutab Enclav, Gurgaon 1 Haryana, 12200, IN)
Kumar, Yatendra (U-26/5, Phase-III DLF Qutab Enclav, Gurgaon 1 Haryana, 12200, IN)
International Classes:
C07D305/12; A61K31/365; A61P3/04
Attorney, Agent or Firm:
RANBAXY LABORATORIES LIMITED c/o Deshmukh (Jay R., 600 College Road East, Suite 210, Princeton NJ, 08540, US)
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Claims:
We claim:
1. Substantially pure N2 [(S)2NFormylamino4methyl pentanoic acid (S)I [[3(S)hydroxy5oxo4hexyl methyl] dodecyl ester] amino4methyl pentanoic acid (S)I [(2S, 3S)3hexyl4oxo2oxetanyl] methyl] dodecyl ester of Formula I, Formula I .
2. A method of determining purity of orlistat or a pharmaceutical composition containing the orlistat, comprising use of dodecyl ester of Formula I as a reference standard compound.
3. A process for the preparation of substantially pure dodecyl ester, the process comprising: a) stirring a mixture of crude orlistat in one or more solvents; b) adding water and separating orlistat enriched with dodecyl ester; c) subjecting the orlistat enriched with dodecyl ester to preparative HPLC and eluting with a gradient mobile phase to get eluent containing dodecyl ester; and d) isolating the substantially pure dodecyl ester from the eluent.
4. The process of claim 3, wherein the enriched orlistat is loaded on 8μHS silica (250 x 21.1 mm) column. 5. The process of claim 3, wherein the mobile phase used is gradient of isopropyl alcohol and hexane. 6. A process for the preparation of pure orlistat, the process comprising: a) deprotecting the compound of Formula II, Formula Il wherein R is an amino protecting group, in the presence of methylene dichloride; b) adding formic acetic anhydride; and c) recovering the pure orlistat.
5. 7 The process of claim 6, wherein the amino protecting group comprises one or more of alkyl, alkoxy, aralkyl, alkoxyalkyl, trialkylsily, benzyloxy, benzyloxy carbonyl, pnitrobenzyloxycarbonyl, tButoxycarbonyl, 9fluorenylmethoxycarbonyl, alkyl aminocarbonyloxy, phthalimides, and sulfonamides.
6. 8 The process of claim 6, wherein the deprotection is carried out by hydrogenation in the presence of a catalyst.
7. 9 The process of claim 8, wherein the hydrogenation catalyst is a transition metal compound.
8. 10 The process of claim 9, wherein the transition metal compound comprises one or more of palladium compounds, platinum compounds, ruthenium compounds, rhodium compounds and nickel compounds.
9. 11 The process of claim 6, wherein the hydrogenation reaction is carried out at about 1 kg/cm2 to about 10 kg/cm2.
10. 12 The process of claim 6, wherein the deprotection is carried out by acid or base hydrolysis.
11. 13 The process of claim 12, wherein the acid hydrolysis is carried out in the presence of a mineral acid comprising one or more of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and mixtures thereof.
12. 14 The process of claim 12, wherein the base hydrolysis is carried out in the presence of organic or inorganic base.
13. 15 The process of claim 14, wherein the organic base comprises one or more of trimethylamine, triethylamine, tributylamine, triisopropylamine, diisopropylethylamine, 1,8diazabicyclo [5.4.0]undec7ene (DBU), 1,5 diazabicyclo[4.3.0]non5ene (DBN), 4dimethylamino pyridine, morpholine, thiomorpholine, piperidine, pyrrolidine, and mixtures thereof.
14. 16 The process of claim 14, wherein the inorganic base comprises one or more of alkali metal carbonates, bicarbonates, hydroxides, and mixtures thereof.
15. 17 The process of claim 6, wherein the addition of formic acetic anhydride is carried out in the presence of a suitable solvent.
16. 18 The process of claim 17, wherein the suitable solvent comprises one or more of chlorinated hydrocarbons, alcohols, ketones, esters, nitriles, dipolar aprotic solvents, alkyl ethers, cyclic ethers, and mixtures thereof.
17. 19 The process of claim 6, wherein the recovering comprises one or more of distillation, distillation under vacuum, evaporation, cooling, filtration, filtration under vacuum, decantation, and centrifugation.
18. Pure orlistat having less than 0.15% by HPLC of dodecyl ester of Formula I. Formula I .
19. Pure orlistat of claim 20 having less than 0.05% of dodecyl ester by HPLC. 22. A pharmaceutical composition comprising a therapeutically effective amount of pure orlistat having less than 0.15% of dodecyl ester; and one or more pharmaceutically acceptable, carriers, excipients or diluents. 23. A method of preventing and treating obesity and hyperlipaemia, the method comprising proving a dosage form that includes a therapeutically effective amount of pure orlistat having less than 0.15% of dodecyl ester.
Description:
PROCESS FOR THE PREPARATION OF AN ORLISTAT DERIVATIVE USEFUL AS REFERENCE STANDA RD IN THE DETERMINATION OF THE PURITY OF ORLISTAT AND PROCESS FOR THE PREPARATIO N OF ORLISTAT

Field of the Invention

The field of the invention relates to a leucine derivative, 2-N-[(S)-2-N- formylamino-4-methyl pentanoic acid (S)-l-[[3(S)-hydroxy-5-oxo-4-hexyl methyl] dodecyl 5 ester] amino-4-methyl pentanoic acid (S)-1-[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl]methyl] dodecyl ester of Formula I,

Formula I and process for producing it. More particularly, it relates to the preparation of pure orlistat and pharmaceutical compositions that include the pure orlistat. 0 The invention also relates to use of pure orlistat or dodecyl ester as reference standards or reference markers for checking the purity of orlistat.

Background of the Invention

Orlistat, a tetrahydrolipstatin is a useful pancreatic lipase-inhibiting agent and can be used for the prevention and treatment of obesity and hyperlipaemia. Chemically, orlistat 5 is (S)-2-Formylamino-4-methyl pentanoic acid (S)-I -[(2S, 3S)-3-hexyl-4-oxo-2- oxetanyl]methyl] dodecyl ester and is known from U.S. Patent No. 4,598,089.

Several processes have been reported for the preparation of orlistat for example, in U.S. Patent Nos. 4,202,824; 4,983,746; J. Org. Chem. 1988, 53, 1218; Tetrahedron Lett. 1990, 31, 3645; Synlett, 1991, 11, 781; J Org. Chem. 1991, 56, 4714; 1993, 58, 7768; and J. Chem. Soc, Perkin Trans. 1, 1998, 17, 2679.

U.S. Patent No. 4,983,746; J. Chem. Soc, Perkin Trans. 1, 1998, 17, 2679; and J. Org. Chem. 1991, 56, 4714 disclose the preparation of orlistat by deprotection of compound of Formula II,

Formula Il wherein R is benzyloxycarbonyl. The process includes hydrogenating the compound of Formula II with palladium black using tetrahydrofuran as a solvent followed by the addition of formic acetic anhydride to obtain orlistat of Formula III.

Formula III

In order to secure marketing approval for a new drug product, a drug manufacturer must submit detailed evidence to the appropriate regulatory authorities to show that the product is suitable for release on to the market. The regulatory authorities must be satisfied, inter alia that the active agent is acceptable for administration to humans and that the particular formulation, which is to be marketed, is free from impurities at the time of release and has an appropriate shelf-life. Submissions made to regulatory authorities therefore typically include analytical records, which demonstrate:

(a) that impurities are absent from the drug at the time of manufacture, or are present only at negligible level, and

(b) that the storage stability i.e. shelf- life of the drug is acceptable.

These details are usually obtained by testing the drug against an external standard, or reference marker, which is a pure sample of a potential impurity or a potential degradation product. Dodecyl ester has a possibility of being used as a reference marker compound in identifying the purity of the orlistat. There is no reference of this impurity in the literature.

Summary of the Invention

In one general aspect there is provided a substantially pure compound of formula I, which is chemically N-2[(S)-2-N-formylamino-4-methyl pentanoic acid (S)-1-[[3(S)- hydroxy-5-oxo-4-hexyl methyl] dodecyl ester] amino-4-methyl pentanoic acid (S)-1-[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl]niethyl] dodecyl ester (hereinafter referred to as dodecyl ester).

In another general aspect there is provided use of dodecyl ester as a reference standard for determination of the purity of orlistat. In another general aspect there is provided a process for the isolation of dodecyl ester.

In another aspect there is provided a process for preparing pure orlistat. The process includes deprotecting the compound of Formula II, wherein R is an amino protecting group, in the presence of methylene dichloride; adding formic acetic anhydride; and recovering the pure orlistat. It has been observed by the inventors that the solvent used in the deprotection reaction has a great impact on the purity of orlistat obtained. Different solvents used in the deprotection reaction results in different amounts of compound of Formula I, as an impurity and therefore different purity of orlistat. It has been observed that the use of methylene dichloride as a solvent in the deprotection reaction minimizes the formation of the impurity of Formula I and thus results in better purity of orlistat.

The process may include further drying of the product obtained.

The process may produce pure orlistat having less than 0.15% dodecyl ester. In particular, it may produce pure orlistat having less than 0.05% dodecyl ester.

- A -

In another general aspect there is provided pure orlistat containing less than 0.15% dodecyl ester.

In another general aspect there is provided pure orlistat having less than 0.05% dodecyl ester. In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of pure orlistat having less than 0.15% dodecyl ester; and one or more pharmaceutically acceptable, carriers, excipients or diluents.

In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of pure orlistat having less than 0.05% dodecyl ester; and one or more pharmaceutically acceptable, carriers, excipients or diluents.

In another aspect there is provided a method of preventing and treating obesity and hyperlipaemia using therapeutically effective amount of pure orlistat having less than 0.15% dodecyl ester. hi another aspect there is provided a method of preventing and treating obesity and hyperlipaemia using therapeutically effective amount of pure orlistat having less than 0.05% dodecyl ester.

The details of one or more embodiments of the invention are set forth in the description below. Other features, objects and advantages of the invention will be apparent from the description and claims. Detailed Description of the Invention

The inventors have identified that the dodecyl ester is formed as an impurity during the synthesis of orlistat. The inventors have isolated dodecyl ester, which can be used as a reference standard for determination of the purity of orlistat.

The process involves: a) stirring a mixture of crude orlistat in one or more solvents; b) adding water and separating orlistat enriched with dodecyl ester;

c) subjecting the orlistat enriched with dodecyl ester to preparative HPLC and eluting with a gradient mobile phase to get eluent containing dodecyl ester; and d) isolating the substantially pure dodecyl ester from the eluent. The term "substantially pure" herein refers to dodecyl ester having a purity of at least 92% by HPLC.

The crude orlistat may contain from about 20% to about 25 % of the dodecyl ester. The mixture of crude orlistat and suitable solvent may be stirred by sonication for about 1 to 5 minutes. The suitable solvent here represents any inert solvent, which does not react under reaction conditions. The addition of water may be carried out till haziness appears and may be allowed to settle at the bottom. The above step may be repeated twice or thrice for enrichment of dodecyl ester. The enriched material may be loaded on to 8/LtHS silica (250 x 21.1 mm) column. Mobile phase used may be a gradient of isopropyl alcohol and hexane. The fractions containing the dodecyl ester may be further combined and concentrated to dryness. The substantially pure dodecyl ester can then be further purified by crystallization or column chromatography.

The inventors also have developed a process for preparing pure orlistat by deprotecting the compound of Formula II, wherein R is an amino protecting group, in the presence of methylene dichloride; adding formic acetic anhydride; and recovering the pure orlistat.

The orlistat may be recovered by a technique which includes, for example, distillation, distillation under vacuum, cooling, evaporation, filtration, filtration under vacuum, decantation and centrifugation.

The orlistat thus recovered may be further purified or additionally purified, by employing commonly practiced recrystallization techniques using solvent / antisolvent mixture to obtain pure orlistat.

The inventors also developed pharmaceutical compositions that contain the pure orlistat having less than 0.15% dodecyl ester, for example, less than 0.05% dodecyl ester, in admixture with one or more solid or liquid pharmaceutical diluents, carriers and/or

excipients. These pharmaceutical compositions may be used for preventing and treating obesity and hyperlipaemia.

The compound of formula II can be obtained by methods known in the art including methods described in U.S. Patent No. 4,983,746; J. Chem, Soc. Perkin. Trans. I, 1998, 17, 2679; and J. Org. Chem. 1991 , 56, 4714, which are incorporated herein by reference.

Examples of amino protecting group include alkyl, alkoxy, aralkyl, alkoxyalkyl, trialkylsily, benzyloxy, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, t-butoxycarbonyl, 9- fluorenylmethoxycarbony, alkyl-aminocarbonyloxy, phthalimides and sulfonamides. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, and tert-butyl groups. Examples of aralkyl include benzyl or substituted benzyl. Examples of substituted benzyl include p-nitro benzyl, p-methoxy benzyl, o-nitro benzyl, p-bromo benzyl or 2,4,6- trimethyl benzyl groups. Examples of alkoxy include methoxy and ethoxy, isopropoxy, and tert-butoxy. Examples of alkoxyalkyl include methoxymethyl, ethoxycarbonyl, isopropoxycarbonyl, and tert-butoxycarbonyl. Examples of trialkylsilyl include trimethylsilyl and tert-butyldimethylsilyl groups. Examples of alkyl-amino carbonyloxy include methyl aminocarbonyloxy and dimethyl aminocarbonyloxy.

When the protecting group is benzyl, benzyloxy, benzyloxycarbonyl, p- nitrobenzyloxycarbonyl or t-butoxycarbonyl, the deprotection may be carried out by hydrogenation in the presence of a catalyst. The hydrogenation catalysts are the customary hydrogenation catalysts known in organic chemistry, such as transition metal compounds. Examples of transition metal compounds include palladium compounds such as palladium/carbon and palladium hydroxide, platinum compounds such as platinum oxide and platinum/carbon, ruthenium compounds such as ruthenium oxide, rhodium compounds such as rhodium/carbon and nickel compounds such as Raney nickel.

The hydrogenation reaction may be carried out at normal pressure, or at elevated pressure depending on the choice of a catalyst. In general, it may be carried out at a hydrogen pressure in the range from about 1 kg/cm 2 to about 10 kg/cm 2 , for example at a hydrogen pressure in the range from about 2 kg/cm 2 to about 4 kg/cm 2 .

The hydrogenation temperature may be varied depending on the choice of a catalyst and/or pressure employed. For example, the hydrogenation may be carried out at a temperature range from about -2O 0 C to about 120 0 C, or at a temperature range from about O 0 C to about 80 0 C. In particular, it may be carried out at a temperature range from about 1O 0 C to about 35 0 C.

When the protecting group is 9- fluorenylmethoxycarbony, it may be deprotected by a base catalyzed reaction. Examples of base include ammonia, piperidine, morpholine and 1,8- diazacyclo [5.4.0] undec-7-ene (DBU). When the protecting group is silyl- protecting groups, it may be removed by treatment with fluoride. Other protecting groups may be removed by hydrolysis. The hydrolysis is a reaction in which the protecting group is removed in the presence of water and acid or a base (alkali). Accordingly, hydrolysis may be acid or alkali hydrolysis.

Alkali hydrolysis may be carried out in the presence of organic and inorganic bases. Examples of organic base include trimethylamine, triethylamine, tributylamine, triisopropylamine, diisopropylethylamine, 1,8-diazabicyclo- [5.4.0]-undec-7-ene (DBU), l,5-diazabicyclo-[4.3.0]-non-5-ene (DBN), 4-dimethylamino pyridine, morpholine, thiomorpholine, piperidine, pyrrolidine and mixtures thereof. Examples of inorganic base include alkali metal carbonate, bicarbonate, hydroxide and mixtures thereof. Examples of alkali metal carbonate include lithium carbonate, sodium carbonate and potassium carbonate. Examples of alkali metal bicarbonate include sodium bicarbonate and potassium bicarbonate. Examples of alkali metal hydroxide include sodium hydroxide and potassium hydroxide.

Acid hydrolysis may be carried out in the presence of an acid. Examples of acid include hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid. The addition of formic acetic anhydride may be carried out in the presence of a suitable solvent. Suitable solvents are inert organic solvents, which do not react under the reaction conditions. Examples of such solvents include chlorinated hydrocarbons such as methylene chloride, ethylene dichloride and carbon tetrachloride; alcohols such as methanol, ethanol, isopropanol and butanol; ketones such as acetone and methyl isobutyl ketone; esters such as ethylacetate and isopropylacetate; nitriles such as acetonitrile and

benzonitrile; dipolar aprotic solvents such as dimethylsulfoxide and dimethylformamide; alkyl ethers such as diethylether, diisopropylether and dimethoxyethane; cyclic ethers such as dioxane and tetrahydrofuran, and mixtures thereof.

The addition of formic acetic anhydride may be performed at temperatures of from about -2O 0 C to about 20°C for 30 minutes to 2 hours. The addition may be carried out at about -10°C to about -5 0 C for 30 minutes to 40 minutes. In particular, the reaction may be carried out at about -20 0 C to about 20 0 C for 30 minutes to 4 hours. The reaction mixture may be stirred at about 0 0 C to about -5°C for 1 to 2 hours in some particular embodiments.

Formic acetic anhydride may be prepared by adding acetic anhydride to formic acid.

The pure orlistat may have purity of more than 99% having less than 0.15% by HPLC of compound of Formula I.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example-1: Synthesis of (SV2-Formylamino-4-methyl pentanoic acid (S)-1-|Y2S, 3SV3- hexyl-4-oxo-2-oxetanyl " |methyl] dodecyl ester (Orlistat)

10 % palladium on charcoal (1.0 g) was added to a solution of N-(benzyloxycarbonyl)-L- leucine(l S)-I -[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester (cbz-orlistat) (50 g; 83.19 mmol) in methylene dichloride (200 ml). The reaction mixture was stirred at 25- 30 0 C for 90 minutes under hydrogen pressure of about 2.5 - 3 Kg. 10 % Palladium on charcoal (0.25 g) was again added to the reaction mixture and the reaction mixture was stirred for another 3 to 4 hours till cbz-orlistat is not more than 0.8 %. The reaction was monitored by high performance liquid chromatography. After the completion of reaction, the catalyst was filtered and washed with methylene dichloride (100 ml).

The filtrate obtained from above was added to methylene dichloride (200 ml), which was cooled at -1O 0 C. To this reaction mixture, freshly prepared acetic formic anhydride (28.02 g; 269.4 mmol) was added slowly at -10 to - 5 0 C within 30 to 40 minutes. The reaction mixture was stirred at 0 to - 5°C for 60 to 120 minutes. After the

completion of reaction, it was quenched in distilled water (500 ml) at 20 to 25°C. The aqueous layer was extracted with methylene dichloride (50 ml). The combined organic layers were washed with aqueous sodium bicarbonate solution (5% solution) twice (200 ml each) and distilled water (250 ml each). Activated carbon (1 g) was then added to the methylene dichloride layer and stirred for 30 minutes. The reaction mixture was filtered through hyflow bed and the bed was washed with methylene dichloride (50 ml). The solvent was recovered completely under reduced pressure at 25 to 30°C. To the oily residue, hexane (25 ml) was added and degassed completely under reduced pressure at 30 to 35°C. The reaction mass was cooled at 20 to 25°C and the product was crystallized from hexane (350 ml). The solid obtained was filtered and recrystallized twice from hexane (350 ml each) at 0 to 5 0 C to get pure orlistat.

HPLC Purity: 99.55% Dodecyl ester: 0.00% Example-2: Synthesis of formic acetic anhydride Acetic anhydride (27.5 g) was added to formic acid (50 g) and the mixture was stirred at 45 to 50°C till acetic anhydride content was not more than 5%.

Example-3: Synthesis of N-2[(S)-2-N-formylamino-4-methyl pentanoic acid (S)-1-IT3(S)- hydroxy-5-oxo-4-hexyl methyl] dodecyl ester! amino-4-methyl pentanoic acid (S)-1-|Y2S. 3S)-3-hexyl-4-oxo-2-oxetanyllmethyl] dodecyl ester The mixture of crude orlistat (5g, dodecyl ester: 23%) and acetonitrile (5ml) was sonicated for 2 minutes. Further, 0.5 ml water was added to the mixture and shaken, as the haziness appeared, it was allowed to settle. An oily mass appeared at the bottom, which was separated by pipette. The sample (dodecyl ester: 40 to 45%) so obtained was subjected to the above step twice for enrichment of dodecyl ester to about 65 to 70%. The sample obtained was loaded on 8μHS silica (250 x 21.1 mm) column. Mobile phase used was gradient of hexane and isopropyl alcohol in 98:2 ratios. The fractions containing the dodecyl ester were combined and concentrated to dryness.

HPLC Purity: 92.72% Weight: 600mg

The spectral data of the isolated dodecyl ester are as follows:

1 H-NMR (300 MHz) in CDCl 3 : 8.207 (s, IH, -NH-CHO); 6.30 (d, IH, -NH); 6.07 (d, IH, -NH); 5.07-5.11 (m, IH, -C4"-H) 5.01 (m, IH, -C2'H); 4.70 (ddd, IH, -C3'-H); 4.69 (ddd, IH, -C5"-H); 4.30 (m, IH, -C4-H); 3.70 (m, 3H, -C2"-H & OH); 3.21 (ddd, IH, - C3-H); 2.17 (ddd, IH, -C1'-H A H B , -C3"-H & -Cl "-H); 2.12 (ddd, IH, -Cl '-HAHB & - C3"-H); 1.77-1.25 (m, 64H, -(CH 2 ) 15 ; 0.98-0.93 (m, 12H, -(CH3) 2 C; 0.88-0.85 (distorted t, 12H, 2 x CH 3 )

IR (Perkin Elmer, Spectrum-one) in CCl 4 : 3317 (NH & OH stretching); 2924(CHO stretching); 1823 (/3-lactone ring (COO) stretching); 1738 (NHCHO (CONH stretching); 1657 (COO stretching).

Mass: 963.8 (M)

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.