The present invention relates to an improved process for the preparation of Orlistat, which is N-formyl-L-leucine derivative, in high purity.
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 is (S)-N-formyl leucine (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2 oxetanyl] methyl] dodecyl ester (Orlistat) and is known from U. S. Patent No. 4,598, 089. It is represented by Formula I,
(Formula Removed)
Several processes have been reported for the preparation of orlistat, such as in US 4202824; US 4983746; US 4931463; J.Org.Chem. 1988, 53, 1218-1221; Tetrahedron Lett. 1990, 31, 3645-3648; Synlett, 1991, 11, 781-782; J.Org.Chem. 1991, 56, 4714-4718; J. Org.Chem. 1993, 58, 7768-7781; and J.Chem.Soc, Perkin Trans. 1, 1998, 17, 2679-2686.
US Patent No. 4,931,463 and WO05/005403 discloses the use of formic acid / acetic acid anhydride for alkanoylating amino orlistat of Formula II,
(Formula Removed)
to produce orlistat.
US Patent No. 4,983,746 and WO05/005403 disclose the use of formic acid anhydride, acetic acid anhydride or a mixed acid anhydride such as formic acid/acetic acid anhydride for alkanoylating amino orlistat but only formic acid/acetic acid anhydride is exemplified (example 2).
The prior art mentioned above discloses the use of formic acid anhydride as an alkanoylating agent but does not contain any teaching about the effect of formic acid anhydride as alkanoylating agent on the preparation of orlistat of Formula (I). It has been observed that there are certain disadvantages in using acetic anhydride and mixed anhydride of formic acid / acetic acid anhydride as alkanoylating agent. In particular, a by-product of this reaction is a compound of Formula (III),
(Formula Removed)
which is chemically (S)-N-acetylleucine (1S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester (deformyl-N-acetyl orlistat).
Therefore, there has been an ongoing search for new alkanoylating agents, which are capable of introducing the formyl group in good yield without producing by-products.
In their endeavor to find a simple, efficient, cost-effective process for the manufacture of Orlistat in high yield and purity, the present inventors have surprisingly found that the selection of alkanoylating agent during alkanoylation of amino orlistat influences the amount of by-products formed. In the prior-art methods, wherein the formic acid/acetic acid anhydride used as alkanoylating agent leads to the formation of by-product of Formula (III).
Accordingly, the present invention provides an improved process for preparing orlistat of Formula I.
(Formula Removed)
comprising alkanoylating an amino orlistat of Formula II
(Formula Removed)
using formic acid anhydride as an alkanoylating agent to obtain Orlistat substantially free of byproduct of Formula (III).
(Formula Removed)
The term "substantially pure" refers to absence of by-product of Formula (III).
Amino orlistat may be obtained by methods known in the art including US 4598089; US 4983746; US 4931463 and WO05/005403, which are incorporated herein by reference. Amino orlistat may be
obtained as a solution directly from a reaction mixture of the last step of a process in which it is prepared and used as such for the preparation of orlistat.
In general amino orlistat may be obtained by deprotecting protected amino orlistat. Deprotection of protected amino orlistat may be carried out by alkali hydrolysis or basic hydrolysis based on the protecting group. Deprotection of protected amino orlistat may also be carried out by catalytic hydrogenation if amino protecting group is such as benzyloxycarbonyl or p-nitrobenzyloxycarbonyl, using palladium or platinum as metal catalyst.
The formic anhydride may be obtained by reacting formic acid with coupling reagent in a suitable solvent.
Examples of coupling reagent include N, N'-dicyclohexylcarbodimide and diisopropyl carbodiimide. Examples of solvent include ethers, such as dioxane and tetrahydrofuran, and chlorinated hydrocarbons, such as methylenedichloride and ethylenedichloride.
The addition of coupling reagent may be carried out at a temperature range from about 0°C to about -20°C. The reaction of formic acid with coupling reagent may be carried out at a temperature range from about 0°C to about -20°C for a period of 30 minutes to 3 hours.
The alkanoylation of amino orlistat may be carried out in a suitable solvent, for example, ethers, such as dioxane and tetrahydrofuran, and chlorinated hydrocarbons, such as methylenedichloride and ethylenedichloride.
The alkanoylation reaction of amino orlistat may be carried out at a temperature range from about -10°C to about 0°C.
The reaction mixture can be quenched by water, and extracted with suitable solvent. The quenching of reaction may be carried out at a temperature range from about -5°C to ambient temperature. The ambient temperature may be in the range of about 0°C to about 30°C.
The solvent used for the extraction of orlistat includes chlorinated hydrocarbon and ester. Examples of chlorinated hydrocarbon include methylenedichloride, ethylenedichloride or mixtures thereof. Examples of esters include ethyl acetate, isopropyl acetate or mixtures thereof.
Orlistat obtained may be recrystallized from suitable solvent to obtain pure orlistat. The solvent used for the crystallization of orlistat includes aliphatic hydrocarbon. Examples of aliphatic hydrocarbon include hexane, pentane, heptane, cyclohexane or mixtures thereof. The crystallization may be performed at temperature of from about 0°C to about -10°C for a period of about 30 minutes to about 12 hours.
The present invention demonstrates the use of a formic anhydride as an alkanoylating agent, which further aids the minimization of impurities in the product and results in product of high purity substantially free of by-product of formula (III). This is further substantiated by experimental evidence, which is tabulated herein below:

(Table Removed)
In the following section preferred embodiments are described by way of examples to illustrate the process. However, these are not intended in any way to limit the scope of the claims. Several variants of these examples would be evident to persons ordinarily skilled in the art.
Examples
Example 1
Preparation of (S)-leucine (S)-l- [[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl dodecyl ester
(amino orlistat)
A solution of the (S)-N- [(benzyloxy) carbonyl] leucine (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester (25g, 0.0415 mol) in dichloromethane (100 mL) was hydrogenated in the presence of 10 % palladium carbon (1.25 g, 50% moisture) at 25°C to 30°C under hydrogen atmosphere (2.5 to 3.0 Kg) for 1.5 hours. After completion of the reaction, reaction mixture was filtered through hyflo bed and hyflo bed was washed with dichloromethane (50 mL). The filtrate so obtained was used as such in the next step
Example 2
Preparation of formic acid anhydride
The mixture of formic acid (20 g, 0.434 mol) and dichloromethane (75 mL) was cooled to -10°C. A solution of N, N'-dicyclohexylcarbodimide (43 g, 0.208mol) in dichloromethane (100 mL) was added slowly to the above mixture at - 5°C to -10°C. The reaction mixture was stirred at -5°C to -10°C for 2.5 hours. The reaction mixture was filtered through hyflo bed at -10°C and used as such for the alkanoylation reaction.
Example 3
Preparation of (S)-N-formyl leucine (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2 oxetanyl] methyl] dodecyl
ester (Orlistat)
To the solution of (S)-leucine (S)-l- [[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester (19.13g, 0.0415 mol) in dichloromethane (150 mL), formic acid/acetic anhydride reagent (obtained by mixing 25 g of formic acid in 13.75 g of acetic anhydride) was added slowly at - 5°C to -10°C. The reaction was monitored by TLC (ethyl acetate: hexane at 30: 70 v/v, 12). After completion of the reaction the reaction mixture was washed with water and sodium bicarbonate solution, the dichloromethane was recovered completely. The residue was diluted with hexanes and resulting
clear solution was treated with activated carbon, filtered and solvent was recovered under reduced pressure.
Dissolve Orlistat residue in hexane (175 ml) and cool hexane solution at 0 to -10°C over a period of 4-6 hour. Maintain temperature at 0 to -10°C for further 6-7 hour. Filter solid material at 0 to -10°C and dry product at 30-35°C under reduced pressure. Yield: 15.75gm (82 %). By-product of formula (III): 0.699 %. Assay: 99.5 % by HPLC.
Example 4
Preparation of (S)-N-formyl leucine (S)-1-[[(2S, 3S)-3-hexyl-4-oxo-2 oxetanyl] methyl] dodecyl
ester (Orlistat)
To the solution of (S)-leucine (S)-l- [[(2S, 3S)-3-hexyl-4-oxo-2-oxetanyl] methyl] dodecyl ester in dichloromethane (obtained from example 1), formic acid anhydride solution (obtained from example 2) was added slowly at - 5°C to -10°C. The reaction mixture was stirred for 1 hour at 0°C to -5°C. After completion of the reaction, the reaction mixture was quenched with water (250 mL). The organic layer was separated and washed with sodium bicarbonate solution. The dichloromethane was recovered under reduced pressure. The residue was diluted with hexane and resulting clear solution was treated with activated carbon. The mixture was filtered through hyflo bed and hyflo bed was washed with hexane. Solvent was recovered under reduced pressure. Dissolve Orlistat residue in hexane (175 ml) and cool hexane solution at 0 to -10°C over a period of 4-6 hour. Maintain temperature at 0 to -10°C for further 6-7 hour. Filter solid material at 0 to -10°C and dry product at 30-35°C under reduced pressure. Yield: 17.5 gm (91 %). By-product of formula (III): Not detected Assay: 99.2 % by HPLC.

WE CLAIM;
1. A process for preparation of orlistat of Formula I,
(Formula Removed)
Orlistat (I) comprising of alkanoylating an amino orlistat of Formula II,
(Formula Removed)
with formic acid anhydride, to give orlistat of Formula I, substantially free of by-product of Formula (III)
(Formula Removed)
2. The process according to claim 1, wherein amino orlistat is obtained as a solution directly
from a reaction mixture of the last step of a process in which it is prepared.
3. The process according to claim 1, wherein amino orlistat is obtained by deprotecting
protected amino orlistat.
4. The process according to claim 1, wherein formic acid anhydride is obtained by reacting
formic acid with coupling reagent in a suitable solvent.
5. The process according to claim 4, wherein coupling reagent is selected from the group
comprising of N, N'-dicyclohexylcarbodimide and diisopropyl carbodiimide.
6. The process according to claim 4, wherein solvent is selected from group comprising of
ethers, chlorinated hydrocarbons or mixtures thereof.
7. The process according to claim 6, wherein ether is selected from group comprising of
dioxane, tetrahydrofuran or mixtures thereof.
8. The process according to claim 6, wherein and chlorinated hydrocarbon is selected from
group comprising of methylenedichloride, ethylenedichloride or mixtures thereof.
9. The process according to claim 4, wherein the reaction of formic acid with coupling reagent
is carried out at a temperature range from about 0°C to about -20°C for a period of about 30
minutes to 3 hours.
10. The process according to claim 1, wherein the alkanoylation reaction is performed in a
solvent selected from the group comprising of ether, chlorinated hydrocarbon or mixtures
thereof.
11. The process according to claim 10, wherein the ether solvent is selected from the group
comprising of diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran or mixtures
thereof.
12. The process according to claim 10, wherein the chlorinated hydrocarbon solvent is selected
from the group comprising of methylene dichloride, ethylene dichloride or mixtures thereof.
13. The process according to claim 1, wherein alkanoylation reaction is carried out at a
temperature range from about -10°C to about 0°C.
14. The process according to claim 1, wherein orlistat is recrystallized with aliphatic
hydrocarbon selected from the group comprising of hexane, pentane, heptane, cyclohexane
or mixtures thereof.
15. The process according to claim 14, wherein the crystallisation is performed at temperatures
of from about 0°C to about -10°C for a period of 30 minutes to about 12 hours.