1. A one-pot process for the preparation of nateglinide, which process comprises reacting an alkyl ester of D-phenylalanine of formula (II):
where R represents C1-4alkyl, either as the free base or in salt form, with trans-4-isopropylcyclohexanecarboxylic acid or trans-4-isopropylcyclohexanecarboxylic acid halide of formula (III):
where X represents hydroxy or halo, to obtain a C1-4 alkyl ester of nateglinide of formula (IV):
followed by hydrolysis to yield nateglinide of formula (I):
2. The process according to claim 1, wherein R in formulae (II) and (IV) represents methyl.
3. The process according to claim 1, wherein said alkyl ester of D-phenylalanine of formula (II) is present in salt form for reaction with trans-4-isopropylcyclohexanecarboxylic acid of formula (III).
4. The process according to claim 3, wherein said alkyl ester of D-phenylalanine of formula (II) is present as the hydrochloride salt for reaction with trans-4-isopropylcyclohexanecarboxylic acid of formula (III).
5. The process according to claim 4, which further comprises initially reacting D-phenyl alanine with a solution of thionyl chloride in a C1-4alcohol to give the corresponding alkyl ester of formula (II) as the hydrochloride salt, which is then reacted directly with trans-4-isopropylcyclohexanecarboxylic acid of above formula (III) in the presence of a dehydrating agent and a base.
6. The process according to claim 5, wherein said dehydrating agent comprises N,N\u2032-dicyclohexylcarbodiimide1-hydroxybenzotriazole.
7. The process according to claim 5, wherein said base comprises triethylamine.
8. The process according to claim 1, wherein said alkyl ester of D-phenylalanine of formula (II) is present as the free base for reaction with trans-4-isopropylcyclohexanecarboxylic acid or trans-4-isopropylcyclohexanecarboxylic acid halide of formula (III).
9. The process according to claim 8, wherein said alkyl ester of D-phenylalanine of formula (II) is present in salt form and is converted in situ to the free base for reaction with trans-4-isopropylcyclohexanecarboxylic acid or trans-4-isopropylcyclohexanecarboxylic acid halide of formula (III).
10. The process according to claim 9, wherein said alkyl ester of D-phenylalanine of formula (II) is present as the hydrochloride salt and is converted in situ to the free base for reaction with trans-4-isopropylcyclohexanecarboxylic acid or trans-4-isopropylcyclohexanecarboxylic acid halide of formula (III).
11. The process according to claim 10, which further comprises initially reacting D-phenyl alanine with a solution of thionyl chloride in a C1-4alcohol to give the corresponding alkyl ester of formula (II) as the hydrochloride salt, which is converted in situ to the free base which is then reacted with trans-4-isopropylcyclohexanecarboxylic acid or trans-4-isopropylcyclohexanecarboxylic acid halide of above formula (III) in the presence of a dehydrating agent.
12. The process according to claim 11, wherein said dehydrating agent comprises N,N\u2032-dicyclohexylcarbodiimide1-hydroxybenzotriazole.
13. The process according to claim 11, wherein said in situ conversion is preferably carried out using a base suitably comprising aqueous ammonia.
14. The process according to claim 8, which further comprises initially reacting D-phenyl alanine with a solution of thionyl chloride in a C1-4 alcohol to give the corresponding alkyl ester of formula (II) as the hydrochloride salt, which is converted in situ to the free base which is then reacted with trans-4-isopropylcyclohexanecarboxylic acid or trans-4-isopropylcyclohexanecarboxylic acid halide of above formula (III) in the presence of base.
15. The process according to claim 14, wherein said base comprises triethylamine N,N-and dimethylamino pyridine.
16. The process according to claim 1, wherein said C1-4 alkyl ester of nateglinide of formula (IV) is subjected to alkali hydrolysis, without isolation, and subsequent acidification to yield nateglinide.
17. The process according to claim 16, wherein said alkali is sodium hydroxide.
18. The process according to claim 17, wherein hydrolysis with said sodium hydroxide provides nateglinide in the form of its sodium salt, which is then subjected to acidification to yield nateglinide.
19. The process according to claim 1, which further comprises purification of nateglinide by one or more solvent washes.
20. The process according to claim 19, wherein following reaction of said alkyl ester of D-phenylalanine of formula (II) with trans-4-isopropylcyclohexanecarboxylic acid or trans-4-isopropylcyclohexanecarboxylic acid halide of formula (III), the reaction solution containing the alkyl ester of nateglinide of formula (IV) is washed with NaOH solution to remove trans-4- isopropyl cyclohexanecarboxylic acid or trans-4-isopropylcyclohexanecarboxylic acid halide and other acid impurities.
21. The process according to claim 19, wherein following hydrolysis to yield nateglinide of formula (I) the reaction mass is washed with one or more water immiscible organic solvents.
22. A one-pot process for the preparation of nateglinide represented by the following reaction scheme:
23. A one-pot process for the preparation of nateglinide represented by the following reaction scheme:
24. A one-pot process for the preparation of nateglinide represented by the following reaction schemes
25. A one-pot process the preparation of nateglinide, which process comprises reacting an alkyl ester of D-phenylalanine of formula (II):
where R represents C1-4alkyl, either as the free base or in salt form, with trans-4-isopropylcyclohexanecarboxylic acid or trans-4-isopropylcyclohexanecarboxylic acid halide of formula (III):
where X represents hydroxy or halo, to obtain a C1-4 alkyl ester of nateglinide of formula (IV):
wherein the reaction solution containing the above C1-4 alkyl ester of nateglinide of formula (IV) is washed with NaOH solution to remove trans-4-isopropyl cyclohexanecarboxylic acid or trans-4-isopropylcyclohexanecarboxylic acid halide and other acid impurities, followed by alkali hydrolysis to yield nateglinide of formula (I):
wherein the resulting reaction mass comprising nateglinide of formula (I) is washed with one or more water immiscible organic solvents, followed by acidification to yield crystalline nateglinide of formula (I).
26. Nateglinide prepared by a process according to claim 1.
27-29. (canceled)
30. A pharmaceutical composition comprising nateglinide according to claim 26, and a pharmaceutically acceptable carrier therefor.
31-34. (canceled)
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
We claim:
1. A method for free-form sketching a renderable 3D model, comprising:
acquiring an input stroke as a sequence of 2D points from an input device;
resampling the 2D points;
assigning depth values to the resampled 2D points to form a 3D contour; and
fitting a variational implicit surface to the 3D contour to generate a 3D blob forming the 3D model to be rendered on an output device.
2. The method of claim 1 wherein the input stroke is sketched on a display screen by a user with a mouse as the input device to generate the sequence of 2D points.
3. The method of claim 1 wherein the resampled points are substantially even spaced.
4. The method of claim 1 further comprising:
closing the input stroke by joining a last point to a first point of the sequence.
5. The method of claim 1 further comprising:
constraining the 3D contour by zero-points and plus-points, the zero-points located on the 3D contour, and the plus-points located outside the 3D contour at a predetermined distance normal to the zero-points.
6. The method of claim 1 wherein the variational implicit surface is based on thin-plate interpolation functions that is a sum of an affine term and a weighted sum of radial basis functions.
7. The method of claim 1 wherein a plurality of input strokes are acquired to generate a plurality of 3D blobs forming the 3D model.
8. The method of claim 7 further comprising:
organizing the 3D blobs as nodes in a hierarchical scenegraph stored in a memory.
9. The method of claim 7 further comprising:
polygonizing the variational implicit surface of each 3D blob as a triangular mesh when rendering the 3D model.
10. The method of claim 8 further comprising:
rendering each 3D blob to an off-screen buffer as an image;
measuring an amount of overlap between a current 3D blob and each previously generates 3D blob; and
selecting a particular 3D blob having a largest amount of overlap with the current 3D blob as a parent 3D blob in the hierarchical scenegraph.
11. The method of claim 7 further comprising:
merging selected 3D blobs with a guidance stroke.
12. The method of claim 7 further comprising:
modifying selected 3D blobs by a target stroke.
13. A system for free-form sketching a renderable 3D model, comprising:
an input device for generating an input stroke as a sequence of 2D points;
means for resampling the 2D points;
means for assigning depth values to the resampled 2D points to form a 3D contour; and
means for fitting a variational implicit surface to the 3D contour to generate a 3D blob forming the 3D model;
an output device for rendering the 3D model.