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Details for Patent: 7,232,924

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Details for Patent: 7,232,924

Title:Methods for synthesis of acyloxyalkyl derivatives of GABA analogs
Abstract: The synthesis of 1-(acyloxy)-alkyl carbamates of GABA analogs from 1-haloalkyl carbamates of GABA analogs are described. Also described are new 1-haloalkyl carbamates of GABA analogs.
Inventor(s): Raillard; Stephen P. (Mountain View, CA), Zhou; Cindy X. (Palo Alto, CA), Yao; Fenmei (Mountain View, CA), Manthati; Suresh Kumar (Cupertino, CA), Xiang; Jia-Ning (Palo Alto, CA), Gallop; Mark A. (Los Altos, CA)
Assignee: Xenoport, Inc. (Santa Clara, CA)
Filing Date:Jun 11, 2003
Application Number:10/460,091
Claims:1. A method of synthesizing a compound of Formula (I) comprising: ##STR00019## contacting a compound of Formula (II), a compound of Formula (III) and at least one equivalent of a metal salt or an organic base or a combination thereof wherein: X is F, Cl, Br or I; n is 0 or 1; R.sup.1 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R.sup.2 and R.sup.3 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R.sup.2 and R.sup.3 together with the atom to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R.sup.4 is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; R.sup.5 is hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, or optionally, R.sup.4 and R.sup.5 together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R.sup.6 and R.sup.9 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; R.sup.7 and R.sup.8 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and substituted heteroarylalkyl, or optionally, R.sup.7 and R.sup.8 together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring; and R.sup.10 hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl or trialkylsilyl.

2. The method of claim 1, wherein the compound of Formula (I) is derived from a GABA analog of Formula (IV): ##STR00020## in which the GABA analog of Formula (IV) is selected from the group consisting of: 1-Aminomethyl-1-cyclohexane acetic acid (i.e., gabapentin); 1-Aminomethyl-1-(3-methylcyclohexane) acetic acid; 1-Aminomethyl-1-(4-methylcyclohexane) acetic acid; 1-Aminomethyl-1-(4-isopropylcyclohexane) acetic acid; 1-Aminomethyl-1-(4-tert-butylcyclohexane) acetic acid; 1-Aminomethyl-1-(3,3-dimethylcyclohexane) acetic acid; 1-Aminomethyl-1-(3,3,5,5-tetramethylcyclohexane) acetic acid; 1-Aminomethyl-1-cyclopentane acetic acid; 1-Aminomethyl-1-(3-methylcyclopentane) acetic acid; 1-Aminomethyl-1-(3,4-dimethylcyclopentane) acetic acid; 7-Aminomethyl-bicyclo[2.2.1]hept-7-yl acetic acid; 9-Aminomethyl-bicyclo[3.3.1]non-9-yl acetic acid; 4-Aminomethyl-4-(tetrahydropyran-4-yl) acetic acid; 3-Aminomethyl-3-(tetrahydropyran-3-yl) acetic acid; 4-Aminomethyl-4-(tetrahydrothiopyran-4-yl) acetic acid; 3-Aminomethyl-3-(tetrahydrothiopyran-3-yl) acetic acid; (S)-3-Aminomethyl-5-methyl-hexanoic acid (i.e. pregabalin); 3-Aminomethyl-5-methyl-heptanoic acid; 3-Aminomethyl-5-methyl-octanoic acid; 3-Aminomethyl-5-methyl-nonanoic acid; 3-Aminomethyl-5-methyl-decanoic acid; 3-Aminomethyl-5-cyclopropyl-hexanoic acid; 3-Aminomethyl-5-cyclobutyl-hexanoic acid; 3-Aminomethyl-5-cyclopentyl-hexanoic acid; 3-Aminomethyl-5-cyclohexyl-hexanoic acid; 3-Aminomethyl-5-phenyl-hexanoic acid; 3-Aminomethyl-5-phenyl-pentanoic acid; 3-Aminomethyl-4-cyclobutyl-butyric acid; 3-Aminomethyl-4-cyclopentyl-butyric acid; 3-Aminomethyl-4-cyclohexyl-butyric acid; 3-Aminomethyl-4-phenoxy-butyric acid; 3-Aminomethyl-5-phenoxy-hexanoic acid; and 3-Aminomethyl-5-benzylsulfanyl-pentanoic acid.

3. The method of claim 1 wherein the compound of Formula (I) is a compound of Formulae (V) or (VI): ##STR00021## and n is 0.

4. The method of claim 3, wherein R.sup.1 is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R.sup.2 is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclohexyl or phenyl, and R.sup.3 is hydrogen.

5. The method of claim 3, wherein R.sup.1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R.sup.2 is methyl and R.sup.3 is methyl.

6. The method of claim 3, wherein R.sup.1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, R.sup.2 is methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or cyclohexyloxycarbonyl and R.sup.3 is methyl.

7. The method of claim 3, wherein, R.sup.1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl and R.sup.2 and R.sup.3 together with the atom to which they are attached form a cyclohexyl ring.

8. The method of claim 3, wherein R.sup.2 is methyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or cyclohexyloxycarbonyl and R.sup.3 is methyl.

9. The method of claim 3, wherein R.sup.1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl or cyclohexyl and R.sup.10 hydrogen, allyl, benzyl or trimethylsilyl.

10. The method of claim 3, wherein R.sup.2 is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl and R.sup.3 is hydrogen.

11. The method of claim 3, wherein R.sup.1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, cyclobutyl, cyclopentyl or cyclohexyl, R.sup.10 is hydrogen, allyl, benzyl or trimethylsilyl, R.sup.2 is hydrogen, methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl and R.sup.3 is hydrogen.

12. The method of claim 3, wherein R.sup.1 is ethyl or isopropyl, R.sup.10 hydrogen, allyl, benzyl or trimethylsilyl, R.sup.2 is methyl, n-propyl or isopropyl and R.sup.3 is hydrogen.

13. The method of claim 3, wherein R.sup.1 is isopropyl R.sup.10 is benzyl R.sup.2 is methyl and R.sup.3 hydrogen.

14. The method of claim 3, wherein R.sup.1 is ethyl or isopropyl, R.sup.10 hydrogen, allyl, benzyl or trimethylsilyl, R.sup.2 is methyl, n-propyl or isopropyl, R.sup.3 is hydrogen and X is chloro.

15. The method of claim 3, wherein R.sup.1 is isopropyl R.sup.10 is benzyl R.sup.2 is methyl, R.sup.3 is hydrogen and X is chloro.

16. The method of claim 1, wherein the ratio of the compound of Formula (II) to the compound of Formula (III) is between about 1:1 and about 1:20.

17. The method of claim 1 further comprising contacting the compound of Formula (II) and the compound of Formula (III) and at least one equivalent of a metal salt or an organic base or a combination thereof with an organic solvent.

18. The method of claim 17, wherein the solvent is dichloromethane, dichloroethane, chloroform, toluene, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethyl sulfoxide, pyridine, ethyl acetate, acetonitrile, acetone, 2-butanone, methyl tert-butyl ether, methanol, ethanol, isopropanol, tert-butanol, water, hexamethylphosphoramide or combinations thereof.

19. The method of claim 1, wherein the metal salt is a Ag, Hg, Na, K, Li, Cs, Ca, Mg or Zn salt.

20. The method of claim 1, wherein the organic base is triethylamine, tributylamine, diisopropylethylamine, dimethylisopropylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylpiperidine, pyridine, 2-methylpyridine, 2,6-dimethylpyridine, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]undec-7-ene or combinations thereof.

21. The method of claim 1 wherein the compound of Formula (III) is a liquid.

22. The method of claim 21, wherein the compound of Formula (III) is acetic acid, methoxyacetic acid, ethoxyacetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid, 2-methylbutyric acid, cyclobutanecarboxylic acid, cyclopentanecarboxylic acid or cyclohexanecarboxylic acid.

23. The method of claim 22, wherein the compound of Formula (III) is isobutyric acid.

24. The method of claim 1, further comprising contacting the compound of Formula (II), the compound of Formula (III) and the metal salt or the organic base or a combination thereof at a temperature between about -25.degree. C. and about 120.degree. C.

25. The method of claim 24, wherein, the temperature is between about 0.degree. C. and about 25.degree. C.

26. The method of claim 1 further comprising contacting the compound of Formula (II), the compound of Formula (III) and the metal salt or the organic base or a combination thereof with a catalytic amount of an iodide salt.

27. The method of claim 26, wherein the iodide salt is sodium iodide, potassium iodide, tetramethylammonium iodide, tetraethylammonium iodide or tetrabutylammonium iodide.
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