Patent EA-002987-B1 (EA)
Title: Method for asymmetric synthesis of benzoxazinones
Inventor: PIERCE MICHAEL ERNST
IPC: C07D265/18
Filed: 1997-12-15
Abstract: 1. A process for the preparation of a compound of formula (VI):   comprising: (1) contacting 4-chloro-2-trifluoroacetylaniline with a compound of formula (VII) selected from p-methoxybenzyl alcohol, 3,4-dimethoxybenzyl alcohol, or 2,4- dimethoxybenzyl alcohol; in a suitable solvent, in the presence of a suitable acid catalyst selected from HCl, methanesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, trifluoroacetic acid, trichloroacetic acid and p-toluene-sulfonic acid; to form a compound of formula (II):   wherein P is p-methoxybenzyl, 3,4-dimethoxybenzyl, or 2,4-dimethoxybenzyl; (2) (a) contacting 1R,2S-pyrrolidinyl norephedrine with an alkyi lithium selected from n-butyl lithium, sec-butyl lithium, t-butyl lithium, iso-butyl lithium, n-hexyl lithium and octyl lithium; and cyclopropylacetylene, in a suitable solvent, to form a mixture of 1R, 2 S-pyrrol idinyl norephedrine and lithium cyclopropylacetylide, and (b) contacting the mixture of step (2) (a) with a compound of formula (II) to form a compound of formula (III):   (3) contacting a compound of formula (III) with a suitable oxidizing agent selected from MnO2, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, p-tetrachlorobenzoquinone, o-tetrachlorobenzoquinone and iodosobenzene diacetate; in a suitable solvent, to form a compound of formula (IV):   wherein P" is (p-methoxyphenyl)methylene, (3,4-dimethoxyphenyl) methylene, or 2,4-dimethoxyphenyl) methylene; (4) contacting a compound of formula (IV) with a suitable cleaving agent selected from sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, NaOH, LiOH, KOH and Ca(OH)2; in a suitable solvent, in the presence of a suitable trapping agent selected from NaBH4, NaHSO3, hydroxylamine, tosylhydrazide or H2O2; to form a compound of formula (V):   and (5) contacting a compound of formula (V) with phosgene, in a suitable solvent, to form a compound of formula (VI). 2. A process according to Claim 2 for the preparation of a compound of formula (VI-i):   comprising (1) contacting 4-chloro-2-trifluoroacetylaniline with p-methoxybenzyl alcohol, in a suitable solvent, in the presence of a suitable acid catalyst selected from methanesulfonic acid and p-toluene-sulfonic acid, to form a compound of formula (II-i):   (2)(a) contacting 1R,2S-pyrrolidinyl norephedrine with n-hexyl lithium and, cyclopropylacetylene, in a suitable solvent, to form a mixture of 1R,2S-pyrrolidinyl norephedrine and lithium cyclopropylacetylide, (b) contacting the mixture of step (2)(a) with a compound of formula (II-i) to form a compound of formula (III-i):   (3) contacting a compound of formula (III-i) with a suitable oxidizing agent selected from 2,3-dichloro-S,6-dicyano-l,4-benzoquinone or p-tetracblorobenzoquinone; in a suitable solvent, to form a compound of formula (IV-i):   (4) contacting a compound of formula (IV-i) with NaOH or KOH, in a suitable solvent, in the presence of NaBH4 to form a compound of formula (V-i):   (5) contacting a compound of formula (V-i) with phosgene, in a suitable solvent, to form a compound of formula (VI-i). 3. A process according to Claim 1 for the preparation of a compound of formula (VI7), wherein the compounds of step (2)(a) and (b) are independently prepared and mixed as solution streams. 4. A process according to Claim 2 for the preparation of a compound of formula (VI-i), wherein the compounds of step (2) (a) and (b) are independently prepared and mixed as solution streams. 5. A process for the preparation of a compound of formula (II-a):   wherein: R<2> is H or phenyl; R<3> is H or phenyl; and R<4>, R<5>, R<4a>, R<5a>, and R<6> are independently selected from H and methoxy; said process comprising: contacting 4-chloro-2-trifluoroacetylaniline with a compound of formula (VII), selected from p-methoxy benzyl alcohol, 3,4 dimethoxybenxyl alcoholor trityl  in a suitable solvent, in the presence of a suitable acid catalyst selected from HC1, methanesulfonic acid, benzenesulfonic acid, phosphoric acid, sulfuric acid, trichloroacetic acid, trifluoroacetic acid and p-toluene-sulfonic acid; to form a compound of formula (II). 6. A process according to Claim 5, wherein: a compound of formula (VII) is p-methoxy benzyl alcohol, 3,4 dimethoxybenxyl alcoholor trityl. 7. A process according to Claim 5 wherein: a suitable acid catalyst is methane sulfonic acid or p-toluene-sulfonic acid. 8. A process according to Claim 5 wherein: a compound of formula (VII) is p-methoxy benzyl alcohol, and the suitable acid catalyst is methane sulfonic acid or p-toluene-sulfonic acid. 9. A process according to Claim 5 wherein: a compound of formula (VII) is trityl alcohol, and the suitable acid catalyst is methane sulfonic acid or p-toluene-sulfonic acid. 10. A process for the preparation of a compound of formula (IV-a):   wherein: R<3> is H and R<4>, R<5>, R<4a> R<5a> and R<6> are independently selected from and methoxy; said process comprising: contacting the compound of formula (IIIa):   wherein R<2> is H, in a nonaqueous solvent, with a suitable oxidizing agent selected from 2,3-dichloro-5,6-dicyano-l, 4-benzoquinone, p-tetrachlorobenzoquinone, and o-tetrachlorobenzoquinone; to form a compound of formula (IV-a). 11. A process according to Claim 10 wherein: a compound of formula (III-a) is:   R<4> is H or methoxy, and R<5> is H or methoxy. 12. A process according to Claim 10 wherein the suitable oxidizing agent is p-tetrachlorobenzoquinone. 13 A process according to Claim 10 wherein the compound of formula (III-a) is:   the suitable oxidizing agent is p-tetrachlorobenzoquinone. 14. A process for the preparation of (S)-5-chloro-alpha-(cyclopropylethynyl)-2-amino-alpha-(trifluoromethyl) benzenemethanol, (V-i), comprising: contacting the compound of formula (IV-a):   (IV"a) wherein: R<3> is H; and R<4>, R<5>, R<4a>, R<5a> and R<6> are independently selected from H and methoxy; with a suitable cleaving agent selected from sodium methoxide, sodium ethoxide, potassium methoxide, otassium ethoxide, NaOH, LiOH, KOH and Ca(OH)2 in a suitable solvent, in the presence of a suitable trapping agent selected from NaBH4 and NaHSO3; to form a compound of formula (V). 15. A process according to Claim 14 wherein a compound of formula (IV-a) is   R<4> is H or methoxy, and R<5> is H or methoxy; the suitable cleaving agent is NaOH or KOH, and the suitable trapping agent is NaBH4. 16. A process according to Claim 14 wherein: R3, R<4>, R<4a>, R<5>, R<5a> are H; R<6> is methoxy; the suitable cleaving agent is NaOH or KOH, and the suitable trapping agent is NaBH4. 17. A process for the preparation of a compound of formula (VI-i):   comprising: (1) contacting 4-chloro-2-trifluoroacetylaniline with trityl alcohol, in a suitable solvent, in the presence of a suitable acid catalyst selected from HC1, methane sulfonic acid, sulfuric acid, trifluoroacetic acid and p-toluene-sulfonic acid; to form a compound of formula (II-ii):   (2) (a) contacting 1R,2S-pyrrolidinyl norephedrine with n-hexyl lithium and cyclopropylacetylene, in a suitable solvent, to form a mixture of 1R,2S-pyrrolidinyl norephedrine and lithium cyclopropylacetylide, and (b) contacting the mixture of step (2) (a) with a compound of formula (II-ii) to form a compound of formula (III-ii):   (3) contacting a compound of formula (III-ii) with a suitable deprotecting agent selected from HC1, HBr, methane sulfonic acid, trifluoroacetic acid and p-toluene-sulfonic acid, in a suitable solvent, to form a compound of formula (V-i):   (4) contacting a compound of formula (V-i) with phosgene, in a suitable solvent, to form a compound of formula (VI-i). 18. A process according to Claim 34 for the preparation of a compound of formula (VI-i), wherein: the suitable acid catalyst is methane sulfonic acid or p-toluene-sulfonic acid; and the suitable deprotecting agent is HC1. 19. A process according to Claim 17 for the preparation of a compound of formula (VI-i), wherein the compounds of step (2) (a) and (b) are independently prepared and mixed as solution streams. 20. A compound of formula:   or a pharmaceutically acceptable salt thereof. 21. A process of Claim 11 wherein the suitable solvent is toluene.