The present invention relates to kinetic resolution of racemic -hydroxyl ester via asymmetric catalytic hydrogenation and an application thereof. In the presence of chiral spiro pyridyl phosphine ligand Iridium catalyst and base, racemic -hydroxyl esters were subjected to asymmetric catalytic hydrogenation to obtain extent optical purity chiral -hydroxyl esters and corresponding 1,5-diols. An optically active chiral -hydroxyl ester and 1,5-diols can be obtained at very high enantioselectivity and yield with relatively low usage of catalyst. The chiral -hydroxyl ester and 1,5-diols obtained by using the method can be used as a critical raw material for asymmetric synthesis of chiral drugs (R)-lisofylline and natural drugs (+)-civet, ()-indolizidine 167B and ()-coniine.

Provided herein is a compound of formula (I): ##STR00001##
wherein each R is independently selected from the group consisting of C.sub.1-8 alkyl, C.sub.1-8 heteroalkyl having 1-4 heteroatoms independently selected from N, O, and S, C.sub.3-6 cycloalkyl, 3-10 membered heterocycloalkyl having 1-4 heteroatoms independently selected from N, O, and S, C.sub.6-10 aryl, and 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S; each X is independently selected from OH, PAr.sub.2, P(O)Ar.sub.2, OPAr.sub.2, C.sub.3-6 cycloalkyl, 3-10 membered heterocycloalkyl having 1-4 heteroatoms independently selected from N, O, and S or each X together form O.sub.2PNR.sub.2; Ar is C.sub.6-10aryl; and each R is independently selected from hydrogen and C.sub.1-8 alkyl. Also provided are methods of making and using the compound of formula (I).

The present invention relates to a chiral spiro phosphine-nitrogen-sulfur (PNS) tridentate ligand, preparation method and application thereof. The PNS tridentate ligand is a compound represented by Formula I or Formula II, their racemates, optical isomers, or catalytically acceptable salts thereof. The ligand has a primary structure skeleton characterized as a chiral spiro indan skeleton structure with a thio group. The chiral spiro phosphine-nitrogen-sulfur tridentate ligand can be synthesized by reacting racemic or optical active compound 7-diary/alkyl phosphine-7-amino-1, 1-spiro-dihydro-indene compound having a spiro-dihydro-indene skeleton as the starting material. The chiral spiro PNS tridentate ligand being complex with transition metal salt can be used in an asymmetric catalytic hydrogenation reaction for catalyzing carbonyl compound. In particular, in asymmetric hydrogenation reaction process, being complex with iridium for catalyzing -alkyl--keto ester can obtain a high catalytic activity (a catalyst amount of 0.0002% mol) and high enantioselectivity (up to 99.9% ee) result. So the present invention has a practical value for industrial and commercial production. ##STR00001##

This invention is based on the discovery that homogeneous catalysts, [Rh(C.sub.2H.sub.4).sub.2Cl].sub.2 and/or [Rh(COD).sub.2][BF.sub.4], can be used to produce spinetoram in higher yields at lower catalyst loadings as compared to previous methodologies. In addition, one or more phosphorus ligand donors can also be added to further increase yields/efficiency. The methods and/or systems provided herein enable cost-effective ways to produce spinetoram in large quantity with relatively simple procedures.

The present invention provides methods of preparing Praziquantel, in particular (R)-Praziquantel and analogues thereof in a stereoselective manner. One method involves asymmetric hydrogenation of the following intermediate compound ##STR00001##
and subsequent cyclization.

Provided herein is a compound of formula (I):

##STR00001##

wherein each R is independently selected from the group consisting of C.sub.1-8 alkyl, C.sub.1-8 heteroalkyl having 1-4 heteroatoms independently selected from N, O, and S, C.sub.3-6 cycloalkyl, 3-10 membered heterocycloalkyl having 1-4 heteroatoms independently selected from N, O, and S, C.sub.6-10 aryl, and 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from N, O, and S; each X is independently selected from OH, PAr.sub.2, P(O)Ar.sub.2, OPAr.sub.2, C.sub.3-6 cycloalkyl, 3-10 membered heterocycloalkyl having 1-4 heteroatoms independently selected from N, O, and S or each X together form O.sub.2PNR.sub.2; Ar is C.sub.6-10aryl; and each R is independently selected from hydrogen and C.sub.1-8 alkyl. Also provided are methods of making and using the compound of formula (I).

The present invention relates to the technical field of chiral synthesis, and specifically provides the synthesis and use of a new type of oxa-spirodiphosphine ligands. The bisphosphine ligand is prepared with oxa-spirobisphenol as a starting material after triflation, palladium catalyzed coupling with diaryl phosphine oxide, reduction of trichlorosilane, further palladium catalyzed coupling with diaryl phosphine oxide, and further reduction of trichlorosilane. The oxa-spiro compound has central chirality, and thus includes L-oxa-spirodiphosphine ligand and R-oxa-spirodiphosphine ligand. The racemic spirodiphosphine ligand is capable of being synthesized from racemic oxa-spirobisphenol as a raw material. The present invention can be used as a chiral ligand in the asymmetric hydrogenation of unsaturated carboxylic acids. The complex of the ligand with ruthenium can achieve an enantioselectivity of greater than 99% in the asymmetric hydrogenation of methyl-cinnamic acid.

The present invention provides methods of preparing Praziquantel, in particular (R)-Praziquantel and analogues thereof in a stereoselective manner. One method involves asymmetric hydrogenation of the following intermediate compound

##STR00001##

and subsequent cyclization.

The present invention relates to a chiral spiro phosphine-nitrogen-sulfur (PNS) tridentate ligand, preparation method and application thereof. The PNS tridentate ligand is a compound represented by Formula I or Formula II, their racemates, optical isomers, or catalytically acceptable salts thereof. The ligand has a primary structure skeleton characterized as a chiral spiro indan skeleton structure with a thio group. The chiral spiro phosphine-nitrogen-sulfur tridentate ligand can be synthesized by reacting racemic or optical active compound 7-diary/alkyl phosphine-7-amino-1,1-spiro-dihydro-indene compound having a spiro-dihydro-indene skeleton as the starting material. The chiral spiro PNS tridentate ligand being complex with transition metal salt can be used in an asymmetric catalytic hydrogenation reaction for catalyzing carbonyl compound. In particular, in asymmetric hydrogenation reaction process, being complex with iridium for catalyzing -alkyl--keto ester can obtain a high catalytic activity (a catalyst amount of 0.0002% mol) and high enantioselectivity (up to 99.9% ee) result. So the present invention has a practical value for industrial and commercial production.

##STR00001##

This invention is based on the discovery that homogeneous catalysts, [Rh(C.sub.2H.sub.4).sub.2Cl].sub.2 and/or [Rh(COD).sub.2][BF.sub.4], can be used to produce spinetoram in higher yields at lower catalyst loadings as compared to previous methodologies. In addition, one or more phosphorus ligand donors can also be added to further increase yields/efficiency. The methods and/or systems provided herein enable cost-effective ways to produce spinetoram in large quantity with relatively simple procedures.