The present invention is directed to a method of producing active pharmaceutical ingredients (APIs). The method includes subjecting a reaction mixture with an API precursor to solvent extraction to produce a reactant stream with the API precursor. The method includes concentrating the API precursor in the reactant stream using at least one membrane. The method includes carrying out a reaction in a membrane reactor. The method includes separating the API precursor from the reaction stream using a separator. The method includes crystallizing the API precursor using a crystallizer to produce APIs.

The present invention is directed to a method of producing active pharmaceutical ingredients (APIs). The method includes subjecting a reaction mixture with an API precursor to solvent extraction to produce a reactant stream with the API precursor. The method includes concentrating the API precursor in the reactant stream using at least one membrane. The method includes carrying out a reaction in a membrane reactor. The method includes separating the API precursor from the reaction stream using a separator. The method includes crystallizing the API precursor using a crystallizer to produce APIs.

The invention relates to monocarbonyl complexes of ruthenium and osmium with bi- and tridentate nitrogen and phosphine ligands. The invention relates to methods for preparing these complexes and the use of these complexes, isolated or prepared in situ, as catalysts for reduction reactions of ketones and aldehydes both via transfer hydrogenation or hydrogenation with hydrogen.

The invention relates to monocarbonyl complexes of ruthenium and osmium with bi- and tridentate nitrogen and phosphine ligands. The invention relates to methods for preparing these complexes and the use of these complexes, isolated or prepared in situ, as catalysts for reduction reactions of ketones and aldehydes both via transfer hydrogenation or hydrogenation with hydrogen.

A method for producing an organometallic nucleophile includes reacting an organohalide and a metal or metal compound with each other by a mechanochemical process in the presence of an ether compound in an amount of 0.5 to 10.0 equivalents relative to 1 equivalent of the organohalide. By utilizing the method, a method for producing an organometallic nucleophile can be performed without using a large-scale apparatus, a reaction method for reactions between an organometallic nucleophile and various organic electrophiles can be performed by an efficient and simplified means, and a simplified method for producing an organometallic nucleophile can be performed with high reactivity.

A method for producing an organometallic nucleophile includes reacting an organohalide and a metal or metal compound with each other by a mechanochemical process in the presence of an ether compound in an amount of 0.5 to 10.0 equivalents relative to 1 equivalent of the organohalide. By utilizing the method, a method for producing an organometallic nucleophile can be performed without using a large-scale apparatus, a reaction method for reactions between an organometallic nucleophile and various organic electrophiles can be performed by an efficient and simplified means, and a simplified method for producing an organometallic nucleophile can be performed with high reactivity.

The invention provides a method comprising hydrogenating a ketone in the presence of (i) a base, (ii) hydrogen gas and (iii) a catalyst comprising a charged or neutral complex of formula (I):

##STR00001## wherein: Mn is a manganese atom or a manganese ion in oxidation state (I) to (VII); R.sup.1 and R.sup.2 are each independently optionally substituted C.sub.4-8monocyclic aryl or C.sub.3-7monocyclic heteroaryl moieties; -Fc- denotes a ferrocene (bis(η.sup.5-cyclopentadienyl)iron) moiety covalently bonded via adjacent carbon atoms of one of the two cyclopentadienyl moieties, and which may be optionally further substituted, in either cyclopentadienyl ring; —Z— is an alkylene linker of the formula —(CH.sub.2).sub.1-6— in which one or more of the hydrogen atoms of the alkylene may be independently substituted; —N.sup.x is an optionally substituted nitrogen-containing heteroaryl moiety, with the proviso that at least one of R.sup.1, R.sup.2 and —N.sup.x is substituted one or more times with an electron donating group; and L.sup.1-L.sup.3 constitute one, two or three ligands, wherein, when the complex of formula (I) is charged, the catalyst comprises one or more additional counterions to balance the charge of the complex.

The invention provides a method comprising hydrogenating a ketone in the presence of (i) a base, (ii) hydrogen gas and (iii) a catalyst comprising a charged or neutral complex of formula (I):

##STR00001## wherein: Mn is a manganese atom or a manganese ion in oxidation state (I) to (VII); R.sup.1 and R.sup.2 are each independently optionally substituted C.sub.4-8monocyclic aryl or C.sub.3-7monocyclic heteroaryl moieties; -Fc- denotes a ferrocene (bis(η.sup.5-cyclopentadienyl)iron) moiety covalently bonded via adjacent carbon atoms of one of the two cyclopentadienyl moieties, and which may be optionally further substituted, in either cyclopentadienyl ring; —Z— is an alkylene linker of the formula —(CH.sub.2).sub.1-6— in which one or more of the hydrogen atoms of the alkylene may be independently substituted; —N.sup.x is an optionally substituted nitrogen-containing heteroaryl moiety, with the proviso that at least one of R.sup.1, R.sup.2 and —N.sup.x is substituted one or more times with an electron donating group; and L.sup.1-L.sup.3 constitute one, two or three ligands, wherein, when the complex of formula (I) is charged, the catalyst comprises one or more additional counterions to balance the charge of the complex.

A method for preparing the borate ester using a lithium compound includes: under the inert gas, stirring and mixing carboxylic acid and borane, and a catalyst lithium compound is added, then the borate ester is obtained with hydroboration; wherein the hydroboration is at room temperature for 10 to 80 min. After the hydroboration and is stopped by contacting air, the solvent is removed under reduced pressure, to obtain the borate esters with different substituents. The lithium compounds are n-butyl lithium, lithium aniline, p-methyl lithium aniline, o-methyl lithium aniline, 2-methoxyaniline lithium, 4-methoxyaniline lithium, 2,6-dimethylaniline lithium, and 2,6-diisopropylaniline lithium. The lithium compounds disclosed in the present invention can catalyze the boron hydrogenation reaction of carboxylic acid and borane with high activity under room temperature conditions; the amount of lithium compound is 0.1-0.9% of the molar amount of carboxylic acid.

A method for preparing the borate ester using a lithium compound includes: under the inert gas, stirring and mixing carboxylic acid and borane, and a catalyst lithium compound is added, then the borate ester is obtained with hydroboration; wherein the hydroboration is at room temperature for 10 to 80 min. After the hydroboration and is stopped by contacting air, the solvent is removed under reduced pressure, to obtain the borate esters with different substituents. The lithium compounds are n-butyl lithium, lithium aniline, p-methyl lithium aniline, o-methyl lithium aniline, 2-methoxyaniline lithium, 4-methoxyaniline lithium, 2,6-dimethylaniline lithium, and 2,6-diisopropylaniline lithium. The lithium compounds disclosed in the present invention can catalyze the boron hydrogenation reaction of carboxylic acid and borane with high activity under room temperature conditions; the amount of lithium compound is 0.1-0.9% of the molar amount of carboxylic acid.