Disclosed is a process for preparing a treprostinil salt. The process involves the step of dissolving treprostinil in a water-miscible organic solvent to form a treprostinil solution. The treprostinil solution is reacted with an aqueous basic solution containing an alkali metal cation to form treprostinil salt. Allowing crystallization of the treprostinil salt to take place, and then collecting the treprostinil salt formed.
A para-methoxy protected benzaldehyde useful in preparation of treprostinil, and of formula: (Formula (1)) is prepared by subjecting to Claisen re-arrangement a substituted benzaldehyde of formula (1a): (Formula (Ia)) to form the m-hydroxy-substituted benzaldehyde of formula (1b): (Formula (Ib)) and then reacting compound (1b) with a p-methoxybenzyl (PMB) compound to form a PMB-substituted benzaldehyde of formula (1).
C07C 45/61 - Preparation of compounds having C=O groups bound only to carbon or hydrogen atomsPreparation of chelates of such compounds by reactions not involving the formation of C=O groups
C07C 45/67 - Preparation of compounds having C=O groups bound only to carbon or hydrogen atomsPreparation of chelates of such compounds by reactions not involving the formation of C=O groups by isomerisationPreparation of compounds having C=O groups bound only to carbon or hydrogen atomsPreparation of chelates of such compounds by reactions not involving the formation of C=O groups by change of size of the carbon skeleton
C07C 45/71 - Preparation of compounds having C=O groups bound only to carbon or hydrogen atomsPreparation of chelates of such compounds by reactions not involving the formation of C=O groups by isomerisationPreparation of compounds having C=O groups bound only to carbon or hydrogen atomsPreparation of chelates of such compounds by reactions not involving the formation of C=O groups by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
C07C 47/575 - Compounds having —CHO groups bound to carbon atoms of six-membered aromatic rings containing ether groups, groups, groups, or groups
Disclosed is a process for preparing a treprostinil salt. The process involves the step of dissolving treprostinil in a water-miscible organic solvent to form a treprostinil solution. The treprostinil solution is reacted with an aqueous basic solution containing an alkali metal cation to form treprostinil salt. Allowing crystallization of the treprostinil salt to take place, and then collecting the treprostinil salt formed.
A para-methoxy protected benzaldehyde useful in preparation of treprostinil, and of formula: (see formula 1) is prepared by subjecting to Claisen re-arrangement a substituted benzaldehyde of formula (Ia): (see formula Ia) to form the m-hydroxy-substituted benzaldehyde of formula (Ib): see formula Ib) and then reacting compound (Ib) with a p-methoxybenzyl (PMB) compound to form a PMB-substituted benzaldehyde of formula 1
C07C 47/575 - Compounds having —CHO groups bound to carbon atoms of six-membered aromatic rings containing ether groups, groups, groups, or groups
C07C 45/64 - Preparation of compounds having C=O groups bound only to carbon or hydrogen atomsPreparation of chelates of such compounds by reactions not involving the formation of C=O groups by introduction of functional groups containing oxygen only in singly bound form
C07C 45/67 - Preparation of compounds having C=O groups bound only to carbon or hydrogen atomsPreparation of chelates of such compounds by reactions not involving the formation of C=O groups by isomerisationPreparation of compounds having C=O groups bound only to carbon or hydrogen atomsPreparation of chelates of such compounds by reactions not involving the formation of C=O groups by change of size of the carbon skeleton
7.
SYNTHESIS OF TREPROSTINIL AND INTERMEDIATES USEFUL THEREIN
Treprostinil is prepared by a process which involves Pauson - Khan cyclization of an an alkene-substituted, alkyne-substituted benzene corresponding to formula: (see above formula) where PMB represents para-methoxybenzyl protecting group and R1 and R2 are alcohol protecting groups. Following cyclization, the resulting compound can be subjected to several chemical transformations followed by alkylation, hydrolysis and salt formation to yield treprostinil sodium. The use of para-methoxybenzyl group as the phenolic protecting group confers several process advantages that result in simplified purification of the final product and improved yields.
C07C 49/755 - Unsaturated compounds containing a keto group being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
C07C 41/08 - Preparation of ethers by addition of compounds to unsaturated compounds by addition of organic compounds only to carbon-to-carbon triple bonds
C07C 43/215 - Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
C07C 43/23 - Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
C07C 45/50 - Preparation of compounds having C=O groups bound only to carbon or hydrogen atomsPreparation of chelates of such compounds by reaction with carbon monoxide by oxo-reactions
C07C 45/67 - Preparation of compounds having C=O groups bound only to carbon or hydrogen atomsPreparation of chelates of such compounds by reactions not involving the formation of C=O groups by isomerisationPreparation of compounds having C=O groups bound only to carbon or hydrogen atomsPreparation of chelates of such compounds by reactions not involving the formation of C=O groups by change of size of the carbon skeleton
C07C 49/84 - Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
C07C 51/367 - Preparation of carboxylic acids or their salts, halides, or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in singly bound form
C07C 59/72 - Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings and other rings
Ready-to-use bivalirudin compositions, methods of using the ready-to-use bivalirudin compositions, and methods of preparing the ready-to-use bivalirudin compositions. The ready-to-use bivalirudin compositions comprise bivalirudin and one or more stabilizing agents. The one or more stabilizing agents may be buffering agents having a pKa of about 2.5 to about 6.5, pH-adjusting agents, polymers, preservatives, antioxidants, sugars or polyols, or a combination thereof. The ready-to-use bivalirudin compositions may also comprise [9-10]-cycloimido bivalirudin, [11-12]-cycloimido bivalirudin, or a combination thereof. The method of using the ready-to-use bivalirudin compositions comprises administering the ready-to-use compositions to a patient in need thereof. Further, the method of preparing the ready-to-use bivalirudin compositions comprises mixing bivalirudin with one or more stabilizing agents.
Ready-to-use bivalirudin compositions, methods of using the ready-to-use bivalirudin compositions, and methods of preparing the ready-to-use bivalirudin compositions. The ready-to-use bivalirudin compositions comprise bivalirudin and one or more stabilizing agents. The one or more stabilizing agents may be buffering agents having a pKa of about 2.5 to about 6.5, pH-adjusting agents, polymers, preservatives, antioxidants, sugars or polyols, or a combination thereof. The ready-to-use bivalirudin compositions may also comprise [9-10]-cycloimido bivalirudin, [11-12]-cycloimido bivalirudin, or a combination thereof. The method of using the ready-to-use bivalirudin compositions comprises administering the ready-to-use compositions to a patient in need thereof. Further, the method of preparing the ready-to-use bivalirudin compositions comprises mixing bivalirudin with one or more stabilizing agents.
Paricalcitol, a synthetic vitamin D analog, is purified to a purity greater than 99.7% by crystallization from solution in isopropyl acetate solvent, followed by filtration and vacuum drying. Isopropyl acetate appears to be unique among commonly available and pharmaceutically acceptable solvents in its ability to precipitate paricalcitol in this high purity, essentially free of isomers thereof.
C07C 401/00 - Irradiation products of cholesterol or its derivativesVitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
C07C 37/84 - SeparationPurificationStabilisationUse of additives by physical treatment by crystallisation
11.
Pharmaceutical formulations of bivalirudin and processes of making the same
9-bivalirudin that does not exceed about 0.6%. Also, the pharmaceutical batch(es) or pharmaceutical formulation(s) may have a reconstitution time that does not exceed about 42 seconds. The method of preparing the pharmaceutical batch(es) or pharmaceutical formulation(s) may comprise dissolving bivalirudin in a solvent to form a first solution, efficiently mixing a pH-adjusting solution with the first solution to form a second solution in which the pH-adjusting solution may comprise a pH-adjusting solution solvent, and removing the solvent and the pH-adjusting solution solvent from the second solution.
9-bivalirudin that does not exceed about 0.6%. Also, the pharmaceutical batch(es) or pharmaceutical formulation(s) may have a reconstitution time that does not exceed about 42 seconds. The method of preparing the pharmaceutical batch(es) or pharmaceutical formulation(s) may comprise dissolving bivalirudin in a solvent to form a first solution, efficiently mixing a pH-adjusting solution with the first solution to form a second solution in which the pH-adjusting solution may comprise a pH-adjusting solution solvent, and removing the solvent and the pH-adjusting solution solvent from the second solution.
where R represents an aromatic ring optionally substituted with one or more electron withdrawing groups, n=0 or 1 and X is oxygen or sulphur; so as to produce a crystallizable THC carbamate of formula II:
10 alkyl group and the dotted lines indicate optional unsaturation including aromatic, separating the compound of formula II from solution in isolation of other THC derivatives, and hydrolyzing the compound of formula II to form the individual tetrahydrocannabinol isomer of interest.
Dronabinol, the tetrahydrocannabinol compound which comprises the active constituent of marijuana and is pharmaceutically useful as an antiemetic, is prepared by a process involving reaction of cis-menth-1-enc-3,8-diol with olivetol to form 1,3-dihydroxy-2-[(1R,6R)-6-(2-hydroxyprop-2-yl)-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene; and cyclizing the 1,3-dihydroxy-2-[(1R,6R)-6-(2-hydroxyprop-2-yl)-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene so formed to obtain dronabinol. A novel synthesis of cis-menth-1-ene-3,8-diol is also provided.
