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US 2003/0199515 A1Published application
Method for the preparation of crystalline tetrahydrobenzothiepines
AssigneeG.D. Searle & Co.
InventorsPartha S. Mudipalli, Mark J. Pozzo, Jung Min Park
Life of this patent
Estimating the term…
Abstract
Among its several embodiments, the present invention provides an improved process for the preparation of tetrahydrobenzothiepine-1,1-dioxide compounds; the provision of a process for preparing a diastereomeric mixture of tetrahydrobenzothiepine-1,1-dioxide compounds from a single diastereomer of such compounds; the provision of a process for the preparation of 3-bromo-2-substituted propionaldehyde compounds; the provision of a process for the preparation of 3-thio-2-substituted propionaldehyde compounds; and the provision of a process for the preparation of single crystals of ASBT inhibitors having high purity and low levels of solvent impurities.
Claims189
A process for reducing solvent impurities in a crystalline form of a compound represented by formula (41):
- 133
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (41) in a solvent system comprising a first solvent comprising water and a second solvent comprising a water miscible solvent;
- and
- (b) under an inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system substantially single crystals of said compound (41).
2 more elements
A process for reducing solvent impurities in a crystalline form of a compound represented by formula (41):
- 134
- said process comprising the steps of :
- (a) under an inert atmosphere, solubilizing said compound (41) in a solvent system comprising a first solvent comprising water and a second solvent comprising a water miscible solvent;
- (b) under an inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system substantially single crystals of said compound (41);
- and
- (c) separating said single crystals from said solvent system.
3 more elements
A process for reducing solvent impurities in a crystalline form of a compound represented by formula (41):
- 135
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (41) in a solvent system comprising a first solvent comprising water having a water concentration and a second solvent comprising a water miscible solvent;
- and
- (b) under inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system single crystals of said compound (41);
- and
- (c) optionally, separating and optionally drying said single crystals from said solvent system.
4 more elements
A process for reducing solvent impurities in a compound represented by formula (60):
- 136
- wherein:
- R1 and R2 independently are C1 to about C20 hydrocarbyl;
- R3, R4, and R5 independently are selected from the group consisting of H and C1 to about C20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R3, R4, and R5 taken together with the atom to which they are attached form a cyclic structure;
- R9 is selected from the group consisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR3, NR3R4, N+R3R4R5A−, SR3, S(O)R3, SO2R3, SO3R3, oxo, CO2R3, CN, halogen, NCO, CONR3R4, SO2OM, SO2NR3R4, PO(OR23)OR24, P+R3R4R5A−, S+R3R4A−, and C(O)OM;
- R23 and R24 are independently selected from the substituents constituting R3 and M;
- n is a number from 0 to 4;
- X− and A− are pharmaceutically acceptable anions and M is a pharmaceutically acceptable cation;
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (60) in a solvent system comprising a first solvent comprising water and a second solvent comprising a water miscible solvent;
- and
- (b) under an inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system substantially single crystals of said compound (60).
9 more elements
A process for reducing solvent impurities in a compound represented by formula (60):
- 137
- wherein:
- R1 and R2 independently are C1 to about C20 hydrocarbyl;
- R3, R4, and R5 independently are selected from the group consisting of H and C1 to about C20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R3, R4, and R5 taken together with the atom to which they are attached form a cyclic structure;
- R9 is selected from the group consisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR3, NR3R4, N+R3R4R5A−, SR3, S(O)R3, SO2R3, SO3R3, oxo, CO2R3, CN, halogen, NCO, CONR3R4, SO2OM, SO2NR3R4, PO(OR23)OR24, P+R3R4R5A−, S+R3R4A−, , and C(O)OM;
- R23 and R24 are independently selected from the substituents constituting R3 and M;
- n is a number from 0 to 4;
- X− and A− are pharmaceutically acceptable anions and M is a pharmaceutically acceptable cation;
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (60) in a solvent system comprising a first solvent comprising water and a second solvent comprising a water miscible solvent;
- (b) under an inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system substantially single crystals of said compound (60);
- and
- (c) separating said single crystals from said solvent system.
10 more elements
A process for reducing solvent impurities in a compound represented by formula (60):
- 138
- wherein:
- R1 and R2 independently are C1 to about C20 hydrocarbyl;
- R3, R4, and R5 independently are selected from the group consisting of H and C1 to about C20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R3, R4, and R5 taken together with the atom to which they are attached form a cyclic structure;
- R9 is selected from the group consisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR3, NR3R4, N+R3R4R5A−, SR3, S(O)R3, SO2R3, SO3R3 , oxo, CO2R3, CN, halogen, NCO, CONR3R4, SO2OM, SO2NR3R4, PO(OR23)OR24, P+R3R4R5A−, S+R3R4A−, and C(O)OM;
- R23 and R24 are independently selected from the substituents constituting R3 and M;
- n is a number from 0 to 4;
- X− and A− are pharmaceutically acceptable anions and M is a pharmaceutically acceptable cation;
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (60) in a solvent system comprising a first solvent comprising water having a water concentration and a second solvent comprising a water miscible solvent;
- and
- (b) under inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system single crystals of said compound (60);
- and
- (c) optionally, separating and optionally drying said single crystals from said solvent system.
11 more elements
A process for reducing solvent impurities in a compound represented by formula (1):
- 139
- wherein:
- R1 and R2 independently are C1 to about C20 hydrocarbyl;
- R3, R4, and R5 independently are selected from the group consisting of H and C1 to about C20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R3, R4, and R5 taken together with the atom to which they are attached form a cyclic structure;
- and
- X− is a pharmaceutically acceptable anion;
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (1) in a solvent system comprising a first solvent comprising water and a second solvent comprising a water miscible solvent;
- and
- (b) under an inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system substantially single crystals of said compound (1).
7 more elements
A process for reducing solvent impurities in a compound represented by formula (1):
- 140
- wherein:
- R1 and R2 independently are C1 to about C20 hydrocarbyl;
- R3, R4, and R5 independently are selected from the group consisting of H and C1 to about C20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R3, R4, and R5 taken together with the atom to which they are attached form a cyclic structure;
- and
- X− is a pharmaceutically acceptable anion;
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (1) in a solvent system comprising a first solvent comprising water and a second solvent comprising a water miscible solvent;
- (b) under an inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system substantially single crystals of said compound (1);
- and
- (c) separating said single crystals from said solvent system.
8 more elements
A process for reducing solvent impurities in a compound represented by formula (1):
- 141
- wherein:
- R1 and R2 independently are C1 to about C20 hydrocarbyl;
- R3, R4, and R5 independently are selected from the group consisting of H and C1 to about C20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R3, R4, and R5 taken together with the atom to which they are attached form a cyclic structure;
- and
- X− is a pharmaceutically acceptable anion;
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (1) in a solvent system comprising a first solvent comprising water having a water concentration and a second solvent comprising a water miscible solvent;
- and
- (b) under inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system single crystals of said compound (1);
- and
- (c) optionally, separating and optionally drying said single crystals from said solvent system.
9 more elements
A process for reducing solvent impurities in a compound represented by formula (71):
- 142
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (71) in a solvent system comprising a first solvent comprising water and a second solvent comprising a water miscible solvent;
- and
- (b) under an inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system substantially single crystals of said compound (71).
2 more elements
A process for reducing solvent impurities in a compound represented by formula (71):
- 143
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (71) in a solvent system comprising a first solvent comprising water and a second solvent comprising a water miscible solvent;
- (b) under an inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system substantially single crystals of said compound (71);
- and
- (c) separating said single crystals from said solvent system.
3 more elements
A process for reducing solvent impurities in a compound represented by formula (71):
- 144
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (71) in a solvent system comprising a first solvent comprising water having a water concentration and a second solvent comprising a water miscible solvent;
- and
- (b) under inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system single crystals of said compound (71);
- and
- (c) optionally, separating and optionally drying said single crystals from said solvent system.
4 more elements
A process for reducing solvent impurities in a compound represented by formula (63):
- 145
- R1 and R2 independently are C1 to about C10 alkyl;
- R3, R4, and R5 independently are selected from the group consisting of H and C1 to about C20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of
- R3, R4, and R5 taken together with the atom to which they are attached form a cyclic structure;
- R9 is selected from the group consisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR3, NR3R4, N+R3R4R5A−, SR3, S(O)R3, SO2R3, SO3R3,oxo, CO2R3, CN, halogen, NCO, CONR3R4, SO2OM, SO2NR3R4, PO(OR23)OR24, P+R3R4R5A−, S+R3R4A−, and C(O)OM;
- R23 and R24 are independently selected from the substituents constituting R3 and M;
- n is a number from 0 to 4;
- A− and Q− are pharmaceutically acceptable anions;
- and
- M is a pharmaceutically acceptable cation;
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (63) in a solvent system comprising a first solvent comprising water and a second solvent comprising a water miscible solvent;
- and
- (b) under an inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system substantially single crystals of said compound (63).
11 more elements
A process for reducing solvent impurities in a compound represented by formula (63):
- 146
- R1 and R2 independently are C1 to about C10 alkyl;
- R3, R4, and R5 independently are selected from the group consisting of H and C 1 to about C20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R3, R4, and R5 taken together with the atom to which they are attached form a cyclic structure;
- R9 is selected from the group consisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR3, NR3R4, N+R3R4R5A−, SR3, S(O)R3,SO2R3,SO3R3,oxo, CO2R3,CN, halogen, NCO, CONR3R4, SO2OM,SO2NR3R4, PO(OR23)OR24, P+R3R4R5A−, S+R3R4A−, and C(O)OM;
- R23 and R24 are independently selected from the substituents constituting R3 and M;
- n is a number from 0 to 4;
- A− and Q− are pharmaceutically acceptable anions;
- and
- M is a pharmaceutically acceptable cation;
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (63) in a solvent system comprising a first solvent comprising water and a second solvent comprising a water miscible solvent;
- (b) under an inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system substantially single crystals of said compound (63);
- and
- (c) separating said single crystals from said solvent system.
11 more elements
A process for reducing solvent impurities in a compound represented by formula (63):
- 147
- R1 and R2 independently are C1 to about C10 alkyl;
- R3, R4, and R5 independently are selected from the group consisting of H and C1 to about C20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R3, R4, and R5 taken together with the atom to which they are attached form a cyclic structure;
- R9 is selected from the group consisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR3, NR3R4, N+R3R4R5A−, SR3, S(O)R3, SO2R3, SO3R3,oxo, CO2R3, CN, halogen, NCO, CONR3R4, SO2OM, SO2 NR3R4, PO(OR23)OR24, P+R3R4R5A−, S+R3R4A, and C(O)OM;
- R23 and R24 are independently selected from the substituents constituting R3 and M;
- n is a number from 0 to 4;
- A− and Q− are pharmaceutically acceptable anions;
- and
- M is a pharmaceutically acceptable cation;
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (63) in a solvent system comprising a first solvent comprising water having a water concentration and a second solvent comprising a water miscible solvent;
- and
- (b) under inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system single crystals of said compound (63);
- and
- (c) optionally, separating and optionally drying said single crystals from said solvent system.
12 more elements
A process for reducing solvent impurities in a compound represented by formula (3):
- 148
- wherein:
- R1 and R2 independently are C1 to about C20 hydrocarbyl;
- and
- X− is a pharmaceutically acceptable anion;
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (3) in a solvent system comprising a first solvent comprising water and a second solvent comprising a water miscible solvent;
- and
- (b) under an inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system substantially single crystals of said compound (3).
6 more elements
A process for reducing solvent impurities in a compound represented by formula (3):
- 149
- wherein:
- R1 and R2 independently are C1 to about C20 hydrocarbyl;
- and
- X− is a pharmaceutically acceptable anion;
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (3) in a solvent system comprising a first solvent comprising water and a second solvent comprising a water miscible solvent;
- (b) under an inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system substantially single crystals of said compound (3);
- and
- (c) separating said single crystals from said solvent system.
7 more elements
A process for reducing solvent impurities in a compound represented by formula (3):
- 150
- wherein:
- R1 and R2 independently are C1 to about C20 hydrocarbyl;
- and
- X− is a pharmaceutically acceptable anion;
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (3) in a solvent system comprising a first solvent comprising water having a water concentration and a second solvent comprising a water miscible solvent;
- and
- (b) under inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system single crystals of said compound (3);
- and
- (c) optionally, separating and optionally drying said single crystals from said solvent system.
8 more elements
A process for reducing solvent impurities in a compound represented by formula (64):
- 151
- wherein:
- R1 and R2 independently are C1 to about C20 hydrocarbyl;
- R3, R4, and R5 independently are selected from the group consisting of H and C1 to about C20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R3, R4, and R5 taken together with the atom to which they are attached form a cyclic structure;
- R9 is selected from the group consisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR3, NR3R4, N+R3R4R5A−, SR3, S(O)R3, SO2R3, SO3R3,oxo, CO2R3, CN, halogen, NCO, CONR3R4, SO2OM, SO2NR3R4, PO(OR23)OR24, P+R3R4R5A−, S+R3R4A−, and C(O)OM;
- R23 and R24 are independently selected from the substituents constituting R3 and M;
- n is a number from 0 to 4;
- A− and Q− independently are pharmaceutically acceptable anions;
- and
- M is a pharmaceutically acceptable cation;
- said process comprising the steps of :
- (a) under an inert atmosphere, solubilizing said compound (64) in a solvent system comprising a first solvent comprising water and a second solvent comprising a water miscible solvent;
- and
- (b) under an inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system substantially single crystals of said compound (64).
11 more elements
A process for reducing solvent impurities in a compound represented by formula (64):
- 152
- wherein:
- R1 and R2 independently are C 1 to about C20 hydrocarbyl;
- R3, R4, and R5 independently are selected from the group consisting of H and C1 to about C20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S , and wherein optionally two or more of R3, R4, and R5 taken together with the atom to which they are attached form a cyclic structure;
- R9 is selected from the group consisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR3, NR3R4, N+R3R4R5A−, SR3, S(O)R3, SO2R3, SO3R3, oxo, CO2R3, CN, halogen, NCO , CONR3R4, SO2OM , SO2NR3R4, PO(OR23)OR24, P+R3R4R5A−, S+R3R4A−, and C(O)OM;
- R23 and R24 are independently selected from the substituents constituting R3 and M;
- n is a number from 0 to 4;
- A− and Q− independently are pharmaceutically acceptable anions;
- and
- M is a pharmaceutically acceptable cation;
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (64) in a solvent system comprising a first solvent comprising water and a second solvent comprising a water miscible solvent;
- (b) under an inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system substantially single crystals of said compound (64);
- and
- (c) separating said single crystals from said solvent system.
12 more elements
A process for reducing solvent impurities in a compound represented by formula (64):
- 153
- wherein:
- R1 and R2 independently are C1 to about C20 hydrocarbyl;
- R3, R4, and R5 independently are selected from the group consisting of H and C1 to about C20 hydrocarbyl, wherein optionally one or more carbon atom of the hydrocarbyl is replaced by O, N, or S, and wherein optionally two or more of R3, R4, and R5 taken together with the atom to which they are attached form a cyclic structure;
- R9 is selected from the group consisting of H, hydrocarbyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, ammoniumalkyl, polyalkoxyalkyl, heterocyclyl, heteroaryl, quaternary heterocycle, quaternary heteroaryl, OR3 , NR3R4, N+R3R4R5A−, SR3, S(O)R3, SO2R3,SO3R3, oxo, CO2R3, CN, halogen, NCO, CONR3R4, SO2OM, SO2NR3R4, PO(OR23)OR24, P+R3R4R5A−, S+R3R4A−, and C(O)OM;
- R23 and R24 are independently selected from the substituents constituting R3 and M;
- n is a number from 0 to 4;
- A− and Q− independently are pharmaceutically acceptable anions;
- and
- M is a pharmaceutically acceptable cation;
- said process comprising the steps of:
- (a) under an inert atmosphere, solubilizing said compound (64) in a solvent system comprising a first solvent comprising water having a water concentration and a second solvent comprising a water miscible solvent;
- and
- (b) under inert atmosphere, adjusting the water concentration in said solvent system sufficient to re-crystallize from said solvent system single crystals of said compound (64);
- and
- (c) optionally, separating and optionally drying said single crystals from said solvent system.
13 more elements
Dependencies are inferred from the claim text.