2,2,2-trichloroethyl carbamate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By cleavage of the 2,2,2-trichloroethyl carbamate and 2,2,2-trichloroethyl carbonate from 2,2,2-trichloro-ethyl (1RS,2RS,3RS,5RS)-3-(4-fluoro-phenyl)-2-(2,2,2-trichloro-ethoxy-carbonyloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate in an analogous manner to that described in Example 12(d) there was obtained (1RS,2RS,3RS,5RS)-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]octan-2-ol as a colourless solid; MS: 221 (M)+.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By cleavage of the 2,2,2-trichloroethyl carbamate and 2,2,2-trichloroethyl carbonate from 2,2,2-trichloro-ethyl (1RS,2RS,3RS,5RS)-3-(4-fluoro-phenyl)-2-(2,2,2-trichloro-ethoxy-carbonyloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate in an analogous manner to that described in Example 12(d) there was obtained (1RS,2RS,3RS,5RS)-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]octan-2-ol as a colourless solid; MS: 221 (M)+.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Me-PRX (150 g) is dissolved in toluene (450 ml) at room temperature. The mixture is then heated to reflux. At reflux, 2,2,2-trichloroethyl-chloroformate (120 ml) is added dropwise for about 2.5 hours. After about 3 hours at reflux, the reaction mixture is cooled, and ammonia 20% (300 ml) and water (300 ml) is added. The organic phase is separated and washed with water (500 ml), followed by brine (500 ml). The organic phase is then separated, dried over MgSO4, filtered. Toluene is then removed under reduced pressure to give 280.2 g of the 2,2,2-trichloroethyl carbamate of paroxetine. The carbamate is then hydrolyzed according to procedures set forth, for example, in Examples 5-7 to give paroxetine base. Paroxetine base may then be converted into the desired polymorphic form of, e.g., the hydrochloride acid addition salt such as the hemihydrate, anhydrate or solvate form as disclosed herein. The mixture is then heated to reflux At reflux After about 3 hours at reflux the reaction mixture is cooled The organic phase is separated washed with water (500 ml) The organic phase is then separated dried over MgSO4 filtered Toluene is then removed under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of amine (2 mmol, 1.00 eq) and pyridine (4 mmol, 2.00 eq) in CH2Cl2 (18 ml) at RT was added Troc-Cl (1.87 mmol, 1.05 eq). After 4 hours the reaction was washed with 3M HCl (1×), satd. NaHCO3 (1×), dried (Na2SO4), filtered and evaporated to afford the target 2,2,2-trichloroethyl carbamate. The material was used as is in the next reaction. After 4 hours the reaction was washed with 3M HCl (1×) NaHCO3 (1×), dried (Na2SO4) filtered evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Scheme 1 depicts a first synthesis of the boronic acid pinacol ester intermediate compound [1]. Specifically, a 4-nitrobenzoic acid [A] is converted to the corresponding amide [B] using an amine such as R7R8NH, a coupling agent such as EDCI.HCl, DCC, HBTU, or HATU, an additive such as HOBt or HOAt, a base such as TEA or DIPEA and solvent such as DMF, THF, or DCM. In one embodiment, the amine may be NH3, NH2CH3, NH(CH3)2, morpholine, piperidine, 1-methyl-piperazine and N(CH3)2CH2CH2N(CH3)2, among others. Typically, this is performed at rt such as about 25 to about 30° C. for about 10 to about 15 h such as about 10 h. The 4-nitro amide [B] is then reduced to the corresponding amine [C] using H2 and a catalyst such as Pd/C 10%, PtO2, or Pd(OH)2. Typically, the reduction is performed under pressures such as 60 psi, in a solvent such as MeOH, dioxane, or ethylacetate, for about 3 to about 5 h such as about 3 h. Amine [C] is then converted to urea [D] using an appropriately substituted isocyanate such as 4-bromophenyl isocyanate. This reaction is typically performed in the presence of a base such as TEA or DIPEA and solvent such as CH2Cl2, CHCl3, or THF at about rt such as about 25 to about 30° C. for about 5 to about 15 h such as about 12 h. As one alternative method, amine [C] can be converted to the corresponding 2,2,2-trichloroethyl carbamate and then reacted with an appropriately substituted aniline or pyridinyl amine, to produce the desired urea [D]. For example, amine [C] would typically be treated with 2,2,2-trichloroethyl chloroformate in the presence of a base such as triethylamine or DIPEA, in a solvent such as CH2Cl2, CHCl3, or THF, at temperatures such as 0° C. to about 30° C. for about 30 minutes to 5 hours, to produce the 2,2,2-trichloroethyl carbamate intermediate. Then the 2,2,2-trichloroethyl carbamate intermediate is typically reacted with the aniline or pyridinyl amine in the presence of a base such as triethylamine or DIPEA, in a solvent such as toluene, 1,4-dioxane or THF, at about room temperature up to elevated temperatures such as about 110° C. for about 1 to 16 hours. This alternative two-step procedure provides the urea [D]. Intermediate boronic acid pinacal ester [1] is then formed by reacting urea [D] with bis(pinacolato)diboron. This reaction may be performed in the presence of a weak base such as KOAc, palladium catalyst such as Pd(dppf)Cl2.DCM or Pd(dppf)Cl2, in a solvent such as 1,4-dioxane or DMF. Desirably, the reaction is performed at elevated temperatures such as the reflux temperatures of the solvent. In one embodiment, this reaction is performed at about 80 to about 120° C. for about 2 to about 15 h. In another embodiment, this reaction is performed at about 110° C. for about 10 h.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Scheme 1 depicts a first synthesis of the boronic acid pinacol ester intermediate compound [1]. Specifically, a 4-nitrobenzoic acid [A] is converted to the corresponding amide [B] using an amine such as R7R8NH, a coupling agent such as EDCI.HCl, DCC, HBTU, or HATU, an additive such as HOBt or HOAt, a base such as TEA or DIPEA and solvent such as DMF, THF, or DCM. In one embodiment, the amine may be NH3, NH2CH3, NH(CH3)2, morpholine, piperidine, 1-methyl-piperazine and N(CH3)2CH2CH2N(CH3)2, among others. Typically, this is performed at rt such as about 25 to about 30° C. for about 10 to about 15 h such as about 10 h. The 4-nitro amide [B] is then reduced to the corresponding amine [C] using H2 and a catalyst such as Pd/C 10%, PtO2, or Pd(OH)2. Typically, the reduction is performed under pressures such as 60 psi, in a solvent such as MeOH, dioxane, or ethylacetate, for about 3 to about 5 h such as about 3 h. Amine [C] is then converted to urea [D] using an appropriately substituted isocyanate such as 4-bromophenyl isocyanate. This reaction is typically performed in the presence of a base such as TEA or DIPEA and solvent such as CH2Cl2, CHCl3, or THF at about rt such as about 25 to about 30° C. for about 5 to about 15 h such as about 12 h. As one alternative method, amine [α] can be converted to the corresponding 2,2,2-trichloro-ethyl carbamate and then reacted with an appropriately substituted aniline or pyridinyl amine, to produce the desired urea [D]. For example, amine [C] would typically be treated with 2,2,2-trichloroethyl chloroformate in the presence of a base such as triethylamine or DIPEA, in a solvent such as CH2Cl2, CHCl3, or THF, at temperatures such as 0° C. to about 30° C. for about 30 minutes to 5 hours, to produce the 2,2,2-tri-chloroethyl carbamate intermediate. Then the 2,2,2-trichloroethyl carbamate intermediate is typically reacted with the aniline or pyridinyl amine in the presence of a base such as triethylamine or DIPEA, in a solvent such as toluene, 1,4-dioxane or THF, at about room temperature up to elevated temperatures such as about 110° C. for about 1 to 16 hours. This alternative two-step procedure provides the urea [D]. Intermediate boronic acid pinacal ester [1] is then formed by reacting urea [D] with bis(pinacolato)diboron. This reaction may be performed in the presence of a weak base such as KOAc, palladium catalyst such as Pd(dppf)Cl2.DCM or Pd(dppf)Cl2, in a solvent such as 1,4-dioxane or DMF. Desirably, the reaction is performed at elevated temperatures such as the reflux temperatures of the solvent. In one embodiment, this reaction is performed at about 80 to about 120° C. for about 2 to about 15 h. In another embodiment, this reaction is performed at about 110° C. for about 10 h.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By cleavage of the 2,2,2-trichloroethyl carbamate and 2,2,2-trichloroethyl carbonate from 2,2,2-trichloro-ethyl (1RS,2RS,3RS,5RS)-3-(4-fluoro-phenyl)-2-(2,2,2-trichloro-ethoxycarbonyloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate in an analogous manner to that described in Example 12(d) there was obtained (1RS,2RS,3RS,5RS)-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]octan-2-ol as a colourless solid; MS: 221 (M)+.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: By cleavage of the 2,2,2-trichloroethyl carbamate and 2,2,2-trichloroethyl carbonate from 2,2,2-trichloro-ethyl (1RS,2RS,3RS,5RS)-3-(4-fluoro-phenyl)-2-(2,2,2-trichloro-ethoxy-carbonyloxy)-8-aza-bicyclo[3.2.1]octane-8-carboxylate in an analogous manner to that described in Example 12(d) there was obtained (1RS,2RS,3RS,5RS)-3-(4-fluoro-phenyl)-8-aza-bicyclo[3.2.1]octan-2-ol as a colourless solid; MS: 221 (M)+.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Me-PRX (150 g) is dissolved in toluene (450 ml) at room temperature. The mixture is then heated to reflux. At reflux, 2,2,2-trichloroethyl-chloroformate (120 ml) is added dropwise for about 2.5 hours. After about 3 hours at reflux, the reaction mixture is cooled, and ammonia 20% (300 ml) and water (300 ml) is added. The organic phase is separated and washed with water (500 ml), followed by brine (500 ml). The organic phase is then separated, dried over MgSO4, filtered. Toluene is then removed under reduced pressure to give 280.2 g of the 2,2,2-trichloroethyl carbamate of paroxetine. The carbamate is then hydrolyzed according to procedures set forth, for example, in Examples 5-7 to give paroxetine base. Paroxetine base may then be converted into the desired polymorphic form of, e.g., the hydrochloride acid addition salt such as the hemihydrate, anhydrate or solvate form as disclosed herein. The mixture is then heated to reflux At reflux After about 3 hours at reflux the reaction mixture is cooled The organic phase is separated washed with water (500 ml) The organic phase is then separated dried over MgSO4 filtered Toluene is then removed under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a stirring solution of amine (2 mmol, 1.00 eq) and pyridine (4 mmol, 2.00 eq) in CH2Cl2 (18 ml) at RT was added Troc-Cl (1.87 mmol, 1.05 eq). After 4 hours the reaction was washed with 3M HCl (1×), satd. NaHCO3 (1×), dried (Na2SO4), filtered and evaporated to afford the target 2,2,2-trichloroethyl carbamate. The material was used as is in the next reaction. After 4 hours the reaction was washed with 3M HCl (1×) NaHCO3 (1×), dried (Na2SO4) filtered evaporated