Olodaterol hydrochloride [USAN]

Medical uses

Adverse effects

Interactions

Pharmacology

Mechanism of action

Pharmacokinetics

History

• 
  
  To a solution of 3.6 g 1,1-dimethyl-2-(4-methoxyphenyl)-ethylamine in 100 mL of ethanol at 70 ° C. 7.5 g of (6-benzyloxy-4H-benzo [1,4] oxazin-3-one )-glyoxal added and allowed to stir for 15 minutes. Then within 30 minutes at 10 to 20 ° C. 1 g of sodium borohydride added. It is stirred for one hour, with 10 mL of acetone and stirred for another 30 minutes. The reaction mixture is diluted with 150 mL ethyl acetate, washed with water, dried with sodium sulfate and concentrated. The residue is dissolved in 50 mL of methanol and 100 mL ethyl acetate and acidified with conc. Hydrochloric acid. After addition of 100 mL of diethyl ether, the product precipitates. The crystals are filtered, washed and recrystallized from 50 mL of ethanol. Yield: 7 g (68%; hydrochloride), mp = 232-234 ° C.

• 
  
  6.8 g of the above obtained benzyl compound in 125 mL of methanol with the addition of 1 g of palladium on carbon (5%) was hydrogenated at room temperature and normal pressure. The catalyst is filtered and the filtrate was freed from solvent. Recrystallization of the residue in 50 mL of acetone and a little water, a solid is obtained, which is filtered and washed.
  Yield: 5.0 g (89%; hydrochloride), mp = 155-160 ° C.
• 
  
  The (R) - and (S)-enantiomers of Example 3 can be obtained from the racemate, for example, by chiral HPLC (for example, column: Chirobiotic T, 250 x 1.22 mm from the company Astec). As the mobile phase, methanol with 0.05% triethylamine and 0.05% acetic acid. Silica gel with a grain size of 5 microns, to which is covalently bound the glycoprotein teicoplanin can reach as column material used. Retention time (R enantiomer) = 40.1 min, retention time (S-enantiomer) = 45.9 min. The two enantiomers can be obtained by this method in the form of free bases. According to the invention of paramount importance is the R enantiomer of Example 3

References

External links

• Striverdi package leaflet (UK)

http://pubs.acs.org/doi/full/10.1021/op040013n

OTHERS

5β-​Cholan-​24-​oic acid, 3α,​12α-​dihydroxy- (8CI); 17β-​[1-​Methyl-​3-​carboxypropyl]​-​etiocholane-​3α,​12α-​diol;

3α,​12α-​Dihydroxy-​5β-​cholan-​24-​oic acid;

3α,​12α-​Dihydroxy-​5β-​cholanic acid;

3α,​12α-​Dihydroxy-​5β-​cholanoic acid; 3α,​12α-​Dihydroxycholanic acid;

5β-​Cholanic acid-​3α,​12α-​diol;

5β-​Deoxycholic acid; 7-​Deoxycholic acid; ATX 101;

Cholerebic; Cholic acid, deoxy-; Cholorebic; Degalol; Deoxycholatic acid; Deoxycholic acid; Desoxycholic acid; Droxolan; NSC 8797; Pyrochol; Septochol

Deleted CAS Registry Numbers: 728917-​93-​9

University of California, Oakland (Originator)
LA BioMed (Originator)

LICENSE….

Kythera Biopharmaceuticals, Inc.

Conversion of Compound 24 to Compound 33:

The hydrogenation of compound 24 on 10.0 g scale using dry 10 % Pd/C (15 wt %) in ethyl acetate (20 parts) was added and applied about 50 psi hydrogen pressure and temperature raised to 70 °C. After reaching temperature 70 °C, observed increase of hydrogen pressure to about 60 psi, at these conditions maintained for 60 h. After 60 hours 0.6% of compound 24 and 2.75% of allylic alcohol were still observed, so further stirred for additional 12 h (observed 0.16% of allylic alcohol and 0.05% of compound 24). After work-up, the reaction provided 9.5g of residue.

Anther hydrogenation reaction on 25 g of compound 24 with above conditions for 76 h provided 24.5 g of residue.

Method A

10% Pd/C (900 mg) was added to a solution of compound 24 (2.0 g, 4.5 mmol) in EtOAc (150 mL) and the resulting slurry was hydrogenated in a Parr apparatus (50 psi) at 50 °C for 16 h. At this point the reaction was determined to be complete by TLC. The mixture was filtered through a small plug of Celite® and the solvent was removed under vacuum, providing compound 33 (1.6 g, 80% yield) as a white solid.

TLC: p-anisaldehyde charring, R_f for 33 = 0.36 and R_f for 25 = 0.32.

TLC mobile phase: 20% – EtOAc in hexanes. 1H NMR (500 MHz, CDC1₃): δ = 4.67-4.71 (m, 1H), 3.66 (s, 3H), 2.45-2.50 (t, J = 15 Hz, 2H), 2.22-2.40 (m, 1H), 2.01 (s, 3H), 1.69-1.96 (m, 9H), 1.55 (s, 4H), 1.25-1.50 (m, 8H), 1.07-1.19 (m, 2H), 1.01 (s, 6H), 0.84-0.85 (d, J= 7.0 Hz, 3H).

¹³C NMR (125 MHz, CDC1₃): δ = 214.4, 174.5, 170.4, 73.6, 58.5, 57.4, 51.3, 46.4, 43.9, 41.2, 38.0, 35.6, 35.5, 35.2, 34.8, 32.0, 31.2, 30.4, 27.4, 26.8, 26.2, 25.9, 24.2, 22.6,

21.2, 18.5,1 1.6,

Mass (m/z) = 447.0 [M⁺ + 1], 464.0 [M⁺ + 18].

IR (KBr) = 3445, 2953, 2868, 1731, 1698, 1257, 1029 cm^-1.

m.p. =142.2-144.4 °C (from EtOAc/hexanes mixture).

[α]_D = +92 (c = 1 % in CHCl₃).

ELSD Purity: 96.6%: Retention time = 9.93 (Inertsil ODS 3 V, 250 ^χ 4.6 mm, 5um, ACN:

0.1 % TFA in water (90: 10)

Method B

A slurry of 10% Pd/C (9 g in 180 mL of ethyl acetate) was added to a solution of compound 24 (36 g, 81 mmol) in EtOAc (720 mL) and the resulting slurry was treated with hydrogen gas (50 psi) at 45-50 °C for 16 h. (A total of 1080 mL of solvent may be used). At this point the reaction was determined to be complete by HPLC (NMT 1% of compound 24). The mixture was filtered through Celite® (10 g) and washed with ethyl acetate (900 mL). The filtrate was concentrated to 50% of its volume via vacuum distillation below 50 °C. To the concentrated solution was added pyridinium

chlorochromate (20.8 g) at 25-35 °C and the mixture was stirred for 2 h at 25-35 °C, when the reaction completed by HPLC (allylic alcohol content is NMT 1%).

The following process can be conducted if compound 24 content is more than 5%. Filter the reaction mass through Celite® (10 g) and wash with ethyl acetate (360 mL). Wash the filtrate with water (3 x 460 mL) and then with saturated brine (360 mL). Dry the organic phase over sodium sulphate (180 g), filter and wash with ethyl acetate (180 mL). Concentrate the volume by 50% via vacuum distillation below 50 °C. Transfer the solution to a clean and dry autoclave. Add slurry of 10% palladium on carbon (9 g in 180 mL of ethyl acetate). Pressurize to 50 psi with hydrogen and stir the reaction mixture at 45-50 °C for 16 h. Upon complete consumption of compound 24 by HPLC (the content of compound 24 being NMT 1%), the reaction mixture was filtered through Celite® (10 g) and the cake was washed with ethyl acetate (900 mL). The solvent was concentrated to dryness via vacuum distillation below 50 °C. Methanol (150 mL) was added and concentrated to dryness via vacuum distillation below 50 °C. Methanol (72 mL) was added to the residue and the mixture was stirred for 15-20 min at 10-15 °C, filtered and the cake was washed with methanol (36 mL). The white solid was dried in a hot air drier at 45-50 °C for 8 h to LOD being NMT 1 % to provide compound 33 (30 g, 83.1 % yield).

Conversion of Compound 33 to Compound 34:

Method A

A THF solution of lithium tri-tert-butoxyaluminum hydride (1 M, 22.4 mL, 22.4 mmol) was added drop wise to a solution of compound 33 (2.5 g, 5.6 mmol) in THF (25 mL) at ambient temperature. After stirring for an additional 4-5 h, the reaction was determined to be complete by TLC. The reaction was quenched by adding aqueous HCl (1 M, 10 mL) and the mixture was diluted with EtOAc (30 mL). The phases were separated and the organic phase was washed sequentially with water (15 mL) and saturated brine solution (10 mL). The organic phase was then dried over anhydrous Na₂S0₄ (3 g) and filtered. The filtrate was concentrated under vacuum and the resulting solid was purified by column chromatography [29 mm (W) ^x 500 mm (L), 60-120 mesh silica, 50 g], eluting with EtOAc/hexane (2:8) [5 mL fractions, monitored by TLC with p- anisaldehyde charring]. The fractions containing the product were combined and concentrated under vacuum to provide compound 34 (2.3 g, 91%) as a white solid.

TLC: p-anisaldehyde charring, R_f for 34 = 0.45 and R_f for 33 = 0.55.

TLC mobile phase: 30% – EtOAc in hexanes.

1H NMR (500 MHz, CDC1₃): δ = 4.68-4.73 (m, 1H), 3.98 (s, 1H), 3.66 (s, 3H), 2.34-2.40 (m, 1H), 2.21-2.26 (m, 1H), 2.01 (s, 3H), 1.75-1.89 (m, 6H), 1.39-1.68 (m, 16H), 1.00-1.38 (m, 3H), 0.96-0.97 (d, J= 5.5 Hz, 3H), 0.93 (s, 3H), 0.68 (s, 3H).

¹³C NMR (125 MHz, CDCI₃): δ = 174.5, 170.5, 74.1, 72.9, 51.3, 48.1, 47.2, 46.4, 41.7, 35.8, 34.9, 34.7, 34.0, 33.5, 32.0, 30.9, 30.8, 28.6, 27.3, 26.8, 26.3, 25.9, 23.4, 22.9, 21.3, 17.2, 12.6 Mass (m/z) = 449.0 [M⁺ + 1], 466.0 [M + 18].

IR ( Br) = 3621, 2938, 2866, 1742, 1730, 1262, 1 162, 1041, cm^-1.

m.p = 104.2-107.7 °C (from EtOAc).

[α]_D = +56 (c = 1% in CHCl₃).

ELSD Purity: 97.0%: Retention time = 12.75 (Inertsil ODS 3V, 250 ^χ 4.6 mm, 5um, ACN: Water (60:40)

Method B

A THF solution of lithium tri-rert-butoxyaluminum hydride (1 M, 107.6 mL, 107.6 mmol) was added over 1 h to a solution of compound 33 (30.0 g, 67 mmol) in dry THF (300 mL) at 0-5 °C. After stirring for an additional 4 h at 5-10 °C, the reaction was determined to be complete by HPLC (NMT 1% of compound 33). The reaction was cooled to 0-5 °C and quenched by adding 4N HCl (473 mL). The phases were separated. The aqueous layer was extracted with DCM (2 x 225 mL) and the combined organic phase was washed sequentially with water (300 mL) and saturated brine solution (300 mL). The organic phase was then was concentrated to dryness by vacuum distillation below 50 °C. Methanol (150 mL) was added to the residue and concentrated to dryness by vacuum distillation below 50 °C. Water (450 mL) was then added to the residue and the mixture was stirred for 15-20 min., filtered and the cake was washed with water (240 mL). The white solid was dried in a hot air drier at 35-40 °C for 6 h to provide compound 34 (30 g, 99.6%).

Conversion of Compound 34 to crude DCA:

Method A

A solution of LiOH (187 mg, 4.4 mmol) in H₂0 (2.0 mL) was added to a solution of compound 34 (500 mg, 1.1 1 mmol) in THF (8 mL) and MeOH (8 mL). The resulting mixture was stirred for 3-4 h at 50 °C. Upon complete disappearance of the starting material by TLC, the reaction mixture was concentrated under vacuum. A mixture of water (10 mL) and 3 N HCl (1 mL) were combined and cooled to 0 °C and then added to the crude product. After stirring for 1 h at 0 °C, the precipitated solids were filtered and then washed with water (10 mL) and hexane (20 mL). Drying under vacuum at room temperature provided deoxycholic acid (DCA, 400 mg, 91% yield) as a white solid. TLC: -anisaldehyde charring, R_f for DC A = 0.32 and R_f for 2.1a = 0.82.

TLC mobile phase: 10% – Methanol in DCM.

1H NMR (500 MHz, DMSO): δ = 11.92 (s, 1H), 4.44 (s, 1H), 4.19 (s, 1H), 3.77 (s, 1H), 3.35-3.36 (m, 1H), 2.19-2.21 (m, 1H), 2.08-2.10 (m, 1H), 1.73-1.80 (m, 4H), 1.43- 1.63 (m, 6H), 1.15-1.35 (m, 12H), 0.98-1.05 (m, 2H), 0.89-0.90 (d, J = 6.0 Hz, 3H),

0.83 (s, 3H), 0.58 (s, 3H).

¹³C NMR (125 MHz, DMSO): δ =174.8, 71.0, 69.9, 47.4, 46.1, 46.0, 41.6, 36.3, 35.6, 35.1, 34.9, 33.8, 32.9, 30.8, 30.7, 30.2, 28.6, 27.1, 27.0, 26.1, 23.5, 23.0, 16.9, 12.4.

Mass (m/z) = 393 [M⁺, + 1].

IR = 3363, 2933, 2863, 1694, 1453, 1372, 1042, cm^-1.

m.p. = 171.4-173.6 °C (from ethanol); 174-176 °C (Alfa Aesar) and 171-174 °C (Aldrich)

[<x]_D = +47 (c = 1% in EtOH ), +54° (c = 2% in ethanol) [Alfa Aesar]

ELSD Purity: 99.7%: Retention time = 5.25 (Inertsil ODS 3 V, 250 ^χ 4.6 mm, 5um, ACN:

0.1% TFA in water (90:10).

Method B

A 20% solution of NaOH (40 g, 270 mmol) in H₂0 (54 mL) was added to a solution of compound 34 (30 g, 67 mmol) in THF (120 mL) and MeOH (120 mL) at 0-5 °C. The resulting mixture was stirred for 4 h at 25-35 °C. Upon completion of reaction by HPLC (NMT 0.5% of compound 34 and intermediates), the solvent was removed via vacuum distillation below 50 °C. The residue was dissolve in water (300 mL) and washed with DCM (2 x 150 mL). The pH of aqueous layer was adjusted to 1-2 with 2N HCl (~ 173 mL). The solids were filtered, washed thoroughly with water (3 L) and dried by a hot air drier at 70-75 °C until the moisture content is less than 2% to provide deoxycholic acid (DCA, 26 g, 99% yield) as a white solid.

EXAMPLE 9

Deoxycholic acid (DCA) Purification

1. Solvent Selection

Two solvent systems were explored for further purification of DCA: • 10% Hexanes in EtOAc

• DCM

The following experiments have been conducted and the experimental results tabulated below.

* The DCA to be purified was dissolved in a mixture of methanol and DCM and then the methanol was removed by azeotropic distillation. The amount of methanol required to dissolve the crude DCA depends on how pure it is to begin with.

Typical crude material was—75% pure and could be dissolved at reflux using 10% methanol-DCA (by volume) using—20 mL per gram. With purer DCA, the percentage of methanol had to be increased to 15%.

Effective purification was achieved by crystallization of the product from DCM following dissolution in a mixture of methanol and DCM and azeotropic removal of the methanol via atmospheric distillation.

2. Solvent Quantity

Experiments have been conducted using different solvent volumes and the experimental results are tabulated below.

Excellent recoveries and product quality were obtained at all solvent levels.

3. Isolation Temperature

The following experiments have been conducted by varying the isolation temperature and the results are tabulated below:

Higher quality product was obtained when isolation is done at 25-30 °C as compared to 10-15 °C. Purification of DCA in 100 g Scale

The final purification procedure for this step is given below:

Crude DCA (110 g) was dissolved in 10% methanol in DCM (2.5 L) at reflux temperature. To this clear solution 2.5 L of dichloromethane was added at reflux temperature and then about 3.0 L of solvent was distilled at atmospheric pressure (GC analysis of reaction mass supernatant revealed the presence of about 3% of methanol). The reaction slurry was cooled to 20-25 °C and then stirred for 3-4 h. The mixture was filtered and the solids were washed with DCM (300 mL). The product was dried in a hot air oven at 50-55 °C for 6-8 h.

The above dried DCA was added to water (1.0 L) and then 10% sodium hydroxide solution (122 mL) was added resulting in a clear solution. This solution was filtered through 5μ filter paper. The filtrate was diluted with water (2.0 L), and the pH was adjusted to 1— 2 with 2N HCl solution (204 mL). The precipitated solids were stirred for 1 h, filtered and the solids were washed with additional water (7.0 L). After drying in a hot air oven at 70-75 °C for 16-20 h, purified DCA (~ 66 g with more than 99% purity by HPLC RI detection) was obtained as a white solid.

TLC: 7-Anisaldehyde charring, R_f for DCA = 0.32 and R_f for compound 34 = 0.82. Eluent = 10% methanol in DCM. 1H NMR (500 MHz, DMSO): δ = 11.92(s, 1H),4.44(s, 1H), 4.19(s, 1H), 3.77 (s, 1H), 3.36-3.35 (m, 1H), 2.21-2.19 (m, 1H), 2.10-2.08 (m, 1H), 1.80-1.73 (m, 4H), 1.63- 1.43(m, 6H), 1.35-1.15(m, 12H), 1.05-0.98(m, 2H), 0.90-0.89 (d, J = 6.0 Hz, 3H), 0.83 (s, 3H), 0.58 (s, 3H).

1 C NMR (125 MHz, DMSO): δ =174.8, 71.0, 69.9, 47.4, 46.1, 46.0, 41.6, 36.3, 35.6, 35.1, 34.9, 33.8, 32.9, 30.8, 30.7, 30.2, 28.6, 27.1, 27.0, 26.1, 23.5, 23.0, 16.9, 12.4.

Mass (m/z) = 393 [M⁺, + 1].

IR = 3363, 2933, 2863, 1694, 1453, 1372, 1042, cm^-1.

m.p. = 171.4-173.6 °C (from ethanol); 174-176 °C (Alfa Aesar) and 171-174 °C (Aldrich).

Recrystallization of Deoxycholic acid (DC A)

DCA obtained from Method B (26 g) above, was charged into a clean and dry flask. Methanol (65 mL) and DCM (585 mL) were added. The mixture was heated to reflux to obtain a clear solution. DCM (650 mL) was charged to the solution and the solvent was distilled atmospherically until 780 mL of solvent was collected. The mixture was assayed by GC to determine the solvent composition. If the methanol content is more than 2%, add DCM (200 mL) and distill atmospherically until 200 mL of distillate have been collected. (Check for the methanol content by GC). The reaction mixture was cooled over 1-2 h to 20-25 °C and stirred at this temperature for 3-4 h. The product was filtered and washed with DCM (81 mL), dried in a hot air drier at 50-55 °C for 8 h. The purity was determined by HPLC. If single max impurity is more than 0.1%, the above process is repeated.

The dried material from the above was charged in to a clean flask. Water (190 mL) was added and followed by 10% aqueous NaOH (3.18 g in 31.8 mL of water). The solution was filtered through 5μ filter paper and the filtrate was diluted with additional water (380 mL). The pH was adjusted to 1-2 with 2 N HCl (53 mL). The resulting solids was filtered, washed thoroughly with water (1.9 L), and dried in a hot air drier at 70-75 °C until the water content is below 1% to give DCA as a white solid (17 g, % of recovery: 65). EXAMPLE 10

Alternate method of Synthesis and purification of DCA from compound 33

Step la— Hydrogenation of methyl 3a-acetoxy-12-oxo—5fi-chol-9(ll)-en-24-oate (24)

Dry Pd/C (75.0 g, 25 wt %) was added to 24 (300.0 g, 0.7 mol) in EtOAc (7.5 L, 25 vol). The reaction mixture was heated to 45°— 50°C and pressurized to 50 psi of H₂. HPLC analysis after 21 hours indicated < 1.0% area under the curve (AUC) of 24 remained; 4.6% AUC of the allylic alcohol impurity 86 and 1 1.1% AUC of the 87 formed. The reaction mixture was cooled to 30° – 35°C, filtered over Hyflo® (300 g) and washed with EtOAc (7.5 L) to remove the catalyst. The resulting filtrate was

concentrated to about 6 L and taken forward without further manipulation (67.8% AUC by HPLC, 5.5% AUC of the allylic alcohol impurity 86 and 13.0% AUC of 87).

Step lb/c – Oxidation of allylic alcohol 86 and 87 and rehydrogenation of 24 to methyl 3a-acetoxy-12-oxo-5fi-cholan-24-oate (33)

Step lb – PCC oxidation of allylic alcohol 86 and 87

A slurry of PCC (149.1 g, 1.03 equiv.) in EtOAc (1.5 L) was added to the 33 solution from above at 20°— 25°C. The reaction was allowed to proceed for 3.5 hours where HPLC analysis showed that < 1% AUC of the allylic alcohol 86 and < 1% AUC of 87 remained. The reaction mixture was filtered over Hyflo® (300 g) and washed with EtOAc (3.0 L). The EtOAc filtrate was washed with deionized (DI) water (2 x 3.6 L) and brine (3.6 L), filtered over Hyflo® (300 g) and washed with EtOAc (3.0 L). The resulting filtrate was concentrated to -7.5 L and taken forward without further manipulation (77.7% AUC by HPLC containing 5.3% AUC of 24).

Step lc— Rehydrogenation of 24 to 33

Powder activated carbon DARCO (60 g, 20 wt %) was added to the crude 33 solution from above containing 24. The resulting slurry was heated to 45°— 50°C for 4 hours, cooled to 30°— 35°C and filtered over Celite®. The filter cake was washed with EtOAc (7.5 L), concentrated to -7.5 L and added to dry Pd/C (60.0 g, 20 wt %). The reaction mixture was heated to 45° – 50°C and pressurized to 50 psi of H₂ for 6 hours. HPLC analysis indicated < 1.0% AUC of 24 remained; 1.1% AUC of 86 impurity and < 1.0% AUC of 87 formed. The reaction was deemed complete and cooled to 30° – 35°C, filtered over Celite® and washed with EtOAc (7.5 L). The EtOAc filtrate was concentrated to—5 volumes and azeotroped with MeOH (2 x 4.5 L) back down to—5 volumes. The resulting slurry was diluted with DI water (2.4 L) and maintained at 20-25 °C. The slurry was filtered, washed with DI water (2 x 600 mL) and dried under vacuum at 40° – 50°C to yield 266 g (88%) of 33 (66.2% AUC by HPLC).

Step 2— Synthesis of 34

A solution of 33 (245 g, 0.5 mol) in THF (2.5 L) was cooled to 0° – 5°C and 1 M solution of Li(t-BuO)₃A1H (822.9 niL, 1.5 equiv.) was added while maintaining the temperature below 5°C. The reaction mixture was stirred at 5° – 10°C for 22 hours. Reaction may be complete in 2-4 hours. HPLC analysis indicated that the reaction was complete with < 1% of 33 remaining. The reaction was quenched with 4 M HCl (3.7 L) while maintaining the temperature below 20°C. The reaction mixture was extracted with CH₂CI₂ (2 x 2.5 L) and the combined organic phases were washed with DI water (2 x 2.5 L). The CH₂C1₂ phase was concentrated to afford 300 g (122%) of 34 (73.5% AUC by HPLC). 1H NMPv analysis indicated that 9.7 wt % of THF and 0.8 wt % of CH₂C1₂ remained.

Step 3 – Synthesis of DCA

A NaOH solution (87.6 g, 4 equiv.) in DI water (438.6 mL) was added to a solution of 34 (245 g, 0.5 mol) in MeOH (980 mL) and THF (475 mL) at 0° – 5°C. The reaction mixture was allowed to warm to 20° – 25°C. HPLC analysis showed that the reaction was complete after 1 hour with < 0.5% 34 and < 0.5% of the hydrolysis intermediates remaining. The reaction was diluted with DI water (2.5 L) and

concentrated to—10 volumes. The aqueous solution was washed with CH₂C1₂(2 x 1.3 L) and adjusted to pH 1.7— 2.0 using 2 M HCl (1.6 L). A white slurry formed and was stirred at 20° – 25 °C for 1 hour. The slurry was filtered, washed with DI water (7 x 1 L) and dried under vacuum to yield 195 g (91%) of DCA (82.2% AUC by HPLC).

Step 4 – Purification of DCA

A solution of DCA obtained above (190 g, 0.48 mol) in MeOH (475 mL) and CH₂C1₂ (4275 mL) was heated to 35° – 40°C. The MeOH/CH₂Cl₂ was distilled out of the mixture while CH₂CI₂ (4740 mL) was added matching the rate of distillation. Analysis of the solvent composition by Ή NMR indicated 4.5 mol % of MeOH remained relative to CH₂C1₂. The slurry was allowed to cool to 20°— 25°C and held for 16 hours. The solids were isolated by filtration, washed with CH₂Cl₂ (600 mL) and dried under vacuum to yield 104 g (55%) of DCA (> 99% AUC by HPLC-RID and 98.7% AUC by HPLC- CAD).

The recrystallization was repeated by heating a mixture of DCA (103 g, 0.3 mol) in MeOH (359 mL) and CH₂C1₂ (1751 mL) to 35° – 40°C. The MeOH/CH₂Cl₂was distilled out of the mixture while CH₂CI₂ (3760 mL) was added matching the rate of distillation. Analysis of the solvent composition by 1H NMR indicated 4.7 mol % of MeOH remained relative to CH₂C1₂. The slurry was allowed to cool to 20°— 25°C. After 1 hour, the solids were isolated by filtration, washed with CH₂CI₂ (309 mL) and dried under vacuum to afford 82 g (79%) of DCA (> 99% AUC by HPLC-RID and 99.3% AUC by HPLC-C AD).

To assess the effect of additional purification and reprocessing, the product was recrystallized a third time prior to the normal final water isolation step. The above sample of DCA (80 g, 0.2 mol) in MeOH (240 mL) and CH₂C1₂ (1400 mL) was heated to 35° – 40°C. The MeOH/CH₂Cl₂ was distilled out of the mixture while CH₂C1₂ (2000 mL) was added matching the rate of distillation. Analysis of the solvent composition by ^!H NMR indicated 6.7 mol % of MeOH remained relative to CH₂C1₂. The slurry was allowed to cool to 20° – 25°C. After 1 hour, the solids were isolated by filtration, washed with CH₂CI₂ (240 mL) and dried under vacuum to afford 72 g (89%) of DCA (99.7% AUC by HPLC-CAD).

The sample was slurried in DI water (840 mL) and diluted with a solution of

NaOH (14.0 g) in DI water (140 mL). The resulting solution was filtered over Celite® and washed with DI water (1.4 L). The filtrate was adjusted to pH 1.6 with 2 M HCl (—300 mL) resulting in a white precipitate which was held for 1 hour at 20°— 25°C. The product was isolated by filtration, washed with DI water (9.0°L) and dried under vacuum to afford 63 g (87%) of DCA (99.7% AUC by HPLC-CAD).

SEE MORE IN PATENT

 

• Reduction of submental fat
  • 87 percent of patients achieved at least a one-grade improvement from baseline on the Clinician-Reported Submental Fat Rating Scale (CR-SMFRS)
  • Similarly 83 percent of patients achieved at least a one-grade improvement on the Patient-Reported Submental Fat Rating Scale (PR-SMFRS)
• 96 percent of patients had unchanged or improved skin laxity based on the clinician rated Submental Skin Laxity Grading Scale (SMSLG)
• 95 percent of patients were satisfied with treatment based on the Global Post Treatment Satisfaction Scale
• Adverse events were of mild to moderate intensity transient and primarily associated with the treatment area

THANKS AND REGARD’S
DR ANTHONY MELVIN CRASTO Ph.D

amcrasto@gmail.com

MOBILE-+91 9323115463

GLENMARK SCIENTIST ,  INDIA
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Uses

FDA-approved use

Femara 2.5 mg oral tablet

Systematic (IUPAC) name
4,4'-((1H-1,2,4-triazol-1-yl)methylene)dibenzonitrile
Clinical data
Trade names	Femara
AHFS/Drugs.com	monograph
MedlinePlus	a698004
Licence data	US FDA:link
Pregnancy cat.	D (US)
Legal status	Schedule VII (CA) POM (UK) ℞-only (US)
Routes	Oral
Pharmacokinetic data
Bioavailability	99.9%
Protein binding	60%, mainly to albumin
Metabolism	pharmacologically-inactive carbinol metabolite (4,4΄-methanol-bisbenzonitrile)[1]
Half-life	2 days[1]
Excretion	Kidneys[1]
Identifiers
CAS number	112809-51-5
ATC code	L02BG04
PubChem	CID 3902
DrugBank	DB01006
ChemSpider	3765
UNII	7LKK855W8I
KEGG	D00964
ChEBI	CHEBI:6413
ChEMBL	CHEMBL1444
Chemical data
Formula	C17H11N5
Mol. mass	285.303 g/mol

Off-label uses

Mechanism of action

Contraindications

Adverse effects

Interactions

Comparison with tamoxifen

Synthesis

Letrozole can by synthesized from 4-cyanobenzyl bromide, triazole, and 4-fluorobenzonitrile:^[19] 

• Letrozole, chemically known as 4-[alpha (4-cyanophenyl)-1-(1,2,4-triazoly)-methyl]-benzonitrile, and represented by formula (I),

  is a therapeutically and commercially important non-steroidal aromatase inhibitor, which is widely used for adjuvant treatment of hormonally responsible breast cancer in postmenopausal women. Estrogens are produced by the conversion of androgen through the activity of aromatase enzyme, the suppression of estrogen biosynthesis in peripheral tissues and in the cancer tissue itself can therefore be achieved by specifically inhibiting the aromatase enzyme.
• [0003]
  1. Bowman et al. were the first to disclose Letrozole in US 4,978,672 , and US 5,352,795 and reported two methods for synthesis of Letrozole, the chemistry for Method-1 is summarized in Scheme-1.
• [0004]
  The Method-1 for synthesis of Letrozole as disclosed by Bowman et al. in US 4,978,672 , and US 5,352,795 and as summarized in Scheme-1, comprises reaction of alpha-bromo-4 tolunitrile or 4-bromomethyl benzonitrile (II) with 1H-1, 2,4-triazole (III), in a mixture of chloroform and acetonitrile as solvent at reflux temperature for 15 hours to give 4-[1-(1,2,4-triazolyl) methyl]-benzonitrile (IV), which on reaction with 4-flurobenzonitrile (VI) in the presence of potassium t-butoxide and in N, N-dimethylformamaide, gives crude Letrozole (I), which is recrystallized from 95% ethanol or a mixture of ether and ethyl acetate to give pure Letrozole (I):
• [0005]
  As would be evident from Examples 9, 25, and 26 of US 4,978,672 , and US 5,352,795 , in the step reaction of alpha-bromo-4 tolunitrile or 4-bromomethyl benzonitrile (II) with 1H-1, 2,4-triazole (III), as per Method-1, Scheme-I, in addition to the desired 4-[1-(1,2,4-triazolyl) methyl]-benzonitrile (IV) an appreciable amount of isomeric 4-[1-(1,3,4-triazolyl) methyl]-benzonitrile (V) is also formed in the reaction, which necessitates separation of the two isomers by column chromatography, subsequent to which the separated pure 4-[1-(1,2,4-triazolyl) methyl]-benzonitrile (IV) is reacted with 4-flurobenzonitrile (VI) to give Letrozole. Example 25 of US 4,978,672 , and US 5,352,795 further report that Letrozole obtained after recrystalization from 95% ethanol has a melting point of 181° - 183°C, while Example 26 reports that Letrozole obtained after recrystalization from a mixture of ether and ethyl acetate has a melting point of 184°- 185° C.
• [0006]
  The major disadvantage and limitation of the Method-1 disclosed in US 4,978,672 , and US 5,352,795 is that it leads to formation of appreciable amounts of the unwanted isomer i.e. 4-[1-(1,3,4-triazolyl) methyl]-benzonitrile (V), calling for tedious chromatographic techniques for its separation from the desired isomer i.e. 4-[1-(1,2,4-triazolyl) methyl]-benzonitrile (IV), which is expected to result in considerable loss and low yield of the desired isomer. Such a method, obviously, cannot be expected to be economically or commercially viable. Further, nowhere in the Specifications and Experimental Descriptions of US 4,978,672 , and US 5,352,795 there is any mention about the yield and purity of Letrozole obtained by the method described therein.
• [0007]
  The second method, Method-2, reported by Bowman et al. in US 4,978,672 , and US 5,352,795 is summarized in Scheme-II, which comprises of reaction of N-tert.butyl-4-bromo benzamide (1) with n-butyllithium and ethyl formate to give Bis- (4-N-tert.butyl carbamoylphenyl) methanol (2), which on reaction with thionyl chloride gives 4-(alpha-chloro-4'cyanobenzyl)benzonitrile (3). Reaction of 4-(alpha-chloro-4'cyanobenzyl) benzonitrile (3) with 1H-1,2,4-triazole (III) gives Letrozole (I).
• [0008]
  The major disadvantage and limitation of the Method-2 disclosed in US 4,978,672 , and US 5,352,795 , as evident from Examples 3, 5 and 28, described therein, is that first of all it utilizes corrosive and hazardous n-butyllithium and thionyl chloride; which require special storage, handling and disposal as well as calls for cryogenic temperatures of -60° C and higher temperatures of about 160° C, which collectively renders the method unsafe and industrially and commercially not of particular viability. Further, as in the case of Method-1, nowhere in the Specifications and Experimental Descriptions of US 4,978,672 , and US 5,352,795 there is any mention about the yield and purity of Letrozole obtained by the Method-2 described therein. Furthermore, the reaction of 4-(alpha-chloro-4'cyanobenzyl) benzonitrile (3) with 1,2,4-triazole (III) would most likely result in formation of the corresponding isomer along with the desired Letrozole, which would involve tedious purification techniques for its separation.
• [0009]
  Improvements over the methods disclosed by Bowman et al. in US 4,978,672 , and US 5,352,795 are the subject matter of the following reports, viz.
• [0010]
  2. Wadhwa et al. in US 2005/0209294 A1 , recite a method for synthesis of the intermediate 4-[1-(1,2,4-triazolyl) methyl]-benzonitrile (IV), comprising reaction of alpha-bromo-4 tolunitrile or 4-bromomethyl benzonitrile (II) with a salt of 1H-1,2,4-triazole, preferably an alkali metal salt of 1H-1,2,4-triazole (4), in a suitable solvent at a temperature of between 10° to 15° C, followed by crystallization of the isolated product. The chemistry is summarized in Scheme-III.
• [0011]
  Wadhwa et al. in US 2005/0209294 A1 , while stating that the method disclosed by Bowman et al. in US 4,978,672 , and US 5,352,795 is not selective in that it produces the undesired isomeric 4-[1-(1,3,4-triazolyl) methyl]-benzonitrile (V) in about 50%, which as mentioned hereinbefore requires tedious chromatographic separation techniques for its removal, emphasize that by virtue of utilization of an alkali metal salt of 1H-1, 2,4-triazole (4), the desired 4-[1-(1,2,4-triazolyl) methyl]-benzonitrile (IV) is obtained in >96% selectivity, thereby circumventing the utilization of tedious chromatographic techniques for its purification. Wadhwa et al., further state that the said intermediate i.e. 4-[1-(1,2,4-triazolyl) methyl]-benzonitrile (IV), obtained by their method can be converted to Letrozole of US Pharmacopoeial Quality, through conventional procedure.
• [0012]
  While the method disclosed by Wadhwa et al. in US 2005/0209294 A1 , reportedly affords the intermediate 4-[1-(1,2,4-triazolyl) methyl]-benzonitrile (IV) in >96% selectivity and further, reportedly does away with chromatographic techniques in its isolation, however, the entire Specification and the Experimental Description given in Example-1 therein, is silent about the actual yield and purity of not only the intermediate 4-[1-(1,2,4-triazolyl) methyl]-benzonitrite (IV) but also that of Letrozole obtained by the method. The industrial or commercial viability of the method, therefore, cannot be commented, in view of insufficient disclosure.
• [0013]
  3. Kompella et al. in WO 2005/047269 A1 , disclose a method for separation of the Letrozole precursor, 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV) from its isomer, 4-[1-(1,3,4-triazolyl) methyl]-benzonitrile (V), comprising treating a solution of the mixture of the two isomeric compounds (IV) and (V) in dichloromethane or chloroform with isopropylalcohol hydrochloride, followed by addition of isopropyl ether, wherein the hydrochloride salt of the undesired 4-[1-(1,3,4-triazolyl) methyl]-benzonitrile (V) precipitates out, which is removed by filtration. Basification of the filtrate, followed by evaporation of solvent and isolation of the residue from hexane or petroleum ether affords the desired 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV). The method is summarized in Scheme-IV.
• [0014]
  The required isomer is obtained in 47-61 % yield and a purity of about 99%.
• [0015]
  4. In another variant of the Method-1 of Bowman et al., an improved regiospecific method disclosed by Patel et al. in US 2006/0128775 A1 for synthesis of Letrozole is summarized in Scheme-V.
• [0016]
  The method disclosed by Patel et al. in US 2006/0128775 A1 utilizes 4-amino-1, 2,4-triazole (5), instead of 1H-1, 2,4-triazole (III) or an alkali metal salt of 1H-1, 2,4-triazole (4), as utilized by Bowman et al. in US 4,978,672 , and US 5,352,795 and Wadhwa et al. in US 2005/0209294 A1respectively, for reaction with alpha-bromo-4 tolunitrile or 4-bromomethyl benzonitrile (II) to give 4-[(4-amino-1,2,4-triazolium-1-yl)methyl]benzonitrile bromide (6), which on diazotisation leads to the required intermediate, 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV), further reaction of which with 4-flurobenzonitrile (VI) gives crude Letrozole, which is recrystallized from polar or non-polar solvents to give pure Letrozole (I).
• [0017]
  The method of Patel et al. in US 2006/0128775 A1 , in the first place provides an elegant regiospecific synthesis of Letrozole in that it like the method of Wadhwa et al. in US 2005/0209294 A1 , minimizes the formation of the undesired isomeric 4-[1-(1,3,4-triazolyl) methyl]-benzonitrile (V) and also does away with tedious chromatographic separation techniques.
• [0018]
  The method of Patel et al. in US 2006/0128775 A1 , albeit, as evident from Example-1, described therein, reportedly gives Letrozole of 99.90% HPLC purity, however, gives Letrozole of the said purity only in an overall yield of 34%, which renders it of not being an particularly economic process. Secondly, the method comprises of an additional step of deamination of the intermediate compound (6), which in turn calls for a diazotization step, through utilization of sodium nitrite, which is hazardous and explosive, more suitable to small scale preparations rather than industrial manufacture. The method, hence, might not be particularly amenable for industrial scale-up and manufacture.
• [0019]
  5. MacDonald et al. in US 2007/0066831 A1 , report another variant of the methods disclosed by Bowman et al. in US 4,978,672 , and US 5,352,795 and Wadhwa et al. in US 2005/0209294 A1 in that the said method, as summarized in Scheme-VI comprises:

  1. a) Reaction of alpha-bromo-4 tolunitrile or 4-bromomethyl benzonitrile (II) with an alkali metal salt of 1H-1,2,4-triazole (4), in presence of a solvent selected from the group consisting of diemthylacetamide, N-methyl-2-pyrrolididone, or a mixture thereof, at a temperature of about -20° to 0°C to give 4-[1-(1,2,4-triazolyl) methyl]-benzonitrile (IV);
  2. b) Extracting the impurities form intermediate compound (IV), in a two phase system, comprising an aqueous phase and a water-immiscible phase; and
  3. c) Reacting compound (IV) with 4-flurobenzonitrile (VI), in presence of a solvent selected from the group consisting of dimethylformamide, diemthylacetamide, N-methyl-2-pyrrolididone, and tetrahydrofuran or a mixture thereof and a base selected from sodium bis(trimethylsilyl)amide, hexyl lithium, butyl lithium, lithium didsopropylamide, alkoxide or mixtures thereof.
• [0020]
  US 2007/0066831 A1 further, states that the steps (a) and (b) could be combined together resulting in a one-pot synthesis of Letrozole.
• [0021]
  In the first place, it might be mentioned herein that the chemistry disclosed by Macdonald et al. in US 2007/0066831 A1 is a nominal variation of the method disclosed by Wadhwa et al. in US 2005/0209294 A1 , in that uses specific solvents such as diemthylacetamide, and N-methyl-2-pyrrolididone for formation of compound (IV) and again utilizes the same solvents for obtaining Letrozole from compound (IV), in addition to use of specific lithium containing bases, most of which are hazardous and expensive, requiring special precautions during storage, handling and disposal.
• [0022]
  6. In yet another variation, Radhakrishnan et al. in WO 2007/039912 provide a method for synthesis of Letrozole, as summarized in Scheme-VII, which is a one-pot synthesis comprising reaction of compounds (II) and (4) to give compound (IV), which without isolation and on further reaction with compound (VI) gives Letrozole.
• [0023]
  The major disadvantage with the method is that is still does not obliterate the use of chromatographic separation/purification of Letrozole.
• [0024]
  7. Haider et al. in WO 2007/054964 A2 provide an improvement, as summarized in Scheme- VIII, over Method-1 disclosed by Bowman et al. in US 4,978,672 and US 5,352.795 . in that the improvement comprises of selective removal of the isomeric 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile (V), formed in the reaction of compound (II) and (III) in isopropanol as solvent, through a method of extraction, which provides the desired 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV), of >99% purity, and relatively free of the isomeric impurity (V).
• [0025]
  The method of extraction, as taught by Haider et al. in WO 2007/054964 A2 comprises repeated extraction of the reaction medium containing mixture of the desired 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV) and the undesired 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile (V) with water and a water-immiscible solvent to afford the pure 4-[1-(1,2,4-triazolyl)methyl]-benzonitrile (IV) in the organic phase, which is then further converted to Letrozole (I) of >99% purity by conventional methods. Haider et al. also teach a process for conversion of the mixture of the desired 4-[1-(1,2,4-triazolyl) methyl]-benzonitrile (IV) and the undesired 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile (V) to Letrozole, from which the isomeric form of Letrozole i.e. Isoletrozole (9) so formed is removed by repeated crystallization to afford Letrozole (I) of >99% purity. -
• [0026]
  It might be noted that the method of Haider et al., primarily is one for purification of the intermediate 4-[1-(1,2,4-triazolyl) methyl]-benzonitrile (IV) as well as Letrozole (I) for removal of the corresponding isomeric impurities and as such does not provide any inputs for controlling or minimization of the formation of the isomeric 4-(1-(1,3,4-triazolyl)methyl]-benzonitrile (V) in the reaction. Secondly, the method of extraction as well as purification taught by Haider et al. is tedious, comprising multiple extractions, with multiple solvents and this coupled with the fact that it does not provide any improvement in controlling or minimization of the formation of the isomeric 4-[1-(1,3,4-triazolyl)methyl]-benzonitrile (V) in the reaction, leads to significant losses, thereby resulting in rather low yields of Letrozole (I). The method, therefore, is not of commercial significance.
• [0027]
  8. Pizzocaro et al. in WO 2007/090464 A1 , a process for preparation of Letrozole (I), as summarized in Scheme-IX, characterized in that it teaches either simultaneous addition of a solution of 4-[1-(1,2,4-triazolyl) methyll-benzonitrile (IV) and a solution of 4-fluorobenzonitrile (VI) in an aprotic dipolar solvent to a solution of an alkali metal alkoxide in the same aprotic dipolar solvent or addition of an unique solution in an aprotic dipolar solvent comprising of compounds (IV) and (VI) to aprotic dipolar solvent, and reacting at a temperature of between -20 to + 40° C.
• [0028]
  The method of Pizzocaro et al., in addition to involving adherence to several critical parameters like temperature, flow rate, etc. moreover, does not provide any details of the yields and purity of Letrozole, obtained by the methods described therein.
• [0029]
  9. Srinivas et al. WO 2007/107733 A1 recite a further variation of Method-1 disclosed by et al. in US 4,978,672 and US 5,352,795 , for synthesis of Letrozole, substantially free from its isomeric impurity, which is summarized in Scheme-X. The method comprises reacting 4-bromomethylbenzonitrile (II), with 1H 1,2,4-triazole (III) in an organic solvent in presence of cesium carbonate and precipitation of 4-[1-(1,2,4-triazolyl) methyl]-benzonitrile (IV), thus formed from the reaction medium using a suitable organic solvent. The intermediate (IV) is further converted to Letrozole by reaction with 4-fluorobenzonitrile (VI) in presence of an organic solvent and silicon amine, which are lithium, sodium, or potassium disilazanes or monosilazane.
• [0030]
  The method utilizes sensitive and expensive silicon compounds like lithium hexamethyldisilazane, which requires highly controlled reaction conditions.
• [0031]
  10. Hasson et al. in US 2007/0112203 A1 , provide a method, as summarized in Scheme-XI, for purification of a mixture containing Letrozole (I) and its isomeric impurity i.e. Isoletrozole (IX), which is an extension of Method-2 disclosed by Bowman et al. in US 4,978,672 and US 5,352,795 . The method takes advantage of the rapid oxidation of Isoletrozole (9) to 4,4'-dicyclobenzophenone (10), in comparison to Letrozole (I), the oxidized compound (10), being easily separable from Letrozole, can be removed by crystallization, affording pure Letrozole. The Letrozole product, in turn is prepared by Method-2 disclosed by Bowman et al. in US 4,978,672 and US 5,352,795 .
• [0032]
  From the Enabling Disclosures of Hasson et al. in US 2007/0112203 A1 , it could be seen that the method of oxidative purification of Letrozole, does not provide the said Letrozole, free of the Isoletrozole impurity (IX), directly and in fact, about 1 to 4% of Isoletrozole (IX) remains in the product, which is further removed by successive crystallizations to provide Letrozole (I) of 99.9% purity.

  It is also noted that Letrozole to some extent also undergoes oxidation, albeit slowly, resulting in formation of additional impurities. Removal of such impurities, coupled with the task of removal of Isoletrozole (IX) and 4,4-dicyclobenzophenone (10) results in significant yield loss, rendering the method not particularly attractive, economically.
• [0033]
  11. Palle et al. in US 2007/0100149 A1 , recite an alternate method for synthesis of Letrozole, as summarized in Scheme-XII.
• [0034]
  The method of Palle et al. comprises reacting 4,4-(hydroxymethylene)bis benzonitrile (12), in turn obtained from 4,4-dibromobenzophenone (11), with p-toluenesulfonyl chloride to give the corresponding p-tolenesulfonate (13), which on reaction with 1H 1,2,4-triazole (III), gives crude Letrozole, which is further purified by successive chromatography and crystallization.
• [0035]
  The yield of the p-tolenesulfonate (13), in the key step is only 21%, indicative of formation of large amount of impurities in the said step. Further, the overall yield of Letrozole obtained by the method is only about 14%, which would render the method not viable commercially.
• [0036]
  12. Friedman et al. in US 2007/0112202 A1 , provide an extension of Method-2 disclosed by Bowman et al. in US 4,978,672 and US 5,352,795 , which is summarized in Scheme-XIII.
• [0037]
  US 2007/0112202 A1 reports synthesis of Letrozole by the abovementioned method in 54-56% yield and having a HPLC purity 99.4%, which may not suit Pharmacopoeial standards, which suggests that the product obtained requires further purification, which, incidentally, is acknowledged by Friedman et al., who state that single purification using various solvents does not give Letrozole of acceptable purity, and hence multiple purifications are required to achieve the same. Needless to mention, this would result in significant loss of the precious product. Further, the novelty and inventiveness of the method is in question, since Bowman et al. in US 4,978,672 and US 5,352,795 have disclosed the same chemistry earlier.
• [0038]
  13. Agarwal et al. in WO 2007/074474 A1 recite a synthesis of Letrozole, utilizing novel intermediates, the chemistry of which is summarized in Scheme-XIV.
• [0039]
  The method is lengthy and the reported overall yield of Letrozole appears to be only 9-11%.

• [0101]
  To a mixture of potassium tertiarybutoxide (635.92 gm; 5.66 mol) and N,N-dimethylformamide (3.75 Lt), under an atmosphere of nitrogen and cooled to a temperature of -20° to -25°C, was added 4-(1H-1,2,4-triazol-1-ylmethyl)benzonitrile hydrochloride (VII, as obtained in Reference Examples 1 or 2; 250 gm; 1.13 mol) within 5 minutes and was stirred for 60 minutes at -20°C to -25°C. To the mixture was added 4-fluoro benzonitrile (VI, 150.9 gm; 1.24 mol) within 5 minutes and the mass agitated for an hour at-20°C to -25°C. After completion of the reaction, pH of the mixture was adjusted to between 6.0 to 6.5 by addition of 50% aqueous hydrochloric acid, maintaining the temperature between -20°C to 0°C. After the addition of the hydrochloric acid solution, the reaction mass was stirred for additional 30 minutes and filtered. To the filtrate was added ethyl acetate and water and the ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum to give a residual solid amounting to 179 gm (55%) of Letrozole (I), having a purity of 83%.
• [0102]
  The solid was chromatogaphed over silica gel (60-120 mesh) using n-Hexane and ethyl acetate as eluent to give Letrozole (100.5 gm; 56%), having a purity of 99%.
• [0103]
  The material (100 gm) was further dissolved in ethyl acetate (1.6 Lt) at 70° to 75°C, and the solution was filtered hot. The filtrate was evaporated under vacuum till the volume was between 200 to 220 ml. The solution was cooled to 0° to 5°C for 4 hours, and the solid filtered, washed with cold ethyl acetate and dried to give Letrozole (I, 95 gm; 95%), having a purity of 99.6%.

• [0104]
  To a mixture of potassium tertiarybutoxide (635.92 gm; 5.66 mol) and N,N-dimethylformamide (3.75 Lt). under an atmosphere of nitrogen and cooled to a temperature of -20° to -25°C, was added 4-(1H-1,2,4-triazol-1-ylmethyl)benzonitrile hydrochloride (VII, as obtained in Examples 1 or 2; 250 gm; 1.13 mol) within 5 minutes and was stirred for 60 minutes at -20°C to -25°C. To the mixture was added 4-fluoro benzonitrile (VI, 150.9 gm; 1.24 mol) within 5 minutes and the mass agitated for an hour at -20°C to -25°C. After completion of the reaction, pH of the mixture, was adjusted to between 6.0 to 6.5 by addition of 50% aqueous hydrochloric acid, maintaining the temperature between -20°C to 0°C. After the addition of the hydrochloric acid solution, the reaction mass was stirred for additional 30 minutes and filtered. To the filtrate was added ethyl acetate and water and the ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum to give a residual solid amounting to 244 gm (75%) of Letrozole (I), having a purity of 99%.
• [0105]
  The material (244 gm) was further dissolved in ethyl acetate (500 ml) at 70° to 75°C, and the solution was filtered hot. The filtrate was cooled to 0° to 5°C for 4 hours, and the solid filtered, washed with cold ethyl acetate and dried to give Letrozole (I, 221 gm; 98.6%), having a purity of 99.7%.

References

External links

• Femara website

Organo-Iodine Compounds Analysis by the 5975-SMB GC-MS with Cold EI

Aviv Amirav, Professor of Chemistry at Tel Aviv University and Director - Aviv Analytical

Larisa Panz Ph.D., Ksenia Kulbitski and Professor Mark Gendelman, Schulich Faculty of Chemistry at the Technion Haifa Israel. 

read at

http://blog.avivanalytical.com/search/label/Chemistry%20by%20MS

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