Diacerein, US 8324411

PATENTS Comments Off

Sep 022016

Patent US 8324,411

https://www.google.com/patents/US8324411

Inventors	Annibale Salvi, Antonio Nardi, Stefano Maiorana, Mara Sada
Original Assignee	Laboratorio Chimico Internazionale S.P.A.

Laboratorio Chimico Internazionale s.p.A., Milan, Italy

Diacerein, 20a, is used in the treatment of arthritis, and there are several methods available for its synthesis. The majority of these are said to involve an oxidation step that uses CrO₃, and as a result, extensive purification is required to remove residues of Cr and reaction byproducts. The patent discloses an oxidation procedure in the preparation of 20a that avoids these problems and is claimed to be suitable for industrial production. Scheme 8 shows the route used to prepare 20athat starts with formation of the protected quinone, 19b. Despite the workup of the compound being quite lengthy, 19b is isolated in 74% yield with 98% purity. The next step is oxidation of the protected dihydroxy quinone 19b using TEMPO and an alkaline chlorite plus an alkaline hypochlorite. The chlorite is used in around 2 mol excess of the substrate and the hypochlorite at around 5 mol % of the substrate. After the oxidation the crude product is isolated in 98% yield and then purified by treatment with Et₃N and DMF. The purified 20b is obtained in 76% yield, and then the protection is removed using FeCl₃/Ac₂O. The yield of crude 20a is 92%, and it is said to be purified by known techniques. The Cr content of the purified material is reported as <1 ppm, and genotoxic impurities such as 19a or acetyl derivatives are reported to be <2 ppm.

Scheme 8. ^a

^aReagents and conditions: (a) (i) K₂CO₃, KI, Bu₄NBr, DMF, 60 °C; (ii) 80 °C, 1 h; (iii) BnCl, 50 °C, 1 h; (iv) 80 °C, 1 h; (v) add MeOH at 50 °C; (vi) cool to <25 °C, filter; (vii) evaporate, add THF; (viii) wash at 60 °C with aq NaOH, H₂O, brine; (ix) evaporate, add EtOAc, concentrate; (x) cool <4 °C, 1 h; (xi) filter, wash, dry. (b) (i) TEMPO, aq NaH₂PO₄, aq Na₂HPO₄, MeCN, 35 °C; (ii) add aq NaClO₂, 35 °C, 50 min; (iii) add aq NaOCl, 65 °C, 3 h; (iv) cool rt, add H₂O; (v) add H₃PO₄, pH 3; (vi) filter, H₂O wash, dry; (vii) Et₃N, DMF, EtOAc, 60 °C, 0.5 h; (viii) filter hot; (ix) add H₂O, separate; (x) extract H₂O phase at 60 °C with EtOAc (×6); (xi) cool organic phases to rt, add HCl to pH 2; (xii) cool <5 °C, 1 h; (xiii) filter, H₂O wash, MeCN wash, dry. (c) (i) FeCl₃, Ac₂O, 65 °C, 1.5 h; (ii) cool <4 °C, 1 h; (iii) filter, wash in Ac₂O, EtOAc wash, dry.

Advantages

The process produces the desired product without using heavy-metal oxidising agents; however, the workup procedures are quite lengthy.

Example 1 Preparation of 1,8-dibenzyloxy-3-(hydroxymethyl)anthraquinone (dibenzyl aloe-emodin)483 g (3.5 moles) of potassium carbonate, 16 g (0.1 moles) of potassium iodide and 16 g (0.05 moles) of tetrabutylammonium bromide are added to a solution of 270 g (1 mole) of 1,8-dihydroxy-3-(hydroxymethyl)anthraquinone (aloe-emodin) in 3500 ml of DMF at 60° C.; the reaction mixture is heated at 80° C. for 1 h. It is cooled to 50° C. and 443 g (3.5 moles) of benzyl chloride are added dropwise in approximately one hour. At the end of the dripping, the reaction mixture is brought back to 80° C. and left at that temperature under stirring for 45-60 minutes. It is then cooled to 50° C. and 200 ml of methyl alcohol are added. It is cooled to 20-25° C. and the inorganic salts are removed by filtering. The organic solvent is distilled at 60-70° C. at reduced pressure and the residue is dissolved in 3200 ml of tetrahydrofuran at 60° C. Maintaining the temperature at 50-60° C., the organic phase is washed twice with 1200 ml of 2.5 molar aqueous sodium hydroxide and once with 1000 ml of a saturated solution of sodium chloride in water. The organic phase is concentrated at reduced pressure at 60° C. and the residue is recovered with 2700 ml of ethyl acetate. The suspension thus obtained is concentrated to approximately ⅓ of the initial volume by distillation of the solvent at reduced pressure. It is gradually cooled to 0-4° C. and kept at that temperature for 1 hour. The solid is filtered and washed with ethyl acetate (100 ml×2). The damp product is dried at 45° C. at reduced pressure for 12-14 hours, providing 334 g (yield 74%) of dibenzyl aloe-emodin having a purity of 98% (HPLC).

melting point: 170-171° C.

IR cm⁻¹: 1655, 1612, 1232

Example 2 Synthesis of 1,8-dibenzyloxyanthraquinone-3-carboxylic acid (dibenzylrhein)10 g (0.06 moles) of radical 2,2,6,6-tetramethyl-1-piperidinyl-oxyl (TEMPO) and 1160 ml of an aqueous solution of 120 g (1 mole) of sodium dihydrogen phosphate and 180 g (1 mole) of disodium hydrogen phosphate are added in sequence to a suspension of 333 g (0.74 moles) of 1,8-dibenzyloxy-3-(hydroxymethyl)anthraquinone in 1660 ml of acetonitrile. The reaction mixture is heated to 35° C. and a solution of 167 g (1.5 moles) of sodium chlorite 80% in 513 ml of water is added dropwise in 40-50 minutes, maintaining the temperature around 35-40° C. 20 ml of aqueous sodium hypochlorite 10-12% are then dripped in and the reaction is heated to 60-65° C. for three hours. It is cooled to room temperature and 1400 ml of water are added. Phosphoric acid 85% is dripped in until reaching a pH of 2.8-3.2. The solid obtained is filtered and washed with water (350 ml×2). The damp product is dried at 50° C. at reduced pressure for 14-16 hours, providing 337 g (yield 98%) of crude dibenzylrhein.

Example 3 Purification of 1,8-dibenzyloxyanthraquinone-3-carboxylic acid (dibenzylrhein)337 g (0.72 moles) of crude 1,8-dibenzyloxyanthraquinone-3-carboxylic acid are dissolved in a solution of 134 ml of triethylamine in 900 ml of dimethylformamide DMF and 1800 ml of ethyl acetate, heating to 60° C. for 20-30 min. Any undissolved elements are removed by hot filtering and 2700 ml of water are added. The organic phase is separated and the aqueous phase is washed 6 times with 800 ml of ethyl acetate each time, maintaining the temperature at 60° C. The organic phase is cooled to room temperature and acidified with hydrochloric acid 33% until pH 2 is reached; the suspension thus obtained is cooled to 0-5° C. for approximately 1 hour. The product is filtered, washing it thoroughly with water (1200 ml) and then with 200 ml of acetonitrile. After drying at 50° C. at reduced pressure for 14-16 hours, 256 g of dibenzylrhein are obtained with a yield of 76%.

melting point: 250-251° C.

IR cm⁻¹: 1666, 1621, 1587, 1524

Example 4 Synthesis of 1,8-diacetoxy-3-carboxyanthraquinone (diacerein)45 g (0.28 moles) of anhydrous iron trichloride are added in portions to a suspension of 255 g (0.55 moles) of 1,8-dibenzyloxyanthraquinone-3-carboxylic acid in 1300 ml of acetic anhydride. The reaction mixture is heated to 65° C. for one hour and thirty minutes. It is gradually cooled to 2-4° C. and maintained at that temperature for 1 hour. The solid obtained is filtered and washed with 150 ml of acetic anhydride and then with 400 ml of ethyl acetate. The damp product is dried at 50° C. at reduced pressure for 14-16 hours, providing 186 g of crude diacerein (yield 92%). The crude diacerein is purified according to the known techniques.

¹H NMR (d6-DMSO) δ: 2.4 (6H, s); 7.6 (1H, dd); 7.9 (1H, t); 8.0 (1H, d); 8.1 (1H, dd); 8.5 (1H, d).

IR cm⁻¹: 1763, 1729, 1655, 1619, 1591, 1183.

Chromium: not detectable (<1 ppm)

Genotoxic impurities (aloe emodin and acetyl derivatives)≦2 ppm.

/////////Diacerein, US 8324411, PATENT

US 8362006, Intervet International B.V., Boxmeer, The Netherlands, Zilpaterol, PATENT

PATENTS Comments Off

Sep 022016

Image result for Zilpaterol,

US 8362006

http://www.google.co.in/patents/US8362006

Inventors	Oliver Krebs, Stephane Dubuis
Original Assignee	Intervet International B.V.

Intervet International B.V., Boxmeer, The Netherlands

Image result for Intervet International B.V.,

Process for Making Zilpaterol and Salts Thereof

Zilpaterol is a known adrenergic β-2 agonist having the following structure:

The IUPAC name for zilpaterol is 4,5,6,7-tetrahydro-7-hydroxy-6-(isopropylamino)imidazo[4,5,1-jk]-[1]benzazepin-2(1H)-one. The Chemical Abstracts name for zilpaterol is 4,5,6,7-tetrahydro-7-hydroxy-6-[(1-methyl-ethyl) amino]-imidazo [4,5,1-jk][1]benzazepin-2(1H)-one.It is well known that zilpaterol, various zilpaterol derivatives, and various pharmaceutically acceptable acid addition salts of zilpaterol and its derivatives may, for example, be used to increase the rate of weight gain, improve feed efficiency (i.e., decrease the amount of feed per amount of weight gain), and/or increase carcass leanness (i.e., increase protein content in carcass soft tissue) in livestock, poultry, and/or fish. In U.S. Pat. No. 4,900,735, for example, Grandadam describes zootechnical compositions of racemic trans zilpaterol and salts thereof that may be used to increase the weight and meat quality of warm-blooded animals, including cattle, pigs, and poultry. And U.S. Patent Appl. Publ. US2005/0284380 describes use of an ionophore/macrolide/zilpaterol dosing regimen to increase beef production, reduce feed intake while maintaining beef production, and reduce incidences of liver abscess in cattle.

Methods for making zilpaterol are known in the art. For example, in U.S. Pat. No. 4,585,770, Fréchet et al. describe compounds encompassed by a genus characterized as 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,1-jk][1]-benzazepin-2[1H]-one derivatives and pharmaceutically acceptable acid addition salts thereof. The derivatives correspond in structure to the following formula:

Here, R can be various substituents, and the wavy lines indicate that the bonds to the 6-amino and 7-OH groups have the trans configuration. This genus encompasses racemic trans zilpaterol when R is isopropyl.The methods reported in U.S. Pat. No. 4,585,770 use 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime as an intermediate. This compound corresponds in structure to the following formula:

As indicated in U.S. Pat. No. 4,585,770, 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime may be formed from starting materials that have been long known in the art. U.S. Pat. No. 4,585,770 illustrates the use of two such starting materials. In both examples, the starting materials are used to form 5,6-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,7-[1H,4H]-dione, which, in turn, may be used to make 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime.In one of the examples in U.S. Pat. No. 4,585,770, the starting material is 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one, which is described in J. Chem. Soc. Perkins, p. 261 (1982):

U.S. Pat. No. 4,585,770 indicates that 1,3-dihydro-1-(1-methylethenyl)-2H-benzimidazol-2-one may be reacted with an alkyl 4-halobutyrate (i.e., R^A—(CH₂)₃—COOR^B(wherein R^Ais Cl, Br, or I; and R^Bis C₁-C₄-alkyl), such as methyl or ethyl 4-bromobutyrate) and a base (e.g., an alkali metal) to form a butanoate, which, in turn may be hydrolyzed with an acid (e.g., H₂SO₄) in an alkanol (e.g., methanol or ethanol) to remove the methylethenyl substituent. The hydrolysis product then may be subjected to saponification by reacting it with a base (e.g., NaOH or KOH) in an alkanol to form a carboxylic acid. Subsequently, the carboxylic-acid-terminated side chain may be cyclized to form 5,6-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,7-[1H,4H]-dione by reacting the carboxylic acid with thionyl chloride to obtain a chloride, and then treating the chloride with a Lewis acid (e.g., aluminum chloride) in an organic solvent (e.g., methylene chloride or dichloroethane):

See U.S. Pat. No. 4,585,770, col. 4, line 3 to col. 5, line 14; and Example 14, col. 12, lines 1-68.In another example in U.S. Pat. No. 4,585,770, the starting material is 1,3-dihydro-1-benzyl-2H-benzimidazol-2-one, which is described in Helv., Vol 44, p. 1278 (1961):

U.S. Pat. No. 4,585,770 indicates that the 1,3-dihydro-1-benzyl-2H-benzimidazol-2-one may be reacted with ethyl 4-bromobutyrate and sodium hydride to form 1,3-dihydro-2-oxo-3-benzyl-1H-benzimidazol-1-butanoate, which, in turn may be subjected to saponification by reacting it with methanolic NaOH to form 1,3-dihydro-2-oxo-3-benzyl-1H-benzimidazol-1-butanoic acid. The butanoic acid side chain may then be cyclized by reacting the 1,3-dihydro-2-oxo-3-benzyl-1H-benzimidazol-1-butanoic acid with thionyl chloride to obtain a chloride, and then treating the chloride with aluminum chloride in dichloroethane. The cyclized product, in turn, may be hydrolyzed using o-phosphoric acid in phenol to form 5,6-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,7-[1H,4H]-dione. See U.S. Pat. No. 4,585,770, Example 1, Steps A-D, col. 6, line 10 to col. 7, line 35.Using the methods reported in U.S. Pat. No. 4,585,770, 5,6-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,7-[1H,4H]-dione may be reacted with an alkyl nitrite (e.g., tert-butyl nitrite or isoamyl nitrite), in the presence of a base or acid (e.g., HCl), to form 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime. The 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime, in turn, is reduced via catalytic hydrogenation (with, for example, hydrogen in the presence of palladium on carbon) or sodium borohydride to form racemic trans 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,1-jk][1]-benzazepin-2[1H]-one:

In the illustrative example in U.S. Pat. No. 4,585,770, the 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime is converted into racemic trans 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,1-jk][1]-benzazepin-2[1H]-one in two steps: the 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime is first reacted with H₂in the presence of Pd-on-carbon, and, then, after filtration, the hydrogenation product is reacted with sodium borohydride. See U.S. Pat. No. 4,585,770, col. 2, line 15 to col. 4, line 2; and Example 1, Steps E & F, col. 7, line 38 to col. 8, line 3.U.S. Pat. No. 4,585,770 reports that the trans stereoisomers of 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,1-jk][1]-benzazepin-2[1H]-one may be alkylated with acetone in the presence of a reducing agent (e.g., an alkali metal borohydride or cyanoborohydride, such as sodium cyanoborohydride) to form racemic trans zilpaterol:

See U.S. Pat. No. 4,585,770, col. 2, line 46 to col. 4, line 2; and Example 13, col. 11, lines 41-68.In view of the importance of zilpaterol and its salts in animal production, there continues to be a need for cost-effective, high-yield processes for making zilpaterol and its salts. The following disclosure addresses this need.

OVERVIEW

Zilpaterol 121 is used to increase the rate of weight gain in livestock, poultry, and fish. The drug is available as Zilmax and is marketed as beef improvement technology. There are a number of methods for preparing 121, and the patent specifically focuses on the method reported in a 1986 patent, U.S. 4,585,770, that is compared with the process described in the current patent.

The new process is outlined in Schemes 37 and 38, and the examples in the patent describe the manufacture of 121 on a commercial scale starting from 525 kg of 116a.

Unfortunately, the yield of the reaction products is not reported in any of the steps. The process starts with the chlorination of the acid 116a to give 116b that is carried out using (COCl)₂, although COCl₂ or triphosgene are also claimed to be suitable. The product is isolated as a solution in DCM after a workup involving transferring between three vessels, adding H₂O, and distilling off the solvent.

In the next stage an intramolecular Friedel–Crafts alkylation of 116b in the presence of AlCl₃ followed by acid hydrolysis forms 117. This is isolated as a wet solid and then is converted to the oxime 118a in DMF by treatment with NaNO₂ followed by addition of HCl.

Scheme 37. ^a

^aReagents and conditions: (a) (i) DMF, DCM, 10 °C; (ii) (COCl)₂, 10 °C, 3 h; (iii) 20 °C, 3 h. (b) (i) AlCl₃, DCM, 60 °C, 3 to 7 h; (ii) cool to <20 °C, add H₂O/33% aq HCl; (iii) cool, evacuate, distill DCM; (iv) centrifuge, wash in PrⁱOH. (c) (i) NaNO₂, DMF, 45 °C; (ii) 33% HCl, 48 °C, 1 h; (iii) 60 °C, 0.5 h; (iv) cool to 45 °C, 2 h; (v) add DMF and H₂O; (vi) cool, to 0 °C, 11 h; (vii) centrifuge at 0 °C; (viii) H₂O wash, wash in Me₂CO, dry.

Compound 118a is isolated as a dry solid that is converted to the potassium salt by treatment with 45% aq KOH as shown in Scheme 38. The salt is isolated as a solution that is treated with active C and then hydrogenated in the presence of Pd/C catalyst to form the amino alcohol salt 119.

This reaction appears to be stereoselective, although no reference to this is made in the patent. The salt, 119, is recovered as an aqueous solution that is used in the next step where it is reacted with Me₂CO in the presence of HOAc at a pH of 7–8. This produces the isopropylidene amino compound, 120, that is not isolated but undergoes hydrogenation in the presence of Pt/C catalyst to give the HOAc salt, 121·HOAc.

The free base form, 121, is obtained by treating the salt with NaOH in EtOH, and from the free base, a HCl salt can be prepared.

Scheme 38. ^a

^aReagents and conditions: (a) (i) H₂O, 45 °C; (ii) 45% aq KOH, 40 °C; (iii) active C, 0.5 h; (iv) filter. (b) (i) Pd/C, H₂O, 15 °C; (ii) H₂, 10 bar, 40 °C, 6 h; (iii) filter, H₂O wash. (c) HOAc to pH 8, 30 °C. (d) (i) cool 15 °C, Pt/C, H₂O; (ii) H₂ 9 bar, 70 °C, 2 h; (iii) add HOAc, 30 °C, pH 6.8; (iv) filter at 30 °C; (v) wash in aq HOAc.

The patent discusses aspects of the process is some detail such as the quantities of washing solvents used.

Advantages

The process provides an effective route to the desired compound and is clearly suitable for large-scale manufacture.

The following Scheme I generically illustrates a scenario wherein all the above reactions are used:

The following Scheme II generically illustrates the above scenario wherein the chlorinating agent comprises oxalyl chloride; the Lewis acid comprises AlCl₃; the hydrolysis acid following the Friedel-Crafts reaction comprises HCl; the inorganic nitrite comprises NaNO₂; the acid used in the oximation comprises HCl; water is added to the oximation product mixture to foster isolation of the oxime product; the base used to form the oxime salt comprises KOH; the catalyst for the first hydrogenation comprises palladium on carbon; the acid used in the formation of the isopropylideneamino compound comprises acetic acid; the catalyst for the second hydrogenation comprises platinum on carbon; and the base and alcohol used to form the zilpaterol free base comprise NaOH and ethanol, respectively:

Example 1 Preparation of 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione Part A. Preparation of chloro 2,3-dihydro-2-oxo-1H-benzimidazol-1-butanoate

4-(2-Oxo-2,3-dihydrobenzimidazol-1-yl)butyric acid (50 g; 0.227 mol), N,N-dimethylformamide (1.84 g; 0.025 mol; 0.11 eq), and dichloromethane (480 g; 5,652 mol; 24.89 eq) were charged to a stirred-tank reactor. Oxalyl chloride (31.12 g; 0.245 mol; 1.08 eq) was then dosed at 10-20° C. over a 1-hour period while stirring. The resulting mixture was then stirred at 10-20° C. for an additional hour. All the above steps were conducted under a N₂atmosphere.Part B. Preparation of 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione.

The reaction product mixture from Part A was added to a slurry of aluminum chloride (100 g; 0.75 mol, 3.3 eq) in dichloromethane (320 g; 3.768 mol; 16.59 eq) over 2-5 hours at 60° C. and a pressure of 2.7 bar (absolute) in a stirred-tank reactor that allowed HCl gas to escape through an overpressure vent. The resulting slurry was stirred for an additional hour at that temperature, and then cooled to 12° C. In a separate stirred-tank reactor, water (800 g; 44.407 mol; 195.59 eq.) and aqueous 32.5% HCl (118 g; 1.052 mol HCl; 4.63 eq. HCl) were mixed. This mixture was cooled to 0° C., and the gas in the headspace was evacuated to 300 mbar (absolute). The slurry from the first reactor was then added portion-wise to the second reactor, whereby the temperature increased to 10-15° C. under distillation of dichloromethane. The first reactor was rinsed with additional dichloromethane (25 g; 0.294 mol; 1.3 eq), which was then added to the second reactor. Distillation of the dichloromethane was then completed at 300 mbar to atmospheric pressure (absolute) and 12-40° C. The resulting suspension was cooled to 0° C. The solid was filtered off, and washed 4 times with water (291.25 g each time; 64.668 mol total; 284.83 eq. total) and once with isopropanol (80 g; 1.331 mol; 1.331 eq) at 0° C. All the above steps were conducted under a N₂atmosphere.Example 2 Preparation of 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime.

8,9-Dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione (50 g; 92.4% purity; 0.228 mol) prepared in accordance with the procedure in Example 1 was dried and mixed with isopropanol (7.23 g; 0.12 mol; 0.53 eq) and water (3.01 g; 0.167 mol; 0.73 eq) (in alternative experiments and in production, 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione prepared in accordance with the procedure in Example 1 was instead used as centrifuge-wet material without the addition of water and isopropanol). The resulting wet 8,9-dihydro-2H-7H-2,9a-diazabenzo[cd]azulene-1,6-dione was combined with sodium nitrite (19.05 g at 99.3% purity; 0.274 mol; 1.2 eq) and N,N-dimethylformamide (800 g; 10.945 mol; 47.9 eq) in a stirred-tank reactor. The mixture was heated to 50° C., and then 32% HCl (41.65 g; 0.366 mol HCl; 1.6 eq HCl) was added over a 30 minute period. Toward the end of the HCl addition (i.e., after greater than 1 eq HCl had been added), the temperature quickly increased to 60-70° C. After all the HCl was added, the mixture was stirred at 60° C. for an additional 30 minutes. The mixture then was cooled to 35° C. over a 2- hour period. Next, water (224.71 g; 12.473 mol; 54.6 eq) was added over a 2-hour period. The resulting mixture was then cooled to 0° C. over a 2-hour period, and maintained at that temperature for 2 hours. Afterward, the solid 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime product was removed by filtration and washed 4 times with water (70.1 ml each time; 15.566 mol total; 68.13 eq total) and once with acetone (115.9 g; 99.9% purity; 1.994 mol; 8.73 eq). All the above steps were conducted under a N₂atmosphere.Example 3 Scale-up Preparation of 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione Part A. Preparation of chloro 2,3-dihydro-2-oxo-1H-benzimidazol-1-butanoate

Dichloromethane (3772 L) and then 4-(2-oxo-2,3-dihydrobenzimidazol-1-yl)butyric acid (525 kg; 2.4 kmol) were charged to a stirred-tank reactor, followed by N,N-dimethylformamide (21 L). The resulting mixture was cooled to 10° C. Afterward, oxalyl chloride (326.8 kg)) was dosed at 10-15° C. over 2-3 hours while stirring. The resulting mixture was then stirred at 15-20° C. for an additional 1-3 hours. All the above steps were conducted under a N₂atmosphere. Conversion was checked by in-process control (“IPC”).Part B. Preparation of 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione.

Aluminum chloride (1050 kg) and dichloromethane (2403 L) at 10-20° C. were charged to a stirred-tank reactor, followed by additional dichloromethane (112 L) at 10-20° C. to rinse the reactor. The reactor was then pressurized with N₂to 2.7 bar (absolute), and heated to 58-60° C. Next, the product mixture from Part A was added over 2−5 hours. The resulting slurry was stirred for an additional 1-2 hours, and then cooled to 10-20° C. Afterward, the pressure was released. In a second stirred-tank reactor at 5° C., water (3675 L) was charged, followed by aqueous 33% HCl (452 L). This mixture was cooled to 0° C., and the gas in the headspace was evacuated to 270-470 mbar (absolute). About half the content from the first reactor was added to the second reactor at from 5-20° C. The mixture was maintained at 10-30° C. for an additional 30-90 minutes. In parallel to and following the transfer, distillation of dichloromethane occurred. The line between the two reactors was rinsed with dichloromethane (150 ml). The resulting rinse and the contents in the second reactor were transferred to a thud stirred-tank reactor. The transfer line between the second and third reactors was rinsed with water (200 L). This rinse also was charged to the third reactor. Water (3675 L) at 5° C. and 33% HCl (452 L) were then added to the second reactor. The resulting mixture was cooled to 0° C., and the pressure in the headspace was set to between 270-470 mbar (absolute). The second half of the content from the first reactor was then added to the second reactor at 5-20° C. This mixture was maintained at 10-30° C. for an additional 30-90 minutes. In parallel to and following the transfer, distillation of dichloromethane occurred. The line between the first and second reactors was rinsed with dichloromethane (150 ml). The resulting rinse and the contents in the second reactor were transferred to the third reactor. The transfer line between the second and third reactors was then rinsed with water (200 L). This rinse was charged to the third reactor. In the third reactor, the dichloromethane was further distilled at 30-40° C. under atmospheric pressure. When the distillation was complete, the suspension was cooled to 0−5° C., and then centrifuged in two parts. Each of the resulting cakes was washed with four times water (390 L for each wash) and once with isopropanol (508 L) at 0−5° C. All the above steps were conducted under a N₂atmosphere.Example 4 Scale-up of Preparation of 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime.

At 20° C., N,N-dimethylformamide (7068 L) was charged to a stirred-tank reactor, followed by 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione (450 kg total wet material, approximately 405 kg pure) prepared in accordance with the procedure in Example 3. The addition funnel was rinsed with N,N-dimethylformamide (105 L), and the rinse was charged to the reactor. The resulting mixture was heated at 45° C. until all the 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione was in solution. IPC was used to check the amount of pure 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione in the mixture, and, from that measurement (together with the mass of wet 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione and N,N-dimethylformamide), the exact amount of 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione was calculated, which, in turn, was used to calculate the amounts of N,N-dimethylformamide (17.3 kg/kg), sodium nitrite (0.412 kg/kg) and HCl 33% (0.873 kg/kg). For the duration of the IPC, the mixture was cooled to 20° C. Next, sodium nitrite (167 kg, based on 405 kg 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione) was added. The addition funnel was rinsed with N,N-dimethylformamide (105 L), and the rinse was charged to the reactor. The temperature was then increased to 45° C. Subsequently, additional N,N-dimethylformamide was charged in the amount calculated earlier (97 L, based on having a total of 7375 L DMF for 405 kg of 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione). Next, the resulting mixture was warmed to 48° C., and then 33% HCl (353 kg, based on the batch size) was added over 1 hour, causing the temperature to increase to 60-65° C. by the end of the addition. The mixture was then stirred at 60° C. for another 30 minutes. Next, the mixture was cooled to 45° C. over 1-2 hours. The resulting mixture was transferred into a second reactor. The first reactor was subsequently rinsed with N,N-dimethylformamide (105 L), and the rinse was charged to the second reactor. Water (2000 L) was then added over a 2-hour period at 38° C. The resulting mixture was cooled to 0° C. over 2-3 hours, and then stirred at that temperature for another 2-8 hours. Afterward, the mixture was centrifuged at 0° C., and the resulting cake was washed with three times with water (810 L each time), washed with acetone (1010 L), and dried at 65° C. under vacuum. All the above steps, except for the IPC, were conducted under a N₂atmosphere.Example 5 Preparation of Zilpaterol Part A. Formation of Aminoalcohol Potassium Salt from Ketooxime

A stirred-tank reactor was purged 3 times with N₂between high pressure (3 bar, absolute) and low pressure (1 bar, absolute) for 10 minutes each. Then a pressure of 0.9 bar (absolute) was established. Water (790 kg) was then charged to the reactor, followed by 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime (255 kg) prepared in accordance with Example 4. The reactor contents were then heated to 40° C. Next, 45% KOH (214 kg) was continuously charged to the reactor, causing 4,5-dihydro-imidazo[4,5,1-jk][1]benzazepin-2,6,7[1H]-trione-6-oxime to form the corresponding potassium salt, which, in turn, dissolved (this could be visually verified). The reactor was then charged with active charcoal (13 kg). The resulting mixture was then stirred for 30 minutes at 40° C. The resulting mixture was filtered through a filter loop for one hour to remove the active charcoal. The mixture was then cooled to 15° C. A 5% palladium-on-carbon catalyst (25.5 kg, Johnson-Matthey) was then charged to the reactor. The reactor was then rinsed with water (50 kg). The resulting mixture in the reactor was stirred for 2-6 hours at 40° C. and a H₂pressure of 5-10 bar (absolute). Afterward, the reactor was vented over 30 minutes, and the reaction was analyzed using HPLC. The contents were then filtered in a filter loop for 90 minutes. The filter cake was washed with water (50 L), and removed to recover palladium. The filtered solution was analyzed via HPLC to confirm complete conversion, and then used in the next step.Part B. Formation of zilpaterol-HOAc.

The solution from Part A was cooled to 30° C. Acetone (625 L) was then charged to the reactor. Acetic acid was added to adjust the pH to 7.5 (a pH of from about 7 to about 8 is preferred). The resulting mixture was then cooled to 15° C. Next, a 5% platinum-on-carbon catalyst (21.3 kg, Degussa) was charged to the reactor, followed by water (50 kg) to rinse the reactor. The head space was purged 3 times with H₂between a high pressure of 5 bar (absolute) and a low pressure of 1 bar (absolute) for 15 minutes each. Then a hydrogen pressure of 9.0 bar (absolute, for hydrogenation) was established. The mixture was heated to 70° C. over 1 hour while being stirred, and then maintained at that temperature for an additional hour while being stirred. The reactor was then vented, and the headspace was purged with N₂. The reaction was analyzed using HPLC. Acetic acid (8 kg) was then charged to the reactor, and the resulting mixture was cooled to 30° C. More acetic acid was added to adjust the pH to 6.8. The mixture was then transferred through a filter loop for 1 hour while being maintained at 30° C. The resulting cake was washed with 7% aqueous acetic acid (75 L). The filtered solution was transferred to another stirred-tank reactor to be used in the next step.Part C. Formation of Zilpaterol Free Base

The stirred-tank reactor containing the product from Part B was purged 3 times with N₂between high pressure (2 bar, absolute) and low pressure (1 bar, absolute) for 10 minutes each. Then a pressure of 0.9 bar (absolute) was established. Next, the mixture was concentrated by distillation to 30-70%. The concentrated mixture was cooled to 65° C. Ethanol (331 L) was charged to the reactor, and the resulting mixture was cooled to 50° C. The pH was adjusted to 10 using 25% NaOH. This caused zilpaterol free base to precipitate. The temperature was decreased to 0° C. to facilitate the precipitation, and maintained at that temperature for an additional hour. The solids were filtered off, and washed with water (700 L).Example 6 Synthesis of an HCl Salt of the ZilpaterolThe free base of zilpaterol is dissolved in ethanol. Subsequently, ethyl acetate saturated with HCl is added. The resulting mixture is vacuum-filtered to obtain a crude product containing the HCl salt of the zilpaterol. The crude product is dissolved in hot methanol. Ethyl acetate is then added, and the mixture is filtered to obtain the final HCl salt product.

Example 7 First Illustration of a Contemplated Suitable Dosage FormA tablet is prepared containing 2.5 or 5 mg of the HCl salt of Example 6, and sufficient excipient of lactose, wheat starch, treated starch, rice starch, talc, and magnesium stearate for a final weight of 100 mg.

Example 8 Second Illustration of a Contemplated Suitable Dosage FormGranules are prepared containing 12.5 or 25 of the HCl salt of Example 6 in each daily dose of granules.

Example 9 Third Illustration of a Contemplated Suitable Dosage FormThe HCl salt of Example 6 is crystallized using the methodology discussed U.S. Pat. No. 5,731,028 for making crystalline racemic trans zilpaterol. Less than 5% of the crystals have a size of less than 15 μm, and at least 95% of the crystals have a size of less than 250 μm. A premix of the crystalline HCl salt secured to a 300-800 μm corn cob support is then obtained using the methodology discussed in European Patent 0197188 (incorporated by reference into this patent). The concentration of the HCl salt in the premix is 3% (by weight).

Cited Patent	Filing date	Publication date	Applicant	Title
US4585770	12 Oct 1983	29 Apr 1986	Roussel Uclaf	Novel 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,1-j-k][1]-benzazepin-2-(1H)-one
US5731028	6 Jun 1996	24 Mar 1998	Roussel Uclaf	Crystallized zilpaterol hydrochloride
US20060040950	17 Dec 2003	23 Feb 2006	Janssens Frans E	Substituted 1-piperidin-4-yl-4-pyrrolidin-3-yl-piperazine derivatives and their use as neurokinin antagonists
US20080267942 *	11 Apr 2008	30 Oct 2008	Pfizer Limited	Benzazepin-2(1h)-one derivatives
US20100173892 *	31 Jan 2008	8 Jul 2010	Juan Jose Almena-Perea	Enantioselective synthesis of 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,1-JK][1]-benzazepin-2[1H]-one and zilpaterol
WO2004056799A2	17 Dec 2003	8 Jul 2004	Janssen Pharmaceutica N.V.	Substituted 1-piperidin-4-yl-4-pyrrolidin-3-yl-piperazine derivatives and their use as neurokinin antagonists
WO2008119754A1	28 Mar 2008	9 Oct 2008	Intervet International B.V.	Processes for making zilpaterol and salts thereof

////////US 8362006, Intervet International B.V., Boxmeer, The Netherlands, Zilpaterol, PATENT

Gefitinib, US 8350029, CIPLA

PATENTS Comments Off

Sep 022016

US 8350029

http://www.google.co.in/patents/US8350029

Inventors	Dharmaraj Ramachandra Rao, Rajendra Narayanrao Kankan, Srinivas Laxminarayan Pathi,
Original Assignee	Cipla Limited

CIPLA Limited, Mumbai, India

Gefitinib is an anilinoquinazoline which is useful in the treatment of a certain type of lung cancer (non-small cell lung cancer or NSCLC) that has not responded to chemotherapy. The chemical name for gefitinib is 4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline. Its structural formula is:

The earliest known synthesis of gefitinib was first disclosed in the patent application WO 96/33980. The synthetic method employed is depicted in the following reaction scheme 1.

The process involves selective demethylation of 6,7-dimethoxy quinazoline-4-one using methanesutfonic acid and L-methionine to get its 6-hydroxyl derivative, which is protected by acetylation. The acetoxy compound is chlorinated and condensed with chloro-fluoroaniline. Hydrolysis of the acetoxy compound followed by etherification with 3-morpholinopropyl chloride gives crude gefitinib which is purified by column chromatography. The process suffers from many disadvantages as it involves several protection and deprotection steps. The selective demethylation using methionine results in isomeric impurities and has to be purified or else the impurity carries over to subsequent steps in the preparation of gefitinib making it more difficult to isolate a pure product. The process also leads to formation of an N-alkylated impurity at the final stage which must be separated by column chromatography to obtain gefitinib.

Several other approaches are also described in the literature to make gefitinib.

WO 2004/024703 discloses a process for the preparation of gefitinib starting from 3-hydroxy-4-methoxy benzonitrile which involves condensation of 3-hydroxy-4-methoxy benzonitrile with morpholino propyl chloride, nitration, reduction with sodium dithionite to amino compound, hydrolysis of nitrile to amide, cyclisation in the presence of formamide to obtain quinazoline, chlorination with phosphorous oxychloride and finally condensation with chloro-fluoro aniline to obtain gefitinib. The process involves multiple steps and hence is time consuming.

WO 2005/023783 discloses a process for the manufacture of gefitinib starting from 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile. The process involves a rearrangement reaction of 3-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)3,4-dihydroqunazoline-4-imine. The process is not feasible industrially, as the basic raw material is not readily available on a commercial scale and involves the use of excess 3-chloro-4-fluoroaniline which is expensive. A further draw back of the process is in the isomerization of the 4-imine compound which requires anhydrous conditions at high temperature for a longer duration of 96 hours. All the problems associated with this prior art process are overcome by the novel process of the present invention.

WO2005/070909 discloses a process for the preparation of gefitinib starting from isovanillin as depicted in scheme 2

The WO’ 909 process has disadvantages as it forms cis-trans geometrical isomers of the oxime, which have different reactivities. Furthermore, the process uses a large excess of acetic anhydride to convert the oxime to the nitrile at higher temperature.

The patent applications 901/CHE/2006 and 903/CHE/2006 disclose another route for preparing gefitinib starting from isovanillin. The process involves formation of a formamido compound [N′-[2-cyano-4-{3-(4-morpholinyl)propoxy}phenyl]-N,N-dimethyl formamide], which is unstable and may result in undesired impurities in the final condensation with 3-chloro-4-fluoro aniline, thereby making the process less feasible on an industrial scale.

The processes disclosed in the prior art are cumbersome. Therefore, there exists a need for a more economical and efficient method of making gefitinib which is suitable for industrial scale-up.

The process of the present invention avoids use of reagents such as sodium dithionite, acetic anhydride and allows substantial reduction in the number of problems associated with these reagents.

Process for Preparation of Gefitinib

Gefitinib, 66, is used in the treatment of certain types of lung cancer, and a number of methods are reported for its synthesis. These are described as cumbersome and can require excessive amounts of reagents or involve difficult purification methods. Some processes use reagents such as sodium dithionite or Ac₂O, and these are said to create problems. This patent discloses two routes for the synthesis of 66 that are claimed to avoid such problems. The first route, shown in Scheme 22, is the subject of the claims of the patent and starts with the nitration of isovanillin 57ain HOAc to give 57b that is recovered in 65% yield. Treatment of 57b with 58 produces 59a that is isolated in 92% yield, and this is then oxidised with H₂O₂ to form the acid 59b that is isolated in 86% yield. Reduction of the nitro group is then carried out to give 60, and there are three methods described for this reaction. The first is catalytic hydrogenation with Pd/C that gives a 90% yield of60. The reaction pressure is reported as being 5–6 kg, a common term in India used as short-hand for the pressure unit of kg/m². Reduction using H₂NNH₂ in the presence of FeCl₃, Al₂O₃, and charcoal gives a 83.6% yield of 60. In a hydrogen-transfer reaction with HCO₂NH₄ and Pd/C compound, 60 is recovered in 84.5% yield. The cyclisation of 60 to form 61 is carried out in a Niementowski reaction using HCO₂NH₄ and HCO₂NH₂, and the product is recovered in 90% yield. Reaction of 61 with SOCl₂ produces 62, and this is isolated in 95% yield. Only the main reagents are shown in the scheme, and workup details are omitted.

Scheme 22. ^a

^aReagents and conditions: (a) (i) HNO₃, HOAc, −5 °C; (ii) 30 °C, 12 h. (b) K₂CO₃, MeCN, reflux, 4 h. (c) (i) 30% NaOH/MeOH, 45 °C; (ii) add 35% H₂O₂ over 4 h, 45 °C, pH 11. (d) Pd/C, H₂, EtOAc, 40 °C, 4 h. (e) HCO₂NH₄, HCO₂NH₂, 180 °C, 4 h. (f) SOCl₂, DMF, reflux, 8 h.

In the next stage of the synthesis, shown in Scheme 23, compound 62 is reacted with morpholine63 to give 64 in 85% isolated yield. In the final step 64 is reacted with 65 to produce 66 that is recovered in 70% yield (purity not reported).

Scheme 23. ^a

^aReagents and conditions: (a) (i) 75 °C, 8 h; (ii) cool to rt, add H₂O; (iii) separate extract in DCM, H₂O wash, dry, evaporate. (b) MeOH, 30 °C, 0.25 h; (ii) add 65, reflux 6 h; (iii) add HCl at 20 °C; (iii) <10 °C, 0.5 h; (iv) filter, MeOH wash; (v) dissolve in PhMe/MeOH, concentrate; (vi) cool <10 °C, filter, PhMe wash, dry.

The patent also describes an alternative route to 66 that is outlined in Schemes 24 and 25although it is not covered by the patent claims. The route starts with the oxidation of 57a using H₂O₂ to give the acid 67a that is esterified to form 67b that is isolated in 83% yield. Nitration of67b with HNO₃ in HOAc produces 68a that is isolated in 74% yield and then reduced to 68b over Pd/C. The amine 68b is recovered in 93% yield and then reacted with 69 to give the quinazoline70a that is recovered in 92% yield and then acetylated to form 70b. There is no example describing this acetylation nor are there any for the remaining steps of this route shown in Scheme25, and the reactions are just generally referred to in the text.

Scheme 24. ^a

^aReagents and conditions: (a) (i) 30% NaOH/MeOH, 45 °C; (ii) add 35% H₂O₂ over 3 h, 45 °C, pH 11. (b) 10% HCl/MeOH, reflux, 6 h. (c) 70% HNO₃, HOAc, −5 °C, 18 h. (d) Pd/C, H₂, EtOAc, 40 °C, 4 h. (e) MeOH, reflux, 10 h. (f) No details.

Scheme 25. ^a

^aReactions: (a) Chlorination. (b) Condensation. (c) Hydrolysis. (d) Coupling.

The examples report experiments carried out on a reasonable scale with some producing up to 200 g of products. Unfortunately, there are no details of the purity of any of the intermediates, and although the patent states that the desired final product 66 is purified by acid/base treatment or crystallisation, there are no details provided.

Advantages

The process does avoid the use of some difficult reagents used elsewhere, but whether the process gives a higher-purity product than alternatives is not clear.

scheme 3.

scheme 4.

EXAMPLE 1 Preparation of 4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)-quinazoline (gefitinib) (Formula I)Methanol (1200 ml) and 6-(3-morpholino propoxy)-7-methoxy-4-chloro quinazoline (200 gm) were stirred for 15 minutes at 25-30° C., then a solution of 4-fluoro-3-chloroaniline in methanol (213 gm in 400 ml) was charged and refluxed for 6 hours. The reaction mass was cooled to 15-20° C., hydrochloric acid (40 ml) was added drop wise, and stirred at 5-10° C. for 30 minutes. The solid obtained was filtered and washed with chilled methanol (150 ml). The solid was dissolved in a mixture of toluene (30 volume) and methanol (5 volume), the reaction mass was concentrated to half the volume and cooled to 5-10° C. The solid obtained was filtered, washed with toluene (200 ml) and dried at 45-50° C. to yield the title compound (183 gm, 70% yield).

EXAMPLE 2 Preparation of 6-(3-morpholino propoxy)-7-methoxy-4-chloroquinazoline (Formula VII)DMF (3 lt), 6-(3-chloropropoxy)-7-methoxy-4-chloro quinazoline (200 gm) and morpholine (210 gm), were heated to 70-75° C. for 6-8 hours. The reaction mass was cooled to room temperature, and methylene chloride (2.5 lt) and water (2.5 lt) were charged. The layers separated and the aqueous layer extracted with methylene chloride twice (500 ml). The combined methylene chloride layer was washed with water, dried over sodium sulphate (10 gm) and concentrated completely at 35-40° C. to yield the title compound (200 gm, 85% yield).

EXAMPLE 3 Preparation of 6-(3-chloropropoxy)-7-methoxy-4-chloroquinazoline (Formula VI)6-(3-chloropropoxy)-7-methoxyquinazoline-4-one (400 gm), thionyl chloride (3.2 lt) and DMF (100 ml) were refluxed for 7-8 hours. Thionyl chloride was distilled off completely under reduced pressure below 45° C. Methylene chloride (2.5 lt) and water (1.5 lt) were charged, stirred for 30 minutes at room temperature and the layers separated. The aqueous layer was extracted twice with methylene chloride (500 ml), the combined methylene chloride layer was washed with 1% sodium bicarbonate solution (1 lt), dried over sodium sulphate (20 gm) and concentrated under reduced pressure at 35-40° C. The residue was stirred with isopropyl alcohol (400 ml) at 40-45° C. for 1 hour, cooled to 0-5° C., the solids filtered, washed with chilled isopropyl alcohol (200 ml) and dried under vacuum at 45° C. to yield the title compound (406 gm, 95% yield).

EXAMPLE 4 Preparation of 6-(3-chloropropoxy)-7-methoxyquinazoline-4-one (Formula V)2-amino-4-methoxy-5-(3-chloropropoxy)benzoic acid (450 gm), formamide (2250 ml) and ammonium formate (200 gm) were heated to 170-180° C. for 3-4 hours. The reaction mass was concentrated under reduced pressure at 140-150° C. The residue was stirred in methanol (1000 ml) at 45-50° C. and cooled to 5-10° C. The solid obtained was filtered to yield the title compound (420 gm, 90% yield).

EXAMPLE 5 Preparation of 2-amino-4-methoxy-5-(3-chloropropoxy)benzoic acid (Formula IV) a) Preparation of 3-(3-chloropropoxy)-4-methoxy-6-nitrobenzoic acidMethanol (4 lt), 3-(3-chloropropoxy)-4-methoxy-6-nitro benzaldehyde (560 gm) and 30% methanolic NaOH solution (5 ml) were heated to 45° C. To this reaction mass 35% of H₂O₂solution (1200 ml) was added drop wise in 3-4 hours maintaining a pH of 10.5-11.5 with 30% methanolic NaOH solution. The reaction mass was quenched into ice water (10 kg) and the pH adjusted to 2.0-3.0 using hydrochloric acid. The solid obtained was filtered, washed with 50% aqueous methanol (500 ml) and dried at 45-50° C. to yield the title compound (510 gm, 86% yield).

bi) Preparation of 2-amino-4-methoxy-5-(3-chloropropoxy)benzoic acid—Using Hydrogen GasEthyl acetate (3 lt), Pd/C (50 gm) and 3-(3-chloropropoxy)-4-methoxy-6-nitrobenzoic acid (500 gm) were hydrogenated under a hydrogen pressure of 5-6 kg at 35-40° C. for 3-4 hours. The reaction mass was filtered and the clear filtrate was distilled under reduced pressure at 45-50° C. To the residue, hexane (1 lt) was charged, stirred at room temperature, the solids filtered and dried at 45-50° C. to yield the title compound (403 gm, 90% yield).

(bii) Preparation of 2-amino-4methoxy-5-(3-chloropropoxy)benzoic acid—Using Hydrazine Hydrate3-(3-chloropropoxy)-4-methoxy-6-nitrobenzoic acid (100 gm), hydrazine hydrate (50 gms), neutral alumina (20 gms), charcoal (10 gms), water (50 ml) and methanol (500 ml) were mixed together. The reaction mass was heated to 50° C. A solution of ferric chloride (2 gms, 0.012M) in 50 ml methanol was introduced slowly at 55-60° C. The reaction mass was filtered over hyflo and the clear filtrate evaporated. The residue obtained was dissolved in 1.0-lit ethyl acetate, washed organic extract with water, evaporated to obtain title compound. (75 gms, 83.6%)

(biii) Preparation of 2-amino-4-methoxy-5-(3-chloropropoxy)benzoic acid—Using Ammonium Formate3-(3-chloropropoxy)-4-methoxy-6-nitro benzoic acid (165 gms), 5% Paladium on carbon (16.5 gms) and DMF (0.66 lit) were mixed together. The reaction mass was heated to 40° C. Ammonium formate (82.5 gms) was charged in lots maintaining temperature below 50° C. The temperature of reaction mass slowly raised to 70° C. and maintained for 2 hours. The reaction mass was cooled to 30° C. and catalyst was removed by filtration and the clear filtrate evaporated. The residue was dissolved in ethyl acetate (0.825 lit), washed with water and evaporated to yield the title compound. (125 gms, 84.5%)

EXAMPLE 6 Preparation of 3-(3-chloropropoxy)-4-methoxy-6-nitro benzaldehyde (Formula III)5-nitro isovanillin (500 gm), acetonitrile (3.5 lts), K₂CO₃(750 gm) and chlorobromopropane (780 gm) were refluxed for 4 hours. The reaction mass was filtered hot, washed with acetonitrile (1 lt) and the filtrate was distilled off to remove solvent. The residue was dissolved in methylene chloride (4 lt) and washed with water. Water (3 lt) was charged to the methylene chloride layer, the pH adjusted to 7.0 to 7.5 with acetic acid, the methylene chloride layer separated, dried over sodium sulphate (50 gm) and distilled out completely under reduced pressure below 40° C. The residue was stirred with 2 volumes of n-Hexane at 40-45° C., cooled slowly to 0-5° C., the solids filtered, washed with n-Hexane (250 ml) and dried at 40-45° C. to yield the title compound (638 gm, 92% yield).

EXAMPLE 7 Preparation of 5-nitro isovanillin (Formula II)Isovanillin (500 gm) and acetic acid (1750 ml) were cooled to −5 to 0° C. To this solution, nitric acid (750 ml) was charged slowly at −5 to 0° C. with stirring. The temperature of the reaction mass was slowly raised to 25-30° C. and maintained for 12 hours. The reaction mass was quenched into ice water (4 kg), the solids filtered and washed with water (2 lt). The solids were stirred with a 1% sodium bicarbonate solution (1 lt), filtered and dried at 45-50° C. The solid was dissolved in 6 volumes of ethyl acetate, ethyl acetate was distilled off up to half the volume and 3 volumes of n-Hexane were charged slowly at 45-50° C. The reaction mass was cooled slowly to 0-5° C., maintained for 1 hour, the solids filtered, washed with 0.5 volumes of 1:1 mixture of ethyl acetate:n-Hexane and dried at 45-50° C. to yield the title compound (423 gm, 65% yield).

EXAMPLE 8 Preparation of Methyl-2-hydroxy-3-methoxy benzoate (Formula VIII) a) Preparation of 3-hydroxy-4-methoxy benzoic acidMethanol (350 ml), isovanillin (50 gm) and 30% methanolic sodium hydroxide solution (1 ml), were heated to 45° C. To this solution, 35% hydrogen peroxide solution (107 ml) was charged slowly maintaining pH at 10.5 to 11.5 using methanolic sodium hydroxide solution over a period of 2-3 hours. The reaction mass was quenched into chilled water (1 lt) and the pH adjusted to 2-3 using hydrochloric acid. The solids were filtered, washed with 50% aqueous methanol (50 ml) and dried at 45-50° C. to yield 3-hydroxy-4-methoxy benzoic acid.

b) Preparation of Methyl-2-hydroxy-3-methoxy benzoateThe solid obtained in step a), was refluxed with 10% methanolic hydrochloric acid solution (250 ml) for 6 hours. The reaction mass was quenched into chilled water (1 lt) and repeatedly extracted with methylene chloride (250 ml). The combined methylene chloride layer was washed with water (100 ml×2) and methylene chloride distilled out completely at 35-40° C. The residue was stirred in hexane (1.50 ml), at 25-30° C. The solid obtained was filtered, washed with: hexane (25 ml) and dried at 40-45° C. to yield the title compound (50 gm, 83% yield).

EXAMPLE 9 Preparation of Methyl-5-hydroxy-4-methoxy-2-nitro benzoate (Formula IX)Methyl-2-hydroxy-3-methoxy benzoate (50 gm) and acetic acid (175 ml) were cooled to 0-5° C. To this solution, 70% nitric acid solution (75 ml) was charged slowly at 0-5° C. under stirring and the reaction mass was further stirred for 18 hours. The reaction mass was quenched into chilled water (800 ml) and extracted repeatedly with methylene chloride (400 ml). The combined methylene chloride layer was washed with water, followed by 1% potassium carbonate solution (100 ml), dried over sodium sulphate and methylene chloride distilled off completely at 35-40° C. The residue was dissolved in 10% aqueous methanol (250 ml). The filtrate was gradually cooled to 0-5° C. and maintained for 1 hour. The solid obtained was filtered, washed with 10% aqueous methanol (100 ml) and dried at 40-45° C. to yield the title compound (46 gm, 74% yield).

EXAMPLE 10 Preparation of Methyl-2-amino-5-hydroxy-4-methoxy benzoate (X)Ethyl acetate (300 ml), methyl-5-hydroxy-4-methoxy-2-nitro benzoate (50 gm) and 10% palladium/carbon (5 gm) were hydrogenated under a hydrogen gas pressure of 5-6 kg for 4 hours. The reaction mass was filtered to remove catalyst. The filtrate was distilled off to remove solvent. The residue obtained was stirred in n-hexane (100 ml) at 0-5° C. The solid obtained was filtered and washed with n-hexane (25 ml) to yield the title compound (40 gm, 93% yield).

EXAMPLE 11 Preparation of 6-hydroxy-7-methoxy-quinazoline-4-one (formula XI)Methyl-2-amino-5-hydroxy-4-methoxy benzoate (50 gm), methanol (400 ml) and formamidine acetate (30 gm) were refluxed for 10 hours. The reaction mass was gradually cooled to 5-10° C. and stirred for 1 hour. The solid obtained was filtered and washed with methanol (150 ml) and dried at 50-55° C. to yield the title compound (45 gm, 92% yield).

Cited Patent	Filing date	Publication date	Applicant	Title
US6297257	17 Dec 1998	2 Oct 2001	Zambon Group S.P.A.	Benzazine derivatives phosphodiesterase 4 inhibitors
EP1477481A1	28 Jan 2003	17 Nov 2004	Ube Industries, Ltd.	Process for producing quinazolin-4-one derivative
IN901CHE2006A				Title not available
IN903CHE2006A				Title not available
WO1996033980A1	23 Apr 1996	31 Oct 1996	Zeneca Limited	Quinazoline derivatives
WO2004024703A1	9 Sep 2003	25 Mar 2004	Astrazeneca Ab	Process for the preparation of 4- (3’-chloro-4’-fluoroanilino) -7-methoxy-6- (3-morpholinopropoxy) quinazoline
WO2005023783A1	1 Sep 2004	17 Mar 2005	Astrazeneca Ab	Process for the manufacture of gefitinib
WO2005070909A1	27 Jul 2004	4 Aug 2005	Natco Pharma Limited	An improved process for the preparation of gefitinib
WO2008125867A2	16 Apr 2008	23 Oct 2008	Cipla Limited	Process for the preparation of gefitinib

/////////Gefitinib, US 8350029, CIPLA

PATENT, US 8344136, PHF S.A., Brinzolamide

PATENTS Comments Off

Sep 022016

Image result for Brinzolamide

US 8344136

http://www.google.co.in/patents/US8344136

PHF S.A., Lugano, Switzerland

Inventors	Alessandro Falchi, Ottorino De Lucchi, Andrea Castellin
Original Assignee	Phf S.A.

Process for the Preparation of Brinzolamide

Brinzolamide is a carbonic anhydrase II inhibitor, used to lower intraocular pressure and glaucoma. It is sold by Alcon under the name of Azopt, as 1% ophthalmic suspension.

EP 527801 claims Brinzolamide and describes a process to prepare it in 14 steps starting from 3-acetylthiophene (scheme 1). It is a synthesis typical of medicinal chemistry not applicable at industrial level, for which no specific preparations are described, because Brinzolamide is not among the preferred compounds of the invention.

This synthesis is not very efficient because requires the change of the oxidation status of the functional group in position 4 for three times; indeed this is first reduced with Sodium borohydride (step (5)) to α-bromoalcohol and then oxidized with Sodium dichromate (step (11)), a very toxic reagent. This sequence is necessary to obtain the cyclization (6), which brings only to degradation products on the ketone, and which requires a complex and not much efficient procedure as far as the quality and yield of the isolated product is concerned. The second reduction (12) occurs in the presence of (+)-β-chlorodiisopinocamphenylborane, an expensive enantioselective reducing agent, with a stoichiometric excess of 5:1, which requires reaction conditions not easily achievable at industrial scale (3 days of reaction at −22° C., difficult work up and chromatography) to isolate the product.

It can be inferred from the patent that there is the possibility to fix the stereogenic centre through selective crystallization of the salt of a chiral acid as di-p-toluoyl-D-tartaric acid, expensive resolution agent, with consequent loss of at least half of the substrate.

EP 617038 describes a process for the preparation of Brinzolamide and its analogues starting from 3-acetyl-2,5-dichlorothiophene (scheme 2).

The reduction (6) with (+)-β-chlorodiisopinocamphenylborane and the cyclization (7) bring to the optically active alcohol 2H-thieno[3,2-e]-1,2-thiazin-4-ol, 6-chloro-3,4-dihydro-, 1,1-dioxide, (4S)-. The formation of a product enriched with one of the enantiomer is too early in the synthesis, with a consequent risk of racemisation during the following steps, while the reduction would be more efficient if performed on a more advanced intermediate. The disadvantages of the use of the enantioselective reducing agent (6) and of the cyclization of the alcohol (7) are the same of the method described in Scheme 1. Another disadvantage is the alkylation (8) with 1-bromo-3-methoxypropane, that, in order to avoid the reaction of the oxydrilic group, is performed portionwise, with low temperatures and long reaction times.

The sulfonamide is introduced in position 6 through metallation with n-butyl lithium, an expensive raw material, and then with a reaction with sulphurous anhydride and hydroxylamino-O-sulphonic acid. The base should be used in substantial excess (2,3 eq.), because the oxydrilic group reacts with the first equivalent. In this case the protection of the oxydrilic group as described in Scheme 1 is not possible without running the risk of racemization of the substrate.

Lastly, the conversion of the secondary alcohol to the amine is difficult and requires the protection (10) of the primary sulfonamide with trimethyl orthoacetate, the activation (11) of the oxydrilic group with tosyl chloride and finally the substitution (12) of the tosyl group with ethylamine and at the same time the aminolysis of the protection of sulfonamide with the excess of ethylamine.

This synthesis is described in Org. Process Res. Dev. 3, 1999, 114, written by the R&D laboratories of Alcon. So it is reasonable to believe that this synthesis is used by Alcon at industrial level. Anyway, due to the low purity of the product obtained (97%), several crystallizations are needed to have a product of acceptable pharmaceutical grade.

U.S. Pat. No. 5,470,973 describes a variant of the synthesis in scheme 1, which involves an alternative preparation of the syntone 2H-thieno[3,2-e]-1,2-thiazin-4-ol, 6-chloro-3,4-dihydro-2-(3-methoxypropyl)-, 1,1-dioxide, (4S)- and the other analogues lacking chlorine in position 6 or the 3-methoxypropylic chain (scheme 3).

To introduce the chiral centre, firstly the oxidation (8) with dichromate is performed, and then the stereoselective reduction (9) with (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrol[1,2-c][1,3,2]oxazaborole are performed. The need of oxidizing first and then reducing was already commented in the description of the first synthetic path; the low enantiomeric excess (92%) is another disadvantage.

So it is evident the need of an alternative process for the preparation of Brinzolamide which can resolve the above mentioned technical problems.

OVERVIEW

Brinzolamide, 56, is used to treat glaucoma and can be synthesised by a 14-step route from acetylthiophene. This route is described as inefficient because of several changes of the oxidation state of one of the functional groups. Other routes have fewer steps but are still not very efficient. This patent describes a method for making compounds that are intermediates in the synthesis of56. The route is outlined in Schemes 20 and 21 and starts from the thiophene 49a or its chloro-derivative 49b (X = Cl). The first step is protection of the carbonyl group in 49a by reaction with 50to form 51a that is isolated in 87% yield. In the next step 51a is treated with K₂CO₃ to effect intermolecular cyclisation and formation of 52a. This can be obtained in 90% yield, or the reaction mixture can be treated with 53 without isolation of 52a to form 54a that is isolated 90% yield.

Scheme 20. ^a

^aReagents and conditions: (a) (i) TsOH, PhMe, reflux, 12 h; (ii) cool to rt, add Et₃N, separate; (iii) H₂O wash, evaporate. (b) (i) K₂CO₃, DMSO, 60 °C, 1 h; (ii) add H₂O/EtOAc, acidify to pH 7; (iii) separate, H₂O wash, evaporate. (c) (i) 60 °C, 8 h; (i) add H₂O/PhMe, separate; (iii)H₂O wash, evaporate.

The next stage is the introduction of the second sulphonamide group as shown in Scheme 21. This begins with treatment of 54a with BuⁿLi followed by addition of liquid SO₂. The intermediate reaction product is isolated as a solid and then treated with H₂NOSO₃H to form 54c that is recovered in 76% yield. The protective diol group is then removed by acid hydrolysis to give 55a in 97% yield. The conversion of 55a to 56 is not described in the patent, and reference to alternative syntheses of 56 indicate that this proceeds via asymmetric reduction of 56 to a hydroxy group that is then converted to the amine.

Scheme 21. ^a

^aReagents and conditions: (a) BuⁿLi, THF, −40 °C, 1 h; (ii) SO₂, −40 °C; (iii) warm to rt, evaporate; (iv) add H₂O, wash in DCM; (v) H₂NOSO₃H, NaOAc, H₂O, rt, 8 h; (vi) extract in EtOAc, wash in aq NaHCO₃, H₂O wash; (vii) evaporate. (b) (i) Aq HCl, PhMe, 80 °C, 16 h; (ii) separate, evaporate. (c) No details.

Compound 55a can be prepared by the same sequence of reactions shown in Schemes 20 and21 when starting from 49b. The yields of the corresponding intermediates are similar to or better than those reported for the method starting from 49a. The patent does not indicate the scale of the reactions, and the examples merely state the amounts of reactants used in terms of equivalents. The purity of the intermediates is not given, although ¹H NMR data are provided. The patent does not disclose how to obtain either of the starting materials, 49a or 49b, that are unlikely to be commercially available, and their synthesis will presumably add more steps to the synthesis of 56.

Advantages

The process provides an alternative route to the desired compound, but whether it is commercially viable and more efficient is not known.

Example 7 2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin]-6′-sulphonamide, 1′,1′-dioxide 9 (X=sulphonamide)

The desired compound is prepared according to general procedure 4 starting from 2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 5 with a yield of 76%.

¹H-NMR (300 MHz, DMSO-d₆): 8.05 (s, 2H), 7.59 (s, 1H), 4.16 (m, 2H), 4.07 (m, 2H), 3.87 (s, 2H), 3.4-3.3 (m, 4H), 3.21 (s, 3H), 1.81 (m, 2H).

LC-MS: [M+H]⁺=399.

Example 8 2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin]-6′-sulphonamide, 1′,1′-dioxide 9 (X=sulphonamide)

The desired compound is prepared according to general procedure 4 starting from 6′-chloro-2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 6 with a yield of 89%.

General Procedure 5 Hydrolisis of the Protective GroupThe compound of formula 5 is dissolved in toluene (10-20 volumes) and an aqueous solution of hydrochloric acid 2-12 N is added. The mixture is stirred at a temperature which can vary between 20° C. and 80° C. for a time between 2 and 16 ore, until complete hydrolysis. The phases are separated and the product 1 is isolated through distillation of the organic solvent under vacuum, obtaining a solid with a HPLC assay of 85-95% and a yield of 65-99%.

Example 9 4H-thieno[3,2-e]-1,2-thiazin-4-one, 2,3-dihydro-, 1,1-dioxide 1 (X and R=hydrogen)

The desired compound is prepared according to the general procedure 5 starting from 2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 3 with a yield of 66%.

¹H-NMR (300 MHz, DMSO-d₆): 8.90 (bt, 1H), 7.98 (d, 1H), 7.46 (d, 1H), 4.23 (d, 2H).

LC-MS: [M+H]⁺=204.

Example 10 4H-thieno[3,2-e]-1,2-thiazin-4-one, 6-chloro 2,3-dihydro-, 1,1-dioxide 1 (X=chlorine and R=hydrogen)

The desired compound is prepared according to general procedure 5 starting from 6′-chloro-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 4 with a yield of 95%.

¹H-NMR (300 MHz, DMSO-d₆): 9.08 (bs, 1H), 7.56 (s, 1H), 4.26 (d, 2H).

GC-MS: [M]^+•=237.

Example 11 4H-thieno[3,2-e]-1,2-thiazin-4-one, 2,3-dihydro-2-(3-methoxypropyl)-, 1,1-dioxide 5 (X=hydrogen)

The desired compound is prepared according to the general procedure 5 starting from 2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 5 with a yield of 97%.

¹H-NMR (300 MHz, DMSO-d₆): 8.05 (d, 1H), 7.49 (m, 1H), 4.58 (s, 2H), 3.3-3.1 (m, 7H), 1.73 (m, 2H).

LC-MS: [M+H]⁺=276.

Example 12 4H-thieno[3,2-e]-1,2-thiazin-4-one, 6-chloro 2,3-dihydro-2-(3-methoxypropyl)-, 1,1-dioxide 5 (X=chlorine)

The desired compound is prepared according to the general procedure 5 starting from 6′-chloro-2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin], 1′,1′-dioxide of example 6 with a yield of 99%.

¹H-NMR (300 MHz, DMSO-d₆): 7.59 (s, 1H), 4.50 (s, 2H), 3.3-3.2 (m, 4H), 3.18 (s, 3H), 1.74 (m, 2H).

LC-MS: [M+H]⁺=310.

Example 13 2H-thieno[3,2-e]-1,2-thiazin-6-sulphonamide, 3,4-dihydro-2-(3-methoxypropyl)-4-oxo-, 1,1-dioxide 5 (X=Sulphonamide)

The desired compound is prepared according to the general procedure 5 starting from 2′-(3-methoxypropyl)-2′,3′-dihydrospiro[1,3-dioxolan-2,4′-thieno[3,2-e][1,2]thiazin]-6′-sulphonamide, 1′,1′-dioxide of examples 7 or 8 with a quantitative yield.

¹H-NMR (300 MHz, DMSO-d₆): 8.20 (s, 2H), 7.77 (s, 1H), 4.54 (s, 2H), 3.4-3.1 (m, 7H), 1.78 (m, 2H).

LC-MS: [M+H]⁺=355.

///////////PATENT, US 8344136, PHF S.A., Brinzolamide

ECA Task Force will publish Draft Data Integrity Guideline at Conference in October

Uncategorized Comments Off

Sep 022016

Image result for Data Integrity

Data Integrity has become one of the most frequently observed GMP deviations at FDA and EU Inspections. For that reason the ECA Foundation decided to set up a Task Force on Data Integrity in December 2015 – with the goal to provide Guidance for the implementation in practice. Read more about the ECA Guidance on Data Integrity.

http://www.gmp-compliance.org/eca_mitt_05545_15488_n.html

Data Integrity has become one of the most frequently observed GMP deviations at FDA and EU Inspections. This is why the topic is currently in the centre of attention of both regulators and industry. And for that reason the ECA Foundation decided to set up a Task Force on Data Integrity in December 2015 – with the goal to provide Guidance for the implementation in practice.

The ECA Task Force will be comprised of members from both the IT Compliance Group and the Analytical QC Group. Current Members are:

– Dr. Wolfgang Schumacher, Hoffmann-La Roche, Switzerland
– Dr. Chris Burgess, Qualified Person and Consultant, UK
– Dr. Bob McDowall, Consultant, UK
– Ms. Margarita Sabater, ALK-Abelló A/S, Denmark

The Task Force decided to develop a Guidance entitled: “Data Governance and Data Integrity for GMP Regulated Facilities“. The ECA Guidance Document will cover – among others – the Roles and Responsibilities of Corporate and Senior Management in Data Governance as well as the necessary Policies, Procedures and Processes. Further information is provided on establishing criteria for Data Integrity and security of records based on ALCOA+Principles and on Auditing for Data Integrity and security of records.

The Guide will contain a Glossary as well as some illustrative appendices for further information.

Margarita Sabater, Member of the ECA Task Force, will present the Draft Version of the ECA Data Integrity Guidance Document during the Lab Data Integrity Conference on 20-21 October 2016 in Vienna, Austria. Every participant will receive a copy of the Draft Document – and is also invited to provide feedback to the Guidance Document.

//////ECA Task Force, Draft Data Integrity Guideline, Conference

New aspects of developing a dry powder inhalation formulation applying the quality-by-design approach

Formulation, regulatory Comments Off

Sep 022016

Image for unlabelled figure

The current work outlines the application of an up-to-date and regulatory-based pharmaceutical quality management method, applied as a new development concept in the process of formulating dry powder inhalation systems (DPIs). According to the Quality by Design (QbD) methodology and Risk Assessment (RA) thinking, a mannitol based co-spray dried formula was produced as a model dosage form with meloxicam as the model active agent.

The concept and the elements of the QbD approach (regarding its systemic, scientific, risk-based, holistic, and proactive nature with defined steps for pharmaceutical development), as well as the experimental drug formulation (including the technological parameters assessed and the methods and processes applied) are described in the current paper.

Findings of the QbD based theoretical prediction and the results of the experimental development are compared and presented. Characteristics of the developed end-product were in correlation with the predictions, and all data were confirmed by the relevant results of the in vitro investigations. These results support the importance of using the QbD approach in new drug formulation, and prove its good usability in the early development process of DPIs. This innovative formulation technology and product appear to have a great potential in pulmonary drug delivery.

Fig. 1.

Steps and elements of the QbD methodology completed by the authors and applied in the early stage of pharmaceutical development.

“By identifying the critical process parameters, the practical development was more effective, with reduced development time and efforts.”

Edina Pallagi, our QbD evangelist from Hungary shares her team’s experience applying QbD to Dry Powder Inhalation Formulation.

The paper covers:

QbD methodology the researchers applied
Formulation of dry powder inhalation – API and excipients
QTPP, CQA and CPPs identified for pulmonary use along with target, justification and explanation
Characterization test methods
Knowledge Space development
QbD software used

New aspects of developing a dry powder inhalation formulation applying the quality-by-design approach

^a Institute of Drug Regulatory Affairs, University of Szeged, Faculty of Pharmacy, Szeged, Hungary
^b Department of Pharmaceutical Technology, University of Szeged, Faculty of Pharmacy, Szeged, Hungary

http://www.sciencedirect.com/science/article/pii/S0378517316306330

International Journal of Pharmaceutics

Volume 511, Issue 1, 10 September 2016, Pages 151–160

http://dx.doi.org/10.1016/j.ijpharm.2016.07.003

///////

Continuous Flow Doebner–Miller Reaction and Isolation Using Continuous Stirred Tank Reactors

PROCESS, Uncategorized Comments Off

Aug 312016

Abstract Image

Continuous flow Doebner–Miller synthesis of different quinaldines from respective anilines is demonstrated using sulfuric acid as a homogeneous catalyst. The extent of reaction was monitored for various parameters, namely, temperature, residence time, mole ratio of sulfuric acid to substrate, mole ratio of crotonaldehyde to substrate, and so forth. Continuous stirred reactors in series were used as a preferred configuration for this rection that generates byproduct in the form of sticky solid material. The approach has been extended for six different anilines, and the results are compared with batch reactions. Continuous stirred reactors in series with distributed dosing of crotonaldehyde facilitated a continuous flow reaction with lower byproduct formation, increased yields, and continuous workup and is a scalable approach.

Continuous Flow Doebner–Miller Reaction and Isolation Using Continuous Stirred Tank Reactors

Maruti B. Yadav^†, Sourabh Kulkarni^†, Ramesh A. Joshi^‡, and Amol A. Kulkarni^*^†

^† Chem. Eng. & Process Dev. Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pashan, Pune 411 008, India

^‡ Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pashan, Pune 411 008, India

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00179

Publication Date (Web): August 22, 2016

*E-mail: [email protected]. Fax: +91-20-25902621.

http://pubs.acs.org/doi/suppl/10.1021/acs.oprd.6b00179

Mr. Maruti Yadav

Project Assistant

M.Sc. Organic Chemistry, Pune University, 2013

Email: [email protected]

Process Development of API production in continuous flow

Dr. Amol A. Kulkarni

Dr. Amol A. Kulkarni is a Scientist in the Chemical Engineering Division at the National Chemical Laboratory. He did his B. Chem. Eng. (1998), M. Chem. Eng (2000) and Ph.D. in chemical engineering (2003) all from the University Dept. of Chem. Technology (UDCT, Mumbai). In 2004 he worked at the Max Planck Institute-Magdeburg (Germany) as a Alexander von Humboldt Research Fellow. At NCL he is driving a research program on the design of microreactors and exploring their applications for continuous syntheses including of nanoparticles. He has been awarded with the Max-Planck-Visiting Fellowship from the Max-Planck-Society, Munich for 2008-2011. His research areas include: (i) design and applications of microreactors, (ii) design of multiphase reactors, (iii) experimental and computational fluid dynamics, and (iv) nonlinear dynamics of coupled systems. He is an active member of Initiative for Research and Innovation in Science (IRIS) supported by Intel’s Education Initiative to organize National Science Fair and popularize science in India.

Research areas

Multiphase reactors and Microreactors
Process Development and Scale-up
Process Intensification & MAGIC Processes
Industrial Flow Processes

Contact

Dr. Amol A. Kulkarni
Scientist
Office: 529, PP-1 Building, CEPD
National Chemical Laboratory
Dr. Homi Bhabha Road
Pune 411008, India
Phone +91 20 2590 2153
Fax +91 20 2590 2621
E-mail [email protected]

///////////Continuous Flow, Doebner–Miller Reaction, Isolation, Continuous Stirred Tank Reactors, chemical engeineering, process, Amol A. Kulkarni, ncl, pune

Multicomponent-Multicatalyst Reactions (MC)2R: Efficient Dibenzazepine Synthesis

spectroscopy, SYNTHESIS Comments Off

Aug 302016

Multicomponent-Multicatalyst Reactions (MC)2R: Efficient Dibenzazepine Synthesis
Jennifer Tsoung, Jane Panteleev, Matthias Tesch, and Mark Lautens

Org. Lett. 2014, 16, 110-113. DOI:10.1021/ol4030925 .

http://pubs.acs.org/doi/abs/10.1021/ol4030925

A Rh^I/Pd⁰ catalyst system was applied to the multicomponent synthesis of aza-dibenzazepines from vinylpyridines, arylboronic acids, and amines in a domino process with no intermediate isolation or purification.

5-(p-tolyl)-3-(trifluoromethyl)-10,11-dihydro-5H-benzo[b]pyrido[2,3-f]azepine (4a)

1H NMR
(400 MHz, CDCl3) δ 8.66 (d, J = 1.1 Hz, 1H), 7.97 (d, J = 1.8 Hz, 1H), 7.43 – 7.38 (m, 1H), 7.38 – 7.29
(m, 3H), 6.98 (d, J = 8.4 Hz, 2H), 6.57 – 6.51 (m, 2H), 3.33 – 3.21 (m, 2H), 3.09 – 2.99 (m, 2H), 2.26 (s,
3H);

13C NMR (101 MHz, CDCl3) δ 161.7 (q, J = 1.3 Hz), 145.8, 143.6, 143.4 (q, J = 4.0 Hz), 139.7,
139.5, 134.9 (q, J = 3.5 Hz), 130.3, 130.0, 129.9, 128.9, 128.2, 127.7, 125.3 (q, J = 33.1 Hz), 123.4 (q, J =
272.5 Hz), 114.0 (2), 35.9, 29.0, 20.4;

19F NMR (377 MHz, CDCl3) δ -62.0;

IR (NaCl, neat): 3063, 3028,
2926, 2862, 1616, 1506, 1489, 1456, 1435, 1429, 1410, 1339, 1319, 1296, 1267, 1240, 1207, 1165, 1128,
1086, 1036, 978, 947, 930, 910, 895, 808, 772, 756, 737, 721, 704, 687, 664, 646, 627 cm-1;

HRMS (ESI):
calcd for C21H18F3N2 (M+H)+: 355.1422; found. 355.1419.

Jennifer Tsoung

PhD graduate, organic chemistry

Department of Chemistry, University of Toronto

Experience

PhD

University of Toronto

September 2010 – October 2015 (5 years 2 months)

Research Intern

Kyoto University

June 2014 – August 2014 (3 months)Kyoto, Japan

Methodology project in asymmetric phase-transfer catalyzed alkylations.

Co-op student

Angiotech

May 2009 – August 2009 (4 months)Vancouver, Canada Area

Formulation chemistry

Co-op student

Boehringer Ingelheim

January 2008 – August 2008 (8 months)Montreal, Canada Area

On two hit-to-lead teams working to synthesize analogues of hit compounds for HIV research.

Publications

Diastereoselective Friedel−Crafts Alkylation of Hydronaphthalenes(Link)

The Journal of Organic Chemistry

September 27, 2011

An efficient and versatile synthesis of chiral tetralins has been developed using both inter- and intramolecular Friedel-Crafts alkylation as a key step. The readily available hydronaphthalene substrates were prepared via a highly enantioselective metal-catalyzed ring opening of meso-oxabicyclic alkenes followed by hydrogenation. A wide variety of complex tetracyclic compounds have been isolated…more

One-Pot Synthesis of Chiral Dihydrobenzofuran Framework via Rh/Pd Catlaysis

Organic Letters

October 12, 2012

A one-pot synthesis of the chiral dihydrobenzofuran framework is described. The method utilizes Rh-catalyzed asymmetric ring opening (ARO) and Pd-catalyzed C-O coupling to furnish the product in excellent enantioselectivity without isolation of intermediates. Systematic metal-ligand studies were carried out to investigate the compatibility of each catalytic system using product enantiopurity as an…more

Rh/Pd Catalysis with Chiral and Achiral Ligands: Domino Synthesis of Aza-Dihydrodibenzoxepines(Link)

Angew. Chem. Int. Ed

July 19, 2013

A game of dominoes: A synthetic route to aza-dihydrodibenzoxepines is described, through the combination of a Rh-catalyzed arylation and a Pd-catalyzed C-O coupling in a single pot. For the first time, the ability to incorporate a chiral and an achiral ligand in a two-component, two-metal transformation is achieved, giving the products in moderate to good yields, with excellent enantioselectivities.

Multicomponent-multicatalyst reactions (MC)(2)R: efficient dibenzazepine synthesis.

Organic Letters

January 13, 2014

A Rh(I)/Pd(0) catalyst system was applied to the multicomponent synthesis of aza-dibenzazepines from vinylpyridines, arylboronic acids, and amines in a domino process with no intermediate isolation or purification.

Formation of substituted oxa- and azarhodacyclobutanes.

Chemistry – A European Journal

December 6, 2013

The preparation of substituted oxa- and azarhodacyclobutanes is reported. After exchange of ethylene with a variety of unsymmetrically and symmetrically substituted alkenes, the corresponding rhodium-olefin complexes were oxidized with H2O2 and PhINTs (Ts=p-toluenesulfonyl) to yield the substituted oxa- and azarhodacyclobutanes, respectively. Oxarhodacyclobutanes could be prepared with excellent…more

Education

University of Toronto

Doctor of Philosophy (PhD), Organic Chemistry

2010 – 2014

Activities and Societies: Pueblo Science executive member, Let’s Talk Science volunteer, International Chemistry Olympiad tutor

The University of British Columbia

Bachelor of Science (BSc), Chemistry

2005 – 2010

Activities and Societies: Undergraduate Chemistry Society (UCS) executive member, Science Undergraduate Society (SUS) executive member, Science Co-op Students Association (SCOOPS) president and founding member

port moody secondary

High school

Image result for Jennifer Tsoung

Mark Nitz presents Jennifer Tsoung certificate for her CTFP award

Image result for Jennifer Tsoung

Women in Chemistry group, 2015

Lautens Research Group :: Group Pictures

www.chem.utoronto.ca

July 2013

Mark Lautens , O.C.

University Professor
J. Bryan Jones Distinguished Professor
AstraZeneca Professor of Organic Chemistry
NSERC/Merck-Frosst Industrial Research Chair

Department of Chemistry
Davenport Chemical Laboratories
80 St. George St.
University of Toronto
Toronto, Ontario
M5S 3H6

Tel: (416) 978-6083
Fax: (416) 946-8185
E-Mail: [email protected]

Curriculum Vitae

Personal
Place and Date of Birth	Hamilton, Ontario, Canada	July 9, 1959
Education
Harvard University	NSERC PDF with D. A. Evans	1985 – 1987
University of Wisconsin-Madison	Ph.D. with B. M. Trost	1985
University of Guelph	B.Sc. – Distinction	1981
Academic Positions
J. Bryan Jones Distinguished Professor	University of Toronto	2013 – 2018
University Professor	University of Toronto	2012 – present
NSERC/Merck Frosst Industrial Research Chair	NSERC/Merck Frosst	2003 – 2013
AstraZeneca Professor of Organic Synthesis	University of Toronto	1998 – present
Professor	University of Toronto	1995 – 1998
Associate Professor	University of Toronto	1992 – 1995
Assistant Professor	University of Toronto	1987 – 1992
Awards & Honors
University of Toronto Alumni Faculty Award	University of Toronto	2016
CIC Catalysis Award	CSC	2016
Officer of the Order of Canada	Governor General	2014
Killam Research Fellowship	Canada Council for the Arts	2013-2015
CIC Medal	Chemical Institute of Canada	2013
Fellow of the Royal Society of UK	Royal Society of Chemistry	2011
Pedler Award	Royal Society of Chemistry	2011
Senior Scientist Award	Alexander von Humboldt Foundation Berlin, Aachen and Gottingen	2009-2014
Visiting Professor	University of Berlin	2009
Visiting Professor	Université de Marseilles	2008
ICIQ Summer School	ICIQ Tarragona, Spain	2008
Attilio Corbella Summer School Professor	Italian Chemical Society	2007
Arthur C. Cope Scholar Award	American Chemical Society	2006
Alfred Bader Award	Canadian Society for Chemistry	2006
R. U. Lemieux Award	Canadian Society for Chemistry	2004
Solvias Prize	Solvias AG	2002
Fellow of the Royal Society of Canada	Royal Society of Canada	2001
Areas of Research Interest and Expertise
new synthetic methods metal catalyzed cycloaddition and annulation reactions asymmetric catalysis with focus on rhodium, nickel and palladium catalysts cyclopropane synthesis and reactions hydrometallation reactions reactions of organosilicon and organotin compounds fragmentation reactions new routes to medicinally/biologically interesting compounds heterocycle synthesis using metal catalysts

///////Multicomponent, Multicatalyst Reactions, (MC)2R, Dibenzazepine Synthesis, Mark Lautens, University of Toronto ,
Toronto, Ontario, Jennifer Tsoung

Continuous Processing and Efficient in Situ Reaction Monitoring of a Hypervalent Iodine(III) Mediated Cyclopropanation Using Benchtop NMR Spectroscopy

spectroscopy, SYNTHESIS Comments Off

Aug 292016

Real-time NMR spectroscopy has proven to be a rapid and an effective monitoring tool to study the hypervalent iodine(III) mediated cyclopropanation. With the ever increasing number of new synthetic methods for carbon–carbon bond formation, the NMR in situ monitoring of reactions is becoming a highly desirable enabling method. In this study, we have demonstrated the versatility of benchtop NMR using inline and online real-time monitoring methods to access mutually complementary information for process understanding, and we developed new approaches for real-time monitoring addressing challenges associated with better integration into continuous processes.

Continuous Processing and Efficient in Situ Reaction Monitoring of a Hypervalent Iodine(III) Mediated Cyclopropanation Using Benchtop NMR Spectroscopy

Batool Ahmed-Omer^*^†, Eric Sliwinski^†, John P. Cerroti^‡, and Steven V. Ley^†

^† Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.

^‡Magritek GmbH, Gebäude VO (Building VO), Triwo Technopark Aachen, Philipsstrasse 8, 52068 Aachen, Germany

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00177

*Email: [email protected].

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00177

Steven V. Ley

Steven V. Ley received his PhD from Loughborough University in 1972, after which he carried out post-doctoral research with Professor Leo Paquette at Ohio State University, followed by Professor Derek Barton at Imperial College London. In 1975, he joined that Department as a lecturer and became Head of Department in 1989. In 1992, he moved to the 1702 BP Chair of Organic Chemistry at the University of Cambridge and became a Fellow of Trinity College. He was elected to the Royal Society in 1990 and was President of the Royal Society of Chemistry (RSC) 2000-02. Steve has been the recipient of many prizes and awards including the Yamada-Koga Prize, Nagoya Gold Medal, ACS Award for Creative Work in Synthetic Organic Chemistry and the Paul Karrer Medal.

Ethyl 2-(4-tert-butylphenyl)-1-nitrocyclopropanecarboxylate (5):

[E]-isomer: 1H NMR (600 MHz, CDCl3): δ 0.80-0.85 (t, J = 7.1 Hz, 3H), 1.29 (s, 9H), 2.16-2.21 (dd, J = 10.7, 6.6 Hz, 1H), 2.41-2.46 (dd, J = 9.1, 6.6 Hz, 1H), 3.72-3.77 (m, 1H), 3.88-4.04 (m, 2H), 7.12-7.15 (d, J = 8.3 Hz, 2H), 7.30-7.37 (d, J = 8.4 Hz, 2H).

13C NMR (150 MHz, CDCl3) δ 161.96, 151.38, 128.96, 128.15, 125.37, 71.71, 62.37, 34.54, 33.91, 31.21, 20.73, 13.35.

HRMS (ESI) Calcd. for C16H21NO4 ([M+H]+): 292.15, Found 292.15:

[Z]-isomer: 1H NMR (600 MHz, CDCl3): δ 1.30 (s, 9H), 1.34-1.37 (t, J = 7.1 Hz, 3H), 2.00-2.04 (dd, J = 9.9, 6.9 Hz, 1H), 2.64-2.68 (dd, J = 9.2, 6.9 Hz, 1H), 3.43-3.48 (t, J = 9.6 Hz, 1H), 4.31-4.41 (m, 2H), 7.14-7.17 (d, J = 8.3 Hz, 2H), 7.32-7.36 (d, J = 8.4 Hz, 2H).

13C NMR (150 MHz, CDCl3) δ 165.40, 151.56, 128.33, 127.99, 125.63, 72.63, 63.14, 34.55, 33.48, 31.22, 20.08, 13.98.

Zhu, S.; Perman, J. A.; Zhang, X. P. Angew. Chem. Int. Ed. 2008, 47, 8460-8463.

Professor Steven V. Ley CBE FRS

ORGANIC CHEMISTRY RESEARCH GROUP

Steve Ley

/////////

Training Course – IN SILICO DRUG DISCOVERY & DESIGNING: INSIGHTS OF PROTEIN-LIGAND INTERACTIONS. Oct 01, 2016 at Le MÃ©ridien Bangalore Hotel in Bengaluru, India.

CONFERENCE Comments Off

Aug 222016

Training Course – IN SILICO DRUG DISCOVERY & DESIGNING: INSIGHTS OF PROTEIN-LIGAND INTERACTIONS. Oct 01, 2016 at Le MÃ©ridien Bangalore Hotel in Bengaluru, India.

https://selectbiosciences.com/trainingCoursesID.aspx?tc=DDD16&pid=4820&conf=DDI16&se=india

http://selectbiosciences.com/conferences/index.aspx?conf=DDI16&se=india

http://selectbiosciences.com/conferences/venue.aspx?pid=4817&conf=DDI16&se=india

Dear Colleague,

SELECTBIO would like to remind you about its Training Course – IN SILICO DRUG DISCOVERY & DESIGNING: INSIGHTS OF PROTEIN-LIGAND INTERACTIONS. This is scheduled to be held on October 01, 2016 from 9:00am to 5:00pm at Le MÃ©ridien Bangalore Hotel in Bengaluru, India. This course will be held in conjunction with our 4^th International Conference “Drug Discovery India 2016“. Attend the Training Course and the Conference andSave 10% against the regular registration charges.

PROFILE OF ATTENDEES
With basic knowledge in Life Science and Drug Design that would like to receive a comprehensive overview or refresher on the Drug Discovery Technology the target audience comprises:
• Student & Faculty: Bachelor, Masters, PhD, students as well as Faculty and Professors from Microbiology, Biochemistry, Biotechnology, Immunology, Pharmacy, Pharmaceutical Chemistry, Biomedical Technology, Genetics, Bioinformatics, Plant Science and Life Sciences.
• Professionals: Biotechnology, Bioinformatics and Pharmaceutical scientists from industry, academia and regulatory agencies.
Hands-on exercises will be performed individually using Software tools (no prior experience required).

COURSE CONTENTS
• Introduction of Drug Designing
• Science involved in Disease Target Identification
• Virtual Screening
Practical application will be done on 5 molecules and the software on which DEMONSTRATION & TRAINING will be given
• In-Silico Generation of Ligands by ChemSketch
• Conversion of mol files to pdf files by Open Babel
• Protein Optimization & Energy Minimization by SPDBV
• Molecular Docking by MGL Tools | Creation of Grid Parameter & Dock Parameter Files by AutoDock Software
• Running the Algorithm by Cygwin
• Selection of Potent Inhibitors on the basis of Binding Energies and Lipinski’s Rule of 5
• Structure Analysis – Protein & Ligand complex H-bond interaction by UCSF Chimera
• Prediction of Molecular Properties- Molinspiration
• Prediction of Bioactivity- Molinspiration & ACD iLabs
• Drug Likeness – Mol Soft
• Bioavailability & ADME- ACD iLabs
• Toxicity- OSIRIS Property Explorer & ACD iLabs

For more information, or to discuss registration options, please contact me on the details given below.

Thanks and Best Regards

Sakshi Modgil
Customer Services Manager
SELECTBIO INDIA
O: +91 172 5025050
M: +91 7696125050
[email protected]

///////////////Training Course, IN SILICO DRUG DISCOVERY & DESIGNING, INSIGHTS OF PROTEIN-LIGAND INTERACTIONS, Oct 01, 2016 at Le MÃ©ridien Bangalore Hotel, Bengaluru, India, selectbio