Duloxetine Hydrochloride, MSN, PATENT, US. 8362279

US. 8362279

http://www.google.co.in/patents/US8362279

Inventors	Manne Satyanarayana Reddy, Muppa Kishore Kumar, Srinivasan Thirumalai Rajan,Durgadas Shyla Prasad,
Original Assignee	Msn Laboratories Limited

Synthesis of duloxetine is described in detail in EP-A-273 658, EP-A-457 559 and EP-A-650965, starting from 2-acetylthiophene, an aminomethylation with dimethylamine and formaldehyde (Mannich reaction) is carried out in step-A. The 3-dimethylamino-1-(2-thienyl)-1-propanone formed is reduced to the corresponding alcohol 1-hydroxy-1-(2-thenyl)-3-dimethylaminopropane by means of complex hydrides in step B. The alcohol is then converted in step C with an alkali metal hydride and 1-fluoro-naphthalene, optionally in the presence of a potassium compound (cf. EP-A-650 965), to the naphthyl derivative, N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine. In the final step D, the amino group is then demethylated by reaction with a chloroformic acid ester, preferably phenyl chloroformate or trichloroethyl chloroformate, optionally in the presence of a mixture of zinc and formic acid (EP-A-457 559), followed by alkaline hydrolysis of the carbamate to give N-methyl-3-(1-naphthyloxy)-3-(2-thienyl) propylamine.

The EP patent 457559 described the process for the preparation of duloxetine comprises of using alkali metal hydride like sodium hydride, which is commercially not recommendable.

The U.S. Pat. No. 5,362,886 described the process for the preparation of (+)Duloxetine hydrochloride by isolating the (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine phosphoric acid salt and preparation of hydrochloride salt using aqueous hydrochloric acid and ethyl acetate as a solvent.

The U.S. Pat. No. 5,023,269 claims Duloxetine and its pharmaceutically acceptable salts and method of treating anxiety and obesity. The patent also discloses the processes for the preparation of Duloxetine and its pharmaceutically acceptable salts, however the patent not disclosed the process for the preparation of hydrochloride salt.

The EP patent 0650965 B1 discloses the process for the preparation of (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine an intermediate of Duloxetine which was isolated as a phosphoric acid salt and disclosed the process for the preparation of Duloxetine hydrochloride using aqueous hydrochloric acid and ethyl acetate as a solvent.

The U.S. Pat. No. 5,491,243 and U.S. Pat. No. 5,362,886 discloses the stereospecific process for the synthesis of (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine and claimed the same. In both the patents the above said compound isolated as a phosphoric acid salt.

Duloxetine hydrochloride prepared as per the prior art process containing the isomer impurity (+)-N-methyl-3(1-naphtalenyloxy)-3-(3-thienyl) propanamine, referred to herein as “DU-I” (represented below) and other undesired isomer i.e., R-isomer of Duloxetine hydrochloride.

The impurity “DU-I” is formed due to the carry over of isomer, i.e., 3-acetyl thiophene compound of formula 2I as an impurity present in 2-acetyl thiophene compound of formula 2. The formation of isomer “DU-I” during the preparation of duloxetine hydrochloride schematically represented in scheme-1, in which the Formula-4I, 5I, 6I and 8I represents the corresponding derivatives of isomer impurity formation in each stage.

The international patent publication WO 2006/099433 disclosed the process for the purification of duloxetine hydrochloride to reduce the (+)-N-methyl-3-(1-napthalenyloxy)-3(3-thineyl) propanamine isomer impurity i.e. “DU-I”. The said patent disclosed the process for the purification of Duloxetine hydrochloride to reduce the level of said isomer content. Generally purification at the final stage of any compound leads to loss of material which increases cost of production which is not recommended for commercial scale-up.

We, the present inventors found the origin of isomer impurity (“DU-I”) formation (represented in scheme-1) is due to the presence of 3-acetyl impurity in the starting material 2-acetyl compound of formula-2.

When we were working to eliminate the “DU-I” impurity in the origin itself, surprisingly found that the purity of Duloxetine hydrochloride has been increased by employing purification at first stage. The purification of compound of formula-4, then usage of this pure intermediate in the preparation of Duloxetine hydrochloride gives high pure Duloxetine hydrochloride which is free from the said isomer impurity. Purification of mandelate salt of (S)-3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol in a suitable solvent to eliminate the corresponding derivative of R-isomer in an early stage. By employing purification at the initial stages instead of final stage avoids the usage of high inputs of raw materials, which avoids increase in cost of production.

The main objective of the present invention is to provide an improved process for the preparation of high pure Duloxetine hydrochloride substantially free from impurities such as (+)-N-methyl-3-(1-napthalenyloxy)-3(3-thineyl) propanamine impurity (“DU-I”) and undesired (R)-isomer of Duloxetine hydrochloride.

DISADVANTAGEOUS OF THE PRIOR ART PROCESSES

• • The EP patent 457559 uses alkali metal hydride like sodium hydride in the preparation of duloxetine, which is commercially not recommended.
  • Duloxetine hydrochloride prepared as per the prior art process having high level of impurities like DU-I and R-isomer of duloxetine hydrochloride.
  • The U.S. Pat. No. 5,362,886 describes the process for the preparation of (+) Duloxetine hydrochloride by isolating the (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2 thienyl)propanamine as phosphoric acid salt leads to one more step and preparation of hydrochloride salt of Duloxetine using aqueous hydrochloric acid and ethyl acetate as a solvent leads to degradation of the obtained compound as shown below.

The present invention schematically represented as follows

 

Example-1 Preparation of 3-(dimethylamino)-1-(thiophen-2-yl) propan-1-one hydrochloride

Added 3.8 Kgs. of hydrochloric acid to a solution of 100 Kgs. of 2-acetyl thiophene, 81.5 Kgs. of dimethylamine hydrochloride, 35.4 Kgs. parafomaldehyde and 250 liters of isopropyl alcohol. Heated the reaction mixture to 75-80° C. Stirred the reaction mixture for 6 hours at 75-80° C. Cooled the reaction mixture to 0-5C. Stirred the reaction mixture for 2 hours at 0-5° C. Filtered the solid and washed with isopropyl alcohol.

Yield: 151 Kgs

M.R: 174-176° C.

Example-2 Purification of 3-(dimethylamino)-1-(thiophen-2-yl) propan-1-one hydrochloride

Added 1500 liters of isopropyl alcohol and 45 liters of water to 151 Kgs of 3-(dimethylamino)-1-(thiophen-2-yl) propan-1-one hydrochloride. Stirred the reaction mixture for 15 minutes at 25-30° C. Heated the reaction mixture to reflux. Stirred the reaction mixture for 2 hours at reflux. Cooled the reaction mixture slowly to 25-30° C. Stirred the reaction mixture for 4 hours at 25-30° C. Filtered the solid and washed with isopropyl alcohol. Dried the material at 25-30° C. for 2 hours followed by drying at 50-55° C. for 6 hours to get the pure title compound.

Yield: 144 Kgs.

M.R: 185-190° C.

Example-3 Purification of 3-(dimethylamino)-1-(thiophen-2-yl) propan-1-one hydrochloride

Added 1500 liters of acetone and 45 liters of water to 151 Kgs of 3-(dimethylamino)-1-(thiophen-2-yl) propan-1-one hydrochloride. Stirred the reaction mixture for 15 minutes at 25-30° C. Heated the reaction mixture to reflux. Stirred the reaction mixture for 2 hours at reflux. Cooled the reaction mixture slowly to 25-30° C. Stirred the reaction mixture for 4 hours at 25-30° C. Filtered the solid and washed with acetone. Dried the material at 25-30° C. for 2 hours followed by drying at 50-55° C. for 6 hours to get the pure title compound.

Yield: 142 Kgs.

M.R: 185-190° C.

Example-4 Preparation of 3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol

Added 50 liters of 20% sodium hydroxide solution to a cooled solution of 100 Kgs. of 3-(dimethylamino)-1-(thiophen-2-yl) propan-1-one hydrochloride, 100 liters of methanol and 25 liters of water at 0-5° C. Added a solution of 10 Kgs. of sodium borohydride in 50 liters of 20% sodium hydroxide to the above reaction mixture slowly at 0-5° C. in 5 hours. Allowed the reaction mixture temperature to 25-30° C. Stirred the reaction mixture for 6 hours at 25-30° C. Extracted the reaction mixture with methylene chloride. Separated the organic and aqueous layers. Extracted the aqueous layer with methylene chloride. Washed the organic layer with 10% sodium chloride solution. Distilled the solvent completely under reduced pressure at below 40° C. Added 25 liters of hexanes to the above reaction mixture. Distilled the solvent completely under reduced pressure at below 40° C. Added 100 liters of hexanes to the above reaction mixture. Heated the reaction mixture to reflux. Stirred the reaction mixture for 60 minutes. Cooled the reaction mixture to 0-5° C. and stirred the reaction mixture for 3 hours. Filtered the precipitated solid and washed with chilled hexanes. Dried the material at 50-55° C. for 6 hours to get the title compound.

Yield: 75 Kgs.

MR: 70-80° C.

Example-5 Preparation of (S) 3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol

Added 35 Kgs. of L(+)-mandelic acid to a solution of 70 Kgs. of 3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol and 700 liters of ethyl acetate at 25-30° C. Stirred the reaction mixture for 90 minutes at 25-35° C. Heated the reaction mixture to 70-75° C. Stirred the reaction mixture for 3 hours at 70-75° C. Cooled the reaction mixture to 25-35° C. Stirred the reaction mixture for 10 hours at 25-35° C. Filtered the precipitated mandelate salt of (S)-3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol compound and washed with ethyl acetate. Added 350 liters of ethyl acetate to the obtained mandelate salt of (S)-3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol compound. Heated the reaction mixture to 60-65° C. Stirred the reaction mixture for 60 minutes. Cooled the reaction mixture to 25-35° C. Stirred the reaction mixture for 90 minutes. Filtered the compound and washed with ethyl acetate. Dried the mandelate salt compound at 60-65° C. for 5 hours to get the pure mandelate salt of (S)-3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol compound free from corresponding derivative of R-isomer.

Yield: 62 Kgs.

• Before Purification: MR: 113-115° C.; SOR: (+) 31° (C=1; Methanol) Corresponding derivative of R-isomer by Chiral HPLC: 7.0%
• After Purification: MR: 121-124° C.; SOR: (+) 33° (C=1; Methanol) Corresponding derivative of R-isomer by Chiral HPLC: Nil

A mixture of 62 Kgs. of mandelate salt of (S)-3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol, 125 liters of water and 375 liters of methylene chloride is cooled to 0-5° C. Adjusted the pH of the reaction mixture to 9.8 with 10% sodium carbonate solution at 0-5° C. Stirred the reaction mixture for 20 minutes at 0-5° C. Separated the organic and aqueous layers. Extracted the aqueous layer with methylene chloride. Washed the organic layer twice with 10% sodium chloride solution. Distilled the solvent completely under reduced pressure at below 35° C. Added 19 liters of cyclohexane to the above reaction mixture. Distilled the solvent completely under reduced pressure at below 35° C. Added 125 liters of cyclohexane to the above reaction mixture. Heated the reaction mixture to 40-45° C. and stirred for 60 minutes. Cooled the reaction mixture to 0-5° C. Filtered the precipitated solid and washed with cyclohexane. Dried the material at 40-45° C. for 6 hours to get the title compound.

Yield: 33 Kgs.

MR: 70-80° C.; SOR: (−) 6.20 (C=1; Methanol).

Example-7 Preparation of (S)-(+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine oxalate

Heated a solution of 125 liters of dimethyl sulfoxide and 27 Kgs. of sodium hydroxide to 50-55° C. and Stirred for 45 minutes. Added a mixture of 25 Kgs. of (S)-3-(dimethylamino)-1-(thiophen-2-yl) propan-1-ol, 2.5 Kgs. of tertiarybutylammonium bromide and 30 Kgs. of 1-fluoronapthalene and 25 liters of dimethyl sulfoxide to the above reaction mixture at 50-55° C. Stirred the reaction mixture for 50 hours at 60-65° C. Cooled the reaction mixture to 15-20° C. Quenched the reaction mixture with water at 15-20° C. Extracted the reaction mixture with toluene. Separated the organic and aqueous layer. Washed the organic layer twice with water. Dried the organic layer with sodium sulphate. Added 27.5 Kgs. of diisopropylethylamine to the above reaction mixture at 25-35° C. Heated the reaction mixture to 43-48° C. Added 36 Kgs. of phenylchloroformate slowly to the reaction mixture at 43-45° C. Stirred the reaction mixture for 4 hours at 43-48° C. Cooled the reaction mixture to 20-25° C. Quenched the reaction mixture with water. Separated the organic and aqueous layers. Organic layer washed with acetic acid solution, oxalic acid followed by sodium bicarbonate solution. Distilled the solvent completely under reduced pressure at below 45° C. Added 500 liters of dimethylsulfoxide to the above obtained crude and heated to 40-45° C. Added sodium hydroxide solution (25 Kgs. in 100 liters of water) to the above reaction mixture at 40-45° C. for 3 hours. Further heated the reaction mixture to 50-55° C. Stirred the reaction mixture for 30 hours at 50-55° C. Cooled the reaction mixture to 15-20° C. and quenched the reaction mixture with water. Extracted the reaction mixture thrice with toluene and washed the organic layer twice with water. Added 17.5 Kgs. of Oxalic acid to the above organic layer at 25-30° C. Stirred the reaction mixture for 4 hours at 25-30° C. Filtered the precipitated solid and washed with toluene. Dried the material at 40-45° C. to get the title compound.

Yield: 36 Kgs.; M.R: 126-130° C.

Example-8 Preparation of (S)-(+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine hydrochloride

A solution of 100 Kgs. of (S)-(+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl) propanamine oxalate, 400 liters of water and 400 liters of methylene chloride is cooled to 0-5° C. Adjusted the pH of the reaction mixture 8.8 with aqueous ammonia. Stirred the reaction mixture for 15 minutes. Separated the organic layer and washed the organic phase with water. Distilled the solvent completely under reduced pressure at below 40° C. Added 400 liters of ethyl acetate to the above obtained crude. Cooled the reaction mixture to 0-5° C. Adjusted the pH of the reaction mixture to 2.0 with ethyl acetate HCl. Stirred the reaction mixture for 2 hours. Filtered the precipitated solid and washed with ethyl acetate. Dried the material at 45-50° C. to get the title compound.

Yield: 45 Kgs.

MR: 164-166° C.

Undesired R-isomer content by Chiral HPLC: 0.13%

HPLC Purity: 99.80%, 0.07% (“DU-I” impurity)

Example-9 Purification of Duloxetine Hydrochloride

Added 500 ml of ethyl acetate and 100 ml of methanol to 100 gr of Duloxetine hydrochloride. Heated the reaction mixture to 55-60° C. and stirred the reaction mixture at 55-60° C. for 90 minutes. Cooled the reaction mixture to 20-25° C. Stirred the reaction mixture for 4 hours at 20-25° C. Filtered the solid and washed with ethyl acetate. Dried the material at 55-60° C.

Yield: 70gr;

MR: 164-166° C.;

SOR: (+) 118° (C=1; Methanol);

Particle size: (d, 90): below 100 microns; Micronized material: (d, 90): below 25 microns;

Undesired R-isomer content by Chiral HPLC: 0.02%; HPLC Purity: 99.80% 0.02% (“DU-I” impurity).

A RECAP

US. 8362279

http://www.google.co.in/patents/US8362279

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MSN Laboratories Limited, Andhra Pradesh, Hyderabad, India

 

Process for Pure Duloxetine Hydrochloride

 

 

 

Duloxetine, 126, is used to treat mild depression and is available as the HCl salt under the name Cymbalta. The current patent points out that alternative processes for the preparation of 126produce a material that contains the impurity 127 as well as the unwanted R-enantiomer. Earlier patents covering the removal of 127 and the synthesis of 126 have been reviewed ( Org. Process Res. Dev. 2009, 13, 829). This patent discloses a method for preparing pure 126 by removing the precursor to 127 during the synthesis. Scheme 39 shows the first step in the synthesis of 126 that starts by reaction of the thiophene 122 with Me2NH and paraformaldehyde to form 124 that is subsequently converted to 126. However, 122 contains the isomer 123 as an impurity, and in the reaction with Me2NH and HCHO, compound 125 is formed that eventually forms impurity 127. Alternative processes that use this reaction sequence generally remove 127at the end of the synthetic procedure. The current patent removes 125 after this first step, and it is claimed that this produces a higher-quality final product. This initial reaction produces the HCl salts of 124 and 125, and the crude solid mixture is heated in refluxing PriOH or Me2CO containing H2O. The purified salt 124·HCl is then recovered from the cooled mixture by filtration, and although the product purity is not reported, the example describes the preparation of >140 kg of the salt.

Scheme 39. a

aReagents and conditions: (a) (i) Concd HCl, PriOH, 80 °C, 6 h; (ii) cool <5 °C, 2 h; (iii) filter. (b) See Scheme 40.

The purified salt is then used to prepare 126 by the reaction sequence shown in Scheme 40. The salt is first treated with NaOH to give the free base 124 that is not isolated but is reduced in situ using NaBH4 to form the racemic alcohol 128. This is resolved using L-mandelic acid, and the enantiomer S-128 is recovered containing no R-enantiomer, and then the L-mandelate salt that is converted to S-128 by treatment with aq Na2CO3. The overall yield of the free base is 47%. In the next stage S-128 is reacted with 129 in the presence of an alkaline base and a PTC. This stage of the reaction takes 50 h and is followed by a demethylation step using ClCO2Ph to give 126 that is recovered as the oxalate salt, and this step takes more than 30 h. In the final step the oxalate salt is converted to the HCl salt of 126 using a solution of HCl in EtOAc. Alternative processes use aq HCl for this step that is said to lead to degradation of 126 by hydrolysis of the ether bond. The HCl salt is isolated with a purity of 99.8% containing 0.13% of the R-enantiomer and 0.07% of impurity 127.

Scheme 40. a

aReagents and conditions: (a) 20% NaOH, MeOH, H2O, <5 °C. (b) (i) NaBH4, 20% NaOH, <5 °C, 5 h; (ii) 30 °C, 6 h; (iii) L-mandelic acid, EtOAc, 75 °C, 3h; (iv) cool, filter; (v) aq Na2CO3, DCM, 5 °C; (vi) separate, brine wash, evaporate; (vii) cyclohexane, 45 °C, 1 h; (viii) cool, filter, dry. (c) (i) NaOH, Bu4NBr, DMSO, 65 °C, 50 h; (ii) add H2O, <20 °C; (iii) extract in PhMe, H2O wash, dry; (iv) add Pri2NEt, 35 °C; (v) add ClCO2Ph, 48 °C, 4 h; (vi) cool <25 °C, add H2O; (vii) separate, wash in HOAc, wash in (CO2H)2, wash in aq NaHCO3, evaporate; (ix) aq NaOH, DMSO, 45 °C, 3 h; (x) 55 °C, 30 h; (xi) cool, add H2O, extract in PhMe; (xii) add (CO2H)2, 30 °C, 4 h; (xiii) filter, wash, dry. (d) (i) DCM, H2O, NH4OH to pH 8.8, 5 °C, 0.25 h; (ii) separate, H2O wash, evaporate; (iii) HCl/EtOAc, 5 °C, 2 h; (iii) filter, EtOAc wash, dry.

All of the examples in the patent involve large-scale batches with the final step being the production of 45 kg of 126·HCl, thereby indicating the commercial status of the process.

Advantages

The process gives higher-purity product with fewer steps and lower production costs.

Cited Patent	Filing date	Publication date	Applicant	Title
US5023269	27 Mar 1990	11 Jun 1991	Eli Lilly And Company	3-aryloxy-3-substituted propanamines
US5362886	12 Oct 1993	8 Nov 1994	Eli Lilly And Company	Asymmetric synthesis
US5491243	18 Jul 1994	13 Feb 1996	Eli Lilly And Company	Intermediate useful for the asymmetric synthesis of duloxetine
US20050197503	16 Feb 2005	8 Sep 2005	Boehringer Ingelheim International Gmbh	Process for the preparation of N-alkyl-N-methyl-3-hydroxy-3-(2-thienyl)-propylamines
US20080015363 *	21 Feb 2007	17 Jan 2008	Santiago Ini	Process for the preparation of (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-hydroxypropananine, a duloxetine intermediate
EP0273658B1	18 Dec 1987	31 Oct 1990	Eli Lilly And Company	3-aryloxy-3-substituted propanamines
EP0457559A2	15 May 1991	21 Nov 1991	Eli Lilly And Company	Chiral synthesis of 1-aryl-3-aminopropan-1-ols
EP0650965B1	7 Oct 1994	7 Feb 2001	Eli Lilly And Company	Asymmetric synthesis of (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine an intermediate in the preparation of duloxetine
WO2006099433A1	14 Mar 2006	21 Sep 2006	Teva Pharmaceutical Industries Ltd.	Pure duloxetine hydrochloride

 

Reference
1	*	English translation of Gao et al. (Chinese Journal of New Drugs, vol. 14, No. 1, pp. 74-76). Translated by Schreiber Translations, Inc in Mar. 2012.
2	*	Gao et al. (Chinese Journal of New Drugs, vol. 14, No. 1, pp. 74-76).
3	*	Gao et al. (Chinese Journal of New Drugs, vol. 14, No. 1, pp. 74-76, 2005).
4		Luo, G., et al. "An Improved Synthesis Method of Antidepressant Drug Duloxetine Hydrochloride. Yaouxue J." (2006), 30(4), 181-184, Columbus Ohio, USA: Chemical Abstracts vol. 146, Jun. 21, 2006, the abstract No. 592369.
5		PCT Written Opinion of the International Searching Authority from PCT/IN2007/000003, Dated: Mar. 3, 2008.

///////Duloxetine Hydrochloride, MSN, PATENT, US. 8362279

Diacerein, US 8324411, Laboratorio Chimico Internazionale s.p.A., Milan, Italy, PATENT

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.

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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

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

 

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^A is Cl, Br, or I; and R^B is 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 H₂ in 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 N₂ atmosphere.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 N₂ atmosphere.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 N₂ atmosphere.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 N₂ atmosphere. 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 N₂ to 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 N₂ atmosphere.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 N₂ atmosphere.Example 5 Preparation of Zilpaterol Part A. Formation of Aminoalcohol Potassium Salt from Ketooxime

A stirred-tank reactor was purged 3 times with N₂ between 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 H₂ pressure 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 H₂ between 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 N₂ between 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).

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