RU2442786C2 - Ways of production of zilpaterol and its salts - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention refers to the means of production of zilpaterol and its salts including: production of chlorine 2,3-dihydro-2-oxo-1H-benzimidazol-1-butanoate (or its salt) by means of the method including interaction between 4-(2-oxo-2,3-dihydrobenzimidazol-1-yl)butanoic acid (or its salt) and at least one chlorating agent chosen from the group consisting of oxalyl chloride, phosgene and triphosgene, and production of 8,9-dihydro-2H,7H-2,9a-diabenzo[c,d]azulene-1,6-dione or its salt, by means of the method including interaction between chlorine 2,3-dihydro-2-oxo-1H-benzimidazol-1-butanoate (or its salt) with the Lewis acid, production of 4,5-dihydro-imidazo[4,5,l-jk][1]benzazepin-2,6,7[1H]-thrion-6-oxime (or its salt) by means of the method including interaction between 8,9-dihydro-2H,7H-2,9a-diazabenzo[cd]azulene-1,6-dione (or its salt) with nonorganic nitrite, production of alkamine salt by means of the method including interaction between 4,5-dihydro-imidazo[4,5,l-jk][1]benzazepin-2,6,7[1H]-thrion-6-oxime (or its salt) with the base and further interacton with H₂ with the presence of hydrogenation catalyst; the alkamine salt corresponds to the structural formula WO-2):

and Z denotes a cation, production of izopropilidenamino compound be means of the method including combination of the alkamine salt with acetone and acetic acid; the izopropilidenamino compound structurally corresponds to the formula (WO-1):

and production of zilpaterol by interaction between the izopropilidenamino compound (or its salt) and H₂ with the presence of hydrogenation catalyst, with further combination with the base and alcohol, and to the ways of production of intermediate compounds that may be used in productioin of zilpaterol and its salts.

EFFECT: new way of production of zilpaterol and its salt that can be used for acceleration of weight gain, improvement of feed efficiency and/or increase of meagreness of a great cattle, poultry and fish carcass.

12 cl, 9 ex

Description

Cross reference to related patent applications

The priority of the claims of this application for US patent application No. 60/920885 (filed March 31, 2007), US patent application No. 60/909611 (filed April 2, 2007) and European patent application No. EP07105551.1 (filed April 3, 2007). The full text of each of these applications is attached by reference to this patent application.

Field of Invention

This invention generally relates to methods for producing zilpaterol and its salts, as well as to methods for producing intermediate compounds, which, inter alia, can be used to obtain zilpaterol and its salts. This invention also relates to methods of treatment using zilpaterol and salts obtained in accordance with this invention to increase the rate of weight gain, improve feed efficiency and / or increase carcass lean in cattle, poultry and fish.

State of the art

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

IUPAC name of zilpaterol is 4,5,6,7-tetrahydro-7-hydroxy-6- (isopropylamino) imidazo [4,5,1-jk] - [1] benzazepine-2 (1H) -one. The name of zilpaterol according to The Chemical Abstracts is 4,5,6,7-tetrahydro-7-hydroxy-6 - [(1-methylethyl) amino] imidazo [4,5,1-jk] [1] benzazepine-2 (1H )-it.

It is well known that zilpaterol, various derivatives of zilpaterol and various pharmaceutically acceptable acid addition salts of zilpaterol and their derivatives can, for example, be used to increase the rate of weight gain, improve feed efficiency (i.e. reduce the amount of feed per amount of weight gain) and / or an increase in carcass leanness (i.e., an increase in the protein content of the soft carcass tissues) in cattle, poultry, and fish. In US Pat. No. 4,900,735, for example, Grandadam describes zootechnical compositions of racemic trans-zilpaterol and its salts, which can be used to increase the mass and quality of meat of warm-blooded animals, including cattle, pigs and poultry. And US Patent Application Publication US2005 / 0284380 describes the use of an ionophore / macrolide / zilpaterol dosage regimen to increase beef production, reduce feed intake while maintaining beef production, and reduce incidences of liver abscesses in cattle.

Methods for producing zilpaterol are known in the art. For example, in US Pat. No. 4,585,770, Frechet et al. Describe compounds belonging to the group characterized as 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo derivatives [4,5,1-jk] [1 ] -benzazepine-2 [1H] -one and their pharmaceutically acceptable acid addition salts. Derivatives correspond in structure to the following formula:

R can be various substituents, and the wavy lines indicate that the bonds with the 6-amino and 7-OH groups have a trans configuration. This group of compounds encompasses racemic trans-zylpaterol when R is isopropyl.

In the methods reported in US patent 4,585,770, 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine ~ 2,6,7 [1H] -trion-6-oxime is used as an intermediate connections. This compound corresponds in structure to the following formula:

As indicated in US Pat. No. 4,585,770, 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6-oxime can be obtained from starting materials which have long been known in the art. US 4,585,770 illustrates the use of two such starting materials. In both examples, the starting materials are used to produce 5,6-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,7- [1H, 4H] dione, which, in turn, can be used to obtain 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6-oxime.

In one example, in US Pat. Soc. Perkins, p. 261 (1982):

1,3-dihydro-1- (1-methylenethenyl) -2H-benzimdazol-2-one

U.S. 4,585,770 teaches that 1,3-dihydro-1- (1-methylenethenyl) -2H-benzimidazol-2-one can react with alkyl 4-halo butyrate (i.e., R ^A - (CH ₂ ) ₃ -COOR ^B (where R ^A is Cl, Br or I; and R ^B is C ₁ -C ₄ alkyl), such as methyl or ethyl 4-bromobutyrate) and a base (for example, an alkali metal) to form butanoate, which in turn can be hydrolyzed by an acid (e.g., H ₂ SO ₄ ) in an alcohol (e.g., methanol or ethanol) to remove the methylenyl substituent. The hydrolysis product can then be saponified by reacting it with a base (e.g., NaOH or KOH) in alcohol to form a carboxylic acid. Subsequently, the carboxylic acid-terminated side chain can be cyclized to form 5,6-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,7- [1H, 4H] dione by reacting the carboxylic acid with thionyl chloride, to obtain chloride, and subsequent treatment of the chloride with a Lewis acid (e.g., aluminum chloride) in an organic solvent (e.g., methylene chloride or dichloroethane):

See U.S. Patent 4,585,770, Art. 4, line 3 to Article 5, line 14; and example 14, art. 12, lines 1-68.

In another example, in US 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):

1,3-dihydro-1-benzyl-2H-benzimidazol-2-one

U.S. 4,585,770 teaches that 1,3-dihydro-1-benzyl-2H-benzimidazole-2-one can be reacted with ethyl 4-bromobutyrate and sodium hydride to form 1,3-dihydro-2-oxo-3-benzyl -1H-benzimidazole-1-butanoate, which, in turn, can be saponified by reacting it with NaOH in methanol to form 1,3-dihydro-2-oxo-3-benzyl-1H-benzimidazole-1-butanoic acid . The butanoic acid side chain can then be cyclized by reacting 1,3-dihydro-2-oxo-3-benzyl-1H-benzimidazole-1-butanoic acid with thionyl chloride to produce chloride and then treating the chloride with aluminum chloride in dichloroethane. The cyclized product, in turn, can be hydrolyzed using o-phosphoric acid in phenol to form 5,6-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,7- [1H, 4H] dione. See US Patent 4,585,770, Example 1, Steps A-D, Art. 6, line 10 to Article 7, line 35.

Using methods described in US Pat. No. 4,585,770, 5,6-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,7- [1H, 4H] dione can be reacted with alkyl nitrite (for example, tert-butyl nitrite or isoamyl nitrite), in the presence of a base or acid (for example, HCl) to form 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [ 1H] -trion-6-oxime. 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6-oxime, in turn, is reduced by catalytic hydrogenation (for example, hydrogen in the presence of palladium on carbon) or sodium borohydride until the formation of racemic trans 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo [4,5,1-jk] [1] benzazepine-2 [1H] -one :

In an illustrative example, in US Pat. No. 4,585,770, 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6-oxime is converted to the racemic trans-6-amino 7-hydroxy-4,5,6,7-tetrahydro-imidazo [4,5,1-jk] [1] benzazepin-2 [1H] -one in two stages: 4,5-dihydro-imidazo [4, 5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6-oxime is first reacted with H ₂ in the presence of Pd-on carbon and then, after filtration, the hydrogenation product is reacted with sodium borohydride . See U.S. Patent 4,585,770, Art. 2, line 15 to Article 4, line 2; and example 1, stages E and F, Art. 7, line 38 to Article 8, line 3.

US Pat. No. 4,585,770 teaches that trans stereoisomers of 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo [4,5,1-jk] [1] benzazepine-2 [1H] -one can be alkylated with acetone in the presence of a reducing agent (for example, an alkali metal borohydride or cyanoborohydride such as sodium cyanoborohydride) to form racemic trans zylpaterol:

See U.S. Patent 4,585,770, Art. 2, line 46 to art. 4, line 2; and example 13, art. 11, lines 41-68.

Due to the importance of zilpaterol and its salts in animal husbandry, there remains a need for cost-effective highly productive methods for producing zilpaterol and its salts. The following disclosure addresses this issue.

SUMMARY OF THE INVENTION

This invention relates to methods for producing zilpaterol and its salts. Such methods include methods for producing zilpaterol and its salts as such, as well as methods for producing compounds which, inter alia, can be used as intermediates for the preparation of zilpaterol and its salts.

In short, this invention relates in part to a process for the preparation of zilpaterol or a salt thereof (e.g., a pharmaceutically acceptable salt). The method includes obtaining chlorine of 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate (or a salt thereof) by a method comprising reacting 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid ( or salts thereof) with at least one chlorinating agent, such as oxalyl chloride, phosgene and / or triphosgene. Alternatively (or additionally), the method includes the preparation of 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6-oxime (or its salt ) by a method comprising reacting 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione (or its salt) with an inorganic nitrite (for example, a nitrite salt such as NaNO ₂ ).

The present invention also relates in part to a method for producing chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate or a salt thereof. This method involves reacting 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid (or a salt thereof) with at least one chlorinating agent, such as oxalyl chloride, phosgene and / or triphosgene.

The invention also relates in part to a process for the preparation of 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione or a salt thereof. This method involves the preparation of chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate (or a salt thereof) by a process comprising reacting 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid (or its salts) with at least one chlorinating agent, such as oxalyl chloride, phosgene or triphosgene. In addition, the method comprises reacting chloro 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate (or a salt thereof) with a Lewis acid (e.g., AlCl ₃ ).

This invention also relates in part to a process for the preparation of 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6-oxime or a salt thereof. This method involves the interaction of 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione (or its salt) with inorganic nitrite.

The present invention also relates in part to a method for feeding an animal. This method includes feeding the animal (eg, cow, pig or bird) with zilpaterol or its salt, obtained by the method according to this invention. Such methods of feeding can be used, for example, to increase the rate of increase in mass of the animal, improve the efficiency of animal feed and / or increase the lean carcass of the animal.

This invention also relates in part to the use of zilpaterol or a salt thereof obtained by the method of this invention for the preparation of a medicament. Applications of such a medicine include increasing the rate of increase in mass of an animal, improving the efficiency of animal feed and / or increasing lean carcasses of an animal.

Additional beneficial effects of the claimed invention should be apparent to a person skilled in the art after reading this description.

Detailed Description of Preferred Embodiments

This detailed description of the preferred embodiments is intended only to familiarize other specialists in this field with the claimed invention, its principles and its practical application so that other specialists in this field can modify and apply this invention in its various forms so that they can best meet the requirements of a specific application. This detailed description and specific examples thereof showing preferred embodiments are intended for purposes of explanation only. The present invention, therefore, is not limited to the preferred embodiments described herein, and may be variously modified.

A. Synthesis of zilpaterol and its salts

A-1. Preparation of 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate chloro

In some embodiments, the synthesis of zilpaterol or salt begins with or involves the preparation of chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate:

In some such embodiments, for example, chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate is prepared from 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid at least one chlorinating agent. In some such embodiments, the implementation of the chlorinating agent contains oxalyl chloride:

In other embodiments, the implementation of the chlorinating agent as an option or additionally contains, for example, phosgene or triphosgene:

The reagent 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid (also known as "2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoic acid") can be obtained from a commercial seller (in available volumes) or prepared from commercially available ingredients using, for example, methods known in the art. As shown in the Background section above, such methods include those described in US Pat. No. 4,585,770 (full text of US Pat. No. 4,585,770 is incorporated herein by reference).

The amount of chlorinating agent may vary. In general, it is preferable to use an excess of the chlorinating agent. In some embodiments, for example, the amount of a chlorinating agent (e.g., oxalyl chloride) charged to the reactor is from about 1.05 to about 1.15 equivalents (or from about 1.05 to about 1.11 equivalents or from about 1, 08 to about 1.10 equivalent) based on moles of 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid. Although it is contemplated that amounts less than the indicated ranges may be used, such amounts may coincide with a reduced degree of conversion. And, although it is believed that higher amounts than the specified limits can be used, such amounts may coincide with the formation of undesirable by-products.

This reaction usually occurs in the presence of a catalyst. One such suitable catalyst contains N, N-dimethylformamide ("DMF"). Typically, at least a catalytic amount of DMF is loaded into the reactor. In some embodiments, the amount of DMF charged to the reactor is from about 0.08 to about 0.22 (or from about 0.10 to about 0.14) equivalent based on moles of 4- (2-oxo-2,3- dihydrobenzimidazol-1-yl) butyric acid. To illustrate, in some embodiments, the amount of DMF is about 0.11 equivalents. Although it is contemplated that amounts less than the indicated ranges may be used, such amounts may coincide with a reduced degree of conversion. And, although it is contemplated that higher amounts than these ranges may be used, such amounts may coincide with the formation of undesirable by-products.

This reaction is usually carried out in the presence of one or more solvents. In some embodiments, the implementation of the solvent contains one or more non-polar solvents. One such suitable solvent contains dichloromethane. In some embodiments, the amount of solvent (eg, dichloromethane) is from about 6.0 to about 9 L (or from about 6.8 to about 7.6 L) per kilogram of 4- (2-oxo-2,3-dihydrobenzimidazole- 1-yl) butyric acid). To illustrate, in some embodiments, the amount of solvent is about 7.2 L per kilogram of 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid.

This reaction can be carried out over a wide range of temperatures. In some embodiments, for example, the reaction is carried out at a temperature of from about 5 to about 25 ° C, from about 10 to about 25 ° C, from about 10 to about 20 ° C, or from about 15 to about 20 ° C. Although it is contemplated that temperatures lower than the indicated ranges may be used, such temperatures may coincide with slower reaction rates. And, although it is contemplated that higher temperatures than these ranges may be used, such temperatures may coincide with undesired solvent losses, especially when the solvent is dichloromethane.

This reaction can be carried out in various atmospheres. In some embodiments, for example, the reaction is carried out in an inert atmosphere. Typically, an "inert atmosphere" is an atmosphere that is not able to interact with reagents, products, any other ingredients in the reaction mixture, or in the reactor during the reaction period. One such atmosphere, for example, contains N ₂ . In some such embodiments, the atmosphere consists of (or consists essentially of) N ₂ .

This reaction can be carried out in a wide range of pressures, including atmospheric pressure, at a pressure below atmospheric and a pressure above atmospheric. It is usually preferred, however, to carry out the reaction at approximately atmospheric pressure.

This reaction can be carried out in various types of reactor. In some embodiments, for example, the reactor is a stirred reactor. Glass or glass lined reactors are often preferred, although some composition that is stable when the reaction mixture is accessible can be used. Shaking (e.g. stirring) of the reaction mixture is preferably maintained at a rate that minimizes (or, more preferably, substantially or completely eliminates) any deposition of the 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl reagent ) butyric acid on the walls of the reactor. In some embodiments using a stirred reaction apparatus, the stirring speed before and during loading of the chlorinating agent is slower than the mixing speed after the chlorinating agent is loaded. The stirring speed during loading of the chlorinating agent, however, is preferably not so low as to prejudice the conversion or adversely delay the evolution of gas.

The reaction time for this reaction may depend on various factors, including, for example, reaction temperature, solvent characteristics, relative amounts of ingredients, and the desired conversion. In a batch reactor, the reaction time is typically at least about 1 minute, usually at least about 5 minutes, and more often at least about 1 hour. In some embodiments, for example, the reaction time is from about 1 hour to about 32 days, or from about 2 to about 7 hours. To illustrate, in some embodiments, the total reaction time is about 4 hours.

In some embodiments, the reaction time includes an extended period during which the chlorinating agent is charged to the reactor. In some such embodiments, for example, a chlorinating agent is charged to the reactor over a period of about 15 minutes to about 10 hours, about 1 to about 3 hours, or about 1 to about 2 hours. Although it is contemplated that shorter periods of time than these limits may be used, such periods of time may coincide with rapid gas evolution, which, in turn, may cause undesired loss of solvent (especially when the solvent contains dichloromethane). And, although it is anticipated that longer periods of time than the specified limits can be used, such periods may coincide with the undesired decomposition of the product of chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate, as well as inefficient use of equipment and labor.

In some embodiments, when the chlorinating agent is charged over an extended period of time, the reaction mixture is then maintained (or “aged”), usually with agitation (eg, stirring) for an additional period. In some embodiments, the additional period is from about 45 minutes to about 31 days, from about 1 to about 4 hours, or from about 1 to about 2 hours. Often during this additional period, the same reaction conditions (for example, temperature, pressure and / or stirring speed) are maintained as during the loading of the chlorinating agent. Conditions, however, may also be different. To illustrate, in some embodiments, the chlorinating agent is charged at a temperature of about 15 ° C and then the mixture is kept at about 20 ° C. Although it is contemplated that shorter time periods than the indicated limits may be used, such time periods may coincide with a reduced degree of conversion. And, although it is contemplated that longer periods of time than these limits may be used, such periods may coincide with the formation of undesirable impurities (such as from the decomposition of the product chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate ), as well as the inefficient use of equipment and labor.

Under these conditions, the product chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate is usually in solution. It is contemplated that this product may be precipitated and purified or isolated using, for example, various methods known in the art. Typically, however, the product is used in the next step without precipitation, purification or isolation. In some such embodiments, the product mixture is used no later than within 31 days, within 24 days, or within 9 days. The use of older product mixtures may coincide with the undesirable decomposition of chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate. In addition, these time limits suggest that the product mixture is not exposed to temperatures exceeding approximately 6 ° C. To the extent that the product mixture is exposed to temperatures higher than about 6 ° C (and especially temperatures higher than about 25 ° C), undesirable decomposition of the product is more likely to occur.

A-2. Preparation of 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione

In some embodiments, the synthesis of zilpaterol or a salt thereof begins with or comprises the preparation of 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione:

In some embodiments, 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione (also known as "5,6-dihydro-imidazo [4,5,1-jk ] [1] -benzazepine-2,7- (1H, 4H) dione ") is obtained, for example, by reacting chloro 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate with a Lewis acid by two reactions ( i.e. Friedel-Crafts reactions and then hydrolysis):

Chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate used in this reaction can be obtained from a commercial seller (in available volumes) or prepared using the method discussed in section A-1 above, or cooked in a different way. In some embodiments, for example, chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate is prepared according to the method described in US Pat. No. 4,585,770, using thionyl chloride as a chlorinating agent to convert 4- (2-oxo -2,3-dihydrobenzimidazol-1-yl) butyric acid to chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate. In other embodiments, chlorine 2,3-dihydro-2-oxo-1H-benzimidazol-1-butanoate is prepared using 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) as the chlorinating agent PCl ₅ butyric acid in chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate. In some preferred embodiments, chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate is prepared using the method and chlorinating agents mentioned in Section A-1 above. The use of the chlorinating agents indicated in section A-1 (especially oxalyl chloride), instead of, for example, thionyl chloride or PCl ₅ , tends to coincide with less difficult to remove impurities. The use of thionyl chloride, for example, tends to form sulfur impurities. And PCl ₅ tends to form phosphorus impurities. The removal of such impurities, in turn, tends to reduce the yield of the desired product.

Although it is contemplated that various Lewis acids (or combinations thereof) are suitable for this reaction, aluminum chloride (AlCl ₃ ) is the preferred Lewis acid. The amount of Lewis acid loaded into the reactor may vary. In general, it is preferable to use an excess of Lewis acid. In some embodiments, for example, the amount of Lewis acid (e.g., AlCl ₃ ) charged to the reactor is from about 2.8 to about 4.0 equivalents (or from about 3.0 to about 3.6 equivalents) based on moles chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate. To illustrate, in some embodiments, the amount of Lewis acid charged to the reactor is about 3.3 equivalents based on moles of chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate. In some embodiments, where chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate is prepared according to section A-1, the amount of Lewis acid used in the Friedel-Crafts reaction is from about 2.8 up to about 4.0 equivalents (or from about 3.0 to about 3.6 equivalents) based on moles of 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid used in the reaction of section A-1 . To illustrate, in some embodiments, the amount of Lewis acid charged to the reactor is about 3.3 equivalents based on moles of 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid used in the A- section reaction one. Although it is contemplated that less amounts of aluminum chloride than these limits may be used, such amounts may coincide with a reduced conversion and / or formation of undesired by-products. And, although it is contemplated that higher amounts of aluminum chloride may be used, such amounts may coincide with performance losses during subsequent hydrolysis.

The Friedel-Crafts reaction is usually carried out in the presence of one or more solvents. In some embodiments, for example, the solvent comprises one or more non-polar solvents. In some embodiments, where the chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate reagent is prepared according to section A-1, the solvent is the same solvent as used in section A-1. One such suitable solvent contains dichloromethane. As will be explained below, a solvent (e.g. dichloromethane) used in the Friedel-Crafts reaction can be removed before, during and / or after hydrolysis by, for example, distillation. Thus, in some embodiments, the solvent has a boiling point that is suitable for such removal.

The total amount of such a solvent used for this reaction may vary. In some embodiments, the amount of solvent (eg, dichloromethane) is about 11.1 per kilogram of chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate. In some embodiments, when the reagent chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate is prepared according to section A-1, the final product mixture from section A-1 (including any solvent, ( for example, dichloromethane) is used in the Friedel-Crafts reaction. In some such embodiments, the total amount of solvent used in the Friedel-Crafts reaction (including the solvent from the A-1 reaction plus any solvent added for the Friedel-Crafts reaction) is about 12.1 liters per kilogram of 4- (2-oxo-2,3-dig fragmentenimidazol-1-yl) butyric acid used in the reaction of section A-1. In other such embodiments, the implementation of the additional amount of solvent loaded into the reactor for the Friedel-Crafts reaction (in addition to the solvent, which is loaded as part of the product mixture of section A-1 ) is from about 0.53 to about 0.91 (or from about 0.60 to about 0.71) of the amount of solvent used in the reaction of section A-1. In some such embodiments, for example, the additional amount is about 0.67 of the quantity, use in the reaction of section A-1. In some embodiments, when the chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate reagent is prepared according to section A-1, the Lewis acid in the Friedel-Crafts reaction is AlCl ₃ and the total amount of solvent contained in a suspension of AlCl ₃ loaded into the reactor, is from about 3.7 to about 5.3 L (or from about 4.5 to about 5.1 L) per kilogram of 4- (2-oxo-2,3-dihydrobenzimidazole- 1-yl) butyric acid used in the reaction of section A-1. For clarification, in some such embodiments, the amount of solvent is about 4.8 liters per kilogram of 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid used in the reaction of section A-1. Although it is contemplated that solvent amounts beyond these ranges may be used, such amounts may coincide with the formation of undesired by-products.

The Friedel-Crafts reaction can be carried out over a wide temperature range. In some embodiments, the Friedel-Crafts reaction is carried out at a temperature higher than about 40 ° C. In some embodiments, the implementation of the temperature is from about 45 to about 65 ° C. In some such embodiments, the implementation of the temperature is from about 55 to about 62 ° C. In other such embodiments, the implementation of the temperature is from about 50 to about 60 ° C. For clarification, in some embodiments, the implementation of the temperature is about 60 ° C. Although it is contemplated that lower temperatures than these ranges may be used, such temperatures may coincide with slower reaction rates and / or the formation of undesired by-products due to intermolecular side reactions. And, although it is contemplated that higher temperatures than these ranges may be used, such temperatures may coincide with an undesired loss of solvent, especially when the solvent is dichloromethane.

In some embodiments, the temperature of the reaction mixture is lowered after the desired conversion occurs. For example, in some such embodiments, the temperature is lowered to about 12 ° C.

The Friedel-Crafts reaction can be carried out over a wide pressure range. In some embodiments, the pressure (absolute) is higher than atmospheric pressure. In some such embodiments, the pressure (absolute) is from about 2.0 to about 3.0 bar, or from about 2.6 to about 2.8 bar. To illustrate, in some embodiments, the pressure (absolute) is about 2.7 bar. Although it is contemplated that higher pressures than the indicated ranges may be used, such pressures may require more expensive equipment designed to efficiently handle such pressures. And, although it is contemplated that lower pressures than these ranges may be used, such pressures may coincide with an undesired loss of solvent, especially when the solvent is dichloromethane. Such pressures may also coincide with the formation of undesirable by-products.

The reaction time for the Friedel-Crafts reaction may depend on various factors, including, for example, reaction temperature, solvent characteristics, relative amounts of ingredients, and the desired conversion. In a batch reactor, the reaction time for the Friedel-Crafts reaction is typically at least about 1 minute, usually at least about 5 minutes, and more often more than about 1 hour. In some embodiments, for example, the reaction time for the Friedel-Crafts reaction is from about 2.5 to about 12 hours, or from about 2 to about 6 hours. To illustrate, in some embodiments, the reaction time is about 4 hours.

In some embodiments, the reaction time includes a period during which chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate and Lewis acid are combined. In some embodiments, for example, chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate is charged to a reactor containing a Lewis acid (e.g., AlCl ₃ ), or vice versa, for a period of from about 2 to about 10 hours. In some embodiments, this download occurs over a period of about 3 to about 6 hours. In other embodiments, the download occurs over a period of about 2 to about 5 hours. For clarification, in some embodiments, chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate is charged to a reactor containing a Lewis acid (e.g., AlCl ₃ ), or vice versa, for a period of about 4 hours. Although it is contemplated that loading time periods less than the indicated limits may be used, such loading time periods may coincide with the formation of undesirable by-products due to intermolecular side reactions. And, although it is contemplated that loading time periods longer than the specified limits may be used, such loading time periods may coincide with loss of performance. When there is a loading period, the reaction mixture is usually subsequently maintained (or “maintained”) for additional time under, for example, the same conditions (eg, temperature and / or pressure) under agitation (eg, stirring). In some embodiments, for example, this additional time is from about 30 minutes to about 2 hours, or from about 45 to about 75 minutes. For clarification, in some embodiments, the reaction mixture is maintained for an additional hour after loading. Although it is contemplated that aging periods shorter than the indicated limits may be used, they may coincide with reduced conversion and yield. And, although it is anticipated that longer aging periods may be used, they may coincide with a more significant decomposition of the product and inefficient use of equipment and labor.

To initiate the hydrolysis reaction, a suspension from the Friedel-Crafts reaction is added to the acid, or vice versa.

Although it is contemplated that various acids (or combinations thereof) may be used in hydrolysis, a strong acid is preferred. In some embodiments, the implementation, for example, the acid is HCl.

The amount of acid charged to the reactor may vary. In general, it is preferable to use an excess of acid. In some embodiments, for example, the amount of acid (eg, HCl) charged to the reactor is about 1.05 equivalent based on moles of chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate. In some embodiments, where chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate is prepared according to section A-1, the amount of acid used in hydrolysis is about 1.05 equivalent based on moles 4 - (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid used in the reaction of section A-1.

Typically, the acid is preferably obtained in the form of an aqueous solution before combining with other reaction ingredients. In some such embodiments, the weight ratio of HCl to water in the acid solution is from about 0.034 to about 0.142, or from about 0.038 to about 0.061. To illustrate, in some embodiments, the weight ratio is about 0.044 or about 0.045. Although it is contemplated that mass ratios that are less than these ratios may be used, such ratios may coincide with a higher concentration of salt impurities in the product. And, although it is assumed that mass relations can be used that are larger than these relations, such relations may coincide with a loss of output.

The amount of water used in the hydrolysis reaction may vary. In some embodiments, for example, the total amount of water is from about 73 to about 245 equivalents (or from about 147 to about 196 equivalents) based on the amount of chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate used . In some embodiments, where chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate is prepared according to section A-1, the amount of water used in the hydrolysis is from about 73 to about 245 equivalents (or from about 147 to about 196 equivalents) based on moles of 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid used in the reaction of section A-1. To illustrate, in some embodiments, the total amount of water used in the hydrolysis is about 171 equivalents based on moles of 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid used in section A-1 reaction. Although it is contemplated that smaller amounts of water than the indicated limits may be used, such amounts may coincide with a higher concentration of undesirable salt impurities in the final product.

Hydrolysis can be carried out over a wide range of temperatures. This reaction is exothermic and, therefore, as the reaction proceeds, the temperature of the reaction mixture will generally increase. In some embodiments, the suspension from the Friedel-Crafts reaction is added (preferably over time, e.g., in portions) to an aqueous acidic mixture (e.g., 33% HCl), which is at a temperature of about 0 ° C, at a rate that allows you to maintain the temperature from about 0 to about 38 ° C, from about 0 to about 20 ° C, from about 10 to about 40 ° C, or from about 10 to about 15 ° C. To illustrate, in some embodiments, the aqueous acidic mixture is charged at a rate that allows the temperature to be maintained at about 12 ° C. Once the batch is completed, the reaction mixture is preferably maintained at a temperature of from about 0 to about 65 ° C. until all (or substantially all) of the solvent is distilled off. In some embodiments, the implementation of the temperature is from about 10 to about 40 ° C. In other embodiments, the implementation of the temperature is from about 35 to about 50 ° C. For clarification, in some embodiments, the implementation of the temperature is about 38 ° C. Although it is contemplated that temperatures lower than these ranges may be used, typically, such temperatures may coincide with ice formation and reduced or delayed hydrolysis. And, although it is contemplated that higher temperatures than these ranges may be used, usually such temperatures may coincide with foaming, loss of solvent (especially when the solvent is dichloromethane) and / or decomposition of the product.

Hydrolysis can be carried out in a wide range of pressures. In some embodiments, the hydrolysis is carried out at a pressure below atmospheric. Such pressures below atmospheric can be advantageous both for the distillation of the solvent (for example, dichloromethane) used in the Friedel-Crafts reaction, and for cooling highly exothermic hydrolysis. This can increase productivity and reduce energy consumption. In some embodiments, the pressure (absolute) is from about 100 to about 1000 millibars, from about 200 to about 900 millibars, or from about 270 to about 470 millibars. In other embodiments, the implementation of the pressure (absolute) is from about 300 mbar to about atmospheric pressure. To illustrate, in some embodiments, the pressure (absolute) is about 300 mbar. Such pressure limits are particularly suitable for the distillation of dichloromethane at a temperature of from about 10 to about 40 ° C. Typically, such pressure limits can be used while the suspension from the Friedel-Crafts reaction is transferred to the acid mixture (or vice versa), as well as during the rest of the reaction. This allows the distillation of the solvent to occur in parallel with the transfer and reaction. In some embodiments, the pressure is increased during hydrolysis. In some such embodiments, for example, hydrolysis is initiated at a (absolute) pressure of about 300 mbar and then allowed to rise to about atmospheric pressure. Although it is contemplated that pressures less than the indicated ranges may be used, such pressures may coincide with an undesired solvent loss rate, especially when the solvent is dichloromethane.

The hydrolysis reaction time may depend on various factors, including, for example, reaction temperature, solvent characteristics, relative amounts of ingredients, pressure and dissolution of aluminum hydroxide formed during hydrolysis. In some embodiments, the reaction conditions are maintained until solvent stripping from the Friedel-Crafts reaction is substantially (or completely) complete.

In some embodiments, the distillate is reused. Under the indicated reaction conditions, the distillate tends to contain a solvent as well as water (for example, about 3% (v / v)). When the solvent is non-polar (e.g. dichloromethane), the non-polar solvent and water in the distillate can be separated, for example, by pumping the distillate through a coagulator. Such a coagulator can be used to obtain a non-polar solvent having a water content of not more than, for example, about 0.2% (v / v). In some embodiments, additional water is removed using, for example, molecular sieves (e.g., 4Å molecular sieves). The dried non-polar solvent can be reused in the method.

Both the Friedel-Crafts reaction and hydrolysis can be carried out in various atmospheres. In some embodiments, for example, both are carried out in inert atmospheres, which may be different, but are preferably the same. One such atmosphere, for example, contains N ₂ . In some such embodiments, the atmosphere consists of (or consists essentially of) N ₂ .

Both the Friedel-Crafts reaction and hydrolysis can be carried out in various types of reactors. In some embodiments, for example, the reactor is a stirred reactor. Glass or glass lined reactors are often preferred, although some composition that is stable when the reaction mixture is accessed can be used. For example, during hydrolysis, the reactor components in contact with the reaction mixture may contain, for example, a stainless steel alloy (HASTELLOY®), which is resistant to degradation under acidic conditions. Since HCl gas is generated during the Friedel-Crafts reaction, the reactor used during the Friedel-Crafts reaction preferably contains a mechanism for safely removing HCl gas, such as, for example, a mechanism containing an outlet for overpressure relief. Also, during the loading of Lewis acid (e.g., AlCl ₃ ) and the remaining later stages of the Friedel-Crafts reaction, the reaction mixture is preferably shaken (e.g. stirred) at a speed that is fast enough to minimize intermolecular side reactions and the formation of undesired side effects products at the same time also slow enough to minimize the deposition of the crust of Lewis acid on the wall of the reactor.

It is contemplated that the product of such hydrolysis can be used in the next step without further purification or isolation. Typically, however, the product is preferably isolated and purified. This can be achieved by various separation and washing methods. For clarification, the temperature of the product mixture can be lowered to the temperature at which precipitation of the desired amount of the product 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione. In some embodiments, the temperature of the product mixture is adjusted to a temperature of from about -5 to about 20 ° C, from about -5 to about 5 ° C, or from about 0 to about 5 ° C. Although it is contemplated that temperatures lower than the indicated ranges may be used, such temperatures may coincide with a higher concentration of undesirable impurities in the product. And, although it is contemplated that temperatures higher than the indicated ranges may be used, such temperatures may coincide with loss of yield.

After adjusting the temperature, the solid 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione can be separated from the aqueous mixture using various separation techniques, such as, for example, centrifugation. Then the product is preferably washed with water one or more times. In some embodiments, for example, the product is washed with water 4 times. The amount of water used during washing may vary. In some embodiments, for example, the amount of water used for washing is from about 0.9 to about 1.8 kg (or from about 1.3 to about 1.7 kg) per kilogram of reagent used, chlorine 2,3-dihydro -2-oxo-1H-benzimidazole-1-butanoate. In some embodiments, where chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate is prepared according to section A-1, the amount of water used for washing is from about 1 to about 2 kg (or from about 1.3 to about 1.8 kg) per kilogram of 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid used in the reaction of section A-1. To illustrate, in some embodiments, the amount of water used for washing is about 1.5 kg per kilogram of 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid used in section A-1 reaction. Although it is contemplated that smaller amounts of water than the indicated limits may be used, such amounts may coincide with a higher concentration of salt impurities remaining in the product. And, although it is contemplated that larger amounts of water may be used than these limits, such amounts may coincide with loss of yield.

In some embodiments, the product is also washed with one or more organic solvents. In some such embodiments, the product is washed with acetone one or more times. In other embodiments, the product is washed with isopropanol one or more times. In some such embodiments, for example, the product is washed with isopropanol once. The amount of isopropanol used during washing may vary. In some embodiments, for example, the amount of isopropanol used for washing is from about 0.9 to about 4.2 kg (or from about 1.4 to about 1.7 kg) per kilogram of reagent chlorine 2,3-dihydro -2-oxo-1H-benzimidazole-1-butanoate. In some embodiments, where chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate is prepared according to section A-1, the amount of isopropanol used for washing is from about 1.0 to about 4, 5 kg (or from about 1.5 to about 1.8 kg) per kilogram of 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid used in the reaction of section A-1. To illustrate, in some embodiments, the amount of isopropanol used for washing is about 1.6 kg per kilogram of 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid used in section A-1 reaction. Although it is contemplated that smaller amounts of isopropanol than the indicated limits may be used, such amounts may coincide with higher concentrations of organic impurities remaining in the product. And, although it is contemplated that greater amounts of isopropanol may be used than the indicated limits, such amounts may coincide with loss of yield.

Each washing of the product with an organic solvent (e.g., isopropanol) is preferably carried out at a temperature of from about -5 to about 20 ° C, from about 0 to about 10 ° C, or from about 0 to about 5 ° C. Although it is contemplated that temperatures less than these ranges may be used, such temperatures may coincide with a higher concentration of impurities remaining in the product. And, although it is contemplated that temperatures higher than the indicated ranges may be used, such temperatures may coincide with loss of yield.

Drying the washed product (especially complete drying) is generally not necessary before using the product in the next step. Thus, in at least some embodiments, the washed product is not dried prior to use in the next step. This provides, for example, energy and time savings.

In some embodiments, where aluminum chloride is used as the Lewis acid in the Friedel-Crafts reaction, aluminum hydroxide is recovered from the aqueous supernatant that forms when the solid product is 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione is separated from the reaction mixture of products. In such embodiments, the aqueous supernatant may, for example, be treated with a base (usually a strong base such as sodium hydroxide) and carbon dioxide. This causes aluminum hydroxide to precipitate, which in turn can be recovered using various separation techniques, such as, for example, centrifugation. The use of the chlorinating agents indicated in Section A-1 (especially oxalyl chloride), and not, for example, PCl ₅ , in the Friedel-Crafts reaction tends to be particularly advantageous in embodiments where aluminum hydroxide is recovered. PCl ₅ , on the contrary, is prone to the formation of phosphorus impurities, which may make aluminum hydroxide less suitable for other applications.

A-3. Preparation of 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6-oxime

In some embodiments, the synthesis of zilpaterol or its salt begins with or includes the preparation of 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6-oxime:

In some embodiments, 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6-oxime is prepared, for example, by the reaction of 8,9-dihydro -2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione with inorganic nitrite by the following oxime reaction:

The 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione used in this reaction can be obtained from a commercial seller (in existing volumes), prepared in the method specified in section A-2, or obtained using another method. In some embodiments, 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione is prepared according to the method described in US Pat. No. 4,585,770. In some preferred embodiments, 8,9-dihydro- 2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione is prepared using the method described in section A-2.

Inorganic nitrite may vary. In some embodiments, inorganic nitrite comprises nitrosyl sulfate:

nitrosyl sulfate

In other embodiments, inorganic nitrite comprises at least one nitrite salt. Such a nitrite salt may be selected from various salts. In some embodiments, the nitrite salt comprises sodium nitrite (NaNO ₂ ).

The amount of inorganic nitrite may vary. In some embodiments, for example, the amount is from about 1.10 to about 1.26 equivalents. In some such embodiments, the amount is from about 1.16 to about 1.26 equivalents (or from about 1.20 to about 1, 22 equivalents), based on moles of the reagent 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione. In other embodiments, the amount is from about 1.10 to about 1.20 equivalent based on moles of the reagent 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione. Although it is contemplated that smaller amounts than the indicated ranges may be used, such amounts may coincide with a reduced degree of conversion. And, although it is contemplated that amounts greater than the indicated ranges may be used, such amounts may coincide with the formation of undesirable by-products.

Acid can be selected from various acids. In some embodiments, the acid contains a strong acid. Preferred acids include HCl. The amount of acid may vary. Typically, an excess of acid is used relative to the amount of the reagent 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione. In some embodiments, for example, the amount is from about 1.24 to about 1.75 equivalents (or from about 1.52 to about 1.68 equivalents) based on moles of the reagent 8.9-dihydro-2H, 7H-2, 9a-diazabenzo [cd] azulene-1,6-dione. To illustrate, in some embodiments, the amount is about 1.60 equivalent. Although it is contemplated that smaller amounts of acid may be used than the indicated ranges, such amounts may coincide with a reduced degree of conversion. And, although it is contemplated that amounts greater than the indicated ranges may be used, such amounts may coincide with a higher concentration of impurities in the product. Higher acid concentrations may also coincide with corrosion of the reactor, depending on the composition of the reactor.

This reaction is usually carried out in the presence of one or more solvents. In some embodiments, the solvent comprises dimethylformamide. In some embodiments, the amount of solvent is from about 15.5 to about 25.6 liters (or from about 17.4 to about 21.0 liters or from about 18.2 to about 18.3 liters) per kilogram of reagent 8.9 -dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione. Although it is contemplated that amounts less than the indicated ranges may be used, such amounts may coincide with reduced dissolution and / or formation of undesired by-products. And, although it is contemplated that amounts greater than the indicated limits may be used, such amounts may coincide with loss of yield.

In some embodiments, this reaction is initially initiated by combining a solvent (eg, dimethylformamide), inorganic nitrite (eg, NaNO ₂ ) and 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione . In some embodiments, this is carried out at a temperature of from about 40 to about 65 ° C or from about 40 to about 50 ° C. To illustrate, in some embodiments, this is carried out at a temperature of about 45 ° C. Although it is contemplated that temperatures lower than the indicated ranges may be used, such temperatures may coincide with reduced dissolution and / or formation of undesired by-products. And, although it is contemplated that temperatures greater than the indicated limits may be used, such temperatures may coincide with the decomposition of the reagent 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione.

In some embodiments, the resulting mixture is preheated before the acid is added. In some such embodiments, for example, the mixture is preheated to from about 47 to about 63 ° C or from about 48 to about 55 ° C. To illustrate, in some embodiments, the mixture is preheated to about 50 ° C. Although it is contemplated that lower temperatures than these ranges may be used, such temperatures may coincide with a reduced degree of conversion. And, although it is contemplated that temperatures higher than the indicated ranges may be used, such temperatures may coincide with the formation of undesirable by-products.

After preheating, acid (e.g., HCl) is charged to the reactor. In some embodiments, the loading acid is in the form of an aqueous solution. When, for example, the acid is HCl, the concentration of HCl in the solution is usually not higher than about 50%, not higher than about 48%, from about 1 to about 40%, or from about 32 to about 33% (w / v). Can also be used, for example, gaseous HCl (100%).

The total reaction time for this reaction may depend on various factors, including, for example, reaction temperature, solvent characteristics, relative amounts of ingredients, and the desired conversion.

The reaction time usually includes a long period during which the acid solution is combined with the remaining components of the reaction. In some such embodiments, for example, the acid is charged over a period of about 10 minutes to about 2 hours, about 30 minutes to about 1 hour, or about 30 to about 45 minutes. Although it is contemplated that shorter time periods than the indicated limits may be used, such time periods may coincide with an excessively large increase in temperature (the reaction is exothermic) and the formation of undesirable by-products. Although it is contemplated that longer periods of time than the indicated limits may be used, such periods may coincide with a reduced degree of conversion, as well as inefficient use of equipment and labor.

As discussed above, the temperature usually rises during acid loading due to the exothermic nature of the reaction. In some embodiments, the implementation of the temperature rises to a temperature of from about 54 to about 73 ° C, from about 55 to about 70 ° C, from about 60 to about 70 ° C, or from about 60 to about 66 ° C. To illustrate, in some embodiments, the temperature rises to about 63 ° C. Although it is contemplated that temperature increases less than these ranges may be appropriate, such temperatures may coincide with a reduced degree of conversion. And, although it is contemplated that temperature increases greater than these ranges may be appropriate, such temperatures may coincide with the formation of undesirable by-products.

After the acid is charged, the reaction mixture is additionally supported (or “maintained”), usually with agitation (eg, stirring), for an additional period. In some embodiments, the additional period lasts from about 15 minutes to about 21 hours, from about 15 minutes to about 10 hours, from about 15 minutes to about 2 hours, or from about 25 to about 40 minutes. For clarification, in some embodiments, the implementation of the additional period is about 30 minutes. Although it is contemplated that shorter time periods than the indicated limits may be used, such time periods may coincide with a reduced degree of conversion. And, although it is contemplated that longer periods of time than these limits may be used, such periods may coincide with the formation of undesirable by-products, as well as with the inefficient use of equipment and labor.

The reaction conditions (e.g., temperature, pressure and / or stirring speed) during the holding period can be kept the same as during the addition of acid. Conditions, however, may also be different. In some embodiments, the temperature during said additional period is from about 55 to about 70 ° C, from about 55 to about 65 ° C, or from about 58 to about 62 ° C. For clarification, in some embodiments, the implementation of the temperature is about 60 ° C. Although it is contemplated that lower temperatures than these ranges may be used, such temperatures may coincide with a reduced degree of conversion. And, although it is contemplated that higher temperatures than these ranges may be used, such temperatures may coincide with the formation of undesirable by-products.

In some embodiments, water is charged to the reactor after a holding period. In some embodiments, the temperature of the reaction mixture is adjusted before adding water to a temperature of from about 0 to about 48 ° C, from about 35 to about 40 ° C, or from about 35 to about 38 ° C. Although it is contemplated that lower temperatures than the indicated ranges may be used, such temperatures may coincide with difficulties in filtering the product and loss of yield. And, although it is contemplated that higher temperatures than these ranges may be used, such temperatures may coincide with the formation of undesirable by-products. In some embodiments, the temperature is adjusted over an extended period of time before adding water. In some such embodiments, for example, the temperature is adjusted over a period of from about 30 minutes to about 5 days, from about 1 to about 10 hours, from about 3 to about 5 hours, or from about 2 to about 4 hours. Although it is contemplated that shorter time periods than the indicated limits may be used, such time periods may coincide with difficulties in filtering the product. And, although it is contemplated that longer periods of time than these ranges may be used, such temperatures may coincide with the formation of undesirable by-products. Typically, the adjusted temperature is maintained during at least part (or substantially all) of the addition of water.

In some embodiments, the addition of water occurs over an extended period of time. For example, in some embodiments, water is added over a period of about 30 minutes to about 5 hours, about 1 to about 4 hours, or about 2 to about 3 hours. Although it is contemplated that shorter time periods than the indicated limits may be used, such time periods may coincide with difficulties in filtering the product and loss of yield. And, although it is contemplated that longer periods of time than these limits may be used, such temperatures may coincide with a higher concentration of impurities in the product.

The amount of water may vary. In some embodiments, for example, the amount is from about 33 to about 88 equivalents (or from about 45 to about 67 equivalents or from about 54 to about 55 equivalents) based on moles of the reagent 8.9-dihydro-2H, 7H-2, 9a-diazabenzo [cd] azulene-1,6-dione. Although it is contemplated that amounts beyond these ranges may be used, such amounts may coincide with a higher concentration of impurities in the product and loss of yield.

In some embodiments, the temperature of the reaction mixture is adjusted to promote precipitation of the product. In embodiments where water is added, this temperature adjustment is usually carried out after the addition of water. In some such embodiments, for example, the temperature is lowered to a temperature of from about -10 to about 10 ° C, from about -5 to about 2 ° C, or from about -2 to about 0 ° C. Although it is contemplated that lower temperatures than these ranges may be used, such temperatures may coincide with ice formation and / or a higher concentration of impurities in the product. And, although it is contemplated that higher temperatures than these ranges may be used, such temperatures may coincide with less crystallization and loss of yield. In some embodiments, the temperature is adjusted over an extended period of time. In some such embodiments, for example, the temperature is controlled over a period of from about 1 to about 10 hours, from about 2 to about 6 hours, from about 2 to about 5 hours, or from about 2 to about 4 hours. Although it is contemplated that shorter periods of time than these limits may be used, such periods of time may coincide with less crystallization and loss of yield.

In some embodiments, when the temperature is adjusted to promote precipitation of the product, the temperature is maintained within the indicated limits for a period of time. In some such embodiments, the temperature is maintained within such limits for a period of not more than about 14 days, from about 1 to about 40 hours, from about 30 minutes to about 2 hours, or from about 45 minutes to about 2 hours. Although it is contemplated that shorter periods of time than these limits may be used, such periods of time may coincide with less crystallization and loss of yield.

This reaction can be carried out in various atmospheres, but preferably it is carried out in an inert atmosphere. One such atmosphere, for example, contains N ₂ .

This reaction can be carried out in a wide range of pressures, including atmospheric pressure (absolute), pressure below atmospheric (absolute) and above atmospheric pressure (absolute). It is usually preferred, however, to carry out the reaction at a pressure close to atmospheric (absolute).

This reaction can be carried out in various types of reactors. In some embodiments, for example, the reactor is a stirred reactor. Glass or glass lined reactors are often preferred, although some composition that is stable when the reaction mixture is accessible can be used.

It is assumed that the product mixture can subsequently be used as a reagent without additional isolation or purification. Typically, however, the product 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -rion-6-oxime is first separated from the product mixture and then purified. In some embodiments, this is achieved, for example, by various methods known in the art.

In some embodiments, the solid 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -rion-6-oxime solid in the product mixture is separated from the mixture using, for example filtering.

In some embodiments, a solvent (eg, dimethylformamide) is returned for reuse from the mother liquor by distillation. In embodiments where the mother liquor contains both water and dimethylformamide, for example, water can be removed by subsequent distillation of dimethylformamide.

After separation, the product is preferably washed using water one or more times. In some embodiments, for example, the product is washed with water 2, 3, or 4 times. The amount of water used during washing may vary. In some embodiments, for example, the total amount of water used during washes is from about 4.4 to about 9.0 L (or from about 5.4 to about 7.5 L) per kilogram of 8.9-dihydro reagent -2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione used in the synthesis. In some embodiments, for example, the total amount of water is about 6.0 L per kilogram of the reagent 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione used in the synthesis. Although it is contemplated that smaller amounts of water than the indicated limits may be used, such amounts may coincide with a higher concentration of impurities remaining in the product. And, although it is contemplated that larger amounts of water may be used than these limits, such amounts may coincide with loss of yield. Centrifugation, for example, can be used to separate water from the product.

In some embodiments, the product is also washed with one or more organic solvents. In some such embodiments, the product is washed with acetone one or more times. In some such embodiments, for example, the product is washed with acetone once. The amount of acetone used during washing may vary. In some embodiments, for example, the total amount of acetone is from about 2.2 to about 8.6 L (or from about 2.8 to about 4.4 L) per kilogram of 8.9-dihydro-2H, 7H-2 reagent , 9a-diazabenzo [cd] azulene-1,6-dione used in the synthesis. In some embodiments, for example, the total amount of acetone is about 3.2 L per kilogram of the reagent 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione used in the synthesis. Although it is contemplated that smaller amounts of acetone than the indicated limits may be used, such amounts may coincide with higher concentrations of impurities and water remaining in the product. And, although it is contemplated that greater amounts of acetone may be used than the indicated limits, such amounts may coincide with loss of yield. Separation of acetone from the product can be achieved using, for example, centrifugation.

In some embodiments, the washed 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -rion-6-oxime washed product is dried. In some embodiments, this is achieved by heating the solid at a temperature of from about 20 to about 80 ° C or from about 20 to about 75 ° C. For clarification, in some such embodiments, the product is heated to a temperature of 65 ° C. Although it is contemplated that lower temperatures than these ranges may be used, such temperatures may coincide with a loss in performance. And, although it is contemplated that higher temperatures than these ranges may be used, such values may coincide with the decomposition of the product. In some embodiments, the heating is maintained in less than about 3 days, or from about 5 to about 10 hours. Although it is contemplated that drying periods longer than the above limits may be used, such longer periods may coincide with loss of productivity as well as inefficient use of equipment and labor. In some embodiments, this drying is carried out under vacuum.

A-4. Getting zilpaterol

Zilpaterol can be obtained from any of the products from sections A-1, A-2 or A-3 using various methods.

For example, the product of section A-3 can be used to produce zilpaterol by its direct use as a reagent in the method illustrated in Example 5 below. The product of section A-2 can be used to obtain zilpaterol, for example, using it as a reagent to obtain the product of section A-3 according to section A-3, followed by the use of the product of section A-3 as a reagent in the method illustrated in example 5. And the product of section A-1 can be used to obtain zilpaterol, for example, by using it as a reagent to obtain the product of section A-2 according to section A-2, followed by the use of the product of section A-2 to obtain the product of section A-3 according to section A-3 then applying section A-3 product as a reagent in the process for explaining an example 5. Such methods are further explained below in the illustrative schemes common in section A-5.

Zilpaterol can also be obtained from the products of sections A-1, A-2 and A-3 by, for example, combining the indications of this patent with other methods known in the art. For clarification, the product of section A-3 can be used as a reagent for producing zilpaterol according to the synthesis technologies discussed, for example, in US Pat. No. 4,585,770. The product of section A-2 can be used to obtain zilpaterol, for example, by using it as a reagent to obtain the product of section A-3 according to section A-3, followed by the use of the product of section A-3 as a reagent for the synthesis technologies discussed, for example, in US patent 4,585,770. And the product of section A-1 can be used to obtain zilpaterol for example, by using it as a reagent to obtain the product of section A-2 according to section A-2, followed by using the product of section A-2 as a reagent to obtain the product of section A-3 according to section A-3, followed by use of the product Section A-3 as a reagent for the synthesis technologies discussed, for example, in US Pat . No. 4,585,770 . See, for example, US Patent 4,585,770, Art. 2, line 33 to Article 4, line 2; Art. 7, lines 51-68 and Art. 11, lines 41-48 (where the preparation of a hydroxyamine compound from 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -rion-6-oxime is discussed and explained and then obtaining zilpaterol-HCl from a hydroxyamine compound).

A-5. Examples of schemes for the alleged reactions

This invention relates to methods that use any of these reactions. In some embodiments, the implementation of the method will include only one of these reactions. In other embodiments, the method will comprise more than one of these reactions. The following diagram I outlines a plan of action where all of the reactions indicated are used:

The following Scheme II illustrates in general terms the indicated action plan where the chlorinating agent contains oxalyl chloride, the Lewis acid contains AlCl ₃ , the hydrolysis acid after the Friedel-Crafts reaction contains HCl, the inorganic nitrite contains NaNO ₂ , the acid used in the oximation contains HCl, water is added to a mixture of oxime products in order to accelerate the isolation of the oxime product, the base used to obtain the oxime salt contains KOH, the initial hydrogenation catalyst contains palladium on carbon, acid, being operated to izopropilidenaminosoedineniya formation comprises acetic acid, the second hydrogenation catalyst comprises platinum on carbon, and the base and the alcohol used to form the free base zilpaterol contain NaOH and ethanol, respectively:

B. Salts

It should be understood that this invention further encompasses embodiments where one or more of the reagents and / or products in said synthesis reactions may be in salt form. This is especially true for the zilpaterol product, which may be, for example, in the form of one or more acid addition salts, such as an HCl salt. Salts may be, for example, base addition salts or acids. Typically, an acid addition salt can be prepared using various inorganic or organic acids, and a base addition salt can be prepared using various inorganic or organic bases. Such salts can usually be formed, for example, by mixing the compound in the form of a free base with an acid or mixing the compound in the form of a free acid with a base, for example, by various methods known in the art. Salt may be preferred due to one or more of its chemical or physical properties, such as stability at various temperatures and humidity or the desired solubility in water, oil, or other solvents. In some circumstances, the salt of the compound may also be used as an auxiliary agent in isolating or purifying the compound. In some embodiments (especially where the salt is intended for administration to an animal or is a reagent for use in the preparation of a compound or salt intended for administration to an animal), the salt is pharmaceutically acceptable. The term "pharmaceutically acceptable" is used to describe a salt as being suitable for use in a pharmaceutical product. Typically, a pharmaceutically acceptable salt has one or more advantages that outweigh any harmful effect that the salt may have.

Examples of inorganic acids that can typically be used to form acid addition salts include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acids. Examples of organic acids include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carbocyclic and sulfonic classes of organic acids. Specific examples of organic salts include cholate, sorbate, laurate, acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid and its derivatives (e.g. dibenzoyl tartrate), citrate, ascorbate, glucuronate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate (and its derivatives), embonate (pamoate), ethanesulfonate, benzenesulfonate, pantothenanesulfonate, 2-pantothenanesulfonate, 2-pantothenanesulfonate, 2 minosulfonate, alginic acid, β-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, butyrate, camphorate, camphosulphonate, cyclopentane propionate, dodecyl sulfate, glucoheptanoate, glycerophosphate, heptanoate naphthalene peptate, hexanoate, hexanoate, hexanoate, hexanoate, hexanoate, hexanoate, hexanoate, hexanoate, hexanoate phenylpropionate, picrate, pivalate, thiocyanate, tosylate and undecanoate.

Examples of base addition salts may include, for example, metal salts and organic salts. Metal salts, for example, include alkali metal salts (group Ia), alkaline earth metal salts (group IIa) and other physiologically acceptable metal salts. Such salts can be obtained from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. For example, a free acid compound can be mixed with NaOH to form such a base addition salt. Organic salts can be obtained from amines such as trimethylamine, diethylamine, N, N'-dibenzylethylenediamine, chlorprocaine, ethanolamine, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Nitrogen-containing groups of a basic nature can be quaternized with agents such as C ₁ -C ₆ alkyl halides (e.g. methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl and diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), arylalkyl halides (e.g. benzyl and phenethyl bromides) and others.

C. Use of zilpaterol and its salts obtained

in accordance with this invention

Compositions containing zilpaterol or salt obtained in accordance with this invention can usually be used, for example, to increase the rate of weight gain, improve feed efficiency and / or increase lean carcasses in cattle, poultry and fish.

Typically, the zilpaterol or salt composition is administered orally. In some embodiments, the composition is added to drinking water intended for the animal recipient. In other embodiments, zilpaterol or salt is added to the intended recipient feed either directly or as part of the premix. Suitable dosage forms for oral administration include, for example, solid dosage forms (e.g., tablets, hard or soft capsules, granules, powders, etc.), pastes and liquid dosage forms (e.g., solutions, suspensions, emulsions, syrups, etc. .d.). Such dosage forms optionally contain one or more suitable excipients. Such excipients typically include, for example, sweetening agents, flavoring agents, coloring agents, spoilage agents, inert diluents (e.g. calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate or kaolin), granulating and disintegrating agents (e.g. corn starch or alginic acid), binders (e.g. gelatin, acacia gum or carboxymethyl cellulose) and lubricants (e.g. magnesium stearate, stearic acid or talc). Liquid compositions will usually contain a solvent. The solvent preferably has sufficient chemical properties and quantity to keep the zilpaterol or salt solubilized at ordinary storage temperatures of the composition. In some circumstances, it may be desirable for the composition to contain one or more preservatives. The presence of a preservative may, for example, allow the composition to be stored for a longer time.

In some embodiments, the implementation of zilpaterol or salt is in the form of particles adhering to a carrier, which, in turn, is fed to the appropriate animal recipient. Zilpaterol or a salt on a carrier can be incorporated into the intended recipient feed, either directly or as part of a premix. Proposed carriers include, for example, added carriers such as calcium carbonate, limestone, oyster shell flour, talcum powder, soybean husk, soybean meal, soybean meal, soybean plantings, wheat bran, rice chaff, cornmeal, corn germ meal , gluten, starch, sucrose and lactose. In particular, the intended carriers include corn cobs, such as the carrier mentioned in US Pat. No. 5,731,028. In some embodiments using corn cobs, the size of the carrier is from about 300 to about 800 microns. Preferably, the zilpaterol or salt particles that adhere to the carrier have a particle size that is less than the size of the carrier. So, for example, in some embodiments, where the carrier has a size of from about 300 to about 800 microns, particles (or at least about 95% of the particles) are less than about 250 microns. In some embodiments, the implementation of the size of most particles is from about 50 to about 200 microns. In order to avoid dust formation in the preparation of zilpaterol or salt on a carrier, it is preferable to avoid using too small particles of zilpaterol or salt. In some embodiments, for example, the particle size distribution of zilpaterol or salt is such that less than about 5% of the particles of zilpaterol or salt has a particle size of less than about 15 microns. Considered, for example, in US patent 5731028 (attached to this link) methods for obtaining a specific size distribution of crystalline zilpaterol can mainly be applied when crystals are obtained having the above size distributions.

To the extent that the composition is incorporated into the feed, the feed mixture will vary depending, for example, on the type (e.g., species and breed), age, weight, activity and condition of the respective recipient. For cows and pigs, various feeds are well known in the art and often contain cereals, sugars, grains, peanut, sunflower and soybean meal, animal meal such as fish meal, amino acids, mineral salts, vitamins, antioxidants, etc. Typically, a zilpaterol or salt composition may be formulated in any feed that is available and used for the respective animal recipient.

It is contemplated that the zilpaterol or salt composition can be administered not only orally, but also, for example, rectally, by inhalation (e.g., through a haze or aerosol), transdermally (e.g., using a transdermal patch), or parenterally (e.g., by subcutaneous injection, intravenous injection, intramuscular injection, implantable device, partially implantable device, etc.). In some specific embodiments, the composition is administered via an implant, such as a subcutaneous implant. For administration to cows or pigs, for example, the composition may be in the form of an implant placed behind the ear.

Typically, the zilpaterol or salt composition is administered in a dosage form that provides an effective amount of zilpaterol or salt. This is especially true when zilpaterol or salt is the only active ingredient in the composition. To the extent that zilpaterol or salt is administered with another active ingredient (s), the dosage preferably contains such an amount of zilpaterol or salt that, together with the amount of other active ingredient (s), it is an effective amount. In the context of zilpaterol or salt, “effective amount” means an amount sufficient to increase the rate of weight gain, improve feed efficiency and / or increase the lean carcass of the corresponding recipient (usually cattle, poultry and / or fish).

When the composition is administered orally, it is usually preferable to use a daily dosage form. The preferred total daily dose of zilpaterol or salt is usually more than about 0.01 mg / kg (i.e. milligram of zilpaterol or salt per kilogram of body weight), especially for cows and pigs. In some such embodiments, the daily dose is from about 0.01 to about 50 mg / kg, from about 0.01 to about 10 mg / kg, from about 0.05 to about 2 mg / kg, from about 0.1 to about 1, or from about 0.1 to about 0.2 mg / kg. For clarification, in some embodiments, the dose is about 0.15 mg / kg.

In some embodiments, where zilpaterol or salt is added to the food intended for the animal recipient, the concentration of zilpaterol or salt in the feed (based on 90% dry material) is at least about 0.01 ppm. (by weight). For cows, the concentration of zilpaterol or salt is preferably not more than about 75 ppm. (by weight). In some embodiments, for example, the concentration of zilpaterol or salt is not more than about 38 ppm, from about 0.5 to about 20 ppm, from about 3 to about 8 ppm, or from about 3 7 to about 7.5 ppm (by weight). For pigs, the concentration of zilpaterol or salt is preferably not more than about 45 ppm. (by weight). In some such embodiments, for example, a concentration of not more than about 23 ppm, from about 0.5 to about 20 ppm, from about 2 to about 5 ppm. or from about 2.2 to about 4.5 ppm. (by weight).

Although single daily doses are generally preferred, it is contemplated that shorter or longer periods between doses may be used depending on, for example, the metabolism of zilpaterol or salt in the recipient's body. It is contemplated that smaller doses may be administered two or more times daily to achieve the desired total daily dose. Such multiple daily doses may, in some circumstances, be used to increase the total daily dose for oral administration, if desired.

When administered via a subcutaneous implant, the preferred total daily dose of zilpaterol or salt is usually more than about 0.05 mg / kg (i.e. milligram of zilpaterol or salt per kilogram of body weight), especially for cows and pigs. In some such embodiments, the daily dose is from about 0.1 to about 0.25 mg / kg.

If the zilpaterol or salt composition is administered parenterally by injection, the concentration of zilpaterol or salt in the dosage form is preferably sufficient to provide the desired therapeutically effective amount of zilpaterol or salt in an amount that is acceptable for parenteral administration. As with oral feeding, an injection dosage form may be administered once a day, although it is contemplated that shorter or longer periods between doses may also be used.

Factors affecting the preferred dosage regimen may include, for example, type (eg, species and breed), age, size, gender, diet, activity, and condition of the respective recipient; type of administration used (e.g., orally with food, orally with drinking water, subcutaneous implant, other parenteral routes, etc.); pharmacological judgments such as activity, efficacy, pharmacokinetic and toxicological profiles of the particular composition administered, and whether zilpaterol or salt is administered as part of a combination of active ingredients. Thus, the preferred amount of zilpaterol or salt may vary and, therefore, may deviate from the typical dosages set forth above. The determination of such dosage adjustments is usually carried out by specialists in this field using traditional methods.

It is contemplated that the zilpaterol or salt composition may be administered to the appropriate recipient once. Typically, however, the composition is administered for some time. In some embodiments, where the animal recipient is a cattle, for example, zilpaterol or salt is administered daily for at least about 2 days, more typically daily for about 10 to about 60 days, and even more usually daily for about 20 up to about 40 days. In some specific embodiments, the composition is administered daily for from about the last 10 to about the last 60 days of the final period, or from about the last 20 to about the last 40 days of the final period. The term "completion period" refers to a later stage in the period of growing an animal. During this period, cattle are usually kept in feedlots. In some embodiments, where the cattle animal is a cow, this period lasts from about 90 to about 225 days and depends, for example, on the initial body weight of the animal. Usually, after the final period, there is a period of discontinuation of the drug during which zilpaterol or its salt is not administered. The duration of this cessation period may depend, for example, on the type (e.g., species and breed), age, weight, activity and condition of the animal recipient, as well as the maximum acceptable residual concentration in the meat of the animal.

EXAMPLES

The following examples are merely illustrative of embodiments of the invention and are not in any way limiting the rest of this disclosure.

Example 1. Obtaining 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione

Part A. Preparation of 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate chloro.

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 equiv.) And dichloromethane ( 480 g, 5.652 mol, 24.89 equiv.) Are loaded into a reaction apparatus with a stirrer. Oxalyl chloride (31.12 g, 0.245 mol, 1.08 equiv.) Is then dosed at 10-20 ° C for more than 1 hour with stirring. The resulting mixture was then stirred at 10-20 ° C for an additional hour. All these steps are carried out in an atmosphere of N ₂ .

Part B. Preparation of 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione.

The reaction mixture of the product from Part A is added to a suspension of aluminum chloride (100 g, 0.75 mol, 3.3 eq.) In dichloromethane (320 g, 3.768 mol, 16.59 eq.) For 2-5 hours at 60 ° C and a pressure of 2.7 bar (absolute) in a reaction apparatus with a stirrer, which allows the flow of gaseous HCl through the outlet to relieve excess pressure. The resulting suspension was stirred for an additional hour at the same temperature and then cooled to 12 ° C. In a separate reaction apparatus, water (800 g, 44.407 mol, 195.59 equiv.) And aqueous 32.5% HCl (118 g, 1.052 mol of HCl, 4.63 equiv. HCl) are mixed with a stirrer. This mixture is cooled to 0 ° C and gas in the free space above the product is pumped out to 300 mbar (absolute). The suspension from the first reactor is then added in portions to the second reactor, thereby raising the temperature to 10-15 ° C during the distillation of dichloromethane. The first reactor was washed with additional dichloromethane (25 g, 0.294 mol, 1.3 eq.), Which was then added to the second reactor. The distillation of dichloromethane is then completed at a pressure of 300 mbar to atmospheric pressure (absolute) and 12-40 ° C. The resulting suspension is cooled to 0 ° C. The solid is filtered and washed 4 times with water (291.25 g each, 64.668 mol in total, 284.83 equiv in total) and once with isopropanol (80 g, 1.333 mol, 1.3131 equiv) at 0 ° C. All these steps are carried out in an atmosphere of N ₂ .

Example 2. Obtaining 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6-oxime.

8,9-Dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione (50 g, 92.4% purity, 0.228 mol) obtained in accordance with the procedure in example 1 is dried and mixed with isopropanol (7.23 g, 0.12 mol, 0.53 equiv.) and water (3.01 g, 0.167 mol, 0.73 equiv.) (instead, in alternative experiments and upon receipt, 8.9- dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione obtained in accordance with the procedure in example 1, as a wet material from a centrifuge without adding 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 equiv .) and N, N-dimethylformamide (800 g, 10.945 mol, 47.9 equiv.) in a reaction apparatus with a stirrer. The mixture was heated to 50 ° C. and then 32% HCl (41.65 g, 0.366 mol HCl, 1.6 equiv. HCl) was added over a 30 minute period. By the end of the HCl addition (i.e., after adding more than 1 equiv. HCl), the temperature rises rapidly to 60-70 ° C. After all HCl was added, the mixture was stirred at 60 ° C for an additional 30 minutes. The mixture was then cooled to 35 ° C over a 2 hour period. Then water (224.71 g, 12.473 mol, 54.6 equiv.) Was added over a 2-hour period. The resulting mixture was then cooled to 0 ° C over a 2-hour period and maintained at this temperature for 2 hours. After that, the solid product 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6-oxime was removed by filtration and washed 4 times with water (70.1 ml each time, a total of 15.566 mol, 68.13 equiv. in total) and once with acetone (115.9 g, 99.9% purity, 1.994 mol, 8.73 equiv.). All these steps are carried out in an atmosphere of N ₂ .

Example 3. Obtaining on an enlarged scale 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione

Part A. Preparation of 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate chloro.

Dichloromethane (3,772 L) and then 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid (525 kg, 2.4 kmol) are charged into the reaction apparatus with a stirrer, followed by the addition of N, N-dimethylformamide ( 21 l). The resulting mixture was cooled to 10 ° C. After this, oxalyl chloride (326.8 kg) is added in portions at 10-15 ° C for 2-3 hours with stirring. The resulting mixture was then stirred at 15-20 ° C for another 1-3 hours. All these steps are carried out in an atmosphere of N ₂ . Conversion is checked by active 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 are charged into a stirred reaction vessel, followed by the addition of additional dichloromethane (112 L) at 10-20 ° C to flush the reactor. Then in the reactor create a pressure supply of N ₂ up to 2.7 bar (absolute) and heated to 58-60 ° C. Then the mixture of the product from part A is added over 2-5 hours. The resulting suspension is stirred for an additional 1-2 hours and then cooled to 10-20 ° C. After that, the pressure is released. Water (3675 L) was charged into a second reaction apparatus with a stirrer at 5 ° C, followed by aqueous 33% HCl (452 L). This mixture is cooled to 0 ° C and gas is pumped from free space to 270-470 mbar (absolute). About half of the contents from the first reactor are added to the second reactor at 5-20 ° C. The mixture is maintained at 10-30 ° C for an additional 30-90 minutes. In parallel with and after the movement, dichloromethane is distilled off. The line between the two reactors was washed with dichloromethane (150 ml). The resulting flush and the contents of the second reactor are transferred to the third reaction apparatus with a stirrer. The line along which the movement occurs between the second and third reactors is washed with water (200 L). This flush is also charged to a third reactor. Water (3675 L) at 5 ° C and 33% HCl (452 L) are then added to the second reactor. The resulting mixture was cooled to 0 ° C and the pressure in the free space was set between 270-470 mbar (absolute). The second half of the contents from the first reactor is then added to the second reactor at 5-20 ° C. This mixture is maintained at 10-30 ° C for an additional 30-90 minutes. In parallel with and after the movement, dichloromethane is distilled off. The line between the first and second reactors is washed with dichloromethane (150 ml). The resulting flush and the contents of the second reactor are transferred to the third reactor. The transfer line between the second and third reactors is then washed with water (200 L). This wash is loaded into the third reactor. In the third reactor, dichloromethane is further distilled off at 30-40 ° C at atmospheric pressure. When the distillation is complete, the suspension is cooled to 0-5 ° C and then centrifuged in two steps. Each of the precipitates obtained is washed four times with water (390 L per wash) and once with isopropanol (508 L) at 0-5 ° C. All these steps are carried out in an atmosphere of N ₂ .

Example 4. Obtaining on an enlarged scale 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6-oxime.

At 20 ° CN, N-dimethylformamide (7068 L) was charged into a stirred reaction vessel followed by the addition of 8.9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione (450 kg total wet material, approximately 405 kg pure) obtained in accordance with the procedure in Example 3. The dropping funnel is washed with N, N-dimethylformamide (105 L) and the flush is charged to the reactor. The resulting mixture was heated at 45 ° C until all 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione was dissolved. IPC is used to check the amount of pure 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione in the mixture and, based on this measurement (together with the wet weight of 8.9-dihydro- 2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione and N, N-dimethylformamide), the actual amount of 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene - is calculated 1,6-dione, which, in turn, is 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). During the IPC, the mixture was cooled to 20 ° C. Sodium nitrite (167 kg, based on 405 kg of 8.9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione) is then added. The dropping funnel is washed with N, N-dimethylformamide (105 L) and the flush is charged to the reactor. The temperature is then raised to 45 ° C. Subsequently, additional N, N-dimethylformamide was charged in the amount calculated previously (97 L to have a total of 7375 L DMF per 405 kg of 8.9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6 dione). The resulting mixture was then heated to 48 ° C and then 33% HCl (353 kg based on batch volume) was added over 1 hour, which caused the temperature to rise to 60-65 ° C by the end of the addition. The mixture was then stirred at 60 ° C for another 30 minutes. Then the mixture is cooled to 45 ° C for 1-2 hours. The resulting mixture is transferred to a second reactor. The first reactor is subsequently washed with N, N-dimethylformamide (105 L) and the flush is charged to the second reactor. Water (2000 L) is then added over a 2-hour period at 38 ° C. The resulting mixture was cooled to 0 ° C for 2-3 hours and then stirred at this temperature for another 2-8 hours. After this, the mixture was centrifuged at 0 ° C and the resulting precipitate was washed three times with water (810 L each time), washed with acetone (1010 L) and dried at 65 ° C in vacuo. All of these steps, except IPC, are carried out in an N ₂ atmosphere.

Example 5. Obtaining zilpaterol.

Part A. Formation of the amino alcohol salt of potassium from ketoxim.

A reaction apparatus with a stirrer is purged 3 times with N ₂ between high pressure (3 bar absolute) and low pressure (1 bar absolute) for 10 minutes each time. Then set the pressure to 0.9 bar (absolute). Then, water (790 kg) was charged into the reactor, then 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6-oxime (255 kg) obtained in accordance with example 4. The contents of the reactor are then heated to 40 ° C. Then, 45% KOH (214 kg) was continuously charged into the reactor, resulting in 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6- oxime forms the corresponding potassium salt, which, in turn, dissolves (this can be checked visually). Activated carbon (13 kg) is then charged to the reactor. 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 activated carbon. The mixture is then cooled to 15 ° C. Then, 5% palladium-carbon catalyst (25.5 kg, Johnson-Matthew) was charged to the reactor. The reactor is then washed with water (50 kg). The resulting mixture in the reactor is stirred for 2-6 hours at 40 ° C and a pressure of H _{2 of} 5-10 bar (absolute). After that, the reactor was ventilated for 30 minutes and the reaction mixture was analyzed by HPLC. The contents are then filtered through a filter loop for 90 minutes. The filter cake was washed with water (50 L) and removed to remove palladium. The filtered solution was analyzed by HPLC to confirm completion of the conversion, and then used in the next step.

Part B. Formation of zilpaterol-HOAc.

The solution from Part A is cooled to 30 ° C. Then acetone (625 L) was charged into the reactor. Acetic acid is 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. Then, 5% platinum-carbon catalyst (21.3 kg, Degussa) was charged to the reactor, followed by the addition of water (50 kg) to flush the reactor. Free space above the product is purged 3 times with H ₂ between a high pressure of 5 bar (absolute) and a low pressure of 1 bar (absolute) for 15 minutes each time. Then set the hydrogen pressure to 9.0 bar (absolute, for hydrogenation). The mixture is heated to 70 ° C for 1 hour with stirring and then maintained at this temperature for an additional hour with stirring. The reactor is then ventilated and N _{2 is} blown over the product. The reaction mixture was analyzed by HPLC. Acetic acid (8 kg) is then loaded into the reactor and the resulting mixture is cooled to 30 ° C. Acetic acid is also added to adjust the pH to 6.8. The mixture is then transferred through the filter loop for 1 hour, maintained at 30 ° C. The resulting precipitate was washed with 7% aqueous acetic acid (75 L). The filtered solution was transferred to another reaction apparatus with a stirrer for use in the next step.

Part C. The formation of the free base of zilpaterol.

A stirred reaction vessel containing the product from Part B was purged 3 times with N ₂ between high pressure (2 bar absolute) and low pressure (1 bar absolute) for 10 minutes each time. Then set the pressure to 0.9 bar (absolute). Then the mixture is concentrated by distillation to 30-70%. The concentrated mixture is cooled to 65 ° C. Ethanol (331 L) was charged into the reactor and the resulting mixture was cooled to 50 ° C. Adjust the pH to 10 with 25% NaOH. This causes the zilpaterol free base to precipitate. The temperature was lowered to 0 ° C to facilitate precipitation, and this temperature was maintained for an additional hour. The solids are filtered off and washed with water (700 L).

Example 6. The synthesis of salts of zilpaterol with HCl.

Zilpaterol free base is dissolved in ethanol. Then ethyl acetate saturated with HCl was added. The resulting mixture was subjected to vacuum filtration to obtain a crude product containing a salt of zilpaterol with HCl. The crude product is dissolved in hot methanol. Ethyl acetate was then added and the mixture was filtered to give the final product HCl salt.

Example 7. The first illustrative example of the proposed suitable dosage form.

A tablet is prepared containing 2.5 or 5 mg of the HCl salt from Example 6 and a sufficient amount of lactose filler, wheat starch, processed starch, rice starch, talc and magnesium stearate to a final weight of 100 mg.

Example 8. The second illustrative example of the proposed suitable dosage form.

Granules are prepared with a content of 12.5 or 25 HCl salt from Example 6 in each daily dose of granules.

Example 9. The third illustrative example of the proposed suitable dosage form.

HCl salt from Example 6 was subjected to crystallization using the methodology disclosed in U.S. Patent 5,731,028, for the preparation of crystalline racemic trans zilpaterol. Less than 5% of the crystals have a size of less than 15 microns, and at least 95% of the crystals have a size of less than 250 microns. Then a premix is prepared from a crystalline salt of HCl attached to a carrier of corn cobs with a particle size of 300-800 μm, using the methodology discussed in European patent 0197188 (incorporated by reference in this description). The concentration of the HCl salt in the premix is 3% (by weight).

The words “comprise,” “comprise” and “comprising” in this description (including the claims) are interpreted inclusively rather than exclusively. It is understood that this interpretation should be the same as the interpretation of these words by United States Patent Law.

All references cited in this patent are incorporated by reference.

The above detailed description of preferred embodiments is intended only to familiarize specialists in this field with the invention, its principles and its practical application so that specialists in this field can adapt and apply the invention in its many forms that they can best adapt to the requirements specific application. The present invention, therefore, is not limited to the above embodiments, and may be variously modified.

Claims (12)

1. The method of producing zilpaterol or its salts, including:
obtaining chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate (or its salt) by a method involving the interaction of 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid (or its salts) with at least one chlorinating agent selected from the group consisting of oxalyl chloride, phosgene and triphosgene, and
obtaining 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione or its salt, by a method involving the interaction of chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1 -butanoate (or its salt) with Lewis acid,
Preparation of 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6-oxime (or its salt) by a method involving the interaction of 8,9-dihydro -2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione (or its salt) with inorganic nitrite,
Obtaining an amino alcohol salt by a method comprising reacting 4,5-dihydro-imidazo [4,5,1-jk] [1] benzazepine-2,6,7 [1H] -trion-6-oxime (or its salt) with a base and subsequent interaction with H ₂ in the presence of a hydrogenation catalyst, wherein the amino alcohol salt corresponds to the structural formula (WO-2):

and
Z means cation,
obtaining an isopropylidene amine compound by a method comprising combining an amino alcohol salt with acetone and acetic acid, wherein the isopropylidene amine compound corresponds in structure to the formula (WO-1):

and obtaining zilpaterol by reacting the isopropylidene amine compound (or its salt) with H ₂ in the presence of a hydrogenation catalyst, followed by combining with a base and an alcohol. 2. A method of producing chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate or a salt thereof, comprising reacting 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid (or its salts) with at least one chlorinating agent selected from the group consisting of oxalyl chloride, phosgene and triphosgene. 3. A method of obtaining 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione or its salt, including:
obtaining chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate (or its salt) by a method involving the interaction of 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid (or its salts) with at least one chlorinating agent selected from the group consisting of oxalyl chloride, phosgene and triphosgene; and
the interaction of chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate (or its salt) with Lewis acid. 4. The method according to claim 3, where the Lewis acid contains AlCl ₃ . 5. The method according to claim 3, including:
obtaining chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate (or its salt) by a method involving the interaction of 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid (or its salts) with oxalyl chloride;
obtaining a mixture of a product containing 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione (or its salt) in a manner comprising: combining chlorine 2,3-dihydro-2-oxo -1H-benzimidazole-1-butanoate (or its salt) with AlCl ₃ and
combining the resulting mixture with acid;
separating 8,9-dihydro-2H, 7H-2,9a-diazabenzo [cd] azulene-1,6-dione from the product mixture; and
separating Al (OH) ₃ from at least a portion of the remainder of the product mixture by a process comprising combining at least a portion of the remaining mixture of the product with a base. 6. The method according to any one of claims 1 to 5, where 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid (or its salt) is reacted with a chlorinating agent in the presence of dichloromethane, in the presence of a catalytic amount dimethylformamide, or in the presence of both dichloromethane and a catalytic amount of dimethylformamide. 7. The method according to any one of claims 1 to 5, where the chlorinating agent contains oxalyl chloride. 8. The method according to claim 1, where 4- (2-oxo-2,3-dihydrobenzimidazol-1-yl) butyric acid (or its salt) is reacted with a chlorinating agent in the presence of dichloromethane, in the presence of a catalytic amount of dimethylformamide or in the presence of both dichloromethane and a catalytic amount of dimethylformamide. 9. The method according to claim 1, where the chlorinating agent contains oxalyl chloride. 10. The method according to claim 1, where the inorganic nitrite contains a salt of nitrite. 11. The method according to claim 10, where the nitrite salt contains NaNO ₂ . 12. The use of chlorine 2,3-dihydro-2-oxo-1H-benzimidazole-1-butanoate or its salt, obtained according to claim 2, as an intermediate in the synthesis of zilpaterol or its salt.