TWI221467B - Process for preparing robenidine or its derivatives - Google Patents

Abstract

A novel process for preparing robenidine or its derivatives of the general formula in which X is a halogen atom, starting from hydrazine hydrate and a cyano compound is described. These two starting materials are initially converted in a C1-4-alcohol, a C1-4-alcohol/water mixture as solvent or in an aprotic polar organic solvent into a diaminoguanidine of the general formula in which Y is a halogen atom or tosyl, which is then reacted directly without isolation with a p-halobenzaldehyde of the general formula in a C1-4-alcohol, a C1-4-alcohol/water mixture or in an aprotic polar organic solvent/water mixture as solvent to give the end product.

Description

1221467 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of Invention (I)

Y-CN II where Y is a halogen atom or tosylsulfonyl group to obtain a diamine guanidine of the following formula

NH-HY fi ^ ΙΠ where Υ is as defined above, and in the second step, in a solvent of a Ck alcohol, a Cm-alcohol / water mixture or a mixture of water and a polar aprotic polar organic solvent, Under separation, p-halogenated benzaldehyde of the following formula directly converts the compound of formula m above

Where X is as defined above to obtain the final product of the following formula or its salts. (Please read the notes on the back before filling this page)

This paper size applies Chinese National Standard (CNS) a4 specification (210X297 mm) 1221467 A7 B7 V. Description of the invention (2;) The Cm-alcohol used can be methanol 'ethanol, propanol, isopropanol, butanol Or tert-butanol. Preferably, isopropyl alcohol is used. The aprotic polar organic solvent used may be an ether, diethanol ether or an organic nitrogen compound. The ether used is, for example, dioxane or tetrahydrofuran, and the diethanol ether used may be mono-, di-, tri · or polyethylene glycol ether. The organic nitrogen compound used is, for example, acetonitrile, propionitrile or dimethylformamide. The first step is preferably performed in an alcohol or Cm-alcohol / water mixture, especially in a Cm-alcohol / water mixture.

Ck alcohol / water mixing ratio is set based advantageously from 1: 1 to 15: 1, more excellent from 4: 1 to 10: 1. Starting materials of hydrazine hydrate and cyano compounds, e.g. cyanogen halide to the commercially available compound can be derived. As used in the first step of the cyano compound may be cyanide, cyanogen bromide or cyanogen chloride or toluene sulfonic acyl. Preferably, cyanogen chloride is used. Suitable guanidinium benzylamino diclofenac or diclofenac benzylamino guanidine derivative of hydrogen halide salts, such as hydrogen chloride or hydrogen bromide. The first step of the reaction is advantageously carried out at the Department of _30 to 50 ° C temperature, preferably at a temperature of -10 to 30 ° C, in particular to the lower square 20〇C temperature. The use of - halogen for the benzaldehyde - _ chlorobenzaldehyde or p-bromophenyl formaldehyde. P-chlorobenzaldehyde is preferably used. The method in the second step is advantageously performed at a temperature of 50 to 90 ° C. _______ 7 This paper size applies to China National Standard (CNS) A4 size (210x297 mm) " '(Please read the precautions on the back before (Fill in this page)-,,? Printed by the Consumers 'Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1221467 Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of the invention (ten), preferably at 65 to 85 ° C. For the second step, a first step it is possible to use the same alcohols and Cm- the same polarity organic solvent. However, as described above, the second step may also be carried out in a mixture of water and of aprotic polar solvent in the. Water / favorable ratio of the polar aprotic organic solvent it is set to 10: 1 to 1._1, preferably 2: 1 to 1: 1. In a particularly preferred embodiment, the solvent system used in the first step of dilution with water before the second step. In the second step, the reaction is advantageously carried out at a pH below 3, more excellent in pH from 0.5 to 1.5. The setting of pH 値 is advantageously performed by adding an inorganic acid, such as hydrochloric acid, nitric acid or sulfuric acid. After a conventional reaction time of 0.5 to 3 hours, diclofenac or a derivative thereof can be conventionally produced by, for example, a hydrogen halide salt such as a hydrogen chloride salt to obtain excellent yield and purity. Example Preparation of Dicloguanidine Example 1 1.1 Within 40 minutes, add 16.0 g (0.26 mol) of cyanogen halide to 25.0 g (0.50 mol) of hydrazine hydrate and 200 ml of isocyanate In a propanol solution, where the solution is cooled to 0X: so that the temperature does not exceed 12. (:. At the end of this time, 'pH was measured to obtain 9.9 9.9. 1.0 g of cyanogen chloride was added as a portion to each case for several times until the pH < 4. After adding 3 X 1.0 g This is the case after cyanogen halide (pH = 3.8). __________ 8 This paper size is applicable _ House Standard (CNS) A4 size (21 () x 297 male thin) (Please read the precautions on the back before filling this page)

1221467 A7 B7 5. Description of the invention (<) After further stirring at 10 ° C for 20 minutes, 130 ml of Ηβ was added, and 10.63 g of HC1 (concentrated) was added dropwise to adjust the pH to 1.0. The reaction mixture was then heated to 70 ° C. At an internal temperature of 61 ° C, 61.55 g (0.44 mole) of molten p-chlorobenzaldehyde (melting point: 46 ° C) was metered in. The dropwise addition method takes 20 minutes. Within 10 minutes, heat the white suspension to 80 QC and stir for another 45 minutes at 80 ° C. The reaction mixture was then cooled to 15 ° C and centrifuged. In each case, take 50 ml of 0 as a washing residue several times until the pH of the washing water is 3.6 x 50 ml 0 as an example. Further rinse with isopropanol (2 X 50 ml) and ethyl acetate (2 X 50 ml) to obtain 81.70 g of wet dichlorobenzylguanidine hydrogen chloride, which was then dried in a drying cabinet at 90 ° C / 20mbar 48 hours. Produced with 99.1. /. (HPLC) content of 75.70 g (81.7%) of dichlorobenzylaminoguanidine hydrogen chloride as a white solid. 1.2 The reaction can be carried out similar to example 1.1; however, without concern in pH is less than that obtained under 4 Zhi, adding a precise amount of cyanogen chloride (0.26 mole). This produced dichlorobenzylguanidine hydrogen chloride with the same yield. Example 2 Within 3 hours, 15.5 g (0.25 mole) of cyanogen chloride was added to 25.0 g (0.50 mole) of hydrazine 215 ml of isopropyl Alcohol / water 88:12 (% by weight) solution 'which has been cooled to 00C so that the temperature does not exceed 2000c. Then react for an additional 10 minutes at 10 ° C, add 155 ml of H20 and use-9 nanometer countersetter (CNS) A4 size (2iQx297 mm) (Please read the precautions on the back before filling in this page) , Τ 丨 printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1221467 A7 _______ B7 V. Description of the invention (b) 16.2 grams of concentrated HC1 to adjust the pH to 1.0. Today Qing of Che was then heated to 70 ° C, and then added dropwise 61.5 g (0.44 mole) of the melt by - chlorobenzaldehyde. The suspension was then heated to 80 ° C and stirred at this temperature for a further 45 minutes. The reaction mixture was cooled to 15 lines. (: And centrifuged to H2O (6x50 mL) and isopropanol (2x50 mL) Qing washed residue was dried (drying cabinet at 90 ° C / 20mbar of 15 hours), such as to produce 77.5 g (84 white solids. %; based on hydrazine hydrate) diclofenac benzylamino guanidine hydrogen chloride with a purity of 99.6% (HPLC) Example 3-10 billion Example 3 to 10 lines under the same conditions for Example 1 or 2 but changing the solvent. the results Department of Example 1-10 are summarized in table 1. table 1 (please read the back issues of the note and then fill in this page) Ministry of economic Affairs intellectual property Office employees consumer cooperatives printed examples of the solvent used in step 1 to step 21) Solvent yield [%] Purity 2) [%] 1 Isopropanol (i-PrOH) i-Pr0H / H20 mixture 82 99.1 2 i-Pr0H / H20 88:12 i-Pr0H / H20 mixture 84 99.6 3 Methanol (MeOH) Me0H / H20 mixture 73 89.0 4 Ethanol (Et0H) / H20 96: 4 Et0H / H20 mixture 77 92.7 5 η-butanol n-Bu0H / H20 mixture 76 92.2 + 6 2-butanol 2-butanol / H20 mixture i 69 89.6 7 Tetrahydrofuran (THF) THF / H20 mixture 75 83.4 ~ 10 This paper size applies to China National Standard (CNS) A4 specification (21 × 297 mm) 12 21467

7 B V. Description of the invention (Π) 8 Diethyl MeCN) MeCN / H20 mixture 75 88.5 9 MeOH MeOH / i-PrOH / H20 4: 3: 1 76 83.2 10 MeOH MeOH 64 85.1 1) It should be understood that the solvent of step 2 is The solvent mixture was obtained by adding water after metered addition of cyanogen chloride, but before metered addition of chlorobenzaldehyde (except for Example 10, where methanol was used for dilution). Typically, the amount of water added in step 2 is to obtain a water / proton-inert polar organic solvent mixture in a ratio of 3: 2 to 1: 1% by weight. 2) Determined by HPLC. (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 11 This paper size applies to China National Standard (CNS) A4 (210X297 mm)

Claims (1)

1221467 A8 B8 C8 D8 VI. Application scope (Please read the notes on the back before writing this page) where X is as defined above to obtain the final product of formula I. 2. The method according to item 1 of the patent application range, characterized in that the reaction in the first step is carried out at a temperature of -30 to 50 ° C. 3- The method according to item 1 or 2 of the scope of patent application, characterized in that the cyano compound used is cyanogen chloride. 4. The method according to item 1 or 2 of the scope of patent application, characterized in that the p-halobenzaldehyde used in the second step is p-chlorobenzaldehyde. 5. The method according to item 1 or 2 of the scope of patent application, characterized in that the reaction in the second step is carried out at a temperature of 50 to 90 ° C. 6. The method according to item 1 or 2 of the scope of patent application, characterized in that the reaction in the first step is performed in an alcohol or CN4-alcohol / water mixture, and the second step is in a Cm-alcohol / water mixture get on. 2 The native scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm> 1221467 printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs i '' Μ Η 1; · ,; r) ζ 2-_ _Β7_J ___ … .. V. Description of the Invention (ί) The present invention relates to a novel method for preparing diclofenac or a derivative thereof from the following general formula, starting from hydrazine hydrate and cyanogen halide: Dicloguanidine or Dicloguanidine derivatives are used to control the harm of coccidiosis in poultry and poultry, and as active anti-malarial agents (DE-A 1 933 1 12) ) 〇 The method for preparing dichloropyrene gas fox is also not disclosed in DE-A 1 933 112. In this process, or p-dichlorobenzaldehyde - chlorobenzaldehyde in ethanol and system I, 3- diamino guanidine (guanadine) nitrate to the reaction of the desired product obtained. The disadvantage of this process is the only product obtained in moderate yield. Object The present invention provides a "one-pot (one-pot) method" to be used from the start of hydrazine hydrate and cyanogen halide prepared diclofenac benzylamino guanidine, wherein the desired product in an excellent yield based and purity is obtained. The method according to item 1 of the scope of patent application can achieve the above purpose. According to the present invention, the present method is performed such that in the first step, the hydrazine hydrate is reacted with a cyano compound of the following formula in a solvent of a Cw alcohol, an alcohol / water mixture or a polar organic solvent inert to aprotons. 5 This paper size is in accordance with China National Standard (CNS) A4 (210 X 297 cm) • ϋ nn nnnn I 1 I n ϋ ϋ · IK IK ϋ ϋ--or I n I ϋ ϋ n I n II n I 1 ϋ ϋ ϋ H n H ϋ ϋ I ϋ I ϋ n I n I (. (Please read the precautions on the back before filling out this page) 1221467 A8 B8 C8 D8, patent application scope 丨 Amendment. Method for diclofenac or its derivative or salt thereof, Wherein X is a halogen atom, it is characterized in that in the first step, the hydrazine hydrate and a cyano compound of the following formula are used in a solvent of a Cm-alcohol, an alcohol / water mixture or a polar organic solvent inert to aproton Reaction Y-CN π where Y is a halogen atom or tosylsulfonyl group, to obtain the diamine guanidine of the following formula Η ΝΗ ^ ΗΥ ΙΠ (Please read the precautions on the back before filling this page) • T: where Y is As defined above, and in the second step, in a solvent of a Cm-alcohol, a Ck alcohol / water mixture or a mixture of water and a polar organic solvent inert to aproton, the following formula is used without separation. on - m halogenated benzaldehyde compound of the formula directly applicable scale conversion sheet of the present China national standard (CNS) A4 size (210 X 297 mm)