TWI221467B - Process for preparing robenidine or its derivatives - Google Patents
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1221467 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明説明(I )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 其中Y爲鹵素原子或甲苯磺醯基,以獲得下列通式之二胺 基胍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 其中Υ係如上述所定義,且在第二步驟中,於Ck醇, Cm-醇/水混合物之溶劑或水及對質子惰性之極性有機溶劑 之混合物中,在不需分離下,以下列通式之對-鹵化苯甲醛 將上式m化合物直接轉化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
其中X係如上述所定義,以獲得下列通式之最終產物或其 鹽類。 (請先閲讀背面之注意事項再填寫本頁)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)
本紙張尺度適用中國國家標準(CNS ) a4規格(210X297公釐) 1221467 A7 B7 五、發明説明(2;) 所使用之Cm-醇類可爲甲醇’乙醇,丙醇,異丙醇, 丁醇或特丁醇。較佳使用異丙醇。 所使用之對質子惰性之極性有機溶劑可爲醚,二乙醇 醚或有機氮化合物。 所使用之醚,例如爲二噁烷或四氫呋喃,且所使用之 二乙醇醚可爲單-,二-,三·或聚乙二醇醚。 所使用之有機氮化合物,例如爲乙腈,丙腈或二甲基 甲醯胺。 第一步驟較佳在醇或Cm-醇/水混合物中進行, 尤其在Cm-醇/水混合物中。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醇/水混合比例之設定係有利地自1:1至15:1,較 佳自4:1至10:1。 起始物質,肼水合物及氰基化合物,例如鹵化氰爲市 售可得之化合物。 在第一步驟中所使用之氰基化合物可爲氯化氰或溴化 氰或甲苯磺醯基氰化物。較佳爲使用氯化氰。 合適雙氯苄氨胍或雙氯苄氨胍衍生物之鹽類爲鹵化氫 鹽類,例如氯化氫或溴化氫。 第一步驟之反應係有利地在_30至50°C溫度下進行, 較佳在-10至30°C溫度下,尤其在〇至20〇C溫度下。 所使用之對-鹵素苯甲醛可爲對-氯苯甲醛或對_溴苯甲 醛。較佳使用對-氯苯甲醛。 在第二步驟中之方法有利地在50至90°C溫度下進行 _______ 7 本紙張尺度適用中國國家標準(CNS ) A4規格(210x297公釐) " ' (請先閱讀背面之注意事項再填寫本頁) -, 、? 經濟部智慧財產局員工消費合作社印製 1221467 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明説明(十) ,較佳在65至85°C溫度下。 對於第二步驟,有可能使用第一步驟中相同Cm-醇類 及相同的對之極性有機溶劑。 然而,如前所述,第二步驟亦可在水及對質子惰性之 極性溶劑之混合物中進行。水/對質子惰性之極性有機溶劑 之有利比例的設定爲10:1至1._1,較佳爲2:1至1:1。 在特別較佳具體實施例中,在第一步驟中所使用之溶 劑係在第二步驟前以水稀釋。 在第二步驟中,反應有利地在pH低於3下進行,較 佳在pH自0.5至1.5。pH値的設定有利地由添加無機酸, 例如氫氯酸,硝酸或硫酸來進行。 在〇·5至3小時之傳統反應時間之後,雙氯苄氨胍或 其衍生物可由傳統產生例如鹵化氫鹽類,如氯化氫鹽的方 法來獲得極佳產率與純度。 實施例 製備雙氯苄氨胍 實施例1 1.1在40分鐘之內,添加16·〇克(0.26莫耳)鹵化氰至 25·〇克(0·5〇莫耳)肼水合物及200 ml異丙醇溶液中,其中 該溶液被冷卻至0X:使得溫度不超過12。(:。在該時間之終 點時’測量pH,得到9.9之値。以1.0克氯化氰爲一份而 添加至每~例中以進行數次,直到pH<4。在添加3 X 1.0 克鹵化氰之後即爲一種情況(pH = 3.8)。 __________ 8 本紙張尺度適用中_家標準(CNS ) A4規格(21()χ297公瘦) (請先閲讀背面之注意事項再填寫本頁)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 五、發明説明(<) 在10°C下進一步攪拌20分鐘之後,添加130毫升 Ηβ,且由逐滴添加10.63克HC1(濃)以調整PH至1.0。反 應混合物係隨後加熱至70°C。在內部溫度爲61°C下,開 始計量添加61.55克(0.44莫耳)經熔融對-氯苯甲醛(熔點 :46°C)。逐滴添加方式需20分鐘。在10分鐘之內,加熱 白色懸浮液至80QC,且在80°C下攪拌另一 45分鐘。然後 冷卻反應混合物至15°C並離心。於每一例中,以50毫升 出0爲一份淸洗殘留物數次直到淸洗水之pH>3。6 X 50毫 升出0爲一例。進一步以異丙醇(2 X 50毫升)及乙基醋酸 酯(2 X 5〇毫升)淸洗以得到81.70克濕雙氯苄氨胍氯化氫, 其然後在90°C/20mbar之乾燥橱中乾燥48小時。產生具 有99.1。/。(HPLC)含量之白色固體之75.70克(81.7%)雙氯苄 氨胍氯化氫。 1.2反應可以相似於實施例1.1來進行;然而,在不需關 注所得之pH値是否小於4之下,添加精確數量之氯化氰 (0·26莫耳)。如此產生具有相同產率之雙氯苄氨胍氯化氫 實施例2 在3小時內,添加15.5克(0.25莫耳)氯化氰至25.0克 (0·50莫耳)肼水合物的215毫升異丙醇/水88:12(%重量比) 溶液中’其已經被冷卻至〇〇C使得溫度不超過2〇〇c。接著 在10°c下額外反應10分鐘,添加155毫升H20並使用 - 9 私娜尺反制家榡準(CNS ) A4規格(2iQx297公釐) (請先閱讀背面之注意事項再填寫本頁) 、τ 丨 經濟部智慧財產局員工消費合作社印製 1221467 A7 _______B7 五、發明説明(b ) 16·2克濃HC1以調整pH至1.0。現今淸澈之溶液接著加熱 至70°C,再逐滴添加61.5克(0.44莫耳)經熔融之對-氯苯 甲醛。然後加熱懸浮液至80°C並在此溫度下攪拌另一 45 分鐘。反應混合物係冷卻至15。(:並離心。以H2O(6x50毫 升)及異丙醇(2x50毫升)淸洗殘留物再乾燥(在 90°C/20mbar之乾燥櫥中15小時),以產生如白色固體之 77.5克(84% ;基於肼水合物)雙氯苄氨胍氯化氫,其純度爲 99.6%(HPLC) 〇 實施例3至10 實施例3至10係在實施例1或2之相同條件下進行, 但改變溶劑。實施例1至10之結果係摘述於表1。 表1 (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 實施例 用於步驟1之溶劑 用於步驟21)之溶劑 產率 [%] 純度2) [%] 1 異丙醇 (i-PrOH) i-Pr0H/H20 混合物 82 99.1 2 i-Pr0H/H20 88:12 i-Pr0H/H20 混合物 84 99.6 3 甲醇(MeOH) Me0H/H20混合物 73 89.0 4 乙醇(Et0H)/H20 96:4 Et0H/H20混合物 77 92.7 5 η-丁醇 n-Bu0H/H20 混合物 76 92.2 + 6 2-丁醇 2-丁醇/H20混合物i 69 89.6 7 四氫呋喃(THF) THF/H20混合物 75 83.4 ~ 10 本紙張尺度適用中國國家標準(CNS ) A4規格(21〇X297公釐) 12214671221467 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 五、發明説明(Π ) 8 乙臟MeCN) MeCN/H20混合物 75 88.5 9 MeOH MeOH/i-PrOH/H20 4:3:1 76 83.2 10 MeOH MeOH 64 85.1 1) 應瞭解步驟2之溶劑爲溶劑混合物,其是在計量添加氯 化氰之後,但在計量添加氯苯甲醛之前,由添加水而獲得 的(除了實施例10之外,在此處使用甲醇來進行稀釋)。典 型地,在步驟2中所添加之水量係能獲得3:2至1:1%重量 比之水/對質子惰性之極性有機溶劑混合物。 2) 以HPLC測定。 (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 11 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐)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)
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