TW201200500A - Process for the preparation of benzimidazoles - Google Patents

Abstract

Substituted benzimidazoles of formula, wherein R1 and R2 independently are hydrogen, C1-6 alkyl or C3-6 cycloalkyl and R3 is cyano or carboxy, are prepared in a multistep synthesis starting from N-acyl-4-halo-anilines of formula, wherein R1 and R2 are as defined above and X is chlorine or bromine.

Description

201200500 六、發明說明： 【發明所屬之技術領域】 本發明係關於製造式（I )之經取代笨并咪唾的方法201200500 VI. Description of the Invention: [Technical Field of the Invention] The present invention relates to a method for producing a substituted (Substituting)

R = CN ( la) R3 = COOH ( lb) 其中R1為氫、Cw烷基或（：3·6環烷基，r2為Cl_6烷基 或C3·6環烷基，且R3為氰基（Ia)或羧基（Ib)。其進一步 係關於本發明之方法中的新穎中間物。 本文中，術語「C! •"烷基」（例如「c,_6烷基」）表示具 有1至《個碳原子之任何直鏈或分支鏈烷基。C16烷基表示 例如甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁 基、第三丁基、以及各種異構戊基及異構己基。術語「c36 %烷基J表示環丙基、環丁基、環戊基及環己基。 式I之苯并味嗤亦可以下文所示之互變異構形式存在。R = CN ( la) R3 = COOH ( lb) wherein R 1 is hydrogen, C w alkyl or (: 3 · 6 cycloalkyl, r 2 is Cl 6 alkyl or C 3 6 cycloalkyl, and R 3 is cyano (Ia Or a carboxyl group (Ib). It is further a novel intermediate in the method of the present invention. Herein, the term "C! • "alkyl" (for example, "c, _6 alkyl") means having 1 to " Any linear or branched alkyl group of a carbon atom. C16 alkyl represents, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, tert-butyl, and various The pentyl group and the isomeric hexyl group. The term "c36 % alkyl group J represents a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group. The benzoxanthene of the formula I can also be present in the tautomeric form shown below.

201200500 本文之所有結構式意欲包括兩種互變異構形式。 【先前技術】 式I之苯并咪唑適用作醫藥活性化合物之合成中的中 門物詳。之，4-甲基丙基苯并咪嗤甲酸（Ri =甲基， 丙基& —叛基）為替米沙坦（telmisartan)工業合 成中之關鍵中間物，替米沙坦為一種用於治療高血麼之血 管收縮素II受體拮抗劑。 此項技術中已知用於製備式I之苯并咪唑或相關化合 物的若干種方法。典型地使用之方法包含製備硝基_醯基胺 基笨甲酸酯及其閉環反應以獲得相應苯并咪唑。自諸如us 4 880 8G4、US 5 591 762 及 DE-A 199 17 524 之早期專利直 至諸如WO-A 2006/044754之最近公開之專利申請案，製備 用於製備替米沙坦及其衍生物之苯并咪唑中間物的已知方 法實質上並無改變。可在諸如Ries，υ·;·等人，丄从以㈣ 1993，36，4040-4051 或 Teram〇t〇，s 等人，j 〜所 2003, 46’ 3033-3044之科學文獻中發現類似策略。儘管此項 技術中已知之合成的大部分步驟為高產率的，但該等合成 過程几長且難以大規模進行。因此，需要一種旨在提供式工 中間物之較簡短的合成。此外，常見合成包含兩個硝化步 驟及兩個硝基還原步驟，該等步驟難以安全地進行。 本發明之一個目標為提供適用於大規模製造式1化合 物以用於製備替米沙坦及其衍生物的更簡短、更經濟、更 201200500 高效及環保的方法。 【發明内容】 根據本發明，式（1)之經取代苯并咪唑201200500 All structural formulae herein are intended to include both tautomeric forms. [Prior Art] The benzimidazole of the formula I is suitable for use as a central substance in the synthesis of a pharmaceutically active compound. 4-methylpropylbenzimidic acid (Ri = methyl, propyl & - rebel) is a key intermediate in the industrial synthesis of telmisartan, and telmisartan is used as a Angiotensin II receptor antagonist for the treatment of hyperemia. Several methods for preparing benzimidazoles of the formula I or related compounds are known in the art. A typical method involves the preparation of a nitro-mercaptoamino benzoate and its ring closure reaction to obtain the corresponding benzimidazole. Prepared for the preparation of telmisartan and its derivatives, from the earlier patents of US 4 880 8G4, US 5 591 762 and DE-A 199 17 524, to the recently published patent application, such as WO-A 2006/044754 The known methods of benzimidazole intermediates are essentially unchanged. Similar strategies can be found in scientific literature such as Ries, υ·;·, et al., (4) 1993, 36, 4040-4051 or Teram〇t〇, s, et al., 2003, 46' 3033-3044 . Although most of the steps of the synthesis known in the art are high yields, the synthetic processes are somewhat long and difficult to perform on a large scale. Therefore, there is a need for a shorter synthesis that is intended to provide a work intermediate. In addition, common synthesis involves two nitrification steps and two nitro reduction steps that are difficult to perform safely. It is an object of the present invention to provide a shorter, more economical, more 201200500 efficient and environmentally friendly process suitable for the large scale manufacture of Formula 1 compounds for the preparation of telmisartan and its derivatives. SUMMARY OF THE INVENTION According to the present invention, substituted benzimidazole of formula (1)

0) 其中R1為氫、Cw烷基或<：3·6環烷基，…為Ci6烷基 或Gw環烷基，且R3為氰基或羧基，係於包含以下步驟之 方法製備： (i)使式（II)之；V-醯基-對鹵基苯胺氰化，0) wherein R1 is hydrogen, Cw alkyl or <:3. 6 cycloalkyl, ... is Ci6 alkyl or Gw cycloalkyl, and R3 is cyano or carboxyl, prepared by a process comprising the following steps: i) cyanating the formula (II); V-mercapto-p-halinoaniline,

ΟΟ

(II) 其中R及R如上文所定義且χ為氣或漠以獲得式 (III)之相應氰基化合物， (»0 201200500 ο(II) wherein R and R are as defined above and are sulphur or indifference to obtain the corresponding cyano compound of formula (III), (»0 201200500 ο

R2 其中R1及V如上夂所定義 (ii)使步驟（〇中獲ρ ’ (IV)之相應硝基化合物，卞之氱基化合物硝化以獲得式R2 wherein R1 and V are as defined above (ii) nitrating the corresponding nitro compound of ρ ' (IV) in the step (〇)

(IV) 其中R1及R2如上 (⑴）使步驟（ii) 獲得其中R〗及R2如上(Ia)，及視情況而定， 文所定義， 中獲得之硝基化合物還原及環化以 文所定義且R3為氰基的目標化合物 (iv)使化合物Ia 目標化合物（lb)。 之氰基水解以獲得其中R3為羧基之 仕一個較佳具體實例中 ^ ^^^ 1 y 、1夕τ夂虮化係在極性 子〖生;谷劑中且在作為催化劑之把膦錯合物存在下用六 8 201200500 亂亞鐵(11)酸鉀實現。此具體實例尤其有利原因在於六氰 亞鐵（II)酸鉀毒性比氰化反應中常用之氰化物毒性小得多。 適合的極性非質子性溶劑為例如常用酿胺類、脲類或亞碾 類，諸如二甲基甲酼脱 . τ驅胺、二曱基乙醯胺、沁甲其 吡嘻咬_、四甲基脲或二甲亞礙。 土 更佳地’鈀膦錯合物為肆(三苯膦)鈀(〇)。 在另-較佳具體實例中，步驟⑶）中之硝化係使用含 ^屬硝㈣之硫㈣為硝化劑來實現。此具體實例尤其 有利，原因在於避免了使用大量硝酸。 在 ^佳具體實例中，步驟（出）中之還原及環化係 離中間物之情形下使用含元素鐵之乙酸作為還原劑 在 車乂佳具體實例中，步驟（iii )中之還原及環化係 在不刀離中間物之情形下使用 原劑來進行。女佔夕 '養e如从 凡兄π文瓜作马還 m '、劑為二硫亞續酸鈉（Na2S2〇4 ) 〇使 用一硫亞磺酸鹽之反應 合物中進^ &應且在4如乙醇水溶液之水性溶劑混 化(二需可使腈Ia(I’R、⑻水解產生相應㈣ — 〇H )該水解較佳使用諸如鹽酸之強酸來進 订0 :發明之方法較佳用於製備R1為甲基之化合物⑴。 發明之方法同樣較佳用於製備汉2為丙基之化合物 0 最佳地’ R丨為曱基且r2為丙基。 9 201200500 在一個較佳具體實例中， 為漠化合物（X = Br)〇 W醯基-對鹵基本胺起始物質 式（la )化合物，(IV) wherein R1 and R2 are as defined above ((1)) wherein step (ii) is obtained wherein R and R2 are as defined above (Ia), and, as the case may be, the nitro compound is reduced and cyclized. The target compound (iv) which is defined and wherein R3 is a cyano group gives the compound Ia the target compound (lb). The cyano hydrolysis is carried out to obtain a preferred embodiment in which R3 is a carboxyl group. ^^^^ 1 y , 1 夂虮 夂虮 夂虮 is in the polar group; in the granule and in the phosphine as a catalyst In the presence of the substance, it is realized with six 8 201200500 chaotic iron (11) potassium. This particular example is particularly advantageous because the toxicity of potassium hexacyanoferrate is much less toxic than the cyanide commonly used in cyanidation. Suitable polar aprotic solvents are, for example, commonly used chelating amines, ureas or sub-millings, such as dimethylformamide, oxime amine, dimercaptoacetamide, guanidine pyridinium _, four Base urea or dimethyl sulphate. Preferably, the palladium phosphine complex is ruthenium (triphenylphosphine) palladium (ruthenium). In another preferred embodiment, the nitration in step (3) is carried out using a nitrating agent containing sulfur (IV) which is a nitrite. This particular example is particularly advantageous because the use of large amounts of nitric acid is avoided. In the specific example, the reduction and cyclization in the step (out) is carried out using the elemental iron-containing acetic acid as a reducing agent in the case of the intermediate, in the specific example of the car, the reduction and the ring in the step (iii) The chemical system is carried out using the original agent without cutting the intermediate. Female eve eve 'cultivation e such as from the brother π wengua for the horse also m ', the agent for sodium disulfide sodium (Na2S2 〇 4) 〇 use of a sulfur sulfinate reaction in the ^ & And mixed in an aqueous solvent such as an aqueous solution of ethanol (the second need to be able to hydrolyze nitrile Ia (I'R, (8) to produce the corresponding (four) - 〇H). The hydrolysis is preferably carried out using a strong acid such as hydrochloric acid. It is preferably used to prepare compound (1) wherein R1 is a methyl group. The method of the invention is also preferably used for the preparation of compound 2 in which han 2 is a propyl group. Optimum 'R丨 is fluorenyl group and r2 is propyl group. 9 201200500 In a specific example, the compound of formula (la) is a compound of the formula (la = Br) 〇W 醯-p-halo basic amine,

其中Rl為Cm烷基或c 〇3·6環烷基，為新潁沾n 3·6環烧基且R2為C,·6烷基或 ^ ., lL ^ *马本發明之一個目標。 車父佳地，R為甲美，日φD , ^ 丞且更佳地，ri為甲基且R2為丙基。 本發明之另一具體實例為式（ΙΠ )化合物，Wherein R1 is a Cm alkyl group or a c 〇3·6 cycloalkyl group, which is a new hydrazine-doped n 3·6 cycloalkyl group and R 2 is a C,·6 alkyl group or ^., lL ^ * horse is one of the objects of the invention. The father of the car, R is a beautiful, day φD, ^ 丞 and more preferably, ri is methyl and R2 is propyl. Another specific embodiment of the invention is a compound of formula (ΙΠ),

其中R1為Cue烷基或c：3·6環烷基且R2為丙基。 在尤佳的化合物中，R〗為曱基且y為丙基，亦即該化 合物為#-(4-氰基-2-甲基苯基）丁醯胺。 本發明之又一具體實例為式（Iv)化合物， 10 (IV) 201200500Wherein R1 is Cue alkyl or c: 3·6 cycloalkyl and R2 is propyl. In a particularly preferred compound, R is fluorenyl and y is propyl, i.e., the compound is #-(4-cyano-2-methylphenyl)butanamine. Yet another embodiment of the invention is a compound of formula (IV), 10 (IV) 201200500

CNCN

其中R1為Ci-6烧基或C3_6環院基且r2為c C 3.6環烧基 4烷基或 在尤佳的化合物中，R1為曱基且R2為丙基 勹円丞亦即該化 合物為#-(4-氰基-2-甲基-6-硝基苯基）丁醯胺。 【實施方式】 以下非限制性實施例將進一步說明本發明 實施例1Wherein R1 is Ci-6 alkyl or C3_6 ring-based and r2 is c C 3.6 cycloalkyl 4 alkyl or in a particularly preferred compound, R1 is a fluorenyl group and R2 is a propyl group, ie the compound is #-(4-Cyano-2-methyl-6-nitrophenyl)butanamine. [Embodiment] The following non-limiting examples will further illustrate the present invention.

CH W-(4-溴-2-曱基苯基）丁醯胺（u，Ri = /2 - C 3 Η 7 ’ X = Β Γ ) 在室溫下，在35分鐘内，將丁醯氣（36.0 g，0.338 mol, Ueq.)添加至 2_ 甲基苯胺（3〇.〇g，〇28m〇i，i〇eq) 及三乙胺（312^ 0.308 mol’U eq)於二氣甲烷(25〇mL) 中之溶液中。在室溫下㈣拌混合物3 5小時，且接著以水 及碳酸納水溶液洗蘇。對有機層以無水硫酸減水，且濃 縮獲得呈白色固體形式之Μ.甲基笨基）丁醯胺（ 45.27 g， 9⑷，其未經進一步純化即用於下—步驟中。 lHNMR(4GGMHZ，DMS〇_MS9.23(s，1H)，7.37(d’ 11 201200500 J = 7.6 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 6.8 HZj 1H)j 2.31 (t, J = 7.3 Hz, 2H), 2.20 (s，3H)，1.63 (m，j = 7 4 Hz，j = 7 3 Hz，2H)，〇 95 (t，；= 7.4 Hz，3H) 〇 將粗 #-(2_甲基苯基）丁醯胺（5.01 g，28 mmol，1.0 eq.) 溶解於曱醇（5〇 mL )中。以一份添加氫溴酸水溶液（4〇0/〇， 5·87 g ’ 29 mmol ’ 1.0 eq.)中。冷卻（冰水浴）混合物， 在15分鐘内緩慢添加過氧化氫水溶液（3〇%，3 67 g，29 mmol ’ 1.0 eq，），且持續攪拌隔夜。移除過量甲醇後，藉由 過遽獲得白色固體。對濕濾餅以碳酸鈉水溶液及水洗滌， 且真空乾燥獲得白色固體。 產量：6.22 g ( 85%)。 ]U NMR (400 MHz, DMSO-i/6): δ 9.26 (s, 1Η), 7.42 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.32 (dd, J = 2.0CH W-(4-bromo-2-indolylphenyl)butanamine (u,Ri = /2 - C 3 Η 7 ' X = Β Γ ) At room temperature, in about 35 minutes, butyl sulfonium (36.0 g, 0.338 mol, Ueq.) was added to 2-methylaniline (3〇.〇g, 〇28m〇i, i〇eq) and triethylamine (312^0.308 mol'U eq) in di-methane ( In a solution of 25 〇 mL). The mixture was mixed at room temperature for four hours, and then washed with water and an aqueous solution of sodium carbonate. The organic layer was reduced with anhydrous sulphuric acid and concentrated to afford EtOAc <RTI ID=0.0>>&&&&&&&&&&&&&&&& 〇_MS9.23(s,1H), 7.37(d' 11 201200500 J = 7.6 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.07 (t, J = 6.8 HZj 1H)j 2.31 (t, J = 7.3 Hz, 2H), 2.20 (s, 3H), 1.63 (m, j = 7 4 Hz, j = 7 3 Hz, 2H), 〇 95 (t,; = 7.4 Hz, 3H) 粗Last #-(2_methylphenyl)butanamine (5.01 g, 28 mmol, 1.0 eq.) was dissolved in methanol (5 mL). Add a solution of hydrobromic acid (4〇0/〇, 5·87 g '29 mmol '1.0 eq.). Cool the mixture (ice bath) and slowly add hydrogen peroxide solution (3〇%, 3) over 15 minutes. 67 g, 29 mmol '1.0 eq,), and stirring was continued overnight. After removal of excess methanol, a white solid was obtained by dryness. The wet cake was washed with aqueous sodium carbonate and water and dried in vacuo to give a white solid. :6.22 g (85%). U NMR (400 MHz, DMSO-i/6): δ 9.26 (s, 1Η), 7.42 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 7.32 (dd, J = 2.0

Hz，J = 8.5 Hz，1H)，2.30 (t，J = 7.2 Hz，2H)，2.18 (s，3H)， 1.61 (m, J = 7.2 Hz, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H)。 13C NMR (100 MHz, DMSO-i/6)： δ 171.6, 136.4, 134.8, 133.1，129.1，127.3, 1 17.5, 38.2, 19.2，18.0, 14.1。 實施例2 #-(4-氣-2-曱基苯基）丁醯胺（π，R1 = CH3，R2 = «-C3H7，X = Cl) 在室溫下，在25分鐘内’將正丁醯氯（1 8.64 g，〇. 175 12 201200500 mol，1.2 eq.)添加至 4-氯-2-曱基苯胺（20 g，0_141 mol， 1.0 eq_ )及三乙胺（17.41 g，0.172 mol，1·2 eq_ )於二氯 甲烷（250 mL )中之混合物中。在室溫下再攪拌反應混合 物1 8小時。接著添加冰水，且以二氯甲烷萃取混合物。對 經合併之有機層以碳酸鈉水溶液及水洗滌，經無水硫酸鈉 脫水，且濃縮獲得白色固體。 產量：25 g ( 80%)。 NMR (400 MHz，DMSO-A): δ 9_27 (s，1H)，7.41 (d， J = 8.5 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.5Hz, J = 8.5 Hz, 1H), 2.30 (t, J = 7.2 Hz, 2H), 2.18 (s, 3H), 1.61 (m, J = 7.2 Hz, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, DMSO-i/6): δ 171.6, 136.4, 134.8, 133.1, 129.1, 127.3, 1 17.5, 38.2, 19.2,18.0, 14.1. Example 2 #-(4-Ga-2-mercaptophenyl)butanamine (π, R1 = CH3, R2 = «-C3H7, X = Cl) At room temperature, within 25 minutes Toluene chloride (1 8.64 g, 175 175 12 201200500 mol, 1.2 eq.) was added to 4-chloro-2-mercaptoaniline (20 g, 0-141 mol, 1.0 eq_) and triethylamine (17.41 g, 0.172 mol, 1·2 eq_ ) in a mixture of dichloromethane (250 mL). The reaction mixture was stirred at room temperature for further 18 hours. Ice water was then added and the mixture was extracted with dichloromethane. The combined organic layers were washed with aqueous sodium bicarbonate and water, dried over anhydrous sodium sulfate. Yield: 25 g (80%). NMR (400 MHz, DMSO-A): δ 9_27 (s, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.5

Hz，J = 2.3 Hz，1H)，2.30 (t，J = 7.4 Hz，2H)，2.10 (s，3H)’ 1.61 (m, J = 7.4 Hz, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H)。 13C NMR (100 MHz，DMSO-A): δ 171.6, 135.9，134.4, 130.2, 129.2, 127.0, 126.1，38.1，19.2, 18.1，14.0。 實施例3 #-(4-氣-2-曱基苯基）丁醯胺（π，r1 = CH3，R2 = «-C3H7，X = Cl) 在裝備有回流冷凝器之開放系統中將TV-(2-甲基苯基） 丁醯胺（1.0 g，6 mmol，1.〇 eq.)、鹽酸（36。/〇，〇 6 mL，7 mmol，1.2 eq.)及過氧化氫水溶液（30%，〇·7 mL，7 mmol， 1_2 eq.)於曱醇（10 mL)中之混合物加熱至4〇χ：歷時18 小時。製備型TLC分離出呈白色固體形式之"_(4_氯_2_曱 基苯基）丁醯胺（119 mg，1〇%)。 13 201200500 實施例4 #-(4·氰基-2-曱基苯基）丁醯胺（III，R1 = CH3 ’ R2 = w-C3H7) 將 #-(4-溴-2-甲基苯基）丁醯胺（20.04 g，78 mmol ’ 1.0 eq·)、六氰亞鐵（II)酸鉀三水合物（13.17 g ’ 31 mmol ’ 0.4 eq.)、肆（三苯膦）鈀（〇) ( 454 mg，0.39 mmol，0.005 eq.)、 碳酸納（9.94g，94 mmol，1.2eq.)於 DMF(200 mL)中 之混合物加熱至12(TC歷時21小時》冷卻反應混合物至室 ，且遽出沈殿之固體。將有機層稀釋於二氣曱烧中且以 水洗滌。移除揮發物獲得粗產物。使用***稀釋粗產物且 濾出不溶性固體。濃縮濾液獲得淡黃色固體。 產量：12.0 g ( 75%)。 4 NMR (400 MHz，DMSO-A): δ 9.41 (s，1H)，7 8〇 (d J = 8.4 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H)> 7.62 (dd, J = 8.4 Hz，J = 1_8 Hz，1H)。 l3C NMR (100 MHz，DMSO-A): δ 172.1，141.6, 134 5 131.2, 130.6, 124.5, 1 19.4, 106.8, 38.3, 19.1，18.〇 14〇e ’ 實施例5 #-(4-氰基-2-曱基苯基）丁醯胺（in，Ri = CH，r2 = «-C3H7) 將 AK4-氣-2-曱基苯基）丁酿胺（0.5〇4g，2 38 mm()i， 1.0 eq.)、六氰亞鐵（π)酸鉀三水合物（〇 4〇 g，〇 95 ，Hz, J = 2.3 Hz, 1H), 2.30 (t, J = 7.4 Hz, 2H), 2.10 (s, 3H)' 1.61 (m, J = 7.4 Hz, J = 7.4 Hz, 2H), 0.92 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, DMSO-A): δ 171.6, 135.9, 134.4, 130.2, 129.2, 127.0, 126.1, 38.1, 19.2, 18.1,14.0. Example 3 #-(4-Ga-2-mercaptophenyl)butanamine (π, r1 = CH3, R2 = «-C3H7, X = Cl) TV- in an open system equipped with a reflux condenser (2-Methylphenyl) Butanamine (1.0 g, 6 mmol, 1. 〇eq.), Hydrochloric acid (36./〇, 〇6 mL, 7 mmol, 1.2 eq.) and aqueous hydrogen peroxide (30) %, 〇·7 mL, 7 mmol, 1_2 eq.) The mixture in decyl alcohol (10 mL) was heated to 4 〇χ: 18 hr. Preparative TLC isolated "_(4-chloro-2-phenylphenyl)butanamine (119 mg, 1%) as a white solid. 13 201200500 Example 4 #-(4·Cyano-2-mercaptophenyl)butanamine (III, R1 = CH3 'R2 = w-C3H7) #-(4-bromo-2-methylphenyl) Butylamine (20.04 g, 78 mmol '1.0 eq·), potassium hexacyanoferrate (II) potassium trihydrate (13.17 g '31 mmol '0.4 eq.), hydrazine (triphenylphosphine) palladium (〇) (454 mg, 0.39 mmol, 0.005 eq.), a mixture of sodium carbonate (9.94 g, 94 mmol, 1.2 eq.) in DMF (200 mL) was heated to 12 (TC over 21 hrs) to cool the reaction mixture to the chamber and The organic layer was taken up in dioxane and washed with water. The volatiles were evaporated to give the crude product. The crude product was diluted with diethyl ether and filtered to give an insoluble solid. g ( 75%) 4 NMR (400 MHz, DMSO-A): δ 9.41 (s, 1H), 7 8 〇 (d J = 8.4 Hz, 1H), 7.69 (d, J = 1.8 Hz, 1H)&gt ; 7.62 (dd, J = 8.4 Hz, J = 1_8 Hz, 1H). l3C NMR (100 MHz, DMSO-A): δ 172.1, 141.6, 134 5 131.2, 130.6, 124.5, 1 19.4, 106.8, 38.3, 19.1 , 18.〇14〇e ' Example 5 #-(4-Cyano-2-mercaptophenyl)butanamine (in, Ri = CH,r2 = «-C3H7) AK4-Ga-2-mercaptophenyl) butylamine (0.5〇4g, 2 38 mm()i, 1.0 eq.), potassium hexacyanoferrate (π) Trihydrate (〇4〇g, 〇95,

0.4 eq.)、碳酸鈉（0.304 g，2.87 mmol，] 9 mA eq.)、乙酸在巴 14 201200500 (Π) ( I2.2 mg，0.05 mmol，0.02 eq.)、三苯膦（62 2 mg , 〇_24mm〇1’ O·1 eq_)於圹沁二曱基乙醯胺（7mL)中之混 合物加熱至U〇°C歷時18小時。獲得#-(4-氰基-2-甲基笨基） 丁酿胺’產率為4〇%，且完全回收未反應之起始物質。發 現NMR光譜與自沁（4_溴_2_曱基苯基）丁醯胺製備之產物的 NMR光譜相同。 實施例6 #-(4-氰基_2_曱基·6_硝基苯基）丁醯胺（IV，Rl = cH3， R = W-C3H7) 在冰水浴中攪拌硝酸鈉（6.73 g，79 mmol，2.0 eq.) 與硫酸（98% ’ 4〇 mL)之混合物歷時15分鐘。接著在55 分鐘内逐份添加#_(4_氰基-2-曱基苯基）丁醯胺（8.00 g，40 mmol ’ 1 ·0 eq.)，且在冰水浴中攪拌混合物歷時3小時。將 反應混合物倒入至冰水中’且以乙酸乙酯萃取。對有機層 以碳酸鈉水溶液及水洗滌。減壓移除揮發物獲得橙色固體。 產量：8.01 g ( 80%)。 'H NMR (400 MHz, DMSO-rf6)： δ 10.12 (s, 1H), 8.30 (d, J = 1.7 Hz, 1H), 8.11 (m, 1H), 2.34 (s, 3H), 2.33 (t, J = 7.1 Hz, 2H), 1.58 (qd, J = 7.3 Hz, J = 7.1 Hz, 2H), 0.91 (t, J = 7.3 Hz，3H)。 13C NMR (100 MHz, DMSO-A): δ 171.8，146.4，138.3, 138.0, 133.5, 126.8, 1 17.5, 108.8, 37.6, 18.7, 18.1，14.0。 15 201200500 實施例7 7-甲基-2-丙基_3//_苯并咪唑_5·曱腈（i，Ri = ch3，R2 = «-C3H7 » R3 = CN ) 將#-(4-氰基-2-甲基-6-硝基苯基）丁醯胺（2.0 g，8 mmo卜 1.0 ecl.)及鐵粉（2.26 g，41 mmol，5.0 eq.)於乙 酸（40 mL )中之混合物加熱至！ 20。〇歷時6小時。hplc 指示反應物完全轉化。接著冷卻反應混合物至室溫，且經0.4 eq.), sodium carbonate (0.304 g, 2.87 mmol,) 9 mA eq.), acetic acid in Ba 14 201200500 (Π) (I2.2 mg, 0.05 mmol, 0.02 eq.), triphenylphosphine (62 2 mg) , 〇 _ 24 mm 〇 1 ' O · 1 eq _) The mixture in decyl decyl acetamide (7 mL) was heated to U 〇 ° C for 18 hours. The yield of #-(4-cyano-2-methylphenyl) butylamine was obtained at 4%, and the unreacted starting material was completely recovered. It was found that the NMR spectrum was identical to the NMR spectrum of the product prepared from bismuth (4-bromo-2-phenylphenyl)butanamine. Example 6 #-(4-Cyano-2-indolyl-6-nitrophenyl)butanamine (IV, Rl = cH3, R = W-C3H7) Stir sodium nitrate (6.73 g, in an ice water bath) A mixture of 79 mmol, 2.0 eq.) with sulfuric acid (98% '4 〇 mL) lasted 15 minutes. Then ##(4-cyano-2-indolylphenyl)butanamine (8.00 g, 40 mmol '1 ·0 eq.) was added portionwise over 55 minutes, and the mixture was stirred in an ice water bath for 3 hours. . The reaction mixture was poured into ice water' and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium carbonate and water. The volatiles were removed under reduced pressure to give an orange solid. Yield: 8.01 g (80%). 'H NMR (400 MHz, DMSO-rf6): δ 10.12 (s, 1H), 8.30 (d, J = 1.7 Hz, 1H), 8.11 (m, 1H), 2.34 (s, 3H), 2.33 (t, J = 7.1 Hz, 2H), 1.58 (qd, J = 7.3 Hz, J = 7.1 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, DMSO-A): δ 171.8, 146.4, 138.3, 138.0, 133.5, 126.8, 1 17.5, 108.8, 37.6, 18.7, 18.1,14.0. 15 201200500 Example 7 7-Methyl-2-propyl_3//_benzimidazole_5·indoleonitrile (i,Ri = ch3, R2 = «-C3H7 » R3 = CN ) #-(4- Cyano-2-methyl-6-nitrophenyl)butanamine (2.0 g, 8 mmo Bu 1.0 ecl.) and iron powder (2.26 g, 41 mmol, 5.0 eq.) in acetic acid (40 mL) The mixture is heated to! 20. It lasted 6 hours. Hplc indicates complete conversion of the reactants. The reaction mixture is then cooled to room temperature and

Celite®短塞過濾。使用旋轉蒸發器濃縮濾液，以二氣甲烧 稀釋且以碳酸鈉溶液洗滌。分離有機相且濃縮獲得灰白色 固體。 產量：0.531 g ( 30%)。 'H NMR (400 MHz, DMSO-J6): δ 12.66 (s, iH) 7 8〇 (g 1H)，7.73 (m，1H)，2.82 (t，J = 7.3 Hz，2H) 7Celite® short plug filter. The filtrate was concentrated using a rotary evaporator, diluted with dimethylbenzene and washed with sodium carbonate. The organic phase was separated and concentrated to give an off white solid. Yield: 0.531 g (30%). 'H NMR (400 MHz, DMSO-J6): δ 12.66 (s, iH) 7 8 〇 (g 1H), 7.73 (m, 1H), 2.82 (t, J = 7.3 Hz, 2H) 7

1 7W n rt)，2·5〇 (s，3H)S1 7W n rt), 2·5〇 (s, 3H)S

1.73 (qd, J = 7.3 Hz, J = 7.4 Hz, 2H), 〇 07 u T 3H)〇 .87 “，卜 7.4 Hz， 13C NMR (100 MHz, DMSO-i/6): δ ΐς〇 . ^03-4, 30.9, 21.3, 16.9, H.! 〇 M，丨以· 1，丨 2。' 在此還原環化反應期間，尤其在轅作 八不元全時，亦可 刀離出作為主要中間物之#·(2_胺基_4_ τ τ 醯胺。中間物之光譜資料如下： 七甲基苯基)丁 'Η NMR (400 MHz, DMS〇-^6)： δ 9 m , τ _ , ^ ττ 1 (s，1H)，6·82 (d， J ~ Hz，1H), 6.76 (m，1H)，2.25 (t，j 〜， (5 〜7.2 Hz，2H)，2.00 (s，3H)，1.55 (qd，j = 7.4 Hz，j = 7 2 7.4Hz33H)〇 ，2H)，0.86 (t，J = 16 201200500 ，3C NMR (100 MHz, DMSO-rf6)： δ 171.7, 146.1, 137.8, 126.7, 121.0，1 19.8, 1 15.8, 109.4, 37.8, 19.1，18.3, 14.2。 實施例8 7 -曱基-2-丙基-3F-笨并咪唑_5_曱腈（i，R1 = CH3，R2 = «-C3H7 > R3 = CN) 將W-(4-氰基-2-曱基-6-硝基苯基）丁醯胺（347 mg，1.42 mmol ’ 1.0 eq·)、二硫亞續酸鈉（733 mg，4.21 mmo卜 3.0 eq.) 於乙醇（5 mL·)及水（10 mL)中之混合物加熱至70°C歷時 4小時。向混合物中添加二氣曱烷及水。相分離及水性處理 獲得呈灰白色固體形式之7-曱基-2-丙基-3丹-苯并咪唑-5-曱 腈。 產量：112 mg ( 40%)。 實施例9 7-甲基-2-丙基-3β-苯并咪唑_5_曱酸（I，r1 = CH3，R2 = n-C3H7 > R3 = COOH) 將7-曱基-2-丙基-3仏苯并咪唑_5-曱腈（250 mg，1 mmol 1 ·〇 eq·)、鹽酸水溶液（36%，2.5 mL，29 mmol，2.3 eq_)於1，4-二噁烷（2.5 mL)中之混合物加熱至100°C歷時 16小時。移除揮發物後’對濃縮物以曱醇稀釋且以活性 碳脫色獲得白色固體。 產量：85 mg ( 30%)。 此產物之光譜資料與商業產品之光譜資料相同： 17 201200500 'H NMR (400 MHz, OMSO-d6): δ 12.42 (s, 1H), 7.82 (s, 1H), 7.56 (s, 1H), 2.80 (t, J = 7.4 Hz, 2H), 2.50 (s, 3H), 1.79 (qd, J = 7.4 Hz, J = 7.32 Hz, 2H), 0.94 (t, J = 7.32 Hz, 3H)。 13C NMR (100 MHz, DMSO-J6): δ 168.6, 157.5, 124.1, 123.3, 31.0, 21.4，17.1，14.2。 【圖式簡單說明】 無 【主要元件符號說明】 無 181.73 (qd, J = 7.3 Hz, J = 7.4 Hz, 2H), 〇07 u T 3H)〇.87 ", 7.4 Hz, 13C NMR (100 MHz, DMSO-i/6): δ ΐς〇. ^ 03-4, 30.9, 21.3, 16.9, H.! 〇M, 丨·· 1,丨2.' During the reduction of the cyclization reaction, especially when the 八 八 不 不 , , , , #·(2_Amino_4_τττ 醯amine of the intermediate. The spectral data of the intermediate is as follows: heptamethylphenyl) butyl 'Η NMR (400 MHz, DMS〇-^6): δ 9 m , τ _ , ^ ττ 1 (s,1H),6·82 (d, J ~ Hz,1H), 6.76 (m,1H), 2.25 (t,j ~, (5 7.2 Hz, 2H), 2.00 (s , 3H), 1.55 (qd, j = 7.4 Hz, j = 7 2 7.4 Hz 33H) 〇, 2H), 0.86 (t, J = 16 201200500 , 3C NMR (100 MHz, DMSO-rf6): δ 171.7, 146.1, 137.8, 126.7, 121.0,1 19.8, 1 15.8, 109.4, 37.8, 19.1, 18.3, 14.2. Example 8 7-mercapto-2-propyl-3F-benzimidazole _5-indoleonitrile (i, R1 = CH3,R2 = «-C3H7 > R3 = CN) W-(4-cyano-2-indolyl-6-nitrophenyl)butanamine (347 mg, 1.42 mmol '1.0 eq·), II Sodium thiosulfate (733 mg, 4.21 mmo b 3.0 eq.) in ethanol (5 mL· The mixture in water (10 mL) was heated to 70 ° C for 4 hours. Dioxane and water were added to the mixture. Phase separation and aqueous treatment gave 7-mercapto-2-propyl as an off-white solid. -3 Dan-benzimidazole-5-indoleonitrile Yield: 112 mg (40%). Example 9 7-Methyl-2-propyl-3β-benzimidazole _5-decanoic acid (I, r1 = CH3, R2 = n-C3H7 > R3 = COOH) 7-Mercapto-2-propyl-3仏benzimidazole_5-indolecarbonitrile (250 mg, 1 mmol 1 ·〇eq·), aqueous hydrochloric acid ( A mixture of 36%, 2.5 mL, 29 mmol, 2.3 eq_) in 1,4-dioxane (2.5 mL) was heated to 100 ° C for 16 hours. After removal of the volatiles, the concentrate was diluted with methanol. Decolorization with activated carbon gave a white solid. Yield: 85 mg (30%). The spectral data of this product are identical to those of the commercial product: 17 201200500 'H NMR (400 MHz, OMSO-d6): δ 12.42 (s, 1H), 7.82 (s, 1H), 7.56 (s, 1H), 2.80 (t, J = 7.4 Hz, 2H), 2.50 (s, 3H), 1.79 (qd, J = 7.4 Hz, J = 7.32 Hz, 2H), 0.94 (t, J = 7.32 Hz, 3H). 13C NMR (100 MHz, DMSO-J6): δ 168.6, 157.5, 124.1, 123.3, 31.0, 21.4, 17.1, 14.2. [Simple diagram description] None [Main component symbol description] None 18

Claims (1)

201200500 七、申請專利範圍： 1. 一種製造式（I)之經取代笨并°米<»坐之方法201200500 VII. Patent application scope: 1. A method for manufacturing the formula (I) by replacing the stupid and ° meter <» sitting method (I) 其中R1為氫、C!.6烷基或C3_6環烷基，R2為Cl_6烷基 或C3·6環烧基，且R3為氰基或緩基，該方法包含以下步驟： (i )使式（Η )之N-醯基-對鹵基苯胺氰化，(I) wherein R1 is hydrogen, C..6 alkyl or C3_6 cycloalkyl, R2 is Cl_6 alkyl or C3.6 cycloalkyl, and R3 is cyano or decyl, the process comprising the steps of: (i Cyanating N-fluorenyl-p-haloaniline of formula (Η), ΟΟ (") 其中R & R如上文所定義且X為氯或漠，以獲得式 (III)之相應氰基化合物， 201200500 CN(") wherein R & R is as defined above and X is chlorine or desert to obtain the corresponding cyano compound of formula (III), 201200500 CN NHNH 其中R1及R2如上文所定義， (ii)使步驟（i)中獲得之氰基化合物硝化以獲得式 (IV )之相應硝基化合物， CNWherein R1 and R2 are as defined above, (ii) nitrating the cyano compound obtained in step (i) to obtain the corresponding nitro compound of formula (IV), CN (IV) 其中R及R2如上文所定義， (in )使步驟（ii )中獲得之硝基化合物還原及環化以 獲付其巾R1及R2如上文所定義且r3 &氛基的目標化合物 (la )’及視情況而定， (IV )使化合物Ia之氰基水解以獲得其中R3為羧基之 目標化合物（lb )。 2 ·如申°月專利範圍第1項之方法，其中步驟（i )中之 亂化係在極性非質子性溶劑中且在作為催化劑之鈀膦錯合 物存在下用六氰亞鐵（Π)酸鉀實現。 201200500 3. 如申請專利範圍第2項之方法， 肆（三苯膦）鈀（〇)β 、 〇、、錯合物為 4. 如申請專利範圍第丨項至第3 ^任一項之方法，甘 中步驟（ii)中之硝化係使用含鹼金 其 化劑來實現。 ’酸鹽之硫酸作為確 5. 如申請專利範圍第1項至第4 中舟賴^…、上 ^干任一項之方法，盆 中步驟(⑴）十之還原及環化係在不 - 用含元素鐵之乙酸作為還原劑來進行。θ《情形下使 6. 如申請專利範圍帛！項至第 令步驟（iii)中之還原環化係在 項之方法’其 驗金屬二硫亞續酸鹽作為還原劑來進： 間物之情形下使用 7. 如申請專利範圍第i項至 仃 中R1為甲基。 $中任一項之方法，其 8·如申請專利範圍帛】項至 中R2為丙基。 中任—項之方法，其 9·如申請專利範圍第〗項至第8 中X為溴。 項之方法’其 丨〇·—種式（la)化合物，(IV) wherein R and R2 are as defined above, (in) reducing and cyclizing the nitro compound obtained in step (ii) to obtain a target of R1 and R2 as defined above and r3 & Compound (la)' and, as the case may be, (IV) hydrolyze the cyano group of compound Ia to obtain the target compound (lb) wherein R3 is a carboxyl group. 2. The method of claim 1, wherein the chaos in step (i) is in a polar aprotic solvent and in the presence of a palladium phosphine complex as a catalyst, hexacyanoferrite (Π) ) Potassium acid is achieved. 201200500 3. For the method of claim 2, 肆(triphenylphosphine)palladium(〇)β, 〇, and complex are 4. The method of claim 3 to 3 The nitration in step (ii) of Ganzhong is carried out using an alkali-containing gold-based chemical. 'Acidate of sulfuric acid as a true 5. As in the scope of patent application No. 1 to 4, the method of the boat, the method of the above, the step of the pot ((1)) ten reduction and cyclization is not - It is carried out using acetic acid containing elemental iron as a reducing agent. θ "In the case of 6. If you apply for a patent scope! The reduction cyclization in the step (iii) of the first step is used in the method of the invention, wherein the metal dithioxetide is used as a reducing agent: in the case of a substance. 7. In the crucible, R1 is a methyl group. Any of the methods of $, such as the scope of the patent application 帛] to R2 is propyl. The method of the middle-item, 9) If the patent scope is from the first to the eighth, X is bromine. The method of the item ’ 丨〇·—the compound of the formula (la), 其中R1為Cw院基或c3 •6環炫•基且R2為C 〗-6烷基或 21 201200500 C 3.6環烧基。 11. 如申請專利範圍第10項之化合物，其中R1為曱基 且R2為丙基。 12. —種式（III)化合物，Wherein R1 is a Cw or a C3 • 6 ring Hyun group and R 2 is a C -6 alkyl group or 21 201200500 C 3.6 ring alkyl group. 11. The compound of claim 10, wherein R1 is an indenyl group and R2 is a propyl group. 12. a compound of formula (III), 其中1^為（^1.6烧基或〇3-6環烧基且尺2為丙基。 13.如申請專利範圍第12項之化合物，其中R1為甲基 且R2為丙基。 14.一種式（IV)化合物， CNWherein 1 is (^1.6 alkyl or oxime 3-6 cycloalkyl and the caliper 2 is propyl. 13. The compound of claim 12, wherein R1 is methyl and R2 is propyl. Compound of formula (IV), CN (IV) 其中R1為Ci_6烷基或（：3_6環烷基且112為Cm烷基或 C 3.6環烧基。 1 5.如申請專利範圍第14項之化合物，其中R1為甲基 22 201200500 且R2為丙基。 八、圖式： 無 23(IV) wherein R1 is Ci_6 alkyl or (: 3-6 cycloalkyl and 112 is Cm alkyl or C 3.6 cycloalkyl. 1 5. The compound of claim 14 wherein R1 is methyl 22 201200500 and R2 is propyl. Eight, schema: no 23