TWI274749B - Process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl]ethanone - Google Patents

Process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl]ethanone Download PDF

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TWI274749B
TWI274749B TW89114808A TW89114808A TWI274749B TW I274749 B TWI274749 B TW I274749B TW 89114808 A TW89114808 A TW 89114808A TW 89114808 A TW89114808 A TW 89114808A TW I274749 B TWI274749 B TW I274749B
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methyl
formula
methylpyridin
reaction
alkali metal
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Chinese (zh)
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Erich Armbruster
Yves Bessard
David Kuo
James Edward Leresche
Ralf Proplesch
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Lonza Ag
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Abstract

A four-step process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl)-ethanone of the formula, starting from 2-methyl-5-ethylpyridine is described. 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)-phenyl]ethanone is an intermediate for preparing COX-2 inhibitors.

Description

12747491274749

五、發明説明(丨) 說明 本發明包括一種製備1-(6-甲基毗啶-3-基)-2-[(4-(甲基 磺醯基)苯基]乙酮之新穎方法,V. DESCRIPTION OF THE INVENTION (丨) Description The present invention includes a novel process for the preparation of 1-(6-methylcyclopyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone,

(請先閱讀背面之注意事項再填寫本頁) S〇2CH3 1-(6-甲基吡啶-3-基)-2-[(4-(甲基磺醯基)苯基]乙酮是 製備所謂之COX-2抑制劑的中間產物,有止痛和抗發炎之 藥學活性的化合物(R.S. Friesen等人,生物有機&醫學的 化學文獻 8(Bioorganic & Medicinal Chemistry Letters 8 )(1998) 2777,2782 ; WO98/03484)。 式I之1-(6-甲基吡啶-3-基)-2-[(4-(甲基磺醯基)苯基] 乙酮在文獻上是未知的新穎化合物。 本發明的目的是提供一種製造COX-2-抑制劑的新穎中 間產物和提供一種製備式I中間產物之工業上可實行的方 法。該目的藉由根據申請專利範圍第1項之新穎方法達成 經濟部智慧財產局員工消費合作社印製 根據本發明之方法以四步驟爲特徵,其中 在第一步驟a)中,2_甲基乙基吡啶在50CTC到700 °C於催化劑存在下轉換成2-甲基-5-乙烯基吡啶, 在第二步驟b)中,2-甲基巧-乙烯基吡啶使用臭氧及然 後還原處理轉換成2-甲基毗啶甲醛, 在第三步驟c)中,2-甲基吡啶-5-甲醛使用二烷基胺和 3 本紙張尺度適用中國國家標準(CNS ) A4規格(2i0X29?公釐) 1274749 A7 B7 五、發明説明(少) CN化合物轉換成相當的N,N-二烷胺基-(6-甲基-3-吡啶基) 乙腈, 和在最後步驟d)中,N,N-二烷胺基-(6-甲基-3-砒啶基) 乙腈在鹼存在下與4-(甲基磺醯基)苯甲基鹵化物反應產生 1-(6-甲基吡啶-3-基)-2-[(4-(甲基磺醯基)苯基]乙酮以獲得最 終產物。 根據本發明方法的顯著優點包括工業上可得之2-甲基-5-乙基吡啶可作爲起始物質使用之事實。 驟步a : 從文獻(例如A. Nenz等人,烴處理(Hydrocarbon Processing),47(11),1968,139-144 ; US-A 2,769,773)可 知2_甲基巧-乙基吡啶的脫水作用產生2-甲基-5_乙烯基吡 啶。反應在很多不同催化劑存在下於50(TC到700°C進行。 大體上,採用基於矽石,矽凝膠,氧化鐵,氧化鋅,氧化 鉻’亞鉻酸銅,氧化鎂,氧化鉀,氧化鋁或磷酸硼之催化 劑’單獨或爲混合物,如果適當的話施用至撐體。特別是 使用施用至當做撐體之浮石的氧化鋅催化劑可獲得好的結 果。以蒸氣或惰性氣體稀釋2-甲基吡啶對反應是有利,但 是較佳爲使用蒸氣。 2_甲基巧-乙烯基吡啶可在簡單的方法中純化,例如藉 由除去水相和後來蒸汽蒸餾或真空蒸餾,以使其適合於後 來的步驟b) 〇 步驟b : ______ 4 本紙張尺度適用中國國豕標準(CNS ) A4規格(210 X 297公麓) (請先閱讀背面之注意事項再填寫本頁) ,τ 經濟部智慧財產局員工消費合作社印製 1274749 7 A7 B7 五、發明説明(4 ) 與臭氧的反應有利地在-20°C到〇°C的溫度於礦物酸存 在下進行,較佳在-15°C到-5°C的溫度進行。適當的礦物酸 爲硫酸或磷酸,和特別是硫酸。適當的反應介質是水及極 性溶劑。作爲極性溶劑,可使用醇能例如甲醇,乙醇 ,丙醇,丁醇,戊醇或己醇。低級醇,例如甲醇或乙醇, 與水之混合物已被發現是有用的。以中間產物之形成的臭 氧錯合物還原性地處理,較佳與鹼金屬亞硫酸氫鹽,以獲 得2-甲基-5-甲醛。 適當的鹼金屬亞硫酸氫鹽是亞硫酸氫鈉或鉀。然而, 也可能選擇其他已知的還原劑,例如,二甲硫醚,硫脲或 三甲基亞磷酸鹽或氫,在適當的催化劑存在下。 在以鹼金屬亞硫酸氫鹽的較佳還原處理之情況中,反 應在與臭氧化作用所使用的介質本質上相同的介質中進行 ,通常在-2(TC到20°C的溫度,較佳從到0°C。 視進一步處理步驟而定,2-甲基吡啶-5-甲醛,或鹼金 屬亞硫酸氫鹽與2-甲基吡啶-5-甲醛的加成物可被形成。 如果需要單離2-甲基-5-甲醛,其可能在pH大約4到 5以適當有機溶劑選擇性萃取物反應混合物,例如,以乙 酸乙酯萃取。但較佳,或者,鹼金屬亞硫酸氫鹽與2-甲基 吡啶-5-甲醛的加成物可首先被形成,其然後在pH大約10 裂解成2-甲基-5-甲醛。 然而,特佳爲鹼金屬亞硫酸氫鹽與2-甲基-啶-5-甲酸 的加成物立刻使用於步驟c)之進一步反應中。因此,在較 佳方式中單離較不穩定的2-甲基吡啶-5-甲醛是可能的。 5 本紙張尺度適用中國國家標準(CNS ) A4規格(210'乂 297公^"5 (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 A7 B7 1274749 五、發明説明(IV ) 鹼金屬亞硫酸氫鹽與2-甲基毗啶-5-甲醛的加成物是新 穎且在文獻上是未知的,因此也爲本發明標的之部份。加 成物具有通式(Please read the notes on the back and fill out this page.) S〇2CH3 1-(6-Methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone is prepared An intermediate product of the so-called COX-2 inhibitor, which has an analgesic and anti-inflammatory pharmaceutically active compound (RS Friesen et al., Bioorganic & Medicinal Chemistry Letters 8 (1998) 2777, 2782; WO98/03484) 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone of formula I is an unknown novel compound in the literature It is an object of the present invention to provide a novel intermediate product for the manufacture of a COX-2-inhibitor and to provide an industrially practicable process for the preparation of an intermediate of the formula I. This object is achieved by a novel method according to the first aspect of the patent application. Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printing The method according to the invention is characterized by four steps, wherein in the first step a), 2-methylethylpyridine is converted to 2 in the presence of a catalyst at 50 CTC to 700 °C. -methyl-5-vinylpyridine, in the second step b), 2-methylco-vinylpyridine uses ozone and then The original treatment is converted to 2-methylpyridinaldehyde. In the third step c), 2-methylpyridine-5-formaldehyde is dialkylamine and 3 paper scales are applicable to the Chinese National Standard (CNS) A4 specification (2i0X29). ??) 1274749 A7 B7 V. Description of the invention (less) Conversion of the CN compound to the equivalent N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile, and in the last step d), N,N-Dialkylamino-(6-methyl-3-acridinyl)acetonitrile is reacted with 4-(methylsulfonyl)benzyl halide in the presence of a base to give 1-(6-methyl) Pyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone to give the final product. Significant advantages of the process according to the invention include the industrially available 2-methyl-5- The fact that ethylpyridine can be used as a starting material. Step a: From the literature (for example, A. Nenz et al., Hydrocarbon Processing, 47 (11), 1968, 139-144; US-A 2,769,773) Dehydration of 2-methyl-ethylpyridine results in 2-methyl-5-vinylpyridine. The reaction is carried out in the presence of many different catalysts at 50 (TC to 700 ° C. In general, based on vermiculite, 矽Gel, iron oxide, oxidation Zinc, chromium oxide 'copper chromite, magnesium oxide, potassium oxide, aluminum oxide or boron phosphate catalysts', either alone or as a mixture, if appropriate applied to the support. In particular, zinc oxide applied to the pumice as a support is used. The catalyst gives good results. Diluting 2-methylpyridine with steam or an inert gas is advantageous for the reaction, but it is preferred to use a vapor. 2-Methyl-vinylpyridine can be purified in a simple process, for example by removing the aqueous phase and later by steam distillation or vacuum distillation to make it suitable for subsequent steps b) 〇Step b: ______ 4 Paper scale Applicable to China National Standard (CNS) A4 specification (210 X 297 麓) (Please read the note on the back and fill out this page), τ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1274749 7 A7 B7 V. Invention Description (4) The reaction with ozone is advantageously carried out at a temperature of from -20 ° C to 〇 ° C in the presence of a mineral acid, preferably at a temperature of from -15 ° C to -5 ° C. Suitable mineral acids are sulfuric acid or phosphoric acid, and especially sulfuric acid. Suitable reaction media are water and polar solvents. As the polar solvent, an alcohol such as methanol, ethanol, propanol, butanol, pentanol or hexanol can be used. Mixtures of lower alcohols such as methanol or ethanol with water have been found to be useful. The ozone complex formed by the intermediate product is reductively treated, preferably with an alkali metal hydrogensulfite, to obtain 2-methyl-5-formaldehyde. A suitable alkali metal bisulfite is sodium or potassium hydrogen sulfite. However, it is also possible to select other known reducing agents, such as dimethyl sulfide, thiourea or trimethyl phosphite or hydrogen, in the presence of a suitable catalyst. In the case of a preferred reduction treatment with an alkali metal hydrogensulfite, the reaction is carried out in a medium substantially the same as the medium used for ozonation, usually at a temperature of -2 (TC to 20 ° C, preferably From 0 to C. Depending on the further processing step, 2-methylpyridine-5-formaldehyde, or an adduct of an alkali metal hydrogensulfite and 2-methylpyridine-5-formaldehyde can be formed. Isolation of 2-methyl-5-formaldehyde, which may be selective extraction of the reaction mixture with a suitable organic solvent at a pH of about 4 to 5, for example, extraction with ethyl acetate. Preferably, alternatively, the alkali metal bisulfite An adduct with 2-methylpyridine-5-formaldehyde can be formed first, which is then cleaved to 2-methyl-5-formaldehyde at a pH of about 10. However, it is particularly preferred to be an alkali metal bisulfite and 2- The adduct of methyl-pyridine-5-formic acid is used immediately in the further reaction of step c). Therefore, it is possible to separate the less stable 2-methylpyridine-5-formaldehyde in a preferred manner. 5 The paper size applies to the Chinese National Standard (CNS) A4 specification (210'乂297 public^"5 (please read the note on the back and fill out this page). The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Print A7 B7 1274749 V. INSTRUCTION DESCRIPTION (IV) Adducts of alkali metal hydrogensulfite and 2-methylpyridin-5-formaldehyde are novel and unknown in the literature and are therefore part of the subject matter of the invention. Has a general formula

0H0H

其中Μ是鹼金屬,且稱爲1-羥基-(6-甲基吡啶-3-基)甲烷 磺酸鹽。驗金屬Μ有利地是Na或Κ。 步驟c : 2_甲基吡啶-5-甲醛或鹼金屬亞硫酸氫鹽與2_二甲基毗 啶-5-甲醛的加成物的反應係依照Strecker合成的原則,使 用CN化合物和二烷基胺以產生相當的N,N-二烷胺基-(6- 甲基吡啶基)乙腈而進行。 HCN水溶液或鹼金屬氰化物的水溶液在這裡可作爲 CN化合物。適當的二烷基胺是Cw二烷基胺’特別是二 甲胺或二乙胺。 反應溫度在到30t的範圍是有利地。 加入水不相混合的溶劑是有利的,例如’甲苯或三級-丁基甲基醚。N,N-二烷胺基_(1-甲基毗啶基)乙腈之處理 和單離然後可藉由簡單的相分離進行。通式111之N,N-二 烷胺基-(1_甲基吡啶基)乙腈類, (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 1 ___-_ 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 1274749 A7 B7 五、發明説明(< )Among them, hydrazine is an alkali metal and is called 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonate. The metal ruthenium is advantageously Na or ruthenium. Step c: The reaction of 2-methylpyridin-5-formaldehyde or an alkali metal bisulfite with an adduct of 2-dimethylpyridin-5-formaldehyde according to the principle of Strecker synthesis, using a CN compound and a dioxane The amine is carried out to give the equivalent N,N-dialkylamino-(6-methylpyridyl)acetonitrile. An aqueous solution of HCN or an aqueous solution of an alkali metal cyanide can be used herein as a CN compound. A suitable dialkylamine is a Cw dialkylamine ', especially dimethylamine or diethylamine. The reaction temperature is advantageously in the range of up to 30 t. It is advantageous to add a water-incompatible solvent such as 'toluene or tertiary-butyl methyl ether. The treatment and sterolization of N,N-dialkylamino-(1-methylpyridinyl)acetonitrile can then be carried out by simple phase separation. N,N-Dialkylamino-(1-methylpyridyl)acetonitrile of the general formula 111, (please read the note on the back and then fill out this page) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives 1 ___ -_ This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1274749 A7 B7 V. Invention Description (< )

(請先閱讀背面之注意事項再填寫本頁) 其中Aik是1到4個碳原子的烷基,在文獻上是未知的新 穎化合物,和因此其也形成本發明標的之部份。 烷基明定爲甲基,乙基,正丙基,異丙基,正丁基, 異丁基或三級丁基。烷基的較佳定義爲甲基或乙基。 步驟d : N,N-二烷胺基-(6_甲基吡啶基)乙腈藉由與4-(甲基 磺醯基)苯甲基鹵化物之反應產生式I的最終產物的轉化係 在鹼存在下進行。適當的心(甲基磺醯基)苯甲基鹵化物是 心(甲基磺醯基)苯甲基氯。 經濟部智慧財產局員工消費合作社印製 所用的鹼可爲鹼金屬氫氧化物的水溶液,較佳爲氫氧 化鈉水溶液,在此情況中使用習知相轉移催化劑。適當的 相轉移催化劑是,例如,鹵化四烷銨,例如,氯化四正丁 基銨或溴化四正丁基銨。反應溫度在40°C到70°C的範圍。 加入與水不相混合的溶劑是有利的,例如,甲苯,二氯甲 烷或三級-丁基甲基醚。 可選擇和較佳地,所使用的鹼爲鹼金屬醇鹽。適當的 鹼金屬醇鹽是,例如,三級丁醇鈉,三級丁醇紳或三級戊 醇鈉,且較佳爲三級丁醇鈉。推薦溶劑是醚,例如,四氫 呋喃。在這個變化方法中的反應溫度通常爲l5°c到25°c。 1-(6-甲基吡啶-3-基)-2-[(4-(甲基磺醯基)苯基]乙酮可 Ί 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐1 一 :'- 經濟部智慧財產局員工消費合作社印製 1274749 A7 B7 五、發明説明(V) 在諳熟該技藝的人所知的方式單離,例如藉由酸化反應混 合物,接著以:,例如,甲苯萃取。進一步的純化作用可藉 由例如在乙腈中再結晶進行。 實施例1 2-甲基-5-乙烯基吡啶的製備。 具有6到8毫米粒子大小之浮石以水溼化及與25%乾 重量之粉末形式氧化鋅式混合,將水氣裝滿反應器(管長度 750毫米,管直徑60毫米)和留在650°C到700°C氮氣流下 經24小時。 在670C到680C和665笔;巴下將76毫升/小時的2_ 甲基-5-乙基吡啶與87毫升/小時之蒸氣一起通過上述之 催化劑。在反應器終端,取出由40.6重量%之2-甲基-5-乙烯基吡啶和56·3%之甲基乙基吡啶所組成的產物流 。以反應的2-甲基乙基吡啶爲基準,達到93.0%的產率 〇 爲了製備純2-甲基-5-乙烯基Dtt啶,產物混合物接著進 行蒸汽蒸餾(266毫巴,塔頂溫度59° C-6CTC)或真空蒸餾 (2〇毫巴,溫度9〇°C)。 實施例2 2-甲基吡啶-5-甲醛的製備 最初進料11.92克之甲基乙烯基吡啶(含量85% ,85毫莫耳),5G毫升的甲醇和10毫升水。計量濃硫酸 ___ 8 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (請先閲讀背面之注意事項再填寫本頁) 衣 訂 1274749 A7 B7 五、發明説明(q ) (9.81克,98毫莫耳)以使溫度沒有超過2〇°C。溶液從-12°C 冷卻,且引入臭氧/氧混合物(於02中的大約5%〇3 ’ 50 升/小時)直到2-甲基-5-乙烯基吡啶完全反應。小心地計 量水(50毫升)和40%水的NaHS03溶液(22.7克,85毫莫 耳)。使反應混合物溫熱到20°C和使用30%NaOH(大約32 克,0.24莫耳)中和。於在30-40°C蒸餾掉甲醇,然後,形 成亞硫酸氫鹽加成物,加入另外的22.7克4〇妬NaHS〇3溶 液。攪拌混合物30分鐘,之後pH重新調整到中性’且接 著使用35毫升的三級-丁基甲基醚萃取中性雜質°水相以 30%Na〇H調整至pH 10,且加入26.5克_2〔〇3(〇·25旲 耳)。所釋出的醛使用280毫升的三級-丁基甲基酸萃取° 濃縮溶劑以產生9克呈微黃色油狀物的2-甲棊卩比α定甲酸 〇 W-NMRCCDCh) : 2.66(s,3H); 7.35(d,J=8 Hz,1H); 8.07(dd,8 Hz 和 2·1 Hz ’ 1H) ’ 8.96(d,J= 2.1 Hz,1H); 10.08(s,1H)。 13C-NMR(CDC13) : 24.98(CH3); 123.72(05); 129.32(03); 135.88(04); 151.87(02); ____ 9____- 本紙張尺度適用中國國家標隼(CNS ) A4規格(210X 297公釐) (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 經濟部智慧財產局員工消費合作社印製 1274749 A7 ______B7 _ ______ 五、發明説明(A ) (6-甲基卩比陡基)乙腈,30毫升的甲苯和10.0克的砂藻土 。然後經15分鐘期間加入72克(5當量)之50%NaOH水溶 液以使溫度能夠維持在20° C。將反應混合物加熱到45°C 。激烈攪拌,同時加入0.32克的第一部分溴化四-正丁基 銨。在那之後立刻,經過1.5小時期間加入0.32克的溴化 四正丁基銨和44,52克(1.2當量)之4-(甲基磺醯基)苯甲基 氯於200毫升的甲苯中的溶液。在加入一半之後,加入 〇·32克的第三部分溴化四正丁基銨,且於45°C繼續攪拌6 小時。 然後將反應混合物溫熱到室溫,然後加入100毫升的 水和100毫升甲苯。過濾混合物,殘餘物以25毫升的甲苯 洗·,然後分開該等相。水相以2x50毫升的甲苯萃取。然 後合併後之有機相以3 80笔升的IN HC1卒取。以29·6克 的50%NaOH水溶液中和到ΡΗ 4.5而結晶出標題產物。過 濾懸浮液,及產物以2X100毫升的水和2x80毫升的異丙醇 /水1 : 1洗滌和然後在20°C/20毫巴乾燥。此產生4〇.19 克(76·4%)具有99.0%含量之標題化合物。 Μ·ρ· 182°C,183°C。 lH-NMR(CDCl3) : 9.15(lH,s); 8·18(1Η,d); 7.92(2H,d); 7.47(2H,d); 7·30(1Η,d); 4.39(2H,s); ___ 13____ 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297讀1 ' ' : '^^ (請先閲讀背面之注意事項再填寫本頁) 訂 1274749 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明説明((>) 3·04(3Η,s); 2·63(3Η,s) 〇 實施例4b。 1-(6-甲基吡啶-3-基)-2-[(4-(甲基-磺醯基)苯基]乙酮(醇鹽, 無水)的製備 於20°C,經30分鐘期間於20毫升的四氫呋喃的 48.16克(84.5%,1.00當量)之N,N-二乙胺基-(6-甲基吡啶-3-基)乙腈加到38.58克(1.7當量)三級-丁醇鉀於60毫升四 氫呋喃之懸浮液中。然後立刻,於20°C到25°C在1.5小時 期間加入在60毫升四氫呋喃中的42.59克(1.03當量)4-(甲 基磺醯基)苯甲基氯。 於20°C攪拌反應混合物0.5小時,然後以100毫升的 水稀釋,和藉由1小時期間加入180毫升2N HC1調整至 pH 2。於20°C另一 0.5小時之後,混合物以10克之30% NaOH水溶液調整至pH 3。於20°C攪拌懸浮液一小時和然 後過濾,且產物以2x150毫升的水和2x100毫升的水/異 丙醇1 : 1洗滌。在2(TC/20毫巴乾燥產生53.72克(92%) 具有99.1%含量之標題化合物。 M.p. 182〇C-183〇C lH-NMR(CDCl3) · 9·15 (1H,s); 8.18 (1H,d); 7.92 (2H,d); 7.47 (2H,d); 14 本紙張尺度適用中國國家標準(CNS ) A4規格(21 OX 297公釐) (請先閱讀背面之注意事項再填寫本頁) 1274749 A7 B7 五、發明説明(U ) 7·30 (1H,d); 4.39 (2H,s); 3·04 (3H,s); 2.63 (3Η,s). (請先閱讀背面之注意事項再填寫本頁) 訂 本紙張尺度適用中國國家標準(CNS ) A4規格(2!0'犬297公釐) 1(Please read the note on the back and then fill out this page.) Aik is an alkyl group of 1 to 4 carbon atoms, which is an unknown novel compound in the literature, and therefore it also forms part of the subject matter of the present invention. The alkyl group is determined to be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. A preferred definition of alkyl is methyl or ethyl. Step d: conversion of N,N-dialkylamino-(6-methylpyridyl)acetonitrile to a final product of formula I by reaction with 4-(methylsulfonyl)benzyl halide It is carried out in the presence of a base. A suitable heart (methylsulfonyl) benzyl halide is the heart (methylsulfonyl) benzyl chloride. The base used for printing by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs may be an aqueous solution of an alkali metal hydroxide, preferably an aqueous solution of sodium hydroxide, in which case a conventional phase transfer catalyst is used. A suitable phase transfer catalyst is, for example, a tetraalkylammonium halide such as tetra-n-butylammonium chloride or tetra-n-butylammonium bromide. The reaction temperature is in the range of 40 ° C to 70 ° C. It is advantageous to add a solvent which is not miscible with water, for example, toluene, methylene chloride or tertiary-butyl methyl ether. Alternatively and preferably, the base used is an alkali metal alkoxide. Suitable alkali metal alkoxides are, for example, tertiary sodium butoxide, tertiary butanol or tertiary sodium pentoxide, and preferably tertiary sodium butoxide. The recommended solvent is an ether such as tetrahydrofuran. The reaction temperature in this variation method is usually from 15 ° C to 25 ° C. 1-(6-Methylpyridin-3-yl)-2-[(4-(methylsulfonyl)phenyl]ethanone oxime Ί This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 public) PCT 1: '- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1274749 A7 B7 V. Description of Invention (V) In a manner known to those skilled in the art, for example by acidifying the reaction mixture, followed by: For example, toluene extraction. Further purification can be carried out, for example, by recrystallization in acetonitrile.Example 1 Preparation of 2-methyl-5-vinylpyridine. Pumice having a particle size of 6 to 8 mm is wetted with water and Mix with 25% dry weight powder form zinc oxide, fill the reactor with water vapor (tube length 750 mm, tube diameter 60 mm) and leave at 650 ° C to 700 ° C for 24 hours under nitrogen flow. 680C and 665 pens; under the bar, 76 ml / h of 2-methyl-5-ethylpyridine was passed through the above catalyst together with 87 ml / h of vapor. At the reactor end, 40.6 wt% of 2-methyl was taken out. a product stream consisting of -5-vinylpyridine and 56.3% methylethylpyridine. Based on pyridine, a yield of 93.0% is achieved. To prepare pure 2-methyl-5-vinyl Dttidine, the product mixture is then subjected to steam distillation (266 mbar, overhead temperature 59 ° C-6 CTC) or vacuum distillation ( 2 mbar, temperature 9 〇 ° C). Example 2 Preparation of 2-methylpyridine-5-carbaldehyde Initially charged 11.92 g of methyl vinyl pyridine (content 85%, 85 mmol), 5 g ml Methanol and 10 ml of water. Measured concentrated sulfuric acid ___ 8 This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) (Please read the note on the back and fill out this page) Clothing Order 1274749 A7 B7 V. Description of the invention (q) (9.81 g, 98 mmol) such that the temperature does not exceed 2 ° C. The solution is cooled from -12 ° C and an ozone/oxygen mixture is introduced (about 5% 02 3 ' in 02) Liters/hour) until 2-methyl-5-vinylpyridine was completely reacted. Carefully metered water (50 ml) and 40% aqueous NaHS03 solution (22.7 g, 85 mmol). Warm the reaction mixture to 20 °C and neutralized with 30% NaOH (approx. 32 g, 0.24 mol). Distill off methanol at 30-40 ° C, then form bisulfite To the mixture, an additional 22.7 g of a 4 〇妒 NaHS 〇3 solution was added. The mixture was stirred for 30 minutes, after which the pH was readjusted to neutral' and then 35 ml of tertiary butyl methyl ether was used to extract neutral impurities. %Na〇H was adjusted to pH 10, and 26.5 g of _2 [〇3 (〇·25 旲 ear) was added. The released aldehyde was extracted with 280 ml of tri-butyl-methyl acid to concentrate the solvent to give 9 g of 2-carboindole as a slightly yellow oil. 〇W-NMR CCD Ch: 2.66 (s, 3H) 7.35 (d, J = 8 Hz, 1H); 8.07 (dd, 8 Hz and 2·1 Hz ' 1H) ' 8.96 (d, J = 2.1 Hz, 1H); 10.08 (s, 1H). 13C-NMR (CDC13): 24.98(CH3); 123.72(05); 129.32(03); 135.88(04); 151.87(02); ____ 9____- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) (Please read the notes on the back and fill out this page.) Order Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printed Economy Ministry Intellectual Property Bureau Staff Consumer Cooperatives Printed 1274749 A7 ______B7 _ ______ V. Invention Description (A) (6-methylindole ratio steep) acetonitrile, 30 ml of toluene and 10.0 g of diatomaceous earth. Then, 72 g (5 equivalents) of a 50% aqueous NaOH solution was added over a period of 15 minutes to maintain the temperature at 20 ° C. The reaction mixture was heated to 45 °C. Stir vigorously while adding 0.32 g of the first portion of tetra-n-butylammonium bromide. Immediately thereafter, 0.32 g of tetra-n-butylammonium bromide and 44,52 g (1.2 equivalents) of 4-(methylsulfonyl)benzyl chloride in 200 ml of toluene were added over a period of 1.5 hours. Solution. After half of the addition, 32 g of the third portion of tetra-n-butylammonium bromide was added and stirring was continued at 45 ° C for 6 hours. The reaction mixture was then warmed to room temperature and then 100 ml of water and 100 ml of toluene were added. The mixture was filtered, and the residue was washed with 25 ml of toluene, and then the phases were separated. The aqueous phase was extracted with 2 x 50 mL of toluene. The combined organic phase was then stroked with 3 80 liters of IN HC1. The title product was crystallized by neutralization with 2.9 g of a 29% aqueous NaOH solution. The suspension was filtered and the product was washed with 2 x 100 ml of water and 2 x 80 ml of isopropanol / water 1:1 and then dried at 20 ° C / 20 mbar. This gave 4 〇.19 g (76. 4%) of the title compound with a 99.0% content. Μ·ρ· 182 ° C, 183 ° C. lH-NMR (CDCl3): 9.15 (lH, s); 8.18 (1 Η, d); 7.92 (2H, d); 7.47 (2H, d); 7·30 (1Η, d); 4.39 (2H, s); ___ 13____ This paper scale applies to China National Standard (CNS) A4 specification (210X 297 read 1 ' ' : '^^ (please read the back note first and then fill out this page) Book 1274749 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Employee Consumption Cooperative Printed 5, Invention Description ((>) 3·04(3Η, s); 2·63(3Η,s) 〇Example 4b. 1-(6-Methylpyridin-3-yl)- Preparation of 2-[(4-(methyl-sulfonyl)phenyl]ethanone (alkoxide, anhydrous) at 20 ° C over 48 ml of 20 ml of tetrahydrofuran over 30 min (84.5%, 1.00 eq. N,N-diethylamino-(6-methylpyridin-3-yl)acetonitrile is added to a suspension of 38.58 g (1.7 equivalents) of potassium tert-butoxide in 60 ml of tetrahydrofuran. 42.59 g (1.03 equivalents) of 4-(methylsulfonyl)benzyl chloride in 60 ml of tetrahydrofuran was added during 20 hours from 20 ° C to 25 ° C. The reaction mixture was stirred at 20 ° C for 0.5 h, then Dilute with 100 ml of water and adjust to pH by adding 180 ml of 2N HC1 over 1 hour. 2. After another 0.5 hour at 20 ° C, the mixture was adjusted to pH 3 with 10 g of 30% aqueous NaOH solution. The suspension was stirred at 20 ° C for one hour and then filtered, and the product was 2 x 150 ml water and 2 x 100 ml water. /Isopropanol 1: 1 wash. Drying at 2 (TC/20 mbar yields 53.72 g (92%) of the title compound with 99.1% content. Mp 182 〇C-183 〇C lH-NMR (CDCl3) · 9· 15 (1H, s); 8.18 (1H, d); 7.92 (2H, d); 7.47 (2H, d); 14 This paper scale applies to the Chinese National Standard (CNS) A4 specification (21 OX 297 mm) (please Read the notes on the back and fill out this page.) 1274749 A7 B7 V. INSTRUCTIONS (U) 7·30 (1H, d); 4.39 (2H, s); 3·04 (3H, s); 2.63 (3Η, s). (Please read the notes on the back and fill out this page.) The paper size is applicable to the Chinese National Standard (CNS) A4 specification (2!0' canine 297 mm) 1

Claims (1)

A8B8C8D8A8B8C8D8 III 1274749 申請專利範圍 ι·—種製備式I之:u(6•甲基毗啶冬基)冬[(4-(甲基磺醯基 )苯基]乙酮之方法,III 1274749 Patent Application ι· a method for preparing a formula II: u(6•methylpyridinyl) winter [(4-(methylsulfonyl)phenyl]ethanone, 其特徵在於’將I甲基-5-乙烯基毗啶先與臭氧反應, 及以鹼金屬亞硫酸氫鹽進行還原反應,產生式Η之^羥基 •(6_甲基Dtt啶!基)甲烷磺酸鹽 II 其中,Μ爲鹼金屬, 其接著與一烷基胺和氰化合物反應,產生式ΠΙ之ν,ν__ 院胺基-(6_甲基_3_1]比卩定基)乙膳 Ν ,R2 XN >τ 其中Rl和R2爲相同或不同,且爲Cm-院基,及其最後 在鹼存在下與4-(甲基磺醯基)苯甲基鹵化物反應產生式I 之1-(6-甲基毗啶-3-基)_2-[(4-(甲基磺醯基)苯基]乙酮。 2·根據申請專利圍第丨項之方法,其特徵在於2-甲 (請先閲讀背面之注意事項再塡寫本頁)It is characterized in that 'I methyl-5-vinylpyridinyl is first reacted with ozone, and is reduced with an alkali metal hydrogensulfite to produce a hydroxy group (6-methyl Dtt pyridine)-based methane. Sulfonate II, wherein hydrazine is an alkali metal, which is then reacted with a monoalkylamine and a cyano compound to give a formula of ν, ν__ aristyl-(6-methyl_3_1) than hydrazine) R2 XN >τ where R1 and R2 are the same or different and are Cm-hospital, and finally reacted with 4-(methylsulfonyl)benzyl halide in the presence of a base to give 1- (6-Methylpyridin-3-yl)_2-[(4-(methylsulfonyl)phenyl]ethanone 2. The method according to the application of the patent, which is characterized by 2-A ( Please read the notes on the back and write this page. 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1274749 C8 D8 六、申請專利範圍 基-5-乙烯基吡啶與臭氧之反應係在無機酸的存在下進行。 3.根據申請專利圍第2項之方法,其特徵在於2-甲基 -5-乙烯基毗啶與臭氧之反應係在-20°C到Ot溫度進行。 4·根據申請專利圍第1項之方法,其特徵在於還原 反應係在-20°C到20°C的溫度進行。 5 ·根據申請專利圍第1或4項之方法,其特徵在於 使用未單離之1-羥基-(6-甲基毗啶-3-基)甲烷磺酸鹽製備式 III之N,N-Z:烷胺基-(6_甲基冬毗啶基)乙腈。 .6.根據申請專利範圍第1至4項中之任一項之方法 ,特徵在於使用於式II之1-羥基-(6-甲基毗啶-3-基)甲烷 磺酸鹽反應中的氰化合物爲HCN水溶液或鹼金屬氰化物的 水溶液。 7.根據申請專利圍第1至4項中任一項之方法,其 特徵在於式II之1-羥基-(6-甲基吡啶-3-基)甲烷磺酸鹽與 二烷基胺和氰化合物反應之溫度爲0°C到30°C。 8·根據申請專利圍第1至4項中任一項之方法,其 特徵在於用於式III之Ν,Ν-二烷胺基-(6-甲基-3-吡啶基)乙 腈反應中之鹼爲水性的鹼金屬氫氧化物溶液與相轉移催化 劑一起,或者爲鹼金屬醇鹽。 9·根據申請專利圍第1至4項中任一項之方法,其 特徵在於2_甲基乙烯基毗啶係以2_甲基-5-乙基吡啶爲 起始物製得。 10·根據申請專利圍第9項之方法,其特徵在於2-甲 基-5-乙基卩比啶係在催化劑的存在下,在5〇〇°C到700°C轉 2 度適用中國國家標準(CNS) A4規格(210 X 297公釐)_ ' ......................... (請先閱讀背面之注意事項再塡寫本頁) -έ 線I 1274749 . I D8 六、申請專利範圍 換成2 -甲基-5'乙嫌基卩比卩定。 11. 根據申請專利圍第10項之方法,其特徵在於所 使用的催化劑是矽石,矽凝膠,氧化鐵,.氧化鋅,氧化鉻 ,亞鉻酸銅,氧化鎂,氧化鉀,氧化鋁或磷酸硼,單獨或 爲混合物。 12. 根據申請專利範圍第11項之方法,其特徵在於所 使用的催化劑係施用至撐體。 13根據申請專利圍第11項之方法,其特徵在於該反 應是在600°C到700°C的溫度進行。 I4· 一種式II之1-羥基-(6-甲基吡啶-3-基)甲烷磺酸鹽This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1274749 C8 D8 VI. Patent Range The reaction of the base-5-vinylpyridine with ozone is carried out in the presence of a mineral acid. 3. The method according to claim 2, characterized in that the reaction of 2-methyl-5-vinylpyridin with ozone is carried out at a temperature of from -20 ° C to Ot. 4. The method of claim 1, wherein the reduction reaction is carried out at a temperature of from -20 ° C to 20 ° C. 5. The method according to claim 1 or 4, characterized in that N,NZ of the formula III is prepared using an unisolated 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonate: Alkylamino-(6-methylbutyryl)acetonitrile. The method according to any one of claims 1 to 4, characterized in that it is used in the reaction of 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonate of the formula II. The cyano compound is an aqueous solution of HCN or an aqueous solution of an alkali metal cyanide. 7. The method according to any one of claims 1 to 4, characterized in that the 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonate of the formula II is dialkylamine and cyanide The temperature of the compound reaction is from 0 ° C to 30 ° C. The method according to any one of claims 1 to 4, characterized in that it is used in the reaction of hydrazine, hydrazine-dialkylamino-(6-methyl-3-pyridyl)acetonitrile of formula III The base is an aqueous alkali metal hydroxide solution together with a phase transfer catalyst or an alkali metal alkoxide. The method according to any one of claims 1 to 4, wherein the 2-methylvinylpyridine is prepared by using 2-methyl-5-ethylpyridine as a starting material. 10. The method according to claim 9 of the patent application, characterized in that 2-methyl-5-ethylpyridinium is used in the presence of a catalyst at a temperature of 5 ° C to 700 ° C for 2 degrees for the Chinese country Standard (CNS) A4 size (210 X 297 mm) _ ' ......................... (Please read the notes on the back and then 塡Write this page) - έ Line I 1274749 . I D8 VI. The scope of the patent application is changed to 2 - methyl-5' B. 11. The method according to claim 10, characterized in that the catalyst used is vermiculite, bismuth gel, iron oxide, zinc oxide, chromium oxide, copper chromite, magnesium oxide, potassium oxide, aluminum oxide. Or boron phosphate, either alone or as a mixture. 12. The method according to claim 11, characterized in that the catalyst used is applied to the support. The method according to claim 11, wherein the reaction is carried out at a temperature of from 600 ° C to 700 ° C. I4· A 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonate of formula II S〇3OM0 « 其中Μ爲鹼金屬。 I5· —種製備如申請專利範圍第14項所請丨_羥基彳6_ 甲基咖!基兩完麵__,浦誠於^甲基_5_ 乙細基’疋脑由顚紐應,接著以_錢亞硫酸氫鹽 還原’轉換成式II之終產物。 !6·-種式III之N,Nq完胺基♦甲基冬〇比陡基)乙 腈, 乂 NS〇3OM0 « Where Μ is an alkali metal. I5·—Preparation as required in the 14th item of the patent application 彳 彳 彳 _ 6_ methyl coffee! After the completion of the two __, Pucheng in ^ methyl _5_ 乙基基' 疋 brain by 顚 New Zealand, and then reduced with _ _ _ bis bisulphite 'converted into the final product of Formula II. !6·-N of formula III, Nq-substituted amine ♦ methylindole ratio steep) acetonitrile, 乂 N (請先閱讀背面之注意事項再填寫本頁) 線I 1274749 A8 B8 C8 D8 一一(Please read the notes on the back and fill out this page) Line I 1274749 A8 B8 C8 D8 One by one 申請專利範圍 其中R及R2爲相同或不同,且爲烷基。 17· —種製備如申請專利範圍第16項所請式πι之N, N-二烷胺基-(6-甲基-3-毗啶基)乙腈的方法,其特徵在於2_ 甲基’定η之丨·經基_(6_甲基雜·3•基)甲院 磺酸鹽 II 與二烷基胺及氰化物反應以產生式ΙΠ之終產物。 18. —種製備式I之ι_(卜甲基吡啶|基甲基 磺醯基)苯基]乙酮的方法, so2ch3 在第一步驟a)中,2-甲基-5-乙基毗啶在50(TC到700 °(:在催化劑存在下轉換成2-甲基-5-乙烯基毗啶, 在第二步驟b)中,2-甲基-5-乙烯基姐Π定藉由與臭氧反 應,和以鹼金屬亞硫酸氫鹽進行還原反應,產生式II之1-經基_(6·甲基〇比卩疋-3-基)甲院礦酸鹽 本纸張尺度適用中國國家標準(CNS)A4規格(210 X 297么'釐) .........……ώτ,..............訂.........—線· (請先閱讀背面之注意事項再填寫本頁) 098 8 99 ABCD 1274749 六、申請專利範圍 0HPatent Application Range wherein R and R2 are the same or different and are alkyl groups. 17. A method for preparing N,N-dialkylamino-(6-methyl-3-pyridyl)acetonitrile of the formula πι, as described in claim 16 of the patent application, characterized in that it is characterized by 2_methyl' η 丨 经 经 经 经 经 经 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 18. A process for the preparation of iota (i-methylpyridyl)-methylsulfonyl) phenyl]ethanone of formula I, so2ch3 in a first step a), 2-methyl-5-ethylpyridinium at 50 (TC to 700 ° (: converted to 2-methyl-5-vinylpyridin in the presence of a catalyst, in the second step b), 2-methyl-5-vinyl is determined by reaction with ozone And the reduction reaction with an alkali metal bisulfite to produce a 1-carbyl-(6-methylpyridin-3-yl)-carboxate of the formula II. The paper scale is applicable to the Chinese national standard ( CNS)A4 specification (210 X 297 么' PCT) ...............ώτ,..............订.........— Line · (Please read the note on the back and fill out this page) 098 8 99 ABCD 1274749 VI. Patent application scope 0H 其中,Μ爲鹼金.屬, 在第三步驟c)中,使用二烷基胺和氰化合物將式π 之1-羥基-(6-甲基吡啶-3-基)甲烷磺酸鹽轉換成對應的Ν,Ν-二烷胺基-(6-甲基-3-吡啶基)乙腈,和最後, 在最後步驟d)中,N,N-二烷胺基-(6-甲基-3-吡啶基)乙 腈在鹼的存在下與4-(甲基磺醯基)苯甲基鹵化物反應產生 1-(6-甲基毗啶-3-基)-2-[(4-(甲基磺醯基)苯基]乙酮。 5 .................>0^—..........、玎·!-............t· (請先閲讀背面之注意事項再塡寫本頁) 本紙張尺度適用妒國國家標準(CNS)A4規格(210 X 297公釐)Wherein, in the third step c), the 1-hydroxy-(6-methylpyridin-3-yl)methanesulfonate of the formula π is converted into a dialkylamine and a cyanide compound. Corresponding oxime, Ν-dialkylamino-(6-methyl-3-pyridyl)acetonitrile, and finally, in the last step d), N,N-dialkylamino-(6-methyl-3 -pyridyl)acetonitrile is reacted with 4-(methylsulfonyl)benzyl halide in the presence of a base to give 1-(6-methyl-pyridin-3-yl)-2-[(4-(A Alkylsulfonyl)phenyl]ethanone. 5 .................>0^-..........,玎·!-. ...........t· (Please read the notes on the back and write this page first.) This paper size applies to National Standard (CNS) A4 (210 X 297 mm).
TW89114808A 1999-07-29 2000-07-25 Process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl]ethanone TWI274749B (en)

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