JP4406294B2 - Process for producing tert-butyl N- (2-bromoethyl) carbamate - Google Patents
Process for producing tert-butyl N- (2-bromoethyl) carbamate Download PDFInfo
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- JP4406294B2 JP4406294B2 JP2004014460A JP2004014460A JP4406294B2 JP 4406294 B2 JP4406294 B2 JP 4406294B2 JP 2004014460 A JP2004014460 A JP 2004014460A JP 2004014460 A JP2004014460 A JP 2004014460A JP 4406294 B2 JP4406294 B2 JP 4406294B2
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- butyl
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- TZRQZPMQUXEZMC-UHFFFAOYSA-N tert-butyl n-(2-bromoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCBr TZRQZPMQUXEZMC-UHFFFAOYSA-N 0.000 title claims description 47
- 238000000034 method Methods 0.000 title claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 239000013078 crystal Substances 0.000 claims description 31
- 238000004519 manufacturing process Methods 0.000 claims description 31
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical group CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 28
- 239000003795 chemical substances by application Substances 0.000 claims description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 21
- 238000002425 crystallisation Methods 0.000 claims description 13
- 230000008025 crystallization Effects 0.000 claims description 13
- 239000003021 water soluble solvent Substances 0.000 claims description 13
- IZQAUUVBKYXMET-UHFFFAOYSA-N 2-bromoethanamine Chemical compound NCCBr IZQAUUVBKYXMET-UHFFFAOYSA-N 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- XBXCNNQPRYLIDE-UHFFFAOYSA-M n-tert-butylcarbamate Chemical compound CC(C)(C)NC([O-])=O XBXCNNQPRYLIDE-UHFFFAOYSA-M 0.000 claims description 6
- 238000001556 precipitation Methods 0.000 claims description 6
- 125000005999 2-bromoethyl group Chemical group 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 239000003125 aqueous solvent Substances 0.000 claims description 4
- 150000004292 cyclic ethers Chemical class 0.000 claims description 3
- 150000002576 ketones Chemical class 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- QQWYQAQQADNEIC-RVDMUPIBSA-N tert-butyl [(z)-[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)O\N=C(/C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-RVDMUPIBSA-N 0.000 claims description 3
- UJJDEOLXODWCGK-UHFFFAOYSA-N tert-butyl carbonochloridate Chemical compound CC(C)(C)OC(Cl)=O UJJDEOLXODWCGK-UHFFFAOYSA-N 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- RPTBUKFXLSZAKD-UHFFFAOYSA-N 2-bromoethylcarbamic acid Chemical compound OC(=O)NCCBr RPTBUKFXLSZAKD-UHFFFAOYSA-N 0.000 claims 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- -1 tert-butyl bromoethyl Chemical group 0.000 claims 1
- 239000000243 solution Substances 0.000 description 34
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- WJAXXWSZNSFVNG-UHFFFAOYSA-N 2-bromoethanamine;hydron;bromide Chemical compound [Br-].[NH3+]CCBr WJAXXWSZNSFVNG-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 2
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000007806 chemical reaction intermediate Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000011027 product recovery Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- RNHDAKUGFHSZEV-UHFFFAOYSA-N 1,4-dioxane;hydrate Chemical compound O.C1COCCO1 RNHDAKUGFHSZEV-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明はＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの新規な製造方法に関する。 The present invention relates to a novel process for producing tert-butyl N- (2-bromoethyl) carbamate.
Ｎ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルは２−ブロモエチルアミン又はその塩とＢｏｃ化剤（例えば二炭酸ジ−ｔｅｒｔ−ブチル）を反応させて得られる化合物であり（下記化学反応式参照）、ＮＯ合成酵素阻害剤を合成するための反応中間体として有用な化合物である。
Ｎ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの製造方法としては例えば以下のものが従来知られている。 As a method for producing tert-butyl N- (2-bromoethyl) carbamate, for example, the following is conventionally known.
即ち、特開２００２−２０１１７８号公報（特許文献１）の［００４８］実施例６には６ａ）として２−ブロモエチルアミン臭化水素酸塩と二炭酸ジ−ｔｅｒｔ−ブチルをアセトニトリルと水の混合物中で水酸化ナトリウムの存在下に反応させるＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの製造方法が開示されている。特開２００２−２０１１７８号公報の方法によれば、反応溶液は酢酸エチルで抽出され、洗浄、乾燥された後、濃縮されて油状物としてのＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルが得られる。 That is, in [Example 6] of JP-A-2002-2011178 (Patent Document 1), Example 6 shows 6a) 2-bromoethylamine hydrobromide and di-tert-butyl dicarbonate in a mixture of acetonitrile and water. Discloses a process for producing tert-butyl N- (2-bromoethyl) carbamate, which is reacted in the presence of sodium hydroxide. According to the method of JP-A-2002-201178, the reaction solution is extracted with ethyl acetate, washed, dried and then concentrated to obtain tert-butyl N- (2-bromoethyl) carbamate as an oil. It is done.
米国特許第６３２９５２３Ｂ１号公報（特許文献２）の第２８欄の実施例１１には２−ブロモエチルアミン臭化水素酸塩と二炭酸ジ−ｔｅｒｔ−ブチルをアセトニトリル中でトリエチルアミンの存在下に反応させるＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの製造方法が開示されている。米国特許第６３２９５２３Ｂ１号公報の方法によれば、反応溶液はエーテルで抽出され、乾燥された後、濃縮されて油状物としてのＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルが得られる。 Example 11 in column 28 of US Pat. No. 6,329,523 B1 describes the reaction of 2-bromoethylamine hydrobromide with di-tert-butyl dicarbonate in acetonitrile in the presence of triethylamine. A method for producing tert-butyl- (2-bromoethyl) carbamate is disclosed. According to the method of US Pat. No. 6,329,523 B1, the reaction solution is extracted with ether, dried and then concentrated to obtain tert-butyl N- (2-bromoethyl) carbamate as an oil.
米国特許第５７４１９１２号公報（特許文献３）の第３３欄の実施例７にはＡ．として２−ブロモエチルアミン臭化水素酸塩と二炭酸ジ−ｔｅｒｔ−ブチルをジオキサンと水の混合物中で水酸化ナトリウムの存在下に反応させるＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの製造方法が開示されている。米国特許第５７４１９１２号公報の方法によれば、反応溶液はエーテルで抽出され、乾燥された後、濃縮されて油状物としてのＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルが得られる。 In Example 7 in the 33rd column of US Pat. No. 5,741,912 (Patent Document 3), A. Process for producing tert-butyl N- (2-bromoethyl) carbamate by reacting 2-bromoethylamine hydrobromide and di-tert-butyl dicarbonate in a mixture of dioxane and water in the presence of sodium hydroxide as Is disclosed. According to the method of US Pat. No. 5,741,912, the reaction solution is extracted with ether, dried and then concentrated to obtain tert-butyl N- (2-bromoethyl) carbamate as an oil.
しかしながら、これらの従来技術のＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの製造方法はいずれも反応溶液からＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルを得るための工程として抽出、洗浄及び濃縮工程を含んでおり、操作が煩雑である上、収率が低い。また、これらの従来技術の製造方法により得られたＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルは油状物又は粘性のある液体であり、冷却すると塊状に固化してしまい、粉末にならないので取扱いが困難である。また、これらの油状物又は粘性のある液体はたとえ冷却下でも分解が進行してしまい、安定性が悪い。さらに、これらの方法では反応に用いる溶媒と抽出に用いる溶媒が全く異なるため、作業効率が悪い。 However, all of these prior art methods for producing tert-butyl N- (2-bromoethyl) carbamate are extracted, washed, and washed as steps for obtaining tert-butyl N- (2-bromoethyl) carbamate from the reaction solution. Containing a concentration step, the operation is complicated and the yield is low. In addition, tert-butyl N- (2-bromoethyl) carbamate obtained by these conventional manufacturing methods is an oily substance or a viscous liquid, which solidifies into a lump when cooled and does not become a powder. Is difficult. In addition, these oily substances or viscous liquids are decomposed even under cooling and have poor stability. Furthermore, in these methods, since the solvent used for the reaction and the solvent used for extraction are completely different, the working efficiency is poor.
これに対し、Ｖ．Ｇ．Ｂｅｙｌｉｎ ＆ Ｏ．Ｐ．Ｇｏｅｌ（Ｏｒｇａｎｉｃ Ｐｒｅｐａｒａｔｉｏｎｓ ａｎｄ Ｐｒｏｃｅｄｕｒｅｓ Ｉｎｔｅｒｎａｔｉｏｎａｌ 第１９巻第１号第７８頁〜第８０頁（１９８７））（非特許文献１）には２−ブロモエチルアミン臭化水素酸塩と二炭酸ジ−ｔｅｒｔ−ブチルをジクロロメタンと水の混合物中で水酸化ナトリウムの存在下で反応させ、反応溶液をジクロロメタンで抽出し、洗浄、乾燥した後、濃縮し、そこに晶析溶媒としてのヘキサンを添加して−２５〜−１５℃で一晩撹拌することによりＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの結晶を析出させるＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの製造方法が開示されている。 On the other hand, V.V. G. Beylin & O. P. Goel (Organic Preparations and Procedures International, Vol. 19, No. 1, pages 78 to 80 (1987)) (Non-patent Document 1) contains 2-bromoethylamine hydrobromide and di-tert-butyl dicarbonate. The reaction is carried out in the presence of sodium hydroxide in a mixture of dichloromethane and water, and the reaction solution is extracted with dichloromethane, washed, dried and concentrated, and hexane as a crystallization solvent is added thereto to add −25 to − A method for producing tert-butyl N- (2-bromoethyl) carbamate is disclosed in which crystals of tert-butyl N- (2-bromoethyl) carbamate are precipitated by stirring at 15 ° C. overnight.
しかしながら、Ｖ．Ｇ．Ｂｅｙｌｉｎ ＆ Ｏ．Ｐ．Ｇｏｅｌに開示の方法は収率が７１％と極めて低い。また、晶析溶媒としてヘキサンを用いるため、作業担当者に神経系傷害を与えるおそれがある上、静電気爆発を起こすおそれもあり、工業化には適さない。さらに、この方法でも反応に用いる溶媒と晶析に用いる溶媒が全く異なるため、作業効率が悪い。 However, V.V. G. Beylin & O. P. The method disclosed in Goel has a very low yield of 71%. In addition, since hexane is used as a crystallization solvent, there is a risk of causing injury to the person in charge of the operation, and there is a risk of causing an electrostatic explosion, which is not suitable for industrialization. Furthermore, since the solvent used for the reaction and the solvent used for crystallization are completely different in this method, the working efficiency is poor.
従って、従来公知のＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの製造方法はいずれも操作の煩雑さ、最終生成物の取扱いの困難さ、作業効率の悪さ、収率の低さ、又は作業の危険さの点で満足の行くものではない。
本発明はかかる従来技術の現状に鑑み創案されたものであり、操作が簡便で最終生成物の取扱いが容易であり、作業効率が良く、収率が高く、しかも安全なＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの製造方法を提供することを目的とする。 The present invention was devised in view of the current state of the prior art, and is easy to handle, easy to handle the final product, has good working efficiency, high yield, and is safe N- (2-bromoethyl). An object is to provide a method for producing tert-butyl carbamate.
本発明者らはかかる目的を達成するため、反応溶液からのＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの効率的な回収方法について鋭意研究した結果、晶析溶媒として水を用いて反応溶液からＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルを結晶析出により回収することを見出し、遂に本発明を完成するに至った。 In order to achieve such an object, the present inventors have conducted intensive research on an efficient method for recovering tert-butyl N- (2-bromoethyl) carbamate from a reaction solution. As a result, the reaction solution was obtained using water as a crystallization solvent. From this, it was found that tert-butyl N- (2-bromoethyl) carbamate was recovered by crystal precipitation, and finally the present invention was completed.
即ち、本発明は２−ブロモエチルアミン又はその塩とＢｏｃ化剤を水溶性溶媒中で水酸化ナトリウムの存在下に反応させ、反応溶液に晶析溶媒としての水及び種結晶を添加することによりＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの結晶を析出させることを特徴とするＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの製造方法である。 That is, in the present invention, 2-bromoethylamine or a salt thereof and a Boc agent are reacted in a water-soluble solvent in the presence of sodium hydroxide, and water and seed crystals are added to the reaction solution as a crystallization solvent. A method for producing tert-butyl N- (2-bromoethyl) carbamate, wherein crystals of tert-butyl-(2-bromoethyl) carbamate are precipitated.
本発明の製造方法の好ましい実施態様においては水溶性溶媒はアルコール（例えばメタノール、エタノール、プロパノール、ブタノール）、環状エーテル（例えばテトラヒドロフラン、１，４−ジオキサン）、ケトン（例えばアセトン）、アセトニトリル、及びこれらの混合物からなる群から選択される。特に好ましい水溶性溶媒はメタノールである。 In a preferred embodiment of the production method of the present invention, the water-soluble solvent is alcohol (for example, methanol, ethanol, propanol, butanol), cyclic ether (for example, tetrahydrofuran, 1,4-dioxane), ketone (for example, acetone), acetonitrile, and these. Selected from the group consisting of: A particularly preferred water-soluble solvent is methanol.
本発明の製造方法の好ましい実施態様においては、Ｂｏｃ化剤は二炭酸ジ−ｔｅｒｔ−ブチル、Ｂｏｃ−ＯＮ，Ｂｏｃ−ＯＮＨ２，Ｂｏｃ−ＯＣＨ（Ｃｌ）ＣＣｌ３，Ｂｏｃ−Ｎ３，Ｂｏｃ−Ｃｌ，Ｂｏｃ−Ｆ、及びこれらの混合物からなる群から選択される。特に好ましいＢｏｃ化剤は二炭酸ジ−ｔｅｒｔ−ブチルである。 In a preferred embodiment of the production method of the present invention, Boc agent di -tert- butyl, Boc-ON, Boc-ONH 2, Boc-OCH (Cl) CCl 3, Boc-N 3, Boc-Cl , Boc-F, and mixtures thereof. A particularly preferred Boc agent is di-tert-butyl dicarbonate.
本発明の製造方法の好ましい実施態様においては、Ｎ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの結晶の析出は−１５〜５℃の温度で行われる。 In a preferred embodiment of the production method of the present invention, the precipitation of crystals of tert-butyl N- (2-bromoethyl) carbamate is carried out at a temperature of -15 to 5 ° C.
本発明の製造方法の好ましい実施態様においては、反応溶液に添加する水の量はＢｏｃ化剤の重量の１倍以上３倍以下であり、より好ましくは３倍である。 In a preferred embodiment of the production method of the present invention, the amount of water added to the reaction solution is 1 to 3 times, more preferably 3 times, the weight of the Boc agent.
本発明の製造方法の好ましい実施態様においては、２−ブロモエチルアミン又はその塩とＢｏｃ化剤を水溶性溶媒と水の混合物中で水酸化ナトリウムの存在下に反応させる。また、製造方法は析出した結晶を濾過して回収し、水溶性溶媒及び水の混合物で洗浄して乾燥させる工程を更に含む。 In a preferred embodiment of the production method of the present invention, 2-bromoethylamine or a salt thereof and a Boc agent are reacted in a mixture of an aqueous solvent and water in the presence of sodium hydroxide. The production method further includes a step of collecting the collected crystals by filtration, washing with a mixture of a water-soluble solvent and water and drying.
本発明の製造方法によれば、反応溶液からのＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの回収は抽出、洗浄及び濃縮によるのではなく、晶析溶媒及び種結晶を反応溶液に添加して反応溶液からＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルを結晶として析出させることにより行われるため、操作が簡便である。また、晶析溶媒として水を用いるため、作業が安全であり、収率も高い。本発明の製造方法によれば、最終生成物は結晶状態で得られるため、取扱いが容易である。さらに、本発明の製造方法によれば、反応に用いる溶媒と晶析に用いる溶媒を共通にすることができるため、作業効率が良い。 According to the production method of the present invention, recovery of tert-butyl N- (2-bromoethyl) carbamate from the reaction solution is not performed by extraction, washing and concentration, but a crystallization solvent and seed crystals are added to the reaction solution. Therefore, the operation is simple because tert-butyl N- (2-bromoethyl) carbamate is precipitated as crystals from the reaction solution. Moreover, since water is used as the crystallization solvent, the operation is safe and the yield is high. According to the production method of the present invention, the final product is obtained in a crystalline state, and therefore it is easy to handle. Furthermore, according to the production method of the present invention, since the solvent used for the reaction and the solvent used for the crystallization can be made common, the working efficiency is good.
本発明のＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの製造方法は２−ブロモエチルアミン又はその塩とＢｏｃ化剤を水溶性溶媒中で水酸化ナトリウムの存在下に反応させてＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルを生成させる反応段階と、反応溶液に晶析溶媒としての水及び種結晶を添加することによりＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの結晶を析出させる反応生成物回収段階の二つの段階に分けることができる。以下、最初に前半の反応段階について説明し、次いで後半の反応生成物回収段階について説明する。 The method for producing tert-butyl N- (2-bromoethyl) carbamate according to the present invention comprises reacting 2-bromoethylamine or a salt thereof with a Boc agent in an aqueous solvent in the presence of sodium hydroxide to produce N- (2 -Reaction stage for producing tert-butyl carbamate, and reaction for precipitating tert-butyl N- (2-bromoethyl) carbamate by adding water and seed crystals as crystallization solvents to the reaction solution It can be divided into two stages, product recovery stage. Hereinafter, the first reaction stage will be described first, and then the second reaction product recovery stage will be described.
本発明の製造方法において原材料として用いる２−ブロモエチルアミンの塩としてはいかなる塩も用いることができるが、例えば臭化水素酸塩を用いることができる。また、Ｂｏｃ化剤としては二炭酸ジ−ｔｅｒｔ−ブチル、Ｂｏｃ−ＯＮ，Ｂｏｃ−ＯＮＨ２，Ｂｏｃ−ＯＣＨ（Ｃｌ）ＣＣｌ３，Ｂｏｃ−Ｎ３，Ｂｏｃ−Ｃｌ，Ｂｏｃ−Ｆ、及びこれらの混合物等の従来公知のいかなるＢｏｃ化剤も用いることができるが、工業的な入手容易性の観点からは二炭酸ジ−ｔｅｒｔ−ブチルを用いることが好ましい。 Any salt of 2-bromoethylamine used as a raw material in the production method of the present invention can be used, and for example, a hydrobromide can be used. Further, di -tert- butyl as Boc agent, Boc-ON, Boc-ONH 2, Boc-OCH (Cl) CCl 3, Boc-N 3, Boc-Cl, Boc-F, and mixtures thereof Any conventionally known Boc agent such as, for example, can be used, but di-tert-butyl dicarbonate is preferably used from the viewpoint of industrial availability.
本発明の製造方法においては原材料の２−ブロモエチルアミン又はその塩とＢｏｃ化剤は水溶性溶媒中で水酸化ナトリウムの存在下に反応させられる。水溶性溶媒としてはメタノール、エタノール、プロパノール、ブタノール等のアルコール、テトラヒドロフラン、１，４−ジオキサン等の環状エーテル、アセトン等のケトン、アセトニトリル、及びこれらの混合物を挙げることができるが、費用の観点からはメタノールを用いることが好ましい。また、水溶性溶媒に加えて水を添加してもよい。これは水酸化ナトリウムの洗い込みのためである。 In the production method of the present invention, the raw material 2-bromoethylamine or a salt thereof and a Boc agent are reacted in an aqueous solvent in the presence of sodium hydroxide. Examples of the water-soluble solvent include alcohols such as methanol, ethanol, propanol, and butanol, cyclic ethers such as tetrahydrofuran and 1,4-dioxane, ketones such as acetone, acetonitrile, and mixtures thereof, from the viewpoint of cost. It is preferable to use methanol. In addition to the water-soluble solvent, water may be added. This is due to the washing of sodium hydroxide.
本発明の製造方法においては反応溶液の調製は例えば以下の手順で行うことができる：２−ブロモエチルアミン又はその塩と水溶性溶媒をフラスコに仕込み、−３０〜２５℃、好ましくは−１０〜０℃にまで冷却した後、Ｂｏｃ化剤を添加する；その後、−３０〜３０℃、好ましくは−２０〜１０℃で水酸化ナトリウム水溶液を滴下し、続いて所望により水を添加する。また、本発明の製造方法においては反応は−３０〜３０℃、好ましくは−１０〜１０℃で５〜３６時間行わせることが反応収率の観点から望ましい。 In the production method of the present invention, the reaction solution can be prepared, for example, by the following procedure: 2-bromoethylamine or a salt thereof and a water-soluble solvent are charged into a flask, -30 to 25 ° C, preferably -10 to 0 After cooling to <RTIgt; C, </ RTI> the Boc agent is added; then sodium hydroxide aqueous solution is added dropwise at -30 to 30 <0> C, preferably -20 to 10 <0> C, followed by water as desired. In the production method of the present invention, the reaction is desirably carried out at −30 to 30 ° C., preferably −10 to 10 ° C. for 5 to 36 hours from the viewpoint of reaction yield.
反応終了後、反応溶液から反応生成物を回収する。本発明の製造方法においては反応生成物の回収は反応溶液に晶析溶媒としての水及び種結晶を添加してＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの結晶を析出させることにより行われる。反応溶液に添加する水の量は特に制限されないが、Ｂｏｃ化剤の重量の１倍以上３倍以下であることが析出効率の観点から好ましい。反応溶液に添加する水の量がＢｏｃ化剤の重量の１倍未満であると、濾液ロスが大きくなりすぎるため好ましくない。濾液ロスは反応溶液に添加する水の量がＢｏｃ化剤の重量の１倍である場合は１０〜１２％であり、２倍である場合は３〜４％であり、３倍である場合は１〜２％である。Ｂｏｃ化剤の重量の３倍より多い量の水を反応溶液に添加しても濾液ロスはそれ以上小さくならず、効果に差がない。従って、特に好ましい水の量はＢｏｃ化剤の重量の３倍である。これらの水は一度に反応溶液に添加することもできるが、一度に添加すると目的物と溶媒が２層に分かれてしまい、結晶形が大きくなりすぎるおそれがあるため、複数回に分けて添加することが望ましい。例えばＢｏｃ化剤の重量の３倍の水を反応溶液に添加する場合、まず１倍量の水を添加して結晶の一部を析出させてから残余の２倍量の水を添加して結晶の全量を析出させればよい。 After completion of the reaction, the reaction product is recovered from the reaction solution. In the production method of the present invention, the reaction product is collected by adding water and a seed crystal as a crystallization solvent to the reaction solution to precipitate crystals of tert-butyl N- (2-bromoethyl) carbamate. . The amount of water added to the reaction solution is not particularly limited, but is preferably 1 to 3 times the weight of the Boc agent from the viewpoint of precipitation efficiency. If the amount of water added to the reaction solution is less than 1 times the weight of the Boc agent, the filtrate loss becomes too large, which is not preferable. The filtrate loss is 10 to 12% when the amount of water added to the reaction solution is 1 times the weight of the Boc agent, 3 to 4% when 2 times, and 3 times when the amount is 3 times. 1-2%. Even when water in an amount greater than 3 times the weight of the Boc agent is added to the reaction solution, the filtrate loss is not further reduced, and there is no difference in effect. Thus, a particularly preferred amount of water is 3 times the weight of the Boc agent. These waters can be added to the reaction solution at one time, but if added at once, the target compound and the solvent will be separated into two layers and the crystal form may become too large. It is desirable. For example, when adding water 3 times the weight of the Boc agent to the reaction solution, first add 1 amount of water to precipitate a part of the crystal, then add the remaining 2 times amount of water to crystal. It is sufficient to deposit the total amount of
本発明の製造方法においてはＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの結晶の析出は−１５〜５℃で行うことが好ましく、−５〜０℃で行うことが更に好ましい。析出時間は１〜４８時間程度であることが好ましい。 In the production method of the present invention, the precipitation of tert-butyl N- (2-bromoethyl) carbamate crystals is preferably performed at −15 to 5 ° C., more preferably −5 to 0 ° C. The deposition time is preferably about 1 to 48 hours.
析出したＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの結晶は例えば濾過により回収し、反応で用いたのと同じ水溶性溶媒と水の混合物で洗浄して乾燥させればよい。 The precipitated crystals of tert-butyl N- (2-bromoethyl) carbamate may be collected, for example, by filtration, washed with the same water-soluble solvent and water mixture used in the reaction, and dried.
以上の工程により、Ｎ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルは取扱いが容易な結晶状態で、簡便な操作で、かつ良好な作業効率及び高収率で安全に製造することができる。 Through the above steps, tert-butyl N- (2-bromoethyl) carbamate can be safely produced in a crystalline state that is easy to handle, with a simple operation, good working efficiency and high yield.
本発明の製造方法を以下、実施例によって更に具体的に説明する。なお、実施例の記載は純粋に発明の理解のためにのみ挙げるものであり、本発明はこれらによっては何ら限定されるものではない。 The production method of the present invention will be described more specifically with reference to the following examples. In addition, description of an Example is given only for understanding of invention, and this invention is not limited at all by these.
実施例１
（反応溶液に添加する水の量をＢｏｃ化剤の重量の３倍にした例）
２−ブロモエチルアミン臭化水素酸塩５７５ｇとメタノール７６５ｇをフラスコに仕込み、−５℃まで冷却した中に二炭酸ジ−ｔｅｒｔ−ブチル５１０ｇを添加した。その後、２９％水酸化ナトリウム水溶液３８７ｇを滴下し、次いで水１０２ｇを加え−１０〜１０℃で５時間反応させた。次に、水５１０ｇを添加し３℃以下まで冷却し種結晶を投入した。さらに、３℃以下で水１０２０ｇを滴下し３℃以下で１時間保持し、析出した結晶を濾取した。得られた結晶をメタノール／水で洗浄して乾燥させ、Ｎ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの結晶４８７ｇ（収率９３％、ＮＭＲ純度１００％）を得た。
Example 1
(Example in which the amount of water added to the reaction solution is three times the weight of the Boc agent)
575 g of 2-bromoethylamine hydrobromide and 765 g of methanol were charged into a flask, and 510 g of di-tert-butyl dicarbonate was added while cooling to −5 ° C. Thereafter, 387 g of 29% aqueous sodium hydroxide solution was added dropwise, then 102 g of water was added, and the mixture was reacted at −10 to 10 ° C. for 5 hours. Next, 510 g of water was added and cooled to 3 ° C. or lower, and seed crystals were added. Further, 1020 g of water was added dropwise at 3 ° C. or lower and held at 3 ° C. or lower for 1 hour, and the precipitated crystals were collected by filtration. The obtained crystals were washed with methanol / water and dried to obtain 487 g of crystals of tert-butyl N- (2-bromoethyl) carbamate (yield 93%, NMR purity 100%).
実施例２
（反応溶液に添加する水の量をＢｏｃ化剤の重量の２倍にした例）
２−ブロモエチルアミン臭化水素酸塩５７５ｇとメタノール７６５ｇをフラスコに仕込み、−５℃まで冷却した中に二炭酸ジ−ｔｅｒｔ−ブチル５１０ｇを添加した。その後、２９％水酸化ナトリウム水溶液３８７ｇを滴下し、次いで水１０２ｇを加え−１０〜１０℃で５時間反応させた。次に、水５１０ｇを添加し３℃以下まで冷却し種結晶を投入した。さらに、３℃以下で水５１０ｇを滴下し３℃以下で１時間保持し、析出した結晶を濾取した。得られた結晶をメタノール／水で洗浄して乾燥させ、Ｎ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの結晶４７７ｇ（収率９１％、ＮＭＲ純度１００％）を得た。
Example 2
(Example in which the amount of water added to the reaction solution is double the weight of the Boc agent)
575 g of 2-bromoethylamine hydrobromide and 765 g of methanol were charged into a flask, and 510 g of di-tert-butyl dicarbonate was added while cooling to −5 ° C. Thereafter, 387 g of 29% aqueous sodium hydroxide solution was added dropwise, then 102 g of water was added, and the mixture was reacted at −10 to 10 ° C. for 5 hours. Next, 510 g of water was added and cooled to 3 ° C. or lower, and seed crystals were added. Further, 510 g of water was added dropwise at 3 ° C. or lower and held at 3 ° C. or lower for 1 hour, and the precipitated crystals were collected by filtration. The obtained crystal was washed with methanol / water and dried to obtain 477 g (yield 91%, NMR purity 100%) of tert-butyl N- (2-bromoethyl) carbamate.
実施例３
（反応溶液に添加する水の量をＢｏｃ化剤の重量の１倍にした例）
２−ブロモエチルアミン臭化水素酸塩５７５ｇとメタノール７６５ｇをフラスコに仕込み、−５℃まで冷却した中に二炭酸ジ−ｔｅｒｔ−ブチル５１０ｇを添加した。その後、２９％水酸化ナトリウム水溶液３８７ｇを滴下し、次いで水１０２ｇを加え−１０〜１０℃で５時間反応させた。次に、水５１０ｇを添加し３℃以下まで冷却し種結晶を投入した。さらに、３℃で１時間保持し、析出した結晶を濾取した。得られた結晶をメタノール／水で洗浄して乾燥させ、Ｎ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルの結晶４３５ｇ（収率８３％、ＮＭＲ純度１００％）を得た。
Example 3
(Example in which the amount of water added to the reaction solution is 1 time the weight of the Boc agent)
575 g of 2-bromoethylamine hydrobromide and 765 g of methanol were charged into a flask, and 510 g of di-tert-butyl dicarbonate was added while cooling to −5 ° C. Thereafter, 387 g of 29% aqueous sodium hydroxide solution was added dropwise, then 102 g of water was added, and the mixture was reacted at −10 to 10 ° C. for 5 hours. Next, 510 g of water was added and cooled to 3 ° C. or lower, and seed crystals were added. Furthermore, it was kept at 3 ° C. for 1 hour, and the precipitated crystals were collected by filtration. The obtained crystal was washed with methanol / water and dried to obtain 435 g (yield 83%, NMR purity 100%) of tert-butyl N- (2-bromoethyl) carbamate.
比較例１（特開２００２−２０１１７８号公報の実施例６の６ａの追試）
２−ブロモエチルアミン臭化水素酸塩５ｇを水（３０．５ｍｌ）とアセトニトリル（３０．５ｍｌ）に溶解し、２Ｎ水酸化ナトリウム水溶液（３０．５ｍｌ）及び二炭酸ジ−ｔｅｒｔ−ブチル５．９ｇを加え１５時間かき混ぜた。反応液を濃縮し残留液に水を加えて酢酸エチルで抽出し、希硫酸水素カリウム水溶液、飽和食塩水の順で洗浄した後、無水硫酸ナトリウムで乾燥した。抽出液を濃縮して油状物としてのＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチル５．０ｇ（収率８２％）を得た（ただし、ＮＭＲによる純度換算収率は６５％）。
Comparative Example 1 (Examination of 6a of Example 6 of JP-A-2002-201178)
2-Bromoethylamine hydrobromide 5 g was dissolved in water (30.5 ml) and acetonitrile (30.5 ml), 2N aqueous sodium hydroxide solution (30.5 ml) and di-tert-butyl dicarbonate 5.9 g were dissolved. Stir for 15 hours. The reaction solution was concentrated, water was added to the residual solution, and the mixture was extracted with ethyl acetate. The extract was washed with a dilute aqueous potassium hydrogen sulfate solution and saturated brine in that order, and then dried over anhydrous sodium sulfate. The extract was concentrated to obtain 5.0 g (yield 82%) of tert-butyl N- (2-bromoethyl) carbamate as an oil (yield: 65% in terms of purity by NMR).
比較例２（米国特許第６３２９５２３Ｂ１号公報の実施例１１の追試）
２−ブロモエチルアミン臭化水素酸塩５ｇをアセトニトリル（８７．４ｍｌ）に溶解し、トリエチルアミン（３．６ｍｌ）と二炭酸ジ−ｔｅｒｔ−ブチル５．０ｇを加えた。反応液を窒素気流下において２０〜２５℃で１２時間撹拌した後、飽和重曹水（７０ｍｌ）を添加しエーテル（１００ｍｌ）にて抽出した。エーテル層を分取し芒硝にて乾燥させた後、エバポレーターにて濃縮し油状物としてのＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチル４．８ｇ（見掛け収率９４％）を得た（ただし、ＮＭＲによる純度換算収率は８２％）。
Comparative Example 2 (Additional test of Example 11 of US Pat. No. 6,329,523 B1)
2-Bromoethylamine hydrobromide 5 g was dissolved in acetonitrile (87.4 ml), and triethylamine (3.6 ml) and 5.0 g of di-tert-butyl dicarbonate were added. The reaction solution was stirred at 20 to 25 ° C. for 12 hours under a nitrogen stream, saturated aqueous sodium hydrogen carbonate (70 ml) was added, and the mixture was extracted with ether (100 ml). The ether layer was separated and dried with sodium sulfate, and then concentrated with an evaporator to obtain 4.8 g of tert-butyl N- (2-bromoethyl) carbamate as an oily substance (apparent yield of 94%) (however, , Purity conversion yield by NMR was 82%).
比較例３（米国特許第５７４１９１２号公報の実施例７のＡの追試）
ジオキサン−水（２：１、４９ｍｌ）に炭酸ナトリウム（２．６ｇ）を分散させた中へ、２−ブロモエチルアミン臭化水素酸塩５ｇを添加し、０℃で１５分撹拌した。次に、二炭酸ジ−ｔｅｒｔ−ブチル５．４ｇを添加し、０℃で１時間撹拌させた後２０〜２５℃で１２時間反応させた。エバポレーターで溶媒を留去した後、水（６５ｍｌ）を加え、エーテル（８０ｍｌ）にて抽出した。エーテル層を水で洗浄後芒硝にて乾燥させ、再びエバポレーターにて濃縮し油状物としてのＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチル４．８ｇ（見掛け収率９４％）を得た（ただし、ＮＭＲによる純度換算収率は６８％）。
Comparative Example 3 (Additional test of A in Example 7 of US Pat. No. 5,741,912)
To a dispersion of sodium carbonate (2.6 g) in dioxane-water (2: 1, 49 ml), 5 g of 2-bromoethylamine hydrobromide was added and stirred at 0 ° C. for 15 minutes. Next, 5.4 g of di-tert-butyl dicarbonate was added, and the mixture was stirred at 0 ° C. for 1 hour and then reacted at 20 to 25 ° C. for 12 hours. After evaporating the solvent with an evaporator, water (65 ml) was added, and the mixture was extracted with ether (80 ml). The ether layer was washed with water, dried with sodium sulfate, and concentrated again with an evaporator to obtain 4.8 g of tert-butyl N- (2-bromoethyl) carbamate (apparent yield of 94%) as an oil (provided that the yield was 94%). , Purity conversion yield by NMR is 68%).
実施例１〜３と比較例１〜３を比較すると明らかな通り、比較例の方法は反応溶媒からの抽出、洗浄及び濃縮によりＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルを回収しており、操作が煩雑である上、収率も低い。また、得られたＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルは油状物であるため、取扱いが困難である。さらに、比較例の方法では反応に用いる溶媒と抽出に用いる溶媒が全く異なるため、作業効率が極めて悪い。 As is clear when Examples 1 to 3 and Comparative Examples 1 to 3 are compared, the method of the comparative example recovers tert-butyl N- (2-bromoethyl) carbamate by extraction from the reaction solvent, washing and concentration. The operation is complicated and the yield is low. Moreover, since the obtained tert-butyl N- (2-bromoethyl) carbamate is an oil, it is difficult to handle. Furthermore, in the method of the comparative example, the working efficiency is extremely poor because the solvent used for the reaction and the solvent used for the extraction are completely different.
これに対し、本発明による実施例の方法は反応溶液からの結晶析出によりＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルを回収するので、操作が簡便である上、収率も高い。また、得られたＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルは結晶状態であるため、取扱いが容易である。さらに、本発明による実施例の方法では反応に用いる溶媒（メタノール／水）と晶析に用いる溶媒（水）が一部共通するため、作業効率が良い。しかも、本発明による実施例の方法では晶析に用いる溶媒は水であるため、安全性が極めて高い。従って、本発明の製造方法によればＮＯ合成酵素阻害剤を合成するための反応中間体として有用なＮ−（２−ブロモエチル）カルバミン酸ｔｅｒｔ−ブチルを工業的規模で効率的に製造することができる。
On the other hand, since the method of the Example by this invention collect | recovers tert- butyl N- (2-bromoethyl) carbamate by crystal precipitation from a reaction solution, operation is simple and the yield is also high. Further, since the obtained tert-butyl N- (2-bromoethyl) carbamate is in a crystalline state, it is easy to handle. Furthermore, in the method according to the embodiment of the present invention, the solvent (methanol / water) used for the reaction and the solvent (water) used for the crystallization are partly common, so that the working efficiency is good. Moreover, in the method of the embodiment according to the present invention, the solvent used for crystallization is water, so that the safety is extremely high. Therefore, according to the production method of the present invention, it is possible to efficiently produce tert-butyl N- (2-bromoethyl) carbamate useful as a reaction intermediate for synthesizing a NO synthase inhibitor on an industrial scale. it can.
Claims (11)
The N- (2-bromoethyl) according to any one of claims 1 to 10, further comprising a step of collecting the collected crystals by filtration, washing with a mixture of a water-soluble solvent and water and drying. ) A process for producing tert-butyl carbamate.
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