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CN104829492A - Preparation method of trans-N-Boc-1,3-cyclobutanediamine - Google Patents

Preparation method of trans-N-Boc-1,3-cyclobutanediamine Download PDF

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CN104829492A
CN104829492A CN201510224945.6A CN201510224945A CN104829492A CN 104829492 A CN104829492 A CN 104829492A CN 201510224945 A CN201510224945 A CN 201510224945A CN 104829492 A CN104829492 A CN 104829492A
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刘雅莉
袁文蛟
刘晓磊
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Hebei University of Technology
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Abstract

本发明为一种反式N-Boc-1,3-环丁二胺的制备方法,该方法以易得的3-亚甲基环丁基甲腈为起始原料,经过水解、Curtius重排、氧化裂解、还原、甲基磺酰氯保护、取代和氢化还原共7歩反应。本法具有反应步骤短,总收率高达49.8%和最终产物纯度高(>99%)等技术特点(当前技术中最短步骤8歩,最高总收率19%),选择性合成了有反式构型的N-Boc-1,3-环丁二胺。本发明是从化学角度强调具有步骤短,反应简单,收率高,中间体纯化方法简单易行,操作简便等特点,具有广阔的商业应用前景。The present invention is a preparation method of trans-N-Boc-1,3-cyclobutanediamine. The method uses easily available 3-methylenecyclobutylcarbonitrile as a starting material, undergoes hydrolysis, Curtius rearrangement, oxidation Cracking, reduction, methanesulfonyl chloride protection, substitution and hydrogenation reduction are a total of 7 steps. This method has technical characteristics such as short reaction steps, a total yield of up to 49.8% and high purity of the final product (>99%) (the shortest step in the current technology is 8 steps, and the highest total yield is 19%). configuration of N-Boc-1,3-cyclobutanediamine. From a chemical point of view, the present invention emphasizes the characteristics of short steps, simple reaction, high yield, simple intermediate purification method, easy operation and the like, and has broad commercial application prospects.

Description

一种反式N-Boc-1,3-环丁二胺的制备方法A kind of preparation method of trans N-Boc-1,3-cyclobutanediamine

技术领域technical field

本发明涉及一种反式N-Boc-1,3-环丁二胺类化合物的高效制备方法,属于药物中间体的制备技术。The invention relates to a high-efficiency preparation method of trans-N-Boc-1,3-cyclobutanediamine compounds, which belongs to the preparation technology of pharmaceutical intermediates.

背景技术Background technique

1,3-环丁二胺作为重要的分子骨架,被广泛的应用在新药物分子设计中。如具有激酶抑制作用的1,3-环丁二胺衍生物CDK1(Engelhardt,H.;WO2007115999)、CDK2、GSK-3(Ahlijanian,M.K.;WO0210141)和PLK(Stadtmueller,H.;WO 2006021544);磷酸二酯酶抑制剂PDE4(Kuang,R.;WO 2005116009)和甘氨酸转运酶抑制剂GLyT-1(Lowe,J.A.;WO 2008065500)。除此之外,以1,3-环丁二胺为骨架的衍生物还被设计为杀虫剂和除螨剂。作为合成1,3-环丁二胺衍生物的基本原料,反式N-Boc-1,3-环丁二胺的合成方法报道较少。其中一种制备方法(Avram,M.;Chem.Ber,90,1424–1427,1957)是以溴代环氧丙烷为起始原料经过10歩反应得到1,3-环丁二胺的顺反混合物,这种方法步骤长、收率低,而且不能得到单一的顺式或者反式产物。另一种方法(Radchenko,D.S.;Journal of Organic Chemistry,75(17),5941–5952,2010)经过8歩反应得到反式N-Boc-1,3-环丁二胺,总收率只有19%,而且反应原料不易得。As an important molecular skeleton, 1,3-cyclobutanediamine is widely used in the design of new drug molecules. Such as 1,3-cyclobutanediamine derivatives CDK1 (Engelhardt, H.; WO2007115999), CDK2, GSK-3 (Ahlijanian, M.K.; WO0210141) and PLK (Stadtmueller, H.; WO 2006021544) with kinase inhibitory effect; The phosphodiesterase inhibitor PDE4 (Kuang, R.; WO 2005116009) and the glycine transporter inhibitor GLyT-1 (Lowe, J.A.; WO 2008065500). In addition, derivatives based on 1,3-cyclobutanediamine have also been designed as insecticides and acaricides. As the basic raw material for the synthesis of 1,3-cyclobutanediamine derivatives, there are few reports on the synthesis methods of trans-N-Boc-1,3-cyclobutanediamine. One of the preparation methods (Avram, M.; Chem.Ber, 90,1424-1427, 1957) is the cis-trans reaction of 1,3-cyclobutylene diamine with bromopropylene oxide as the starting material through 10 steps of reaction. Mixture, this method has long steps, low yield, and cannot obtain a single cis or trans product. Another method (Radchenko, D.S.; Journal of Organic Chemistry, 75 (17), 5941-5952, 2010) obtains trans N-Boc-1,3-cyclobutylene diamine through 8 steps of reaction, and the total yield is only 19 %, and the reaction raw materials are not easy to get.

鉴于现有制备反式N-Boc-1,3-环丁二胺的方法步骤长、收率低难以商业化,本发明提供一种易于商业化的高效制备反式N-Boc-1,3-环丁二胺的方法。In view of the fact that the existing methods for preparing trans-N-Boc-1,3-cyclobutanediamine have long steps and low yields and are difficult to be commercialized, the present invention provides an efficient preparation of trans-N-Boc-1,3 that is easy to commercialize - The method of cyclobutylene diamine.

发明内容Contents of the invention

本发明的目的是针对当前技术的不足,提供一种反式N-Boc-1,3-环丁二胺的制备方法,该方法通过简单、可靠的7歩化学反应合成了单一保护的反式N-Boc-1,3-环丁二胺。合成路线设计巧妙,仅通过简单的还原剂三仲丁基硼氢化锂(L-selectride)高效构建顺式构型,然后经过经典的SN2类型的取代反应得到了反式N-Boc-1,3-环丁二胺。本发明条件温和,收率高,纯化简单,易于大规模制备。The purpose of the present invention is to provide a kind of preparation method of trans-N-Boc-1,3-cyclobutanediamine for the deficiencies of the current technology, which has synthesized a single protected trans N-Boc-1,3-cyclobutanediamine. The synthetic route is ingeniously designed, and only the simple reducing agent tri-sec-butyl lithium borohydride (L-selectride) efficiently constructs the cis configuration, and then obtains the trans N-Boc-1,3 through a classic SN2 type substitution reaction - cyclobutylene diamine. The invention has mild conditions, high yield, simple purification and easy large-scale preparation.

本发明的技术方案为:Technical scheme of the present invention is:

一种反式N-Boc-1,3-环丁二胺的制备方法,其特征为包括以下步骤:A kind of preparation method of trans-N-Boc-1,3-cyclobutanediamine is characterized in that comprising the following steps:

步骤一),将3-亚甲基环丁基甲腈溶于乙醇和水的混合溶液中,然后加入氢氧化钾,回流反应1-5小时后,用盐酸调节溶液的pH=2;将析出的白色固体过滤,水洗,干燥得到化合物2;Step 1), dissolving 3-methylenecyclobutylcarbonitrile in the mixed solution of ethanol and water, then adding potassium hydroxide, and after reflux reaction for 1-5 hours, adjust the pH=2 of the solution with hydrochloric acid; the precipitated white The solid was filtered, washed with water, and dried to obtain compound 2;

其中,物料摩尔配比为3-亚甲基环丁基甲腈:氢氧化钾=1:1~10;体积比为乙醇:水=1~5:5~1;Wherein, the material molar ratio is 3-methylenecyclobutylcarbonitrile:potassium hydroxide=1:1~10; the volume ratio is ethanol:water=1~5:5~1;

步骤二)依次将碱、叠氮化物和化合物2在83℃溶于叔丁醇中,然后回流0.5-12小时;用水淬灭反应,将溶液浓缩至原体积的1/5时,向剩余溶液中加入乙酸乙酯;有机相经过水洗,饱和食盐水洗,干燥,旋干后得到化合物3;Step 2) Dissolve the base, azide and compound 2 in tert-butanol at 83°C in turn, and then reflux for 0.5-12 hours; quench the reaction with water, concentrate the solution to 1/5 of the original volume, and pour the remaining solution Ethyl acetate was added; the organic phase was washed with water, washed with saturated brine, dried, and spin-dried to obtain compound 3;

其中,物料摩尔配比为碱:叠氮化合物:化合物2=1~3:1~3:1;每摩尔化合物2加2L乙酸乙酯;Wherein, the material molar ratio is alkali: azide compound: compound 2=1~3:1~3:1; every mole of compound 2 adds 2L ethyl acetate;

步骤三)将化合物3溶于溶剂,再加入氧化剂;待反应完全后,经萃取、干燥和蒸馏后得到化合物4;摩尔比为化合物3:氧化剂=1:1~10;Step 3) dissolving compound 3 in a solvent, and then adding an oxidizing agent; after the reaction is complete, compound 4 is obtained after extraction, drying and distillation; the molar ratio is compound 3:oxidizing agent=1:1~10;

其中,溶剂为二氯甲烷和甲醇的混合溶液,体积比为(10~1):(1~10);Wherein, the solvent is a mixed solution of methylene chloride and methanol, and the volume ratio is (10~1):(1~10);

步骤四)在-78℃-0℃下,将还原剂加至化合物4的四氢呋喃溶液中,滴加完后室温再继续搅拌0.5-12小时;将反应淬灭后,然后向反应液中依次加入水和乙酸乙酯后搅拌,有机相经过水洗,饱和食盐水洗,干燥,旋干后得到化合物5;Step 4) Add the reducing agent to the tetrahydrofuran solution of compound 4 at -78°C-0°C, and continue stirring at room temperature for 0.5-12 hours after the dropwise addition; after quenching the reaction, add Water and ethyl acetate were stirred, and the organic phase was washed with water, washed with saturated brine, dried, and spin-dried to obtain compound 5;

其中,摩尔比为化合物4:还原剂=1:1~10;体积比为四氢呋喃:水:乙酸乙酯=1~10:1~10:1~10;Wherein, the molar ratio is compound 4:reducing agent=1:1~10; the volume ratio is tetrahydrofuran:water:ethyl acetate=1~10:1~10:1~10;

步骤五)将化合物5和三乙胺溶于二氯甲烷中,在-78℃~5℃,将甲基磺酰氯滴加至上述反应液中;滴加完毕后,该反应液在室温搅拌0.5-12小时后,此有机相经过水洗,饱和食盐水洗,干燥,旋干后得到白色固体即化合物6;Step 5) Dissolve compound 5 and triethylamine in dichloromethane, add methanesulfonyl chloride dropwise to the above reaction solution at -78°C to 5°C; after the dropwise addition, stir the reaction solution at room temperature for 0.5 After -12 hours, the organic phase was washed with water, washed with saturated brine, dried, and spin-dried to obtain a white solid, namely compound 6;

其中,摩尔比为化合物5:三乙胺:甲基磺酰氯=1:1~3:1~3;Wherein, the molar ratio is compound 5: triethylamine: methylsulfonyl chloride=1:1~3:1~3;

步骤六)将化合物6和叠氮钠溶于溶剂中,此反应液在5℃~180℃搅拌0.5-12小时后,加入乙酸乙酯和水;有机相经过水洗,饱和食盐水洗,干燥,旋干后得到白色固体即化合物7;Step 6) Dissolving compound 6 and sodium azide in a solvent, stirring the reaction solution at 5° C. to 180° C. for 0.5-12 hours, then adding ethyl acetate and water; the organic phase was washed with water, washed with saturated brine, dried, and spun After drying, a white solid, compound 7, was obtained;

其中,摩尔比为化合物6:叠氮钠=1:1~10;每克化合物6加入乙酸乙酯13~18mL,体积比乙酸乙酯:水=1:1;Wherein, the molar ratio is compound 6:sodium azide=1:1~10; every gram of compound 6 is added ethyl acetate 13~18mL, volume ratio ethyl acetate:water=1:1;

步骤七)在氢化釜中,将Pd/C加入化合物7的乙醇溶液中,在15-150Psi氢气、5℃~100℃下搅拌反应为0.5~1小时,然后将Pd/C滤除后,浓缩得到浅黄色液体,精馏后得到反式N-Boc-1,3-环丁二胺;Step 7) In the hydrogenation kettle, add Pd/C to the ethanol solution of compound 7, stir the reaction under 15-150Psi hydrogen, 5°C-100°C for 0.5-1 hour, then filter out Pd/C, and concentrate A light yellow liquid was obtained, and trans-N-Boc-1,3-cyclobutanediamine was obtained after rectification;

其中,质量比为化合物7:Pd/C=1:0.1%~10%。Wherein, the mass ratio is compound 7:Pd/C=1:0.1%˜10%.

步骤二)所述碱为三乙胺、吡啶、N,N-二异丙基乙胺、碳酸钾、碳酸钠的一至多种。Step 2) The base is one or more of triethylamine, pyridine, N,N-diisopropylethylamine, potassium carbonate and sodium carbonate.

步骤二)所述叠氮化合物为NaN3,KN3,Ca(N3)2,TMSN3和叠氮磷酸二苯酯(DPPA)。Step 2) The azide compound is NaN 3 , KN 3 , Ca(N 3 ) 2 , TMSN 3 and diphenylphosphoryl azide (DPPA).

步骤三)所述氧化剂为三氯化钌、四氧化锇、高碘酸钠、过氧叔丁醇、过氧化氢、氧化铬、高锰酸钾、氧气和臭氧中的一至多种。Step 3) The oxidant is one or more of ruthenium trichloride, osmium tetroxide, sodium periodate, tert-butanol peroxide, hydrogen peroxide, chromium oxide, potassium permanganate, oxygen and ozone.

步骤四)所述还原剂为硼氢化锂、硼氢化钠和三仲丁基硼氢化锂(L-selectride)。Step 4) The reducing agent is lithium borohydride, sodium borohydride and lithium tri-sec-butyl borohydride (L-selectride).

步骤六)所述溶剂为甲苯、环己烷、氯仿、四氯化碳、乙腈、N,N-二甲基甲酰胺、二甲基亚砜、环丁砜和四氢呋喃的一至多种。其中反应温度优选为110℃。Step 6) The solvent is one or more of toluene, cyclohexane, chloroform, carbon tetrachloride, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, sulfolane and tetrahydrofuran. Wherein the reaction temperature is preferably 110°C.

本发明有益效果为:以易得的3-亚甲基环丁基甲腈为起始原料,经过水解、Curtius重排、氧化裂解、还原、甲基磺酰氯保护、取代和氢化还原,步骤只需短短7歩(当前技术中最短步骤8歩),总收率49.8%(当前技术中最高总收率19%)和纯度>99%是均远远高于当前技术(见背景介绍),通过7歩简单的反应,巧妙的合成了具有反式构型的N-Boc-1,3-环丁二胺是本发明的核心内容。因此,本发明是从化学角度强调具有步骤短,反应简单,收率高,中间体纯化方法简单易行,操作简便等特点,具有广阔的商业应用前景。The beneficial effects of the present invention are as follows: using the readily available 3-methylenecyclobutylcarbonitrile as the starting material, the steps are only short after hydrolysis, Curtius rearrangement, oxidative cracking, reduction, methylsulfonyl chloride protection, substitution and hydrogenation reduction. Short 7 steps (the shortest step 8 steps in the current technology), the total yield 49.8% (the highest total yield 19% in the current technology) and purity > 99% are all far higher than the current technology (see background introduction), through 7 Step simple reaction, skillfully synthesized N-Boc-1,3-cyclobutanediamine with trans configuration is the core content of the present invention. Therefore, the present invention emphasizes from a chemical point of view that it has the characteristics of short steps, simple reaction, high yield, simple and easy intermediate purification method, easy operation, etc., and has broad commercial application prospects.

具体实施方式Detailed ways

为了使公众能充分了解本发明的技术实质和发明优点,申请人将在下面对本发明的具体实施方式详细描述,但申请人对实施例的描述不是对技术方案的限制,任何依据本发明构思作形式而非实质的变化都应当视为本发明的保护范围。In order to enable the public to fully understand the technical essence and advantages of the present invention, the applicant will describe in detail the specific embodiments of the present invention below, but the applicant's description of the embodiments is not a limitation to the technical solution. Changes in form rather than substance should be regarded as the protection scope of the present invention.

本发明的原理如以下反应式所示:Principle of the present invention is shown in following reaction formula:

实施例1Example 1

步骤一:step one:

向3-亚甲基环丁基甲腈(400g,4.3mol)的乙醇(5L)和水(5L)溶液中加入氢氧化钾(2408g,43mol)。回流2小时后,用浓盐酸调节溶液的pH=2。将析出的白色固体过滤,水洗,干燥得到化合物2(450g),收率93.4%。氢核磁共振谱(400MHz,CDCl3)δ:2.67-3.56(5H,m),4.68-4.98(2H,m),10.73(1H,br,s),说明得目标产物。其分子量为112.13。To a solution of 3-methylenecyclobutanecarbonitrile (400 g, 4.3 mol) in ethanol (5 L) and water (5 L) was added potassium hydroxide (2408 g, 43 mol). After refluxing for 2 hours, the pH of the solution was adjusted to 2 with concentrated hydrochloric acid. The precipitated white solid was filtered, washed with water, and dried to obtain Compound 2 (450 g), with a yield of 93.4%. Proton NMR spectrum (400MHz, CDCl 3 ) δ: 2.67-3.56 (5H, m), 4.68-4.98 (2H, m), 10.73 (1H, br, s), indicating that the target product was obtained. Its molecular weight is 112.13.

步骤二:Step two:

依次将三乙胺(590g,5.9mol)、叠氮磷酸二苯酯(DPPA)(1273g,4.7mol)和化合物2(440g,3.9mol)在回流温度83℃溶于叔丁醇(8L)中,然后回流12小时。用水(2L)淬灭反应,将溶液浓缩至原体积的1/5后,向剩余溶液中加入乙酸乙酯(7.8L)。有机相经过水洗,饱和食盐水洗,干燥,旋干后得到白色固体即化合物3(649g),收率91%。氢核磁共振谱(400MHz,CDCl3)δ:1.36(9H,s),2.56-2.65(2H,m),2.97-3.18(2H,m),4.05-4.23(1H,m),4.05-4.23(1H,m),4.85(1H,br s),5.08(2H,m),说明得目标产物。其分子量为183.25。Triethylamine (590g, 5.9mol), diphenylphosphoryl azide (DPPA) (1273g, 4.7mol) and compound 2 (440g, 3.9mol) were dissolved in tert-butanol (8L) at a reflux temperature of 83°C in sequence , and then reflux for 12 hours. The reaction was quenched with water (2 L), and after the solution was concentrated to 1/5 of the original volume, ethyl acetate (7.8 L) was added to the remaining solution. The organic phase was washed with water, washed with saturated brine, dried, and spin-dried to obtain a white solid, compound 3 (649 g), with a yield of 91%. Proton NMR spectrum (400MHz, CDCl 3 ) δ: 1.36(9H,s), 2.56-2.65(2H,m), 2.97-3.18(2H,m), 4.05-4.23(1H,m), 4.05-4.23( 1H, m), 4.85 (1H, br s), 5.08 (2H, m), indicating that the target product was obtained. Its molecular weight is 183.25.

步骤三:Step three:

将化合物3(800g,4.4mol)溶于二氯甲烷(12L)和甲醇(3L)中。在-78℃下,通入臭氧气体,直至溶液由浅黄色变为蓝色(说明反应液中化合物3消失,均转化为化合物4)。二甲硫醚(2L)加入到反应液中,然后自然升温至室温。减压蒸馏将溶剂蒸除,得到白色固体即化合物4(706.4g),收率88.3%。氢核磁共振谱(400MHz,CDCl3)δ:1.40(9H,s),2.97-3.04(2H,m),3.26-3.33(2H,m),4.18-4.37(1H,m),说明得目标产物。其分子量为185.22。Compound 3 (800 g, 4.4 mol) was dissolved in dichloromethane (12 L) and methanol (3 L). At -78°C, ozone gas was introduced until the solution changed from light yellow to blue (indicating that compound 3 in the reaction solution disappeared and was converted into compound 4). Dimethyl sulfide (2 L) was added to the reaction solution, and then the temperature was naturally raised to room temperature. The solvent was distilled off under reduced pressure to obtain compound 4 (706.4 g) as a white solid with a yield of 88.3%. Proton NMR spectrum (400MHz, CDCl 3 ) δ: 1.40(9H,s), 2.97-3.04(2H,m), 3.26-3.33(2H,m), 4.18-4.37(1H,m), indicating that the target product was obtained . Its molecular weight is 185.22.

步骤四:Step four:

在-20℃,缓慢将三仲丁基硼氢化锂(L-selectride)(2700mL,1M,2.7mol)滴加至化合物4(420g,2.3mol)的四氢呋喃(10L)溶液中,滴加完后,在室温下继续搅拌1小时。饱和氯化铵水溶液(2.5L)将反应淬灭后,向反应液中依次加入水(10L)和乙酸乙酯(10L)。有机相经过水洗,饱和食盐水洗,干燥,旋干后得到黄色油状液体即化合物5(383.7g),收率88.3%。氢核磁共振谱(400MHz,CDCl3)δ:1.42(9H,s),1.79(2H,br s),2.43(1H,br s),2.73(2H,br s),3.63(1H,br s),3.99(1H,quint,J=6.9Hz),4.72(1H,br s),说明得目标产物。其分子量为187.24。At -20°C, lithium tri-sec-butylborohydride (L-selectride) (2700mL, 1M, 2.7mol) was slowly added dropwise to a solution of compound 4 (420g, 2.3mol) in tetrahydrofuran (10L). , stirring was continued for 1 hour at room temperature. Saturated aqueous ammonium chloride solution (2.5 L) quenched the reaction, and then added water (10 L) and ethyl acetate (10 L) to the reaction solution in sequence. The organic phase was washed with water, washed with saturated brine, dried and spin-dried to obtain compound 5 (383.7 g), a yellow oily liquid, with a yield of 88.3%. Proton NMR spectrum (400MHz, CDCl 3 ) δ: 1.42(9H, s), 1.79(2H, br s), 2.43(1H, br s), 2.73(2H, br s), 3.63(1H, br s) , 3.99 (1H, quint, J=6.9Hz), 4.72 (1H, br s), indicating that the target product was obtained. Its molecular weight is 187.24.

步骤五:Step five:

将化合物5(320g,1.7mol)和三乙胺(260g,2.6mol)溶于二氯甲烷(10L)。在0℃,将重蒸过的甲基磺酰氯(230g,2.0mol)滴加至上述反应液中。滴加完毕后,该反应液在室温搅拌2小时后,此有机相经过水洗,饱和食盐水洗,干燥,旋干后得到白色固体即化合6(380g),收率84.8%。氢核磁共振谱(400MHz,CDCl3)δ:1.37(9H,s),2.08-2.92(2H,m),2.83-2.91(2H,m),2.92(3H,s),3.76(1H,s),说明得目标产物。其分子量为265.33。Compound 5 (320 g, 1.7 mol) and triethylamine (260 g, 2.6 mol) were dissolved in dichloromethane (10 L). At 0°C, redistilled methanesulfonyl chloride (230 g, 2.0 mol) was added dropwise to the above reaction solution. After the dropwise addition, the reaction solution was stirred at room temperature for 2 hours, and the organic phase was washed with water and saturated brine, dried, and spin-dried to obtain a white solid, compound 6 (380 g), with a yield of 84.8%. Proton NMR spectrum (400MHz, CDCl 3 ) δ: 1.37(9H,s), 2.08-2.92(2H,m), 2.83-2.91(2H,m), 2.92(3H,s), 3.76(1H,s) , indicating the target product. Its molecular weight is 265.33.

步骤六:Step six:

向反应器中依次加入N,N-二甲基甲酰胺(4L)、化合物6(190g,0.72mol)和叠氮钠(56g,0.86mol)。此反应液在110℃搅拌2小时后,加入乙酸乙酯(3L)和水(3L)。有机相经过水洗,饱和食盐水洗,干燥,旋干后得到白色固体即化合物7(189g),收率98.1%。氢核磁共振谱(400MHz,CDCl3)δ:1.39(9H,s),2.21(2H,br s),2.46(2H,br s),4.08(1H,m),4.18(1H,br s),4.65(1H,br s),说明得目标产物。其分子量为212.25。N,N-Dimethylformamide (4 L), compound 6 (190 g, 0.72 mol) and sodium azide (56 g, 0.86 mol) were sequentially added to the reactor. After the reaction solution was stirred at 110° C. for 2 hours, ethyl acetate (3 L) and water (3 L) were added. The organic phase was washed with water, washed with saturated brine, dried, and spin-dried to obtain a white solid, compound 7 (189 g), with a yield of 98.1%. Proton NMR spectrum (400MHz, CDCl 3 ) δ: 1.39(9H,s),2.21(2H,br s),2.46(2H,br s),4.08(1H,m),4.18(1H,br s), 4.65 (1H, br s), indicating that the target product was obtained. Its molecular weight is 212.25.

步骤七:Step seven:

向氢化釜中加入乙醇(5L)、化合物7(95g,0.45mol)和负载量为5%的Pd/C(9.5g)。在50Psi压力的氢气下搅拌1小时。将Pd/C滤除后,浓缩得到浅黄色液体,精馏后得到反式N-Boc-1,3-环丁二胺(75g),收率90%。氢核磁共振谱(400MHz,CDCl3)δ:1.37(9H,s),2.04-2.05(2H,m),2.12-2.13(2H,m),3.57(1H,s),4.14(1H,s),说明得目标产物。其分子量为186.25。Add ethanol (5 L), compound 7 (95 g, 0.45 mol) and Pd/C with a loading of 5% (9.5 g) into the hydrogenation kettle. Stir under hydrogen at a pressure of 50 Psi for 1 hour. After filtering off Pd/C, it was concentrated to obtain a light yellow liquid, and trans-N-Boc-1,3-cyclobutanediamine (75 g) was obtained after rectification, with a yield of 90%. Proton NMR spectrum (400MHz, CDCl 3 ) δ: 1.37(9H,s), 2.04-2.05(2H,m), 2.12-2.13(2H,m), 3.57(1H,s), 4.14(1H,s) , indicating the target product. Its molecular weight is 186.25.

实施例2Example 2

步骤一:step one:

同实施例1中步骤一。Same as Step 1 in Example 1.

步骤二:Step two:

依次将碳酸钾(814g,5.9mol)、NaN3(305.5g,4.7mol)和化合物2(440g,3.9mol)在回流温度83℃溶于叔丁醇(8L)中,然后回流12小时。用水(2L)淬灭反应,将溶剂浓缩后,向剩余溶液中加入乙酸乙酯(7.8L)。有机相经过水洗,饱和食盐水洗,干燥,旋干后得到白色固体即化合物3(520.6g),收率73%。氢核磁共振谱(400MHz,CDCl3)δ:1.36(9H,s),2.56-2.65(2H,m),2.97-3.18(2H,m),4.05-4.23(1H,m),4.05-4.23(1H,m),4.85(1H,br s),5.08(2H,m)。Potassium carbonate (814g, 5.9mol), NaN 3 (305.5g, 4.7mol) and compound 2 (440g, 3.9mol) were successively dissolved in tert-butanol (8L) at a reflux temperature of 83°C, and then refluxed for 12 hours. The reaction was quenched with water (2 L), and after the solvent was concentrated, ethyl acetate (7.8 L) was added to the remaining solution. The organic phase was washed with water, washed with saturated brine, dried, and spin-dried to obtain a white solid, compound 3 (520.6 g), with a yield of 73%. Proton NMR spectrum (400MHz, CDCl 3 ) δ: 1.36(9H,s), 2.56-2.65(2H,m), 2.97-3.18(2H,m), 4.05-4.23(1H,m), 4.05-4.23( 1H, m), 4.85 (1H, br s), 5.08 (2H, m).

步骤三:Step three:

将化合物3(8.0g,0.044mol)溶于二氯甲烷(50mL)和水(50mL)中。然后,向此反应液加入RuCl3(0.32g)、NaIO4(14.1g,0.066mol)。室温搅拌1小时后,将水相分出,有机相经水洗、饱和食盐水洗后,干燥,减压蒸馏将溶剂蒸除,得到白色固体即化合物4(5.4g),收率69.1%。氢核磁共振谱(400MHz,CDCl3)δ:1.40(9H,s),2.97-3.04(2H,m),3.26-3.33(2H,m),4.18-4.37(1H,m)。Compound 3 (8.0 g, 0.044 mol) was dissolved in dichloromethane (50 mL) and water (50 mL). Then, RuCl 3 (0.32 g) and NaIO 4 (14.1 g, 0.066 mol) were added to the reaction liquid. After stirring at room temperature for 1 hour, the aqueous phase was separated, the organic phase was washed with water and saturated brine, dried, and the solvent was distilled off under reduced pressure to obtain a white solid, compound 4 (5.4 g), with a yield of 69.1%. Proton NMR spectrum (400MHz, CDCl 3 ) δ: 1.40 (9H, s), 2.97-3.04 (2H, m), 3.26-3.33 (2H, m), 4.18-4.37 (1H, m).

步骤四:Step four:

在0℃,缓慢将硼氢化锂(0.588g,0.027mol)分批加至化合物4(4.20g,0.023mol)的四氢呋喃(100mL)溶液中,滴加完后,在室温下继续搅拌1小时。饱和氯化铵水溶液(2.5L)将反应淬灭后,向反应液中依次加入水(100mL)和乙酸乙酯(100mL)。有机相经过水洗,饱和食盐水洗,干燥,旋干后得到黄色油状液体,经柱色谱纯化后得到化合物5(0.43g),收率9.8%。氢核磁共振谱(400MHz,CDCl3)δ:1.42(9H,s),1.79(2H,br s),2.43(1H,br s),2.73(2H,br s),3.63(1H,br s),3.99(1H,quint,J=6.9Hz),4.72(1H,br s)。At 0° C., lithium borohydride (0.588 g, 0.027 mol) was slowly added to compound 4 (4.20 g, 0.023 mol) in tetrahydrofuran (100 mL) in batches, and after the dropwise addition, stirring was continued at room temperature for 1 hour. Saturated ammonium chloride aqueous solution (2.5 L) quenched the reaction, and water (100 mL) and ethyl acetate (100 mL) were successively added to the reaction liquid. The organic phase was washed with water, washed with saturated brine, dried, and spin-dried to obtain a yellow oily liquid, which was purified by column chromatography to obtain compound 5 (0.43 g), with a yield of 9.8%. Proton NMR spectrum (400MHz, CDCl 3 ) δ: 1.42(9H, s), 1.79(2H, br s), 2.43(1H, br s), 2.73(2H, br s), 3.63(1H, br s) , 3.99 (1H, quint, J=6.9Hz), 4.72 (1H, br s).

其余步骤同实施例1。All the other steps are the same as in Example 1.

实施例3Example 3

步骤一:step one:

同实施例1中步骤一。Same as Step 1 in Example 1.

步骤二:Step two:

依次将N,N-二异丙基乙胺(762.5g,5.9mol)、TMSN3(541.4g,4.7mol)和化合物2(440g,3.9mol)在回流温度83℃溶于叔丁醇(8L)中,然后回流12小时。用水(2L)淬灭反应,将溶剂浓缩后,向剩余溶液中加入乙酸乙酯(7.8L)。有机相经过水洗,饱和食盐水洗,干燥,旋干后得到白色固体即化合物3(534.8g),收率75%。氢核磁共振谱(400MHz,CDCl3)δ:1.36(9H,s),2.56-2.65(2H,m),2.97-3.18(2H,m),4.05-4.23(1H,m),4.05-4.23(1H,m),4.85(1H,br s),5.08(2H,m)。N,N-diisopropylethylamine (762.5g, 5.9mol), TMSN 3 (541.4g, 4.7mol) and compound 2 (440g, 3.9mol) were dissolved in tert-butanol (8L ), and then reflux for 12 hours. The reaction was quenched with water (2 L), and after the solvent was concentrated, ethyl acetate (7.8 L) was added to the remaining solution. The organic phase was washed with water, washed with saturated brine, dried, and spin-dried to obtain a white solid, compound 3 (534.8 g), with a yield of 75%. Proton NMR spectrum (400MHz, CDCl 3 ) δ: 1.36(9H,s), 2.56-2.65(2H,m), 2.97-3.18(2H,m), 4.05-4.23(1H,m), 4.05-4.23( 1H, m), 4.85 (1H, br s), 5.08 (2H, m).

步骤三:Step three:

将化合物3(8.0g,0.044mol)溶于DMF(80mL)中。然后,向此反应液加入OsO4(0.11g)和过氧叔丁醇(26.1g,0.176mol)。室温搅拌3小时后,加入乙酸乙酯(100mL)和水(100mL)。将水相分出,有机相经水洗、饱和食盐水洗后,干燥,减压蒸馏将溶剂蒸除,得到白色固体即化合物4(5.4g),收率69.1%。氢核磁共振谱(400MHz,CDCl3)δ:1.40(9H,s),2.97-3.04(2H,m),3.26-3.33(2H,m),4.18-4.37(1H,m)。Compound 3 (8.0 g, 0.044 mol) was dissolved in DMF (80 mL). Then, OsO 4 (0.11 g) and tert-butanol peroxide (26.1 g, 0.176 mol) were added to the reaction solution. After stirring at room temperature for 3 hours, ethyl acetate (100 mL) and water (100 mL) were added. The aqueous phase was separated, and the organic phase was washed with water and saturated brine, dried, and evaporated to remove the solvent under reduced pressure to obtain a white solid, compound 4 (5.4 g), with a yield of 69.1%. Proton NMR spectrum (400MHz, CDCl 3 ) δ: 1.40 (9H, s), 2.97-3.04 (2H, m), 3.26-3.33 (2H, m), 4.18-4.37 (1H, m).

步骤四:Step four:

在0℃,缓慢将硼氢化钠(1.74g,0.046mol)分批加至化合物4(4.20g,0.023mol)的甲醇(100mL)溶液中,滴加完后,在室温下继续搅拌1小时。饱和氯化铵水溶液(2.5L)将反应淬灭后,向反应液中依次加入水(100mL)和乙酸乙酯(100mL)。有机相经过水洗,饱和食盐水洗,干燥,旋干后得到黄色油状液体,经柱色谱纯化后得到化合物5(0.33g),收率7.6%。氢核磁共振谱(400MHz,CDCl3)δ:1.42(9H,s),1.79(2H,br s),2.43(1H,br s),2.73(2H,br s),3.63(1H,br s),3.99(1H,quint,J=6.9Hz),4.72(1H,br s)。At 0°C, sodium borohydride (1.74 g, 0.046 mol) was slowly added in portions to a solution of compound 4 (4.20 g, 0.023 mol) in methanol (100 mL). After the addition was complete, stirring was continued at room temperature for 1 hour. Saturated ammonium chloride aqueous solution (2.5 L) quenched the reaction, and water (100 mL) and ethyl acetate (100 mL) were successively added to the reaction liquid. The organic phase was washed with water, washed with saturated brine, dried, and spin-dried to obtain a yellow oily liquid, which was purified by column chromatography to obtain compound 5 (0.33 g), with a yield of 7.6%. Proton NMR spectrum (400MHz, CDCl 3 ) δ: 1.42(9H, s), 1.79(2H, br s), 2.43(1H, br s), 2.73(2H, br s), 3.63(1H, br s) , 3.99 (1H, quint, J=6.9Hz), 4.72 (1H, br s).

其余步骤同实施例1。All the other steps are the same as in Example 1.

实施例4Example 4

步骤三:Step three:

将化合物3(8.0g,0.044mol)溶于丙酮(100mL)中。然后,向此反应液加入OsO4(0.11g)和三氧化铬(15.4g,0.154mol)。室温搅拌12小时后,加入乙酸乙酯(100mL)和水(100mL)。将水相分出,有机相经水洗、饱和食盐水洗后,干燥,减压蒸馏将溶剂蒸除,得到白色固体即化合物4(4.0g),收率50.9%。氢核磁共振谱(400MHz,CDCl3)δ:1.40(9H,s),2.97-3.04(2H,m),3.26-3.33(2H,m),4.18-4.37(1H,m)。Compound 3 (8.0 g, 0.044 mol) was dissolved in acetone (100 mL). Then, OsO 4 (0.11 g) and chromium trioxide (15.4 g, 0.154 mol) were added to the reaction solution. After stirring at room temperature for 12 hours, ethyl acetate (100 mL) and water (100 mL) were added. The aqueous phase was separated, and the organic phase was washed with water and saturated brine, dried, and evaporated to remove the solvent under reduced pressure to obtain compound 4 (4.0 g) as a white solid with a yield of 50.9%. Proton NMR spectrum (400MHz, CDCl 3 ) δ: 1.40 (9H, s), 2.97-3.04 (2H, m), 3.26-3.33 (2H, m), 4.18-4.37 (1H, m).

其余步骤同实施例1。All the other steps are the same as in Example 1.

以上所述仅为本发明的优选实施例而已,并不用于限制本发明,对于本领域的技术人员来说,本发明可以有各种更改和变化。凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。The above descriptions are only preferred embodiments of the present invention, and are not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and changes. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included within the protection scope of the present invention.

本发明未尽事宜为公知技术。Matters not covered in the present invention are known technologies.

Claims (7)

1.一种反式N-Boc-1,3-环丁二胺的制备方法,其特征为包括以下步骤:1. a preparation method of trans N-Boc-1,3-cyclobutanediamine, characterized in that it comprises the following steps: 步骤一),将3-亚甲基环丁基甲腈溶于乙醇和水的混合溶液中,然后加入氢氧化钾,回流反应1-5小时后,用盐酸调节溶液的pH=2;将析出的白色固体过滤,水洗,干燥得到化合物2;Step 1), dissolving 3-methylenecyclobutylcarbonitrile in the mixed solution of ethanol and water, then adding potassium hydroxide, and after reflux reaction for 1-5 hours, adjust the pH=2 of the solution with hydrochloric acid; the precipitated white The solid was filtered, washed with water, and dried to obtain compound 2; 其中,物料摩尔配比为3-亚甲基环丁基甲腈:氢氧化钾=1:1~10;体积比为乙醇:水=1~5:5~1;Wherein, the material molar ratio is 3-methylenecyclobutylcarbonitrile:potassium hydroxide=1:1~10; the volume ratio is ethanol:water=1~5:5~1; 步骤二)依次将碱、叠氮化物和化合物2在83℃溶于叔丁醇中,然后回流0.5-12小时;用水淬灭反应,将溶液浓缩至原体积的1/5时,向剩余溶液中加入乙酸乙酯;有机相经过水洗,饱和食盐水洗,干燥,旋干后得到化合物3;Step 2) Dissolve the base, azide and compound 2 in tert-butanol at 83°C in turn, and then reflux for 0.5-12 hours; quench the reaction with water, concentrate the solution to 1/5 of the original volume, and pour the remaining solution Ethyl acetate was added; the organic phase was washed with water, washed with saturated brine, dried, and spin-dried to obtain compound 3; 其中,物料摩尔配比为碱:叠氮化合物:化合物2=1~3:1~3:1;每摩尔化合物2加2L乙酸乙酯;Wherein, the material molar ratio is alkali: azide compound: compound 2=1~3:1~3:1; every mole of compound 2 adds 2L ethyl acetate; 步骤三)将化合物3溶于溶剂,再加入氧化剂;待反应完全后,经萃取、干燥和蒸馏后得到化合物4;摩尔比为化合物3:氧化剂=1:1~10;Step 3) dissolving compound 3 in a solvent, and then adding an oxidizing agent; after the reaction is complete, compound 4 is obtained after extraction, drying and distillation; the molar ratio is compound 3:oxidizing agent=1:1~10; 其中,溶剂为二氯甲烷和甲醇的混合溶液,体积比为(10~1):(1~10);Wherein, the solvent is a mixed solution of methylene chloride and methanol, and the volume ratio is (10~1):(1~10); 步骤四)在-78℃-0℃下,将还原剂加至化合物4的四氢呋喃溶液中,滴加完后室温再继续搅拌0.5-12小时;将反应淬灭后,然后向反应液中依次加入水和乙酸乙酯后搅拌,有机相经过水洗,饱和食盐水洗,干燥,旋干后得到化合物5;Step 4) Add the reducing agent to the tetrahydrofuran solution of compound 4 at -78°C-0°C, and continue stirring at room temperature for 0.5-12 hours after the dropwise addition; after quenching the reaction, add Water and ethyl acetate were stirred, and the organic phase was washed with water, washed with saturated brine, dried, and spin-dried to obtain compound 5; 其中,摩尔比为化合物4:还原剂=1:1~10;体积比为四氢呋喃:水:乙酸乙酯=1~10:1~10:1~10;Wherein, the molar ratio is compound 4:reducing agent=1:1~10; the volume ratio is tetrahydrofuran:water:ethyl acetate=1~10:1~10:1~10; 步骤五)将化合物5和三乙胺溶于二氯甲烷中,在-78℃~5℃,将甲基磺酰氯滴加至上述反应液中;滴加完毕后,该反应液在室温搅拌0.5-12小时后,此有机相经过水洗,饱和食盐水洗,干燥,旋干后得到白色固体即化合物6;Step 5) Dissolve compound 5 and triethylamine in dichloromethane, add methanesulfonyl chloride dropwise to the above reaction solution at -78°C to 5°C; after the dropwise addition, stir the reaction solution at room temperature for 0.5 After -12 hours, the organic phase was washed with water, washed with saturated brine, dried, and spin-dried to obtain a white solid, namely compound 6; 其中,摩尔比为化合物5:三乙胺:甲基磺酰氯=1:1~3:1~3;Wherein, the molar ratio is compound 5: triethylamine: methylsulfonyl chloride=1:1~3:1~3; 步骤六)将化合物6和叠氮钠溶于溶剂中,此反应液在5℃~180℃搅拌0.5-12小时后,加入乙酸乙酯和水;有机相经过水洗,饱和食盐水洗,干燥,旋干后得到白色固体即化合物7;Step 6) Dissolving compound 6 and sodium azide in a solvent, stirring the reaction solution at 5° C. to 180° C. for 0.5-12 hours, then adding ethyl acetate and water; the organic phase was washed with water, washed with saturated brine, dried, and spun After drying, a white solid, compound 7, was obtained; 其中,摩尔比为化合物6:叠氮钠=1:1~10;每克化合物6加入乙酸乙酯13~18mL,体积比乙酸乙酯:水=1:1;Wherein, the molar ratio is compound 6:sodium azide=1:1~10; every gram of compound 6 is added ethyl acetate 13~18mL, volume ratio ethyl acetate:water=1:1; 步骤七)在氢化釜中,将Pd/C加入化合物7的乙醇溶液中,在15-150Psi氢气、5℃~100℃下搅拌反应为0.5~1小时,然后将Pd/C滤除后,浓缩得到浅黄色液体,精馏后得到反式N-Boc-1,3-环丁二胺;Step 7) In the hydrogenation kettle, add Pd/C to the ethanol solution of compound 7, stir the reaction under 15-150Psi hydrogen, 5°C-100°C for 0.5-1 hour, then filter out Pd/C, and concentrate A light yellow liquid was obtained, and trans-N-Boc-1,3-cyclobutanediamine was obtained after rectification; 其中,质量比为化合物7:Pd/C=1:0.1%~10%。Wherein, the mass ratio is compound 7:Pd/C=1:0.1%˜10%. 2.如权利要求1所述的反式N-Boc-1,3-环丁二胺的制备方法,其特征为步骤二)所述碱为三乙胺、吡啶、N,N-二异丙基乙胺、碳酸钾、碳酸钠的一至多种。2. the preparation method of trans N-Boc-1,3-cyclobutanediamine as claimed in claim 1 is characterized in that step 2) described alkali is triethylamine, pyridine, N, N-diisopropyl One or more of ethyl ethylamine, potassium carbonate, and sodium carbonate. 3.如权利要求1所述的反式N-Boc-1,3-环丁二胺的制备方法,其特征为步骤二)所述叠氮化合物为NaN3,KN3,Ca(N3)2,TMSN3和叠氮磷酸二苯酯(DPPA)。3. The preparation method of trans N-Boc-1,3-cyclobutanediamine as claimed in claim 1, characterized in that the azide compound in step 2) is NaN 3 , KN 3 , Ca(N 3 ) 2 , TMSN 3 and diphenylphosphoryl azide (DPPA). 4.如权利要求1所述的反式N-Boc-1,3-环丁二胺的制备方法,其特征为步骤三)所述氧化剂为三氯化钌、四氧化锇、高碘酸钠、过氧叔丁醇、过氧化氢、氧化铬、高锰酸钾、氧气和臭氧中的一至多种。4. the preparation method of trans N-Boc-1,3-cyclobutanediamine as claimed in claim 1 is characterized in that step 3) described oxygenant is ruthenium trichloride, osmium tetroxide, sodium periodate , peroxy tert-butanol, hydrogen peroxide, chromium oxide, potassium permanganate, oxygen and ozone in one or more. 5.如权利要求1所述的反式N-Boc-1,3-环丁二胺的制备方法,其特征为步骤四)所述还原剂为硼氢化锂、硼氢化钠和三仲丁基硼氢化锂(L-selectride)。5. the preparation method of trans N-Boc-1,3-cyclobutylene diamine as claimed in claim 1 is characterized in that step 4) described reducing agent is lithium borohydride, sodium borohydride and tri-sec-butyl Lithium borohydride (L-selectride). 6.如权利要求1所述的反式N-Boc-1,3-环丁二胺的制备方法,其特征为步骤六)所述溶剂为甲苯、环己烷、氯仿、四氯化碳、乙腈、N,N-二甲基甲酰胺、二甲基亚砜、环丁砜和四氢呋喃的一至多种。6. the preparation method of trans N-Boc-1,3-cyclobutylene diamine as claimed in claim 1 is characterized in that step 6) described solvent is toluene, cyclohexane, chloroform, carbon tetrachloride, One or more of acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, sulfolane and tetrahydrofuran. 7.如权利要求1所述的反式N-Boc-1,3-环丁二胺的制备方法,其特征为步骤六)所述的反应温度优选为110℃。7. The preparation method of trans-N-Boc-1,3-cyclobutanediamine as claimed in claim 1, characterized in that the reaction temperature in step 6) is preferably 110°C.
CN201510224945.6A 2015-05-06 2015-05-06 Preparation method of trans-N-Boc-1,3-cyclobutanediamine Pending CN104829492A (en)

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