CN1251574A - O-(3-氨基-2-羟基-丙基)-肟酰卤类的制备方法 - Google Patents
O-(3-氨基-2-羟基-丙基)-肟酰卤类的制备方法 Download PDFInfo
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Abstract
本发明涉及制备式(Ⅰ)的0-(3-氨基-2-羟基-丙基)-肟酰卤类的新方法,该方法是将其中R1的含义是如上述说明的式Ⅱ的羧酰胺肟与活性的3-氨基-2-羟基丙烷衍生物反应,将得到的0-取代羧酰胺肟用亚硝酸钠在氢卤酸存在下重氮化,分解重氮盐,如果需要,分离其旋光对映体和/或用有机或无机酸与得到的碱反应,该方法包括将式Ⅱ的羧酰胺肟与式(Ⅲ)的3-羟基-氮杂环丁烷鎓盐在用碱性氢氧化物制成碱性的低级醇,优选乙醇介质中进行反应,其中R2和R3具有上面说明的含义和Y-是成盐阴离子,所述介质可选择性地含有水,中和反应混合物和除去有机溶剂之后,将得到的0-取代羧酰胺肟中间体重氮化。本发明方法比现有技术的方法更高的产率提供式(Ⅰ)化合物。
Description
技术领域
本发明涉及式(I)的O-(3-氨基-2-羟基-丙基)-肟酰卤类的新制备方法,其中
R1是苯基,吡啶基或噻吩基或取代的苯基,其中一个或多个取代基可以是卤素和/或卤代烷基和/或硝基,
X是卤素,
R2和R3各自独立地是直链或支链的低级烷基或
R2和R3与它们连接的氮原子一起形成饱和5-7元杂环基,其可以含有其他杂原子并且可以被取代。
本发明还涉及上述化合物的酸加成盐和旋光形式的制备方法。
背景技术
通式(I)的O-(3-氨基-2-羟基-丙基)-肟酰卤是治疗与糖尿病,尤其是与糖尿病血管病有关的血管病理学变化中公知的活性物质。这些化合物在匈牙利专利207988中被具体描述。
通式(I)的O-(3-氨基-2-羟基-丙基)-肟酰卤可以用多种不同方法制备,其中一些方法也在匈牙利专利207988中被描述。
尽管已知的合成途径适合于制备式(I)化合物,但是它们不能以工业规模制备所述化合物。这些方法的缺陷是它们需要难于操作或制备的试剂,或者它们包含由可能的副反应引起的产率不理想的不利反应。人们对式(I)化合物的大量需求需要一种安全的具有令人满意产率的可以在工业条件下进行的制备式(I)化合物的新方法。
发明描述
本发明的目的是提供以工业规模制备O-(3-氨基-2-羟基-丙基)-肟酰卤类的方法。
本发明提供了通过下列步骤以工业化制备式(I)化合物的方法:i)将式II的氨肟化合物与3-羟基-氮杂环丁烷翁盐在碱性-醇介质中反应,其中
R2和R3具有上面说明的含义和
Y-是成盐阴离子,ii)中和混合物,除去有机溶剂,iii)将剩余物与亚硝酸钠在含水介质中在盐酸存在下反应iv)分解由此得到的重氮盐,和v)从混合物中分离式(I)粗产物。
式II的氨肟化合物与适当被取代的3-氨基-2-羟基丙烷衍生物(通常是1-卤-或1,2-环氧衍生物)的反应在例如匈牙利专利177578中被描述。但是,式(III)的3-羟基氮杂环丁烷翁盐是比用于已知反应中的1-卤-或1,2-环氧衍生物更适当的试剂。即,式(III)化合物是可以容易被制备、分离和贮存的固体物料,而不象以前使用的试剂那样难于分离和处理并且通常是液体物料。其用途在匈牙利专利207305中已知,但是在其中描述的方法中这些以及其他两种试剂都没有直接与式(II)化合物反应,而是与氨肟配合物反应,后者由碱性氢氧化物或碱与二甲基甲酰胺醇化物或1,3-二甲基-2-咪唑啉酮在含二甲基甲酰胺的介质中制备。因此,分离得到O-取代的氨肟衍生物,但是它显然仅仅是根据本发明反应路线的未分离的中间体。
根据我们的观察,本发明达到了排除在方法中形成技术上困难的配合物的步骤和避免使用二甲基甲酰胺作为溶剂。二甲基甲酰胺对健康是有害的,因为它会致癌,而且它难于再生和提纯,并且相当难于制成无水。在匈牙利专利207305中指出二甲基甲酰胺杂质必须最少是特别重要的。而且,优选溶剂仅仅含有非常少量的水,尤其是低于1%以获得适当的产率。使用二甲基甲酰胺的另一缺陷是当其见光时会分解,因此被所涉及的毒性化合物污染。现已发现反应可以通过将式(II)和(III)化合物在可以含水的碱性醇介质中直接反应安全和容易地进行。根据合成结果,不将O-取代的羧酰胺肟中间体从反应混合物中分离出来,而是在中和混合物和除去有机溶剂之后直接进一步反应是非常有用的。现在还发现在收缩步骤中形成的副产物都可以通过一种适当的分离步骤除去,因此该合成方法适合于生产所需纯度的产物。
根据这些观察,本发明提供了制备式(I)化合物及其酸加成盐和旋光形式的方法,其中
R1是苯基,吡啶基或噻吩基或取代的苯基,其中一个或多个取代基可以是卤素和/或卤代烷基和/或硝基,
X是卤素,
R2和R3各自独立地是直链或支链的低级烷基或
R2和R3与它们连接的氮原子一起形成饱和5-7元杂环基,其可以含有其他杂原子并且可以被取代,
该方法是将其中R1的含义是如上述说明的式II的羧酰胺肟与3-氨基-2-羟基丙烷衍生物反应,将得到的O-取代羧酰胺肟用亚硝酸钠在盐酸存在下重氮化,分解重氮盐,分离得到的产物,如果需要,分离其旋光对映体和/或用有机或无机酸与得到的碱反应;该方法包括将式II的羧酰胺肟与式(III)的3-羟基-氮杂环丁烷翁盐在用碱性氢氧化物制成碱性的低级醇优选乙醇介质中进行反应,其中R2和R3具有上面说明的含义和Y-是成盐阴离子,所述介质可选择性地含有水,中和反应混合物和除去有机溶剂之后,将得到的O-取代羧酰胺肟中间体重氮化。实施本发明的最佳方式
实施本发明方法的优选方式如下:
将式(II)的羧酰胺肟与式(III)的3-羟基氮杂环丁烷翁盐按照化学计量的比率反应,但是,有利的是以稍过量使用式(III)化合物。可以按任何顺序加入试剂进行反应,优选将式(II)化合物加入式(III)化合物的碱性醇溶液中。优选使用C1-4烷醇作为溶剂,优选使用乙醇,优选加热,最优选在溶剂的沸点温度下进行反应。停止反应之后,将混合物冷却并且用无机酸,优选盐酸中和,在较低压力下适当地蒸出醇。除去溶剂之后,用水稀释反应混合物,加入重氮化所需的浓盐酸,冷却至重氮化温度,在0-5℃温度冷却条件下加入亚硝酸钠进行重氮化。将重氮盐就地分解成相应的羟肟酰卤衍生物。为了分离粗产物,用无机碱将反应混合物成碱性,用与水不混溶的有机溶剂,优选用乙酸乙酯提取,将提取物干燥和浓缩,或混合物中加入适当的酸由产物直接形成酸加成盐,过滤分离酸加成盐。通过重结晶或者通过现有技术中的任何其他已知方法可以提纯粗产物。
通过使用上述方法,可以以经济和令人满意的产率制备得到适当纯的产物。
本发明的优点在于可以以安全和简单的方法在工业条件下生产O-(3-氨基-2-羟基丙基)-羟肟酰卤。
下面的实施例进一步说明本发明。实施例1N-[2-羟基-3-(1-哌啶基)-丙氧基]-3-吡啶亚氨酸酰氯(Z)-2-丁烯二酸盐
在搅拌条件下将50.4千克2-羟基-4-氮翁螺[3,5]-壬烷氯化物溶于28升水中。向溶液中加入11.4千克氢氧化钠,将得到的乳状混合物再搅拌1小时。在搅拌过程中加入420升乙醇和35千克3-吡啶羧酰胺肟,将混合物加热回流1.5小时,然后冷却反应混合物。蒸出270-290升醇,加入110升去离子水和45.5升浓盐酸,接着蒸出剩余的乙醇。在冷却以使温度保持在低于30℃下向油状剩余物中加入160升浓盐酸。然后将溶液冷却至0℃,在稳定搅拌和保持反应混合物的温度在0-5℃的冷却条件下加入17.7千克亚硝酸钠和60升去离子水的混合物以进行重氮化。加入之后,在该温度下再搅拌混合物1小时,为了分解过量的亚硝酸盐加入1.5千克尿素,向反应混合物中加入350升乙酸乙酯,亚硝酸盐充分分解约1.5小时后,然后在搅拌和强冷却条件下加入150-200升浓氢氧化钠进行碱化。进行层分离,有机相用2×70升水洗涤,用15千克无水硫酸钠干燥。过滤干燥剂,用20升乙酸乙酯洗涤,合并有机层,测定N-[2-羟基-3-(哌啶-1-基)丙氧基-3-吡啶亚氨酸酰氯碱的量。加入计算量马来酸(21-22千克),将该混合物搅拌4小时。将产物离心分离,用30升丙酮洗涤,得到的粗产物溶于70升温热的丙酮中重结晶。将产物离心分离,用30升丙酮洗涤。重结晶之后,得到50-55千克N-[2-羟基-3-(1-哌啶基)-丙氧基]-3-吡啶亚氨酸酰氯(Z)-2-丁烯二酸盐(1∶1)粉红米色结晶。(熔点:123-124℃,丙酮,产率:53%)。IR(v,KBr/cm-1):3350,2941,1580,1480,1350,1022,982,867,702,1H-NMR(250MHz,DMSO-d6;ref.:DMSO-d6=2.5.δ(ppm):9.00(1H,s);8.74(1H,d);8.18(1H,d),7.56(1H,dd);6.03(2H,s);5.85-6.00(1H,s/br);4.21-4.37(3H,m):3.2-3.33(2H,m);2.49-2.55(4H,m);1.54-1.77(6H,m).13C-NMR(63MHz,solvent:DMSO-d6;ref.:DMSO-d6=39.3.δ(ppm):167.0(COOH);151.4,127.9,134.3,123.5,147.2(吡啶 2-3-4-5-6);135.4(CH=CH);134.9(C/Cl/=NO);77.2(NOCH2);63.5(CHOH,58.3(NCH2);52.9.22.1,21.2(哌啶).
根据实施例1制备下列化合物:实施例2N-[2-羟基-3-(1-哌啶基)-丙氧基]-苯并咪唑甲酰氯盐酸盐(熔点:140-144℃,异丙醇,产率:66%)IR(KBr):3234,2951,1504,1448,1389,1289,1119,1059,972,768,690.实施例3N-{2-羟基-3-[1-(4-甲基)-哌嗪基]-丙氧基}-3-吡啶-亚氨酸酰氯(Z)-2-丁烯二酸盐(1∶2)(熔点:174-175℃,乙醇,产率:48%)IR(KBr):3207,1693,1578,1456,1358,1304,1020,974,864,702.实施例4N-[2-羟基-3-(二乙基氨基)-丙氧基]-3-吡啶亚氨酸酰氯盐酸盐(熔点:118-119℃,丙酮,产率:67%)IR(KBr):3425,3289,2951,2667,1818,1443,1337,1238,1178,1115,1078,1049,997,910,804,781,696,683cm-1实施例5N-[2-羟基-3-(4-吗啉基)-丙氧基]-3-吡啶-亚氨酸酰氯(Z)-2-丁烯二酸盐(熔点:137-138℃,异丙醇,产率:52%)IR(KBr):3310,1580,1483,1464,1443,1354,1072,1024,982实施例6N-[2-羟基-3-(1-哌啶基)-丙氧基]-2-噻吩-亚氨酸酰氯盐酸盐(熔点:115-123℃,异丙醇-己烷,产率:38%)1H-NMR(250MHz,DMSO-d6;ref.:DMSO-d6=2.5δ(ppm):10.2(1H,s/br);7.81,7.63,7.20(1H,1H,1H,d,d,dd);5.98(1H,s/b);4.42(1H,s/b),4.35(2H,d);3.60-2.90(6H,m);1.95-1.60(4H,m);1.45-1.20(2H,m).13C-NMR(63MHz,DMSO-d6;ref.:DMSO-d6=39.3δ(ppm);133.8[C(Cl)=N];132.1.130.3,130.1,127.6(噻吩3-2-5-4);76.8(NOCH2);63.2(CHOH);58.5(CH2N);53.3,51.8(哌啶 2×NCH2)22.0,21.9,21.0(哌啶 3×CH2).实施例7N-[2-羟基-3-(1-哌啶基)-丙氧基]-2-三氟甲基苯并咪唑甲酰氯盐酸盐(熔点:119-123℃,乙酸乙酯,产率:30%)IR(KBr):3366,2937,2854,2737,2673,2538,1616,1570,1439,1404,1337,1290,1236,1199,1165,1129,1101,1074,1030,984,972,933,901,829,804,788,717,699,685,646cm-1.实施例8N-[2-羟基-3-(1-哌啶基)-丙氧基]-2’-硝基苯并咪唑甲酰氯盐酸盐(熔点:159-162℃,异丙醇,产率:43%)IR(KBr):3298,2983,2932,2746,1593,1574,1535,1445,1391,1354,1317,1288,1242,1198,1117,1092,1069,1020,968,947,914,852,793,756,708,577 cm-1.实施例9(+)N-[2-羟基-3-(1-哌啶-1-基)-丙氧基]-3-吡啶-亚氨酸酰氯(Z)-2-丁烯二酸盐(1∶1)
根据实施例1的方法将2-羟基-4-氮翁螺[3,5]壬烷氯化物和3-吡啶羧酸酰胺肟反应,反应之后用乙酸乙酯分离N-[2-羟基-3-(1-哌啶-1-基)-丙氧基]-3-吡啶-亚氨酸酰氯。将在乙酸乙酯中的15克(50毫摩尔)N-[2-羟基-3-(1-哌啶-1-基)-丙氧基]-3-吡啶-亚氨酸酰氯滴加入由13.52克(50毫摩尔)N-(叔丁氧羰基)-L-苯基丙氨酸和5.0毫升氯代甲酸乙酯在二氯甲烷中通过已知的方法就地制备的混合酸酐中,混合物在室温下搅拌1小时。溶液用2×200毫升乙酸水溶液(10%)和1×200毫升水提取以分离因此得到的酯,有机层用无水硫酸钠干燥并且浓缩。将油状剩余物溶于140毫升丙酮中,溶液中加入3.0克马来酸。由此得到5.2克(7.8毫摩尔,16%)(-)N-[2-(N’-BOC-/L/-苯基丙氨酰氧基)-3-(1-哌啶基)-丙氧基]-3-吡啶-亚氨酸酰氯(Z)-2-丁烯二酸盐(1∶1)盐(熔点:146.5-148℃)。
将5.2克如上面制备的盐在甲醇中沸腾1小时。将溶液蒸干,剩余物从50毫升乙酸乙酯重结晶得到3.18克(98%)(+)N-[2-羟基-3-(1-哌啶-1-基)-丙氧基]-3-吡啶-亚氨酸酰氯(Z)-2-丁烯二酸盐(1∶1)(熔点:136-137℃)。该化合物的IR和NMR光谱与其外消旋化合物的相对应。根据手性位移光谱学,该化合物是同质对映体。(-)异构体可以用类似的方法制备,但是使用N-(叔丁氧羰基)-/D/-苯基丙氨酸作试剂。
将本发明的方法与上面提到的现有技术中的方法比较。将3-吡啶-羧酰胺肟与根据匈牙利专利177578中描述的方法制备的3-哌啶子基-2-羟基-1-氯丙烷在无水醇介质中反应。反应结束之后将溶液变成碱性,产物用苯提取,用气相盐酸从该碱形成二盐酸盐。根据匈牙利专利HU207988中描述的方法将由此得到的O-(3-哌啶子基-2-羟基-1-丙基)-3-吡啶-羧酰胺肟盐酸盐重氮化,分解重氮盐,得到的产物与马来酸反应得到根据实施例1的产物。该方法基于起始产物的最终产率是38%,而实施例1的相应产率是53%,在商业生产中该产率高达60%。
因此可以认为本发明的方法以比现有技术的方法更高的产率提供了式(I)化合物。本发明方法的另一优点是能够节约溶剂。根据本发明中描述的方法,制备1千克产物仅仅需要17千克溶剂,而根据前面已知的方法,需要的溶剂量是40千克。本发明工业规模的方法的另一优点是制备式(I)化合物所需的技术时间较短。根据本发明,生产相应于3立方米反应器体积的1批产物需要4个连续轮班,而现有技术的方法需要8个轮班。
总之,本发明的方法提供了比以前已知的方法更高产率和实际上降低技术成本制备O-(3-氨基-2-羟基-丙基)-肟酰卤的方法。
Claims (1)
1.一种式(I)的O-(3-氨基-2-羟基-丙基)-肟酰卤类及其酸加成盐和旋光形式的制备方法,其中:
R1是苯基,或吡啶基或噻吩基或取代的苯基,其中一个或多个取代基可以是卤素和/或卤代烷基和/或硝基,
X是卤素,
R2和R3各自独立地是直链或支链的低级烷基或
R2和R3与它们连接的氮原子一起形成饱和5-7元杂环基,其可以含有其他杂原子并且可以被取代,
该方法是将其中R1的含义是如上述说明的式II的羧酰胺肟与活性的3-氨基-2-羟基丙烷衍生物反应,将得到的O-取代羧酰胺肟用亚硝酸钠在氢卤酸存在下重氮化,分解重氮盐,如果需要,分离其旋光对映体和/或用有机或无机酸与得到的碱反应,其在于将式II的羧酰胺肟与式(III)的3-羟基-氮杂环丁烷翁盐在用碱性氢氧化物制成碱性的低级醇优选乙醇介质中进行反应,其中R2和R3具有上面说明的含义和Y-是成盐阴离子,所述介质可选择性地含有水,中和反应混合物和除去有机溶剂之后,将得到的O-取代羧酰胺肟中间体重氮化。
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CN104364070A (zh) * | 2012-06-14 | 2015-02-18 | 诺华股份有限公司 | 含氮杂环丁烷鎓的共聚物及其用途 |
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CN103804309B (zh) * | 2012-11-09 | 2019-08-02 | 广州喜鹊医药有限公司 | 一种氯肟类化合物及其制备方法和在制药中的应用 |
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CN103974936A (zh) * | 2011-12-23 | 2014-08-06 | 阿克佐诺贝尔化学国际公司 | 化学化合物 |
CN103974936B (zh) * | 2011-12-23 | 2016-10-05 | 阿克佐诺贝尔化学国际公司 | 用于提供疏水性的含氮化合物 |
CN104364070A (zh) * | 2012-06-14 | 2015-02-18 | 诺华股份有限公司 | 含氮杂环丁烷鎓的共聚物及其用途 |
CN104364070B (zh) * | 2012-06-14 | 2017-05-10 | 诺华股份有限公司 | 含氮杂环丁烷鎓的共聚物及其用途 |
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