CN104974164B - 一种6‑氨甲基‑6,11‑二氢‑5H‑二苯并[b,e]氮杂卓的制备方法 - Google Patents
一种6‑氨甲基‑6,11‑二氢‑5H‑二苯并[b,e]氮杂卓的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- UZVGSSNIUNSOFA-UHFFFAOYSA-N dibenzofuran-1-carboxylic acid Chemical compound O1C2=CC=CC=C2C2=C1C=CC=C2C(=O)O UZVGSSNIUNSOFA-UHFFFAOYSA-N 0.000 title abstract description 4
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- DTHMTBUWTGVEFG-UHFFFAOYSA-N methyl 2-amino-2-phenylacetate;hydrochloride Chemical compound [Cl-].COC(=O)C([NH3+])C1=CC=CC=C1 DTHMTBUWTGVEFG-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
本发明涉及一种6‑氨甲基‑6,11‑二氢‑5H‑二苯并[b,e]氮杂卓的制备方法,属于药物合成技术领域,所述制备方法包括如下步骤:①将苯甘氨酸甲酯盐酸盐通过酰胺化反应得到苯甘氨酰胺;②将步骤①所得产品通过偶合反应得到2‑((2‑氨基‑2‑氧代‑1‑苯乙基)氨基)苯甲酸甲酯;③将步骤②所得产品通过还原反应得到2‑((2‑(羟甲基)苯基)氨基)‑2‑苯基乙酰胺;④将步骤③所得产品通过烷基化反应得到6‑氨甲基‑6,11‑二氢‑5H‑二苯并[b,e]氮杂卓,本发明有益效果为本发明的制备方法不使用现有方法中的剧毒物质氰化物。
Description
技术领域
本发明涉及一种6-氨甲基-6,11-二氢-5H-二苯并[b,e]氮杂卓的制备方法,属于药物合成技术领域。
背景技术
依匹斯汀及其盐酸盐是一种比较理想的抗过敏药物。最早关于依匹斯汀合成的文献报道是1970年美国化学会杂志上介绍的一种合成方法,即6-氯-11-二氢-二苯并[b,e]氮杂卓与氰化钠反应生成6-氰基-11-二氢-二苯并[b,e]氮杂卓,经氢化锂铝还原得到6-氨甲基-6,11-二氢-5H-二苯并[b,e]氮杂卓,与溴化氰反应成环得到依匹斯汀。此路线用到高毒性的氰化物,不适合工业化生产。合成路线如下:
2007年,中国专利CN 101130544A介绍了一种依匹斯汀的化学合成方法。6-氯甲基-11-二氢-二苯并[b,e]氮杂卓与氨气反应得到6-氨甲基-11-二氢-二苯并[b,e]氮杂卓,经过硼氢化钠还原,与溴化氰环合得到依匹斯汀。氨气很容易溢出反应体系,污染大气,不利于环保。6-氨甲基-11-二氢-5H-二苯并[b,e]氮杂卓不稳定,不易存放,易变质。后一步反应副反应多,不易纯化。合成路线如下:
2013年,杨军发表的专利CN 103172638介绍了一种盐酸依匹斯汀的合成方法。6-氨甲基-11-二氢-5H-二苯并[b,e]氮杂卓与N,N-二叔丁氧羰基-S-甲基异硫脲在有机溶剂中反应,然后与对甲苯磺酸在醇中反应生成N-叔丁氧羰基依匹斯汀,经盐酸的乙醇溶液处理得到盐酸依匹斯汀。反应步骤繁琐,不利于工业化生产。合成路线如下:
从上述几种方法中,我们可以看出,依匹斯汀的合成大多是通过6-氨甲基-6,11-二氢-5H-二苯并[b,e]氮杂卓这一中间体来实现的,而目前这一中间体的制备方法,很多使用了剧毒的氰化物,有些是在高压的条件下进行的。寻找一种低毒环保、更加温和的合成方法来合成依匹斯丁中间体,成为抗过敏药物领域的一项重要课题。
发明内容
本发明通过提供一种绿色合成方法得到6-氨甲基-6,11-二氢-5H-二苯并[b,e]氮杂卓,解决了上述合成6-氨甲基-6,11-二氢-5H-二苯并[b,e]氮杂卓的问题。
本发明提供了一种6-氨甲基-6,11-二氢-5H-二苯并[b,e]氮杂卓的制备方法,所述制备方法包括如下步骤:
①将苯甘氨酸甲酯盐酸盐通过酰胺化反应得到苯甘氨酰胺;
②将步骤①所得产品通过偶合反应得到2-((2-氨基-2-氧代-1-苯乙基)氨基)苯甲酸甲酯;
③将步骤②所得产品通过还原反应得到2-((2-(羟甲基)苯基)氨基)-2-苯基乙酰胺;
④将步骤③所得产品通过烷基化反应得到6-氨甲基-6,11-二氢-5H-二苯并[b,e]氮杂卓。
本发明所述步骤①优选为将苯甘氨酸甲酯盐酸盐溶于饱和碳酸钠溶液中反应得到苯甘氨酸甲酯,加入氨化试剂反应得到苯甘氨酰胺,进一步优选为将苯甘氨酸甲酯盐酸盐溶于饱和碳酸钠溶液中10~60℃反应0.5~24h,萃取,洗涤,干燥得到苯甘氨酸甲酯,向苯甘氨酸甲酯中加入氨化试剂10~50℃反应6~48h,萃取,干燥得到苯甘氨酰胺,所述苯甘氨酸甲酯盐酸盐、饱和碳酸钠溶液与氨化试剂的重量比为1:10~60:1~35。
本发明所述步骤②优选为在惰性氛围下,将步骤①所得产品、碳酸钾、邻碘基苯甲酸甲酯、N,N-二甲基乙二胺与溶剂在催化剂催化条件下反应得到2-((2-氨基-2-氧代-1-苯乙基)氨基)苯甲酸甲酯,进一步优选为在惰性氛围下,将步骤①所得产品、碳酸 钾、邻碘基苯甲酸甲酯、N,N-二甲基乙二胺与溶剂在催化剂催化条件下50~130℃回流反应1~10h,洗涤,干燥,柱层析得到2-((2-氨基-2-氧代-1-苯乙基)氨基)苯甲酸甲酯,所述步骤①所得产品、碳酸钾、邻碘基苯甲酸甲酯、N,N-二甲基乙二胺、溶剂与催化剂的重量比为1:1~5:0.5~2.5:0.1~2:50~80:0.02~1。
本发明所述步骤③优选为在冰浴条件下,将步骤②所得产品溶于溶剂中,加入负氢试剂反应得到2-((2-(羟甲基)苯基)氨基)-2-苯基乙酰胺,进一步优选为在冰浴条件下,将步骤②所得产品溶于溶剂,加入负氢试剂0~30℃反应1~8h,过滤,干燥,柱层析得到2-((2-(羟甲基)苯基)氨基)-2-苯基乙酰胺,所述步骤②所得产品、溶剂与负氢试剂的重量比为1:20~50:0.1~10。
本发明所述步骤④优选为将步骤③所得产品在路易斯酸催化下反应得到6-氨甲基-6,11-二氢-5H-二苯并[b,e]氮杂卓,进一步优选为将步骤③所得产品在路易斯酸催化下90~110℃反应24~48h,冷却至室温,加水,调pH至8~9,洗涤,除去溶剂,柱层析得到6-氨甲基-6,11-二氢-5H-二苯并[b,e]氮杂卓,所述步骤③所得产品与路易斯酸的重量比为1:5~20。
本发明所述氨化试剂优选为氨水或液氨。
本发明所述催化剂优选为一价铜盐,进一步优选为碘化亚铜或溴化亚铜。
本发明所述负氢试剂优选为氢化锂铝。
本发明所述路易斯酸优选为三氯化铝、四氯化锡、三氟化硼或多聚磷酸。
本发明所述6-氨甲基-6,11-二氢-5H-二苯并[b,e]氮杂卓的合成路线如下:
本发明有益效果为:
①本发明制备方法不使用现有方法中的剧毒物质氰化物;
②本发明制备方法反应条件温和。
具体实施方式
下述非限制性实施例可以使本领域的普通技术人员更全面地理解本发明,但不以任何方式限制本发明。
实施例1
一种6-氨甲基-6,11-二氢-5H-二苯并[b,e]氮杂卓的制备方法,所述制备方法包括如下步骤:
①苯甘氨酰胺(2)的合成:
将1.47g苯甘氨酸甲酯盐酸盐(1)溶于80g饱和碳酸钠溶液中室温反应1h,二氯甲烷萃取,饱和食盐水洗涤,干燥得到苯甘氨酸甲酯,向苯甘氨酸甲酯中加入47.7g 25wt%氨水25℃反应24h,二氯甲烷萃取,无水硫酸钠干燥,过滤,干燥得到白色固体苯甘氨酰胺(2)0.94g,产率86%。
②2-((2-氨基-2-氧代-1-苯乙基)氨基)苯甲酸甲酯(3)的合成:
在氮气保护下,将2.16g化合物2、0.12g碘化亚铜、3.98g碳酸钾、2.1g邻碘基苯甲酸甲酯、1gN,N-二甲基乙二胺与113g甲苯110℃回流反应6h,水洗,饱和食盐水洗涤,无水硫酸钠干燥,过滤,干燥,柱层析(石油醚:乙酸乙酯的体积比为3:1)得到淡黄色固体2-((2-氨基-2-氧代-1-苯乙基)氨基)苯甲酸甲酯(3)3.15g,产率77%;mp:81~85℃。1H NMR(500MHz,CDCl3)δ12.11(s,1H,N-H),8.74(d,J=10Hz,1H,Ar-H),8.03(d,J=10Hz,1H,Ar-H),7.51(t,J=10Hz,3H,Ar-H),7.35(t,J=10Hz,2H,Ar-H),7.29(t,J=10Hz,1H,Ar-H),7.07(t,J=10Hz,1H,Ar-H),4.70(s,1H,-CH),3.94(s,3H,OCH3),1.99(s,2H,N-H);13C NMR(400MHz,CDCl3)δ172.54,168.23,140.96,140.87,134.48,130.94,128.90,128.12,126.98,122.72,120.50,115.74,61.51,52.41;HRMS(ESI),对于[M+H]+准分子离子峰,计算值:285.1239实测值:285.1239
③2-((2-(羟甲基)苯基)氨基)-2-苯基乙酰胺(4)的合成:
在冰浴条件下,将102mg化合物3溶于3.8g无水四氢呋喃中,加入54mg氢化锂铝30℃反应4h,加入乙醇淬灭,过滤,干燥,柱层析(氯仿:甲醇的体积比为20:1)得到白色固体2-((2-(羟甲基)苯基)氨基)-2-苯基乙酰胺(4)23.43mg,产率47%;1H NMR(400MHz,DMSO-d6)δ7.85(d,J=4.0Hz,1H,Ar-H),7.46(d,J=4.0Hz,2H,Ar-H),7.34-7.28(m,3H,Ar-H),7.26-7.18(m,2H,Ar-H),7.04(t,J=8.0Hz,1H,Ar-H),5.44(s,1H,OH),4.53(s,1H,C-H),4.50(s,2H,C-H);13C NMR(500MHz,DMSO-d6)δ177.21,147.29,141.62,137.53,133.50,133.25,132.68,132.54,132.20,128.98,126.96,126.85,66.35,65.43;HRMS(ESI),对于[M+H]+准分子离子峰,计算值:257.1290,实测值: 257.1292
④6-氨甲基-6,11-二氢-5H-二苯并[b,e]氮杂卓的合成:
将242mg化合物4溶于3g多聚磷酸中100℃反应48h,冷却至室温,加水20mL,加NaOH调pH至8~9,水洗,盐水洗涤,除去溶剂,柱层析(氯仿:甲醇的体积比为40:1)得到白色固体6-氨甲基-6,11-二氢-5H-二苯并[b,e]氮杂卓135mg,产率60%。
Claims (3)
1.一种6-氨甲基-6,11-二氢-5H-二苯并[b,e]氮杂卓的制备方法,其特征在于:所述制备方法包括如下步骤:
①将苯甘氨酸甲酯盐酸盐通过酰胺化反应得到苯甘氨酰胺;
②在惰性氛围下,将步骤①所得产品、碳酸钾、邻碘基苯甲酸甲酯、N,N-二甲基乙二胺与溶剂在催化剂催化条件下反应得到2-((2-氨基-2-氧代-1-苯乙基)氨基)苯甲酸甲酯,所述催化剂为一价铜盐;
③在冰浴条件下,将步骤②所得产品溶于溶剂中,加入负氢试剂反应得到2-((2-(羟甲基)苯基)氨基)-2-苯基乙胺,所述负氢试剂为氢化锂铝;
④将步骤③所得产品在路易斯酸催化下反应得到6-氨甲基-6,11-二氢-5H-二苯并[b,e]氮杂卓,所述路易斯酸为三氯化铝、四氯化锡、三氟化硼或多聚磷酸,所述6-氨甲基-6,11-二氢-5H-二苯并[b,e]氮杂卓的合成路线图如下:
2.根据权利要求1所述的制备方法,其特征在于:所述步骤①为将苯甘氨酸甲酯盐酸盐溶于饱和碳酸钠溶液中反应得到苯甘氨酸甲酯,加入氨化试剂反应得到苯甘氨酰胺。
3.根据权利要求2所述的制备方法,其特征在于:所述氨化试剂为氨水或液氨。
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