CN107739385A - 一种达比加群环状衍生物的制备方法 - Google Patents
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Abstract
本发明公开了一种如式VI所示的达比加群环状衍生物制备方法,该方法以达比加群乙酯为起始原料,经过脒基上保护基,酯基水解,羧基上保护基,最后缩合得到式VI所示达比加群环状衍生物。
Description
技术领域
本发明涉及医药技术领域,具体涉及一种达比加群环状衍生物的制备方法。
背景技术
达比加群酯,化学名称为β-丙氨酸,N-[[2-[[[4-[[[(己氧基)羰基]氨基]亚氨基甲基]苯基]氨基]甲基]-1-甲基-1H-苯并咪唑-5-基]羰基]-N-2-嘧啶-,乙酯,甲磺酸盐,结构式如式VII所示,由德国勃林格殷格翰公司开发,于2008 年4 月在德国和英国率先上市,是继华法林之后50 年来上市的首个新类别口服抗凝血药物,是直接凝血酶抑制剂,具有可以口服、强效、无需特殊检测、药物相互作用少等优点。2010 年10 月19 日,FDA 宣布正式批准达比加群酯上市销售,适应症为心房颤动引发的中风预防。此后,心房颤动适应症陆续获得加拿大、日本、欧盟等国家和地区的批准。
但是,由于达比加群酯口服生物利用度很低(6.5%),本领域仍然需要开发安全、具有较高口服生物利用度且抗凝血作用明显的新型达比加群衍生物。专利申请CN105646531A公开了一种达比加群环状衍生物,结构式如式VI所示,其实施例7描述的抗凝活性评价试验中,化合物式VI比达比加群酯具有更高的抗凝活性,但未公开该化合物式VI的具体合成步骤,因此,本领域需要一种化合物式VI的具体制备方法。
。
发明内容
本发明所要解决的技术问题在于提供一种达比加群环状衍生物VI的具体制备方法。
一种如式VI所示的达比加群环状衍生物的制备方法, 包括如下步骤:将如式V所示的化合物经过缩合反应,得到如式VI所示的化合物;
。
上述所述的制备方法,使用N'N-羰基二咪唑或三光气进行缩合反应,优选为三光气。
上述所述的制备方法,还包括如下步骤:
(1)将如式I所示化合物经保护基保护后,得到如式II所示的化合物;
(2)将如式II所示的化合物经过水解反应,得到如式III所示的化合物;
(3)将如式III所示的化合物经过酯化反应,得到如式IV所示的化合物;
(4)将如式IV所示的化合物经过脱保护反应,得到如V所示的化合物;
。
其中,R1为-C(CH3)3,-CH2Ph,-CH3或,优选为-CH(CH3)3;R2为-Si(CH3)2C(CH3)3,-COCH3,-CH2Ph或,优选为- Si(CH3)2C (CH3)3。
上述步骤(4)中使用三氟乙酸进行脱保护。
一种如式I所示的达比加群环状衍生物的制备方法,优选地,包括如下步骤:
(1)将如式I所示化合物在三乙胺作用下经叔丁基羰基保护基保护后,得到如式IIa所示的化合物;
(2)将如式IIa所示的化合物在氢氧化钠作用下经水解反应,得到如式IIIa所示的化合物;
(3)将如式IIIa所示的化合物在2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和4-二甲氨基吡啶共同作用下,与叔丁基二甲基硅氧基乙醇酯化反应,得到如式IVa所示的化合物;
(4)将如式IVa所示的化合物经过三氟乙酸脱保护反应,得到如V所示的化合物;
(5)将如式V所示的化合物经过三光气缩合反应,得到如式VI所示的化合物;
。
本发明的另一方面提供了一种全新的化合物及其在制备达比加群环状衍生物中的应用,结构式如式V所示:
。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
(1)提供一种达比加群环状衍生物V的具体制备方法;
(2)本发明起始原料方便易得,且与达比加群相比,溶解度更高;
(3)本发明提供的制备方法成本低、反应条件温和、收率高、易于工业化。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件。
实施例1 式IIa化合物的制备
在室温下将二碳酸二叔丁酯(3.05 g, 0.014 mol)加入到化合物式I(5 g, 9.33 mol)的二氯甲烷(200 mL)溶液中,再加入三乙胺(5.65 g, 0.056 mol),混合溶液在室温下搅拌16小时。减压浓缩,水洗,乙酸乙酯萃取后旋干,乙酸乙酯打浆得到白色固体即为化合物式IIa,重量为4.9 g,收率为88%;
1H NMR (400 MHz, DMSO-d6): d8.39-8.36 (m, 1H), 7.77-7.75(d, J=8.4 Hz,2H), 7.54-7.53(m, 1H), 7.47 (s, 1H), 7.40-7.39 (d, J=8.4 Hz, 1H), 7.17-7.10(m, 2H), 6.91-6.87 (m, 2H), 6.76-6.74 (m, 2H), 4.59-4.57 (d, J=8.0 Hz, 1H) ,4.24-4.20 (t, J=7.2 Hz, 2H), 4.00-3.94 (m, 2H) , 3.76 (s, 3H), 2.69-2.66 (t,J=7.2 Hz, 2H), 1.42(s, 9H), 1.14-1.10 (t, J=7.2 Hz,3H)。
实施例2 式IIIa化合物的制备
在室温下将氢氧化钠(0.98 g, 0.025 mol)加入到化合物式IIa(4.9 g, 8.18 mmol)的乙醇(250 mL)和水(50 mL)混合溶液中,在室温下搅拌4小时后,用醋酸调PH<7,减压浓缩,水洗,乙酸乙酯萃取后旋干,乙酸乙酯打浆得到白色固体即为化合物式IIIa,重量为4.01 g,收率为86%。
实施例3 式IV化合物的制备
将化合物式IIIa(3.0 g, 5.25 mmol), 2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯( 4.0 g ,10.5 mmol) 和4-二甲氨基吡啶 (1.28 g, 10.5 mmol) 的N,N-二甲基甲酰胺(30 mL) 溶液在室温下搅拌10分钟, 然后加入2-(叔丁基-二甲基-硅烷基氧基)-乙醇 (2.64 g, 15.8 mmol), 加完后混合溶液室温下搅拌16小时。 将反应液倾倒入水中并用乙酸乙酯萃取,合并有机相用盐水洗涤,用无水硫酸钠干燥,减压浓缩。 残留物用硅胶色谱柱纯化,得到黄色固体即为式IV化合物,重量为1.6g,收率42%;
1H NMR (400 MHz, DMSO-d6): d 8.75 (d, J = 4.4 Hz 1H), 8.75 (d, J = 4.4Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 7.64-7.48 (m, 5H), 7.46-7.41 (m, 2H),7.17-7.09 (m, 2H), 6.90 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 4.68(s, 2H), 4.20 (t, J = 7.2 Hz, 2H), 399-3.94 (m, 2H), 3.85 (s, 3H), 3.69 (t, J= 4.4 Hz, 2H), 2.69 (t, J = 7.2 Hz, 2H), 1.52 (s, 9H), 0.81 (s, 9H), 0.00 (s,6H)。
实施例4 式V化合物的制备
室温下向化合物式IVa(400 mg, 0.549 mmol)的二氯甲烷(10 mL )溶液中加入0.5mL三氟乙酸, 混合溶液室温搅拌24小时。减压浓缩,将残留物溶于10毫升乙醇中,然后加入400 mg的碳酸钠并室温搅拌16 小时, 减压浓缩得到残留物,用制备液相色谱制备得到白色固体,即为式V化合物,重量为195mg, 收率69%;
1H NMR (300 MHz, DMSO-d6): d 8.40 (d, J = 2.4 Hz 1H), 7.57-7.53(m, 3H),7.47 (s, 1H), 7.37 (d, J = 1.8 Hz, 1H), 7.13-7.12 (m, 2H), 6.92 (d, J = 1.8Hz, 2H), 6.76 (dd, J = 8.1, 0.6 Hz, 2H), 4.57 (s, 2H), 3.96 (t, J =1.8 Hz,2H), 3.94 (t, J =2.1 Hz, 2H), 3.75 (s, 3H), 3.51 (t, J = 4.8 Hz, 2H), 2.69(t, J = 1.8 Hz, 2H)。
实施例5 式VI化合物的制备
将化合物式V(108 mg, 0.194 mmol)和N,N-羰基二咪唑(35 mg, 0.214 mmol)的N,N-二甲基甲酰胺(12 mL)加热到60度搅拌24小时,加完后室温反应2小时,浓缩后用乙酸乙酯/乙腈打浆得到白色固体,即为式VI化合物,重量为35毫克,产率为33%。
Claims (10)
1.一种如式VI所示的达比加群环状衍生物的制备方法,其特征在于,包括如下步骤:将如式V所示的化合物经过缩合反应,得到如式VI所示的化合物;
。
2.如权利要求1所述的制备方法,其特征在于,使用N'N-羰基二咪唑或三光气进行缩合反应。
3.如权利要求1所述的制备方法,其特征在于,使用三光气进行缩合反应。
4.如权利要求1至3任一权利要求所述的制备方法,其特征在于,还包括如下步骤:
将如式I所示化合物经保护基保护后,得到如式II所示的化合物;
将如式II所示的化合物经过水解反应,得到如式III所示的化合物;
将如式III所示的化合物经过酯化反应,得到如式IV所示的化合物;
将如式IV所示的化合物经过脱保护反应,得到如V所示的化合物;
其中,R1为-C(CH3)3,-CH2Ph,-CH3或;
R2为-Si(CH3)2C(CH3)3,-COCH3,-CH2Ph或 。
5.如权利要求4所述的制备方法,其特征在于,R1为-COOCH(CH3)3。
6.如权利要求4所述的制备方法,其特征在于,R2为-Si(CH3)2C (CH3)3。
7.如权利要求4所述的制备方法,其特征在于,步骤(4)中使用三氟乙酸进行脱保护。
8.一种如式I所示的达比加群环状衍生物的制备方法,其特征在于,包括如下步骤:
(1)将如式I所示化合物在三乙胺作用下经叔丁基羰基保护基保护后,得到如式IIa所示的化合物;
(2)将如式IIa所示的化合物在氢氧化钠作用下经水解反应,得到如式IIIa所示的化合物;
(3)将如式IIIa所示的化合物在2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯和4-二甲氨基吡啶共同作用下,与叔丁基二甲基硅氧基乙醇酯化反应,得到如式IVa所示的化合物;
(4)将如式IVa所示的化合物经过三氟乙酸脱保护反应,得到如V所示的化合物;
(5)将如式V所示的化合物经过三光气缩合反应,得到如式VI所示的化合物;
。
9.一种化合物V,其结构式如下:
。
10.如权利要求9所示的化合物V在制备达比加群环状衍生物中的应用。
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