CN111039846A - 一种阿普斯特杂质化合物及其用途 - Google Patents
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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Abstract
本发明公开一种阿普斯特的杂质化合物（IV）及制备方法。以及该杂质化合物在控制阿普斯特质量中的用途，为阿普斯特质量研究提供保障。
Description
技术领域
本发明属于化学医药领域，具体涉及一种阿普斯特杂质化合物及其制备方法，以及在控制阿普斯特质量中的用途。
背景技术
阿普斯特(Apremilast) 的CAS号为608141-41-9，化学名称为( S )-2-[1-( 3-乙氧基-4-甲氧基苯基)-2-甲磺酰基乙基]-4-乙酰基氨基异吲哚啉-1,3-二酮，是美国生物制药公司(Gelgene Corporation) 开发的磷酸二酯酶4(PDE-4) 抑制剂类新型小分子口服药，抑制参与银屑病发病机制中的多个炎症标志物的活性，该化合物通过调节胞内促炎与抗炎因子作用网络而发挥作用，可有效治疗银屑病关节炎。1-( 3-乙氧基-4-甲氧基)苯基-2-甲磺酰基乙胺(II)是制备阿普斯特的关键中间体。国内外对其合成进行了较多研究。
欧洲专利EP1126839首次报道了其合成方法
该合成路线以3-乙氧基-4-甲氧基苯甲醛 (I) 为原料，六甲基二硅基氨基锂作为氨基供体，在正丁基锂作用下与二甲基砜缩合制备化合物II，文献报道收率39%。利用本路线制备化合物II时，发现会生成一个工艺专属性杂质即式III化合物，该化合物可进一步衍生得到阿普斯特成品中的杂质 (IV)。
药物的质量控制主要是控制活性成分的含量和有关物质的含量，特别是有关物质的含量需要满足药用要求，其杂质主要来源于合成过程以及药物降解产生。本发明人在阿普斯特及中间体的制备中，发现了未见报道的杂质，并且合成了该杂质，用于控制阿普斯特原料药和制剂产品的质量。
发明内容
本发明的目的在于提供一种阿普斯特成品中的杂质即式IV化合物及制备方法。以及该IV化合物用于控制阿普斯特原料药和制剂产品的质量的用途。同时也提供一种将该杂质化合物的含量控制在合规范围的方法。
本发明的IV化合物具有如下化学结构，
上述IV化合物还包括其三个手性异构体如RR，SS，RS构型，分别是IV-1化合物、IV-2化合物、IV-3化合物，如无特别说明，所述式IV化合物视为前述三个手性异构体的组合物
本发明还提供了一种制备式IV化合物的方法，包括：将式III化合物与3-乙酰胺基邻苯二甲酸酐、3-乙酰胺基邻苯二甲酸中的一种或其任意比例混合物在反应溶剂中混合反应，分离纯化获得，其中，反应溶剂选自N,N-二甲基甲酰胺，N,N-二甲基乙酰胺，乙腈，四氢呋喃，乙酸，丙酸和二氯甲烷中的一种或其任意比例混合物。
反应式如下：
本发明所述式IV化合物在控制阿普斯特原料药及其制剂产品中的用途，所述控制是采用高效液相色谱法测定阿普斯特原料药及其制剂中杂质IV化合物的含量，用面积归一化法计算得到。
具体实施方式
下面结合实施例对本发明作进一步说明。但本发明的保护范围不能认为仅局限于下述具体实施方式。在不脱离本发明基本构思的前提下，所属领域的技术人员据此作出的简单推演或同等替换方案，均属于本发明的保护范围。
实施例1
式III化合物的制备及分离：
向3 L干燥三口瓶中依次加入Me2SO2 141 g (1.5 mol)，THF (833 mL)，降温，加入正丁基锂的正己烷溶液500 mL (1.25 mol)。滴加完毕后，保温反应1 h，制备得反应液R1。在上述操作同时，向另一个1 L的干燥三口瓶中依次加入式I化合物75 g (0.416 mol)和THF(333 mL)，降温，滴加六甲基二硅基氨基锂的四氢呋喃溶液500 mL (0.5 mol)，完毕后，保温反应1 h，制备得反应液R2。将反应液R1降温至-20 ~ -10 ℃，加入反应液R2，滴加完毕后，保温搅拌1 h。向反应液中滴加三氟化硼乙醚293 g (2.08 mol)，滴加完毕后，自然升温至0℃。将反应液加入碳酸钾水溶液中淬灭反应，加完后过滤，分液，滤饼用DCM洗涤两次，合并有机相，减压浓缩至干。然后加入DCM 300 mL，4 N HCl 330 mL，30℃搅拌0.5 h，分液，有机层用150 mL 4 N HCl萃取一次，合并水相，DCM 300 mL萃洗。水层加4 N NaOH 调节pH至12 ~ 14，DCM 400mL萃取两次，浓缩后得1-(3-乙氧基-4-甲氧基苯基)-2-(甲磺酰基)乙胺粗品，加入甲苯450 mL，加热至回流溶解，降温至室温析出固体，抽滤后母液浓缩干，残留物经柱层析(DCM/MeOH = 30/1)得式III化合物6.7 g。
质谱[ESI-MS，m/z]中[M-NH2]＋峰为436，[M+H]+峰为453。
1H NMR (600 MHz, DMSO) δ (ppm): 1.32 (t, J = 7.2 Hz, 6 H), 2.50 -2.58 (m, 4 H), 3.26 - 4.30 (m, 2 H), 3.40 - 3.44 (m, 1H), 3.49 - 3.53 (m, 1H), 3.72 (s, 6 H), 3.99 - 4.04 (m, 4 H), 4.31 - 4.35 (m, 2 H), 6.85 - 6.88(m, 4 H), 6.98 - 7.00 (m, 2 H)。
13C NMR (151 MHz, DMSO) δ (ppm): 148.68, 148.47, 137.89, 118.89,118.84, 112.43, 112.41, 112.11, 64.25, 62.35, 62.26, 56.07, 51.06, 50.98,15.24。
实施例2
式IV化合物的制备
将3-乙酰氨基邻苯二甲酸酐4.3 g (21 mmol) 和式III化合物4.0 g (8.8 mmol) 加入50 mL单口瓶中，加入12 mL冰醋酸。120℃油浴搅拌，加热至回流开始计时，1~2 h后TLC检测无III (TLC检测 MeOH/DCM =1/20)。降至室温，向反应液中加入水25 mL搅拌分散后转入100 mL烧杯，再加入25 mL水搅拌1 h后抽滤。滤饼用水洗涤至滤液呈中性。45℃减压干燥（放置无水CaCl2）至恒重，收料得5.6 g浅黄绿色固体式IV化合物。
质谱[ESI-MS，m/z]中[M+H]＋峰为827，[M-H]-峰为825。
1H NMR (600 MHz, DMSO) δ(ppm): 1.31 - 1.33 (m, 6 H), 2.18 -2.20 (m, 6H), 3.73 (s, 6 H), 3.99 - 4.02 (m, 4 H), 4.12 - 4.20 (m, 2H), 4.31 - 4.41 (m,1 H), 4.48 - 4.52 (m, 1 H), 5.75 - 5.81 (m, 2 H), 6.91 - 6.95 (m, 4 H), 7.02(s, 2H), 7.51 - 7.54 (m, 2 H), 7.76 - 7.78 (m, 2 H), 8.42 - 8.45 (m, 2 H),9.64 - 9.68 (m, 2 H)。
13C NMR (151 MHz, DMSO) δ(ppm): 169.69, 168.21, 168.16, 167.28,167.21, 149.55, 148.45, 148.41, 137.07, 136.45, 136.40, 131.79, 131.74,129.91, 129.83, 126.54, 126.44, 120.23, 118.65, 118.57, 117.00, 112.97,112.47, 64.44, 56.05, 53.29, 53.07, 47.12, 47.03, 24.69, 24.67, 15.14。
实施例3
式IV化合物的制备
将3-乙酰氨基邻苯二甲酸酐4.3 g (21 mmol) 和式III化合物 4.0 g (8.8 mmol) 加入50 mL单口瓶中，加入12 mL N,N-二甲基甲酰胺。120℃油浴搅拌，加热至回流开始计时，1~2 h后TLC检测无式III化合物(TLC检测 MeOH/DCM =1/20)。降至室温，向反应液中加入水25 mL搅拌分散后转入100 mL烧杯，再加入25 mL水搅拌1 h后抽滤。滤饼用水洗涤至滤液呈中性。45℃减压干燥（放置无水CaCl2）至恒重，收料得5.1 g浅黄绿色固体IV化合物。
实施例4
式IV化合物的制备
将3-乙酰氨基邻苯二甲酸4.4 g (21 mmol) 和式III化合物4.0 g (8.8 mmol) 加入50 mL单口瓶中，加入12 mL N,N-二甲基甲酰胺。120℃油浴搅拌，加热至回流开始计时，1~2h后TLC检测无式III化合物(TLC检测 MeOH/DCM =1/20)。降至室温，向反应液中加入水25mL搅拌分散后转入100 mL烧杯，再加入25 mL水搅拌1 h后抽滤。滤饼用水洗涤至滤液呈中性。45℃减压干燥（放置无水CaCl2）至恒重，收料得5.2 g浅黄绿色固体IV。
实施例5
阿普斯特成品的制备：将3-乙酰氨基邻苯二甲酸酐3.1 g (15 mmol) 和式II 化合物2.7 g (10 mmol，其中含有0.1%的式III化合物) 加入50 mL单口瓶中，加入10 mL 冰醋酸。120℃油浴搅拌，加热至回流开始计时，1~2 h后TLC检测无式III化合物(TLC检测 MeOH/DCM=1/20)。降至室温，向反应液中加入水25 mL搅拌分散后转入100 mL烧杯，再加入25 mL水搅拌1 h后抽滤。滤饼用水洗涤至滤液呈中性。45℃减压干燥（放置无水CaCl2）至恒重，收料得4.3 g灰白色固体（阿普斯特成品），利用HPLC测得该固体中式IV化合物的含量为0.06%。阿普斯特质量符合相关医药法规要求。
Claims (5)
1.一种式IV化合物
2.如权利要求1所述的式IV化合物，进一步包含三个不同构型的手性异构体：式IV-1、式IV-2或/和式IV-3，
3.一种制备权利要求1的式IV化合物的方法，包括如下步骤：将式III化合物与3-乙酰氨基邻苯二甲酸酐或/和3-乙酰氨基邻苯二甲酸在反应溶剂中混合反应，分离纯化而得。
4.如权利要求3所述的方法，所述反应溶剂选自N,N-二甲基甲酰胺，N,N-二甲基乙酰胺，乙腈，四氢呋喃，乙酸，丙酸和二氯甲烷中的一种或其任意比例混合物，
5.权利要求1或2所述的式IV化合物在控制阿普斯特原料药及其制剂质量中的用途。
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