CN115246781B - 一种沙芬酰胺的制备方法 - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
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- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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Abstract
本发明提供了一种沙芬酰胺的制备方法,本发明沙芬酰胺的制备方法反应条件温和,收率高,该合成方法具有操作简便,后处理简单,成本低,对环境友好等特点,并可以获得高质量的目标产物,有利于工业生产。
Description
技术领域
本发明涉及有机合成技术领域,具体涉及一种沙芬酰胺的制备方法。
背景技术
沙芬酰胺甲磺酸盐(Safinamidemesilate),化学名为(S)-2-[4-(3-氟苄氧基)苄胺基]丙酰胺甲磺酸盐,是由 Newron制药公司研发的抗帕金森病药。本品具有多种作用机制,不仅可高选择性及可逆性抑制单胺氧化酶B(MAO-B),还可以抑制多巴胺再摄取,阻断电压依赖的钠通道、调节钙通道,从而抑制谷氨酸释放。沙芬酰胺的中枢神经***生物利用度高,临床显示可以提高帕金森病患者的运动和认知功能,防止患者出现运动障碍,且具有良好的耐受性
发明内容
本发明的技术方案是提供一种制备沙芬酰胺的新方法。本发明的制备方法条件温和、收率高、后处理简便、制得的产品纯度高、生产成本低、适合工业化生产。
本发明提供了一种沙芬酰胺的制备方法,包括步骤d:
在一些实施方案中,所述的沙芬酰胺的制备方法,其采用1-((4-(氯甲基)苯氧基)甲基)-3-氟苯与L-丙氨酰胺在有机溶剂和碱性物质存在下反应制得沙芬酰胺。
在一些典型的实施方案中,所述沙芬酰胺的制备方法,所采用的碱性物质选自碳酸钾、碳酸钠、三乙胺和二异丙基乙胺中的一种或两种;优选为三乙胺。
在一些典型的实施方案中,所述沙芬酰胺的制备方法,所采用的有机溶剂选自乙腈、N-甲基吡咯烷酮、 N,N-二甲基甲酰胺和二甲基亚砜的一种或者多种;优选为N,N-二甲基甲酰胺。
在一些典型的实施方案中,所述沙芬酰胺的制备方法,所采用的温度选自0~100℃;优选为0~30℃。
在一些典型的实施方案中,所述沙芬酰胺的制备方法,所采用的L-丙氨酰胺可以其酸式盐的形式使用或者是其游离碱;优选L-丙氨酰胺盐酸盐。
进一步的,本发明提供的一种沙芬酰胺的制备方法,还包括以下步骤c:
在一些典型的实施方案中,所述的步骤c采用4-((3-氟苄基)氧基)苯甲醇在室温下以二氯甲烷作溶剂,与二氯亚砜反应得到1-((4-(氯甲基)苯氧基)甲基)-3-氟苯。
进一步的,本发明提供的一种沙芬酰胺的制备方法,还包括以下步骤b:
在一些典型的实施方案中,所述的步骤b采用4-((3-氟苄基)氧基)苯甲醛在室温下以甲醇作溶剂,与硼氢化钠反应得到4-((3-氟苄基)氧基)苯甲醇。
进一步的,本发明提供的一种沙芬酰胺的制备方法,还包括以下步骤a:
在一些典型的实施方案中,所述的步骤a采用对羟基苯甲醛与3-氟氯苄在50~60℃下以N,N-二甲基甲酰胺作溶剂,碳酸钾作缚酸剂,反应得到4-((3-氟苄基)氧基)苯甲醛。
更进一步的,本发明提供的一种沙芬酰胺的制备方法,包括以下步骤:
步骤a:对羟基苯甲醛与3-氟氯苄在50~60℃下以N,N-二甲基甲酰胺作溶剂,碳酸钾作缚酸剂反应得到4-((3-氟苄基)氧基)苯甲醛;
步骤b:4-((3-氟苄基)氧基)苯甲醛在室温下以甲醇作溶剂,与硼氢化钠反应得到4-((3-氟苄基) 氧基)苯甲醇;
步骤c:4-((3-氟苄基)氧基)苯甲醇在室温下以二氯甲烷作溶剂,与二氯亚砜反应得到1-((4-(氯甲基)苯氧基)甲基)-3-氟苯;
步骤d:1-((4-(氯甲基)苯氧基)甲基)-3-氟苯与L-丙氨酰胺盐酸盐在室温下,以N,N-二甲基甲酰胺作溶剂,三乙胺作缚酸剂反应得到沙芬酰胺游离碱。
本发明还提供一种甲磺酸沙芬酰胺的合成方法,具体步骤如下:
步骤a:对羟基苯甲醛与3-氟氯苄在50~60℃下以N,N-二甲基甲酰胺作溶剂,碳酸钾作缚酸剂反应得到4-((3-氟苄基)氧基)苯甲醛;
步骤b:4-((3-氟苄基)氧基)苯甲醛在室温下以甲醇作溶剂,与硼氢化钠反应得到4-((3-氟苄基) 氧基)苯甲醇;
步骤c:4-((3-氟苄基)氧基)苯甲醇在室温下以二氯甲烷作溶剂,与二氯亚砜反应得到1-((4-(氯甲基)苯氧基)甲基)-3-氟苯;
步骤d:1-((4-(氯甲基)苯氧基)甲基)-3-氟苯与L-丙氨酰胺盐酸盐在室温下,以N,N-二甲基甲酰胺作溶剂,三乙胺作缚酸剂反应得到沙芬酰胺游离碱;
步骤e:沙芬酰胺游离碱在室温条件下,以乙酸乙酯作溶剂,与甲磺酸反应制得甲磺酸沙芬酰胺。
本发明通过上述制备工艺获得了如下的有益效果:本发明沙芬酰胺的制备方法反应条件温和,收率高,该合成方法具有操作简便,后处理简单,成本低,对环境友好等特点,并可以获得高质量的目标产物,有利于工业生产。
具体定义
室温:0~30℃
DMF:N,N-二甲基甲酰胺
DMSO:二甲基亚砜
DCM:二氯甲烷
EA:乙酸乙酯
TEA:三乙胺
具体实施方式
下面结合优选实施例对本发明作进一步说明,下述实施例仅用于说明本发明而并非对本发明的限制。
HPLC纯度测定条件:用十八烷基硅烷-五氟苯基键合硅胶为填充剂[ACEExcel3C18-PFP (4.6mm×150mm,3μm)或效能相当的色谱柱];以10mmol/L磷酸氢二钾缓冲液(取磷酸氢二钾1.74g,加水1000ml使溶解,用磷酸调节pH值至6.8)为流动相A,以甲醇为流动相B,按下表进行梯度洗脱;流速为每分钟0.8ml;柱温为35℃;检测波长为226nm。
实施例1 4-((3-氟苄基)氧基)苯甲醛的合成
反应瓶中加入对羟基苯甲醛(10.0g,81.9mmol),无水碳酸钾(12.4g,90.1mmol)和40mlDMF,室温搅拌15min,3-氟氯苄(12.1g,83.5mmol)用10mlDMF溶解后,滴加至反应瓶中,升温至50~60℃反应6h。TLC检测反应结束,抽滤,滤饼水洗,干燥得白色固体18.4g,收率97.6%,纯度:98.9%。1HNMR (DMSO-d6,500Hz)δ:9.91(s,1H),7.91~7.89(m,2H),7.48~7.44(m,1H),7.34~7.31(m,2H),7.24~7.16(m,3H),5.27(s,2H).GC-MSm/z:230.0{[M]}.
实施例2(4-((3-氟苄基)氧基)苯基)甲醇的合成
反应瓶中加入4-((3-氟苄基)氧基)苯甲醛(5.0g,21.7mmol)和25ml甲醇,冰浴搅拌下,分批加入硼氢化钠(0.82g,21.7mmol),室温搅拌。反应完毕后,滴加50ml水,室温搅拌1h后抽滤,干燥得白色固体4.6g,收率91.2%,纯度:98.5%。1H-NMR(DMSO-d6,500Hz)δ:7.44~7.40(m,1H),7.29~7.26(m,4H), 7.15~7.12(m,1H),6.98~6.96(m,2H),5.12(s,2H),5.06~5.04(t,J=5.5Hz,1H),4.44~4.43(d,J=5.0Hz,2H).GC-MSm/z:232.0{[M]}.
实施例3 1-((4-(氯甲基)苯氧基)甲基)-3-氟苯的合成
反应瓶中加入(4-((3-氟苄基)氧基)苯基)甲醇(4.0g,17.2mmol)和40ml二氯甲烷,冰浴搅拌下,滴加SOCl2(2.7g,22.4mmol),冰浴反应。反应完毕后,反应液减压浓缩,得无色油状物4.0g,收率92.6%,纯度:98.8%,直接用于下步反应。1H-NMR(DMSO-d6,300Hz)δ:7.47~7.36(m,3H),7.30~7.27(d,J=8.1Hz, 2H),7.18~7.13(t,J=8.0Hz,1H),7.03(s,1H),7.00(s,1H),5.14(s,1H),4.72(s,1H).
实施例4(S)-2-((4-((3-氟苄基)氧基)苄基)氨基)丙酰胺的合成
反应瓶中加入1-((4-(氯甲基)苯氧基)甲基)-3-氟苯(3.0g,12.0mmol),L-丙氨酰胺盐酸盐(1.8g,14.4 mmol)、三乙胺(4.8g,47.9mmol)和30mlDMF,室温搅拌。反应完毕后,反应液滴加至90ml水中,冰浴搅拌1h后抽滤,干燥得白色固体2.7g,收率74.6%,纯度:98.0%。1H-NMR(DMSO-d6,500Hz)δ:9.07 (s,1H),8.00~7.62(s,2H),7.48~7.43(m,3H),7.32~7.28(t,J=10.0Hz,2H),7.18~7.14(t,J=10.0Hz,1H), 7.10~7.09(d,J=5.0Hz,2H),5.19(s,2H),4.10~4.01(m,2H),3.87~3.83(m,1H),1.48~1.47(d,J=5.0Hz,3H).ESI-MSm/z:303.2{[M+H]+}.
实施例5(S)-2-((4-((3-氟苄基)氧基)苄基)氨基)丙酰胺的合成
反应瓶中加入1-((4-(氯甲基)苯氧基)甲基)-3-氟苯(1.0g,4.0mmol),L-丙氨酰胺盐酸盐(0.6g,4.8 mmol)、碳酸钾(2.2g,16.0mmol)和10mlDMF,室温搅拌。反应完毕后,反应液滴加至30ml水中,冰浴搅拌1h后抽滤,干燥得白色固体0.68g,收率56%,纯度:94.6%。
实施例6(S)-2-((4-((3-氟苄基)氧基)苄基)氨基)丙酰胺的合成
反应瓶中加入1-((4-(氯甲基)苯氧基)甲基)-3-氟苯(1.0g,4.0mmol),L-丙氨酰胺盐酸盐(0.6g,4.8 mmol)、三乙胺(1.6g,12.0mmol)和10mlNMP,室温搅拌。反应完毕后,反应液滴加至30ml水中,冰浴搅拌1h后抽滤,干燥得白色固体0.78g,收率65%,纯度:96.8%。
实施例7(S)-2-((4-((3-氟苄基)氧基)苄基)氨基)丙酰胺甲磺酸盐的合成
反应瓶中加入(S)-2-((4-((3-氟苄基)氧基)苄基)氨基)丙酰胺(2.0g,6.6mmol)和40ml乙酸乙酯,升温至50~60℃搅拌溶清后趁热过滤,滤液中滴加甲磺酸(0.6g,6.6mmol),室温搅拌析晶1~2h后抽滤,干燥得粗品,白色固体2.5g,收率94.7%,纯度:99.5%。1H-NMR(DMSO-d6,500Hz)δ:9.07(s,2H),8.00~7.62 (s,2H),7.48~7.43(m,3H),7.32~7.28(t,J=10.0Hz,2H),7.18~7.14(t,J=10.0Hz,1H),7.10~7.09(d,J=5.0Hz,2H),5.19(s,2H),4.10~4.01(m,2H),3.87~3.83(m,1H),2.43(s,3H),1.48~1.47(d,J=5.0Hz,3H). ESI-MSm/z:303.2{[M+H-CH3SO3H]+} 。
Claims (8)
1.一种沙芬酰胺的制备方法,包括步骤d,
步骤d:在室温下,1-((4-(氯甲基)苯氧基)甲基)-3-氟苯与L-丙氨酰胺在N,N-二甲基甲酰胺和三乙胺存在下反应制得沙芬酰胺。
2.如权利要求1所述的制备方法,其特征在于,所采用的L-丙氨酰胺可以其酸式盐的形式使用或者是其游离碱。
3.如权利要求1所述的制备方法,其特征在于,所采用的L-丙氨酰胺为L-丙氨酰胺盐酸盐。
4.如权利要求1所述的制备方法,其特征在于,还包括以下步骤c,
步骤c:4-((3-氟苄基)氧基)苯甲醇在室温下以二氯甲烷作溶剂,与二氯亚砜反应得到1-((4-(氯甲基)苯氧基)甲基)-3-氟苯。
5.如权利要求1所述的制备方法,其特征在于,还包括以下步骤b,
步骤b:4-((3-氟苄基)氧基)苯甲醛在室温下以甲醇作溶剂,与硼氢化钠反应得到4-((3-氟苄基)氧基)苯甲醇。
6.如权利要求1所述的制备方法,其特征在于,还包括以下步骤a,
步骤a:对羟基苯甲醛与3-氟氯苄在50~60℃下以N,N-二甲基甲酰胺作溶剂,碳酸钾作缚酸剂,反应得到4-((3-氟苄基)氧基)苯甲醛。
7.如权利要求1所述的制备方法,其特征在于,还包括以下步骤,
步骤a:对羟基苯甲醛与3-氟氯苄在50~60℃下以N,N-二甲基甲酰胺作溶剂,碳酸钾作缚酸剂反应得到4-((3-氟苄基)氧基)苯甲醛;
步骤b:4-((3-氟苄基)氧基)苯甲醛在室温下以甲醇作溶剂,与硼氢化钠反应得到4-((3-氟苄基)氧基)苯甲醇;
步骤c:4-((3-氟苄基)氧基)苯甲醇在室温下以二氯甲烷作溶剂,与二氯亚砜反应得到1-((4-(氯甲基)苯氧基)甲基)-3-氟苯;
步骤d:1-((4-(氯甲基)苯氧基)甲基)-3-氟苯与L-丙氨酰胺盐酸盐在室温下,以N,N-二甲基甲酰胺作溶剂,三乙胺作缚酸剂反应得到沙芬酰胺游离碱。
8.一种甲磺酸沙芬酰胺的制备方法,包括以下步骤,
步骤a:对羟基苯甲醛与3-氟氯苄在50~60℃下以N,N-二甲基甲酰胺作溶剂,碳酸钾作缚酸剂反应得到4-((3-氟苄基)氧基)苯甲醛;
步骤b:4-((3-氟苄基)氧基)苯甲醛在室温下以甲醇作溶剂,与硼氢化钠反应得到4-((3-氟苄基)氧基)苯甲醇;
步骤c:4-((3-氟苄基)氧基)苯甲醇在室温下以二氯甲烷作溶剂,与二氯亚砜反应得到1-((4-(氯甲基)苯氧基)甲基)-3-氟苯;
步骤d:1-((4-(氯甲基)苯氧基)甲基)-3-氟苯与L-丙氨酰胺盐酸盐在室温下,以N,N-二甲基甲酰胺作溶剂,三乙胺作缚酸剂反应得到沙芬酰胺游离碱;
步骤e:沙芬酰胺游离碱在室温条件下,以乙酸乙酯作溶剂,与甲磺酸反应制得甲磺酸沙芬酰胺。
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