Psychosis in patients with Parkinson’s disease (PD) is a common, at times debilitating, condition and represents a major unmet need in the treatment of PD. Pimavanserin (1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea) is a potent and selective serotonin 5-HT2A receptor inverse agonist without adrenergic, dopaminergic, muscarinic affinity or histaminergic actions approved by the FDA in 2016. It is in development as a treatment for psychosis symptoms, such as delusions and hallucinations, associated with Parkinson’s disease (PDP), which have an impact on up to 50% of these patients during their lifetimes. To date, reports of real-world experience with Pimavanserin have been restricted by small sample sizes or limited scope; however, preliminary evidence shows that Pimavanserin provides antipsychotic benefits and good tolerability to PDP patients. Also, Pimavanserin, a non-dopamine neurotransmitter analog, does not affect dopamine function, and it has no side effects of exacerbation that traditional antipsychotic drugs have caused in PDP patients. This is likely due to its selectivity to the 5-HT2A serotonin receptor. As a result, Pimavanserin has good prospects which make its synthetic process more meaningful. In recent years, several methods for synthesizing Pimavanserin have been reported. 1) The procedure for the preparation of Pimavanserin by Thygesen published in 2006 is illustrated in Scheme 1, which includes O-alkylation followed by an addition-elimination reaction and oxime reduction to give an intermediate which is then reacted with the hazardous phosgene. 2) In 2008, a synthetic route to Pimavanserin was published by Gant (Scheme 2). That method has low process safety and uses the dangerous reagent diphenylphosphoryl azide. In addition, column chromatography in the last step is a disadvantage. 3) In 2015, Balazs published another preparation of Pimavanserin (Scheme 3). In that method, the starting material is expensive and not easy to obtain. This process also uses the toxic reagent methyl chloroformate and the total yield is low. All the above methods have such drawbacks as harsh reaction conditions, hazardous reagents, high cost, low yields, or the necessity of column chromatography for purification. Accordingly, there is a need for finding optimized preparations with low cost and more eco-friendly reagents. In this article, to obviate the drawbacks of the previously reported methods, we introduce a new, safe and efficient procedure leading to

中文翻译：

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Pimavanserin 的新合成：选择性血清素 5-HT2A 受体反向激动剂

帕金森病 (PD) 患者的精神病是一种常见的、有时使人虚弱的病症，并且代表了 PD 治疗中的一个主要未满足的需求。Pimavanserin (1-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1-(1-methylpiperidin-4-yl)urea) 是一种有效的选择性血清素 5-HT2A 受体反向激动剂，没有肾上腺素能、多巴胺能、毒蕈碱亲和力或 FDA 于 2016 年批准的组胺能作用。 它正在开发用于治疗与帕金森病 (PDP) 相关的精神病症状，例如妄想和幻觉，这些症状在其一生中对多达 50% 的患者产生影响. 迄今为止，关于 Pimavanserin 的实际经验报告受到样本量小或范围有限的限制；然而，初步证据表明 Pimavanserin 为 PDP 患者提供抗精神病益处和良好的耐受性。此外，Pimavanserin 是一种非多巴胺神经递质类似物，不影响多巴胺功能，也没有传统抗精神病药物对 PDP 患者造成的恶化副作用。这可能是由于其对 5-HT2A 血清素受体的选择性。因此，匹马万色林具有良好的前景，使其合成过程更有意义。近年来，已经报道了几种合成匹马万色林的方法。1) Thygesen 于 2006 年发表的 Pimavanserin 制备程序如方案 1 所示，包括 O-烷基化，然后进行加成-消除反应和肟还原，得到中间体，然后与危险的光气反应。2) 2008 年，Gant 发表了 Pimavanserin 的合成路线（方案 2）。该方法工艺安全性低，并使用危险试剂二苯基磷酰叠氮化物。此外，最后一步的柱层析也是一个缺点。3) 2015 年，Balazs 发表了 Pimavanserin 的另一种制剂（方案 3）。在该方法中，起始材料昂贵且不易获得。该工艺还使用有毒试剂氯甲酸甲酯，总收率低。上述方法均存在反应条件苛刻、试剂危险、成本高、收率低或需要柱层析纯化等缺点。因此，需要寻找具有低成本和更环保试剂的优化制剂。在本文中，为了消除之前报道的方法的缺点，