嘧啶环药物合成路线汇总

嘧啶环是一种常见的杂环结构，在一些重要的生物活性分子结构中（如核糖核苷酸）都包含有嘧啶环结构单元，而且嘧啶环可以通过成熟的缩合反应很容易的制备。

拉米夫定（Lamivudine），是一种抗病毒药物，属于核苷类似物，对病毒DNA链的合成和延长有竞争性抑制作用。

The oxathiolane ring in lamivudine for instance can be prepared via an acetal exchange reaction between glyoxilic acid monohydrate and 1,4-dithiane-2,5-diol.

Subsequent acetylation of the hydroxy group followed by ester formation using (−)-L-menthol permits crystallisation separation of the two diastereoisomers.

The use of bis-TBDMS-cytosine as a coupling partner in the presence of trimethylsilyl iodide together with oxathiolane 3.15 produces lamivudine  after reduction of the menthyl ester.

雷特格韦(Raltegravir)，是艾滋病抗病毒药物中第一个整合酶抑制剂,于2007年获得美国FDA批准上市,2008年在欧洲获批上市,用于治疗2岁及以上HIV感染者的抗病毒治疗。

The central pyrimidone core was accessed in a linear fashion starting by amination of acetone cyanohydrin (3.19) followed by CBz-protection of the resulting amine and finally aminolysis of the nitrile 3.20 with hydroxylamine.

The resulting amidoxime 3.21 was then reacted with dimethylacetylene dicarboxylate (DMAD) which upon heating in xylenes undergoes ring-closure yielding the desired pyrimidine 3.22 but unfortunately only in modest yield.

However, this key intermediate could be readily N-methylated, and in a simple extension to the sequence subjected to direct amide formation, debenzylation and finally coupled with the corresponding acid chloride of oxadiazole derivative 3.23.

This particular oxadiazole 3.23 was prepared via a clever sequence involving acylation of methyl tetrazole (3.24) with ethyl oxalylchloride (3.25) to form intermediate 3.26 which when heated extrudes nitrogen gas and subsequently collapses to the desired oxadiazole 3.23, all progressing in high yield.

伊马替尼（Imatinib），由Novartis研发，首先于2001年5月10日获美国食品药品管理局（FDA）批准上市，之后于2001年11月7日获欧洲药物管理局（EMA)批准上市，用于治疗各期慢性髓细胞白血病(CML),也用于治疗CD117阳性的胃肠道间质细胞瘤(GIST)。

In a patented route the aldol product 3.47 undergoes a condensation reaction with guanidine 3.48 in basic media to give the 2-aminopyrimidine 3.49.

After generating the functional pyrimidine core a hydrazine-mediated reduction of the nitro group in the side chain was conducted with Raney-Nickel as the catalyst. Amide formation with 4-chloromethylbenzoyl chloride (3.50) and a direct displacement of the benzylic chloride with N-methylpiperazine complete this synthesis of imatinib in excellent overall yields.

埃罗替尼(Erlotinib)，是继伊马替尼之后另一个用于NSCLC治疗的酪氨酸激酶抑制剂，美国食品与药品管理局(FDA)已批准埃罗替尼(Tarceva)联合吉西他滨作为局部晚期和转移性胰腺癌的一线治疗。

The structure feature of this compound is the trisubstituted quinazoline core bearing an aniline moiety and two polyether appendages. A representative route to 3.37 enlists ethyl 3,4-dihydroxybenzoate (3.59) which after double etherification and incorporation of an amine was then subjected to a condensation reaction with formamide (3.60) at elevated temperature.

Chlorination of the resulting quinazolinone 3.61 with phosphorous oxychloride in the presence of N,N-dimethylaniline ultimately generates the starting material for the final SNAr reaction with 3-aminophenylacetylene (3.62) and completes the optimised synthesis of 3.37.

拉帕替尼(lapatinib)，是由英国葛兰素史克公司研发的乳腺癌靶向治疗新药，是一种酪氨酸激酶抑制剂，能有效抑制人类表皮生长因子受体-1（ErbB1）和人类表皮生长因子受体-2（ErbB2）酪氨酸激酶活性。

It consists of a 2,5-disubstituted furan ring, which is directly linked to the aminoquinazoline unit. The quinazoline heterocycle was prepared starting from 5-iodoanthranilic acid (3.72) via initial condensation with formamidine acetate (3.73) followed by chlorination using oxalyl chloride or phosphorous oxychloride.

Performing a nucleophilic aromatic substitution on the chloride 3.74 with aniline 3.75 renders the extended core of lapatinib. This intermediate (3.76) was then coupled with 5-formyl-2-furanoboronic acid (3.77) using standard Suzuki cross-coupling conditions. Finally, a reductive amination of the pendant aldehyde of 3.78 with 2-(methylsulfonyl) ethylamine (3.79) furnishes the desired product lapatinib.

瑞舒伐他汀(Rosuvastatin)，一种选择性HMG-CoA还原酶抑制剂，是一种他汀类药物，与运动、饮食控制和减肥联合来治疗高胆固醇血症和其他相关症状，也用来预防心血管疾病。

A classical cyclocondensation strategy converting 4-fluorobenzaldehyde(1.46) and an α-ketoester 3.81 to the desired pyrimidine system 3.82 utilising S-methylisothiourea hemisulfate(3.83) with a DDQ-mediated dehydrogenation.

Oxidation of the thioether 3.82 followed by nucleophilic aromatic substitution and subsequent mesylation installs the sulfonamide moiety 3.83, after which the ester on the pyrimidine was converted to the required aldehyde functionality 3.84, then allowing for the introduction of the side chain 3.85 via a Horner–Wadsworth–Emmons olefination.

The newly furnished advanced intermediate 3.86 was next desilylated and subjected to a Narasaka reduction yielding rosuvastatin after saponification and formation of the calcium salt.

（内容摘自：Beilstein J. Org. Chem. 2013, 9, 2265–2319.）

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