CN117597130A - 一种合成甲基利比里亚碱及其多晶体的高效工艺 - Google Patents
一种合成甲基利比里亚碱及其多晶体的高效工艺 Download PDFInfo
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- ZVQXCXPGLSBNCX-UHFFFAOYSA-N methylliberine Chemical group O=C1N(C)C(OC)=NC2=C1N(C)C(=O)N2C ZVQXCXPGLSBNCX-UHFFFAOYSA-N 0.000 description 5
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- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
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- FPJBSRSPRSFLBR-UHFFFAOYSA-N 1-methoxy-7,9-dihydro-3H-purine-2,6,8-trione Chemical compound CON1C(=O)NC=2NC(=O)NC=2C1=O FPJBSRSPRSFLBR-UHFFFAOYSA-N 0.000 description 1
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- RMAHPRNLQIRHIJ-UHFFFAOYSA-N methyl carbamimidate Chemical compound COC(N)=N RMAHPRNLQIRHIJ-UHFFFAOYSA-N 0.000 description 1
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
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- 229930002161 purine alkaloid Natural products 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种简单高效地制备甲基利比里亚碱及其多晶体的合成工艺。
Description
发明领域
本发明涉及一种以简单高效的方式制备甲基利比里亚碱及其多晶体的合成工艺。
发明背景
甲基利比里亚碱(Methylliberine)是一种甲氧基尿酸,也是一种咖啡因代谢物,在各种咖啡植物中含量较低。在化学上,甲基利比里亚碱是2-甲氧基-1,7,9-三甲基-7,9-二氢-1H-嘌呤-6,8-二酮,具有如下结构;
近年来的研究发现,由于在结构上与甲基黄嘌呤相似,咖啡因和甲基利比里亚碱具有相似的生理特性,但没有不良的刺激作用。有关该分子的现有毒理学资料表明,甲基利比里亚碱不会造成任何遗传毒性和可能的健康危害,因此人们对甲基利比里亚碱作为功能食品和膳食补充剂的成分一直很感兴趣。
这种嘌呤生物碱在咖啡植物中的含量很低,提取过程也很繁琐。从文献报道中可以看出,将咖啡因等天然原料生物转化为甲基利比里亚碱化合物的成本高、效率低,且由于原子经济性差,很难实现商业化。本发明可提供相对较高产率的甲基利比里亚碱,且工艺成本相对低廉。关于甲基利比里亚碱纤维素(5)的化学合成,目前基本上很少技术报道。仅在《植物化学》1975,14,747-750中报道了O(2)-甲基尿酸甲基化的方法,没有工业价值。
张、简、廖和齐林等人在《发明专利申请;108912121》中提出的合成方法是:6-氨基-2-甲氧基嘧啶-4(3H)-酮经甲基化、亚硝基化、还原、环化和甲基化后得到所需的甲基利比里亚碱。这种方法采用7步合成法,需要使用有毒的硫化铵和有毒金属来还原亚硝基化合物。该方法的主要缺点是甲基化分两个阶段进行。
因此,本发明者认为,为了填补工业规模生产甲基利比里亚碱方面的空白,可以通过成本效益高、原子经济性好的无危险化学合成方法来生产甲基利比里亚碱(5)。
发明概述
为实现上述目标,本发明提供了一种通过中间体(4)高效合成甲基利比里亚碱的工艺,包括;(a)将溶于甲酸中的6-氨基-2-甲氧基-5-亚硝基嘧啶-4-(3H)-酮(3)与乙二酸反应生成中间体(3a),中间体(3a)随后转化为中间体(3b),中间体(3b)随后羟化并同时脱羧,生成2-甲氧基-1H-嘌呤-6,8-(7H,9H)-二酮(4);以及
(b)在碱存在下将中间体(4)甲基化,得到甲基利比里亚碱(5)。
一方面,中间体(3)由脲获得,其工艺包括
(a)将脲(1)转化为O-甲基异脲半硫酸盐(1a),然后与氰乙酸乙酯原位环化,得到6-氨基-2-甲氧基嘧啶-4(3H)-酮(2);以及
(b)将6-氨基-2-甲氧基嘧啶-4(3H)-酮(2)进行亚硝基化,得到6-氨基-2-甲氧基-5-亚硝基嘧啶-4(3H)-酮(3)。
另一方面,本发明制备甲基利比里亚碱(5)的工艺包括以下步骤;
(a)将脲(1)转化为O-甲基异脲半硫酸盐(1a),然后与氰乙酸乙酯原位环化,得到6-氨基-2-甲氧基嘧啶-4(3H)-酮(2);
(b)将6-氨基-2-甲氧基嘧啶-4(3H)-酮(2)进行亚硝基化,得到6-氨基-2-甲氧基-5-亚硝基嘧啶-4(3H)-酮(3)
(c)将溶于甲酸中的6-氨基-2-甲氧基-5-亚硝基嘧啶-4(3H)-酮(3)与乙二醇酸反应生成中间体(3a),中间体(3a)转化为中间体(3b),随后中间体(3b)发生羟基化反应并同时发生脱羧反应,得到2-甲氧基-1H-嘌呤-6,8(7H,9H)-二酮(4);以及
(d)在碱存在的情况下,将中间体(4)甲基化,得到甲基利比里亚碱(5)。
一方面,本发明公开了分子式(2)的6-氨基-2-甲氧基-4(3H)-酮化合物、
另一方面,本发明公开了分子式(3)的新型中间体6-氨基-2-甲氧基-5-亚硝基嘧啶-4(3H)-酮。
在另一个实施方案中,本发明公开了分子式(4)的新型中间体。
一方面,本发明提供了一种制备甲基利比里亚碱(5)多晶体的工艺,该工艺包括将制备的甲基利比里亚碱(5)从选自低级醇(如乙醇、甲醇、异丙醇、丙醇、正丁醇、叔丁醇)的合适溶剂中结晶;卤代烃,如二氯甲烷、二氯乙烷;酮类,如丙酮、甲乙酮;醚类,如二乙基醚、四氢呋喃;烃类,如己烷、庚烷、甲苯、二甲苯;以及类似的单独溶剂或其混合物。
本发明的详细说明
现将参照本发明的各种优选和可选实施方案对本发明进行详细解释,但这些实施方案不应被解释为限制本发明的范围。
在一个实施方案中,本发明涉及一种通过中间体(4)高效制备甲基利比里亚碱(5)的工艺,该工艺包括
(a)将溶于甲酸的6-氨基-2-甲氧基-5-亚硝基嘧啶-4(3H)-酮(3)与乙二酸反应生成中间体(3a),中间体(3a)转化为中间体(3b),随后中间体(3b)羟化并同时脱羧生成2-甲氧基-1H-嘌呤-6,8-(7H,9H)-二酮(4);以及
(b)在碱存在下,将中间体(4)甲基化,得到甲基利比里亚碱(5)。
在一个实施方案中,中间体(3)由脲通过以下工艺获得;
(a)将脲(1)与硫酸二甲酯和硫酸反应,得到O-甲基异脲半硫酸盐(1a),然后与氰乙酸乙酯原位环化,得到6-氨基-2-甲氧基嘧啶-4(3H)-酮(2);和
(b)硝化6-氨基-2-甲氧基嘧啶-4(3H)-酮(2),得到6-氨基-2-甲氧基-5-亚硝基嘧啶-4(3H)-酮(3)。
在一个实施方案中,高效制备甲基利比里亚碱(5)的工艺包括以下步骤;
(a)将脲(1)与硫酸二甲酯和硫酸反应,得到O-甲基异脲半硫酸盐(1a),然后与氰乙酸乙酯原位环化,得到6-氨基-2-甲氧基嘧啶-4(3H)-酮(2);
(b)亚硝化6-氨基-2-甲氧基嘧啶-4(3H)-酮2,得到6-氨基-2-甲氧基-5-亚硝基嘧啶-4-(3H)-酮(3)
(c)将溶于甲酸中的6-氨基-2-甲氧基-5-亚硝基嘧啶-4(3H)-酮(3)与乙二醇酸反应生成中间体(3a),中间体(3a)转化为中间体(3b),随后中间体(3b)发生羟基化反应并同时发生脱羧反应,得到2-甲氧基-1H-嘌呤-6,8(7H,9H)-二酮(4);以及
(d)在碱存在的情况下,将中间体(4)甲基化,得到甲基利比里亚碱(5)。
具体流程如下图:
因此,工艺步骤1包括硫酸二甲酯和脲在50%硫酸存在的情况下,于约70℃反应,生成O-甲基异脲(1a),在甲醇钠存在的情况下与氰乙酸乙酯原位环化后得到6-氨基-2-甲氧基嘧啶-4-(3H)-酮(2)。
工艺步骤2包括使用亚硝酸钠和50%的乙酸对6-氨基-2-甲氧基嘧啶-4-(3H)-酮(2)进行亚硝基化,得到6-氨基-2-甲氧基-5-亚硝基嘧啶-4(3H)-酮(3)。
本发明的工艺步骤3包括向6-氨基-2-甲氧基-5-亚硝基嘧啶-4-(3H)-酮(3)在甲酸中的搅拌溶液中加入乙醛酸,并将混合物加热至约50℃约一小时。将混合物冷却至0℃,过滤并洗涤沉淀的固体,得到二酮中间体(4)。
本工艺的步骤4包括向二酮中间体(4)中加入硫酸二甲酯和甲醇中的NaOH溶液,得到甲基利比里亚碱(5)。
步骤4的甲基化试剂选自硫酸二甲酯或碳酸二甲酯或N,N-二甲基甲酰胺-二甲基乙缩醛(DMF-DMA)、磷酸三甲酯或任何此类合适的甲基化剂。碱选自碱金属或碱金属氢氧化物、碳酸盐或碳酸氢盐,碱金属或碱金属甲氧基化物,如甲醇钠、乙醇钠、叔丁醇钠、叔丁醇钾,或二乙胺、三乙胺、二异丙基乙胺或吡啶或1,8-二氮杂双环[5.4.0]十一-7-烯(DBU)或1,5-二氮杂双环[4.3.0]壬-5-酮。
本工艺的溶剂选自极性或非极性、质子或非质子有机溶剂,如DMF、DMA、酮、醚、酯、低脂或芳香烃、单独的低级醇或它们的混合物。
本发明提供了一种高效的甲基利比里亚碱(5)合成工艺,避免有毒化学品和溶剂,并以良好的原子经济性和高纯度形成中间体和最终产品。
在另一个实施方案中,本发明公开了式(2)的化合物6-氨基-2-甲氧基-4(3H)-酮。
在另一个实施方案中,本发明公开了分子式(3)的化合物6-氨基-2-甲氧基-5-亚硝基嘧啶-4(3H)-酮。
在另一个实施方案中,本发明公开了分子式(4)的化合物。
在另一个实施方案中,本发明公开了一种制备甲基利比里亚碱(5)多晶体的工艺,该工艺包括将制备的甲基利比里亚碱(5)从一种合适的溶剂中结晶,该溶剂选自水、低级醇,如乙醇、甲醇、异丙醇、丙醇、正丁醇、叔丁醇;卤代烃,如二氯甲烷、二氯乙烷;酮类,如丙酮、甲乙酮;醚类,如二乙醚、四氢呋喃;烃类,如二氯甲烷、二氯乙烷;酮类,如丙酮、甲乙酮;卤代烃,如二氯甲烷、二氯乙烷;酮类,如丙酮、甲乙酮;醚类,如二乙基醚、四氢呋喃;烃类,如己烷、庚烷、甲苯、二甲苯;以及类似的单独溶剂或其混合物。
实验:
例1:制备6-氨基-2-甲氧基嘧啶-4(3H)-酮(2)
在装有机械搅拌器、加热浴、回流冷凝器和干燥管的20升三颈烧瓶中,加入硫酸二甲酯(700克,5.55摩尔)和50%硫酸水溶液(7克,0.071摩尔)的混合物,然后在70℃下分批加入尿素(333.3克,5.55摩尔)。反应混合物在相同温度下继续搅拌1小时。然后将反应混合物冷却至60℃,接着加入尿素(333.3克,5.55摩尔),并在70℃下滴加硫酸二甲酯(700克,5.55摩尔)。将反应混合物冷却至室温,然后加入甲醇(12升)和甲醇钠(1.65千克,30.73摩尔)。反应混合物在室温下搅拌10分钟,然后加入氰乙酸乙酯(1.73千克,15.37摩尔)。反应混合物在80℃搅拌3小时后冷却至室温。过滤反应混合物,蒸发挥发物至干燥状态。将得到的残留物溶于水,缓慢加入醋酸进行酸化,直到溶液呈酸性(pH~6)。过滤析出的固体,用水洗涤,在40-45℃真空条件下干燥,得到6-氨基-2-甲氧基嘧啶-4(3H)-酮(2),为米白色固体。产出:800克,(34%);熔点202-204℃;1HNMR(400MHz,DMSO-d6):δ3.78(3H,s),4.72(1H,s),6.39(2H,bs),11.12(1H,bs)。13C NMR(400MHz,DMSO-d6):δ54.1,79.3,158.2,164.2。MS(m/z):141.97(M+H)+,IR:vKBr:3326、3249、1651、1620、1343和1162cm-1。
例2:制备6-氨基-2-甲氧基-5-亚硝基嘧啶-4(3H)-酮(3)
向例1中得到的6-氨基-2-甲氧基嘧啶-4(3H)-酮(2)(970克,6.87摩尔)在水(9.7升)中的搅拌溶液中加入亚硝酸钠(570克,8.25摩尔),然后缓慢加入乙酸(1.9升)。反应混合物在50℃下搅拌2小时。将反应混合物冷却至室温,过滤析出的固体并用冷水洗涤,得到6-氨基-2-甲氧基-5-亚硝基嘧啶-4-(3H)-酮(3),呈亮紫色固体。产出:830克(71%)。1HNMR(400MHz,DMSO-d6):δ3.84(3H,s),11.65(1H,bs).13C NMR(400MHz,DMSO-d6):δ53.8,144.1,154.1,169.2,173.8.MS(m/z):171.04(M-H).IR:vKBr:3489,3478,1681,1617,1505,1303and 1118cm-1.
例3:制备2-甲氧基-1H-嘌呤-6,8(7H,9H)-二酮(4)
向例2中得到的6-氨基-2-甲氧基-5-亚硝基嘧啶-4(3H)-酮(3)(670.0克,3.95摩尔)在水(3.35升)中的搅拌溶液中加入甲酸(640克,11.8摩尔),然后在50-55℃下滴加50%乙醛酸(583克,7.88摩尔)。过滤收集沉淀并用冷水洗涤,得到2-甲氧基-1H-嘌呤-6,8(7H,9H)-二酮(4),为类白色固体。产量:520克(73%)。1HNMR(400MHz,DMSO-d6):δ3.85(3H,s),10.63(1H,s),11.27(1H,s),12.18(1H,bs).13C NMR(400MHz,DMSO-d6):δ54.9,102.8,145.5,151.4,153.0,155.2.MS(m/z):180.95(M-H).IR:vKBr:3457,3471,2346,1711,1665,and 1155cm-1.
例4:制备2-甲氧基-1,7,9-三甲基-7,9-二氢-1H-嘌呤-6,8-二酮(甲基利比里亚碱5)。
向实例3中得到的中间体(4)(510.0克,2.80摩尔)在MeOH(5升)中的搅拌溶液中加入30%aq.NaOH溶液(672.0克,16.8摩尔),然后加入硫酸二甲酯(1.5升,16.8摩尔)。反应混合物在50℃下搅拌4小时。4小时后,将反应混合物冷却至室温,加入水并用DCM(3x 1000mL)萃取。合并的有机层在Na2SO4上干燥,真空浓缩。将粗品溶于MeOH(5体积),回流加热2小时,然后在40℃下冷却,过滤形成的固体,用热MeOH(1体积,40℃)洗涤,得到白色固体甲基利比里亚碱(5)。产量:350克(56%)。1HNMR谱(400MHz,DMSO-d6,δ,ppm,J/Hz):3.21(3H,s),3.30(3H,s),3.40(3H,s),4.01(3H,s).13C NMR(400MHz,DMSO-d6)δ25.8,27.4,28.2,56.0,101.5,142.8,151.2,152.0,154.5.MS(m/z):225.22(M+H)+.IR:vKBr:2102,1717,1693,1554,1519and 1063cm-1.
例5:制备2-甲氧基-1,7,9-三甲基-7,9-二氢-1H-嘌呤-6,8-二酮(甲基利比里亚碱5)。向例3中得到的中间体(4)(600克,3.3摩尔)在丙酮(500毫升)中的搅拌溶液中加入碳酸钾(1637克,11.86摩尔),然后加入硫酸二甲酯(1.5千克,11.86摩尔)。滤液中的挥发物在真空中去除。将粗品溶解在MeOH(5体积)中,在回流条件下加热2小时,然后在40℃下冷却,过滤形成的固体并用热MeOH(1体积,40℃)洗涤,得到甲基利比里亚碱(5)。产出:360克(49%)1HNMR谱(400MHz,DMSO-d6,δ,ppm,J/Hz):3.21(3H,s),3.30(3H,s),3.40(3H,s),4.01(3H,s).13C NMR(DMSO-d6,400MHz)δ25.8,27.4,28.2,56.0,101.5,142.8,151.2,152.0,154.5.MS(m/z):225.22(M+H)+.IR:vKBr2102,1717,1693,1554,1519and 1063cm-.
例6:制备2-甲氧基-1,7,9-三甲基-7,9-二氢-1H-嘌呤-6,8-二酮(甲基利比里亚碱5)。
向例3中得到的中间体4(500毫克,2.75毫摩尔)中加入DMF-DMA(1.64毫升,12.38毫摩尔)。将反应混合物冷却至室温并加入石油醚(5毫升)。过滤形成的固体,用石油醚洗涤。将标题化合物在真空中干燥,得到粗化合物,在MeOH中结晶,得到甲基利比里亚碱(5)。产出:200毫克(33%)。1HNMR谱(400MHz,DMSO-d6,δ,ppm,J/Hz):3.21(3H,s),3.30(3H,s),3.40(3H,s),4.01(3H,s).13C NMR(400MHz,DMSO-d6)δ25.8,27.4,28.2,56.0,101.5,142.8,151.2,152.0,154.5.MS(m/z):225.22(M+H)+.IR:vKBr2102,1717,1693,1554,1519and1063cm-1.
例7:制备2-甲氧基-1,7,9-三甲基-7,9-二氢-1H-嘌呤-6,8-二酮(甲基利比里亚碱5)。
向例3中得到的中间体4(0.5克,2.75毫摩尔)在磷酸三甲酯(3.85克,27.5毫摩尔)中的搅拌溶液中加入碳酸钾(1.14克,8.25毫摩尔)。5小时后,将反应混合物冷却至室温,加水并用DCM(3x25毫升)萃取。合并的有机层在Na2SO4上干燥,真空浓缩。将粗品溶于MeOH(5体积),回流加热2小时,然后在40℃下冷却。过滤形成的固体,用热(40℃)MeOH(1体积)洗涤,得到白色固体甲基利比里亚碱(5)。产量:220毫克(36%)。1HNMR谱(400MHz,DMSO-d6,δ,ppm,J/Hz):3.21(3H,s),3.30(3H,s),3.40(3H,s),4.01(3H,s).13C NMR(400MHz,DMSO-d6)δ:25.8,27.4,28.2,56.0,101.5,142.8,151.2,152.0,154.5.MS(m/z):225.22(M+H)+.IR:vKBr2102,1717,1693,1554,1519and 1063cm-1.
例8:制备甲基利比里亚碱多晶体的一般程序
(i)在60摄氏度的温度下,将甲基利比里亚碱(3.0克)溶于50毫升甲醇中,过滤,滤液在室温下放置过夜。将形成的晶体过滤并真空干燥,得到甲基利比里亚碱多晶体。PXRD:2θ(%相对强度):9.31(0.2);10.34(42.5);10.70(1.0);11.21(100);12.1(10.0);15.09(0.3);16.19(1.2);18.57(1.1);19.86(0.4);20.79(13.3);21.08(1.0);22.54(1.7);24.4(1.2);25.7(4.6);26.92(16.2);27.68(4.9);28.83(0.4);30.10(0.1);31.43(0.6);34.12(0.6);36.69(0.3);38.27(0.5);39.45(0.7);40.87(0.6);42.33(0.3);43.11(0.3);45.57(0.3).
(ii)在60摄氏度的温度下,将甲基利比里亚碱(3.0克)溶于50毫升乙醇中,过滤,滤液在室温下放置过夜,过滤并在真空下干燥,得到甲基利比里亚碱多晶体。PXRD:2θ(%相对强度):9.29(0.1);10.32(21.3);10.72(1.0);11.19(100);12.19(7.6);14.15(0.1);16.18(1.3);18.63(1.3);19.25(0.2);19.84(0.4);20.77(6.8);21.03(1.1);21.61(0.4);22.52(1.6);23.60(0.4);24.41(1.3);25.71(4.3);26.91(13.2);27.70(4.7);28.62(0.6);28.97(0.2);30.66(0.5);31.33(0.4);31.63(0.7);34.09(0.3);35.97(0.2);36.75(0.3);37.63(0.5);39.41(0.6);40.11(0.5);40.83(0.5);42.27(0.3);43.11(0.4);45.48(0.4);47.66(0.2).
(iii)在60摄氏度的温度下,将甲基利比里亚碱(3.0克)溶于60毫升乙酸乙酯中,过滤,滤液在室温下放置过夜,过滤并真空干燥,得到甲基利比里亚碱多晶体。PXRD:2θ(%相对强度):10.23(22.2);10.70(0.9);11.17(100);12.17(8.1);15.07(0.7);16.17(0.4);18.52(0.3);20.61(6.9);20.82(5.0);22.51(1.7);24.07(0.5);24.37(0.5);25.70(1.3);26.35(0.3);26.90(4.4);27.69(1.5);31.65(0.4);34.04(0.2);39.42(0.4);40.17(0.2);43.08(0.2);45.39(0.1).
(iv)在60摄氏度的温度下,将甲基利比里亚碱(3.0克)溶于30毫升二氯甲烷(DCM)中,过滤,滤液在室温下放置过夜,过滤并真空干燥,得到甲基利比里亚碱多晶体。PXRD:2θ(%相对强度):10.35(27.7);10.72(0.9);11.19(100);12.1 7(21.8);15.09(1.9);16.17(0.8);16.96(0.2);18.58(0.7);19.85(0.2);20.62(6.9);22.53(1.6);24.12(3.4);24.72(1.5);25.70(2.6);26.35(2.9);26.89(10.5);27.70(2.9);28.16(0.4);28.79(0.8);30.64(0.3);31.42(0.6);31.69(0.6);34.11(0.4);39.42(0.5);40.20(0.3);43.09(0.3).
(v)在60摄氏度的温度下将甲基利比里亚碱(3.0克)溶解于80毫升丙酮中,在60摄氏度的温度下过滤,滤液在室温下放置过夜,过滤并在真空下干燥,得到甲基利比里亚碱多晶体。PXRD:2θ(%相对强度):9.25(0.6);10.25(100);12.19(32.5);15.09(3.2);17.00(0.3);20.64(35.6);22.19(0.3);24.13(2.9);24.72(1.9);26.37(3.8);26.65(1.2);27.15(3.7);28.17(0.3);28.84(0.6);29.95(0.2);31.64(0.3);33.11(0.5);33.58(0.5);35.07(0.7);40.04(0.2);42.07(0.3);43.39(0.5);46.67(0.1);47.97(0.1);48.91(0.3).
尽管上文已详细描述了本发明,以作说明,但应理解的是,这种详细描述仅仅是为了说明本发明,本领域技术人员可以在不脱离本发明的精神和范围的情况下对本发明进行修改,但权利要求所限定的内容除外。
Claims (10)
1.一种通过中间体(4)高效制备甲基利比里亚碱(5)的工艺,包括
(a)将溶于甲酸的6-氨基-2-甲氧基-5-亚硝基嘧啶-4-(3H)-酮(3)与乙二酸反应生成中间体(3a),中间体(3a)转化为中间体(3b),随后中间体(3b)羟化并同时脱羧生成2-甲氧基-1H-嘌呤-6,8-(7H,9H)-二酮(4);以及
(b)在碱存在的情况下,将中间体(4)甲基化,得到甲基利比里亚碱(5)。
2.如权利要求1所述的工艺,其中中间体6-氨基-2-甲氧基-5-亚硝基嘧啶-4-(3H)-酮(3)由以下工艺制备;
(a)将脲(1)与硫酸二甲酯和硫酸反应,得到O-甲基异脲半硫酸盐(1a),然后与氰乙酸乙酯原位环化,得到6-氨基-2-甲氧基嘧啶-4-(3H)-酮(2);和
(b)将6-氨基-2-甲氧基嘧啶-4-(3H)-酮(2)进行亚硝基化,得到6-氨基-2-甲氧基-5-亚硝基嘧啶-4-(3H)-酮(3)。
3.根据权利要求1和2所述的高效制备甲基利比里亚碱(5)的工艺,包括
(a)将脲(1)与硫酸二甲酯和硫酸反应,得到O-甲基异脲半硫酸盐(1a),然后与氰乙酸乙酯原位环化,得到6-氨基-2-甲氧基嘧啶-4-(3H)-酮2;
(b)亚硝化6-氨基-2-甲氧基嘧啶-4(3H)-酮2,得到6-氨基-2-甲氧基-5-亚硝基嘧啶-4-(3H)-酮3;
(c)将溶于甲酸中的6-氨基-2-甲氧基-5-亚硝基嘧啶-4-(3H)-酮(3)与乙二醇酸反应生成中间体(3a),中间体(3a)转化为中间体(3b),随后中间体(3b)发生羟基化反应并同时发生脱羧反应,得到2-甲氧基-1H-嘌呤-6,8(7H,9H)-二酮(4);以及
(d)在碱存在的情况下,将中间体(4)甲基化,得到甲基利比里亚碱(5)。
4.如权利要求1至3中任一项所述的工艺,其中甲基化剂选自硫酸二甲酯、碳酸二甲酯、N,N-二甲基甲酰胺-二甲基乙缩醛(DMF-DMA)或磷酸三甲酯单独或它们的混合物;碱选自碱金属或碱金属氢氧化物、碳酸盐、碳酸氢盐;碱金属或碱金属甲氧基化物;二乙胺、三乙胺、二异丙基乙胺或吡啶或1,8-二氮杂双环[5.4.0]十一-7-烯(DBU)或1,5-二氮杂双环[4.3.0]壬-5-酮。
5.如权利要求1至3中任一项所述的工艺,其中溶剂选自水、有机溶剂如DMF、DMA、酮、醚、酯、低脂或芳香烃、单独的低级醇或它们的混合物。
6.式(2)的化合物6-氨基-2-甲氧基-4-(3H)-酮。
7.式(3)的6-氨基-2-甲氧基-5-亚硝基嘧啶-4-(3H)-酮化合物。
8.式(4)的化合物2-甲氧基-1H-嘌呤-6,8-(7H,9H)-二酮。
9.一种制备甲基利比里亚碱(5)多晶型物的工艺,包括甲基利比里亚碱(5)从以下溶剂中结晶:水;低级醇,如乙醇、甲醇、丁醇;卤代烃,如二氯甲烷、二氯乙烷;酮类,如丙酮;醚类,如二乙醚、四氢呋喃;烃类,如己烷、庚烷、甲苯、二甲苯;以及类似物质或其混合物。
10.如权利要求9所述的工艺,其中多晶体的特征在于PXRD(相对强度%)峰值在以下位置:
(i)9.31(0.2);10.34(42.5);10.70(1.0);11.21(100);12.1(10.0);15.09(0.3);16.19(1.2);18.57(1.1);19.86(0.4);20.79(13.3);21.08(1.0);22.54(1.7);24.4(1.2);25.7(4.6);26.92(16.2);27.68(4.9);28.83(0.4);30.10(0.1);31.43(0.6);34.12(0.6);36.69(0.3);38.27(0.5);39.45(0.7);40.87(0.6);42.33(0.3);43.11(0.3);45.57(0.3);
(ii)9.29(0.1);10.32(21.3);10.72(1.0);11.19(100);12.19(7.6);14.15(0.1);16.18(1.3);18.63(1.3);19.25(0.2);19.84(0.4);20.77(6.8);21.03(1.1);21.61(0.4);22.52(1.6);23.60(0.4);24.41(1.3);25.71(4.3);26.91(13.2);27.70(4.7);28.62(0.6);28.97(0.2);30.66(0.5);31.33(0.4);31.63(0.7);34.09(0.3);35.97(0.2);36.75(0.3);37.63(0.5);39.41(0.6);40.11(0.5);40.83(0.5);42.27(0.3);43.11(0.4);45.48(0.4);47.66(0.2);
(iii)10.23(22.2);10.70(0.9);11.17(100);12.17(8.1);15.07(0.7);16.17(0.4);18.52(0.3);20.61(6.9);20.82(5.0);22.51(1.7);24.07(0.5);24.37(0.5);25.70(1.3);26.35(0.3);26.90(4.4);27.69(1.5);31.65(0.4);34.04(0.2);39.42(0.4);40.17(0.2);43.08(0.2);45.39(0.1);
(iv)10.35(27.7);10.72(0.9);11.19(100);12.17(21.8);15.09(1.9);16.17(0.8);16.96(0.2);18.58(0.7);19.85(0.2);20.62(6.9);22.53(1.6);24.12(3.4);24.72(1.5);25.70(2.6);26.35(2.9);26.89(10.5);27.70(2.9);28.16(0.4);28.79(0.8);30.64(0.3);31.42(0.6);31.69(0.6);34.11(0.4);39.42(0.5);40.20(0.3);43.09(0.3);
(v)9.25(0.6);10.25(100);12.19(32.5);15.09(3.2);17.00(0.3);20.64(35.6);22.19(0.3);24.13(2.9);24.72(1.9);26.37(3.8);26.65(1.2);27.15(3.7);28.17(0.3);28.84(0.6);29.95(0.2);31.64(0.3);33.11(0.5);33.58(0.5);35.07(0.7);40.04(0.2);42.07(0.3);43.39(0.5);46.67(0.1);47.97(0.1);48.91(0.3)。
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