CN117285573B - 一种β-烟酰胺单核苷酸金属络合物及其制备方法 - Google Patents
一种β-烟酰胺单核苷酸金属络合物及其制备方法 Download PDFInfo
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- CN117285573B CN117285573B CN202311250044.5A CN202311250044A CN117285573B CN 117285573 B CN117285573 B CN 117285573B CN 202311250044 A CN202311250044 A CN 202311250044A CN 117285573 B CN117285573 B CN 117285573B
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- nicotinamide mononucleotide
- metal
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- -1 Beta-nicotinamide mononucleotide metal complex Chemical class 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 63
- 238000005915 ammonolysis reaction Methods 0.000 claims abstract description 15
- FZAQROFXYZPAKI-UHFFFAOYSA-N anthracene-2-sulfonyl chloride Chemical compound C1=CC=CC2=CC3=CC(S(=O)(=O)Cl)=CC=C3C=C21 FZAQROFXYZPAKI-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000006482 condensation reaction Methods 0.000 claims abstract description 13
- 230000035484 reaction time Effects 0.000 claims abstract description 9
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 claims description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 44
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 239000011618 nicotinamide riboside Substances 0.000 claims description 27
- 239000002777 nucleoside Substances 0.000 claims description 27
- JLEBZPBDRKPWTD-TURQNECASA-O N-ribosylnicotinamide Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=C1 JLEBZPBDRKPWTD-TURQNECASA-O 0.000 claims description 25
- 235000020956 nicotinamide riboside Nutrition 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 25
- 229940064982 ethylnicotinate Drugs 0.000 claims description 24
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 24
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- 238000000034 method Methods 0.000 claims description 18
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 16
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 16
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- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 12
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- IHNHAHWGVLXCCI-FDYHWXHSSA-N [(2r,3r,4r,5s)-3,4,5-triacetyloxyoxolan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O IHNHAHWGVLXCCI-FDYHWXHSSA-N 0.000 claims description 7
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- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims description 6
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 6
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Abstract
本发明公开了一种β‑烟酰胺单核苷酸金属络合物及其制备方法,现有技术中制备β‑烟酰胺单核苷酸,在缩合反应后会进行氨解反应,氨解反应一般需要20‑36h,时间很长,而本发明所述的一种β‑烟酰胺单核苷酸金属络合物制备方法,通过高压反应后,反应时间为0.5‑1.0h,将密闭反应容器中压力瞬间卸除,使反应产物颗粒中的蒸汽瞬间冲出,由于是瞬间卸压,反应的物料在蒸汽的冲击下翻滚,迅速完成反应,大幅减少了氨解反应的时间,整个氨解反应可以控制在0.5‑1h。
Description
技术领域
本发明属于核苷酸制备技术领域,具体涉及一种β-烟酰胺单核苷酸金属络合物及其制备方法。
背景技术
核苷酸是一类由嘌呤碱或嘧啶碱、核糖或脱氧核糖以及磷酸三种物质组成的化合物,又称核甙酸。戊糖与有机碱合成核苷,核苷与磷酸合成核苷酸,8种核苷酸组成核酸。核苷酸主要参与构成核酸,许多单核苷酸也具有多种重要的生物学功能,如与能量代谢有关的三磷酸腺苷(ATP)、脱氢辅酶等。
核甙酸是一类由嘌呤碱基或嘧啶碱基、核糖或脱氧核糖以及磷酸三种物质组成的化合物。五碳糖与有机碱合成核苷,核苷与磷酸合成核苷酸,4种核苷酸组成核酸。核苷酸主要参与构成核酸,许多单核苷酸也具有多种重要的生物学功能,如与能量代谢有关的三磷酸腺苷(ATP)、脱氢辅酶等。某些核苷酸的类似物能干扰核苷酸代谢,可作为抗癌药物。根据糖的不同,核苷酸有核糖核苷酸及脱氧核糖核苷酸两类。根据碱基的不同,又有腺嘌呤核苷酸(腺苷酸,AMP)、鸟嘌呤核苷酸(鸟苷酸,GMP)、胞嘧啶核苷酸(胞苷酸,CMP)、尿嘧啶核苷酸(尿苷酸,UMP)、胸腺嘧啶核苷酸(胸苷酸,TMP)及次黄嘌呤核苷酸(肌苷酸,IMP)等。核苷酸中的磷酸又有一分子、两分子及三分子几种形式。此外,核苷酸分子内部还可脱水缩合成为环核苷酸。核苷酸是核糖核酸及脱氧核糖核酸的基本组成单位,是体内合成核酸的前身物。核苷酸随着核酸分布于生物体内各器官、组织、细胞核及细胞质中,并作为核酸的组成成分参与生物的遗传、发育、生长等基本生命活动。生物体内还有相当数量以游离形式存在的核苷酸。三磷酸腺苷在细胞能量代谢中起着主要的作用。体内的能量释放及吸收主要是以产生及消耗三磷酸腺苷来体现的。此外,三磷酸尿苷、三磷酸胞苷及三磷酸鸟苷也是有些物质合成代谢中能量的来源。腺苷酸还是某些辅酶,如辅酶Ⅰ、辅酶Ⅱ及辅酶A等的组成成分。在生物体内,核苷酸可由一些简单的化合物合成。这些合成原料有天门冬氨酸、甘氨酸、谷氨酰胺、一碳单位及CO2等。嘌呤核苷酸在体内分解代谢可产生尿酸,嘧啶核苷酸分解生成CO2、β-丙氨酸及β-氨基异丁酸等。嘌呤核苷酸及嘧啶核苷酸的代谢紊乱可引起临床症状。
核苷酸类化合物也有作为药物用于临床治疗者,例如肿瘤化学治疗中常用的5-氟尿嘧啶及6-巯基嘌呤等。有些核苷酸分子中只有一个磷酸基,所以可称为一磷酸核苷(NMP)。5'-核苷酸的磷酸基还可进一步磷酸化生成二磷酸核苷(NDP)及三磷酸核苷(NTP),其中磷酸之间是以高能键相连。脱氧核苷酸的情况也是如此。体内还有一类环化核苷酸,即单核苷酸中磷酸部分与核糖中第三位和第五位碳原子同时脱水缩合形成一个环状二酯、即3',5'-环化核苷酸,重要的有3',5'-环腺苷酸(cAMP)和3',5'-环鸟苷酸(cGMP)。
β-烟酰胺单核苷酸(NMN)是辅酶NAD+的合成前体,同时NMN也被用于抗衰老研究。日本庆应义别墅大学和美国华盛顿大学合作,正在对β-NMN的抗衰老效果和安全性进行人体临床试验。研究表明,β-烟酰胺单核苷酸(NMN)具有以下作用:1、延缓衰老:恢复衰老细胞的功能,让虚弱的人体器官恢复活力,从而达到延缓衰老的目的;2、提高心血管健康:提高心肌细胞和血管细胞的功能,还能降低心血管系统中血脂水平,所以,能提高心血管功能;3、提高大脑健康:提高脑细胞和其他神经细胞的活力,提高整个神经系统的功能,因此,能提高大脑健康,对老年痴呆症有较好的效果,轻度认知功能障碍和阿尔茨海默症患者的脑线粒体会发生特征性改变,线粒体能量输出也会随着疾病的发展而减少;4、提高脂肪代谢:减少人体对食物中脂类物质的吸收,提高脂肪细胞内脂肪的消耗,达到减肥的目的:5、提高人体对癌细胞的抵抗力:提高人体内各种免疫细胞的功能,增强对癌细胞的抵抗力,对癌症有辅助治疗的作用:6、戒毒作用:大剂量的服用,能解除毒瘾,有较好的戒毒作用;7、美容作用:提高表皮细胞功能,以及人体内其他细胞的功能,能让皮肤保持青春光彩。
现有文献报道的合成β-烟酰胺单核苷酸的方法主要有两种,其中β-烟酰胺核糖是作为β-烟酰胺单核苷酸(NMN)合成的中间体的方式来进行的。第一种方法:以烟酰胺为起始物(参见Bioorganic and Medicinal Chemistry Letters 2002,12,1135–1137);第二种方法:以烟酸乙酯为起始物:(参见Journal of Medicinal Chemistry,2007,50,6458–6461;AngewandteChemie-International Edition,2004,43,4637-4640);这两条路线都存在收率低(低于28%)、反应纯化难、中间体稳定性差、放大难(都需要通过活性炭色谱分离)等问题。
目前研究较多的是β-烟酰胺单核苷酸的合成方法,还缺少对β-烟酰胺单核苷酸金属络合物制备方法的研究。
发明内容
针对现有技术缺少对于β-烟酰胺单核苷酸金属络合物的制备方法的研究,本发明提供一种β-烟酰胺单核苷酸金属络合物及其制备方法,工艺步骤简单,产品纯度高。
本发明的目的通过以下技术方案来实现:
一种β-烟酰胺单核苷酸金属络合物及其制备方法,包括如下步骤:
1)缩合反应:将烟酸乙酯、四乙酰核糖、催化剂和第一溶剂,按照1:(1-2):(1-2):(2-5)的摩尔比,混合后进行缩合反应,反应温度控制在80-100℃,反应时间为0.5-1.0h,得到含有烟酸乙酯三乙酰核苷的溶液;
所述的催化剂,选自三氟甲磺酸三甲基硅脂或三甲基氯硅烷;
所述的第一溶剂,选自二氯甲烷、1,2-二氯乙烷、氯仿或乙腈中的一种;
2)高压反应:将含有烟酸乙酯三乙酰核苷的溶液和氨水混合于密闭容器中,氨水与含有烟酸乙酯三乙酰核苷溶液的重量比为1:(3-10),氨水的质量浓度为25-30%,再加入相当于水质量0.2-0.5%的N-甲基哌嗪,进行高压反应,同时进行氨解反应,高压反应的压力控制在0.2-0.5MPa,反应时间为0.5-1.0h,高压反应完成后,将高压反应的密闭容器瞬间卸压,时间为1-3s,加入含氯化氢的溶液,得到烟酰胺核苷盐酸盐;
所述含氯化氢的溶液中含有乙酸乙酯、二氯甲烷或甲基叔丁基醚,其质量相当于含氯化氢的溶液的5-10%;
3)磷酸化反应:将上步骤得到的烟酰胺核苷盐酸盐、三氯氧磷和第二溶剂按照1:(1-3):(2-5)的摩尔比混合,加入金属原料,进行反应,所述金属与β-烟酸胺单核苷酸的摩尔比为1:(0.5-3),温度为-20℃~5℃,时间为8-16h,反应完毕后,往体系中加碳酸钾至pH值>5.0,搅拌后过滤,滤液加入纯净水,使用甲叔醚萃取分液除杂,将水相再放置-5℃~0℃,搅拌析出无机盐,过滤,液体用离子交换树脂进行纯化,得到β-烟酸胺单核苷酸金属络合物;
所述的第二溶剂,选自乙腈、磷酸三乙酯、磷酸三甲酯或四氢呋喃中的一种;
所述金属原料,选自金属氧化物、金属氯化物、金属硫酸盐中的一种或多种,混合时为任意比例;其中的金属,选自铜、铁、锌、锰中的一种。
本发明中:
步骤1)所述的催化剂,优选三氟甲磺酸;所述的第一溶剂,优选二氯甲烷或氯仿。
步骤2)所述的高压反应,也是氨解反应,是将含有烟酸乙酯三乙酰核苷的溶液经氨气溶液进行氨解反应,得到烟酰胺核苷盐酸盐。
步骤3)所述的第二溶剂,优选乙腈或磷酸三乙酯。
本发明还涉及采用上述一种β-烟酰胺单核苷酸金属络合物制备方法得到的β-烟酰胺单核苷酸金属络合物,纯度≥99.5%,该β-烟酰胺单核苷酸金属络合物可应用于免疫营养、抗病营养、系统动物营养、全方位营养等领域。
与现有技术相比,本发明具有以下优点:
1、现有技术中制备β-烟酰胺单核苷酸,在缩合反应后会进行氨解反应,氨解反应一般需要20-36h,时间很长,而本发明所述的一种β-烟酰胺单核苷酸金属络合物制备方法,通过高压反应后,反应时间为0.5-1.0h,将密闭反应容器中压力瞬间卸除,使反应产物颗粒中的蒸汽瞬间冲出,由于是瞬间卸压,反应的物料在蒸汽的冲击下翻滚,迅速完成反应,大幅减少了氨解反应的时间,整个氨解反应可以控制在0.5-1h。
2、本发明所述的一种β-烟酰胺单核苷酸金属络合物制备方法,通过在高压反应过程中加入N-甲基哌嗪,会随着水形成蒸汽并进入到产物烟酰胺核苷盐酸盐颗粒中,在后续瞬间卸压的过程中,N-甲基哌嗪会进入到烟酰胺核苷盐酸盐颗粒中,利用N-甲基哌嗪具有比较好的分散效果,使烟酰胺核苷盐酸盐颗粒与颗粒之间分开不产生硬团聚,使生成的烟酰胺核苷盐酸盐颗粒变小表面能增大,从而在反应的时候形成团聚颗粒,能迅速沉降,避免形成悬浮状态而不易实现烟酰胺核苷盐酸盐和液相的分离,而且单颗粒烟酰胺核苷盐酸盐也不会形成大颗粒。
附图说明
图1是本发明实施例1制备得到的β-烟酸胺单核苷酸铜的SEM图。
具体实施方式
以下通过实施例进一步详细描述本发明,但这些实施例不应认为是对本发明的限制。
实施例1:
一种β-烟酰胺单核苷酸金属络合物的制备方法,包括如下步骤:
1)缩合反应:将烟酸乙酯、四乙酰核糖、催化剂和第一溶剂,按照1:1:1:2的摩尔比,混合后进行缩合反应,反应温度控制在80℃,反应时间为1.0h,得到含有烟酸乙酯三乙酰核苷的溶液;
所述的催化剂,选自三氟甲磺酸三甲基硅脂;
所述的第一溶剂,选自二氯甲烷;
2)高压反应:将含有烟酸乙酯三乙酰核苷的溶液和氨水混合于密闭容器中,氨水与含有烟酸乙酯三乙酰核苷溶液的重量比为1:3,氨水的质量浓度为30%,再加入相当于水质量0.2%的N-甲基哌嗪,进行高压反应,高压反应的压力控制在0.2MPa,反应时间为1.0h,高压反应完成后,将高压反应的密闭容器瞬间卸压,时间为1-3s,加入含氯化氢的溶液,含氯化氢的溶液中含有相当于含氯化氢溶液质量5%的乙酸乙酯,得到烟酰胺核苷盐酸盐;
3)磷酸化反应:将上步骤得到的烟酰胺核苷盐酸盐、三氯氧磷和第二溶剂按照1:1:2的摩尔比混合,按五水硫酸铜与烟酰胺核苷盐酸盐摩尔比为1:0.3的比例加入五水硫酸铜,进行反应,温度为-20℃,时间为16h,反应完毕后,往体系中加碳酸钾至pH值>5.0,搅拌后过滤,滤液加入纯净水,使用甲叔醚萃取分液除杂,将水相再放置-5℃~0℃,搅拌析出无机盐,过滤,液体用离子交换树脂进行纯化,得到β-烟酸胺单核苷酸络合铜;
所述的第二溶剂,选自乙腈。
结果:
β-烟酸胺单核苷酸收率86.85%,β-烟酸胺单核苷酸铜纯度99.5%。
图1是实施例1制备得到的β-烟酸胺单核苷酸铜的SEM图。
实施例2:
一种β-烟酰胺单核苷酸金属络合物的制备方法,包括如下步骤:
1)缩合反应:将烟酸乙酯、四乙酰核糖、催化剂和第一溶剂,按照1:2:2:5的摩尔比,混合后进行缩合反应,反应温度控制在100℃,反应时间为0.5h,得到含有烟酸乙酯三乙酰核苷的溶液;
所述的催化剂,选自三甲基氯硅烷;
所述的第一溶剂,选自氯仿;
2)高压反应:将含有烟酸乙酯三乙酰核苷的溶液和氨水混合于密闭容器中,氨水与含有烟酸乙酯三乙酰核苷溶液的重量比为1:10,氨水的质量浓度为25%,再加入相当于水质量0.5%的N-甲基哌嗪,进行高压反应,高压反应的压力控制在0.5MPa,反应时间为0.5h,高压反应完成后,将高压反应的密闭容器瞬间卸压,时间为1-3s,加入含氯化氢的溶液,含氯化氢的溶液中含有相当于含氯化氢溶液质量10%的二氯甲烷,得到烟酰胺核苷盐酸盐;
3)磷酸化反应:将上步骤得到的烟酰胺核苷盐酸盐、三氯氧磷和第二溶剂按照1:3:5的摩尔比混合,按氧化锌与烟酰胺核苷盐酸盐摩尔比为1:1的比例加入氧化锌,进行反应,温度为5℃,时间为8h,反应完毕后,往体系中加碳酸钾至pH值>5.0,搅拌后过滤,滤液加入纯净水,使用甲叔醚萃取分液除杂,将水相再放置-5℃~0℃,搅拌析出无机盐,过滤,液体用离子交换树脂进行纯化,得到β-烟酸胺单核苷酸络合锌;
所述的第二溶剂,选自磷酸三乙酯。
结果:
β-烟酸胺单核苷酸收率86.92%,β-烟酸胺单核苷酸锌纯度99.6%。
实施例3:
一种β-烟酰胺单核苷酸金属络合物的制备方法,包括如下步骤:
1)缩合反应:将烟酸乙酯、四乙酰核糖、催化剂和第一溶剂,按照1:1:1:2的摩尔比,混合后进行缩合反应,反应温度控制在80℃,反应时间为1.0h,得到含有烟酸乙酯三乙酰核苷的溶液;
所述的催化剂,选自三氟甲磺酸三甲基硅脂;
所述的第一溶剂,选自二氯甲烷;
2)高压反应:将含有烟酸乙酯三乙酰核苷的溶液和氨水混合于密闭容器中,氨水与含有烟酸乙酯三乙酰核苷溶液的重量比为1:3,氨水的质量浓度为30%,再加入相当于水质量0.2%的N-甲基哌嗪,进行高压反应,高压反应的压力控制在0.2MPa,反应时间为1.0h,高压反应完成后,将高压反应的密闭容器瞬间卸压,时间为1-3s,加入含氯化氢的溶液,含氯化氢的溶液中含有相当于含氯化氢溶液质量8%的甲基叔丁基醚,得到烟酰胺核苷盐酸盐;
3)磷酸化反应:将上步骤得到的烟酰胺核苷盐酸盐、三氯氧磷和第二溶剂按照1:1:2的摩尔比混合,按氯化铁与烟酰胺核苷盐酸盐摩尔比为1:3的比例加入一水硫酸亚铁,进行反应,温度为-20℃,时间为16h,反应完毕后,往体系中加碳酸钾至pH值>5.0,搅拌后过滤,滤液加入纯净水,使用甲叔醚萃取分液除杂,将水相再放置-5℃~0℃,搅拌析出无机盐,过滤,液体用离子交换树脂进行纯化,得到β-烟酸胺单核苷酸络合铁;
所述的第二溶剂,选自磷酸三甲酯。
结果:
β-烟酸胺单核苷酸铁收率87.12%,β-烟酸胺单核苷酸铁纯度99.6%。
对比例1:
一种制备β-烟酸胺单核苷酸的方法,包括以下步骤:
a、缩合(即制备烟酸乙酯三乙酰核苷):
500ml三口瓶中加入四乙酰核糖(50g,0.157mol),100mL二氯甲烷,搅拌溶解,再加入烟酸乙酯(28.5g,0.188mol),搅拌均匀;室温下,滴加用50mL二氯甲烷稀释的三氟甲磺酸三甲基硅酯(TMsOTf 41.8g,0.188mol),滴加过程放热,控制温度在20℃以下,约0.5小时内加完,滴加完毕,接着搅拌反应1小时以完成反应(TLC监控四乙酰核糖消失);反应完成,反应液冷却至-5℃以下,滴加15mL乙醇,加完搅拌15min以破坏TMSOTf淬灭反应,从而终止反应;将反应体系室温减压浓缩干,无需后处理直接用于下一步;
b、氨解脱乙酰基(制备烟酰胺核糖盐酸盐):
在-5℃,向步骤a制得的含有烟酸乙酯三乙酰核苷体系加入5mol/L氨乙酸乙酯溶液300ml,在-5~0℃搅拌反应20小时以完成反应(TLC监控至原料和中间体1消失);反应完成,低温减压浓缩除去溶剂;再加入含氯化氢的甲基叔丁醚溶液,体系变粘稠,析出固体,搅拌30min,过滤,固体再用400ml甲叔醚室温打浆2h,过滤干燥,得到36.5g产品(收率80.0%,纯度98.3%);
c、磷酸化(即制备β-烟酰胺单核苷酸):
称取步骤b所得β-烟酰胺核糖盐酸盐(14.6g,0.05mol),加至250mL三口瓶,再加入磷酸三甲酯50ml,冷却至-5℃以下,滴加三氯氧磷(15.3g,0.10mol),滴加过程放热,控制温度在5℃以下,约30分钟加完;按氧化锌与烟酰胺核苷盐酸盐摩尔比为1:1的比例加入氧化锌。接着在-10~-5℃搅拌反应过夜(20小时,HPLC监控);反应完,往体系中加碳酸钾,条件pH值>5.0;搅拌,并且过滤,滤液加入50ml水,使用甲叔醚萃取分液除杂,将水相再放置-5~0℃,搅拌析出无机盐,过滤,液体用离子交换树脂进行纯化,得到β-烟酰胺单核苷酸14.1g(收率84.40%,纯度99.2%)。
对比例2:
一种β-烟酰胺单核苷酸金属络合物的制备方法,和实施例相比,将步骤2)中的N-甲基哌嗪替换成甘油硬脂酸酯,其他同实施例1。
结果:
β-烟酸胺单核苷酸收率87.22%,β-烟酸胺单核苷酸铜纯度99.1%。
结果分析:
1、通过实施例1-3和对比例1的比较说明:对比例1代表的现有技术中制备β-烟酰胺单核苷酸,在缩合反应后会进行氨解反应,氨解反应一般需要20-36h,时间很长,而本发明实施例1-3的一种β-烟酰胺单核苷酸金属络合物的制备方法,通过高压反应后,反应时间为0.5-1.0h,将密闭反应容器中压力瞬间卸除,使反应产物颗粒中的蒸汽瞬间冲出,由于是瞬间卸压,反应的物料在蒸汽的冲击下翻滚,迅速完成反应,大幅减少了氨解反应的时间,整个氨解反应可以控制在0.5-1h,极大地缩短了整个工序的时间,节约成本。
2、通过实施例1和对比例2的比较说明:通过在高压反应过程中加入甘油硬脂酸酯,会随着水形成蒸汽并进入到产物烟酰胺核苷盐酸盐颗粒中,在后续瞬间卸压的过程中,甘油硬脂酸酯会进入到烟酰胺核苷盐酸盐颗粒中,利用甘油硬脂酸酯在耐热性好、粘度高、耐水解好的特点,具有很强的乳化性能和特殊的稳定性,可以支撑产物烟酰胺核苷盐酸盐颗粒介孔的形成,防止烟酰胺核苷盐酸盐颗粒中孔洞结构坍塌,从而得到多孔烟酰胺核苷盐酸盐颗粒;但是甘油硬脂酸酯和N-甲基哌嗪相比,加入甘油硬脂酸酯,其防止形成团聚颗粒的效果没有N-甲基哌嗪号,会影响最终的β-烟酰胺单核苷酸金属络合物的纯度。
通过实施例和对比例的基本性能的比较,说明实施例的制备方法明显优于对比例。
Claims (3)
1.一种β-烟酰胺单核苷酸金属络合物的制备方法,其特征在于:包括如下步骤:
1)缩合反应:将烟酸乙酯、四乙酰核糖、催化剂和第一溶剂,按照1:(1-2):(1-2):(2-5)的摩尔比,混合后进行缩合反应,反应温度控制在80-100℃,反应时间为0.5-1.0h,得到含有烟酸乙酯三乙酰核苷的溶液;
所述的催化剂,选自三氟甲磺酸三甲基硅脂或三甲基氯硅烷;
所述的第一溶剂,选自二氯甲烷、1,2-二氯乙烷、氯仿或乙腈中的一种;
2)高压反应:将含有烟酸乙酯三乙酰核苷的溶液和氨水混合于密闭容器中,氨水与含有烟酸乙酯三乙酰核苷溶液的重量比为1:(3-10),氨水的质量浓度为25-30%,再加入相当于水质量0.2-0.5%的N-甲基哌嗪,进行高压反应,同时进行氨解反应,高压反应的压力控制在0.2-0.5MPa,反应时间为0.5-1.0h,高压反应完成后,将高压反应的密闭容器瞬间卸压,时间为1-3s,加入含氯化氢的溶液,得到烟酰胺核苷盐酸盐;
所述含氯化氢的溶液中含有乙酸乙酯、二氯甲烷或甲基叔丁基醚,其质量相当于含氯化氢的溶液的5-10%;
3)磷酸化反应:将上步骤得到的烟酰胺核苷盐酸盐、三氯氧磷和第二溶剂按照1:(1-3):(2-5)的摩尔比混合,加入金属原料,进行反应,所述金属与β-烟酸胺单核苷酸的摩尔比为1:(0.5-3),温度为-20℃~5℃,时间为8-16h,反应完毕后,往体系中加碳酸钾至pH值>5.0,搅拌后过滤,滤液加入纯净水,使用甲叔醚萃取分液除杂,将水相再放置-5℃~0℃,搅拌析出无机盐,过滤,液体用离子交换树脂进行纯化,得到β-烟酸胺单核苷酸金属络合物;
所述的第二溶剂,选自乙腈、磷酸三乙酯、磷酸三甲酯或四氢呋喃中的一种;
所述金属原料,选自金属氧化物、金属氯化物、金属硫酸盐中的一种或多种,混合时为任意比例;其中的金属,选自铜、铁、锌、锰中的一种。
2.根据权利要求1所述的一种β-烟酰胺单核苷酸金属络合物的制备方法,其特征在于:步骤1)所述的催化剂,选自三氟甲磺酸三甲基硅脂;所述的第一溶剂,选自二氯甲烷或氯仿。
3.根据权利要求1所述的一种β-烟酰胺单核苷酸金属络合物的制备方法,其特征在于:步骤3)所述的第二溶剂,选自乙腈或磷酸三乙酯。
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WO2022233923A1 (en) * | 2021-05-04 | 2022-11-10 | Bohan & Co As. | A process for synthesis of nicotinamide riboside chloride (nrcl) |
CN113912653A (zh) * | 2021-06-04 | 2022-01-11 | 天津大学 | 一种提高β-烟酰胺单核苷酸结晶粉末松堆密度的方法 |
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