CN114437162A - 一种无定型烟酰胺腺嘌呤二核苷酸的制备方法 - Google Patents
一种无定型烟酰胺腺嘌呤二核苷酸的制备方法 Download PDFInfo
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- BAWFJGJZGIEFAR-NNYOXOHSSA-N NAD zwitterion Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-N 0.000 title claims abstract description 31
- 229950006238 nadide Drugs 0.000 title claims abstract description 31
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 14
- 239000007864 aqueous solution Substances 0.000 claims abstract description 13
- 239000007787 solid Substances 0.000 claims abstract description 11
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 7
- 230000008569 process Effects 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
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- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 description 8
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- 238000001291 vacuum drying Methods 0.000 description 4
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- 238000006479 redox reaction Methods 0.000 description 3
- SRNWOUGRCWSEMX-UHFFFAOYSA-N Adenosine diphosphate ribose Natural products C1=NC=2C(N)=NC=NC=2N1C(C(C1O)O)OC1COP(O)(=O)OP(O)(=O)OCC1OC(O)C(O)C1O SRNWOUGRCWSEMX-UHFFFAOYSA-N 0.000 description 2
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- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 2
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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Abstract
本发明公开了一种无定型烟酰胺腺嘌呤二核苷酸的制备方法,该方法为特定pH和温度下,将烟酰胺腺嘌呤二核苷酸水溶液与低级醇类溶剂按特定流量比瞬时混合,得到的固体即为无定型的烟酰胺腺嘌呤二核苷酸。本发明所述的制备方法工艺简单、产率高、生产周期短、易于实现规模化生产。
Description
技术领域:
本发明属于晶型药物技术领域,具体涉及一种无定型烟酰胺腺嘌呤二核苷酸磷酸的制备方法。
背景技术:
烟酰胺腺嘌呤二核苷酸(简称:辅酶I,英文名:nicotinamide adeninedinucleotide,NAD+)是生物体内不可缺少的小分子化合物,参与氧化还原反应,能量传递,物质代谢和信号传导等过程。
NAD+/NADH是电子载体,在各种酶促氧化还原反应中起着重要作用。目前氧化还原酶中80%以NAD+/NADH为辅酶,依赖于NAD+的脱氢酶至少催化6种不同类型的反应,包括氢转移反应、脱氨基反应、氧化脱羧反应、醛氧化反应、碳-碳键氧化反应、碳-氮键氧化反应。另外,NAD+在医药化工领域各种酶促的氧化还原反应中起着重要的作用,如在酶催化制备手性化合物如手性醇、手性胺、羟基酸、氨基酸等具有极大的优势。除了氧化还原功能外,在细胞的生长、分化、调节和疾病等非氧化还原生命过程中,NAD+同样起到非常重要的作用,如参与衰老相关的组蛋白脱乙酰化反应、DNA修复过程中发挥重要作用的聚腺苷二磷酸核糖反应、调控钙离子通道的腺苷二磷酸核糖环化反应等。由于NAD+的多重作用,因此越来越受到人们的重视。
多晶状态是研究产品存在状态的重要内容,对于多数产品而言,一般都存在多晶现象。多晶型现象会直接影响产品的稳定性、溶解度、生物利用度、安全性、有效性和制剂加工性能等。其中,无定型具有较好的体外溶出和体内吸收性质,并可能达到更好的临床疗效,因此,相关研究愈来愈受到重视。
目前通用的NAD+制备方法是用冻干法得到无定形粉末,该无定形粉末存在稳定性差、易潮解、储存和运输条件要求高(需要冷藏运输和储存)、生产成本高等问题。
专利CN105131065B及专利CN105481923B中均公开了一种NAD+的分离纯化方法,其中都是主要采用树脂柱进行分离和纯化。这在利用树脂柱进行分离和纯化的方法操作繁琐、耗时长且溶剂使用量大,不利于大工业化生产。
专利CN111065644A中公开了一种制备高纯度NAD+的方法,经过多阶段调节pH和温度得到新晶型,纯度99%以上,收率85%以上。操作方法繁琐,需要多次降温和调节pH。
发明内容:
本发明的目的在于针对现有技术的不足,提供一种操作简单易于产业化的无定型的烟酰胺腺嘌呤二核苷酸的制备方法。
本发明采用的技术方案如下:
本发明提供一种制备无定型烟酰胺腺嘌呤二核苷酸的制备方法,具体包括如下步骤:控制pH为3.0~6.0,温度为5~25℃时,将烟酰胺腺嘌呤二核苷酸水溶液与低级醇类溶剂按特定流量比瞬时混合,得到的固体为无定型烟酰胺腺嘌呤二核苷酸。
进一步,用氢氧化钠溶液调节烟酰胺腺嘌呤二核苷酸水溶液至pH为3.0~6.0。
进一步,所述烟酰胺腺嘌呤二核苷酸水溶液的浓度为10%~30%,优选15%。
进一步,所述烟酰胺腺嘌呤二核苷酸水溶液与低级醇类溶剂的流量比为5:95~20:80,优选1:9。
更进一步,所述低级醇类溶剂选自甲醇、乙醇、异丙醇,优选乙醇。
进一步,将烟酰胺腺嘌呤二核苷酸水溶液与低级醇类溶剂混合搅拌的反应温度为5~25℃。
进一步,本发明提供的无定型烟酰胺腺嘌呤二核苷酸,具有图1所示的X射线粉末衍射图谱。
更具体的技术方案为,将烟酰胺腺嘌呤二核苷酸水溶液用5%的氢氧化钠水溶液调节至pH为3.0~6.0后,与低级醇类溶剂按特定流量比瞬时混合流加至反应瓶,5~25℃搅拌,有大量固体析出,抽滤,真空干燥,得到的白色固体即为无定型烟酰胺腺嘌呤二核苷酸。
本发明的有益效果在于,本发明所述的无定型烟酰胺腺嘌呤二核苷酸的制备方法具有工艺简单、产率高、生产周期短、易于实现规模化生产等优点。
附图说明
图1实施例1得到的无定型烟酰胺腺嘌呤二核苷酸X射线粉末衍射图谱
具体实施方式
下面结合具体实施例对本发明的技术内容作进一步的阐述,其目的是为了更好的理解本发明的内容,但本发明的保护范围不限于此。
实施例1
20g烟酰胺腺嘌呤二核苷酸磷酸水溶液(15%)用5%的氢氧化钠水溶液调节pH=3.0后,与180g的乙醇分别同时使用蠕动泵按流量比1:9同时流加至反应瓶中,有大量固体析出,5℃搅拌1小时后,抽滤,25℃下真空干燥20小时,得到2.9g白色固体即为无定型烟酰胺腺嘌呤二核苷酸,X射线粉末衍射图谱见图1。
实施例2
将500g烟酰胺腺嘌呤二核苷酸磷酸水溶液(10%)用5%的氢氧化钠水溶液调节pH=4.5后,与3.0kg异丙醇分别同时使用蠕动泵按流量比1:6同时流加至反应瓶中,有大量固体析出,10℃搅拌1小时后,抽滤,25℃下真空干燥20小时,得到的47g白色固体即为无定型的烟酰胺腺嘌呤二核苷酸。
实施例3
将2kg氧化型烟酰胺腺嘌呤二核苷酸磷酸水溶液(30%)用10%的氢氧化钠水溶液调节pH=6.0后,与18kg甲醇分别同时使用蠕动泵按流量比1:9同时流加至反应瓶中,有大量固体析出,5℃搅拌1小时后,抽滤,25℃下真空干燥20小时,得到的0.573kg白色固体即为无定型的烟酰胺腺嘌呤二核苷酸。
Claims (3)
1.一种无定型烟酰胺腺嘌呤二核苷酸的制备方法,其特征在于,包括如下步骤:控制pH为3.0~6.0,温度为5~25℃时,将烟酰胺腺嘌呤二核苷酸水溶液与低级醇类溶剂按特定流量比瞬时混合,得到的固体即为无定型烟酰胺腺嘌呤二核苷酸。
2.一种如权利要求1所述的烟酰胺腺嘌呤二核苷酸的制备方法,其特征在于,所述烟酰胺腺嘌呤二核苷酸水溶液与低级醇类溶剂的流量比为5:95~20:80。
3.一种如权利要求1所述的无定型烟酰胺腺嘌呤二核苷酸的制备方法,其特征在于,所述低级醇类溶剂选自甲醇、乙醇、异丙醇。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4148994A (en) * | 1976-08-20 | 1979-04-10 | Boehringer Mannheim Gmbh | Crystalline metal salts of β-nicotinamide-adenine-dinucleotide |
US4515943A (en) * | 1980-10-12 | 1985-05-07 | Kohjin Co., Ltd. | Crystal of beta-nicotinamide-adenine-dinucleotide and process for preparing the same |
CN104876994A (zh) * | 2015-05-19 | 2015-09-02 | 邦泰生物工程(深圳)有限公司 | 一种纯化氧化型β-烟酰胺腺嘌呤二核苷酸的方法 |
CN105481923A (zh) * | 2015-12-30 | 2016-04-13 | 平光制药股份有限公司 | 一种烟酰胺腺嘌呤二核苷酸的制备方法 |
RU2658426C1 (ru) * | 2017-05-31 | 2018-06-21 | Общество с ограниченной ответственностью "Научно-производственная фирма "ЭЛЕСТ"(ООО"НПФ"ЭЛЕСТ") | Способ получения никотинамидадениндинуклеотида (над) |
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Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4148994A (en) * | 1976-08-20 | 1979-04-10 | Boehringer Mannheim Gmbh | Crystalline metal salts of β-nicotinamide-adenine-dinucleotide |
US4515943A (en) * | 1980-10-12 | 1985-05-07 | Kohjin Co., Ltd. | Crystal of beta-nicotinamide-adenine-dinucleotide and process for preparing the same |
CN104876994A (zh) * | 2015-05-19 | 2015-09-02 | 邦泰生物工程(深圳)有限公司 | 一种纯化氧化型β-烟酰胺腺嘌呤二核苷酸的方法 |
CN105481923A (zh) * | 2015-12-30 | 2016-04-13 | 平光制药股份有限公司 | 一种烟酰胺腺嘌呤二核苷酸的制备方法 |
RU2658426C1 (ru) * | 2017-05-31 | 2018-06-21 | Общество с ограниченной ответственностью "Научно-производственная фирма "ЭЛЕСТ"(ООО"НПФ"ЭЛЕСТ") | Способ получения никотинамидадениндинуклеотида (над) |
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