CN107892692A - (6s)‑5‑甲基四氢叶酸锌盐的制备方法及其应用 - Google Patents
(6s)‑5‑甲基四氢叶酸锌盐的制备方法及其应用 Download PDFInfo
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- CN107892692A CN107892692A CN201711456528.XA CN201711456528A CN107892692A CN 107892692 A CN107892692 A CN 107892692A CN 201711456528 A CN201711456528 A CN 201711456528A CN 107892692 A CN107892692 A CN 107892692A
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- zinc
- methyltetrahydrofolate
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- salt
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- 239000011701 zinc Substances 0.000 title claims abstract description 51
- 229910052725 zinc Inorganic materials 0.000 title claims abstract description 51
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- 235000007635 levomefolic acid Nutrition 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 47
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- 238000004153 renaturation Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 230000014860 sensory perception of taste Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
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- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HXMWJLVXIHYART-UHFFFAOYSA-M sodium;2-hydroxypropane-1,2,3-tricarboxylic acid;hydroxide;hydrochloride Chemical compound [OH-].[Na+].Cl.OC(=O)CC(O)(C(O)=O)CC(O)=O HXMWJLVXIHYART-UHFFFAOYSA-M 0.000 description 1
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- 239000004246 zinc acetate Substances 0.000 description 1
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- C07D475/04—Heterocyclic compounds containing pteridine ring systems with an oxygen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A23L33/16—Inorganic salts, minerals or trace elements
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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Abstract
本发明公开了(6S)‑5‑甲基四氢叶酸锌盐的制备方法,包括如下步骤,a)将(6S)‑5‑甲基四氢叶酸溶解;b)加入含锌物质,(6S)‑5‑甲基四氢叶酸与锌离子的摩尔比为1:0.05~20;c)控制pH为5~8,控制温度,静置析出(6S)‑5‑甲基四氢叶酸锌盐。本发明的(6S)‑5‑甲基四氢叶酸锌盐的制备方法具有制备工艺具有操作简单,重复性好,应用前景巨大,适用于工业化生产等优点,同时应用范围广,用于同时提供叶酸和锌,应用于作为优良补锌剂;叶酸缺乏症;治疗因叶酸缺乏引发的贫血、神经系统疾病、自身免疫疾病;降低化学疗法中二脱氢氨四氢叶酸的毒性;阿兹海默征;小儿腹泻。
Description
技术领域
本发明属于药物合成技术领域,具体涉及(6S)-5-甲基四氢叶酸锌盐的制备方法及其应用。
背景技术
(6S)-5-甲基四氢叶酸可用于口服避孕药,防止孕妇叶酸缺乏而导致的胎儿先天性神经管缺陷,心室阀缺陷、泌尿生殖缺陷,兔唇,腭裂等,但又不会掩蔽体内维生素B12的缺乏;能够穿过血脑屏障的叶酸类药物,可用于治疗阿兹海默征;是生物体内还原性叶酸的主要存在形式,在人体中不需要经过烦琐的酶促步骤,较快的被利用,是叶酸的有效替代品。(6S)-5-甲基四氢叶酸的化学名称为(6S)-N-[4-[[(2-氨基-1,4,5,6,7,8-六氢-4-氧-5-甲基-6- 喋啶基)甲基]氨基]苯甲酰]-L-谷氨酸,简称(6S)-5-MTHF。结构式如下式所示:
由于(6S)-5-甲基四氢叶酸及其无定形盐易氧化,不易保存,所以市面上常常是以其晶型盐的形式存在。
WO2008144953中取EP0600460中得到的92~96%的(6S)-四氢叶酸为原料,首先甲基化后,而后通过种晶法纯化,得到高纯度的(6S)-四氢叶酸,而后加入氯化钙,最终得到高纯度的无定形(6S)-5-甲基四氢叶酸钙盐。
WO2013025203中描述了一类N-烷基-D-葡糖胺拆分剂,有效的手性拆分(6R,S)-5-甲基四氢叶酸得到了纯度较高的(6S)-5-甲基四氢叶酸,然后与氯化钙反应得到(6S)-5-甲基四氢叶酸钙盐,但该专利并没有公布钙盐的晶型。
EP1044975A1中描述了(6S)-5-甲基四氢叶酸钙的稳定晶型的制备方法,通过改变加热温度、真空干燥温度及真空干燥时间而得到四种不同稳定晶型。
现有专利提到了关于(6S)-5-甲基四氢叶酸钙及其特定晶型的盐类的制备,并没有具体的提到(6S)-5-甲基四氢叶酸锌盐的制备。
锌是微量元素的一种,参与酶的合成与激活,维持机体正常代谢,促进生长发育、组织再生,增强免疫功能,促进智力发育,改善味觉并促进食欲。目前,青少年缺锌已成为世界特别是发展中国家的一个严重的公共卫生问题。
《叶酸过量可致孕期妇女体内缺锌》(中华妇幼临床医学杂志2011年03期)中提出补充叶酸过量,干扰锌代谢,引起机体锌缺乏。若孕期妇女体内锌含量低,则可加重妊娠反应及增加分娩合并症,就胎儿而言,锌缺乏可能导致其生长发育障碍、后天性发育不良及智力损伤等问题。曹建平、李秋华在《口服叶酸及锌剂预防自然流产37例观察分析》中也建议孕妇加强营养同时注意维生素和微量元素的摄人特别是叶酸和锌剂摄人以预防自然流产。
目前为止,没有专利具体的公布(6S)-5-甲基四氢叶酸锌盐及其晶型的制备,由于其不仅仅具有(6S)-5-甲基四氢叶酸的功效,作为叶酸的有效替代品,又可以作为补锌剂,特别用于必须长期服用叶酸而造成的机体锌缺乏,并且有助于预防自然流产。
发明内容
为了解决以上技术问题,本发明提供了(6S)-5-甲基四氢叶酸锌盐的制备方法及其应用,包括(6S)-5-甲基四氢叶酸锌无定型盐和晶型盐的制备方法及其应用。
一种(6S)-5-甲基四氢叶酸锌盐的制备方法,包括如下步骤,
a)将(6S)-5-甲基四氢叶酸加入水性介质制成悬浊液,再加入碱性溶液使其完全溶解后,调节pH为4~10,制得(6S)-5-甲基四氢叶酸溶液;
b)在(6S)-5-甲基四氢叶酸溶液中加入含锌物质,搅拌均匀,制得(6S)-5-甲基四氢叶酸锌溶液,其中(6S)-5-甲基四氢叶酸与锌离子的摩尔比为1:0.05~20;
c)控制pH为5~8,控制温度为0~30℃,静置析出(6S)-5-甲基四氢叶酸锌的无定型盐;
d)过滤、洗涤、滤饼真空干燥后制得(6S)-5-甲基四氢叶酸锌的无定型盐粉末。
一种(6S)-5-甲基四氢叶酸锌盐的制备方法,包括如下步骤,
a)将(6S)-5-甲基四氢叶酸加入水性介质制成悬浊液,再加入碱性溶液使其完全溶解后,调节pH为4~10,制得(6S)-5-甲基四氢叶酸溶液;
b)在(6S)-5-甲基四氢叶酸溶液中加入含锌物质,搅拌均匀,制得(6S)-5-甲基四氢叶酸锌溶液,其中(6S)-5-甲基四氢叶酸与锌离子的摩尔比为1:0.05~20;
c)控制pH为5~8,在惰性气体保护下加热,控制温度为50~120℃,冷却后静置析出 (6S)-5-甲基四氢叶酸锌的晶型盐;
d)过滤、洗涤、滤饼真空干燥后制得(6S)-5-甲基四氢叶酸锌的晶型盐粉末。
作为优选的技术方案,所述步骤a)中(6S)-5-甲基四氢叶酸包括但不限于光学纯的(6S) -5-甲基四氢叶酸、化学纯的(6S)-5-甲基四氢叶酸、(6R)-5-甲基四氢叶酸、(6R,S)-5- 甲基四氢叶酸。
其中光学纯度大于99%,化学纯度大于98.5%。
作为优选的技术方案,所述步骤a)中水性介质包括但不限于水、水与有机溶剂的混合液、碱性溶液、中性溶液、酸性溶液;制得的(6S)-5-甲基四氢叶酸溶液浓度为20~100ml/g。
其中有机溶剂包括但不限于甲醇、乙醇、丙酮等;(6S)-5-甲基四氢叶酸所加溶剂量不限,优选20~100ml/g。
碱性溶液包括但不限于碱金属的碱、碳酸盐、碳酸氢盐、氨水、吡啶类或哌嗪类,磷酸氢二钠-柠檬酸缓冲液、磷酸氢二钠/钾-磷酸二氢钠/钾缓冲液、磷酸二氢钾–氢氧化钠缓冲液、巴比妥钠-盐酸缓冲液、三羟甲基氨基甲烷-盐酸缓冲液。
中性溶液包括但不限于硫酸钠、硫酸钾、氯化钠、氯化钾、硝酸钾,磷酸氢二钠–柠檬酸缓冲液、磷酸氢二钠/钾–磷酸二氢钠/钾缓冲液、磷酸二氢钾–氢氧化钠缓冲液、巴比妥钠-盐酸缓冲液。
酸性溶液包括但不限于硝酸、盐酸、硫酸、乙酸、磷酸、亚硫酸、碳酸、柠檬酸及其他有机酸、无机酸,乙酸-乙酸钠缓冲液、磷酸氢二钠-柠檬酸缓冲液、柠檬酸-氢氧化钠- 盐酸缓冲液、柠檬酸-柠檬酸钠缓冲液、磷酸氢二钠/钾-磷酸二氢钠/钾缓冲液、柠檬酸–氢氧化钠-盐酸缓冲液、柠檬酸–柠檬酸钠缓冲液、巴比妥钠-盐酸缓冲液。
其中酸性、中性、碱性的溶液及其缓冲盐两者之间不发生副反应,可以相互混合,进行调节pH,使(6S)-5-甲基四氢叶酸溶解。酸性、中性、碱性溶液及其酸性缓冲溶液、中性缓冲溶液、碱性缓冲溶液的溶剂为水或水与能与水混溶的有机溶剂的混合溶剂。
作为优选的技术方案,所述步骤a)中碱性溶液为显碱性的溶液,包括但不限于碱金属、碱性盐、氨水、生物碱、碱性缓冲液。具体的,包括但不限于碱金属的碱、碳酸盐、碳酸氢盐、氨水、吡啶类或哌嗪类,磷酸氢二钠-柠檬酸缓冲液、磷酸氢二钠/钾-磷酸二氢钠/钾缓冲液、磷酸二氢钾–氢氧化钠缓冲液、巴比妥钠-盐酸缓冲液、三羟甲基氨基甲烷- 盐酸缓冲液。
作为优选的技术方案,所述步骤b)中含锌物质包括但不限于含锌的化合物或含锌元素的混合物。
锌为可以提供锌元素的化合物和混合物,包括但不限于氢氧化锌、氧化锌、醋酸锌、硫酸锌、硝酸锌、氯化锌等及其锌盐的结晶水合物中的一种或多种或其中两种及两种以上的混合物,优选七水合硫酸锌、醋酸锌、氯化锌、硝酸锌六水合物。
所加入的锌元素可以溶液方式加入,包括但不限于任何能溶解所用的锌又不发生副反应的溶剂,优选水,也可以固体方式加入,优选将其粉碎,以粉末形式加入。
作为优选的技术方案,所述步骤b)中(6S)-5-甲基四氢叶酸与锌离子的摩尔比为1: 0.3~5。
作为优选的技术方案,所述步骤a)中和c)中的调节pH通过加入碱性缓冲液、中性缓冲液或酸性缓冲液进行调节。
(6S)-5-甲基四氢叶酸锌的晶型盐的制备时,惰性气体不限于氮气、氩气、氦气、氢气等;加热温度为50~120℃,最优为80~100℃;加热时间为0.5~24h,优选为5~15h。
(6S)-5-甲基四氢叶酸锌盐的应用,包括(6S)-5-甲基四氢叶酸锌无定型盐和晶型盐,其中(6S)-5-甲基四氢叶酸锌的无定型盐粉末作为药物活性成分或食品添加剂成分,与药用辅料或载体(包括稀释剂、粘合剂、崩解剂、润滑剂等)混合,制得(6S)-5-甲基四氢叶酸锌的无定型盐的药物组合物或保健药品,用于同时提供叶酸和锌,应用于作为优良补锌剂;叶酸缺乏症;治疗因叶酸缺乏引发的贫血、神经系统疾病、自身免疫疾病;降低化学疗法中二脱氢氨四氢叶酸的毒性;阿兹海默征;小儿腹泻。
(6S)-5-甲基四氢叶酸锌的晶型盐粉末作为药物活性成分或食品添加剂成分,与药用辅料或载体(包括稀释剂、粘合剂、崩解剂、润滑剂等)混合,制得(6S)-5-甲基四氢叶酸锌的晶型盐的药物组合物或保健药品,用于同时提供叶酸和锌,应用于作为优良补锌剂;叶酸缺乏症;治疗因叶酸缺乏引发的贫血、神经系统疾病、自身免疫疾病;降低化学疗法中二脱氢氨四氢叶酸的毒性;阿兹海默征;小儿腹泻。
本发明的(6S)-5-甲基四氢叶酸锌盐可用于治疗疾病和症状的例子包括但不限于:叶酸缺乏症;由于缺乏叶酸引起的巨红细胞性贫血;妇女哺乳期间体内叶酸浓度下降;神经紊乱,神经精神障碍,神经系统等损伤等;牛皮癣和风湿性关节炎的自身免疫疾病;降低在化学疗法中二脱氢氨四氢叶酸的毒性;阿兹海默征;小儿腹泻等。
本发明的(6S)-5-甲基四氢叶酸锌盐较以往所制备钙盐有另外一大优点,可以作为优良的补锌剂,即可以缓解孕妇因长期服用叶酸补剂而导致的机体锌元素吸收不足,并且预防孕妇自然流产。
本发明的(6S)-5-甲基四氢叶酸锌盐的制备方法具有制备工艺具有操作简单,重复性好,应用前景巨大,适用于工业化生产等优点,同时应用范围广,用于同时提供叶酸和锌,应用于作为优良补锌剂;叶酸缺乏症;治疗因叶酸缺乏引发的贫血、神经系统疾病、自身免疫疾病;降低化学疗法中二脱氢氨四氢叶酸的毒性;阿兹海默征;小儿腹泻。
附图说明
图1为本实施例(6S)-5-甲基四氢叶酸锌无定型盐的X-射线衍射图谱;
图2为本实施例(6S)-5-甲基四氢叶酸锌晶型盐的X-射线衍射图谱。
具体实施方式
下面将结合本发明实施例中的实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
实施例1
取50ml三口烧瓶,先加入0.1896g(6S)-5-MTHF,再加入5ml去离子水,氮气置换内部空气3次,氮气保护下磁力搅拌,滴加1N NaOH溶液直至溶液澄清,测定此时溶液pH 为6.56,取0.13g七水合硫酸锌溶于5ml去离子水中,一次性将溶液迅速倒入三口烧瓶,氮气保护下搅拌18h,过滤,去离子水、无水乙醇分别清洗3次,室温下放于含有五氧化二磷的真空干燥器中10h,获得0.1599g(6S)-5-甲基四氢叶酸无定形锌盐。
实施例2
取50ml三口烧瓶,先加入0.1896g(6S)-5-MTHF,再加入5ml去离子水,氮气置换内部空气3次,氮气保护下磁力搅拌,滴加1N NaOH溶液直至溶液澄清,测定此时溶液pH 为5.83,取0.13g七水合硫酸锌溶于5ml去离子水中,每30min向三口烧瓶内滴加1ml溶液,滴加完毕后,氮气保护下搅拌18h,过滤,去离子水、无水乙醇分别清洗3次,室温下放于含有五氧化二磷的真空干燥器中10h,获得0.1314g(6S)-5-甲基四氢叶酸无定形锌盐。
实施例3
取50ml三口烧瓶,先加入0.2318g(6S)-5-MTHF,再加入6ml去离子水,氮气置换内部空气3次,氮气保护下磁力搅拌,滴加1N NaOH溶液直至溶液澄清,测定此时溶液pH 为6.76,取0.16g七水合硫酸锌溶于5ml去离子水中,先缓慢滴加至溶液变浑浊,而后将剩余溶液一次性倒入三口烧瓶,氮气保护下搅拌18h,过滤,去离子水、无水乙醇分别清洗3次,室温下放于含有五氧化二磷的真空干燥器中10h,获得0.1644g(6S)-5-甲基四氢叶酸无定形锌盐。
实施例4
取50ml三口烧瓶,先加入0.5899g(6S)-5-MTHF,再加入10ml去离子水,氮气置换内部空气3次,氮气保护下磁力搅拌,滴加1N NaOH溶液直至溶液澄清,测定此时溶液 pH为6.62,取0.37g七水合硫酸锌溶于15ml去离子水中,先缓慢滴加至溶液变浑浊,而后将剩余溶液一次性倒入三口烧瓶,氮气保护下搅拌18h,过滤,去离子水、无水乙醇分别清洗3次,室温下放于含有五氧化二磷的真空干燥器中10h,获得0.4580g(6S)-5-甲基四氢叶酸无定形锌盐。
实施例5
取50ml三口烧瓶,先加入0.1419g(6S)-5-MTHF,再加入4.5ml去离子水,氮气置换内部空气3次,氮气保护下磁力搅拌,滴加1N NaOH溶液直至溶液澄清,测定此时溶液 pH为6.60,取0.09g七水合硫酸锌溶于15ml去离子水中,先缓慢滴加至溶液变浑浊,而后将剩余溶液一次性倒入三口烧瓶,氮气保护下搅拌3h,过滤,去离子水、无水乙醇分别清洗3次,室温下放于含有五氧化二磷的真空干燥器中10h,获得0.0879g(6S)-5-甲基四氢叶酸无定形锌盐。
实施例6
取50ml三口烧瓶,先加入0.1896g(6S)-5-MTHF,再加入5ml去离子水,氮气置换内部空气3次,氮气保护下磁力搅拌,滴加1N NaOH溶液直至溶液澄清,测定此时溶液pH 为6.56,取0.13g七水合硫酸锌溶于5ml去离子水中,一次性将溶液迅速倒入三口烧瓶,氮气保护下搅拌18h,过滤,去离子水、无水乙醇分别清洗3次,室温下放于含有五氧化二磷的真空干燥器中10h,获得0.1599g(6S)-5-甲基四氢叶酸无定形锌盐。
取无定形锌盐0.0412g加入到25ml史莱克管中,再加入2ml去离子水,用氮气置换内部空气3次,而后磁力搅拌、氮气保护下回流加热9.5h,分别沸腾的去离子水、无水乙醇各清洗3次,室温下放于含有五氧化二磷的真空干燥器中12h,获得0.0158g(6S)-5-甲基四氢叶酸锌晶型盐。
实施例7
取50ml三口烧瓶,先加入0.1896g(6S)-5-MTHF,再加入5ml去离子水,氮气置换内部空气3次,氮气保护下磁力搅拌,滴加1N NaOH溶液直至溶液澄清,测定此时溶液pH 为6.56,取0.13g七水合硫酸锌溶于5ml去离子水中,一次性将溶液迅速倒入三口烧瓶,氮气保护下搅拌18h,过滤,去离子水、无水乙醇分别清洗3次,室温下放于含有五氧化二磷的真空干燥器中10h,获得0.1599g(6S)-5-甲基四氢叶酸无定形锌盐;
取无定形锌盐0.0413g加入到25ml史莱克管中,再加入2ml pH为5.50的0.1N乙酸-乙酸钠缓冲液,用氮气置换内部空气3次,而后磁力搅拌、氮气保护下回流加热9.5h,分别沸腾的去离子水、无水乙醇各清洗3次,室温下放于含有五氧化二磷的真空干燥器中12h,获得0.0097g(6S)-5-甲基四氢叶酸锌晶型盐。
实施例8(6S)-5-甲基四氢叶酸的无定形锌盐的表征
仪器型号:Rigaku XRD(D/Max-2000X射线衍射仪)
衍射线:CuKα(40kV,20mA)
扫描速率:4°/min(2θ值)
扫描范围:5°~80°(2θ值)
X-射线衍射图谱见图1。
实施例9(6S)-5-甲基四氢叶酸锌的晶型盐的表征
仪器型号:Rigaku XRD(D/Max-2000X射线衍射仪)
衍射线:CuKα(40kV,20mA)
扫描速率:4°/min(2θ值)
扫描范围:5°~60°(2θ值)
Peak Search Report(22Peaks,Max P/N=10.9)
PEAK:17-pts/Parabolic Filter,Threshold=3.0,Cutoff=0.1%,BG=3/1.0,Peak-Top=Summit
X-射线衍射图谱见图2,X-射线衍射图谱数据见表1。
表1:(6S)-5-甲基四氢叶酸锌的晶型的X-射线衍射图谱数据
# | 2-Theta | d(A) | BG | Height | I% | Area | I% | FWHM |
1 | 8.599 | 10.2742 | 61 | 144 | 25.2 | 1689 | 33.2 | 0.399 |
2 | 10.318 | 8.5659 | 68 | 354 | 61.9 | 4471 | 87.8 | 0.429 |
3 | 12.199 | 7.249 | 114 | 349 | 61.0 | 4007 | 78.7 | 0.390 |
4 | 13.237 | 6.6833 | 118 | 572 | 100.0 | 4618 | 90.7 | 0.274 |
5 | 14.637 | 6.0467 | 76 | 233 | 40.7 | 2216 | 43.5 | 0.323 |
6 | 16.798 | 5.2735 | 104 | 161 | 28.1 | 1690 | 33.2 | 0.357 |
7 | 17.999 | 4.9241 | 109 | 300 | 52.4 | 3050 | 59.9 | 0.346 |
8 | 19.757 | 4.4898 | 126 | 433 | 75.7 | 5093 | 100.0 | 0.400 |
9 | 20.723 | 4.2828 | 149 | 299 | 52.3 | 2767 | 54.3 | 0.315 |
10 | 21.721 | 4.0882 | 182 | 427 | 74.7 | 4256 | 83.6 | 0.339 |
11 | 22.719 | 3.9108 | 91 | 193 | 33.7 | 2845 | 55.9 | 0.501 |
12 | 23.920 | 3.7171 | 121 | 43 | 7.5 | 162 | 3.2 | 0.128 |
13 | 24.761 | 3.5927 | 112 | 190 | 33.2 | 2870 | 56.4 | 0.514 |
14 | 26.478 | 3.3635 | 122 | 90 | 15.7 | 788 | 15.5 | 0.298 |
15 | 27.280 | 3.2663 | 121 | 47 | 8.2 | 1346 | 26.4 | 0.974 |
16 | 27.846 | 3.2013 | 101 | 93 | 16.3 | 1368 | 26.9 | 0.500 |
17 | 30.244 | 2.9527 | 82 | 65 | 11.4 | 741 | 14.5 | 0.388 |
18 | 33.079 | 2.7058 | 87 | 48 | 8.4 | 620 | 12.2 | 0.439 |
19 | 34.120 | 2.6256 | 77 | 80 | 14.0 | 1060 | 20.8 | 0.451 |
20 | 37.719 | 2.3829 | 71 | 42 | 7.3 | 589 | 11.6 | 0.477 |
21 | 40.360 | 2.2329 | 74 | 43 | 7.5 | 1158 | 22.7 | 0.916 |
22 | 42.881 | 2.1073 | 76 | 49 | 8.6 | 784 | 15.4 | 0.544 |
此外,应当理解,虽然本说明书按照实施方式加以描述,但并非每个实施方式仅包含一个独立的技术方案,说明书的这种叙述方式仅仅是为清楚起见,本领域技术人员应当将说明书作为一个整体,各实施例中的技术方案也可以经适当组合,形成本领域技术人员可以理解的其他实施方式。
Claims (10)
1.一种(6S)-5-甲基四氢叶酸锌盐的制备方法,其特征在于:包括如下步骤,
a)将(6S)-5-甲基四氢叶酸加入水性介质制成悬浊液,再加入碱性溶液使其完全溶解后,调节pH为4~10,制得(6S)-5-甲基四氢叶酸溶液;
b)在(6S)-5-甲基四氢叶酸溶液中加入含锌物质,搅拌均匀,制得(6S)-5-甲基四氢叶酸锌溶液,其中(6S)-5-甲基四氢叶酸与锌离子的摩尔比为1:0.05~20;
c)控制pH为5~8,控制温度为0~30℃,静置析出(6S)-5-甲基四氢叶酸锌的无定型盐;
d)过滤、洗涤、滤饼真空干燥后制得(6S)-5-甲基四氢叶酸锌的无定型盐粉末。
2.一种(6S)-5-甲基四氢叶酸锌盐的制备方法,其特征在于:包括如下步骤,
a)将(6S)-5-甲基四氢叶酸加入水性介质制成悬浊液,再加入碱性溶液使其完全溶解后,调节pH为4~10,制得(6S)-5-甲基四氢叶酸溶液;
b)在(6S)-5-甲基四氢叶酸溶液中加入含锌物质,搅拌均匀,制得(6S)-5-甲基四氢叶酸锌溶液,其中(6S)-5-甲基四氢叶酸与锌离子的摩尔比为1:0.05~20;
c)控制pH为5~8,在惰性气体保护下加热,控制温度为50~120℃,冷却后静置析出(6S)-5-甲基四氢叶酸锌的晶型盐;
d)过滤、洗涤、滤饼真空干燥后制得(6S)-5-甲基四氢叶酸锌的晶型盐粉末。
3.根据权利要求1或2所述的(6S)-5-甲基四氢叶酸锌盐的制备方法,其特征在于:所述步骤a)中(6S)-5-甲基四氢叶酸包括但不限于光学纯的(6S)-5-甲基四氢叶酸、化学纯的(6S)-5-甲基四氢叶酸、(6R)-5-甲基四氢叶酸、(6R,S)-5-甲基四氢叶酸。
4.根据权利要求1或2所述的(6S)-5-甲基四氢叶酸锌盐的制备方法,其特征在于:所述步骤a)中水性介质包括但不限于水、水与有机溶剂的混合液、碱性溶液、中性溶液、酸性溶液;制得的(6S)-5-甲基四氢叶酸溶液浓度为20~100ml/g。
5.根据权利要求1或2所述的(6S)-5-甲基四氢叶酸锌盐的制备方法,其特征在于:所述步骤a)中碱性溶液为显碱性的溶液,包括但不限于碱金属、碱性盐、氨水、生物碱、碱性缓冲液。
6.根据权利要求1或2所述的(6S)-5-甲基四氢叶酸锌盐的制备方法,其特征在于:所述步骤b)中含锌物质包括但不限于含锌的化合物或含锌元素的混合物。
7.根据权利要求1或2所述的(6S)-5-甲基四氢叶酸锌盐的制备方法,其特征在于:所述步骤b)中(6S)-5-甲基四氢叶酸与锌离子的摩尔比为1:0.3~5。
8.根据权利要求1或2所述的(6S)-5-甲基四氢叶酸锌盐的制备方法,其特征在于:所述步骤a)中和c)中的调节pH通过加入碱性缓冲液、中性缓冲液或酸性缓冲液进行调节。
9.根据权利要求1所述的(6S)-5-甲基四氢叶酸锌盐的应用,其特征在于:所述(6S)-5-甲基四氢叶酸锌的无定型盐粉末作为药物活性成分或食品添加剂成分,与药用辅料或载体混合,制得(6S)-5-甲基四氢叶酸锌的无定型盐的药物组合物或保健药品,用于同时提供叶酸和锌,应用于作为优良补锌剂;叶酸缺乏症;治疗因叶酸缺乏引发的贫血、神经系统疾病、自身免疫疾病;降低化学疗法中二脱氢氨四氢叶酸的毒性;阿兹海默征;小儿腹泻。
10.根据权利要求2所述的(6S)-5-甲基四氢叶酸锌盐的应用,其特征在于:所述(6S)-5-甲基四氢叶酸锌的晶型盐粉末作为药物活性成分或食品添加剂成分,与药用辅料或载体混合,制得(6S)-5-甲基四氢叶酸锌的晶型盐的药物组合物或保健药品,用于同时提供叶酸和锌,应用于作为优良补锌剂;叶酸缺乏症;治疗因叶酸缺乏引发的贫血、神经系统疾病、自身免疫疾病;降低化学疗法中二脱氢氨四氢叶酸的毒性;阿兹海默征;小儿腹泻。
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