CN112110862A - 一种1,4,5,6-四氢-5-羟基嘧啶化合物及其盐酸盐的制备方法及应用 - Google Patents
一种1,4,5,6-四氢-5-羟基嘧啶化合物及其盐酸盐的制备方法及应用 Download PDFInfo
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- CN112110862A CN112110862A CN202011011312.4A CN202011011312A CN112110862A CN 112110862 A CN112110862 A CN 112110862A CN 202011011312 A CN202011011312 A CN 202011011312A CN 112110862 A CN112110862 A CN 112110862A
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- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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- C—CHEMISTRY; METALLURGY
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- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
本发明属于药物技术领域,具体涉及一种1,4,5,6‑四氢‑5‑羟基嘧啶化合物及其盐酸盐的制备方法。该方法以化合物II为原料在碱作用下与羟基保护剂反应后和原乙酸酯类反应,脱去保护基得到1,4,5,6‑四氢‑5‑羟基嘧啶化合物及其盐酸盐。本发明提供的方法反应条件相对温和,不需要特殊的装置,合成方法稳定,目标产物用于药品杂质对照品,对于控制药品的安全性、有效性和提升药品质量具有十分重要的意义。
Description
技术领域
本发明属于药物技术领域,具体涉及一种1,4,5,6-四氢-5-羟基嘧啶化合物及其盐酸盐的制备方法。
背景技术
利奈唑胺是美国辉瑞公司开发的噁唑烷酮类抗生素药物,2000年获得FDA批准用于治疗革兰阳性(G+)球菌引起的感染,包括由MRSA引起的疑似或确诊院内获得性肺炎(HAP)、社区获得性肺炎(CAP)、复杂性皮肤或皮肤软组织感染(SSTI)以及耐万古霉素肠球菌(VRE)感染,商品名为斯沃(Zyvox)。
利奈唑胺为细菌蛋白质合成抑制剂,作用于细菌50S核糖体亚单位,并且最接近作用部位。与其它药物不同,利奈唑胺不影响肽基转移酶活性,只是作用于翻译系统的起始阶段,抑制mRNA与核糖体连接,阻止70S起始复合物的形成,从而抑制了细菌蛋白质的合成。利奈唑胺的作用部位和方式独特,因此在具有本质性或获得性耐药特征的阳性细菌中,都不易与其它抑制蛋白合成的抗菌药发生交叉耐药,在体外也不易诱导细菌耐药性的产生。
杂质研究是控制药品质量的一个重要指标,对于药品的质量评价,药品本身的疗效及安全性均有重要影响。利奈唑胺干混悬剂进品注册标准中关键杂质PNU-143797,化学名称为1-(3-氟-4-吗啉基苯基)-2-甲基-1,4,5,6-四氢-5-羟基嘧啶(化合物I)的合成方法目前未见相关文献报道;化合物I结构式如下:
发明内容
有鉴于此,本发明的目的之一在于提供一种高效、便捷、反应条件不严苛的制备1,4,5,6-四氢-5-羟基嘧啶化合物及盐酸盐的中间体的制备方法。
为了实现上述目的,本发明的技术方案为:
一种制备1,4,5,6-四氢-5-羟基嘧啶化合物及其盐酸盐的中间体的制备方法,所述方法具体包括如下步骤:
1).化合物II与氯硅烷类羟基保护试剂在碱作用下发生反应,得化合物III;
2).化合物III与原乙酸酯类反应,生成化合物IV;
所述中间体为化合物IV;所述化合物II-IV的结构式如下:
具体的,步骤1)中反应后采用柱层析纯化得到反应物III;
具体的,步骤2)中反应后采用减压浓缩得到化合物IV;
进一步,所述步骤1)中碱为咪唑、三乙胺、二异丙基乙胺中的一种或多种;
进一步,所述步骤1)中氯硅烷类羟基保护试剂为三甲基氯硅烷、三乙基氯硅烷、三异丙基氯硅烷、叔丁基二甲基氯硅烷、叔丁基二苯基氯硅烷中的一种或多种;
进一步,所述步骤1)中化合物Ⅱ与氯硅烷类试剂的摩尔比为1:1~1:5;
具体的,所述步骤1)中化合物Ⅱ与氯硅烷类试剂的摩尔比为1:2.5;
进一步,所述步骤1)的反应时长为3~10小时;
进一步,所述步骤1)的反应温度为10℃~30℃(室温);
进一步,所述步骤2)中原乙酸酯类为原乙酸三甲酯、原乙酸三乙酯、原乙酸三丙酯;
进一步,所述步骤2)中反应温度为60~142℃;
具体的,所述步骤2)的反应时长为0.5~3小时。
本发明目的之二是提供一种利用目的一所述方法制备的中间体制备1,4,5,6-四氢-5-羟基嘧啶化合物及其盐酸盐的方法;通过所述方法制备得到的1,4,5,6-四氢-5-羟基嘧啶化合物及其盐酸盐纯度高,可以作为研究利奈唑胺质量的标准物。
为了实现上述目的,本发明的技术方案为:
利用目的一种所述方法制备的中间体制备1,4,5,6-四氢-5-羟基嘧啶化合物及其盐酸盐的方法,所述化合物IV溶解于溶剂中脱去保护基,处理得到1,4,5,6-四氢-5-羟基嘧啶化合物及其盐酸盐;
具体的,所述1,4,5,6-四氢-5-羟基嘧啶化合物为化合物I,结构式如下:
具体的,所述化合物I化学名称为1-(3-氟-4-吗啉基苯基)-2-甲基-1,4,5,6-四氢-5-羟基嘧啶;
具体的,步骤3)中反应后纯化得到化合物I及其盐酸盐;
进一步,所述方法中溶剂为有机溶剂或有机溶剂与水的混合溶剂;所述有机溶剂为四氢呋喃、乙腈、甲醇、乙醇中的一种或多种;
进一步,所述方法中脱去保护基所用的脱保护试剂为四正丁基氟化铵、氢氟酸、盐酸、三氟乙酸、三(二甲氨基甲基)锍二氟三甲基氨酸硅酸盐中的一种或多种;
进一步,所述方法反应温度为-10~70℃;
具体的,所述步骤3)中反应时长为1~8小时。
本发明目的之三是提供一种通过目的二中所述方法进行分析利奈唑胺葡萄糖注射液中1,4,5,6-四氢-5-羟基嘧啶化合物的方法。
为了实现上述目的,本发明的技术方案为:
一种分离测定利奈唑胺葡萄糖注射液中1,4,5,6-四氢-5-羟基嘧啶化合物的方法,具体包括以下步骤:
1)利用目的二中所述的方法制备1,4,5,6-四氢-5-羟基嘧啶化合物,将其溶解于稀释剂中,得对照溶液;将供试品溶解于稀释剂中得供试品溶液;
2)利用高效液相色谱法进行分离检测;所述高效液相色谱法色谱柱以用十八烷基硅烷键合硅胶为填充剂;以三氟醋酸水溶液为流动相A、三氟醋酸乙腈溶液为流动相B进行梯度洗脱,通入检测波长为254nm的检测器中进行检测;
3)根据步骤2)中得到的供试溶液色谱图与对照溶液色谱图进行含量计算;
所述稀释剂为体积比为1:9的乙腈和水的混合溶液;
所述梯度洗脱如下:
时间/分钟 | 流动相A/% | 流动相B/% |
0 | 90 | 10 |
2.5 | 90 | 10 |
20.5 | 80 | 20 |
35.5 | 25 | 75 |
36.5 | 90 | 10 |
43.5 | 90 | 10 |
;
进一步,所述流动相A为10%三氟醋酸溶液10ml加入到1000ml水中而得;
进一步,所述流动相B为10%三氟醋酸溶液10ml加入到1000ml乙腈中而得;
具体的,流速为1.0ml/min;柱温为25℃;进样量为10μl。
本发明的有益效果在于:本发明提供了一种1,4,5,6-四氢-5-羟基嘧啶化合物、其盐酸盐及其中间体的合成方法,该合成方法可操作产强,合成条件不苛刻,产物易于纯化。本发明所得目标产物可作为杂质对照品,用于利奈唑胺检测分析中该杂质的定性和定量分析,有利于提高利奈唑胺产品质量,降低临床用药风险。
附图说明
图1为化合物Ⅰ及其盐酸盐的合成路线图;
图2为实施例1得到的化合物Ⅰ的HPLC图;
图3为实施例1得到的化合物Ⅰ的MS图;
图4为实施例1得到的化合物Ⅰ的1H NMR图;
图5为实施例1得到的化合物Ⅰ的13C NMR图;
图6为实施例2得到的化合物Ⅰ盐酸盐的HPLC图;
图7为实施例3分析利奈唑胺葡萄糖注射液中1,4,5,6-四氢-5-羟基嘧啶化合物的色谱图。
具体实施方式
所举实施例是为了更好地对本发明进行说明,但并不是本发明的内容仅局限于所举实施例。所以熟悉本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整,仍属于本发明的保护范围。
实施例1
如图1所示,1,4,5,6-四氢-5-羟基嘧啶化合物(化合物Ⅰ)的合成方法,包括以下步骤:
步骤(1):化合物Ⅲ的制备
500ml三口反应瓶中加入9.4g化合物Ⅱ、220ml二氯甲烷、11.8g咪唑,搅拌,滴加13g三乙基氯硅烷,室温反应5小时,反应液用2×100ml水洗涤,100ml饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤饼用100ml二氯甲烷洗涤,合并滤液40℃减压浓缩,残余物通过硅胶柱层析纯化(二氯甲烷:甲醇=15:1),收集目标馏份40℃减压浓缩得12.1g化合物Ⅲ,收率90.4%。
步骤(2):化合物Ⅳ的制备
250ml三口反应瓶中加入12g化合物Ⅲ、60g原乙酸三乙酯,搅拌,加热至120℃反应1小时,75℃减压浓缩至断流得油状物12.8g化合物Ⅳ,收率100%。
步骤(3):化合物Ⅰ的制备
500ml三口反应瓶中加入12.8g化合物Ⅳ、四氢呋喃150ml,控温0~10℃,加入四正丁基氟化铵29.8g,搅拌反应2小时,向反应液中加入100ml水,用乙酸乙酯200ml×2提取,弃水相,合并有机相用无水硫酸钠搅拌干燥2小时,过滤,滤液60℃减压浓缩至断流得油状物,油状物加入50ml甲基叔丁基醚搅拌2小时,油状物固化,过滤,滤饼以20ml甲基叔丁基醚洗涤,40℃减压干燥3小时得7.2g化合物Ⅰ,收率78.2%,纯度98.23%(HPLC面积归一化法)。[M+H]+=294.3;1H NMR(DMSO,600MHz)δ:7.098-7.073(dd,1H)、7.021-6.973(m,2H)、5.005(br,1H)、3.902-3.868(m,1H)、3.741-3.727(t,4H)、3.487-3.468(m,1H)、3.376-3.351(d,1H)、3.186-3.155(m,1H)、3.100-3.064(dd,1H)、3.003-2.987(t,4H)、1.634(s,3H);13CNMR(DMSO,150MHz)δ:155.165、153.525、151.310、140.603、140.542、137.737、137.676、123.352、118.930、118.907、114.998、114.868、87.553、66.140、61.273、55.227、51.119、50.452、22.670。具体检测结果见附图2-5,HPLC积分结果见表1。
表1实施例1化合物I HPLC积分结果
实施例2
如图1所示,1,4,5,6-四氢-5-羟基嘧啶化合物盐酸盐(化合物Ⅰ盐酸盐)的合成方法,包括以下步骤:
步骤(1):化合物Ⅲ的制备
500ml三口反应瓶中加入10g化合物Ⅱ、250ml二氯甲烷、18.8g二异丙基乙胺,搅拌,滴加10.1g三甲基氯硅烷,室温反应5小时,反应液用2×100ml水洗涤,100ml饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤饼用100ml二氯甲烷洗涤,合并滤液40℃减压浓缩,残余物通过硅胶柱层析纯化(二氯甲烷:甲醇=15:1),收集目标馏份40℃减压浓缩得11.2g化合物Ⅲ,收率89.1%。
步骤(2):化合物Ⅳ的制备
250ml三口反应瓶中加入11.2g化合物Ⅲ、55g原乙酸三乙酯,搅拌,加热至80℃反应1小时,75℃减压浓缩至断流得油状物11.9g化合物Ⅳ,收率99.3%。
步骤(3):化合物Ⅰ盐酸盐的制备
500ml三口反应瓶中加入11.9g化合物Ⅳ、甲醇80ml、1mol/L盐酸80ml,室温搅拌反应4小时,反应液60℃减压浓缩至断流,残余物加入40ml无水乙醇升温回流溶清,降至室温析晶2小时,过滤,滤饼以25ml无水乙醇洗涤,60℃减压干燥3小时得8.7g化合物Ⅰ盐酸盐,收率81.0%,纯度99.94%(HPLC面积归一化法),具体检测结果见附图6,HPLC积分结果见表2。
表2实施例2化合物I盐酸盐HPLC积分结果
实施例3
利奈唑胺葡萄糖注射液中1,4,5,6-四氢-5-羟基嘧啶化合物的分析方法
色谱条件用十八烷基硅烷键合硅胶为填充剂(YMC-Pack ODS-A4.6mm×150mm,3μm,或效能相当的色谱柱),以三氟醋酸水溶液(取10%三氟醋酸溶液10ml加入到1000ml水中)为流动相A,以三氟醋酸乙腈溶液(取10%三氟醋酸溶液10ml加入到1000ml乙腈中)为流动相B,按表3进行线性梯度洗脱;检测波长为254nm;流速为每分钟1.0ml;柱温为25℃;进样体积10μl。
表3梯度洗脱程序
时间(分钟) | 流动相A(%) | 流动相B(%) |
0 | 90 | 10 |
2.5 | 90 | 10 |
20.5 | 80 | 20 |
35.5 | 25 | 75 |
36.5 | 90 | 10 |
43.5 | 90 | 10 |
稀释剂乙腈-水(10:90)
供试品溶液:精密量取本品5ml,至10ml量瓶中,用稀释剂稀释至刻度。
对照溶液:精密量取供试品溶液0.2ml,置100ml量瓶中,用稀释剂稀释至刻度,摇匀。
按高效液相检测方法得到色谱图(附图7),图中杂质H为化合物I,可以看出该方法与其他杂质分离度高,可以适用于利奈唑胺葡萄糖注射液质量分析。
最后说明的是,以上实施例仅用以说明本发明的技术方案而非限制,尽管参照较佳实施例对本发明进行了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的宗旨和范围,其均应涵盖在本发明的权利要求范围当中。
Claims (10)
2.根据权利要求1所述的制备方法,其特征在于,所述步骤1)中碱为咪唑、三乙胺、二异丙基乙胺中的一种或多种;所述步骤1)中氯硅烷类羟基保护试剂为三甲基氯硅烷、三乙基氯硅烷、三异丙基氯硅烷、叔丁基二甲基氯硅烷、叔丁基二苯基氯硅烷中的一种或多种。
3.根据权利要求1所述的制备方法,其特征在于,所述步骤1)中化合物Ⅱ与氯硅烷类试剂的摩尔比为1:1~1:5。
4.根据权利要求1所述的制备方法,其特征在于,所述步骤2)中原乙酸酯类为原乙酸三甲酯、原乙酸三乙酯、原乙酸三丙酯。
5.根据权利要求1所述的制备方法,其特征在于,所述步骤2)中反应温度为60~142℃。
6.利用权利要求1所述方法制备的中间体制备1,4,5,6-四氢-5-羟基嘧啶化合物及其盐酸盐的方法,其特征在于,所述化合物IV溶解于溶剂中脱去保护基,处理得到1,4,5,6-四氢-5-羟基嘧啶化合物及其盐酸盐。
8.根据权利要求7所述的制备方法,其特征在于,所述方法中溶剂为有机溶剂或有机溶剂与水的混合溶剂;所述有机溶剂为四氢呋喃、乙腈、甲醇、乙醇中的一种或多种。
9.根据权利要求7中所述的制备方法,其特征在于,所述方法中脱去保护基所用的脱保护试剂为四正丁基氟化铵、氢氟酸、盐酸、三氟乙酸、三(二甲氨基甲基)锍二氟三甲基氨酸硅酸盐中的一种或多种;所述方法反应温度为-10~70℃。
10.一种分离测定利奈唑胺葡萄糖注射液中1,4,5,6-四氢-5-羟基嘧啶化合物的方法,其特征在于,具体包括以下步骤:
1)利用权利要求7中所述的方法制备1,4,5,6-四氢-5-羟基嘧啶化合物,将其溶解于稀释剂中,得对照溶液;将供试品溶解于稀释剂中得供试品溶液;
2)利用高效液相色谱法进行分离检测;所述高效液相色谱法色谱柱以用十八烷基硅烷键合硅胶为填充剂;以三氟醋酸水溶液为流动相A、三氟醋酸乙腈溶液为流动相B进行梯度洗脱,通入检测波长为254nm的检测器中进行检测;
3)根据步骤2)中得到的供试溶液色谱图与对照溶液色谱图进行含量计算;
所述稀释剂为体积比为1:9的乙腈和水的混合溶液;
所述梯度洗脱如下:
。
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