CN100348581C - 烷氧基烟酸的制备方法 - Google Patents
烷氧基烟酸的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 235000001968 nicotinic acid Nutrition 0.000 claims abstract description 24
- 239000011664 nicotinic acid Substances 0.000 claims abstract description 24
- 229960003512 nicotinic acid Drugs 0.000 claims abstract description 23
- -1 hydroxy niacin Chemical compound 0.000 claims abstract description 15
- 230000007062 hydrolysis Effects 0.000 claims abstract description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 9
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims abstract description 6
- 238000011065 in-situ storage Methods 0.000 claims abstract description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 16
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- 239000011734 sodium Substances 0.000 claims description 3
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- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims 1
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- 239000000376 reactant Substances 0.000 description 8
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
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- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
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- BLHCMGRVFXRYRN-UHFFFAOYSA-N 6-hydroxynicotinic acid Chemical compound OC(=O)C1=CC=C(O)N=C1 BLHCMGRVFXRYRN-UHFFFAOYSA-N 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
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- NCYVXEGFNDZQCU-UHFFFAOYSA-N nikethamide Chemical compound CCN(CC)C(=O)C1=CC=CN=C1 NCYVXEGFNDZQCU-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910000108 silver(I,III) oxide Inorganic materials 0.000 description 2
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- 235000019160 vitamin B3 Nutrition 0.000 description 2
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- OMMRNSLAFWRKOH-UHFFFAOYSA-N 2-hydroxyethyl pyridine-3-carboxylate Chemical compound OCCOC(=O)C1=CC=CN=C1 OMMRNSLAFWRKOH-UHFFFAOYSA-N 0.000 description 1
- KCDNYRPDKSGQCM-UHFFFAOYSA-N 4-[4-(3-chlorophenyl)-4-(pyrrolidine-1-carbonyl)piperidin-1-yl]-1-(4-fluorophenyl)butan-1-one Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC(C=2C=C(Cl)C=CC=2)(C(=O)N2CCCC2)CC1 KCDNYRPDKSGQCM-UHFFFAOYSA-N 0.000 description 1
- VRCWSYYXUCKEED-UHFFFAOYSA-N 6-Hydroxypicolinic acid Chemical compound OC(=O)C1=CC=CC(=O)N1 VRCWSYYXUCKEED-UHFFFAOYSA-N 0.000 description 1
- KIWBPDUYBMNFTB-UHFFFAOYSA-N Ethyl hydrogen sulfate Chemical compound CCOS(O)(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
Abstract
本发明涉及一种使用相应的羟基烟酸制备通式I所示的烷氧基烟酸的新的单罐式方法。该方法包括使羟基烟酸与二烷基硫酸盐在碱和水中反应,然后使用经溶剂稀释的碱金属氢氧化物对所产生的酯进行原位水解,以制备通式I所示的烷氧基烟酸。本发明还公开了所用有机溶剂的回收方法和重复使用方法。
Description
技术领域
本发明主要涉及一种制备烟酸衍生物的方法。具体而言,本发明提供一种新的制备烷氧基烟酸的单罐式方法,其中,使用适当的烷基化剂和无机碱,通过对羟基烟酸的烷基化制得烷氧基烟酸。
背景技术
烟酸是一种用于制备各类重要药物的吡啶衍生物,这些药物包括维生素PP(vitamin PP)、可地阿明(cordiamine)、尼古丹(nicodan)、叶新阿森(ethiacin)等等。其他农业及畜牧业上的应用也正在研发之中。烷氧基烟酸是属于烟酸的烷氧基衍生物的种类,而此类衍生物已普遍地做为医药原料及医药中间体。
现今已有几种制备吡啶衍生物的方法,而所遵循的各种化学程序是这些已知方法的不同之处。
EP1250340公开了制备6-甲氧吡啶-2-羧酸和5-甲氧基烟酸的方法。该方法包含将氧化银及碘甲烷与6-羟吡啶甲酸反应,以及水解在碱性溶液和有机溶剂中(例如四氢呋喃)所产生的酯。
再者,某篇文章报导了一种制备方法,其中包含5-羟基烟酸甲酯,在二甲基甲酰胺中,与氢化钠和碘甲烷所产生的化学反应,以及水解在碱性溶液和有机溶剂中所产生的烷氧基酯。
L.W.Deady,O.L.Korytsky and J.E.Rowe所写的文章(Austatralian Journal of Chemistry,1982,35,2025-34),公开了一种使卤代吡啶烷氧化的方法,其方法应用了溶解于甲醇中的金属钠(溶于甲醇的钠溶液)。该方法包括在高温密封的试管里,把卤代吡啶和溶在甲醇中的钠金属一起加热数小时,调整酸碱度以分离产物,其后以残留物的型态抽提和蒸发,以及用(苯∶轻石油,1∶1)溶液的再结晶。然而,以该方法获取的产物是低产量的。
这些现有技术所公开的方法,应用了钠金属和氢化钠,来制备烷氧基烟酸。这些化合物的处理,在实验室的规模里,或者在商业生产线的规模里,都是非常危险的。再者,这些方法所用的原料,像氧化银、二甲基甲酰胺、碘甲烷,都是非常昂贵的。
所以,为了克服现有技术中存在的所有上述问题,有必要开发一种使用低成本原料的,具有商业可行性的烷氧基烟酸制备方法。
发明内容
本发明的主要方向是提供一种具有商业可行性的,新的单罐式制备方法。所述制备方法利用适当的烷基化剂和无机碱,把羟基烟酸(通式II)转成相应的烷氧基烟酸(通式I)。
根据本发明的优选实施例,本发明提供了一种制备烷氧基烟酸(通式I)的方法。其中方法包含,将羟基烟酸(通式II)与二烷基硫酸盐处理,在含有无机碱的水(0℃-40℃)中,形成烷氧基烟酸烷基酯;以及在水、稀释的无机碱和适当的有机溶剂中,对烷氧基烟酸烷基酯进行原位水解,以制备相应的烷氧基烟酸(通式I)。
根据本发明的另一个优选实施例提供了一种制备通式I所示的烷氧基烟酸的方法,其中用于水解步骤的有机溶剂经由层分法分离,而且在该方法中循环使用。
具体实施方式
本发明的公开实施例涉及一种制备烷氧基烟酸的方法。这方法的优点在于避免处理危险的原料,同时把这过程中用过的原料,有效地再循还使用。再者,本方法包括了应用适合工业用的溶剂,以及删除无益的处理步骤,以求更具有安全性和成本效益。
本发明公开的方法提供了一种由相应的羟基烟酸制备烷氧基烟酸的单罐式方法。所述方法包括羟基烟酸(通式II)的烷基化,
其中,
a)R1代表OH,而R2、R3和R4选自氢、C1-C4直链和支链烷基;
b)R2代表OH,而R1、R3和R4选自氢、C1-C4直链和支链烷基;
c)R3代表OH,而R1、R2和R4选自氢、C1-C4直链和支链烷基;
d)R4代表OH,而R1、R2和R3选自氢、C1-C4直链和支链烷基。
所述烷基化反应是在0℃至40C之间使用烷基化剂和溶解于水的无机碱进行。所述反应之后,用水、适当的有机溶剂和稀释的无机碱,将烷氧基烟酸烷基酯水解,从而产生相应的烷氧基烟酸(通式I)。
其中,
a)R1代表OR,其中R是甲基或者乙基,而R2、R3和R4选自氢、C1-C4直链和支链烷基;
b)R2代表OR,其中R是甲基或者乙基,而R1、R3和R4选自氢、C1-C4直链和支链烷基;
c)R3代表OR,其中R是甲基或者乙基,而R1、R2和R4选自氢、C1-C4直链和支链烷基;
d)R4代表OR,其中R是甲基或者乙基,而R1、R2和R3选自氢、C1-C4直链和支链烷基。
所述的方法包括:在20-40℃温度范围内,最好使羟基烟酸与碱在水中反应;将反应物冷却到0至15℃之间;加入二烷基硫酸盐以产生烷氧基烟酸烷基酯;使用碱金属氢氧化物、水和有机溶剂,在15-40℃温度范围内水解烷氧基烟酸烷基酯;分离有机溶剂层和调整水层的酸碱度,维持酸碱度在pH=2-4的范围内,从而制得固体产物;纯化最终的产物以获得高纯度的烷氧基烟酸。
本方法所用的二烷基硫酸盐可选自硫酸二甲酯或者硫酸二乙酯。无机碱可选自包含碱金属氢氧化物及碳酸盐的组,最好是氢氧化钠、氢氧化钾、碳酸钠和碳酸钾。
烷氧基烟酸烷基酯的水解是在原位进行的,利用有机溶剂(最好用四氢呋喃或二氧六环),然后与氢氧化钠溶液和水在室温下水解,促使烷氧基烟酸钠盐的形成。这些烷氧基烟酸钠盐,在水层里具有高的水溶度。所以能将对水有高互溶性的有机层分离出来。该方法保证了从水层里完全的除去有机层,而不需要任何附加的程序。
所产生的烷氧基烟酸钠盐,转变成相应的烟酸。其转变的完成是经由加入无机酸把酸碱度调到pH=2-4。最终形成的产物,以固体物质的形态收集。
以下结合实施例进一步阐明本发明,而不意欲以任何方式限制本发明的范围。
实施例-1:6-甲氧基烟酸的制备
将氢氧化钾(30.2g)和水(75ml)加入装有调温槽和空气冷凝器的圆底烧瓶。再加入6-羟基烟酸(25.0g),同时保持25℃的温度。冷却反应物至10℃,把硫酸二甲酯(56.6g)加入反应溶液中。把反应混合物搅拌半个小时,接着加热到25℃,继续搅拌。借助其中使用(甲醇∶乙酸乙酯比=1∶1)的溶剂体系的薄层色谱法,测定以上反应的完成。将四氢呋喃(750ml)加入到反应物中,之后再加入氢氧化钠水溶液(350ml)和水(85.0ml),持续四个小时的搅拌。再用薄层色谱法测定反应的完成。分离有机层(750ml),以备循环使用。将水层冷却到5℃,用18%氢氯酸溶液,在5℃下将酸碱度调整到pH=2-4。过滤所产生的白色沉淀物,并用水冲洗。在25℃,把水(250ml)加到湿的结块上。慢慢把反应物加热到回流温度。将活性碳(2.5g)加入到均匀的溶液中,保持一个小时的回流。趁热将反应物经由(Hyflo bed)滤垫过滤,再用水(10ml)洗涤。再把滤液冷却以产生固状体,用冰水将结块滤过。在真空状态下,把湿的结块烘干(60-65℃)8-10小时,制得6-甲氧基烟酸(25.1g)。甲氧基烟酸的产率达到93%,而高压液相色谱法测出的纯度超过99%。使用质谱分析与熔点分析(240-242℃)对产物进行了鉴定。
实施例-2:用回收的四氢呋喃(THF)制备6-甲氧基烟酸
将氢氧化钾(30.2g)和水(75ml)加入装有调温槽和空气冷凝器的圆底烧瓶。再加入6-羟基烟酸(25.0g),同时保持25℃的温度。冷却反应物至10℃,把硫酸二甲酯(56.6g)加入反应溶液中。将反应混合物搅拌半个小时,接着加热到25℃,继续搅拌。借助其中使用(甲醇∶乙酸乙酯比=1∶1)的溶剂体系的薄层色谱法,测定以上反应的完成。把实施例1中回收的四氢呋喃(750ml)加到反应混合物中,然后再加氢氧化钠水溶液(350ml)和水(85.0ml),持续四个小时的搅拌。再用薄层色谱法测定反应的完成。分离有机层(750ml),留下作为再循环用途。冷却水层到5℃,用18%氢氯酸溶液,在5℃下将酸碱度调整到pH=2-4。过滤所产生的白色沉淀物,并用水冲洗。在25℃,把水(250ml)加到湿的结块上。慢慢把反应物加热到回流温度。将活性碳(2.5g)加入到均匀的溶液中,保持一个小时的回流。趁热将反应物经由(Hyflo bed)滤垫过滤,再用水(10ml)洗过。再把滤液冷却以产生固状体,用冰水将结块滤过。在真空状态下,把湿的结块烘干(60-65℃)8-10小时,制得6-甲氧基烟酸(25.1g)。甲氧基烟酸的产率达到93%,而高压液相色谱法测出的纯度超过99%。使用质谱分析与熔点分析(240-242℃)对产物进行了鉴定。
本领域技术人员可对本发明公开的技术作出某些修改及改良,而不超出由权利要求书所限定的范围。
Claims (7)
1.一种制备通式I所示的烷氧基烟酸的方法,其包括使通式II所示的羟基烟酸与二烷基硫酸盐在在含有无机碱的水中制备烷氧基烟酸烷基酯;使用碱金属氢氧化物、水和有机溶剂对所述烷基酯进行原位水解;通过层分法将有机层分离;并纯化最终反应物以取得通式I所示的烷氧基烟酸,其中在通式I所示的烷氧基烟酸中:
a)R1代表OR,其中R是甲基或者乙基,而R2、R3和R4选自氢、C1-C4直链和支链烷基;
b)R2代表OR,其中R是甲基或者乙基,而R1、R3和R4选自氢、C1-C4直链和支链烷基;
c)R3代表OR,其中R是甲基或者乙基,而R1、R2和R4选自氢、C1-C4直链和支链烷基;
d)R4代表OR,其中R是甲基或者乙基,而R1、R2和R3选自氢、C1-C4直链和支链烷基;其中在通式II所示的羟基烟酸里:
a)R1代表OH,而R2、R3和R4选自氢、C1-C4直链和支链烷基;
b)R2代表OH,而R1、R3和R4选自氢、C1-C4直链和支链烷基;
c)R3代表OH,而R1、R2和R4选自氢、C1-C4直链和支链烷基;
d)R4代表OH,而R1、R2和R3选自氢、C1-C4直链和支链烷基。
2.根据权利要求1的方法,其中所述无机碱是碱金属氢氧化物或碱金属碳酸盐。
3.根据权利要求2的方法,其中所述碱金属是钠或者钾。
4.根据权利要求1的方法,其中所述有机溶剂是水溶性环醚。
5.根据权利要求4的方法,其中所述有机溶剂选自四氢呋喃和二氧六环。
6.根据权利要求1的方法,其中所述的碱金属氢氧化物选自氢氧化钾和氢氧化钠。
7.根据权利要求1的方法,其中所述有机溶剂循环使用。
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