CN111320588A - 一种纯化Lesinurad杂质的方法 - Google Patents
一种纯化Lesinurad杂质的方法 Download PDFInfo
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- CN111320588A CN111320588A CN201811531715.4A CN201811531715A CN111320588A CN 111320588 A CN111320588 A CN 111320588A CN 201811531715 A CN201811531715 A CN 201811531715A CN 111320588 A CN111320588 A CN 111320588A
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- lesinurad
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- dihydrogen phosphate
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- potassium dihydrogen
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- FGQFOYHRJSUHMR-UHFFFAOYSA-N lesinurad Chemical compound OC(=O)CSC1=NN=C(Br)N1C(C1=CC=CC=C11)=CC=C1C1CC1 FGQFOYHRJSUHMR-UHFFFAOYSA-N 0.000 title claims abstract description 49
- 229960003838 lesinurad Drugs 0.000 title claims abstract description 47
- 238000000034 method Methods 0.000 title claims abstract description 20
- 239000012535 impurity Substances 0.000 title claims abstract description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 72
- 238000005406 washing Methods 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 16
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 9
- 239000012266 salt solution Substances 0.000 claims description 7
- 239000000243 solution Substances 0.000 claims description 7
- SPOMEWBVWWDQBC-UHFFFAOYSA-K tripotassium;dihydrogen phosphate;hydrogen phosphate Chemical compound [K+].[K+].[K+].OP(O)([O-])=O.OP([O-])([O-])=O SPOMEWBVWWDQBC-UHFFFAOYSA-K 0.000 claims description 7
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 4
- LEAHFJQFYSDGGP-UHFFFAOYSA-K trisodium;dihydrogen phosphate;hydrogen phosphate Chemical compound [Na+].[Na+].[Na+].OP(O)([O-])=O.OP([O-])([O-])=O LEAHFJQFYSDGGP-UHFFFAOYSA-K 0.000 claims description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000337 buffer salt Substances 0.000 claims description 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- KFGJICJPSZZEEP-UHFFFAOYSA-L dipotassium;hydrogen phosphate;hydrate Chemical compound O.[K+].[K+].OP([O-])([O-])=O KFGJICJPSZZEEP-UHFFFAOYSA-L 0.000 claims 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 1
- 239000008363 phosphate buffer Substances 0.000 claims 1
- XKMYEGSKUFKYQL-UHFFFAOYSA-L potassium sodium dihydrogen phosphate hydrogen carbonate Chemical compound [Na+].[K+].OC(O)=O.OP([O-])([O-])=O XKMYEGSKUFKYQL-UHFFFAOYSA-L 0.000 claims 1
- LJSOLTRJEQZSHV-UHFFFAOYSA-L potassium;sodium;hydron;hydroxide;phosphate Chemical compound [OH-].[Na+].[K+].OP(O)([O-])=O LJSOLTRJEQZSHV-UHFFFAOYSA-L 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 19
- 238000003756 stirring Methods 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- 201000005569 Gout Diseases 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 201000001431 Hyperuricemia Diseases 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- LEHOTFFKMJEONL-UHFFFAOYSA-N Uric Acid Chemical compound N1C(=O)NC(=O)C2=C1NC(=O)N2 LEHOTFFKMJEONL-UHFFFAOYSA-N 0.000 description 2
- TVWHNULVHGKJHS-UHFFFAOYSA-N Uric acid Natural products N1C(=O)NC(=O)C2NC(=O)NC21 TVWHNULVHGKJHS-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 231100000086 high toxicity Toxicity 0.000 description 2
- NAFSTSRULRIERK-UHFFFAOYSA-M monosodium urate Chemical group [Na+].N1C([O-])=NC(=O)C2=C1NC(=O)N2 NAFSTSRULRIERK-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 229940116269 uric acid Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- NYKSBMRQNSCVMO-UHFFFAOYSA-N 4-cyclopropylnaphthalen-1-amine Chemical compound C12=CC=CC=C2C(N)=CC=C1C1CC1 NYKSBMRQNSCVMO-UHFFFAOYSA-N 0.000 description 1
- 208000036487 Arthropathies Diseases 0.000 description 1
- 101000821902 Homo sapiens Solute carrier family 22 member 11 Proteins 0.000 description 1
- 101000821903 Homo sapiens Solute carrier family 22 member 12 Proteins 0.000 description 1
- 208000012659 Joint disease Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 102100030935 Solute carrier family 2, facilitated glucose transporter member 9 Human genes 0.000 description 1
- 102100021493 Solute carrier family 22 member 11 Human genes 0.000 description 1
- 102100021495 Solute carrier family 22 member 12 Human genes 0.000 description 1
- 229940123769 Xanthine oxidase inhibitor Drugs 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 description 1
- MKIJJIMOAABWGF-UHFFFAOYSA-N methyl 2-sulfanylacetate Chemical compound COC(=O)CS MKIJJIMOAABWGF-UHFFFAOYSA-N 0.000 description 1
- POVXOWVFLAAVBH-UHFFFAOYSA-N n-formamidoformamide Chemical compound O=CNNC=O POVXOWVFLAAVBH-UHFFFAOYSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000004144 purine metabolism Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- 108010078530 urate transporter Proteins 0.000 description 1
- 239000003064 xanthine oxidase inhibitor Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
- C07D249/12—Oxygen or sulfur atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种纯化Lesinurad杂质的方法。所述方法通过下面的路线纯化,该方法操作简捷安全,收率良好,产品纯度高,有很好的经济效应,适宜工业生产。
Description
技术领域
本发明涉及一种纯化Lesinurad杂质的方法。
背景技术
痛风是由单钠尿酸盐(MSU)沉积所致的晶体相关性关节病,与嘌呤代谢紊乱和/或尿酸排泄减少所致的高尿酸血症直接相关。全球痛风患者高达2000多万。Lesinurad是一款口服的 SLC22A12抑制剂,SLC22A12也被称为尿酸盐转运体1(URAT1)和有机阴离子转运蛋白4 (OAT4)。2015年12月欧洲药品管理局(EMA)批准阿斯利康的药物Lesinurad与另一种降低体内尿酸生成的黄嘌呤氧化酶抑制剂联用作为与痛风关联高尿酸血症的治疗。
以下文献报道了Lesinurad化合物的合成路线:
(1)专利WO2006026356报道的合成路线如下:
该路线为原研厂家报道的化合物专利路线,反应步骤冗长,以化合物D为起始物料来计算,总收率为25.8%左右,且路线中使用了高毒性的硫光气,对环境,健康和安全有一定的影响。
(2)专利WO2014008295报道的合成路线如下:
该路线为原研厂家的制备专利,总收率较好,但路线中使用高毒性的硫光气。
(3)中国专利CN102040546报道的合成路线如下
该路线虽然避免使用对环境,健康及安全有害的硫光气,但具有所使用的起始原料不易得,价格昂贵,且总收率也只有25%左右等缺点。
(4)中国专利CN103524440报道的合成路线如下:
该路线和原研厂家的制备路线所用思路类似,都是通过不同的联肼类试剂环合得到巯基三氮唑环,然后上溴再水解得到Lesinurad。但该方法反应步骤长,且路线中使用了高毒性的二硫化碳,该工艺在溴化步骤中需要过柱纯化,操作复杂,不适合工业化生产。
综合分析现有的Lesinurad制备方法可知,发现Lesinurad结构上的溴大多是通过氨基转化而来,该步骤操作复杂且所用原料或试剂价格昂贵,生产成本高。另外现有的制备方法大多用到高毒性的硫光气或二硫化碳,从而造成这些路线在反应操作安全性,经济性以及规模化生产上存在诸多不利因素。
发明内容
本发明所要解决的技术问题是克服现有技术的不足,提供Lesinurad杂质一种新的纯化方法,相比于现有技术,能够很好的获得高纯度的Lesinurad,简化了繁琐的操作步骤,同时解决了多次纯化收率低的问题,提高生产效率;本方法具有后处理简单,收率高,纯度高,易于工业化等优点。
本发明通过以下技术方案实现:通过特定pH的盐溶液的洗涤作用,去除Lesinurad反应液或后处理溶液中的式I化合物和式II化合物,得到均一高纯度Lesinurad,其结构式如下:
本发明涉及一种Lesinurad杂质的纯化方法。
一种Lesinurad杂质的纯化方法,概括如下:
通过特定pH的盐溶液的洗涤作用,去除Lesinurad反应液或后处理溶液中的式I化合物和式II化合物,得到均一高纯度Lesinurad,其结构式如下:
在该制备方法中,其特征在于盐溶液pH为3.5~6.8;盐溶液选自缓冲盐;溶剂选自乙酸乙酯、乙酸异丙酯、二氯甲烷、乙酸甲酯、乙酸丁酯、甲酸乙酯、4-甲基-2-戊酮、丙酸乙酯的一种或几种;洗涤后式I化合物和式II化合物残留HPLC纯度分别<0.5%;析晶体积为1倍~12倍体积;析晶温度为-10~50℃;其特征在于高纯度Lesinurad纯度为≥98.0%。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。
实施例1:4-(4-环丙基萘)-1,2,4-三氮唑的制备
在三口瓶中,加入4-环丙基-1-萘胺(化合物1 20.00g,110.00mmol),二甲酰肼(29.06g, 330.00mmol)以及吡啶(200.00ml,10V),在室温下,缓慢滴加三甲基氯硅烷(59.75g,550.00 mmol),反应随后升温回流2小时。LC确认反应结束后,过滤除去不溶性固体盐,滤液浓缩至干,所得残余物加乙酸乙酯溶解,有机相用水洗涤两次,干燥有机相,减压浓缩至约30.00ml, 向浓缩液加甲基叔丁基醚90.00ml,所得悬浮液打浆搅拌1小时,抽滤得化合物2(纯度:98%),产率(70%)。
1H NMR(400MHz,CDCl3)δ8.56(d,J=8.4Hz,1H),8.41(s,2H),7.70-7.66(m,1H),7.60-7.56(m,1H),7.44(d,J=8.4Hz,1H),7.38(d,7.6Hz,1H),7.36(d,7.6Hz,1H),2.44-2.40(m, 1H),1.20-1.15(m,2H),0.86-0.82(m,2H);MS(ESI)m/z 236.11([M+H]+)。
实施例2:4-(4-环丙基萘)-3,5-二溴-1,2,4-三氮唑的制备
在三口瓶中,加入4-(4-环丙基萘)-1,2,4-三氮唑(化合物2 11.50g,48.91mmol),四氢呋喃(69.00ml,6V),在室温下,分批加入N-溴代丁二酰亚胺(34.96g,122.28mmol)。反应随后在40℃下搅拌2小时。LC确认反应结束后。乙酸乙酯稀释反应液,有机相分别用30%硫代硫酸钠以及饱和碳酸氢钠溶液洗涤两次,干燥浓缩。残余物加甲基叔丁基醚40.00ml,悬浮液搅拌打浆1小时,抽滤,滤饼用甲基叔丁基醚10.00ml洗涤两次,得式III化合物(纯度: 99%),产率(85%)。
1H NMR(400MHz,CDCl3)δ8.58(d,J=8.4Hz,1H),7.71-7.67(m,1H),7.62-7.58(m,1H),7.41(d,7.6Hz,1H),7.35(d,7.6Hz,1H),7.18(d,J=8.4Hz,1H),2.47-2.44(m,1H),1.21-1.18(m,2H),0.92-0.88(m,2H);MS(ESI)m/z 391.93([M+H]+)。
实施例3:
Lesinurad粗品的合成:
20~30℃条件下,将2.5kg式III化合物和DMF10L加入到反应釜中搅拌,将DBU(18.5kg) 加入反应体系中继续搅拌;继续加入巯基乙酸甲酯14.5kg,加料毕,继续保温20~30℃反应2 小时,继续向反应体系内缓慢加入氯乙酸甲酯3.5kg,继续保温搅反应1小时,停止反应;向体系缓慢加入乙酸乙酯25L,保温搅拌,继续向体系中缓慢加入1N盐酸10L,搅拌10~20分钟,静置分层;收集有机相,有机相减压蒸发至基本无馏分,继续向浓缩物中加入四氢呋喃 18L溶解。控温25~35℃下,向其中滴加预先配制的氢氧化钠溶液(9.3kg氢氧化钠溶于20L 纯化水);加毕,保温反应2小时,反应完毕后,减压蒸馏反应体系至体系基本无馏分,将反应体系用盐酸调pH至6~7,用乙酸乙酯萃取两次,合并两次乙酸乙酯层,去除乙酸乙酯,得到Lesinurad粗品3.3kg待用(理论2.57kg)。
实施例4:Lesinurad的合成:
将Lesinurad粗品液330g溶于乙酸乙酯中(3750ml,15vol),用pH为4.5的磷酸二氢钾 -磷酸氢二钾水溶液洗涤两次,洗涤后保留乙酸乙酯相,蒸发去除乙酸乙酯至2500ml(10vol) 将体系降温至15℃搅拌2h,过滤,滤渣去除溶剂,得到白色纯品Lesinurad,HPLC检测纯度 99.65%(218.5g,产率85.0%)。1H NMR(400MHz,CDCl3)δ8.57(d,J=8.4Hz,1H),8.26(bs, 1H),7.70-7.66(m,1H),7.62-7.58(m,1H),7.38(s,2H),7.23(d,J=8.4Hz,1H),4.03(d,J=15.6 Hz,1H),3.96(d,J=15.6Hz,1H),2.47-2.43(m,1H),1.22-1.17(m,2H),0.91-0.87(m,2H);MS (ESI)m/z 404.00([M+H]+)。
实施例5:Lesinurad的合成:
将Lesinurad粗品液330g溶于乙酸乙酯中(3750ml,15vol),用pH为3.5的磷酸二氢钾-磷酸氢二钾水溶液洗涤两次,洗涤后保留乙酸乙酯相,蒸发去除乙酸乙酯至2500ml(10vol) 将体系降温至15℃搅拌2h,过滤,滤渣去除溶剂,得到白色纯品Lesinurad,HPLC检测纯度 98.95%(205g,产率79.7%)。MS(ESI)m/z 404.00([M+H]+)。
实施例6:Lesinurad的合成:
将Lesinurad粗品液33g溶于乙酸乙酯中(375ml,15vol),用pH为6.8的磷酸二氢钾- 磷酸氢二钾水溶液洗涤两次,洗涤后保留乙酸乙酯相,蒸发去除乙酸乙酯至250ml(10vol) 将体系降温至15℃搅拌2h,过滤,滤渣去除溶剂,得到白色纯品Lesinurad,HPLC检测纯度 98.5%(19g,产率73.8%)。MS(ESI)m/z 404.00([M+H]+)。
实施例7:Lesinurad的合成:
将Lesinurad粗品液33g溶于二氯甲烷中(375ml,15vol),用pH为4.5的磷酸二氢钾- 磷酸氢二钾水溶液洗涤两次,洗涤后保留二氯甲烷相,蒸发去除二氯甲烷至250ml(10vol) 将体系降温至15℃搅拌2h,过滤,滤渣去除溶剂,得到白色纯品Lesinurad,HPLC检测纯度 99.1%(20.3g,产率78.9%)。MS(ESI)m/z 404.00([M+H]+)。
实施例8:Lesinurad的合成:
将Lesinurad粗品液330g溶于乙酸丁酯中(3750ml,15vol),用pH为4.5的磷酸二氢钾-磷酸氢二钾水溶液洗涤两次,洗涤后保留乙酸丁酯相,蒸发去除乙酸丁酯至2500ml(10vol) 将体系降温至15℃搅拌2h,过滤,滤渣去除溶剂,得到白色纯品Lesinurad,HPLC检测纯度 99.0%(200g,产率77.7%)。MS(ESI)m/z 404.00([M+H]+)。
实施例9:Lesinurad的合成:
将Lesinurad粗品液33g溶于乙酸乙酯中(375ml,15vol),用pH为4.5的磷酸二氢钠- 磷酸氢二钠水溶液洗涤两次,洗涤后保留乙酸乙酯相,蒸发去除乙酸乙酯至250ml(10vol) 将体系降温至15℃搅拌2h,过滤,滤渣去除溶剂,得到白色纯品Lesinurad,HPLC检测纯度 98.9%(19.7g,产率76.6%)。MS(ESI)m/z 404.00([M+H]+)。
实施例9:Lesinurad的合成:
将Lesinurad粗品液33g溶于乙酸乙酯中(375ml,15vol),用pH为4.5的磷酸二氢钠- 磷酸氢二钠水溶液洗涤两次,洗涤后保留乙酸乙酯相,蒸发去除乙酸乙酯至250ml(10vol) 将体系降温至15℃搅拌2h,过滤,滤渣去除溶剂,得到白色纯品Lesinurad,HPLC检测纯度 98.9%(19.7g,产率76.6%)。MS(ESI)m/z 404.00([M+H]+)。
Claims (8)
2.根据权利要求1所述的方法,其特征在于盐溶液pH为3.5~6.8,进一步优选pH为4.5~5.5。
3.根据权利要求1所述的方法,其特征在于盐溶液选自缓冲盐,优先选择磷酸盐缓冲盐,如磷酸二氢钾-磷酸氢二钾、磷酸二氢钠-磷酸氢二钠、磷酸二氢钾-氢氧化钠、磷酸二氢钾-氢氧化钾、磷酸二氢钾-碳酸钠,进一步优选磷酸二氢钾-磷酸氢二钾。
4.根据权利要求1所述的方法,其特征在于溶剂选自乙酸乙酯、乙酸异丙酯、二氯甲烷、乙酸甲酯、乙酸丁酯、甲酸乙酯、4-甲基-2-戊酮、丙酸乙酯的一种或几种,进一步优选乙酸乙酯为溶剂。
5.根据权利要求1所述的方法,其特征在于洗涤后式I化合物和式II化合物残留HPLC纯度分别<0.5%,进一步优选≤0.3%。
6.根据权利要求1所述的方法,其特征在于析晶体积为1倍~12倍体积,进一步优选体积为4倍~6倍。
7.根据权利要求1所述的方法,其特征在于析晶温度为-10~50℃,进一步优选温度为5~20℃。
8.根据权利要求1所述的方法,其特征在于高纯度Lesinurad纯度为≥98.0%,进一步优选纯度为≥99.0%。
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