CN103012301B - 缬沙坦甲酯碱金属盐及其制备方法 - Google Patents
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- -1 Valsartan methyl ester alkali metal salt Chemical class 0.000 title claims abstract description 50
- 229910052783 alkali metal Inorganic materials 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 239000000126 substance Substances 0.000 claims abstract description 10
- 239000004072 C09CA03 - Valsartan Substances 0.000 claims description 28
- 229960004699 valsartan Drugs 0.000 claims description 28
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 19
- 239000007864 aqueous solution Substances 0.000 claims description 14
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 13
- 239000000243 solution Substances 0.000 claims description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims description 8
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 229910001414 potassium ion Inorganic materials 0.000 claims description 8
- 229910001415 sodium ion Inorganic materials 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 4
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 3
- 239000011736 potassium bicarbonate Substances 0.000 claims description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 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
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 229940043232 butyl acetate Drugs 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims description 2
- 229940093499 ethyl acetate Drugs 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 2
- 229940090181 propyl acetate Drugs 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 2
- 230000003287 optical effect Effects 0.000 abstract description 8
- 238000000746 purification Methods 0.000 abstract description 5
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 10
- 238000005516 engineering process Methods 0.000 description 7
- 238000007363 ring formation reaction Methods 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- UJTNRXYTECQKFO-QHCPKHFHSA-N methyl (2s)-3-methyl-2-[pentanoyl-[[4-[2-(2h-tetrazol-5-yl)phenyl]phenyl]methyl]amino]butanoate Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(=O)OC)=CC=C1C1=CC=CC=C1C1=NN=NN1 UJTNRXYTECQKFO-QHCPKHFHSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 0 CCCCC(N(Cc(cc1)ccc1-c(cccc1)c1C1=N[N+](C)(C2)[N-][*+]1)[C@]2C(C)C)=O Chemical compound CCCCC(N(Cc(cc1)ccc1-c(cccc1)c1C1=N[N+](C)(C2)[N-][*+]1)[C@]2C(C)C)=O 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 230000006340 racemization Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 150000003536 tetrazoles Chemical group 0.000 description 2
- 239000004474 valine Substances 0.000 description 2
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- 229940127088 antihypertensive drug Drugs 0.000 description 1
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- 230000007062 hydrolysis Effects 0.000 description 1
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- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了缬沙坦甲酯碱金属盐，结构式如下。本发明还公开了上述缬沙坦甲酯碱金属盐的其制备方法。通过成盐纯化，缬沙坦甲酯碱金属盐的化学纯度和光学纯度比未成盐时有显著提高。
Description
技术领域
本发明涉及一种缬沙坦甲酯碱金属盐及其制备方法，属于药物化学技术领域。
背景技术
缬沙坦甲酯是制备抗高血压药物缬沙坦（Valsartan）的关键中间体，中文名称是：N-(1-戊酰基)-N-[4-[2-(1H-四氮唑-5-基)苯基]苄基]-L-缬氨酸甲酯，结构式如下：
美国专利US5399578A公开了缬沙坦甲酯和缬沙坦原料药的制备方法：N-（1-戊酰基）-N-[4-[2-(5-氰基)苯基]苄基]-L-缬氨酸甲酯与叠氮钠在有机锡化合物的参与下进行环合反应，得到缬沙坦甲酯，不经纯化直接水解用于生产缬沙坦原料药。
该方法使用高毒性的有机锡化合物参与环合反应，缬沙坦甲酯中间体又未经分离纯化，所以生产出的缬沙坦原料药中不可避免残留有微量的有机锡化合物。
中国专利CN101270096A公开的方法中，改用在三乙胺盐酸盐代替高毒的有锡化合物参与反应，避免了产品的毒性物质残留，但该方法在环合过程中，产品消旋化明显，且缬沙坦甲酯中间体也没有分离纯化步骤，导致最终产品缬沙坦需要多次重结晶，其化学纯度和光学纯度才能达到药典标准，操作复杂，收率低，成本高。
目前尚未见到对缬沙坦甲酯中间体进行分离纯化的报道。
发明内容
本发明所要解决的技术问题是提供一种缬沙坦甲酯碱金属盐，为了解决现有工艺技术生产的缬沙坦甲酯化学纯度低、光学纯度低的问题。
本发明还要解决的技术问题是提供上述缬沙坦甲酯碱金属盐的制备方法。
为解决上述技术问题，本发明采用的技术方案如下：
缬沙坦甲酯碱金属盐，结构式如下：
上述缬沙坦甲酯碱金属盐的制备方法，将缬沙坦甲酯或缬沙坦甲酯的有机溶剂溶液，与含钠离子或钾离子的无机碱水溶液混合，搅拌反应成盐，再过滤、洗涤、干燥，得到缬沙坦甲酯碱金属盐。
其中，所述的有机溶剂为酯类、芳烃类、醚类、醇类或其它水溶性极性溶剂。所述的酯类溶剂为乙酸甲酯、乙酸乙酯、乙酸丙酯或乙酸丁酯；所述的芳烃类溶剂为苯、甲苯、乙苯、异丙基苯或二甲苯；所述的醚类溶剂为乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、1,4-二氧六环、乙二醇二甲醚或二乙二醇二甲醚；所述的醇类溶剂为甲醇、乙醇、丙醇、正丁醇或乙二醇；所述的其他水溶性极性溶剂为丙酮、丁酮、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或二甲基亚砜。所述的有机溶剂优选为甲苯或二甲苯。
其中，所述的含钠离子或钾离子的无机碱水溶液为氢氧化钠水溶液、氢氧化钾水溶液、碳酸钠水溶液、碳酸钾水溶液、碳酸氢钠水溶液或碳酸氢钾水溶液。所述的含钠离子或钾离子的无机碱水溶液优选为碳酸氢钠或碳酸氢钾。
其中，缬沙坦甲酯与钠离子或钾离子的反应摩尔比为1:(1~3)，优选1:(1.3~1.6)。
其中，搅拌反应成盐条件为：温度10~40℃、反应时间4~6小时。
其中，干燥温度为80℃真空干燥。
上述缬沙坦甲酯碱金属盐的制备方法中，可以使用经过简单分离纯化的缬沙坦甲酯粗品，也可以使用缬沙坦甲酯的有机溶剂溶液，特别是制备缬沙坦甲酯的环合反应溶液。
有益效果：本发明的缬沙坦甲酯碱金属盐具有以下有益效果：
1）化学纯度高：传统工艺生产的缬沙坦甲酯，由于未进行分离纯化，其化学程度通常低于90%，本发明的缬沙坦甲酯碱金属盐，化学纯度高达99%以上；
2）光学纯度高，传统工艺生产的缬沙坦甲酯，由于在反应过程中不可避免的消旋化，光学纯度通常低于95%，本发明的缬沙坦甲酯碱金属盐，光学纯度高达99%以上；
3）传统工艺生产的缬沙坦甲酯，通常是油状物，难以分离提纯，本发明的缬沙坦甲酯碱金属盐，是白色固体，易于分离、干燥、储存。
具体实施方式
根据下述实施例，可以更好地理解本发明。然而，本领域的技术人员容易理解，实施例所描述的具体的物料配比、工艺条件及其结果仅用于说明本发明，而不应当也不会限制权利要求书中所详细描述的本发明。
实施例1：缬沙坦甲酯钠盐的制备。
在3000ml四口烧瓶中加入1000g缬沙坦甲酯甲苯溶液（环合反应液，含缬沙坦甲酯22%），再加入60g碳酸氢钠和540g水配成的溶液，室温搅拌成盐4小时，过滤，用100g甲苯洗涤，再100g水洗涤，80℃真空干燥到恒重，得到白色缬沙坦甲酯钠盐220g。
HPLC检测，化学纯度为99.4%。
手性HPLC检测，光学纯度为99.2%。
1HNMR分析，没有相应于四唑环上质子的峰。
元素分析：C，63.49%，H，6.45%，N，14.80%，Na，4.85%（理论值：C，63.68%，H，6.41%，N，14.85%，Na，4.88%）。
实施例2：缬沙坦甲酯钾盐的制备。
在3000ml四口烧瓶中加入1000g缬沙坦甲酯乙酸乙酯溶液（含缬沙坦甲酯25%），再加入80g碳酸氢钠和600水配成的溶液，室温搅拌成盐6小时，过滤，用100g甲苯洗涤，再100g水洗涤，80℃真空干燥到恒重，得到白色缬沙坦甲酯钾盐260g。
HPLC检测，化学纯度为99.5%。
手性HPLC检测，光学纯度为99.1%。
1HNMR分析，没有相应于四唑环上质子的峰。
元素分析：C，61.33%，H，6.31%，N，14.28%，K，7.99%（理论值：C，61.58%，H，6.20%，N，14.36%，K，8.02%）。
Claims (3)
1.一种缬沙坦甲酯碱金属盐的制备方法，其特征在于，将缬沙坦甲酯或缬沙坦甲酯的有机溶剂溶液，与含钠离子或钾离子的无机碱水溶液混合，搅拌反应成盐，再过滤、洗涤、干燥，得到缬沙坦甲酯碱金属盐；
其中，所述缬沙坦甲酯碱金属盐，结构式如下：
其中，所述的有机溶剂为酯类、芳烃类、醚类、醇类或其它水溶性极性溶剂；所述的酯类溶剂为乙酸甲酯、乙酸乙酯、乙酸丙酯或乙酸丁酯；所述的芳烃类溶剂为苯、甲苯、乙苯、异丙基苯或二甲苯；所述的醚类溶剂为乙醚、异丙醚、甲基叔丁基醚、四氢呋喃、1，4-二氧六环、乙二醇二甲醚或二乙二醇二甲醚；所述的醇类溶剂为甲醇、乙醇、丙醇、正丁醇或乙二醇；所述的其他水溶性极性溶剂为丙酮、丁酮、N，N-二甲基甲酰胺、N，N-二甲基乙酰胺或二甲基亚砜；
所述的含钠离子或钾离子的无机碱水溶液为氢氧化钠水溶液、氢氧化钾水溶液、碳酸钠水溶液、碳酸钾水溶液、碳酸氢钠水溶液或碳酸氢钾水溶液；
缬沙坦甲酯与钠离子或钾离子的反应摩尔比为1:(1～3)；
搅拌反应成盐条件为：温度10～40℃、反应时间4～6小时；
干燥温度为80℃真空干燥。
2.根据权利要求1所述的缬沙坦甲酯碱金属盐的制备方法，其特征在于，所述的有机溶剂为甲苯或二甲苯。
3.根据权利要求1所述的缬沙坦甲酯碱金属盐的制备方法，其特征在于，所述的含钠离子或钾离子的无机碱水溶液为碳酸氢钠水溶液或碳酸氢钾水溶液。
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| CA2776902A1 (en) * | 2002-02-04 | 2003-08-14 | Novartis Ag | Salts of valsartan |
| US20060149079A1 (en) * | 2005-01-03 | 2006-07-06 | Padi Pratap R | Process for preparing valsartan |
| WO2007006531A1 (en) * | 2005-07-11 | 2007-01-18 | Novartis Ag | Metal salts of 2 ' - ( 1h-tetraz0l-5-yl) -1 . 1 ' -biphenyl-4-carboxaldehyde |
| CN102649780A (zh) * | 2011-02-28 | 2012-08-29 | 广东东阳光药业有限公司 | 一种合成缬沙坦的改进工艺 |
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| US20060149079A1 (en) * | 2005-01-03 | 2006-07-06 | Padi Pratap R | Process for preparing valsartan |
| WO2007006531A1 (en) * | 2005-07-11 | 2007-01-18 | Novartis Ag | Metal salts of 2 ' - ( 1h-tetraz0l-5-yl) -1 . 1 ' -biphenyl-4-carboxaldehyde |
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