CN116375687A - 一种高纯度的氯沙坦钾及其制备方法 - Google Patents
一种高纯度的氯沙坦钾及其制备方法 Download PDFInfo
- Publication number
- CN116375687A CN116375687A CN202111577590.0A CN202111577590A CN116375687A CN 116375687 A CN116375687 A CN 116375687A CN 202111577590 A CN202111577590 A CN 202111577590A CN 116375687 A CN116375687 A CN 116375687A
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- Prior art keywords
- compound
- losartan
- azide
- compounds
- organic solvent
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- 229960000519 losartan potassium Drugs 0.000 title claims abstract description 33
- OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 238000000034 method Methods 0.000 claims abstract description 27
- -1 azide compounds Chemical class 0.000 claims abstract description 16
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- 229940125904 compound 1 Drugs 0.000 claims abstract description 9
- 229940125782 compound 2 Drugs 0.000 claims abstract description 5
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 22
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 20
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 claims description 19
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- 229960004773 losartan Drugs 0.000 claims description 16
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 claims description 16
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
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- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims description 8
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
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- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
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- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 claims description 4
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- DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 claims description 4
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- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical group Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 claims description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- UCSVJZQSZZAKLD-UHFFFAOYSA-N ethyl azide Chemical compound CCN=[N+]=[N-] UCSVJZQSZZAKLD-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- 230000020477 pH reduction Effects 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- GMRIOAVKKGNMMV-UHFFFAOYSA-N tetrabutylazanium;azide Chemical compound [N-]=[N+]=[N-].CCCC[N+](CCCC)(CCCC)CCCC GMRIOAVKKGNMMV-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- SEDZOYHHAIAQIW-UHFFFAOYSA-N trimethylsilyl azide Chemical compound C[Si](C)(C)N=[N+]=[N-] SEDZOYHHAIAQIW-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
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- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 2
- 239000011574 phosphorus Substances 0.000 abstract description 2
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 abstract 1
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- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明属于医药化工领域,涉及一种高纯度的氯沙坦钾及其制备方法。本发明公开了一种含有化合物I和II的氯沙坦钾及其控制方法、新化合物I和III与化合物II和IV及其制备方法。化合物1或2经叠氮化可以分别得到化合物I或化合物II,利用有机磷将叠氮化合物I和II可以还原成氨基化合物III和IV,降低叠氮化合物I和II的含量从而可以较好的控制氯沙坦钾中的基因毒性,具有很强的实用性。
Description
技术领域:
本发明涉及一种高纯度的氯沙坦钾及其制备方法,属于医药化工领域。
背景技术:
氯沙坦钾是由美国默克公司开发的抗高血压药,1994年首次上市,也是全球第一个治疗高血压的血管紧张素II受体拮抗剂。通过阻滞I型血管紧张素Ⅱ受体,抑制血管收缩和醛固酮的释放而降低血压。结构如下所示:
氯沙坦钾的常用的合成路线如下所示:
发明人在研究上述制备过程中发现存在一种未曾被报道过的新的叠氮化合物,且在后处理很难除去,严重影响氯沙坦钾成品质量。由于叠氮化合物能够抑制细胞色素氧化酶以及多种酶的活性,并导致磷酸化及细胞呼吸的异常,引起血管张力极度降低;损害生物细胞,阻碍生物的新陈代谢;在较低浓度水平时也可能会直接引起DNA损伤,导致DNA的诱变,从而引发癌症,叠氮化物应根据人用药物注册技术要求国际协调会(ICH)-M7指导原则作为致遗传突变杂质进行控制,因此在药物生产过程中,必须严格控制药物和医药中间体中叠氮化物的含量。
发明内容:
本发明的目的是提供一种高纯度的氯沙坦钾及其制备方法,将叠氮化合物转化为氨基化合物,有效控制药物的基因毒性从而提高药品安全性。
第一方面,本发明提供一种高纯度的氯沙坦钾,其中化合物I和II的含量小于0.1%,优选小于10ppm,化合物I和II结构式如下所示:
本发明提供一种制备上述的氯沙坦钾的方法,其特征在于包含以下步骤:
a)在水溶液用有机膦试剂处理氯沙坦使其中的化合物I转化为化合物III,和化合物II转化为化合物IV:
b)从水溶液分离得到氯沙坦;
c)氯沙坦和氢氧化钾成盐并分离得到氯沙坦钾。
优选步骤a)中的氯沙坦由以下方法制备得到:由化合物1与叠氮试剂在芳香烃类溶剂、催化剂存在下反应,反应结束后加入碱性溶液使反应体系分为三层,分去水层和有机层,得到含氯沙坦、化合物I和化合物II的中间层,所述化合物1结构式如下所示:
优选所述的叠氮试剂是叠氮化钠;芳香烃类溶剂是甲苯;催化剂是三乙胺盐酸盐。
优选所述碱性溶液是碳酸钠溶液。
优选步骤a)反应温度是20~70℃,反应时间是0.5~2h。
其中步骤b)中后处理还包括以下步骤:降温、酸化、升温、析晶。
优选步骤b)的降温温度为0~10℃;所述酸化pH至2~6;所述升温温度为20~25℃。
所述的水溶液是水或亲水性有机溶剂与水的混合溶液,优选亲水性有机溶剂为四氢呋喃,丙酮,甲醇,乙腈中一种或几种;优选水溶液中水的含量大于等于50%,进一步优选为大于等于90%。
优选所述的有机膦试剂为三价有机磷化合物,进一步优选三苯基膦,三对苯甲基膦,三(2-呋喃基)膦,三叔丁基膦中一种或几种,更进一步优选三苯基膦。
优选所述的有机膦用量相对于氯沙坦的摩尔比为1:50~1000,进一步优选1:50~500,更进一步优选1:100。
本发明还提供一种由上述的氯沙坦钾与药用辅料组成的组合物。
第二方面,本发明提供了一种新的化合物I,
第三方面,本发明提供一种化合物I或II的制备方法,包括如下步骤:
碱性条件下在有机溶剂和和叠氮化试剂体系中,用化合物1制备得化合物I,或用化合物2制备得化合物II。
优选所述的有机溶剂为非质子有机溶剂,进一步优选甲苯,二甲苯,乙酸乙酯,乙酸丁酯,二氯甲烷,四氢呋喃中的一种或几种。
优选所述的碱为有机胺,优选1,8-二氮杂二环十一碳-7-烯,三乙胺,N-甲基吗啉,吡啶中的一种或几种。
优选所述的叠氮化试剂为叠氮磷酸二苯酯,叠氮钠,叠氮乙酸乙酯,三甲基硅叠氮,叠氮化四丁基铵中的一种或几种。
第四方面,本发明提供一种控制氯沙坦钾质量的方法,步骤如下:
1)在水溶液中将含化合物I和II的氯沙坦用有机膦试剂处理,使其中化合物I转化为化合物III,和/或使化合物II转化为化合物IV,
2)检测步骤1)得到的氯沙坦钾,其中化合物I和II含量分别小于0.1%,优选分别小于10ppm。
所述的水溶液是水或亲水性有机溶剂与水的混合溶液,优选亲水性有机溶剂为四氢呋喃,丙酮,甲醇,乙腈中一种或几种;优选水溶液中水的含量大于等于50%,进一步优选为大于等于90%。
优选所述的有机膦试剂为三价有机磷化合物,进一步优选三苯基膦,三对苯甲基膦,三(2-呋喃基)膦,三叔丁基膦中一种或几种,更进一步优选三苯基膦。
优选所述的有机膦用量相对于氯沙坦的摩尔比为1:50~1000,进一步优选1:50~500,更进一步优选1:100。
第五方面,本发明提供一种新的化合物III,其特征在于结构式如下所示:
第六方面,本发明提供一种制备化合物III和IV的方法,包括如下步骤:
在水溶液和有机膦试剂体系中,由化合物I制备得化合物III,或由化合物II制备得化合物IV。
所述的水溶液是亲水性有机溶剂与水的混合溶液,优选亲水性有机溶剂为四氢呋喃,丙酮,甲醇,乙腈中一种或几种;亲水性有机溶剂与水的体积比是0.5-100:1,优选1-50:1,更优选1-30:1。
优选所述的有机膦试剂为三价有机磷化合物,进一步优选三苯基膦,三对苯甲基膦,三(2-呋喃基)膦,三叔丁基膦中一种或几种,更进一步优选三苯基膦。
优选所述的有机膦试剂的用量相至于化合物I或化合物II的摩尔比为5~100:1,进一步优选10~50:1,更进一步优选20:1。
本发明还提供了一种化合物I和II或化合物III和IV的用途,可作为氯沙坦钾有关物质检查或分析的标准对照品。
本发明还提供了一种化合物I和II或化合物III和IV的检测方法,其特征在于检测条件如下:流动相A:0.01mol/L的磷酸二氢钾溶液,用浓磷酸调pH=3.3;流动相B:乙腈;柱温:25℃;检测波长:215nm;流速:1.0mL/min;进样量:20μL,梯度洗脱,优选以下洗脱梯度程序:
时间(min) | 流动相A(%V/V) | 流动相B(%V/V) |
0 | 62 | 38 |
10 | 62 | 38 |
35 | 20 | 80 |
45 | 20 | 80 |
46 | 62 | 38 |
55 | 62 | 38 |
。
本发明通过提供一种氯沙坦钾及其制备方法。化合物1和碱性条件下在有机溶剂和碱性条件下和叠氮化试剂反应体系中,用化合物1制备得化合物I和II,或用化合物2制备的化合物II。化合物I和II可用于氯沙坦钾粗品及成品分析方法中对该杂质进行准确定位及外标法定量研究。利用有机磷将叠氮化合物还原成氨基化合物,降低叠氮化合物I和II的含量从而可以较好的控制氯沙坦钾中的基因毒性,具有很强的实用性。
附图说明:
图1为实施例中制备得到的4'-((5-(叠氮甲基)-2-丁基-4-氯-1H-咪唑-1-基)甲基)-[1,1'-联苯]-2-腈(化合物I)质谱图。
图2为实施例制备得到的4'-((5-(叠氮甲基)-2-丁基-4-氯-1H-咪唑-1-基)甲基)-[1,1'-联苯]-2-腈(化合物I)核磁共振H1-NMR图。
图3为实施例制备得到的4'-((5-(氨基甲基)-2-丁基-4-氯-1H-咪唑-1-基)甲基)-[1,1'-联苯]-2-腈(化合物III)质谱图。
图4为实施例制备得到的4'-((5-(氨基甲基)-2-丁基-4-氯-1H-咪唑-1-基)甲基)-[1,1'-联苯]-2-腈(化合物III)核磁共振H1-NMR图。
图5为实施例五制备得到的4'-((5-(叠氮甲基)-2-丁基-4-氯-1H-咪唑-1-基)甲基)-[1,1'-联苯]-2-腈(化合物I)的LCMS-MS检测图谱。
图6为实施例五制备得到氯沙坦钾中化合物I的LCMS-MS检测图谱。
图7为实施例五制备得到的5-(4'-((5-(叠氮甲基)-2-丁基-4-氯-1H-咪唑-1-基)甲基)-[1,1'-联苯]-2-基)-1H-四唑(化合物II)的LCMS-MS检测图谱。
图8为实施例五制备得到氯沙坦钾中化合物II的LCMS-MS检测图谱。
具体实施方式:
以下具体的制备实施例在于详细说明本发明,实施例仅用于更详细具体说明之用,而非以任何形式限制本发明。
本发明采用的HPLC检测方法:
1.色谱条件
仪器:高效液相色谱仪配备紫外检测器(UV)
色谱柱:Shimpack CLC-ODS 150×6.0mm,5μm
流动相A:0.01mol/L的磷酸二氢钾溶液,用浓磷酸调pH=3.3
流动相B:乙腈
柱温:25℃ 检测波长:215nm
流速:1.0mL/min 进样量:20μL
梯度表:
时间(min) | 流动相A(%V/V) | 流动相B(%V/V) |
0 | 62 | 38 |
10 | 62 | 38 |
35 | 20 | 80 |
45 | 20 | 80 |
46 | 62 | 38 |
55 | 62 | 38 |
2.试剂
乙腈:色谱纯 浓磷酸:分析纯或色谱纯
磷酸二氢钾:分析纯或色谱纯 水:超纯水
3.溶液配制
稀释液:水:乙腈=65:35(%V/V)
空白溶液:稀释液
供试品溶液:称取40mg供试品,精密称定于100mL容量瓶中,用稀释液超声溶解并稀释至刻度,混匀。
注:供试品溶液在35h内稳定(室温贮存)。
4.步骤:分别进样空白溶液1针、供试品溶液1针,记录色谱过程。
化合物I和II的制备路线:
实例一:
三口瓶中依次加入10g化合物1和100ml甲苯,降温至5℃,然后缓慢加入10g叠氮磷酸二苯酯保温搅拌30min,随后缓慢加入8g 1,8-二氮杂二环十一碳-7-烯保温搅拌至固体全部溶清,继续保温搅拌1小时。保温结束后反应液升至室温,继续搅拌2~3小时,停止反应,反应液水洗两次(50ml*2),有机相浓缩,浓缩液通过柱色谱分离得棕黄色油状物I(展开剂:正己烷:乙酸乙酯=5:1),收率72%,HPLC纯度大于96%。
实例二:
三口瓶中依次加入10g化合物2(氯沙坦)和100ml甲苯,降温至5℃,然后缓慢加入12g叠氮磷酸二苯酯保温搅拌30min,随后缓慢加入9g 1,8-二氮杂二环十一碳-7-烯保温搅拌至固体全部溶清,继续保温搅拌1小时。保温结束后反应液升至室温,继续搅拌2~3小时,停止反应,反应液水洗两次(50ml*2),有机相浓缩,浓缩液通过柱色谱分离得浅黄色固体II(展开剂:正己烷:乙酸乙酯=5:1),收率75%,HPLC纯度大于98%。
化合物III和IV的制备路线:
实例三:
三口瓶中依次加入10g化合物I、100ml四氢呋喃和10g三苯基膦,升温至50℃保温反应5~6小时,然后加入20ml水继续保温1~2小时,反应结束后反应液浓缩去除四氢呋喃,浓缩液中加入100ml乙酸乙酯搅拌溶清。溶清液中缓慢滴加6N盐酸调pH至1~3,分液,水相用乙酸乙酯洗涤两次(50ml*2),洗涤后的水相加入100ml乙酸乙酯,滴加30%氢氧化钠水溶液调节pH>11,分液,有机相用50ml饱和食盐水洗涤一次,浓缩有机相得浅黄色固体III,收率68%,HPLC纯度95%。
实例四:
三口瓶中依次加入10g化合物II、100ml四氢呋喃和10g三苯基膦,升温至50℃保温反应5~6小时,然后加入20ml水继续保温1~2小时,反应结束后反应液浓缩去除四氢呋喃,浓缩液中加入100ml乙酸乙酯搅拌溶清。溶清液中缓慢滴加6N盐酸调pH至1~3,分液,水相用乙酸乙酯洗涤两次(50ml*2),洗涤后的水相加入100ml乙酸乙酯,滴加30%氢氧化钠水溶液调节pH=4.5~5.5,分液,有机相用50ml饱和食盐水洗涤一次,浓缩有机相得浅黄色固体IV,收率60%,HPLC纯度95%。
高纯度氯沙坦钾的制备方法:
实施例五
依次向反应瓶加入200mL甲苯,47.6g三乙胺盐酸盐,58.2g化合物1,0.8g TBAB,21.6g叠氮钠。加入完毕,升温至100℃反应48h。保温反应结束后,用饱和碳酸钠溶液150mL洗涤三次,分去下层水层和上层甲苯层,料层加入140mL水,检测叠氮氯沙坦化合物I含量为500ppm,化合物II含量为2000ppm。加入0.5g三苯基膦,45℃,保温反应1h。降温至0~10℃,滴加6mol/L盐酸,调节pH至4,调酸结束后,升温20~25℃,保温析晶2h。抽滤,固体在氢氧化钾的异丙醇水混合溶液中成盐,重结晶、抽滤、干燥得到氯沙坦钾,收率75%,HPLC纯度大于99.9%。检测氯沙坦钾中的化合物I和II的含量低于检测限(检测限为3.0ppm)。
Claims (24)
4.根据权利要求3所述的方法,其特征在于所述的叠氮试剂是叠氮化钠;芳香烃类溶剂是甲苯;催化剂是三乙胺盐酸盐。
5.根据权利要求3所述的方法,其特征在于所述碱性溶液是碳酸钠溶液。
6.根据权利要求2所述的方法,其特征在于步骤a)反应温度是20~70℃,反应时间是0.5~2h。
7.根据权利要求2所述的方法,所述的步骤b)中后处理还包括以下步骤:降温、酸化、升温、析晶。
8.根据权利要求7所述的方法,所述降温温度为0~10℃;所述酸化pH至2~6;所述升温温度为20~25℃。
9.一种氯沙坦钾组合物,其特征在于包含权利要求1所述的氯沙坦钾与药用辅料组成的混合物。
12.根据权利要求11所述的制备方法,其特征在于所述的有机溶剂为非质子有机溶剂,优选甲苯,二甲苯,乙酸乙酯,乙酸丁酯,二氯甲烷,四氢呋喃中的一种或几种。
13.根据权利要求11所述的制备方法,其特征在于所述的碱为有机胺,优选1,8-二氮杂二环十一碳-7-烯,三乙胺,N-甲基吗啉,吡啶中的一种或几种。
14.根据权利要求11所述的制备方法,其特征在于所述的叠氮化试剂为叠氮磷酸二苯酯,叠氮钠,叠氮乙酸乙酯,三甲基硅叠氮,叠氮化四丁基铵中的一种或几种。
16.根据权利要求2、15所述的方法,其特征在于所述的水溶液是水或亲水性有机溶剂与水的混合溶液,优选亲水性有机溶剂为四氢呋喃,丙酮,甲醇,乙腈中一种或几种;优选水溶液中水的含量大于等于50%,进一步优选为大于等于90%。
19.根据权利要求18所述的方法,其特征在于所述的水溶液是亲水性有机溶剂与水的混合溶液,优选亲水性有机溶剂为四氢呋喃,丙酮,甲醇,乙腈中一种或几种;亲水性有机溶剂与水的体积比是0.5-100:1,优选1-50:1,更优选1-30:1。
20.根据权利要求2、15或18所述的方法,其特征在于所述的有机膦试剂为三价有机磷化合物,优选三苯基膦,三对苯甲基膦,三(2-呋喃基)膦,三叔丁基膦中一种或几种。
21.根据权利要求2或15的方法,其特征在于所述的有机膦用量相对于氯沙坦的摩尔比为1:50~1000,进一步优选1:50~500,更进一步优选1:100。
22.根据权利要求18中的方法,其特征在于所述的有机膦试剂的用量相至于化合物I或化合物II的摩尔比为5~100:1,进一步优选10~50:1,更进一步优选20:1。
23.一种如权利要求10或17所述化合物的用途,其特征在于可作为氯沙坦钾质量控制的标准品或对照品。
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