TW201946899A - 一種苯基氨基丙酸鈉衍生物、其製備方法和應用 - Google Patents
一種苯基氨基丙酸鈉衍生物、其製備方法和應用 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- FRWYRVGNKNAGHE-UHFFFAOYSA-M sodium;2-anilinopropanoate Chemical class [Na+].[O-]C(=O)C(C)NC1=CC=CC=C1 FRWYRVGNKNAGHE-UHFFFAOYSA-M 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 81
- 239000012535 impurity Substances 0.000 claims abstract description 38
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- 239000000126 substance Substances 0.000 claims abstract description 16
- 238000001514 detection method Methods 0.000 claims abstract description 15
- 238000003908 quality control method Methods 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 12
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
- XAVRUNDYBRCFEO-UHFFFAOYSA-N O1C(CCC1)CC(=O)O.O.CO Chemical compound O1C(CCC1)CC(=O)O.O.CO XAVRUNDYBRCFEO-UHFFFAOYSA-N 0.000 claims description 5
- 229940088679 drug related substance Drugs 0.000 claims description 5
- 239000008186 active pharmaceutical agent Substances 0.000 claims description 3
- YZFWTZACSRHJQD-UHFFFAOYSA-N ciglitazone Chemical compound C=1C=C(CC2C(NC(=O)S2)=O)C=CC=1OCC1(C)CCCCC1 YZFWTZACSRHJQD-UHFFFAOYSA-N 0.000 claims description 3
- 229950009226 ciglitazone Drugs 0.000 claims description 3
- 238000007689 inspection Methods 0.000 claims description 3
- 238000005259 measurement Methods 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 abstract description 24
- 239000011734 sodium Substances 0.000 abstract description 24
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 abstract description 22
- 239000000203 mixture Substances 0.000 abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 6
- 159000000000 sodium salts Chemical class 0.000 abstract description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 abstract description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 2
- 238000009472 formulation Methods 0.000 abstract description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 abstract description 2
- QNLWMPLUWMWDMQ-YTTGMZPUSA-N (2s)-3-[4-(2-carbazol-9-ylethoxy)phenyl]-2-[2-(4-fluorobenzoyl)anilino]propanoic acid Chemical compound N([C@@H](CC=1C=CC(OCCN2C3=CC=CC=C3C3=CC=CC=C32)=CC=1)C(=O)O)C1=CC=CC=C1C(=O)C1=CC=C(F)C=C1 QNLWMPLUWMWDMQ-YTTGMZPUSA-N 0.000 abstract 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
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- 239000012043 crude product Substances 0.000 description 6
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- SPAKMVQVTSVXES-UHFFFAOYSA-N methanol;oxolane;hydrate Chemical compound O.OC.C1CCOC1 SPAKMVQVTSVXES-UHFFFAOYSA-N 0.000 description 6
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- 238000005481 NMR spectroscopy Methods 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
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- LYALWRHNPJTVRU-UHFFFAOYSA-N COC(C(Cc(cc1)ccc1OCC[n]1c2ccccc2c2c1cccc2)Nc(cccc1)c1C(c(cc1)ccc1F)=O)=O Chemical compound COC(C(Cc(cc1)ccc1OCC[n]1c2ccccc2c2c1cccc2)Nc(cccc1)c1C(c(cc1)ccc1F)=O)=O LYALWRHNPJTVRU-UHFFFAOYSA-N 0.000 description 1
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- 108010016731 PPAR gamma Proteins 0.000 description 1
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/26—Conditioning of the fluid carrier; Flow patterns
- G01N30/28—Control of physical parameters of the fluid carrier
- G01N30/34—Control of physical parameters of the fluid carrier of fluid composition, e.g. gradient
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
- G01N2001/2893—Preparing calibration standards
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
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- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
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- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G01N2030/042—Standards
- G01N2030/047—Standards external
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- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
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- G01N2030/062—Preparation extracting sample from raw material
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
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- G01N30/02—Column chromatography
- G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
- G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
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Abstract
本發明公開了苯基氨基丙酸鈉衍生物、其製備方法和應用。具體來說,公開了如式(I)所示的3-(4-(2-(9H-哢唑-9-基)乙氧基)苯基)-2-((2-(4-(4-(2-甲酸鈉-2-((2-(4-氟苯甲醯基)苯基)氨基)乙基)苯氧基)苯甲醯基)苯基)氨基)丙酸鈉,其製備方法及其用於西格列他或其衍生物的原料藥或製劑的品質控制的用途。特別地,該式(I)化合物可以用作西格列他或其鈉鹽藥物中雜質/有關物質檢查的對照品或標準品。
Description
本發明屬於化學製藥領域,具體涉及一種苯基氨基丙酸鈉衍生物,本發明還涉及所述苯基氨基丙酸鈉衍生物的製備方法以及其用作西格列他或其衍生物藥物中的原料藥或製劑的品質控制的用途;特別地,所述苯基氨基丙酸鈉衍生物可以用作西格列他或其鹽(例如鈉鹽)的原料藥或製劑中雜質或有關物質檢查的對照品或標準品。
在中國專利申請CN03126974.5和美國專利申請US7,268,157中均記載了該化合物的藥理活性。西格列他具有選擇性啟動PPAR-α、PPAR-γ和PPAR-δ的能力,可以用於治療與代謝綜合症相關的疾病,如糖尿病、高血壓、肥胖、胰島素抵抗、高甘油三酯血症、高血糖、 高膽固醇、動脈粥樣硬化、冠心病等。
在現有技術中,中國專利申請201610855107.3和中國專利申請201410856282.5中公開了西格列他及其鈉鹽的合成方法。
該方法適合工業化生產,所得目標化合物純度高。然而,由於西格列他的穩定性較差,在藥物製造、貯存和運輸過程中易分解,嚴重影響了該藥物的安全性和有效性,因此,需將其製成穩定性更好的鈉鹽,即西格列他鈉。在中國專利申請201410856282.5中公開了西格列他鈉的製備方法,所述方法如下:
按照上述現有技術中的製備方法,可以製得純度大於99%的西格列他鈉,且工藝穩定可控,適合工業化生產。然而,本發明人通過大量研究意外地發現,HPLC分析(色譜柱:C18柱,Shim-pack VP-ODS 5μm 250L×4.6;流動相:甲醇-水-四氫呋喃-醋酸40:30:30:0.5;檢測波長:236nm;流速:1.5mL/min)表明,在相對保留值約2.4處始終有一未知結構雜質,該雜質隨原料1和原料2的用量相對比例變化在一定範圍內波動。當原料1與原料2的比例為1:1時,該雜質含量約為0.18%(面積歸一化法);當原料1與原料2的比例為1:1.5時,該雜質含量約為0.06%(面積歸一化法)。由於現有技術中一直未公開和報導該雜質的存在及其結構,其藥理毒理性質也是未知的,因此給安全用藥帶來風險。同時,由於該雜質結構未知,且現有技術也未公開報導西格列他鈉的任何雜質資訊及分離方法,這給該雜質的分離和鑒定帶來極大困難。
一方面,為了保證患者的用藥安全,需要確認該未知雜質的結構;另一方面,需要研究該雜質化合物的製備方法,獲得其對照品或參比標準品,用於西格列他或西格列他鈉等藥物的品質控制,尤其是用作有關物質/雜質檢查的對照品或參比標準品。
基於現有技術中的上述需要,本發明的目的之一在於公開現有技術工藝製得的西格列他或西格列他鈉鹽等藥物中存在的上述未知結構化合物。
本發明人研究發現,該雜質為3-(4-(2-(9H-哢唑-9-基)乙氧基)苯基)-2-((2-(4-(4-(2-甲酸鈉-2-((2-(4-氟苯甲醯基)苯基)氨基)乙基)苯氧基)苯 甲醯基)苯基)氨基)丙酸鈉,其結構如式(I)所示:
事實上,上述式(I)化合物的產生並不局限於上述製備西格列他鈉的反應途徑,其同樣可存在於西格列他的合成產物中。
需要指出的是,上述反應路線中所用的反應溶劑和鹼均是示例性的而不是限定性的,本領域技術人員可以進行適當的變換和調整。
在示例性的實施方案中,使化合物(a)與化合物(b)進行縮合反應得到化合物(c)。該反應可以以碳酸銫為催化劑,優選以N,N-二甲基甲醯胺為溶劑,反應溫度可以為80~120℃,反應時間可為20~30小時。所得粗產品可未經進一步純化,直接用於下一步反應。
將化合物(c)酸化得到化合物(d)。所述酸化優選用鹽酸進行。該反應優選以乙酸乙酯和水為溶劑,反應溫度可以為室溫,反應時間可為4~5小時。所得粗產品可以未經進一步純化,直接用於下一步反應。
將化合物(d)在氫氧化鋰存在下進行水解得到化合物(e)。 該反應優選以四氫呋喃和水為溶劑,反應溫度可以為室溫,反應時間可為12~16小時。所得粗產品可以未經進一步純化,直接用於下一步反應。
將化合物(e)酸化得到合物(f)。所述酸化優選用鹽酸進行。該反應優選以乙酸乙酯和水為溶劑,反應溫度可以為室溫,反應時間可為4~5小時。在一個示例性的實施方案中,所得粗產品用半製備液相色譜柱分離(色譜柱:YMC-Pack ODS-AQ 5μm 250L×20;流動相:甲醇-水-四氫呋喃-冰醋酸48:22:30:0.5;檢測波長:236nm;流速:8ml/min),得到純度大於97%的化合物(f)。
將化合物(f)用氫氧化鈉中和得到式(I)化合物。該反應可以以甲醇為溶劑,反應溫度可為室溫,反應時間可為20~40min。
在另一方面,本發明還提供了式(I)化合物用於西格列他或其衍生物的原料藥或製劑的品質控制的用途。特別地,本發明提供了式(I)化合物作為西格列他或西格列他鈉藥物中雜質或有關物質檢查的對照品或標準品的用途。
作為對照品或標準品。
優選地,上述檢測方法優選HPLC方法。
在本發明的一個示例性實施方案中,所述HPLC法的條件如下:色譜柱:C18柱,Shim-pack VP-ODS 5μm 250L×4.6;流動相:甲醇-水-四氫呋喃-醋酸40:30:30:0.5;檢測波長:236nm;流速:1.5mL/min)。
以式(I)化合物作對照品,在西格列他鈉樣品溶液中加入適量式(I)化合物,記錄色譜圖,確認式(I)化合物就是相對保留值約2.4的雜質。分別記錄西格列他鈉樣品溶液和式(I)化合物標準品溶液的色譜圖,採用外標法計算西格列他鈉藥物中式(I)化合物的含量。
本發明的上述HPLC檢測方法的優點是測定結果準確可靠,專屬性強,實用性強,可以有效檢出上述雜質,且所述雜質與西格列他或其鹽之間達到良好分離。
雜質研究是藥品研發的重要內容,貫穿於藥品研發的始終,直接影響到藥物的品質和安全性。為了給西格列他或其衍生物的品質研究提供有關物質對照品,提高西格列他或其衍生物、以及含有西格列他或其衍生物的組合物(包括藥物製劑)的品質標準,為安全用藥提供重要的指導,本發明研究、合成並鑒定了所述工藝雜質。
下面結合實施例進一步闡明本發明的內容,但本發明的保護 範圍並不僅僅局限於這些實施例。本發明所述的百分比除特別注明外,均為重量百分比。說明書中所描述的數值範圍,如計量單位或百分比,均是為了提供明白無誤的書面參考。本領域熟練技術人員在實踐本專利時,基於本發明的教導和原則,使用在此範圍之外或有別於單個數值的溫度、濃度、數量等,仍然可以得到預期的結果。
術語與定義:
“衍生物”:在本發明中,西格列他衍生物不僅包括西格列他游離酸,還包括其鹽,例如無機鹽,例如鈉鹽,以及其水合物。
“雜質”與“相對保留值”:任何影響藥物純度的物質均稱為雜質,一般而言,雜質是指在生產和儲存過程中引進或產生的活性藥物物質以外的其他化學物質。本領域技術人員公知,可以利用光譜方法和通過其它物理方法識別次要產物、副產物和附加試劑(總稱為“雜質”),於是雜質與色譜中的峰位置(或薄層色譜板上的斑點)有關(Strobel,H.A.;Heineman,W.R.,Chemical Instrumentation:Asystematic Approach,3rd.(Wiley&Sons:New York1989))。此後,雜質可以通過其在所述色譜中的位置被識別出來,色譜中的位置通常用樣品注射到柱上和特定的組分經檢測器流出之間的時間以分鐘計算,被稱為“保留時間”。這一時間段基於使用儀器的條件和許多其它因素每天變化。為減輕這樣變化對雜質準確鑒別的影響,專業人員使用“相對保留時間”(或相對保留值)來鑒別雜質。雜質的相對保留值是其保留時間除以參考標記物(例如對照品或參比標準品)的保留時間的比值。
“對照品”與“標準品”:製藥領域的研發人員都知道,相當純 態的化合物可用作“標準品”或“對照品”。對照品一般系指用於鑒別、檢查、含量測定和校正檢定儀器性能的標準物質,而標準品系通常指用於生物檢定、抗生素或生物藥品中含量或效價測定的標準物質。本發明中對二者不做嚴格區分。標準品可用於定性分析,也用於定量測定未知混合物中待檢測化合物的含量。在採用相同技術分析已知濃度的標準品的溶液以及未知混合物時,標準品是“外標物”。化合物在混合物中的含量可以通過比較檢測器回應值大小來測定。同樣也可參見美國專利6,333,198,其內容在此引作參考。如果補償檢測器對兩個化合物的敏感度差異的“回應因數”已經預先確定,則標準品也可以用於測量混合物中另一化合物的含量。為此,將標準物直接加到混合物中,其被稱為“內標物”。在不特意加入標準品而是利用稱作“標準品加入”的技術使未知混合物包含可檢測量的參比標準品時,則標準品可用作內標物。
起始原料和試驗儀器:
西格列他鈉:按照中國專利申請201410856282.5和201610855107.3的方法製備,純度>99%。
2-[(2-(4-氟苯甲醯基)苯基)氨基]-3-(4-羥基苯基)丙酸甲酯(化合物(b)):北京樂威泰克醫藥科技有限公司生產,純度>96%。
高效液相色譜:儀器:UltiMate3000;色譜柱:C18柱,Shim-pack VP-ODS 5μm 250L×4.6;檢測器:VWD-3100。
半製備液相色譜:儀器:UltiMate3000;色譜柱:YMC-Pack ODS-AQ 5μm 250L×20;檢測器:VWD-3100。
質子核磁共振:儀器:Varian INOVA 500;溶劑:DMSO-d6。
高分辨質譜:儀器:VG ZAB-HS色質聯用儀;檢測方法:快原子轟擊電離(FAB)。
實施例1:式(I)化合物的分離、製備與鑒定
1.分離
將0.5g西格列他鈉(按照中國專利申請201410856282.5和201610855107.3的方法製備)用半製備液相色譜柱分離(色譜柱:YMC-Pack ODS-AQ 5μm 250L×20;流動相:甲醇-水-四氫呋喃-冰醋酸48:22:30:0.5;檢測波長:236nm;流速:8ml/min),收集30~42min的流出液,用1mol/L的碳酸氫鈉水溶液中和至pH 7。重複上述分離操作40次,合併每次中和後的液體,真空濃縮除去有機溶劑,用1mol/L稀鹽酸中和至pH 5~6,過濾,水洗,收集固體,室溫真空乾燥24h得5mg化合物(f),純度(HPLC)97.8%,LC-MS(m/z)933(M+1)。
在反應瓶中依次加入5mg(0.0054mmol)化合物(f)和1mL甲醇,攪拌溶解。將0.43mg(0.011mmol)氫氧化鈉溶於0.5mL甲醇,滴加到上述溶液中,室溫攪拌30min。將反應液滴加到15mL無水乙醚中,過濾,於60℃真空乾燥8h得5mg式(I)化合物,純度(HPLC)98.4%。
結構鑒定:
HRMS(M++1)(C58H45N3O8FN2)計算值(%):976.2986;實測值(%):976.2992。
1H NMR(DMSO-d6)δ 2.87(dd,1H,CH2之一),3.02(dd,1H,CH2之一),3.05(dd,1H,CH2之一),3.22(dd,1H,CH2之一),3.91(m,1H,CH),4.06(m,1H,CH),4.24(t,2H,CH2),4.71(t,2H,CH2),6.40(m,2H,Ar-H),6.58(d,2H,Ar-H),6.65(d,1H,Ar-H),6.69(d,1H,Ar-H),6.90(d,4H,Ar-H),7.00(d,2H,Ar-H),7.17(t,2H,Ar-H),7.27(m,8H,Ar-H),7.42(m,2H,Ar-H),7.47(m,2H,Ar-H),7.57(m,2H,Ar-H),7.62(d,2H,Ar-H),8.11(d,2H,Ar-H),8.60(d,1H,NH),8.81(dd,1H,NH)。
2.製備
在反應瓶中依次加入400mL N,N-二甲基甲醯胺、23.76g(40mmol)2-(2-(4-氟苯甲醯基)苯基氨基)-3-(4-(2-(9H-哢唑-9-基)乙氧基)苯基)丙酸鈉(即化合物(a))、19.65g(50mmol)2-[(2-(4-氟苯甲醯基)苯基)氨基]-3-(4-羥基苯基)丙酸甲酯(即化合物(b))和16.25g(50mmol)碳酸銫,於120℃反應25h,過濾,將濾液加入4000mL飽和氯化鈉溶液中,過濾,水洗,收集固體,將所得固體真空乾燥得化合物(c)粗產品,純度(HPLC)12.2%,LC-MS(m/z)969(M+1)。所得產品未經進一步純化,直接用於下一步反應。
在反應瓶中依次加入400mL乙酸乙酯和上述化合物(c),攪拌30min,加入230mL水,滴加150mL 3mol/L稀鹽酸,攪拌4h,分離有機相,真空濃縮得化合物(d)粗產品,所得產品未經進一步純化,直接用於下一步反應。
將上述化合物(d)溶於350mL四氫呋喃,加入48mL 12mol/L氫氧化鋰水溶液,室溫攪拌反應14h,分離有機相,真空濃縮得化合物(e)粗產品,所得產品未經進一步純化,直接用於下一步反應。
在反應瓶中依次加入480mL乙酸乙酯和上述化合物(e),攪拌30min,加入230mL水,滴加150mL 3mol/L稀鹽酸,攪拌4h,分離有機相,真空濃縮得化合物(f)粗產品,純度(HPLC)18.9%,LC-MS(m/z)933(M+1)。
將0.5g化合物(d)的粗產品用半製備液相色譜柱分離(色譜柱:YMC-Pack ODS-AQ 5μm 250L×20;流動相:甲醇-水-四氫呋喃-冰醋酸48:22:30:0.5;檢測波長:236nm;流速:8ml/min),收集30~42min的流出液,用1mol/L的碳酸氫鈉水溶液中和至pH 7。重複上述分離操作5次,合併每次中和後的液體,真空濃縮除去有機溶劑,用1mol/L稀鹽酸中和至pH 5~6,過濾,水洗,收集固體,室溫真空乾燥24h得230mg化合物(f),純度(HPLC)98.0%,LC-MS(m/z)933(M+1)。
在反應瓶中依次加入230mg(0.247mmol)化合物(f)和5mL甲醇,攪拌溶解。將19.76mg(0.494mmol)氫氧化鈉溶於1mL甲醇,滴加到上述溶液中,室溫攪拌30min。將反應液滴加到45mL無水乙醚中,過濾,於60℃真空乾燥8h得236mg式(I)化合物,純度(HPLC)98.6%。
經結構鑒定表明,所製備的化合物與上述分離得到的化合物的HRMS和1HNMR均相符。
實施例2:式(I)化合物用作西格列他鈉藥物中雜質含量測定的對照品
一、測試條件
儀器:UltiMate3000;色譜柱:C18柱,Shim-pack VP-ODS 5μm 250L×4.6;檢測器:VWD-3100,流動相:甲醇-水-四氫呋喃-醋酸40:30:30:0.5;檢測波長:236nm;流速:1.5mL/min。
二、測試方法
(1)取西格列他鈉樣品約10mg,精密稱定,置於100ml容量瓶中,用溶劑甲醇-水-四氫呋喃(40:30:30)溶解並稀釋至刻度,搖勻,作為供試品溶液A,精密吸取20μl,注入液相色譜儀,記錄色譜圖。
(2)取式(I)化合物約10mg,精密稱定,置於100ml容量瓶中,用溶劑甲醇-水-四氫呋喃(40:30:30)溶解並稀釋至刻度,搖勻,精密移取1mL置於100ml容量瓶中,用溶劑甲醇-水-四氫呋喃(40:30:30)溶解並稀釋至刻度,搖勻,作為供試品溶液B,精密吸取20μl,注入液相色譜儀,記錄色譜圖。
(3)分別移取0.5mL供試液A和0.5mL供試液B,搖勻,作為供試品溶液C,精密吸取20μl,注入液相色譜儀,記錄色譜圖。
三、測試結果
在供試品溶液A的色譜圖中,西格列他鈉的出峰時間為15.1min,同時,在35.8min處有一雜質峰,相對面積為0.05%。
在供試品溶液B的色譜圖中,式(I)化合物的出峰時間35.8min。
在供試品溶液C的色譜圖中,西格列他鈉的出峰時間為15.1min,同時,在35.8min處有一雜質峰,相對面積為0.7%。
結論:式(I)化合物被確認是西格列他鈉樣品中相對保留值約2.4的雜質。
實施例3:式(I)化合物用作西格列他鈉藥物中雜質含量測定的標準品
一、測試條件
儀器:UltiMate3000;色譜柱:C18柱,Shim-pack VP-ODS 5μm 250L×4.6;檢測器:VWD-3100,流動相:甲醇-水-四氫呋喃-醋酸40:30:30:0.5;檢測波長:236nm;流速:1.5mL/min。
二、測試方法
取西格列他鈉樣品約10mg,精密稱定,置於100ml容量瓶中,用溶劑甲醇-水-四氫呋喃(40:30:30)溶解並稀釋至刻度,搖勻,作為供試品溶液。另取式(I)化合物標準品約10mg,精密稱定,置於100ml容量瓶中,用溶劑甲醇-水-四氫呋喃(40:30:30)溶解並稀釋至刻度,搖勻,精密移取1mL置於1000ml容量瓶中,用溶劑甲醇-水-四氫呋喃(40:30:30)溶解並稀釋至刻度,搖勻,作為對照品溶液。分別精密吸取上述兩種溶液各20μl,注入液相色譜儀,記錄色譜圖。按外標法以峰面積計算西格列他鈉樣品中式(I)化合物的含量。
三、測試結果
共測定了三批西格列他鈉樣品,測定結果見表1。
Claims (11)
- 如申請專利範圍第1項所述的式(I)化合物用於西格列他或其衍生物的原料藥或製劑的品質控制的用途。
- 如申請專利範圍第7項所述的用途,其中,所述式(I)化合物用作西格列他或其衍生物藥物中雜質或有關物質檢查的對照品或標準品。
- 如申請專利範圍第9項所述的檢測方法,所述方法為HPLC法,其中,式(I)化合物作為外標使用,測定條件為:色譜柱:C 18柱;流動相:甲醇-水-四氫呋喃-醋酸40:30:30:0.5;檢測波長:236nm。
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