WO2020248341A1 - 一种缬沙坦的制备方法 - Google Patents

一种缬沙坦的制备方法 Download PDF

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WO2020248341A1
WO2020248341A1 PCT/CN2019/097895 CN2019097895W WO2020248341A1 WO 2020248341 A1 WO2020248341 A1 WO 2020248341A1 CN 2019097895 W CN2019097895 W CN 2019097895W WO 2020248341 A1 WO2020248341 A1 WO 2020248341A1
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valsartan
preparation
reaction
azide
compound
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PCT/CN2019/097895
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English (en)
French (fr)
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姚成志
郭少征
潘启娇
余奎
王邦凤
周广军
周国斌
黄想亮
金佳英
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宁波美诺华药业股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the field of synthesis of drugs and drug intermediates, in particular to a method for preparing valsartan.
  • Valsartan (Valsartan), chemical name: N-valeryl-N-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl] -L-Valine has the advantages of long-lasting and stable blood pressure lowering effect, few side effects and can be used in combination with other sartan drugs. It is a widely used antihypertensive drug in clinical practice.
  • the structural formula of valsartan is as follows:
  • biphenyl tetrazolium in the valsartan drug molecule is a key step in the synthesis process of valsartan.
  • biphenyl cyano compounds (II) and azide compounds are usually used for cycloaddition under the catalysis of Lewis acid.
  • the biphenyltetrazolium ring (III) is synthesized by reaction, and the commercial production route is shown in the figure below:
  • the lipophilic lipid compound valsartan cyano intermediate (II) and the hydrophilic inorganic salt azide compound undergo a heterogeneous reaction.
  • DMF is usually used.
  • excessive azide compounds are used.
  • oxidants such as sodium nitrite or sodium hypochlorite need to be used for azide compounds.
  • Harmless quenching treatment there are two shortcomings in such a process operation, one is that a certain amount of genotoxic impurities (NDMA and NDEA) and potential genotoxic impurities V320 will inevitably be produced during the quenching process of azide compounds; Polar organic solvents are difficult to recover and process in the water phase, and at the same time, they will take away part of the product and cause the yield to decrease; therefore, a valsha with high yield, less three wastes and no impurities such as NDMA, NDEA and V320 has been developed Tan preparation process is very necessary.
  • NDMA and NDEA genotoxic impurities
  • the inventors of the present application have unexpectedly discovered in their research that the valsartan nitrile compound (II) is subjected to tetrazolium cyclization reaction with an azide compound, Lewis acid and a phase transfer catalyst in a non-hydrophilic organic solvent. It effectively overcomes the shortcomings of valsartan tetrazolium cyclization in the past, and realizes the advantages of simple and convenient operation, high product yield and no impurities such as NDMA, NDEA and V320, and has high industrial value.
  • the present invention provides a method for preparing valsartan, which includes the following steps:
  • valsartan nitrile-based compound (II) is subjected to a tetrazolium cyclization reaction with an azide compound, Lewis acid and a phase transfer catalyst in a non-hydrophilic organic solvent.
  • the preparation method of the present invention further includes a step of subjecting the reaction product of step (1) to an alkaline hydrolysis reaction.
  • the present invention catalyzes the tetrazolium cyclization reaction of the biphenyl cyano compound (II) and the inorganic salt of azide in a non-hydrophilic organic solvent by designing a phase transfer catalyst, and then preferably The catalyst and the inorganic salt of azide acid are removed by water washing under alkaline conditions, the organic phase is optionally hydrolyzed under alkaline conditions and then the toluene layer is separated, the aqueous layer is acidified and then extracted with ethyl acetate, cooled and crystallized to obtain valsartan.
  • the present invention discloses a preparation method of valsartan, which comprises the following steps:
  • valsartan nitrile-based compound (II) is dissolved in a non-hydrophilic organic solvent, and then azide compound, Lewis acid and phase transfer catalyst are sequentially added in batches to carry out the tetrazolium cyclization reaction. After the reaction is completed, cool and add water , Then add an inorganic base and wash with alkaline water to obtain a reaction mixture of valsartan intermediate (III);
  • the crude valsartan is added to ethyl acetate, heated and stirred until it is clear, then stirred and cooled for crystallization, centrifuged, and dried to obtain the valsartan product;
  • the reaction route is as follows:
  • the azide compound is selected from one or any combination of sodium azide, potassium azide, lithium azide and zinc azide; preferably sodium azide , Relative to the amount of the compound of formula (II) is 1.0-5.0 equivalents.
  • the Lewis acid is selected from zinc chloride, zinc bromide, zinc iodide, zinc trifluoromethanesulfonate, zinc acetate, zinc trifluoroacetate, zinc azide, etc. Or any combination thereof, the amount relative to the compound of formula (II) is 0.5-2 equivalents.
  • the non-hydrophilic organic solvent is selected from one or any combination of toluene, xylene, o-xylene, meta-xylene, p-xylene, chlorobenzene and dichlorobenzene, etc. .
  • the phase transfer catalyst is preferably selected from organic amine compounds, including alkyl amines and amide compounds.
  • the preferred alkyl tertiary amine compounds are those with 6 to 12 carbon atoms.
  • Alkyl tertiary amine compounds, preferred amide compounds are N,N-dimethylformamide (DMF) and N,N-diethylacetamide (DMAC).
  • DMF N,N-dimethylformamide
  • DMAC N,N-diethylacetamide
  • Particularly preferred is one or any combination selected from the following triethylamine, tri-n-butylamine, tetramethylethylenediamine, tetramethylpropanediamine, DMF and DMAC, and the structural formula is shown below.
  • the amount of the phase transfer catalyst used in the preparation method of the present invention relative to the compound of formula (II) is preferably 0.5-2 equivalents.
  • organic amine compounds are preferably used as catalysts, which are different from phase transfer catalysts in the conventional sense.
  • the tetrazolium cyclization reaction temperature is 70-150°C, and the reaction time is 10-60 hours.
  • the inorganic base is selected from one or any combination of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and ammonia.
  • the pH value of the alkaline water washing is 8-12.
  • the lye used for the alkaline hydrolysis reaction is an aqueous solution selected from one or any combination of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, etc., with a concentration of 1-20 %, which is 1 to 5 equivalents relative to the amount of the compound of formula (II).
  • the alkali hydrolysis reaction temperature of the valsartan methyl ester is 10-60°C, and the reaction time is 1-6 hours.
  • step (3) of the preparation method of the present invention the degree of the cooling crystallization is -10 to 10°C.
  • the preparation method of valsartan uses a phase transfer catalyst and a cyclization reaction solvent to select a non-hydrophilic organic solvent, and preferably uses water washing under alkaline conditions to separate the azide compound and the catalyst. Avoid the generation of impurities such as N-nitrosodimethylamine NDMA, N-nitrosodiethylamine NDEA and V320; azide compounds are safe and stable in aqueous solutions under alkaline conditions, and have good industrial production safety and easy operation , Good continuity, while improving the yield and purity of valsartan, ensuring the safety of valsartan medication, and having high industrial application value.
  • impurities such as N-nitrosodimethylamine NDMA, N-nitrosodiethylamine NDEA and V320
  • azide compounds are safe and stable in aqueous solutions under alkaline conditions, and have good industrial production safety and easy operation , Good continuity, while improving the yield and purity of valsartan, ensuring the safety of valsartan medication,
  • the N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in the valsartan product are analyzed by GC-MS method.
  • the valsartan impurity V320 in the valsartan product was detected by LC-MS; firstly, the GC-MS (gas chromatography-mass spectrometry) and LC-MS used in the following examples and comparative examples of the present invention
  • the MS liquid chromatography-mass spectrometry
  • N-nitrosodimethylamine (NDMA) reference substance Weigh an appropriate amount of N-nitrosodimethylamine (NDMA) reference substance and dilute with diluent to NDMA concentration: 0.2, 0.8, 3.2 , 6.4, 20 ⁇ g/mL, shake until completely dissolved before use.
  • NDMA N-nitrosodimethylamine
  • NDEA N-nitrosodiethylamine
  • Carrier gas helium (He)
  • Standard solution accurately weigh about 10mg of VAL320 reference substance, put it in a 50mL volumetric flask, add an appropriate amount of methanol to dissolve and dilute to the mark, shake well; accurately pipette 1mL, place in a 100mL volumetric flask, dilute to the mark with methanol, shake ; Precisely pipette 1mL, put it in a 10mL volumetric flask, dilute to the mark with methanol, and shake well. (VAL320: 0.2 ⁇ g/mL)
  • Sample solution accurately weigh about 100mg of this product, place it in a 10mL volumetric flask, add an appropriate amount of methanol to dissolve, and dilute to the mark with methanol, shake well, and prepare 2 solutions in parallel. (Valsartan: 10.0mg/mL)
  • a Sas the peak area of VAL320 in the sample solution
  • a Ss the peak area of VAL320 in the standard solution
  • Mobile phase A accurately pipette 0.5 mL of formic acid, add 1000 mL of water to dissolve, mix, and degas by ultrasonic.
  • HPLC detects N-[(2'-cyanobiphenyl-4-yl)methyl]-N-(1-oxopentyl)-L- Valine methyl ester (II) residue ⁇ 1%, stop the reaction, cool to 40 ⁇ 50°C, add 200g water and 11.5g sodium carbonate, separate the water layer, then wash twice with 200g 20% salt water, the organic layer Add 50g 32% sodium hydroxide solution and 200g water, control the temperature at 40 ⁇ 45°C and react for 3 ⁇ 6 hours, HPLC detects the residual valsartan methyl (III) ⁇ 1%, separate the toluene layer, and adjust the pH value of the water layer If it is less than 1, a large amount of white solid is precipitated.
  • the GC-MS method was used to quantitatively detect the NDMA and NDEA in the crude valsartan, and the results were not detected; the LC-MS method was used to quantitatively detect the V320 in the crude valsartan, and the result was not detected; Quantitative detection of nitrogen residues was not detected.
  • HPLC detects N-[(2'-cyanobiphenyl-4-yl)methyl]-N-(1-oxopentyl)-L- Valine methyl ester (II) residue ⁇ 1%, stop the reaction, cool to 40 ⁇ 50°C, add 200g water and 50g ammonia water, separate the water layer, then wash twice with 200g 20% salt water, add 50g to the organic layer 32% sodium hydroxide solution and 200g water, react at 40 ⁇ 45°C for 3 ⁇ 6 hours, HPLC detects the residual valsartan methyl (III) ⁇ 1%, separate the toluene layer, adjust the pH of the water layer to less than 1 , A large amount of white solid was precipitated, then 250g ethyl acetate was added and stirred to dissolve, the water layer was separated, the organic layer was washed twice with 200g water, the ethyl acetate layer was evaporated to dryness
  • Quantitative detection of NDMA and NDEA in crude valsartan by GC-MS method was undetected; the quantitative detection of V320 in crude valsartan by LC-MS method was undetected; Quantitative detection of nitrogen residues was not detected.
  • the GC-MS method was used to quantitatively detect the NDMA and NDEA in the crude valsartan, and the results were not detected; the LC-MS method was used to quantitatively detect the V320 in the crude valsartan, and the result was not detected; Quantitative detection of nitrogen residues was not detected.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明提供了一种缬沙坦的制备方法，包括在非亲水性有机溶剂中使缬沙坦腈基化合物(II)与叠氮化合物、Lewis酸和相转移催化剂进行四氮唑环合反应的步骤。本发明提供的方法安全性高，工艺操作简单方便，产品收率高，产品纯度好，具有较高的工业化价值。

Description

一种缬沙坦的制备方法
本申请要求于2019年06月13日提交到中国专利局、申请号为201910508659.0、发明名称为“一种缬沙坦的制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及药物及药物中间体合成领域，具体涉及一种缬沙坦制备方法。
背景技术
缬沙坦(Valsartan)，化学名：N-戊酰基-N-[[2'-(1H-四氮唑-5-基)[1,1'-联苯]-4-基]甲基]-L-缬氨酸，具有降血压效果持久稳定，副作用少以及能与其他沙坦类药物联合使用等优点，是一种临床上使用广泛的抗高血压药物。缬沙坦结构式如下所示：
Figure PCTCN2019097895-appb-000001
国内外公开的有关很多有关缬沙坦合成的文献和专利，主要有两种路线：1)、后环合路线，Arlesheim等报道的以2’-氰基-4-甲酰基联苯为原料，与L-缬氨酸苄酯的对甲苯磺酸盐经还原胺化反应，正戊酰化反应，成四氮唑环，去保护得缬沙坦。该方法的缺点主要是：①需要采用三烷基叠氮化锡与氰基在120～140℃下反应生成四氮唑，三烷基叠氮化锡毒性很大；②采用催化加氢的方法脱去苄基保护基，需要加氢设备。2)、后环合路线，Donatienne等报道以四氮唑被保护过的2’-四氮唑基-4-甲酰基联苯为原料， 与L-缬氨酸或其衍生物缩合生成席夫碱，再经催化加氢或金属氢化物还原，所得仲胺与正戊酰氯在水存在下进行酰化反应，最后得到缬沙坦。该方法的缺点：①2’-四氮唑基-4-甲酰基联苯(或四氮唑被保护的2’-四氮唑基-4-甲酰基联苯)需要另行制备，原料成本高；②需要采用催化加氢或金属氢化物还原席夫碱；③正戊酰化反应中，水的存在一方面可提高缬沙坦的光学活性，但同时也导致正戊酰氯的部分水解，所得副产物正戊酸影响产品缬沙坦的纯化。
缬沙坦药物分子中联苯四氮唑的合成是缬沙坦合成工艺中的关键步骤，在工业化生产中通常采用联苯氰基化合物(Ⅱ)与叠氮化合物在Lewis酸催化下进行环加成反应合成联苯四氮唑环(Ⅲ)，商业化生产路线如下图所示：
Figure PCTCN2019097895-appb-000002
在联苯四氮唑环合反应中亲油性脂类化合物缬沙坦氰基中间体(II)和亲水性无机盐类叠氮化合物进行不均相反应，为了提高反应收率通常采用DMF，DMAC，NMP，二乙二醇二甲基醚等极性非亲水性有机溶剂，同时使用过量的叠氮化合物，反应结束后需要使用到亚硝酸钠或次氯酸钠等氧化剂对叠氮化和物进行无害化淬灭处理；这样的工艺操作存在两个缺点，一是叠氮化合物的淬灭过程中不可避免的会有一定量的基因毒性杂质(NDMA和NDEA)和潜在基因毒性杂质V320产生；二是极性有机溶剂在水相难以回收和处理，同时也会带走一部分产品造成产率下降；因此，开发一种具有高收率、三废少且不含NDMA、NDEA和V320等杂质的缬沙坦制备工艺是非常有必要的。
Figure PCTCN2019097895-appb-000003
发明内容
本申请发明人在研究中，意外发现：通过在非亲水性有机溶剂中使缬沙坦腈基化合物(II)与叠氮化合物、Lewis酸和相转移催化剂进行四氮唑环合反应，可以有效克服以往缬沙坦四氮唑环合的缺点，实现操作简单方便、产品收率高且不含NDMA、NDEA和V320等杂质等优点，具有较高的工业化价值。
在此发现的基础上，在第一方面，本发明提供了一种缬沙坦的制备方法，包括以下步骤：
(1)在非亲水性有机溶剂中使缬沙坦腈基化合物(II)与叠氮化合物、Lewis酸和相转移催化剂进行四氮唑环合反应。
Figure PCTCN2019097895-appb-000004
优选地，本发明的制备方法还包括使步骤(1)的反应产物进行碱水解反应的步骤。
不受理论限制且更优选地，本发明通过设计使用相转移催化剂在非亲水性有机溶剂中催化联苯氰基化合物(Ⅱ)与叠氮酸无机盐的四氮唑环合反应，然后优选在碱性条件下水洗除去催化剂和叠氮酸无机盐，任选地使有机相在碱性条件下水解后分去甲苯层，水层酸化然后乙酸乙酯萃取， 冷却结晶得缬沙坦。
更优选地，本发明公开了一种缬沙坦的制备方法，包括如下步骤：
(1)中间体缬沙坦甲酯(Ⅲ)的制备
将缬沙坦腈基化合物(II)溶于非亲水性有机溶剂中，然后分批依次加入叠氮化合物、Lewis酸和相转移催化剂，进行四氮唑环合反应，反应结束后，冷却加水，再加入无机碱，碱水洗涤，得到缬沙坦中间体(Ⅲ)的反应混合物；
(2)缬沙坦粗品的制备
向缬沙坦甲酯(Ⅲ)的反应混合物中加入碱液，加热搅拌进行水解反应，反应结束，得缬沙坦粗品；
(3)缬沙坦成品的制备
将缬沙坦粗品加入到乙酸乙酯中，升温搅拌至溶清，然后搅拌降温析晶，离心，干燥，得到缬沙坦成品；
反应路线如下：
Figure PCTCN2019097895-appb-000005
在本发明的制备方法中：所述的叠氮化合物选自叠氮化钠，叠氮化钾，叠氮化锂及叠氮化锌等中一种或其任意组合；优选为叠氮化钠，其相对于式(II)化合物的用量为1.0～5.0当量。
在本发明的制备方法中，所述的Lewis酸选自氯化锌，溴化锌，碘化锌，三氟甲磺酸锌，乙酸锌，三氟乙酸锌，叠氮化锌等中一种或其任意组合，其相对于式(II)化合物的用量为0.5～2当量。
在本发明的制备方法中，所述的非亲水性有机溶剂选自甲苯，二甲苯，邻二甲苯，间二甲苯，对二甲苯，氯苯和二氯苯等中一种或其任意组合。
在本发明的制备方法中，所述的相转移催化剂优选选自有机胺类化合物，包括烷基胺类和酰胺类化合物，优选的烷基叔胺类化合物是总碳原子数为6至12的烷基叔胺类化合物，优选的酰胺类化合物是N,N-二甲基甲酰胺(DMF)和N,N-二乙基乙酰胺(DMAC)。特别优选的是选自以下的三乙胺，三正丁胺，四甲基乙二胺，四甲基丙二胺，DMF和DMAC等中一种或其任意组合，其结构式如下所示。本发明制备方法中的相转移催化剂相对于式(II)化合物的用量优选为0.5～2当量。不受理论限制，在本发明的方法中，优选有机胺类化合物作为催化剂使用，其不同于常规意义上的相转移催化剂。
Figure PCTCN2019097895-appb-000006
在本发明的制备方法中，所述的四氮唑环合反应温度为70～150℃，反应时间为10～60小时。
在本发明的制备方法中，所述的无机碱选自氢氧化钠，碳酸钠，碳酸氢钠，碳酸钾和氨水等中一种或其任意组合。
在本发明的制备方法中，所述的碱水洗涤的pH值为8～12。
在本发明的制备方法中，所述用于碱水解反应的碱液选自氢氧化钠，氢氧化锂，氢氧化钾以及碳酸钠等中一种或其任意组合的水溶液，浓度为1～20％，其相对于式(II)化合物的用量为1～5当量。
在本发明的制备方法中，所述的缬沙坦甲酯的碱水解反应温度为10～60℃，反应时间为1～6小时。
在本发明的制备方法步骤(3)中，所述的降温结晶的度为-10～10℃。
本发明所提供的缬沙坦的制备方法，通过采用相转移催化剂以及环合反应溶剂选用非亲水性有机溶剂，以及优选采用在碱性条件下水洗分离出叠氮化合物和催化剂，从根源上避免了N-亚硝基二甲胺NDMA、N-亚硝基二乙胺NDEA和V320等杂质的产生；碱性条件下叠氮化合物在水溶液中安全稳定，工业生产的安全性好，操作方便，连续性好，同时提高了缬沙坦的收率和纯度，保证了缬沙坦用药的安全性，具有较高的工业化应用价值。
具体实施方式
为使本发明的目的、技术方案和有益效果更加清楚，下面将结合具体实施例对本发明进行进一步描述，这些实施例仅供举例说明和特例代表，但本发明的保护范围并不仅限于此。下面进一步提供具体实施例的技术方案。
在本发明的下述各实施实例及对比例中，用GC-MS方法对缬沙坦成品中的N-亚硝基二甲胺(NDMA)和N-亚硝基二乙胺(NDEA)进行检测，用LC-MS方法对缬沙坦成品中的缬沙坦杂质V320进行检测；首先，对本发明下述实施例及对比例所采用的GC-MS(气相色谱-质谱联用)及LC-MS(液相色谱-质谱联用)测试方法进行说明。
1、GC-MS的色谱条件及检测方法：
N-亚硝基二甲胺(NDMA)对照品的标准溶液配制：称取适量N-亚硝基二甲胺(NDMA)对照品，用稀释液稀释至NDMA浓度分别为：0.2、0.8、3.2、6.4、20μg/mL，振摇至完全溶解后备用。
N-亚硝基二乙胺(NDEA)对照品的标准溶液配制：称取适量N-亚硝基二乙胺(NDEA)对照品，用稀释液稀释至NDEA浓度分别为：0.05、0.2、0.8、3.2、6.4μg/mL，振摇至完全溶解后备用。
待测样品(下述各实施实例及对比例中缬沙坦成品)中NDMA和 NDEA含量检测：
称取400mg待测样品，配置成20mL溶液，振摇至完全溶解后待检测。用下述的GC-MS方法对待测品溶液及不同浓度的NDMA和NDEA标准溶液进行检测，并用标准曲线法计算待测样品中NDMA和NDEA的含量。
仪器与设备：气相色谱仪、电子轰击离子源(EI)和质谱检测器
方法：GC-MS(气相色谱-质谱联用)
色谱条件：色谱柱VF-WAX ms(30m×0.25mm,0.25μm)或等效色谱柱
载气：氦气(He)
载气流速：2.0mL/min
分流比 无
Figure PCTCN2019097895-appb-000007
进样量    1.0μL
进样压力  250Kpa,1min
质谱检测器条件
离子源 电子轰击离子源(EI)
碰撞气体 氩气
离子源温度 200℃
接口温度 240℃
气体流速 11L/min
雾化压力 45psi
检测器电压 相对协调电压+0.3KV
溶剂切除时间 7min
2、LC-MS的色谱条件及检测方法：
空白溶液：甲醇
标准溶液：精密称取VAL320对照品约10mg，置50mL容量瓶中，加入甲醇适量使溶解并稀释至刻度，摇匀；精密移取1mL，置100mL容量瓶中，用甲醇稀释至刻度，摇匀；精密移取1mL，置10mL容量瓶中，用甲醇稀释至刻度，摇匀。(VAL320：0.2μg/mL)
样品溶液：精密称取本品约100mg，置10mL容量瓶中，加入甲醇适量使溶解，并用甲醇稀释至刻度，摇匀，平行配制2份溶液。(缬沙坦：10.0mg/mL)
进样序列：
序号 溶液名称 进样针数
1 空白溶液 2
2 标准溶液 3
3 样品溶液(1) 1
4 样品溶液(2) 1
系统适应性评估:
Figure PCTCN2019097895-appb-000008
计算：
按下式计算缬沙坦中VAL320含量：
Figure PCTCN2019097895-appb-000009
其中：
A Sas＝样品溶液中VAL320的峰面积；
A Ss＝标准溶液中VAL320的峰面积；
C Sas＝样品溶液的浓度(mg/mL)；
C Ss＝标准溶液中VAL320的浓度(mg/mL)；
备注：若空白溶液中有残留，扣除空白。
限度：VAL320:≤20ppm
仪器与设备：液相色谱仪、电子轰击离子源(EI)和质谱检测器
方法：LC-MS(液相色谱-质谱联用)
色谱条件：Agilent poroshell Infinity 120-EC-C18,4.6mm×50mm,2.7μm
流动相A：精密移取0.5mL甲酸，加水1000mL使溶解，混匀，超声脱气。
流动相B：乙腈
‐梯度洗脱表：
时间(min) MP A％ MP B％
0 60 40
18 60 40
18.2 20 80
23.7 20 80
24 60 40
30 60 40
‐检测波长：225nm
‐流速：0.5mL/min
‐进样体积：5μL
‐柱温：25℃
MS条件：
‐离子源：电子喷雾ESI
‐雾化气：氮气
‐气体温度：350℃
‐气体流速：12L/min
‐雾化压力：50psi
‐毛细管电压：4kV
‐扫描模式：MRM
‐极性：正
采集参数：
Figure PCTCN2019097895-appb-000010
时间分割：
Figure PCTCN2019097895-appb-000011
实施例1：缬沙坦粗品的制备
在500mL的四口反应瓶中加入34g(83.7mmol)N-[(2'-氰基联苯-4- 基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯(Ⅱ)浓缩液(HPLC：N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯含量≥98％)，120g甲苯，搅拌均匀，依次分批加入16.3g(263mmol)叠氮化钠、14.8g(108.8mmol)无水氯化锌和12.6g(108.4mmol)四甲基乙二胺，搅拌均匀，然后升温至90～100℃，反应约40小时，HPLC检测N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯(Ⅱ)残留≤1％，停止反应，冷却至40～50℃，加入200g水和11.5g碳酸钠，分去水层，然后用20％食盐水200g洗涤两次，有机层加入50g 32％的氢氧化钠溶液和200g水，控温40～45℃反应3～6小时，HPLC检测缬沙坦甲酯(Ⅲ)残留≤1％，分去甲苯层，水层调节PH值小于1，析出大量白色固体，然后加入250g乙酸乙酯搅拌溶清，分去水层，有机层用200g水洗涤两次，乙酸乙酯层蒸干，加入150g乙酸乙酯升温溶清，冷却搅拌结晶得缬沙坦粗品30.7g，收率84.3％。
用GC-MS方法对缬沙坦粗品中的NDMA和NDEA进行定量检测，结果均为未检出；用LC-MS方法对缬沙坦粗品中的V320进行定量检测，结果为未检出；叠氮根残留定量检测为未检出。
实施例2：缬沙坦粗品的制备
在500mL的四口反应瓶中加入34g(83.7mmol)N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯(Ⅱ)浓缩液(HPLC：N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯含量≥98％)，120g甲苯，搅拌均匀，依次分批加入16.3g(263mmol)叠氮化钠、14.8g(108.8mmol)无水氯化锌和12.6g(108.4mmol)四甲基乙二胺，搅拌均匀，然后升温至90～100℃，反应约40小时，HPLC检测N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯(Ⅱ)残留≤1％，停止反应，冷却至40～50℃，加入200g水和50g氨水，分去水层，然后用20％食盐水200g洗涤两次，有机层加入50g 32％的氢氧化钠溶液和200g水，控温40～45℃反应3～6小时，HPLC检测缬沙坦甲酯(Ⅲ)残留≤1％，分去甲苯层，水层调节PH值小于1，析出大量白色固体，然后加入250g乙酸乙酯搅拌溶清，分去水层，有机层用200g水洗涤两次，乙酸乙酯层蒸干，加入150g乙酸乙酯升温溶清，冷却搅拌结晶得缬沙坦粗品32.1g，收率88.2％。
用GC-MS方法对缬沙坦粗品中的NDMA和NDEA进行定量检测， 结果均为未检出；用LC-MS方法对缬沙坦粗品中的V320进行定量检测，结果为未检出；叠氮根残留定量检测为未检出。
实施例3：缬沙坦粗品的制备
在1500L的反应釜中加入235.2kg(579.3mol)N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯(Ⅱ)浓缩液(HPLC：N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯含量≥98％)，800kg甲苯，搅拌均匀，依次分批加入113.5kg叠氮化钠、98.2kg无水氯化锌和83.6kg四甲基乙二胺，搅拌均匀，然后升温至90～100℃，反应约40小时，HPLC检测N-[(2'-氰基联苯-4-基)甲基]-N-(1-氧代戊基)-L-缬氨酸甲酯(Ⅱ)残留≤1％，停止反应，冷却至40～50℃，加入1200kg水和330kg氨水，分去水层，然后用20％食盐水1200kg洗涤两次，有机层加入330kg32％的氢氧化钠溶液和1200kg水，控温40～45℃反应3～6小时，HPLC检测缬沙坦甲酯(Ⅲ)残留≤1％，分去甲苯层，水层调节PH值小于1，析出大量白色固体，然后加入1600kg乙酸乙酯搅拌溶清，分去水层，有机层用1200kg水洗涤两次，乙酸乙酯层蒸干，加入1000kg乙酸乙酯升温溶清，冷却搅拌结晶得缬沙坦粗品227.1kg，收率89.8％。
用GC-MS方法对缬沙坦粗品中的NDMA和NDEA进行定量检测，结果均为未检出；用LC-MS方法对缬沙坦粗品中的V320进行定量检测，结果为未检出；叠氮根残留定量检测为未检出。
实施例4：缬沙坦成品的制备
在250mL的四口反应瓶中加入上述得到的32.1g缬沙坦粗品，加入150g乙酸乙酯升温至50℃，搅拌至溶清，然后搅拌降温结晶，过滤，干燥，得到缬沙坦成品27.4g，收率85.3％。(杂质A：0.04％；单个未知杂质≤0.10％；总杂质≤0.1％；乙酸乙酯残留：2218ppm；戊酸残留：75ppm；重金属＜10ppm；NDMA(GC-MS)：未检出；NDEA(GC-MS)：未检出；V320(LC-MS)：未检出)，叠氮根残留定量检测为未检出。

Claims (13)

  1. 一种缬沙坦的制备方法，包括以下步骤：
    (1)在非亲水性有机溶剂中使缬沙坦腈基化合物(II)与叠氮化合物、Lewis酸和相转移催化剂进行四氮唑环合反应
    Figure PCTCN2019097895-appb-100001
  2. 根据权利要求1所述的制备方法，还包括使步骤(1)的反应产物进行碱水解反应的步骤。
  3. 根据权利要求1或2所述的制备方法，包括如下步骤：
    (1)中间体缬沙坦甲酯(Ⅲ)的制备
    Figure PCTCN2019097895-appb-100002
    在非亲水性有机溶剂中使缬沙坦腈基化合物(II)与叠氮化合物、Lewis酸和相转移催化剂进行四氮唑环合反应，得到中间体缬沙坦甲酯(Ⅲ)的反应混合物；和
    (2)缬沙坦粗品的制备
    向中间体缬沙坦甲酯(Ⅲ)的反应混合物中加入碱液，进行水解反应，得缬沙坦粗品。
  4. 根据权利要求1至3中任一项所述的制备方法，包括如下步骤：
    (1)中间体缬沙坦甲酯(Ⅲ)的制备
    将缬沙坦腈基化合物(II)溶于非亲水性有机溶剂中，然后分批依次加入叠氮化合物、Lewis酸和相转移催化剂，进行四氮唑环合反应，反应结束后，冷却加水，再加入无机碱，碱水洗涤，得到缬沙坦中间体(Ⅲ)的反应混合物；
    (2)缬沙坦粗品的制备
    向缬沙坦甲酯(Ⅲ)的反应混合物中加入碱液，加热搅拌进行水解反应，反应结束，得缬沙坦粗品；
    (3)缬沙坦的纯化
    将缬沙坦粗品加入到乙酸乙酯中，升温搅拌至溶清，然后搅拌降温析晶，离心，干燥，得到纯化的缬沙坦。
  5. 根据权利要求1至4中任一项所述的制备方法，其中步骤(1)中，所述的叠氮化合物选自叠氮化钠，叠氮化钾，叠氮化锂及叠氮化锌中一种或其任意组合。
  6. 根据权利要求1至5中任一项所述的制备方法，其中在步骤(1)中，所述的Lewis酸选自氯化锌，溴化锌，碘化锌，三氟甲磺酸锌，乙酸锌，三氟乙酸锌，叠氮化锌中一种或其任意组合，其相对于式(II)化合物的用量为0.5～2当量。
  7. 根据权利要求1至6中任一项所述的制备方法，其中在步骤(1)中，所述非水性有机溶剂选自甲苯，二甲苯，邻二甲苯，间二甲苯，对二甲苯，氯苯和二氯苯中一种或其任意组合。
  8. 根据权利要求1至7中任一项所述的制备方法，其中在步骤(1)中，所述的相转移催化剂选自三乙胺，三正丁胺，四甲基乙二胺，四甲基丙二胺，DMF和DMAC等中一种或其任意组合，其相对于式(II)化合物的用量为0.5～2当量。
  9. 根据权利要求1至8中任一项所述的制备方法，其中在步骤(1)中，所 述的四氮唑环合反应温度为70～150℃，反应时间为10～60小时。
  10. 根据权利要求2至9中任一项所述的制备方法，其中在步骤(1)中，所述的碱选自氢氧化钠，碳酸钠，碳酸氢钠，碳酸钾和氨水中一种或其任意组合。
  11. 根据权利要求4至10中任一项所述的制备方法，其中在步骤(1)中，所述的碱水洗涤的pH值为8～12。
  12. 根据权利要求4至11中任一项所述的制备方法，其中在步骤(2)中，所述的碱液选自氢氧化钠，氢氧化锂，氢氧化钾以及碳酸钠中一种或其任意组合的水溶液，浓度为1～20wt％，其相对于式(II)化合物的用量为1～5当量。
  13. 根据权利要求2至12中任一项所述的制备方法，其中在步骤(2)中，所述的缬沙坦甲酯(Ⅲ)的水解反应温度为10～60℃，反应时间为1～6小时。
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