WO2021104483A1 - 磺酸季铵盐化合物及其制备方法和用途 - Google Patents

磺酸季铵盐化合物及其制备方法和用途 Download PDF

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WO2021104483A1
WO2021104483A1 PCT/CN2020/132400 CN2020132400W WO2021104483A1 WO 2021104483 A1 WO2021104483 A1 WO 2021104483A1 CN 2020132400 W CN2020132400 W CN 2020132400W WO 2021104483 A1 WO2021104483 A1 WO 2021104483A1
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reaction
quaternary ammonium
oxo
diazabicyclo
water
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French (fr)
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乔红炜
陈照行
王帅
魏宏成
张睿
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北京耀诚惠仁科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
    • C07D295/037—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements with quaternary ring nitrogen atoms

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  • the invention relates to the field of pharmaceutical compounds and synthetic methods, in particular to a sulfonic acid quaternary ammonium salt compound of a ⁇ -lactamase inhibitor and a preparation method thereof, and its use as an intermediate for preparing a ⁇ -lactamase inhibitor.
  • the compound of formula (II) is chemically known as ( ⁇ [(2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]-oct-6 -Yl]oxy ⁇ sulfonyl)quaternary ammonium salt, which is used as an important intermediate in the production of avibactam in the synthesis of ⁇ -lactamase inhibitors disclosed in CN 103649051 A and CN 105283458 B patents . Therefore, the high-purity and high-yield preparation of the sulfonic acid quaternary ammonium salt can greatly improve the production quality of Avibactam and can reduce the production cost.
  • the compound of formula (II) is an important intermediate for the synthesis of ⁇ -lactamase inhibitors, such as avibactam.
  • the preparation of the compound of formula (II) with high purity and high yield is very important in the production of avibactam sodium and other novel azabicyclic sulfonic acid compounds.
  • the first object of the present invention is to provide a new sulfonic acid quaternary ammonium salt compound (Formula II);
  • the second object of the present invention is to provide a method for preparing sulfonic acid quaternary ammonium salt compounds, including:
  • Method b Wash with ethyl acetate once, (2S,5R)-6-(sulfooxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide React with 60% of the total mass of the quaternary ammonium salt, extract the product with dichloromethane; then add water and isopropanol, then add 40% of the total mass of the quaternary ammonium salt to continue the reaction, extract with dichloromethane, and combine the two extracts , Rotary steaming, add solvent to crystallize.
  • the third object of the present invention is to provide the use of sulfonic acid quaternary ammonium salt formula (II) to prepare high-purity Avibactam sodium product, which includes: dissolving sulfonic acid quaternary ammonium salt compound in absolute ethanol and at room temperature The ethanol solution of sodium isooctanoate was added dropwise, the addition was completed, and the reaction was carried out at room temperature for 3 hours to obtain a white solid, which was filtered with suction, dried, and the purity as determined by HPLC was as high as 99.93%.
  • a synthetic method for preparing the sulfonic acid quaternary ammonium salt compound which includes:
  • step (1) (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide, trioxide Thiotrimethylamine and triethylamine are dissolved in a mixed solution of alcohol and water, and a catalyst is added, (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.
  • the molar ratio of octane-2-carboxamide, sulfur trioxide trimethylamine, and triethylamine is 1:1.12:0.2
  • the catalyst is palladium carbon with 10% palladium and 50% water content
  • the amount of catalyst is (2S, 5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide 0.025 times the mass
  • the reaction temperature is 20-35°C
  • the reaction time is 1-8h
  • the reaction solvent is selected from methanol-water, ethanol-water or isopropanol-water mixed solvent, preferably isopropanol and water mixed solvent, the volume ratio of the reaction solvent is 1:1;
  • Step (2) In method a, the temperature of rotary evaporation is 25-60°C, preferably 45°C, (2S,5R)-6-(sulfooxy)-7-oxo-1,6-diazabicyclo [3.2.1]
  • the molar ratio of octane-2-carboxamide to quaternary ammonium bromide is 1:(1-1.3)
  • the amount of solvent added is 1-15% of the volume of the remaining solvent after the alcohol is removed, and the solvent is selected from Acetonitrile, 1,4-dioxane, acetone, tetrahydrofuran, water, preferably 5%
  • the reaction crystallization temperature is -5-10°C
  • the reaction crystallization time is 1-5h.
  • Step (2) In method b, the amount of ethyl acetate is (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane- 5 times the mass of 2-formamide, the amount of water and isopropanol added are (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2 .1] 2.4 times the mass of octane-2-carboxamide, the reaction crystallization solvent is selected from ethanol-ethyl acetate, methanol-ethyl acetate, ethanol-methyl tert-butyl ether, acetone-ethyl acetate, acetonitrile-acetic acid Ethyl ester, preferably ethanol and ethyl acetate, the volume ratio of the crystallization solvent is 2:1-4:1, preferably 3:1, and the crystallization temperature is 0-5°C.
  • the third object of the present invention is to provide the use of sulfonic acid quaternary ammonium salt compound formula (II) to prepare high-purity Avibactam sodium product, including: 1 molar equivalent of sulfonic acid quaternary ammonium salt compound is dissolved in absolute ethanol , Add 2 molar equivalents of sodium isooctanoate in ethanol solution dropwise at room temperature, after the dropwise addition is completed, react for 3 hours to obtain a white solid, suction filtration, and drying to obtain Avibactam sodium, with a purity of 99.93% as determined by HPLC.
  • the invention provides a new sulfonic acid quaternary ammonium salt compound and a preparation method and application.
  • the preparation method has simple operation, low cost, high degree of greenness, and is suitable for production scale-up.
  • Figure 1 shows the hydrogen spectrum of sulfonic acid quaternary ammonium salt
  • Figure 2 shows the carbon spectrum of quaternary ammonium sulfonic acid
  • a preparation method of avibactam intermediate which is characterized in that: the structural formula of avibactam intermediate is shown in formula (I):
  • n is equal to 1, 2, 3 (five-membered, six-membered, seven-membered ring), and the R group is selected from propyl, butyl, and pentyl; the method for preparing the compound of formula (I) includes the following steps:
  • Step (1) (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide is dissolved in alcohol and water, Blow in hydrogen to remove the benzyl group, and then react with the sulfonating reagent for sulfonation;
  • Step (2) Wash once, (2S,5R)-6-(sulfooxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide and 60 % Quaternary ammonium salt reaction, extract the product with dichloromethane; then add part of water and isopropanol, then add the remaining 40% quaternary ammonium salt to continue the reaction;
  • Step (3) After the completion of the reaction, extract twice with dichloromethane. The extracts are combined and concentrated, rotary evaporated, and then a solvent is added for crystallization to obtain a white solid, which is filtered with suction and dried to obtain the intermediate compound of the quaternary ammonium sulfonic acid compound of formula ( I); Further, the catalyst is palladium on carbon, the reaction temperature is 20°C-35°C, and the reaction time is 1-8h; the reaction solvent is methanol-water, ethanol-water, isopropanol-water and other mixed solvents.
  • n is equal to 3
  • the R group is a pentyl group.
  • step (1) the product obtained in step (1) is washed once with ethyl acetate, and the quaternary ammonium salt is combined with (2S,5R)-6-(sulfooxy)-7-oxo-1,6-diazabicyclo[3.2 .1]
  • the feed ratio of octane-2-carboxamide is 1.2-1.5: the reaction temperature is 30°C-45°C, and the reaction time is 1-5h.
  • reaction crystallization solvent is ethanol-ethyl acetate, methanol-ethyl acetate, ethanol-methyl tert-butyl ether, acetone-ethyl acetate, acetonitrile-ethyl acetate; the ratio of the crystallization solvent is 2:1-4:1 ,
  • the crystallization temperature is 0-5°C.
  • the obtained sulfonic acid quaternary ammonium salt intermediate is dissolved in ethanol or acetonitrile, and the ethanol or acetonitrile solution of sodium isooctanoate is added, and a white solid is precipitated, filtered and dried to obtain avibactam sodium.
  • the palladium carbon was removed by suction filtration, the filter cake was washed with water, and the filtrate was washed once with 25ml ethyl acetate, and then 60% 1,1-dipentylcyclohexamethylene ammonium bromide (4.2g) was added and the reaction was maintained at 40°C. Extract with dichloromethane (25ml ⁇ 2); add water (12ml) and isopropanol (12ml), add the remaining 40% 1,1-dipentylcyclohexamethylene ammonium bromide (2.8g) and The reaction was maintained at 40°C and extracted with dichloromethane (25ml ⁇ 2).
  • the palladium carbon was removed by suction filtration, the filter cake was washed with water, and the filtrate was washed once with 25ml ethyl acetate, and then 60% 1,1-dipentylcyclohexamethylene ammonium bromide (4.2g) was added and the reaction was maintained at 40°C. Extract with dichloromethane (25ml ⁇ 2); add water (12ml) and isopropanol (12ml), add the remaining 40% 1,1-dipentylcyclohexamethylene ammonium bromide (2.8g) and The reaction was maintained at 40°C and extracted with dichloromethane (25ml ⁇ 2).
  • the palladium-carbon was removed by suction filtration, the filter cake was washed with water, the isopropanol was removed by rotary evaporation at 45°C, 5% tetrahydrofuran was added, and then 1,1-dibutylcyclohexamethylene ammonium bromide (6.4g, 1.2eq) was added and kept The reaction was crystallized at 0°C.
  • the filtrate was washed once with 25ml ethyl acetate, and then 80% 1,1-dipentylcyclohexamethylene ammonium bromide (5.6g) was added, and the reaction was maintained at 40°C. 2h. It was extracted with dichloromethane (25ml ⁇ 2), and then the remaining 20% 1,1-dipentylcyclohexamethylene ammonium bromide (1.4g) was added and the reaction was carried out at 40°C for 2h.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

提供了式（I）所示的阿维巴坦季铵盐化合物及其制备方法和用途，式中n等于1、2或3，R基团选自丙基、丁基和戊基。所述阿维巴坦季铵盐化合物纯度大于99.89%，其制备的β-内酰胺酶抑制剂阿维巴坦钠纯度大于99.90%，满足了原料药药学质量标准，适合放大生产。

Description

磺酸季铵盐化合物及其制备方法和用途 技术领域
本发明涉及医药化合物及合成方法领域，具体涉及一种β-内酰胺酶抑制剂的磺酸季铵盐化合物及其制备方法，以及其作为中间体制备β-内酰胺酶抑制剂方面的用途。
背景技术
式(Ⅱ)的化合物，化学上被称为({[(2S,5R)-2-氨基甲酰基-7-氧代-1，6-二氮杂二环[3.2.1]-辛-6-基]氧基}磺酰基)季铵盐，在CN 103649051 A、CN 105283458 B专利中公开的β-内酰胺酶抑制剂的合成中，其作为阿维巴坦(avibactam)生产的重要中间体。因此，该磺酸季铵盐高纯度、高产率的制备能够极大的提升阿维巴坦的生产质量而且可以降低生产成本。
Figure PCTCN2020132400-appb-000001
式(Ⅱ)化合物是合成β-内酰胺酶抑制剂，例如阿维巴坦药物的重要中间体。制备高纯度、高收率的式(Ⅱ)化合物在生产阿维巴坦钠及其他新型的氮杂双环类磺酸化合物方面非常重要。
发明内容
本发明的第一目的是提供一种新的磺酸季铵盐化合物(式Ⅱ)；
Figure PCTCN2020132400-appb-000002
本发明的第二目的在于提供制备磺酸季铵盐化合物的方法，包括：
(1)(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺、三氧化硫三甲胺、三乙胺溶于醇和水中，加入催化剂，通入氢气脱除苄基，然后与磺化试剂进行磺化反应；
(2)方法a：反应完全，抽滤除去钯碳，旋蒸除去醇，加入溶剂，(2S,5R)-6-(磺基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺与溴化季铵盐反应析晶；
方法b：乙酸乙酯洗涤一次，(2S,5R)-6-(磺基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺与季铵盐总质量的60％进行反应，用二氯甲烷萃取产物；然后加入水和异丙醇，再加入季铵盐总质量的40％继续反应，二氯甲烷萃取，合并两次萃取液，旋蒸，加入溶剂析晶。
(3)反应结束后，抽滤，干燥得磺酸季铵盐化合物式(Ⅱ)；
本发明的第三目的在于提供利用磺酸季铵盐式(Ⅱ)制备高纯度的阿维巴坦钠产品的用途，包括：取磺酸季铵盐化合物溶解于无水乙醇中，在室温条件下滴加异辛酸钠的乙醇溶液，滴加完毕,室温条件下反应3h得白色固体，抽滤，干燥，HPLC检测纯度高达99.93％。
针对具体的发明步骤进行详细描述：
总体上来讲，我们提供了一种新的磺酸季铵盐化合物式(Ⅱ)：
Figure PCTCN2020132400-appb-000003
本发明目的二中提供了制备该磺酸季铵盐化合物的合成方法，包括：
步骤(1)中，(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺、三氧化硫三甲胺、三乙胺溶于醇和水混合溶液中，加入催化剂，(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺、三氧化硫三甲胺、三乙胺其摩尔比为1：1.12：0.2，催化剂为含钯10％、含水量50％的钯碳，催化剂用量为(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺质量的0.025倍，反应温度在20-35℃，反应时间在1-8h，反应溶剂选自甲醇-水、乙醇-水或异丙醇-水混合溶剂，优选异丙醇和水混合溶剂，反应 溶剂体积比为1：1；
步骤(2)方法a中，旋蒸温度在25-60℃，优选45℃，(2S,5R)-6-(磺基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺与溴化季铵盐的摩尔比为1:(1-1.3)，所加溶剂的量为除去醇剩余溶剂体积的1-15％，溶剂选自乙腈、1,4-二氧六环、丙酮、四氢呋喃、水，优选5％，反应析晶温度为-5-10℃，反应析晶时间在1-5h。
步骤(2)方法b中，乙酸乙酯用量为(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺质量的5倍，加入水和异丙醇的量分别为(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺质量的2.4倍，反应结晶溶剂选自乙醇-乙酸乙酯，甲醇-乙酸乙酯，乙醇-甲基叔丁基醚，丙酮-乙酸乙酯，乙腈-乙酸乙酯，优选乙醇和乙酸乙酯，结晶溶剂体积比为2：1-4：1，优选3：1，析晶温度为0-5℃。
本发明的第三目的在于提供利用磺酸季铵盐化合物式(Ⅱ)制备高纯度的阿维巴坦钠产品的用途，包括：1摩尔当量的磺酸季铵盐化合物溶解于无水乙醇中，在室温条件下滴加2摩尔当量的异辛酸钠的乙醇溶液，滴加完毕，反应3h得白色固体，抽滤，干燥得阿维巴坦钠，HPLC检测纯度达99.93％。
本发明提供了一种新的磺酸季铵盐化合物及制备方法和用途，，制备方法操作简单，成本低，绿色化程度高，适合生产放大。
附图说明
图1为磺酸季铵盐的氢谱图
图2为磺酸季铵盐的碳谱图
具体实施方式：
一种阿维巴坦中间体的制备方法，其特征在于：阿维巴坦中间体的结构式如式(Ⅰ)所示：
Figure PCTCN2020132400-appb-000004
其中，n等于1，2，3(五元，六元，七元环)，R基团选自丙基，丁基，戊基；制备式(Ⅰ)化合物的方法，包括以下步骤：
步骤(1)(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺溶于醇和水中，通入氢气脱除苄基，然后与磺化试剂反应进行磺化；
步骤(2)洗涤一次，(2S,5R)-6-(磺基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺与60％季铵盐反应，用二氯甲烷萃取产物；然后加入部分水和异丙醇，再加入剩余40％的季铵盐继续反应；
步骤(3)反应结束后，用二氯甲烷二次萃取，将萃取液合并浓缩、旋蒸，然后加溶剂进行析晶得到白色固体，抽滤并干燥得磺酸季铵盐中间体化合物式(Ⅰ)；进一步，催化剂为钯碳，反应温度在20℃-35℃，反应时间在1-8h；反应溶剂为甲醇-水，乙醇-水，异丙醇-水等混合溶剂。
进一步，所述式(Ⅰ)中n等于3，R基团是戊基。
进一步，步骤(1)所得产物利用乙酸乙酯洗涤一次，季铵盐与(2S,5R)-6-(磺基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺投料比为1.2-1.5：反应温度为30℃-45℃，反应时间为1-5h。
进一步，反应结晶溶剂为乙醇-乙酸乙酯，甲醇-乙酸乙酯，乙醇-甲基叔丁基醚，丙酮-乙酸乙酯，乙腈-乙酸乙酯；结晶溶剂比例为2：1-4：1，析晶温度为0-5℃。
进一步，将得到得磺酸季铵盐中间体溶于乙醇或乙腈中，加入异辛酸钠的乙醇或乙腈溶液，析出白色固体过滤干燥得阿维巴坦钠。
实施例1
将(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(5g,)、钯碳(125mg,10％钯)、三氧化硫三甲胺复合物(2.78g,1.12eq)、三乙胺(0.5ml，0.2eq)、异丙醇(25ml)和水(25ml)依次加入100ml反应瓶中，在搅拌条件下通入氢气，25℃条件下进行至反应完全。抽滤除去钯碳，用水洗涤滤饼，25ml乙酸乙酯洗涤一次滤液，然后加入60％的1，1-二戊基环六亚甲基溴化铵(4.2g)并保持40℃条件反应，用二氯甲烷(25ml×2)萃取；再加入水(12ml)和异丙醇(12ml)，加入剩余40％的1，1-二戊基环六亚甲基溴化铵(2.8g)并保持40℃条件反应，用二氯甲烷(25ml×2)萃取。合并有机相旋蒸，加入乙酸乙酯和乙醇(1：3)5℃条件下析晶，过滤、洗涤，干燥得({[(2S,5R)-2-氨基甲酰基-7-氧代-1，6-二氮杂二环[3.2.1]-辛-6-基]氧基}磺酰基)(1，1-二戊基环六亚甲基铵盐)(6.3g)。(收率68％)
1H NMR(400MHz,Chloroform-d)δ6.68(s,1H),5.69(s,1H),4.34(s,1H),3.93(d,J＝7.7Hz,1H),3.64–3.50(m,4H),3.35(dd,J＝10.8,6.1Hz,5H),2.88(d,J＝11.6Hz,1H),2.39(dd,J＝15.0,6.8Hz,1H),2.16(s,1H),1.98(s,4H),1.93–1.84(m,1H),1.75(d,J＝14.4Hz,9H),1.40(d,J＝6.8Hz,8H),0.93(t,J＝6.6Hz,6H).
13C NMR(101MHz,Chloroform-d)δ172.30,166.13,62.98,61.21,60.44,57.92,47.97,28.39,27.58,22.15,22.07,21.82,20.79,17.36,13.81.
HRMS Calcd for C 7H 10N 3O 6S:264.0296；HRMS found[M-H] -:264.0298
称取磺酸季铵盐5g并溶解于乙醇(25ml)中，将异辛酸钠(3.3g，2eq)的乙醇溶液滴加到磺酸季铵盐的乙醇溶液中，析出白色固体过滤并干燥得2.5g阿维巴坦钠(收率88％)。
1HNMR(400MHz,DMSO)δH1.63(2H,m),1.83(1H,m),2.05(1H,m),2.90(1H,d,J＝11.8Hz),3.00(1H,d,J＝11.6Hz),3.67(1H,d,J＝6.9Hz),3.98(1H,s),7.29(1H,s),7.44(1H,s).
13C NMR(100MHz,D 2O)δH 18.1(s),19.9(s),47.2(s),59.8(s),60.3(s),169.4(s),174.7(s).
实施例2
将(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(5g,)、钯碳(125mg,10％钯)、三氧化硫三甲胺复合物(2.78g,1.12eq)、三乙胺(0.5ml，0.2eq)、异丙醇(25ml)和水(25ml)依次加入100ml反应瓶中，在搅拌条件下通入氢气，25℃条件下进行至反应完全。抽滤除去钯碳，用水洗涤滤饼，25ml乙酸乙酯洗涤一次滤液，然后加入60％的1，1-二戊基环六亚甲基溴化铵(4.2g)并保持40℃条件反应，用二氯甲烷(25ml×2)萃取；再加入水(12ml)和异丙醇(12ml)，加入剩余40％的1，1-二戊基环六亚甲基溴化铵(2.8g)并保持40℃条件反应，用二氯甲烷(25ml×2)萃取。合并有机相旋蒸，加入乙醇(30ml)溶解，然后滴加异辛酸钠(3.3g，2eq)的乙醇溶液，析出白色固体过滤并干燥得3.17g阿维巴坦钠。(两步收率61％)
1HNMR(400MHz,DMSO)δH1.63(2H,m),1.83(1H,m),2.05(1H,m),2.90(1H,d,J＝11.8Hz),3.00(1H,d,J＝11.6Hz),3.67(1H,d,J＝6.9Hz),3.98(1H,s),7.29(1H,s),7.44(1H,s).
13C NMR(100MHz,D 2O)δH 18.1(s),19.9(s),47.2(s),59.8(s),60.3(s),169.4(s),174.7(s).
实施例3
将(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(5g,18.2mmol)、钯碳(125mg,10％钯)、三氧化硫三甲胺复合物(2.78g,1.12eq)、三乙胺(0.5ml，0.2eq)、异丙醇(25ml)和水(25ml)依次加入100ml反应瓶中，在搅拌的条件下通入氢气，25℃条件下进行至反应完全。抽滤除去钯碳，用水洗涤滤饼，45℃旋蒸除去异丙醇，加入5％的乙腈(剩余体系的体积比)，然后加入1，1-二戊基环六亚甲基溴化铵(7g，1.1eq)，保持在0℃条件下反应析晶3h。过滤、干燥得8g({[(2S,5R)-2-氨基甲酰基-7-氧代-1，6-二氮杂二环[3.2.1]-辛-6-基]氧基}磺酰基)(1，1-二戊基环六亚甲基铵盐)(收率：87％)。
1H NMR(400MHz,Chloroform-d)δ6.68(s,1H),5.69(s,1H),4.34(s,1H),3.93(d,J＝7.7Hz,1H),3.64–3.50(m,4H),3.35(dd,J＝10.8,6.1Hz,5H),2.88(d,J＝11.6Hz,1H),2.39(dd,J＝15.0,6.8Hz,1H),2.16(s,1H),1.98(s,4H),1.93–1.84(m,1H),1.75(d,J＝14.4Hz,9H),1.40(d,J＝6.8Hz,8H),0.93(t,J＝6.6Hz,6H).
13C NMR(101MHz,Chloroform-d)δ172.30,166.13,62.98,61.21,60.44,57.92,47.97,28.39,27.58,22.15,22.07,21.82,20.79,17.36,13.81.
HRMS Calcd for C 7H 10N 3O 6S:264.0296；HRMS found[M-H] -:264.0298
取3g({[(2S,5R)-2-氨基甲酰基-7-氧代-1，6-二氮杂二环[3.2.1]-辛-6-基]氧基}磺酰基)(1，1-二戊基环六亚甲基铵盐)溶解于无水乙醇中，在室温条件下滴加异辛酸钠的乙醇溶液，滴加完毕反应3h得白色固体，抽滤，干燥，HPLC检测。(收率：90％，纯度：99.92％)。
1HNMR(400MHz,DMSO)δH1.63(2H,m),1.83(1H,m),2.05(1H,m),2.90(1H,d,J＝11.8Hz),3.00(1H,d,J＝11.6Hz),3.67(1H,d,J＝6.9Hz),3.98(1H,s),7.29(1H,s),7.44(1H,s).
13C NMR(100MHz,D2O)δH 18.1(s),19.9(s),47.2(s),59.8(s),60.3(s),169.4(s),174.7(s).
HRMS Calcd for C 7H 10N 3O 6S:264.0296；HRMS found[M-H] -:264.0298
实施例4
将(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(5g,18.2mmol)、钯碳(125mg,10％钯)、三氧化硫三甲胺复合物(2.78g,1.12eq)、三乙胺(0.5ml，0.2eq)、异丙醇(25ml)和水(25ml)依次加入100ml反应瓶中，在搅拌的条件下通入氢气，25℃条件下进行至反应完全。抽滤除去钯碳，用水洗涤滤饼，45℃旋蒸除去异丙醇，加入5％的四氢呋喃，然后加入1，1-二丁基环六亚甲基溴化铵(6.4g，1.2eq)，保持在0℃条件下反应析晶。过滤、干燥得7g({[(2S,5R)-2-氨基甲酰基-7-氧代-1，6-二氮杂二环[3.2.1]-辛-6-基]氧基}磺酰基)(1，1-二丁基环六亚甲基铵盐)(收率80％)
1H NMR(400MHz,Chloroform-d)δ6.68(s,1H),5.69(s,1H),4.34(s,1H),3.93(d,J＝7.7Hz,1H),3.71–3.64(m,4H),3.47–3.39(m,5H),2.88(d,J＝11.6Hz,1H),2.39(dd,J＝15.0,6.8Hz,1H),2.16(s,1H),2.08–1.97(m,4H),1.93–1.84(m,1H),1.71(dd,J＝10.4,5.9Hz,4H),1.34(td,J＝6.4,5.7,2.7Hz,8H),0.95–0.85(m,6H).
HRMS Calcd for C 7H 10N 3O 6S:264.0296；HRMS found[M-H] -:264.0298
取3g({[(2S,5R)-2-氨基甲酰基-7-氧代-1，6-二氮杂二环[3.2.1]-辛-6-基]氧基}磺酰基)(1，1-二丁基环六亚甲基铵盐)溶解于无水乙醇中，在室温条件下滴加异辛酸钠的乙醇溶液，滴加完毕反应3h得白色固体，抽滤，干燥，HPLC检测。(收率：91％，纯度：99.94％)。
1HNMR(500MHz,DMSO)δH1.63(2H,m),1.83(1H,m),2.05(1H,m),2.90(1H,d,J＝11.8Hz),3.00(1H,d,J＝11.6Hz),3.67(1H,d,J＝6.9Hz),3.98(1H,s),7.29(1H,s),7.44(1H,s).
13C NMR(100MHz,D2O)δH 18.1(s),19.9(s),47.2(s),59.8(s),60.3(s),169.4(s),174.7(s).
HRMS Calcd for C 7H 10N 3O 6S:264.0296；HRMS found[M-H] -:264.0298
实施例5
将(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(5g,18.2mmol)、钯碳(125mg,10％钯)、三氧化硫三甲胺复合物(2.78g,1.12eq)、三乙胺(0.5ml，0.2eq)、异丙醇(25ml)和水(25ml)依次加入100ml反应瓶中，在搅拌的条件下通入氢气，25℃条件下进行至反应完全。抽滤除去钯碳，用水洗涤滤饼，45℃旋蒸除去异丙醇，加入5％的1，4-二氧六环，然后加入1，1-二戊基环四亚甲基溴化铵(7g，1.2eq)，保持在0℃条件下反应析晶。过滤、干燥得g({[(2S,5R)-2-氨基甲酰基-7-氧代-1，6-二氮杂二环[3.2.1]-辛-6-基]氧基}磺酰基)(1，1-二戊基环四亚甲基铵盐)(收率76％)。
1H NMR(400MHz,Chloroform-d)δ6.68(s,1H),5.69(s,1H),4.34(s,1H),3.93(d,J＝7.7Hz,1H),3.88–3.78(m,4H),3.48–3.39(m,5H),2.88(d,J＝11.6Hz,1H),2.39(dd,J＝15.0,6.8Hz,1H),2.36–2.26(m,4H),2.16(s,1H),1.93–1.84(m,1H),1.76–1.65(m,4H),1.38–1.28(m,8H),0.95–0.85(m,6H).
HRMS Calcd for C 7H 10N 3O 6S:264.0296；HRMS found[M-H] -:264.0298
取3g({[(2S,5R)-2-氨基甲酰基-7-氧代-1，6-二氮杂二环[3.2.1]-辛-6-基]氧基}磺酰基)(1，1-二己基环四亚甲基铵盐)溶解于无水乙醇中，在室温条件下滴加异辛酸钠的乙醇溶液，滴加完毕反应3h得白色固体，抽滤，干燥，HPLC检测。(收率：89％，纯度：99.90％)
1HNMR(500MHz,DMSO)δH1.63(2H,m),1.83(1H,m),2.05(1H,m),2.90(1H,d,J＝11.8Hz),3.00(1H,d,J＝11.6Hz),3.67(1H,d,J＝6.9Hz),3.98(1H,s),7.29(1H,s),7.44(1H,s).
13C NMR(100MHz,D2O)δH 18.1(s),19.9(s),47.2(s),59.8(s),60.3(s),169.4(s),174.7(s).
HRMS Calcd for C 7H 10N 3O 6S:264.0296；HRMS found[M-H] -:264.0298
实施例6
将(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(5g,18.2mmol)、钯碳(125mg,10％钯)、三氧化硫三甲胺复合物(2.78g,1.12eq)、三乙胺(0.5ml，0.2eq)、异丙醇(25ml)和水(25ml)依次加入100ml反应瓶中，在搅拌的条件下通入氢气，25℃条件下进行至反应完全。抽滤除去钯碳，用水洗涤滤饼，45℃旋蒸除去异丙醇，然后加入1，1-二戊基环六亚甲基溴化铵(7g，1.2eq)，保持在0℃条件下反应析晶3h。过滤、干燥得7.7g({[(2S,5R)-2-氨基甲酰基-7-氧代-1，6-二氮杂二环[3.2.1]-辛-6-基]氧基}磺酰基)(1，1-二戊基环六亚甲基铵盐)(收率86％)
1H NMR(400MHz,Chloroform-d)δ6.68(s,1H),5.69(s,1H),4.34(s,1H),3.93(d,J＝7.7Hz,1H),3.64–3.50(m,4H),3.35(dd,J＝10.8,6.1Hz,5H),2.88(d,J＝11.6Hz,1H),2.39(dd,J＝15.0,6.8Hz,1H),2.16(s,1H),1.98(s,4H),1.93–1.84(m,1H),1.75(d,J＝14.4Hz,9H),1.40(d,J＝6.8Hz,8H),0.93(t,J＝6.6Hz,6H).
HRMS Calcd for C 7H 10N 3O 6S:264.0296；HRMS found[M-H] -:264.0298
取3g({[(2S,5R)-2-氨基甲酰基-7-氧代-1，6-二氮杂二环[3.2.1]-辛-6-基]氧基}磺酰基)(1，1-二戊基环六亚甲基铵盐)溶解于无水乙醇中，在室温条件下滴加异辛酸钠的乙醇溶液，滴加完毕，反应3h得白色固体，抽滤，干燥，HPLC检测。(收率92％，纯度99.94％)
实施例6
将(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(5g,18.2mmol)、钯碳(125mg,10％钯)、三氧化硫三甲胺复合物(2.78g,1.12eq)、 三乙胺(0.5ml，0.2eq)、异丙醇(25ml)和水(25ml)依次加入100ml反应瓶中，在搅拌的条件下通入氢气，室温条件下反应至完全。抽滤除去钯碳并用水洗涤滤饼，用25ml乙酸乙酯(25ml)洗涤一次滤液，然后加入1，1-二戊基环六亚甲基溴化铵(7g，1.2eq)，保持在40℃条件下反应2h。用二氯甲烷(25ml×2)萃取，合并有机相旋蒸，然后加入乙醇和乙酸乙酯(3:1)溶剂5℃条件下析晶，过滤、洗涤并干燥得5.8g阿维巴坦中间体化合物(该步收率为63％)。
称取磺酸季铵盐5g溶解于乙醇(25ml)中，将异辛酸钠(3.3g，2eq)的乙醇溶液滴加到季铵盐的乙醇溶液中，反应析出白色固体，过滤并干燥得2.4g阿维巴坦钠(收率87％)。
实施例7
将(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(5g,)、钯碳(125mg,10％钯)、三氧化硫三甲胺复合物(2.78g,1.12eq)、三乙胺(0.5ml，0.2eq)、异丙醇(25ml)和水(25ml)依次加入100ml反应瓶中，在搅拌的条件下通入氢气，30℃条件下反应至完全。抽滤除去钯碳并用水洗涤滤饼，用25ml乙酸乙酯洗涤一次滤液，然后加入80％的1，1-二戊基环六亚甲基溴化铵(5.6g)，保持40℃条件反应2h。用二氯甲烷(25ml×2)萃取，然后再将剩余20％的1，1-二戊基环六亚甲基溴化铵(1.4g)加入并在40℃条件下进行反应2h,用二氯甲烷萃取(25ml×2)，合并有机相并旋蒸，加入乙醇和乙酸乙酯溶剂5℃条件下析晶，过滤、洗涤并干燥得5.56g阿维巴坦中间体化合物(收率60％)。称取季铵盐5g并溶解于乙醇(25ml)中，将异辛酸钠(3.3g，2eq)的乙醇溶液滴加到磺酸季铵盐的乙醇溶液中，析出白色固体过滤并干燥得2.5g阿维巴坦钠(收率88％)。
实施例8
将(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(5g,)、钯碳(125mg,10％钯)、三氧化硫三甲胺复合物(2.78g,1.12eq)、三乙胺(0.5ml，0.2eq)、异丙醇(25ml)和水(25ml)依次加入100ml反应瓶中，在搅拌条件下通入氢气，30℃条件下反应至完全。抽滤除去钯碳并用水洗涤滤饼，用25ml乙酸乙酯洗涤一次滤液，然后加入1，1-二丁基环六亚甲基溴化铵(8.7g，1.5eq)，保持40℃条件下反应2h。用二氯甲烷(25ml×2)萃取，合并有机相旋蒸，加入乙醇和乙酸乙酯溶剂5℃条件下析晶，然后过滤、洗涤并干燥得5.67g阿维巴坦中间体化合物(收率62％)。
称取季铵盐5g并溶解于乙醇(25ml)中，将异辛酸钠(3.3g，2eq)的乙醇溶液滴加到磺酸季铵盐的乙醇溶液中，析出白色固体过滤并干燥得2.43g阿维巴坦钠(收率86％)。
实施例9
将(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(5g,)、钯碳(125mg,10％钯)、三氧化硫三甲胺复合物(2.78g,1.12eq)、三乙胺(0.5ml，0.2eq)、异丙醇(25ml)和水(25ml)依次加入100ml反应瓶中，在搅拌条件下通入氢气，30℃下反应至完全。抽滤除去钯碳并用水洗涤滤饼，用25ml乙酸乙酯洗涤一次滤液，然后加入60％的1，1-二戊基环六亚甲基溴化铵(4.2g)并保持40℃条件反应2h，用二氯甲烷(25ml×2)萃取；再加入水(12ml)和异丙醇(12ml)，加入剩余40％的1，1-二戊基环六亚甲基溴化铵(2.8g)并保持40℃条件反应2h，用二氯甲烷(25ml×2)萃取。合并有机相旋蒸，加入乙醇和乙酸乙酯溶剂5℃条件下析晶，然后过滤、洗涤并干燥得阿维巴坦中间体化合 物(6.3g)(收率68％)。
称取磺酸季铵盐5g并溶解于乙醇(25ml)中，将异辛酸钠(3.3g，2eq)的乙醇溶液滴加到磺酸季铵盐的乙醇溶液中，析出白色固体过滤并干燥得2.5g阿维巴坦钠(收率88％)。
实施例10
将(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺(5g,)、钯碳(125mg,10％钯)、三氧化硫三甲胺复合物(2.78g,1.12eq)、三乙胺(0.5ml，0.2eq)、异丙醇(25ml)和水(25ml)依次加入100ml反应瓶中，在搅拌条件下通入氢气，30℃条件下反应至完全。抽滤除去钯碳并用水洗涤滤饼，用25ml乙酸乙酯洗涤一次滤液，然后加入60％的1，1-二戊基环六亚甲基溴化铵(4.2g)并保持40℃条件反应2h，用二氯甲烷(25ml×2)萃取；再加入水(12ml)和异丙醇(12ml)，加入剩余40％的1，1-二戊基环六亚甲基溴化铵(2.8g)并保持40℃条件反应2h，用二氯甲烷(25ml×2)萃取。合并有机相旋蒸，加入乙醇(30ml)溶解，然后滴加异辛酸钠(3.3g，2eq)的乙醇溶液，析出白色固体过滤并干燥得3.17g阿维巴坦钠(两步收率61％)。

Claims (8)

  1. 下述式(Ⅰ)化合物：
    Figure PCTCN2020132400-appb-100001
    式中：
    n是表示亚甲基的数目，其中n等于1，2或3，即为五元、六元或七元环；
    R基团选自丙基、丁基或戊基。
  2. 根据权利要求1所述化合物，其中所述化合物具有下述式(Ⅱ)的结构
    Figure PCTCN2020132400-appb-100002
    其中，n等于1，2或3，R基团选自丙基、丁基或戊基。
  3. 根据权利要求2所述化合物，其中，所述化合物选自：
    Figure PCTCN2020132400-appb-100003
    Figure PCTCN2020132400-appb-100004
  4. [根据细则91更正 05.01.2021]
    制备如权利要求2所述化合物的制备方法，其特征在于制备方法包括如下步骤：
    (1)(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺、三氧化硫三甲胺、三乙胺溶于醇和水中,加入催化剂，通入氢气脱除苄基，然后与磺化试剂进行磺化反应；
    (2)方法a：抽滤除去钯碳，旋蒸除去醇，加入溶剂，(2S,5R)-6-(磺基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺与溴化季铵盐反应析晶；
    方法b：乙酸乙酯洗涤一次，(2S,5R)-6-(磺基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺与季铵盐总质量的60％反应，用二氯甲烷萃取产物；然后加入水和异丙醇，再加入季铵盐总质量的40％继续反应，二氯甲烷萃取，合并两次萃取液，旋蒸，加入溶剂进行析晶。
    (3)反应结束后，抽滤，干燥得磺酸季铵盐化合物式(Ⅱ)；
  5. [根据细则91更正 05.01.2021]　
    根据权利要求4所述的一种磺酸季铵盐化合物的制备方法，其特征在于：所述步骤(1)中，(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺、三氧化硫三甲胺、三乙胺其摩尔比为1：1.12：0.2，催化剂为含钯10％及含水量50％的钯碳，催化剂用量为(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺质量的0.025倍，反应温度在20℃-35℃，反应时间在1-8h，反应溶剂选自甲醇-水、乙醇-水或异丙醇-水混合溶剂反应溶剂体积比例为1：1。
  6. [根据细则91更正 05.01.2021]　
    根据权利要求4所述的一种磺酸季铵盐化合物的制备方法，其特征在于：所述步骤(2)的方法a中，旋蒸温度在25-60℃，(2S,5R)-6-(磺基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺与溴化季铵盐的摩尔比为1:(1-1.3)，所加溶剂的量为除去醇剩余溶剂体积的1％-15％，溶剂选自乙腈、1,4-二氧六环、丙酮、四氢呋喃或水，反应析晶温度为-5-10℃，反应析晶时间在1-5h。
  7. [根据细则91更正 05.01.2021]　
    根据权利要求4所述得一种磺酸季铵盐化合物的制备方法，其特征在于：所述步骤(2)的方法b中，乙酸乙酯用量为(2S,5R)-6-(苄基氧基)-7-氧代-1， 6-二氮杂二环[3.2.1]辛烷-2-甲酰胺质量的5倍，加入水和异丙醇的量分别为(2S,5R)-6-(苄基氧基)-7-氧代-1，6-二氮杂二环[3.2.1]辛烷-2-甲酰胺质量的2.4倍，反应结晶溶剂选自乙醇-乙酸乙酯，甲醇-乙酸乙酯，乙醇-甲基叔丁基醚，丙酮-乙酸乙酯，乙腈-乙酸乙酯，结晶溶剂体积比为2：1-4：1，析晶温度为0-5℃。
  8. [根据细则91更正 05.01.2021]　
    满足权利要求1-3所述化合物的制备在阿维巴坦钠原料药生产中具有重要的应用价值，具体包括：1摩尔当量的磺酸季铵盐溶解于乙醇中，将2摩尔当量的异辛酸钠的乙醇溶液滴加到磺酸季铵盐的乙醇溶液中，析出白色固体，过滤，干燥得阿维巴坦钠。
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