CN109983005A - 4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羟基-3-(5-巯基-1h-1,2,4-***-1-基)丙基)吡啶-3-基)氧基)苄腈及制备方法 - Google Patents

4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羟基-3-(5-巯基-1h-1,2,4-***-1-基)丙基)吡啶-3-基)氧基)苄腈及制备方法 Download PDF

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CN109983005A
CN109983005A CN201780071374.4A CN201780071374A CN109983005A CN 109983005 A CN109983005 A CN 109983005A CN 201780071374 A CN201780071374 A CN 201780071374A CN 109983005 A CN109983005 A CN 109983005A
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fluoro
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difluorobenzene base
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K·格雷
Q·杨
N·R·巴比吉
Y·郝
J·伦加
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Corteva Agriscience LLC
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Abstract

本文提供了一种制备4‑((6‑(2‑(2,4‑二氟苯基)‑1,1‑二氟‑2‑羟基‑3‑(5‑巯基‑1H‑1,2,4‑***‑1‑基)丙基)吡啶‑3‑基)氧基)苄腈的方法。

Description

4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羟基-3-(5-巯基- 1H-1,2,4-***-1-基)丙基)吡啶-3-基)氧基)苄腈及制备 方法
相关申请的交叉引用
本申请要求基于35U.S.C.§119(e)于2016年11月18日提交的美国临时专利申请U.S.S.N.62/423,868的优先权，其全部内容通过引用并入本申请中。
技术领域
本文提供了4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羟基-3-(5-巯基-1H-1,2,4-***-1-基)丙基)吡啶-3-基)氧基)苄腈及制备方法。
背景技术
美国专利申请系列号62/163,106尤其描述了某些金属酶抑制剂化合物及其作为杀真菌剂的用途。该申请的公开内容通过引用清楚地并入本文。该专利申请描述了产生抑制金属酶的杀真菌剂的各种途径。可能有益的是(例如)通过使用提供改进的时间和成本效率的试剂和/或化学中间体来提供更直接和有效的制备抑制金属酶的杀真菌剂和相关化合物的方法。
发明内容
本文提供了化合物4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羟基-3-(5-巯基-1H-1,2,4-***-1-基)丙基)吡啶-3-基)氧基)苄腈(I)及其制备方法。在一个实施方式中，本文提供了一种用于制备式I的化合物的方法：
该方法包括使式II的化合物与酸和碱接触
在另一个实施方式中，式II的化合物可以通过使式III的化合物与甲酸接触来制备，
其中R为H或t-BuO(CO)。
本公开的另一方面是在本发明方法中产生的新型中间体，即，由以下组成的化合物：
术语“卤素”或“卤代”是指一个或多个卤素原子，定义为F、Cl、Br和I。
术语“有机金属”是指含有金属的有机化合物，尤其是其中金属原子直接与碳原子键合的化合物。
在本文中，室温(RT)定义为约20℃至约25℃。
在整个公开内容中，对式I-III化合物的提及被认为也包括光学异构体和盐。具体而言，当式I-III的化合物含有手性碳时，应理解这些化合物包括其光学异构体和外消旋物。示例性盐可包括：盐酸盐、氢溴酸盐、氢碘酸盐等。
本申请中公开的某些化合物可以作为一种或多种异构体存在。本领域技术人员将理解，一种异构体可能比其它异构体更具活性。为清楚起见，本公开中公开的结构仅以一种几何形式绘出，但旨在表示分子的所有几何和互变异构形式。例如，式I和Ia的化学结构是相同分子的互变异构形式。
上述实施方式仅仅是示例性的，并且本领域技术人员将认识到或将能够使用仅仅常规的实验确定具体方法、材料和程序的许多等同物。所有这些等同物都被认为是在本发明的范围内，并且包含在所附权利要求中。
具体实施方式
4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羟基-3-(5-巯基-1H-1,2,4-***-1-基)丙基)吡啶-3-基)氧基)苄腈(I)可以由如实施例1中所示的1-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)-2-甲酰肼-1-硫代甲酰胺(II)制备。
实施例1：4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羟基-3-(5-巯基-1H-1,2,4-***-1-基)丙基)吡啶-3-基)氧基)苄腈(I)的制备
向1-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)-2-甲酰肼-1-硫代甲酰胺(II)(0.73g，1.405mmol)中加入2N氢氧化钠(3.51mL，7.03mmol)，并在室温将反应物搅拌1小时，此时反应物从浆料转变为澄清溶液。加入HCl(2N，3.6mL)，形成白色沉淀物(pH 2)。通过过滤分离沉淀物，并用水冲洗固体。使该物质风干，从而得到白色固体4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羟基-3-(5-巯基-1H-1,2,4-***-1-基)丙基)吡啶-3-基)氧基)苄腈(I)(676.8mg，1.350mmol，产率：96％)。1H NMR(400MHz,CDC13)δ8.44(d,J＝2.7Hz,1H),7.72-7.65(m,2H),7.62(s,1H),7.58(d,J＝8.6Hz,1H),7.50-7.36(m,2H),7.10-7.02(m,2H),6.80(ddd,J＝11.5,8.6,2.6Hz,1H),6.76-6.69(m,1H),5.93(s,1H),5.31-5.21(m,2H)。19F NMR(376MHz,CDCl3)δ-103.15(ddd,J＝31.2,23.4,9.4Hz),-108.46(d,J＝29.1Hz),-109.02(d,J＝23.2Hz),-109.39(d,J＝9.2Hz)。ESIMS m/z 502.0[(M+H)+]。
用于该方法步骤中的合适的碱可包括金属碳酸盐、金属醇盐和金属氢氧化物，例如碳酸钠、碳酸钾、甲醇钠、甲醇钾、氢氧化钠和氢氧化钾。
用于该方法步骤中的合适的酸可包括，例如，盐酸(HCl)、氢溴酸(HBr)、乙酸、甲酸、硫酸(H2SO4)、磷酸(H3PO4)和硝酸(HNO3)。
1-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)-2-甲酰肼-1-硫代甲酰胺(II)可以由实施例2中所示的1-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-硫代甲酰胺(III，R＝H)制备。
实施例2：1-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)-2-甲酰肼-1-硫代甲酰胺(II)的制备
向1-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-硫代甲酰胺(III，R＝H)(0.25g，0.509mmol)中加入甲酸(0.780mL，20.35mmol)，并在室温将反应混合物搅拌22小时。在乙酸乙酯和盐水之间分配反应混合物，并分离各层。用饱和碳酸氢钠水溶液洗涤有机层。将有机层用无水硫酸钠干燥，过滤，浓缩，得到白色固体(240mg)。加入二氯甲烷(3mL)，得到浆料，将该浆料过滤，将所得固体真空干燥，从而得到白色固体1-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)-2-甲酰肼-1-硫代甲酰胺(II)(207.3mg，0.379mmol，产率：75％)。1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),8.45(d,J＝2.7Hz,1H),7.99-7.84(m,2H),7.69(dd,J＝8.6,2.9Hz,1H),7.56(dt,J＝24.6,9.2Hz,2H),7.23-7.15(m,2H),7.11(td,J＝10.5,9.1,2.4Hz,1H),7.03(d,J＝9.6Hz,1H),6.56(s,1H),5.45(s,1H),4.44(s,1H)。19F NMR(376MHz,DMSO-d6)δ-105.46,-108.14,-108.54,-111.06(d,J＝9.0Hz)。ESIMS m/z 520.1[(M+H)+]。
或者，1-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)-2-甲酰肼-1-硫代甲酰胺(II)可以由实施例3中所示的2-氨基甲酰硫基-2-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-甲酸叔丁酯(III，R＝t-BuO(CO))制备。
实施例3：1-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)-2-甲酰肼-1-硫代甲酰胺(II)的制备
向2-氨基甲酰硫基-2-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-甲酸叔丁酯(III，R＝t-BuO(CO))(1.33g，2.248mmol)中加入甲酸(3.45mL，90mmol)，并在室温将反应物搅拌22小时。在乙酸乙酯和水之间分配反应物并分离各层。用饱和碳酸氢钠水溶液洗涤有机层。将有机层用无水硫酸钠干燥，过滤，并浓缩成油状物。加入二氯甲烷并将物质浓缩成固体。加入二氯甲烷(5mL)，形成白色沉淀物，通过过滤分离该白色沉淀物并用二氯甲烷洗涤。将白色固体真空干燥，得到1-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)-2-甲酰肼-1-硫代甲酰胺(II)(733.4mg，1.412mmol，产率：63％)。分析数据与实施例2中制备的产物的数据匹配。
实施例2和3中示例说明的方法可以在约10℃至约100℃，或约20℃至约50℃的温度进行，并且可以使用溶剂如THF、2-Me-THF、二噁烷、DME、乙腈及其混合物来进行。
1-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-硫代甲酰胺(III，R＝H)可以由实施例4所述的2-氨基甲酰硫基-2-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-甲酸叔丁酯(III，R＝t-BuO(CO))制备。
实施例4：1-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-硫代甲酰胺(III，R＝H)的制备
向2-氨基甲酰硫基-2-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-甲酸叔丁酯(III，R＝t-BuO(CO))(2g，3.38mmol)的甲醇(16.90mL)浆料中加入氯化氢(4M，在二噁烷中；4.23mL，16.90mmol)并将反应物加热至50℃。1小时后，用饱和碳酸氢钠淬灭反应，并用乙酸乙酯萃取。将有机层用水和盐水洗涤，用无水硫酸钠干燥，过滤并浓缩，从而得到黄色泡沫状物(1.65g)。将粗物质溶解在二氯甲烷中，并通过使用乙酸乙酯/己烷作为洗脱液的硅胶柱色谱法进行纯化。收集包含产物的级分并浓缩，从而得到白色泡沫状物1-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-硫代甲酰胺(III，R＝H)(1.38g，2.81mmol，产率：83％)。1H NMR(400MHz,CDC13)δ8.33(d,J＝2.7Hz,1H),7.74-7.62(m,3H),7.56(d,J＝8.6Hz,1H),7.39(dd,J＝8.7,2.7Hz,1H),7.08-7.00(m,2H),6.90-6.75(m,2H),6.49(s,1H),5.25(d,J＝15.5Hz,1H),4.89(d,J＝15.5Hz,1H)。19F NMR(376MHz,CDCl3)δ-104.41(t,J＝26.1Hz),-108.49(d,J＝77.7Hz),-109.07(d,J＝8.9Hz)。ESIMS m/z 492.1[(M+H)+]。
用于该方法步骤中的合适的酸可包括盐酸(HCl)、氢溴酸(HBr)、硫酸(H2SO4)、磷酸(H3PO4)、硝酸(HNO3)和三氟乙酸(TFA)。
用于该方法步骤中的合适的溶剂可包括醇(例如甲醇、乙醇、异丙醇)、二噁烷、THF、DME和MeCN。
实施例4中示例的方法可在约10℃至约100℃之间，或约20℃至约70℃之间的温度进行。
实施例3：2-氨基甲酰硫基-2-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-甲酸叔丁酯(III)的制备
方法A：在0℃下向2-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-甲酸叔丁酯(IV)(5g，9.39mmol)的THF(31.3mL)溶液中加入异硫氰酸苯甲酰酯(1.199mL，8.92mmol)。30分钟后，加入另外的异硫氰酸苯甲酰酯(0.1mL，0.74mmol)。通过LCMS鉴定苯甲酰基中间体(ESIMS m/z 696.1[(M+H)+])。再过30分钟后，加入无水肼(1.47mL，46.9mmol)。将混合物在0℃搅拌1小时，然后在室温搅拌30分钟。用乙酸乙酯稀释反应物并用饱和氯化铵水溶液洗涤。将有机层用无水硫酸钠干燥，过滤，并浓缩成淡黄色油状物。向油状物中加入甲醇(25mL)，搅拌几分钟后，形成白色沉淀物。过滤浆料，用甲醇冲洗固体，从而得到白色固体2-氨基甲酰硫基-2-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-甲酸叔丁酯(III)(4.29g，7.25mmol，产率：77％)。1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),8.45(d,J＝11.9Hz,2H),7.96-7.86(m,2H),7.70(dd,J＝8.6,2.8Hz,2H),7.58(d,J＝8.4Hz,1H),7.53 7.40(m,1H),7.22-7.15(m,2H),7.12(t,J＝11.0Hz,1H),7.01(d,J＝8.8Hz,1H),6.37(s,1H),5.45(d,J＝15.7Hz,1H),4.47(d,J＝15.3Hz,1H),1.40(s,9H)。19F NMR(376MHz,DMSO-d6)δ-104.72(d,J＝122.8Hz),-107.49--109.12(m),-111.08--111.85(m)。ESIMS m/z 592.2[(M+H)+]。
方法B：向2-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-甲酸叔丁酯(IV，1g，1.596mmol)的乙酸乙酯(9.4mL)溶液中加入异硫氰酸三甲基硅烷(0.540mL，3.83mmol)并将反应物在80℃搅拌18小时。NMR表明转化不完全，因此加入另外的异硫氰酸三甲基硅烷(0.540mL，3.83mmol)并将反应物在80℃搅拌6小时。NMR表明反应仍然不完全，因此加入更多的异硫氰酸三甲基硅烷(0.540mL，3.83mmol)并将反应物在80℃搅拌17小时。使反应冷却至室温并加入1N HCl(10mL)。分离各相，有机层用无水硫酸钠干燥，过滤，并浓缩成黄色泡沫状物。将黄色泡沫状物溶解在二氯甲烷中，并通过用0-60％乙酸乙酯/己烷洗脱的硅胶柱色谱法纯化。收集含有产物的级分并浓缩，从而得到黄色泡沫状物2-氨基甲酰硫基-2-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-甲酸叔丁酯(III)(460mg，0.778mmol，产率：49％)。分析数据与先前获得的样品的数据一致。
用于该方法步骤的有机异硫氰酸酯可包括异硫氰酸酰基酯(例如异硫氰酸苯甲酰酯)和异硫氰酸甲硅烷基酯(例如，异硫氰酸三甲基甲硅烷基酯)。
用于从未分离的中间体中除去R-基团(其中R是苯甲酰基)以制备式III的化合物的裂解试剂可选自肼、氨、甲醇钠和甲胺。用于从未分离的中间体中除去R-基团(其中R是三甲基甲硅烷基)以制备式III的化合物的裂解试剂可选自a)氟化物，例如氟化四烷基铵和氟化钾，和b)酸，例如盐酸(HCl)、氢溴酸(HBr)或硫酸(H2SO4)。
式IV的化合物与有机异硫氰酸酯的接触可在约-20℃至约100℃进行，以及与裂解试剂的接触可在约-20℃至约100℃进行。
用于该方法步骤的溶剂可包括THF(四氢呋喃)、EtOAc、2-Me-THF、二噁烷、MeCN(乙腈)和DME(1,2-二甲氧基乙烷)中的一种或多种。
2-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-羧酸叔丁酯(II)可以由如实施例2中所示4-((6-((2-(2,4-二氟苯基)环氧乙烷-2-基)二氟甲基)吡啶-3-基)氧基)苄腈(III)制备。
实施例4：2-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-羧酸叔丁酯(IV)的制备
向4-((6-((2-(2,4--二氟苯基)环氧乙烷-2-基)二氟甲基)吡啶-3-基)氧基)苄腈(V)(5g，12.49mmol)的乙醇(40.0ml)浆料中加入肼基甲酸叔丁酯(4.13g，31.2mmol)，并将反应物在80℃加热24小时，此时起始环氧化物(V)完全消耗。使反应物冷却至45℃并用产物IV的晶体接种，从而使反应物混浊。加入另外的乙醇(40mL)，并将反应物冷却至室温过夜。将所得浆料用冰浴冷却30分钟并过滤。将固体用乙醇(30mL)冲洗并在真空下干燥，得到白色固体2-(3-(5-(4-氰基苯氧基)吡啶-2-基)-2-(2,4-二氟苯基)-3,3-二氟-2-羟丙基)肼-1-羧酸叔丁酯(IV)(5.42g，9.67mmol，产率：77％)。1H NMR(400MHz,CDC13)δ8.37(d,J＝2.7Hz,1H),7.72-7.64(m,2H),7.55(td,J＝8.8,6.6Hz,1H),7.48(d,J＝8.6Hz,1H),7.37(dd,J＝8.7,2.7Hz,1H),7.10-7.02(m,2H),6.77(dddd,J＝20.9,11.4,8.6,2.6Hz,2H),3.83(d,J＝13.7Hz,1H),3.74(dd,J＝13.4,2.8Hz,1H),1.41(s,9H)。19F NMR(376MHz,CDC13)δ-105.15,-108.68(d,J＝22.1Hz),-109.24,-110.29。ESIMS m/z 533.1[(M+H)+]。
式V的化合物与肼基甲酸叔丁酯的接触可以在约25℃至约100℃或约60℃至约90℃进行。
在该方法步骤中使用的溶剂可包括醇，例如甲醇、乙醇和异丙醇，以及非质子溶剂，例如THF(四氢呋喃)、乙腈、DMSO(二甲基亚砜)、DMF(N,N-二甲基甲酰胺)，以及这些溶剂的任意混合物。

Claims (7)

1.一种制备式I的化合物的方法，其包括：
使式II的化合物与碱和酸接触
2.权利要求1所述的方法，其中所述碱选自金属碳酸盐、金属醇盐和金属氢氧化物。
3.权利要求1所述的方法，其中所述碱选自氢氧化钠或氢氧化钾。
4.权利要求1所述的方法，其中所述酸选自HCl、HBr、H2SO4、H3PO4和HNO3。
5.权利要求1所述的方法，其还包括以下步骤：
使式III的化合物与甲酸接触以制备式II的化合物，
其中R为H或t-BuO(CO)。
6.权利要求5所述的方法，其中所述接触在约10℃至约100℃进行。
7.一种化合物，其由以下组成：
CN201780071374.4A 2016-11-18 2017-11-17 4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羟基-3-(5-巯基-1h-1,2,4-***-1-基)丙基)吡啶-3-基)氧基)苄腈及制备方法 Pending CN109983005A (zh)

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