CN102803219B - 6-(芳基)-4-氨基皮考啉酸酯的制备方法 - Google Patents
6-(芳基)-4-氨基皮考啉酸酯的制备方法 Download PDFInfo
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- 0 *c1c(*)c(C#C)c(C(C2)NC(C([U]N)=N)=CC2=N)c(*)c1 Chemical compound *c1c(*)c(C#C)c(C(C2)NC(C([U]N)=N)=CC2=N)c(*)c1 0.000 description 4
- AOTJCWDXKHFUHM-SRZZPIQSSA-N CC(O/N=C(\C1)/C(Cl)=C(C(OC)=O)NC1c(ccc(Cl)c1OC)c1F)=O Chemical compound CC(O/N=C(\C1)/C(Cl)=C(C(OC)=O)NC1c(ccc(Cl)c1OC)c1F)=O AOTJCWDXKHFUHM-SRZZPIQSSA-N 0.000 description 2
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- CCGIPGLCPGHPMR-UDWIEESQSA-N CCOC(C(NC(C/C1=N\OS(C)(=O)=O)c(ccc(Cl)c2)c2F)=C1Cl)=O Chemical compound CCOC(C(NC(C/C1=N\OS(C)(=O)=O)c(ccc(Cl)c2)c2F)=C1Cl)=O CCGIPGLCPGHPMR-UDWIEESQSA-N 0.000 description 1
- UIBLXORJFBEVBV-UDWIEESQSA-N CCOC(C(NC(C1)c(ccc(Cl)c2)c2[F]/[O]=S/C)=C/C1=N/CC=O)=O Chemical compound CCOC(C(NC(C1)c(ccc(Cl)c2)c2[F]/[O]=S/C)=C/C1=N/CC=O)=O UIBLXORJFBEVBV-UDWIEESQSA-N 0.000 description 1
- OXEASEWQMDKFSU-UHFFFAOYSA-N CCOC(c1nc(-c(ccc(Cl)c2)c2F)cc(N)c1Cl)=O Chemical compound CCOC(c1nc(-c(ccc(Cl)c2)c2F)cc(N)c1Cl)=O OXEASEWQMDKFSU-UHFFFAOYSA-N 0.000 description 1
- WZFDSIRUFSWEOJ-UHFFFAOYSA-N CCOC(c1nc(-c(ccc(Cl)c2OC)c2F)cc(N)c1Cl)=O Chemical compound CCOC(c1nc(-c(ccc(Cl)c2OC)c2F)cc(N)c1Cl)=O WZFDSIRUFSWEOJ-UHFFFAOYSA-N 0.000 description 1
- LGJRJLFDCPXEBI-CNHKJKLMSA-N COC(C(NC(C1)c(ccc(Cl)c2OC)c2F)=C/C1=N/O)=O Chemical compound COC(C(NC(C1)c(ccc(Cl)c2OC)c2F)=C/C1=N/O)=O LGJRJLFDCPXEBI-CNHKJKLMSA-N 0.000 description 1
- NRZVLUNJXQKGJW-UHFFFAOYSA-N COC(C(NC(C1)c(ccc(Cl)c2OC)c2[F][O]=S(C)(O)=O)=CC1=N)=O Chemical compound COC(C(NC(C1)c(ccc(Cl)c2OC)c2[F][O]=S(C)(O)=O)=CC1=N)=O NRZVLUNJXQKGJW-UHFFFAOYSA-N 0.000 description 1
- DBTIABVPXMIFAZ-UHFFFAOYSA-N COC(C(NC(CC1=O)c(ccc(Cl)c2OC)c2F)=C1Cl)=O Chemical compound COC(C(NC(CC1=O)c(ccc(Cl)c2OC)c2F)=C1Cl)=O DBTIABVPXMIFAZ-UHFFFAOYSA-N 0.000 description 1
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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Abstract
与极性溶剂一起加热3-卤代-6-(芳基)-4-亚氨基四氢皮考啉酸酯以制备6-(芳基)-4-氨基皮考啉酸酯。
Description
技术领域
本申请要求2009年6月8日提交的美国临时专利申请序列号61/184,874的权益。本发明涉及6-(芳基)-4-氨基皮考啉酸酯的制备方法。更具体地,本发明涉及由相应的3-卤代-6-(芳基)-4-亚氨基四氢皮考啉酸酯制备6-(芳基)-4-氨基皮考啉酸酯的方法。
背景技术
美国专利6,784,137(B2)和7,314,849(B2)描述了某些6-(芳基)-4-氨基皮考啉酸酯化合物和它们作为除草剂的用途。这两篇专利均描述了由在皮考啉环的6-位具有易离去基团或金属衍生物的皮考啉制备6-(芳基)-4-氨基皮考啉酸酯。有利的是由非吡啶来源有效地和以高收率制备6-(芳基)-4-氨基皮考啉酸酯。
发明内容
本发明涉及由相应的3-卤代-6-(芳基)-4-亚氨基四氢皮考啉酸酯制备6-(芳基)-4-氨基皮考啉酸酯的方法。更具体地,本发明涉及制备下式的6-(芳基)-4-氨基皮考啉酸酯的方法,
其中
Q表示Cl或Br;
R表示C1-C4烷基;以及
W表示H、F或Cl;
X表示H、F、Cl或C1-C4烷氧基;
Y表示卤素;以及
Z表示H或F;
所述方法包括在极性溶剂的存在下在25℃-150℃的温度加热式(I)的3-卤代-6-(芳基)-4-亚氨基四氢皮考啉酸酯,以及回收产物,
其中
R表示C1-C4烷基;
R1表示-OS(O)2R2、-OC(O)R2或-OC(O)OR2;
R2表示C1-C4烷基或者未取代或取代的苯基;
Q表示Cl或Br;以及
W表示H、F或Cl;
X表示H、F、Cl或C1-C4烷氧基;
Y表示卤素;以及
Z表示H或F。
本申请使用的术语“烷基”以及衍生术语如“链烷(alkanoic)”在它们的范围内包括直链、支链和环状部分(moieties)。
3-卤代-6-(芳基)-4-亚氨基四氢皮考啉酸酯原料可用许多方式制备。在方案I的步骤a中,式II的芳族醛(其中W、X、Y和Z如前面所定义)可以在碱如氢氧化钠的存在下与酮如丙酮缩合,以提供式III的α,β-不饱和酮。然后,可将这些化合物在草酸二烷基酯的存在下与碱如乙醇钠反应,以生成如步骤b中所示的式IV的β-二酮酯,其中R表示C1-C4烷基,例如在美国专利4,304,728中。在方案I的步骤c中,胺源如乙酸铵与式IV化合物的反应导致式V的烯胺的形成。在反应中大约需要1∶2比率的式IV的β-二酮酯和胺源。反应在25℃-80℃的温度进行。通常优选60℃-80℃的温度。反应优选在极性质子溶剂中进行。优选的溶剂包括醇。甲醇或乙醇为最优选的溶剂。最后,在方案I的步骤d中,式VI的4-氧代-四氢皮考啉酸酯通过在压力容器中在高温加热式V的化合物形成。反应在125℃-200℃的温度进行。通常优选150℃-200℃的温度。反应优选在极性质子惰性溶剂中进行。优选的溶剂包括醚如1,4-二噁烷。
方案I
生成式VI的4-氧代-四氢皮考啉酸酯的另一种方式可参见方案II。在方案II的步骤a中,用亚硫酰氯和醇如甲醇处理2-皮考啉酸,以提供式VII的4-烷氧基-2-皮考啉酸酯,其中R如前面所定义。用氯甲酸酯处理式VII化合物,接着向所得混合物原位添加芳族锌卤化物(aryl zinc halide)(其中W、X、Y和Z如前面所定义),得到如步骤b中所示的式VIII的二氢皮考啉酸酯,其中R3表示苯基。在这种两个步骤一锅法(one pot protocol)的第一部分中,要求氯甲酸酯相对于式VII化合物稍过量。反应在-5℃-20℃的温度进行。通常优选-5℃-10℃的温度。反应优选在极性质子惰性溶剂中进行。优选的溶剂包括醚。四氢呋喃(THF)或***为最优选的溶剂。在该步骤的第二部分中,要求芳族锌卤化物相对于式VII化合物稍过量,并且反应在-5℃-30℃的温度进行。通常优选20℃-30℃的温度。在方案II的步骤c中,式VIII化合物在极性质子惰性溶剂如THF中的酸性水解提供式IX的作为氨基甲酸酯保护的4-氧代-四氢皮考啉酸酯。在反应中需要相对于式VIII化合物过量的酸。反应在-5℃-30℃的温度进行。通常优选20℃-30℃的温度。反应优选在极性溶剂混合物中进行。优选的溶剂包括醚-水混合物,例如THF-水。最后,在方案II的步骤d中,用碱如甲醇钠处理式IX化合物,接着含水后处理(aqueous workup)得到式VI的4-氧代-四氢皮考啉酸酯。在反应中要求所述碱相对于式IX化合物稍过量。反应在-5℃-20℃的温度进行。通常优选-5℃-10℃的温度。反应优选在极性质子溶剂中进行。优选的溶剂包括醇,例如甲醇。
方案II
通过以下方法可将式VI化合物(其中W、X、Y、Z和R如前面定义)转化成式X的相应的肟:在碱如吡啶的存在下和在溶剂如甲苯或甲醇中与羟胺或羟胺盐酸盐反应,如在方案III的步骤a中所示。在反应中要求羟胺相对于式VI化合物过量。反应在25℃-80℃的温度进行。通常优选60℃-80℃的温度。反应优选在极性质子溶剂中进行。优选的溶剂包括醇。甲醇或乙醇为最优选的溶剂。在方案III的步骤b中,可将式X的肟在碱的存在下用磺酰氯、酰氯、氯甲酸烷基酯或氯甲酸芳基酯处理,以提供式XI的相应的磺酰化的、酰化的或含碳酸酯基的肟,其中R1表示-OS(O)2R2、-OC(O)R2和-OC(O)OR2,R2表示C1-C4烷基或者未取代或取代的苯基以及R如上面所定义。在反应中需要的磺酰化、酰化或羰基化试剂相对于式X化合物的比率大约为2∶1。需要至少一个当量的叔胺碱,优选1当量至2当量。反应在-5℃-30℃的温度进行。通常优选-5℃-20℃的温度。优选的溶剂包括惰性溶剂,例如氯化烃。式XI的取代的肟与氯化剂如磺酰氯或溴化剂如溴或N-溴代琥珀酰亚胺的反应得到式I的3-卤代-(6-芳基)-4-亚氨基四氢皮考啉酸酯,其中Q如前面定义,如方案III的步骤c中所示。在反应中需要大约等摩尔量的氯化剂或溴化剂和式XI化合物。反应在-5℃-30℃的温度进行。通常优选-5℃-20℃的温度。优选的溶剂包括惰性溶剂如二氯甲烷。可选择地,式I化合物的形成可通过以下方法实现:以不同的次序处理式VI化合物-步骤c,a,然后是b。
方案III
通过这些方法中的任意方法得到的3-卤代-6-(芳基)-4-亚氨基四氢皮考啉酸酯原料可通过常规方法回收。
6-(芳基)-4-氨基皮考啉酸酯除草剂
通过在极性溶剂的存在下加热3-卤代-6-(芳基)-4-亚氨基四氢皮考啉酸酯常规地制备
以摩尔量计,所述极性溶剂优选极大地过量使用。所述极性溶剂可为极性质子溶剂或极性质子惰性溶剂。极性质子溶剂包括烷酸(alkanoic acid),优选为C1-C4烷酸,最优选冰乙酸。极性质子惰性溶剂包括酰胺如N,N-二甲基甲酰胺、 N,N-二甲基乙酰胺或N-甲基-2-吡咯烷酮,和亚砜如二甲亚砜。任选地,可将助溶剂与极性溶剂一起使用。助溶剂应与极性溶剂和3-卤代-6-(芳基)-4-亚氨基-四氢皮考啉酸酯原料可混溶。
3-卤代-6-(芳基)-4-亚氨基四氢皮考啉酸酯向6-(芳基)-4-氨基皮考啉酸酯的转化在25℃-150℃的温度进行。优选温度范围为25℃-90℃。
通过以下方法制备3-卤代-6-(芳基)-4-亚氨基四氢皮考啉酸酯经常是适宜的:用氯化剂或溴化剂氯化或溴化磺酰化的、酰化的或含碳酸酯基的下式的肟,
其中W、X、Y、Z、R、R1和R2如前面所定义。典型的氯化剂和溴化剂包括氯、磺酰氯、N-氯代琥珀酰亚胺、溴、磺酰溴和N-溴代琥珀酰亚胺。在反应中需要大约等摩尔量的氯化剂或溴化剂。反应典型地在-5℃-30℃的温度进行。通常优选-5℃-20℃的温度。优选的溶剂包括惰性溶剂如二氯甲烷。
通过这些方法中的任何方法得到的产物可通过常规方法如蒸发或萃取回收,以及可通过标准操作如通过重结晶或色谱法纯化。
具体实施方式
提供下列实施例以说明本发明。
实施例
实施例1.制备(E)-4-(4-氯-2-氟苯基)-丁-3-烯-2-酮(1)
在室温向4-氯-2-氟苯甲醛(23.8克(g),0.15摩尔(mol))在丙酮(100毫升(mL))中的机械搅拌着的溶液添加氢氧化钠(NaOH,6.6g,0.165mol)在水(H2O,400mL)中的溶液,历时20分钟(min)。搅拌反应混合物过夜之后,添加二氯甲烷(CH2Cl2,100mL)。将水层分离并用CH2Cl2(100mL)萃取,然后将合并的有机萃取液用盐水洗涤并用硫酸镁(MgSO4)干燥。除去溶剂,接着Kugelrohr蒸馏,得到4-(4-氯-2-氟苯基)-3-丁烯-2-酮(1;22.5g,76%),为无色液体,其在放置时固化:bp 70-80℃,0.1mmHg(13.33帕斯卡(Pa));1H NMR(400MHz,CDCl3)δ7.59(d,J=16.5Hz,1H),7.50(t,J=8.1Hz,1H),7.22-7.12(m,2H),6.76(d,J=16.5Hz,1H),2.39(s,3H);HRMS-ESI(m/z):C10H8ClFO计算值,198.024;实测值198.025。
(E)-4-(4-氯-2-氟-3-甲氧基苯基)-丁-3-烯-2-酮(2)
使用实施例1的操作,使4-氯-2-氟-3-甲氧基-苯甲醛(200g,1.6mol)、NaOH(46.6g,1.16mol)和丙酮(1L)反应,得到(E)-4-(4-氯-2-氟-3-甲氧基苯基)-3-丁烯-2-酮(2;180g,74%,93%纯,通过HPLC测定),为淡棕色液体:1HNMR(400MHz,CDCl3)δ7.59(d,J=16.5Hz,1H),7.50(t,J=8.1Hz,1H),7.26-7.07(m,2H),6.76(d,J=16.5Hz,1H),2.39(s,3H);HRMS-ESI(m/z):C11H10ClFO2计算值,228.035;实测值,228.036。
实施例2.制备(E)-6-(4-氯-2-氟苯基)-2,4-二氧代-己-5-烯酸乙酯(3)
将钠球(2.88g,0.125mol)缓慢添加至纯乙醇(EtOH,125mL)中。在钠已经反应后,在减压下除去溶剂,并添加无水***(ether)(200mL)。将反应混合物冷却至-5℃,并添加(E)-4-(4-氯-2-氟苯基)-丁-3-烯-2-酮(1;24.75g,0.125mol)和草酸二乙酯(21.9g,0.15mol)在无水***(25mL)中的溶液,历时30min。在室温搅拌2天(d)后,过滤黄色固体并用***洗涤。在室温干燥1小时(h)后,使固体在CH2Cl2(200mL)和1N硫酸(H2SO4,150mL)之间分配。将有机层干燥(MgSO4),并除去溶剂,得到(E)-6-(4-氯-2-氟-苯基)-2,4-二氧代-己-5-烯酸乙酯(3;32.3g,86%),为黄色固体。将小样用EtOH重结晶,得到黄色晶体:mp 84-85℃;1H NMR(400MHz,CDCl3)δ14.72(s,1H),7.76(d,J=16.1Hz,1H),7.49(d,J=8.3Hz,1H),7.24-7.12(m,2H),6.73(d,J=16.1Hz,1H),6.53(s,1H),4.38(q,J=7.1Hz,2H),1.40(t,J=7.1Hz,3H);HRMS-ESI(m/z):C14H12ClFO4计算值,298.041;实测值,298.041。
(E)-6-(4-氯苯基)-2,4-二氧代-己-5-烯酸乙酯(4)
使用实施例2的操作,使钠球(6.33g,0.275mol)、(E)-4-(4-氯苯基)-丁-3-烯-2-酮(45.16g,0.25mol)和草酸二乙酯(43.8g,0.30mol)反应,得到(E)-6-(4-氯苯基)-2,4-二氧代-己-5-烯酸乙酯(4;61.1g,87%),为黄色晶体:mp117-118℃;1H NMR(400MHz,CDCl3)δ14.80(s,1H),7.68(d,J=15.9Hz,1H),7.53-7.35(m,4H),6.62(d,J=15.9Hz,1H),6.53(s,1H),4.38(q,J=7.2Hz,2H),1.40(t,J=7.1Hz,3H);HRMS-ESI(m/z):C14H13ClO4计算值,280.050;实测值,280.050。
(E)-6-(4-氯-2-氟-3-甲氧基苯基)-2,4-二氧代-己-5-烯酸乙酯(5)
使用实施例2的操作,使钠球(5.52g,0.24mol)、(E)-4-(4-氯-2-氟-3-甲氧基苯基)-丁-3-烯-2-酮(2;45.73g,0.20mol)和草酸二乙酯(36.54g,0.25mol)反应,得到(E)-6-(4-氯-2-氟-3-甲氧基苯基-2,4-二氧代-己-5-烯酸乙酯(5;61.1g,93%),为黄色晶体:mp 67.5-69℃;1H NMR(400MHz,CDCl3)δ14.71(s,1H),7.78(d,J=16.1Hz,1H),7.27-7.18(m,2H),6.73(d,J=16.1Hz,1H),6.54(s,1H),4.38(q,J=7.1Hz,2H),3.99(d,J=1.2Hz,3H),1.41(t,J=7.1Hz,3H);HRMS-ESI(m/z):C15H14ClFNO5计算值,328.051;实测值,328.051。
实施例3.制备(E)-6-(4-氯苯基)-2,4-二氧代-己-5-烯酸甲酯(6)
将(E)-6-(4-氯苯基)-2,4-二氧代-己-5-烯酸乙酯(4;33.39g,0.12mol)和浓H2SO4(0.5mL)的溶液在甲醇(MeOH,400mL)中在回流下搅拌6h。在冷却并浓缩溶剂后,收集(E)-6-(4-氯苯基)-2,4-二氧代-己-5-烯酸甲酯(6;22.7g,71%),为黄色晶体:mp 135-136℃;1H NMR(400MHz,CDCl3)δ14.74(s,1H),7.67(d,J=15.9Hz,1H),7.49(d,J=8.5Hz,2H),7.38(d,J=8.5Hz,2H),6.61(d,J=15.9Hz,1H),6.53(s,1H),3.92(s,3H);HRMS-ESI(m/z):C13H11ClO4计算值,266.034;实测值,266.034。
实施例4.制备(2Z,5E)-2-氨基-6-(4-氯-2-氟苯基)-4-氧代-己-2,5-二烯酸乙 酯(7)
将(E)-6-(4-氯-2-氟苯基)-2,4-二氧代-己-5-烯酸乙酯(3;15.0g,0.05mol)和乙酸铵(7.7g,0.1mol)在EtOH(100mL)中的混合物搅拌并加热至回流,并保持回流1h。在减压下除去溶剂,将残留物溶解在CH2Cl2(200mL)中并用碳酸钠饱和水溶液(Na2CO3,100mL)洗涤。在用MgSO4干燥后,添加硅胶(50g)并除去溶剂。用20%乙酸乙酯(EtOAc)/己烷(300mL)洗涤残留物,在除去溶剂后得到(2z,5E)-2-氨基-6-(4-氯-2-氟苯基)-4-氧代-己-2,5-二烯酸乙酯(7;6.1g,41%),为淡橙色固体:mp 102-103℃;1H NMR(400MHz,CDCl3)δ9.4(br s,1H),7.62(d,J=15.9Hz,1H),7.52(t,J=8.5Hz,1H),7.49(d,J=8.3Hz,1H),7.19-7.08(m,2H),6.87(d,J=15.9Hz,1H),6.14(s,1H),6.05(br s,1H),4.37(q,J=7.1Hz,2H),1.39(t,J=7.1Hz,3H);HRMS-ESI(m/z):C14H13ClFNO3计算值,297.056;实测值,297.056。用40%EtOAc/己烷(400mL)进一步洗涤硅胶,得到更多(2Z,5E)-2-氨基-6-(4-氯-2-氟苯基)-4-氧代-己-2,5-二烯酸乙酯(7;8.8g,70%纯度,通过1H NMR光谱测定),总共12.2g(82%)。
(2Z,5E)-2-氨基-6-(4-氯苯基)-4-氧代-己-2,5-二烯酸乙酯(8)
使用实施例4的操作,使(E)-6-(4-氯苯基)-2,4-二氧代-己-5-烯酸乙酯(4;79.5g,0.284mol)和乙酸铵(43.78g,0.568mol)在EtOH(795mL)中反应,提供(2Z,5E)-2-氨基-6-(4-氯苯基)-4-氧代-己-2,5-二烯酸乙酯(8;47g,86%),为黄色固体:mp 105-107℃;1H NMR(400MHz,CDCl3)δ9.40(br s,1H),7.52(d,J=15.9Hz,1H),7.50-7.47(m,2H),7.38-7.32(m,2H),6.78(d,J=15.9Hz,1H),6.14(s,1H),6.01(s,1H),4.37(q,J=7.1Hz,2H),1.39(t,J=7.1Hz,3H);HRMS-ESI(m/z):C14H14ClNO3计算值,279.067;实测值,279.066。
(2Z,5E)-2-氨基-6-(4-氯苯基)-4-氧代-己-2,5-二烯酸甲酯(9)
使用实施例4的操作,使(E)-6-(4-氯苯基)-2,4-二氧代-己-5-烯酸甲酯(6;21.3g,0.008mol)和乙酸铵(12.33g,0.16mol)在MeOH(150mL)中反应,得到(2Z,5E)-2-氨基-6-(4-氯苯基)-4-氧代-己-2,5-二烯酸甲酯(9;15.7g,74%),为黄色固体:mp 112-113℃;1H NMR(400MHz,CDCl3)δ9.37(br s,1H),7.64-7.42(m,3H),7.38-7.32(m,2H),6.75(d,J=15.9Hz,1H),6.14(s,1H),5.99(br s,1H),3.91(s,3H);HRMS-ESI(m/z):C13H12ClNO3计算值,265.050;实测值,265.050。
(2Z,5E)-2-氨基-6-(4-氯-2-氟-3-甲氧基苯基)-4-氧代-己-2,5-二烯酸乙酯
(10)
使用实施例4的操作,使(E)-6-(4-氯-2-氟-3-甲氧基苯基)-2,4-二氧代-己-5-烯酸乙酯(5;37.8g,0.115mol)和乙酸铵(15.4g,0.2mol)在EtOH(200mL)中反应,得到(2Z,5E)-2-氨基-6-(4-氯-2-氟-3-甲氧基苯基)-4-氧代-己-2,5-二烯酸乙酯(10;38.5g,92%,90%纯度,通过1H NMR光谱测定),为深橙色固体。用硅胶(50g)处理,接着用40%EtOAc/己烷(400mL)洗脱,得到黄色固体(25.3g,67%):mp 103-104℃;1H NMR(400MHz,CDCl3)δ9.44(br s,1H),7.63(d,J=16.1Hz,1H),7.23(dd,J=8.6,7.0Hz,1H),7.16(dd,J=8.6,1.6Hz,1H),6.87(d,J=16.1Hz,1H),6.15(s,1H),6.04(br s,1H),4.37(q,J=7.1Hz,2H),3.98(d,J=1.2Hz,3H),1.40(t,J=7.1Hz,3H);HRMS-ESI(m/z):C15H15ClFNO4计算值,327.067;实测值,327.068。
实施例5.制备6-(4-氯-2-氟苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸乙酯 (11)
在200mL Parr反应器中,在正氮气(N2)压力下,将(2Z,5E)-2-氨基-6-(4-氯-2-氟苯基)-4-氧代-己-2,5-二烯酸乙酯(7;5.26g,0.0177mol)在无水1,4-二噁烷(100mL)中的溶液加热至185℃。在9h后,冷却反应器,并在减压下除去溶剂,留下深橙色油状物(5.85g)。通过1H NMR光谱,所述物质为75%的期望的6-(4-氯-2-氟苯基)-4-氧代-1,4,5,6-四氢吡啶-2-甲酸乙酯(11)和25%的未环化的7。在碱性氧化铝上用40%EtOAc/己烷洗脱纯化,得到米色固体(1.4g,26%):mp 107-109℃;1H NMR(400MHz,CDCl3)δ7.40(t,J=8.1Hz,1H),7.22-7.06(m,2H),5.84(s,1H),5.73(s,1H),5.09(t,J=8.9Hz,1H),4.35(q,J=7.1Hz,2H),2.69(d,J=8.9Hz,2H),1.36(t,J=7.1Hz,3H);HRMS-ESI(m/z):C14H13ClFNO3计算值,297.057;实测值,297.057。
使用实施例5的操作,在2升Parr反应器中,在1,4-二噁烷(880mL)中的(2Z,5E)-2-氨基-6-(4-氯-2-氟-苯基)-4-氧代-己-2,5-二烯酸乙酯(7;88g,0.296mol)在通过硅胶色谱法用40%EtOAc/己烷洗脱纯化后得到6-(4-氯-2-氟苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸乙酯(11;43g,49%,96%纯度,通过HPLC测定),为褐色固体。
6-(4-氯苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸乙酯(12)
使用实施例5的操作,在2升Parr反应器中,在1,4-二噁烷(470mL)中的(2Z,5E)-2-氨基-6-(4-氯苯基)-4-氧代-己-2,5-二烯酸乙酯(8;47g,0.168mol)在通过硅胶色谱法用40%EtOAc/己烷洗脱纯化后得到6-(4-氯苯基)-4-氧代-1,4,5,6-四氢吡啶-2-甲酸乙酯(12;25g,49%,99%纯度,通过HPLC测定),为灰白色固体:mp 93-94℃;1H NMR(400MHz,CDCl3)δ7.36(q,J=8.6Hz,4H),5.82(s,1H),5.72(br s,1H),4.74(dd,J=14.2,5.0Hz,1H),4.35(q,J=7.1Hz,2H),2.68(dd,J=16.3,14.2Hz,1H),2.58(dd,J=16.4,5.0Hz,1H),1.36(t,J=7.1Hz,3H);HRMS-ESI(m/z):C14H14ClNO3计算值,279.067;实测值,279.066。
6-(4-氯苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸甲酯(13)
使用实施例5的操作,在200mL Parr反应器中,在1,4-二噁烷(100mL)中的(2Z,5E)-2-氨基-6-(4-氯苯基)-4-氧代-己-2,5-二烯酸甲酯(9;6.64g,0.025mol)在用***/戊烷研磨后得到6-(4-氯苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸甲酯(13;6.12g,91%,98%纯度,通过GC测定),为灰白色固体:mp113-114℃;1H NMR(400MHz,CDCl3)δ7.36(q,J=8.6Hz,4H),5.82(s,1H),5.72(br s,1H),4.74(dd,J=14.2,5.0Hz,1H),4.74(dd,J=14.2,5.0Hz,1H),3.90(s,3H),2.68(dd,J=16.3,14.2Hz,1H),2.58(dd,J=16.4,5.0Hz,1H);HR S-ESI(m/z):C13H12ClNO3计算值,265.050;实测值,265.051。
6-(4-氯-2-氟-3-甲氧基苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸乙酯(14)
使用实施例5的操作,在200mL Parr反应器中,在1,4-二噁烷(100mL)中的(2Z,5E)-2-氨基-6-(4-氯-2-氟-3-甲氧基苯基)-4-氧代-己-2,5-二烯酸乙酯(10;6.55g,0.02mol)在用***/戊烷研磨后得到6-(4-氯-2-氟-3-甲氧基苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸乙酯(14;5.9g,90%,98%纯度,通过GC测定),为灰白色固体:mp 116-118℃;1H NMR(400MHz,CDCl3)δ7.22(dd,J=8.5,1.8Hz,1H),7.09(dd,J=8.4,7.1Hz,1H),5.93(s,1H),5.90(s,1H),5.21-5.08(m,1H),4.37(q,J=7.1Hz,2H),3.99(d,J=1.3Hz,3H),2.87-2.73(m,2H),1.38(t,J=7.1Hz,3H);HRMS-ESI(m/z):C15H15ClFNO4计算值,327.067;实测值,327.067。
实施例6.制备6-(4-氯-2-氟-3-甲氧基苯基)-4-氧代-5,6-二氢-4H-吡啶-1,2- 二羧酸2-甲酯1-苯酯(15)
在氮气气氛下,将2-氯-6-氟苯甲醚(24.5g,0.153mol)溶解在无水THF(150mL)中。将溶液冷却至-60℃,并滴加正丁基锂(67mL,在己烷中的2.5M溶液,0.168mol),历时30min。在添加期间,反应温热至-48℃。将反应混合物在-50℃搅拌30min,然后冷却至-60℃。首先通过作为固体添加,然后通过添加在无水THF中的溶液,将无水ZnCl2(25g,0.183mol)添加至反应混合物。将反应混合物在-45℃搅拌2.5h,直到几乎所有的固体ZnCl2溶解。将反应溶液温热至室温,并通过氮气吹洗蒸发溶剂。将残留物再次溶解在THF中,形成储液。
在N2下,将4-甲氧基皮考啉酸甲酯(11.92g,0.0713mol)溶解在无水THF(300mL)中。在冰浴中冷却溶液。添加纯的氯甲酸苯酯(10.5mL,0.0837mol)。在45min后,滴加氯化(4-氯-2-氟-3-甲氧基苯基)锌(II)(1.19M,在THF中,76.0mL,0.0904mol)的储液,历时1h。将溶液在室温搅拌3天(d),然后通过添加氯化铵(NH4Cl)饱和水溶液(200mL)淬灭。分离有机层,并用***(2x100mL)萃取水层。将合并的有机萃取液先后用H2O和盐水洗涤。将溶液干燥(MgSO4)并蒸发成嫩黄色液体,将所述嫩黄色液体溶解在THF(250mL)和1M HCl(250mL)中。将反应混合物在室温搅拌2d,然后用NaHCO3饱和溶液中和。用***萃取反应混合物。将***萃取液先后用H2O和盐水洗涤,然后干燥(MgSO4)并蒸发,得到黄色油状物。通过硅胶色谱法(己烷-EtOAc梯度)纯化粗产物,得到黄色油状物。将油状物用MeOH结晶,得到6-(4-氯-2-氟-3-甲氧基苯基)-4-氧代-5,6-二氢-4H-吡啶-1,2-二羧酸2-甲酯1-苯酯(15;17.67g,57%),为白色固体:mp 112-114℃;1H NMR(300MHz,)δ7.40(m,2H),7.27(m,1H),7.14(m,4H),6.22(d,J=6.6Hz,1H,H6),5.90(d,J=1.2Hz,1H,H3),3.97(d,JF-H=0.9Hz,3H,OMe),3.87(s,3H,CO2Me),3.30(dd,J=6.6,17.4Hz,1H,H5a),3.05(d,J=18Hz,1H,H5b);13C{1H}NMR(75.4MHz,CDCl3)δ191.7(C4),163.8(CO2Me),153.9(d,JF-C=250Hz,C2’),151.0,150.3,145.0,144.8,129.6(间Ph),128.8(d,JF-C=3Hz,C4’),126.5(对Ph),125.2(d,JF-C=3Hz,C5’),124.5(d,JF-C=12Hz,C1’),121.0(d,JF-C=4Hz,C6’),120.9(邻Ph),114.5(C3),61.6(d,JF-C=5Hz,OMe),53.8,53.4,41.6;C21H17ClFNO6分析计算值:C,58.14;H,3.95;N,3.23。实测值:C,57.82;H,3.90;N,3.18。
实施例7.制备6-(4-氯-2-氟-3-甲氧基苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧 酸甲酯(16)
将6-(4-氯-2-氟-3-甲氧基苯基)-4-氧代-5,6-二氢-4H-吡啶-1,2-二羧酸2-甲酯1-苯酯(15;7.213g,0.0166mol)在MeOH(80mL)中浆化。将悬浮液在冰浴中冷却,并添加固体甲醇钠(NaOMe;1.08g,0.02mol)。在1h后,将反应用NH4Cl饱和水溶液(80mL)和H2O(50mL)淬灭,然后在冰中冷却。将沉淀物过滤,先后用H2O和冷MeOH洗涤,并在空气中干燥,得到6-(4-氯-2-氟-3-甲氧基苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸甲酯(16;4.93g,94%),为白色粉末:mp 164.9-166.2℃;1H NMR(300MHz,CDCl3)δ7.20(dd,JF-H=1.8Hz,JH-H=8.7Hz,1H,芳族的),7.10(dd,JF-H=6.9Hz,JH-H=8.7Hz,1H,芳族的),5.84(d,J=0.9Hz,1H,H3),5.68(br s,1H,NH),5.10(t,J=9.3Hz,1H,H6),3.98(d,JF-H=1.5Hz,3H,OMe),3.91(s,3H,CO2Me),2.71(d,J=9Hz,2H,H5);13C{1H}NMR(75.4MHz,CDCl3)δ193.0(C4),163.6(CO2Me),153.8(d,JF-C=251Hz,C2’),147.9(C2),144.6(d,JF-C=13Hz,C3’),128.6(d,JF-C=3Hz,C1’/C4’),126.8(d,JF-C=11Hz,C1’/C4’),125.5(d,JF-C=3Hz,C5’),121.5(d,JF-C=4Hz,C6’),102.0(C3),61.6(d,JF-C=5Hz,OMe),53.4,50.8,42.0;HRMS-ESI(m/z):C14H13ClFNO4计算值,313.0512;实测值,313.0511;C14H13ClFNO4分析计算值:C,53.60;H,4.18;N,4.46。实测值:C,53.30;H,4.14;N,4.35。
实施例8.制备6-(4-氯-2-氟苯基)-4-羟基亚氨基-1,4,5,6-四氢吡啶-2-羧酸 乙酯(17)
将6-(4-氯-2-氟苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸乙酯(11,41g,0.138mol)、羟胺盐酸盐(38.3g,0.552mol)和吡啶(82mL)在EtOH(400mL)中的混合物加热至回流,并保持回流1h。将反应混合物冷却至室温并除去溶剂。用冰冷的H2O研磨残留物,得到6-(4-氯-2-氟苯基)-4-羟基亚氨基-1,4,5,6-四氢吡啶-2-羧酸乙酯的顺式和反式异构体的3∶2混合物(17;24g,56%,98%纯度,通过HPLC测定),为褐色固体:mp 124-126℃;1H NMR(400MHz,DMSO-d6)较多异构体δ9.3(br s,1H),7.40(m,1H),7.27(m,2H),6.76(br s,1H),6.21(s,1H),4.80(br s,1H),4.42-4.13(m,2H),2.69(dd,J=14.9,4.9Hz,1H),2.62-2.45(m,1H),1.30(t,J=6.8Hz,3H);1H NMR(400MHz,DMSO-d6)较少异构体δ9.3(brs,1H),7.40(m,1H),7.27(m,2H),6.12(br s,1H),5.95(s,1H),4.64(dd,J=8.4,5.1Hz,1H),4.42-4.13(m,2H),2.91(dd,J=16.5,4.9Hz,1H),2.52(m,1H),1.27(t,J=6.5Hz,3H);HRMS-ESI(m/z):C14H14ClFN2O3计算值,312.068;实测值,312.067。
6-(4-氯-2-氟-3-甲氧基苯基)-4-羟基亚氨基-1,4,5,6-四氢吡啶-2-羧酸甲酯
(18)
将6-(4-氯-2-氟-3-甲氧基苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸甲酯(16,5.19g,16.5mmol)在甲醇(160mL)中浆化。添加羟胺盐酸盐(3.35g,48.3mmol),接着添加吡啶(10.0mL,123mmol)。将反应混合物在回流下搅拌120min。真空蒸发甲醇。添加H2O(200mL),并将残留物萃取到***(4x150mL)中。将合并的萃取液用盐水洗涤,干燥(MgSO4)并真空蒸发,得到6-(4-氯-2-氟-3-甲氧基苯基)-4-羟基亚氨基-1,4,5,6-四氢吡啶-2-羧酸甲酯(18;4.54g,80%),为白色固体:mp 136-138℃。通过NMR光谱和HPLC观察到顺式异构体和反式异构体的1∶1混合物。1H NMR(400MHz,C6D6)δ8.34(br,1H,NOH),8.25(br,1H,NOH),7.00(s,1H,H3),6.71(dd,JF-H=1.5Hz,JH-H=9Hz,1H,芳族的),6.69(dd,JF-H=1.8Hz,JH-H=9Hz,1H,芳族的),6.57(dd,JF-H=JH-H=7.5Hz,1H,芳族的),6.53(s,1H,H3),6.50(dd,JF-H=JH-H=7.5Hz,1H,芳族的),4.72(s,1H,NH),4.52(s,1H,NH),4.38(dd,JF-H=3.6,10.2Hz,1H,H6,异构体A),4.23(dd,JH-H=3.9,11.4Hz,1H,H6,异构体B),3.53(s,6H,CO2Me),3.24(s,3H,OMe),3.23(s,3H,OMe),3.30(dd,JH-H=4.2,16.8Hz,1H,H5,异构体B),2.63(dd,JH-H=4.2,15.3Hz,1H,H5,异构体A),2.44(dd,JH-H=10.5,15.3Hz,1H,H5,异构体A),2.33(dd,JH-H=11.1,16.8Hz,1H,H5,异构体B);13C{1H}NMR(CDCl3)δ164.2(CO2Me),163.9(CO2Me),153.7(d,JF-C=250Hz,C2’),153.6(d,JF-C=251Hz,C2’),152.6(C4),149.6(C4),144.3(d,JF-C=3Hz,C3’),144.1(d,JF-C=3Hz,C3’),139.2,138.3,128.6(d,JF-C=12Hz),127.9(d,JF-C=11Hz),127.8(d,JF-C=3Hz),127.7(d,JF-C=3Hz),125.3,121.7,101.7(C3),92.6(C3),61.42,61.38,52.7,52.6,49.3,48.3,33.6(C5),28.7(C5)。HRMS-ESI(m/z)C14H14ClFN2O4计算值,328.0621;实测值,328.0620。C14H14ClFN2O4分析计算值:C,51.15;H,4.29;N,8.52。实测值:C,51.31;H,4.34;N,8.40。
实施例9.制备6-(4-氯苯基)-4-羟基亚氨基-1,4,5,6-四氢吡啶-2-羧酸乙酯 (19)
将6-(4-氯苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸乙酯(12;5.6g,0.02mol)和50%羟胺水溶液(3mL,0.045mol)在甲苯(100mL)中的混合物在回流下搅拌2h。在除去溶剂后,将残留物添加至CH2Cl2(100mL),用NaCl饱和水溶液洗涤,干燥(MgSO4),并除去溶剂,得到橙色固体(5.8g)。用***/戊烷研磨,得到6-(4-氯苯基)-4-羟基亚氨基-1,4,5,6-四氢吡啶-2-羧酸乙酯的顺式和反式异构体的3∶2混合物(19;4.85g,85%),为灰白色固体:mp 159-160℃;1HNMR(400MHz,CDCl3)较多异构体δ9.3(br,1H),7.35-7.25(m,4H),6.19(s,1H),4.88(s,1H),4.36-4.25(m,3H),3.35-3.23(m,1H),2.35(dd,J=16.8,12.8Hz,1H),1.34(t,J=7.1Hz,3H);1H NMR(400MHz,CDCl3)较少异构体δ9.3(br s,1H),7.35-7.25(m,4H),6.57(s,1H),5.19(s,1H),4.57-4.38(m,1H),4.36-4.25(m,2H),2.72-2.54(m,2H),1.34-1.31(m,3H);HRMS-ESI(m/z):C14H15ClN2O3计算值,294.077;实测值,294.077。
实施例10.制备6-(4-氯-2-氟苯基)-4-[(E,Z)-甲烷磺酰基肟基]-1,4,5,6-四 氢吡啶-2-羧酸乙酯(20)
向6-(4-氯-2-氟苯基)-4-羟基亚氨基-1,4,5,6-四氢吡啶-2-羧酸乙酯(17;22.0g,0.0705mol)在CH2Cl2(220mL)中的磁力搅拌着的溶液中添加三乙胺(19.6mL,0.141mol)。在冰浴中冷却反应混合物,并滴加甲烷磺酰氯(8.8mL,0.113mol),历时30min。在温热至室温过夜后,将反应混合物用CH2Cl2(200mL)稀释,用NaHCO3和NaCl的饱和水溶液洗涤,并干燥(Na2SO4)。除去溶剂,接着用***/戊烷研磨,得到6-(4-氯-2-氟苯基)-4-[(E,Z)-甲烷磺酰基-肟基]-1,4,5,6-四氢吡啶-2-羧酸乙酯的异构体的8∶1混合物(20;10.5g,39%,95%纯度,通过1H NMR测定),为灰白色固体:mp 114-116℃;1H NMR(400MHz,CDCl3)较多异构体δ7.36(t,J=8.1Hz,1H),7.19(dd,J=8.3,1.6Hz,1H),7.15(dd,J=10.1,1.9Hz,1H),6.37(s,1H),5.59(s,1H),4.93(dd,J=10.9,4.4Hz,1H),4.35(q,J=7.1Hz,2H),3.15(s,3H),2.92-2.68(m,2H),1.38(t,J=7.1Hz,3H);HRMS-ESI(m/z):C15H16ClFN2O5S计算值,390.0447;实测值,390.0444。
6-(4-氯苯基)-4-[(E,Z)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸乙酯(21)
使用实施例10的操作,6-(4-氯苯基)-4-羟基亚氨基-1,4,5,6-四氢吡啶-2-羧酸乙酯(19;13.0g,0.0442mol)、甲烷磺酰氯(5.5mL,0.0707mol)和三乙胺(12.3mL,0.0884mol)得到6-(4-氯苯基)-4-[(E,Z)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸乙酯的异构体的8∶1混合物(21;10.5g,86%,97%纯度,通过HPLC测定),为灰白色固体:mp 113-115℃;1H NMR(400MHz,CDCl3)较多异构体δ7.45-7.29(m,4H),6.36(s,1H),5.59(s,1H),4.56(dd,J=11.7,5.3Hz,1H),4.35(q,J=7.1,1.3Hz,2H),3.15(s,3H),2.82-2.67(m,2H),1.38(t,J=7.1Hz,3H);HRMS-ESI(m/z):C15H17ClN2O5S计算值,372.055;实测值,372.055。
实施例11.制备6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E,Z)-对-甲苯磺酰基肟 基]-1,4,5,6-四氢吡啶-2-羧酸甲酯(22)
向6-(4-氯-2-氟-3-甲氧基苯基)-4-羟基亚氨基-1,4,5,6-四氢吡啶-2-羧酸甲酯(18;0.657g,0.002mol)在吡啶(5mL)中的磁力搅拌着的在冰浴中冷却的溶液中添加对甲苯磺酰氯(0.572g,0.003mol),历时5min。在使反应混合物温热至室温2d后,在减压下除去溶剂。将残留物溶解在CH2Cl2(50mL)中,用NaHCO3和NaCl的饱和水溶液洗涤,并干燥(MgSO4)。除去溶剂,得到粘性橙色油状物(1.12g)。用***/戊烷研磨,得到6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E,Z)-对-甲苯磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸甲酯的异构体的4∶1混合物(22;0.818g,85%),为灰白色固体:mp 147-148℃;1H NMR(400MHz,CDCl3)δ7.85(d,J=8.3Hz,2H),7.32(d,J=8.0Hz,2H),7.11(dd,J=8.5,1.7Hz,1H),6.95(dd,J=8.3,7.2Hz,1H),6.39(s,1H),5.47(s,1H),4.84(dd,J=10.6,4.5Hz,1H),3.95(d,J=1.1Hz,3H),3.89(s,3H),2.71(ddd,J=26.3,15.5,7.7Hz,2H),2.45(s,3H);HRMS-ESI(m/z):C21H20ClFN2O6S计算值,482.0709;实测值,482.0701。
实施例12.制备6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E,Z)-甲烷磺酰基肟 基]-1,4,5,6-四氢吡啶-2-羧酸甲酯(23)
步骤A:在室温,向6-(4-氯-2-氟-3-甲氧基苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸甲酯(16;4.70g,0.015mol)在MeOH(100mL)中的磁力搅拌着的溶液中添加羟胺盐酸盐(2.08g,0.03mol),接着添加吡啶(8mL)。在将混合物回流1h之后,在减压下除去溶剂。将残留物溶解在CH2Cl2(100mL)中并用NaHCO3和NaCl的饱和水溶液洗涤。在干燥(MgSO4)后除去溶剂,得到6-(4-氯-2-氟-3-甲氧基苯基)-4-羟基亚氨基-1,4,5,6-四氢吡啶-2-羧酸甲酯的异构体的1∶1混合物(18;4.95g,100%粗产率),为黄色固体。
步骤B:向6-(4-氯-2-氟-3-甲氧基苯基)-4-羟基亚氨基-1,4,5,6-四氢吡啶-2-羧酸甲酯(18;4.95g,0.015mol)在吡啶(30mL)中的磁力搅拌着的在冰浴中冷却的溶液中添加甲烷磺酰氯(3.43g,0.03mol),历时5min。在使反应混合物温热至室温2d后,在减压下除去溶剂。将残留物溶解在CH2Cl2(100mL)中,用NaHCO3和NaCl的饱和水溶液洗涤,并干燥(MgSO4)。除去溶剂,得到发粘的淡橙色固体(5.5g)。用***/戊烷研磨,得到6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E,Z)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸甲酯的异构体的8∶1混合物(23;4.14g,68%),为白色固体:mp 134-135℃;1H NMR(400MHz,CDCl3)较多异构体δ7.20(dd,J=8.8,1.3Hz,1H),7.06(dd,J=8.5,6.7Hz,1H),6.4(s,1H),5.59(br s,1H),4.93(dd,J=10.8,4.7Hz,1H),3.96(s,3H),3.90(s,3H),3.15(s,3H),2.81(m,2H);HRMS-ESI(m/z):C15H16ClFN2O6S计算值,406.040;实测值,406.040。
6-(4-氯苯基)-4-[(E,Z)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸甲酯(24)
使用实施例12的操作,6-(4-氯苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸甲酯(13;6.64g,0.025mol)、羟胺盐酸盐(3.47g,0.05mol)和吡啶(10mL)在后处理后得到橙色油状物(9.1g)。将这种物质再次溶解在吡啶(40mL)中并用甲烷磺酰氯(5.72g,0.05mol)处理,提供6-(4-氯苯基)-4-[(E,Z)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸甲酯的异构体的4∶1混合物(24;3.5g,39%,95%纯度,通过1H NMR测定),为灰白色固体:mp 62-64℃;1H NMR(400MHz,CDCl3)较多异构体δ7.42-7.28(m,4H),6.39(s,1H),5.55(s,1H),4.57(dd,J=11.6,5.1Hz,1H),3.90(s,3H),3.14(s,3H),2.93-2.65(m,2H);较少异构体δ7.45-7.28(m,4H),6.15(s,1H),5.23(s,1H),4.41(dd,J=13.4,4.3Hz,1H),3.90(s,3H),3.30(dd,J=17.2,4.3Hz,1H),3.15(s,3H),2.56(dd,J=17.1,13.5Hz,1H);HRMS-ESI(m/z):C14H15ClN2O5S计算值,358.0384;实测值,358.0385。
6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E,Z)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶
-2-羧酸乙酯(25)
使用实施例12的操作,6-(4-氯-2-氟-3-甲氧基苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸乙酯(14;3.93g,0.012mol)、羟胺盐酸盐(2.08g,0.03mol)和吡啶(8mL)在后处理后得到发粘的橙色固体(5.1g)。将这种物质再次溶解在吡啶(30mL)中并用甲烷磺酰氯(2.75g,0.024mol)处理,得到6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E,Z)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸乙酯的异构体的4∶1混合物(25;2.6g,52%,95%纯度,通过1H NMR测定),为白色固体:mp 130-132℃;1H NMR(400MHz,CDCl3)δ7.20(dd,J=8.5,1.5Hz,1H),7.10-7.05(m,1H),6.37(s,1H),5.60(s,1H),4.93(dd,J=11.1,4.4Hz,1H),4.45-4.34(m,2H),3.98(d,J=1.1Hz,3H),3.16(s,3H),2.95-2.74(m,2H),1.40(d,J=7.1Hz,3H);HRMS-ESI(m/z):C16H18ClFN2O6S计算值,420.056;实测值,420.056。
实施例13.制备3-氯-6-(4-氯-2-氟苯基)-4-[(E)-甲烷磺酰基肟基]-1,4,5,6- 四氢吡啶-2-羧酸乙酯(26)
向6-(4-氯-2-氟苯基)-4-[(E,Z)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸乙酯(20;2.74g,0.007mol)在CH2Cl2(20mL)中的磁力搅拌着的用冰浴冷却的溶液中添加磺酰氯(SO2Cl2,0.94g,0.007mol)在CH2Cl2中的溶液,历时5min。在使反应混合物温热至室温1h后,添加CH2Cl2(50mL)。在用NaCl的饱和水溶液洗涤反应混合物并干燥(MgSO4)后,除去溶剂,得到3-氯-6-(4-氯-2-氟-苯基)-4-[(E)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸乙酯(26;2.91g,98%,95%纯度,通过1H NMR测定),为蓬松淡黄色固体:mp 63-64℃;1HNMR(400MHz,CDCl3)δ7.37(t,J=8.1Hz,1H),7.20(dd,J=8.4,1.7Hz,1H),7.16(dd,J=10.1,2.0Hz,1H),5.31(s,1H),4.78(dd,J=12.6,4.5Hz,1H),4.41(q,J=7.1Hz,2H),3.39(dd,J=16.9,4.4Hz,1H),3.22(s,3H),2.91-2.76(m,1H),1.40(t,J=7.1Hz,3H);HRMS-ESI(m/z):C15H15Cl2FN2O5S计算值,425.240;实测值,425.240。
3-氯-6-(4-氯苯基)-4-[(E)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸甲酯
(27)
使用实施例13的操作,在CH2Cl2(25mL)中的6-(4-氯苯基)-4-[(E,Z)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸甲酯(24;2.78g,0.008mol)和SO2Cl2(1.08g,0.005mol)得到3-氯-6-(4-氯苯基)-4-[(E)-甲烷磺酰基肟基]-3-氯-1,4,5,6-四氢吡啶-2-羧酸甲酯(27;3.20g,99%,95%纯度,通过1H NMR测定),为蓬松淡黄色固体:mp 60-62℃;1H NMR(400MHz,CDCl3)δ7.41-7.29(m,4H),5.33(s,1H),4.44(dd,J=13.8,4.1Hz,1H),3.94(s,3H),3.40(ddd,J=16.9,4.2,1.8Hz,1H),3.21(s,3H),2.88-2.57(m,1H);HRMS-ESI(m/z):C15H14Cl2N2O5S计算值,391.9995;实测值,391.9997。
3-氯-6-(4-氯苯基)-4-[(E)-甲烷磺酰基肟基]-1,4,5,6-四氧吡啶-2-羧酸乙酯
(28)
使用实施例13的操作,在CH2Cl2(50mL)中的6-(4-氯苯基)-4-[(E,Z)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸乙酯(21;5.97g,0.016mol)和SO2Cl2(2.16g,0.016mol)得到3-氯-6-(4-氯苯基)-4-[(E)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸乙酯(28;6.43g,99%,92%纯度,通过1H NMR测定),为蓬松淡黄色固体:57-59℃;1H NMR(400MHz,CDCl3)δ7.35(m,4H),5.35(s,1H),4.44(dd,J=13.0,3.2Hz,1H),4.39(t,J=7.1Hz,2H),3.39(ddd,J=16.9,4.2,1.8Hz,1H),3.22(s,3H),2.65(dd,J=16.9,13.9Hz,1H),1.40(t,J=7.1Hz,3H);HRMS-ESI(m/z):C125H16Cl2N2O5S计算值,406.015;实测值,406.016。
3-氯-6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E)-甲烷磺酰基肟基]-1,4,5,6-四氢吡
啶-2-羧酸甲酯(29)
使用实施例13的操作,在CH2Cl2(10mL)中的6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E,Z)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸甲酯(23;2.04g,0.005mol)和SO2Cl2(0.68g,0.005mol)得到3-氯-6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸甲酯(29;2.18g,99%,95%纯度,通过1H NMR测定),为蓬松淡黄色固体:mp 64-66℃;1H NMR(400MHz,CDCl3)δ7.24(dd,J=8.8,1.3Hz,1H),7.09(dd,J=8.5,6.7Hz,1H),5.38(s,1H),4.78(dd,J=12.7,4.5Hz,1H),3.98(s,3H),3.93(s,3H),3.42(dd,J=16.7,4.5Hz,1H),3.24(s,3H),2.77(dd,J=16.9,12.8Hz,1H);HRMS-ESI(m/z):C15H15ClFN2O5S计算值,441.001;实测值,441.002。
3-氯-6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E)-甲烷磺酰基肟基]-1,4,5,6-四氢吡
啶-2-羧酸乙酯(30)
使用实施例13的操作,在CH2Cl2(10mL)中的6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E,Z)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸乙酯(25;2.11g,0.005mol)和SO2Cl2(0.68g,0.005mol)得到3-氯-6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸乙酯(30;2.21g,97%,95%纯度,通过1H NMR测定),为蓬松淡黄色固体:mp 60-62℃;1H NMR(400MHz,CDCl3)δ7.21(dd,J=8.5,1.8Hz,1H),7.08(dd,J=8.6,6.9Hz,1H),5.32(s,1H),4.78(dd,J=12.8,4.5Hz,1H),4.41(q,J=7.1Hz,2H),3.99(d,J=1.3Hz,3H),3.41(dd,J=16.9,4.5Hz,1H),3.23(s,3H),2.76(dd,J=11.7,5.2Hz,1H),1.40(t,J=7.1Hz,3H);HRMS-ESI(m/z):C16H17Cl2FNO6S计算值,454.016;实测值,454.017。
3-氯-6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E)-对-甲苯磺酰基肟基]-1,4,5,6-四氢
吡啶-2-羧酸甲酯(31)
使用实施例13的操作,在CH2Cl2(5mL)中的6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E,Z)-对-甲苯磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸甲酯(22;0.628g,0.0013mol)和SO2Cl2(0.175g,0.0013mol)得到3-氯-6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E)-对-甲苯磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸甲酯(31;0.616g,98%,95%纯度,通过1H NMR测定),为蓬松淡黄色固体:mp 62-64℃;1HNMR(400MHz,CDCl3)δ7.91(d,J=8.3Hz,2H),7.34(d,J=8.0Hz,2H),7.16(dd,J=8.5,1.7Hz,1H),7.01(dd,J=8.4,7.1Hz,1H),5.25(s,1H),4.70(dd,J=12.6,4.3Hz,1H),3.97(d,J=1.2Hz,3H),3.91(s,3H),3.33(ddd,J=16.8,4.4,1.6Hz,1H),2.88-2.64(m,1H),2.45(s,3H);HRMS-ESI(m/z):C21H19Cl2FN2O5S计算值,516.0322;实测值,516.0319。
实施例14.制备3-溴-6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E)-甲烷磺酰基肟 基]-1,4,5,6-四氢吡啶-2-羧酸甲酯(32)
将N-溴代琥珀酰亚胺(0.512g,2.88mmo1)添加至6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E,Z)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸甲酯(23;1.17g,2.88mmol)在CH2Cl2(10mL)中的溶液。将反应混合物在环境温度搅拌1h,然后用CH2Cl2稀释并用H2O洗涤。将有机层分离并用Biotage相分离器SPE干燥。真空除去溶剂,得到棕色油状物(1.4g)。通过硅胶色谱法(40%EtOAc/10%CH2Cl2/50%戊烷)纯化,提供3-溴-6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸甲酯(32;1.17g,84%),为黄色玻璃状物:1HNMR(300MHz,CDCl3)δ7.21(dd,J=8.6,1.8Hz,1H),7.07(dd,J=8.4,6.7Hz,1H),5.39(s,1H),4.81(d,J=12.2Hz,1H),4.01-3.97(m,4H),3.94(d,J=2.0Hz,3H),3.43(dd,J=16.8,2.8Hz,1H),3.23(d,J=1.9Hz,3H),2.79(dd,J=16.8,12.7Hz,1H);HRMS-ESI(m/z):C15H17BrClFN2O6S计算值,485.9663;实测值,485.9663。
实施例15.制备3-氯-6-(4-氯-2-氟-3-甲氢基苯基)-4-氢代-1,4,5,6-四氧吡 啶-2-羧酸甲酯(33)
将6-(4-氯-2-氟-3-甲氧基苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸甲酯(16;483mg,1.54mmol)在CH2Cl2(10mL)中浆化并在冰浴中冷却。滴加SO2Cl2(209mg,1.55mmol)在CH2Cl2(5mL)中的溶液。在30min后,用10%亚硫酸氢钠水溶液淬灭反应溶液。将有机层分离,用NaHCO3饱和水溶液、H2O和盐水洗涤,然后干燥(MgSO4)。将溶液蒸发成黄色油状物,将所述黄色油状物从冷甲醇结晶,得到3-氯-6-(4-氯-2-氟-3-甲氧基苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸甲酯(33;0.437g,81%),为淡黄色固体:mp 127-129℃;1H NMR(300MHz,CDCl3)δ7.20(dd,JF-H=1.5Hz,JH-H=8.1Hz,1H,芳族的),7.10(dd,JF-H=6.9Hz,JH-H=8.1Hz,1H,芳族的),5.82(br s,1H,NH),5.10(t,J=9.3Hz,1H,H6),3.98(d,JF-H=1.5Hz,3H,OCH3),3.97(s,3H,CO2CH3),2.88(d,J=9Hz,2H,H5);ESIMS m/z347.9([M+H]+)。
实施例16.制备3-氯-6-(4-氯-2-氟-3-甲氧基苯基)-4-羟基亚氨基-1,4,5,6- 四氢吡啶-2-羧酸甲酯(34)
将3-氯-6-(4-氯-2-氟-3-甲氧基苯基)-3-氯-4-氧代-1,4,5,6-四氢吡啶-2-羧酸甲酯(33;1.612g,4.63mmol)悬浮在MeOH(20mL)中。添加羟胺盐酸盐(966mg,13.9mmol),接着添加吡啶(3mL)。将反应混合物在室温搅拌18h,然后在40℃搅拌4h。通过旋转蒸发除去溶剂。添加H2O(100mL),将所得固体过滤,先后用H2O和MeOH洗涤,得到3-氯-6-(4-氯-2-氟-3-甲氧基苯基)-4-羟基亚氨基-1,4,5,6-四氢吡啶-2-羧酸甲酯(34;1.353g,81%),为白色粉末:mp174-176℃;1H NMR(300MHz,DMSO-d6)δ11.23(s,1H,NOH),7.35(dd,JF-H=1.5Hz,JH-H=8.7Hz,1H,芳族的),7.17(dd,JF-H=JH-H=8.7Hz,1H,芳族的),6.93(br s,1H,NH),4.69(m,1H,H6),3.88(s,3H),3.79(s,3H),3.03(dd,J=4.5,16Hz,1H,H5a),2.74(dd,J=9.0,16Hz,1H,H5b);C14H13Cl2FN2O4分析计算值:C,46.30;H,3.61;N,7.71。实测值:C,46.77;H,3.64;N,7.42。
实施例17.制备3-氯-6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E)-乙酰氧基亚氨 基]-3-氯-1,4,5,6-四氢吡啶-2-羧酸甲酯(35)
将3-氯-6-(4-氯-2-氟-3-甲氧基苯基)-3-氯-4-羟基亚氨基-1,4,5,6-四氢吡啶-2-羧酸甲酯(34,756mg,2.08mmol)在冰乙酸(10mL)中浆化。在室温滴加乙酸酐(241mg,2.36mmol)。将反应混合物在80℃加热2h。真空浓缩溶液,将残留物溶解在CH2Cl2(50mL)中并用NaHCO3饱和水溶液洗涤。将萃取液用盐水洗涤,干燥(MgSO4)并蒸发,得到3-氯-6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E)-乙酰氧基亚氨基]-3-氯-1,4,5,6-四氢吡啶-2-羧酸甲酯(35;842mg,99%),为淡橙色固体:1H NMR(400MHz,CDCl3)δ7.21(dd,JF-H=1.5Hz,JH-H=8.4Hz,1H,芳族的),7.11(dd,JF-H=6.9Hz,JH-H=8.4Hz,1H,芳族的),5.24(br s,1H,NH),4.76(dd,J=4.2,12.3Hz,1H,H5a),3.98(d,JF-H=1.5Hz,3H,OMe),3.94(s,3H,CO2Me),3.40(ddd,JF-H=1.8Hz,JH-H=4.2,16.5Hz,1H,H6),2.72(dd,J=12.3,16.5Hz,1H,H5b),2.23(s,3H,NOAc)。C16H15Cl2FN2O5的HRMS计算值:404.034.实测值:404.034.
实施例18.制备4-氨基-3-氯-6-(4-氯-2-氟苯基)吡啶-2-羧酸乙酯(36)
步骤1.在200mL Parr反应器中,在正N2压力下,将(2Z,5E)-2-氨基-6-(4-氯-2-氟苯基)-4-氧代-己-2,5-二烯酸乙酯(7;6.0g,0.02mol)在无水1,4-二噁烷(100mL)中的溶液加热至185℃。在14h后,冷却反应器,并在减压下除去溶剂,留下深橙色油状物(7.1g)。通过1H NMR光谱测定,所述物质为90%的期望的6-(4-氯-2-氟苯基)-4-氧代-1,4,5,6-四氢吡啶-2-羧酸乙酯(11).
步骤2.将上面的物质和50%羟胺水溶液(4.0g)在甲苯(150mL)中的混合物加热至回流,并保持回流4h。将反应混合物冷却至室温并添加CH2Cl2(150mL)。将有机层用NaCl饱和溶液洗涤并干燥(MgSO4)。除去溶剂,得到6-(4-氯-2-氟苯基)-4-羟基亚氨基-1,4,5,6-四氢吡啶-2-羧酸乙酯的异构体的混合物(17,4.3g),为棕色固体。
步骤3.将上面的物质溶解在冰乙酸(30mL)中,将混合物冷却至5℃,并添加SO2Cl2(4.05g,0.03mol)在冰乙酸(5mL)中的溶液,历时10min。在室温5d后,在旋转蒸发器上除去溶剂,并将残留物溶解在CH2Cl2(100mL)中。在将所述溶液用NaHCO3饱和溶液洗涤并干燥(MgSO4)之后,除去溶剂,得到橙色油状物(4.6g),通过1H NMR测定其含有65%的4-氨基-3-氯-6-(4-氯-2-氟苯基)吡啶-2-羧酸乙酯。实施硅胶柱色谱法(20%EtOAc/己烷),得到化合物36(2.2g,33%,历经3个步骤),为灰白色固体:mp 109-110℃;1H NMR(400MHz,CDCl3)δ7.96(t,J=8.5Hz,1H),7.20(dd,J=8.4,1.7Hz,1H),7.16(d,J=1.4Hz,1H),7.13(dd,J=11.1,2.0Hz,1H),4.91(s,2H),4.47(q,J=7.1Hz,2H),1.43(t,J=7.1Hz,3H);C14H11Cl2FN2O2分析值::C,51.09;H,3.37;N,8.51。实测值:C,50.90;H,3.31;N,8.47。
实施例19.制备4-氨基-3-氯-6-(4-氯苯基)吡啶-2-羧酸乙酯(37)
向6-(4-氯苯基)-4-羟基亚氨基-1,4,5,6-四氢吡啶-2-羧酸乙酯(19;0.589g,0.002mol)在冰乙酸(5mL)中的磁力搅拌着的冷却至5℃的溶液中添加SO2Cl2(0.16mL,0.002mol)。在温热至室温2h后,添加另外的SO2Cl2(0.225mL,0.0028mol)。在室温2d后,在旋转蒸发器上除去溶剂并将残留物溶解在CH2Cl2(50mL)中。在将溶液用NaHCO3饱和溶液洗涤并干燥(MgSO4)之后,除去溶剂,得到淡黄色固体(0.65g)。实施制备性薄层硅胶色谱法(20%EtOAc/己烷),得到4-氨基-3-氯-6-(4-氯苯基)-吡啶-2-羧酸乙酯(37;0.325g,52%,93%纯度,通过1H NMR测定),为白色固体:mp 128-130℃;1H NMR(400MHz,CDCl3)δ7.90-7.82(m,2H),7.46-7.36(m,2H),7.07(s,1H),4.81(s,2H),4.48(q,J=7.1Hz,2H),1.44(t,J=7.1Hz,3H);HRMS-ESI(m/z):C14H12Cl2N2O2计算值,310.027;实测值,310.028。还收集了4-氨基-3,5-二氯-6-(4-氯苯基)吡啶-2-羧酸乙酯(38;0.092g,13%收率),为白色固体:mp 143-145℃;1H NMR(400MHz,CDCl3)δ7.73-7.58(m,2H),7.49-7.36(m,2H),5.31(s,2H),4.45(q,J=7.1Hz,2H),1.41(t,J=7.1Hz,3H);HRMS-ESI(m/z):C14H11Cl3N2O2计算值,344.013;实测值,344.013。
实施例20.制备4-氨基-3-氯-6-(4-氯-2-氟-3-甲氧基-苯基)吡啶-2-羧酸甲 酯(39)
将3-氯-6-(4-氯-2-氟-3-甲氧基苯基)-4-[(Z)-羟基亚氨基]-1,4,5,6-四氢吡啶-2-羧酸甲酯(18,756mg,2.08mmol)在冰乙酸(10mL)中浆化。在室温滴加乙酸酐(241mg,2.36mmol)。将反应混合物在回流下在氮气下搅拌6h。真空浓缩溶液。将残留物溶解在CH2Cl2(50mL)中并用NaHCO3饱和水溶液洗涤。将萃取液用盐水洗涤,干燥(MgSO4)并蒸发,得到棕色固体。通过硅胶色谱法用己烷-EtOAc梯度纯化,得到4-氨基-3-氯-6-(4-氯-2-氟-3-甲氧基-苯基)吡啶-2-羧酸甲酯(39;0.204g,28%),为褐色固体:1H NMR(400MHz,CDCl3)δ7.65(dd,J=8.6,7.8Hz,1H),7.23(dd,J=8.7,1.8Hz,1H),7.18(d,J=1.7Hz,1H),4.85(s,2H),4.00(s,3H),3.97(d,J=0.9Hz,3H).);HRMS-ESI(m/z):C14H11Cl2FN2O3计算值,344.013;实测值,344.013。
实施例21.制备4-氨基-3-氯-6-(4-氯-2-氟-3-甲氧基-苯基)吡啶-2-羧酸甲 酯(39)
将6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E)-甲烷磺酰基肟基]-3-氯-1,4,5,6-四氢吡啶-2-羧酸甲酯(29,0.441g(0.001mol))在冰乙酸(2mL)中的磁力搅拌着的溶液温热至90℃并在此温度保持4h。在旋转蒸发器上除去溶剂之后,将残留物溶解在CH2Cl2(25mL)中并用NaHCO3和NaCl的饱和溶液洗涤。在干燥(MgSO4)后,除去溶剂,得到4-氨基-3-氯-6-(4-氯-2-氟-3-甲氧基苯基)吡啶-2-羧酸甲酯(39;0.332g,96%;93%纯度,通过GC和1H NMR光谱测定),为白色固体:mp 141-143℃。1H NMR(400MHz,CDCl3)δ7.65(dd,J=8.6,7.8Hz,1H),7.23(dd,J=8.7,1.8Hz,1H),7.18(d,J=1.7Hz,1H),4.85(s,2H),4.00(s,3H),3.97(d,J=0.9Hz,3H)。HRMS-ESI(m/z):C14H11Cl2FN2O3计算值,344.013;实测值,344.013。
实施例22.制备4-氨基-3-氯-6-(4-氯-2-氟-3-甲氧基苯基)吡啶-2-羧酸乙 酯(40)
向6-(4-氯-2-氟-3-甲氧基苯基)-4-[E,Z)-甲烷磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸乙酯(25,4.20g,0.01mol)在冰乙酸(100mL)中的磁力搅拌着的冷却至5℃的溶液中添加SO2Cl2(1.35g,0.01mol)在冰乙酸(3mL)中的溶液,历时5min。将反应混合物温热至室温并在室温保持1h,然后加热至90℃并在此温度保持4h。在旋转蒸发器上除去溶剂之后,将残留物溶解在CH2Cl2(100mL)中并用NaHCO3和NaCl的饱和溶液洗涤。在干燥(MgSO4)后,除去溶剂,得到黄色固体(3.55g),通过1H NMR光谱测定其含有81%的4-氨基-3-氯-6-(4-氯-2-氟-3-甲氧基苯基)吡啶-2-羧酸乙酯(40)。实施硅胶柱色谱法(20%EtOAc/己烷),得到产物,为灰白色固体(2.75g,78%,93%纯度,通过GC和1H NMR光谱测定):mp 73-74℃;1H NMR(400MHz,CDCl3)δ7.67(dd,J=8.6,7.8Hz,1H),7.23(dd,J=8.7,1.7Hz,1H),7.18(d,J=1.7Hz,1H),4.83(s,2H),4.48(q,J=7.1Hz,2H),3.97(d,J=0.8Hz,3H),1.43(t,J=7.1Hz,3H);HR S-ESI(m/z):C15H13Cl2FN2O3计算值,358.028;实测值,358.059。
实施例23.制备4-氨基-3-溴-6-(4-氯-2-氟-3-甲氧基苯基)吡啶-2-羧酸甲 酯(41)
将3-溴-6-(4-氯-2-氟-3-甲氧基苯基)-4-[(E)-甲磺酰基肟基]-1,4,5,6-四氢吡啶-2-羧酸甲酯(23,900mg,1.856mmol)在冰乙酸(4.6mL)中的溶液在Biotage微波中在150℃加热5min。在冷却至环境温度后,用H2O稀释反应混合物并将pH用Na2CO3饱和溶液调节为中性。将所得混合物用乙酸乙酯萃取3次。将合并的有机萃取液用盐水洗涤,用Na2SO4干燥,过滤并真空浓缩。实施硅胶柱色谱法(20%EtOAc/戊烷),得到4-氨基-3-溴-6-(4-氯-2-氟-3-甲氧基苯基)吡啶-2-羧酸甲酯(41;0.60g,83%),为淡棕色固体:mp 148-149℃;1HNMR(300MHz,CDCl3)δ7.65(dd,J=8.6,7.7Hz,1H),7.26-7.20(m,1H),7.14(d,J=1.8Hz,1H),4.91(s,2H),3.99(s,3H),3.97(d,J=0.9Hz,3H);HRMS-ESI(m/z):C14H11BrClFN2O3计算值,387.962;实测值,387.963。
Claims (3)
1.制备下式的6-(芳基)-4-氨基皮考啉酸酯的方法,
其中
Q表示Cl或Br;
R表示C1-C4烷基;以及
W表示H、F或Cl;
X表示H、F、Cl或C1-C4烷氧基;
Y表示卤素;以及
Z表示H或F;
所述方法包括在极性溶剂的存在下在25℃-150℃的温度加热式(I)的3-卤代-6-(芳基)-4-亚氨基四氢皮考啉酸酯,以及回收产物,所述极性溶剂为C1-C4烷酸、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮,或者二甲亚砜,
其中
R表示C1-C4烷基;
R1表示–OS(O)2R2、–OC(O)R2或–OC(O)OR2;
R2表示C1-C4烷基或苯基;
Q表示Cl或Br;以及
W表示H、F或Cl;
X表示H、F、Cl或C1-C4烷氧基;
Y表示卤素;以及
Z表示H或F。
2.权利要求1的方法,其中所述极性溶剂为C1-C4烷酸。
3.权利要求1的方法,其中所述3-卤代-6-(芳基)-4-亚氨基四氢皮考啉酸酯通过以下方法制备:用氯化剂或溴化剂氯化或溴化下式的磺酰化的、酰化的或含碳酸酯基的肟,
其中W、X、Y、Z、R、R1和R2如前面所定义。
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