CN116589376A - 一种温和条件下合成手性α-(N -羟基)氨基酸酰胺的方法 - Google Patents
一种温和条件下合成手性α-(N -羟基)氨基酸酰胺的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 26
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 213
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- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 235000001014 amino acid Nutrition 0.000 claims abstract description 23
- 235000008206 alpha-amino acids Nutrition 0.000 claims abstract description 17
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- 239000000243 solution Substances 0.000 claims description 23
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- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 6
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- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 4
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- 229960000583 acetic acid Drugs 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
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- 238000004128 high performance liquid chromatography Methods 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
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- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 7
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- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 1
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- 239000000706 filtrate Substances 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- SQDFHQJTAWCFIB-UHFFFAOYSA-N n-methylidenehydroxylamine Chemical compound ON=C SQDFHQJTAWCFIB-UHFFFAOYSA-N 0.000 description 1
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- 229920001184 polypeptide Polymers 0.000 description 1
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- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
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- C07C239/00—Compounds containing nitrogen-to-halogen bonds; Hydroxylamino compounds or ethers or esters thereof
- C07C239/08—Hydroxylamino compounds or their ethers or esters
- C07C239/18—Hydroxylamino compounds or their ethers or esters having nitrogen atoms of hydroxylamino groups further bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
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Abstract
本发明涉及一种温和条件下合成手性α‑(N‑羟基)氨基酸酰胺的方法,在乙酸乙酯中加入外消旋的α‑氨基酸酰胺,加入手性催化剂,然后加入过氧化氢作为氧化剂进行反应,得到手性的α‑(N‑羟基)氨基酸酰胺;手性的α‑(N‑羟基)氨基酸酰胺的化学结构式为式Ⅱ所示
Description
技术领域
本发明涉及一种温和条件下合成手性α-(N-羟基)氨基酸酰胺的方法。
背景技术
手性的α-(N-羟基)氨基酰胺结构的广泛存在于许多重要的天然多肽中,比如,已显示出强大的抗生素和抗肿瘤活性的天然产物azinothricin(J.Chem.Commun.2010,46,4021)及其相关环缩肽。同时,许多人工合成的含有手性α-(N-羟基)氨基酰胺结构的化合物也具有广泛的生物活性。因此,在医药领域有着非常广阔的应用前景。
然而,当前实现手性的α-(N-羟基)氨基酸酰胺的合成方法报道很少。现有实现手性的α-(N-羟基)氨基酸酰胺的合成方法主要是通过对二级胺的氧化(Org.Lett.2017,19,1862-1865)和通过硝基酮与羰基化合物反应(J.Org.Chem.2014,79,5895-5902)得到手性的α-(N-羟基)氨基酸酰胺化合物。但是这两种方法反应底物均是手性底物,合成手性的α-(N-羟基)氨基酰胺需要首先合成手性底物,反应步骤较长,成本高。
氧化是合成高氧化态化合物最重要且直接的方法。另一方面,动力学拆分是一种很好的制备光学纯化合物的方法。虽然该方法得到的目标化合物的预期产率仅有50%,但因其可得到极高光学纯度的化合物以及经济省时的优势,在有机合成中得到广泛得应用。因此,通过氧化的策略,对外消旋的α-氨基酸酰胺进行动力学拆分,将是一种合成光学纯α-(N-羟基)氨基酸酰胺化合物的直接且高效的手段。而且该领域目前尚未任何相关报道。
发明内容
针对现有合成手性的α-(N-羟基)氨基酸酰胺反应步骤长,成本高,反应条件苛刻的难题,本发明提供一种温和条件下合成手性α-(N-羟基)氨基酸酰胺的方法,本发明的方法绿色环保,条件温和,操作简单,收率和光学纯度高。
本发明是通过如下技术方案实现的:
为达到上述目的,本发明提供一种温和条件下合成手性α-(N-羟基)氨基酸酰胺的方法,包括步骤如下:
在乙酸乙酯中加入外消旋的α-氨基酸酰胺,加入手性催化剂,然后加入过氧化氢作为氧化剂进行反应,得到手性的α-(N-羟基)氨基酸酰胺;
其中:
外消旋α-氨基酸酰胺的化学结构式为式Ⅰ所示
手性的α-(N-羟基)氨基酸酰胺的化学结构式为式Ⅱ所示
式Ⅰ、式Ⅱ中,R1为烷基,R2选自烷氧基、芳香基、取代的芳香基,或者R1与R2相结合共同形成环烷基。
根据本发明优选的,所述的手性催化剂为手性Ti-salen二聚体、手性Ti-salalen二聚体或手性Ti-salan二聚体。
根据本发明优选的,所述的手性催化剂为催化剂L2~L7。
根据本发明优选的,
催化剂L2的化学结构式为
催化剂L3的化学结构式为
催化剂L4的化学结构式为
催化剂L5的化学结构式为
催化剂L6的化学结构式为
催化剂L7的化学结构式为。
根据本发明优选的,催化剂L2-L7是按如下方法制备得到:
氮气保护下,向干燥的二氯甲烷中依次加入配体C2-C7其中之一和四异丙氧基钛Ti(OiPr)4,室温反应,然后加水反应,最后加二氯甲烷将体系过滤浓缩,残留物用乙醚重结晶,得到催化剂L2-L7。
根据本发明优选的,配体的摩尔数与二氯甲烷的体积比为(0.1-1):(2-10),单位mmol/mL,Ti(OiPr)4与配体的摩尔比为(0.5-3):(0.1-1),水与配体的摩尔比为(1-4):(0.1-1)。
根据本发明优选的,室温反应时间为3天,加水反应时间为2-8h。
根据本发明优选的,配体C2是按如下方法制得:
(1)将0.5-3.0mmol的A溶于40-60mL乙醚中,剧烈搅拌溶液,同时在15分钟内滴加1.0mmol无水HCl(36%乙醚),观察到放热反应,并形成沉淀物,在完全加入酸后,使混合物在室温下搅拌8-12小时,真空过滤收集沉淀物,用过量醚洗涤并真空干燥,得到B;(参见文献Tetrahedron Lett.2001,42,1221-1225.)
(2)将1.0-3.0mmol的B加入10-30ml乙醇和甲醇混合液中(乙醇:甲醇体积比1:1),然后加入1.0-3.0mmol的C,将所得黄色溶液在室温下搅拌18小时,将溶液真空浓缩,残留物用乙醚洗涤纯化,真空除去溶剂,得到纯的D;(参见文献Adv.Synth.Catal.2007,349,2385)
(3)将0.3-1.0mmol的D加入10-30ml冰乙酸中,然后加入0.5-1.5 mmol氰基硼氢化钠,将所得混合物在室温下搅拌0.5-2小时,并加入第二部分0.3-0.6 mmol氰基硼氢化钠,在室温下搅拌1-6小时后,将溶液移至冰浴中,使用6M的KOH水溶液调节至pH=8,悬浮液用二氯甲烷(3x)萃取,合并的有机层用饱和NaHCO3水溶液洗涤,有机层用无水MgSO4干燥,并在真空中除去溶剂获得E;(参见文献Adv.Synth.Catal.2007,349,2385);
(4)将0.3-0.8 mmol的E加入10-30ml乙醇和甲醇混合液中(乙醇:甲醇体积比1:1),然后加入0.3-0.8 mmol的C,将所得黄色溶液在室温下搅拌18小时,将溶液真空浓缩,残留物用乙醚(2x)洗涤纯化,真空除去溶剂,得到纯的C2。
根据本发明优选的,配体C3,C5,C6,C7是按如下方法制得:
C3 R=Ph C5 R=Me C6 R=Br C7 R=iPr
1)将0.5-3.0mmol的A和1.0-4.0mmol B的混合物溶解在10mL甲醇中,将得到的黄色溶液加热回流0.5-3小时,冷却至室温后,除去溶剂,粗产物用乙酸乙酯和石油醚的混合溶剂重结晶,得到黄色固体D;
2)将0.5-3.0mmol的D溶于5-20mL甲醇中,然后在室温下于30分钟内向上述溶液中分批加入2.0-4.0mmol的NaBH4,在室温下搅拌反应混合物,直到黄色消失后将无色溶液再搅拌30分钟,然后加入5-20mL水淬灭反应,混合物用二氯甲烷萃取,将合并的有机层用无水硫酸钠干燥,并在减压下蒸发,得到C3、C5、C6或C7。(参见文献Polymer 2011,52,6029–6036.)
根据本发明优选的,配体C4是按如下方法制得:
C4 R=Ph
制备方法同C3,C5,C6或C7,A原料不同。
最为优选的,所述的手性催化剂为催化剂L5。
根据本发明优选的,所述反应温度为-20~0℃。
根据本发明优选的,所述反应温度为-20~-10℃。
根据本发明优选的,外消旋的α-氨基酸酰胺与手性催化剂的摩尔比1:0.05%-1:2%,外消旋的α-氨基酸酰胺与过氧化氢的摩尔比为1:0.5-1:2。
进一步优选的,外消旋的α-氨基酸酰胺与手性催化剂的摩尔比为1:0.5%,外消旋的α-氨基酸酰胺与过氧化氢的摩尔比为1:1。
根据本发明优选的,外消旋的α-氨基酸酰胺的摩尔量与乙酸乙酯的体积比为1:5-20,单位mmol/mL。
本发明的技术特点及优点:
1、本发明首次使用手性的Ti配合物为催化剂,绿色环保的过氧化氢为氧化剂,在温和条件下选择性氧化外消旋的α-氨基酸酰胺生成光活纯的α-(N-羟基)氨基酸酰胺,可供选择底物范围广泛,本发明的制备方法不需要加热加压,在低温常压条件下就可以进行反应,而且使用了温和氧化剂过氧化氢,催化剂的量很少,无需加入其他额外试剂。
2、本发明方法与传统合成方法相比具有绿色环保、操作简单、条件温和、收率和光学纯度高的手性等诸多优点。
具体实施方式
以下结合实施例,对本发明上述的和另外的技术特征和优点作更详细的说明。
实施例中,外消旋α-(N-羟基)氨基酸酰胺是按如下方法制得:
(1)向苯胺(1eq)和2-溴丙酸乙酯(1eq)在CH3CN(5mL)中的溶液中加入K2CO3(2eq)和KI(0.1eq)。将悬浮液回流搅拌40小时,冷却至室温后,用乙酸乙酯稀释混合物并过滤。滤液在减压下浓缩,残留物通过硅胶柱色谱法纯化,得到氨基酸酯。(参见文献ACSCatal.2020,10,13196-13201)
(2)将氨基酸酯(3.3mmol)溶解在THF(15ml)和H2O(2ml)中的溶液中,加入LiOH(0.17g,4.0mmol),并将混合物在60℃下搅拌3小时。加入4N HCl将溶液PH调节至7,然后蒸发混合物并干燥,得到相应的酸。将酸(1eq)溶解在DMF(5ml)中,依次加入二取代胺(1eq)、EDC(1eq)和HOBt(1eq),将混合物在室温下搅拌过夜。反应结束后加入10mL水,水相用乙酸乙酯萃取3次,合并有机相,残留物以乙酸乙酯和石油醚为流动相过硅胶柱纯化得到底物。(参见文献J.Am.Chem.Soc.2011,133,16605–16616)。
催化剂L1是按如下方法制备得到:
在氮气保护下,往干燥的2mL的二氯甲烷溶剂中依次加入0.5mmol的配体C1和1.0mmol的四异丙氧基钛Ti(OiPr)4,室温反应三天后,加2.0mmol的水反应4小时,然后加10mL的二氯甲烷,将体系过滤浓缩,残留物用乙醚重结晶,得到催化剂L1。
配体C1是按如下方法制得:
将1.0mmol A和2.0mmol B的混合物溶解在10mL甲醇中,将得到的黄色溶液加热回流1小时,冷却至室温后,除去溶剂,粗产物用乙酸乙酯和石油醚的混合溶剂重结晶,得到黄色固体C1,C1中,R=Ph。(参见文献Polymer 2011,52,6029–6036.)
实施例1:(S)-N,N-二乙基-2-(羟基(苯基)氨基)丙酰胺的合成
a):取一10mL圆底烧瓶,0℃下,加入外消旋N,N-二乙基-2-(苯基氨基)丙酰胺22.0mg,30%的过氧化氢溶液10μL,催化剂L2 5.4mg,乙酸乙酯1mL,常压搅拌1h。反应结束后加入10mL乙酸乙酯稀释,加盐水5mL洗涤,分出有机相,水相用乙酸乙酯萃取3次,合并有机相,残留物以乙酸乙酯和石油醚为流动相过硅胶柱纯化得到(S)-N,N-二乙基-2-(羟基(苯基)氨基)丙酰胺纯品,收率为20%,ee为72%。
b):取一10mL圆底烧瓶,0℃下,加入外消旋N,N-二乙基-2-(苯基氨基)丙酰胺22.0mg,30%的过氧化氢溶液10μL,催化剂L3 5.4mg,乙酸乙酯1mL,常压搅拌1h。反应结束后加入10mL乙酸乙酯稀释,加盐水5mL洗涤,分出有机相,水相用乙酸乙酯萃取3次,合并有机相,残留物以乙酸乙酯和石油醚为流动相过硅胶柱纯化得到(S)-N,N-二乙基-2-(羟基(苯基)氨基)丙酰胺纯品,收率为37%,ee为65%。
c):取一10mL圆底烧瓶,0℃下,加入外消旋N,N-二乙基-2-(苯基氨基)丙酰胺22.0mg,30%的过氧化氢溶液10μL,催化剂L4 6.4mg,乙酸乙酯1mL,常压搅拌1h。反应结束后加入10mL乙酸乙酯稀释,加盐水5mL洗涤,分出有机相,水相用乙酸乙酯萃取3次,合并有机相,残留物以乙酸乙酯和石油醚为流动相过硅胶柱纯化得到(S)-N,N-二乙基-2-(羟基(苯基)氨基)丙酰胺纯品,收率为8%,ee为64%。
d):取一10mL圆底烧瓶,0℃下,加入外消旋N,N-二乙基-2-(苯基氨基)丙酰胺22.0mg,30%的过氧化氢溶液10μL,催化剂L5 4.2mg,乙酸乙酯1mL,常压搅拌1h。反应结束后加入10mL乙酸乙酯稀释,加盐水5mL洗涤,分出有机相,水相用乙酸乙酯萃取3次,合并有机相,残留物以乙酸乙酯和石油醚为流动相过硅胶柱纯化得到(S)-N,N-二乙基-2-(羟基(苯基)氨基)丙酰胺纯品,收率为38%,ee为83%。
e):取一10mL圆底烧瓶,0℃下,加入外消旋N,N-二乙基-2-(苯基氨基)丙酰胺22.0mg,30%的过氧化氢溶液10μL,催化剂L6 5.5mg,乙酸乙酯1mL,常压搅拌1h。反应结束后加入10mL乙酸乙酯稀释,加盐水5mL洗涤,分出有机相,水相用乙酸乙酯萃取3次,合并有机相,残留物以乙酸乙酯和石油醚为流动相过硅胶柱纯化得到(S)-N,N-二乙基-2-(羟基(苯基)氨基)丙酰胺纯品,收率为25%,ee为82%。
f):取一10mL圆底烧瓶,0℃下,加入外消旋N,N-二乙基-2-(苯基氨基)丙酰胺22.0mg,30%的过氧化氢溶液10μL,催化剂L7 4.7mg,乙酸乙酯1mL,常压搅拌1h。反应结束后加入10mL乙酸乙酯稀释,加盐水5mL洗涤,分出有机相,水相用乙酸乙酯萃取3次,合并有机相,残留物以乙酸乙酯和石油醚为流动相过硅胶柱纯化得到(S)-N,N-二乙基-2-(羟基(苯基)氨基)丙酰胺纯品,收率为30%,ee为79%。
g):取一10mL圆底烧瓶,-10℃下,加入外消旋N,N-二乙基-2-(苯基氨基)丙酰胺22.0mg,30%的过氧化氢溶液10μL,催化剂L5 4.2mg,乙酸乙酯1mL,常压搅拌8h。反应结束后加入10mL乙酸乙酯稀释,加盐水5mL洗涤,分出有机相,水相用乙酸乙酯萃取3次,合并有机相,残留物以乙酸乙酯和石油醚为流动相过硅胶柱纯化得到(S)-N,N-二乙基-2-(羟基(苯基)氨基)丙酰胺纯品,收率为43%,ee为84%。
h):取一10mL圆底烧瓶,-20℃下,加入外消旋N,N-二乙基-2-(苯基氨基)丙酰胺22.0mg,30%的过氧化氢溶液10μL,催化剂L5 4.2mg,乙酸乙酯1mL,常压搅拌24h。反应结束后加入10mL乙酸乙酯稀释,加盐水5mL洗涤,分出有机相,水相用乙酸乙酯萃取3次,合并有机相,残留物以乙酸乙酯和石油醚为流动相过硅胶柱纯化得到(S)-N,N-二乙基-2-(羟基(苯基)氨基)丙酰胺纯品,收率为44%,ee为85%。
1H NMR(500MHz,Acetone)δ8.60(s,1H),7.33–7.19(m,2H),7.18–7.07(m,2H),6.91–6.81(m,1H),4.83(q,J=6.9Hz,1H),3.50(q,J=7.1Hz,2H),3.34(dq,J=14.2,7.2Hz,1H),3.23(dq,J=14.2,7.1Hz,1H),1.43(d,J=6.7Hz,3H),1.20(t,J=7.2Hz,3H),0.99(t,J=7.1Hz,3H);13C NMR(126MHz,Acetone)δ174.29,153.09,129.40,121.57,116.46,59.14,42.32,40.29,14.86,14.26,13.01.HPLC:the ee value was determinedby HPLC analysis(Chiralpak IG,i-PrOH/Hexane=20/80,1.0mL/min,246nm),retentiontime:tmajor=13.100min,tminor=14.823min,ee=85%.
对比例1
(S)-N,N-二乙基-2-(羟基(苯基)氨基)丙酰胺的合成
取一10mL圆底烧瓶,0℃下,加入外消旋N,N-二乙基-2-(苯基氨基)丙酰胺22.0mg,30%的过氧化氢溶液10μL,催化剂L1 5.4mg,乙酸乙酯1mL,常压搅拌1h。反应结束后加入10mL乙酸乙酯稀释,加盐水5mL洗涤,分出有机相,水相用乙酸乙酯萃取3次,合并有机相,残留物以乙酸乙酯和石油醚为流动相过硅胶柱纯化得到(S)-N,N-二乙基-2-(羟基(苯基)氨基)丙酰胺纯品,收率为4%,ee为0%。
对比实施例1和对比例1可以看出,催化剂L2-L7在温和条件下可以选择性氧化外消旋的α-氨基酸酰胺生成光活纯的α-(N-羟基)氨基酸酰胺,而催化剂L1则不能。
实施例2:(S)-N,N-二甲基-2-(羟基(苯基)氨基)丙酰胺的的合成
取一10mL圆底烧瓶,-20℃下,加入外消旋N,N-二乙基-2-(苯基氨基)丙酰胺19.2mg,30%的过氧化氢溶液10μL,催化剂L5 4.2mg,乙酸乙酯1mL,常压搅拌24h。反应结束后加入10mL乙酸乙酯稀释,加盐水5mL洗涤,分出有机相,水相用乙酸乙酯萃取3次,合并有机相,残留物以乙酸乙酯和石油醚为流动相过硅胶柱纯化得到(S)-N,N-二甲基-2-(羟基(苯基)氨基)丙酰胺的的合成,收率为43%,ee为82%。
1H NMR(500MHz,Acetone)δ8.19(s,1H),7.26(dd,J=8.8,7.3Hz,2H),7.08–7.03(m,2H),6.92–6.86(m,1H),4.78(q,J=6.9Hz,1H),3.06(s,3H),2.81(s,3H),1.43(d,J=6.9Hz,3H).13C NMR(126MHz,Acetone)δ175.02,152.63,129.40,121.34,115.55,58.16,37.03,34.94,13.51.HPLC:the ee value was determined by HPLC analysis(ChiralpakIG,i-PrOH/Hexane=35/65,1.0mL/min,252nm),retention time:tmajor=7.977min,tminor=9.253min,ee=82%.
实施例3:(S)-2-(羟基(苯基)氨基)-N-甲氧基-N-甲基丙酰胺
取一10mL圆底烧瓶,-20℃下,加入外消旋N,N-二乙基-2-(苯基氨基)丙酰胺20.8mg,30%的过氧化氢溶液10μL,催化剂L5 4.2mg,乙酸乙酯1mL,常压搅拌24h。反应结束后加入10mL乙酸乙酯稀释,加盐水5mL洗涤,分出有机相,水相用乙酸乙酯萃取3次,合并有机相,残留物以乙酸乙酯和石油醚为流动相过硅胶柱纯化得到(S)-2-(羟基(苯基)氨基)-N-甲氧基-N-甲基丙酰胺纯品,收率为43%,ee为83%。
1H NMR(500MHz,CD3CN)δ7.50–7.44(m,1H),7.31–7.25(m,2H),7.11(dt,J=8.0,2.5Hz,2H),6.92(t,J=7.3Hz,1H),4.86(s,1H),3.74(s,3H),3.10(s,3H),1.43(d,J=6.9Hz,3H).13C NMR(126MHz,CD3CN)δ152.74,129.76,122.04,116.34,114.25,62.44,59.38,32.14,13.62.HPLC:the ee value was determined by HPLC analysis(ChiralpakIC,i-PrOH/Hexane=35/65,1.0mL/min,247nm),retention time:tmajor=7.283min,tminor=9.010min,ee=83%.
实施例4:(S)-2-羟基(苯基)氨基-1-(哌啶-1-基)丙酮
取一10mL圆底烧瓶,-20℃下,加入外消旋N,N-二乙基-2-(苯基氨基)丙酰胺23.2mg,30%的过氧化氢溶液10μL,催化剂L5 4.2mg,乙酸乙酯1mL,常压搅拌24h。反应结束后加入10mL乙酸乙酯稀释,加盐水5mL洗涤,分出有机相,水相用乙酸乙酯萃取3次,合并有机相,残留物以乙酸乙酯和石油醚为流动相过硅胶柱纯化得到(S)-2-羟基(苯基)氨基-1-(哌啶-1-基)丙酮纯品,收率为42%,ee为82%。
1H NMR(500MHz,CD3CN)δ8.26(s,1H),7.31–7.19(m,2H),7.12–6.99(m,2H),6.89(tt,J=7.3,1.1Hz,1H),4.80(q,J=6.9Hz,1H),3.56–3.32(m,4H),1.65–1.52(m,4H),1.45(d,J=6.9Hz,3H),1.41–1.27(m,2H);13C NMR(126MHz,CD3CN)δ173.70,153.13,129.73,121.65,115.87,58.16,47.24,43.06,27.31,26.41,24.99,14.63.HPLC:the ee value wasdetermined by HPLC analysis(Chiralpak IC,i-PrOH/Hexane=35/65,1.0mL/min,252nm),retention time:tmajor=12.663min,tminor=20.083min,ee=82%.
实施例5:(S)-2-(羟基(苯基)氨基)-N-苄基-N-甲基丙酰胺
取一10mL圆底烧瓶,-20℃下,加入外消旋N,N-二乙基-2-(苯基氨基)丙酰胺26.8mg,30%的过氧化氢溶液10μL,催化剂L5 4.2mg,乙酸乙酯1mL,常压搅拌24h。反应结束后加入10mL乙酸乙酯稀释,加盐水5mL洗涤,分出有机相,水相用乙酸乙酯萃取3次,合并有机相,残留物以乙酸乙酯和石油醚为流动相过硅胶柱纯化得到(S)-2-(羟基(苯基)氨基)-N-苄基-N-甲基丙酰胺纯品,收率为45%,ee为83%。
1H NMR(500MHz,CD3CN)δ8.23–8.08(m,1H),7.39–7.21(m,5H),7.19–7.09(m,2H),7.03–6.86(m,3H),4.92–4.74(m,1H),4.69–4.30(m,2H),3.02–2.73(m,3H),1.56–1.41(m,3H).13C NMR(126MHz,CD3CN)δ175.77,175.68,153.09,152.66,137.91,137.73,129.79,129.74,129.70,129.43,128.49,128.24,128.06,127.75,122.00,121.94,116.30,116.17,59.45,58.95,53.48,51.06,35.43,34.01,14.38,14.10.HPLC:the ee value wasdetermined by HPLC analysis(Chiralpak IC,i-PrOH/Hexane=35/65,1.0mL/min,251nm),retention time:tmajor=10.533min,tminor=13.713min,ee=83%.
实施例6:(S)-2-(羟基(苯基)氨基)-N-(4-甲氧基苄基)-N-甲基丙酰胺
取一10mL圆底烧瓶,-20℃下,加入外消旋N,N-二乙基-2-(苯基氨基)丙酰胺29.8mg,30%的过氧化氢溶液10μL,催化剂L5 4.2mg,乙酸乙酯1mL,常压搅拌24h。反应结束后加入10mL乙酸乙酯稀释,加盐水5mL洗涤,分出有机相,水相用乙酸乙酯萃取3次,合并有机相,残留物以乙酸乙酯和石油醚为流动相过硅胶柱纯化得到(S)-2-(羟基(苯基)氨基)-N-(4-甲氧基苄基)-N-甲基丙酰胺纯品,收率为43%,ee为84%。
1H NMR(500MHz,CD3CN)δ7.25–7.04(m,4H),6.95–6.83(m,2H),6.77–6.39(m,3H),4.77(s,1H),4.70–4.40(m,3H),3.82–3.72(m,3H),3.07–2.82(m,3H),1.31(dd,J=14.9,6.6Hz,3H).13C NMR(126MHz,CD3CN)δ174.42,174.23,159.68,159.45,148.25,148.09,130.24,129.72,129.68,129.65,129.50,128.75,114.64,114.37,114.08,113.98,55.50,55.42,52.33,50.57,49.24,49.06,34.47,33.94,18.72,17.95.HPLC:the ee value wasdetermined by HPLC analysis(Chiralpak IC,i-PrOH/Hexane=35/65,1.0mL/min,245nm),retention time:tmajor=12.037min,tminor=15.640min,ee=84%.
实施例7:(S)-2-(羟基(苯基)氨基)-N-(4-氟苄基)-N-甲基丙酰胺
取一10mL圆底烧瓶,-20℃下,加入外消旋N-(4-氟苄基)-N-甲基-2-苯氨基丙酰胺28.6mg,30%的过氧化氢溶液10μL,催化剂L5 4.2mg,乙酸乙酯1mL,常压搅拌24h。反应结束后加入10mL乙酸乙酯稀释,加盐水5mL洗涤,分出有机相,水相用乙酸乙酯萃取3次,合并有机相,残留物以乙酸乙酯和石油醚为流动相过硅胶柱纯化得到(S)-2-(羟基(苯基)氨基)-N-(4-氟苄基)-N-甲基丙酰纯品,收率为44%,ee为85%。
1H NMR(500MHz,CD3CN)δ8.11–7.99(m,1H),7.32–7.22(m,2H),7.20–7.05(m,3H),7.02–6.93(m,4H),4.89–4.74(m,1H),4.65–4.56(m,1H),4.29(d,J=15.0Hz,1H),3.00–2.76(m,3H),1.51–1.40(m,3H).13C NMR(126MHz,CD3CN)δ175.64,163.81,161.88,153.09,134.10,130.31,130.25,129.82,129.74,122.09,116.25,116.13,115.96,59.12,50.47,35.42,13.97.HPLC:the ee value was determined by HPLC analysis(Chiralpak IC,i-PrOH/Hexane=35/65,1.0mL/min,247nm),retention time:tmajor=8.217min,tminor=
9.930min,ee=85%.
以上所述的实施例仅仅是对本发明的优选实施方式进行描述,并非对本发明的范围进行限定,在不脱离本发明设计精神的前提下,本领域普通技术人员对本发明的技术方案作出的各种变形和改进,均应落入本发明权利要求书确定的保护范围内。
Claims (10)
1.一种温和条件下合成手性α-(N-羟基)氨基酸酰胺的方法,包括步骤如下:
在乙酸乙酯中加入外消旋的α-氨基酸酰胺,加入手性催化剂,然后加入过氧化氢作为氧化剂进行反应,得到手性的α-(N-羟基)氨基酸酰胺;
其中:
外消旋α-氨基酸酰胺的化学结构式为式Ⅰ所示
手性的α-(N-羟基)氨基酸酰胺的化学结构式为式Ⅱ所示
式Ⅰ、式Ⅱ中,R1为烷基,R2选自烷氧基、芳香基、取代的芳香基,或者R1与R2相结合共同形成环烷基。
2.根据权利要求1所述的方法,其特征在于,所述的手性催化剂为手性Ti-salen二聚体、手性Ti-salalen二聚体或手性Ti-salan二聚体。
3.根据权利要求1所述的方法,其特征在于,所述的手性催化剂为催化剂L2~L7;
催化剂L2的化学结构式为
催化剂L3的化学结构式为
催化剂L4的化学结构式为
催化剂L5的化学结构式为
催化剂L6的化学结构式为
催化剂L7的化学结构式为。
4.根据权利要求3所述的方法,其特征在于,催化剂L2-L7是按如下方法制备得到:
氮气保护下,向干燥的二氯甲烷中依次加入配体C2-C7其中之一和四异丙氧基钛Ti(OiPr)4,室温反应,然后加水反应,最后加二氯甲烷将体系过滤浓缩,残留物用乙醚重结晶,得到催化剂L2-L7。
5.根据权利要求4所述的方法,其特征在于,配体的摩尔数与二氯甲烷的体积比为(0.1-1):(2-10),单位mmol/mL,Ti(OiPr)4与配体的摩尔比为(0.5-3):(0.1-1),水与配体的摩尔比为(1-4):(0.1-1),室温反应时间为3天,加水反应时间为2-8h。
6.根据权利要求4所述的方法,其特征在于,配体C2是按如下方法制得:
(1)将0.5-3.0mmol的A溶于40-60mL乙醚中,剧烈搅拌溶液,同时在15分钟内滴加1.0mmol无水HCl(36%乙醚),观察到放热反应,并形成沉淀物,在完全加入酸后,使混合物在室温下搅拌8-12小时,真空过滤收集沉淀物,用过量醚洗涤并真空干燥,得到B;
(2)将1.0-3.0mmol的B加入10-30ml乙醇和甲醇混合液中(乙醇:甲醇体积比1:1),然后加入1.0-3.0mmol的C,将所得黄色溶液在室温下搅拌18小时,将溶液真空浓缩,残留物用乙醚洗涤纯化,真空除去溶剂,得到纯的D;
(3)将0.3-1.0mmol的D加入10-30ml冰乙酸中,然后加入0.5-1.5mmol氰基硼氢化钠,将所得混合物在室温下搅拌0.5-2小时,并加入第二部分0.3-0.6mmol氰基硼氢化钠,在室温下搅拌1-6小时后,将溶液移至冰浴中,使用6M的KOH水溶液调节至pH=8,悬浮液用二氯甲烷(3x)萃取,合并的有机层用饱和NaHCO3水溶液洗涤,有机层用无水MgSO4干燥,并在真空中除去溶剂获得E;
(4)将0.3-0.8mmol的E加入10-30ml乙醇和甲醇混合液中(乙醇:甲醇体积比1:1),然后加入0.3-0.8mmol的C,将所得黄色溶液在室温下搅拌18小时,将溶液真空浓缩,残留物用乙醚(2x)洗涤纯化,真空除去溶剂,得到纯的C2;
配体C3,C5,C6,C7是按如下方法制得:
C3 R=Ph C5 R=Me C6 R=Br C7 R=iPr
1)将0.5-3.0mmol的A和1.0-4.0mmol B的混合物溶解在10mL甲醇中,将得到的黄色溶液加热回流0.5-3小时,冷却至室温后,除去溶剂,粗产物用乙酸乙酯和石油醚的混合溶剂重结晶,得到黄色固体D;
2)将0.5-3.0mmol的D溶于5-20mL甲醇中,然后在室温下于30分钟内向上述溶液中分批加入2.0-4.0mmol的NaBH4,在室温下搅拌反应混合物,直到黄色消失后将无色溶液再搅拌30分钟,然后加入5-20mL水淬灭反应,混合物用二氯甲烷萃取,将合并的有机层用无水硫酸钠干燥,并在减压下蒸发,得到C3、C5、C6或C7;
配体C4是按如下方法制得:
C4 R=Ph
制备方法同C3,C5,C6或C7,A原料不同。
7.根据权利要求3所述的方法,其特征在于,所述的手性催化剂为催化剂L5。
8.根据权利要求3所述的方法,其特征在于,所述反应温度为-20~0℃,优选的,所述反应温度为-20~-10℃。
9.根据权利要求3所述的方法,其特征在于,外消旋的α-氨基酸酰胺与手性催化剂的摩尔比1:0.05%-1:2%,外消旋的α-氨基酸酰胺与过氧化氢的摩尔比为1:0.5-1:2。
10.根据权利要求3所述的方法,其特征在于,外消旋的α-氨基酸酰胺的摩尔量与乙酸乙酯的体积比为1:5-20,单位mmol/mL。
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