CN114573473B - 一种(R)-α-芳基丙氨酸酯衍生物的制备方法 - Google Patents
一种(R)-α-芳基丙氨酸酯衍生物的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- 235000004279 alanine Nutrition 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 93
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 75
- 239000003054 catalyst Substances 0.000 claims abstract description 64
- 239000002904 solvent Substances 0.000 claims abstract description 62
- 239000001257 hydrogen Substances 0.000 claims abstract description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 51
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 50
- 238000004821 distillation Methods 0.000 claims abstract description 43
- 239000012074 organic phase Substances 0.000 claims abstract description 25
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 14
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 6
- -1 alanine ester Chemical class 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 96
- 239000003446 ligand Substances 0.000 claims description 36
- 239000002184 metal Substances 0.000 claims description 27
- 229910052751 metal Inorganic materials 0.000 claims description 27
- 239000012300 argon atmosphere Substances 0.000 claims description 24
- LYXHWHHENVLYCN-QMDOQEJBSA-N (1z,5z)-cycloocta-1,5-diene;rhodium;tetrafluoroborate Chemical compound [Rh].F[B-](F)(F)F.C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1 LYXHWHHENVLYCN-QMDOQEJBSA-N 0.000 claims description 19
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
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- 239000000758 substrate Substances 0.000 abstract description 5
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- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 44
- 239000010948 rhodium Substances 0.000 description 28
- 229910052786 argon Inorganic materials 0.000 description 22
- 239000012298 atmosphere Substances 0.000 description 19
- 238000000605 extraction Methods 0.000 description 19
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical compound PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 6
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical group [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- HTCSFFGLRQDZDE-SECBINFHSA-N (2r)-2-azaniumyl-2-phenylpropanoate Chemical compound OC(=O)[C@@](N)(C)C1=CC=CC=C1 HTCSFFGLRQDZDE-SECBINFHSA-N 0.000 description 2
- 108010011485 Aspartame Proteins 0.000 description 2
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 2
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 2
- XUIIKFGFIJCVMT-LBPRGKRZSA-N L-thyroxine Chemical compound IC1=CC(C[C@H]([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-LBPRGKRZSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- CUJRVFIICFDLGR-UHFFFAOYSA-N acetylacetonate Chemical compound CC(=O)[CH-]C(C)=O CUJRVFIICFDLGR-UHFFFAOYSA-N 0.000 description 2
- 150000001371 alpha-amino acids Chemical class 0.000 description 2
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- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 2
- 229960003438 aspartame Drugs 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 150000004696 coordination complex Chemical class 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229950008325 levothyroxine Drugs 0.000 description 2
- 125000005394 methallyl group Chemical group 0.000 description 2
- IKGHIFGXPVLPFD-LLVKDONJSA-N methyl (2r)-2-acetamido-3-phenylpropanoate Chemical compound COC(=O)[C@H](NC(C)=O)CC1=CC=CC=C1 IKGHIFGXPVLPFD-LLVKDONJSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
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- XUIIKFGFIJCVMT-UHFFFAOYSA-N thyroxine-binding globulin Natural products IC1=CC(CC([NH3+])C([O-])=O)=CC(I)=C1OC1=CC(I)=C(O)C(I)=C1 XUIIKFGFIJCVMT-UHFFFAOYSA-N 0.000 description 2
- VUTUHLLWFPRWMT-QMDOQEJBSA-M (1z,5z)-cycloocta-1,5-diene;rhodium;trifluoromethanesulfonate Chemical compound [Rh].C\1C\C=C/CC\C=C/1.C\1C\C=C/CC\C=C/1.[O-]S(=O)(=O)C(F)(F)F VUTUHLLWFPRWMT-QMDOQEJBSA-M 0.000 description 1
- QKZWXPLBVCKXNQ-UHFFFAOYSA-N (2-methoxyphenyl)-[2-[(2-methoxyphenyl)-phenylphosphanyl]ethyl]-phenylphosphane Chemical compound COC1=CC=CC=C1P(C=1C=CC=CC=1)CCP(C=1C(=CC=CC=1)OC)C1=CC=CC=C1 QKZWXPLBVCKXNQ-UHFFFAOYSA-N 0.000 description 1
- XXZOEDQFGXTEAD-UHFFFAOYSA-N 1,2-bis(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC=CC=C1C(F)(F)F XXZOEDQFGXTEAD-UHFFFAOYSA-N 0.000 description 1
- LWZYUACNWRVDDJ-UHFFFAOYSA-N 1-benzoxepine Chemical compound O1C=CC=CC2=CC=CC=C12 LWZYUACNWRVDDJ-UHFFFAOYSA-N 0.000 description 1
- 235000017166 Bambusa arundinacea Nutrition 0.000 description 1
- 235000017491 Bambusa tulda Nutrition 0.000 description 1
- 241001330002 Bambuseae Species 0.000 description 1
- 229910020366 ClO 4 Inorganic materials 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- 235000015334 Phyllostachys viridis Nutrition 0.000 description 1
- 229910018286 SbF 6 Inorganic materials 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000011425 bamboo Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229930007927 cymene Natural products 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000005610 enamide group Chemical group 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical group FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- HFPZCAJZSCWRBC-UHFFFAOYSA-N p-cymene Chemical compound CC(C)C1=CC=C(C)C=C1 HFPZCAJZSCWRBC-UHFFFAOYSA-N 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 150000003283 rhodium Chemical class 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
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Abstract
本发明公开了一种(R)‑α‑芳基丙氨酸酯衍生物的制备方法,向高压釜中加入α‑脱氢芳基丙氨酸酯衍生物、催化剂[Rh]/L*和溶剂B,于10℃~80℃以及0.1~6.0MPa的氢气压力下进行不对称加氢反应,反应1~24小时后,减压蒸馏回收溶剂B,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)‑α‑芳基丙氨酸酯衍生物。本发明方法具有较低的催化剂用量(TON高达100,000)、优异的对映选择性(ee值一般在99%以上),底物适用性广等优点,且原料易得、操作简单,反应条件温和,易于工业化,符合绿色化学的要求,具有较大的实施价值和社会经济效益。
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种(R)-α-芳基丙氨酸酯衍生物的制备方法。
背景技术
手性α-氨基酸在药学、生物学及合成化学领域都有广泛的应用,其重要性不言而喻。在众多手性的α-氨基酸中,手性α-芳基丙氨酸的分布极其广泛,在药物分子、食品添加剂等处都能找到它们的身影。如治疗甲状腺功能减退的左旋甲状腺素(Levothyroxine);能对抗多重耐药病菌感染的ADEP4,β2受体拮抗剂CPD-15A5,光谱抗癌剂LY355703以及甜味剂阿斯巴甜(Aspartame)等。
正因如此,它们的合成方法也备受人们关注。手性α-芳基丙氨酸的合成主要是以对其相应不对称氢化为主。1972年,Kagan报道了首例对烯酰胺的不对称氢化(H.B.Kagan,J.Am.Chem.Soc.,1972,94,6429.),该体系使用DIOP的铑配合物以72%的ee值得到了N-乙酰基保护的α-苯丙氨酸,自此之后烯氨酸衍生物作为一类重要的氢化底物被广泛研宄,取得了一系列非常重要的成果。2002年,Knowles(W.S.Knowles,Angew.Chem.,Int.Ed.,2002,41,1998-2007.)运用DIPAMP/Rh催化体系参与α-苯丙氨酸的不对称氢化,成功制备了高光学纯度的L-DOPA(97.5%ee),他也因此获得了2001年诺贝尔化学奖,该工艺至今依然是生产L-DOPA的主流方法。
此后,针对α-脱氢芳基丙氨酸衍生物不对称氢化的配体如雨后春笋般涌现,取得了十分优异的效果,如胡向平课题组(X.-P.Hu,Tetrahedron Lett.,2020,61,151860.)开发的二茂铁骨架配体IndoFerroPhos,可以得到高收率的(R)-α-芳基丙氨酸酯衍生物,但其ee值最高只有97%,且对杂环底物适用性较差;汤文军课题组(W.J.Tang,Org.Lett.,2018,20,1725-1729.)开发的苯并氧杂磷配体BABIPhos可以得到ee值为99%的(R)-α-芳基丙氨酸酯衍生物,但其催化剂TON值只有100;同样,张绪穆教授(X.Zhang,Org.Lett.,2002,4,4471-4474.)开发的甘露醇衍生的二茂铁骨架环状膦配体也存在上述问题。
2021年,CN112824423A公开了一种手性二茂铁膦-吲哚氨基膦配体,能高效地催化合成高光学纯度α-脱氢氨基酸酯,TON可达10000,但其对映选择性最高为96%ee。虽然利用不对称氢化技术制备(R)-α-芳基丙氨酸酯衍生物有了长足的进展,但现已报道的催化剂仍存在上述部分问题,故急需寻找一种高效、高立体选择性,底物适用性广的不对称催化氢化新方法。
发明内容
针对现有技术中存在的上述问题,本发明的目的在于提供一种(R)-α-芳基丙氨酸酯衍生物的制备方法,适用于工业化生产应用,可以较方便地制备公斤级且具有较高纯度高对映选择性的(R)-α-芳基丙氨酸酯衍生物。
本发明采用的技术方案是:
一种(R)-α-芳基丙氨酸酯衍生物的制备方法,包括如下步骤:
1)在氩气氛围下,金属Rh络合物与手性配体L*加入到溶剂A中反应0.5~6小时,制得金属Rh络合物与手性配体L*配位结合的催化剂[Rh]/L*;
2)向高压釜中加入如式(2)所示的α-脱氢芳基丙氨酸酯衍生物、上述制得的催化剂[Rh]/L*和溶剂B,于10℃~80℃以及0.1~6.0MPa的氢气压力下进行不对称加氢反应,反应1~24小时后,减压蒸馏回收溶剂B,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到如式(1)所示的(R)-α-芳基丙氨酸酯衍生物;
具体反应路线如下:
式(1)和式(2)中,芳基Ar选自苯基、杂环基、萘基或取代苯基,取代苯基中的取代基为C1~6烷基、C1~6烷氧基或卤素、硝基;R1选自乙酰基、苄氧羰基、叔丁氧羰基;R2选自C1~6烷基;
进一步,所述的手性配体L*的化学结构式如通式(L)所示:
通式(L)中:R3和R4各自独立的取代或不取代,取代时,取代基R3和取代基R4各自独立的选自卤素、芳基、C1~C6烷基。
进一步地,通式(L)所示的手性配体L*的化学结构式为式(L-1)~式(L-4)中的任意一种所示:
进一步地,所述的金属Rh络合物为[Rh(C2H4)2Cl]2、[Rh(NBD)Cl]2、[Rh(COD)Cl]2、[Rh(NBD)2]BF4、[Rh(COD)2]X、Rh(ethylene)2(acac)、[Rh(acac)(CO)]2、[Rh(C2H4)2Cl]2、RhCl(PPh3)3、[Rh(CO)2C1]2、Rh(arene)X2(diphosphine)、Rh(aryl group)X2、Rh(COD)(COT)、Rh(COD)(COT)X、Rh(COD)(methallyl)2、RhX2(diphosphine)、RhCl2(COD)、RhX2(cymene)、Rh(arylgroup)X2(PPh3)3、Rh(methallyl)2(diphosphine)和Rh(aryl group)X2(diphosphine)中的任意一种,其中aryl为芳基,X为BF4 -、OTf-、ClO4 -、SbF6 -、PF6 -、CF3SO3 -或B(Y)4 -中的任意一种,Y为二(三氟甲基)苯或氟苯。
进一步地,步骤2)中,催化剂[Rh]/L*与α-脱氢芳基丙氨酸酯衍生物的摩尔比为1:100~1:100000。
进一步地,步骤1)中,制备催化剂[Rh]/L*的温度为10℃~40℃,反应时间为0.5~3小时。
进一步地,步骤2)中,进行不对称氢化反应的温度为10℃~60℃,氢气压力为0.1~3.0MPa,反应时间为4~24小时。
进一步地,式(2)所示的α-脱氢芳基丙氨酸酯衍生物在溶剂B中的浓度为0.05mol/L~5.0mol/L。
进一步地,步骤1)中的溶剂A和步骤2)中的溶剂B各自独立地选自二氯甲烷、四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚,甲苯、甲醇、乙醇、正丙醇、异丙醇、叔丁醇中的一种或者两种以上混合溶剂,溶剂A和溶剂B可以相同。
通过采用上述技术,与现有技术相比,本发明具有以下特点:
本发明发展了一种含二茂铁骨架的手性膦-螺二氢茚亚磷酰胺双齿配体与金属络合物组成的催化剂,催化剂易于制备;本发明制备的催化剂不需要进行特别的提纯处理,可直接用于催化加氢制备(R)-α-芳基丙氨酸酯衍生物的反应;与现有不对称氢化方法相比,本发明具有较低的催化剂用量(TON高达100000)、优异的对映选择性(ee值一般在99%以上),底物适用性广等优点,且原料易得、操作简单,反应条件温和,易于工业化,符合绿色化学的要求,具有较大的实施价值和社会经济效益。
具体实施方式
下面结合具体实施例对本发明作进一步说明,但本发明的保护范围并不限于此。
实施例1:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.09g,4.94mmol),收率:99%,纯度:99%,ee值为99.9%。
实施例2:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(47.3mg,55.0μmol)与金属络合物[Rh(COD)2]BF4(20.3mg,50.0μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(30mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1kg,5.0mol)、步骤1)所制得的催化剂和二氯甲烷(3.0L),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.07kg,4.81mol),收率:96%,纯度:98%,ee值为99.0%。
实施例3:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(15mL),分别用氩气和氢气置换三次,充入氢气至3.0MPa,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.07g,4.85mmol),收率:97%,纯度:98%,ee值为98.7%。
实施例4:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入四氢呋喃(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和四氢呋喃(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.08g,4.89mmol),收率:98%,纯度:99%,ee值为99.1%。
实施例5:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入甲苯(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和甲苯(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.06g,4.80mmol),收率:96%,纯度:97%,ee值为96.2%。
实施例6:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入甲醇(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和甲醇(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.09g,4.94mmol),收率:99%,纯度:99%,ee值为99.3%。
实施例7:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入异丙醇(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和异丙醇(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.08g,4.89mmol),收率:98%,纯度:98%,ee值为97.9%。
实施例8:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在10℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.04g,4.69mmol),收率:94%,纯度:96%,ee值为99.9%。
实施例9:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在40℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.08g,4.90mmol),收率:98%,纯度:98%,ee值为99.0%。
实施例10:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在60℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.06g,4.80mmol),收率:96%,纯度:97%,ee值为96.1%。
实施例11:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),10℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-N-乙酰基苯丙氨酸甲酯(1.06g,4.80mmol),收率:96%,纯度:98%,ee值为98.3%。
实施例12:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),40℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.09g,4.92mmol),收率:98%,纯度:99%,ee值为99.0%。
实施例13:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(NBD)2]BF4(1.87mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.09g,4.94mmol),收率:97%,纯度:98%,ee值为97.3%。
实施例14:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(COD)2]OTf(2.34mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.06g,4.80mmol),收率:96%,纯度:98%,ee值为96.8%。
实施例15:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(NBD)Cl]2(1.15mg,2.5μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-N-乙酰基苯丙氨酸甲酯(1.04g,4.71mmol),收率:94%,纯度:98%,ee值为91.2%。
实施例16:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(C2H4)2Cl]2(0.97mg,2.5μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.05g,4.75mmol),收率:95%,纯度:97%,ee值为92.2%。
实施例17:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-2(5.28mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.04g,4.70mmol),收率:94%,纯度:97%,ee值为92.9%。
实施例18:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-3(4.05mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.04g,4.68mmol),收率:94%,纯度:96%,ee值为92.1%。
实施例19:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-4(3.89mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.09g,4.91mmol),收率:98%,纯度:99%,ee值为98.3%。
实施例20:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),25℃反应0.5h,制得催化剂;
2)向到高压反应釜中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(100mL),封闭反应釜后,分别用氩气和氢气置换三次,充入氢气至1.0MPa,25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.09g,4.91mmol),收率:98%,纯度98%,ee值为98.3%。
实施例21:(R)-α-N-乙酰基苯丙氨酸甲酯的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),25℃反应0.5h,制得催化剂;
2)向到高压反应釜中加入(Z)-N-乙酰基-α-脱氢苯基丙氨酸甲酯(1.1g,5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(1mL),封闭反应釜后,分别用氩气和氢气置换三次,充入氢气至1.0MPa,25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-N-乙酰基苯丙氨酸甲酯(1.06g,4.79mmol),收率:96%,纯度97%,ee值为97.2%。
实施例22~40:(R)-α-芳基丙氨酸酯衍生物的制备
1)将手性配体L-1(4.73mg,5.5μmol)与金属络合物[Rh(COD)2]BF4(2.03mg,5.0μmol)加入到反应瓶中,在氩气氛围下加入二氯甲烷(5mL),25℃反应0.5h,制得催化剂;
2)向反应瓶中加入(Z)-α-脱氢芳基丙氨酸酯衍生物(5.0mmol)、步骤1)所制得的催化剂和二氯甲烷(15mL),分别用氩气和氢气置换三次,保持0.1MPa氢气氛围,在25℃下反应12h,反应结束后,减压蒸馏回收溶剂,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到(R)-α-芳基丙氨酸酯衍生物,产物的收率,纯度,ee值见表1。
反应通式如下:
表1实施例22~40的实验结果
本说明书所述的内容仅仅是对发明构思实现形式的列举,本发明的保护范围不当被视为仅限于实施例所陈述的具体形式。
Claims (5)
1.一种(R)-a-芳基丙氨酸酯衍生物的制备方法,包括如下步骤:
1)在氩气氛围下,金属Rh络合物与手性配体L*加入到溶剂A中反应0.5~6小时,制得金属Rh络合物与手性配体L*配位结合的催化剂[Rh]/L*;
2)向高压釜中加入如式(2)所示的a-脱氢芳基丙氨酸酯衍生物、上述制得的催化剂[Rh]/L*和溶剂B,于10℃~80℃以及0.1~6.0MPa的氢气压力下进行不对称加氢反应,反应1~24小时后,减压蒸馏回收溶剂B,再加入适量水,用乙酸乙酯萃取,收集有机相后经干燥,减压蒸馏回收溶剂,得到如式(1)所示的(R)-a-芳基丙氨酸酯衍生物;
具体反应路线如下:
式(1)和式(2)中,芳基Ar选自苯基、杂环基、萘基或取代苯基,取代苯基中的取代基为C1~6烷基、C1~6烷氧基或卤素、硝基;R1选自乙酰基、苄氧羰基、叔丁氧羰基;R2选自C1~6烷基;
手性配体L*的化学结构式如通式(L)所示:
通式(L)中:取代基R3为氢、苯基;取代基R4为氢、甲基、碘原子;
所述的金属Rh络合物为[Rh(C2H4)2Cl]2、[Rh(NBD)Cl]2、[Rh(NBD)2]BF4、
[Rh(COD)2]BF4、[Rh(COD)2]OTf中的任意一种;
步骤1)中的溶剂A和步骤2)中的溶剂B各自独立地选自二氯甲烷、四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、甲苯、甲醇、乙醇、正丙醇、异丙醇、叔丁醇中的一种或者两种以上混合溶剂;
步骤2)中,催化剂[Rh]/L*与a-脱氢芳基丙氨酸酯衍生物的摩尔比为1:1000~1:100000。
2.根据权利要求1所述的一种(R)-a-芳基丙氨酸酯衍生物的制备方法,其特征在于,通式(L)所示的手性配体L*的化学结构式为式(L-1)~式(L-4)中的任意一种所示:
3.根据权利要求1所述的一种(R)-a-芳基丙氨酸酯衍生物的制备方法,其特征在于步骤1)中,制备催化剂[Rh]/L*的温度为10℃~40℃,反应时间为0.5~3小时。
4.根据权利要求1所述的一种(R)-a-芳基丙氨酸酯衍生物的制备方法,其特征在于步骤2)中,进行不对称氢化反应的温度为10℃~60℃,氢气压力为0.1~3.0MPa,反应时间为4~24小时。
5.根据权利要求1所述的一种(R)-a-芳基丙氨酸酯衍生物的制备方法,其特征在于式(2)所示的a-脱氢芳基丙氨酸酯衍生物在溶剂B中的浓度为0.05mol/L~5.0mol/L。
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