CN108610358A - 3-(三甲基硅基)吡咯烷-2-羧酸、其中间体及制备与应用 - Google Patents
3-(三甲基硅基)吡咯烷-2-羧酸、其中间体及制备与应用 Download PDFInfo
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- 150000003235 pyrrolidines Chemical class 0.000 title claims abstract description 137
- 239000000758 substrate Substances 0.000 title claims abstract description 107
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 title claims abstract description 75
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 239000002253 acid Substances 0.000 claims abstract description 14
- 239000000126 substance Substances 0.000 claims abstract description 12
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims abstract description 11
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 10
- 239000002671 adjuvant Substances 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000000903 blocking effect Effects 0.000 claims abstract description 5
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 4
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 230000004913 activation Effects 0.000 claims abstract 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 134
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 20
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 20
- 238000000926 separation method Methods 0.000 claims description 20
- 239000000741 silica gel Substances 0.000 claims description 20
- 229910002027 silica gel Inorganic materials 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims description 16
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 16
- NEXSMEBSBIABKL-UHFFFAOYSA-N hexamethyldisilane Chemical compound C[Si](C)(C)[Si](C)(C)C NEXSMEBSBIABKL-UHFFFAOYSA-N 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 11
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 claims description 10
- 150000005012 8-aminoquinolines Chemical group 0.000 claims description 10
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims description 10
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 229940005561 1,4-benzoquinone Drugs 0.000 claims description 8
- -1 pyrroles Alkane Chemical class 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 6
- 229910052710 silicon Inorganic materials 0.000 claims description 6
- 239000010703 silicon Substances 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 5
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000001967 indiganyl group Chemical group [H][In]([H])[*] 0.000 claims description 4
- 229910052738 indium Inorganic materials 0.000 claims description 4
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims 4
- 238000006683 Mannich reaction Methods 0.000 claims 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 2
- 150000002148 esters Chemical class 0.000 claims 2
- 235000019253 formic acid Nutrition 0.000 claims 2
- 238000006957 Michael reaction Methods 0.000 claims 1
- 238000005575 aldol reaction Methods 0.000 claims 1
- 150000003233 pyrroles Chemical class 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000013459 approach Methods 0.000 abstract description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract 6
- 229960001866 silicon dioxide Drugs 0.000 description 14
- 235000011167 hydrochloric acid Nutrition 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 230000004224 protection Effects 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- WREVVZMUNPAPOV-UHFFFAOYSA-N 8-aminoquinoline Chemical compound C1=CN=C2C(N)=CC=CC2=C1 WREVVZMUNPAPOV-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 150000004054 benzoquinones Chemical class 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
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- QCCWVNLOJADEAV-UHFFFAOYSA-N n,n-dimethyl-1h-pyrrol-3-amine Chemical class CN(C)C=1C=CNC=1 QCCWVNLOJADEAV-UHFFFAOYSA-N 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical class CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
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- 125000002252 acyl group Chemical group 0.000 description 1
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- 229940127088 antihypertensive drug Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
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- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000003863 metallic catalyst Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 150000003961 organosilicon compounds Chemical class 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000037452 priming Effects 0.000 description 1
- 150000004040 pyrrolidinones Chemical class 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si
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- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0272—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255
- B01J31/0275—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing elements other than those covered by B01J31/0201 - B01J31/0255 also containing elements or functional groups covered by B01J31/0201 - B01J31/0269
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- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
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- C07F7/02—Silicon compounds
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- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
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- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
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Abstract
本发明涉及3‑(三甲基硅基)吡咯烷‑2‑羧酸、其中间体及制备与应用,所述的3‑(三甲基硅基)吡咯烷‑2‑羧酸的结构式为或
Description
技术领域
本发明属于有机化学技术领域,涉及3-(三甲基硅基)吡咯烷-2-羧酸及其制备方法与应用,尤其是涉及新化合物(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸、(2S,3S)-3-(三甲基硅基)吡咯烷-2-羧酸、其中间体及制备应用。
背景技术
α-氨基酸是构成生物活性肽、肽模拟物以及蛋白质的重要骨架,如L-脯氨酸是合成人体蛋白质的重要氨基酸之一,是氨基酸输液的重要原料,也是合成卡托普利、依那普利等一线降压药物的主要中间体,现已被广泛应用于食品与医药等工业。
有机硅化合物是一类含C-Si键的有机化合物,在不对称合成及功能材料的研制中具有极其重要的作用。研究表明,硅的引入将会对α-氨基酸的溶解性、稳定性、亲油性以及药物代谢方面产生积极影响。
脯氨酸作为一种结构简单且自然界含量丰富的手性分子,不仅可以在过渡金属不对称催化中作为双齿配体,而且本身可以直接作为催化剂,催化Aldol、Mannich、Michael等有机合成反应,达到很好的不对称诱导效果。与一般的金属催化剂相比,脯氨酸无毒廉价、两种对映体易得;反应不需要惰性气体保护,室温下即可进行;反应无需对底物进行预修饰;具有水溶性,通过简单的水萃取即可很容易除去,反应的后处理十分方便,其作为催化剂在有机合成领域的应用越来越广泛。
发明内容
本发明的目的就是提供一种条件温和、可控性好、重复性好且产率高的3-(三甲基硅基)吡咯烷-2-羧酸的制备方法及由该方法制备得到的3-(三甲基硅基)吡咯烷-2-羧酸。
本发明的另一个目的就是提供上述3-(三甲基硅基)吡咯烷-2-羧酸及其中间体的应用。
本发明的目的可以通过以下技术方案来实现:
3-(三甲基硅基)吡咯烷-2-羧酸,包括(2S,3S)-3-(三甲基硅基)吡咯烷-2-羧酸及其对映异构体(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸,其中,所述的(2S,3S)-3-(三甲基硅基)吡咯烷-2-羧酸的化学结构式为式(I):
所述的(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸的化学结构式为式(II):
3-(三甲基硅基)吡咯烷-2-羧酸的中间体,包括(2S,3S)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺及其对映异构体(2R,3R)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺,其中,所述的(2S,3S)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺的化学结构式为式(III):
所述的(2R,3R)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺的化学结构式为式(IV):
3-(三甲基硅基)吡咯烷-2-羧酸的制备方法,该方法是以手性脯氨酸为原料,通过引入保护基团和辅助剂后,与硅烷化试剂进行C-H键活化反应,再脱除保护基团得到中间体,该中间体在酸作用下脱除辅助基团,即可制得(2S,3S)-3-(三甲基硅基)吡咯烷-2-羧酸或(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸。
所述的保护基团为苄氧羰基,所述的辅助剂为8-氨基喹啉,所述的硅烷化试剂为六甲基二硅烷,所述的酸为盐酸。
制备(2S,3S)-3-(三甲基硅基)吡咯烷-2-羧酸时,所述的方法具体包括以下步骤:
(1)将D-脯氨酸溶于NaOH溶液中,于0℃滴加氯甲酸苄酯进行反应,后经萃取、洗涤、干燥、浓缩、硅胶柱分离,制得(R)-1-(苄氧羰基)吡咯烷-2-羧酸;
(2)将(R)-1-(苄氧羰基)吡咯烷-2-羧酸溶于干燥的二氯甲烷中,依次加入8-氨基喹啉、4-二甲氨基吡啶,冷却至0℃,再缓慢加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,于室温下,反应过夜,经洗涤、干燥、浓缩,制得(R)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯;
(3)将(R)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯溶于干燥的N-甲基吡咯烷酮中,依次加入Pd(OAc)2、对苯醌、六甲基二硅烷及NaF,于Ar氛围中,110℃下反应24h,后经洗涤、干燥、浓缩、硅胶柱分离,制得(2S,3S)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯;
(4)将(2S,3S)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯溶于甲醇中,加入Pd/C,于H2氛围中,室温反应过夜,后经过滤、浓缩、硅胶柱分离,制得中间体(2S,3S)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺;
(5)将中间体(2S,3S)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺溶于浓盐酸中,于Ar氛围中,100℃下反应48h,浓缩,再加入水,用碱调节至中性,经洗涤、浓缩、重结晶,制得(2S,3S)-3-(三甲基硅基)吡咯烷-2-羧酸。
步骤(1)中所述的D-脯氨酸与氯甲酸苄酯的摩尔比为10:11;
步骤(2)中所述的(R)-1-(苄氧羰基)吡咯烷-2-羧酸与8-氨基喹啉、4-二甲氨基吡啶、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐的摩尔比为10:10:3:15;
步骤(3)中所述的(R)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯与Pd(OAc)2、对苯醌、六甲基二硅烷及NaF的摩尔比为1:0.1:4:10:1.2;
步骤(4)中所述的(2S,3S)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯在甲醇中的摩尔浓度为0.11mmol/mL,所述的Pd/C在甲醇中的质量浓度为5mg/mL;
步骤(5)中所述的中间体(2S,3S)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺在浓盐酸中的摩尔浓度为0.1mmol/mL。
制备(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸时,所述的方法具体包括以下步骤:
(A)将L-脯氨酸溶于NaOH溶液中,于0℃滴加氯甲酸苄酯进行反应,后经萃取、洗涤、干燥、浓缩、硅胶柱分离,制得(S)-1-(苄氧羰基)吡咯烷-2-羧酸;
(B)将(S)-1-(苄氧羰基)吡咯烷-2-羧酸溶于干燥的二氯甲烷中,依次加入8-氨基喹啉、4-二甲氨基吡啶,冷却至0℃,再缓慢加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,于室温下,反应过夜,经洗涤、干燥、浓缩,制得(S)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯;
(C)将(S)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯溶于干燥的N-甲基吡咯烷酮中,依次加入Pd(OAc)2、对苯醌、六甲基二硅烷及NaF,于Ar氛围中,110℃下反应24h,后经洗涤、干燥、浓缩、硅胶柱分离,制得(2R,3R)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯;
(D)将(2R,3R)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯溶于甲醇中,加入Pd/C,于H2氛围中,室温反应过夜,后经过滤、浓缩、硅胶柱分离,制得中间体(2R,3R)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺;
(E)将中间体(2R,3R)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺溶于浓盐酸中,于Ar氛围中,100℃下反应48h,浓缩,再加入水,用碱调节至中性,经洗涤、浓缩、重结晶,制得(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸。
步骤(A)中所述的L-脯氨酸与氯甲酸苄酯的摩尔比为10:11;
步骤(B)中所述的(S)-1-(苄氧羰基)吡咯烷-2-羧酸与8-氨基喹啉、4-二甲氨基吡啶、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐的摩尔比为10:10:3:15;
步骤(C)中所述的(S)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯与Pd(OAc)2、对苯醌、六甲基二硅烷及NaF的摩尔比为1:0.1:4:10:1.2;
步骤(D)中所述的(2R,3R)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯在甲醇中的摩尔浓度为0.11mmol/mL,所述的Pd/C在甲醇中的质量浓度为5mg/mL;
步骤(E)中所述的中间体(2R,3R)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺在浓盐酸中的摩尔浓度为0.1mmol/mL。
3-(三甲基硅基)吡咯烷-2-羧酸的中间体的应用,所述的(2S,3S)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺、(2R,3R)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺应用于不对称催化反应中,所述的不对称催化反应包括Aldol反应、Mannich反应、Michael反应或羰基α-位胺基化反应。
3-(三甲基硅基)吡咯烷-2-羧酸的应用,所述的3-(三甲基硅基)吡咯烷-2-羧酸应用于不对称催化反应中,所述的不对称催化反应包括Aldol反应、Mannich反应、Michael反应或羰基α-位胺基化反应。
本发明是以L-脯氨酸为原料,先通过苄氧羰基(Cbz)保护N-H键,再与辅助剂8-氨基喹啉反应得到(S)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯,后与六甲基二硅烷反应得到(2R,3R)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯,在Pd/C催化剂作用下脱保护基团得到酰胺中间体,最后在盐酸作用下脱除辅助剂得到(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸,可用下式表示:
与现有技术相比,本发明具有以下特点:
1)通过硅烷化试剂进行C-H键官能团化来合成新化合物(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸和(2S,3S)-3-(三甲基硅基)吡咯烷-2-羧酸;
2)反应条件温和,化学产率较高,为含硅结构类似物的合成提供了新的途径。
3)(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸和(2S,3S)-3-(三甲基硅基)吡咯烷-2-羧酸可以用做不对称反应的手性催化剂,具有很好的应用前景。
具体实施方式
下面结合具体实施例对本发明进行详细说明。
实施例1:
将20.0mmol L-脯氨酸溶于12.0mL、2mol/L的NaOH溶液中,0℃滴加22mmol氯甲酸苄酯,后加入NaOH溶液反应,待反应完成后,经萃取、洗涤、干燥、浓缩、硅胶柱分离后,得(S)-1-(苄氧羰基)吡咯烷-2-羧酸,产率为95%。
后将(S)-1-(苄氧羰基)吡咯烷-2-羧酸10mmol溶于干燥的二氯甲烷中,加入10mmol 8-氨基喹啉、3mmol 4-二甲氨基吡啶,冷却至0℃后缓慢加入15mmol 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,室温反应过夜后,洗涤、干燥、浓缩,经硅胶柱分离后得到(S)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯,产率为90%。
后将(S)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯4mmol溶于8mL干燥的N-甲基吡咯烷酮中,加入0.4mmol Pd(OAc)2、16mmol对苯醌、40mmol六甲基二硅烷、4.8mmol NaF,Ar保护下110℃下反应24h后洗涤、干燥、浓缩,经硅胶柱分离得到(2R,3R)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯,产率为86%。
后将(2R,3R)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯3.3mmol溶于30mL甲醇中,加入150mg Pd/C,室温下H2氛围中反应过夜。过滤、浓缩,经硅胶柱分离得中间体(2R,3R)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺,产率为79%。
后将中间体(2R,3R)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺0.2mmol溶于2mL浓盐酸中,Ar保护,100℃反应48h,浓缩,向体系加入水,用微量1mol/LNaOH溶液调至中性,乙酸乙酯洗涤3次,浓缩,重结晶得(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸,产率为83%。
中间体(2R,3R)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺的化学结构式为:
表征数据为:
1H NMR(400MHz,CDCl3)δ11.55(s,1H),8.87(dd,J=4.2and 1.6Hz,1H),8.82(dd,J=7.3and 1.6Hz,1H),8.13(dd,J=8.2and 1.2Hz,1H),7.57–7.45(m,2H),7.42(t,J=8.3and 4.2Hz,1H),4.10(d,J=9.3Hz,1H),3.41(ddd,J=8.9,7.4and 1.5Hz,1H),3.02(m,1H),2.21(s,1H),1.94(m,1H),1.66(m,1H),1.46(m,1H),0.10(s,9H).
13C NMR(100MHz,CDCl3)δ173.70,148.53,139.12,136.09,134.52,128.07,127.28,121.39,121.34,116.24,63.88,47.66,33.45,27.79,-1.51.
(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸的化学结构式为:
表征数据分别为:
1H NMR(400MHz,D2O)δ3.56(d,J=11.0Hz,1H),3.18(ddd,J=11.0,8.0and2.8Hz,1H),3.06(m,1H),2.05(m,1H),1.63(m,1H),1.29(m,1H),-0.08(s,9H).
13C NMR(100MHz,D2O)δ175.08,64.76,46.12,30.60,27.98,-3.83.
实施例2:
将20.0mmol D-脯氨酸溶于12.0mL、2mol/L的NaOH溶液中,0℃滴加22mmol氯甲酸苄酯,后加入NaOH溶液反应,萃取、洗涤、干燥、浓缩,经硅胶柱分离后得(R)-1-(苄氧羰基)吡咯烷-2-羧酸,产率为95%。
后将(R)-1-(苄氧羰基)吡咯烷-2-羧酸10mmol溶于干燥的二氯甲烷中,加入10mmol 8-氨基喹啉、3mmol 4-二甲氨基吡啶,冷却至0℃后缓慢加入15mmol 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,室温反应过夜后,洗涤、干燥、浓缩,经硅胶柱分离后得到(R)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯,产率为90%。
后将(R)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯4mmol溶于干燥的N-甲基吡咯烷酮中,加入0.4mmol Pd(OAc)2、16mmol对苯醌、40mmol六甲基二硅烷、4.8mmol NaF,Ar保护下110℃下反应24h后洗涤、干燥、浓缩,经硅胶柱分离得到(2S,3S)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯,产率为86%。
后将(2S,3S)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯3.3mmol溶于30mL甲醇中,加入150mg Pd/C,室温下H2氛围中反应过夜。过滤、浓缩,经硅胶柱分离得化合物(2S,3S)-N(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺,产率为79%。
后将(2S,3S)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺0.2mmol溶于2mL浓盐酸中,Ar保护,100℃下反应48h,浓缩,向体系加入水,用微量1mol/L NaOH溶液调至中性,乙酸乙酯洗涤3次,浓缩,重结晶得(2S,3S)-3-(三甲基硅基)吡咯烷-2-羧酸,产率为83%。
实施例3:
将实施例1所得(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸应用于Aldol反应,反应式如下所示:
称取0.2mmol对硝基苯甲醛溶于1.6mL甲苯和0.4mL丙酮中,加入0.02mmol(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸,室温反应36h后,经柱层析分离得化合物。产率为57%,经HPLC检测ee值为81%。
实施例4:
称取0.2mmol对硝基苯甲醛溶于1.6mL甲苯和0.4mL丙酮中,加入0.02mmol实施例1所得中间体(2R,3R)-N(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺,室温进行实施例3所示反应,反应36h后,经柱层析分离得化合物。产率为43%,经HPLC检测ee值为70%。
上述的对实施例的描述是为便于该技术领域的普通技术人员能理解和使用发明。熟悉本领域技术的人员显然可以容易地对这些实施例做出各种修改,并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此,本发明不限于上述实施例,本领域技术人员根据本发明的揭示,不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (10)
1.3-(三甲基硅基)吡咯烷-2-羧酸,其特征在于,包括(2S,3S)-3-(三甲基硅基)吡咯烷-2-羧酸及其对映异构体(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸,其中,所述的(2S,3S)-3-(三甲基硅基)吡咯烷-2-羧酸的化学结构式为式(I):
所述的(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸的化学结构式为式(II):
2.如权利要求1所述的3-(三甲基硅基)吡咯烷-2-羧酸的中间体,其特征在于,包括(2S,3S)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺及其对映异构体(2R,3R)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺,其中,所述的(2S,3S)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺的化学结构式为式(III):
所述的(2R,3R)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺的化学结构式为式(IV):
3.如权利要求1所述的3-(三甲基硅基)吡咯烷-2-羧酸的制备方法,其特征在于,该方法是以手性脯氨酸为原料,通过引入保护基团和辅助剂后,与硅烷化试剂进行C-H键活化反应,再脱除保护基团得到中间体,该中间体在酸作用下脱除辅助基团,即可制得(2S,3S)-3-(三甲基硅基)吡咯烷-2-羧酸或(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸。
4.根据权利要求3所述的3-(三甲基硅基)吡咯烷-2-羧酸的制备方法,其特征在于,所述的保护基团为苄氧羰基,所述的辅助剂为8-氨基喹啉,所述的硅烷化试剂为六甲基二硅烷,所述的酸为盐酸。
5.根据权利要求4所述的3-(三甲基硅基)吡咯烷-2-羧酸的制备方法,其特征在于,制备(2S,3S)-3-(三甲基硅基)吡咯烷-2-羧酸时,所述的方法具体包括以下步骤:
(1)将D-脯氨酸溶于NaOH溶液中,于0℃滴加氯甲酸苄酯进行反应,后经萃取、洗涤、干燥、浓缩、硅胶柱分离,制得(R)-1-(苄氧羰基)吡咯烷-2-羧酸;
(2)将(R)-1-(苄氧羰基)吡咯烷-2-羧酸溶于干燥的二氯甲烷中,依次加入8-氨基喹啉、4-二甲氨基吡啶,冷却至0℃,再缓慢加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,于室温下,反应过夜,经洗涤、干燥、浓缩,制得(R)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯;
(3)将(R)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯溶于干燥的N-甲基吡咯烷酮中,依次加入Pd(OAc)2、对苯醌、六甲基二硅烷及NaF,于Ar氛围中,110℃下反应24h,后经洗涤、干燥、浓缩、硅胶柱分离,制得(2S,3S)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯;
(4)将(2S,3S)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯溶于甲醇中,加入Pd/C,于H2氛围中,室温反应过夜,后经过滤、浓缩、硅胶柱分离,制得中间体(2S,3S)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺;
(5)将中间体(2S,3S)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺溶于浓盐酸中,于Ar氛围中,100℃下反应48h,浓缩,再加入水,用碱调节至中性,经洗涤、浓缩、重结晶,制得(2S,3S)-3-(三甲基硅基)吡咯烷-2-羧酸。
6.根据权利要求5所述的3-(三甲基硅基)吡咯烷-2-羧酸的制备方法,其特征在于,步骤(1)中所述的D-脯氨酸与氯甲酸苄酯的摩尔比为10:11;
步骤(2)中所述的(R)-1-(苄氧羰基)吡咯烷-2-羧酸与8-氨基喹啉、4-二甲氨基吡啶、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐的摩尔比为10:10:3:15;
步骤(3)中所述的(R)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯与Pd(OAc)2、对苯醌、六甲基二硅烷及NaF的摩尔比为1:0.1:4:10:1.2;
步骤(4)中所述的(2S,3S)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯在甲醇中的摩尔浓度为0.11mmol/mL,所述的Pd/C在甲醇中的质量浓度为5mg/mL;
步骤(5)中所述的中间体(2S,3S)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺在浓盐酸中的摩尔浓度为0.1mmol/mL。
7.根据权利要求4所述的3-(三甲基硅基)吡咯烷-2-羧酸的制备方法,其特征在于,制备(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸时,所述的方法具体包括以下步骤:
(A)将L-脯氨酸溶于NaOH溶液中,于0℃滴加氯甲酸苄酯进行反应,后经萃取、洗涤、干燥、浓缩、硅胶柱分离,制得(S)-1-(苄氧羰基)吡咯烷-2-羧酸;
(B)将(S)-1-(苄氧羰基)吡咯烷-2-羧酸溶于干燥的二氯甲烷中,依次加入8-氨基喹啉、4-二甲氨基吡啶,冷却至0℃,再缓慢加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,于室温下,反应过夜,经洗涤、干燥、浓缩,制得(S)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯;
(C)将(S)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯溶于干燥的N-甲基吡咯烷酮中,依次加入Pd(OAc)2、对苯醌、六甲基二硅烷及NaF,于Ar氛围中,110℃下反应24h,后经洗涤、干燥、浓缩、硅胶柱分离,制得(2R,3R)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯;
(D)将(2R,3R)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯溶于甲醇中,加入Pd/C,于H2氛围中,室温反应过夜,后经过滤、浓缩、硅胶柱分离,制得中间体(2R,3R)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺;
(E)将中间体(2R,3R)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺溶于浓盐酸中,于Ar氛围中,100℃下反应48h,浓缩,再加入水,用碱调节至中性,经洗涤、浓缩、重结晶,制得(2R,3R)-3-(三甲基硅基)吡咯烷-2-羧酸。
8.根据权利要求7所述的3-(三甲基硅基)吡咯烷-2-羧酸的制备方法,其特征在于,步骤(A)中所述的L-脯氨酸与氯甲酸苄酯的摩尔比为10:11;
步骤(B)中所述的(S)-1-(苄氧羰基)吡咯烷-2-羧酸与8-氨基喹啉、4-二甲氨基吡啶、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐的摩尔比为10:10:3:15;
步骤(C)中所述的(S)-2-(喹啉-8-氨基甲酰)吡咯烷-1-甲酸苄酯与Pd(OAc)2、对苯醌、六甲基二硅烷及NaF的摩尔比为1:0.1:4:10:1.2;
步骤(D)中所述的(2R,3R)-2-(喹啉-8-氨基甲酰)-3-(三甲基硅基)吡咯烷-1-甲酸苄酯在甲醇中的摩尔浓度为0.11mmol/mL,所述的Pd/C在甲醇中的质量浓度为5mg/mL;
步骤(E)中所述的中间体(2R,3R)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺在浓盐酸中的摩尔浓度为0.1mmol/mL。
9.如权利要求2所述的3-(三甲基硅基)吡咯烷-2-羧酸的中间体的应用,其特征在于,所述的(2S,3S)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺、(2R,3R)-N-(喹啉-8)-(三甲基硅基)吡咯烷-2-甲酰胺应用于不对称催化反应中,所述的不对称催化反应包括Aldol反应、Mannich反应、Michael反应或羰基α-位胺基化反应。
10.如权利要求1所述的3-(三甲基硅基)吡咯烷-2-羧酸的应用,其特征在于,所述的3-(三甲基硅基)吡咯烷-2-羧酸应用于不对称催化反应中,所述的不对称催化反应包括Aldol反应、Mannich反应、Michael反应或羰基α-位胺基化反应。
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