CN108707057B - 脂肪三氟乙酯类化合物及其制备方法 - Google Patents
脂肪三氟乙酯类化合物及其制备方法 Download PDFInfo
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- CN108707057B CN108707057B CN201810249894.6A CN201810249894A CN108707057B CN 108707057 B CN108707057 B CN 108707057B CN 201810249894 A CN201810249894 A CN 201810249894A CN 108707057 B CN108707057 B CN 108707057B
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- -1 Aliphatic trifluoroethyl ester compound Chemical class 0.000 title claims abstract description 38
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- 238000000034 method Methods 0.000 claims abstract description 19
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- 229930195729 fatty acid Natural products 0.000 claims abstract description 18
- 239000000194 fatty acid Substances 0.000 claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- 150000004665 fatty acids Chemical class 0.000 claims abstract description 12
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000012414 tert-butyl nitrite Substances 0.000 claims abstract description 10
- KIPSRYDSZQRPEA-UHFFFAOYSA-N 2,2,2-trifluoroethanamine Chemical compound NCC(F)(F)F KIPSRYDSZQRPEA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000003756 stirring Methods 0.000 claims abstract description 6
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 6
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 claims description 6
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- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 3
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- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 3
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- NWCHELUCVWSRRS-UHFFFAOYSA-N atrolactic acid Chemical compound OC(=O)C(O)(C)C1=CC=CC=C1 NWCHELUCVWSRRS-UHFFFAOYSA-N 0.000 claims description 2
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- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 98
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- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 12
- 238000004984 proton decoupled 19F NMR spectroscopy Methods 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
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- 125000000217 alkyl group Chemical group 0.000 description 3
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 3
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- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
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- 108090000765 processed proteins & peptides Proteins 0.000 description 3
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- JXOHGGNKMLTUBP-HSUXUTPPSA-N shikimic acid Chemical compound O[C@@H]1CC(C(O)=O)=C[C@@H](O)[C@H]1O JXOHGGNKMLTUBP-HSUXUTPPSA-N 0.000 description 3
- JXOHGGNKMLTUBP-JKUQZMGJSA-N shikimic acid Natural products O[C@@H]1CC(C(O)=O)=C[C@H](O)[C@@H]1O JXOHGGNKMLTUBP-JKUQZMGJSA-N 0.000 description 3
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- OVRWUZYZECPJOB-UHFFFAOYSA-N 2,2-difluoroethanamine Chemical compound NCC(F)F OVRWUZYZECPJOB-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- 229910020323 ClF3 Inorganic materials 0.000 description 2
- 108010016626 Dipeptides Proteins 0.000 description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 2
- HBBGRARXTFLTSG-UHFFFAOYSA-N Lithium ion Chemical compound [Li+] HBBGRARXTFLTSG-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
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- 125000003118 aryl group Chemical group 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 description 2
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- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 2
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- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- YWUIUNGMQOICND-UHFFFAOYSA-N (2z)-2-diazo-1,1,1-trifluoroethane Chemical compound FC(F)(F)C=[N+]=[N-] YWUIUNGMQOICND-UHFFFAOYSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
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- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- VOXXWSYKYCBWHO-UHFFFAOYSA-N 3-phenyllactic acid Chemical compound OC(=O)C(O)CC1=CC=CC=C1 VOXXWSYKYCBWHO-UHFFFAOYSA-N 0.000 description 1
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- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
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- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
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- 239000007810 chemical reaction solvent Substances 0.000 description 1
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- IXORZMNAPKEEDV-OBDJNFEBSA-N gibberellin A3 Chemical class C([C@@]1(O)C(=C)C[C@@]2(C1)[C@H]1C(O)=O)C[C@H]2[C@]2(C=C[C@@H]3O)[C@H]1[C@]3(C)C(=O)O2 IXORZMNAPKEEDV-OBDJNFEBSA-N 0.000 description 1
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- AQYSYJUIMQTRMV-UHFFFAOYSA-N hypofluorous acid Chemical class FO AQYSYJUIMQTRMV-UHFFFAOYSA-N 0.000 description 1
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- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B41/00—Formation or introduction of functional groups containing oxygen
- C07B41/12—Formation or introduction of functional groups containing oxygen of carboxylic acid ester groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
- C07D209/28—1-(4-Chlorobenzoyl)-2-methyl-indolyl-3-acetic acid, substituted in position 5 by an oxygen or nitrogen atom; Esters thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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Abstract
本发明涉及脂肪三氟乙酯类化合物及其制备方法。其中，脂肪酸三氟乙酯类化合物定义与权利要求书相同。制备方法包括步骤如下：低温条件下，将2,2,2‑三氟乙胺和亚硝酸特丁酯加入溶有脂肪酸的有机溶液之中，搅拌均匀后，室温继续反应，即可得到脂肪酸三氟乙酯产物。其中，脂肪酸与2,2,2‑三氟乙胺及亚硝酸特丁酯的摩尔比为1:(1～2.5):(1～2.5)。本发明的方法不需加入催化剂及其他添加物即可得目标产物，操作简单、反应条件温和、成本低、收率高、对环境友好，可以得到脂肪类和药物分子羧酸的三氟乙酯化合物，应用广泛。
Description
技术领域
本发明属于有机合成技术领域，具体涉及脂肪三氟乙酯类化合物及其制备方法。本发明还涉及所述脂肪三氟乙酯类化合物在制药、食品、材料等行业的用途。
背景技术
随着有机氟化学的发展，脂肪酸三氟乙基酯类(RCO2CH2CF3)的化合物备受关注。由于其特点如可生物降解性、毒性弱甚至无毒、部分无刺激性及抗菌抗氧化等性质，常常被应用于制药、食品、美容、加工等行业。目前已知的用于医药和材料领域的脂肪酸三氟乙基酯，主要以不饱和脂肪酸三氟乙酯为主，主要用来合成离子交换膜、药物传递媒介、修饰物质表面以及锂离子电池的电解液材料。
2001年，Hochberg课题组报道了雌二醇-16-羧酸的氟烷基酯化反应，该反应在对甲基苯磺酸催化，氟醇化合物作为反应溶剂，加热至85℃，以中等产率制得氟烷基羧酸酯。反应条件苛刻且难操作，产率不高。[D.C.Labaree,T.Y.Reynolds,R.B.Hochberg,Journalof Medicinal Chemistry 2001,44,1802-1814]
2005年，Brückner课题组报道了2-丁炔酸与三氟乙醇的酯化反应，他们使用Dean-Stark分水装置，并以硫酸促进酯化反应进行，以81％的产率得到2-丁炔羧三氟乙酯。反应体系较复杂，操作不方便。[Schmidt-Leithoff,J.；Brückner,R.Helv.Chim.Acta2005,88, 1943-1959]
2016年，张成潘，韩秋燕等人的专利中报道：将脂肪酸与碳酸铯或氢氧化钾等强碱混合均匀后，加入三氟甲磺酸三氟乙基苯基的三价碘盐，于室温下搅拌反应48-72h，也可获得相应的脂肪酸三氟乙酯类化合物。但是此法化学环境苛刻，使用经济效益不高的且价格相对较昂贵三价碘盐，其收率并不高。[C.P.Zhang,Q.Y.Han,Jing.Yang,CN 106349071.Jan25, 2017]
2017年，Mykhailiuk课题组报道了羧酸与二氟重氮乙烷两步一锅法制备羧酸二氟乙酯化合物。该研究主要应用于各种普通羧酸或者官能团化的羧酸以及多肽羧酸与2，2-二氟甲基重氮甲烷官能团化形成羧酸二氟乙酯化合物，主要用于生物分子中的选择性19F标记；该反应使用了4倍当量的2，2-二氟乙胺和亚硝酸叔丁酯，该反应为分步反应，总体效率不高，使得生产成本高，造成了资源浪费。[P.K.Mykhailiuk,Chem.–Eur.J.,2014,20,4942–4947.]
2017年，本申请人的课题组内研发了一种一锅法制备羧酸二氟乙酯化合物的方法。该方法是将羧酸与亚硝酸叔丁酯以及2,2-二氟乙胺，在乙腈中35℃搅拌即可得到偕二氟乙酯。该方法使用到的氟代酯化的试剂价格便宜，用量少；反应条件温和、高效，操作简便；该方法操作简单、反应条件温和、成本低、副产物少、收率高，可以得到芳香族，脂肪二氟乙酯化合物，不受底物局限[S.Q.Peng,X.W.Zhang,L.Zhang,X.G.Hu,Organic Letters2017,19, 5689-5692.]
发明内容
针对脂肪三氟乙酯的反应条件苛刻操作不便利、反应效率低下、原子利用率差等原因，本发明目的在于一步一锅法无催化剂地制备脂肪三氟乙酯。与其他方法相比，本发明操作简单、反应条件温和、成本低、副产物少、收率高，可以得到烷基类、药物分子羧酸酯类化合物，且应用广泛，不受底物局限。
为达到上述目的，本发明采用的技术方案如下：
一步一锅法无催化剂的制备脂肪三氟乙酯的方法，包括步骤如下：将脂肪酸溶于有机溶剂中，低温条件下加入亚硝酸叔丁酯以及2,2,2-三氟乙胺，搅拌均匀后，升至室温继续反应1～10h，将反应体系中的溶液减压旋干，残留物经柱层析纯化，即得脂肪三氟乙酯类化合物。
所述的低温是指低于室温，优选为0℃。
有机溶剂是指二氯甲烷、氯仿、2,2,2-三氟乙醇、1,1,1,3,3,3-六氟-2-丙醇、DMF、THF、 DCE、NMP、三乙胺中的任意一种。较优选为：二氯甲烷、氯仿、2,2,2-三氟乙醇、1,1,1,3,3,3- 六氟-2-丙醇中的一种；最优选为1,1,1,3,3,3-六氟-2-丙醇。
脂肪酸与2,2,2-三氟乙胺的摩尔比为1:(1～2.5)，优选为1:2.5；脂肪酸与亚硝酸特丁酯的摩尔比为1:(1～2.5)，优选为1:2.5。
脂肪酸为长链烷基酸、α-取代苯丙酸、多肽酸或药物分子羧酸。其中，长链烷基酸可以为壬酸、庚酸或3,5,5-三甲基己酸；α-取代苯丙酸可以为α-羟基苯丙酸或α-NHFmoc苯丙酸；多肽酸可以为二肽羧酸；药物分子羧酸可以为氯贝特、非诺贝特、胆酸、赤霉素、莽草酸、吲哚美辛、4-甲基伞型酮-β-D-葡糖苷酸或2,3-邻异亚丙基-1-邻甲基-D-核糖酸。所述的二肽羧酸可以为Boc-D-Ala-L-Phg-OH、Cbz-L-Ala-D-Ile-OH或Fmoc-D-Ala-L-Pro-OH。
本发明中脂肪三氟乙酯化合物是采用一步一锅法制备。2,2,2-三氟乙胺与亚硝酸叔丁酯在1,1,1,3,3,3-六氟-2-丙醇溶剂促进下，生成三氟甲基重氮甲烷，然后与羧酸作用酯化得到脂肪三氟乙酯化合物。本发明的方法高效，不受底物局限，应用范围广泛。
本方法合成脂肪三氟乙酯化合物的收率达到79～97％，最优选的脂肪三氟乙酯化合物如下列式1～16所示：
所述脂肪三氟乙酯类化合物能够应用在制药、食品、材料等行业，例如链状脂肪酸三氟乙酯化合物(壬酸三氟乙酯化合物，庚酸三氟乙酯化合物等)可用作锂离子电池的电解液材料；赤霉素的三氟乙酯化产物可作为赤霉素的前药，提高稳定性，用于农业生产，刺激芽和叶的生长，提高产率；对莽草酸的三氟乙酯化产物可影响花生四烯酸的代谢，同时可作为抗病毒和抗癌药物的中间体；药物氯贝特和非诺贝特的三氟乙酯化可应用于降脂；4-甲基伞型酮-β-D-葡糖苷酸或2,3-邻异亚丙基-1-邻甲基-D-核糖酸药物酸的三氟乙酯化的产物，可作可作为抗病毒和抗癌药物前药物质。
相对现有技术，本发明的技术方案带来以下技术优势：
(1)本发明制备三氟乙酯类化合物的过程操作简单、条件温和；
(2)本发明制备三氟乙酯类化合物采用的羧酸原料来源广，可以在市场上大量购买到或者采用现有的成熟工艺简单合成；
(3)本发明制备三氟乙酯类化合物过程中无需添加催化剂降低了生产成本，有利于环保；
(4)本发明的三氟乙酯类化合物制备使用的原料为小分子化合物，后处理操作简便，具有副反应少，收率高的特点，收率达到79～97％；
(5)本发明的方法可以制备芳香和脂肪三氟乙酯类化合物，不受底物局限，以便建立三氟乙酯类化合物库，为药物筛选和新药合成提供原料来源。
具体实施方式
下列实施例旨在进一步说明本发明内容，而不是限制本发明权利要求的保护范围。
本发明实施例里用到的羧酸化合物购买于安耐吉化学。
以下实施1～16按照以下合成路线制备，可以制备化合物1～16：
具体操作为：将脂肪酸(0.5mmol，1equiv)底物溶于1,1,1,3,3,3-六氟-2-丙醇中，温度为0℃条件下加入亚硝酸叔丁酯(150μL，1.25mmol，2.5equiv)以及2,2,2-三氟乙胺(100 μL，1.25mmol，2.5equiv)，搅拌5min后升至室温继续反应0.5～10h，将反应体系中的溶液减压旋干，残留物经柱层析纯化，即得脂肪三氟乙酯类化合物。
实施实例1
底物：壬酸
产物：
化合物1:colorless oil(107mg,93％yield)；IR(KBr)νmax/cm-1:2959,2930,2859,1762, 1457,1412,1283,1170,1111,1067,979,842,807；1H NMR(400MHz,CDCl3)δ4.39(q,J＝8.5 Hz,2H,CH 2CF3),2.34(t,J＝7.5Hz,2H,COCH 2),1.72–1.48(m,2H,COCH2CH 2),1.22(dd,J＝12.8,6.6Hz,10H,CH 2),0.81(t,J＝6.8Hz,3H,CH2CH 3)；13C NMR(100MHz,CDCl3)δ 171.2(CO),122.0(q,J＝277.1Hz,CF3),59.1(q,J＝36.5Hz,CCF3),32.6(COCH2), 30.8(COCH2 CH2),28.13,28.08,28.0,23.7,21.6,13.0(CH2 CH3)；19F NMR(376MHz,CDCl3)δ -73.97(t,J＝8.3Hz,CF 3)；19F{1H}NMR(376MHz,CDCl3)δ-73.97(s,CF 3)；HRMS(ESI):m/zcalcd for C11H29F3O2Na+[M+Na]+263.1229,found 263.1242.
实施实例2
底物:庚酸
产物：
化合物2:colorless oil(89mg,84％yield)；IR(KBr)νmax/cm-1:2961,2931,2858,1756,1419, 1285,1172,1107,909,807,735；1H NMR(400MHz,CDCl3)δ4.47(q,J＝8.5Hz,2H,CH 2CF3), 2.42(t,J＝7.5Hz,2H,COCH 2),1.66(p,J＝7.5Hz,2H,CH 2CH3),1.48–1.22(m,6H),0.88(t,J ＝6.9Hz,3H,CH 3)；13C NMR(100MHz,CDCl3)δ172.2(CO),123.0(q,J＝277.1Hz,CH2CF3), 60.1(q,J＝36.4Hz,CF3),33.7(COCH2),31.4(CH2),28.7(CH2),24.7(CH2),22.5(CH2),14.0 (CH3)；19F NMR(376MHz,CDCl3)δ-73.85(t,J＝8.5Hz,CF 3)；19F{1H}NMR(376MHz,CDCl3) δ-73.85(s,CF 3)；HRMS(ESI):m/z calcd for C9H15F3O2Na+[M+Na]+235.0916,found235.0916.
实施实例3
底物：3,5,5-三甲基己酸
产物：
化合物3:colorless oil(96mg,80％yield)；IR(KBr)νmax/cm-1:2961,2873,1762,1472,1410, 1367,1285,1170,1086,1019,979,804；1H NMR(400MHz,CDCl3)δ4.39(qd,J＝8.5,3.8Hz, 2H,CH 2CF3),2.34(dd,J＝14.9,6.2Hz,1H,COCH),2.18(dd,J＝14.9,8.0Hz,1H,COCH),2.00 (dddd,J＝10.5,8.0,6.2,4.1Hz,1H,CCH),1.17(dd,J＝14.1,4.1Hz,1H,CHC),1.07(dd,J＝ 14.1,6.6Hz,1H,CHCH3),0.93(d,J＝6.6Hz,3H,CH 3),0.84(s,9H,3CH 3)；13CNMR(100MHz, CDCl3)δ170.4(CO),122.0(q,J＝277.1Hz,CF3),59.0(q,J＝36.5Hz,CCF3),49.3(CH), 42.2(CCH3),30.0(CH3),28.9(CH3),26.0(CH3),21.5(CH3)；19F NMR(376MHz,CDCl3)δ-73.81(t, J＝8.5Hz,CF 3)；19F{1H}NMR(376MHz,CDCl3)δ-73.81(t,J＝8.5Hz,CF 3)；HRMS(ESI)m/z calcd for C11H20F3O2 +[M+H]+241.1410,found 241.1407.
实施实例4
底物：α-羟基苯丙酸
产物：
化合物4:colorless oil(103mg,83％yield)；IR(KBr)νmax/cm-1:3347,3090,3032,2930, 1762,1456,1419,1285,1167,1099,1042,980,842,748,701,668；1H NMR(400MHz,CDCl3)δ 7.28–7.15(m,3H,Ar),7.15–7.08(m,2H,Ar),4.56–4.32(m,3H,CH 2CF3and CHOH),3.09 (dd,J＝14.0,4.6Hz,1H),2.93(dd,J＝14.0,6.7Hz,1H),2.60(s,1H)；13C NMR(100MHz, CDCl3)δ171.6,134.5,128.4,127.6,126.2,121.6(q,J＝277.2Hz,CF3),70.1,60.0(q,J＝37.1Hz, CCF3),39.2；19F NMR(376MHz,CDCl3)δ-73.60(t,J＝8.6Hz,CF 3)；19F{1H}NMR(376MHz, CDCl3)δ-73.60(s,CF 3)；HRMS(ESI)m/z calcd for C11H12F3O3 +[M+H]+249.0733,found 249.0729.
实施实例5
底物：α-NHFmoc苯丙酸
产物：
化合物5:pale yellow solid(202mg,86％yield)；IR(KBr)νmax/cm-1:3348,3086,3037,2957, 2917,1740,1700,1533,1447,1419,1283,1267,1164,1103,1085,1041,967,760,741,643；1H NMR(400MHz,CDCl3)δ7.76(d,J＝7.5Hz,2H,Ar),7.54(dd,J＝7.5,5.4Hz,2H,Ar),7.40(t, J＝7.5Hz,2H,Ar),7.29(q,J＝8.3,7.8Hz,5H,Ar),7.15–7.06(m,2H,Ar),5.24(d,J＝8.4Hz, 1H),4.76(dt,J＝8.4,6.1Hz,1H),4.62–4.29(m,3H,CH 2CF3and CHNH),4.19(t,J＝7.0Hz, 1H),3.30–2.94(m,2H)；13C NMR(100MHz,CDCl3)δ170.3(CONH),155.6(CO),143.8,143.7, 141.3,135.1,129.2,128.8,127.8,127.5,127.1,125.1,125.0,122.7(q,J＝277.2Hz,CF3),120.1, 120.0,67.1,61.0(q,J＝37.0Hz,CCF3),54.7,47.1,37.9；19FNMR(376MHz,CDCl3)δ-73.47(t, J＝8.4Hz,CF 3)；19F{1H}NMR(376MHz,CDCl3)δ-73.47(s,CF 3)；HRMS(ESI)m/z calcd for C26H23F3NO4 +[M+H]+470.1574,found 470.1571.
实施实例6
底物：Boc-D-Ala-L-Phg-OH
产物：
化合物6：pale yellow oil(71mg,88％yield)；IR(KBr)νmax/cm-1:3307,3067,2981,1768, 1668,1506,1500,1456,1410,1369,1285,1251,1165,1028,981,913,841,758,698；1H NMR (400MHz,CDCl3)δ7.35(d,J＝3.1Hz,6H),5.64–5.55(m,1H),5.15(d,J＝7.5Hz,1H),4.47 (qd,J＝8.2,2.3Hz,2H,CH 2CF3),4.36–4.16(m,1H),1.42(d,J＝14.4Hz,9H),1.34(t,J＝6.8 Hz,3H)；13C NMR(100MHz,CDCl3)δ172.5,169.3,155.8,134.8,129.1,129.0,127.3,122.5(q, J＝277.3Hz,CF 3),80.4,61.0(q,J＝37.0Hz,CCF3),56.5(d,J＝8.9Hz),49.7,28.2,17.4；19F NMR(376MHz,CDCl3)δ-73.73(t,J＝8.2Hz,CF 3)；19F{1H}NMR(376MHz,CDCl3)δ-73.73 (s,CF 3)；HRMS(ESI):m/z calcd for C18H22O5N2F3 -[M-H]-403.1481,found403.1486.
实施实例7
底物：Cbz-L-Ala-D-Ile-OH
产物：
化合物7：white solid(75mg,89％yield)；IR(KBr)νmax/cm-1:3308,3000,2881,1763, 1709,1667,1532,1455,1387,1283,1170,1141,1073,979,832,697；1H NMR(400MHz,CDCl3) δ7.38–7.28(m,5H),6.81(d,J＝8.4Hz,1H),5.52(d,J＝7.7Hz,1H),5.11(s,2H),4.72–4.57 (m,2H),4.36(dt,J＝15.3,8.0Hz,2H),1.97–1.86(m,1H),1.37(d,J＝7.0Hz,4H),1.18(dt,J＝ 14.4,7.8Hz,1H),0.93–0.87(m,6H)；13C NMR(100MHz,CDCl3)δ172.5,170.3,156.1,136.1, 128.6,128.2,128.0,122.7(q,J＝277.3Hz,CF3),67.1,60.6(q,J＝36.9Hz,CCF3),56.4,50.3, 37.5,25.0,18.2,15.4,11.5；19F NMR(376MHz,CDCl3)δ-73.65(t,J＝8.3Hz,CF 3)；19F {1H}NMR(376MHz,CDCl3)δ-73.65(s,CF 3)；HRMS(ESI):m/z calcdfor C19H26F3N2O5 + [M+H]+419.1788,found 419.1788.
实施实例8
底物：Fmoc-D-Ala-L-Pro-OH
产物：
化合物8:colorless oil(81mg,83％yield)；IR(KBr)νmax/cm-1:3307,3086,2982,2844,1773, 1689,1522,1447,1409,1377,1247,1158,1111,1055,1034,759,740,668；1HNMR(400MHz, CDCl3)δ7.76(d,J＝7.5Hz,2H),7.60(d,J＝7.6Hz,2H),7.40(t,J＝7.4Hz,2H),7.31(t,J＝7.4 Hz,2H),5.72(d,J＝7.8Hz,1H),4.70–4.47(m,3H),4.50–4.27(m,3H),4.21(t,J＝7.4Hz,1H), 3.97–3.72(m,1H),3.68–3.48(m,1H),2.27(qd,J＝11.8,10.3,5.3Hz,1H),2.19–1.94(m,3H), 1.34(dd,J＝23.5,6.8Hz,3H)；13C NMR(100MHz,CDCl3)δ171.3,170.3,155.5,144.0,143.8, 141.3,127.7,127.1,121.4(q,J＝277.0Hz,CF 3),67.0,60.7(q,J＝36.8Hz,CCF3),58.8,48.4, 47.2,46.9,29.0,24.7,18.7；19F NMR(376MHz,CDCl3)δ-73.80(t,J＝8.3Hz,CF 3)；19F {1H}NMR(376MHz,CDCl3)δ-73.80(s,CF 3)；HRMS(ESI):m/z calcd for C25H26F3N2O5 + [M+H]+491.1788,found 491.1790.
实施实例9
底物：氯贝特
产物：
化合物9：pale yellow oil(136mg,95％yield)；IR(KBr)νmax/cm-1:2998,2944,1758,1596, 1490,1408,1288,1237,1174,1128,1093,1040,1013,976,828,668；1H NMR(400MHz, CDCl3)δ7.27–7.15(m,2H,Ar),6.86–6.75(m,2H,Ar),4.56(q,J＝8.3Hz,2H,CH 2CF3),1.61 (s,6H,2CH 3)；13C NMR(100MHz,CDCl3)δ172.5(CO),153.6(Ar),129.2(Ar),127.9(Ar),122.7 (q,J＝277.4Hz,CF3),121.1(Ar),79.5(CCH3),60.8(q,J＝37.0Hz,CCF3),25.2(CH3)；19F NMR (376MHz,CDCl3)δ-73.74(t,J＝8.3Hz,CF 3)；19F{1H}NMR(376MHz,CDCl3)δ-73.74(s, CF 3)；HRMS(ESI)m/z calcd for C12H12ClF3O3Na+[M+Na]+319.0319,found 319.0317.
实施实例10
底物：赤霉素
产物：
化合物10:white solid(78mg,92％yield)；m.p.:114～115℃；IR(KBr)νmax/cm-1:3374,2925, 1735,1413,1287,1233,1170,1099,1061,985；1H NMR(400MHz,Methanol-d4)δ6.40(dd,J＝ 9.4,0.9Hz,1H),5.91(dd,J＝9.4,3.7Hz,1H),5.25(t,J＝2.3Hz,1H),4.98(d,J＝2.1Hz,1H), 4.74(q,J＝8.7Hz,2H,CH 2CF3),4.03(d,J＝3.7Hz,1H),3.30(d,J＝10.8Hz,1H),2.87(d,J＝ 10.8Hz,1H),2.26(dt,J＝5.4,2.4Hz,2H),2.12–1.97(m,3H),1.94–1.67(m,4H),1.20(s,3H)；13C NMR(100MHz,Methanol-d4)δ179.2(CO),170.5(CO),156.4,132.7,131.7,123.3(q,J＝ 276.7Hz,CF3),106.6,90.8,77.1,69.1,59.9(q,J＝36.3Hz,CCF3),53.5,52.8,50.9,50.5,50.3, 44.0,42.7,38.4,16.6,13.6；19F NMR(376MHz,Methanol-d4)δ-75.07(t,J＝8.7Hz,CF 3)；19F {1H}NMR(376MHz,Methanol-d4)δ-75.07(s,CF 3)；HRMS(ESI)m/z calcd for C21H23F3O6Na+ [M+Na]+451.1339,found451.1336.
实施实例11
底物：莽草酸
产物：
化合物11：colorless oil(77mg,97％yield)；IR(KBr)νmax/cm-1:3378,2916,1737,1654, 1414,1288,1233,1173,1098,1063,986,850,745,666；1H NMR(400MHz,Methanol-d4)δ6.91 (dt,J＝3.6,2.1Hz,1H),4.91(s,3H),4.70(qd,J＝8.8,1.7Hz,2H,CH 2CF3),4.43(tt,J＝3.6,1.8 Hz,1H),4.05(dt,J＝6.9,4.5Hz,1H),3.76(dd,J＝6.9,4.1Hz,1H),2.72(ddt,J＝18.2,4.5,2.1 Hz,1H),2.27(ddt,J＝18.2,4.9,1.7Hz,1H)；13C NMR(100MHz,Methanol-d4)δ164.7(CO), 139.9(d,J＝3.3Hz),127.5,123.4(q,J＝276.4Hz,CF3),70.8,67.0,65.8(d,J＝3.6Hz),59.9(q, J＝36.3Hz,CCF3),29.6；19F NMR(376MHz,Methanol-d4)δ-75.52(t,J＝8.7Hz,CF 3)；19F {1H}NMR(376MHz,Methanol-d4)δ-75.52(s,CF 3)；HRMS(ESI)m/zcalcd for C9H11F3O5Na+ [M+Na]+279.0451,found 279.0453.
实施实例12
底物：非诺贝特酸
产物：
化合物12：pale yellow oil(190mg,95％yield)；IR(KBr)νmax/cm-1:2997,2946,1919,1759, 1654,1506,1487,1468,1418,1400,1304,1250,1171,1126,1091,1016,973,854,764,662；1H NMR(400MHz,CDCl3)δ7.79–7.65(m,4H,Ar),7.49–7.40(m,2H,Ar),6.93–6.82(m,2H, Ar),4.59(q,J＝8.3Hz,2H,CH 2CF3),1.72(s,6H,2CH 3)；13C NMR(100MHz,CDCl3)δ 194.2(CO),172.3(CO),159.1(Ar),138.5(Ar),136.2(Ar),132.0(Ar),131.2(Ar),130.9(Ar),128.6, 125.4(q,J＝277.5Hz,CF3),117.6(Ar),79.2(CCH3),60.8(q,J＝37.0Hz,CCF3),25.4(CH3)；19F NMR(376MHz,CDCl3)δ-73.64(t,J＝8.3Hz,CF 3)；19F{1H}NMR(376MHz,CDCl3)δ-73.64 (s,CF 3)；HRMS(ESI):m/z calcd for C19H17O4ClF3 +[M+H]+401.0762,found401.0756.
实施实例13
底物：胆酸
产物：
化合物13：white solid(77mg,78％yield)；m.p.:159～160℃；IR(KBr)νmax/cm-1:3384,2937, 2869,1761,1448,1412,1378,1283,1169,1077,1045,980,857,758；1H NMR(400MHz, Methanol-d4)δ4.92(s,3H),4.60(q,J＝8.9Hz,2H,CH 2CF3),3.97(d,J＝2.9Hz,1H),3.82(q,J ＝2.9Hz,1H),3.39(tt,J＝11.1,4.3Hz,1H),2.51(ddd,J＝14.3,9.3,4.6Hz,1H),2.39(ddd,J＝ 16.2,8.9,7.3Hz,1H),2.28(td,J＝12.1,5.7Hz,2H),2.07–1.75(m,7H),1.74–1.22(m,12H), 1.14(tt,J＝11.9,5.5Hz,1H),1.04(d,J＝6.1Hz,3H),0.94(s,3H),0.73(s,3H)；13C NMR(100 MHz,Methanol-d4)δ172.4(CO),123.4(q,J＝276.5Hz,CF3),72.6(d,J＝5.4Hz),71.5,67.7(d,J ＝4.9Hz),59.6(q,J＝36.3Hz,CCF3),46.6,46.1,41.8,41.6,39.6,39.1,35.2,35.16,34.54,34.5, 30.6,30.0,29.8,28.2,27.3,26.5,22.9,21.9,16.2,11.7；19F NMR(376MHz,Methanol-d4)δ -71.39(t,J＝8.9Hz,CF 3)；19F{1H}NMR(376MHz,Methanol-d4)δ-71.39(s,CF 3)；HRMS(ESI) m/z calcd for C26H41F3O5Na+[M+Na)]+513.2798,found 513.2797.
实施实例14
底物：吲哚美辛
产物：
化合物14：yellow solid(230mg,93％yield)；1H NMR(400MHz,CDCl3)δ7.69–Rf＝0.37 (petroleum:EtOAc＝15:1)；yellow solid(230mg,93％yield)；m.p.:81～82℃；IR(KBr)νmax/cm-1: 3107,2990,2831,1753,1676,1604,1486,1401,1328,1272,1182,1171,1089,951,855,831；1H NMR(400MHz,CDCl3)δ7.69–7.60(m,2H,Ar),7.51–7.39(m,2H,Ar),6.93(d,J＝2.5Hz, 1H,Ar),6.89(d,J＝9.0Hz,1H,Ar),6.68(dd,J＝9.0,2.5Hz,1H,Ar),4.49(q,J＝8.2Hz,2H, CH 2CF3),3.82(s,3H,OCH 3),3.76(s,2H,CH 2CO),2.37(s,3H,ArCH 3)；13C NMR(100MHz, CDCl3)δ169.2(CO),168.3(CO),156.1,139.4,136.3,133.8,131.2,130.8,130.3,129.2,122.9(q,J ＝277.3Hz,CF3),115.0,112.0,111.3,100.9,60.7(q,J＝36.6Hz,CCF3),55.6,29.7,13.3；19F NMR(376MHz,CDCl3)δ-73.69(t,J＝8.2Hz,CF 3)；19F{1H}NMR(376MHz,CDCl3)δ-73.69 (s,CF 3).
实施实例15
底物：2,3-邻异亚丙基-1-邻甲基-D-核糖酸
产物：
化合物15：colorless oil(141mg,94％yield)；IR(KBr)νmax/cm-1:2984,2843,1742,1465, 1448,1374,1242,1170,1098,918,847,735,607；1H NMR(400MHz,CDCl3)δ5.14(d,J＝5.8 Hz,1H,C1 H),4.98(s,1H,CHO),4.63(s,1H,CHO),4.52–4.38(m,3H,CH 2CF3andC4 H),3.32 (s,3H,OCH 3),1.42(s,3H,OCH 3),1.26(s,3H,OCH 3)；13C NMR(100MHz,CDCl3)δ167.9 (CO),121.7(q,J＝277.2Hz,CF3),112.0(CCH3),108.6(C1),83.2(C2),82.2(C4),81.1(C3),59.9(q, J＝37.0Hz,CCF3),54.5(OCH3),25.3(OCH3),24.0(OCH3)；19F NMR(376MHz,CDCl3)δ -73.56(t,J＝8.4Hz,CF 3)；19F{1H}NMR(376MHz,CDCl3)δ-73.56(s,CF 3)；HRMS(ESI)m/z calcd for C11H16F3O6 +[M+H]+301.0894,found 301.0893.
实施实例16
底物：4-甲基伞型酮-β-D-葡糖苷酸
产物：
化合物16：white solid(200mg,92％yield)；m.p.＝103～104℃；IR(KBr)νmax/cm-1:3436, 2985,2941,1740,1614,1563,1510,1447,1427,1391,1374,1245,1166,1070,1048,979,850, 643；1H NMR(400MHz,DMSO-d6)δ7.71(d,J＝8.8Hz,1H,Ar),7.13(d,J＝2.4Hz,1H,Ar), 7.05(dd,J＝8.8,2.4Hz,1H,Ar),6.26(d,J＝1.4Hz,1H,CHCOO),5.62(d,J＝19.0Hz,2H), 5.35(d,J＝7.1Hz,1H),4.95–4.74(m,2H),4.38(d,J＝9.3Hz,1H),3.40(dp,J＝24.6,8.5Hz, 4H),2.40(d,J＝1.2Hz,3H,CH 3)；13C NMR(100MHz,DMSO-d6)δ168.0,160.5,160.0,154.8, 153.7,127.0,123.8(q,J＝277.4Hz,CF3),114.8,113.7,112.3,103.5,99.7,75.9,75.1,73.2,71.9, 60.8(q,J＝35.3Hz,CCF3),18.6(CH3)；19F NMR(376MHz,DMSO-d6)δ-72.13(t,J＝9.0Hz, CF 3)；19F{1H}NMR(376MHz,DMSO-d6)δ-72.13(s,CF 3)；HRMS(ESI):m/z calcd for C18H18O9F3 +[M+H]+435.0903,found 435.0912。
Claims (1)
1.一步法制备脂肪三氟乙酯类化合物的方法，其特征在于，具体包括以下步骤，将脂肪酸溶于1,1,1,3,3,3-六氟-2-丙醇中，0℃低温条件下加入亚硝酸叔丁酯以及2,2,2-三氟乙胺，搅拌5min后升至室温继续反应1~10h，将反应体系中的溶液减压旋干，残留物经柱层析纯化，即得脂肪三氟乙酯类化合物；其中，脂肪酸与2,2,2-三氟乙胺的摩尔比为1:2.5；脂肪酸与亚硝酸叔丁酯的摩尔比为1:2.5；所述脂肪酸为壬酸、3,5,5-三甲基己酸、α-羟基苯丙酸、Boc-D-Ala-L-Phg-OH、Cbz-L-Ala-D-Ile-OH、Fmoc-D-Ala-L-Pro-OH、胆酸、2,3-邻异亚丙基-1-邻甲基-D-核糖酸或4-甲基伞型酮-β-D-葡糖苷酸；
其中，通过上述方法制备得到的产物脂肪酸三氟乙酯类化合物具有如下列式所示结构中的任意一种：
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