CN109251163B - Resolution method of indoline-2-formic acid compound and intermediate thereof - Google Patents
Resolution method of indoline-2-formic acid compound and intermediate thereof Download PDFInfo
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- 238000000034 method Methods 0.000 title claims abstract description 39
- -1 indoline-2-formic acid compound Chemical class 0.000 title claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 239000000203 mixture Substances 0.000 claims abstract description 25
- QNRXNRGSOJZINA-UHFFFAOYSA-N indoline-2-carboxylic acid Chemical class C1=CC=C2NC(C(=O)O)CC2=C1 QNRXNRGSOJZINA-UHFFFAOYSA-N 0.000 claims abstract description 21
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 14
- 230000006340 racemization Effects 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 52
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 4
- 150000008065 acid anhydrides Chemical class 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 229910017604 nitric acid Inorganic materials 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 claims description 3
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 claims description 3
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 claims description 3
- USYGMXDJUAQNGU-JTQLQIEISA-N methyl (2s)-2-amino-3-(4-methoxyphenyl)propanoate Chemical compound COC(=O)[C@@H](N)CC1=CC=C(OC)C=C1 USYGMXDJUAQNGU-JTQLQIEISA-N 0.000 claims description 3
- VSDUZFOSJDMAFZ-VIFPVBQESA-N methyl L-phenylalaninate Chemical compound COC(=O)[C@@H](N)CC1=CC=CC=C1 VSDUZFOSJDMAFZ-VIFPVBQESA-N 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 235000019260 propionic acid Nutrition 0.000 claims description 3
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 3
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 2
- CJGXMNONHNZEQQ-JTQLQIEISA-N ethyl (2s)-2-amino-3-phenylpropanoate Chemical compound CCOC(=O)[C@@H](N)CC1=CC=CC=C1 CJGXMNONHNZEQQ-JTQLQIEISA-N 0.000 claims description 2
- MLSGRWDEDYJNER-UHFFFAOYSA-N ethyl 2-anilinoacetate Chemical compound CCOC(=O)CNC1=CC=CC=C1 MLSGRWDEDYJNER-UHFFFAOYSA-N 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- SZJUWKPNWWCOPG-UHFFFAOYSA-N methyl 2-anilinoacetate Chemical compound COC(=O)CNC1=CC=CC=C1 SZJUWKPNWWCOPG-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- CNFICIURFRWLFF-UHFFFAOYSA-N propan-2-yl 2-phenylbutanoate Chemical compound CC(C)OC(=O)C(CC)C1=CC=CC=C1 CNFICIURFRWLFF-UHFFFAOYSA-N 0.000 claims description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims 3
- 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 claims 1
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 150000008064 anhydrides Chemical class 0.000 claims 1
- WEBPOSHSGIUPNO-UHFFFAOYSA-N butyl 2-amino-2-(4-nitrophenyl)acetate Chemical compound C(CCC)OC(C(C1=CC=C(C=C1)[N+](=O)[O-])N)=O WEBPOSHSGIUPNO-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 6
- 239000000463 material Substances 0.000 abstract description 3
- 238000003756 stirring Methods 0.000 description 45
- 238000001914 filtration Methods 0.000 description 25
- 238000001816 cooling Methods 0.000 description 19
- 238000010992 reflux Methods 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 239000000843 powder Substances 0.000 description 14
- 238000000967 suction filtration Methods 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 239000012452 mother liquor Substances 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- 238000005406 washing Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 3
- OGMIMMRKTFZDKW-UHFFFAOYSA-N 1-acetyl-2,3-dihydroindole-2-carboxylic acid Chemical compound C1=CC=C2N(C(=O)C)C(C(O)=O)CC2=C1 OGMIMMRKTFZDKW-UHFFFAOYSA-N 0.000 description 3
- SFLORBIZNYJOFA-UHFFFAOYSA-N 1-propanoyl-2,3-dihydroindole-2-carboxylic acid Chemical compound C1=CC=C2N(C(=O)CC)C(C(O)=O)CC2=C1 SFLORBIZNYJOFA-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- IPVQLZZIHOAWMC-QXKUPLGCSA-N perindopril Chemical compound C1CCC[C@H]2C[C@@H](C(O)=O)N(C(=O)[C@H](C)N[C@@H](CCC)C(=O)OCC)[C@H]21 IPVQLZZIHOAWMC-QXKUPLGCSA-N 0.000 description 3
- 229960002582 perindopril Drugs 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- QNRXNRGSOJZINA-QMMMGPOBSA-N (2s)-2,3-dihydro-1h-indole-2-carboxylic acid Chemical compound C1=CC=C2N[C@H](C(=O)O)CC2=C1 QNRXNRGSOJZINA-QMMMGPOBSA-N 0.000 description 2
- KWTSXDURSIMDCE-MRVPVSSYSA-N (R)-amphetamine Chemical compound C[C@@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-MRVPVSSYSA-N 0.000 description 2
- 239000005541 ACE inhibitor Substances 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- HPAKCFAOSIGBHE-UHFFFAOYSA-N 1-benzoyl-2,3-dihydroindole-2-carboxylic acid Chemical compound OC(=O)C1CC2=CC=CC=C2N1C(=O)C1=CC=CC=C1 HPAKCFAOSIGBHE-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- WEBPOSHSGIUPNO-NSHDSACASA-N butyl (2S)-2-amino-2-(4-nitrophenyl)acetate Chemical compound C(CCC)OC([C@@H](N)C1=CC=C(C=C1)[N+](=O)[O-])=O WEBPOSHSGIUPNO-NSHDSACASA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 208000018459 dissociative disease Diseases 0.000 description 1
- VWKGPFHYXWGWEI-VIFPVBQESA-N ethyl (2s)-2-amino-2-phenylacetate Chemical compound CCOC(=O)[C@@H](N)C1=CC=CC=C1 VWKGPFHYXWGWEI-VIFPVBQESA-N 0.000 description 1
- CJGXMNONHNZEQQ-UHFFFAOYSA-N ethyl 2-amino-3-phenylpropanoate Chemical compound CCOC(=O)C(N)CC1=CC=CC=C1 CJGXMNONHNZEQQ-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- VSDUZFOSJDMAFZ-SECBINFHSA-N methyl (2r)-2-amino-3-phenylpropanoate Chemical compound COC(=O)[C@H](N)CC1=CC=CC=C1 VSDUZFOSJDMAFZ-SECBINFHSA-N 0.000 description 1
- BHFLUDRTVIDDOR-QMMMGPOBSA-N methyl (2s)-2-amino-2-phenylacetate Chemical compound COC(=O)[C@@H](N)C1=CC=CC=C1 BHFLUDRTVIDDOR-QMMMGPOBSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a resolution method of indoline-2-formic acid compounds and intermediates thereof. The resolution method of the indoline-2-formic acid compound comprises the following steps: in a solvent, carrying out a salt forming reaction on the compound V and a resolving agent compound II to obtain compounds III and III'; the compound V is a mixture of a compound shown in a formula I and a compound shown in a formula I'. The resolution method has the advantages of high yield, high resolution purity, stable compound in the resolution process, high subsequent racemization yield, repeated resolution and optimized material utilization, and the compound can be recycled for multiple times.
Description
Technical Field
The invention relates to a resolution method of indoline-2-formic acid compounds and intermediates thereof.
Background
Perindopril (Perindopril), which was marketed in france in 1989 as a mercapto-free ACE inhibitor, was mainly used for the treatment of essential hypertension and heart failure. The preparation has the advantages of other ACE inhibitors, longer action time, smaller side effect, better tolerance and good market prospect.
S-indoline-2-carboxylic acid (I) is an important intermediate for synthesizing perindopril, and the conventional synthesis process is as follows:
the resolving agent for resolving in the two routes is chiral organic alkali, commonly used is R-alpha-methyl phenethylamine, and the structural formula is as follows:
the R-alpha-methyl phenethylamine has poor resolution effect, the resolution salt obtained by one-time resolution cannot achieve better separation effect, and the resolution effect can be achieved only by recrystallizing the resolution salt for many times. Therefore, the method has poor resolution effect, low yield and higher production cost.
The chemical resolution of S (-) -indoline-2-formic acid, and the resolution of R, S-indoline-2-formic acid and R (+) -alpha-phenylethylamine to obtain S (-) -indoline-2-formic acid. Due to unstable chemical property of indoline-2-formic acid, the method has low resolution yield. The racemization of the recovered R (+) -indoline-2-formic acid generates a large amount of tar and has low yield.
Disclosure of Invention
The invention aims to overcome the defects of low yield of a resolution method of an indoline-2-formic acid compound and unstable compound in the resolution process in the prior art, and provides the resolution method of the indoline-2-formic acid compound and an intermediate thereof. The resolution method has the advantages of high yield, high resolution purity, stable compound in the resolution process, high subsequent racemization yield, repeated resolution and optimized material utilization, and the compound can be recycled for multiple times.
The invention provides a resolution method of indoline-2-formic acid compounds, which comprises the following steps: in a solvent, carrying out a salt forming reaction on the compound V and a resolving agent compound II to obtain compounds III and III';
the compound V is a mixture of a compound shown in a formula I and a compound shown in a formula I';
the compound II is a compound shown as a formula II-1 or a compound shown as a formula II-2;
wherein R is 1 is-H, -OH, -NO 2 Or C 1 ～C 3 Alkyl of (2)An oxy group;
R 2 is absent or C 1 ～C 3 Alkyl groups of (a);
R 3 is C 1 ～C 4 Alkyl groups of (a);
R 4 is C 1 ～C 3 Alkyl, phenyl or tert-butoxy of (a);
when the compound II is a compound II-1, the compounds III and III 'are respectively a compound III-1 and a compound III' -1 shown as follows:
when the compound II is a compound II-2, the compounds III and III 'are respectively a compound III-2 and a compound III' -2 shown as follows:
through the resolution method, the indoline-2-formic acid compound can be resolved to obtain the indoline-2-formic acid compound with a single configuration, wherein the indoline-2-formic acid compound with the single configuration refers to the indoline-2-formic acid compound which is completely in the single configuration or exists in the configuration with a certain configuration as a main advantage configuration.
In the invention, R is 1 preferably-H, -NO 2 Or a methoxy group.
R is as described 2 Preferably absent or C 1 ～C 2 Alkyl group of (1).
Said C 1 ～C 4 The alkyl group of (a) is preferably a methyl group, an ethyl group, an isopropyl group or a butyl group.
In the present invention, the compound V is preferably a compound I and a compound I' at a molar ratio of (2:3) to (3:2), and more preferably at a molar ratio of 1:1.
The compound II is preferably selected from one of phenyl glycine methyl ester, phenyl glycine ethyl ester, 4-nitrophenyl glycine butyl ester, phenylalanine methyl ester, phenylalanine ethyl ester, phenyl butyric acid isopropyl ester or enantiomer of 4-methoxy phenylalanine methyl ester.
In the invention, the solvent can be a conventional solvent for resolving the compounds in the field, for example, the solubility difference of the salified chiral compounds is large, which is beneficial to separation; in the present invention, water and/or alcohol solvents are preferable; the alcohol solvent is preferably one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and benzyl alcohol.
In the present invention, the molar ratio of the compound V to the compound II can be determined by referring to the conventional amounts in chiral resolution in the art, such as (10; more preferably (1:1) to (1.05).
The temperature of the reaction may be a temperature conventional in the art for such salt-forming reactions, for example, heating to reflux the solvent, preferably 50 ℃ to 100 ℃ in the present invention; also, the temperature should not exceed the reflux temperature, as is common knowledge in the art.
In the present invention, the mass ratio of the indoline-2-carboxylic acid compound to the solvent is preferably (1:3) to (1.
After the salt-forming reaction is finished, the method can further comprise the following post-treatment operations: cooling and filtering; both the cooling and the filtration can be performed according to methods conventional in the art.
The resolution method of the indoline-2-formic acid compound can also comprise the following steps: the compound III or III 'and acid are subjected to free reaction to obtain a compound I or I',
wherein, the substituent R 1 、R 2 、R 3 And R 4 The definitions of (A) and (B) are as described above.
Said R 1 preferably-H, -NO 2 Or a methoxy group.
Said R 2 Preferably absent or C 1 ～C 2 The alkyl group of (1).
Said C 1 ～C 4 The alkyl group of (a) is preferably a methyl group, an ethyl group, an isopropyl group or a butyl group.
The acid is conventional in the art for such free reaction, such as one or more of sulfuric acid, nitric acid, phosphoric acid and hydrochloric acid, preferably hydrochloric acid in the present invention.
The molar ratio of said compound III or III' to said hydride ion in the acid may be a molar ratio customary in the art for such free reactions, and in the present invention is preferably (1:1) - (1.2; more preferably (1.
The reaction temperature may be a temperature conventional in the art for such dissociation reactions, and in the present invention, is preferably 10 to 30 ℃.
The resolution method of the indoline-2-formic acid compound can also comprise the following steps: hydrolyzing the compound I or I 'with acid to obtain a compound IV or IV',
wherein, the substituent R 4 The definition of (A) is as described above.
The acid is an acid conventional in the art for such hydrolysis reactions, such as one or more of sulfuric acid, phosphoric acid and hydrochloric acid, with hydrochloric acid being particularly preferred in the present invention.
The amount of said acid may be that conventionally used in the art for such hydrolysis reactions, and the molar ratio of the hydrogen radical ion in said acid to said compound I or I' in the present invention is preferably (2.5; more preferably 3:1.
The acid concentration can be the concentration conventional in the hydrolysis reaction of the type in the field, and is preferably 10-15 percent in the invention; more preferably 10%.
The reaction temperature can be the temperature conventional in the hydrolysis reaction, and is preferably 100-110 ℃ in the invention; more preferably from 100 to 105 ℃.
The progress of the hydrolysis reaction can be monitored by methods of testing conventional in the art (e.g., TLC, HPLC or NMR), typically by the end point of the reaction being the disappearance or no longer being reacted with the starting material. In the present invention, the reaction is preferably carried out for 3 to 5 hours.
After the hydrolysis reaction is finished, the method also comprises the following post-treatment steps: after the reaction is finished, cooling and adjusting the pH value to 4.0; preferably cooling to 35 deg.C, adjusting pH to 4.0 with liquid alkali or ammonia water, and filtering.
The resolution method of the indoline-2-formic acid compound can also comprise the following steps: and carrying out racemization reaction on the compound IV or IV 'and acid anhydride to obtain a mixture of the compound IV and the compound IV'.
The mixture of said compound IV and said compound IV' can be further subjected to said resolution by further subjecting said compound V to an acylation reaction as is conventional in the art.
The acid anhydride may be an acid anhydride conventional in the art for such racemization reaction, and in the present invention, one or more of acetic anhydride, propionic anhydride, butyric anhydride and phthalic anhydride are preferable.
The racemization reaction can be added with an organic solvent which is conventional in the racemization reaction in the field, and in the invention, one or more of acetic acid, propionic acid, butyric acid and toluene are preferred.
The temperature of the reaction may be a temperature conventional in the art for such racemization, for example, 100 to 180 ℃ and, in the present invention, preferably 100 to 120 ℃.
The invention also provides any one of the following compounds:
wherein, the substituent R 1 、R 2 、R 3 And R 4 The definitions of (A) and (B) are as described above.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the invention provides a resolution method of the indoline-2-formic acid compound and an intermediate thereof. The resolution method has the advantages of high yield, high resolution purity, stable compound in the resolution process, high subsequent racemization yield, repeated resolution and optimized material utilization, and the compound can be recycled for multiple times.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
1) 100g of N-acetylindoline-2-carboxylic acid and 500g of water are put into a 1000ml three-necked bottle, and 92g of L-phenylglycine ethyl ester is added under stirring. After the addition, the temperature is raised to reflux, and the temperature is kept for 1 hour. Stirring and cooling to 10 deg.C, suction-filtering to obtain white solid A1:65g (yield 69.4% based on L-compound, purity 84% ee), optically rotating [ alpha ]] 25 D And = 90. The mother liquor was adjusted to pH =1 with 30% hydrochloric acid and filtered to give white dextrorotatory B1:67g.
2) And preparation of S-N-acetyl indoline-2-formic acid: 100g of A1 resolving salt and 400g of water are put into a 1000ml three-necked bottle, and 35g of 30% concentrated hydrochloric acid is dropwise added into the bottle while stirring at 10-30 ℃. After the dropping, 51g of white powder was obtained by suction filtration. (yield 95.8%)
3) 150g of concentrated hydrochloric acid and 250g of water were put into a 1000ml three-necked flask, and 100g of white powder was added thereto with stirring. After the addition, the temperature is slowly raised, the mixture is refluxed at 105 ℃ for 5 hours, and then is cooled to 35 ℃ after the reflux. Liquid caustic soda was added dropwise to adjust pH =4.0, and the mixture was washed with suction filtration and water to obtain 65g of a white solid (yield 82.3%, isomer <0.5%, optical rotation-115 ℃).
4) 100g of the B1 dextrorotatory substance, 700g of glacial acetic acid and 100g of acetic anhydride are put into a 1000ml three-neck bottle. Stirring and heating to 120 ℃, refluxing and preserving heat for 5 hours. Finish the heat preservationAnd concentrating under reduced pressure to dryness. Adding 800g water, dispersing at 80 deg.C, stirring, cooling to 10 deg.C, vacuum filtering to obtain 95g racemic mixture, optically rotating [ alpha ]] 25 D ＝0-0.5°。
Example 2
1) 100g of N-propionyl indoline-2-carboxylic acid and 500g of methanol were put into a 1000ml three-necked flask, and 82g of L-phenylalanine methyl ester was added thereto with stirring. After the addition, the temperature is raised to 50 to 60 ℃ and the temperature is kept for 1 hour. Stirring and cooling to 10 deg.C, suction-filtering to obtain white solid A2:63g (yield 69.4% based on L-compound, purity 99% ee) & alpha] 25 D = 88 °. The mother liquor was concentrated in methanol under reduced pressure, 500g of water was added to the residue, and the mixture was adjusted to pH =1 with 30% hydrochloric acid and filtered to obtain white dextrorotatory substance B2:62g.
2) And preparation of S-N-propionyl indoline-2-formic acid: 100g of A2 resolving salt and 400g of water are put into a 1000ml three-necked bottle, and 35g of 30% concentrated hydrochloric acid is dropwise added into the bottle while stirring at 10-30 ℃. After the dropping, 52g of white powder was obtained by suction filtration. (yield 94.4%)
3) 150g of concentrated hydrochloric acid and 250g of water were put into a 1000ml three-necked flask, and 100g of white powder was added thereto with stirring. After the addition, the temperature is slowly raised, the mixture is refluxed at 105 ℃ for 3 hours, and then is cooled to 35 ℃ after the reflux. Adding liquid caustic soda dropwise to adjust pH =4.0, filtering and washing with water to obtain 62g of white solid (yield 83.8%, isomer)<0.5%, optically active [ alpha ]] 25 D ＝-115°)。
4) 100g of the B2D-isomer, 700g of propionic acid and 100g of propionic anhydride were put into a 1000ml three-necked flask. Stirring and heating to 120 ℃, and keeping the temperature for 5 hours. After the temperature preservation is finished, concentrating under reduced pressure to be dry. Adding 800g water, dispersing at 80 deg.C, stirring, cooling to 10 deg.C, vacuum filtering to obtain 95g racemic mixture, optically rotating [ alpha ]] 25 D ＝0-0.5°。
Example 3
1) 100g of N-butyrylindoline-2-carboxylic acid and 500g of isopropanol are put into a 1000ml three-necked flask, and 95g of isopropyl L-phenylbutyrate acetate is added under stirring. After the addition, the temperature is raised to reflux, and the temperature is kept for 1 hour. Stirring and cooling to 10 deg.C, suction-filtering to obtain white solid A3:68g (yield 69.8% based on L-compound, purity 99% ee) & alpha & lt] 25 D And = 90. The mother liquor was concentrated under reduced pressure to isopropanol and 400g of water were added to the residueThe mixture was adjusted to pH =1 with 30% hydrochloric acid and filtered to obtain 61g of white dextrorotatory substance B3.
2) And preparation of S-N-butyryl indoline-2-formic acid: 100g of A3 resolving salt and 400g of water are put into a 1000ml three-necked bottle, and 30g of 30 percent concentrated hydrochloric acid is dropwise added into the bottle while stirring at 10 to 30 ℃. After the dripping, 48g of white powder was obtained by suction filtration. (yield 93.6%)
3) 150g of concentrated hydrochloric acid and 250g of water were put into a 1000ml three-necked flask, and 100g of white powder was added thereto with stirring. After the addition, the temperature is slowly raised, the mixture is refluxed at 105 ℃ for 3 hours, and then is cooled to 35 ℃ after the reflux. Liquid caustic soda was added dropwise to adjust pH =4.0, and the mixture was washed with suction filtration and water to obtain 60g of a white solid (yield 86.3%, isomer <0.5%, optical rotation-115 ℃).
4) 100g of B3D-isomer, 700g of butyric acid and 100g of butyric anhydride were put into a 1000ml three-necked flask. Stirring and heating to 120 ℃, and keeping the temperature for 5 hours. After the temperature preservation is finished, concentrating under reduced pressure to be dry. Adding 800g water, dispersing at 80 deg.C, stirring, cooling to 10 deg.C, vacuum filtering to obtain 95g racemic mixture, optically rotating [ alpha ]] 25 D ＝0-0.5°。
Example 4
1) 100g of N-benzoylindoline-2-carboxylic acid and 500g of ethanol were put into a 1000ml three-necked flask, and 72g of L-phenylalanine ethyl ester was added thereto with stirring. After the addition, the temperature is raised to reflux, and the temperature is kept for 1 hour. Stirring and cooling to 10 deg.C, suction-filtering to obtain white solid A4:60g (yield 69.6% based on L-compound, purity 99% ee), optically rotating [ alpha ]] 25 D And = 90. The mother liquor was concentrated in ethanol under reduced pressure, 400g of water was added to the residue, the pH was adjusted with 30% hydrochloric acid =1, and filtration was carried out to obtain 60g of white dextrorotatory B4.
2) And preparation of S-N-benzoyl indoline-2-formic acid: 100g of A4 split salt and 400g of water are put into a 1000ml three-neck flask, and 28g of 30% concentrated hydrochloric acid is added dropwise with stirring at 10-30 ℃. After dropping, 55g of white powder was obtained by suction filtration. (yield 94.8%)
3) 150g of concentrated hydrochloric acid and 250g of water were put into a 1000ml three-necked flask, and 100g of white powder was added thereto with stirring. After the addition, the temperature is slowly raised, the mixture is refluxed at 105 ℃ for 5 hours, and then is cooled to 35 ℃ after the reflux. Dropwise adding concentrated ammonia water to adjust pH =4.0, filtering and washing to obtain 53g of white solid (yield is 87.4%, isomer)<0.5%, optically active [ alpha ]] 25 D ＝-115°)。
4) 100g of B4D-isomer, 700g of toluene and 100g of phthalic anhydride were put into a 1000ml three-necked flask. Stirring and heating to reflux, and keeping reflux for 5 hours. After the heat preservation is finished, concentrating under reduced pressure to be dry. Adding 800g water, dispersing at 80 deg.C, stirring, cooling to 10 deg.C, vacuum filtering to obtain 95g racemic mixture, optically rotating [ alpha ]] 25 D ＝0-0.5°。
Example 5
1) 100g of N-acetyl indoline-2-formic acid and 500g of ethanol are put into a 1000ml three-necked bottle, and 123g of L-4-nitrophenylglycine butyl ester is added under stirring. After the addition, the temperature is raised to reflux, and the temperature is kept for 1 hour. Stirring and cooling to 10 deg.C, suction-filtering to obtain white solid A5:78g (yield 70% based on L-compound, purity 98%] 25 D And = 90. The mother liquor was concentrated in ethanol under reduced pressure, 400g of water was added to the residue, the pH was adjusted with 30% hydrochloric acid =1, and filtration was carried out to obtain 60g of white dextrorotatory substance B5.
2) And preparation of S-N-acetyl indoline-2-formic acid: 100g of A5 resolving salt and 400g of water are put into a 1000ml three-necked bottle, and 118.6g of 10% dilute sulfuric acid is dropwise added into the bottle at 10-30 ℃ while stirring. After the dripping, 42g of white powder was obtained by suction filtration. (yield 93.6%)
3) 400g of 15% sulfuric acid was added to a 1000ml three-necked flask, and 100g of S-N-acetylindoline-2-carboxylic acid white powder was added thereto with stirring. After the addition, the temperature was slowly raised, the mixture was refluxed at 105 ℃ for 5 hours, and then cooled to 35 ℃ after the reflux. Adding liquid caustic soda dropwise to adjust the pH to be =4.0, and performing suction filtration and water washing to obtain 67g of white solid (the yield is 84.3 percent, and the isomer is obtained<0.5%, optically active [ alpha ]] 25 D ＝-115°)。
Example 6
1) 100g of N-butyrylindoline-2-carboxylic acid and 500g of methanol were put into a 1000ml three-necked flask, and 84g of L-phenylglycine methyl ester was added thereto with stirring. After the addition, the temperature is raised to reflux, and the temperature is kept for 1 hour. Stirring and cooling to 10 deg.C, suction-filtering to obtain white solid A6:64g (66% yield based on L-compound, 98% purity) optically active [ alpha ] alpha] 25 D And = 90. The mother liquor was concentrated in methanol under reduced pressure, 400g of water was added to the residue, and the mixture was adjusted to pH =1 with 30% hydrochloric acid and filtered to obtain 58g of white dextrorotatory substance B6.
2) And preparation of S-N-butyryl indoline-2-formic acid: 100g of A6 resolving salt and 400g of water are put into a 1000ml three-necked flask, and 174g of 10% nitric acid is dropwise added into the flask under stirring at 10-30 ℃. After the dripping, 53.5g of white powder was obtained by suction filtration. (yield 91.6%)
3) 400g of 15% nitric acid was added to a 1000ml three-necked flask, and 100g of white powder was added thereto with stirring. After the addition, the temperature was slowly raised, the mixture was refluxed at 105 ℃ for 3 hours, and then cooled to 35 ℃ after the reflux. Adding liquid caustic soda dropwise to adjust pH =4.0, filtering and washing with water to obtain 59.5g of white solid (yield 85.1%, isomer)<0.5%, optically active [ alpha ]] 25 D ＝-115°)。
Example 7
1) 100g of N-propionyl indoline-2-carboxylic acid and 500g of methanol were put into a 1000ml three-necked flask, and 96g of L-4-methoxyphenylalanine methyl ester was added thereto under stirring. After the addition, the temperature is raised to reflux, and the temperature is kept for 1 hour. Stirring and cooling to 10 deg.C, suction-filtering to obtain white solid A7:68g (yield 69.6% based on L-compound, purity 99% ee) (. Alpha.) with optical rotation] 25 D And = 90. The mother liquor was concentrated in methanol under reduced pressure, 400g of water was added to the residue, and the mixture was adjusted to pH =1 with 30% hydrochloric acid and filtered to obtain 62g of white dextrorotatory B7.
2) And preparation of S-N-propionyl indoline-2-formic acid: 100g of A7 resolving salt and 400g of water are put into a 1000ml three-necked flask, and 90g of 10% phosphoric acid is dropwise added into the flask under stirring at 10-30 ℃. After the dripping, 52.5g of white powder was obtained by suction filtration. (yield 95.4%)
3) 400g of 10% phosphoric acid was added to a 1000ml three-necked flask, and 100g of white powder was added thereto with stirring. After the addition, the temperature is slowly raised, the mixture is refluxed at 105 ℃ for 5 hours, and then is cooled to 35 ℃ after the reflux. Adding liquid caustic soda dropwise to adjust pH =4.0, filtering and washing with water to obtain 62g of white solid (yield 83.8%, isomer)<0.5%, optically active [ alpha ]] 25 D ＝-115°)。
Example 8
100g of N-propionyl indoline-2-carboxylic acid and 500g of methanol were put into a 1000ml three-necked flask, and 82g of D-phenylalanine methyl ester was added thereto with stirring. After the stirring is finished, the temperature is raised to 50-60 ℃, and the temperature is kept for 1 hour. Stirring, cooling to 10 deg.C, and vacuum filtering to obtain white solid A2:63g (yield 69.4% calculated by dextrorotatory compound, purity ee = 99%), optically active [ alpha ] ("alpha")] 25 D ＝88°。
Comparative example 1
1) 70g of racemic indoline-2-formic acid, 630g of acetone and 70g of water are put into a 1000ml three-necked bottle, and 57g R (+) -alpha-phenylethylamine 57g is added under stirring. Stirring, heating to 30 deg.C, incubating for 2 hours, cooling to 10 deg.C, and filtering to obtain white solid A8:35g (yield 57.4% based on L-compound, purity 76% ee), optically rotating [ alpha ] -alpha] 25 D And = 45. The mother liquor was concentrated in acetone solution under reduced pressure, and 300g of water and 30% hydrochloric acid were added to the residue to adjust PH =3.5. Filtration gave 40g of recovered D-isomer B8 as a gray color.
2) Preparation of S (-) -indoline-2-carboxylic acid: to a 1000ml three-necked flask was added the salified solid A8:100g of water 400g, 47g of 30% hydrochloric acid was added dropwise with stirring at 30 to 40 ℃ to adjust the pH =3.5 to 4.0. This was filtered off with suction to give 40g of an off-white solid (yield 69.8%).
3) Recovering racemization of dextrorotatory substance: and recovering the dextrorotatory substance B8, weighing 16.3g, putting into a 500ml pressure reaction kettle, and adding 8.8g of potassium hydroxide and 200ml of water. Uniformly mixing, stirring and heating to 180-190 ℃, keeping the temperature for reaction for 5 hours, cooling to 80 ℃ after the reaction is finished, adding activated carbon into the reaction solution for decolorization, adjusting the pH of the filtrate to be =3.5 by hydrochloric acid, and filtering to obtain 12.2g of racemic indoline-2-formic acid with yield of 75%, and optically rotating [ alpha ], [ alpha ]] 25 D ＝0°。
Comparative example 2
100g of N-acetyl indoline-2-formic acid and 500g of ethanol are put into a 1000ml three-neck flask, and 62g of R (+) -alpha-phenylethylamine is added under stirring. After the addition, the temperature is raised to reflux, and the temperature is kept for 1 hour. Stirring and cooling to 10 deg.C, suction filtering to obtain 120g (purity 3% ee, optically active [ alpha ]] 25 D ＝-0.5°)。
Claims (13)
1. A resolution method of indoline-2-formic acid compounds is characterized by comprising the following steps: in a solvent, carrying out a salt forming reaction on the compound V and a resolving agent compound II to obtain compounds III and III';
the compound V is a mixture of a compound shown in a formula I and a compound shown in a formula I';
the compound II is a compound shown as a formula II-1 or a compound shown as a formula II-2;
wherein R is 1 is-H, -OH, -NO 2 Or C 1 ～C 3 Alkoxy group of (a);
R 2 is absent or C 1 ～C 3 An alkylene group of (a);
R 3 is C 1 ～C 4 Alkyl groups of (a);
R 4 is C 1 ～C 3 Alkyl, phenyl or tert-butoxy of (a);
when the compound II is a compound II-1, the compounds III and III 'are respectively a compound III-1 and a compound III' -1 shown as follows:
when the compound II is a compound II-2, the compounds III and III 'are respectively a compound III-2 and a compound III' -2 shown as follows:
2. the method for resolving indoline-2-carboxylic acid compounds of claim 1 wherein R is 1 is-H, -NO 2 Or a methoxy group;
and/or, said R 2 Is absent or C 1 ～C 2 An alkylene group of (a);
and/or, said R 3 Is methyl, ethyl, isopropyl or butyl;
and/or the compound V is a mixture of the compound I and the compound I', and the molar ratio is (2:3) - (3:2);
and/or the compound II is one of enantiomers of phenylglycine methyl ester, phenylglycine ethyl ester, 4-nitrophenylglycine butyl ester, phenylalanine methyl ester, phenylalanine ethyl ester, phenyl butyric acid isopropyl ester or 4-methoxy phenylalanine methyl ester;
and/or the solvent is water and/or an alcohol solvent;
and/or the molar ratio of the compound V to the compound II is (0.95;
and/or the temperature of the salt forming reaction is 50-100 ℃;
and/or the mass ratio of the indoline-2-carboxylic acid compound to the solvent is (1:3) - (1.
3. The method for resolving indoline-2-carboxylic acid compounds according to claim 2 wherein the alcoholic solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and benzyl alcohol;
and/or the compound V is a mixture of the compound I and the compound I ', and the molar ratio of the compound V to the compound I' is 1:1;
and/or the molar ratio of the compound V to the compound II is (1:1) - (1.05;
and/or the mass ratio of the indoline-2-formic acid compound to the solvent is 1:5.
4. The method for resolving indoline-2-carboxylic acid compounds of claim 1 further comprising the steps of: the compound III or III 'and acid are subjected to free reaction to obtain a compound I or I',
wherein, the substituent R 1 、R 2 、R 3 And R 4 Are as defined in claim 1.
5. The method for resolving indoline-2-carboxylic acid compounds of claim 4 wherein R is 1 is-H, -NO 2 Or a methoxy group;
and/or, said R 2 Is absent or C 1 ～C 2 An alkylene group of (a);
and/or, said R 3 Is methyl, ethyl, isopropyl or butyl;
and/or the acid is one or more of sulfuric acid, nitric acid, phosphoric acid and hydrochloric acid;
and/or the molar ratio of the compound III or III' to the hydrogen radical ions in the acid is (1:1) - (1.2;
and/or the free reaction temperature is 10-30 ℃.
6. The method for resolving indoline-2-carboxylic acid compounds of claim 5 wherein the acid is hydrochloric acid;
and/or the molar ratio of the compound III or III' to the hydrogen radical ion in the acid is (1.
7. The method for resolving indoline-2-carboxylic acid compounds of claim 4 further comprising the steps of: hydrolyzing the compound I or I 'with acid to obtain a compound IV or IV',
wherein, the substituent R 4 Is determined byAs defined in claim 1.
8. The method for resolving indoline-2-carboxylic acid compounds of claim 7 wherein the acid is one or more of sulfuric acid, phosphoric acid and hydrochloric acid;
and/or the molar ratio of the hydrogen radical ions in the acid to the compound I or I' is (2.5;
and/or, the concentration of the acid is 10-15%;
and/or the hydrolysis reaction temperature is 100-110 ℃.
9. The method for resolving indoline-2-carboxylic acid compounds of claim 8 wherein the acid is hydrochloric acid;
and/or the molar ratio of hydrogen radical ions in the acid to the compound I or I' is 3:1;
and/or, the acid concentration is 10%;
and/or the hydrolysis reaction temperature is 100-105 ℃.
10. The method for resolving indoline-2-carboxylic acid compounds of claim 7 further comprising the steps of: and performing racemization reaction on the compound IV or IV 'and acid anhydride to obtain a mixture of the compound IV and the compound IV'.
11. The method for resolving indoline-2-carboxylic acid compounds of claim 10 wherein the anhydride is one or more of acetic anhydride, propionic anhydride, butyric anhydride and phthalic anhydride;
and/or adding an organic solvent in the racemization reaction, wherein the organic solvent is one or more of acetic acid, propionic acid, butyric acid and toluene;
and/or the temperature of the racemization reaction is 100-180 ℃;
and/or, the compound IV and the compound IV' are mixed, and the compound V is further prepared through acylation reaction and the resolution is further carried out.
12. The method for resolving indoline-2-carboxylic acid compounds of claim 11 wherein the temperature of the racemization reaction is 100-120 ℃.
13. A compound of any one of the following:
wherein, the substituent R 1 、R 2 、R 3 And R 4 Are as defined in claim 1.
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