CN109251163A - A kind of method for splitting of indoline -2- formic acid compound and wherein mesosome - Google Patents
A kind of method for splitting of indoline -2- formic acid compound and wherein mesosome Download PDFInfo
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- CN109251163A CN109251163A CN201710576038.7A CN201710576038A CN109251163A CN 109251163 A CN109251163 A CN 109251163A CN 201710576038 A CN201710576038 A CN 201710576038A CN 109251163 A CN109251163 A CN 109251163A
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- compound
- acid
- indoline
- iii
- formic acid
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- -1 indoline -2- formic acid compound Chemical class 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 57
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 13
- 230000006340 racemization Effects 0.000 claims abstract description 12
- 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 abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 7
- 238000005194 fractionation Methods 0.000 claims abstract description 6
- 239000002955 immunomodulating agent Substances 0.000 claims abstract description 3
- 229940121354 immunomodulator Drugs 0.000 claims abstract description 3
- 230000002584 immunomodulator Effects 0.000 claims abstract description 3
- 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 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 12
- 235000019441 ethanol Nutrition 0.000 claims description 12
- 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 description 11
- 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 10
- 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
- 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
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 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
- 150000008065 acid anhydrides Chemical class 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
- 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
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 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
- 239000000126 substance Substances 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 class COC(=O)[C@@H](N)CC1=CC=C(OC)C=C1 USYGMXDJUAQNGU-JTQLQIEISA-N 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 235000019260 propionic acid Nutrition 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
- OGNSCSPNOLGXSM-UHFFFAOYSA-N (+/-)-DABA Natural products NCCC(N)C(O)=O OGNSCSPNOLGXSM-UHFFFAOYSA-N 0.000 claims description 2
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 2
- 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 description 2
- 239000003795 chemical substances by application Substances 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
- 229960003692 gamma aminobutyric acid Drugs 0.000 claims description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutanoic acid Natural products NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 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
- 150000004702 methyl esters Chemical class 0.000 claims description 2
- DAFOCGYVTAOKAJ-UHFFFAOYSA-N phenibut Chemical compound OC(=O)CC(CN)C1=CC=CC=C1 DAFOCGYVTAOKAJ-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
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- ZJIVVFUSMATLTN-UHFFFAOYSA-N propan-2-yl 2-aminobutanoate Chemical compound CCC(N)C(=O)OC(C)C ZJIVVFUSMATLTN-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
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 claims 1
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropyl alcohol Natural products CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 claims 1
- 238000005917 acylation reaction Methods 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 239000000463 material Substances 0.000 abstract description 4
- 238000005457 optimization Methods 0.000 abstract description 3
- 230000006641 stabilisation Effects 0.000 abstract 1
- 238000011105 stabilization Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 45
- 238000010992 reflux Methods 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- QNRXNRGSOJZINA-UHFFFAOYSA-N indoline-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)CC2=C1 QNRXNRGSOJZINA-UHFFFAOYSA-N 0.000 description 16
- 239000000843 powder Substances 0.000 description 15
- 238000010792 warming Methods 0.000 description 15
- 150000003839 salts Chemical class 0.000 description 11
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 10
- 238000013019 agitation Methods 0.000 description 8
- 239000012452 mother liquor Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 239000007788 liquid Substances 0.000 description 7
- 238000000967 suction filtration Methods 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 238000004321 preservation Methods 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 230000000694 effects Effects 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
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 238000001914 filtration Methods 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
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 2
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 238000004064 recycling Methods 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
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 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
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 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
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 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
- VSDUZFOSJDMAFZ-VIFPVBQESA-N methyl L-phenylalaninate Chemical class COC(=O)[C@@H](N)CC1=CC=CC=C1 VSDUZFOSJDMAFZ-VIFPVBQESA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- BAJDQLCFWFVRGK-LBPRGKRZSA-N propan-2-yl (2s)-2-amino-4-phenylbutanoate Chemical compound CC(C)OC(=O)[C@@H](N)CCC1=CC=CC=C1 BAJDQLCFWFVRGK-LBPRGKRZSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method 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 kind of method for splitting of indoline -2- formic acid compound and wherein mesosome.The method for splitting of the indoline -2- formic acid compound comprising following steps: in a solvent, by compound V and immunomodulator compounds II progress salt-forming reaction is split, obtains compound III and III ';The compound V be compound shown in formula I and such as Formulas I ' shown in compound mixture.Method for splitting of the invention, high income, fractionation is with high purity, and compound stabilization, subsequent racemization high income, compound can be recycled repeatedly in split process, repeats to split, and reaches material and utilizes optimization.
Description
Technical field
The present invention relates to a kind of method for splitting of indoline -2- formic acid compound and wherein mesosome.
Background technique
Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phe of the Perindopril (Perindopril) as no sulfydryl, be mainly used for treat essential hypertension with
Heart failure was listed in 1989 in France.It not only has the advantages that other Vel-Tyr-Pro-Trp-Thr-Gln-Arg-Phes, and action time is longer, secondary work
With smaller, tolerance is more preferable, there are good market prospects.
S- indoline -2- formic acid (I) is the important intermediate of synthesis of perindopril, and it is as follows to be conventionally synthesized technique:
Both the above route is chiral organic bases for the resolving agent of fractionation, there are commonly R- Alpha-Methyl phenyl ethylamine,
Structural formula is as follows:
R- Alpha-Methyl phenyl ethylamine is bad for splitting effect, once splits resulting fractionation salt and is often unable to reach preferable point
From effect, fractionation effect need to be can be only achieved to salt repeated recrystallize is split.Therefore split effect it is poor, yield is low, and production cost compared with
It is high.
S (-)-indoline -2- formic acid chemical resolution is also with R, S- indoline -2- formic acid and R (+)-α-phenylethylamine
It is split to obtain S (-)-indoline -2- formic acid.Due to the unstable chemcial property of indoline -2- formic acid, tear open in this way
The yield divided is low.A large amount of tar is generated when the R (+) of recycling-indoline -2- formic acid racemization and yield is low.
Summary of the invention
The technical problem to be solved by the present invention is in order to overcome tearing open for indoline -2- formic acid compound in the prior art
Point method yield is low, the unstable defect of compound in split process, and provides a kind of indoline -2- formic acid compound
Method for splitting and wherein mesosome.Method for splitting of the invention, high income split purity is high, in split process compound it is stable, after
Continuous racemization high income, compound can be recycled repeatedly, repeat to split, and reach material using optimization.
The present invention provides a kind of method for splitting of indoline -2- formic acid compound comprising following steps: in solvent
In, by compound V and immunomodulator compounds II progress salt-forming reaction is split, obtains compound III and III ';
The compound V be compound shown in formula I and such as Formulas I ' shown in compound mixture;
The compound II is -1 compound represented of Formula II or such as -2 compound represented of Formula II;
Wherein, R1For-H ,-OH ,-NO2Or C1~C3Alkoxy;
R2To be not present or C1~C3Alkyl;
R3For C1~C4Alkyl;
R4For C1~C3Alkyl, phenyl or tert-butoxy;
When compound II is compound II-1, compound that the compound III and III ' are as follows respectively
III-1 and III ' -1:
When compound II is compound II-2, compound that the compound III and III ' are as follows respectively
III-2 and III ' -2:
By above-mentioned method for splitting, it can be realized and split the indoline -2- formic acid compound, had
Indoline -2- the formic acid compound of the indoline -2- formic acid compound of single configuration, the single configuration refers to the Yin
In diindyl quinoline -2- formic acid compound all single configurations or with certain be configured as main advantage configuration exist.
In the present invention, the R1Preferably-H ,-NO2Or methoxyl group.
The R2Preferably there is no or C1~C2Alkyl.
The C1~C4The preferred methyl of alkyl, ethyl, isopropyl or butyl.
In the present invention, the compound V is preferably that the molar ratio of compound I and compound I ' is (2:3)~(3:2),
Further preferred molar ratio is 1:1.
The compound II be better selected from Phenylglycine methyl ester, phenylglycine ethyl ester, 4- nitro Phenylglycine butyl ester,
The enantiomter of phenyalanine methyl ester, phenylalanine ethyl ester, phenyl Gamma Amino Butyric Acid isopropyl ester or 4- methoxyphenylalanine methyl esters
One of.
In the present invention, the Conventional solvents that the solvent can split for such compound of this field, such as at the hand after salt
Property compound dissolubility differ greatly, be conducive to separation;Water and/or alcohols solvent are preferably in the present invention;The alcohols
It is preferred solvents one of methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutanol and benzyl alcohol or a variety of.
In the present invention, the mole dosage ratio of the compound V and compound II can refer to this field chirality and tear open
The conventional amount used of timesharing, such as (10:1)~(1:10), the present invention in preferably (0.95:1)~(1:1.2);More preferably it is
(1:1)~(1:1.05).
The temperature of the reaction can be the ordinary temperature of such salt-forming reaction in this field, such as be heated to the solvent
It flows back, preferably 50 DEG C~100 DEG C in the present invention;Meanwhile according to common sense in the field, the temperature should be not to be exceeded described
Reflux temperature.
In the present invention, the mass ratio of the indoline -2- formic acid compound and the solvent preferably (1:3)~(1:
10), further preferred 1:5.
It can also further comprise post-processing operation below after the salt-forming reaction: cooling and filtering;It is described cold
But this field conventional practices be can refer to filtering.
The method for splitting of the indoline -2- formic acid compound, can comprise the further steps of: compound III
Or III ' dissociate with acid and react, and obtains compound I or I ',
Wherein, substituent R1、R2、R3And R4Definition it is same as above.
The R1Preferably-H ,-NO2Or methoxyl group.
The R2Preferably there is no or C1~C2Alkyl.
The C1~C4The preferred methyl of alkyl, ethyl, isopropyl or butyl.
The acid is the conventional acid of the free reaction of such in this field, such as in sulfuric acid, nitric acid, phosphoric acid and hydrochloric acid
It is one or more, hydrochloric acid is preferably in the present invention.
The molar ratio of hydrogen radical ion can be free for such in this field in the compound III or III ' and the acid
The conventional molar ratio of reaction, the present invention in preferably (1:1)~(1:1.2);It is more preferably (1:1.05)~(1:1.1).
The reaction temperature can be the ordinary temperature of the free reaction of such in this field, preferably 10 in the present invention~
30℃。
The method for splitting of the indoline -2- formic acid compound, may also include the steps of: the chemical combination
Object I or I ' are hydrolyzed with acid to react, and obtains compound IV or IV ',
Wherein, substituent R4It is defined as above described.
The acid is conventional one of the acid, such as sulfuric acid, phosphoric acid and hydrochloric acid of such hydrolysis in this field
Or a variety of, particularly preferred hydrochloric acid in the present invention.
The dosage of the acid can be the dosage of such hydrolysis routine in this field, hydrogen radical in heretofore described acid
The molar ratio of ion and the compound I or I ' are preferably (2.5:1)~(3:1);It is more preferably 3:1.
The acid concentration can be the concentration of such hydrolysis routine in this field, it is preferably 10% in the present invention~
15%;It is more preferably 10%.
The reaction temperature can be the temperature of such hydrolysis routine in this field, be preferably 100 in the present invention
~110 DEG C;It is more preferably 100~105 DEG C.
The process of the hydrolysis can be using the traditional test methods (such as TLC, HPLC or NMR) in this field
It is monitored, is generally disappeared with raw material or no longer reaction is the terminal reacted.Preferably reaction 3~5 hours in the present invention.
After the hydrolysis, may also include following post-processing step: after reaction, cooling, tune pH is
4.0;35 DEG C are preferably cooled to, is 4.0 with liquid alkaline or ammonium hydroxide tune pH, filtering.
The method for splitting of the indoline -2- formic acid compound, may also include the steps of: the chemical combination
Object IV or IV ' and acid anhydrides carry out racemization, obtain the mixture of the compound IV and the compound IV '.
The mixture of the compound IV and the compound IV ', can further pass through the acyl group of this field routine
Change the compound V that reaction is made described, and fractionation described in further progress.
The acid anhydrides can be the acid anhydrides of such racemization routine in this field, be preferably aceticanhydride, third in the present invention
One of acid anhydrides, butyric anhydride and phthalic anhydride are a variety of.
Can also be added the organic solvent of such racemization routine in this field in the racemization, in the present invention compared with
It goodly is one of acetic acid, propionic acid, butyric acid and toluene or a variety of.
The temperature of the reaction can be the temperature of such racemization routine in this field, such as 100~180 DEG C, this hair
100~120 DEG C are preferably in bright.
The present invention also provides a kind of any compounds as follows:
Wherein, substituent R1、R2、R3And R4Definition it is all as described above.
On the basis of common knowledge of the art, above-mentioned each optimum condition, can any combination to get each preferable reality of the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is that: the present invention provides the indoline -2- formic acid compounds described in one kind
Method for splitting and wherein mesosome.Method for splitting of the invention, high income split purity is high, in split process compound it is stable,
Subsequent racemization high income, compound can be recycled repeatedly, repeat to split, and reach material using optimization.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.In the following examples, the experimental methods for specific conditions are not specified, according to conventional methods and conditions, or according to quotient
The selection of product specification.
Embodiment 1
1) N- acetylindole quinoline -2- formic acid 100g, water 500g, are put into 1000ml there-necked flask is added with stirring L-
Phenylglycine ethyl ester 92g.It adds stirring and is warming up to reflux, keep the temperature 1 hour.Stirring is cooled to 10 DEG C, filters to obtain white solid A1:
65g (in terms of levo-compound, yield 69.4%, purity 84%ee), optically-active [α]25 D=-90 °.30% hydrochloric acid of mother liquor
PH=1 is adjusted, white dextrogyre B1:67g is filtered to obtain.
2), the preparation of S-N- acetylindole quinoline -2- formic acid: A1 is put into 1000ml there-necked flask and splits salt 100g, water
400g, 10 DEG C~30 DEG C 30% concentrated hydrochloric acid 35g of agitation and dropping.It drips off and filters to obtain white powder 51g.(yield 95.8%)
3) concentrated hydrochloric acid 150g, is added into 1000ml there-necked flask, water 250g is added with stirring white powder 100g.It adds
Slowly heating, 105 DEG C are flowed back 5 hours, and reflux, which finishes, is cooled to 35 DEG C.Liquid alkaline tune PH=4.0 is added dropwise, suction filtration is washed white solid
Body 65g (yield 82.3%, isomers < 0.5%, -115 ° of optically-active).
4) B1 dextrogyre 100g, glacial acetic acid 700g, aceticanhydride 100g, are put into 1000ml there-necked flask.Stirring is warming up to 120
DEG C, reflux heat preservation 5 hours.Heat preservation finishes, and is concentrated to dryness.800g water is added to be uniformly dispersed in 80 DEG C, stirring is cooled to 10
DEG C, filter to obtain racemoid 95g, optically-active [α]25 D=0-0.5 °.
Embodiment 2
1) N- propiono indoline -2- formic acid 100g, is put into 1000ml there-necked flask, methanol 500g is added with stirring
L-phenylalanine methyl esters 82g.It adds stirring and is warming up to 50-60 DEG C, keep the temperature 1 hour.Stirring is cooled to 10 DEG C, filters white solid
Body A2:63g (in terms of levo-compound, yield 69.4%, purity 99%ee), optically-active [α]25 D=-88 °.Mother liquor decompression is dense
Contracting methanol, residue are added 500g water and filter to obtain white dextrogyre B2:62g with 30% hydrochloric acid tune PH=1.
2), the preparation of S-N- propiono indoline -2- formic acid: A2 is put into 1000ml there-necked flask and splits salt 100g, water
400g, 10 DEG C~30 DEG C 30% concentrated hydrochloric acid 35g of agitation and dropping.It drips off and filters to obtain white powder 52g.(yield 94.4%)
3) concentrated hydrochloric acid 150g, is added into 1000ml there-necked flask, water 250g is added with stirring white powder 100g.It adds
Slowly heating, 105 DEG C are flowed back 3 hours, and reflux, which finishes, is cooled to 35 DEG C.Liquid alkaline tune PH=4.0 is added dropwise, suction filtration is washed white solid
Body 62g (yield 83.8%, isomers < 0.5%, optically-active [α]25 D=-115 °).
4) B2 dextrogyre 100g, propionic acid 700g, propionic andydride 100g, are put into 1000ml there-necked flask.Stirring is warming up to 120
DEG C, keep the temperature 5 hours.Heat preservation finishes, and is concentrated to dryness.800g water is added to be uniformly dispersed in 80 DEG C, stirring is cooled to 10 DEG C, takes out
Filter to obtain racemoid 95g, optically-active [α]25 D=0-0.5 °.
Embodiment 3
1) N- bytyry indoline -2- formic acid 100g, isopropanol 500g, are put into 1000ml there-necked flask, stirring is lower to be added
Enter L-homophenylalanine isopropyl ester 95g.It adds stirring and is warming up to reflux, keep the temperature 1 hour.Stirring is cooled to 10 DEG C, filters white
Color solid A3:68g (in terms of levo-compound, yield 69.8%, purity 99%ee), optically-active [α]25 D=-90 °.Mother liquor subtracts
Pressure concentration isopropanol, residue are added 400g water and filter to obtain white dextrogyre B3:61g with 30% hydrochloric acid tune PH=1.
2), the preparation of S-N- bytyry indoline -2- formic acid: A3 is put into 1000ml there-necked flask and splits salt 100g, water
400g, 10 DEG C~30 DEG C 30% concentrated hydrochloric acid 30g of agitation and dropping.It drips off and filters to obtain white powder 48g.(yield 93.6%)
3) concentrated hydrochloric acid 150g, is added into 1000ml there-necked flask, water 250g is added with stirring white powder 100g.It adds
Slowly heating, 105 DEG C are flowed back 3 hours, and reflux, which finishes, is cooled to 35 DEG C.Liquid alkaline tune PH=4.0 is added dropwise, suction filtration is washed white solid
Body 60g (yield 86.3%, isomers < 0.5%, -115 ° of optically-active).
4) B3 dextrogyre 100g, butyric acid 700g, butyric anhydride 100g, are put into 1000ml there-necked flask.Stirring is warming up to 120
DEG C, keep the temperature 5 hours.Heat preservation finishes, and is concentrated to dryness.800g water is added to be uniformly dispersed in 80 DEG C, stirring is cooled to 10 DEG C, takes out
Filter to obtain racemoid 95g, optically-active [α]25 D=0-0.5 °.
Embodiment 4
1) N- benzoyl indoline -2- formic acid 100g, ethyl alcohol 500g, are put into 1000ml there-necked flask, stirring is lower to be added
Enter L-phenylalanine ethyl ester 72g.It adds stirring and is warming up to reflux, keep the temperature 1 hour.Stirring is cooled to 10 DEG C, filters white solid
Body A4:60g (in terms of levo-compound, yield 69.6%, purity 99%ee), optically-active [α]25 D=-90 °.Mother liquor decompression is dense
Contracting ethyl alcohol, residue are added 400g water and filter to obtain white dextrogyre B4:60g with 30% hydrochloric acid tune PH=1.
2), the preparation of S-N- benzoyl indoline -2- formic acid: putting into A4 into 1000ml there-necked flask and split salt 100g,
Water 400g, 10 DEG C~30 DEG C 30% concentrated hydrochloric acid 28g of agitation and dropping.It drips off and filters to obtain white powder 55g.(yield 94.8%)
3) concentrated hydrochloric acid 150g, is added into 1000ml there-necked flask, water 250g is added with stirring white powder 100g.It adds
Slowly heating, 105 DEG C are flowed back 5 hours, and reflux, which finishes, is cooled to 35 DEG C.Concentrated ammonia liquor tune PH=4.0 is added dropwise, suction filtration is washed white
Solid 53g (yield 87.4%, isomers < 0.5%, optically-active [α]25 D=-115 °).
4) B4 dextrogyre 100g, toluene 700g, phthalic anhydride 100g, are put into 1000ml there-necked flask.Stirring is warming up to reflux,
Reflux heat preservation 5 hours.Heat preservation finishes, and is concentrated to dryness.800g water is added to be uniformly dispersed in 80 DEG C, stirring is cooled to 10 DEG C,
Filter to obtain racemoid 95g, optically-active [α]25 D=0-0.5 °.
Embodiment 5
1) N- acetylindole quinoline -2- formic acid 100g, is put into 1000ml there-necked flask, ethyl alcohol 500g is added with stirring
L-4- nitro Phenylglycine butyl ester 123g.It adds stirring and is warming up to reflux, keep the temperature 1 hour.Stirring is cooled to 10 DEG C, filters white
Color solid A5:78g (in terms of levo-compound, yield 70%, purity 98%ee), optically-active [α]25 D=-90 °.Mother liquor decompression
Ethyl alcohol is concentrated, residue is added 400g water and filters to obtain white dextrogyre B5:60g with 30% hydrochloric acid tune PH=1.
2), the preparation of S-N- acetylindole quinoline -2- formic acid: A5 is put into 1000ml there-necked flask and splits salt 100g, water
400g, 10 DEG C~30 DEG C 10% dilute sulfuric acid 118.6g of agitation and dropping.It drips off and filters to obtain white powder 42g.(yield 93.6%)
3) 15% sulfuric acid 400g, is added into 1000ml there-necked flask, is added with stirring S-N- acetylindole quinoline -2- formic acid
White powder 100g.Slow heating is added, 105 DEG C are flowed back 5 hours, and reflux, which finishes, is cooled to 35 DEG C.Liquid alkaline tune PH=is added dropwise
4.0, suction filtration washes to obtain white solid 67g (yield 84.3%, isomers < 0.5%, optically-active [α]25 D=-115 °).
Embodiment 6
1) N- bytyry indoline -2- formic acid 100g, is put into 1000ml there-necked flask, methanol 500g is added with stirring
L- Phenylglycine methyl ester 84g.It adds stirring and is warming up to reflux, keep the temperature 1 hour.Stirring is cooled to 10 DEG C, filters to obtain white solid
A6:64g (in terms of levo-compound, yield 66%, purity 98%ee), optically-active [α]25 D=-90 °.First is concentrated under reduced pressure in mother liquor
Alcohol, residue are added 400g water and filter to obtain white dextrogyre B6:58g with 30% hydrochloric acid tune PH=1.
2), the preparation of S-N- bytyry indoline -2- formic acid: A6 is put into 1000ml there-necked flask and splits salt 100g, water
400g, 10 DEG C~30 DEG C 10% nitric acid 174g of agitation and dropping.It drips off and filters to obtain white powder 53.5g.(yield 91.6%)
3) 15% nitric acid 400g, is added into 1000ml there-necked flask, is added with stirring white powder 100g.Add slow liter
Temperature, 105 DEG C are flowed back 3 hours, and reflux, which finishes, is cooled to 35 DEG C.Liquid alkaline tune PH=4.0 is added dropwise, suction filtration washes to obtain white solid
59.5g (yield 85.1%, isomers < 0.5%, optically-active [α]25 D=-115 °).
Embodiment 7
1) N- propiono indoline -2- formic acid 100g, is put into 1000ml there-necked flask, methanol 500g is added with stirring
L-4- methoxyphenylalanine methyl esters 96g.It adds stirring and is warming up to reflux, keep the temperature 1 hour.Stirring is cooled to 10 DEG C, filters
White solid A7:68g (in terms of levo-compound, yield 69.6%, purity 99%ee), optically-active [α]25 D=-90 °.Mother liquor
Methanol is concentrated under reduced pressure, residue is added 400g water and filters to obtain white dextrogyre B7:62g with 30% hydrochloric acid tune PH=1.
2), the preparation of S-N- propiono indoline -2- formic acid: A7 is put into 1000ml there-necked flask and splits salt 100g, water
400g, 10 DEG C~30 DEG C 10% phosphatase 79 0g of agitation and dropping.It drips off and filters to obtain white powder 52.5g.(yield 95.4%)
3) 10% phosphatase 24 00g, is added into 1000ml there-necked flask, is added with stirring white powder 100g.Add slow liter
Temperature, 105 DEG C are flowed back 5 hours, and reflux, which finishes, is cooled to 35 DEG C.Liquid alkaline tune PH=4.0 is added dropwise, suction filtration washes to obtain white solid 62g
(yield 83.8%, isomers < 0.5%, optically-active [α]25 D=-115 °).
Embodiment 8
N- propiono indoline -2- formic acid 100g, methanol 500g are put into 1000ml there-necked flask is added with stirring D- benzene
Methyl lactamine 82g.It adds stirring and is warming up to 50-60 DEG C, keep the temperature 1 hour.Stirring is cooled to 10 DEG C, filters to obtain white solid
A2:63g (in terms of dextro-compound, yield 69.4%, purity ee=99%), optically-active [α]25 D=88 °.
Comparative example 1
1) indoline -2- formic acid 70g, acetone 630g, the water 70g of mixed, are put into 1000ml there-necked flask, stirring is lower to be added
Enter 57g R (+)-α-phenylethylamine 57g.Stirring is warming up to 30 DEG C and keeps the temperature 2 hours, is cooled to 10 DEG C, filters to obtain white solid A8:
35g (in terms of levo-compound, yield 57.4%, purity 76%ee), optically-active [α]25 D=-45 °.Mother liquor is concentrated under reduced pressure third
300g water, 30% hydrochloric acid tune PH=3.5 is added in ketone solution, residue.Filter grey recycling dextrogyre B8:40g.
2) it, S (-)-indoline -2- formic acid preparation: is added into 1000ml there-necked flask into salt solid A8:100g, water
400g, 30-40 DEG C of 30% hydrochloric acid 47g of agitation and dropping adjust PH=3.5-4.0.Filter to obtain off-white powder 40g (yield
69.8%).
3), recycle the racemization of dextrogyre: recycling dextrogyre B8 weighs 16.3g, puts into 500ml pressure reaction still, is added
Potassium hydroxide 8.8g, water 200ml.After mixing, stirring is warming up to 180~190 DEG C, and insulation reaction 5 hours, reaction terminated,
Be cooled to 80 DEG C, active carbon decoloring be added in reaction solution, filtrate adjusts PH=3.5 with hydrochloric acid, filter mixed indoline -2-
Formic acid 12.2g yield 75%, optically-active [α]25 D=0 °.
Comparative example 2
N- acetylindole quinoline -2- formic acid 100g, ethyl alcohol 500g are put into 1000ml there-necked flask is added with stirring R
(+)-α-phenylethylamine 62g.It adds stirring and is warming up to reflux, keep the temperature 1 hour.Stirring is cooled to 10 DEG C, filters to obtain white solid
120g (purity 3%ee, optically-active [α]25 D=-0.5 °).
Claims (10)
1. a kind of method for splitting of indoline -2- formic acid compound, which is characterized in that itself the following steps are included: in a solvent,
By compound V and immunomodulator compounds II progress salt-forming reaction is split, obtains compound III and III ';
The compound V be compound shown in formula I and such as Formulas I ' shown in compound mixture;
The compound II is -1 compound represented of Formula II or such as -2 compound represented of Formula II;
Wherein, R1For-H ,-OH ,-NO2Or C1~C3Alkoxy;
R2To be not present or C1~C3Alkyl;
R3For C1~C4Alkyl;
R4For C1~C3Alkyl, phenyl or tert-butoxy;
When compound II is compound II-1, compound III-1 that the compound III and III ' are as follows respectively
And III ' -1:
When compound II is compound II-2, compound III-2 that the compound III and III ' are as follows respectively
And III ' -2:
2. the method for splitting of indoline -2- formic acid compound as described in claim 1, which is characterized in that the R1For-
H、-NO2Or methoxyl group;
And/or the R2It is not present or C1~C2Alkyl;
And/or the R3For methyl, ethyl, isopropyl or butyl;
And/or the compound V is compound I and the molar ratio of compound I ' is (2:3)~(3:2);
And/or the compound II is Phenylglycine methyl ester, phenylglycine ethyl ester, 4- nitro Phenylglycine butyl ester, phenylpropyl alcohol ammonia
Sour methyl esters, phenylalanine ethyl ester, phenyl Gamma Amino Butyric Acid isopropyl ester or 4- methoxyphenylalanine methyl esters enantiomter in one
Kind;
And/or the solvent is water and/or alcohols solvent;
And/or the mole dosage ratio of the compound V and compound II is (0.95:1)~(1:1.2);
And/or the temperature of the reaction is 50 DEG C~100 DEG C;
And/or the mass ratio of the indoline -2- formic acid compound and the solvent is (1:3)~(1:10).
3. the method for splitting of indoline -2- formic acid compound as claimed in claim 2, which is characterized in that the alcohols is molten
Agent is one of methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutanol and benzyl alcohol or a variety of;
And/or the compound V is compound I and the molar ratio of compound I ' is 1:1;
And/or the mole dosage ratio of the compound V and compound II is (1:1)~(1:1.05);
And/or the mass ratio of the indoline -2- formic acid compound and the solvent is 1:5.
4. the method for splitting of indoline -2- formic acid compound as described in claim 1, which is characterized in that its further include with
Lower step: compound III or III ' dissociate with acid and is reacted, compound I or I ' are obtained,
Wherein, substituent R1、R2、R3And R4Definition it is as described in claim 1.
5. the method for splitting of indoline -2- formic acid compound as claimed in claim 4, which is characterized in that the R1For-
H、-NO2Or methoxyl group;
And/or the R2To be not present or C1~C2Alkyl;
And/or the R3For methyl, ethyl, isopropyl or butyl;
And/or the acid is one of sulfuric acid, nitric acid, phosphoric acid and hydrochloric acid or a variety of, preferably hydrochloric acid;
And/or the molar ratio of hydrogen radical ion is (1:1)~(1:1.2) in the compound III or III ' and the acid;
Preferably (1:1.05)~(1:1.1);
And/or the reaction temperature is 10~30 DEG C.
6. the method for splitting of indoline -2- formic acid compound as described in claim 1, which is characterized in that its further include with
Lower step: the compound I or I ' being hydrolyzed with acid and reacted, compound IV or IV ' are obtained,
Wherein, substituent R4Definition it is as described in claim 1.
7. the method for splitting of indoline -2- formic acid compound as claimed in claim 6, which is characterized in that the acid is
One of sulfuric acid, phosphoric acid and hydrochloric acid are a variety of, preferably hydrochloric acid;
And/or the molar ratio of hydrogen radical ion and the compound I or I ' are (2.5:1)~(3:1) in the acid;Preferably
3:1;
And/or the acid concentration is 10%~15%;Preferably 10%;
And/or the reaction temperature is 100~110 DEG C;Preferably 100~105 DEG C.
8. the method for splitting of indoline -2- formic acid compound as described in claim 1, which is characterized in that its further include with
Lower step: the compound IV or IV ' and acid anhydrides are subjected to racemization, obtain the compound IV and the chemical combination
The mixture of object IV '.
9. the method for splitting of indoline -2- formic acid compound as claimed in claim 8, which is characterized in that the acid anhydrides
For one of aceticanhydride, propionic andydride, butyric anhydride and phthalic anhydride or a variety of;
And/or organic solvent is added in the racemization, the organic solvent is in acetic acid, propionic acid, butyric acid and toluene
It is one or more;
And/or the temperature of the reaction is 100~180 DEG C, preferably 100~120 DEG C;
And/or the mixture of the compound IV and the compound IV ', institute is further made by acylation reaction
The compound V stated, and fractionation described in further progress.
10. a kind of any compound as follows:
Wherein, substituent R1、R2、R3And R4Definition it is as claimed in claim 1 or 2.
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