CN102675183B - Method for preparing medical intermediate on large scale - Google Patents
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- CN102675183B CN102675183B CN201110058030.4A CN201110058030A CN102675183B CN 102675183 B CN102675183 B CN 102675183B CN 201110058030 A CN201110058030 A CN 201110058030A CN 102675183 B CN102675183 B CN 102675183B
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- 238000000034 method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 16
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 claims description 14
- XVDPVYKAINSREY-UHFFFAOYSA-N C(CCC)(=O)O.N1C=CC=C1 Chemical class C(CCC)(=O)O.N1C=CC=C1 XVDPVYKAINSREY-UHFFFAOYSA-N 0.000 claims description 13
- 230000035484 reaction time Effects 0.000 claims description 10
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 claims description 8
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 239000001488 sodium phosphate Substances 0.000 claims description 5
- PTDQUWYFMZSJJM-UHFFFAOYSA-K [Na+].[Na+].[Na+].[Cl-].OP([O-])([O-])=O Chemical compound [Na+].[Na+].[Na+].[Cl-].OP([O-])([O-])=O PTDQUWYFMZSJJM-UHFFFAOYSA-K 0.000 claims description 4
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 4
- 229910000397 disodium phosphate Inorganic materials 0.000 claims description 4
- 235000019800 disodium phosphate Nutrition 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 26
- 239000007787 solid Substances 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 238000001914 filtration Methods 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 7
- 239000007810 chemical reaction solvent Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
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- 238000001816 cooling Methods 0.000 description 3
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- 150000007529 inorganic bases Chemical class 0.000 description 3
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- 230000000630 rising effect Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
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- 229910019142 PO4 Inorganic materials 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
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- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
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- 150000003384 small molecules Chemical class 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 description 2
- 235000011008 sodium phosphates Nutrition 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
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- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
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- 229940084651 iressa Drugs 0.000 description 1
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- 238000011275 oncology therapy Methods 0.000 description 1
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 description 1
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- 238000012805 post-processing Methods 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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- Indole Compounds (AREA)
Abstract
The invention discloses a method for preparing a medical intermediate on a large scale, and relates to a method for preparing 2-methyl-7-oxo-4,5,6,7-tetralin-1H-indol-3-carboxylic acid (which is shown in a formula IV) on a large scale. By the method, a reaction reagent is readily available, steps are simple, reaction conditions are mild, an aftertreatment process is simple and convenient, and the obtained product is high in purity and yield; and the method is suitable for industrial mass production.
Description
Technical field
The present invention relates to taking 6-amino-5-oxo caproic acid or its salt (formula I) with methyl aceto acetate as raw material preparation of industrialization 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid's (formula IV) method.
Background technology
Glivec and Iressa are the small molecule tyrosine kinase inhibitors that is early applied to clinical cancer therapy, its good clinical application effect has greatly excited global Ge great drugmaker and the research institution research interest to this type of target spot, therefore investigator, for multiple Tyrosylprotein kinase target spots wherein, has carried out the design of a large amount of micromolecular inhibitors, synthetic and preclinical study.At present, existing multiple small molecule tyrosine kinase inhibitors are approved for clinical treating malignant tumor, and simultaneously a lot of medicines are being carried out clinical trial, more demonstrate the wide DEVELOPMENT PROSPECT of this type of molecular targeted antitumor drug.Referring to: Zhang Shige, Chinese Hospitals medication is evaluated and is analyzed 2010,10,1:4-6.
3-pyrrole ring caproic subunit-2-indoline ketone compounds has significant restraining effect to the activity of multiple Tyrosylprotein kinase, wherein 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid is the key intermediate of synthetic above-mentioned 3-pyrrole ring caproic subunit-2-indoline ketone compounds, therefore, and 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid preparation method's quality directly affects the feasibility of the convenient and suitability for industrialized production of synthetic cost, the technological operation of 3-pyrrole ring caproic subunit-2-dihydroindolone derivatives.Referring to: Tang Feng, etc., WO2008/067756, (2008).
2-methyl-7-oxo-4 of existing open source literature report, 5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid synthetic method is: the first step, and taking 6-amino-5-oxo hexanoate hydrochlorate and methyl aceto acetate as initial action raw material, sodium dihydrogen phosphate is reaction solvent, back flow reaction generates 2-methyl-3-ethyl formate-4 butyric acid pyrroles; Second step, taking polyphosphoric acid as reaction solvent, 2-methyl-3-ethyl formate-4 butyric acid pyrroles dehydrating condensation generates 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid ethyl ester; The 3rd step, taking lithium hydroxide aqueous solution as solvent, 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
hthe hydrolysis of-Indole-3-Carboxylic Acid ethyl ester generates 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid.In above-mentioned disclosed preparation method, be solvent because the first step reaction is used sodium dihydrogen phosphate, 22.4 g 6-amino-5-oxo hexanoate hydrochlorates are dissolved in 6100 mL solvents, raw material and solvent ratio reach 1 g:272 mL, solvent usage quantity is larger, and the waste liquid of generation is more, and transformation efficiency and productive rate are lower simultaneously, complex operation, is unsuitable for large-scale industrialization preparation; Second step is taking polyphosphoric acid as reaction solvent, and reaction solution viscosity is larger, stir difficulty, and three-step reaction is taking lithium hydroxide solution as reaction solvent, and the reaction times reaches 48 hours, and productive rate is all lower simultaneously, is neither suitable for industry and amplifies.Referring to: Tang Feng, etc., WO2008/067756, (2008).
In a word, above-mentioned existing 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid synthetic method is owing to there being all factors such as complicated operation, reaction conversion ratio or productive rate are lower, reaction solvent usage quantity is excessive, the reaction times is long, thereby limited the application of the method in scale operation.
Summary of the invention
The technical problem to be solved in the present invention is: by improving synthesis technique, select different reaction solvents, simplify operation and post-processing step, reduce the reaction times, improve the environment friendly of reaction yield and reaction, thereby reduce preparation cost, be applicable to 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid large-scale industrial production.
The term " protonic acid " using in the present invention refers to anyly can discharge proton (H
+) material.Comprise liquid protonic acid and solid proton acid, liquid protonic acid refers to that under normal temperature, (25 DEG C) are the protonic acids of liquid, as methanesulfonic, sulfuric acid, phosphoric acid etc.; Solid proton acid refers to that (25 DEG C) under normal temperature are that the protonic acid of solid is as tosic acid, trichoroacetic acid(TCA), Periodic acid etc.Protonic acid preferred liquid protonic acid of the present invention.
The present invention prepares 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid's (shown in IV) reactions steps is expressed as follows:
The 6-amino-5-oxo caproic acid of step (1): formula I or its salt react 2-methyl-3-ethyl formate-4 butyric acid pyrroles of production II with methyl aceto acetate;
2-methyl-3-ethyl formate-4 butyric acid pyrroles of step (2): formula II reacts 2-methyl-7-oxo-4 that generate formula III, 5,6,7-tetrahydrochysene-1 in the protonic acid that contains dewatering agent
h-Indole-3-Carboxylic Acid ethyl ester, described protonic acid does not comprise polyphosphoric acid;
Step (3): 2-methyl-7-oxo-4 of formula III, 5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid ethyl ester is through hydrolysis reaction, 2-methyl-7-oxo-4 of production IV, 5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid, described hydrolysis is hydrolyzed not included in lithium hydroxide aqueous solution.
Preferably in step (1), 6-amino-5-oxo caproic acid or its salt are 6-amino-5-oxo hexanoate hydrochlorate; 6-amino-5-oxo hexanoate hydrochlorate and methyl aceto acetate back flow reaction in phosphate solution, reflux time is 0.5 to 10 hour.In step (2), dewatering agent is Vanadium Pentoxide in FLAKES, and protonic acid is selected from methanesulfonic, sulfuric acid, phosphoric acid; Temperature of reaction is 50 DEG C to 90 DEG C, and the reaction times is 1 to 12 hour.In step (3), hydrolysis reaction refers to be hydrolyzed in inorganic base aqueous solution, 50 DEG C-90 DEG C of temperature of reaction, and the reaction times is 2-24 hour.
Further preferably, the phosphate solution described in step (1) is sodium phosphate-hydrochloric acid soln or disodium phosphate soln, and pH is 8 ~ 10; Reflux time is 1-2h.Protonic acid described in step (2) is methanesulfonic; Temperature of reaction is 50 DEG C to 80 DEG C, and the reaction times is 3 to 6 hours.The described inorganic base aqueous solution of step (3) is aqueous sodium hydroxide solution or potassium hydroxide aqueous solution, and the reaction times is 6-12 hour.
Further in step (2), the mol ratio of protonic acid and Vanadium Pentoxide in FLAKES is preferably 6:1 ~ 20:1, more preferably 12:1 ~ 14:1.The described inorganic base aqueous solution concentration of step (3) is 0.5 ~ 2mol/L.
Technical scheme reaction reagent of the present invention is easy to get, and step is simple, reaction conditions gentleness, and product aftertreatment and method of purification are easy and simple to handle, and productive rate and purity are higher.Meanwhile, this programme has reduced the usage quantity of reaction solvent, has shortened the reaction times, more friendly to environment, is more suitable in industrial scale operation.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.
Raw material sources and specification:
It is synthetic that 6-amino-5-oxo hexanoate hydrochlorate (formula I) is pressed literature method, with reference to Lartillot, and Serge. et al, Bulletin de la Societe Chimique de France, 1964,4:783.
Other reagent and solvent are commercial goods, chemical pure or analytical pure.
Preparation 2-methyl-3-ethyl formate-4 butyric acid pyrroles (formula II)
Embodiment 1:
6-amino-5-oxo hexanoate hydrochlorate (formula I) 128 g (0.70 mol) are dissolved in that in sodium phosphate-hydrochloric acid soln, (sodium phosphate 643g is dissolved in pure water 3100 ml, concentrated hydrochloric acid regulates pH to 10 left and right), add methyl aceto acetate 93 g(0.71 mol), temperature rising reflux reaction 1 hour.Question response liquid cooling is but 1 left and right with hcl acidifying to pH afterwards, and separate out a large amount of solids, filtration drying obtains off-white color solid 2-methyl-3-ethyl formate-4 butyric acid pyrroles (formula II) 131 g(0.55 mol), HPLC purity 95%, productive rate 78.5%.
1HNMR(500?MHz,?DMSO-d
6)?δ?11.92(s,?1H),?10.86(s,?1H),?6.37(s,?1H),?4.10(q,?2H),?2.45(t,?2H),?2.30(s,?3H),?2.17(t,?2H),?1.70(m,?2H),?1.23(t,?3H)。
Embodiment 2:
6-amino-5-oxo hexanoate hydrochlorate (formula I) 128 g (0.70 mol) are dissolved in that in sodium phosphate-hydrochloric acid soln, (sodium phosphate 643g is dissolved in pure water 3100 ml, concentrated hydrochloric acid regulates pH to 8 left and right), add methyl aceto acetate 93 g(0.71 mol), temperature rising reflux reaction 2 hours.Question response liquid cooling is but 1 left and right with hcl acidifying to pH afterwards, and separate out a large amount of solids, filtration drying obtains off-white color solid 2-methyl-3-ethyl formate-4 butyric acid pyrroles (formula II) 135 g(0.56 mol), HPLC purity 96%, productive rate 80.7%.
Embodiment 3:
6-amino-5-oxo hexanoate hydrochlorate (formula I) 926 g(5.10 mol) be dissolved in that in disodium phosphate soln, (Sodium phosphate dibasic 2100 g are dissolved in pure water 14 L, pH is 9 left and right), add methyl aceto acetate 679 g(5.22 mol), temperature rising reflux reaction 1.5 hours.Question response liquid cooling is but 1 left and right with hcl acidifying to pH afterwards, and separate out a large amount of solids, filtration drying obtains off-white color solid 2-methyl-3-ethyl formate-4 butyric acid pyrroles (formula II) 990 g(4.14 mol), HPLC purity 96%, productive rate 81.2%.
Preparation 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid ethyl ester (formula III)
Embodiment 4:
At methanesulfonic 1262 ml(19.4 mol) in add Vanadium Pentoxide in FLAKES 138 g(0.97 mol), be heated to 100 DEG C, be stirred to reaction solution and clarify completely.Reaction solution is cooled to after 30 DEG C, add 2-methyl-3-ethyl formate-4 butyric acid pyrroles (formula II) 130 g (0.54 mol) in batches, after reinforced end, mixture stirring reaction at 68 DEG C, after 4 hours, is poured in frozen water, saturated sodium hydroxide solution alkalize to pH value of solution be 7 left and right, filter, after filtration cakes torrefaction, obtain off-white color solid 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid ethyl ester 113 g (0.51 mol), HPLC purity is 98%, productive rate 94.4%.
1H?NMR(500?MHz,?CDCl
3)?δ?10.24(s,?1H),?4.29(q,?2H),?2.98(t,?2H),?2.59(s,?3H),?2.53(t,?2H),?2.10(m,?2H),?1.36(t,?3H)。
Embodiment 5:
At methanesulfonic 1262 ml(19.4 mol) in add Vanadium Pentoxide in FLAKES 459 g(3.23 mol), be heated to 100 DEG C, be stirred to reaction solution and clarify completely.Reaction solution is cooled to after 30 DEG C, add 2-methyl-3-ethyl formate-4 butyric acid pyrroles (formula II) 130 g(0.54 mol) in batches, after reinforced end, mixture stirring reaction at 80 DEG C, after 3 hours, is poured in frozen water, saturated sodium hydroxide solution alkalize to pH value of solution be 7 left and right, filter, after filtration cakes torrefaction, obtain white solid 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid ethyl ester 115 g(0.52mol), HPLC purity is 97%, productive rate 96.3%.
Embodiment 6:
At methanesulfonic 1262 ml(19.4 mol) in add Vanadium Pentoxide in FLAKES 195 g(1.37 mol), be heated to 100 DEG C, be stirred to reaction solution and clarify completely.Reaction solution is cooled to after 30 DEG C, add 2-methyl-3-ethyl formate-4 butyric acid pyrroles (formula II) 130 g(0.54 mol) in batches, after reinforced end, mixture stirring reaction at 60 DEG C, after 5 hours, is poured in frozen water, saturated sodium hydroxide solution alkalize to pH value of solution be 7 left and right, filter, after filtration cakes torrefaction, obtain white solid 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid ethyl ester 117 g(0.53 mol), HPLC purity is 98%, productive rate 98.0%.
Embodiment 7:
At methanesulfonic 9478 ml(146 mol) in add Vanadium Pentoxide in FLAKES 1704 g(12 mol), be heated to 100 DEG C, be stirred to reaction solution and clarify completely.Reaction solution is cooled to after 30 DEG C, add 2-methyl-3-ethyl formate-4 butyric acid pyrroles (formula II) 974 g(4.07 mol) in batches, after reinforced end, mixture stirring reaction at 50 DEG C, after 6 hours, is poured in frozen water, saturated sodium hydroxide solution alkalize to pH value of solution be 7 left and right, filter, after filtration cakes torrefaction, obtain white solid 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid ethyl ester 891 g(4.03 mol), HPLC purity is 99%, productive rate 99.0%.
Preparation 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid (formula IV)
Embodiment 8:
By 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid ethyl ester 110 g(0.50 mol) to add to 1800 ml concentration be in the aqueous sodium hydroxide solution of 1 mol/L, add 180 mL methyl alcohol again, be warming up to 70 DEG C of stirring reactions after 8 hours, reaction solution is cooled to room temperature (25 DEG C), filter, filtrate with hcl acidifying to pH be 1 ~ 2, separate out a large amount of off-white color solids, filter, after filtration cakes torrefaction, obtain 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid 90 g(0.47mol), HPLC purity is 98%, productive rate 94.0%.
1H?NMR(500?MHz,?DMSO-d
6)?δ?12.05(s,?1H),?11.97(s,1H),?2.88(t,?2H),?2.44(s,?3H),?2.37(t,?2H),?1.99(m,?2H)。
Embodiment 9:
By 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid ethyl ester 100 g(0.45 mol) to add to 1600 ml concentration be in the aqueous sodium hydroxide solution of 2 mol/L, add 160 mL methyl alcohol again, be warming up to 90 DEG C of stirring reactions after 6 hours, reaction solution is cooled to room temperature (25 DEG C), filter, filtrate with hcl acidifying to pH be 1 ~ 2, separate out a large amount of off-white color solids, filter, after filtration cakes torrefaction, obtain 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid 81 g (0.42 mol), HPLC purity is 99%, productive rate 93.3%.
Embodiment 10:
By 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid ethyl ester 889 g(4.02 mol) to add to 14.4 L concentration be in the potassium hydroxide aqueous solution of 0.5 mol/L, add 1.4 L methyl alcohol again, be warming up to 50 DEG C of stirring reactions after 12 hours, reaction solution is cooled to room temperature (25 DEG C), filter, filtrate with hcl acidifying to pH be 1 ~ 2, separate out a large amount of off-white color solids, filter, after filtration cakes torrefaction, obtain 2-methyl-7-oxo-4,5,6,7-tetrahydrochysene-1
h-Indole-3-Carboxylic Acid 761 g (3.94 mol), HPLC purity is 99%, productive rate 98.0%.
Claims (1)
1. prepare 2-methyl-7-oxo-4 for one kind, 5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid's (formula IV) method, is made up of the following step:
Step (1): by 6-amino-5-oxo hexanoate hydrochlorate and methyl aceto acetate with sodium phosphate-hydrochloric acid soln or disodium phosphate soln in back flow reaction, pH is 8～10, reflux time is 1-2 hour;
2-methyl-3-ethyl formate-4 butyric acid pyrroles of step (2): formula II is in the methanesulfonic that contains dewatering agent Vanadium Pentoxide in FLAKES, reaction generates 2-methyl-7-oxo-4 of formula III, 5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid ethyl ester, temperature of reaction is 50 DEG C-80 DEG C, and the reaction times is 3-6 hour;
Step (3): 2-methyl-7-oxo-4 of formula III, 5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid ethyl ester is through hydrolysis reaction, 2-methyl-7-oxo-4 of production IV, 5,6,7-tetrahydrochysene-1H-Indole-3-Carboxylic Acid, described hydrolysis refers in aqueous sodium hydroxide solution and is hydrolyzed, temperature of reaction is 50 DEG C-90 DEG C, and the reaction times is 6-12 hour.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110058030.4A CN102675183B (en) | 2011-03-11 | 2011-03-11 | Method for preparing medical intermediate on large scale |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110058030.4A CN102675183B (en) | 2011-03-11 | 2011-03-11 | Method for preparing medical intermediate on large scale |
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| Publication Number | Publication Date |
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| CN102675183A CN102675183A (en) | 2012-09-19 |
| CN102675183B true CN102675183B (en) | 2014-07-16 |
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| "Aldisin及其衍生物的合成和表征";徐石海等;《化学试剂》;20070228;第29卷(第2期);第65-68页 * |
| 徐石海等."Aldisin及其衍生物的合成和表征".《化学试剂》.2007,第29卷(第2期),第65-68页. |
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