CN107868069A - The preparation technology of the carboxylic acid of 7 hydroxyl, 8 methyl, 6 nitro, 2 oxygen 2H chromenes 3 - Google Patents
The preparation technology of the carboxylic acid of 7 hydroxyl, 8 methyl, 6 nitro, 2 oxygen 2H chromenes 3 Download PDFInfo
- Publication number
- CN107868069A CN107868069A CN201711046847.3A CN201711046847A CN107868069A CN 107868069 A CN107868069 A CN 107868069A CN 201711046847 A CN201711046847 A CN 201711046847A CN 107868069 A CN107868069 A CN 107868069A
- Authority
- CN
- China
- Prior art keywords
- methyl
- oxygen
- hydroxyls
- chromene
- hydroxyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000005516 engineering process Methods 0.000 title claims abstract description 11
- -1 oxygen 2H chromenes Chemical class 0.000 title abstract description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 title abstract 7
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 title abstract 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 title abstract 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 title abstract 5
- 229910052760 oxygen Inorganic materials 0.000 title abstract 5
- 239000001301 oxygen Substances 0.000 title abstract 5
- 230000017858 demethylation Effects 0.000 claims abstract description 22
- 238000010520 demethylation reaction Methods 0.000 claims abstract description 22
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims abstract description 10
- 238000006396 nitration reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 28
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 8
- 230000000802 nitrating effect Effects 0.000 claims description 8
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- VWDWKYIASSYTQR-UHFFFAOYSA-N sodium nitrate Chemical compound [Na+].[O-][N+]([O-])=O VWDWKYIASSYTQR-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical group [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 5
- 229940071870 hydroiodic acid Drugs 0.000 claims description 5
- JCZMXVGQBBATMY-UHFFFAOYSA-N nitro acetate Chemical compound CC(=O)O[N+]([O-])=O JCZMXVGQBBATMY-UHFFFAOYSA-N 0.000 claims description 5
- 150000003053 piperidines Chemical class 0.000 claims description 5
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 claims description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid group Chemical group S(O)(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000004317 sodium nitrate Substances 0.000 claims description 3
- 235000010344 sodium nitrate Nutrition 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 229910015900 BF3 Inorganic materials 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 5
- 208000001647 Renal Insufficiency Diseases 0.000 abstract description 4
- 201000006370 kidney failure Diseases 0.000 abstract description 4
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- YNKMHABLMGIIFX-UHFFFAOYSA-N benzaldehyde;methane Chemical compound C.O=CC1=CC=CC=C1 YNKMHABLMGIIFX-UHFFFAOYSA-N 0.000 abstract 2
- 230000000977 initiatory effect Effects 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 239000012074 organic phase Substances 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical class O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000012043 crude product Substances 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- 238000007670 refining Methods 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 230000002378 acidificating effect Effects 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000010813 municipal solid waste Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000013517 stratification Methods 0.000 description 6
- 208000020832 chronic kidney disease Diseases 0.000 description 5
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 5
- 238000011160 research Methods 0.000 description 4
- FPEUDBGJAVKAEE-UHFFFAOYSA-N 1,3-dimethoxy-2-methylbenzene Chemical compound COC1=CC=CC(OC)=C1C FPEUDBGJAVKAEE-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N coumarin Chemical compound C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 102000004887 Transforming Growth Factor beta Human genes 0.000 description 2
- 108090001012 Transforming Growth Factor beta Proteins 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 230000003907 kidney function Effects 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000008085 renal dysfunction Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- WTMJHBZSSSDBFQ-UHFFFAOYSA-N 2,3,4-trimethyl-1h-pyrrole Chemical compound CC1=CNC(C)=C1C WTMJHBZSSSDBFQ-UHFFFAOYSA-N 0.000 description 1
- 102000005862 Angiotensin II Human genes 0.000 description 1
- 101800000733 Angiotensin-2 Proteins 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- PQMOXTJVIYEOQL-UHFFFAOYSA-N Cumarin Natural products CC(C)=CCC1=C(O)C(C(=O)C(C)CC)=C(O)C2=C1OC(=O)C=C2CCC PQMOXTJVIYEOQL-UHFFFAOYSA-N 0.000 description 1
- 206010066786 Diabetic keratopathy Diseases 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- FSOGIJPGPZWNGO-UHFFFAOYSA-N Meomammein Natural products CCC(C)C(=O)C1=C(O)C(CC=C(C)C)=C(O)C2=C1OC(=O)C=C2CCC FSOGIJPGPZWNGO-UHFFFAOYSA-N 0.000 description 1
- 102000046299 Transforming Growth Factor beta1 Human genes 0.000 description 1
- 101800002279 Transforming growth factor beta-1 Proteins 0.000 description 1
- GPWHDDKQSYOYBF-UHFFFAOYSA-N ac1l2u0q Chemical compound Br[Br-]Br GPWHDDKQSYOYBF-UHFFFAOYSA-N 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229950006323 angiotensin ii Drugs 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000007882 cirrhosis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 229960000956 coumarin Drugs 0.000 description 1
- 235000001671 coumarin Nutrition 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229950000023 diarbarone Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- OGWJLWKFDHLZHV-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-4-hydroxy-2-oxochromene-3-carboxamide Chemical compound C1=CC=C2OC(=O)C(C(=O)NCCN(CC)CC)=C(O)C2=C1 OGWJLWKFDHLZHV-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 208000037922 refractory disease Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229940099456 transforming growth factor beta 1 Drugs 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrane Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides the preparation technology of the carboxylic acid of 7 hydroxyl, 8 methyl, 6 nitro, 2 oxygen 2H chromenes 3, belong to technical field of medicine synthesis；The carboxylic acid of 7 hydroxyl, 8 methyl, 6 nitro, 2 oxygen 2H chromenes 3 is the key intermediate of renal failure resistant medicine thing 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin, the present invention is using the tolyl aldehyde of 2 hydroxyl, 4 methoxyl group 3 as initiation material, first step elder generation demethylation obtains the tolyl aldehyde of 2 hydroxyl, 4 methoxyl group 3, second step carries out nitration reaction and obtains the nitrobenzaldehyde of 2 hydroxyl, 4 methoxyl group, 3 methyl 5, 3rd step is condensed to yield the carboxylic acid of 7 methoxyl group, 8 methyl, 6 nitro, 2 oxygen 2H chromenes 3 with diethyl malonate, 4th step carries out demethylation and obtains the carboxylic acid of 7 hydroxyl, 8 methyl, 6 nitro, 2 oxygen 2H chromenes 3.
Description
Technical field
The present invention is 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin key intermediate 7- hydroxyl -8- methyl -6- nitro -2- oxygen -2H- chromene -3- carboxylics
The preparation of acid, belongs to technical field of medicine synthesis.
Background technology
Chronic renal failure (CRF) refers to that slow progressive kidney function damage finally results in caused by various kidney troubles
Uremia and renal function completely lose, the Comprehensive Clinical for causing a series of metabolic disorder such as clinical symptoms and biochemical endocrine to form
For disease since protopathy onset to renal insufficiency, interval time can be the several years to more than ten years.Chronic renal failure (CRF) is for I
One of most commonly seen refractory disease of state.
At present, dialysis treatment is the effective means for treating CRF, but because it is limited by the medical condition of dialysis machine,
And there is cardiovascular complication is high, the problems such as poor compliance and financial burden, the application in China is still extremely limited.Therefore it is new
The development and exploitation of type renal failure resistant medicine thing are particularly important.
A series of new cumarins and its amides compound have been synthesized in continuing to the research of coumarin kind compound,
It was found that this kind of Diarbarone class compound has good inhibiting effect to transforming growth factor-beta 1, cumarin is to TGF-β 1
Material is to treat the relevant material such as chronic renal dysfunction, diabetic keratopathy renal dysfunction.Also can very significantly it drop simultaneously
Low Angiotensin II, thus it to chronic kidney hypofunction, ephritis, hypertension, even cirrhosis and pulmonary fibrosis drug research
All it is related.
3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin is that institute of Materia Medica,Chinese Academy of Medical Sciences tracks the research of international forward position, in vitro with kidney fibrous
It is target spot to change one of two related most critical factors of lesion TGF-β 1, autotelic design, synthesis, screening, structural modification and
Optimization, verify that toxicologic study, what is developed has clear and definite renal insufficiency therapeutic action and toxicity through internal pharmacodynamics repeatedly
The novel compound of a low, active Diarbarone micromolecular higher, the mechanism of action is new.A phase is completed at present
Clinical trial.So to 3-(3'-carboxy-4'-hydroxy-anilino-carbo-)-6-nitro-7-hydroxy-8-methyl-coumarin key intermediate 7- hydroxyl -8- methyl -6- nitro -2- oxygen -2H- chromene -3- carboxylic acids
The research of preparation technology be also even more important.
Currently without publication or document report.
The content of the invention
The invention provides the preparation technology of 7- hydroxyl -8- methyl -6- nitro -2- oxygen -2H- chromene -3- carboxylic acids.
The present invention is to be achieved through the following technical solutions above-mentioned purpose：
A kind of preparation technology of 7- hydroxyls -8- methyl -6- nitros -2- oxygen -2H- chromene -3- carboxylic acids, including following step
Suddenly：
(1) 2- hydroxyls -4- methoxyl groups -3- tolyl aldehyde demethylations obtain 2- hydroxyl -4- methoxyl group -3- tolyl aldehydes
(2) 2- hydroxyls -4- methoxyl group -3- tolyl aldehydes carry out nitration reaction and obtain 2- hydroxyl -4- methoxyl group -3- first
Base -5- nitrobenzaldehydes
(3) 2- hydroxyls -4- methoxyl groups -3- methyl-5-nitros benzaldehyde and diethyl malonate be condensed to yield 7- methoxyl groups -
8- methyl -6- nitro -2- oxygen -2H- chromene -3- carboxylic acids
(4) 7- methoxyl groups -8- methyl -6- nitros -2- oxygen -2H- chromene -3- carboxylic acid demethylations obtain 7- hydroxyls -8-
Methyl -6- nitro -2- oxygen -2H- chromene -3- carboxylic acids
The preparation technology of described 7- hydroxyl -8- methyl -6- nitro -2- oxygen -2H- chromene -3- carboxylic acids：
Demethylation reagent is zinc chloride, trim,ethylchlorosilane, one kind of aluminium chloride in step (1)；
Nitrating agent is sulfuric acid and sodium nitrate system in step (2), one in acetyl nitric acid anhydride, acetic anhydride and nitric acid system
Kind；
Catalyst is one kind in trimethylpyridine, piperidines, triethylamine in step (3)；
Demethylation reagent is alchlor, hydroiodic acid, one kind of boron trifluoride in step (4).
The preparation technology of described 7- hydroxyl -8- methyl -6- nitro -2- oxygen -2H- chromene -3- carboxylic acids：
The mol ratio of 2- hydroxyls -4- methoxyl group -3- tolyl aldehydes and demethylation reagent is 1 in step (1):1.1~
1.5, reaction temperature is 0 DEG C~-20 DEG C；
The molar ratio of 2- hydroxyls -4- methoxyl group -3- tolyl aldehydes and nitrating agent is 1 in step (2):2~4, instead
It is 0 DEG C~-20 DEG C to answer temperature；
2- hydroxyls -4- methoxyl groups -3- methyl-5-nitros benzaldehyde and diethyl malonate and catalyst in step (3)
Molar ratio is 1:1.2:1.2~2, reaction temperature is room temperature；
7- methoxyl groups -8- methyl -6- nitro -2- oxygen -2H- chromene -3- carboxylic acids and demethylation reagent in step (4)
Molar ratio is 1:1.2~1.8, reaction temperature is 0 DEG C~-20 DEG C.
The preparation technology of described 7- hydroxyl -8- methyl -6- nitro -2- oxygen -2H- chromene -3- carboxylic acids, preferable side
Case is：
Demethylation reagent is trim,ethylchlorosilane in step (1)；
Nitrating agent is acetyl nitric acid anhydride in step (2)；
Catalyst is piperidines in step (3)；
Demethylation reagent is hydroiodic acid in step (4).
The mol ratio of 2- hydroxyls -4- methoxyl group -3- tolyl aldehydes and demethylation reagent is 1 in step (1):1.2；
The molar ratio of 2- hydroxyls -4- methoxyl group -3- tolyl aldehydes and nitrating agent is 1 in step (2):3；
2- hydroxyls -4- methoxyl groups -3- methyl-5-nitros benzaldehyde and diethyl malonate and catalyst in step (3)
Molar ratio is 1:1.2:1.5；
7- methoxyl groups -8- methyl -6- nitro -2- oxygen -2H- chromene -3- carboxylic acids and demethylation reagent in step (4)
Molar ratio is 1:1.5.
The preparation technology of 7- hydroxyls -8- methyl -6- nitros -2- oxygen -2H- chromene -3- carboxylic acids provided by the invention, tool
Standby following process advantage：(1) raw materials used is common agents, and cost is low；
(2) reaction condition readily satisfies, and is adapted to big industrial production；
(3) post processing of this technique is simple, and yield is higher, does not pollute the environment simultaneously.
Brief description of the drawings
Fig. 1 is the nucleus magnetic hydrogen spectrum figure of 7- hydroxyl -8- methyl -6- nitro -2- oxygen -2H- chromene -3- carboxylic acids；
Fig. 2 is the mass spectrogram of 7- hydroxyl -8- methyl -6- nitro -2- oxygen -2H- chromene -3- carboxylic acids.
Embodiment
Following embodiment is only used for further describing the present invention, is not intended to limit the present invention.
Embodiment 1
100ml dichloromethane, 9g (0.05mol) 2,4- dimethoxy -3- methylbenzene first are added in 250ml four-hole bottles
Aldehyde, stirring and dissolving.Under argon gas protection, 7.50g (0.055mol) zinc chloride is added portionwise, ice salt bath control temperature of reaction system exists
0 DEG C~-20 DEG C, TLC monitoring reaction ends.Reaction terminates to add appropriate trash ice in backward mixture, and uses saturated sodium bicarbonate
Solution adjusts PH weakly acidic pHs, stratification, separates organic phase, and organic phase dries half an hour with anhydrous magnesium sulfate, filters, is concentrated to give
To crude product.Crude product is refining to obtain product 2- hydroxyl -4- methoxyl group -3- tolyl aldehydes 4.62g with absolute ethyl alcohol
(0.0278mol), yield 55.6%.
100ml dichloromethane is added in 250ml four-hole bottles, 4.25g (0.05mol) sodium nitrate is added, adds
(4.15g 0.025mol) 2- hydroxyl -4- methoxyl group -3- tolyl aldehydes, ice bath cooling is lower to be added dropwise 4.9g (0.05mol) dense sulphur
Acid, temperature is no more than 0 DEG C in control.TLC detects terminal.Neutrality is adjusted to saturated sodium bicarbonate solution, separates organic phase, anhydrous sulphur
Sour magnesium dries half an hour, filters, is concentrated to give yellow solid.Light yellow solid 2- hydroxyl -4- first is refining to obtain with absolute ethyl alcohol
Epoxide -3- methyl-5-nitro benzaldehyde 2.33g (0.011mol), yield 44%.
50ml toluene, 2.11g (0.01mol) 2- hydroxyl -4- methoxyl group -3- methyl -5- nitre are added in 100ml four-hole bottles
Benzaldehyde, 1.92g (0.012mol) diethyl malonate, is stirred at room temperature dissolving.1.45g (0.012mol) trimethyl pyrrole is added dropwise
Pyridine, it is warming up to backflow, TLC detection terminals.After completion of the reaction, concentrated mother liquor.As adding 50ml dichloromethane in residue, then
10ml water is added, is completely dissolved residue.Organic phase is separated, half an hour is dried with anhydrous magnesium sulfate.Filter, be concentrated to give Huang
Color solid.Crude product is refining to obtain product 7- methoxyl group -8- methyl -6- nitro -2- oxygen -2H- chromene -3- carboxylics with absolute ethyl alcohol
Sour 2.11g (0.007mol), yield 70%.
The addition 50ml dichloromethane in 100ml four-hole bottles, 1.4g (0.005mol) 7- methoxyl group -8- methyl -6- nitros -
2- oxygen -2H- chromene -3- carboxylic acids, stirring and dissolving.Under argon gas protection, 1.6g (0.006mol) alchlor, ice is added portionwise
Salt bath controls temperature of reaction system, and at 0 DEG C~-20 DEG C, TLC monitors reaction end.Reaction terminates to add in right amount in backward mixture
Trash ice, and PH weakly acidic pHs are adjusted with saturated sodium bicarbonate solution, stratification, separate organic phase, organic phase anhydrous magnesium sulfate
Half an hour is dried, filters, is concentrated to give crude product.Crude product with absolute ethyl alcohol be refining to obtain product 7- hydroxyl -8- methyl -6- nitros -
2- oxygen -2H- chromene -3- carboxylic acids 1.03g (0.0039mol), yield 78%.
Embodiment 2
200ml dichloromethane, 18g (0.1mol) 2,4- dimethoxy -3- methylbenzene first are added in 500ml four-hole bottles
Aldehyde, stirring and dissolving.Under argon gas protection, 13.04g (0.12mol) trim,ethylchlorosilane, ice salt bath control reaction system temperature are added dropwise to
For degree at 0 DEG C -20 DEG C, TLC monitors reaction end.Reaction terminates to add appropriate trash ice in backward mixture, and with unsaturated carbonate hydrogen
Sodium solution adjusts PH weakly acidic pHs, stratification, separates organic phase, and organic phase dries half an hour with anhydrous magnesium sulfate, filters, concentration
Obtain crude product.Crude product is refining to obtain product 2- hydroxyl -4- methoxyl group -3- tolyl aldehydes 13.63g with absolute ethyl alcohol
(0.082mol), yield 82%.
The addition 150ml dichloromethane in 500ml four-hole bottles, addition 13.28g (0.08mol) 2- hydroxyl -4- methoxyl groups -
3- tolyl aldehydes, ice bath cooling is lower to be added dropwise 25.2g (0.24mol) acetyl nitric acid anhydride, and temperature is no more than 0 DEG C in control.After dripping off
0 DEG C of continuation is stirred below.TLC detects terminal.Neutrality is adjusted to saturated sodium bicarbonate solution, separates organic phase, anhydrous magnesium sulfate
Half an hour is dried, filters, is concentrated to give yellow solid.With absolute ethyl alcohol be refining to obtain light yellow solid 2- hydroxyl -4- methoxyl groups -
3- methyl-5-nitro benzaldehyde 14.02g (0.066mol), yield 82.5%.
100ml toluene, 10.55g (0.05mol) 2- hydroxyl -4- methoxyl group -3- methyl -5- are added in 250ml four-hole bottles
Nitrobenzaldehyde, 9.6g (0.06mol) diethyl malonate, is stirred at room temperature dissolving.6.39g (0.075mol) piperidines is added dropwise, rises
For temperature to flowing back, TLC detects terminal.After completion of the reaction, concentrated mother liquor.As adding 200ml dichloromethane in residue, then add
30ml water, is completely dissolved residue.Organic phase is separated, half an hour is dried with anhydrous magnesium sulfate.Filter, be concentrated to give yellow and consolidate
Body.Crude product is refining to obtain product 7- methoxyl group -8- methyl -6- nitro -2- oxygen -2H- chromene -3- carboxylic acids with absolute ethyl alcohol
12.48g (0.045mol), yield 90%.
The addition 50ml dichloromethane in 100ml four-hole bottles, 5.58g (0.02mol) 7- methoxyl group -8- methyl -6- nitros -
2- oxygen -2H- chromene -3- carboxylic acids, stirring and dissolving.Under argon gas protection, 6.62g (0.03mol) 58% hydroiodic acid, ice is added dropwise
Salt bath controls temperature of reaction system, and at 0 DEG C~-20 DEG C, TLC monitors reaction end.Reaction terminates to add in right amount in backward mixture
Trash ice, and PH weakly acidic pHs are adjusted with saturated sodium bicarbonate solution, stratification, separate organic phase, organic phase anhydrous magnesium sulfate
Half an hour is dried, filters, is concentrated to give crude product.Crude product with absolute ethyl alcohol be refining to obtain product 7- hydroxyl -8- methyl -6- nitros -
2- oxygen -2H- chromene -3- carboxylic acids 4.52g (0.017mol), yield are 85%.MS m/z:263.9[M-H]-.1H-NMR
(300MHz,DMSO-d6)δ:13.06(s,1H),8.74(s,1H),8.55(s,1H),2.21(s,3H)。
Embodiment 3
200ml dichloromethane, 14.4g (0.08mol) 2,4- dimethoxy -3- methylbenzenes are added in 500ml four-hole bottles
Formaldehyde, stirring and dissolving.Under argon gas protection, 23.18g (0.12mol) aluminium chloride is added, ice salt bath controls temperature of reaction system 0
DEG C~-20 DEG C, TLC monitoring reaction ends.Reaction terminates to add appropriate trash ice in backward mixture, and molten with saturated sodium bicarbonate
Liquid adjusts PH weakly acidic pHs, stratification, separates organic phase, and organic phase dries half an hour with anhydrous magnesium sulfate, filters, is concentrated to give
Crude product.Crude product is refining to obtain product 2- hydroxyl -4- methoxyl group -3- tolyl aldehydes 8.95g (0.054mol) with absolute ethyl alcohol, receives
Rate is 67.5%.
80ml acetic anhydride is added in 250ml four-hole bottles, adds 6.64g (0.04mol) 2- hydroxyl -4- methoxyl group -3- first
Benzaldehyde, 10.61g (0.16mol) 95% fuming nitric aicd is added dropwise under ice bath cooling, temperature is no more than 0 DEG C in control.After dripping off
0 DEG C of continuation is stirred below.TLC detects terminal.Neutrality is adjusted to saturated sodium bicarbonate solution, separates organic phase, anhydrous magnesium sulfate
Half an hour is dried, filters, is concentrated to give yellow solid.With absolute ethyl alcohol be refining to obtain light yellow solid 2- hydroxyl -4- methoxyl groups -
3- methyl-5-nitro benzaldehyde 6.11g (0.029mol), yield 72.5%.
50ml toluene, 5.63g (0.027mol) 2- hydroxyl -4- methoxyl group -3- methyl -5- are added in 250ml four-hole bottles
Nitrobenzaldehyde, 5.12g (0.032mol) diethyl malonate, is stirred at room temperature dissolving.5.40g (0.053mol) three second is added dropwise
Amine, it is warming up to backflow, TLC detection terminals.After completion of the reaction, concentrated mother liquor.As adding 100ml dichloromethane in residue, so
20ml water is added afterwards, is completely dissolved residue.Organic phase is separated, half an hour is dried with anhydrous magnesium sulfate.Filter, be concentrated to give
Yellow solid.Crude product is refining to obtain product 7- methoxyl group -8- methyl -6- nitro -2- oxygen -2H- chromenes -3- with absolute ethyl alcohol
Carboxylic acid 5.44g (0.0195mol), yield 72.22%.
50ml dichloromethane, 3.35g (0.012mol) 7- methoxyl group -8- methyl -6- nitre are added in 100ml four-hole bottles
Base -2- oxygen -2H- chromene -3- carboxylic acids, stirring and dissolving.Under argon gas protection, 1.46g (0.022mol) tribromide is added portionwise
Aluminium, ice salt bath controls temperature of reaction system, and at 0 DEG C~-20 DEG C, TLC monitors reaction end.Reaction terminates to add in backward mixture
Add appropriate trash ice, and PH weakly acidic pHs are adjusted with saturated sodium bicarbonate solution, stratification separates organic phase, and organic phase is with anhydrous
Magnesium sulfate dries half an hour, filters, is concentrated to give crude product.Crude product is refining to obtain product 7- hydroxyl -8- methyl -6- with absolute ethyl alcohol
Nitro -2- oxygen -2H- chromene -3- carboxylic acids 2.01g (0.0077mol), yield 64.17%.
Claims (5)
- A kind of 1. preparation technology of 7- hydroxyls -8- methyl -6- nitros -2- oxygen -2H- chromene -3- carboxylic acids, it is characterised in that： Comprise the following steps：(1) 2- hydroxyls -4- methoxyl groups -3- tolyl aldehyde demethylations obtain 2- hydroxyl -4- methoxyl group -3- tolyl aldehydes；(2) 2- hydroxyls -4- methoxyl group -3- tolyl aldehydes carry out nitration reaction and obtain 2- hydroxyl -4- methoxyl group -3- methyl -5- Nitrobenzaldehyde；(3) 2- hydroxyls -4- methoxyl groups -3- methyl-5-nitros benzaldehyde is condensed to yield 7- methoxyl group -8- first with diethyl malonate Base -6- nitro -2- oxygen -2H- chromene -3- carboxylic acids；(4) 7- methoxyl groups -8- methyl -6- nitros -2- oxygen -2H- chromene -3- carboxylic acid demethylations obtain 7- hydroxyl -8- methyl - 6- nitro -2- oxygen -2H- chromene -3- carboxylic acids.。
- 2. the preparation work of 7- hydroxyls -8- methyl -6- nitros -2- oxygen -2H- chromene -3- carboxylic acids according to claim 1 Skill, it is characterised in that：Demethylation reagent is zinc chloride, trim,ethylchlorosilane, one kind of aluminium chloride in step (1)；Nitrating agent is sulfuric acid and sodium nitrate system in step (2), one kind in acetyl nitric acid anhydride, acetic anhydride and nitric acid system；Catalyst is one kind in trimethylpyridine, piperidines, triethylamine in step (3)；Demethylation reagent is alchlor, hydroiodic acid, one kind of boron trifluoride in step (4).
- 3. the system of 7- hydroxyls -8- methyl -6- nitros -2- oxygen -2H- chromene -3- carboxylic acids according to claim 1 or 2 Standby technique, it is characterised in that：The mol ratio of 2- hydroxyls -4- methoxyl group -3- tolyl aldehydes and demethylation reagent is 1 in step (1):1.1~1.5, instead It is 0 DEG C~-20 DEG C to answer temperature；The molar ratio of 2- hydroxyls -4- methoxyl group -3- tolyl aldehydes and nitrating agent is 1 in step (2):2~4, reaction temperature Degree is 0 DEG C~-20 DEG C；2- hydroxyls -4- methoxyl groups -3- methyl-5-nitros benzaldehyde and diethyl malonate and mole of catalyst in step (3) Ratio is 1:1.2:1.2~2, reaction temperature is room temperature；Mole of 7- methoxyl groups -8- methyl -6- nitro -2- oxygen -2H- chromene -3- carboxylic acids and demethylation reagent in step (4) Ratio is 1:1.2~1.8, reaction temperature is 0 DEG C~-20 DEG C.
- 4. the system of 7- hydroxyls -8- methyl -6- nitros -2- oxygen -2H- chromene -3- carboxylic acids according to claim 1 or 2 Standby technique, it is characterised in that：Demethylation reagent is trim,ethylchlorosilane in step (1)；Nitrating agent is acetyl nitric acid anhydride in step (2)；Catalyst is piperidines in step (3)；Demethylation reagent is hydroiodic acid in step (4).
- 5. the system of 7- hydroxyls -8- methyl -6- nitros -2- oxygen -2H- chromene -3- carboxylic acids according to claim 1 or 2 Standby technique, it is characterised in that：The mol ratio of 2- hydroxyls -4- methoxyl group -3- tolyl aldehydes and demethylation reagent is 1 in step (1):1.2；The molar ratio of 2- hydroxyls -4- methoxyl group -3- tolyl aldehydes and nitrating agent is 1 in step (2):3；2- hydroxyls -4- methoxyl groups -3- methyl-5-nitros benzaldehyde and diethyl malonate and mole of catalyst in step (3) Ratio is 1:1.2:1.5；Mole of 7- methoxyl groups -8- methyl -6- nitro -2- oxygen -2H- chromene -3- carboxylic acids and demethylation reagent in step (4) Ratio is 1:1.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711046847.3A CN107868069A (en) | 2017-10-31 | 2017-10-31 | The preparation technology of the carboxylic acid of 7 hydroxyl, 8 methyl, 6 nitro, 2 oxygen 2H chromenes 3 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711046847.3A CN107868069A (en) | 2017-10-31 | 2017-10-31 | The preparation technology of the carboxylic acid of 7 hydroxyl, 8 methyl, 6 nitro, 2 oxygen 2H chromenes 3 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107868069A true CN107868069A (en) | 2018-04-03 |
Family
ID=61752868
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711046847.3A Pending CN107868069A (en) | 2017-10-31 | 2017-10-31 | The preparation technology of the carboxylic acid of 7 hydroxyl, 8 methyl, 6 nitro, 2 oxygen 2H chromenes 3 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107868069A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109136935A (en) * | 2018-10-25 | 2019-01-04 | 西南石油大学 | A kind of purposes of pyran derivate and preparation method thereof |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1207392A (en) * | 1997-07-31 | 1999-02-10 | 中国医学科学院药物研究所 | Viformyl cumarins compound, process for preparing same and pharmaceutical composition contg. same |
| CN1440399A (en) * | 2000-07-03 | 2003-09-03 | 奥赖恩公司 | Coumarin derivatives with COMT inhibiting activity |
| CN1768050A (en) * | 2003-03-31 | 2006-05-03 | 法玛西雅公司 | Benzopyran compounds useful for treating inflammatory conditions |
| CN1955175A (en) * | 2004-10-28 | 2007-05-02 | 中国医学科学院药物研究所 | Cumarin derivative and its preparation method and its drug composite and use |
| CN100488504C (en) * | 2002-12-05 | 2009-05-20 | 中国医学科学院药物研究所 | Novel coumarin-amide derivatives and its preparation, its drug composition and use |
| CN101747305A (en) * | 2008-11-28 | 2010-06-23 | 中国医学科学院药物研究所 | Five crystal forms of nicousamide compound and preparation method, pharmaceutical composition and usage thereof |
| CN102686574A (en) * | 2009-10-23 | 2012-09-19 | 阿勒根公司 | Coumarin compounds as receptor modulators with therapeutic utility |
-
2017
- 2017-10-31 CN CN201711046847.3A patent/CN107868069A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1207392A (en) * | 1997-07-31 | 1999-02-10 | 中国医学科学院药物研究所 | Viformyl cumarins compound, process for preparing same and pharmaceutical composition contg. same |
| CN1440399A (en) * | 2000-07-03 | 2003-09-03 | 奥赖恩公司 | Coumarin derivatives with COMT inhibiting activity |
| CN100488504C (en) * | 2002-12-05 | 2009-05-20 | 中国医学科学院药物研究所 | Novel coumarin-amide derivatives and its preparation, its drug composition and use |
| CN1768050A (en) * | 2003-03-31 | 2006-05-03 | 法玛西雅公司 | Benzopyran compounds useful for treating inflammatory conditions |
| CN1955175A (en) * | 2004-10-28 | 2007-05-02 | 中国医学科学院药物研究所 | Cumarin derivative and its preparation method and its drug composite and use |
| CN101747305A (en) * | 2008-11-28 | 2010-06-23 | 中国医学科学院药物研究所 | Five crystal forms of nicousamide compound and preparation method, pharmaceutical composition and usage thereof |
| CN102686574A (en) * | 2009-10-23 | 2012-09-19 | 阿勒根公司 | Coumarin compounds as receptor modulators with therapeutic utility |
Non-Patent Citations (2)
| Title |
|---|
| KUWABARA, NAGAKO等: "Syntheses of the antibiotic alkaloids renierone, mimocin, renierol, renierol acetate, renierol propionate, and 7-methoxy-1,6-dimethylisoquinoline-5,8-dione", 《TETRAHEDRON》 * |
| SHUANGHAN 等: "Design, syntheses, structure–activity relationships and docking studies of coumarin derivatives as novel selective ligands for the CB2 receptor", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109136935A (en) * | 2018-10-25 | 2019-01-04 | 西南石油大学 | A kind of purposes of pyran derivate and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111423452B (en) | Intermediate of Rayleigh Lu Geli and preparation method and application thereof | |
| CN106478482A (en) | A kind of synthetic method of Oxiracetam | |
| CN104672238B (en) | A kind of Li Gelieting preparation method | |
| CN104311536A (en) | Method for preparing lenalidomide | |
| CN109206317B (en) | Preparation process of amantadine nitrate derivative | |
| CN103965282A (en) | Preparation method for abiraterone acetate | |
| CN105367486A (en) | New impurity of cinitapride tartrate and preparation method and application thereof | |
| CN105330582A (en) | Preparation method for (R)-4-hydroxy-2-oxo-1-pyrrolidine acetamide | |
| CN105330581A (en) | Preparation method for (S)-oxiracetam | |
| CN110872247A (en) | Xofluza sulfur-containing heterocyclic compound, intermediate thereof and preparation method | |
| CN110305018A (en) | A kind of preparation method of the bromo- 2- fluoronitrobenzene of 3- | |
| CN107868069A (en) | The preparation technology of the carboxylic acid of 7 hydroxyl, 8 methyl, 6 nitro, 2 oxygen 2H chromenes 3 | |
| CN113512000A (en) | Method for large-scale production of 4 '-bromo-2, 2', 6 ', 2' -terpyridine | |
| CN103450005B (en) | A kind of preparation method of clopidogrel and the alpha-brominated (2-Chlorophenyl)acetic acid of intermediate and α-thiophene ethamine base substituted acetic acid hydrochlorate | |
| CN102336710B (en) | Method for synthesizing edaravone derivative | |
| CN103965065B (en) | Onglyza intermediate, its salt, Its Preparation Method And Use | |
| CN104592122A (en) | Preparation method for 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline | |
| CN111116493A (en) | Method for preparing Apabetalone, intermediate and preparation method of intermediate | |
| CN102516215A (en) | Preparation method of C-glucoside containing saturated cyclohexane structure | |
| CN113735798A (en) | Preparation method of roxatidine acetate hydrochloride | |
| CN113429379A (en) | LH-1801 intermediate and preparation method and application thereof | |
| CN102863347B (en) | Preparation method of chiral baclofen | |
| CN103772284B (en) | A kind of preparation method of 4,5-diaminostilbene-(2-hydroxyethyl) pyrazoles vitriol | |
| CN101812072B (en) | Method for preparing anti-platelet aggregation compounds | |
| CN105130806A (en) | Method of reducing impurities in synthesis process of emtricitabine intermediate MGH |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180403 |