CN1765895A - Nolatrexed hydrochloride synthesis process - Google Patents
Nolatrexed hydrochloride synthesis process Download PDFInfo
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- CN1765895A CN1765895A CN 200510084232 CN200510084232A CN1765895A CN 1765895 A CN1765895 A CN 1765895A CN 200510084232 CN200510084232 CN 200510084232 CN 200510084232 A CN200510084232 A CN 200510084232A CN 1765895 A CN1765895 A CN 1765895A
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- methyl
- bromo
- bromine
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title claims abstract description 14
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 10
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 10
- XHWRWCSCBDLOLM-UHFFFAOYSA-N nolatrexed Chemical compound CC1=CC=C2NC(N)=NC(=O)C2=C1SC1=CC=NC=C1 XHWRWCSCBDLOLM-UHFFFAOYSA-N 0.000 title description 9
- 229950000891 nolatrexed Drugs 0.000 title description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000001816 cooling Methods 0.000 claims abstract description 5
- 239000001117 sulphuric acid Substances 0.000 claims abstract description 5
- 235000011149 sulphuric acid Nutrition 0.000 claims abstract description 5
- FHTDDANQIMVWKZ-UHFFFAOYSA-N 1h-pyridine-4-thione Chemical compound SC1=CC=NC=C1 FHTDDANQIMVWKZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000003054 catalyst Substances 0.000 claims abstract description 3
- 238000010992 reflux Methods 0.000 claims abstract description 3
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims description 15
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 11
- 229910052794 bromium Inorganic materials 0.000 claims description 11
- PJKVJJYMWOCLIJ-UHFFFAOYSA-N 2-amino-6-methyl-5-pyridin-4-ylsulfanyl-1h-quinazolin-4-one;hydron;dichloride Chemical compound Cl.Cl.CC1=CC=C2NC(N)=NC(=O)C2=C1SC1=CC=NC=C1 PJKVJJYMWOCLIJ-UHFFFAOYSA-N 0.000 claims description 9
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 claims description 6
- VAJCSPZKMVQIAP-UHFFFAOYSA-N 5-methyl-1h-indole-2,3-dione Chemical compound CC1=CC=C2NC(=O)C(=O)C2=C1 VAJCSPZKMVQIAP-UHFFFAOYSA-N 0.000 claims description 5
- -1 added highly basic Chemical compound 0.000 claims description 4
- 238000006386 neutralization reaction Methods 0.000 claims description 4
- 150000001879 copper Chemical class 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 238000006237 Beckmann rearrangement reaction Methods 0.000 claims 1
- DKAVQCARZCYRIS-UHFFFAOYSA-N 4-bromo-5-methyl-1h-indole-2,3-dione Chemical compound CC1=CC=C2NC(=O)C(=O)C2=C1Br DKAVQCARZCYRIS-UHFFFAOYSA-N 0.000 abstract description 2
- 230000003472 neutralizing effect Effects 0.000 abstract 2
- DESUDZIADGQZIJ-UHFFFAOYSA-N 6-amino-2-bromo-3-methylbenzoic acid Chemical compound CC1=CC=C(N)C(C(O)=O)=C1Br DESUDZIADGQZIJ-UHFFFAOYSA-N 0.000 abstract 1
- 239000012670 alkaline solution Substances 0.000 abstract 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 abstract 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 108010022394 Threonine synthase Proteins 0.000 description 2
- 102000005497 Thymidylate Synthase Human genes 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 201000007270 liver cancer Diseases 0.000 description 2
- 208000014018 liver neoplasm Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000004062 sedimentation Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- RYTLGWCJESCDMY-UHFFFAOYSA-N carbamimidoyl chloride Chemical compound NC(Cl)=N RYTLGWCJESCDMY-UHFFFAOYSA-N 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 208000021045 exocrine pancreatic carcinoma Diseases 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 201000010536 head and neck cancer Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000010813 municipal solid waste Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention discloses a synthesis technique for THY-110, which comprises: Beckmann rearranging the 3-bromo-4- methyl -alpha-oximinoacetanilide in strong sulphuric acid at 50-100Deg for 0.5-2.0h ato obtain 4- bromo 5- methylisatin; adding the later in strong alkaline solution at 40-100Deg to oxidate by H2O2 for 1.0-4.0h and obtain 5- methyl -6- bromo o-aminobenzoic acid; heating and dissloving the later in 3.5-10.0% dilute sulphuric acid to loop with dicyandiamide; neutralizing to obtain 2- guanidino-3,4-dihydro-5- bromo -6- methylquinazoline-4-ketone; dissolving the later into ethandiol, adding strong base, 4-mercaptopyridine and nantokite catalyst to heat and reflux for 1-10h, cooling, neutralizing with hydrochloric acid, and obtaining the product. This technique needs short process, and has high yield and low cost.
Description
Technical field
The present invention relates to a kind of synthesis technique of Thymitaq.
Background technology
Nolatrexed is a kind of thymidylate synthetase (Thymidylate Synthase, TS) inhibitor.Its chemistry 2-amino by name-6-methyl-5-(4-pyridine sulfydryl)-4 (1H)-quinazolinones.The nolatrexed preparation of clinical application is its dihydrochloride compound.Nolatrexed the earliest by the crystalline structure of U.S. Agouron company based on TS, utilization area of computer aided medicinal design technology and the antitumor drug of a kind of brand new of designing and developing.It is mainly used in treatment liver cancer, colorectal carcinoma, lung cancer, prostate cancer, carcinoma of the pancreas and tumor of head and neck.Wherein be used for liver cancer treatment and be in III phase conceptual phase.
It is nolatrexed that (US5430148 US5707992) synthesizes by people such as Webber the earliest.Its technology is by intermediate 3-bromo-4-methyl-α-oximido antifebrin is a starting raw material, and through just obtaining target product after the reaction of 6 steps, concrete synthetic route is seen Fig. 1.Mainly there is following point in this technology, and the one, step is longer, and overall yield is low, and overall yield only is about 10%.The 2nd, reaction conditions is relatively harsher, comprises needing waterless operation etc.The 3rd, raw material is difficult to obtain, for example chlorine amidine (chloroformamidine) just not supply at home.Therefore, seek new synthetic method, improving synthesis technique is purposes of the present invention to satisfy the needs that amplify production.
Summary of the invention
The objective of the invention is to overcome the defective of prior art, a kind of synthesis technique of Thymitaq is provided.
The synthesis technique of Thymitaq of the present invention is that 3-bromo-4-methyl-α-oximido antifebrin (compound 2) is reset acquisition 4-bromine 5-methyl isatin (compound 3) at 50 ℃-100 ℃ through 0.5-2.0 hour Beckman Beckmann in the vitriol oil.With 1.0-4.0 hour H of process in the strong base solution of compound 3 under 40 ℃-100 ℃
2O
2Oxidation prepares 5-methyl-6-bromine anthranilic acid (compound 4).Compound 4 after the dilute sulphuric acid heating for dissolving of 3.5-10.0% with Dyhard RU 100 at Cheng Huan, obtain 2-guanidine radicals-3 after the neutralization, 4-dihydro-5-bromo-6-methyl quinazoline-4-one (compound 9).After compound 9 is dissolved in ethylene glycol, add highly basic, 4-mercaptopyridine and copper salt catalyst (CuBr and Cu
2O) reflux 1-10 hour, add the hydrochloric acid neutralization after the cooling and obtain 2-amino-3,4-dihydro-6-methyl-5-(4 '-the pyridine sulfydryl) quinazoline-4-one (nolatrexed, compound 1).
The invention has the advantages that: the one, reactions steps is short, only needs for three steps just can obtain target product, and overall yield improves greatly.The 2nd, the reaction conditions gentleness, easy handling is convenient to amplify and is produced.The 3rd, raw material domesticizes fully, low price, and production cost reduces greatly.
Description of drawings
Fig. 1 is existing nolatrexed synthesis technique synoptic diagram;
Fig. 2 is the synthesis technique synoptic diagram of Thymitaq of the present invention.
The figure number explanation:
1 is compound 2-amino-3,4-dihydro-6-methyl-5-(4 '-pyridine sulfydryl) quinazoline-4-one is a Thymitaq, 2 is compound 3-bromo-4-methyl-α-oximido antifebrin, 3 is compound 4-bromine 5-methyl isatin, 4 is compound 5-methyl-6-bromine anthranilic acid, 9 is compound 2-guanidine radicals-3,4-dihydro-5-bromo-6-methyl quinazoline-4-one.
Embodiment
Below in conjunction with description of drawings the specific embodiment of the present invention.
As shown in Figure 2,
Embodiment 1
Synthesizing of 4-bromine 5-methyl isatin (compound 3)
Slowly add 500g (1.95mol) 3-bromo-4-methyl-α-oximido antifebrin (compound 2), stirring reaction 1 hour after the vitriol oil of 2000ml is heated to 90 ℃.Reaction mixture is chilled to room temperature, is poured in the trash ice then.Sedimentation and filtration, washing.Solid adds the water and the heating of capacity, transfers to strong basicity with NaOH and makes the solid dissolving, filters.Filtrate adds hydrochloric acid again and transfers to pH value about 3.Sedimentation and filtration, washing gets 343g shiny red solid (yield: 73.2%).m.p.245-248℃。
1HNMR (CDCl
3) δ 2.26 (3H, s), 6.8 (1H, d), 7.5 (1H, d), 11.06 (1H, s). intermediate 3-bromo-4-methyl-α-oximido antifebrin is a starting raw material.Market is on sale.
Synthesizing of 5-methyl-6-bromine anthranilic acid (compound 4)
4-bromo-5-methyl isatin 700g (2.92mol, compound 3) is dissolved in the 3mol/L NaOH solution, is heated to 60 ℃, drips 600ml H
2O
2, stir 2h.Add hydrochloric acid after the cooling and transfer to pH value 5.With its evaporate to dryness, add 10000ml methyl alcohol.Filter, filtrate again evaporate to dryness get 572g tawny solid (yield: 85.2%), m.p.290-294 ℃,
1HNMR (DMSO-d6): δ 2.13 (s, 3H), 4.9 (s, 2H), 6.4 (d, 1H), 6.74 (d, 1H).
2-guanidine radicals-3,4-dihydro-5-bromo-6-methyl quinazoline-4-one (compound 9) synthetic
5-methyl-6-bromine anthranilic acid 500g (2.17mol, compound 4) adds 7.5% dilute sulphuric acid 2000ml, is heated to dissolving fully.Add Dyhard RU 100 350g (3.98mol), intense reaction adds 50%NaOH after cold slightly and transfers to alkalescence (pH=10), heating 20min.Suction filtration, washing, drying gets 378g pale solid (yield: 62.0%).Because sample is insoluble in organic solvent and water, does not do recrystallization, is directly used in next step reaction.MS(EI)：295，297(12)，211，213(70)，185，187(100)，132(33)，106(44)，77(40)。
2-amino-3,4-dihydro-6-methyl-5-(4 '-pyridine sulfydryl) quinazoline-4-one (nolatrexed, compound 1) synthetic
2-guanidine radicals-5-bromo-6-methyl quinazoline-4-one 400.0g (1.35mol, compound 9) adds 4000ml ethylene glycol, 400.0g KOH, 4-mercaptopyridine 450g (4.09mol), 114g CuBr and 114g Cu
2O, mixture heating up backflow 6h.Be chilled to room temperature and filter, filtrate is poured in the 4000ml water, adds hydrochloric acid and transfers to neutrality, filters washing, drying.Solid is dissolved in 5000ml 80% methyl alcohol again, and logical hydrogen sulfide is to saturated.Boil off methyl alcohol, filter, filtrate adds 5000ml water, transfers to neutrality with highly basic, separates out light grey precipitation.Suction filtration, washing, drying.Get light grey nolatrexed solid 310.6g (yield: 77.8%).Behind dried solid adding 188ml (2.19mol) concentrated hydrochloric acid and 270ml water, heating for dissolving, cooling, separate out crystallization, filter, a small amount of washing, vacuum-drying, 2-amino-3,4-dihydro-6-methyl-5-(4 '-pyridine sulfydryl) quinazoline-4-one is Thymitaq 270g.m.p.301-302℃。IR(KBr)：3325，3149，2762，1672，1574，1468，1307，1222，800，709，484cm
-1。
1HNMR(DMSO-d
6)δ2.31(s，3H)，6.38(bs，2H)，6.86(bs，2H)，7.27(d，1H)，7.58(d，1H)，8.53(bs，2H)，10.82(bs，1H)ppm.MS(FAB)：285(M+1，100％).
Claims (1)
1, a kind of synthesis technique of Thymitaq, its processing step comprises that 3-bromo-4-methyl-α-oximido antifebrin is passed through Beckmann rearrangement in 0.5-2.0 hour at 50 ℃-100 ℃ in the vitriol oil obtain 4-bromine 5-methyl isatin, and it is characterized in that: its processing step also comprises 1.0-4.0 hour H of process in the strong base solution of 4-bromine 5-methyl isatin under 40 ℃-100 ℃
2O
2Oxidation prepares 5-methyl-6-bromine anthranilic acid, 5-methyl-6-bromine anthranilic acid after the dilute sulphuric acid heating for dissolving of 3.5-10.0% with Dyhard RU 100 at Cheng Huan, obtain 2-guanidine radicals-3 after the neutralization, 4-dihydro-5-bromo-6-methyl quinazoline-4-one, 2-guanidine radicals-3, after the 4-dihydro-5-bromo-6-methyl quinazoline-4-one is dissolved in ethylene glycol, added highly basic, 4-mercaptopyridine and copper salt catalyst reflux 1-10 hour, add the hydrochloric acid neutralization after the cooling and obtain Thymitaq.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100842320A CN1303080C (en) | 2005-07-18 | 2005-07-18 | Nolatrexed hydrochloride synthesis process |
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|---|---|---|---|
| CNB2005100842320A CN1303080C (en) | 2005-07-18 | 2005-07-18 | Nolatrexed hydrochloride synthesis process |
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| Publication Number | Publication Date |
|---|---|
| CN1765895A true CN1765895A (en) | 2006-05-03 |
| CN1303080C CN1303080C (en) | 2007-03-07 |
Family
ID=36742033
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100842320A Expired - Fee Related CN1303080C (en) | 2005-07-18 | 2005-07-18 | Nolatrexed hydrochloride synthesis process |
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| CN (1) | CN1303080C (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104140416A (en) * | 2013-05-10 | 2014-11-12 | 北京康辰药业有限公司 | Crystal form of nolatrexed hydrochloride, and preparation method and application thereof |
| CN104177334A (en) * | 2013-05-27 | 2014-12-03 | 北京康辰药业有限公司 | Nolatrexed dihydrochloride crystal form II and preparation method and application thereof |
| CN104177335A (en) * | 2013-05-27 | 2014-12-03 | 北京康辰药业有限公司 | Nolatrexed dihydrochloride crystal form III and preparation method and application thereof |
| CN105092752B (en) * | 2014-05-20 | 2017-03-01 | 北京康辰药业股份有限公司 | A kind of with liquid chromatography separation nolatrexed dihydrochloride and the method about material |
| CN109380304A (en) * | 2018-11-28 | 2019-02-26 | 吉林大学 | A kind of oxide-based nanomaterial of anti-plant decay disease, preparation method and applications |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5430148A (en) * | 1992-03-31 | 1995-07-04 | Agouron Pharmaceuticals, Inc. | Antiproliferative quinazolines |
| US5340148A (en) * | 1993-11-03 | 1994-08-23 | Trw Vehicle Safety Systems Inc. | Air bag inflator with composite stored gas container |
| CN1335307A (en) * | 2000-07-20 | 2002-02-13 | 中国人民解放军第一军医大学 | Synthesis process of 2-amino quinbolone compounds |
-
2005
- 2005-07-18 CN CNB2005100842320A patent/CN1303080C/en not_active Expired - Fee Related
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104140416A (en) * | 2013-05-10 | 2014-11-12 | 北京康辰药业有限公司 | Crystal form of nolatrexed hydrochloride, and preparation method and application thereof |
| CN104140416B (en) * | 2013-05-10 | 2016-08-10 | 北京康辰药业股份有限公司 | A kind of nolatrexed dihydrochloride crystal formation and preparation method and application |
| CN104177334A (en) * | 2013-05-27 | 2014-12-03 | 北京康辰药业有限公司 | Nolatrexed dihydrochloride crystal form II and preparation method and application thereof |
| CN104177335A (en) * | 2013-05-27 | 2014-12-03 | 北京康辰药业有限公司 | Nolatrexed dihydrochloride crystal form III and preparation method and application thereof |
| CN106831715A (en) * | 2013-05-27 | 2017-06-13 | 北京康辰药业股份有限公司 | A kind of nolatrexed dihydrochloride crystal formation II and preparation method and application |
| CN106892899A (en) * | 2013-05-27 | 2017-06-27 | 北京康辰药业股份有限公司 | A kind of nolatrexed dihydrochloride crystal formation III and preparation method and application |
| CN105092752B (en) * | 2014-05-20 | 2017-03-01 | 北京康辰药业股份有限公司 | A kind of with liquid chromatography separation nolatrexed dihydrochloride and the method about material |
| CN109380304A (en) * | 2018-11-28 | 2019-02-26 | 吉林大学 | A kind of oxide-based nanomaterial of anti-plant decay disease, preparation method and applications |
| CN109380304B (en) * | 2018-11-28 | 2020-12-01 | 吉林大学 | Oxide nano material for resisting plant rot disease, preparation method and application thereof |
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| CN1303080C (en) | 2007-03-07 |
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