CN105367477A - 1-methyl tryptophan synthesis method - Google Patents
1-methyl tryptophan synthesis method Download PDFInfo
- Publication number
- CN105367477A CN105367477A CN201410391864.0A CN201410391864A CN105367477A CN 105367477 A CN105367477 A CN 105367477A CN 201410391864 A CN201410391864 A CN 201410391864A CN 105367477 A CN105367477 A CN 105367477A
- Authority
- CN
- China
- Prior art keywords
- methyl
- reaction
- tryptophan
- solid
- methyl tryptophan
- 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.)
- Granted
Links
- ZADWXFSZEAPBJS-UHFFFAOYSA-N C[n]1c(cccc2)c2c(CC(C(O)=O)N)c1 Chemical compound C[n]1c(cccc2)c2c(CC(C(O)=O)N)c1 ZADWXFSZEAPBJS-UHFFFAOYSA-N 0.000 description 1
Abstract
The present invention provides a direct and efficient 1-methyl tryptophan synthesis method, and specifically relates to a method for synthesizing 1-methyl tryptophan represented by the following formula I. The method comprises that: in an inert solvent, in the presence of an alkaline agent, tryptophan and a methylating agent CH3X (X is defined in the specification) are subjected to a reaction, and separation is performed to obtain the desired product 1-methyl tryptophan. According to the present invention, the organic solvent is adopted as the reaction medium, the suitable alkaline reagent is adopted as the dehydrogenating agent, the tryptophan reacts with the methyl halide, and the crude product is subjected to extraction, washing, re-crystallization and other operations so as to obtain the high purity 1-methyl tryptophan; and the method has characteristics of good yield, strong selectivity, simple operation, safety, and easy control. The formula I is defined in the specification.
Description
Technical field
The invention belongs to the field of chemical synthesis, relate more specifically to the method for synthesizing 1-methyl tryptophan.
Background technology
The disease of a lot of serious threat human health is all weakened with human immune system relevant, and such as cancer cells will destroy the effective immunne response of patient gradually, and the transmissible diseases such as HIV and HCV are also cause viral longer-term persistence because human immunological competence weakens.In recent years research finds, the enzyme indoles amine-2,3-dioxygenase (indoleamine-2,3-dioxygenase, IDO) of catalysis tryptophan degradation is in regulation and control immunosuppression.This enzyme is long term activation in a lot of cancer patients, and the activity of this fermentoid is higher, then cancer patients's prognosis is poorer.Preclinical study shows, suppresses IDO effectively can improve cancer therapy drug chemotherapeutic treatment effect common at present.Verified in experiment in vitro, 1-methyl tryptophan (1-MT) is competitive inhibitor (Cady, the S.G. of IDO; Sono, M., Arch.Biochem.Biophys.1991,291,326-333.), its chemical structural formula is:
Recently, 1-methyl tryptophan and a series ofly gone up clinical chemotherapeutics as endoxan, cis-platinum, Zorubicin, or paclitaxel plus uses, and demonstrates splendid synergistic effect, become a kind of get a good chance of chemistry, immune conjoint therapy medicine (MullerA.J., DuhadawayJ.B., DonoverP.S., Sutanto-WardE., PrendergastG.C., Nat.Med., 2005,11,312 – 9).1-methyl tryptophan is expected to play a significant role in anticancer therapy, and its synthetic method exploitation will bring favourable Social benefit and economic benefit.
Japanese scholars Yamada, S.; Shioiri, T.; Itaya, T.; Hara, T.; The people such as Matsueda, R. at Chem.Pharm.Bull.1965,13, report a kind of synthetic method of 1-methyl tryptophan on 88.The method sodium Metal 99.5 makes sodium amide in liquefied ammonia, then adds tryptophane and iodomethane reaction, and the purifying through complexity obtains 1-methyl tryptophan.Use sodium Metal 99.5 in this method, this material habitually under very easily burn, and general industry product are again large bulks, need to shred to feed intake under protection of inert gas during reaction.Operation also needs at low temperatures, and require high to production unit, operative employee's personnel safety is also subject to very large threat.In addition, the leakage of ammonia also may have extreme influence to surrounding enviroment, industrial very difficult realization.
As mentioned above, Japanese scholars Yamada, S.; Shioiri, T.; Itaya, T.; Hara, T.; The method that the people such as Matsueda, R. report on Chem.Pharm.Bull. uses sodium Metal 99.5, also needs special cyrogenic equipment, requires high to operative employee, dangerous large, and the security of suitability for industrialized production is difficult to ensure.In the report of published 1-methyl tryptophan synthetic method, the method effectively do not addressed these problems.
Summary of the invention
In view of above-mentioned, the object of this invention is to provide that productive rate is good, selectivity is strong, simple to operate, safe and be easy to the method for the synthesis 1-methyl tryptophan controlled.
In one aspect, the invention provides the method for a kind of synthesis by the 1-methyl tryptophan shown in following formula I,
Described method comprises: in inert solvent, under alkaline reagents exists, makes the tryptophane shown in Formula Il and methylating reagent CH
3x reacts, through being isolated required product 1-methyl tryptophan, at described methylating reagent CH
3in X, X represents Cl, Br, I, OSO
2(OCH
3), OPO (OCH
3)
2, OSO
2cF
3or OSO
2c
6h
4cH
3,
Preferably, described inert solvent is one or more in toluene, tetrahydrofuran (THF), acetonitrile, acetone, butanols, DMF and dimethyl sulfoxide (DMSO).
Preferably, described alkaline reagents is one or more in Quilonum Retard, sodium carbonate, salt of wormwood, sodium phosphate, potassiumphosphate, sodium amide, lithium hydride, sodium hydride, potassium hydride KH, diisopropylamine lithium, hexamethyldisilazane lithium, hmds base sodium, hmds base potassium and butyllithium.
Preferably, described reaction is carried out under protection of inert gas.
Preferably, described tryptophane: alkaline reagents: methylating reagent CH
3the mol ratio of X is 1:1 ~ 10:0.5 ~ 2.5.
Preferably, described separation is included in after completion of the reaction, to go out reaction with shrend, in recrystallization solvent, then carrying out recrystallization and obtaining solid by filtering, finally carrying out drying.
Further preferably, described recrystallization solvent is one or more in toluene, ether, acetone, methyl-phenoxide, ethanol and t-butyl methyl ether.
Further preferably, described recrystallization carries out at the temperature of-20-5 DEG C.
Further preferably, by filtering the solid that obtains before the drying, form the aqueous solution by water dissolution, and with acid by pH regulator to 5.5 ~ 7.5 of the described aqueous solution to separate out solid, by filtering the acquisition solid of separating out, after washing, carry out drying.
Further preferably, the product obtained is pure 1-methyl tryptophan.
The present invention is by using organic solvent as reaction medium, and at suitable alkaline reagents as under dehydrogenating agent, tryptophane and methyl halogenated thing react, and crude product can obtain highly purified 1-methyl tryptophan through operations such as extraction, washing, recrystallizations.
Accompanying drawing explanation
Fig. 1 is the 1-methyl tryptophan synthesized according to the embodiment of the present invention 1
1h-NMR nmr spectrum.
Fig. 2 is the 1-methyl tryptophan synthesized according to the embodiment of the present invention 1
13c-NMR nmr spectrum.
The infrared spectrogram of the 1-methyl tryptophan that Fig. 3 synthesizes according to the embodiment of the present invention 1.
Fig. 4 is the mass spectrum of the 1-methyl tryptophan according to the embodiment of the present invention 1 synthesis.
Embodiment
In order to provide, productive rate is good, selectivity is strong, simple to operate, safe and be easy to the method for synthesis 1-methyl tryptophan that controls, the present invention's organic solvent is as reaction medium, suitable alkaline reagents is as dehydrogenating agent, tryptophane can react with methyl halogenated thing, the 1-methyl tryptophan crude product generated, through operations such as extraction, washing, recrystallizations, just can obtain highly purified 1-methyl tryptophan.
In one embodiment, the invention provides the method for a kind of synthesis by the 1-methyl tryptophan shown in following formula I,
Described method comprises: in inert solvent, under alkaline reagents exists, makes the tryptophane shown in Formula Il and methylating reagent CH
3x reacts, through being isolated required product 1-methyl tryptophan, at described methylating reagent CH
3in X, X represents Cl, Br, I, OSO
2(OCH
3), OPO (OCH
3)
2, OSO
2cF
3or OSO
2c
6h
4cH
3,
Preferably, described inert solvent is one or more in toluene, tetrahydrofuran (THF), acetonitrile, acetone, butanols, DMF and dimethyl sulfoxide (DMSO).
Preferably, described alkaline reagents is one or more in Quilonum Retard, sodium carbonate, salt of wormwood, sodium phosphate, potassiumphosphate, sodium amide, lithium hydride, sodium hydride, potassium hydride KH, diisopropylamine lithium, hexamethyldisilazane lithium, hmds base sodium, hmds base potassium and butyllithium.In the present invention, adopt commercial alkaline reagents to prepare without the need to original position, no longer need directly to use sodium Metal 99.5, as with sodium amide just without the need to sodium and liquefied ammonia original position preparation; The present invention's organic solvent replaces liquefied ammonia to make solvent in addition, just without the need to using low temperature pressure-resistant equipment on slave unit, operation being got up more safe and simple, reaction can be made industrially well to apply.
Preferably, described reaction is carried out under protection of inert gas.
Preferably, described tryptophane: alkaline reagents: methylating reagent CH
3the mol ratio of X is 1:1 ~ 10:0.5 ~ 2.5.
Preferably, described separation is included in after completion of the reaction, to go out reaction with shrend, in recrystallization solvent, then carrying out recrystallization and obtaining solid by filtering, finally carrying out drying.
Further preferably, described recrystallization solvent is one or more in toluene, ether, acetone, methyl-phenoxide, ethanol and t-butyl methyl ether.
Further preferably, described recrystallization carries out at the temperature of-20-5 DEG C.
Further preferably, by filtering the solid that obtains before the drying, form the aqueous solution by water dissolution, and with acid by pH regulator to 5.5 ~ 7.5 of the described aqueous solution to separate out solid, by filtering the acquisition solid of separating out, after washing, carry out drying.
By aforesaid method, the present invention can obtain pure 1-methyl tryptophan product.
In a more particular embodiment, first, in reaction vessel such as there-necked flask, cool in the suspension of 1 weight part tryptophane in 50-150mL inert solvent at low temperatures such as 0 DEG C of ice-water bath, afterwards preferred at rare gas element as N
2under protective atmosphere, in such as 30-50min, add the alkaline reagents of 1-10 equivalent part in batches.After adding alkaline reagents, preferably reaction system is at room temperature stirred 0.5-2 hour, reaction system can become muddy lilac solution from settled solution during this period.After stirring completes, again reaction system to be moved under low temperature in such as 0 DEG C of ice-water bath, by the methylating reagent of 0.5-2.5 equivalent part as the solution of methyl iodide in 10-50mL inert solvent, be added dropwise within reaction system within such as 20-40min, the purple of reaction system can take off gradually, and the opacity of reaction mixture solution also can reduce.After dropwising, more at room temperature continue reaction 2 ~ 10h.After completion of the reaction, by carrying out recrystallization in recrystallization solvent, filtering also dry afterwards and obtaining required product.
More preferably, after completion of the reaction, add about 2-10mL water and react with cancellation.Gained mixed solution is poured into 300-600mL in the recrystallization solvent of such as about 0 DEG C, a large amount of solid is separated out, direct suction filtration.Further preferably, the pH of this aqueous solution, to obtain the aqueous solution, is adjusted between 5.5 ~ 7.5 with acid such as concentrated hydrochloric acid, separates out a large amount of solid by gained solid 30-100mL water dissolution, by the solid suction filtration of separating out.The solid product of gained preferably washs with the frozen water of 50-200mL again, optionally uses 50-200mL at the recrystallization solvent wash of about 0 DEG C afterwards.White solid powder product 8.5g (productive rate 78%) is obtained, the specific rotatory power [α] of product with anhydrous sodium sulfate drying
d 20+ 7.5 (c=1.0,2MHCl) show that the optical purity of product is maintained.
Be noted that in the inventive method, to reaction raw materials add or order by merging is not particularly limited.Such as, in one embodiment, tryptophane can first be dissolved in inert solvent, then adds alkaline reagents, finally reacts with methylating reagent again.In another embodiment, tryptophane and methylating reagent can first be dissolved in inert solvent, add alkaline reagents afterwards again and react.
The following example is for detailed description of the present invention, and unrestricted the present invention.
Embodiment 1
In the there-necked flask that ice-water bath is housed; 10.2g tryptophane is added the tetrahydrofuran (THF) (THF) of 100mL; under nitrogen protection condition; within 50min; add the commercial sodium amide of 5g in batches; remove ice-water bath after adding sodium amide to stir 2 hours in room temperature (about 25 DEG C), then with ice-water bath, temperature of reaction system is down to 0 DEG C.The solution of 7.46g methyl iodide in 50mLTHF is added dropwise in above-mentioned mixing solutions with constant pressure funnel in 30min, dropwises rear continuation stirring reaction 15 hours.After completion of the reaction, the water at room temperature adding 30mL reacts with quencher.Reaction mixture is poured in 400mL ether, observe a large amount of solid to separate out, use Büchner funnel suction filtration, the solid 100mL water dissolution obtained obtains solution, adds concentrated hydrochloric acid 25mL and regulates pH to 6.5, and by the solid of separating out, suction filtration is out again, with anhydrous sodium sulfate drying, obtain white solid powder product, 8.5g (productive rate 78%, m.p.269 DEG C).
To the nuclear-magnetism test compounds of the product Bruker400MHz obtained by aforesaid method
1h-NMR and
13c-NMR spectrogram, infrared and mass spectroscopy.Fig. 1 to Fig. 4 is respectively the product obtained according to the present embodiment 1
1h-NMR nmr spectrum,
13c-NMR nmr spectrum, infrared spectrogram and mass spectroscopy figure.As can be seen from the figure, the product obtained
1h-NMR nmr spectrum has following characteristics and absorbs:
1h-NMR (400MHz, CDCl
3): δ=2.96 (t, J=8.8Hz, 1H), 3.73 (s, 3H), 7.02 (d, J=8Hz, 1H), 7.14 (t, J=8Hz, 2H), 7.38 (d, J=8Hz, 1H), 7.57 (d, J=8Hz, 1H);
13c-NMR nmr spectrum has following characteristics and absorbs:
13c-NMR (100MHz, CDCl
3) δ (ppm)=25.3,32.0,52.9,104.6,109.9,118.2,119.1,121.7,126.7,129.4,129.5,136.7,171.3; Infrared spectrum has following characteristics and absorbs: ν
max(KBr) cm
-1: 3423,3066,2569,2077,1593,1408,1132,918,732,557; And mass spectral characteristic peak is as follows: 217.0973,218.1006.Can find out clearly from above result, the solid product obtained is 1-methyl tryptophan, and its purity is 100%.
Embodiment 2
10.2g tryptophane is added the dimethyl sulfoxide (DMSO) (DMSO) of 130mL, under nitrogen protection condition, within 30min, add 5g sodium hydroxide in batches, to add after sodium hydroxide stirring at room temperature one hour, then with ice, system temperature is down to 0 DEG C, the solution of the 30mLDMSO of 7.46g methyl iodide is instilled tryptophane within 30min, the DMSO solution of sodium amide, dropwise rear continuation stirring reaction 15h, make tryptophane complete reaction, the water quencher reaction of 50mL is added in system, reaction mixture is poured in 400mL ether, a large amount of solid is had to separate out, suction filtration, the solid water dissolution obtained obtains solution, adding concentrated hydrochloric acid adjusts between pH to 6 ~ 7, by the solid suction filtration of precipitation out, drying obtains white solid powder product 8.7g (productive rate 80%, m.p.269 DEG C).
Identical with embodiment 1, obtained product is carried out
1h-NMR and
13c-NMR nucleus magnetic resonance, infrared and mass spectroscopy.Result (not shown) shows, the solid product obtained is 1-methyl tryptophan, and its purity is 100%.
Embodiment 3
Tryptophane (10.2g) and methyl iodide (7.46g) are put into toluene and acetonitrile (1:1, mixed solvent 50mL) dissolves, add KOH (8.4g) within 2h in batches, solution becomes brown, room temperature for overnight, solution colour is colorless cleared solution by brown stain, add frozen water (150mL), acetonitrile is revolved and removes, extract with propyl carbinol (3 × 100mL), obtained organic phase anhydrous sodium sulfate drying is spent the night, then the organic phase being spin-dried for gained is filtered, obtain the 1-methyl tryptophan (7.7g that white is pure, 71%, m.p.269 DEG C).
Identical with embodiment 1, obtained product is carried out
1h-NMR and
13c-NMR nucleus magnetic resonance, infrared and mass spectroscopy.Result (not shown) shows, the solid product obtained is 1-methyl tryptophan, and its purity is 100%.
The above; be only the preferred embodiments of the disclosure; but protection scope of the present invention is not limited thereto; any those skilled in the art are in the technical scope of present disclosure; the change that can expect easily or replacement; all should be encompassed in protection scope of the present invention, therefore, the protection domain that protection scope of the present invention should limit with claim is as the criterion.
Claims (10)
1. synthesis is by a method for the 1-methyl tryptophan shown in following formula I,
Described method comprises: in inert solvent, under alkaline reagents exists, makes the tryptophane shown in Formula Il and methylating reagent CH
3x reacts, through being isolated required product 1-methyl tryptophan, at described methylating reagent CH
3in X, X represents Cl, Br, I, OSO
2(OCH
3), OPO (OCH
3)
2, OSO
2cF
3or OSO
2c
6h
4cH
3,
2. method according to claim 1, is characterized in that, described inert solvent is one or more in toluene, tetrahydrofuran (THF), acetonitrile, acetone, butanols, DMF and dimethyl sulfoxide (DMSO).
3. method according to claim 1, it is characterized in that, described alkaline reagents is one or more in Quilonum Retard, sodium carbonate, salt of wormwood, sodium phosphate, potassiumphosphate, sodium amide, lithium hydride, sodium hydride, potassium hydride KH, diisopropylamine lithium, hexamethyldisilazane lithium, hmds base sodium, hmds base potassium and butyllithium.
4. method according to claim 1, is characterized in that, described reaction is carried out under protection of inert gas.
5. method according to claim 1, is characterized in that, described tryptophane: alkaline reagents: methylating reagent CH
3the mol ratio of X is 1:1 ~ 10:0.5 ~ 2.5.
6. the method according to any one of claim 1-5, is characterized in that, described separation is included in after completion of the reaction, to go out reaction with shrend, in recrystallization solvent, then carrying out recrystallization and obtaining solid by filtering, finally carrying out drying.
7. method according to claim 6, is characterized in that, described recrystallization solvent is one or more in toluene, ether, acetone, methyl-phenoxide, ethanol and t-butyl methyl ether.
8. method according to claim 6, is characterized in that, described recrystallization carries out at the temperature of-20-5 DEG C.
9. method according to claim 6, is characterized in that, by filtering the solid of acquisition before the drying, the aqueous solution is formed by water dissolution, and with acid by pH regulator to 5.5 ~ 7.5 of the described aqueous solution to separate out solid, obtaining the solid of separating out by filtering, after washing, carrying out drying.
10. method according to claim 9, is characterized in that, the product obtained is pure 1-methyl tryptophan.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410391864.0A CN105367477B (en) | 2014-08-11 | 2014-08-11 | A method of synthesis 1- methyl tryptophan |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410391864.0A CN105367477B (en) | 2014-08-11 | 2014-08-11 | A method of synthesis 1- methyl tryptophan |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105367477A true CN105367477A (en) | 2016-03-02 |
| CN105367477B CN105367477B (en) | 2018-11-27 |
Family
ID=55370170
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410391864.0A Active CN105367477B (en) | 2014-08-11 | 2014-08-11 | A method of synthesis 1- methyl tryptophan |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105367477B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109400517A (en) * | 2017-08-17 | 2019-03-01 | 上海时莱生物技术有限公司 | 1- methyl-tryptophan class compound and its preparation method and application |
| CN110790696A (en) * | 2018-08-03 | 2020-02-14 | 田海滨 | 11Preparation method and preparation system of C- α -methyl-L-tryptophan |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101121717A (en) * | 2007-05-17 | 2008-02-13 | 四川大学 | Synthesis for natural medicament physostigmine for resisting senile dementia disease and phenylaminoformic acid ester phenserine |
| CN102167766A (en) * | 2011-03-21 | 2011-08-31 | 北京化工大学 | Vinyl amino acid (ester) polymer and preparation method thereof |
| CN103570603A (en) * | 2012-07-19 | 2014-02-12 | 杭州中肽生化有限公司 | Novel synthetic method of hemiasterlin |
-
2014
- 2014-08-11 CN CN201410391864.0A patent/CN105367477B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101121717A (en) * | 2007-05-17 | 2008-02-13 | 四川大学 | Synthesis for natural medicament physostigmine for resisting senile dementia disease and phenylaminoformic acid ester phenserine |
| CN102167766A (en) * | 2011-03-21 | 2011-08-31 | 北京化工大学 | Vinyl amino acid (ester) polymer and preparation method thereof |
| CN103570603A (en) * | 2012-07-19 | 2014-02-12 | 杭州中肽生化有限公司 | Novel synthetic method of hemiasterlin |
Non-Patent Citations (3)
| Title |
|---|
| HE, BIN ET AL: "Total Synthesis of (-)-Ardeemin", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| SUN, TING ET AL: "Synthesis and biological evaluation of novel 1-alkyltryptophan analogs as potential antitumor agents", 《MOLECULES》 * |
| YAMADA, SHUNICHI ET AL: "Ind.-N-alkylation of tryptophan and synthesis of 1-alkyl-tryptophan hydrazides", 《CHEMICAL & PHARMACEUTICAL BULLETIN》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109400517A (en) * | 2017-08-17 | 2019-03-01 | 上海时莱生物技术有限公司 | 1- methyl-tryptophan class compound and its preparation method and application |
| CN110790696A (en) * | 2018-08-03 | 2020-02-14 | 田海滨 | 11Preparation method and preparation system of C- α -methyl-L-tryptophan |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105367477B (en) | 2018-11-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103910679A (en) | Method for preparing enzalutamide | |
| KR20140079770A (en) | Production method for 4,4-difluoro-3,4-dihydroisoquinoline derivative | |
| AU2011281421A1 (en) | Process for preparing aminobenzoylbenzofuran derivatives | |
| CN102993102A (en) | Synthetic method of [1-methyl-2-(8'-octyl hydroxamic acid group)-5-N,N-bi(2'-chloroethyl)]-1H-benzimidazole | |
| CN102746210A (en) | Synthesis method for key intermediate of silodosin | |
| JP2023524626A (en) | Method for synthesizing roxadustat and intermediates thereof and intermediates thereof | |
| CN104045602A (en) | Improved method for preparing tetrazole for valsartan | |
| CN105367477A (en) | 1-methyl tryptophan synthesis method | |
| CN107200707B (en) | Preparation method of pimavanserin | |
| CN111100128A (en) | Synthetic method of Ribocini intermediate product and intermediate compound thereof | |
| CN105859686A (en) | Preparation technology of high-purity dabigatran etexilate | |
| CN103242251B (en) | Preparation method of letrozole | |
| CN104744336B (en) | A kind of Silodosin intermediate and preparation method thereof, and the method for preparing with the intermediate silodosin | |
| CN106674281B (en) | A kind of Rosuvastatin midbody compound, preparation method and its usage | |
| NO179517B (en) | Process for the preparation of 8-chloroquinolone derivatives | |
| CN107325078B (en) | Preparation method of cilostazol | |
| Qiu et al. | Microwave-assisted synthesis and antibacterial activity of novel chenodeoxycholic acid thiosemicarbazone derivatives | |
| KR20140028433A (en) | Proces for purifying fluvoxamine free base and process for preparing high purity fluvoxamine maleate using the same | |
| CN107759603B (en) | Preparation method of heterocyclic compound | |
| US20080194822A1 (en) | Imiquimod production process | |
| AU2008358758A1 (en) | A process for preparing atovaquone and associate intermediates | |
| CN104496900A (en) | Method for preparing 2-methoxy-6-one-5,7,8-trihydro-quinoline | |
| Shahroudi et al. | Synthesis of 2-selanylidene-1, 9a-dihydro-2H-pyrido [1, 2-a] pyrimidine derivatives | |
| CN102050709B (en) | Method for preparing 2-[2-(2,2,2-trifluoro-ethyoxyl) phenoxyl] alcohol | |
| CN106866774B (en) | For antitumor compound and its preparation method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |