CN100457732C - Method for preparing ropinirole - Google Patents
Method for preparing ropinirole Download PDFInfo
- Publication number
- CN100457732C CN100457732C CNB200610081218XA CN200610081218A CN100457732C CN 100457732 C CN100457732 C CN 100457732C CN B200610081218X A CNB200610081218X A CN B200610081218XA CN 200610081218 A CN200610081218 A CN 200610081218A CN 100457732 C CN100457732 C CN 100457732C
- Authority
- CN
- China
- Prior art keywords
- acid
- compounds
- reaction
- formula
- temperature
- 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.)
- Expired - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
This invention adopts commercially available phenylacetic acid or 4-substituted phenylacetic acid as the starting material, and comprises nitrifying, reacting into acyl chloride and amide, reducing amide, reducing nitryl, condensing, cyclizating, reducing carbanyl and dehalogenating to obtain ropinirole.
Description
Invention field
The present invention relates to Ropinirole, especially the preparation method of ropinirole hydrochloride.
Background technology
Ropinirole hydrochloride (Ropinirole hydrochloride) in Britain's Initial Public Offering in 1996, is used for the treatment of Parkinson's disease by the exploitation of SmithklineBeecham company.Soon, the France and the U.S. also get permission listing.Trade(brand)name ReQuip, different name SKF101468.Ropinirole is the non-ergot woods of a selectivity d2 dopamine receptor agonist, be different from other dopamine agonist, this product has the simple chemical structure similar to natural Dopamine HCL, and it is effective to early stage Parkinson's disease treatment with as the levodopa treatment adjuvant drug.
Up to now, the synthetic route of bibliographical information can be divided into three kinds according to dissimilar starting raw materials.First method is patent US4452808 (1984) and Journal of MedicinalChemistry, 1985,28 (10), and 1533-6; 1986,29 (6), 939-47] to have disclosed with 3-nitro-2-tolyl acid be starting raw material, through the synthetic Ropinirole of ten single step reactions.The shortcoming of this method is that step is oversize, and raw material is not easy to obtain, and also uses the highly toxic product sodium cyanide.
EP300614 (1989) and US4997954 (1991)] reported with the phenylethyl alcohol to be starting raw material, get ropinirole hydrochloride through the reaction of eight steps.This method is compared step with first method and is significantly reduced, but the 3rd step bromination reaction needs illumination, and producing needs specific installation; In addition, bromide and one step of dipropyl amine reaction yield are low, and can produce considerable bromide elimination by product, cause this step to be difficult for purifying, and yield is low.
WO9415918,1994 have reported that with a position substituted aniline be raw material, and through the isatin intermediate, dipropyl amine replaces then, and reduction obtains Ropinirole.This method raw material is not easy to obtain, and cyclization time location is not strong, produces a large amount of isomer, thereby is difficult for purifying, is not suitable for industrial production.
Therefore, to produce the method for Ropinirole be very necessary for simpler, economy of exploitation and suitability for industrialized.
Summary of the invention
The objective of the invention is to develop the method that a kind of simple, economy and suitability for industrialized are produced Ropinirole.Based on this purpose, the contriver has now finished the present invention.
First aspect present invention relates to a kind of preparation method who comprises the ropinirole hydrochloride of Ropinirole, and it comprises:
I) change formula 1 compound into formula 2 compounds
Wherein R is H or halogen,
Ii) change formula 2 compounds into formula 3
Iii) change formula 3 compounds into formula 4 compounds
Iv) change formula 4 compounds into formula 5 compounds
V) change formula 5 compounds into formula 6 compounds
Vi) change formula 6 compounds into formula 7 compounds
VII) change formula 7 compounds into formula 8 compounds, i.e. Ropinirole
VIII) formula 8 compounds are become the salt formation ropinirole hydrochloride with hydrogenchloride.
The invention further relates to formula 3 compounds and the purposes in the preparation Ropinirole thereof,
Wherein R is H, halogen.
The invention still further relates to formula 4 compounds and the preparation Ropinirole in purposes,
Wherein R is H, halogen.
The invention still further relates to formula 5 compounds and the preparation Ropinirole in purposes,
Wherein R is H, halogen.
The invention still further relates to formula 6 compounds and the preparation Ropinirole in purposes,
Wherein R is H, halogen.
According to the present invention, term " halogen " refers to fluorine, chlorine, bromine or iodine, preferred chlorine or bromine.
According to the present invention, term among the present invention " Ropinirole " can be regarded as Ropinirole itself or its hydrochloride.
The preparation method of Ropinirole of the present invention further can pass through shown in the following reaction scheme:
Reaction scheme
Wherein, R is H, halogen.
Can see by reaction scheme shown in top, in the methods of the invention, with the toluylic acid or the 4-substituted phenylacetic acid that are easy to get on the market is starting raw material 1, through nitration reaction, get this acetogenin of 3-nitro 2, the carboxyl of toluylic acid generates acid amides, the perhaps direct condensation of the carboxyl of toluylic acid and Diisopropylamine with the Diisopropylamine reaction after becoming acyl chlorides, after reduction obtains acid amides 4, just finished the introducing of the diisopropylaminoethyl of Ropinirole.Reduction 3-position nitro obtains corresponding aminocompound 5, adopt the preparation method of isatin class then, be aminocompound and Chloral Hydrate and azanol condensation cyclization, gained isatin compound 7 is through reducing carbonyl, if the toluylic acid that replaces with the contraposition halogen is a raw material, then remove halogen simultaneously, can obtain the target compound Ropinirole.Target compound and hydrogenchloride salify obtain final bulk drug ropinirole hydrochloride.
The advantage of this method is that step is short, and starting raw material cheaply is easy to get, each step reaction agents useful for same and all environmental protection of raw material, and reaction conditions gentleness and each step reaction are fit to industrialized production, gained final product purity height.
Further, above in the route the first step or the step (i) nitration reaction reagent be nitric acid, nitrosonitric acid, SODIUMNITRATE, saltpetre, ammonium nitrate etc., the solvent of nitration reaction is conventional nitration reaction solvent, as the vitriol oil, and formic acid, acetic acid, organic acid such as propionic acid, butyric acid, aceticanhydride etc.The nitration reaction temperature is-15 ℃～100 ℃, and wherein optimal reaction temperature is 0～40 ℃.
Second step of top route or step (ii) in, formula 2 compounds and dipropyl amine react under the effect of condensing agent and make, condensing agent wherein comprises dicyclohexylcarbodiimide (DCC), N-cyclohexyl-N-(3-dimethylamino-propyl) carbodiimide, DIC (DIC), carbodiimide class condensing agents such as ethyl [3-(dimethylin) propyl group] carbodiimide (EDC) or hydrochloric acid ethyl [3-(dimethylin) propyl group] carbodiimide EDC-HCl; The acyl chlorides of perhaps corresponding formula 2 acid and dipropyl amine reaction obtain.Range of reaction temperature is-10 ℃～100 ℃, and wherein optimal reaction temperature is 0～50 ℃.
Top the 3rd step of route or the (ii) middle reduction reagent of step comprise, Lithium Aluminium Hydride, borine, the combination of boron trifluoride and/or sodium borohydride, sodium borohydride or POTASSIUM BOROHYDRIDE and lewis acidic combination, Lewis acid wherein comprises boron trifluoride, aluminum chloride, alchlor, zinc chloride, iron(ic) chloride, ferric sulfate etc., perhaps its arbitrary combination.Reduction reaction temperature is-30 ℃～70 ℃, and wherein optimal reaction temperature is 0～30 ℃.
Pd-C is adopted in top the 4th step of route or the (iv) middle reduction of step, and Pt-C, PtO2, RaneyNi, Rh-C are the hydrogen of catalyzer or the catalytic hydrogenation that hydrazine hydrate participates in, the reduction that iron powder, tin protochloride, hydrazine hydrate participate in etc.Reduction reaction temperature is 0 ℃～150 ℃, and wherein optimal reaction temperature is 40～100 ℃.
The 5th step of top route or step (are carried out condensation reaction with formula 5 compounds and oxammonium hydrochloride or oxammonium sulfate and Chloral Hydrate or Chloral Hydrate monoether v).Setting-up point is 0 ℃～150 ℃, and wherein optimal reaction temperature is 60～120 ℃.
(ring-closure reaction is finished in acidic medium vi) for top the 6th step of route or step, acid wherein comprises mineral acid hydrofluoric acid, hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, polyphosphoric acid etc., sulfonic acid such as organic acid methylsulfonic acid, Phenylsulfonic acid, tosic acid, and acetic acid etc., perhaps arbitrary combination wherein.The ring-closure reaction temperature is-30 ℃～250 ℃, and wherein optimal reaction temperature is 50～140 ℃.
In the reduction reaction, when the R=halogen, adopt catalytic hydrogenation in top the 7th step of route or the step (VII); When R=H, can adopt catalytic hydrogenation, can also adopt reduction such as hydrazine hydrate.
Become hydrochloric acid to adopt known method in top the 8th step of route or the step (VIII), i.e. logical dry hydrogen chloride in solution.
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
Embodiment 13-nitro-4-chlorobenzene acetic acid
68.2 gram 4-chloro-benzoic acids are dissolved in the 800mL vitriol oil fully, down nitrosonitric acid 20mL are added, stirred then 1 hour in 0 degree.After reaction finishes, reaction solution is slowly poured in the frozen water of 1000mL, stirred 30 minutes after-filtration.The filter cake frozen water of usefulness 2000mL again stirs 30 minutes after-filtration in reactor, be washed till neutrality with frozen water again, afterwards gets the title compound of 75.14 gram light yellow solids in 50 ℃ of vacuum dryings, yield 88.7%.
1HNMR(300MHz，DMSO-d6)：7.82(d，J＝2.7，1H)，7.52(d，J＝8.1，1H)，7.44(dd，J＝8.1，2.7，1H)，3.72(s，2H)。
Embodiment 2N, N-dipropyl-3-nitro-4-chlorobenzene ethanamide
The SOCl2 of 21.3 gram 3-nitro-4-chlorobenzene acetic acids and 200mL is joined in the reaction flask of 500mL back flow reaction 2.5 hours.Reaction is finished, and reclaims SOCl2 and gets sundown oily matter.
The ethyl acetate that in this oily matter, adds 100mL, the dissolving back is added dropwise under room temperature in the ethyl acetate solution that fills the 27.3mL dipropyl amine, and adularescent smog produces when beginning to drip.Finish stirring at room 3 hours.Add 5%NaOH liquid 100mL then and wash, wash with 10% hydrochloric acid 100mL again, tell organic layer.Reclaim the title compound that solvent gets sundown oily matter, yield 84.8%, purity 96.4%.This oily matter is directly used in next step.
Embodiment 3N, N-dipropyl-3-nitro-4-chlorobenzene ethamine
With 15 gram N, N-dipropyl-3-nitro-4-chlorobenzene ethanamide is dissolved in the 100mL THF liquid, at room temperature adds 5 gram LiAlH4 then in batches.Room temperature reaction spends the night.Be added dropwise to the frozen water of 15mL, just begun to emit a large amount of gas, finish, solution becomes paste, filters.Organic phase with anhydrous MgSO4 drying after solvent evaporated get 14.3 the gram title compounds, yield is almost quantitative, purity 96.1%.
1HNMR(400MHz，DMSO-d6)：7.93(1H，d，J＝2.4Hz)，7.68(1H，d，J＝8.4Hz)，7.54(1H，dd，J
1＝8.4Hz，J
2＝2.4Hz)，3.82(2H，s)，3.26(2H，m)，3.18(2H，m)，1.52(2H，m)，1.44(2H，m)，0.854(3H，t，J＝7.3Hz)，0.776(3H，t，J＝7.6Hz)。
Embodiment 4N, N-dipropyl-3-amino-4-chlorobenzene ethamine
With 7.88 gram N, N-dipropyl-3-nitro-4-chlorobenzene ethamine adds in 200mL 5% hydrochloric acid, adds 19 gram iron powders then.Reflux 2 hours.Filtered while hot, filtrate extracts with 100mLCH2Cl2, anhydrous magnesium sulfate drying, after the recovery the title compound of oily matter.
1HNMR(400MHz，DMSO-d6)：7.12(1H，d，J＝7.8Hz)，6.68(1H，d，J＝1.8Hz)，6.47(1H，dd，J
1＝8.1Hz，J
2＝1.8Hz)，282～3.17(8H，m)，1.66(4H，m)，0.90(6H，t，J＝7.5Hz)。
Embodiment 53-(N, N-dipropyl ethyl)-6-chlorobenzene aminocarboxyl formoxime
With 15 gram N, N-dipropyl-3-amino-4-chlorobenzene ethamine, 16.3mL hydrochloric acid and 33mL water are added in the reaction flask, add CCl3CH (OH) 2 and NH2OH.HCl then, and reaction solution becomes white casse immediately.Be warming up to backflow, after reaction finishes, separate out the khaki color solid when being cooled to 60 ℃ naturally, be cooled to 20 ℃ naturally after stirring filtered in 5 hours khaki color solid title compound, yield 71.87%, purity 96.4%.
1HNMR(400MHz，DMSO-d6)：12.44(1H，s)，10.40(1H，brs)，9.57(1H，s)，7.85(1H，d，J＝1.6Hz)，7.69(1H，s)，7.49(1H，d，J＝8.5Hz)，7.16(1H，dd，J
1＝8.5Hz，J
2＝1.6Hz)，3.19(2H，brs)，3.0(6H，brs)，1.63(4H，m)，0.89(6H，t，J＝7.2Hz)
Embodiment 64-(N, N-dipropyl ethyl)-7-chlorisatide
10.4 gram 3-(N, N-dipropyl ethyl)-6-chlorobenzene aminocarboxyl formoximes and 60mL polyphosphoric acid are added in the reaction flask, in 120-130 ℃ of reaction 1 hour.Reaction is finished, and is cooled to 20 ℃, pours in the 150 gram frozen water, adds the CH2CL2 of 60ml again, and temperature is no more than 15 ℃.Transfer PH to 9-10 about 15 ℃, organic phase is got in phase-splitting, and water with the 30mlCH2CL2 extraction, merges organic phase, anhydrous magnesium sulfate drying again.Filter, be recycled to dried brown oil 8.09 grams, be the brown solid title compound after cold.Yield: 81.5%.Purity 95.8%.In ethyl acetate behind the recrystallization, purity reaches 99.2% with product.
1HNMR(300MHz，CDCl3)：7.34(d，J＝4.0，1H)，6.86(d，J＝4.0，1H)，3.01(m，2H)，2.64(m，2H)，2.43(m，4H)，1.41(m，4H)，0.82(m，6H)。
Embodiment 74-(N, N-dipropyl ethyl)-1,3-dihydro-2-indolone (Ropinirole)
Get 21.9 gram 4-(N, N-dipropyl ethyl)-7-chlorisatides and 5 gram Raney Ni are added in the methyl alcohol of 300mL, change autoclave hydrogenation over to.In 50 ℃, 50psi reacted 45 hours down.Cooling is filtered, and concentrated filtrate filters, and gets yellow solid 14.5 gram title compounds, yield 79%, purity 99.1%.
1HNMR(400MHz，DMSO-d6)：11.1(1H，s)，10.47(1H，brs)，7.50(1H，t，J
1＝8.0Hz，J
2＝7.4Hz)，6.97(1H，d，J＝8.1Hz)，6.81(1H，d，J＝7.7Hz)，3.18(4H，m)，3.05(4H，m)，1.72(4H，m)，0.94(6H，t，J＝7.3Hz)
Embodiment 84-(N, N-dipropyl ethyl)-1,3-dihydro-2-indolone hydrochloride (ropinirole hydrochloride)
With 10.0 gram 4-(N, N-dipropyl ethyl)-1,3-dihydro-2-indolone is added in the saturated hydrogen chloride solution of 100mL Virahol, refluxes 1 hour.After then reaction solution being concentrated into 1/3rd volumes, place crystallization.Filter, get solid 9.3 gram title compounds, yield 82%, purity 99.4%.Further adopt ethyl alcohol recrystallization, can get the single impurity of product less than 0.1%.
Claims (11)
1. the preparation method of Ropinirole, it comprises:
I) change formula 1 compound into formula 2 compounds
Wherein R is H or halogen
Ii) change formula 2 compounds into formula 3
Iii) change formula 3 compounds into formula 4 compounds
Iv) change formula 4 compounds into formula 5 compounds
V) change formula 5 compounds into formula 6 compounds
Vi) change formula 6 compounds into formula 7 compounds
VII) change formula 7 compounds into formula 8 compounds, i.e. Ropinirole
VIII) formula 8 compounds are become the salt formation ropinirole hydrochloride with hydrogenchloride.
2. the described method of claim 1, wherein nitration reaction reagent is nitric acid in the step (i), nitrosonitric acid, SODIUMNITRATE, saltpetre or ammonium nitrate, the solvent of nitration reaction are conventional nitration reaction solvent, it is selected from the vitriol oil, formic acid, acetic acid, propionic acid, butyric acid or aceticanhydride, the nitration reaction temperature is-15 ℃～100 ℃.
3. the described method of claim 2, wherein said temperature of reaction is 0-40 ℃.
4. the described method of claim 1, wherein step (ii) formula 3 compounds be to react under the effect of condensing agent by formula 2 compounds and dipropyl amine to make, condensing agent wherein is selected from dicyclohexylcarbodiimide, N-cyclohexyl-N-(3-dimethylamino-propyl) carbodiimide, DIC, ethyl [3-(dimethylin) propyl group] carbodiimide or hydrochloric acid ethyl [3-(dimethylin) propyl group] carbodiimide; The acyl chlorides of perhaps corresponding formula 2 compounds and dipropyl amine reaction obtain, and range of reaction temperature is-10 ℃～100 ℃.
5. the described method of claim 4, wherein said temperature of reaction is 0-50 ℃.
6. the described method of claim 1, wherein step is gone back original reagent in (iii) and is selected from Lithium Aluminium Hydride, borine, the combination of boron trifluoride and/or sodium borohydride, reduction reaction temperature is-30 ℃～70 ℃.
7. the described method of claim 1, wherein step is gone back original reagent in (iii) and is selected from sodium borohydride or POTASSIUM BOROHYDRIDE and lewis acidic combination, and Lewis acid wherein is selected from boron trifluoride, aluminum chloride, alchlor, zinc chloride, iron(ic) chloride, ferric sulfate or its arbitrary combination; Reduction reaction temperature is-30 ℃～70 ℃.
8. claim 6 or 7 described methods, wherein said temperature of reaction is 0-30 ℃.
9. the described method of claim 1, wherein step (iv) in method of reducing be that Pd-C, Pt-C, PtO2, Raney's nickel, Rh-C are the hydrogen of catalyzer or the catalytic hydrogenation that hydrazine hydrate participates in, or iron powder, tin protochloride, the reduction that hydrazine hydrate participates in; Reduction reaction temperature is 0 ℃～150 ℃;
(with formula 5 compounds and oxammonium hydrochloride or oxammonium sulfate and Chloral Hydrate or the reaction of Chloral Hydrate monoether, setting-up point is 0 ℃～150 ℃ to step v);
Step (finish in acidic medium vi) by ring-closure reaction, acid wherein is the mineral acid that is selected from hydrofluoric acid, hydrochloric acid, Hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid or polyphosphoric acid, or be selected from methylsulfonic acid, Phenylsulfonic acid, tosic acid or sulfonic acid, or the organic acid of acetic acid, perhaps arbitrary combination wherein; The ring-closure reaction temperature is-30 ℃～250 ℃;
Step (VII) is a reduction reaction, when the R=halogen, adopts catalytic hydrogenation; When R=H, adopt catalytic hydrogenation or hydrazine hydrate reduction.
10. the described method of claim 9, wherein step (iv) described in temperature of reaction be 40-100 ℃; (temperature of reaction v) is 60-120 ℃ to step; (temperature of reaction vi) is 50-140 ℃ to step.
11. the described method of claim 1, wherein step (VII) reduction reaction becomes the step of hydrochloride to be combined into single step reaction with step (VIII).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200610081218XA CN100457732C (en) | 2006-05-25 | 2006-05-25 | Method for preparing ropinirole |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200610081218XA CN100457732C (en) | 2006-05-25 | 2006-05-25 | Method for preparing ropinirole |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1958570A CN1958570A (en) | 2007-05-09 |
| CN100457732C true CN100457732C (en) | 2009-02-04 |
Family
ID=38070435
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200610081218XA Expired - Fee Related CN100457732C (en) | 2006-05-25 | 2006-05-25 | Method for preparing ropinirole |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100457732C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102276530B (en) * | 2010-06-10 | 2013-09-11 | 齐鲁制药有限公司 | Method for preparing 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one |
| CN108993496B (en) * | 2018-10-30 | 2021-01-15 | 山东第一医科大学(山东省医学科学院) | Preparation method of ropinirole intermediate for treating dyskinesia |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4452808A (en) * | 1982-12-07 | 1984-06-05 | Smithkline Beckman Corporation | 4-Aminoalkyl-2(3H)-indolones |
| US4997954A (en) * | 1987-06-19 | 1991-03-05 | Smith Kline & French Laboratories Limited | Process for preparing substituted isoindolinone derivatives |
-
2006
- 2006-05-25 CN CNB200610081218XA patent/CN100457732C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4452808A (en) * | 1982-12-07 | 1984-06-05 | Smithkline Beckman Corporation | 4-Aminoalkyl-2(3H)-indolones |
| US4997954A (en) * | 1987-06-19 | 1991-03-05 | Smith Kline & French Laboratories Limited | Process for preparing substituted isoindolinone derivatives |
Non-Patent Citations (2)
| Title |
|---|
| development of large-scale syntheses of ropinirole inthepursuit of a manufacturing process. John D.Hayler et al.organic process research&development. 1998 |
| development of large-scale syntheses of ropinirole inthepursuit of a manufacturing process. John D.Hayler et al.organic process research&development. 1998 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1958570A (en) | 2007-05-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102639486B (en) | Process for manufacture of N-acylbphenyl alanine | |
| CN112851646A (en) | Preparation method of Tegolrazan | |
| WO2011109932A1 (en) | Novel process for the manufacture of 5-halogenated-7-azaindoles | |
| CN100457732C (en) | Method for preparing ropinirole | |
| CN100381430C (en) | Process for producing substituted alkylamines or salts thereof | |
| JPH06500800A (en) | Method for producing 3-amino-2-chloro-4-alkylpyridines | |
| CN100462357C (en) | Preparing method of 8-bromo-5,6-difluoro-2-methylquinoline | |
| US6861525B2 (en) | Process for the preparation imidazo[1,2-A]pyridine-3-acetamides | |
| CN100402508C (en) | Alkoxytetrazol-1-ylbenzaldehyde compound and process for producing the same | |
| JP2007522206A (en) | Process for producing substituted benzopyran compounds | |
| WO2015012271A1 (en) | Method for producing heterocyclic compound | |
| CN104592222A (en) | Preparation method for antiplatelet medicine AZD6482 | |
| CN115197086B (en) | Preparation method of difluoromethoxy-containing m-diamide compound | |
| JP3959994B2 (en) | Method for producing 4-phthalonitrile derivative | |
| JP2003506312A (en) | Meta-nitrophenol derivative and method for producing the same | |
| JPH08208591A (en) | 2-aminobenzenesulfonic acid derivative and 2-aminobenzenesulfonyl chloride,derivative their production,and their use as synthetic intermediates | |
| WO2003091200A1 (en) | Process for preparation of 2-aminoketones | |
| WO2002014284A1 (en) | Processes for the preparation of pyrazole compounds | |
| JPH0523255B2 (en) | ||
| JP3761206B2 (en) | Method for producing 1H-pyrazolo [3,2-C] -1,2,4-triazole compound | |
| JP3961049B2 (en) | 3-Amino-4- (1-hydroxyalkyl) pyrazoline compound, method for producing the same and method for producing the same | |
| KR100760015B1 (en) | Intermediates for preparing benzopyran compounds | |
| KR100716274B1 (en) | Intermediates for preparing substituted benzopyran compounds | |
| KR100740325B1 (en) | Intermediates for preparing substituted benzopyran compounds | |
| JP5164755B2 (en) | Method for producing crystals of bis-acetylaminophenyl compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090204 Termination date: 20120525 |