WO1997047598A1 - A process for the manufacture of 1-(amino-alkyl)-indoles - Google Patents
A process for the manufacture of 1-(amino-alkyl)-indoles Download PDFInfo
- Publication number
- WO1997047598A1 WO1997047598A1 PCT/EP1997/002895 EP9702895W WO9747598A1 WO 1997047598 A1 WO1997047598 A1 WO 1997047598A1 EP 9702895 W EP9702895 W EP 9702895W WO 9747598 A1 WO9747598 A1 WO 9747598A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- accordance
- formula
- compound
- protecting group
- amino protecting
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
Definitions
- the present invention relates to a process for the manufacture of l-(amino-alkyl)-indole derivatives of the general formula
- R 1 -!. 4 signifies hydrogen, halogen, lower alkyl, cycloalkyl or trifluoromethyl
- R 5 and R 6 signify hydrogen, lower alkyl, cycloalkyl, trifluoromethyl, hydroxy or lower alkoxy
- R 7 signifies hydrogen or lower alkyl, as well as pharmaceutically acceptable acid addition salts thereof.
- lower denotes residues with a maximum of 7, preferably up to 4, carbon atoms
- alkyl denotes straight-chain or branched. Saturated hydrocarbon residues such as methyl, ethyl, isopropyl or t-butyl and "alkoxy” denotes an alkyl group bonded via an oxygen atom, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy.
- Halogen is Cl, Br, F or I.
- pharmaceutically acceptable acid addition salts embraces salts with inorganic and organic acids such as hydrochloric acid, hydro- bromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulfonic and the like.
- aving group refers to groups conventionally used, for example to halogen, alkylsulfonyloxy, arylsulfonyloxy and the like.
- the most preferred leaving group is the group methylsulfonyloxy.
- amino protecting group means a protecting group conventionally used to protect primary amines.
- R 1 , R 4 , R 5 and R 6 are hydrogen, R 2 is fluoro, R 3 is chlorine and R 7 is methyl, namely (S)-2-(6-chloro-5-fluoro-indol-l-yl)-l- methyl-ethylamine.
- R i -R 7 , X and R are as defined above.
- a corresponding lH-indole-2,3-dione of formula V is reduced by a reducing agent, such as boron trifluoride etherate and sodium borohydride, in conventional manner to give a compound of formula II, wherein R 5 and R6 are hydrogen.
- a reducing agent such as boron trifluoride etherate and sodium borohydride
- Corresponding indole derivatives of formula II can be prepared, for example, by known methods according to the Fischer indole synthesis, where arylhydrazones of formula VI are cyclized under the influence of acids or metal hydrides as the catalyst with the cleavage of ammonia.
- the alkylation of a compound of formula II with a compound of formula III is carried out in a polar or apolar, protic or aprotic solvent under phase transfer conditions at a temperature between 0°C and 90°C.
- Suitable solvents are toluene, chlorinated solvents, water, DMSO or DMF. Most preferred is DMSO at a temperature of about 35°C.
- Suitable bases are alkali hydroxides, amines, alkali metal hydrides, alkoxides or amides. Most preferred is an alkali hydroxide, such as KOH.
- a compound of formula IV is deprotected to yield a compound of formula I with a free amino group.
- the amino protecting group may be cleaved off by acid.
- the cleavage is generally carried out at room temperature, although it can be carried out at slightly higher or slightly lower temperature (e.g. at a temperature in the range of about 0°C to 90°C).
- the compounds of formula I can be used as medicaments in the treatment or prevention of central nervous system disorders such as depressions, bipolar disorders, anxiety states, sleep and sexual disorders, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or pain of different kind, personality disorders or obsessive- compulsive disorders, social phobias or panic states, mental organic disorders, mental disorders in childhood, aggressiveness, age-associated memory impairment and behavioural disorders, addiction, obesity, bulimia etc.; central nervous system damage caused by trauma, stroke, neurodegenerative diseases etc.; cardiovascular disorders such as hypertension, thrombosis, stroke, and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility.
- central nervous system disorders such as depressions, bipolar disorders, anxiety states, sleep and sexual disorders, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or pain of different kind, personality disorders or obsessive- compulsive disorders, social phobias or panic states, mental organic disorders, mental disorders in childhood, aggressiveness, age-associated memory impairment and behavioural disorders, addiction, obesity
- Example 1 illustrates the present invention in more detail. However, they are not intended to limit its scope in any manner. Example 1
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a process for the manufacture of compounds of formula (I) wherein R1-R4 signifies hydrogen, halogen, lower alkyl, cycloalkyl or trifluoromethyl, R?5 and R6¿ signify hydrogen, lower alkyl, cycloalkyl, trifluoromethyl, hydroxy or lower alkoxy and R7 signifies hydrogen or lower alkyl, by alkylating of a corresponding indole.
Description
A process for the manufacture of l-(amino-alkyl)-indoles
The present invention relates to a process for the manufacture of l-(amino-alkyl)-indole derivatives of the general formula
wherein R1-!.4 signifies hydrogen, halogen, lower alkyl, cycloalkyl or trifluoromethyl, R5 and R6 signify hydrogen, lower alkyl, cycloalkyl, trifluoromethyl, hydroxy or lower alkoxy and R7 signifies hydrogen or lower alkyl, as well as pharmaceutically acceptable acid addition salts thereof.
The term "lower" denotes residues with a maximum of 7, preferably up to 4, carbon atoms, "alkyl" denotes straight-chain or branched. Saturated hydrocarbon residues such as methyl, ethyl, isopropyl or t-butyl and "alkoxy" denotes an alkyl group bonded via an oxygen atom, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy.
Halogen is Cl, Br, F or I.
The term "pharmaceutically acceptable acid addition salts" embraces salts with inorganic and organic acids such as hydrochloric acid, hydro- bromic acid, nitric acid, sulphuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid, p-toluenesulfonic and the like.
Compounds of formula I are known compounds, described, e.g., in US 5,494,928. This patent discloses a three step method for the preparation of the compounds of the present invention of formula I. According to that method a compound of formula II is reacted with a suitable alkylating agent
to yield a l-(halogenalkyl)-indol derivative which is converted into the corresponding l-(aminoalkyl)-indol derivative via the corresponding 1- (azidoalkyl)-indol derivative.
It has now been surprisingly found that compounds of formula I can be manufactured by a process which comprises:
a) alkylating a compound of the formula
X
^ i R? s NHR m wherein X is a leaving group, R signifies an amino protecting group and R7 has the significance given above, in the presence of a base, to get a compound of the formula
b) cleaving off the amino protecting group and
c) if desired, converting the compound of formula I obtained into a pharmaceutically acceptable acid addition salt.
The term "leaving group" refers to groups conventionally used, for example to halogen, alkylsulfonyloxy, arylsulfonyloxy and the like. The most preferred leaving group is the group methylsulfonyloxy.
The term "amino protecting group" means a protecting group conventionally used to protect primary amines.
Examples of such groups are described in Green, T., Protective Groups in Organic Synthesis, Chapter 7, John Wiley and Sons, Inc. (1981), pp. 218- 287. Preferred are the groups benzyloxycarbonyl and allyl oxy carbonyl. Most preferred is BOC (t-butoxycarbonyl).
The compounds of general formulae II, III, IV, V and VI in scheme 1 can be prepared according to methods known per se.
Compounds of formula IV are new compounds and therefore also an aspect of the invention.
The process of the present invention has several advantages over the prior art process since:
- the process steps have been reduced, and the overall yield increased,
- the process is considerably cheaper and safer,
- the correct stereochemistry of the side chain is introduced, without any racemization, - the amine is in the correct oxidation state so that reduction of a potentially explosive azide can be avoided.
Especially preferred is a compound which is prepared by the above mentioned process, wherein R1, R4, R5 and R6 are hydrogen, R2 is fluoro, R3 is chlorine and R7 is methyl, namely (S)-2-(6-chloro-5-fluoro-indol-l-yl)-l- methyl-ethylamine.
In Scheme 1 and in the following description and examples the process steps are explained in more detail.
wherein Ri-R7, X and R are as defined above.
A corresponding lH-indole-2,3-dione of formula V is reduced by a reducing agent, such as boron trifluoride etherate and sodium borohydride, in conventional manner to give a compound of formula II, wherein R5 and R6 are hydrogen.
Corresponding indole derivatives of formula II (R5 and R6 other than hydrogen) can be prepared, for example, by known methods according to the Fischer indole synthesis, where arylhydrazones of formula VI are cyclized under the influence of acids or metal hydrides as the catalyst with the cleavage of ammonia.
The alkylation of a compound of formula II with a compound of formula III is carried out in a polar or apolar, protic or aprotic solvent under phase transfer conditions at a temperature between 0°C and 90°C. Suitable solvents are toluene, chlorinated solvents, water, DMSO or DMF. Most preferred is DMSO at a temperature of about 35°C.
Suitable bases are alkali hydroxides, amines, alkali metal hydrides, alkoxides or amides. Most preferred is an alkali hydroxide, such as KOH.
A solution of a base and a solvent is treated with the corresponding indole of formula II. Compounds of formula IV can be obtained by reaction of the above mentioned solution with a compound of formula III.
Compounds of formula III are known compounds. Most preferred are compounds of formula III, in which the leaving group is a methylsulfonyl- oxy group and the amino protecting group is the BOC group.
According to variant b) of the process a compound of formula IV is deprotected to yield a compound of formula I with a free amino group. The amino protecting group may be cleaved off by acid. The cleavage is generally carried out at room temperature, although it can be carried out at slightly higher or slightly lower temperature (e.g. at a temperature in the range of about 0°C to 90°C).
The compounds of formula I can be used as medicaments in the treatment or prevention of central nervous system disorders such as depressions, bipolar disorders, anxiety states, sleep and sexual disorders, psychoses, schizophrenia, migraine and other conditions associated with cephalic pain or pain of different kind, personality disorders or obsessive- compulsive disorders, social phobias or panic states, mental organic disorders, mental disorders in childhood, aggressiveness, age-associated memory impairment and behavioural disorders, addiction, obesity, bulimia etc.; central nervous system damage caused by trauma, stroke, neurodegenerative diseases etc.; cardiovascular disorders such as hypertension, thrombosis, stroke, and gastrointestinal disorders such as dysfunction of the gastrointestinal tract motility.
The following Examples illustrate the present invention in more detail. However, they are not intended to limit its scope in any manner.
Example 1
6-Chloro-5-fluoro-lH-indole
25 g (0.125 mol) of 6-chloro-5-fluoro-lH-indole-2,3-dione was dissolved in 1.4 1 of tetrahydrofuran and warmed to 52°C. Then the solution was cooled to 0-20°C in a CO2/E.OH bath and then 62.8 ml (0.5 mol) of BF3(OEt)2 and subsequently 14.2 g (0.375 mol) NaBHj were added. The suspension was stirred 1 hour at -20°C and then the temperature was allowed to reach room temperature. The reaction mixture was poured onto ice water and extracted with ether. The ether phase was washed with water, dried over Na2SO4 and filtered. The filtrate was concentrated and suspended in n-hexane and then evaporated. The residue was chromatographed over 10 cm Grade II neutral Alumina with n-hexane. The fraction containing the product was evaporated and the residue was crystallized from n-hexane to yield 10 g (47%) with m.p. 106-107°C.
Example 2
(S)-2-(6-Chloro-5-fluoro-indol-l-yl)-l-methyl-ethyl-carbamic acid-tert-butyl ester
a) A suspension of 25.0 g (-0.4 mol) KOH and 250 ml DMSO was treated with 17.0 g (0.1 mol) 6-chloro-5-fluoro-lH-indole and warmed to 35°C for 30 minutes. Then a solution of 63.4 g (0.25 mol) (S)-methanesulphonic acid 2-tert-butoxycarbonylamino-propylester in 120 ml DMSO was added dropwise within 4 hours and the suspension was stirred for 16 hours at 35 °C. The mixture was cooled to about 15°C, poured onto ice and then stirred for about 30 minutes. The resulting precipitate was filtered, washed with 200 ml water and then dried at 35°C/10 mbar to give 29.0 g (89%) of a crude product which was recrystallized from ethanol. Yield of white crystals: 22.25 g (68%), m.p. 171.5-172.5°C.
b) A solution of 1.70 g (10 mmol) 6-chloro-5-fluoro-lH-indole in 35 ml DMSO was heated to 50°C and treated with 125 mg (2 mmol) KOH, stirred for 10 minutes and then treated with 380 mg (1.5 mmol) (S)-methanesulphonic acid 2-tert-butoxycarbonylamino-propylester and stirred for 10 minutes. This process was repeated a further nine times such that a total of 20 mmol of KOH and 15 mmol of the mesylate were added. After stirring for 19 hours at 50°C, the resulting suspension was cooled to room temperature and treated with 0.68 g (3.12 mmol) di-tert-butyl dicarbonate, stirred for 2 hours, and
poured onto 100 ml of ice-water. The resulting white precipitate was filtered and washed with 30 ml of water and then dried at 35°C/8 mbar to give 3.08 g of crude product. Recrystallization from ethanol gave 2.30 g (70%) of product.
Example 3
(S)-2-(6-Chloro-5-fluoro-indol-l-yl)-l-methyl-ethylamine hydrochloride
9.8 g (30 mmol) of (S)-2-(6-chloro-5-fluoro-indol-l-yl)-l-methyl-ethyl- carbamic acid tert-butylester was dissolved in 150 ml of ethyl acetate and then treated with 5.6 ml (45 mmol) 25% HCI. This mixture was heated to 68°C. After 1 hour a white suspension formed, from which 70 ml of ethyl acetate was evaporated. 70 ml of fresh ethyl acetate was added, the mixture was stirred over night at room temperature and then 4 hours at 0°C. The crystals were separated, washed with 100 ml of cold ethyl acetate and dried (35°C/10 mbar) to give the title compound. Yield: 7.12 g of white crystals (90%).
Claims
Claims
1. A process for the manufacture of compounds of formula
wherein Ri-R4 signifies hydrogen, halogen, lower alkyl, cycloalkyl or trifluoromethyl, R5 and R6 signify hydrogen, lower alkyl, cycloalkyl, trifluoromethyl, hydroxy or lower alkoxy and R7 signifies hydrogen or lower alkyl, which process comprises
a) alkylating a compound of the formula
wherein R1-R6 have the significances given above, with a compound of the formula
X i i
NHR m
wherein X is a leaving group, R signifies an amino protecting group and R7 has the significance given above, in the presence of a base, to get a compound of the formula
NHR rv
wherein the substituents have the significances given above,
b) cleaving off the amino protecting group and
c) if desired, converting the compound of formula I obtained into a pharmaceutically acceptable acid addition salt.
2. A process in accordance with claim 1, wherein the leaving group is halogen, lower alkylsulfonyloxy or arylsulfonyloxy.
3. A process in accordance with claims 1 and 2, wherein the leaving group is methylsulfonyloxy.
4. A process in accordance with claim 1, wherein the amino protecting group is t-butoxycarbonyl (BOC), benzyloxycarbonyl or allyloxycarbonyl.
5. A process in accordance with claims 1 and 4, wherein the amino protecting group is t-butoxycarbonyl (BOC).
6. A process in accordance with claim 1, wherein the base is an alkali hydroxide, an amine, an alkali metal hydride, an alkoxide or an amide.
7. A process in accordance with claim 1, wherein the process is carried out at temperatures between 0°C and 90°C.
8. A process in accordance with claim 1, wherein the process is carried out in a polar or apolar or in a protic or aprotic solvent as well as under phase transfer conditions.
9. A process in accordance with claim 8, wherein the process is carried out in toluene, chlorinated solvents, water, DMSO or DMF.
10. A process in accordance with claim 1, wherein Rl, R^, R5 and R*> are hydrogen, R^ is fluoro, R^ is chlorine and R? is methyl.
- lO - ll. A process in accordance with claim 1, wherein (S)-2-(6-chloro-5- fluoro-indol-l-yl)-l-methyl-ethylamine is prepared.
12. A compound of formula IV, wherein the substituents have the significances given in claim 1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU32556/97A AU3255697A (en) | 1996-06-12 | 1997-06-04 | A process for the manufacture of 1-(amino-alkyl)-indoles |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP96109386 | 1996-06-12 | ||
| EP96109386.1 | 1996-06-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997047598A1 true WO1997047598A1 (en) | 1997-12-18 |
Family
ID=8222887
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1997/002895 WO1997047598A1 (en) | 1996-06-12 | 1997-06-04 | A process for the manufacture of 1-(amino-alkyl)-indoles |
Country Status (5)
| Country | Link |
|---|---|
| AU (1) | AU3255697A (en) |
| HR (1) | HRP970322A2 (en) |
| MA (1) | MA24206A1 (en) |
| WO (1) | WO1997047598A1 (en) |
| ZA (1) | ZA974986B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001040183A1 (en) * | 1999-12-03 | 2001-06-07 | Alcon Universal Ltd. | 1-aminoalkyl-1h-indoles for treating glaucoma |
| CN105732462A (en) * | 2016-02-03 | 2016-07-06 | 常州工程职业技术学院 | Method for synthesizing 7-halogenoindoles |
| CN105732461A (en) * | 2016-02-03 | 2016-07-06 | 常州工程职业技术学院 | Preparation method of 5-methoxy group-6-halogenated indole |
| CN105732460A (en) * | 2016-02-03 | 2016-07-06 | 常州工程职业技术学院 | Method for synthesizing indole compound |
| WO2021252692A1 (en) * | 2020-06-10 | 2021-12-16 | Delix Therapeutics, Inc. | Isotryptamine psychoplastogens and uses thereof |
| CN115215782A (en) * | 2022-07-22 | 2022-10-21 | 常州琦诺生物科技有限公司 | Preparation method of 4-bromoindole |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993014113A1 (en) * | 1992-01-10 | 1993-07-22 | Fujisawa Pharmaceutical Co., Ltd. | Peptides with tachykinin antagonist activity |
| EP0622356A1 (en) * | 1993-04-28 | 1994-11-02 | Sumitomo Pharmaceuticals Company, Limited | Indoloylguanidine derivatives as inhibitors of sodium-hydrogen exchange |
| US5494928A (en) * | 1993-01-22 | 1996-02-27 | Hoffmann-La Roche Inc. | Indole derivatives |
-
1997
- 1997-06-04 WO PCT/EP1997/002895 patent/WO1997047598A1/en active Application Filing
- 1997-06-04 AU AU32556/97A patent/AU3255697A/en not_active Abandoned
- 1997-06-05 ZA ZA9704986A patent/ZA974986B/en unknown
- 1997-06-11 HR HR96109386.1A patent/HRP970322A2/en not_active Application Discontinuation
- 1997-06-11 MA MA24656A patent/MA24206A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993014113A1 (en) * | 1992-01-10 | 1993-07-22 | Fujisawa Pharmaceutical Co., Ltd. | Peptides with tachykinin antagonist activity |
| US5494928A (en) * | 1993-01-22 | 1996-02-27 | Hoffmann-La Roche Inc. | Indole derivatives |
| EP0622356A1 (en) * | 1993-04-28 | 1994-11-02 | Sumitomo Pharmaceuticals Company, Limited | Indoloylguanidine derivatives as inhibitors of sodium-hydrogen exchange |
Non-Patent Citations (3)
| Title |
|---|
| CHEMICAL ABSTRACTS, vol. 123, no. 15, 1995, Columbus, Ohio, US; abstract no. 198739x, XP002040347 * |
| S. NARUTO ET AL, CHEM. PHARM. BULL., vol. 28, no. 3, 1980, pages 900 - 909, XP002040346 * |
| V.I. TERENIN ET AL, KHIM. GETEROTSIKL. SOEDIN., no. 3, 1995, pages 331 - 335 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2001040183A1 (en) * | 1999-12-03 | 2001-06-07 | Alcon Universal Ltd. | 1-aminoalkyl-1h-indoles for treating glaucoma |
| CN105732462A (en) * | 2016-02-03 | 2016-07-06 | 常州工程职业技术学院 | Method for synthesizing 7-halogenoindoles |
| CN105732461A (en) * | 2016-02-03 | 2016-07-06 | 常州工程职业技术学院 | Preparation method of 5-methoxy group-6-halogenated indole |
| CN105732460A (en) * | 2016-02-03 | 2016-07-06 | 常州工程职业技术学院 | Method for synthesizing indole compound |
| CN105732462B (en) * | 2016-02-03 | 2019-01-04 | 常州工程职业技术学院 | A method of synthesis 7- halogeno indole |
| WO2021252692A1 (en) * | 2020-06-10 | 2021-12-16 | Delix Therapeutics, Inc. | Isotryptamine psychoplastogens and uses thereof |
| CN115215782A (en) * | 2022-07-22 | 2022-10-21 | 常州琦诺生物科技有限公司 | Preparation method of 4-bromoindole |
| CN115215782B (en) * | 2022-07-22 | 2024-09-03 | 常州琦诺生物科技有限公司 | Preparation method of 4-bromoindole |
Also Published As
| Publication number | Publication date |
|---|---|
| MA24206A1 (en) | 1997-12-31 |
| HRP970322A2 (en) | 1998-04-30 |
| AU3255697A (en) | 1998-01-07 |
| ZA974986B (en) | 1997-12-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5494928A (en) | Indole derivatives | |
| US7452888B2 (en) | Quinoline derivatives and their use as 5-ht6 ligands | |
| US5561150A (en) | Tricyclic pyrazole derivatives | |
| JP4172717B2 (en) | Process for producing substituted 2,5-diamino-3-hydroxyhexane | |
| KR900006681B1 (en) | Process for preparing heterocyclic compounds | |
| JP3560986B2 (en) | 5-HT2C receptor agonist and aminoalkylindazole derivative | |
| Stanton et al. | Synthesis and anticonvulsant activity of some tetracyclic indole derivatives | |
| AP1305A (en) | Process for preparing a protected 4-aminomethyl-pyrrolidin-3-one. | |
| WO1997047598A1 (en) | A process for the manufacture of 1-(amino-alkyl)-indoles | |
| EP0773921B1 (en) | Process for the preparation of a substituted 2.5-diamino-3-hydroxyhexane | |
| CA1294618C (en) | Pyridopyrimidinediones | |
| WO1994015918A1 (en) | Process for the preparation of substituted indolone derivatives | |
| KR100338916B1 (en) | Process for preparing pyrrolidinyl hydroxamic acid compounds | |
| US5786500A (en) | Process for the preparation of a substituted 2.5-diamino-3-hydroxyhexane | |
| US4506077A (en) | Tin complexes of indoline-2-carboxylic acids and esters prepared from o-nitrophenylpyruvic acids and esters | |
| US6313315B1 (en) | Methods for producing N-protected-azetidine-2-carboxylic acids | |
| US20040242879A1 (en) | Process for preparing 1-methyl-3-phenylpiperazine using a novel intermediate | |
| JP2003530404A (en) | Method for producing 3-amino-1,5-benzodiazepine derivative | |
| Pipaud et al. | A Convenient Synthesis of 4, 5-Benzodiazepin-1-one-2-carboxylic Acid and a 3-Cyanoindole | |
| JPH0632777A (en) | Production of 5-chlorooxyindole | |
| EP1131313A1 (en) | Enantioselective alkylation of tricyclic compounds | |
| MXPA00004847A (en) | Process for obtaining zolpidem hemi-tartrate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU BR CA CN CZ HU IL JP KR KZ MX NO NZ PL RU SG TR UA YU |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| NENP | Non-entry into the national phase |
Ref country code: CA |
|
| NENP | Non-entry into the national phase |
Ref country code: JP Ref document number: 98501150 Format of ref document f/p: F |
|
| 122 | Ep: pct application non-entry in european phase |