WO1999057095A2 - Process for the preparation of a pharmaceutical intermediate - Google Patents
Process for the preparation of a pharmaceutical intermediate Download PDFInfo
- Publication number
- WO1999057095A2 WO1999057095A2 PCT/HU1999/000034 HU9900034W WO9957095A2 WO 1999057095 A2 WO1999057095 A2 WO 1999057095A2 HU 9900034 W HU9900034 W HU 9900034W WO 9957095 A2 WO9957095 A2 WO 9957095A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- process according
- reaction
- dichlorophenyl
- naphthalene
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000012450 pharmaceutical intermediate Substances 0.000 title abstract description 5
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims abstract description 44
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- 239000012024 dehydrating agents Substances 0.000 claims abstract description 9
- JGMBHJNMQVKDMW-UHFFFAOYSA-N 4-(3,4-dichlorophenyl)-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1=C(Cl)C(Cl)=CC=C1C1C2=CC=CC=C2C(=O)CC1 JGMBHJNMQVKDMW-UHFFFAOYSA-N 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000011541 reaction mixture Substances 0.000 claims description 9
- 239000000725 suspension Substances 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 230000009466 transformation Effects 0.000 claims 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 abstract 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 8
- 239000004408 titanium dioxide Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 2
- 230000004888 barrier function Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000001627 detrimental effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 229910052719 titanium Inorganic materials 0.000 description 2
- 239000010936 titanium Substances 0.000 description 2
- IOHGCXDWUOZSRD-UHFFFAOYSA-N Cl.Cl.Cl.Cl.[Ti] Chemical compound Cl.Cl.Cl.Cl.[Ti] IOHGCXDWUOZSRD-UHFFFAOYSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 239000002262 Schiff base Substances 0.000 description 1
- 150000004753 Schiff bases Chemical class 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 201000003102 mental depression Diseases 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/02—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of compounds containing imino groups
Definitions
- This invention relates to a new and improved process for the preparation of a pharmaceutical intermediate. More particularly the invention is concerned with the preparation of ( ⁇ ) ⁇ -(S,R)-[(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalene- 1 -ylidene]-methylamine.
- the invention is concerned with the preparation of ( ⁇ ) ⁇ -(S,R)-[(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalene- 1 -ylidene]-methylamine.
- the compound of the Formula III has the INN sertraline and is a medicine effective against mental depression.
- the compound of the Formula I may be prepared by reacting 4-(3,4- dichlorophenyl)-3,4-dihydro-1(2H)-naphthalene-1-one of the Formula
- titanium tetrahydrochloride methyl amine in tetrahydrofurane as medium in the presence of titanium tetrahydrochloride.
- Methyl amine is used in a six-fold excess and the methyl amine chlorohydrate and titanium dioxide formed are removed from the reaction mixture by filtration.
- the process is accompanied by several drawbacks. Titanium tetrachloride is very difficult to be handled and is a highly corrosive material which causes serious problems of environmental pollution.
- the titanium dioxide and methyl amine chlorohydrate formed in the reaction can be filtered only with difficulties and can be only circumstantially washed out; the separation of these byproducts is encountered with difficulties and reduces the yield. Moreover there is a risk of titanium contamination of the product.
- the present invention is based on the surprising recognition that when carrying out the reaction of 4-(3,4- dichlorophenyl)-3,4-dihydro-1(2H)-naphthalene-1-one of the Formula II and methyl amine in an alkanol as medium in the absence of a dehydrating agent, the desired ( ⁇ )-4-(S,R)-[(3,4- dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalene-1-ylidene]- methylamine of the Formula I is obtained with an excellent yield of 97-98 % in a simple manner on industrial scale too.
- lower alkanol straight or branched chain alkanols having 1-3 carbon atoms can be used (methanol, ethanol, n- propanol or isopropanol).
- methanol, ethanol, n- propanol or isopropanol One may preferable use methanol or ethanol.
- the process according to the present invention can be carried out at a temperature between 0°C and 40°C, preferably at 10-30°C.
- One may particularly advantageously work at room temperature.
- the reaction time is 10-48 hours, preferably 10-30 hours. At room temperature the reaction takes place within about 24 hours.
- the compound of the Formula II is suspended in a lower alkanol, preferably methanol or ethanol, whereupon a solution of methyl amine formed with a lower alkanol is added.
- a lower alkanol preferably methanol or ethanol
- One may proceed particularly preferably by dissolving the methyl amine and suspending the compound of the Formula II in the same alkanol.
- the reaction may be carried out preferably at a temperature of about room temperature under stirring.
- the process of the present invention provides a very high yield of about 99 %.
- the reaction mixture may be worked up in a very simple manner.
- the compound of the Formula I may be isolated by cooling the reaction mixture and separating the precipitated product by filtration or centrifuging.
- the compound of the Formula I is sufficiently pure for further chemical transformations and no recrystallization is required.
- One may also proceed by omitting the isolation step of the compound of the Formula I and directly reducing the suspension obtained as reaction mixture into the end-product of the Formula III.
- reaction mixture can be worked up in a simple manner
- Example 1 the yields are higher than those of the known methods. Further details of the present invention are to be found in the Examples without limiting the scope of protection to said working Examples.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a process for the preparation of (±)-4-(S,R)- [(3,4-dichlorophenyl) -3,4-dihydro-1(2H) -naphthalene-1-ylidene] -methylamine of Formula (I) by reacting 4-(3,4-dichlorophenyl) -3,4-dihydro-1(2H) -naphthalene-1-one of Formula (II) with methyl amine which comprises carrying out the reaction in the absence of a dehydrating agent, in a lower alkanol. The compound of Formula (I) is a useful pharmaceutical intermediate.
Description
Process for the preparation of a pharmaceutical intermediate
Background of the invention
This invention relates to a new and improved process for the preparation of a pharmaceutical intermediate. More particularly the invention is concerned with the preparation of (±)^-(S,R)-[(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalene- 1 -ylidene]-methylamine. State of the prior art
The (±)-4-(S,R)-[(3,4-dichlorophenyl)-3,4-dihydro-1 (2H)- naphthalene-1-ylidene]-methylamine of the Formula
/CH3
The compound of the Formula III has the INN sertraline and is a medicine effective against mental depression.
In prior art several procedures are disclosed for the preparation of Schiff-bases having a similar structure to the compound of the Formula I. Since this is an equilibrium reaction, the equilibrium is to be shifted. This can be carried out in several ways. According to a process the water formed is removed by azeotropic distillation [Morimoto, Sekiya Chem. Lett. 1371 (1985)]. According to other methods the reaction is carried out in the presence of a dehydrating agent. As dehydrating agent titanium tetrachloride [Chup, White J. Org. Chem. 32, 3246 (1967)], magnesium sulphate [Evans J. Am. Chem. Soc. 100, 8170 (1978)] or dehydrating molecular sieve [Bonnett, Emerson J. Chem. Soc. 4508 (1965)] may be used.
According to US patent No. 4,536,518 the compound of the Formula I may be prepared by reacting 4-(3,4- dichlorophenyl)-3,4-dihydro-1(2H)-naphthalene-1-one of the Formula
According to US patent No. 4,855,550 the reaction of the compound of the Formula II and methyl amine is carried out under pressure in the presence of molecular sieve as dehydrating agent. The disadvantage of this process is the use of pressure and a dehydrating agent.
Summary of the invention
It is the object of the invention to eliminate the disadvantages of the known procedures and to elaborate an industrial scale process for the preparation of the compound of the Formula I, which can be simply carried out by good yields, without using pressure and a dehydrating agent.
The above object is solved by the process of the present invention.
According to the present invention there is provided a process for the preparation of (±)-4-(S,R)-[(3,4-dichlorophenyl)- 3,4-dihydro-1(2H)-naphthalene-1-ylidene]-methylamine of the Formula I by reacting 4-(3,4-dichlorophenyl)-3,4-dihydro- 1(2H)-naphthalene-1-one of the Formula II with methyl amine which comprises carrying out the reaction in the absence of a dehydrating agent, in a lower alkanol. Detailed description of the invention
The present invention is based on the surprising recognition that when carrying out the reaction of 4-(3,4- dichlorophenyl)-3,4-dihydro-1(2H)-naphthalene-1-one of the Formula II and methyl amine in an alkanol as medium in the absence of a dehydrating agent, the desired (±)-4-(S,R)-[(3,4- dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalene-1-ylidene]- methylamine of the Formula I is obtained with an excellent yield of 97-98 % in a simple manner on industrial scale too.
As lower alkanol straight or branched chain alkanols having 1-3 carbon atoms can be used (methanol, ethanol,
n- propanol or isopropanol). One may preferable use methanol or ethanol.
The process according to the present invention can be carried out at a temperature between 0°C and 40°C, preferably at 10-30°C. One may particularly advantageously work at room temperature.
The reaction time is 10-48 hours, preferably 10-30 hours. At room temperature the reaction takes place within about 24 hours.
According to a preferred embodiment of the present invention one may proceed as follows:
The compound of the Formula II is suspended in a lower alkanol, preferably methanol or ethanol, whereupon a solution of methyl amine formed with a lower alkanol is added. One may proceed particularly preferably by dissolving the methyl amine and suspending the compound of the Formula II in the same alkanol. The reaction may be carried out preferably at a temperature of about room temperature under stirring.
The process of the present invention provides a very high yield of about 99 %. The reaction mixture may be worked up in a very simple manner. Thus the compound of the Formula I may be isolated by cooling the reaction mixture and separating the precipitated product by filtration or centrifuging. The compound of the Formula I is sufficiently pure for further chemical transformations and no recrystallization is required.
One may also proceed by omitting the isolation step of the compound of the Formula I and directly reducing the suspension obtained as reaction mixture into the end-product of the Formula III.
The process of the present invention has the following advantages over prior art:
- the use of titanium tetrachloride difficult to handle, corrosive and detrimental to the environment is eliminated;
- no other dehydrating agents are used either;
- in the reaction no titanium dioxide difficult to handle and detrimental to the environment is formed;
- there is no risk of contaminating the compound of the Formula I with titanium;
- in the reaction no titanium dioxide and methyl amine are formed which substances can be removed with difficulties, can be separated from the desired product only with the aid of circumstantial methods and reduce the yield;
- as solvent in the place of expensive tetrahydrofurane considerably more economical methanol or ethanol can be used;
- in the process of the invention no high temperature or high pressure are required;
- the reaction mixture can be worked up in a simple manner;
- the yields are higher than those of the known methods. Further details of the present invention are to be found in the Examples without limiting the scope of protection to said working Examples.
Example 1
2 g (6.86 millimoles) of 4-(3,4-dichlorophenyl)-3,4- dihydro-1(2H)-naphthalene-1-one are suspended in 40 ml of methanol whereupon 20 ml of 20 % methanolic methyl amine are added at room temperature under stirring. The reaction vessel is closed with a liquid barrier in order to keep the methyl amine in solution. The reaction mixture is stirred at room temperature for 24 hours.
The suspension thus obtained is cooled to 0°C and the precipitated crystals are filtered. Thus 1.94 g of (±)-4-(S,R)- [(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalene-1-ylidene]- methylamine are obtained. Yield 93.5 %, mp.: 146-148°C. Example 2
4 g (13.72 millimoles) of 4-(3,4-dichlorophenyl)-3,4- dihydro-1(2H)-naphthalene-1-one are suspended in 80 ml of ethanol, whereupon 25 ml of 33 % ethanolic methyl amine are added under stirring at room temperature. The reaction vessel is closed with a liquid barrier in order to keep the methyl amine in solution. The reaction mixture is stirred at room temperature for 24 hours.
The reaction mixture is cooled to 0°C and the precipitated crystals are filtered. Thus 3.75 g of (±)-4-(S,R)- [(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalene-1-ylidene]- methylamine are obtained. Yield 90.3 %, mp.: 146-148°C.
Claims
1. Process for the preparation of (±)-4-(S,R)-[(3,4- dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalene-1 -ylidene]- methylamine of the Formula
/CH3
2. Process according to Claim 1 which comprises using methanol or ethanol as lower alkanol.
3. Process according to Claim 1 or 2 which comprises carrying out the reaction at 0-40°C.
4. Process according to Claim 3 which comprises carrying out the reaction at 0-30°C, preferably at room temperature.
5. Process according to any of Claims 1-4 which comprises adding a solution of methyl amine formed with a lower alkanol to a suspension of the compound of the Formula II and a lower alkanol.
6. Process according to Claim 5 which comprises dissolving the methyl amine and suspending the compound of the Formula II in the same solvent.
7. Process according to any of Claims 1-6 which comprises isolating the compound of the Formula I by cooling the reaction mixture and filtering or centrifuging the precipitated product.
8. Process according to any of Claims 1-6 which comprises directly subjecting the suspension formed in the reaction to further transformation without isolating the compound of the Formula I.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU38401/99A AU3840199A (en) | 1998-05-05 | 1999-05-03 | Process for the preparation of a pharmaceutical intermediate |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU9801024A HU226423B1 (en) | 1998-05-05 | 1998-05-05 | Process for producing a 1(2h)-naphtalene-1-ylidene derivative |
| HUP9801024 | 1998-05-05 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO1999057095A2 true WO1999057095A2 (en) | 1999-11-11 |
| WO1999057095A3 WO1999057095A3 (en) | 2000-01-13 |
Family
ID=89996510
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU1999/000034 WO1999057095A2 (en) | 1998-05-05 | 1999-05-03 | Process for the preparation of a pharmaceutical intermediate |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU3840199A (en) |
| HU (1) | HU226423B1 (en) |
| WO (1) | WO1999057095A2 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1059287A1 (en) * | 1999-06-09 | 2000-12-13 | Pfizer Products Inc. | Process for preparing sertraline from chiral tetralone |
| WO2003099761A1 (en) * | 2002-05-10 | 2003-12-04 | Stohandl Jiri | Process for the manufacture of sertraline |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4536518A (en) * | 1979-11-01 | 1985-08-20 | Pfizer Inc. | Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine |
| US4855500A (en) * | 1988-05-04 | 1989-08-08 | Pfizer Inc. | Process for preparing a ketimine |
| WO1999036394A1 (en) * | 1998-01-16 | 1999-07-22 | Pfizer Products Inc. | Novel process for preparing a ketimine |
-
1998
- 1998-05-05 HU HU9801024A patent/HU226423B1/en not_active IP Right Cessation
-
1999
- 1999-05-03 WO PCT/HU1999/000034 patent/WO1999057095A2/en active Application Filing
- 1999-05-03 AU AU38401/99A patent/AU3840199A/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4536518A (en) * | 1979-11-01 | 1985-08-20 | Pfizer Inc. | Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine |
| US4855500A (en) * | 1988-05-04 | 1989-08-08 | Pfizer Inc. | Process for preparing a ketimine |
| WO1999036394A1 (en) * | 1998-01-16 | 1999-07-22 | Pfizer Products Inc. | Novel process for preparing a ketimine |
Non-Patent Citations (1)
| Title |
|---|
| OSHIRO Y ET AL: "Novel cerebroprotective agents with central nervous system stimulating activity. 1. Synthesis and pharmacology of the 1-amino-7-hydroxyindan derivatives" JOURNAL OF MEDICINAL CHEMISTRY,US,AMERICAN CHEMICAL SOCIETY. WASHINGTON, vol. 34, page 2004-2013 XP002113231 ISSN: 0022-2623 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1059287A1 (en) * | 1999-06-09 | 2000-12-13 | Pfizer Products Inc. | Process for preparing sertraline from chiral tetralone |
| US6593496B1 (en) | 1999-06-09 | 2003-07-15 | Pfizer Inc | Process for preparing sertraline from chiral tetralone |
| WO2003099761A1 (en) * | 2002-05-10 | 2003-12-04 | Stohandl Jiri | Process for the manufacture of sertraline |
Also Published As
| Publication number | Publication date |
|---|---|
| HUP9801024A1 (en) | 2000-08-28 |
| HU9801024D0 (en) | 1998-06-29 |
| WO1999057095A3 (en) | 2000-01-13 |
| HU226423B1 (en) | 2008-12-29 |
| AU3840199A (en) | 1999-11-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US7319171B2 (en) | Sertraline hydrochloride form II and methods for the preparation thereof | |
| WO2008047388A2 (en) | Improved process for the preparation of ranolazine | |
| EP1138677B1 (en) | Process for the preparation of 11-amino-3-chloro-6,11-dihydro-5,5-dioxo-6-methyl-dibenzo[c,f][1,2]-thiazepine and application to the synthesis of tianeptine | |
| JP2009515945A (en) | Improved synthesis and preparation of intermediates and novel polymorphs useful for the preparation of donepezil hydrochloride | |
| WO1999057095A2 (en) | Process for the preparation of a pharmaceutical intermediate | |
| JPH07119219B2 (en) | Method for producing 4-isothiazolin-3-one | |
| US10640465B2 (en) | Method for preparing phenylalanine compound | |
| FR2696742A1 (en) | Process for the manufacture of formylimidazoles from 4- or 5-hydroxymethylimidazoles. | |
| SK50932005A3 (en) | Method for the preparation of N-(1-oxopentyl)-N-[[2'-(1H- tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-L-valine (valsartan) | |
| US5663365A (en) | Process for the preparation of pyrazolones | |
| JP4173599B2 (en) | Process for producing 6-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline | |
| EP0169602B1 (en) | Preparation of n-substituted azetidine 3-carboxylic acid derivatives | |
| EP0481118A1 (en) | A method for producing butyl 3'-(1H-tetrazol-5-yl) oxanilate | |
| EP0230127A1 (en) | Synthesis of nizatidine | |
| US4010160A (en) | Process for the manufacture of 1,3-bis-(β-ethylhexyl)-5-amino-5-methyl-hexahydropyrimidine | |
| EP0412892A1 (en) | Pyranon, process for its preparation, its application for the preparation of a pyridon and preparation process for the latter | |
| CN113683608B (en) | N-substituted-2-amino-4-saccharin substituted methylthiazole compound with bactericidal activity, preparation method and application | |
| JPH082848B2 (en) | Process for producing 4-nitrosodiphenylamines | |
| AU680989B2 (en) | Method of preparing 6-aryloxymethyl-1-hydroxy-4-methyl-2-pyridones | |
| EP1651590B1 (en) | Process for the preparation of an imine intermediate | |
| CA1334102C (en) | Production of aniline compound | |
| KR20050043131A (en) | Preparation method of 4-biphenylacetic acid | |
| CA1327203C (en) | Preparation of heterocyclic compounds | |
| JPH10338679A (en) | Production of thiazolidine derivative | |
| JPH0674250B2 (en) | Method for producing thiocarbamate derivative |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A2 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM HR ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
| AK | Designated states |
Kind code of ref document: A3 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM HR ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A3 Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG |
|
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| NENP | Non-entry into the national phase |
Ref country code: KR |
|
| REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
| 122 | Ep: pct application non-entry in european phase |