AU2004235898A1 - Method for producing the purest rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl] piperazin-1-yl}-2,2-diphenylethan-1-one fumarate and the purest rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]piperazin-1-yl}-2,2-diphenylethan-1-one fumarate - Google Patents
Method for producing the purest rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl] piperazin-1-yl}-2,2-diphenylethan-1-one fumarate and the purest rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]piperazin-1-yl}-2,2-diphenylethan-1-one fumarate Download PDFInfo
- Publication number
- AU2004235898A1 AU2004235898A1 AU2004235898A AU2004235898A AU2004235898A1 AU 2004235898 A1 AU2004235898 A1 AU 2004235898A1 AU 2004235898 A AU2004235898 A AU 2004235898A AU 2004235898 A AU2004235898 A AU 2004235898A AU 2004235898 A1 AU2004235898 A1 AU 2004235898A1
- Authority
- AU
- Australia
- Prior art keywords
- piperazin
- fumarate
- quinolyloxy
- diphenylethan
- propyl
- 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.)
- Abandoned
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Description
VERIFICATION OF TRANSLATION I, Melissa Stanford, a translator with Chillson Translating Service, 3530 Chas Drive, Hampstead, Maryland, 21074, hereby declare as follows: That I am familiar with the German and English languages; That I am capable of translating from German to English; That the translation attached hereto is a true and accurate translation of German Application titled, "Process for the Production of High-Purity rac- 1- {4-[2-Hydroxy-3-(5 quinolyloxy)propyl]- piperazin-1-yl}-2,2-diphenylethan-1-one Fumarate and High-Purity rac-1 {4-[2-Hydroxy-3-(5- quinolyloxy)propyl]piperazin- 1-yl} -2,2-diphenylethan- 1-one Fumarate;" That all statements made herein of my own knowledge are true and that all statements made on information and belief are believed to be true; And further that these statements were made with the knowledge that willful false statements and the like so made are punishable by fine or imprisonment, or both, under Section 1001 of Title 18 of the United States Code and that such willful false statements may jeopardize the validity of the application or any registration resulting therefrom. By f Executed this j day of / o O . Witness 6 A Translator's Note: There are two different versions of Claim 6 on German page 15 (English page 16).
Process for the Production of High-Purity rac-1-{4-[2-Hydroxy-3-(5-quinolyloxy)propyl] piperazin-1-yI}-2,2-diphenylethan-1-one Fumarate and High-Purity rac-1-{4-[2-Hydroxy-3-(5 quinolyloxy)propyl]piperazin-1-yl}-2,2-diphenylethan-1-one Furmarate The invention relates to a process for the production of high-purity rac-1-{4-[2-hydroxy-3 (5-quinolyloxy)propyl]-piperazin-1-yl}-2,2-diphenylethan-1-one fumarate as well as rac-1-{4-[2 hydroxy-3-(5-quinolyloxy)propyl]piperazin-1-yl} -2,2-diphenylethan- 1-one fumarate at a purity of at least 99.55%. The multidrug-resistance modulator rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl] piperazin- 1 -yl} -2,2-diphenylethan-1 -one fumarate, its production and use as carcinostatic pharmaceutical agent, in addition to other derivatives of this compound, is described in EP 575890. According to the process for the production of pure rac-l-{4-[2-hydroxy-3-(5 quinolyloxy)propyl]-piperazin-1-yl}-2,2-diphenylethan-1 -one fumarate that is described in EP 575890, the free base 5-[3-{4-(2,2-diphenylacetyl)piperazin-1-yl}-2-hydroxypropoxy]quinoline is first isolated as a crude product by coupling the two components epoxiline (B) (5-(2,3 epoxypropoxy)-quinoline) and diphenepiperazide (C) (N-(2,2-diphenylacetyl)piperazine). This reaction contains two partial stages. First, the epoxylate is reacted with hydroxyquinoline (A). In the second step, the epoxiline (B) (5-(2,3-epoxypropoxy)-quinoline) is opened by diphenepiperazide (C) (N-(2,2-diphenylacetyl)piperazine); it produces the secondary alcohol (D). This reaction takes place in ethanol; water catalyzes the reaction. The working-up/isolation is then carried out by precipitation from acetone/water and drying in a vacuum at 60'C. The total reaction is produced from the diagram below: 2 1,23 eq. N Hydroxyquinolin HN N (A) 1,0 eq. HN 1,53 eq. CS2CO3, Diphenpiperazid I, N Ethanol, 50 C (C) 5-[3-{4-(2,2-Diphenylacetyl)piperazin-1-y Epoxilin (B) VE-Wasser, 40 00 2-hydroxypropoxy]quinolin (D) [Key:] Hydroxyquinolin = hydroxyquinoline Epoxilin = epoxiline Diphenpiperazid = diphenepiperazide VE-Wasser = VE water -quinolin = -quinoline In the next step, a very expensive purification process follows the isolation of the free base, which still contains many contaminants (purity of the crude product typically about 80%). After the free base is treated with activated carbon and after the fumarate is formed in methanol, the free base is produced again for purification by treatment with dilute sodium hydroxide solution. Then, as a last step, repeated fumarate formation is carried out. The two fumarate formations are identical as far as processing is concerned and are distinguished only by the batch size (T. Suzuki et al., J. Med. Chem. (1997) 40, 2047) (JP 2000281653). Starting from the free base crude product, the typical laboratory yield for this purification sequence is 45% of theory. In this case, not only the low yield (over 50% loss in the final stage) but also the expensive technical execution, which binds many operational capacities and thus produces elevated costs, is disadvantageous in this process. Especially disadvantageous in this case is the extremely poor filterability of the free base, which must be partially filter-dried over several weeks.
3 Despite the high expense as far as processing is concerned, the extremely high purification requirements of rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]piperazin-1-yl}-2,2-diphenylethan-1 one fumarate are not always achieved in a completely satisfactory manner according to this known process. Also, the process that is described in EP 575 890 does not provide any reasonable results in the scale-up. The following diagram provides an overview of the individual reactions: 2,52 eq. Fumarsaure, N ,,Ne hanol 60 *C, 0 C H NN "IN N Nkikol NH N N free Base des 1,5 HOOC 5-[3-{4-(2,2-Diphenylacetyl)piperazin- COOH 1-yl-2-hydroxypropoxy)quinolins Fumarat des 5-[3-{4-(2,2-Diphenylacetyl)piperazin. 1-yi-2-hydroxypropoxy)quinolins (E) IMethanol/Wasser 60 C N- 2,52 eq. Fumarsaure, 0 N~~ Aktivkohle N H N Methanol, 60 "C, 'C H N~~ N 'K. NH NN 1,5. HOOC,' ... COOH N free gereinigte Base des relies Fuarat des 5-(3-4-(2,2-Diphenylacetyl)piperazin 5-[3-{4.(2,2.Diphenylacetyl)piperazin- I .yi.2.hydroxypropoxy)quinolins 1 .y.2-hydrMxypropoxy)qeuitnohins (D) (E) [Key:] freie Base des = free base of -quinolins = quinoline Fumarsaure = fumaric acid Aktivkohle = activated carbon Fumarat des = fumarate of 4 Wasser = water freie gereinigte Base des = free purified base of reines Fumarat des = pure fumarate of It has now been found that with the process according to the invention, these known drawbacks can be overcome. In the process according to the invention, the epoxiline (B) and diphenepiperazide (C) are first also coupled by opening the epoxide. Then, however, not the free base (D), but rather, after the solid fumaric acid is added directly, fumarate salt (E) is isolated as a crude product. The subject of the application is thus a process for the production of high-purity rac-1-{4-[2 hydroxy-3-(5-quinolyloxy)propyl]-piperazin-1-yl} -2,2-diphenylethan-1-one fumarate, which is characterized in that first a) an epoxytosylate of structure I 0 L-W .OTs (I) can be reacted with b) 5-hydroxyquinoline (II) H 1,0 eq. N
(II)
5 and cesium carbonate in a suitable solvent and at a suitable temperature to form the 5-(2,3 epoxypropoxy)-quinoline of formula III I N (III) and then the 5-(2,3-epoxypropoxy)-quinoline of formula III c) is reacted with N-(2,2-diphenylacetyl)piperazine of formula IV o N HN (IV) in a suitable solvent and at a suitable temperature with the subsequent addition of solid fumaric acid to form crude rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-1-yl}-2,2-diphenylethan-1 one fumarate of formula V 0 NN (N N O% -1,5 HOOC COOH (V) and then 6 d) the thus formed crude rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-1-yl}-2,2 diphenylethan-1-one fumarate (V) is isolated and is dissolved in a solvent mixture that consists of methanol and methylene chloride, is treated with activated carbon, and then is filtered through a pressure filter with silica gel as a column material, and the thus obtained pure rac-1-{4-[2-hydroxy 3-(5-quinolyloxy)propyl]-piperazin-1-yl}-2,2-diphenylethan-1-one fumarate (V) is crystallized from a suitable alcohol. The reaction is preferably carried out in a temperature range of 35 to 60'C. Suitable solvents are, e.g., ketones, such as acetone, methyl-isobutylketone, etc., alcohols, such as methanol, ethanol, isopropanol etc., amides, such as dimethylformamide, dirmethylacetamide, N-methyl-pyrrolidone, etc. In comparison to the known process, the crude rac-1-{4-[2-hydroxy-3-(5 quinolyloxy)propyl]-piperazin- l-yl} -2,2-diphenylethan-1-one of process stage c) that is isolated via the process according to the invention already exhibits a dramatically increased purity of 90-96%. The purification step that is included in process stage d) is preferably performed in a solvent mixture that consists of MeOH/MeCl 2 at a ratio of 3:7, v:v. Norit SX Plus is preferably used as activated carbon. The amount of silica gel is preferably 3x the amount relative to the starting material. The temperature in the crystallization in process stage (d) is preferably 0 0 C. The typical laboratory yield for purification step (d) is 84% of theory.
7 Production Example Production of rac-1-{4-[2-Hydroxy-3-(5-quinolyloxy)propyl]-piperazin-1-yl}-2,2 diphenylethan-1-one fumarate A) Under nitrogen, 44.2 g of 5-hydroxy-quinoline and 151.9 g of cesium carbonate are added together with 560 ml of acetone at room temperature and stirred for 30 minutes at a bath temperature of 60C. At an internal temperature of 50*C, 73.0 g of 5-(2,3-epoxypropoxy)-quinoline, dissolved in 153.3 g of dichloromethane, is added. Stirring is continued for two hours at 50*C. The batch is filtered at 50'C. The filter residue (inorganic salts) is rewashed with 560 ml of acetone heated to 50C. Then, 85.4 g of N-(2,2-diphenyl-acetyl)piperazine is added, and it is concentrated by evaporation at a bath temperature of 40'C in a vacuum to 374 g of final weight. Then, 374 g of VE-water is added, and it is stirred for 2 hours at 40'C. Then, 255 g of acetone and 201 g of VE water are added. The batch is cooled to room temperature, and 89.1 g of fumaric acid in solid form is added. It is stirred for 60 minutes at a bath temperature of 60'C and then stirred for 2 hours at 0*C. Then, the solid is suctioned off and rewashed with 150 ml of ice-cold methanol. The filter residue is dried at 60'C in a vacuum. Yield: 65-85% of theory B) 56.0 g of the thus produced rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-1 yl}-2,2-diphenylethan-1-one fumarate was mixed under nitrogen and at room temperature with 5.6 g of activated carbon, Norit SX plus, 672 ml of methanol and 1008 ml of dichloromethane. The suspension that is produced is heated at a bath temperature of 75'C to reflux temperature and is kept at reflux for 30 minutes. At an internal temperature of 40*C, rac-1-{4-[2-hydroxy-3-(5- 8 quinolyloxy)propyl]-piperazin- l-yl} -2,2-diphenylethan-1-one fumarate goes into solution. Then, the batch is hot-filtered through 300% silica gel, and the silica gel is rewashed with 560 ml of a mixture that consists of 168 ml of methanol and 392 ml of dichloromethane at room temperature RT. The solution is concentrated by evaporation at a bath temperature of 40*C and an initial vacuum of 400 mbar to a final volume of 517 ml. The final vacuum is 350 mbar. The distilled volume corresponds approximately to the volume difference (about 1.7 1). 404 ml of methanol is added, such that a final volume of 921 ml is reached. The solution is cooled to 0 0 C, whereby the product precipitates. The suspension that is produced is stirred for 2 hours at 0 0 C and then filtered through a paper filter. The filter residue is washed with 56.0 ml of ice-cold methanol. The filter residue is dried at 60'C and dried in a vacuum at 100 mbar for 10 hours. Yield (uncorr.): 47.29 g ( 84.45% of the experiment) Purity: 99.65% (HPLC, 100% method) 9 Comparison of the Purification Process that is Known in the Literature with the Purification Process According to the Invention Purification Process that is Purification Process Known in the Literature According to the Invention Total Yield of the Synthesis 28% of Theory 43% of Theory over All Stages Purity (HPLC, 100% 98.54%, several VU over 99.55 - 99.89%, no VU Method) 0.1% over 0.1% Technical Expense High, several intermediate Significantly reduced time isolations are necessary, also requirement in operation extremely poor filterability due to greater ease of technical implementation. VU= contaminants From the results, it can be seen that the total yield of rac-1-{4-[2-hydroxy-3-(5 quinolyloxy)propyl]-piperazin-1 -yl} -2,2-diphenylethan- 1-one fumarate (V) can be increased by more than 50%. From the results, it can also be seen that with the process according to the invention, the necessary extremely high purities can be reached, by which the technical expense could be greatly reduced at the same time. It can also be noted that contaminants (VU) 1-4, which are formed during the reaction, can be completely avoided. A comparison of feedstocks, which had been produced according to the known process and according to the process of the invention, is indicated in the table below.
10 Contaminant (VU) Known Process Process According to the Invention VU 1 0.80% n. d. HOOC, Z COOMe VU 2 0.44% n. d. HO N N 0 N X OH N VU 3 0.08% n. d. N N 0 N 0 N 0 VU 4 0.11% n. d.
N
11 Contaminant (VU) Known Process Process According to the Invention VU 5 Unknown Structure < 0.1 % *) 0.01 *) VU 6 < 0.1 %*) 0.02*) NN 0oH N 1,5 HOC COH Purity 98.54 % 99.84 % n. d. = not detectable, since under the detection limit *) Dependent on the purity of the commercially available products (educts): if contained in the educt at < 0.2%. Additional contaminants, which are formed during synthesis and also are removed effectively by the process according to the invention: 0 / OH N - N OH0 VU 8 VU 7 12 0 / N o | HN VU 9 VU 10 OH N VU 11 The subject of this invention is thus also rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl] piperazin-1-yl}-2,2-diphenylethan-1-one fumarate at a purity of more than 98.54%. In addition, a subject of this invention is also rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl] piperazin-1-yl}-2,2-diphenylethan-1-one fumarate at a purity of at least 98.55%, especially at a purity of at least 99.55%, especially at a purity of at least 99.65% as well as at a purity of at least 99.84%. The process according to the invention is suitable in particular for the production of rac- I {4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-1-yl} -2,2-diphenylethan-1-one fumarate on a process-technology scale. Thus, with this process, rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl] piperazin-1-yl}-2,2-diphenylethan-1-one fumarate can be produced for the first time in amounts of more than 1000 g in the purity described.
13 A subject of this invention is also rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)-propyl]-piperazin 1-yl}-2,2-diphenylethan-1-one fumarate, which as a contaminant comprises less than 0.1%, preferably less than 0.01%, of at least one of the individual contaminants (VU I - VU 11). With conventional purification processes, such as chromatography, high-pressure liquid chromatography (HPLC), ion exchangers, etc., rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)-propyl] piperazin-1-yl}-2,2-diphenylethan-1-one fumarate cannot be produced in the purity according to the invention.
Claims (10)
- 3-(5-quinolyloxy)propyl]-piperazin-1-yl} -2,2-diphenylethan-1-one fumarate (V) is crystallized from a suitable alcohol. 2. Process according to claim 1, wherein acetone is used as a solvent. 16 3. Process according to claim 1, wherein the reaction is performed in a temperature range of 35 to 60'C.
- 4. Process according to claim 1, wherein the amount of silica gel is 3x the amount relative to the starting material.
- 5. Process according to claim 1, wherein the temperature in the crystallization in process stage (d) is 0 0 C.
- 6. rac- 1- {4-[2-Hydroxy-3-(5-quinolyloxy)propyl]-piperazin- 1-yl} -2,2-diphenylethan- 1-one fumarate at a purity of more than 98.54%. 6. rac- 1- {4-[2-Hydroxy-3-(5-quinolyloxy)propyl]-piperazin- 1-yl} -2,2-diphenylethan- 1-one fumarate at a purity of at least 98.55%.
- 7. rac-1- {4-[2-Hydroxy-3-(5-quinolyloxy)propyl]-piperazin-1-yl} -2,2-diphenylethan-1-one fumarate at a purity of at least 99.55%.
- 8. rac- 1- {4-[2-Hydroxy-3-(5-quinolyloxy)propyl]-piperazin- 1-yl} -2,2-diphenylethan-1-one fumarate at a purity of at least 99.65%.
- 9. rac- 1- {4-[2-Hydroxy-3-(5-quinolyloxy)propyl]-piperazin- 1-yl} -2,2-diphenylethan- 1-one fumarate at a purity of at least 99.84%.
- 10. rac-1-{4-[2-Hydroxy-3-(5-quinolyloxy)propyl]-piperazin-1-yl}-2,2-diphenylethan-1 one fumarate according to claims 6 to 9 in an amount of more than 1000 g.
- 11. rac-1-{4-[2-Hydroxy-3-(5-quinolyloxy)-propyl]-piperazin-1-yl}-2,2-diphenylethan-1 one fumarate according to claims 6 to 9, which as a contaminant comprises less than 0.1% of at least one of the individual contaminants (VU 1 - VU 11).
- 12. rac-1-{4-[2-Hydroxy-3-(5-quinolyloxy)-propyl]-piperazin-1-yl}-2,2-diphenylethan-1 one fumarate according to claims 6 to 9, which as a contaminant comprises less than 0.01% of at least one of individual contaminants (VU 1 - VU 11).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10321255A DE10321255B4 (en) | 2003-05-06 | 2003-05-06 | Process for the preparation of purest rac-1 {4- [2-hydroxy-3- (5-quinolyloxy) propyl] -piperazin-1-yl} -2,2-diphenylethane-1-one fumarate and purest rac-1 {4 - [2-hydroxy-3- (5-quinolyloxy) propyl] piperazine-1-yl} -2,2 |
| DE10321255.8 | 2003-05-06 | ||
| PCT/EP2004/004277 WO2004099151A1 (en) | 2003-05-06 | 2004-04-22 | Method for producing the purest rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl] piperazin-1-yl}-2,2-diphenylethan-1-one fumarate and the purest rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]piperazin-1-yl}-2,2-diphenylethan-1-one fumarate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2004235898A1 true AU2004235898A1 (en) | 2004-11-18 |
Family
ID=33426754
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2004235898A Abandoned AU2004235898A1 (en) | 2003-05-06 | 2004-04-22 | Method for producing the purest rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl] piperazin-1-yl}-2,2-diphenylethan-1-one fumarate and the purest rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]piperazin-1-yl}-2,2-diphenylethan-1-one fumarate |
Country Status (25)
| Country | Link |
|---|---|
| EP (1) | EP1622873B1 (en) |
| JP (1) | JP2006525256A (en) |
| KR (1) | KR20060009894A (en) |
| CN (2) | CN101348462A (en) |
| AR (1) | AR044172A1 (en) |
| AT (1) | ATE455101T1 (en) |
| AU (1) | AU2004235898A1 (en) |
| BR (1) | BRPI0409979A (en) |
| CA (1) | CA2524621A1 (en) |
| CL (1) | CL2004000970A1 (en) |
| CO (1) | CO5720999A2 (en) |
| CR (1) | CR7996A (en) |
| DE (2) | DE10321255B4 (en) |
| EA (1) | EA008687B1 (en) |
| EC (1) | ECSP056197A (en) |
| HK (1) | HK1088319A1 (en) |
| MX (1) | MXPA05011854A (en) |
| NO (1) | NO20055762L (en) |
| NZ (1) | NZ542196A (en) |
| PE (2) | PE20050151A1 (en) |
| TW (1) | TW200505863A (en) |
| UA (1) | UA89165C2 (en) |
| UY (1) | UY28308A1 (en) |
| WO (1) | WO2004099151A1 (en) |
| ZA (1) | ZA200509859B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA1340821C (en) * | 1988-10-06 | 1999-11-16 | Nobuyuki Fukazawa | Heterocyclic compounds and anticancer-drug reinforcing agents containing them as effective components |
| JP3076672B2 (en) * | 1992-06-18 | 2000-08-14 | 三井化学株式会社 | Fumarate of quinoline derivative |
| JP4014329B2 (en) * | 1999-03-29 | 2007-11-28 | 三井化学株式会社 | Purification method of quinoline derivatives |
-
2003
- 2003-05-06 DE DE10321255A patent/DE10321255B4/en not_active Withdrawn - After Issue
-
2004
- 2004-04-22 EA EA200501693A patent/EA008687B1/en not_active IP Right Cessation
- 2004-04-22 AT AT04728780T patent/ATE455101T1/en not_active IP Right Cessation
- 2004-04-22 MX MXPA05011854A patent/MXPA05011854A/en active IP Right Grant
- 2004-04-22 UA UAA200511539A patent/UA89165C2/en unknown
- 2004-04-22 DE DE502004010639T patent/DE502004010639D1/en not_active Expired - Fee Related
- 2004-04-22 NZ NZ542196A patent/NZ542196A/en unknown
- 2004-04-22 BR BRPI0409979-6A patent/BRPI0409979A/en not_active IP Right Cessation
- 2004-04-22 AU AU2004235898A patent/AU2004235898A1/en not_active Abandoned
- 2004-04-22 CN CNA2008101302022A patent/CN101348462A/en active Pending
- 2004-04-22 CA CA002524621A patent/CA2524621A1/en not_active Abandoned
- 2004-04-22 KR KR1020057020998A patent/KR20060009894A/en not_active Application Discontinuation
- 2004-04-22 WO PCT/EP2004/004277 patent/WO2004099151A1/en active Application Filing
- 2004-04-22 CN CNB2004800121829A patent/CN100404507C/en not_active Expired - Fee Related
- 2004-04-22 EP EP04728780A patent/EP1622873B1/en not_active Expired - Lifetime
- 2004-04-22 JP JP2006505231A patent/JP2006525256A/en active Pending
- 2004-05-05 UY UY28308A patent/UY28308A1/en not_active Application Discontinuation
- 2004-05-05 AR ARP040101531A patent/AR044172A1/en unknown
- 2004-05-06 TW TW093112821A patent/TW200505863A/en unknown
- 2004-05-06 CL CL200400970A patent/CL2004000970A1/en unknown
- 2004-05-06 PE PE2004000461A patent/PE20050151A1/en not_active Application Discontinuation
- 2004-05-06 PE PE2009000454A patent/PE20091280A1/en not_active Application Discontinuation
-
2005
- 2005-09-19 CR CR7996A patent/CR7996A/en unknown
- 2005-12-02 CO CO05122785A patent/CO5720999A2/en not_active Application Discontinuation
- 2005-12-02 EC EC2005006197A patent/ECSP056197A/en unknown
- 2005-12-05 NO NO20055762A patent/NO20055762L/en not_active Application Discontinuation
- 2005-12-05 ZA ZA200509859A patent/ZA200509859B/en unknown
-
2006
- 2006-08-08 HK HK06108787A patent/HK1088319A1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CA2524621A1 (en) | 2004-11-18 |
| EP1622873A1 (en) | 2006-02-08 |
| HK1088319A1 (en) | 2006-11-03 |
| CL2004000970A1 (en) | 2005-04-01 |
| UY28308A1 (en) | 2004-09-30 |
| DE502004010639D1 (en) | 2010-03-04 |
| CN100404507C (en) | 2008-07-23 |
| BRPI0409979A (en) | 2006-05-09 |
| NZ542196A (en) | 2009-10-30 |
| AR044172A1 (en) | 2005-08-24 |
| UA89165C2 (en) | 2010-01-11 |
| EA200501693A1 (en) | 2006-06-30 |
| JP2006525256A (en) | 2006-11-09 |
| DE10321255A1 (en) | 2005-01-27 |
| ZA200509859B (en) | 2007-02-28 |
| NO20055762L (en) | 2005-12-05 |
| DE10321255B4 (en) | 2006-09-28 |
| EP1622873B1 (en) | 2010-01-13 |
| CO5720999A2 (en) | 2007-01-31 |
| PE20091280A1 (en) | 2009-09-27 |
| EA008687B1 (en) | 2007-06-29 |
| WO2004099151A1 (en) | 2004-11-18 |
| CN101348462A (en) | 2009-01-21 |
| CN1784384A (en) | 2006-06-07 |
| PE20050151A1 (en) | 2005-04-28 |
| ATE455101T1 (en) | 2010-01-15 |
| ECSP056197A (en) | 2006-04-19 |
| CR7996A (en) | 2006-05-30 |
| TW200505863A (en) | 2005-02-16 |
| MXPA05011854A (en) | 2006-02-17 |
| KR20060009894A (en) | 2006-02-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2405787C2 (en) | Method for synthesis of 4beta-amino-4'-demethyl-4-desoxypodophyllotoxin | |
| US11414388B2 (en) | Crystal form of 3-(4-methyl-1h-imidazol-1-yl)-5-trifluoromethylaniline monohydrochloride and use thereof | |
| IL182439A (en) | Intermediates useful for the preparation of aripiprazole and methods for the preparation of the intermediates and aripiprazole | |
| EP0678501B1 (en) | Process for producing N-chloroacetylglutamine | |
| CN112592320A (en) | Related substance of linagliptin intermediate and synthesis method thereof | |
| SU645557A3 (en) | Method of obtaining bezamide derivatives or salts thereof | |
| AU2004235898A1 (en) | Method for producing the purest rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl] piperazin-1-yl}-2,2-diphenylethan-1-one fumarate and the purest rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]piperazin-1-yl}-2,2-diphenylethan-1-one fumarate | |
| EA024202B1 (en) | Crystalline polymorphs b, c and d of 7-chloro-4-(piperazin-1-yl)quinoline and processes for preparation thereof | |
| US20050014945A1 (en) | Process for the production of high-purity rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]-piperazin-1-yl}-2,2-diphenylethan-1-one fumarate and high-purity rac-1-{4-[2-hydroxy-3-(5-quinolyloxy)propyl]piperazin-1-yl}-2,2-diphenylethan-1-one fumarate | |
| JP4162274B2 (en) | Process for producing bis (2-hydroxyphenyl-3-benzotriazole) methanes | |
| CN113943265A (en) | Method for preparing vortioxetine | |
| RU2248974C2 (en) | Method for preparing {2-[4-(alpha-phenyl-para-chlorobenzyl)piperazine-1-yl]ethoxy}-acetic acid and new intermediate compounds | |
| DK149624B (en) | PROCEDURE FOR THE PREPARATION OF (+) - TRANS-3 - (((4-METHOXYPHENOXY) -METHYL) -1-METHYL-4-PHENYLPIPERIDINE OR A PHARMACEUTICAL ACCEPTABLE SALT FROM A MIXTURE OF ENANTIOMY | |
| CN1326846C (en) | Process for the production of N-(2,6-dimethyl-phenyl)-2-piperazin-1-yl-acetamide | |
| JPH04290877A (en) | Process for producing symmetric 2,2'-methylenebisbenzotriazolyl phenols | |
| US20100081668A1 (en) | Polymorphs of 5--6-chloro-1,3-dihydro-2h-indol-2-one hydrobromide and processes for preparation thereof | |
| CN107365299B (en) | Preparation method of dabigatran etexilate and intermediate thereof | |
| CN1450056A (en) | Novel process for preparing Aripiprazole | |
| JP3522945B2 (en) | Method for producing optically active diphenylpiperazine derivative | |
| CN113045446A (en) | Preparation method of transpeptidase biochemical test reagent substrate | |
| WO2023118061A1 (en) | Method of preparation of 1-(n-(quinolin-2-yl)- (phenylamino)-1-deoxy-βeta-d-glucopyranuronic acid derivatives | |
| CN113045491A (en) | Preparation method of Lunvatinib and intermediate | |
| DE20321542U1 (en) | Pure rac-1- {4- [2-hydroxy-3- (5-quinolyloxy) propyl] -piperazin-1-yl-β-2,2-diphenylethane-1-one-fumarate | |
| WO2008050162A1 (en) | Process for the preparation of desloratadine adduct formed with carbon dioxide | |
| JPH03167181A (en) | Purification of carboxylic acid anhydride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK4 | Application lapsed section 142(2)(d) - no continuation fee paid for the application |