WO2006106136A1 - Intermediate compounds for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1h-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole - Google Patents
Intermediate compounds for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1h-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole Download PDFInfo
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- WO2006106136A1 WO2006106136A1 PCT/EP2006/061409 EP2006061409W WO2006106136A1 WO 2006106136 A1 WO2006106136 A1 WO 2006106136A1 EP 2006061409 W EP2006061409 W EP 2006061409W WO 2006106136 A1 WO2006106136 A1 WO 2006106136A1
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- OOUVAHYYJVOIIB-CZUORRHYSA-N CN(C[C@@H]([C@H]1c2c3)c4ccccc4Oc2ccc3Cl)C1=O Chemical compound CN(C[C@@H]([C@H]1c2c3)c4ccccc4Oc2ccc3Cl)C1=O OOUVAHYYJVOIIB-CZUORRHYSA-N 0.000 description 1
- VSWBSWWIRNCQIJ-HUUCEWRRSA-N CN(C[C@@H]12)C[C@@H]1c(cc(cc1)Cl)c1Oc1c2cccc1 Chemical compound CN(C[C@@H]12)C[C@@H]1c(cc(cc1)Cl)c1Oc1c2cccc1 VSWBSWWIRNCQIJ-HUUCEWRRSA-N 0.000 description 1
- OOUVAHYYJVOIIB-XJKSGUPXSA-N CN(C[C@H]([C@H]1c2c3)c(cccc4)c4Oc2ccc3Cl)C1=O Chemical compound CN(C[C@H]([C@H]1c2c3)c(cccc4)c4Oc2ccc3Cl)C1=O OOUVAHYYJVOIIB-XJKSGUPXSA-N 0.000 description 1
- FDEBVKYOGYXKFY-CZUORRHYSA-N CNC[C@@H]([C@@H]1C(O)=O)c(cccc2)c2Oc(cc2)c1cc2Cl Chemical compound CNC[C@@H]([C@@H]1C(O)=O)c(cccc2)c2Oc(cc2)c1cc2Cl FDEBVKYOGYXKFY-CZUORRHYSA-N 0.000 description 1
- CDCWWLYYNIFTQA-CZUORRHYSA-N CNC[C@@H]1c2cc(Cl)ccc2Oc2ccccc2[C@H]1C(O)=O Chemical compound CNC[C@@H]1c2cc(Cl)ccc2Oc2ccccc2[C@H]1C(O)=O CDCWWLYYNIFTQA-CZUORRHYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/14—[b,f]-condensed
Definitions
- This invention relates to novel amino acid derivatives, to processes for the preparation thereof, and to the use of the amino acid derivatives in the preparation of frans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1 H-dibenz- [2,3:6,7]oxepino[4,5-c]pyrrole.
- Asenapine exhibits potential antipsychotic activity and may be useful in the treatment of depression (see international patent application WO 99/32108).
- a pharmaceutical preparation suitable for sublingual or buccal administration of asenapine maleate has been described (see international patent application WO 95/23600). Asenapine maleate is now the subject of clinical studies, making large scale syntheses of the drug substance necessary.
- the unfavorable product ratio can be improved by subsequent partial isomerization of the unwanted c/s-isomer (V) into the trans- isomer (IV) using 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN), leading to a thermodynamic equilibrium ratio of frans-isomer (IV) to c/s-isomer (V) of 1 :2. Separation of the frans-isomer (IV) and the c/s-isomer (V) is done by chromatography over silica gel.
- DBN 1,5-diazabicyclo[4.3.0]non-5-ene
- compounds represented by structural formulae having a pair of bold and hashed wedged bonds as shown, e.g., in compound (IV) of Scheme I, or a pair of bold wedged bonds, as shown, e.g., in compound (V) of Scheme I, refer to "trans" or "cis" diastereoisomers, respectively.
- Each of the compounds may exist as a single enantiomer having the absolute stereochemical configuration indicated by the wedged bonds, or having the opposite absolute configuration, or as a mixture of enantiomers (e.g., racemate) having the relative stereochemical configuration indicated by the wedged bonds.
- the present invention provides a process (Scheme III) in which the mixture of lactams, frans-11 -chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz[2,3:6,7]- oxepino[4,5-c]pyrrol-1-one (IV) and c/s-11-chloro-2,3,3a,12b-tetrahydro-2- methyl-1/-/-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (V), is treated in an alcoholic solution comprising an excess of strong alkaline base thereby producing a mixture of fraA7S-8-chloro-10,11-dihydro-11-[(methylamino)- methyl]-dibenz[b,/]oxepin-10-carboxylic acid (I) and c/s-8-chloro-10,11- dihydro-11-[(methylamino)methyl]-dibenz[b
- the ring-opening reaction is stereoselective, resulting in a 10:1 ratio of the frans-isomer (I) to the c/s-isomer (Ia).
- the trans-amino acid derivative (I) is subsequently isolated and cyclized to give frans-11-chloro-2,3,3a,12b-tetra- hydro-2-methyl-1 /-/-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1 -one (IV) with preservation of the frans-stereochemistry.
- the yield of the frans-isomer (IV) is approximately 62%.
- the starting material for the ring-opening reaction may be a mixture of the frans-isomer (IV) and the c/s-isomer (V). Alternatively, the starting material may be the pure c/s-isomer (V).
- the mixture of isomers (IV), (V) may be obtained from compound (III) in accordance with Scheme I, above, or may be obtained in a number of synthesis steps such as described in Example 8.
- the hydrolysis of the lactams (IV), (V) can be carried out in an alcoholic solution at reflux temperature in the presence of a stoichiometric excess of a strong alkaline base.
- Preferred bases include alkali metal hydroxides, such as potassium hydroxide or sodium hydroxide, which are used in 2- to 20-fold or in 10- to 20-fold molar excess based on the amount of the isomers (IV), (V).
- Useful alcohols include C1 to C6 alkanols, including methanol, ethanol, n- propanol, 2-propanol, n-butanol, and mixtures thereof. The use of higher boiling alcohols, such as n-propanol and n-butanol, appears to provide shorter reaction times for the ring-opening reaction.
- amino acid derivatives (I), (Ia) are extracted into the water/alcohol phase and acidified to a pH of 1 using hydrochloric acid. Subsequent evaporation of the alcoholic solvents selectively crystallizes the amino acid derivative, trans-8- chloro-10,11 -dihydro-11 -[(methylamino)methyl]-dibenz[b,/]oxepin-10- carboxylic acid (I), as the hydrochloride salt.
- Trans- ⁇ -chloro-i 0,11 -dihydro-11 -[(methylamino)methyl]-dibenz[b,/]oxepin-10- carboxylic acid (I) may be obtained as the crystalline zwitterion, i.e. free base, when the pH is lowered to 6 instead of 1.
- oxepin-10- carboxylic acid (I) may be prepared from the hydrochloride salt by dissolution in a mixture of methanol and water, neutralization to pH 6 with ammonia or sodium hydroxide solution, and evaporation of the methanol to give the free base (I) as a solid.
- the ring-closure reaction (cyclization) of the amino acid derivative (I) to produce the trans lactam derivative (IV) may be carried out using the hydrochloride salt or the zwitterionic form by heating a suspension of the amino acid (I) in a solvent, including an aromatic solvent such as toluene or xylene, either with or without an additive to increase the rate of this reaction.
- a solvent including an aromatic solvent such as toluene or xylene, either with or without an additive to increase the rate of this reaction.
- Suitable additives are silica gel, aluminum oxide, sodium hydroxide, and sodium acetate.
- a preferred solvent to carry out the ring closure is toluene; preferred additives are sodium hydroxide and sodium acetate. Sodium acetate is most preferred as it typically results in the shortest reaction time.
- the amino acid derivative (I) is converted into an activated acid form, such as an acid chloride, which upon neutralization with a base, spontaneously cyclizes to the desired lactam (IV).
- an activated acid form such as an acid chloride
- a further aspect of the invention relates to a process (Scheme IV) for the preparation of fraA7S-2-chloro-10,11 -dihydro-11 -[(methylamino)methyl]-dibenz- [b,/]oxepine-10-carboxylic acid (II), which is a regioisomer of the amino acid derivative (I) depicted in Scheme III.
- the process comprises the steps of: (a) reduction of an enamide, 5-chloro-2,3-dihydro-2-methyl-1 /-/-dibenz[2, 3:6,7]- oxepino[4,5-c]pyrrol-1-one (Vl), to provide a mixture of lactams, trans-5- chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrol- 1-one (VII), and c/s- ⁇ -chloro ⁇ .S.Sa. ⁇ b-tetrahydro ⁇ -methyl-IH-dibenz- [2,3:6,7]oxepino[4,5-c]pyrrol-1-one (VIII); (b) hydrolysis of the lactams (VII), (VIII) by treatment in an alcoholic solution with an excess of a strong (alkali) base thereby producing a mixture of the amino acid derivative (II) and its
- the enamide, 5-chloro-2,3-dihydro-2-methyl-1 /-/-dibenz[2,3:6,7]oxepino[4,5- c]pyrrol-1-one (Vl), can for instance be prepared in a number of synthesis steps starting from 4-chlorophenol and methyl 2-bromophenylacetate as described in Example 9.
- Another aspect of the invention provides an alternative process for preparing asenapine (A) as shown in Scheme V.
- the process provides for treatment of an amino acid derivative (I) or (II) with a reducing agent such as borane or lithium aluminum hydride, optionally in combination with a Lewis acid, such as aluminum chloride.
- a Lewis acid such as aluminum chloride
- a further aspect of the invention provides the trans-amino acid derivatives of formula (I) or (II), as depicted in Schemes Ml-V, or the enantiomer of each trans-amino acid derivative having the opposite absolute configuration, or a racemic mixture of each trans-amino acid derivative, or a salt thereof.
- Suitable salts include alkali metal salts, such as sodium, potassium or lithium salts, or salts obtained from the combination with an organic base, such as trimethyl- amine, triethylamine and the like.
- Suitable salts include acid addition salts, which may be obtained by treating the free compounds (I) or (II) with a mineral acid such as hydrochloric acid or hydrobromic acid, or with an organic acid such as maleic acid, acetic acid, methane sulfonic acid, and the like.
- a mineral acid such as hydrochloric acid or hydrobromic acid
- an organic acid such as maleic acid, acetic acid, methane sulfonic acid, and the like.
- Suitable acid addition salts of asenapine (A) can be obtained from the treatment with a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid and methane sulfonic acid.
- the preferred acid addition salt of asenapine is the maleate salt, i.e. Org 5222.
- the compounds Org 5222, asenapine (A), and all cis- and frans-precursors — e.g., compounds (I), (II), (IV), (V), (VII) and (VIII) — are racemates, and the pairs of bold wedged bonds or bold and hashed wedged bonds used in their structural formulae indicate relative stereochemical configuration.
- NMR spectra were recorded on a Bruker DPX 400. 1 H-NMR chemical shifts ( ⁇ ) are reported in parts per million (ppm) and are referenced to TMS as an internal standard using the following abbreviations: s (singlet), d (doublet), dd (double doublet) and m (multiplet). Mass spectra were recorded on a PE SCIEX API 165. GC chromatograms were recorded on a HP6890N with a Restek RTX-column.
- Toluene (50 ml_) was added, the layers were separated, and the water layer was extracted with toluene (2 x 100 ml_). The combined toluene layers were washed with water (200 ml_), dried over magnesium sulfate, filtered and evaporated.
- the toluene layer is washed with water (200 L), concentrated to a volume of 25 L and purified by chromatography on silica (100 kg) with toluene (115 L) and toluene:ethyl acetate 95:5 v/v (900 L).
- the fractions are pooled and fractions containing exclusively compound trans- ⁇ 1-chloro-2,3,3a,12b- tetrahydro-2-methyl-1/-/-dibenz[2,3:6,7]oxepino[4,5-c] pyrrol-1-one (IV) are combined and concentrated to a volume of 50 L.
- Potassium hydroxide (333.8 g, 6.30 mole) was added to a mixture of c/s-11-chloro-2,3,3a, 12b-tetrahydro-2-methyl-1 H-dibenz[2,3:6,7]oxepino[4,5- c]pyrrol-1-one (V) and frans-11-chloro-2,3,3a,12b-tetrahydro-2-methyl-1/-/- dibenz[2,3:6,7]oxepino[4,5-c]pyrrol-1-one (IV) (105 g, 351 mmol, trans/cis ratio 1 :3) dissolved in ethanol (1050 ml_). The mixture was heated to reflux for 18 hours.
- Tetrahydrofuran (5 L) is added, stirring is continued for 1 hour at 10°C, and 0.6 N sodium hydroxide solution (100 L) is added keeping the temperature below 10°C. Stirring is continued for 15 minutes at 20°C and toluene (150 L) and of water (100 L) are added. Stirring is continued for 15 minutes at 20°C and the salt layer is separated. The salt layer is extracted with toluene (2 x 50 L). The combined filtrates are separated and the aqueous layer is extracted with of toluene (50 L).
- Free base frans-5-chloro-2,3,3a,12b-tetrahydro-2-methyl-1/-/- dibenz[2,3:6,7]oxepino[4,5-c] pyrrole (A) (1.23 kg) was dissolved in ethanol (2 L) at 60°C.
- Charcoal (74 g) was added; after stirring for 30 minutes at 60°C, the charcoal was filtered and washed with ethanol (1.2 L). The filtrate was warmed to 65°C and was maintained at this temperature while a warm (60°C) solution of maleic acid (554 g) in ethanol (3.5 L) was added over a 15 minute period. The solution was cooled and seeded at 15°C.
- the product is 90% E as shown by NMR.
- 1 H NMR 400 MHz, CDCI 3 ) 3.6 (s, 3H, E methyl group; Z methyl is at 3.7), 6.8 (d, 1 H), 6.9 (m, 2H), 7.0 (t, 1 H), 7.2 (m, 3H), 7.3 (m, 2H), 11.8 (d, 1 H, E hydroxy proton; Z hydroxy proton is at 4.7).
- HPLC area% 45% toluene, 48% frans-nitro ester, 6% c/s-nitro ester, 1% starting material.
- HPLC conditions column- 3.5 ⁇ m Zorbax SB-Phenyl, 3 mm x 150 mm; solvent- gradient from 55% water (0.1% HOCI 4 )/45% methanol (0.1% HOCI 4 ) to 100% methanol (0.1% HOCI 4 ) in 10 minutes and hold for 2 minutes; flow 0.5 mL/minute; detection at 210 nm.
- the catalyst slurry was then charged to a 1500-mL Hastelloy-C stirred autoclave with the aid of THF (200 mL).
- the vessel was sealed, purged with hydrogen, and pressurized to about 50 psig with hydrogen.
- the mixture was stirred at 1100 rpm at room temperature and a solution of frans-8-chloro-11-nitromethyl- 10,11-dihydro-dibenzo[b,/]oxepine-10-carboxylic acid methyl ester (ca. 369 g, 1.06 mol in 500 mL THF) diluted to 850 mL with THF was added at a rate of about 3.1 mL/minute over the course of about 4.5 hours.
- the temperature of the reaction mixture rose from the exotherm but was maintained between 20 to 32°C by the application of an external water cooling bath.
- the total pressure in the reactor was maintained at 50 to 60 psig by supplying hydrogen on-demand through a pressure regulator from high-pressure reservoir of known volume.
- the addition system was rinsed with THF (2 x 25 mL) into the reactor.
- the completed reaction mixture was stirred at room temperature under about 60 psig hydrogen overnight. After venting of the hydrogen, the reaction mixture was cautiously vacuum filtered and the cake washed with THF (Note: care is required to avoid drying of the catalyst cake in air) to afford a mixture of the titled compounds (1.06 mol, theoretical) as a THF solution.
- HPLC area% assay the combined filtrate and washings (1266 g) was devoid of starting material, and consisted of a mixture of the expected amino ester and cis- and trans- lactams. HPLC conditions: same as step C, above.
- the resultant aqueous layer contained product solids that were extracted into ethyl acetate (2.5 L, 0.5 L) at elevated temperature (55°C).
- the combined organic layers were concentrated in vacuo to a volume of less than 1 L; octane (0.25 L) was added, and the resultant suspension was warmed to 50°C followed by cooling to 0°C.
- the suspension was filtered, washed with octane and dried under vacuum at 50°C to afford predominantly the c/s-isomer (V) (215.7 g, 68% yield from oxepine ester).
- HPLC area% 1.6% unknown, 98.4% c/s-isomer (V), and trace frans-isomer (IV).
- reaction mixture was filtered over dicalite, which was washed with dioxane (40 ml). The dioxane was removed in vacuo to leave a brownish oil.
- Ethyl acetate 100 ml was added to the oil and the pH of the resulting mixture was adjusted to 1 by addition of 1 M HCI (300 ml).
- the organic phase was washed with saturated brine (300 ml), dried on magnesium sulphate and then concentrated under vacuum to yield 57.2 grams (206 mmol; 95 %) of 2-(4-chloro-phenoxy)- phenyl]-acetic acid methyl ester as a brown oil.
- P2O 5 (90 grams) was added in portions to H 3 PO4 (90 grams) while maintaining the temperature below 140 0 C.
- the mixture was heated at 115 0 C for 1.5 hour, whereupon 3-[2-(4-chloro-phenoxy)-phenyl]-1-methyl-pyrrolidine- 2,4-dione (Xl) (30 grams; 95 mmol) was added.
- the resulting mixture was stirred for 4 days at 115 0 C to 130 0 C with extra P 2 O 5 (in total 5 portions of 5 grams each were added).
- the mixture was poured into water (200 ml) and the resulting precipitate was stirred overnight.
- the mixture was extracted with dichloromethane (250 ml) and washed with sat.
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Priority Applications (9)
Application Number | Priority Date | Filing Date | Title |
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CN2006800167535A CN101175741B (en) | 2005-04-07 | 2006-04-06 | Intermediate compounds useful for the preparation of trans-5-chloro-2-methyl-2, 3,3a,12 b-tetrahydro-1H-dibenzo [2,3:6,7]-oxa and [4,5-C] pyrroles |
BRPI0610677-3A BRPI0610677A2 (en) | 2005-04-07 | 2006-04-06 | trans-amino acid derivative, and processes for its preparation and for the preparation of asenapine |
AU2006231281A AU2006231281B2 (en) | 2005-04-07 | 2006-04-06 | Intermediate compounds for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1H-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole |
MX2007012446A MX2007012446A (en) | 2005-04-07 | 2006-04-06 | Intermediate compounds for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1h-dibenz[2,3:6, 7]oxepino[4,5-c]pyrrole. |
CA002603181A CA2603181A1 (en) | 2005-04-07 | 2006-04-06 | Intermediate compounds for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1h-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole |
NZ562125A NZ562125A (en) | 2005-04-07 | 2006-04-06 | Compounds and intermediates for the preparation of asenapine |
JP2008504777A JP2008534657A (en) | 2005-04-07 | 2006-04-06 | Intermediate compound for the preparation of trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1H-dibenz [2,3: 6,7] -oxepino [4,5-c] pyrrole |
IL186354A IL186354A0 (en) | 2005-04-07 | 2007-10-07 | INTERMEDIATE COMPOUNDS FOR THE PREPARATION OF TRANS -5-CHLORO-2-METHYL-2,3,3a,12b-TETRAHYDRO-1H -DIBENZ[2,3:6,7] OXEPINO [4,5-c] PYRROLE |
NO20075152A NO20075152L (en) | 2005-04-07 | 2007-10-10 | Intermediates for the preparation of trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro-1H-dibenz [2,3: 6,7] oxepino [4,5-C] pyrrole |
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EP05102742 | 2005-04-07 | ||
EP05102742.3 | 2005-04-07 |
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PCT/EP2006/061409 WO2006106136A1 (en) | 2005-04-07 | 2006-04-06 | Intermediate compounds for the preparation of trans-5-chloro-2-methyl-2,3,3a,12b-tetrahydro-1h-dibenz[2,3:6,7]oxepino[4,5-c]pyrrole |
Country Status (28)
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EP (2) | EP1710241B1 (en) |
JP (1) | JP2008534657A (en) |
KR (1) | KR20070116973A (en) |
CN (2) | CN101175741B (en) |
AR (1) | AR063188A1 (en) |
AT (1) | ATE447564T1 (en) |
AU (1) | AU2006231281B2 (en) |
BR (1) | BRPI0610677A2 (en) |
CA (1) | CA2603181A1 (en) |
CY (1) | CY1109722T1 (en) |
DE (1) | DE602006010132D1 (en) |
DK (1) | DK1710241T3 (en) |
ES (1) | ES2333980T3 (en) |
HK (1) | HK1094800A1 (en) |
HR (1) | HRP20100031T1 (en) |
IL (1) | IL186354A0 (en) |
MX (1) | MX2007012446A (en) |
NO (1) | NO20075152L (en) |
NZ (1) | NZ562125A (en) |
PL (1) | PL1710241T3 (en) |
PT (1) | PT1710241E (en) |
RS (1) | RS51341B (en) |
RU (1) | RU2397164C2 (en) |
SI (1) | SI1710241T1 (en) |
TW (1) | TW200716589A (en) |
UA (2) | UA93043C2 (en) |
WO (1) | WO2006106136A1 (en) |
ZA (2) | ZA200708493B (en) |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008003460A1 (en) * | 2006-07-05 | 2008-01-10 | N.V. Organon | Process for the preparation of asenapine and intermediate products used in said process. |
WO2008078482A1 (en) * | 2006-12-22 | 2008-07-03 | Sumitomo Chemical Company, Limited | Process for producing intermediate of asenapine synthesis |
WO2008081010A1 (en) * | 2007-01-05 | 2008-07-10 | Synthon B.V. | Process for making asenapine |
WO2009008405A1 (en) * | 2007-07-06 | 2009-01-15 | Sumitomo Chemical Company, Limited | Process for producing trans-dibenzoxenopyrrole compound and intermediate therefor |
WO2009087058A1 (en) * | 2008-01-04 | 2009-07-16 | N.V. Organon | Process for the preparation of asenapine and intermediate products used in said process |
WO2010149727A2 (en) | 2009-06-24 | 2010-12-29 | N.V. Organon | Injectable formulations containing asenapine and method of treatment using same |
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