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WO2000030589A2 - Synthese d'intermediaires utiles a la preparation de composes tricycliques - Google Patents

Synthese d'intermediaires utiles a la preparation de composes tricycliques Download PDF

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Publication number
WO2000030589A2
WO2000030589A2 PCT/US1999/026010 US9926010W WO0030589A2 WO 2000030589 A2 WO2000030589 A2 WO 2000030589A2 US 9926010 W US9926010 W US 9926010W WO 0030589 A2 WO0030589 A2 WO 0030589A2
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group
compound
formula
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pbr
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WO2000030589A3 (fr
Inventor
Charles F. Bernard
Michael Casey
Frank Xing Chen
Denise C. Grogan
Marc Poirier
Robert P. Williams
Yee-Shing Wong
George G. Wu
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Merck Sharp and Dohme LLC
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Schering Corp
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Priority to HK02100248.8A priority Critical patent/HK1038698A1/zh
Priority to JP2000583474A priority patent/JP4663122B2/ja
Priority to AU37902/00A priority patent/AU3790200A/en
Priority to EP99972525A priority patent/EP1131296A2/fr
Priority to CA002351693A priority patent/CA2351693C/fr
Publication of WO2000030589A2 publication Critical patent/WO2000030589A2/fr
Publication of WO2000030589A3 publication Critical patent/WO2000030589A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered

Definitions

  • This invention provides an improved process for preparing intermediates useful in the preparation of tricyclic compounds known as antihistamines and as inhibitors of famesyl protein transferase (FPT).
  • the compounds of this invention are useful in the preparation of antihistamines such as those disclosed in U.S. Patents 4,282,233 and 5,151,423, and of FPT inhibitors disclosed in PCT Publication No. WO97/23478, published July 3, 1997.
  • R, R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of H, Br, Cl, F, alkyl, or alkoxy, said process comprising:
  • R A , R B , R c , R D , and R E are independently selected from the group consisting of H, halo, alkyl, or alkoxy, and R 5 is aryl or heteroaryl, with a dehydrating agent to produce an imine having the formula:
  • step (B) hydrolyzing the imine produced in step (A) to produce the compound having formula (I).
  • This invention also provides novel intermediates having the formula
  • R ⁇ , R B , R c , R D , and R E are independently selected from the group consisting of H, halo, alkyl, or alkoxy, and R 5 is aryl or heteroaryl.
  • This invention further provides a process for preparing a compound having the formula: comprising: reacting a compound having the formula:
  • ethylene glycol dimethyl ether i.e., CH 3 OCH 2 CH 2 OCH 3
  • 2-methoxyethyl ether i.e, CH 3 OCH 2 CH 2 OCH 2 CH 2 OCH 3
  • triethylene glycol dimethyl ether i.e, CH 3 OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3
  • X is H, Br, Cl, or F
  • R 5 is aryl or heteroaryl.
  • alkyl means straight or branched hydrocarbon chains of 1 to 6 carbon atoms.
  • Halo refers to fluorine, chlorine, bromine or iodine radicals.
  • Aryl means phenyl; benzyl; or a polyaromatic ring (e.g., napthyl), each of the foregoing being optionally substituted by 1 to 3 substituents independently selected from the group consisting of Ci to C ⁇ alkyl, Ci to Cg alkoxy, and halo.
  • Heteroaryl means a 5- or 6-membered aromatic ring having one or two nitrogen atoms, e.g., pyridyl, pyrimidyl, imidazolyl or pyrrolyl.
  • Et refers to -C 2 H 5 .
  • Ph refers to phenyl
  • the present process for preparing compounds of formula (I) offers a more simplified synthesis that can be carried out in one pot.
  • A, B H, halo or C ⁇ -C 6 alkyl
  • a tert-butyl substituted compound is reacted with POCl 3 in toluene at reflux to form the nitrile, the nitrile is reacted with CF 3 SO 3 H to form an imine, and the imine is hydrolyzed to form the ketone.
  • the present process can be carried out in one pot.
  • L 1 is a leaving group selected from the group consisting of Cl and Br, to obtain a compound of the formula
  • This compound is converted to the corresponding piperidylidene, the nitrogen is deprotected, and the compound is reduced to the piperidyl form.
  • the piperidinyl nitrogen can then be reacted with a variety of compounds, e.g., an acyl compound such as an ester or acyl chloride to form the desired amide.
  • the compounds made by the present process may be reduced by treating with Zn and 2 equivalents of trifluoroacetic acid in acetic anhydride to remove the carbonyl oxygen.
  • the reduced compound can then be reacted with about 3.5 equivalents of lithium diisopropylamide, about 1.3 equivalents of quinine or a compound of the formula
  • This chiral compound can then be deprotected by treatment with acid (e.g., H 2 SO 4 ), reacted with a suitable acid (e.g., N-acetyl-L-phenylalanine) to form a stable salt, and the stable salt can then be acylated with the desired acyl group.
  • acid e.g., H 2 SO 4
  • a suitable acid e.g., N-acetyl-L-phenylalanine
  • Preferred compounds of formula (I) are those in which R 2 is Cl, Br or F, more preferably Cl or Br, most preferably, Cl.
  • Another group of preferred compounds are those in which R, R 1 , R 3 and R 4 are each hydrogen, and R 2 is Cl, Br or F, more preferably Cl or Br, most preferably, Cl.
  • Still another group of preferred compounds are those in which R 1 , R 3 , and R 4 are each hydrogen and R and R 2 are independently selected from Cl, Br and F, more preferably from Cl and Br, and most preferably, in which R is Br and R 2 is Cl.
  • R 1 and R 3 are each hydrogen, and R, R 2 and R 4 are independently selected from Cl, Br and F, more preferably from Cl and Br, and most preferably, in which R is Br, R 2 is Cl and R 4 is Br.
  • R 1 and R 3 are each hydrogen
  • R, R 2 and R 4 are independently selected from Cl, Br and F, more preferably from Cl and Br, and most preferably, in which R is Br, R 2 is Cl and R 4 is Br.
  • These preferred compounds may be made from compounds of formula (II) having correspondingly positioned halo substituents. It will be appreciated by those skilled in the art that when the compounds of formula (II) have iodo substituents, those iodo substituents are displaced by H when the present process is carried out.
  • R 5 is preferably aryl, most preferably, phenyl, 4-methoxyphenyl, 4- chlorophenyl, or 3-chlorophenyl.
  • the dehydrating agent is preferably selected from the group consisting of P 2 O 5 , P 2 O 3 , P 2 O 3 Cl 4 , POClj, PCI 3 , PClj, C 6 H 6 P(O)Cl 2 (phenyl phosphonic dichloride), PBr 3 , PBr 5 , SOCl 2 , SOBr 2 , COCl 2 , H 2 SO 4 , super acids, and anhydrides of super acids.
  • the dehydrating agent is selected from P 2 O 5 , P 2 O 3 Cl 4 , PBr 3 , PC1 5 , POCl 3 , C 6 H 6 P(O)Cl 2 , (CF 3 SO 2 ) 2 O, and (CF 3 CF 2 SO 2 ) 2 O.
  • step (A) of our process is carried out by contacting the reaction mixture of the compound of formula (II) and the dehydrating agent with an additional agent selected from the group consisting of a Lewis acid or a super acid.
  • Lewis acids include A1C1 3 , FeCl 3 , ZnCl 2 , AlBr 3 , ZnBr 2 , TiCl 4 , and SnCl 4 .
  • A1C1 3 , ZnCl 2 , FeCl 3 , SnCl 4 , and ZnBr 2 are particularly preferred.
  • Non-limitative examples of super acids include CF 3 SO 3 H,
  • CF 3 SO 3 H is particularly preferred.
  • the contacting by the Lewis acid or the super acid may be accomplished by adding it prior to, contemporaneously with, or after the time at which the dehydrating agent is brought into contact with the compound of formula (II).
  • Particularly preferred combinations of dehydrating agents and Lewis acids or super acids include P 2 O 5 / CF 3 SO 3 H, PC1 5 / AlCl j , POCl 3 / ZnCl 2 , PCl 5 /FeCl 3 , PCl 5 /SnCl 4 , and POCl 3 / ZnBr 2 .
  • the dehydrating agent is used in amounts ranging from 1 to 20 equivalents, more preferably, 1 to 10 equivalents, most preferably, 1.0 to 8.0 equivalents.
  • the dehydrating agent is an anhydride of a super acid, it is preferably used in amounts ranging from 0.5 to 10 equivalents, more preferably 1.0 to 5.0 equivalents, most preferably, 1.2 to 2.0 equivalents.
  • the Lewis acid is preferably used in amounts ranging from 1 to 20 equivalents, more preferably 1.5 to 10 equivalents, most preferably 2 to 5 equivalents.
  • the super acid is preferably used in amounts ranging from 0.5 to 10 equivalents, more preferably, 1 to
  • Step (A) is preferably carried out at a temperature of 10 to 120 °C, more preferably, 15 to 90 °C, most preferably 20 to 90 °C.
  • the time for reaction ranges from 1 to 60 hours, preferably 2 to 40 hours, most preferably 5 to 35 hours.
  • the imine formed in step (A) is preferably hydrolyzed by adding water, preferably in an amount ranging from 1 to 10 volumes of the amide of formula (II), more preferably 1.5 to 7 volumes, most preferably 2 to 5 volumes.
  • the hydrolysis is preferably carried out at a temperature of from 20 to 120 °C, more preferably from 30 to 100 °C, most preferably from 40 to 80 °C.
  • steps (A) and (B) are carried out in an aprotic organic solvent.
  • the aprotic organic solvent is preferably selected from dichloroethane, methylene chloride, benzene, and halogenated aromatic solvents, e.g., chlorobenzene, dichlorobenzene trichlorobenzene, and trifluoromethylbenzene.
  • the pyridine compound 1 is reacted with NH 2 R 5 in the presence of a palladium catalyst, (e.g., Pd(OAc), / dipyridyl or (Ph 3 P) 2 PdCl 2 ), carbon monoxide, and a base, in a suitable solvent (e.g., tetrahydrofuran (“THF”), dimethylformamide (“DMF”), acetonitrile (CH 3 CN) and toluene, or combinations thereof, most preferably, CH 3 CN) at a temperature of about 35°to 100°C, preferably about 55° C, and a pressure of about 5 psi to 500 psi, preferably about 50 to 150 psi, to form amide compound 2.
  • a palladium catalyst e.g., Pd(OAc), / dipyridyl or (Ph 3 P) 2 PdCl 2
  • a suitable solvent e.g., tetrahydrofuran (“THF
  • Non- limitative examples of suitable bases for the foregoing reaction include C, to C 10 alkyl amines, such as triethylamine, t ⁇ -n- butylamine and l,8-diazabicyclo-[5.4.0]undec-7-ene (“DBU”), and inorganic bases such as K 2 CO 3 , Na ⁇ CO-,, Na 2 HPO 4 and NaOH.
  • the base is selected from K 2 CO 3 , DBU, and triethylamine, with DBU being preferred for use with Pd(OAc) 2 / dipyridyl, and triethylamine being preferred for use with (Ph 3 P) 2 PdCl 2 .
  • Amide compound 2 is reacted with compound 3 in the presence of a strong base (e.g., lithium diisopropylamide (“LDA”), w-butyl lithium, lithium hexamethyldisilylamide, or sodium amide, preferably LDA or «-butyl lithium) in a suitable solvent, e.g., THF, at a temperature of about -50° C to -20° C, preferably about -30° C to -20° C to form the compound of formula (II).
  • a strong base e.g., lithium diisopropylamide (“LDA”), w-butyl lithium, lithium hexamethyldisilylamide, or sodium amide, preferably LDA or «-butyl lithium
  • a suitable solvent e.g., THF
  • the amide compound 2 may be prepared as shown in the scheme below:
  • Picolinic acid compound 4 is reacted with an organic base, e.g., triethylamine, followed by an acid chloride, e.g., pivaloyl chloride or a chloroformate, e.g., C 2 H 5 OCOCl in a suitable solvent such as dichloromethane at a temperature of about -30°C to 0°C to give a mixed anhydride.
  • an organic base e.g., triethylamine
  • an acid chloride e.g., pivaloyl chloride or a chloroformate, e.g., C 2 H 5 OCOCl
  • a suitable solvent such as dichloromethane
  • the process for preparing compounds of formula (III) from compounds of formula (IV) is carried out by reacting the compound of formula (IV) with NH 2 R 5 in the presence of a palladium catalyst, carbon monoxide, a base, and an ether selected from the group consisting of: ethylene glycol dimethyl ether (i.e., CH 3 OCH 2 CH 2 OCH 3 ); 2-methoxyethyl ether (i.e, CH 3 OCH 2 CH 2 OCH 2 CH 2 OCH 3 ); and triethylene glycol dimethyl ether (i.e, CH 3 OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 ).
  • a palladium catalyst i.e., CH 3 OCH 2 CH 2 OCH 3
  • 2-methoxyethyl ether i.e, CH 3 OCH 2 CH 2 OCH 2 CH 2 OCH 3
  • triethylene glycol dimethyl ether i.e, CH 3 OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3
  • X is preferably Br, Cl or F, most preferably, Br
  • R 5 is preferably phenyl, 4- methoxyphenyl, 4-chlorophenyl, or 3-chlorophenyl.
  • palladium catalysts that may be used in this process, include Pd(OAc) 2 , PdCl 2 , (PPh 3 ) 2 PdCl 2 , PdBr 2 , and (PPh 3 ) 4 Pd.
  • Pd(OAc) 2 and PdCl 2 are particularly preferred.
  • This process is preferably carried out at at a temperature of about 35°to 120°C, preferably about 40 to 100 °C, most preferably about 45 to 90 °C, and a pressure of about 5 psi to 500 psi, preferably about 30 to 150 psi, most preferably about 40 to 100 psi.
  • Non-limitative examples of suitable bases for this process include C ⁇ to C 10 alkyl amines, such as diisopropylethylamine, diisopropylbenzylamine, t ⁇ -n- butylamine, triisopropylamine, triethylamine, t-butylamine and 1,8-diazabicyclo- [5.4.0]undec-7-ene (“DBU”), and inorganic bases such as K 2 CO 3 , KHCO 3 , Na ⁇ O;,, NaHCO 3 , Na 3 PO 3 , Na ⁇ HPO ⁇ and NaOH.
  • DBU 1,8-diazabicyclo- [5.4.0]undec-7-ene
  • the base is selected from K 2 CO 3 , DBU, triethylamine, and diisopropylethylamine, and most preferably, is selected from DBU and diisopropylethylamine.
  • this process is carried out in a solvent in addition to the ethylene glycol dimethyl ether, or 2-methoxyethyl ether, or triethylene glycol dimethyl ether.
  • Non-limitative examples of suitable solvents include toluene, chlorobenzene, dichlorobenzene, acetonitrile, trifluoromethylbenzene, N,N- dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, and xylene, with toluene, and chlorobenzene being particularly preferred. Because the ethylene glycol dimethyl ether, or 2-methoxyethyl ether, or triethylene glycol dimethyl ether functions as a ligand for the palladium catalyst, this process can be carried out without having to use dipyridyl as a ligand.
  • the amount of NH 2 R 5 used preferably ranges from 0.9 to 5 equivalents, more preferably from 1.0 to 3 equivalents, most preferably from 1.1 to 1.5 equivalents.
  • the amount of base preferably ranges from 0.8 to 10 equivalents, more preferably from 1.0 to 5 equivalents, most preferably from 1.2 to 2.0 equivalents.
  • the amount of ethylene glycol dimethyl ether, or 2-methoxyethyl ether, or triethylene glycol dimethyl ether is preferably from 0.2 to 5.0 volumes of 2,5- dibromo-3-methylpyridne used, more preferably from 0.4 to 2.0 volumes, most preferably from 0.5 to 1.5 volumes.
  • the amount of additional solvent e.g., toluene or chlorobenzene
  • the content in the autoclave was vented under vacuum, flushed with nitrogen, and transferred to a 10 L flask with the aid of water and toluene.
  • To the mixture were added 25 g of Darco and 25 g of Supercel.
  • the contents were filtered through a pad of celite and washed with toluene.
  • the filtrate was extracted with 2 X 1 L of toluene.
  • the combined extract was washed with brine, and concentrated to 750 mL.
  • the residual toluene was chased with isopropanol (z ' -PrOH).
  • the content of the autoclave was vented under vacuum, flushed with nitrogen and transferred into a separatory funnel with the aid of water and acetonitrile.
  • To the mixture were added 40 g of Darco and 40 g of Supercel. The contents were stirred for 30 min, filtered and washed with acetonitrile. The filtrate was concentrated to a final volume of 1.6 L. Addition of 3.0 L of water precipitates the product as a yellow solid. The solid was filtered and dried to give 427 g amide (90%). Mp. 66-67 °C.
  • the mixture was heated to 80-85°C for another 20 hours. To the resulting mixture at 10 °C was added 500 mL of water. The hydrolysis was accomplished by heating the mixture to 70 °C for 2 hours. The reaction mixture was cooled to room temperature and 200 mL of n-butanol (n-BuOH) was added. The layers were separated and the organic layer was washed with brine, diluted sodium hydroxide solution, and diluted HC1 solution. The organic layer was concentrated to 300 mL. Addition of 500 mL of THF and 2.4 eq. of concentrated HC1 precipitated the product.
  • the reaction mixture was cooled to room temperature and the pH of the reaction mixture was adjusted to 5-6 with sodium hydroxide. The layers were separated and the aqueous layer was extracted with t-butyl methyl ether (t-BuOMe). The combined organic layer was sequentially washed with NH 4 C1 and NaHCO 3 solutions, and concentrated to a residue. Addition of t-BuOMe precipitated the product. The solid was filtered and washed with cold t-BuOMe and dried to give 2.4 g (68.5%o) yellow solid. An NMR spectrum of the product matches that of a reference for the desired tricyclic ketone.
  • Phosphorous pentachloride (95%, 97.5g; 0.45 mol) was added to a solution of N- phenyl-3-[2-(3-chlorophenyl)ethyl]-2-pyridine carboxamide 4 (lOOg; 0.30 mol) in dichloromethane (500 ml). The resulting mixture was stirred at room temperature for one hour. Aluminum chloride (158.5g; 1.19 mol) was then added to the mixture followed by stirring at room temperature for one hour. The solution was then poured onto ice (500g) and the resulting mixture heated to reflux for one hour before cooling to room temperature.
  • reaction mixture After addition of 15.6 g (96.2 mmol) of FeCl 3 , the reaction mixture was heated to between 30 and 35 °C for 3 hrs and then to 80 and 85 °C for about 18 hours as followed by HPLC. The reaction mixture was cooled to between 10 and 20 °C and 50 mL of acetone was added. The mixture was agitated for 15 minutes and poured slowly into 200 mL of an aqueous solution of 30 g (224 mmol) of D, L-malic acid. After stirring at room temperature for 1 hour, the product was extracted sequentially with 200 mL and then 100 ml of EtOAc.
  • the combined organic layer was washed with a 200 mL aqueous solution of 20 g (149 mmol) of D, L-malic acid.
  • To the combined organic layer were added 50 mL of acetone, 20 mL of MeOH, and 10 mL of 48% HBr (88 mmol) solution.
  • the mixture was stirred at 45 °C for 2 hours to complete the hydrolysis and then cooled to between 5 and 10 °C with an ice-bath.
  • the precipitate was filtered, washed with 50 mL of acetone, and dried at 25 °C in a vacuum oven to give 16.1 g (82%) of the cyclized product.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Indole Compounds (AREA)

Abstract

L'invention concerne une méthode de préparation d'un composé de formule (I) dans laquelle R, R?1, R2, R3 et R4¿ sont sélectionnés de manière indépendante dans le groupe constitué par H, Br, Cl, F, alkyle ou alkoxy. Cette méthode consiste à A) faire réagir un composé de formule (II) dans laquelle R?A, RB, RC, RDt RE¿ sont sélectionnés de manière indépendante dans le groupe constitué par H, halo, alkyle ou alkoxy, et R5 est un aryle ou un hétéroaryle, avec un agent déshydrateur pour produire une imine de formule (IIa); B) hydrolyser l'imine produite au cours de l'étape A) afin de produire le composé de formule (I). L'invention concerne également de nouveaux intermédiaires de formule (IIb) dans laquelle R?A, RB, RC, RDt RE¿ sont sélectionnés de manière indépendante dans le groupe constitué par H, halo, alkyle ou alkoxy, et R5 est un aryle ou un hétéroaryle. L'invention concerne aussi une méthode de préparation d'un composé de formule (III) consistant à faire réagir un composé de formule (IV) avec NH¿2R?5 en présence d'un catalyseur de palladium, de monoxyde de carbone, d'une base et d'un éther sélectionné dans le groupe constitué par CH¿3?OCH2CH2OCH3, CH3OCH2CH2OCH2CH2OCH3, et CH3OCH2CH2OCH2CH2OCH2CH2OCH3, dans laquelle X est H, Br, Cl ou F, et R?5¿ est un aryle ou un hétéroaryle. Les composés préparés selon ces méthodes sont des intermédiaires utiles à la préparation de composés antihistaminiques ou inhibiteurs de la farnesyl protéine transférase.
PCT/US1999/026010 1998-11-20 1999-11-18 Synthese d'intermediaires utiles a la preparation de composes tricycliques Ceased WO2000030589A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
HK02100248.8A HK1038698A1 (zh) 1998-11-20 1999-11-18 合成有效制备三环化合物的中间体
JP2000583474A JP4663122B2 (ja) 1998-11-20 1999-11-18 三環式化合物の調製において有用な中間体の合成
AU37902/00A AU3790200A (en) 1998-11-20 1999-11-18 Synthesis of intermediates useful in preparing tricyclic compounds
EP99972525A EP1131296A2 (fr) 1998-11-20 1999-11-18 Synthese d'intermediaires utiles a la preparation de composes tricycliques
CA002351693A CA2351693C (fr) 1998-11-20 1999-11-18 Synthese d'intermediaires utiles a la preparation de composes tricycliques

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US19700398A 1998-11-20 1998-11-20
US09/197,003 1998-11-20

Publications (2)

Publication Number Publication Date
WO2000030589A2 true WO2000030589A2 (fr) 2000-06-02
WO2000030589A3 WO2000030589A3 (fr) 2001-01-04

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EP (1) EP1131296A2 (fr)
JP (2) JP4663122B2 (fr)
CN (1) CN1162404C (fr)
AR (1) AR028138A1 (fr)
AU (1) AU3790200A (fr)
CA (1) CA2351693C (fr)
CO (1) CO5150169A1 (fr)
HK (1) HK1038698A1 (fr)
MY (1) MY121795A (fr)
PE (1) PE20001243A1 (fr)
TW (1) TW509680B (fr)
WO (1) WO2000030589A2 (fr)
ZA (1) ZA200103246B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001079175A1 (fr) * 2000-04-18 2001-10-25 Schering Corporation Synthese d'intermediaires utiles dans la preparation de composes tricycliques
WO2004058719A1 (fr) * 2002-12-26 2004-07-15 Cadila Healthcare Limited Procede de preparation de benzocyclohetapyridin-11-ones

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108218773A (zh) * 2018-02-28 2018-06-29 朱路英 一种制备抗过敏性鼻炎药物氯雷他定中间体的方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4282233A (en) 1980-06-19 1981-08-04 Schering Corporation Antihistaminic 11-(4-piperidylidene)-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridines
US5151423A (en) 1989-05-01 1992-09-29 Schering Corporation Heterocyclic n-oxide derivatives of substituted benzo[5,6]cycloheptapyridines, compositions and methods of use
WO1997023478A1 (fr) 1995-12-22 1997-07-03 Schering Corporation Amides tricycliques destines a l'inhibition de la fonction de la proteine-g et au traitement des maladies proliferatives

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4731447A (en) * 1985-05-13 1988-03-15 Schering Corporation Process for preparing piperidylidene dihydro-dibenzo(a,d)-cycloheptenes or aza-derivatives thereof
EP0208855B1 (fr) * 1985-05-13 1991-03-06 Schering Corporation Procédé de préparation de dihydrodibenzo(a,d)cycloheptènes pipéridylidène et leurs dérivés azotés, composés ainsi obtenus et leur utilisation dans la préparation de médicaments
CA2245055C (fr) * 1989-02-28 2003-03-25 F. Hoffmann-La Roche Ag Amidation des pyridines
US5672750A (en) * 1994-12-16 1997-09-30 Eastman Chemical Company Preparation of aromatic amides from carbon monoxide, an amine and an aromatic chloride
IL117798A (en) * 1995-04-07 2001-11-25 Schering Plough Corp Tricyclic compounds useful for inhibiting the function of protein - G and for the treatment of malignant diseases, and pharmaceutical preparations containing them
EP0806415B1 (fr) * 1996-05-09 2000-02-16 Lonza Ag Procédé pour la préparation d'arylamides d'acides carboxyliques hétéroaromatiques
US5958890A (en) * 1996-09-13 1999-09-28 Schering Corporation Tricyclic compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
IN186464B (fr) * 1997-03-25 2001-09-08 Schering Corp

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4282233A (en) 1980-06-19 1981-08-04 Schering Corporation Antihistaminic 11-(4-piperidylidene)-5H-benzo-[5,6]-cyclohepta-[1,2-b]-pyridines
US4282233B1 (en) 1980-06-19 2000-09-05 Schering Corp Antihistaminic 11-(4-piperidylidene)-5h-benzoÄ5,6Ü-cyclohepta-Ä1,2Ü-pyridines
US5151423A (en) 1989-05-01 1992-09-29 Schering Corporation Heterocyclic n-oxide derivatives of substituted benzo[5,6]cycloheptapyridines, compositions and methods of use
US5151423B1 (en) 1989-05-01 1994-08-30 Schering Corp Heterocyclic n-oxide derivatives of substituted benzo(5,6)cycloheptapyridines, compositions and methods of use
WO1997023478A1 (fr) 1995-12-22 1997-07-03 Schering Corporation Amides tricycliques destines a l'inhibition de la fonction de la proteine-g et au traitement des maladies proliferatives

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001079175A1 (fr) * 2000-04-18 2001-10-25 Schering Corporation Synthese d'intermediaires utiles dans la preparation de composes tricycliques
US6492519B2 (en) 2000-04-18 2002-12-10 Schering Corporation Synthesis of intermediates useful in preparing tricyclic compounds
US6750347B2 (en) 2000-04-18 2004-06-15 Schering-Corporation Synthesis of intermediates useful in preparing tricyclic compounds
WO2004058719A1 (fr) * 2002-12-26 2004-07-15 Cadila Healthcare Limited Procede de preparation de benzocyclohetapyridin-11-ones

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CA2351693C (fr) 2009-01-20
CN1162404C (zh) 2004-08-18
CA2351693A1 (fr) 2000-06-02
AU3790200A (en) 2000-06-13
CN1326444A (zh) 2001-12-12
MY121795A (en) 2006-02-28
JP2002530307A (ja) 2002-09-17
JP4663122B2 (ja) 2011-03-30
HK1038698A1 (zh) 2002-03-28
PE20001243A1 (es) 2000-11-15
JP2010132701A (ja) 2010-06-17
CO5150169A1 (es) 2002-04-29
EP1131296A2 (fr) 2001-09-12
ZA200103246B (en) 2002-07-22
WO2000030589A3 (fr) 2001-01-04
AR028138A1 (es) 2003-04-30

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