CN1326444A - Synthesis of intermediates useful in preparing tricyclic compounds - Google Patents

Synthesis of intermediates useful in preparing tricyclic compounds Download PDF

Info

Publication number
CN1326444A
CN1326444A CN99813515A CN99813515A CN1326444A CN 1326444 A CN1326444 A CN 1326444A CN 99813515 A CN99813515 A CN 99813515A CN 99813515 A CN99813515 A CN 99813515A CN 1326444 A CN1326444 A CN 1326444A
Authority
CN
China
Prior art keywords
compound
formula
hydrogen
described method
och
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.)
Granted
Application number
CN99813515A
Other languages
Chinese (zh)
Other versions
CN1162404C (en
Inventor
C·F·博纳德
M·卡西
F·X·陈
D·C·格罗甘
M·波伊里尔
R·P·威廉斯
Y·S·王
G·G·吴
Original Assignee
Schering Corp
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Schering Corp filed Critical Schering Corp
Publication of CN1326444A publication Critical patent/CN1326444A/en
Application granted granted Critical
Publication of CN1162404C publication Critical patent/CN1162404C/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • 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

Abstract

Disclosed is a process for preparing a compound having formula (I): wherein R, R<1>, R<2>, R<3>, and R<4> are independently selected from the group consisting of H, Br, C1, F, alkyl, or alkoxy, by (A) reacting a compound having formula (II), wherein 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 formula (IIa); and (B) hydrolyzing the imine produced in step (A) to produce the compound having formula (I). Also disclosed are novel intermediates having a formula (IIb), wherein 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. Also disclosed is a process for preparing a compound having formula (III), comprising: reacting a compound having formula (IV) with NH2R<5> in the presence of a palladium catalyst, carbon monoxide, a base, and an ether selected from the group consisting of: CH3OCH2CH2OCH3; CH3OCH2CH2OCH2CH2OCH3; and CH3OCH2CH2OCH2CH2OCH2CH2OCH3, wherein X is H, Br, C1, or F, and R<5> is aryl or heteroaryl. The compounds made by these processes are useful intermediates for preparing compounds that are antihistamines or inhibitors of farnesyl protein transferase.

Description

The synthetic method that is used to prepare the intermediate of tricyclic compound
Background of invention
The invention provides improved preparation and be used for the method for intermediate that preparation is called as the tricyclic compound of antihistaminic agent or farnesyl protein transferase (FPT) inhibitor.Especially, compound of the present invention can be used for as United States Patent (USP) 4,282, the preparation of disclosed fpt inhibitor among the open No.WO97/23478 of disclosed antihistaminic agent and the disclosed PCT of 1997.7.3 in 233 and 5,151,423.
Summary of the invention
The invention provides the method for preparation formula (I) compound,
Figure A9981351500071
Wherein, R, R 1, R 2, R 3And R 4Be independently selected from H, Br, Cl, F, alkyl or alkoxyl group, this method comprises:
(A) with formula (II) compound and dewatering agent reaction
Figure A9981351500072
Wherein, R A, R B, R C, R DAnd R EBe independently selected from H, halogen, alkyl or alkoxyl group, R 5Be aryl or heteroaryl, generate the imines of following formula, And
(B) with the imines hydrolysis that produces in the step (A), production (I) compound.
The present invention also provides the new intermediate of following formula:
Figure A9981351500082
Wherein, R A, R B, R C, R DAnd R EBe independently selected from H, halogen, alkyl or alkoxyl group, R 5Be aryl or heteroaryl.
The present invention also provides the method for preparation formula (III) compound: Comprise:
At palladium catalyst, CO, alkali and to be selected from glycol dimethyl ether (be CH 3OCH 2CH 2OCH 3), 2-methoxy ethyl ether (is CH 3OCH 2CH 2OCH 2CH 2OCH 3) and triglyme (be CH 3OCH 2CH 2OCH 2CH 2OCH 2CH 2OCH 3) ether exist down, make formula (IV) compound and NH 2R 5Reaction: Wherein X is H, Br, Cl or F, R 5Be aryl or heteroaryl.In the presence of highly basic, formula (III) compound can generate wherein R with the compound reaction with following structural formula ABe formula (II) compound of Br, Cl or F,
Figure A9981351500092
Wherein U is Br or Cl, R B, R C, R DAnd R EAs hereinbefore defined.
Detailed Description Of The Invention
Term used herein " alkyl " refers to the straight or branched hydrocarbon chain of 1 to 6 carbon atom.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" aryl " refers to phenyl, benzyl or multi-aromatic ring (as naphthyl), they each can choose wantonly by 1 to 3 and be independently selected from C 1To C 6Alkyl, C 1To C 6The substituting group of alkoxyl group and halogen replaces.
" heteroaryl " refers to contain 5 or 6 yuan of aromatic rings of 1 or 2 nitrogen-atoms, for example, and pyridyl, pyrimidyl, imidazolyl or pyrryl.
" Ac " refers to ethanoyl.
" Et " refers to ethyl.
" Ph " refers to phenyl.
Present method is the significant improvement of art methods of the tricycle kentones of preparation formula (I).For example, U.S.4,731,447 disclose following method: In this method, carrying out next step (friedel-crafts cyclisation) before, the product that must obtain from hydrolysing step separates and purifying, and compares with this method, and the method for preparation formula of the present invention (I) compound provides the simpler synthetic method of can a still finishing.
1996.10.10 the open WO96/31478 of disclosed PCT discloses following method: A, B=H, halogen or C 1-C 6Alkyl in this method, compound and POCl that the tertiary butyl replaces 3Reaction generates nitrile, nitrile and CF under refluxing in toluene 3SO 3The H reaction generates imines, and the imines hydrolysis generates ketone.Because at nitrile and CF 3SO 3Before the H reaction, nitrile must be separated and purifying, so this method is the reactions of two stills, and method is compared therewith, and the inventive method can be finished by a still.
The intermediate that the compound of present method preparation can be used as in the process that the open No.WO97/23478 of PCT and United States Patent (USP) 5,151,423 describe is substituted compound with preparation nitrogen that need, piperidine ring.Use these processes, compound of the present invention reacts with the piperidines of the replacement with following structural formula: L wherein 1Be the leavings group that is selected from Cl and Br, generated the compound of following structural formula:
Figure A9981351500121
This compound is converted into piperidylidene, makes the nitrogen deprotection, compound is reduced to the pyridyl form.Can for example acyl compounds such as ester or acyl chloride reaction generate desired acid amides with the nitrogen of pyridyl and all cpds.
In addition, when needing chirality fpt inhibitor such as PCT to disclose those that describe among the No.WO97/23478, handle to remove ketonic oxygen the compound reduction that present method can be made with the trifluoroacetic acid that Zn and 2 equivalents are dissolved in the acetic anhydride.Reductive compound and about 3.5 normal lithium diisopropylamines, about 1.3 normal quinines or following formula: compound, about 1.2 normal 4-methylsulfonyl-N-tertbutyloxycarbonyl-piperidines and about 1.1 normal water can be reacted in toluene then,
Figure A9981351500122
Generate following chipal compounds:
Figure A9981351500131
Then, can handle the chipal compounds deprotection, generate stable salt with acid (as the N-ethanoyl-L-phenylalanine) reaction that is fit to acid (as sulfuric acid), then, can be with the carboxyl groups that needs with stable salt acidylate.
Can utilize method well known in the art that the compound of formula (I) is converted into the compound of other formula (I), i.e. wherein R, R 1, R 2, R 3Or R 4The compound that is hydrogen can be converted into accordingly wherein R, R 1, R 2, R 3Or R 4It is the compound of halogen.Provide such method steps among the WO97/23478, wherein, for example, incited somebody to action wherein R 2Be chlorine, R 1, R 3And R 4Be the nitrogen usefulness-COOCH of hydrogen and pyridyl 2CH 3The compound of radical protection and KNO 3Reaction, the compound that the nitro that obtains is replaced is reduced to amine, compound that obtains and Br 2Reaction, and remove amino group, obtained wherein R 2Be chlorine, R 4Be bromine and R 1And R 3It is the compound of hydrogen.
Preferred formula (I) compound is R wherein 2For chlorine, bromine or fluorine, more preferably chlorine or bromine, most preferably be the compound of chlorine.Another organizes preferred compound is wherein R, R 1, R 3And R 4Be hydrogen and R independently 2For chlorine, bromine or fluorine, more preferably chlorine or bromine, most preferably be the compound of chlorine.Also have other one group of preferred compound to be R wherein 1, R 3And R 4Be hydrogen and R and R independently 2Be independently selected from chlorine, bromine and fluorine, more preferably be selected from chlorine and bromine, most preferably R is bromine and R 2It is the compound of chlorine.Also have other one group of preferred compound to be R wherein 1And R 3Be hydrogen and R, R independently 2And R 4Be independently selected from chlorine, bromine and fluorine, more preferably be selected from chlorine and bromine, most preferably R is bromine, R 2Be chlorine and R 4It is the compound of bromine.Can be from these preferred compounds of compound of the formula (II) of halogenic substituent with corresponding position.It will be understood by those of skill in the art that when formula (II) compound has the iodine substituting group when implementing present method, those iodine substituting groups can be replaced to fall by hydrogen.
R 5Preferred aryl groups, most preferably phenyl, 4-p-methoxy-phenyl, 4-chloro-phenyl-or 3-chloro-phenyl-.
Dewatering agent is preferably selected from P 2O 5, P 2O 3, P 2O 3Cl 4, POCl 3, PCl 3, PCl 5, C 6H 6P (O) Cl 2(phenyl phosphonyl chloride), PBr 3, PBr 5, SOCl 2, SOBr 2, COCl 2, H 2SO 4, peracid or cross acid anhydrides, dewatering agent more preferably is selected from P 2O 5, P 2O 3Cl 4, PBr 3, PCl 5, POCl 3, C 6H 6P (O) Cl 2, (CF 3SO 2) 2O and (CF 3CF 2SO 2) 2O.
Preferably contact the step (A) of carrying out present method with the other reagent that is selected from Lewis acid or peracid by reaction mixture with formula (II) compound and dewatering agent.Infinite lewis acidic example comprises AlCl 3, FeCl 3, ZnCl 2, AlBr 3, ZnBr 2, TiCl 4And SnCl 4In the aforesaid Lewis acid, preferred especially AlCl 3, ZnCl 2, FeCl 3, SnCl 4And ZnBr 2The example of infinite peracid comprises CF 3SO 3H,
Figure A9981351500141
And HF/BF 3In the aforesaid peracid, preferred especially CF 3SO 3H.Can be before the reaction of dewatering agent and formula (II) compound, simultaneously or add Lewis acid or peracid afterwards and finish and the contacting of Lewis acid or peracid.The combination of particularly preferred dewatering agent and Lewis acid or peracid comprises P 2O 5/ CF 3SO 3H, PCl 5/ AlCl 3, POCl 3/ ZnCl 2, PCl 5/ FeCl 3, PCl 5/ SnCl 4And POCl 3/ ZnBr 2
When step (A) is used dewatering agent except that acid anhydride, preferred 1 to 20 equivalent of the consumption of dewatering agent, more preferably 1 to 10 equivalent, most preferably 1.0 to 8.0 equivalents.When utilizing acid anhydrides to make dewatering agent, preferred 0.5 to 10 equivalent of the consumption of dewatering agent, more preferably 1.0 to 5.0 equivalents, most preferably 1.2 to 2.0 equivalents.When except using dewatering agent, also using Lewis acid, preferred 1 to 20 equivalent of lewis acidic consumption, more preferably 1.5 to 10 equivalents, most preferably 2 to 5 equivalents.When except using dewatering agent, also using peracid, preferred 0.5 to 10 equivalent of the consumption of peracid, more preferably 1 to 5 equivalent, most preferably 2 to 4 equivalents.
Preferably be 10 to 120 ℃, more preferably 15 to 90 ℃, most preferably carry out step (A) under 20 to 90 ℃ in temperature.Reaction times is 1 to 60 hour, preferred 2 to 40 hours, and most preferably 5 to 35 hours.
Preferably add water and make the imines hydrolysis that generates in the step (A), the preferably water consumption is the acid amides of the formula (II) of 1 to 10 times of volume, more preferably 1.5 to 7 times of volumes, most preferably 2 to 5 times of volumes.Preferably be 20 to 120 ℃, more preferably 30 to 100 ℃, most preferably be hydrolyzed under 40 to 80 ℃ in temperature.
Preferably in sprotic organic solvent, carry out step (A) and (B).Sprotic organic solvent is preferably selected from ethylene dichloride, methylene dichloride, benzene and halogenated aromatic solvent such as chlorobenzene, dichlorobenzene, trichlorobenzene and trifluoromethylbenzene.
Can be with the initial compounds of following scheme preparation formula (II):
Figure A9981351500151
(R wherein shown in above-mentioned scheme A, R B, R C, R D, R EAnd R 5As hereinbefore defined), at palladium catalyst (as Pd (OAc) 2/ dipyridyl or (Ph 3P) 2PdCl 2), carbon monoxide and alkali exists down, at suitable solvent (as tetrahydrofuran (THF) (" THF "), dimethyl formamide (" DMF "), acetonitrile (CH 3CN) and toluene or its combination, most preferably acetonitrile (CH 3CN)) pyridine compounds 1 and NH in 2R 5Reaction generates amide compound 2, and wherein temperature of reaction is about 35 to 100 ℃, is preferably about 55 ℃, and reaction pressure is about 5 to 500psi, is preferably about 50 to 150psi.The example of the alkali that is suitable for previous reaction of indefiniteness comprises C 1To C 10Alkylamine, as triethylamine, tri-n-butylamine and 1,8-diazabicyclo [5.4.0] hendecene-7 (" DBU ") and mineral alkali such as K 2CO 3, Na 2CO 3, Na 2HPO 4And NaOH.Alkali is preferably selected from K 2CO 3, DBU and triethylamine, DBU preferably with Pd (OAc) 2/ dipyridyl uses together, triethylamine preferably with (Ph 3P) 2PdCl 2Use together.Exist down at highly basic (as lithium diisopropylamine (" LDA "), n-Butyl Lithium, hexamethyl dimethyl silanyl Lithamide or sodium amide, preferred LDA or n-Butyl Lithium), in suitable solvent such as THF, under-50 to-20 ℃ approximately, preferred-30 to-20 ℃ temperature approximately, make amide compound 2 and compound 3 reaction production (II) compounds.
Also can select scheme as follows to prepare amide compound 2: In suitable solvent such as methylene dichloride, under about-30 to 0 ℃, pyridine carboxylic acid compound 4 reacts with organic bases such as triethylamine, follows and acyl chlorides such as pivalyl chloride or chloro-formic ester such as C 2H 5The OCOCl reaction generates mixed anhydride.With pure or be dissolved in NH in the suitable solvent 2R 5Add generation amide compound 2 in the mixture down in-30 ℃ to 0 ℃.
At palladium catalyst, carbon monoxide, alkali and to be selected from glycol dimethyl ether (be CH 3OCH 2CH 2OCH 3), 2-methoxy ethyl ether (is CH 3OCH 2CH 2OCH 2CH 2OCH 3) and triglyme (be CH 3OCH 2CH 2OCH 2CH 2OCH 2CH 2OCH 3) ether have down formula (IV) compound and NH 2R 5Prepared in reaction formula (III) compound.X is preferably Br, Cl or F, most preferably is Br, R 5Be preferably phenyl, 4-p-methoxy-phenyl, 4-chloro-phenyl-or 3-chloro-phenyl-.The infinite example of the spendable palladium catalyst of present method comprises Pd (OAc) 2, PdCl 2, (PPh 3) 2PdCl 2, PdBr 2(PPh 3) 4Pd, preferred especially Pd (OAc) 2And PdCl 2Present method about 35 to 120 ℃, preferred about 40 to 100 ℃, most preferably from about carry out under 45 to 90 ℃ temperature and about 5 to 500psi, preferred about 30 to 150psi, most preferably from about 40 to 100psi the pressure.The example that is suitable for the infinite alkali of previous reaction comprises C 1To C 10Alkylamine, as diisopropylethylamine, di-isopropyl benzyl amine, tri-n-butylamine, tri-isopropyl amine, triethylamine, TERTIARY BUTYL AMINE and 1,8-diazabicyclo [5.4.0] hendecene-7 (" DBU ") and mineral alkali such as K 2CO 3, KHCO 3, Na 2CO 3, NaHCO 3, Na 3PO 4, Na 2HPO 4And NaOH.Alkali is preferably selected from K 2CO 3, DBU, triethylamine and diisopropylethylamine, most preferably be selected from DBU and diisopropylethylamine.Present method is preferably also carried out in solvent except glycol dimethyl ether, 2-methoxy ethyl ether or triglyme.The example of infinite suitable solvent comprises toluene, chlorobenzene, dichlorobenzene, acetonitrile, trifluoromethylbenzene, N, dinethylformamide, N,N-dimethylacetamide, tetrahydrofuran (THF) and dimethylbenzene, preferred especially toluene and chlorobenzene.Because glycol dimethyl ether, 2-methoxy ethyl ether or triglyme are as the part of palladium catalyst, present method can be implemented under without the situation of dipyridyl as part.NH 2R 5Consumption be preferably 0.9 to 5 equivalent, more preferably 1.0 to 3 equivalents most preferably are 1.1 to 1.5 equivalents.The consumption of alkali is preferably 0.8 to 10 equivalent, and more preferably 1.0 to 5 equivalents most preferably are 1.2 to 2.0 equivalents.The consumption of glycol dimethyl ether, 2-methoxy ethyl ether or triglyme be preferably 0.2 to 5.0 times of volume used 2,5-two bromo-3-picolines, more preferably 0.4 to 2.0 times of volume most preferably is 0.5 to 1.5 times of volume.The amount of other solvent (as toluene or chlorobenzene) be preferably 1.0 to 20 times of volumes used 2,5-two bromo-3-picolines, more preferably 1.5 to 10 times of volumes most preferably are 2 to 5 times of volumes.
Used starting raw material is compound 1, NH in the preceding method 2R 5, compound 3 and compound 4 is well known in the art or those skilled in the art can make at an easy rate.
Following embodiment specifies foregoing invention, but these embodiment do not constitute limiting the scope of the invention.Other reagent and similar approach in the scope of the invention is conspicuous to one skilled in the art.
Embodiment A
With 250g (949mmol) 2,5-two bromo-3-picolines, 4.5g (20mmol) Pd (OAc) 2, 127mL (1.1mol) aniline, 210mL (1.4mol) 1,8-diazabicyclo [5.4.0] hendecene-7,500mL toluene and 250mL glycol dimethyl ether add in 4 liters the autoclave continuously.Autoclave is sealed, finds time, uses nitrogen purging, charge into carbon monoxide to 80psi.Reaction mixture is heated to 65 ℃, if necessary, periodically fills carbon monoxide, be incubated about 2 days, be cooled to room temperature then.Vacuumizing, under the nitrogen purging condition, the material in the autoclave discharged, by means of water and toluene material is being transferred in 10 liters the flask.25 gram gacs (Darco) and 25 gram diatomite (Supercel) are added in the mixture.By diatomite (Celite) pad filter material, use the toluene wash material.Toluene extraction filtrate with 2 * 1 liters.Extraction liquid with the salt water washing merges is concentrated into 750ml with it.(i-PrOH) removes residual toluene with Virahol.With filter residue recrystallize from hot Virahol (i-PrOH), throw out is filtered.Use washed with isopropyl alcohol,, obtain the white solid acid amides of 220 grams (76%) 50 ℃ of following dryings.
Preparation 1
With 400g (2.21mol) 2-bromo-3-picoline, 8.2g (12mmol) (Ph 3P) 2PDcL 2, 1.0L acetonitrile, 295g (3.16mol) aniline and 515g (3.38mmol) DBU add in 4 liters the autoclave continuously.Autoclave is sealed, finds time, uses nitrogen purging, fill carbon monoxide to 80psi.Reaction mixture is heated to 65 ℃, if necessary, periodically fills carbon monoxide, be incubated 9 hours, then cool to room temperature.Vacuumize with nitrogen purging under, the material in the autoclave is discharged, by means of water and acetonitrile material is transferred in the separating funnel.40 gram gacs (Darco) and 40 gram diatomite (Supercel) are added in the mixture.Material was stirred 30 minutes, filter, wash with acetonitrile.It finally is 1.6 liters that filtrate is concentrated into.Add the product precipitation that 3.0 premium on currency make yellow solid.With solid filtering, drying, obtain the acid amides of 427 grams (90%).Mp.66-67℃。 1H?NMR(CDCl 3)：δ10.23(bs，1H)，8.37(dd，J＝4.6Hz，0.8Hz，1H)，7.71(m，2H)，7.62(dd，J＝6.95Hz，1H)，7.31-7.36(m，3H)，7.10(t，J＝7.42Hz，1H)，2.79(s，3H)。 13CNMR(CDCl 3)：δ163.52，146.70，145.21，141.28，138.02，136.13，128.94，125.95，123.97，119.62，20.80。IR：3330(w)，2920(s)，1680(m)cm -1。C 13H 12N 2The analytical calculation value of O: C, 73.58, H, 5.66, N, 13.21; Measured value: C, 73.29, H, 5.76, N, 12.81.
Preparation 2
(225mL, (7.05mL, (50g is 0.168mol) in the solution for acid amides 1 0.050mol) 0.336mol) to add-25 ℃ be dissolved in THF (400mL) and Diisopropylamine in the dropping mode with the solution of 1.5M lithium diisopropylamine list (tetrahydrofuran (THF)).The dianion solution that obtains was worn out 1 hour down at-20 to-25 ℃, and (22.0mL is 0.176mol) with its quenching with the 3-chlorobenzyl chloride.Allow mixture to be warmed to 0 ℃, after 1 hour, quenching in saturated aqueous ammonium chloride.Be separated, with t-butyl methyl ether (350mL) aqueous layer extracted.Organic solution with the salts solution washing merges is concentrated into oily matter with it.With product crystallization in Virahol (200mL), obtain 62.7 gram (89.8%) coupling product then.Mp.102-103℃。 1H?NMR(CDCl 3)：δ10.07(s，1H)，8.56(d，J＝2.1Hz，1H)，7.77(dd，J＝8.7Hz，1.1Hz，2H)，7.70(d，J＝2.1Hz，1H)，7.42(t，J＝8.4Hz，2H)，7.28(d，J＝2.4Hz，1H)，7.16-7.25(m，4H)，3.49-3.53(m，2H)，2.99-3.03(m，2H)。 13C?NMR(CDCl 3)：δ162.45，146.85，145.17，143.16，142.95，140.95，137.70，134.10，129.63，129.06，128.74，126.90，126.33，124.36，123.24，119.84，36.91，35.35。IR：2930(s)，1690(m)cm -1。C 20H 16BrClN 2The analytical calculation of O: C, 57.83, H, 3.85, N, 6.75; Measured value: C, 58.05, H, 4.06, N, 6.80.
Preparation 3
Figure A9981351500201
The 2.5M butyllithium is dissolved in the solution of hexane, and (185mL, (50g is 0.231mol) in the solution 0.462mol) to add-25 ℃ of acid amides 2 that are dissolved in THF (500mL) in the dropping mode.The dianion solution that obtains was worn out 1 hour down at-20 to-25 ℃, and (31.0mL is 0.248mol) with its quenching with the 3-chlorobenzyl chloride.Allow mixture to be warmed to 0 ℃, after 1 hour, quenching in saturated aqueous ammonium chloride.Be separated, with t-butyl methyl ether (350mL) aqueous layer extracted.Organic solution with the salts solution washing merges is concentrated into oily matter with it.With product crystallization in Virahol (200mL), obtain 71.6 gram (91.5%) coupling product then.Mp.80-81℃。 1H?NMR(CDCl 3)：δ10.23(s，1H)，8.48(dd，J＝4.6Hz，1.6Hz，1H)，7.78(dd，J＝0.8Hz，8.4Hz，2H)，7.48(dd，J＝7.9Hz，1.5Hz，1H)，7.39-7.12(m，8H)，3.54-3.50(m，2H)，3.02-2.98(m，2H)。 13C?NMR(CDCl 3)：δ164.09，147.63，146.72，144.63，141.91，140.16，138.97，134.98，130.55，130.05，129.82，128.03，127.16，127.03，125.17，120.84，38.30，36.77。IR：2930(s)，1690(m)cm -1。C 20H 17ClN 2The analytical calculation of O: C, 71.43, H, 5.06, N, 8.33; Measured value: C, 71.37, H, 5.12, N, 8.35.
Embodiment 1
With 100g (241mmol) acid amides 3,137g (963mmol) P 2O 5And the 700mL chlorobenzene adds in 3 liters of three-necked flasks of the oven dry of having assembled mechanical stirrer, thermometer and addition funnel.The trifluoromethanesulfonic acid of 64.2mL (722mmol) is added dropwise in the above-mentioned slurries, maintains the temperature at simultaneously below 35 ℃.To 85 ℃, stir about is 20 hours under this temperature with the mixture heating up to 80 that obtains.Mixture is cooled to 45 ℃, will be dissolved in 102g (722mmol) P in the 300mL chlorobenzene 2O 5Add in the mixture.Mixture heating up to 80 to 85 ℃, was stirred 20 hours under this temperature again.In the mixture that obtains, add 500mL water at 10 ℃.With mixture heating up to 70 ℃, hydrolysis 2 hours.Reaction mixture is cooled to room temperature, the 200mL propyl carbinol is added in the mixture.Be separated, with salt solution, diluted sodium hydroxide solution and dilute hydrochloric acid solution washing organic layer.Organic layer is concentrated into 300mL.Add 500mLTHF and 2.4 normal concentrated hydrochloric acids and make the product precipitation.Solids is leached,,, obtain the cyclic ketone that exists with hydrochloride of 61.7 grams (71%) the solids drying with cold propyl carbinol washing solids.Under the situation of free alkali, analyze.Mp.119-120℃。 1H?NMR(CDCl 3)：δ8.66(d，J＝2.0Hz，1H)，7.96(d，J＝8.0Hz，1H)，7.75(d，J＝1.5Hz，1H)，7.27(dd，J＝8.0Hz，2.0Hz，1H)，7.18(d，J＝1.0Hz，1H)，3.17-3.09(m，4H)。 13C?NMR(CDCl 3)：δ192.7，153.3，150.6，143.8，140.7，140.1，139.3，136.2，133.9，130.6，128.4，124.4，35.4，33.5。IR (KBr, whiteruss) 1660,1590,1290cm -1C 14H 9The analytical calculation value of BrClNO: C, 52.11, H, 2.80, N, 4.34, Br, 24.80, Cl, 11.00; Measured value: C, 52.03, H, 2.82, N, 4.38, Br, 24.95, Cl, 10.09.
Embodiment 2
With 68.35g (481mmol) P 2O 5, 170mL ethylene dichloride and 10g (24mmol) acid amides 3 add in the 250mL three-necked flask of the oven dry of having assembled mechanical stirrer.Mixture heating up to 55 to 60 ℃, was kept 16 hours, obtain about 70% imines product, as measuring with HPLC with respect to standard substance.Utilize embodiment 1 described method steps with the imines hydrolysis, obtain desired tricycle kentones.
Embodiment 3
With 250mL ethylene dichloride, 4.2g (15mmol) P 2O 5, 2mL (12mmol) trifluoromethanesulfanhydride anhydride and 2mL (30mmol) trifluoromethanesulfonic acid add in the 250mL three-necked flask of the oven dry of having assembled mechanical stirrer, thermometer and addition funnel.5.0g (14.9mmol) acid amides 4 is added in this mixture.With mixture heating up to 80 ℃ maintenance 18 hours.Mixture is cooled to 10 ℃, adds 70mL water.With mixture heating up to 70 ℃, hydrolysis 1 hour.Reaction mixture is cooled to room temperature, the pH value of reaction mixture is adjusted to 5-6 with sodium hydroxide.Be separated, use the t-butyl methyl ether aqueous layer extracted.Wash the organic layer of merging continuously with ammonium chloride and sodium hydrogen carbonate solution, organic layer is concentrated obtain residue.Add t-butyl methyl ether and make the product precipitation.Solids is leached,,, obtain 2.4 gram (68.5%) yellow solid the solids drying with cold t-butyl methyl ether washing solids.The NMR spectrum of product is the same with the spectrogram of the cyclisation ketone of expectation.
Embodiment 48-chloro-5,6-dihydro-11H-benzo [5,6] suberane is [1,2-b] pyridine-11-ketone also
Figure A9981351500231
To be dissolved in chlorobenzene (400mL) trifluoromethanesulfonic acid (63.2mL, 0.71mol) and phosphoryl chloride (66.4mL, mixture 0.71mo1) at room temperature stirs half an hour.To be dissolved in N-phenyl-3-[2-(3-chloro-phenyl-) ethyl of chlorobenzene (240mL)]-(120g, 0.36mol) solution adds in the said mixture 2-pyridine carboxamide 4.With mixture heating up to 110 ℃ maintenance 18 hours, be cooled to 50 ℃ subsequently.Add 400mL water, biphase mixture is heated to 80 ℃ keeps half an hour.Mixture is cooled to room temperature, and vigorous stirring 10 minutes was placed 10 minutes then.By filtering and between water (300mL) and toluene (500mL), distributing and remove product.With the sodium hydroxide solution of 10M the pH value of water is adjusted to 10.Remove the 100mL organic phase by underpressure distillation.Gac (5.5g) is added in the mixture, allow mixture filtration over celite (celite) fill up.Under the vacuum, solution concentration to 300mL, is added the 150mL normal hexane in the mixture.Before filtering, mixture is cooled to 0-10 ℃, and under this temperature, stirred 1 hour.With the cold toluene wash product of 100mL, then with air-dry several hours of product.Output=44.1 grams (50.8%).
Embodiment 58-chloro-5,6-dihydro-11H-benzo [5,6] suberane is [1,2-b] pyridine-11-ketone also
Figure A9981351500241
With PCl 5(95%, 97.5g 0.45mol) adds N-phenyl-3-[2-(3-chloro-phenyl-) ethyl that is dissolved in methylene dichloride (500mL)]-(100g is 0.30mol) in the solution for 2-pyridine carboxamide 4.The mixture that obtains was at room temperature stirred 1 hour.Then with AlCl 3(158.5g 1.19mol) adds in the mixture, at room temperature stirs subsequently 1 hour.Then solution is poured on the ice (500g), before the mixture that will obtain is cooled to room temperature, is heated and refluxed 1 hour.With the sodium hydroxide (700mL) of 10M the pH value of water is adjusted to 14, immobilized suspension is filtered sintered glass funnel.With the methylene dichloride (solids that 2 * 100mL) washings are collected.Isolate the organic layer in the filtrate, with the hydrochloric acid of 1M (the washing organic layer of 1 * 200+1 * 100mL).Under the vacuum, organic layer is concentrated into oily matter, adds 100mL toluene, once more mixture is concentrated under vacuum.Oily matter is dissolved in toluene (150mL), and gac (3.5g) is added wherein.With mixture filtration over celite (celite) pad, then hexane (100mL) is added in the filtrate.Before filtering, mixture is cooled to 0 ℃ kept 1 hour.With the product collected in vacuum drying oven in 60 ℃ of dried overnight.Output=44.2 grams (61%).
Embodiment 6
Figure A9981351500251
Under 5 ℃, with the N-that will be dissolved in methylene dichloride (60mL) in 20 minutes (4-chloro-phenyl-)-3-[2-(3-chloro-phenyl-) ethyl]-(30g, 0.081mol) drips of solution adds the PCl that is dissolved in methylene dichloride (60mL) to the 2-pyridine carboxamide 5(95%, 26.6g is 0.121mol) in the solution.The mixture that obtains was stirred 1 hour down at 5 to 10 ℃.Then with being heated room temperature in 30 minutes.Follow with 45 minutes AlCl 3(43.1g 0.323mol) adds in the mixture in four batches, maintains the temperature at simultaneously below 30 ℃.Mixture was stirred 1 hour, it is poured on the ice (300g) then.Remove methylene dichloride in the mixture by distillation, subsequently, the remaining aqueous solution is heated to 80 ℃ kept 1 hour.(70g 0.24mol) adds wherein, and (10M 140mL) is adjusted to 7 with its pH value to use aqueous sodium hydroxide solution subsequently with trisodium citrate monocalcium salt compound.Add toluene (150mL), subsequently, (12.0g, 0.122mol) solution adds wherein will to be dissolved in the maleic anhydride of toluene (50mL).The mixture that obtains is stirred half an hour, and (10M, 60mL) the pH value with mixture is adjusted to 12 with aqueous sodium hydroxide solution.With mixture heating up to 70 ℃, and be separated.With toluene (2 * 90mL) further aqueous phase extracted, the organic layer that water (90mL) washing merges.HPlC analysis revealed solution ketone product amount is 95%.With product mixtures recrystallization from toluene/hexane, obtain the tricycle kentones (13.96g, 71%) of required Off-white solid shape.
Embodiment 7
5g (85.5mmol) sodium-chlor, 20g (45.7mmol) acid amides 3 and the adding of 100mL chlorobenzene have been assembled in the 250mL three-necked flask of magnetic stirring apparatus, thermometer and reflux exchanger.In nitrogen atmosphere, mixture was at room temperature stirred 15 minutes.With 16g (76.8mmol) PCl 5Add in the solution that obtains, maintain the temperature at simultaneously below 40 ℃.Reaction mixture was stirred 2 hours down at 30 to 35 ℃.With 15.6g (96.2mmol) FeCl 3Add reaction mixture, afterwards, reaction mixture is heated to 30-35 ℃ kept 3 hours, then be heated to 80-85 ℃ and kept about 18 hours, carry out HPLC subsequently and analyze.Reaction mixture is cooled to 10-20 ℃ and 50mL acetone added wherein.Mixture was stirred 15 minutes, pour it 30g (224mmol) D of 200mL at leisure, in the aqueous solution of L MALIC ACID.At room temperature stirred 1 hour, and subsequently, used 200mL and 100mLEtOAc extraction product continuously.With 20g (149mmol) D of 200mL, the organic layer that the solution washing of L MALIC ACID merges.HBr (88mmol) solution of 50mL acetone, 20mL methyl alcohol and 10mL48% is added in the organic layer that merges.Mixture is stirred 2 hours down with complete hydrolysis at 45 ℃, with ice bath it is cooled to 5-10 ℃ then.Throw out is filtered, use the 50mL washing with acetone, in vacuum drying oven,, obtain the cyclisation product of 16.1g (82%) in 25 ℃ of dryings.
Although invention has been described in conjunction with above-mentioned specific embodiment, for the person of ordinary skill of the art, many replacements, modification and variation thereof are conspicuous.All these replacements, modification and variations thereof are all within the spirit and scope of the present invention.

Claims (21)

1. the method for preparation formula (I) compound, Wherein R, R 1, R 2, R 3And R 4Be independently selected from H, Br, Cl, F, alkyl or alkoxyl group, this method comprises:
(A) with formula (II) compound and dewatering agent reaction, R wherein A, R B, R C, R DAnd R EBe independently selected from hydrogen, halogen, alkyl or alkoxyl group, R 5Be aryl or heteroaryl, generate the imines of following formula: And
(B) with imines hydrolysis production (I) compound that produces in the step (A).
2. the described method of claim 1, wherein, R A, R B, R C, R DAnd R EBe independently selected from hydrogen or halogen, R, R 1, R 2, R 3And R 4Be independently selected from hydrogen, bromine, fluorine or chlorine.
3. the described method of claim 2, wherein, R 5Be phenyl, 4-p-methoxy-phenyl, 4-chloro-phenyl-or 3-chloro-phenyl-.
4. the described method of claim 3, wherein, R, R 1, R 3And R 4Be hydrogen, R 2Be chlorine.
5. the described method of claim 4 wherein, contacts with other reagent that is selected from Lewis acid or peracid by the reaction mixture with formula (II) compound and dewatering agent and to carry out step (A).
6. the described method of claim 5, wherein, dewatering agent is selected from P 2O 5, P 2O 3, P 2O 3Cl 4, POCl 3, PCl 3, PCl 5, C 6H 6P (O) Cl 2, PBr 3, PBr 5, SOCl 2, SOBr 2, COCl 2, H 2SO 4, peracid and cross acid anhydrides, and other reagent is selected from AlCl 3, FeCl 3, ZnCl 2, AlBr 3, ZnBr 2, TiCl 4, SnCl 4, CF 3SO 3H,
Figure A9981351500032
FSO 3H and HF/BF 3
7. the described method of claim 6, wherein, dewatering agent is selected from P 2O 5, P 2O 3Cl 4, PBr 3, PCl 5, POCl 3, C 6H 6P (O) Cl 2, (CF 3SO 2) 2O and (CF 3CF 2SO 2) 2O, and other reagent is selected from AlCl 3, ZnCl 2, FeCl 3, SnCl 4, ZnBr 2And CF 3SO 3H.
8. the described method of claim 3, wherein, R 1, R 3And R 4Be hydrogen, R is a bromine, R 2Be chlorine.
9. the described method of claim 8 wherein, contacts with other reagent that is selected from Lewis acid or peracid by the reaction mixture with formula (II) compound and dewatering agent and to carry out step (A).
10. the described method of claim 9, wherein, dewatering agent is selected from P 2O 5, P 2O 3, P 2O 3Cl 4, POCl 3, PCl 3, PCl 5, C 6H 6P (O) Cl 2, PBr 3, PBr 5, SOCl 2, SOBr 2, COCl 2, H 2SO 4, peracid and cross acid anhydrides, and other reagent is selected from AlCl 3, FeCl 3, ZnCl 2, AlBr 3, ZnBr 2, TiCl 4, SnCl 4, CF 3SO 3H,
Figure A9981351500041
FSO 3H and HF/BF 3
11. the described method of claim 10, wherein, dewatering agent is selected from P 2O 5, P 2O 3Cl 4, PBr 3, PCl 5, POCl 3, C 6H 6P (O) Cl 2, (CF 3SO 2) 2O and (CF 3CF 2SO 2) 2O, and other reagent is selected from AlCl 3, ZnCl 2, FeCl 3, SnCl 4, ZnBr 2And CF 3SO 3H.
12. the described method of claim 3, wherein, R 1And R 3Be hydrogen, R and R 4Be bromine, and R 2Be chlorine.
13. the described method of claim 12 wherein, contacts with other reagent that is selected from Lewis acid or peracid by the reaction mixture with formula (II) compound and dewatering agent and to carry out step (A).
14. the described method of claim 13, wherein, dewatering agent is selected from P 2O 5, P 2O 3, P 2O 3Cl 4, POCl 3, PCl 3, PCl 5, C 6H 6P (O) Cl 2, PBr 3, PBr 5, SOCl 2, SOBr 2, COCl 2, H 2SO 4, peracid and cross acid anhydrides, and other reagent is selected from AlCl 3, FeCl 3, ZnCl 2, AlBr 3, ZnBr 2, TiCl 4, SnCl 4, CF 3SO 3H, FSO 3H and HF/BF 3
15. the described method of claim 14, wherein, dewatering agent is selected from P 2O 5, P 2O 3Cl 4, PBr 3, PCl 5, POCl 3, C 6H 6P (O) Cl 2, (CF 3SO 2) 2O and (CF 3CF 2SO 2) 2O, and other reagent is selected from AlCl 3, ZnCl 2, FeCl 3, SnCl 4, ZnBr 2And CF 3SO 3H.
16. the compound of following formula R wherein A, R B, R C, R DAnd R EBe independently selected from hydrogen, halogen, alkyl or alkoxyl group, R 5Be aryl or heteroaryl.
17. the described compound of claim 16, wherein, R 5Be phenyl, 4-p-methoxy-phenyl, 4-chloro-phenyl-or 3-chloro-phenyl-, and R wherein A, R B, R C, R DAnd R EBe independently selected from hydrogen and halogen.
18. the described compound of claim 17, wherein, R A, R B, R DAnd R ERespectively be hydrogen, R CBe chlorine.
19. the described compound of claim 17, wherein, R B, R DAnd R ERespectively be hydrogen, R ABe bromine, and R CBe chlorine.
20. the described compound of claim 17, wherein, R AAnd R ERespectively be bromine, R BAnd R DRespectively be hydrogen, and R CBe chlorine.
21. the method for preparation formula (III) compound
Figure A9981351500061
Comprise:
At palladium catalyst, carbon monoxide, alkali and be selected from CH 3OCH 2CH 2OCH 3, CH 3OCH 2CH 2OCH 2CH 2OCH 3And CH 3OCH 2CH 2OCH 2CH 2OCH 2CH 2OCH 3Ether exist down, make the compound and the NH of formula (IV) 2R 5Reaction:
Figure A9981351500062
Wherein X is hydrogen, bromine, chlorine or fluorine, R 5Be aryl or heteroaryl.
CNB998135151A 1998-11-20 1999-11-18 Synthesis of intermediates useful in preparing tricyclic compounds Expired - Lifetime CN1162404C (en)

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
CN1326444A true CN1326444A (en) 2001-12-12
CN1162404C CN1162404C (en) 2004-08-18

Family

ID=22727622

Family Applications (1)

Application Number Title Priority Date Filing Date
CNB998135151A Expired - Lifetime CN1162404C (en) 1998-11-20 1999-11-18 Synthesis of intermediates useful in preparing tricyclic compounds

Country Status (13)

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

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108218773A (en) * 2018-02-28 2018-06-29 朱路英 A kind of method for preparing resisting allergic rhinitis drug loratadine intermedite

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2004501081A (en) 2000-04-18 2004-01-15 シェーリング　コーポレイション Synthesis of intermediates useful in the preparation of tricyclic compounds
WO2004058719A1 (en) * 2002-12-26 2004-07-15 Cadila Healthcare Limited A process for preparing benzocyclohetapyridin-11-ones

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4282233B1 (en) 1980-06-19 2000-09-05 Schering Corp Antihistaminic 11-(4-piperidylidene)-5h-benzoÄ5,6Ü-cyclohepta-Ä1,2Ü-pyridines
US4731447A (en) * 1985-05-13 1988-03-15 Schering Corporation Process for preparing piperidylidene dihydro-dibenzo(a,d)-cycloheptenes or aza-derivatives thereof
EP0208855B1 (en) * 1985-05-13 1991-03-06 Schering Corporation process for preparing piperidylidene dihydrodibenzo(a,d)cycloheptenes and aza derivatives thereof, compounds obtained by such process and the use of such compounds for preparing useful pharmaceutical compositions
US5089496A (en) 1986-10-31 1992-02-18 Schering Corporation Benzo[5,6]cycloheptapyridine compounds, compositions and method of treating allergies
CA2245055C (en) * 1989-02-28 2003-03-25 F. Hoffmann-La Roche Ag Amidation of 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 inhibition of g-protein function and for treatment of proliferative diseases and pharmaceutical compositions comprising them
CN1326847C (en) 1995-12-22 2007-07-18 先灵公司 Tricyclic amides useful for inhibition of G-protein function and for treatment of proliferative diseases
ATE189815T1 (en) * 1996-05-09 2000-03-15 Lonza Ag METHOD FOR PRODUCING ARYLAMIDES OF HETEROAROMATIC CARBOXYLIC ACIDS
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
DE69819316T2 (en) * 1997-03-25 2004-07-22 Schering Corp. SYNTHESIS OF INTERMEDIATE PRODUCTS APPLICABLE IN THE PRODUCTION OF TRICYCLIC COMPOUNDS

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108218773A (en) * 2018-02-28 2018-06-29 朱路英 A kind of method for preparing resisting allergic rhinitis drug loratadine intermedite

Also Published As

Publication number Publication date
JP2010132701A (en) 2010-06-17
JP2002530307A (en) 2002-09-17
CN1162404C (en) 2004-08-18
AR028138A1 (en) 2003-04-30
CA2351693C (en) 2009-01-20
CO5150169A1 (en) 2002-04-29
AU3790200A (en) 2000-06-13
TW509680B (en) 2002-11-11
MY121795A (en) 2006-02-28
WO2000030589A3 (en) 2001-01-04
EP1131296A2 (en) 2001-09-12
ZA200103246B (en) 2002-07-22
JP4663122B2 (en) 2011-03-30
HK1038698A1 (en) 2002-03-28
WO2000030589A2 (en) 2000-06-02
PE20001243A1 (en) 2000-11-15
CA2351693A1 (en) 2000-06-02

Similar Documents

Publication Publication Date Title
CN101516819B (en) Process and intermediates for preparing integrase inhibitors
CN112638869A (en) Salt of methyl 6- (2, 4-dichlorophenyl) -5- [4- [ (3S) -1- (3-fluoropropyl) pyrrolidin-3-yl ] oxyphenyl ] -8, 9-dihydro-7H-benzo [7] annulene-2-carboxylate and process for preparing same
CN110498770B (en) Method for preparing intermediate of oxaagolide
CN102336705B (en) Method for preparing N-(3,5-dichloropyridyl-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxybenzoyl amine
AU2002309769B2 (en) Processes for the synthesis of derivatives of 2,3-dihydro-1,4-dioxino-[2,3-f] quinoline
CN1162404C (en) Synthesis of intermediates useful in preparing tricyclic compounds
CN111995565B (en) Preparation method of (S) -2-piperidinecarboxylic acid
CN109761884B (en) Preparation method and application of chiral amine B
KR102500124B1 (en) Production method for 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1h-pyrrol-3-yl]-n-methylmethanamine monofumarate
CN1300141C (en) Process and intermediates for making non-nucleoside HIV-1 reverse transcriptase inhibitors
CN112300123B (en) Preparation method of voronoi intermediate
US6372909B1 (en) Synthesis of intermediates useful in preparing tricyclic compounds
EP1421068B1 (en) A process of synthesis of a tricyclic ketone intermediate
IE58270B1 (en) Substituted dihydroquinolone carboxylic acids, anti-bacterial compostitions containing them
CN105820106B (en) The preparation method of Aiweimopan intermediate
CN114773316B (en) Preparation method of 2- (2,6-dioxo-piperidine-3-yl) -5-fluoro-isoindole-1,3-diketone
CN114133323B (en) Preparation method of polysubstituted phenylacetic acid derivative
CN117486747A (en) Synthesis method of N- (4-amino-2, 5-diethoxyphenyl) benzamide
CN1257484A (en) Synthesis of intermediates useful in preparing tricyclic compounds
TW201534607A (en) Methods for the preparation of substituted [1,2,4]triazolo[1,5-a]pyridines
CN116554170A (en) Preparation method of 4-fluoro-7-azaindole
CN113402446A (en) 3-amino 4-hydroxycarbazole compound, preparation method and application
TW202311242A (en) Method for producing benzoxazole derivative having bicyclic piperazine ring or salt thereof, and method for producing material thereof
JPH09104663A (en) Production of optically active 1-(m-benzyloxyphenyl) alkylamine compounds
CN115197139A (en) Preparation method of roxasistat and intermediate thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C56 Change in the name or address of the patentee

Owner name: MSD CORP.

Free format text: FORMER NAME: SCHERING CORP (US)

CP01 Change in the name or title of a patent holder

Address after: new jersey

Patentee after: Schering Corporation

Address before: new jersey

Patentee before: SCHERING CORP (US)

CX01 Expiry of patent term

Granted publication date: 20040818

CX01 Expiry of patent term