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AU2002309769A1 - Processes for the synthesis of derivatives of 2,3-dihydro-1,4-dioxino-[2,3-f] quinoline - Google Patents

Processes for the synthesis of derivatives of 2,3-dihydro-1,4-dioxino-[2,3-f] quinoline

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AU2002309769A1
AU2002309769A1 AU2002309769A AU2002309769A AU2002309769A1 AU 2002309769 A1 AU2002309769 A1 AU 2002309769A1 AU 2002309769 A AU2002309769 A AU 2002309769A AU 2002309769 A AU2002309769 A AU 2002309769A AU 2002309769 A1 AU2002309769 A1 AU 2002309769A1
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carbon atoms
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alkyl
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Anita Wai-Yin Chan
Warren Chew
Timothy Thomas Curran
Zhixian Ding
Gregg Feigelson
Silvio Iera
John Hamilton Sellstedt
Galina Vid
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Wyeth LLC
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Wyeth LLC
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Description

PROCESSES FOR THE SYNTHESIS OF DERIVATIVES OF 2, 3-DIHYDRO-1. 4-DIOXINO- T2, 3-fl QUINOLINE
FIELD OF THE INVENTION
This invention relates to novel processes of producing derivatives of 2,3- dihydro-1 , 4-dioxino [2, 3-fj quinoline in a highly convergent and efficient manner, as well as intermediates thereof. Compounds of the present invention are SSRI/5-HT1A antagonists useful for the treatment of diseases which are caused or affected by disorders of the serotonin-affected neurological systems such as depression, including childhood depression, obsessive compulsive disorders, panic disorder, generalized anxiety disorder, social anxiety disorders, sexual dysfunction, eating disorders such as bulimia, obesity, addictive disorders caused by ethanol or cocaine abuse and dysthymia as described in copending application 60/275,564 filed March 14, 2001 (now PCT/US02/07192).
SUMMARY OF THE INVENTION
In accordance with the present invention is provided methods of making compounds of Formula I:
wherein
R"* is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms; R2, R3, R4) and Rβ are, independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms R5 is hydrogen or alkyl of 1 to 6 carbon atoms; The dotted line represents an optional double bond; A and D are selected from carbon, substituted by R^ , and nitrogen, provided that at least one of A and D is nitrogen;
E and G are carbon, substituted by R"* ; and Z is N or CR6; or pharmaceutically acceptable salts thereof, comprising the steps of: a) halogenating a compound of the formula:
wherein R' is alkyl of 1-6 carbon atoms; with a halogenating reagent to afford a compound of the formula:
wherein X is Br, CI, or I; b) dealkylating the compound of Formula 3 in an acid to afford a compound of the formula:
c) alkylating the compound of Formula 4 with R" protected glycidyl ethers ( OR"
). wherein R" is benzyl or substituted benzyl to afford a compound of the formula
d) cyclizing the compound of Formula 5 with palladium or copper catalyst to afford a compound of the formula:
e) debenzylating the compound of Formula 6 to afford the compound of the formula:
f) activating the hydroxy moiety of the compound of Formula 7 with a sulfonating reagent to afford a compound of the formula:
wherein R"' is an aryl-, or alkyl- sulfonate and g) coupling the compound of Formula 8 with the appropriate azaheterocycle of Formula 9
9 in the presence of base to provide a compound of Formula I.
In alternative embodiments of the present invention the hydroxy moiety of compounds of Formula 7 may be activated to halide to afford a compound of the formula:
wherein X1 is I, Br, or CI and the compound of Formula 10 may be coupled with the appropriate azaheterocycle of Formula 9
in the presence of base to provide a compound of Formula I. In other embodiments of the present invention are provided methods of making compounds of Formula la
comprising the steps of: a) halogenating a compound of the formula
wherein R' is alkyl of 1-6 carbon atoms; with a halogenating reagent in a solvent to afford a compound of the formula:
wherein X is Br, CI, or I; b) dealkylating the compound of Formula 3 in an acid to afford a compound of the formula:
4 o i 0R„ c) alkylating the compound of Formula 4 with R" protected glycidyl ethers ( ^^ ), wherein R" is benzyl or substituted benzyl to afford compound of the formula:
d) cyclizing the compound of Formula 5a with palladium or copper catalyst to afford a compound of the formula:
e) debenzylating the compound of Formula 6a to afford the compound of the formula:
f) activating the hydroxy moiety of the compound of Formula 7a with a sulfonating reagent to afford a compound of the formula:
wherein R'" is an aryl- or alkyl-sulfonate; and g) coupling the compound of Formula 8a with the appropriate azaheterocycle of Formula 9
9 in the presence of base to provide a compound of Formula I.
In alternative embodiments of the present invention the hydroxy moiety of compounds of Formula 7 may be activated to halide to afford a compound of the formula:
10a wherein X"* is I, Br, or CI and
the compound of Formula 10a may be coupled with the appropriate azaheterocycle of Formula 9
in the presence of base to provide a compound of Formula I. In some embodiments of the present invention is provided a method of making a compound of Formula lb
lb comprising the steps: a) halogenating a compound of the formula:
2a wherein R' is alkyl of 1-6 carbon atoms; with a halogenating reagent to afford a compound of the formula:
3a wherein X is Br, CI, or I; b) dealkylating the compound of Formula 3a in an acid to afford a compound of the formula:
4a c) alkylating the compound of Formula 4a with R" protected glycidyl ethers wherein R" is benzyl or substituted benzyl; to afford a compound of the formula:
5b
d) cyclizing the compound of Formula 5b with palladium or copper catalyst to afford a compound of the formula:
6b
e) debenzylating the compound of Formula 6b to afford a compound of the formula:
7b
f) activating the hydroxy moiety of the compound of Formula 7b with a sulfonating reagent to afford a compound of the formula:
8b wherein R'" is an aryl- or alkyl- sulfonate; and g) coupling the compound of Formula 8b with 3-tetrahydropyridinyl-indole in the presence of base to provide a compound of Formula lb.
Alternatively, the hydroxy moiety of compounds of Formula 7b may be activated to halide to afford a compound of Formula 10b
-X
10b wherein X"* is I, Br, or CI and
the compound of Formula 10b may be coupled with 3-tetrahydropyridinyl-indole in the presence of base to provide a compound of Formula lb.
In accordance with other aspects of the invention is provided a method of preparing compounds of Formula 5:
wherein A, D, E, G, X and R" are as defined for Formula I and R" is benzyl or substituted benzyl, comprising alkylating the compound of Formula 4
with R" protected glycidyl ethers ( '0R"), wherein R" is benzyl or substituted benzyl. In some embodiments of the invention A is nitrogen, D is carbon substituted with methyl, and E and G are unsubstituted carbon. Further in accordance with the present invention is provided a method of preparing compound of Formula 6
where A, D, E and G are as defined for Formula I, and R" is benzyl or substituted benzyl, comprising the step of cyclizing a compound of Formula 5
with palladium or copper catalyst. In some embodiments of the invention A is nitrogen, D is carbon substituted with methyl, and E and G are unsubstituted carbon.
Further in accordance with the invention is provided a method of preparing compound of Formula 8
8 wherein A, D, E and G are defined as for Formula I and R'" is an aryl- or alkyl- sulfonate; comprising activating the hydroxy moiety of the compound of Formula 7
with a sulfonating reagent. In some embodiments of the invention A is nitrogen, D is carbon substituted with methyl, and E and G are unsubstituted carbon.
Further in accordance with the invention is provided a method of preparing compound of Formula 10
10 wherein A, D, E and G are as defined for Formula I, and χ1 is I, CI or Br, comprising activating compound of Formula 7
to halide with halophosphorous such as phosphorous triiodide, phosphorous tribromide or phosphorous pentachloride, or with thionyl halide or any standard halogenating reagent.
Further in accordance with the present invention is provided a method of preparing compound of Formula 7
wherein A, D, E and G are as defined Formula I, comprising debenzylating a compound of Formula 6
6 where R" is benzyl or substituted benzyl.
In some embodiments of the invention A is nitrogen, D is carbon substituted with methyl and E and G are unsubstituted carbon.
In some embodiments of the invention compounds of Formula 2 or 2a
are halogenated with a halogenating agent such as N-halosuccinimide wherein halo means bromo-, chloro-, or iodo- in a suitable solvent such as acetonitrile.
In other embodiments of the invention compound of Formula 3 or 3a
are demethylated with a Lewis acid in a solvent or a strong protic acid. Preferred Lewis acids include, but are not limited to, boron tribromide, boron trichloride, aluminum trichloride, ferric chloride, trimethylsilyl iodine. The preferred solvent is methylene chloride. Strong protic acids include, but are not limited to, HBr and HCl. Compounds of Formula 4 or 4a
4 o may be alkylated with R" protected glycidyl ethers (^^*-0R "), wherein R" is benzyl or substituted benzyl in a polar solvent. For instance R" may be benzyl, 4-bromobenzyl, 4-chlorobenzyl, 3, 4-dimethoxybenzyl, 2- or 4-nitrobenzyl, or 4-methoxyphenyl.
Exemplary polar solvents useful in alkylation of compounds of Formula 4 or 4a include dimethylsulfoxide (DMSO), dimethylforamide (DMF), dimethylacetamide (DMA).
Alkylation may be performed in the presence of a base such as, but not limited to, triethylamine, sodium carbonate, or potassium carbonate.
Compounds of Formula 5, 5a, or 5b can be cyclized using palladium catalysts such as, but not limited to, tris(dibenzylideneacetone)dipalladium, tetrakis(triphenyl- phosphine)-palladium, or palladium acetate with phosphine ligands including but not limited to (±) 2,2'-bis(diphenyl-phosphino)-1 ,1'-binaphthyl (BINAP) and separate enantiomers thereof; (±) 2,2'-bis(di-p-tolyl-phosphino)-1 ,1'-binaphthyl (Tol-BINAP) and separate enantiomers thereof; 1-1 '-bis(diphenylphosphino)ferrocene; 1 ,3-bis(diphenyl- phosphino)propane; and 1 ,2 bis(diphenylphosphino)ethane in the presence of bases such as sodium hydride (NaH), lithium hydride (LiH), potassium hydride (KH), potassium carbonate, sodium carbonate, titanium carbonate, cesium carbonate, potassium f-butoxide or potassium phosphate tribasic in suitable solvent such as toluene.
Alternatively, compounds of Formula 5, 5a, or 5b can be cyclized with copper catalyst such as copper iodide in the presence of bases such as NaH, LiH, KH in a suitable solvent such as toluene. Debenzylation of compounds of Formula 6, 6a, or 6b can be carried out with Lewis acids such as boron tribromide, boron trichloride, aluminum trichloride, ferric chloride, trimethylsilyl iodine in a suitable solvent such as methylene chloride.
Debenzylation of compounds of Formula 6, 6a, or 6b may also be carried out with strong protic acids such as HBr and HCl, or alternatively, under reductive cleavage conditions using Pd catalyst and hydrogen transfer reagents such as hydrogen, cyclohexene, methyl cyclohexene, or ammonium formate.
The hydroxy moiety of compounds of Formula 7, 7a, or 7b is activated with a sulfonating reagent such as aryl or alkyl sulfonyl chloride or alkyl or aryl sulfonic anhydride in the presence of a base such as triethylamine or pyridine in suitable solvents such as methylene chloride, tetrahydrofuran (THF), or toluene. Alkyl, as used herein preferably refers to alkyl of 1-6 carbon atom. Aryl, as used herein preferably refers to phenyl. Preferred sulfonating reagents include, but are not limited to p-toluenesulfonyl chloride, methanesulfonyl chloride, 2-, 3- or 4-nitrobenzene- sulfonyl chloride, 2- or 4-bromo-benzenesulfonyl chloride, or halo-alkylsulfonating agents such as trifluoromethylsulfonic anhydride.
Alternatively the hydroxy moiety of compounds of Formula 7, 7a, or 7b is activated as halogen, such as I, Br or CI with reagent such as I3P, B^P CI5P or SOCI2 to provide a compound of Formula 8, 10 or 10a.
Compounds of Formula 8, 8a, 8b, 10 or 10a are coupled with azaheterocycles of Formula 9 including 3-tetrahydropyridinyl-indole in the presence of bases such as sodium carbonate, potassium carbonate, or Hϋnig's base in suitable polar solvents such as THF, dioxane, DMSO, DMF, or DMA to afford compound of Formula I, la or lb.
Still further in accordance with the present invention are provided novel intermediates of the formula
wherein:
A, D, E and G are as defined herein;
R7 is hydroxy, alkoxy of 1-6 carbon atoms, or alkoxy of the formula -A wherein R9 is hydroxy, benzyl ether, substituted benzyl ethers such as 4-bromo-benzyl ether, 4-chlorobenzyl ether, 3, 4-dimethoxybenzyl ether, 2- or 4-nitrobenzyl ether, or
4-methoxyphenyl; and
R8 is halogen or hydrogen; and salts thereof.
A is nitrogen and D is carbon substituted by R"* (e.g. R^=H) in preferred intermediates of Formula II.
Also in accordance with the present invention are novel intermediates of the formula
III wherein:
A, D, E and G are as defined herein;
R-io is hydroxy, halide or aryl or alkyl sulfonates; and salts thereof.
A is nitrogen and D is carbon substituted by R^ (e.g. R^=H) in preferred intermediates of Formula III.
An example of A is nitrogen.
R1 may be for example hydrogen or methyl.
An example of D is CR"* e.g. where R-* is methyl.
Examples of E and G are CR^ , e.g. where R^ is hydrogen. Examples of R2, R3, R4, and R5 are hydrogen.
An example of Z is CR6 e.g. where R6 is hydrogen.
R' may be for example methyl.
An example of X is bromo.
An example of R" is benzyl.
Examples of L are 4-methylbenzenesulfonate and 4-bromobenzenesulfonate.
Alkyl, as used herein refers to an aliphatic hydrocarbon chain and includes straight and branched chains e.g. of 1 to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl. Lower alkyl refers to alkyl having 1 to 3 carbon atoms.
Alkanamido as used herein refers to the group R-C(=O)-NH- where R is an alkyl group of 1 to 5 carbon atoms.
Alkanoyloxy as used herein refers to the group R-C(=O)-O- where R is an alkyl group of 1 to 5 carbon atoms.
Alkanesulfonamido as used herein refers to the group R-S(O)2-NH- where R is an alkyl group of 1 to 6 carbon atoms.
Alkoxy as used herein refers to the group R-O- where R is an alkyl group of 1 to 6 carbon atoms. Carboxamido, as used herein refers to the group -CO-NH2.
Carboalkoxy as used herein refers to the group R-O-C(=O)- where R is an alkyl group of 1 to 5 carbon atoms.
Where a group, e.g. aryl or benzyl, is "substituted" as used herein it may be substituted by any group or radical commonly used in organic chemistry including for example from 1 to 3 substituents the same or different selected from halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms.
Certain compounds of the present invention contain one asymmetric carbon atom, giving rise to enantiomeric forms of the compounds. It is to be understood that the invention encompasses the enantiomers thereof including racemic mixtures.
It is known that compounds possessing a basic nitrogen can be complexed with many different acids (both protic and non-protic). The invention also includes acceptable salt forms formed from the addition reaction with either inorganic or organic acids. Inorganic acids such as hydrochloric acid (HCl), hydrobromic acid (HBr), hydroiodic acid (HI), sulfuric acid, phosphoric acid, nitric acid are useful as well as organic acids such as acetic acid, propionic acid, citric acid, maleic acid, malic acid, tartaric acid, phthalic acid, succinic acid, methanesulfonic acid, toluenesulfonic acid, napthalenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid are useful.
"Halo" as used herein, such as in the term "halosuccinimide" refers to halogen and preferably bromo-, chloro-, or iodo-.
DETAILED DESCRIPTION OF INVENTION
Thus, in accordance with the present invention is provided a process for preparing in high yield enantiomerically pure compounds of Formula I as well as intermediate thereof.
The process of the present invention can be illustrated by the following reaction scheme (Scheme I), wherein A, D, E, G, R', R", R", and X are as stated above. The reagents and the solvents for the individual step are given for illustrative purposes only and may be replaced by reagents and solvents known to those skilled in the art. Scheme I
N-halosuccinimide Lewis acid/CH?Cl-> CH, —CN - or strong protic acid tc
-0R" base, polar solvent
This process is characterized by high yields and purity of the products and technical convenience. The synthesis of compound I comprises steps that begin with halogenation of 2 with halogenating reagents such as N-halosuccinimide in acetonitrile to give 3. Deprotecting 3 with Lewis acids such as boron tribromide, boron trichloride, aluminum trichloride, ferric chloride, or trimethylsilyl iodide in a suitable solvent such as methylene chloride, or with strong protic acids such as HBr and HCl to give the salt of 4. Free base 4 is very water soluble and neutralization is achieved from an Amberlyst A-21 resin slurry in polar solvents such as ethanol or methanol.
Alkylation of 4, either as the free base or as the salt, with benzyl or substituted benzyl protected glycidyl ethers in suitable polar solvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), or dimethyl acetamide (DMA) in the presence of bases such as sodium carbonate, potassium carbonate, or triethylamine gives 5.
Compound 5 is cyclized using palladium catalysts such as tris(dibenzylidene- acetone)dipalladium, tetrakis(triphenylphosphine)palladium, or palladium acetate with ligands from the group consisting of (+) 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl (BINAP) and separate enantiomers thereof; (+) 2,2'-bis(di-p-tolyl-phosphino)-1 ,1'- binaphthyl (Tol-BINAP) and separate enantiomers thereof; 1-1'-bis(diphenyl- phosphino) ferrocene; 1 ,3-bis(diphenyl-phosphino)propane; and 1 ,2-bis(diphenyl- phosphino)ethane in the presence of bases such as NaH, LiH, KH, potassium carbonate, sodium carbonate, titanium carbonate, cesium carbonate, potassium t- butoxide or potassium phosphate tribasic in suitable solvent such as toluene; or alternatively, with copper catalyst such as copper iodide in the presence of bases such NaH, LiH, KH in a suitable solvent such as toluene to afford quinoline 6. Similar dioxanes may also be prepared using the above reagents.
Deprotection of quinoline 6 with Lewis acids such as boron tribromide, boron trichloride, aluminum trichloride, ferric chloride, trimethylsilyl iodide in a suitable solvent such as methylene chloride, or with strong protic acids such as HBr and HCl or under reductive cleavage conditions using Pd catalyst and hydrogen transfer reagents such as hydrogen, cyclohexene, methyl cyclohexene, or ammonium formate to gives 7. The hydroxyl moiety of 7 can be activated with a sulfonating reagent such as an aryl or alkyl sulfonyl , chloride or aryl or alkyl sulfonic anhydride such as p- toluenesulfonyl chloride, methanesulfonyl chloride, 2-, 3- or 4-nitro-benzenesulfonyl chloride, 2- or 4-bromobenzenesulfonyl chloride, or trifluoromethylsulfonic anhydride in the presence of bases such as triethylamine or pyridine in suitable solvents such as methylene chloride, THF, or toluene to afford 8. The final coupling of 8 with azaheterocycle 9, prepared by reaction of indole with the hydrochloride salt of 4- piperidone, in the presence of bases such as Hϋnig's base, potassium carbonate, or sodium carbonate in polar solvents such as THF, dioxane, DMSO, DMF, or DMA affords final compound I.
The following examples illustrate the process of the present invention but are not meant to be limiting thereof. EXAMPLE 1 Preparation of 5-Bromo-6-Methoxy-2-Methylquinoline
A solution of 6-methoxy-2-methylquinoline (177 g, 1.02 mol) in acetonitrile (1.77 L) was cooled to 0-3°C followed by portion-wise addition of N-bromo- succinimide (200 g, 1.12 mol) over a period of 30 min while maintaining the same temperature. The resulted brown slurry was warmed to ambient temperature and stirred for an additional 6 h. The reaction was then quenched by a 10% NaHSO3 solution (211 mL). The reaction mixture was concentrated to a volume of 600 mL then slowly poured into 0.1 N NaOH (2.5 L). The slurry (pH=9) was stirred at room temperature for 1 h then filtered, washed with water (2 x 1 L) and dried in a vacuum oven to give 253 g (98.6%) of the title compound as a brown solid. Rf = 0.39 (3:7) EtOAc:heptane; 1H NMR (DMSO) δ 8.30 (d, J=6.5 Hz, 1 H), 7.98 (d, J=6.9 Hz, 1 H), 7.70 (d, J=7.0 Hz, 1 H), 7.47 (d, J=6.5 Hz, 1 H), 4.02 (s, 3H), 2.66 (s, 3H);
13C NMR (DMSO) 6 156.9, 153.1 , 143.2, 133.6, 129.3, 126.0, 123.6, 117.0, 106.1 , 56.9, 24.3;
IR (KBr): υmax 3435, 3197, 2943, 2843, 1699, 1613, 1599, 1495, 1342, 1305, 1267, 1131 , 1067, 968, 870, 811 , 629 cm"1; Analysis for CnH10NOBr: Calculated: C 52.40 H 3.97 N 5.56
Found: C 52.13 H 3.94 N 5.61
EXAMPLE 2
Preparation of the Hvdrobromide Salt of 5-Bromo-2-Methyl-6-Quinolinol
A mixture of 5-bromo-2-methyl-6-methoxyquinoline (30 g, 0.12 mol) in 48% HBr (135 mL) was heated to reflux for 7 h then cooled to 5°C in 1 h to give a brown and thick slurry. The slurry was stirred at 0-5°C for 1 h then filtered, washed with EtOAc (2 x 50 mL) and dried in a vacuum oven to give 34.9 g (92%) of the title compound as a brown solid.
1H NMR (DMSO) δ 8.26 (d, J=8.7 Hz, 1H), 7.85 (d, J=9.1 Hz, 1 H), 7.56 (d, J=9.1 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 2.64 (s, 3H); 13C NMR (DMSO) δ 155.7, 152.0, 142.8, 133.3, 128.9, 126.4, 123.3, 121.2, 103.3, 24.1.
EXAMPLE 3 Preparation of 5-Bromo-2-Methyl-6-Quinolinol
A slurry of the hydrobromide salt of 5-bromo-2-methyl-6-quinolinol (3.4 g, 10.5 mmol) and Amberlyst A-21 ion-exchange resin (1.7 g, pre-washed with MeOH then dried in oven) in MeOH (35 mL) was stirred at room temperature for 3 h. The mixture was then filtered and concentrated in vacuo to give 2.5 g (100%) of a yellow solid. Rf = 0.36 (1 :1) EtO Ac: heptane;
1H NMR (DMSO) δ 8.26 (d, J=8.4 Hz, 1H), 7.82 (d, J=9.3 Hz, 1H), 7.47 (t, J=9.1 Hz, 2H), 2.66 (s, 3H);
EXAMPLE 4 Preparation of (2SV1-(Benzyloxy)-3-F(5-Bromo-2-Methyl-6-QuinolinvnOxyn-2-Propanol
A solution of 5-bromo-2-methyl-6-quinolinol (30.1 g, 126 mmol), (R)-benzyl glycidyl ether (24.9 g, 152 mmol) and triethylamine (17.4 g, 172 mmol) in DMA (200 mL) was heated in a 95-98°C oil bath for 2 days. The solution was cooled and poured into water (300 mL) while stirring. The tan precipitate formed was filtered, washed with water (100 mL) and dried in a vacuum oven to give 37 g (73%) of the title compound as a tan solid. Rf = 0.35 (EtOAc); 1H NMR (DMSO) δ 8.31 (d, J=8.8 Hz, 1H), 7.96 (d, J=9.2 Hz, 1 H), 7.72 (d, J=9.3 Hz, 1H), 7.74 (d, J=8.7Hz, 1 H), 7.25-7.36 (m, 5H), 5.28 (d, J=5.1 Hz, 1 H), 4.56 (s, 2H), 4.22-4.29 (m, 2H), 4.08-4.15 (m, 1 H), 3.61-3.73 (m, 2H), 2.66 (s, 3H); 13C NMR (DMSO) δ 157.0, 152.7, 143.4, 138.4, 133.7, 129.2, 128.1 , 127.4, 127.3, 126.0, 123.6, 118.4, 106.8, 72.4, 71.3, 71.2, 68.1 , 24.3; IR (KBr): υmax 3391 , 3188, 2938, 28/5, 1597, 1497, 1268, 1061 , 817, 697 cm"1; Specific rotation = +6.2 ° (c=1 , CH3OH); Analysis for C2oH2oBrNO3: Calculated: C 59.66 H 4.97 N 3.48
Found: C 59.43 H 4.97 N 3.55
EXAMPLE 5 Preparation of (2S)-1 -(Benzyloxy)-3-r5-Brorno-2-Methyl-6-Quinolinyl)Oxyl1-2-Propanol from 5-Bromo-2-Methyl-6-Quinolinol Salt
In a rapidly stirred mixture of K2CO3 (597 g, 4.32 mol)) in DMF (3 L), HBr salt of 5-bromo-2-methyl-6-quinolinol (551 g, 1.73 mol) was added over 30-60 min at rt. After cooling the mixture to room temperature, (R)-benzyl glycidyl ether (353 g, 2.07 mol) was added rapidly. The reaction mixture was then heated to 70°C for from 50-70 h before cooling to 20-23°C. Water (6.05 L) was added over a period of 30-120 min. The reaction mixture was filtered and the filtered cake was washed with additional water (1 L). The solid was then stirred in water (3 L) for 30-40 min and filtered. The filtered cake was washed with water (1 L). The solid obtained was then dried in a vacuum oven (5-0.5 mm Hg) at 65°C over 8-16 h to give 662 g of the title compound. The crude product was then recrystallized in EtOH (2.5 L) to give 487 g (70%) of the title compound as an off-white solid. EXAMPLE 6
Palladium Catalyzed Preparation of (2S1-2r(Benzyloxy)methyll-8-methyl-2.3-
Dihvdroπ ,41Dioxinor2.3-flQuinoline
A solution of (2S)-1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2- propanol (10 g, 24.9 mmol), potassium phosphate tribasic (11.4 g, 50 mmol), Pd(OAc)2 (280 mg, 1.25 mmol) and racemic BINAP (1.55 g, 2.49 mmol) in toluene (50 mL) was heated in a 100-102°C oil bath for 3 d. The solution was cooled to room temperature then EtOAc (50 mL) and water (50 mL) were added. The reaction mixture was filtered through a bed of celite. The two layers were separated. The aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 8 g (100%) of the crude product as a brown syrup. The crude product can be carried through the debenzylation step before purification. A sample of the crude mixture was purified on SiO2, eluted with (3:1) hexane:EtOAc gave the title compound as a yellow oil which solidified upon standing. R, = 0.5 (EtOAc); 1H NMR (DMSO) δ 8.24 (d, J=8.6 Hz, 1H), 7.46 (d, J=9.2 Hz, 1H), 7.27-7.38 (m, 7H); 3C NMR (DMSO) δ 156.4, 143.3, 138.1 , 137.9, 135.2, 128.4, 128.2, 127.2, 127.4, 121.4, 121.0, 120.9, 118.1 , 72.5, 72.4, 68.2, 65.1 , 24.5;
IR (KBr): υmax 3413, 3280, 3028, 2917, 2886, 3798, 1628, 1601 , 1572, 1485, 1453, 1374, 1257, 1100, 1056, 982 cm"1; Specific Rotation = +7.9 ° (c=1.2, CHCI3); Analysis for C20H19NO3: Calculated: C 74.68 H 5.91 N 4.36
Found: C 74.48 H 6.03 N 4.14 EXAMPLE 7
Copper Catalyzed Preparation of (2S)-2r(Benzyloxy)methyl-8-methyl-2,3-
Dihydroπ ,41Dioxino r2,3-HQuinoline
To a mixture of (2S)-1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2- propanol (100 g, 0.249 mol) and copper (I) iodide (47.4 g, 0.249 mol) in toluene (2 L), NaH (10.9 g, 0.45 mol) was added in portions at 30-35°C over 20 min. The reaction mixture was kept at 35°C for 30 min then heated to 110 °C slowly. After 30 min, the reaction was cooled to 60°C, additional NaH (10.9 g, 0.45 mol) was added. This was warmed to 110 °C for an additional 2 hours then cooled to rt before dropwise addition of water (200 mL). After stirring for 15 min, the mixture was filtered through a bed of celite then washed with toluene (3 x 50 mL) and water (50 mL). The two layers were separated. The organic layer was extracted with water (100 mL), NH4OH (100 mL), 25%o NaCI (100 mL) and concentrated in vacuo to give 387.6 g of the crude product as a brown syrup. The crude product was carried through to the debenzylation step before purification (see example 10).
EXAMPLE 8 Lewis Acid Catalyzed Preparation of r(2R)-8-Methyl-2,3-Dihvdroπ ,41Dioxinor2,3- flQuinolin-2-yllMethanol
To a solution of (2R)-2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino
[2,3-f]quinoline (0.74 g, 2.3 mmol) in CH2CI2 (16 mL) being cooled in an ice-bath,
FeCI3 (1.9 g, 12 mmol) was added. After 1 h, the ice-bath was removed and the reaction mixture was stirred for another 17 h. CHCI3 (30 mL) and 1N NaOH (50 mL) were added to result in a suspension which was then filtered. The filtered solid was washed with CH3OH (50 mL). The combined organic layers were concentrated in vacuo. Purification on SiO2, eluted with (10:1) CHCI3:/PrOH gave 0.45 g (84%) of the title compound as an off-white solid. Rf= 0.34 (EtOAc);
1H NMR (DMSO) δ 8.29 (d, J=6.6 Hz, 1H), 7.42 (d, J=6.6 Hz, 1H), 7.30-7.37 (m, 2H), 5.13 (t, J=4.3 Hz, 1H), 4.43-4.46 (m, 1H), 4.31-4.33 (m, 1H), 4.09-4.14 (m, 1H), 3.70- 3.78 (m, 2H), 2.60 (s, 3H);
13C NMR (DMSO) δ 156.7, 143.6, 138.4, 135.9, 129.0, 121.7, 121.4, 121.1, 118.5, 78.4,74.4,65.6,60.3,24.9;
IR (KBr): υmax3200, 2917, 2849, 1628, 1601, 1488, 1374, 1341, 1265, 1107, 1079,
1050,809 cm"1;
GC/MS231.212, 200, 186, 175, 168,156,145, 129, 117,110,102,89,76,64,57,
50,39,31.
EXAMPLE 9 Palladium Catalyzed Preparation of r(2S)-8-Methyl-2.3-Dihvdroπ ,41Dioxinor2.3-fl
Quinolin-2-vnMethanol
To a solution of (2S)-2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino
[2,3-f]quinoline (0.16 g, 0.5 mmol) in EtOH (1 mL) was added cyclohexene (0.5 mL) then 10% Pd/C (0.016 g, 10 mol %). The mixture was heated to reflux under N2 for
18 h then cooled and filtered. The catalyst was rinsed with methanol and the filtrate was concentrated in vacuo to afford 0.113 g (98%) of the title alcohol as an off-white solid.
1H NMR (CD3OD) δ 8.46 (m, 1H), 7.47 (m, 1H), 7.38-7.31 (m, 2H), 4.40 (m, 1H), 4.36
(m, 1H), 4.18 (m, 1H), 3.91 (m, 2H), 2.68 (s, 3H). EXAMPLE 10 Protic Acid Catalyzed Preparation of f(2S)-8-Methyl-2.3-Dihvdroπ .41DioxinoF2,3-f1
Quinolin-2-yll Methanol
A mixture of crude (2S)-2[(benzyloxy)methyl-2,3-dihydro[1 ,4]dioxino [2,3-f]- quinoline product mixture (57.6 g, 0.179 mol) from example 7 in toluene (300 mL) was mixed with 20% HCl (436 g, 3.59 mol) and heated at 80°C. After 30 min, the reaction mixture was cooled to room temperature. The two layers were separated. A 30% NH4OH solution (400 mL) was added to the aqueous layer at 10-20 °C to pH 10. This was stirred for 30 min, the solid was filtered, washed with water and recrystallized from CH3OH (200 mL) to give 25.7 g (61.9%) of the title alcohol as an off-white solid.
EXAMPLE 11 Preparation of IT2R)-8-Methyl-2,3-DihvdroH .41Dioxinor2.3-flQuinolin-2-vπMethyl 4-
Bromobenzenesulfonate
A solution of [(2S)-8-methyl-2,3-dihydro[1 ,4]dioxino[2,3-f]quinolin-2-yl]-methanol (4.0 g, 17.3 mmol), brosyl chloride (4.86 g, 19.0 mmol), dimethylamino pyridine (20 mg, 0.16 mmol) and triethylamine (3.62 mL, 25.8 mmol) in toluene (40 mL) was stirred at 60°C for 6 h. The reaction mixture was cooled to room temperature then water (20 mL) was added. After 30 min, the two layers were separated. The organic layer was extracted with 8% NaHCO3 (20 mL) and H2O (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The solid obtained was dissolved in isopropyl alcohol (50 mL) and toluene (10 mL) at 80°C, cooled to room temperature over 1 then filtered, washed with (5:1) IPA: toluene (2 x 5 mL) and dried in a vacuum oven to give 5.99 g (76.9%) of the title compound as an off-white solid.
13C NMR (CDCI3) δ 157.9, 144.3, 138.1 , 134.7, 132.9, 129.7, 129.6, 129.0, 122.4, 121.7, 121.3, 118.8, 70.7, 67.6, 64.5, 25.4
EXAMPLE 12 Preparation of r(2RV8-Methyl-2.3-Dihvdroπ .41Dioxino[2.3-f1Quinolin-2-vπMethyl 4-
Methylbenzenesulfonate
A solution of [(2S)-8-methyl-2,3-dihydro[1 ,4]dioxino[2,3-f]quinolin-2-yl]- methanol (0.13 g, 0.57 mmol), tosyl chloride (0.16 g, 0.82 mmol) and triethylamine
(0.65 mL, 4.7 mmol) in CH2CI2 (8 mL) was stirred at room temperature for 18 h.
CHCI3 (30 mL) and H2O (30 mL) were added. The two layers were separated. The aqueous layer was extracted with CHCI3 (20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification on SiO2, eluting with (1 :1 ) hexane:EtOAc gave 0.19 g (88%) of the title compound as a brown syrup.
Rf = 0.43 (CHCI3: PrOH); mp: 115-117°C;
1H NMR (CDCI3) δ 8.12 (d, J=8.6 Hz, 1 H), 7.76 (m, 2H), 7.51 (d, J=9 Hz, 1 H), 7.20- 7.60 (m, 4H), 4.5-4.6 (m, 1 H), 4.2-4.4 (m, 3H), 4.1-4.2 (m, 1 H), 2.70 (s, 3H), 2.39 (s,
3H);
13C NMR (DMSO) δ 156.9, 145.4, 143.6, 137.9, 134.7, 132.2, 130.4, 128.7, 128.0,
121.8, 121.6, 121.3, 121.3, 118.3, 70.9, 68.6, 64.1 , 60.1 , 24.9, 21.4, 21.1 , 14.4;
GC/MS 385, 213, 186, 174, 145, 130, 117, 102, 91 , 77, 65, 52, 41 , 30; IR (KBr): υmax 3625, 3374, 2924, 1732, 1628, 1601, 1573, 1485, 1359, 1251 , 1177,
1096, 1049, 941 , 818, 664, 554 cm"1. EXAMPLE 13 Formation of 3-(1 ,2,3,6-Tetrahvdropyridin-4-yl)-1 H-lndole
A mixture of indole (1.01 g, 8.59 mmol), 4-piperidone monohydrate hydrochloride (1.99 g, 12.9 mmol) and KOH (1.74 g, 31 mmol) in CH3OH (9 mL) was heated to reflux for 21 h. After cooling the reaction mixture to room temperature, H2O (14 mL) was added. The suspension was filtered, the solid was washed with (1 :1) MeOH:H2O (20 mL) and air-dried to give 1.49 g (87%) of the title compound as an off- white solid. 1H NMR (DMSO) δ 11.1 (s, 1H), 7.80 (d, J=8.0 Hz, 1 H), 7.3-7.5 (m, 2H), 7.0-7.2 (m, 2H), 6.16 (m, 2H), 3.3-3.5 (m, 2 H), 2.9 (t, J=5.7 Hz, 2H), 2.38 (m, 2H); 3C NMR (DMSO) δ 137.0, 130.1 , 124.7, 122.3, 121.1 , 120.1 , 119.9, 119.1 , 116.7, 111.7, 45.0, 43.0, 40.1 , 39.9, 39.7, 39.5, 39.3, 39.3, 39.1 , 38.9, 28.3.
EXAMPLE 14
Preparation of (2S)-2-r4-(1 H-lndol-3-vD-3. 6-Dihvdro-2H-Pyridin-1-ylmethyll-8-Methyl- 2. 3-Dihvdro-1 , 4-Dioxino [2. 3-fl Quinoline
A solution of [(2R)-8-methyl-2,3-dihydro[1 ,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-methylbenzenesulfonate (0.192 g, 0.499 mmol), 3-(1 ,2,3,6-tetrahydropyridin-4-yl)-
1 H-indole (0.119 g, 0.601 mmol) and K2CO3 (0.104 g, 0.753 mmol) in (1:1) THF:DMF
(1.4 mL) was heated to 80-83°C for 10 h. After this time, H2O (3 mL) was added and the suspension was filtered. The filtered solid was washed with CH3OH (2 x 3 mL), Et2O (2 x 5 mL) and air-dried to give 0.148 g (72%) of the title compound as a tan solid.
Rf = 0.18 (EtOAc); 1H NMR (DMSO) δ 11.1 (s, 1H), 8.26 (d, J=8.6 Hz, 1 H), 7.82 (d, J-7.8 Hz, 1 H), 7.25- 7.50 (m, 4H), 6.9-7.2 (m, 2H), 6.14 (s, 1 H), 4.4-4.7 (m, 2H), 4.0-4.2 (m, 1H), 2.7-3.0 (m, 4H), 2.4-2.7 (m, 8H);
13C NMR (DMSO) δ 156.8, 146.8, 143.6, 138.4, 137.3, 135.6, 130.0, 128.9, 125.0, 123.1 , 121.8, 121.6, 121.5, 121.2, 120.4, 119.6, 118.5, 117.9, 116.2, 112.1 , 72.1 , 66.8, 58.0, 53.8, 51.1 , 28.9, 24.9;
IR (KBr): υmax 3410 3240, 3059, 2848, 1601 , 1484, 1403, 1352, 1255, 1096, 982, 818, 745 cm"1.
EXAMPLE 15 Preparation of (2SV2-r4-(1 H-lndol-3-yl)-3. 6-Dihvdro-2H-Pyridin-1-ylmethyll-8-Methyl-
2. 3-Dihvdro-1. 4-Dioxino F2, 3-fl Quinoline
A solution of [(2R)-8-methyl-2,3-dihydro[1 ,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-bromobenzenesulfonate (2.0 g, 4.44 mmol), 3-(1 ,2,3,6-tetrahydropyridin-4-yl)-1 H- indole (1.01 g, 5.09 mmol) and diisopropylethyl amine (0.86 g, 6.65 mmol) in DMSO (10 mL) was heated to 80-83°C. After 10 h, the reaction mixture was cooled to 65- 70°C before CH3OH (3 mL) was added. The resulted suspension was cooled to room temperature, filtered, washed with CH3OH and dried in a vacuum oven to give 1.3 g (71%o) of the title compound as a yellow solid. EXAMPLE 16 Preparation of (2R)-1 -(Benzyloxy)-3-r5-Bromo-2-Methyl-6-QuinolinvOOxyll-2-Propanol from 5-Bromo-2-Methyl-6-Quinolinol
A solution of 5-bromo-2-methyl-6-quinolinol (2.50 g, 10.5 mmol), (S)-benzyl glycidyl ether (2.1 g, 12.8 mmol) and triethylamine (0.54 g, 5.3 mmol) in DMA (25 mL) was heated in a 80-83°C oil bath for 2 d. The solution was cooled and poured into water (20 mL) while stirring. The tan precipitate formed was filtered, washed with water (10 mL) and dried in a vacuum oven to give 3.0 g (71%) of the title compound as a tan solid.
EXAMPLE 17
Preparation of 1-(Benzyloxy)-3-r5-Bromo-2-Methyl-6-QuinolinvDOxyπ-2-Propanol from 5-Bromo-2-Methyl-6-Quinolinol Salt
A solution of 5-bromo-2-methyl-6-quinolinol (1.0 g, 4.2 mmol), benzyl glycidyl ether (0.83 g, 5.1 mmol) and triethylamine (0.21 g, 2.1 mmol) in DMA (15 mL) was heated in a 90-95°C oil bath for 18 h. The solution was cooled and poured into water (30 mL) and Et2O (100 mL). The two layers were separated. The aqueous layer was extracted with Et2O (2 x 50 mL). The organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give 1.3 g (74%) of the titled compound as a tan solid. EXAMPLE 18
Palladium Catalyzed Preparation of (2R -2r(Benzyloxy)methyll-8-methyl-2,3-
Dihydro[1 ,4lDioxinor2,3-f1Quinoline
A mixture of (2R)-1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2- propanol (2.9 g, 7.2 mmol) and NaH (0.48 g, 12 mmol) in toluene (15 mL) was stirred in a 50-52 °C oil bath for 40 min. This was then canulated into a mixture of Pd(OAc)2 (82 mg, 0.36 mmol) and racemic BINAP (451 mg, 0.724 mmol) in toluene (10 mL) in a 50-52°C oil bath. The resulted reaction mixture was degassed 3 times with Ar before heated to 100-102 °C in an oil bath. After 20 h, the reaction mixture was cooled to room temperature then sat'd NH CI (60 mL) and EtOAc (60 mL) were added. This was stirred for 20 min before filtering through a bed of celite. The two layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification on SiO2, eluting with (3:1) hexane:EtOAc gave 1.4 g (56%) of the title compound as a brown oil.
EXAMPLE 19
Palladium Catalyzed Preparation of 2r(Benzyloxy)methyll-8-methyl-2,3-
Dihydroπ ,41Dioxinor2.3-flQuinoline
A mixture of 1-(benzyloxy)-3-[5-bromo-2-methyl-6-quinolinyl)oxyl]-2-propanol (1.1 g, 2.7 mmol) and NaH (175 mg, 4.4mmol) in toluene (10 mL) was stirred in a 50- 52 °C oil bath for 30 min. This was then canulated into a mixture of Pd(OAc)2 (31 mg, 0.14 mmol) and (R)-Tol-BINAP (186 mg, 0.274 mmol) in toluene (10 mL) in a 50-52°C oil bath. The resulted reaction mixture was degassed 3 times with Ar before heated to 100-102 °C in an oil bath. After 18 h, the reaction mixture was cooled to room temperature then sat'd NH4CI (30 mL) and EtOAc (30 mL) were added. This was filtered through a bed of celite. The two layers were separated. The aqueous layer was extracted with EtOAc (2 x 20 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. Purification on SiO2, eluting with (3:1) hexane:EtOAc gave 0.52 g (58%) of the title compound as a yellow oil.
EXAMPLE 20 Preparation of r8-Methyl-2,3-DihvdroM .41Dioxinor2.3-flQuinolin-2-yllMethyl 4- Methylbenzenesulfonate
A solution of [8-methyl-2,3-dihydro[1 ,4]dioxino[2,3-f]quinolin-2-yl]-methanol (0.13 g, 0.57 mmol), tosyl chloride (0.16 g, 0.82 mmol) and triethylamine (0.65 mL, 4.7 mmol) in CH2CI2 (8 mL) was stirred at room temperature for 18 h. CHCI3 (30 mL) and H2O (30 mL) were added. The two layers were separated. The aqueous layer was extracted with CHCI3 (20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification on SiO2, eluting with (1 :1) hexane: EtOAc gave 0.19 g (88%) of the title compound as a brown syrup. Rf = 0.44 (EtOAc); 1H NMR (CDCI3) δ 8.12 (d, J=8.6 Hz, 1 H), 7.76 (m, 2H), 7.51 (d, J=9 Hz, 1 H), 7.20- 7.60 (m, 4H), 4.5-4.6 (m, 1 H), 4.2-4.4 (m, 3H), 4.1-4.2 (m, 1 H), 2.70 (s, 3H), 2.39 (s, 3H). EXAMPLE 21 Lewis Acid Catalyzed Preparation of r8-Methyl-2,3-DihvdroH ,41Dioxino[2,3-f1Quinolin-
2-yll Methanol
To a solution of 2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1 ,4]dioxino [2,3- fjquinoline (0.30 g, 0.94 mmol) in CH2CI2 (8 mL) being cooled in an ice-bath, FeCI3 (0.77 g, 4.7 mmol) was added. After 1 h, the ice-bath was removed and the reaction mixture was stirred for another 4 h. CH2CI2 (30 mL) and 1 N NaOH (25 mL) were added to result in a suspension which was then filtered. The filtered solid was washed with CH3OH (50 mL). The combined organic layers were concentrated in vacuo. Purification on SiO , eluted with (10:1) CHCI3:/PrOH gave 0.15 g (68%) of the title compound as an off-white solid.

Claims (1)

  1. What is claimed is:
    1. A method of preparing a compound of Formula I:
    wherein
    R1 is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms; R2, R3, R4; and R6 are, independently, hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to
    6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms R5 is hydrogen or alkyl of 1 to 6 carbon atoms; the dotted line represents an optional double bond;
    A and D are selected from carbon, substituted by R"* , and nitrogen, provided that at least one of A and D is nitrogen; E and G are carbon, substituted by R"* ; and Z is N or CR6; or pharmaceutically acceptable salts thereof, comprising the steps of: a) halogenating a compound of the formula:
    wherein R' is alkyl of 1-6 carbon atoms; with a halogenating reagent to afford a compound of the formula:
    wherein X is Br, CI, or I; b) dealkylating the compound of Formula 3 in an acid to afford a compound of the formula:
    c) alkylating the compound of Formula 4 with R" protected glycidyl ethers (^^^0R "), wherein R" is benzyl or substituted benzyl to afford a compound of the formula:
    d) cyclizing the compound of Formula 5 with palladium or copper catalyst to afford a compound of the formula:
    e) debenzylating the compound of Formula 6 to afford the compound of the formula:
    f) activating the hydroxy moiety of the compound of Formula 7 to a halide or with a sulfonating reagent to afford a compound of the formula:
    8 wherein L is Br, CI, I or OR'" wherein R" is an aryl- or alkyl- sulfonyl group; and
    g) coupling the compound of Formula 8 with the appropriate azaheterocycle of Formula 9
    in the presence of base to provide a compound of Formula I
    and optionally isolating as free base or a pharmaceutically acceptable salt thereof.
    A method according to Claim 1 of preparing a compound of formula la:
    la wherein R"*-6, A, D, E, G, Z and the dotted line are as defined in Claim 1 or a pharmaceutically acceptable salt thereof, comprising the steps of
    a) halogenating a compound of the formula:
    wherein R' is alkyl of 1-6 carbon atoms; with a halogenating reagent to afford a compound of the formula:
    wherein X is Br, CI, or I;
    b) dealkylating the compound of Formula 3 in an acid to afford a compound of the formula:
    4 o
    ZΛ- OR- c) alkylating the compound of Formula 4 with R" protected glycidyl ethers ( ^ ), wherein R" is benzyl or substituted benzyl, or alkyl alcohol of 1 to 6 carbon atoms to afford compound of the formula:
    5a
    d) cyclizing the compound of Formula 5a with palladium or copper catalyst to afford a compound of the formula:
    6a e) debenzylating the compound of Formula 6a to afford the compound of the formula:
    7a
    f) activating the hydroxy moiety of the compound of Formula 7a with alkyl- or aryl- sulfonyl chloride or with alkyl or aryl sulfonic anhydride in the presence of a base to afford a compound of the formula:
    8a wherein OR'" is an alkyl- or aryl- sulfonate; and
    g) coupling the compound of Formula 8a with the appropriate azaheterocycle of Formula 9
    in the presence of base to provide a compound of Formula la, and optionally isolating as free base or a pharmaceutically acceptable salt thereof.
    3. A method according to Claim 1 of preparing a compound of formula 1b:
    or a pharmaceutically acceptable salt thereof comprising the steps:
    a) halogenating a compound of the formula:
    2a wherein R' is alkyl of 1-6 carbon atoms; with a halogenating reagent to afford a compound of the formula:
    3a wherein X is Br, CI, or I; b) dealkylating the compound of Formula 3a in an acid to afford a compound of the formula:
    4a o c) alkylating the compound of Formula 4a with R" protected glycidyl ethers ( ^OR"
    ). wherein R" is benzyl or substituted benzyl; to afford compound of the formula:
    5b d) cyclizing the compound of Formula 5b with palladium or copper catalyst to afford a compound of the formula:
    6b e) debenzylating the compound of Formula 6b to afford the compound of the formula:
    7b f) activating the hydroxy moiety of the compound of Formula 7b with alkyl or aryl sulfonyl chloride with alkyl or aryl sulfonic anhydride in the presence of a base to afford a compound of the formula:
    8b wherein OR'" is a alkyl- or aryl- sulfonate; and g) coupling the compound of Formula 8b with 3-tetrahydropyridinyl-indole in the presence of base to provide a compound of Formula lb and optionally isolating as free base or a pharmaceutically acceptable salt thereof.
    4. A method according to claim 1 wherein the compound of Formula 7 is activated with aryl or alkyl sulfonic chloride or with an aryl or alkyl sulfonic anhydride in the presence of a base.
    5. A method according to any one of Claims 2 to 4 wherein the compound of Formula 7, 7a or 7b is activated with p-toluenesulfonyl chloride, methanesulfonyl chloride, 2-, 3- or 4-nitrobenzenesulfonyl chloride, 2- or 4-bromobenzenesulfonyl chloride or trifluoromethylsulfonic anhydride.
    6. A method according to Claim 5 wherein the compound of Formula 7, 7a or 7b is activated with 4-bromobenzenesulfonylchloride.
    7. A method according to any one of Claims 4 to 6 wherein the base in step (f) is triethylamine or pyridine in methylene chloride, tetrahydrofuran or toluene.
    8. A method according to claim 1 making a compound of Formula I:
    wherein R^' , A, D, E, G, Z and the dotted line are as defined in Claim 1 or a pharmaceutically acceptable salt thereof, comprising the steps of a) halogenating a compound of the formula:
    wherein R' is alkyl of 1-6 carbon atoms; with a halogenating reagent to afford a compound of the formula:
    wherein X is Br, CI, or I; b) dealkylating the compound of Formula 3 in an acid to afford a compound of the formula:
    c) alkylating the compound of Formula 4 with R" protected glycidyl ethers (^ /0R") wherein R" is benzyl or substituted benzyl to afford compound of the formula:
    d) cyclizing the compound of Formula 5 with palladium or copper catalyst to afford a compound of the formula:
    e) debenzylating the compound of Formula 6 to afford the compound of the formula:
    f) activating the hydroxy moiety of the compound of Formula 7 to a halide to afford a compound of the formula:
    wherein X'* is I, Br or CI and g) coupling the compound of Formula 10 with an appropriate azaheterocycle of
    Formula 9
    in the presence of base to provide a compound of Formula I.
    9. A method of making a compound of Formula la:
    wherein R-*-6, A, D, E, G, Z and the dotted line are as defined in Claim 1 or a pharmaceutically acceptable salt thereof, comprising the steps of a) halogenating a compound of the formula
    wherein R' is alkyl of 1-6 carbon atoms; with a halogenating reagent to afford a compound of the formula:
    wherein X is Br, CI, or I; b) dealkylating the compound of Formula 3 in an acid to afford a compound of the formula:
    o c) alkylating the compound of Formula 4 with R" protected glycidyl ethers ( ^- 0R" wherein R" is benzyl or substituted benzyl to afford compound of the formula
    d) cyclizing the compound of Formula 5a with palladium or copper catalyst to afford a compound of the formula:
    6a e) debenzylating the compound of Formula 6a to afford the compound of the formula:
    7a f) activating the hydroxy moiety of the compound of Formula 7a to a halide to afford a compound of the formula:
    .X1
    10a wherein X1 is I, Br or CI; and
    g) coupling the compound of Formula 10a with the appropriate azaheterocycle of Formula 9
    in the presence of base to provide a compound of Formula la.
    10. A method of making a compound of Formula lb:
    comprising the steps: a) halogenating a compound of the formula:
    2a wherein R' is alkyl of 1-6 carbon atoms; with a halogenating reagent to afford a compound of the formula:
    3a wherein X is Br, CI, or I; b) dealkylating the compound of Formula 3a in an acid to afford a compound of the formula:
    OR\ c) alkylating the compound of Formula 4a with R" protected glycidyl ethers ( ^ wherein R" is benzyl or substituted benzyl; to afford compound of the formula
    5b d) cyclizing the compound of Formula 5b with palladium or copper catalyst to afford a compound of the formula:
    6b e) debenzylating the compound of Formula 6b to afford the compound of the formula:
    7b
    f) activating the hydroxy moiety of the compound of Formula 7b to a halide to afford a compound of the formula:
    10b wherein X1 is I, Br or CI; and g) coupling the compound of Formula 10b with 3-tetrahydropyridinyl-indole in the presence of base to provide a compound of Formula lb.
    11. A method according to any one of Claims 1 and 8 to 10 wherein the compound of Formula 7, 7a or 7b is activated with a halogenating reagent.
    12. A method according to any one of Claims 1 and 8 to 11 wherein the compound of Formula 7, 7a or 7b is activated as a halide with phosphorous triiodide, phosphorous tribromide, phosphorous pentachloride or thionyl chloride.
    13. A method according to any one of claims 1 to 12 wherein the base in step (g) is sodium carbonate, potassium carbonate, or Hϋnig's base.
    14. A method according to any of Claims 1 to 13 wherein the compound of formula 2 or 2a is halogenated with an N-halosuccinimide.
    15. A method according to Claim 14 wherein the compound of Formula 2 or 2a is treated with an N-halosuccinimide in acetonitrile.
    16. A method according to any one of Claims 1 to 15 wherein the halogenation reaction of step (a) is quenched with a 10% NaHSO3 solution and the product precipitated with NaOH.
    17. A method according to any one of Claims 1 to 16 wherein the compound of Formula 3 or 3a is dealkylated with a Lewis acid.
    18. A method according to any one of Claims 1 to 17 wherein the compound of Formula 3 or 3a is dealkylated with a protic acid.
    19. A method according to Claim 18 wherein the protic acid is HBr.
    20. A method according to Claim 19 wherein the compound of Formula 3 or 3a is heated to reflux in HBr for from about 6 to about 7 hours.
    21. A method according to any one of Claims 1 to 20 wherein the compound of Formula 4 or 4a is alkylated with benzyl- or substituted benzyl-glycidyl ether in a polar solvent.
    22. A method according to Claim 21 wherein the polar solvent is dimethylsulfoxide, dimethyl-formamide, or dimethylacetamide.
    23. A method according to any one of Claims 1 to 22 wherein the compound of Formula 4 or 4a is alkylated with benzyl glycidyl ether, 4-bromobenzyl glycidyl ether, 4-chlorobenzyl glycidyl ether, 3, 4-dimethoxybenzyl glycidyl ether, 2- or 4-nitrobenzyl glycidyl ether, or 4-methoxy-phenyl glycidyl ether.
    24. A method according to any one of claims 1 to 23 wherein the alkylation of the compound of formula 4 or 4a is conducted in the presence of a base.
    25. A method according to Claim 24 wherein the base is triethylamine, sodium carbonate, or potassium carbonate.
    26. A method according to any one of Claims 1 to 25 wherein the compound of Formula 5 or 5a is cyclized using palladium catalyst in the presence of phosphine ligand and base.
    27. A method according to Claim 26 wherein the palladium catalyst is tris(dibenzylidene-acetone)dipalladium, tetrakis(triphenylphosphine)palladium, or palladium acetate with phosphine ligands selected from the group consisting of (+) 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and separate enantiomers thereof; (±) 2,2'-bis(di-p-tolyl-phosphino)-1 ,1'-binaphthyl and separate enantiomers thereof; 1,1'-bis(diphenylphosphino)ferrocene; 1,3-bis(diphenyl-phosphino)propane; and 1 ,2- bis(diphenylphosphino)ethane.
    28. A method according to Claim 26 or 27 wherein the base is sodium hydride, lithium hydride, potassium hydride, potassium carbonate, sodium carbonate, titanium carbonate, cesium carbonate, potassium f-butoxide or potassium phosphate tribasic.
    29. A method according to any one of Claims 1 to 28 wherein the compound of Formula 5 or 5a is cyclized using copper catalyst in the presence of base.
    30. A method according to Claim 29 wherein the copper catalyst is copper iodide.
    31. A method according to Claim 29 or 30 wherein the base is sodium hydride, lithium hydride or potassium hydride.
    32. A method according to any one of Claims 1 to 31 wherein the compound of Formula 6, 6a or 6b is debenzylated with Lewis acid, strong protic acid or under reductive cleavage conditions.
    33. A method according to Claim 32 wherein the Lewis acid is boron tribromide, boron trichloride, aluminum trichloride, ferric chloride or trimethylsilyl iodine.
    34. A method according to Claim 32 wherein the protic acid is hydrobromic acid or hydrochloric acid.
    35. A method according to Claim 1 wherein a) the compound of Formula 5 is cyclized using copper catalyst in the presence of NaH to provide compound of Formula 6, and b) compound of Formula 6 is debenzylated with HCl to provide compound of Formula 7.
    36. A method according to Claim 32 wherein reductive cleavage is performed using palladium catalyst and hydrogen transfer reagents.
    37. A method according to Claim 36 wherein the palladium catalyst is Pd/C.
    38. A method according to Claim 36 or 37 wherein the transfer reagent is cyclohexene, methylcyclohexene, ammonium formate or hydrogen.
    39. A method according to Claim 36 wherein the palladium catalyst is Pd/C and the transfer reagent is cyclohexene.
    40. A method of preparing a compound of the formula 5:
    wherein
    R is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms; A and D are selected from carbon substituted by R^ and nitrogen, provided that at least one of A and D is nitrogen;
    E and G are carbon, substituted by R^ ;
    R" is benzyl or substituted benzyl; and X is halogen; which comprises alkylating a compound of formula 4
    with R" protected glycidyl ethers ( OR"
    41. A method according to Claim 40 wherein A is nitrogen, and D is carbon substituted by R"* .
    42. A method of preparing a compound of Formula 6
    R"* is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms; A and D are selected from carbon substituted by R1 and nitrogen, provided that at least one of A and D is nitrogen; E and G are carbon, substituted by R1 ; and R" is benzyl or substituted benzyl, which comprises cyclizing a compound of Formula 5
    with palladium or copper catalyst.
    43. A method according to Claim 42 wherein the catalyst is a palladium catalyst.
    44. A method according to Claim 42 or 43 wherein A is nitrogen and D is carbon substituted by R1.
    45. A method of preparing a compound of Formula 10
    wherein
    R1 is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
    A and D are selected from carbon substituted by R^ and nitrogen, provided that at least one of A and D is nitrogen; E and G are carbon, substituted by R^ ; and
    X1 is I, CI or Br: which comprises activating compound of Formula 7
    to halide with a halogenating reagent.
    46. A method according to Claim 45 wherein the halogenating agent is halophosphorous.
    47. A method according to Claim 46 wherein the halophosphorous is phosphorous triiodide, phosphorous tribromide or phosphorous pentachloride.
    48. A method according to any one of Claims 45 to 47 wherein A is nitrogen, and D is carbon substituted by R^ .
    49. A method of preparing a compound of Formula 8
    wherein R"* is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
    A and D are selected from carbon substituted by R*- and nitrogen, provided that at least one of A and D is nitrogen;
    E and G are carbon, substituted by R"* ; and
    R'" is an aryl- or alkyl- sulfonate; which comprises activating the hydroxy moiety of the compound of formula 7
    with aryl or alkyl sulfonyl chloride or with aryl or alkyl sulfonic anhydride in the presence of a base.
    50. A method according to Claim 49 wherein A is nitrogen and D is carbon substituted by R^ .
    51. A method of preparing a compound of Formula 7
    wherein R"* is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of
    1 to 6 carbon atoms;
    A and D are selected from carbon substituted by R-- and nitrogen, provided that at least one of A and D is nitrogen; and E and G are carbon, substituted by R"* ; which comprises debenzylating a compound of Formula 6
    where R" is benzyl or substituted benzyl.
    52. A method according to Claim 51 wherein A is nitrogen, and D is carbon substituted by R"* .
    53. A compound of the formula
    wherein:
    R"- is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
    A and D are selected from carbon substituted by R-* and nitrogen, provided that at least one of A and D is nitrogen;
    E and G are carbon, substituted by R1 ;
    R7 is hydroxy, alkoxy of 1-6 carbon atoms, or alkoxy of the formula
    wherein R9 is hydroxy, benzyl ether, substituted benzyl ethers such as 4-bromobenzyl ether, 4-chlorobenzyl ether, 3, 4-dimethoxybenzyl ether, 2- or 4-nitrobenzyl ether, or 4-methoxyphenyl; and R8 is halogen or hydrogen; and salts thereof.
    54. A compound according to Claim 53 wherein A is nitrogen and D is carbon substituted by R"* .
    55. A compound of the formula
    wherein:
    R1 is hydrogen, hydroxy, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
    A and D are selected from carbon substituted by R"* and nitrogen, provided that at least one of A and D is nitrogen;
    E and G are carbon, substituted by R^; and
    R10 is hydroxy, halide or alkyl- or aryl- sulfonates; and salts thereof.
    56. A compound according to Claim 51 wherein A is nitrogen and D is carbon substituted by R"* .
AU2002309769A 2001-05-17 2002-05-14 Processes for the synthesis of derivatives of 2,3-dihydro-1,4-dioxino-[2,3-f] quinoline Ceased AU2002309769B2 (en)

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US6800637B2 (en) * 2002-09-12 2004-10-05 Wyeth Antidepressant indolealkyl derivatives of heterocycle-fused benzodioxan methylamines
EP2332940B1 (en) 2004-03-30 2012-10-31 Vertex Pharmaceuticals Incorporated Azaindoles useful as inhibitors of JAK and other protein kinases
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EP2124951B1 (en) 2006-12-21 2014-05-21 Vertex Pharmaceuticals Inc. 5-cyan0-4- (pyrrolo[2, 3b]pyridine-3-yl) -pyrimidine derivatives useful as protein kinase inhibitors
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Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3986833A (en) * 1975-09-08 1976-10-19 Miles Laboratories, Inc. Test composition, device, and method for the detection of peroxidatively active substances
FR2537139B2 (en) * 1982-03-15 1985-09-20 Roussel Uclaf NOVEL D-DERIVATIVE OF N-DIHYDROTHIAZOLYL 3-QUINOLEINE CARBOXAMIDE, METHOD OF PREPARATION, APPLICATION AS MEDICAMENT AND COMPOSITIONS CONTAINING THE SAME
DE4135474A1 (en) 1991-10-28 1993-04-29 Bayer Ag 2-AMINOMETHYL-chromans
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US5741789A (en) 1995-01-17 1998-04-21 Eli Lilly And Company Compounds having effects on serotonin-related systems
US5756532A (en) 1995-11-06 1998-05-26 American Home Products Corporation Aminomethyl-2 3 8 9-tetrahydro-7H-1 4-dioxino 2 3-E!-indol-8-ones and derivatives
US5869490A (en) 1996-10-15 1999-02-09 American Home Products Corporation Azaheterocyclymethyl derivatives of 2,3,8,9-tetrahydro-7h-1,4-dioxino (2,3-e) indol-8-one
EP1392697B1 (en) 2001-03-14 2004-11-03 Wyeth Antidepressant azaheterocyclymethyl derivatives of 2,3-dihydro-1,4-dioxino 2,3-f]quinoline
US6458802B1 (en) * 2001-03-14 2002-10-01 Wyeth Antidepressant azaheterocyclymethyl derivatives of 2,3-dihydro-1,4-dioxino [2,3-f]quinoline
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