ZA200303908B - New process for the preparation diaryl-4-amino-piperidinyl compounds. - Google Patents
New process for the preparation diaryl-4-amino-piperidinyl compounds. Download PDFInfo
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- ZA200303908B ZA200303908B ZA200303908A ZA200303908A ZA200303908B ZA 200303908 B ZA200303908 B ZA 200303908B ZA 200303908 A ZA200303908 A ZA 200303908A ZA 200303908 A ZA200303908 A ZA 200303908A ZA 200303908 B ZA200303908 B ZA 200303908B
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- amino
- alkyl
- mmol
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- hydrogen
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- 238000000034 method Methods 0.000 title claims description 24
- 230000008569 process Effects 0.000 title claims description 24
- 238000002360 preparation method Methods 0.000 title claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 19
- -1 cyano, amino Chemical group 0.000 claims description 15
- 150000002431 hydrogen Chemical class 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical class 0.000 claims description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000002541 furyl group Chemical group 0.000 claims description 7
- 125000002883 imidazolyl group Chemical group 0.000 claims description 7
- 125000004076 pyridyl group Chemical group 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- 125000004423 acyloxy group Chemical group 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 27
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000006254 arylation reaction Methods 0.000 description 15
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 13
- 238000005580 one pot reaction Methods 0.000 description 12
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 11
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 7
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000003818 flash chromatography Methods 0.000 description 6
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 229960005235 piperonyl butoxide Drugs 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- YUBDLZGUSSWQSS-UHFFFAOYSA-N 1-benzylpiperidin-4-amine Chemical compound C1CC(N)CCN1CC1=CC=CC=C1 YUBDLZGUSSWQSS-UHFFFAOYSA-N 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical class NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 description 3
- STXAVEHFKAXGOX-UHFFFAOYSA-N 3-bromobenzonitrile Chemical compound BrC1=CC=CC(C#N)=C1 STXAVEHFKAXGOX-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000003377 acid catalyst Substances 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 238000006268 reductive amination reaction Methods 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 2
- LDUPVXSXLZOQAF-UHFFFAOYSA-N 4-bromo-n,n-diethylbenzamide Chemical compound CCN(CC)C(=O)C1=CC=C(Br)C=C1 LDUPVXSXLZOQAF-UHFFFAOYSA-N 0.000 description 2
- 229910015845 BBr3 Inorganic materials 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000005518 carboxamido group Chemical group 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 2
- SYXYWTXQFUUWLP-UHFFFAOYSA-N sodium;butan-1-olate Chemical compound [Na+].CCCC[O-] SYXYWTXQFUUWLP-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 2
- KYLUAQBYONVMCP-UHFFFAOYSA-N (2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P KYLUAQBYONVMCP-UHFFFAOYSA-N 0.000 description 1
- REXBHXOYMGXVAB-UHFFFAOYSA-N 1-benzyl-n-(3-methoxyphenyl)piperidin-4-amine Chemical compound COC1=CC=CC(NC2CCN(CC=3C=CC=CC=3)CC2)=C1 REXBHXOYMGXVAB-UHFFFAOYSA-N 0.000 description 1
- PLDWAJLZAAHOGG-UHFFFAOYSA-N 1-bromo-3-methoxybenzene Chemical compound COC1=CC=CC(Br)=C1 PLDWAJLZAAHOGG-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- VOIZNVUXCQLQHS-UHFFFAOYSA-N 3-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC(Br)=C1 VOIZNVUXCQLQHS-UHFFFAOYSA-N 0.000 description 1
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 1
- ZRHGXOKPARSBQA-UHFFFAOYSA-N 4-bromo-n,n-di(propan-2-yl)benzamide Chemical compound CC(C)N(C(C)C)C(=O)C1=CC=C(Br)C=C1 ZRHGXOKPARSBQA-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- WBLIXGSTEMXDSM-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH2] WBLIXGSTEMXDSM-UHFFFAOYSA-N 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 238000007339 nucleophilic aromatic substitution reaction Methods 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical compound NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Landscapes
- Hydrogenated Pyridines (AREA)
Description
> WO 02/48108 PCT/SE01/02780
NEW PROCESS FOR THE PREPARATION DIARYL-4-AMINO-PIPERIDINYL . COMPOUNDS "FIELD OF THE INVENTION
The present invention is directed to a new process for the preparation of 1-substituted s diaryl-4-amino-piperidinyl compounds. In further aspects, the present invention also relates to new intermediates used in said process.
BACKGROUND AND PRIOR ART
WO 98/28270 discloses a group of compounds, and processes for their preparation, to which 1-substituted diaryl-4-amino-piperidinyl compounds belongs.
WO 99/33806 discloses 4-[aryl(piperidin-4-yl)] aminobenzamide compounds and processes for their preparation. The core of the process disclosed in W099/33806 consists of a reductive amination followed by a second step wherein the previously prepared N-aryl- piperidineamine is reacted with a bromo, iodo or trifluoromethanesulfonyloxy substituted benzamide in the presence of a palladium catalyst, a phosphine ligand and a base to give said (N-aryl,N-piperidin-4-yl)aminobenzamide.
The first reaction step (reductive amination) is performed using an appropriate solvent/reducing agent combination such as 1,2-dichloroethane or acetonitrile/NaBH(OAc)3 + acid catalyst; methanol/NaBH3CN + acid catalyst; titanium isopropoxide/ NaBH3CN; methanol, ethanol or isopropanol/NaBH4; alcoholic solvent/Hs + noble metal catalyst or 1,2-dichloroethane or acetonitrile/NaBH(OAc); + acid catalyst. . 25 The product of the first step is thereafter isolated and purified before the second step is performed. The second step is thereafter performed in a different solvent.
Thomas et al. in J. Med. Chem. discloses 4-[aryl(piperidin-4-yl)] aminobenzamide of . similar structure as WO 99/33806. The compounds are prepared by a reductive amination step followed by a nucleophilic aromatic substitution step.
The process of the present invention provides 1-substituted diaryl-4-amino-piperidinyl ‘compounds in an improved and simplified manufacturing process that, e.g. uses only sommecially available starting materials and reagents, has less reaction and purification steps, gives easier purification of the final and intermediate compounds, uses only one solvent system throughout the whole process.
Thus, the object of the. present invention is to provide a novel process suitable for use in large-scale synthesis. A further object of the present invention is to provide a process containing as few reaction steps as possible. :
OUTLINE OF THE INVENTION Co
The present invention provides a new process for preparation of 1-substituted diaryl-4- amino-piperidinyl compounds, hereinafter referred to as compounds of the invention. The compounds of the invention are useful in therapy, and in particular for the treatment of pain. 0
The process for preparing of 1-substituted diaryl-4-amino-piperidinyl compounds is schematically shown in Scheme 1 below.
v WO 02/48108 PCT/SE01/02780 } RS Rr? L wt CL
Br R®—Ar Ro. 03°
HN N CH —R’ - N . 2 + 2ln Palladium catalyst; R2 R® 4 Phosphine ligand
R R Base
R* N R® 2. 2_Ar- I 1
R oa Ar—Br Lr
Rn
Scheme 1 wherein : :
R! and rR? are independently selected from the group consisting of hydrogen, hydroxy, 5 halogen, C;~Cg alkyl, C;—Cg alkoxy, C;~Cg acyl, C;—Cg acyloxy, cyano, amino, nitro, C;— g Cg acylamino, C;—Cg alkylamino, (C,—Cg alkyl),amino, C1~Cg alkylthio, C;—Cg alkylsulfonyl, halogenated C1—Ceg alkyl, halogenated C;~Cg alkoxy, cO-NR®R® and C1—Cs alkoxycarbonyl; rR, RY, Rr’ and R® are independently selected from hydrogen and C;-Cg alkyl;
R’ is selected from the group consisting of imidazolyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl and phenyl, all optionally and independantly mono-, di-, or tri-substituted with aR’ group;
RS and R? are independently selected from hydrogen, C;~Cg alkyl, halogenated C;~Cg . alkyl, phenyl, benzyl, all optionally and independantly mono-, di-, or tri-substituted with a
R’’ group; Ar- is phenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with 0 to 3 R? groups;
R’ is independently selected from the group consisting of hydroxy, halogen, C;—Cjg alkyl, . C—Ci alkoxy, C1—Cg acyl, C1—Cg acyloxy, cyano, amino, nitro, C;—Cg¢ acylamino, C;—Cg alkylamino, (C;—Cg alkyl),amino, C;—Cg alkylthio, C{—Cg alkylsulfonyl, halogenated C,- ’ Cg alkyl, halogenated C1~Cg alkoxy;
R’’ is independently selected from the group consisting of hydroxy, halogen, C;—Cg alkyl,
C;-Cjg alkoxy, cyano, amino, nitro, C1~Cj alkylthio, halogenated C{—Cg alkyl, halogenated
C;—Cg alkoxy; and nisl, 2,3,4,5,0r6. :
A preferred embodiment of the present invention is the process according to Scheme 1, wherein
R! and R? are independently selected from hydrogen, C1—Cg alkyl, C;—Cg alkoxy, hydroxy, halogen, cyano, amino, Cco-NR®R’ and C;-Cg¢ alkoxycarbonyl;
Rr’, RY, R’ and RS are independently selected from hydrogen and C,-C4 alkyl;
R’ is selected from the group consisting of imidazolyl, thienyl, furanyl, pyridinyl, and phenyl; )
R8 and R? are independently selected from hydrogen, C;—Cg alkyl, phenyl or benzyl; and n is an integer from 1 to 6.
A more preferred embodiment of the present invention is the process according to Scheme 1, wherein
R1 and R? are independently selected from hydrogen, C1—Cg alkyl, C;—Cg¢ alkoxy, hydroxy, halogen, cyano, amino, co-Nr%R’ and C;-Cg4 alkoxycarbonyl;
Rr? RY rR’ and RS are hydrogen;
R’ is selected from the group consisting of imidazolyl, furanyl, pyridinyl, and phenyl;
R8 and RY are independently selected from hydrogen, ethyl and isopropyl, and _ nis L. ' An even more preferred embodiment of the present invention is the process according to 5 Scheme 1, wherein :
R! and R2 are independently selected from hydrogen, hydroxy, halogen, cyano, amino, CO-
NR®R’ and C,—Cg¢ alkoxycarbonyl; rR’, R* Rr’ and RS are hydrogen; CC
R’ is selected from the group consisting of imidazolyl, furanyl, pyridinyl, and phenyl;
R8 and RY are independently selected from hydrogen, ethyl and isopropyl, and : nis 1.
Most preferred embodiment of the present invention is the process according to Scheme 1, wherein
RI! and R? are independently selected from hydrogen, halogen, cyano CO-NR®R® and Ci- . Cg alkoxycarbonyl; :
RS, R* rR’ and r® are hydrogen,
R’ is selected from the group consisting of imidazolyl, pyridinyl, and furanyl;
R38 and R? are independently selected from hydrogen, ethyl and isopropyl; and © 20 nisl. oo
Thus the process of the present invention can be described as comprising a one-pot double arylation step. It will be apparent for the skilled person that an optional deprotection step might have to be introduced after the one-pot double arylation step, due to interference/reactivity of the substituents. Reference is made to “Protective Groups in
Organic Synthesis”, 2nd edition, T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1991).
Example of a substituent that might need to be protected is hydroxy. A hydroxy substituent is preferably protected as its methyl ether. Such methyl ether would then have to be cleaved after the one-pot double arylation step. This could for example be done by treating the wore Eri
R PCT/SE01/02780 . 03-01-2003 6 product of the one-pot double arylation step with BBr; under standard conditions, such as ) 2-5 molar equivalents of BBr3 in dichloromethatne at ~78°C.
The One-pot Double Arylation Step
A one-pot double arylation step is a reaction that is performed in one pot but consists of two separate and distinct reaction steps (arylation couplings) that are performed consecutively without the need for any purification of intermediate compounds, work-up procedure, or change of solvent. The two reagents are added separately and the addition of ‘the reagents is so timed as to allow the first reaction step to be completed before the next reagent is added to start the second reaction step.
The one-pot double arylation step of the present invention is performed by reacting 4- amino-piperidine of Formula II
RL R* 7 odode 8 3
R R 1 wherein R’ to rR, n, and R’ are as described above in Scheme 1, with a first bromo compound of Formula ITI, 1 wt)
Br I Co , wherein r, RS, rR, and R are as decribed above in Scheme 1, in the presence of a strong base, a palladium catalyst and a phosphine ligand. Upon completion of the first arylation step, a second bromo compound of Formula IV
AMENDED SHEET -
) ‘ ES Sweadiah Patent Ofics 1, 100354-1wWo POT 7 amiaiione! Applicedon } : PCT/SE01/02780 . : 03-01-2003 ) 7
RE—Ar-Br 0-3 Iv . wherein Rr, RS, rR’, R and Ar are as described above in Scheme 1, and a strong base are added, without any isolation or purification of the reaction product of the first reaction step, to give the final product of Formula I in high yield. 2 R!
R—Ar 0-3 : 0-3 N “TX R®
R* x Re
Lo : Rn ; - wherein Rr! to rR’, Ar, R’,R’’ and n are as described above in Scheme 1. The final product might optionally have to been taken through a deprotection step.
Each reaction step of the one-pot double arylation in preferably done in an inert non-polar solvent system, such as toluene, at elevated temperature, such as around 80°C or reflux, -. and for a few hours. . Ce ——— am
Palladium catalysts to be used in process of the present invention is chosen from a group consisting of PdCly, Pd(OAc),, Pd(PhaP)4(0) and tris(dibenzylideneacetone)- ’ dipalladium(0), of which the last is preferred. Phosphine ligands to be used in process of the present invention is chosen from a group of tri(o-tolyl phosphine), xantphos, 2-(di-z-butylphosphino)biphenyl and racemic BINAP, of which the latter is preferred.
AMENDED SHEET ]
: Examples of strong bases that can be used in the process of the present invention comprise, but is not limited to, sodium fer. butoxide, cesium carbonate and sodium methoxide, of which sodium fer. butoxide is preferred.
The one-pot double arylation of the present invention is thus done without any isolation or purification of intermediate compounds. The one-pot double arylation of the present invention is further done in one solvent system for both arylation steps.
Possible as well as preferred amounts and reaction conditions in the one-pot double arylation step are the following.
The molar equivalents relative to 4-aminopiperidine compound are for; 1** bromo compound 0.9 - 1.2, preferably 0.95 - 1.1, strong base, first addition 1.05 - 1.5, preferably 1.1 - 1.4, palladium catalyst and phosphine reagent catalytic amount, preferably 0.01 - 0.2 2" bromo compound 1.0 - 2.0, preferable 1.3 - 1.7 strong base, second addition 1.0 2.0, preferable 1.3 - 1.7 ) :
It is also recommended to have the molar ratio between palladium catalyst and phosphine reagent as close to 1 as practically possible and the molar ratio between 2* bromo compound and the second addition of base as close to 1 as practically possible.
The Deprotection Step :
The optional deprotection can be accomplished by any known standard method to remove protecting groups that do not degrade the other parts of the molecule of the present invention. Reference is made to “Protective Groups in Organic Synthesis”, 2nd edition,
T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1991).
To = Sraadiish Patent Office ~, 100354-1 WO FCT i amalicns! Apciication , : + PCT/SE01/02780 03-01-2003 9
The final product prepared according to the process of the present invention may thereafter ' be taken through further standard additional purification steps and/or converted into a . suitable pharmaceutically acceptable salt.
It has also surprisingly been found that the two separate and distinct reaction steps (arylation couplings) can be performed in any order. This means that the process of the present invention can also be performed as is shown below in Scheme 2. 2 1. R=—Ar-Br
RS R® : 0-3 R'
RAL 0-3
H,N N CH —R _ 2 tor; n Palladium catalyst; RY R®
R® =O Phosphine ligand
R* R® 2. R! T 0-3 CH,
Br ~~,
R” n .- . - Scheme 2 x 10 .
INTERMEDIATES
To Another object of the present invention is to provide new intermediates that can be used in the preparation of compound of formula I.
Accordingly, a further aspect of the present invention is intermediate compound of
Formula V and VI shown below,
AMENDED SHEET }
H, TF Ros - N . oo : R kd R®
Lo 7
Rn Vv - 2 ‘
Ris ALAM
IX R® i : wherein Rr! to rR, Ar, R’, R” and n are as described in all the embodiments above.
The compounds prepared by the present invention can thereafter be converted into a pharmaceutically acceptable salt thereof, or optionally one of the substituents R! or RZ can be converted into another functional groupas described in Larock, Richard; Brown H.C.;
Comprehensive Organic Transformations: A Guide to Functional Group Preparations, New
York : VCH (1989), ISBN #- 0471187186.
In one embodiment of the present invention rR! is'C1—Cg alkoxycarbonyl, e.g. tert. butyl ester, and Rr? to rR’, Ar, R’, R*’ and n are as described in all the embodiments above. The rR! C,~C alkoxycarbonyl group is eventually converted into a carboxamido group, e.g.
N,N-diethylcarboxamido, using standard procedure, e.g. by treating the ester with the corresponding amine in a suitable solvent.
In a preferred embodiment of the present invention rR! is N,N-diethylcarboxamido or N,N- diisopropylcarboxamido.
In a preferred embodiment of the present invention R? is independently selected from hydroxy, carboxamido, and halogen.
Ina preferred embodiment of the present invention rR? , R* rR’, and RS are all hydrogen.
In a preferred embodiment of the present invention n is 1 and R’ is a imidazolyl, furanyl, pyridinyl, or phenyl group.
The present invention will now be described in more detail by the following examples, which should not be construed as limiting the invention. The process parameters given below can be adopted and adapted by the skilled person to suit his particular need.
Example 1
Preparation of N, N-diethyl-4-[[(3-methoxyphenyl)[I-(phenyimethyl)-4- piperidinyl] amino ] benzamide ‘To a solution of 500 UL of 3-bromoanisole (3.95 mmol) in 10 ml dry toluene was added 800 pL of 4-amino-N-benzyl piperidine (3.93 mmol), 197 mg racemic BINAP (0.32 mmol), 145 mg tris(dibenzylideneacetone)dipalladium(0) (0.16 mmol) and 530 mg sodium tert butoxide (5.52 mmol). The reaction was heated at 80 °C under a nitrogen atmosphere : for 2 hours. The reaction was cooled to room temperature and 1.42 g of N, N-diethyl-4- bromobenzamide (5.55 mmol) and 530 mg of sodium fer¢ butoxide (5.52 mmol) were added and the reaction heated to reflux. After 3 hours the solution was cooled to room temperature and the reaction diluted with ethyl acetate (50 ml) and water (30 ml) was added, filtered through celite and then the organic layer was separated, dried MgSOy), filtered and concentrated. The residue was purified by flash chromatography and then bya second flash chromatography to yield a pale orange oil. Finally, the oil was crystallized from hexanes containing a small amount of ethyl acetate and the solid collected by filtration to yield 1.163g of a colourless solid (2.47 mmol; 63%). 1H NMR: (400 MHz, CDCl3, TMS,): 7.31-7.23 (8H, m, Ar-H), 6.74-6.71 (1H, m, Ar), 6.66 (2H, d, J=9Hz, Ar), 6.57-6.52 (2H, m, Ar), 3.87-3.80 (1H, m, CH), 3.77 (3H, s, OCH), 3.49 (2H, s, NCHA), 3.48 (4H, br s, NCH,), 2.96 (2H, d, J=11.5Hz, NCH,), 2.11 (2H, t,
J=12.5Hz, NCH), 1.92 (2H, d, J=12.5Hz, CH), 1.58-1.48 (2H, m, CH,), 1.18 (6H, t, 1s J=6.5Hz,CH3)
Example 2
Preparation of N N-diethyl-4-[[(3-hydroxyphenyl)[1-(phenylmethyl)-4- piperidinyl [amino] benzamide
To a solution of N,N-diethyl-4-[[(3-methoxyphenyl)[1 (phenylmethyl)4-piperidiny1]- amino}benzamide (1 eq) in CHCl, at —78 °C was added 3 eq of BBr3 (1 M'in CH2Cl).
Stirred for approx. 45 minutes then at room temperature for 2 hours. MeOH was added followed by saturated NaHCOs. The phases were separated and the aqueous layer extracted several times with CH,Cl,. The combined organic layers were dried over MgSO, and concentrated. Purification by flash chromatography over silica gel gave the title compound in 50-63% yield. :
MS: (M+1) calculated: 458.62 (MH+); (M+1) observed: 458.24 (MH+). IR: Film
HCI salt: 3047, 2974, 2531, 1600, 1471, 1455, 1283, 1186, 1093, 735, 701cm™. 1H
NMR: (400MHz, CD30D) &y 1.16 (br s, 6H, CH) ; 1.69-1.73 (m, 2H, CH) ; 2.22 (d, J=14Hz, 2H, CH) ; 3.27 (t, J=8Hz, 2H, NCH;) ; 3.35-3.51 (m, 6H, NCHy) ;
4.27 (s, 2H, NCHA) ; 4.28-4.35 (m, 1H, NCHA) ; 6.69 (d, J=9Hz, 3H, Ar-H) ; : 7.20-7.23 (m, 4H, Ar-H) ; 7.46 (s, 6H, Ar-H).
Example 3 5s Preparation of N N-diethyl-4-[[(3-cvanophenyl)[1-(phenylmethyl)-4- piperidinylJamino [benzamide ee
Br CN o
NH | Pd,(dba),, BINAP Ww) jg ® NaOBu, toluene, 80°C N CN : .
N
Cw Lael . : Br Ph
NaOBu, toluene, 110°C, 93%
To a solution of 1.07g of 3-bromobenzonitrile (5.88 mmol) in 15 ml dry toluene was added 1.2 mL of 4-amino-N-benzyl piperidine (5.89 mmol), 293 mg racemic BINAP (0.47 mmol), 215 mg tris(dibenzylideneacetone)dipalladium(0) (0.23 mmol) and 790 mg sodium tert butoxide (8.23 mmol). The reaction was heated at 80 °C under a nitrogen atmosphere for 4 hours. The reaction was cooled to room temperature and 2.26 g of N, N-diethyl-4- bromobenzamide (8.83 mmol) and 790 mg of sodium tert butoxide (8.23 mmol) were added and the reaction heated to reflux. After 20 hours the solution was cooled to room temperature and the reaction diluted with ethyl acetate (50 ml) and water (30 ml) was added, filtered through celite and then the organic layer was separated, dried (MgSO,), : filtered and concentrated. The residue was purified by flash chromatography, to yield an oil (2.54g, 5.45 mmol; 93%). (400MHz, CDCl3) oy 1.36 (br s, 6H, CHs) ; 1.44-1.54 (m, 2H, CH) ; 1.91 (d, J=12.5Hz, 2H, CH,) ; 2.12 (t, J=12Hz, 2H, NCH,) ; 2.97 (d, J=12Hz, 2H, NCH;) ; 3.26-3.60 (m, 4H,
NCH) ; 3.51 (s, 2H, NCH,Ar) ; 3.79-3.86 (m, 1H, NCH) ; 6.86-6.89 (m, 1H, Ar-H) ; 6.92- : 6.97 (m, 2H, Ar-H) ; 7.12-7.15 (m, 1H, Ar-H) ; 7.23-7.32 (m, 6H, Ar-H) ; 7.37-7.41 (m, 3H, Ar-H). Co
Example 4
Preparation of N,N-diisopropyl-4-[[(3-cyanophenyl)[1-(phenylmethyl)-4- piperidinyl]amino]benzamide
ER J @ © Br CN 0
NH, Pd,(dba)s, BINAP hy J gH E ) NaOtBu, toluene, 80°C N CN
N 2. 2 | ) on Lael hb;
Br Ph . | NaO'Bu, toluene, 110°C, 76% oo To a solution of 1.07g of 3-bromobenzonitrile (5.88 mmol) in 15 ml dry toluene was added 1.2 mL of 4-amino-N-benzyl piperidine (5.89 mmol), 293 mg racemic BINAP (0.47 mmol), 215 mg tris(dibenzylideneacetone)dipaliadium(0) (0.23 mmol) and 790 mg sodium tert butoxide (8.23 mmol). The reaction was heated at 80 °C under a nitrogen atmosphere for 4 hours. The reaction was cooled to room temperature and 2.34 g of N, N-diisopropyl- 4-bromobenzamide (8.24 mmol) and 790 mg of sodium fert butoxide (8.23 mmol) were added and the reaction heated to reflux. After 20 hours the solution was cooled to room temperature and the reaction diluted with ethyl acetate (50 ml) and water (30 ml) was added, filtered through celite and then the organic layer was separated, dried (MgSO), filtered and concentrated. The residue was purified by flash chromatography to yield . afoamn (2.20g, 4.45 mmol; 76%). . (400MHz, CDCl3) dy, 1.37 (brs, 12H, CH3) ; 1.45-1.55 (m, 2H, CH,) ; 1.91 (d, J=13Hz,
2H, CHy) ; 2.12 (t, J=12Hz, 2H, NCH) ; 2.97 (d, J=12Hz, 2H, NCH) ; 3.51 (s, 2H,
NCH,Ar) ; 3.75 (br s, 2H, NCH) ; 3.77-3.84 (m, 1H, NCH) ; 6.82-6.84 (m, 1H, Ar-H) ; 6.93-6.96 (m, 3H, Ar-H) ; 7.10'(d, J=7.5Hz, 1H, Ar-H) ; 7.22-7.36 (m, 8H, Ar-H).
Example 5
Preparation of-3-[[(3-cvanophenyl)[1-(phenylmethyl)-4-piperidinyl Jamino benzoic acid, tert. butyl ester . CL ® Pd,(dba),, BINAP, NaO'Bu >° N oN toluene, 80°C 0
N
Je e
Ph o. J or Br Ph
NaO'Bu, toluene, 110°C, 34%
SE
To a solution of 2.68g of 3-bromobenzonitrile (14.72 mmol) in 40 ml dry toluene was added 3.0 mL of 4-amino-N-benzyl piperidine (14.73 mmol), 734 mg racemic BINAP (1.18 mmol), 540 mg tris(dibenzylideneacetone)dipalladium(0) (0.59 mmol) and 1.98 g sodium tert butoxide (20.63 mmol). The reaction was heated at 80 °C under a nitrogen atmosphere for 2 hours. The reaction was cooled to room temperature and 5.30 g of 3-bromobenzoic acid, tert butyl ester (20.62 mmol) and 1.98 mg of sodium fer? butoxide (20.63 mmol) were added and the reaction heated to reflux. After 20 hours the solution was cooled to room temperature and the reaction diluted with ethyl acetate (100 ml) and water (50 ml) was added, filtered through celite and then the organic layer was separated, dried (MgSO), . 20 filtered and concentrated. The residue was purified by flash chromatography, eluting 30% ethyl acetate in hexanes to yield a yellow foam (2.36g, 5.05 mmol; 34%). (400MHz, CDCl3) 8y 1.42-1.52 (m, 2H, CHy) ; 1.60 (s, 9H, ‘Bu) ; 1.92 (d, J=12.5Hz, 2H,
J
CH) ; 2.09-2.15 (m, 2H, NCH)) ; 2.97 (d, J=12Hz, 2H, NCH,) ; 3.50 (s, 2H, NCHA) ; -3.78-3.86 (m, 1H, NCH) ; 6.75-6.81 (m, 2H, Ar-H) ; 7.01-7.05 (m, 1H, Ar-H) ; 7.14-7.31 (m, 7H, Ar-H) ; 7.45 (t, J=8Hz, 1H, Ar-H) ; 7.63-7.64 (m, 1H, Ar-H) ; 7.89-7.91 (m, 1H,
Ar-H) . CL
INTERMEDIATES E
(1-Benzyl-piperidin-4-yl)-(3-methoxy-phenyl)-amine prepared according to Example 1 above has the following physical data. 1H NMR: (400 MHz, CDCl3, TMS,): 7.32-7.25 (5H, m, Ar), 7.05 (1H, t, J=8Hz, Ar) ; 6.25-6.19 (2H, m, Ar), 6.14 (1H, s, Ar), 3.76 (3H, s, OCH3), 3.52 (2H, s, CH), 3.31-3.22 (1H, m, CH), 2.85 (2H, d, J=11Hz, CH), 2.14 (2H, t, J=11Hz, CH), 2.03 2H, d, J=11Hz,
CH,), 1.47 (2H, q, J=11Hz, CH) a
Claims (3)
1.A process for the preparation 1-substituted diaryl-4-amino-piperidinyl compound of . Formula I
2 R! R=—Ar 0-3 0-3 N R* Sh Re 7 Rn | § : wherein Rr! and rR? are independently selected from the group consisting of hydrogen, hydroxy, halogen, C1~Cg alkyl, C;—Cg alkoxy, C;—Cg acyl, C;—Cg acyloxy, cyano, amino, nitro, . 10 . C1=C¢ acylamino, Ci1—Cq alkylamino, (C1+—Cs alkyl),amino, Ci—Cs alkylthio, Ci—Cs alkylsulfonyl, halogenated C;~Cg alkyl, halogenated C;~Cg alkoxy, CO-NR*R® and C, Cg alkoxycarbonyl;
3.4.5 6 , ee R,R,R and R" are independently selected from hydrogen and C,-Cg alkyl; R’ is selected from the group consisting of imidazolyl, thienyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl and phenyl, all optionally and independantly mono-, di-, or tri-substituted with a R’ group; R® and Rr’ are independently selected from hydrogen, C;—Cg alkyl, halogenated C;—Cg alkyl, phenyl, benzyl, all optionally and independantly mono-, di-, or tri-substituted with a R’’ group; AMENDED SHEET _
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/SE2000/002560 WO2001046263A1 (en) | 1999-12-20 | 2000-12-15 | Novel compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200303908B true ZA200303908B (en) | 2004-04-05 |
Family
ID=33448608
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200303908A ZA200303908B (en) | 2000-12-15 | 2003-05-20 | New process for the preparation diaryl-4-amino-piperidinyl compounds. |
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| Country | Link |
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| ZA (1) | ZA200303908B (en) |
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2003
- 2003-05-20 ZA ZA200303908A patent/ZA200303908B/en unknown
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