WO2008140646A2 - Process for the synthesis of cmhtp and intermediates thereof - Google Patents
Process for the synthesis of cmhtp and intermediates thereof Download PDFInfo
- Publication number
- WO2008140646A2 WO2008140646A2 PCT/US2008/002652 US2008002652W WO2008140646A2 WO 2008140646 A2 WO2008140646 A2 WO 2008140646A2 US 2008002652 W US2008002652 W US 2008002652W WO 2008140646 A2 WO2008140646 A2 WO 2008140646A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phosphorus
- cmbp
- cmhp
- partially removed
- cmhtp
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 154
- 230000008569 process Effects 0.000 title claims abstract description 147
- 239000000543 intermediate Substances 0.000 title abstract description 16
- 230000015572 biosynthetic process Effects 0.000 title description 10
- 238000003786 synthesis reaction Methods 0.000 title description 9
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 179
- 239000011574 phosphorus Substances 0.000 claims abstract description 179
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 179
- PMXMIIMHBWHSKN-UHFFFAOYSA-N 3-{2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl}-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCC(O)C4=NC=3C)=NOC2=C1 PMXMIIMHBWHSKN-UHFFFAOYSA-N 0.000 claims abstract description 55
- 229960001057 paliperidone Drugs 0.000 claims abstract description 49
- DFZLZGAIWJGCIJ-UHFFFAOYSA-N 3-(2-chloroethyl)-2-methyl-9-phenylmethoxypyrido[1,2-a]pyrimidin-4-one Chemical compound C=1C=CN2C(=O)C(CCCl)=C(C)N=C2C=1OCC1=CC=CC=C1 DFZLZGAIWJGCIJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- OZMLUMPWPFZWTP-UHFFFAOYSA-N 2-(tributyl-$l^{5}-phosphanylidene)acetonitrile Chemical compound CCCCP(CCCC)(CCCC)=CC#N OZMLUMPWPFZWTP-UHFFFAOYSA-N 0.000 claims abstract 98
- 101100226004 Rattus norvegicus Erc2 gene Proteins 0.000 claims abstract 90
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 78
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 66
- 239000000203 mixture Substances 0.000 claims description 66
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 52
- 238000004519 manufacturing process Methods 0.000 claims description 51
- 239000000047 product Substances 0.000 claims description 50
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 46
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 43
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 40
- 239000003054 catalyst Substances 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 239000000243 solution Substances 0.000 claims description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 30
- 229910052739 hydrogen Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 28
- 239000007787 solid Substances 0.000 claims description 28
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 229910019213 POCl3 Inorganic materials 0.000 claims description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- 239000011541 reaction mixture Substances 0.000 claims description 22
- 238000005984 hydrogenation reaction Methods 0.000 claims description 20
- 238000002156 mixing Methods 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
- 239000002244 precipitate Substances 0.000 claims description 14
- 239000008346 aqueous phase Substances 0.000 claims description 13
- 239000003960 organic solvent Substances 0.000 claims description 11
- NMCBWICNRJLKKM-UHFFFAOYSA-N 3-(benzyloxy)pyridin-2-amine Chemical compound NC1=NC=CC=C1OCC1=CC=CC=C1 NMCBWICNRJLKKM-UHFFFAOYSA-N 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- 239000012074 organic phase Substances 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- OMQHDIHZSDEIFH-UHFFFAOYSA-N 3-Acetyldihydro-2(3H)-furanone Chemical compound CC(=O)C1CCOC1=O OMQHDIHZSDEIFH-UHFFFAOYSA-N 0.000 claims description 6
- 239000012320 chlorinating reagent Substances 0.000 claims description 6
- 150000007529 inorganic bases Chemical class 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 6
- 239000003039 volatile agent Substances 0.000 claims description 5
- 239000002250 absorbent Substances 0.000 claims description 4
- 230000002745 absorbent Effects 0.000 claims description 4
- 239000003849 aromatic solvent Substances 0.000 claims description 4
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- 238000005660 chlorination reaction Methods 0.000 claims description 2
- 239000011874 heated mixture Substances 0.000 claims 3
- 229920006233 biaxially oriented polyamide Polymers 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 238000000634 powder X-ray diffraction Methods 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 238000002425 crystallisation Methods 0.000 description 13
- 230000008025 crystallization Effects 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 238000001556 precipitation Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 7
- 239000012452 mother liquor Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000000284 extract Substances 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 238000001144 powder X-ray diffraction data Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 239000000908 ammonium hydroxide Substances 0.000 description 4
- 238000005119 centrifugation Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 239000011521 glass Substances 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- -1 methyl ether ketone Chemical class 0.000 description 3
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 3
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- BMTSZVZQNMNPCT-UHFFFAOYSA-N 2-aminopyridin-3-ol Chemical compound NC1=NC=CC=C1O BMTSZVZQNMNPCT-UHFFFAOYSA-N 0.000 description 2
- AYNDDJMEHBUOGI-UHFFFAOYSA-N 3-(2-hydroxyethyl)-2-methyl-9-phenylmethoxypyrido[1,2-a]pyrimidin-4-one Chemical compound C=1C=CN2C(=O)C(CCO)=C(C)N=C2C=1OCC1=CC=CC=C1 AYNDDJMEHBUOGI-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- JBJSVEVEEGOEBZ-SCZZXKLOSA-N coenzyme B Chemical compound OP(=O)(O)O[C@H](C)[C@@H](C(O)=O)NC(=O)CCCCCCS JBJSVEVEEGOEBZ-SCZZXKLOSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- SVPFCJPWFQRBQX-UHFFFAOYSA-N 2-methyl-9-phenylmethoxypyrido[1,2-a]pyrimidin-4-one Chemical compound C12=NC(C)=CC(=O)N2C=CC=C1OCC1=CC=CC=C1 SVPFCJPWFQRBQX-UHFFFAOYSA-N 0.000 description 1
- LLBZPESJRQGYMB-UHFFFAOYSA-N 4-one Natural products O1C(C(=O)CC)CC(C)C11C2(C)CCC(C3(C)C(C(C)(CO)C(OC4C(C(O)C(O)C(COC5C(C(O)C(O)CO5)OC5C(C(OC6C(C(O)C(O)C(CO)O6)O)C(O)C(CO)O5)OC5C(C(O)C(O)C(C)O5)O)O4)O)CC3)CC3)=C3C2(C)CC1 LLBZPESJRQGYMB-UHFFFAOYSA-N 0.000 description 1
- WTLQGBXULYAERE-UHFFFAOYSA-N CCCC1=C(C)N=C(C(OCc2ccccc2)=CC=C2)N2C1=O Chemical compound CCCC1=C(C)N=C(C(OCc2ccccc2)=CC=C2)N2C1=O WTLQGBXULYAERE-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 241001104043 Syringa Species 0.000 description 1
- 235000004338 Syringa vulgaris Nutrition 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 239000003420 antiserotonin agent Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 150000008316 benzisoxazoles Chemical class 0.000 description 1
- 238000005574 benzylation reaction Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- KGVVLDOJDFWSCL-UHFFFAOYSA-N deca-3,5-dien-2-one Chemical compound CCCCC=CC=CC(C)=O KGVVLDOJDFWSCL-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229940013946 invega Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical class FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Definitions
- Paliperidone is a metabolite of Risperidone. Marketed under the name,
- Paliperidone is a psychotropic agent approved in the United States for the treatment of schizophrenia.
- CHTP 6,7,8,9-tetrahydro-9-hydroxy-2 -methyl -4H-pyrrido[ 1 ,2-a]- pyrimidin-4-one
- Patent 5,158,952 discloses the hydrogenation of 3.3 parts of 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[l,2-a]pyrimidine- 4-one (CMBP) in 120 parts of methanol with hydrogen at normal pressure and room temperature and 2 parts of 10% palladium-on-carbon catalyst to form 3-(2- chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4- one (CMHTP).
- CMBP 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[l,2-a]pyrimidine- 4-one
- step (B) reacting the product of step (A) with hydrogen and a hydrogenation catalyst to form CMHTP;
- Another embodiment of the invention provides a process for preparing
- step (c) reacting the product of step (b) with hydrogen and a hydrogenation catalyst to form CMHTP;
- An embodiment of the invention provides a process for preparing 3-(2- chloroethyl)-2-methyl-9-hydoxy-4H-pyrido[ 1 ,2-a]pyrimidine-4-one (CMHP), comprising:
- One of the embodiments of the invention provides a process for preparing 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[ 1 ,2-a]pyrimidine-4-one (CMBP), comprising:
- step (B) heating the mixture formed in step (A) to obtain 3-(2-hydroxyethyl)- 6,7,8,9-tetrahydro-9-benzyloxy-2-methyl-4H-pyrrido[ 1 ,2-a]- pyrimidin-4-one (HMBP);
- the present invention also provides a process for preparing 3-(2- hydroxyethyl)-6,7,8,9-tetrahydro-9-benzyloxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one (HMBP), comprising:
- the present invention also provides processes for preparing paliperidone by converting recovered or substantially isolated CMHTP prepared by any of the processes for preparing CMHTP of the invention into paliperidone. These processes may be combined with other processes of the invention for preparing one or. more of the intermediates.
- the present invention also provides processes for preparing paliperidone by converting CMHTP into paliperidone, wherein the conversion is preceded, albeit not immediately, by a step using recovered or substantially isolated HMBP. These processes may be combined with other processes of the invention for preparing the HMBP or another intermediate preceding the formation of HMBP. [00020] The present invention also provides processes for preparing paliperidone by converting CMHTP into paliperidone, wherein the conversion is preceded, albeit not immediately, by a step reacting HAP with benzyl bromide to prepare BOPA as one of the intermediates.
- the present invention also provides processes for preparing paliperidone by combining two or more processes of the present invention in an appropriate sequential order.
- One of the embodiments of the invention provides a process for preparing paliperidone, comprising:
- CMBP 3-(2-chloroethyl)-2-methyl-9-benzyloxy- 4H-pyrido[l,2-a]pyrimidine-4-one
- CMHP 3-(2-chloroethyl)-2-methyl-9- hydoxy-4H-pyrido[l,2-a]pyrimidine-4-one
- optionally phosphorus is at least partially removed from the CMBP before the benzyl group is removed from the CMBP and/or phosphorus is at least partially removed from the CMHP after the CMHP is formed;
- step (B) reacting the product of step (A) with hydrogen and a hydrogenation catalyst to form 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l,2-a]- pyrimidin-4-one (CMHTP);
- step (c) reacting the product of step (b) with hydrogen and a hydrogenation catalyst to form 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[ 1 ,2-a]- pyrimidin-4-one (CMHTP);
- the present invention provides a process of preparing paliperidone, comprising: condensing recovered or substantially isolated 3-(2-chloroethyl)-6,7,8,9- tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one (CMHTP) with 6-fiuoro-3-piperidino-l,2-benisoxazol (FPBI) to form paliperidone.
- CHTP 3-(2-chloroethyl)-6,7,8,9- tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one
- FPBI 6-fiuoro-3-piperidino-l,2-benisoxazol
- the present invention also provides recovered or substantially isolated
- the present invention also provides crystalline 3-(2-chloroethyl)-
- CHTP 6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one
- PXRD powder X-ray diffraction
- CHTP 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[ 1 ,2-a]- pyrimidin-4-one
- PXRD powder X-ray diffraction
- the present invention provides a process for preparing crystalline 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l,2-a]- pyrimidin-4-one (CMHTP), characterized by powder X-ray diffraction (PXRD) peaks at about 9.7, 19.4, 22.9 and 24.9 +/- 0.2 degrees 2 ⁇ , comprising crystallizing CMHTP from ethyl acetate.
- CMHTP powder X-ray diffraction
- the present invention provides a process for preparing crystalline 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l,2-a]- pyrimidin-4-one (CMHTP), characterized by powder X-ray diffraction (PXRD) peaks at about 8.5, 11.2, 15.3, 23.8 +/- 0.2 degrees 2 ⁇ , comprising: stirring starting solid CMHTP in water to form the product CMHTP characterized by powder X-ray diffraction (PXRD) peaks at about 8.5, 11.2, 15.3,
- CMHTP 3-(2- chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4- one (CMHTP), characterized by powder X-ray diffraction (PXRD) peaks at about 9.7, 19.4, 22.9 and 24.9 +/- 0.2 degrees 2 ⁇ .
- PXRD powder X-ray diffraction
- the solid obtained by filtration is further optionally washed with water, then washed with ethyl acetate and dried.
- the present invention provides 3-(2-chloroethyl)-2- methyl-9-hydoxy-4H-pyrido[l ,2-a]pyrimidine-4-one (CMHP).
- the present invention also provides recovered or substantially isolated
- the present invention also provides CMHP comprising less than 26 ppm phosphorus, which includes CMHP containing no phosphorus and CMHP containing phosphorus at less than 26 ppm.
- the present invention also provides 3-(2-chloroethyl)-2-methyl-9- benzyloxy-4H-pyrido[l,2-a]pyrimidine-4-one (CMBP) comprising less than 26 ppm phosphorus, which includes CMBP containing no phosphorus and CMBP containing phosphorus at less than 26 ppm.
- CMBP 3-(2-chloroethyl)-2-methyl-9- benzyloxy-4H-pyrido[l,2-a]pyrimidine-4-one
- the present invention provides a process for at least partially removing phosphorus from CMBP, comprising: treating the starting CMBP containing phosphorus with activated charcoal to obtain the CMBP having no phosphorus or less phosphorus than the starting CMBP; and optionally recovering or isolating the CMBP having no phosphorus or less phosphorus than the starting CMBP, e.g., by removing the activated charcoal with filtration or centrifugation, followed by optional precipitation of the CMBP from the filtrate and recovering the CMBP precipitate by filtration or centrifugation.
- the present invention provides a process for at least partially removing phosphorus from CMHP, comprising: treating the starting CMHP containing phosphorus with activated charcoal to obtain the CMHP having no phosphorus or less phosphorus than the starting CMHP; and optionally recovering or isolating the CMHP having no phosphorus or less phosphorus than the starting CMHP, e.g., by removing the activated charcoal with filtration or centrifugation, followed by optional precipitation of the CMHP from the filtrate and recovering the CMHP precipitate by filtration or centrifugation.
- the present invention provides a process for at least partially removing phosphorus from CMBP, comprising: mixing a solution of the starting CMBP containing phosphorus in an organic solvent with an aqueous solution OfNH 4 OH to obtain a CMBP precipitate having no phosphorus or less phosphorus than the starting CMBP, wherein the aqueous phase of the mixture preferably has a pH of about 7; and recovering or isolating the CMBP precipitate.
- the present invention provides a process for at least partially removing phosphorus from CMHP, comprising: mixing a solution of the starting CMHP containing phosphorus in an organic solvent with an aqueous solution OfNH 4 OH to obtain a CMHP precipitate having no phosphorus or less phosphorus than the starting CMHP, wherein the aqueous phase of the mixture preferably has a pH of about 7; and recovering or isolating the CMHP precipitate.
- the present invention provides 3-(2-hydroxyethyl)-
- HMBP 2-methyl-9-benzyloxy-4H-pyrido[ 1 ,2-a]pyrimidine-4-one
- the present invention provides recovered or substantially isolated HMBP.
- Figure 1 illustrates a representative powder X-ray diffraction (PXRD) pattern for CMHTP Form I.
- Figure 2 illustrates a representative powder X-ray diffraction pattern for CMHTP Form II.
- CMBP can be contaminated with phosphorus.
- the expression "phosphorus is at least partially removed from the CMBP” means that part or all of the phosphorus is removed from the CMBP contaminated with phosphorus so that the CMBP product contains less than about 26 ppm, preferably less than about 20 ppm, more preferably less than about 15 ppm, further more preferably less than about 10 ppm, even more preferably about 5 ppm or less, and most preferably about 0 ppm, phosphorus, e.g., CMBP free of phosphorus.
- the low phosphorus content of the CMBP or the absence of phosphorus in the CMBP results in a high CMHTP yield of at least about 83%, preferably at least about 90% and more preferably at least about 94%, when the CMBP is hydrogenated with about 1% (per weight of 10% Pd/C 50% wet), by weight (based on the weight of the entire reaction mixture, so that the entire reaction mixture is 100% by weight) of 10% palladium/carbon (50% wet) as a catalyst.
- CMHP can be contaminated with phosphorus.
- the expression "phosphorus is at least partially removed from the CMHP" means that part or all of the phosphorus is removed from the CMHP contaminated with phosphorus so that the CMHP product contains less than about 26 ppm, preferably less than about 20 ppm, more preferably less than about 15 ppm, further more preferably less than about 10 ppm, even more preferably about 5 ppm or less, and most preferably about 0 ppm, phosphorus, e.g., CMHP free of phosphorus.
- the low phosphorus content of the CMHP or the absence of phosphorus in the CMHP results in a high CMHTP yield of at least about 83%, preferably at least about 90% and more preferably at least about 94%, when the CMHP is hydrogenated with about
- the present invention is based on a new synthetic route for obtaining
- the present invention provides a process for preparing 3-benzyloxy-2-aminopyridine (BOPA) using a benzyl bromide derivative.
- BOPA 3-benzyloxy-2-aminopyridine
- the present invention provides a process for preparing
- the starting material, HAP is commercially available.
- a mixture of HAP, benzyl bromide, sodium hydroxide, water, dichloromethane and tetrabutylammonium bromide is provided, then maintained at a temperature of about 20° C for about 12 hours to obtain a two phase system.
- the temperature and time will be dependant on many factors such as the choice of base used, the amount of starting material and the yield desired.
- the BOPA can them be recovered from the organic phase by any means known in the art.
- HAP is first combined with a solution of sodium hydroxide, water and dichloromethane, and then tetrabutylammonium bromide is combined with the reaction mixture.
- tetrabutylammonium bromide is combined with the reaction mixture.
- the reaction mixture is maintained for about 15 minutes.
- BOPA may be recovered from the organic phase by any method known in the art.
- the present invention also provides a process for preparing 3-(2- chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[ 1 ,2-a]pyrimidine-4-one (CMBP) by condensation of BOPA with 3-acetyl-4,5-dihydro-3H-2-furanone (ADHF) to produce 3-(2-hydroxyethyl)-6,7,8,9-tetrahydro-9-benzyloxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one (HMBP) and further chlorinating HMBP to produce CMBP.
- the process can be conducted as described in the following scheme.
- CMBP CMBP
- BOPA and ADHF are reacted to obtain HMBP, which is then recovered and optionally subsequently converted into CMBP.
- the HMBP may be produces according to any method known in the art but is then recovered and preferably isolated.
- HMBP may be prepared by a process comprising: providing a mixture of BOPA, ADHF and one or more water absorbents such as /?-toluenesulfonic acid (TsOH), H 2 SO 4 or a water separator such as a Dean Stark water extraction system as well as one or more aromatic solvents such as xylene or toluene; heating to reflux to obtain crude HMBP.
- the mixture is maintained at room temperature to reflux for about 12 hours to about 30 hours, although the time and temperature necessary are dependant on a number of factors including materials chosen and quantity.
- water is removed. More preferably, the water removal is done by using a water separator.
- the crude HMBP is further crystallized from one or more polar, aprotic organic solvents such as methyl ether ketone, acetone, nitromethane, acetonitrile, N-methylpyrrolidone, dimethyl formamide or DMSO and preferably acetonitrile.
- polar, aprotic organic solvents such as methyl ether ketone, acetone, nitromethane, acetonitrile, N-methylpyrrolidone, dimethyl formamide or DMSO and preferably acetonitrile.
- Recovery may be by crystallization. Crystallization may be caused by reducing the volume of the solvents and/or by cooling. In one example, the solvents present with the crude HMBP is reduced to induce crystallization. Subsequently, the HMBP may be recrystallized. Specifically, useful solvents in the crystallization process include: organic solvent for example: methyl ether ketone, acetone, nitromethane, acetonitrile, N-methylpyrrolidone, dimethyl formamide or DMSO and preferably acetonitrile. [00055] In another embodiment of the present invention, the HMBP is solid or isolated.
- the HMBP is substantially pure. Purity may be at least 50% chemically pure, preferably at least 70% chemically pure, more preferably at least 90% chemically pure and most preferably at least 95% chemically pure.
- the HMBP can then be converted into CMBP.
- the HMBP is converted by a process comprising: providing a second mixture of HMBP and POCl 3 ; heating the mixture to obtain a reaction residue; combining the reaction residue with ammonium hydroxide to obtain a two phase system having an aqueous and an organic phase, and recovering crude CMBP from the organic phase.
- the mixture is heated to a temperature of greater than 90°C.
- the POCl 3 used is distilled.
- the reaction residue is cooled.
- the crude CMBP is further extracted with toluene. More preferably, extractions are performed with toluene at a temperature of about 9O 0 C.
- CMHTP solid 3-(2- chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[ 1 ,2-a]- pyrimidin-4- one
- This solid CMHTP can be in crystalline form.
- crystalline CMHTP Form I is presented characterized as having PXRD peaks at about 9.7, 19.4, 22.9 and 24.9 +/- 0.2 degrees 2 ⁇ . Additional PXRD peaks may additionally be present at one or more of the following positions: about 22.0, 27.4, 28.1 and 39.4 +/- 0.2 degrees 2 ⁇ .
- the PXRD pattern of CMHTP Form I can be substantially as the PXRD shown in Figure 1.
- the CMHTP Form I has a polymorphic purity of at least about 50%, preferably at least about 90%, more preferably at least about 95% and most preferably at least about 99%.
- solid CMHTP Form II is presented, having characteristic PXRD peaks at about: 8.5, 11.2, 15.3, 23.8 +/- 0.2 two theta.
- the characteristic PXRD pattern of CMHTP Form II also includes one or more additional peaks of the following: about 17.0, 22.6, 25.6 and 29.7 +/- 0.2 degrees 2 ⁇ .
- the PXRD pattern of CMHTP form II can be substantially as the PXRD pattern shown in Figure 2.
- the CMHTP Form II has a polymorphic purity of at least about 50%, preferably at least about 90%, and more preferably at least about 95% and most preferably at least about 99%.
- the CMHTP described above is converted into paliperidone.
- the present invention provides a process for preparing 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l, 2- a]- pyrimidin-4-one (CMHTP) from CMBP comprising via hydrogenation using hydrogen, preferably hyperbaric hydrogen, more preferably hydrogen at about 1.5 bar to about 3.5 bar, most preferably hydrogen at 2.5 bar to 3.0 bar, with a catalyst selected from the group of: 10% Pd/C, Pd/C/338, Pd/C/871 , Pd/C/490, Raney-Nickel, platinum oxide, rhodium on carbon and platinum on carbon to form CMHTP, followed by recovery or isolation of the CMHTP formed.
- phosphorus is at least partially removed from the CMBP.
- the present invention provides a process for preparing 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[ 1 ,2- a]- pyrimidin-4-one (CMHTP) from CMBP comprising removing the benzyl protection from CMBP to produce 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H- pyrido[l,2-a]pyrimidine-4-one (CMHP) and further hydrogenating the condensed pyridine ring in the CMHP using hydrogen with a hydrogenation catalyst to form CMHTP and then recovering the CMHTP.
- CMHTP 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[ 1 ,2- a]- pyrimidin-4-one
- CMHP 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H- pyrido[l
- the hydrogenation catalyst can be selected from the group of: 10% Pd/C, Pd/C/338, Pd/C/871 , Pd/C/490, Raney-Nickel, platinum oxide, rhodium on carbon and platinum on carbon.
- the hydrogen used is preferably hyperbaric hydrogen, more preferably hydrogen at about 1.5 bar to about 3.5 bar, most preferably hydrogen at 2.5 bar to 3.0 bar.
- phosphorus is at least partially removed from the CMBP, and/or before the CMHP is hydrogenated in the process, phosphorus is at least partially removed from the CMHP.
- the CMHP may be produced by removing the benzyl protection from HMBP during the chlorination.
- the process for preparing CMHTP can be conducted as described in the following scheme, wherein optionally phosphorus is at least partially removed from the CMBP before the benzyl group is removed from the CMBP and/or phosphorus is at least partially removed from the CMHP after the CMHP is formed and before the hydrogenation of the CMHP to obtain CMHTP at high yield:
- the present invention provides 3-(2-chloroethyl)-
- CMHP 2-methyl-9-hydroxy-4H-pyrido[l ,2-a]pyrimidine-4-one
- a process for preparing CMHTP comprising: providing a mixture of CMBP, HCl and a catalyst such as palladium on charcoal in a solvent such as methanol; treating with hydrogen; and removal of the solvent to obtain CMHTP.
- a catalyst such as palladium on charcoal
- a solvent such as methanol
- phosphorus is at least partially removed from the CMBP.
- the HCl is combined with a solution of CMBP and methanol, and the mixture is then combined with the catalyst.
- the catalyst can be any hydrogenation catalyst known to a skilled artisan including: 10% Pd/C, 10%Pd/C/338, 10%Pd/C/87L, 10%Pd/C/490, Ra-Ni5, 5%Rh/C/592, PtO, 5%Pt/C/117. Most preferably, the catalyst is 10%Pd/C/338.
- the mixture is heated to a temperature of about 65 °C.
- the mixture is cooled to about 20°C.
- the solvent is removed by evaporation, more preferably, under reduced pressure.
- the process may further comprise neutralizing the obtained CMHTP
- CMHTP may then be recovered by any method known in the art.
- the present invention provides CMHTP with less than 10%, preferably less than 5%, more preferably less than 4% and most preferably less than 0.5% of MHDP based on area percent as measured by HPLC.
- the present invention also provides substantially pure CMHTP having less than 17%, preferably less than 13%, more preferably less than 6% and most preferably less than
- the intermediate CMHP can also be obtained directly from HMBP.
- phosphorus is at least partially removed from the CMHP obtained.
- the process for preparing CMHP comprises reacting a mixture of HMBP and POCl 3 to form a reaction residue; combining the reaction residue with a solution of methanol and toluene to obtain a precipitate of crude CMHP, and recovering the crude CMHP.
- phosphorus is at least partially removed from the CMHP obtained.
- the mixture of HMBP and POCl 3 is heated to obtain the reaction residue.
- the mixture of HMBP and POCl 3 is heated to about 70°C to about reflux.
- reaction residue is maintained at a temperature of about 60°C.
- the crude CMHP is recovered by any method known to the skilled in the art. Such methods include, but are not limited to, washing with toluene and further drying the obtained CMHP.
- the present invention provides a process for preparing paliperidone by coupling CMHTP with 6-fluoro-3-piperidino-l,2- benisoxazol (FPBI).
- FPBI 6-fluoro-3-piperidino-l,2- benisoxazol
- the CMHTP is subsequently used to prepare paliperidone.
- the general process for conversion of CMHTP to paliperidone is known in the art, the present invention provides a novel method of converting CMHTP to paliperidone using a recovered or isolated form of CMHTP (e.g., solid such as amorphous or, preferably, crystalline form of CMHTP) as the starting material which differs from the oily or liquid CMHTP residue used as the starting material without isolation in prior art processes for the preparation of paliperidone.
- CMHTP e.g., solid such as amorphous or, preferably, crystalline form of CMHTP
- the liquid or oily CMHTP residue used as the starting material in prior art processes is replaced with an isolated form of CMHTP (e.g., solid such as amorphous or preferably crystalline, form of CMHTP) as the starting material.
- an isolated form of CMHTP e.g., solid such as amorphous or preferably crystalline, form of CMHTP
- the present invention provides an embodiment of a process for converting CMHTP to paliperidone, wherein a mixture of CMHTP which is isolated,e.g., in a solid such as amorphous or preferably crystalline form, FPBI, sodium carbonate, potassium iodide and dimethylformamide (DMF) is heated to a temperature of about 90° C, then combined with water and extracted with dichloromethane (DCM) to obtain crude paliperidone.
- a mixture of CMHTP which is isolated,e.g., in a solid such as amorphous or preferably crystalline form, FPBI, sodium carbonate, potassium iodide and dimethylformamide (DMF) is heated to a temperature of about 90° C, then combined with water and extracted with dichloromethane (DCM) to obtain crude paliperidone.
- DCM dichloromethane
- Both CMHTP and FPBI starting materials can be in the form of a base or hydrogen halide salts.
- the FPBI starting material is commercially available.
- the crude paliperidone is purified, for example, by recrystallization such as recrystallization from acetonitrile.
- the present invention provides recovered or substantially isolated CMHTP, e.g., in a solid form such as amorphous or preferably crystalline form.
- the present invention provides processes for the preparation of paliperidone by converting substantially isolated or solid CMHTP to paliperidone. [00082] In an ambodiment, the present invention also provides recovered or substantially isolated HMBP in a solid form such as amorphous or preferably crystalline form.
- the present invention provides processes for the preparation of paliperidone by using substantially isolated or solid HMBP as an intermediate.
- the processes can use substantially isolated or solid HMBP and substantially isolated or solid CMHTP as intermediates in different steps of the processes.
- the present invention also provides sequential combination of a number of the reaction steps disclosed herein.
- the present invention includes a process for preparing
- CMBP comprising performing the process for preparing BOPA described above followed by performing the process for preparing CMBP described above using the
- BOPA prepared.
- phosphorus is at least partially removed from the CMBP obtained.
- the present invention includes a process for preparing
- CMHTP comprising performing the process for preparing BOPA described above, followed by performing the process for preparing CMBP described above, and followed by converting the CMBP to CMHTP according to the process described above.
- phosphorus is at least partially removed from the CMBP before its conversion to CMHTP.
- the present invention includes a process for preparing 9- hydroxy risperidone, comprising performing the process for preparing BOPA described above, followed by performing the process for preparing CMBP described above, followed by converting the CMBP to CMHTP according to the process described above, and followed by performing the process for preparing 9-hydroxy risperidone using the CMHTP according to the process described above.
- phosphorus is at least partially removed from the CMBP before its conversion to
- the present invention includes a process for preparing paliperidone, comprising performing a process for preparing CMHTP as described above, followed by performing the process for preparing paliperidone using the CMHTP according to the process described above, wherein the process for preparing CMHTP can start with CMHTP HCl or CMBP.
- the present invention includes a process for preparing paliperidone, comprising performing a process for preparing CMBP as described above, followed by converting the CMBP to CMHTP according to the process described above, and followed by performing the process for preparing paliperidone using the CMHTP according to the process described above, wherein the process for preparing the CMBP can start with HMBP or BOPA.
- the process for preparing the CMBP can start with HMBP or BOPA.
- phosphorus is at least partially removed from the CMBP before its conversion to CMHTP.
- the present invention includes a process for preparing a process for preparing CMBP as described above, followed by converting the CMBP to CMHTP according to the process described above, and followed by performing the process for preparing paliperidone using the CMHTP according to the process described above, wherein the process for preparing the CMBP can start with HMBP or BOPA.
- phosphorus is at least partially removed from the CMBP before its conversion to CMH
- CMHTP comprising performing the process for preparing CMBP described above, followed by converting the CMBP to CMHTP according to the process described above, wherein the preparation of CMBP can start with HMBP or BOPA.
- phosphorus is at least partially removed from the CMBP before its conversion to CMHTP.
- Example 1 NaOH (40.04 g, 1 mol) was dissolved in water (60 ml) and covered with DCM (100 ml). AHP (20.04 g, 0.178 mol) was added to the reaction mixture in portions, under stirring, followed by the catalyst, TBAB (1.05 g). The reaction mixture was stirred for 15 min at 25-30°C and treated with a solution of benzyl bromide (33.90 g, 0.194 mol) in DCM (80 ml). The reaction mixture was stirred overnight at 20°C and diluted with water (100 ml). The organic phase was separated, and the aqueous phase was extracted with DCM (100 ml).
- Example 2 A mixture of BOPA (28.22 g, 0.131 mol), ADHF (34.3 g,
- the organic phase was separated, the aqueous phase was extracted with DCM (3x200 ml), and discarded.
- the organic extracts were combined, washed with water (4x200 ml), dried with anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to afford 14.4 g crude product as a solidifying oil.
- the residue was extracted with hot toluene (90°C, 150 and 50 ml).
- the toluene extracts were combined and concentrated to '/--volume, to cause crystallization.
- the residue was filtered off, washed with cold toluene and dried at 45°C under reduced pressure to afford 7.34 g of the title product, as a pink solid. Additional amounts of the title product (1.92 and 1.0 g) were isolated from the filtrate by repeat crystallization. Total yield 68%, purity 94%.
- Example 5 Diglyme (bis(2-methoxyethyl) ether) (420 ml), wet 3-(2- hydroxyethyl)-2-methyl-9-benzyloxy-4H-pyrido[ 1 ,2-a]-pyrimidine-4-one (HMBP, 351.2 g, assay 90%), and POCl 3 (351.5 g) were charged into a reactor, under inert atmosphere. The reaction suspension was heated to 90°C, under stirring, to afford a clear solution. The solution was stirred for 4.5 h at 90-92°C until the level of HMBP reduced to ⁇ 0.5%.
- reaction mixture was diluted with toluene (850 ml) allowing the mixture to cool to 40-50°C. Water (800 ml) was carefully fed to the reaction mixture for 15 min, maintaining the temperature below 71°C.
- the stirrer was stopped to afford two clear phases.
- the lower aqueous phase (1539 g, colored liquid, pH 7) was separated and discarded.
- the hot organic phase was washed twice with hot ( ⁇ 50°C) water (205 and 200 ml) at 65-70°C.
- Lower aqueous phases (205.3 g and 216 g, respectively) were separated and discarded.
- the mixture was cooled to 5°C for 1.7 h.
- the crystallization started at 46°C.
- the crystalline mixture was aged overnight at 5°C and filtered.
- the cake was washed with cold toluene (50 ml) to afford 371.0 g of the wet crystalline product.
- the wet product was dried for 2 h at 75-80°C to afford 289 g of the dry CMBP, as lilac powder. Purity 99.8% (HPLC). Yield 85%.
- Example 6 A mixture of 3-(2-hydroxyethyl)-2-methyl-9-benzyloxy-4H-pyrido[l,2- a]-pyrimidine-4-one (HMBP, 60.25 g) and POCl 3 (87.29 g) was charged into a 0.5 L reactor. The reaction mixture was brought to reflux ( ⁇ 100-105°C) and stirred for 1.5 h, until the level of the substrate reduced to ⁇ 0.5%. The remaining POCl 3 (33.11 g) was distilled off and the hot residue was dissolved with N,N-dimethylformamide [DMF] (84 ml) at 100°C.
- DMF N,N-dimethylformamide
- Example 7 To a solution of 3-(2-hydroxyethyl)-2-methyl-9-hydroxy-4H-pyrido[l,2- a]pyrimidine-4-one (45.08 g) in N,N-dimethylformamide (DMF) (68 ml) POCl 3 (72.92 g) was fed, maintaining the temperature below 100°C. The resulting viscous liquid was aged for 2 h and cooled to 30°C, under stirring
- the water ( ⁇ 20 ml) was fed for 1 min to the cold reaction mixture to afford the precipitation. The temperature rose to 105°C to afford clear solution. The feeding was stopped to allow the mixture to cool to 65 0 C. The remaining water (100 ml, total 120 ml) was added for 3 min, followed by a 25% NH 4 OH (134 ml) to adjust pH 7. New precipitation occurred. The mixture was cooled for 0.5 h to 10°C and aged for 1 h, under stirring, to complete the precipitation. The crystalline mass was filtered and the cake was washed with water (2 x 100 ml) to afford 55.38 g of the wet product which was dried overnight at 75-80 0 C to afford 30.5 g of dry CMHP. Yield 71%.
- Example 8 Diglyme (80 ml), 3-(2-hydroxyethyl)-2-methyl-9-hydroxy-4H-pyrido[l,2- a]-pyrimidine-4-one (50.74 g), and POCl 3 (75.35 g) were charged into reactor. The reaction mixture was heated to 80-82°C, under stirring. The mixture was converted at 60°C to a heavy paste which was finally transformed into a clear viscous liquid. The mixture was stirred for 4 h at 80-82°C and cooled to 30 0 C. The mixture was carefully quenched with water (120 ml), maintaining the temperature below 85°C. Precipitation occurred.
- the reaction suspension was treated with a 25% NH 4 OH (115 ml) for 20 min to adjust pH 7, maintaining the temperature below 65°C (cooling agent 30 0 C).
- the mixture was cooled to room temperature (20-25 0 C), under stirring, and aged for 1 h to complete the precipitation.
- the crystalline mass was filtered and the cake was washed with water (2 x 100 ml) to afford 51.70 g of the wet product, which was dried overnight at 75-80 0 C, under reduced pressure to afford 29.0 g of the dry CMHP. Yield 62%.
- Example 9 Mixture of 3-(2-hydroxyethyl)-2-methyl-9-benzyloxy-4H-pyrido[l ,2-a]- pyrimidine-4-one (HMBP, 5.03 g) in POCl 3 (2.45 ml) was heated to 91-95°C, under stirring, to afford a clear solution. The mixture converted to heavy paste at the end of the reaction. The mixture was heated to 60 0 C and treated with a solution of methanol (10 ml) and toluene (25 ml) to afford the precipitation of the product. The cake was washed with toluene (3 ml) to afford 2.43 g of wet product, which was dried in air for 3 days to afford 1.69 g of the crystalline CMHP. Yield 46%.
- Example 10 A mixture of CMBP (10.3 g, 0.031 mol) in methanol (100 ml) was treated with 32% HCl (4.3 g, 0.0376 mol) in an autoclave.
- the catalyst (10% Pd/C, 0.52 g) was added, the mixture was flushed twice with nitrogen, then hydrogen, finally filled with hydrogen to a pressure of 5 bar, heated to 65°C and stirred over a 6 h period.
- the mixture was cooled to 20 0 C, the hydrogen was replaced with nitrogen and the mixture was filtered.
- the residue of the catalyst was washed with a little methanol.
- the filtrates were combined and evaporated under reduced pressure to afford 12.11 g of the product, as a crystallizing oil.
- the product was mixed with water (50 ml) and extracted with ethyl acetate (50 ml). The aqueous phase was neutralized with 10% NaHCO 3 solution (50 ml) and the organic products were extracted with DCM (5 x 25 ml). The extracts were washed with 10% NaHCO 3 (2 x 25 ml), followed by water (2 x 50 ml), dried overnight over anhydrous magnesium sulfate, filtered and evaporated, to afford 5.80 g of the crude CMHTP product.
- Example IQA Crystallization from ethyl acetate (25 ml) afforded 3.16 g of the title product. Additional amounts of the title product (total 1.35 g) were isolated from the filtrate by repeat crystallization from ethyl acetate to obtain CMHTP Form I having characterizing PXRD peaks at about 9.7, 19.4, 22.9 and 24.9 +/- 0.2 degrees 2 ⁇ and one or more additional PXRD peaks at about 22.0, 27.4, 28.1 and 39.4 +/- 0.2 degrees 2 ⁇ . The total yield of the CMHTP Form I product, in a purity of >93%, was 4.51 g (60%).
- Example IQB A slurry of CMHTP Form I (2Og) in 100ml water was stirred at room temperature for 10 minutes. The solid was vacuum filtrated and washed with water (3x60ml), ethyl acetate (60ml) and dried overnight in a vacuum oven at 55°C. The solid was analyzed by XRD to give CMHTP Form II (Figure 2) characterized by PXRD diffraction peaks at about: 8.5, 11.2, 15.3, 23.8 +/- 0.2 two theta. Preferably, this form also includes one or more additional PXRD peaks of the following: 17.0, 22.6, 25.6 and 29.7 +/- 0.2 two theta.
- Example 11 A suspension of 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[l,2- a]pyrimidine-4-one (CMBP, 5.00 g) in methanol (30 ml) was treated with 32% HCl (1.72 g) to afford clear solution with pH 2. The solution was charged into a glass autoclave. The 10% Pd/C (50% wet) catalyst (0.12 g) was added. The mixture was heated to 48°C and hydrogenated under hydrogen pressure of 3 bar over a 7.5-h period, until the level of CMBP reduced to ⁇ 0.1%.
- CMBP 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[l,2- a]pyrimidine-4-one
- the reaction mixture was filtered and the used catalyst was washed with methanol (5 ml). The mother liquor and the washing were combined and charged into glass autoclave. Fresh 10% Pd/C (50% wet) catalyst (0.253 g) was added. The mixture was heated to 55°C and hydrogenated under hydrogen pressure of 3 bars over a 24-h period, until the level of CMHP reduced to 0.9%.
- the reaction mixture was filtered and the used catalyst was washed with methanol (5 ml). The mother liquor and the washing were combined to afford 17.05 g clear solution (pH 1). The solution was evaporated under reduced pressure to remove volatiles and the viscous residue was dissolved in water (5 ml, pH 1-1.5).
- the aqueous solution was treated with 10%NaHCO3 (13.2 g) to adjust pH 7-8.
- the aqueous solution was extracted twice with dichloromethane (2x25 ml) and discarded. Extracts were combined and evaporated to afford 2.8 g of the crude CMHTP product, as solidifying oil. Yield 70%, purity 90.5%.
- Example 12 A mixture of CMHTP (4.393 g, 0.0168 mol), 6-fluoro-3-piperidino-l,2- benzisoxazol (FPBI, 4.695 g, 0.0203 mol), sodium carbonate (4.968 g, 0.0422 mol) and potassium iodide (0.288 g, 0.0017 mol) in DMF (50 ml) was heated for 8 h at 85°C. The mixture was poured into water (500 ml) and extracted with DCM (4 x 100 ml). The extracts were combined, washed with water (4 x 100 ml), dried with anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to afford the crude title product. Crystallization from acetonitrile (100 ml) afforded 4.63 g of the title product, in a purity of >90%. Yield 58%.
- FPBI 6-fluoro-3-piperidino-l,2- benzisoxazol
- 1 CC stands for the catalyst concentration regarding to the substrate, % w/w.
- 5 ND represents not detected even though the level of the compound was analyzed.
- Example 13 A one liter reactor equipped with a mechanical stirrer and a reflux condenser was charged with 41 g CMBP (containing 345 ppm phosphorus) and 600 ml toluene. The mixture was heated to reflux. Five grams of activated charcoal were added to the hot solution, and the resulting mixture was hot filtrated, and cooled to room temperature. The resulting solid was filtered, and dried in a vacuum oven at 50 0C under reduced pressure to give 24 g of CMBP containing 5 ppm of phosphorus.
- CMBP containing 345 ppm phosphorus
- CMBP containing 345 ppm phosphorus
- 800 ml toluene 80 g CMBP (containing 345 ppm phosphorus) and 800 ml toluene.
- the mixture was heated to 70 °C and washed 4 times with water (200 ml each time).
- Eight grams of activated charcoal were added to the hot solution, and the resulting mixture was hot filtrated, and cooled to room temperature.
- the resulting solid was filtered, and dried in a vacuum oven at 50 0 C under reduced pressure to give 68 g of CMBP containing less than 5 ppm of phosphorus.
- CMBP 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[ 1 ,2- a]pyrimidine-4-one
- 32% HCl 20 ml
- the solution was charged into a glass autoclave.
- the 10% Pd/C (50% wet) catalyst (0.6 g) was added.
- the mixture was heated to 50 °C and hydrogenated under hydrogen pressure of 2 bar over a 2-h period, until the level of CMBP reduced to ⁇ 0.1%.
- the reaction mixture was filtered and the used catalyst was washed with methanol. The mother liquor and the washing were combined.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides processes of preparing 3-(2-chloroethyl)- 6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[ 1,2-a]- pyrimidin-4-one (CMHTP) useful as intermediates for the preparation of paliperidone, wherein the processes use 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[ 1,2-a]pyrimidine-4- one (CMBP) and/or 3-(2-chloroethyl)-2-methyl-9-hydoxy-4H-pyrido[l,2- a]pyrimidine-4-one (CMHP) having phosphorus at least partially removed as the intermediate.
Description
PROCESS FOR THE SYNTHESIS OF CMHTP AND INTERMEDIATES
THEREOF
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This patent application claims the benefits of U.S. Non-Provisional
Application No. 11/892,532 filed August 23, 2007, and U.S. Provisional Application Nos. 60/963,019 filed on August 1, 2007, 60/928,745 filed May 10, 2007 and 60/935,093 filed July 26, 2007, wherein the disclosures of all of these prior filed applications are hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The invention concerns processes for reducing or removing phosphorus contaminants in CMBP or CMHP, which is useful in processes for the synthesis of CMHTP, an intermediate in the synthesis of Paliperidone.
BACKGROUND OF THE INVENTION
[0003] Paliperidone, 3-[2-[4-(6-fluorobenzo[d]isoxazol-3-yl)-l- piperidyl]ethyl]-7-hydroxy-4-methyl-l ,5-diazabicyclo[4.4.0]deca-3,5-dien-2-one, is a 5 -HT antagonist belonging to the chemical class of benzisoxazole derivatives and a racemic mixture having the following structural formula:
Paliperidone
[0004] Paliperidone is a metabolite of Risperidone. Marketed under the name,
Invega®, Paliperidone is a psychotropic agent approved in the United States for the treatment of schizophrenia.
[0005] A process for the synthesis of Paliperidone, is described in U.S. Patent
[0006] The preparation of paliperidone via the intermediate 3-(2-chloroethyl)-
6,7,8,9-tetrahydro-9-hydroxy-2 -methyl -4H-pyrrido[ 1 ,2-a]- pyrimidin-4-one (CMHTP) is depicted in the last step of the above scheme. This process is performed in the presence of an organic base. U.S. Patent 5,158,952 discloses the hydrogenation of 3.3 parts of 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[l,2-a]pyrimidine- 4-one (CMBP) in 120 parts of methanol with hydrogen at normal pressure and room temperature and 2 parts of 10% palladium-on-carbon catalyst to form 3-(2- chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4- one (CMHTP).
[0007] Process for the synthesis of intermediates of Paliperidone is described also in U.S. Patent No. 5,688,799.
[0008] The processes described in the above publications are long, and result in low chemical yields, making their application in the industry very hard. There is a need in the art for a new process for preparing Paliperidone and its intermediates.
SUMMARY OF THE INVENTION
One of the embodiments of the invention provides a process for preparing 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[ 1 ,2- a]- pyrimidin-4-one (CMHTP), comprising:
(A) removing the benzyl group from 3-(2-chloroethyl)-2-methyl-9-benzyloxy- 4H-pyrido[l,2-a]pyrimidine-4-one (CMBP) to form 3-(2-chloroethyl)-2-methyl-9- hydoxy-4H-pyrido[l,2-a]pyrimidine-4-one (CMHP), wherein optionally phosphorus is at least partially removed from the CMBP before the benzyl group is removed from the CMBP and/or phosphorus is at least partially removed from the CMHP after the CMHP is formed;
(B) reacting the product of step (A) with hydrogen and a hydrogenation catalyst to form CMHTP; and
(C) recovering or isolating the CMHTP.
[00010] Another embodiment of the invention provides a process for preparing
CMHTP, comprising:
(a) mixing 3-(2-hydroxyethyl)-2-methyl-9-benzyloxy-4H-pyrido[l,2- a]pyrimidine-4-one (HMBP) and POCl3 to form a reaction residue;
(b) combining the reaction residue with methanol and toluene to obtain a precipitate of 3-(2-chloroethyl)-2-methyl-9-hydoxy-4H-pyrido[l,2-a]pyrimidine-4- one (CMHP), wherein optionally phosphorus is at least partially removed from the CMHP after the CMHP is formed;
(c) reacting the product of step (b) with hydrogen and a hydrogenation catalyst to form CMHTP; and
(d) recovering or isolating the CMHTP.
[00011 ] An embodiment of the invention provides a process for preparing 3-(2- chloroethyl)-2-methyl-9-hydoxy-4H-pyrido[ 1 ,2-a]pyrimidine-4-one (CMHP), comprising:
(a) mixing 3-(2-hydroxyethyl)-2-methyl-9-benzyloxy-4H-pyrido[l,2- a]pyrimidine-4-one (HMBP) and POCl3 to form a reaction residue;
(b) combining the reaction residue with methanol and toluene to obtain a precipitate of CMHP, wherein optionally phosphorus is at least partially removed from the CMHP after the CMHP is formed; and
(c) recovering or isolating the CMHP.
[00012] One of the embodiments of the invention provides a process for preparing 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[ 1 ,2-a]pyrimidine-4-one (CMBP), comprising:
(I) mixing 3-(2-hydroxyethyl)-6,7,8,9-tetrahydro-9-benzyloxy-2-methyl-4H- pyπϊdo[l,2-a]- pyrimidin-4-one (HMBP) and POCl3 to form a mixture;
(II) heating the mixture from step (I) to obtain a reaction residue;
(III) combining the reaction residue with ammonium hydroxide to obtain a two phase system; and
(IV) recovering or isolating 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H- pyrido[l,2-a]pyrimidine-4-one (CMBP) from the organic phase of the two phase system of step (III).
[00013] The present invention also provides a process for preparing 3-(2- chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[ 1 ,2-a]pyrimidine-4-one (CMBP), comprising:
(A) mixing 3-benzyloxy-2-aminopyridine (BOPA), 3-acetyl-4,5-dihydro-3H- 2-furanone (ADHF), at least one water absorbent and at least one aromatic solvent to form a mixture;
(B) heating the mixture formed in step (A) to obtain 3-(2-hydroxyethyl)- 6,7,8,9-tetrahydro-9-benzyloxy-2-methyl-4H-pyrrido[ 1 ,2-a]- pyrimidin-4-one (HMBP);
(C) recovering or isolating the HMBP; and
(D) reacting the HMBP with a chlorinating agent to form the CMBP, wherein optionally phosphorus is at least partially removed from the CMBP after the CMBP is formed, and then optionally the CMBP is recovered or isolated.
[00014] The present invention also provides a process for preparing 3-(2- chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[ 1 ,2-a]pyrimidine-4-one (CMBP), comprising:
(A) providing 3-(2-hydroxyethyl)-6,7,8,9-tetrahydro-9-benzyloxy-2-methyl- 4H-pyrrido[l,2-a]- pyrimidin-4-one (HMBP); and
(B) reacting the HMBP with a chlorinating agent to form the CMBP, wherein optionally phosphorus is at least partially removed from the CMBP after the CMBP is formed, , and then optionally the CMBP is recovered or isolated, and wherein an example of the chlorinating agent is POCl3.
[00015] The present invention also provides a process for preparing 3-(2- hydroxyethyl)-6,7,8,9-tetrahydro-9-benzyloxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one (HMBP), comprising:
(A) mixing 3-benzyloxy-2-aminopyridine (BOPA), 3-acetyl-4,5-dihydro-3H- 2-furanone (ADHF), at least one water absorbent and at least one aromatic solvent to form a mixture;
(B) heating the mixture formed in step (A) to obtain 3-(2-hydroxyethyl)- 6,7,8,9-tetrahydro-9-benzyloxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one (HMBP); and
(C) recovering or isolating the HMBP.
[00016] One of the embodiments of the invention provides a process for preparing 3-benzyloxy-2-aminopyridine (BOPA), comprising: alkylating 2-amino-3-hydroxypyridine (HAP) with benzyl bromide in the presence of a base to form 3-benzyloxy-2-aminopyridine (BOPA); and recovering or isolating the BOPA.
[00017] hi some of the embodiments of the present invention, two or more of the above processes of the invention are combined sequentially. [00018] The present invention also provides processes for preparing paliperidone by converting recovered or substantially isolated CMHTP prepared by any of the processes for preparing CMHTP of the invention into paliperidone. These processes may be combined with other processes of the invention for preparing one or. more of the intermediates.
[00019] The present invention also provides processes for preparing paliperidone by converting CMHTP into paliperidone, wherein the conversion is preceded, albeit not immediately, by a step using recovered or substantially isolated HMBP. These processes may be combined with other processes of the invention for preparing the HMBP or another intermediate preceding the formation of HMBP. [00020] The present invention also provides processes for preparing paliperidone by converting CMHTP into paliperidone, wherein the conversion is preceded, albeit not immediately, by a step reacting HAP with benzyl bromide to prepare BOPA as one of the intermediates.
[00021] The present invention also provides processes for preparing paliperidone by combining two or more processes of the present invention in an appropriate sequential order.
[00022] One of the embodiments of the invention provides a process for preparing paliperidone, comprising:
(A) removing the benzyl group from 3-(2-chloroethyl)-2-methyl-9-benzyloxy- 4H-pyrido[l,2-a]pyrimidine-4-one (CMBP) to form 3-(2-chloroethyl)-2-methyl-9- hydoxy-4H-pyrido[l,2-a]pyrimidine-4-one (CMHP), wherein optionally phosphorus is at least partially removed from the CMBP before the benzyl group is removed from
the CMBP and/or phosphorus is at least partially removed from the CMHP after the CMHP is formed;
(B) reacting the product of step (A) with hydrogen and a hydrogenation catalyst to form 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l,2-a]- pyrimidin-4-one (CMHTP);
(C) recovering or isolating the CMHTP; and
(D) condensing the recovered or isolated CMHTP with 6-fluoro-3-piperidino- 1,2-benisoxazol (FPBI) to form paliperidone.
[00023] In an embodiment, the present invention provides a process for preparing paliperidone, comprising:
(a) mixing 3-(2-hydroxyethyl)-2-methyl-9-benzyloxy-4H-pyrido[l,2- a]pyrimidine-4-one (HMBP) and POCl3 to form a reaction residue;
(b) combining the reaction residue with methanol and toluene to obtain a precipitate of 3-(2-chloroethyl)-2-methyl-9-hydoxy-4H-pyrido[ 1 ,2-a]pyrimidine-4- one (CMHP), wherein optionally phosphorus is at least partially removed from the CMHP after the CMHP is formed;
(c) reacting the product of step (b) with hydrogen and a hydrogenation catalyst to form 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[ 1 ,2-a]- pyrimidin-4-one (CMHTP);
(d) recovering or isolating the CMHTP; and
(e) condensing the recovered or isolated CMHTP with 6-fluoro-3-piperidino- 1,2-benisoxazol (FPBI) to form paliperidone.
[00024] In an embodiment, the present invention provides a process of preparing paliperidone, comprising: condensing recovered or substantially isolated 3-(2-chloroethyl)-6,7,8,9- tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one (CMHTP) with 6-fiuoro-3-piperidino-l,2-benisoxazol (FPBI) to form paliperidone. [00025] The present invention also provides recovered or substantially isolated
CMHTP, and processes of using the recovered or substantially isolated CMHTP to form paliperidone.
[00026] The present invention also provides crystalline 3-(2-chloroethyl)-
6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one (CMHTP) characterized by powder X-ray diffraction (PXRD) peaks at about 9.7, 19.4, 22.9 and 24.9 +/- 0.2 degrees 2Θ.
[00027] The present invention also provides crystalline 3-(2-chloroethyl)-
6,7,8, 9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[ 1 ,2-a]- pyrimidin-4-one (CMHTP) characterized by powder X-ray diffraction (PXRD) peaks at about 8.5, 11.2, 15.3, 23.8 +/- 0.2 degrees 20.
[00028] In an embodiment, the present invention provides a process for preparing crystalline 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l,2-a]- pyrimidin-4-one (CMHTP), characterized by powder X-ray diffraction (PXRD) peaks at about 9.7, 19.4, 22.9 and 24.9 +/- 0.2 degrees 2Θ, comprising crystallizing CMHTP from ethyl acetate.
[00029] In an embodiment, the present invention provides a process for preparing crystalline 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l,2-a]- pyrimidin-4-one (CMHTP), characterized by powder X-ray diffraction (PXRD) peaks at about 8.5, 11.2, 15.3, 23.8 +/- 0.2 degrees 2Θ, comprising: stirring starting solid CMHTP in water to form the product CMHTP characterized by powder X-ray diffraction (PXRD) peaks at about 8.5, 11.2, 15.3,
23.8 +/- 0.2 degrees 2Θ, wherein the starting solid CMHTP is crystalline 3-(2- chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4- one (CMHTP), characterized by powder X-ray diffraction (PXRD) peaks at about 9.7, 19.4, 22.9 and 24.9 +/- 0.2 degrees 2Θ.
[00030] Optionally, in the above process, after the starting solid CMHTP is stirred in water, a solid is obtained by filtration as the crystalline CMHTP characterized by powder X-ray diffraction (PXRD) peaks at about 9.7, 19.4, 22.9 and
24.9 +/- 0.2 degrees 2Θ. The solid obtained by filtration is further optionally washed with water, then washed with ethyl acetate and dried.
[00031 ] In an embodiment, the present invention provides 3-(2-chloroethyl)-2- methyl-9-hydoxy-4H-pyrido[l ,2-a]pyrimidine-4-one (CMHP).
[00032] The present invention also provides recovered or substantially isolated
CMHP.
[00033] The present invention also provides CMHP comprising less than 26 ppm phosphorus, which includes CMHP containing no phosphorus and CMHP containing phosphorus at less than 26 ppm.
[00034] The present invention also provides 3-(2-chloroethyl)-2-methyl-9- benzyloxy-4H-pyrido[l,2-a]pyrimidine-4-one (CMBP) comprising less than 26 ppm
phosphorus, which includes CMBP containing no phosphorus and CMBP containing phosphorus at less than 26 ppm.
[00035] In an embodiment, the present invention provides a process for at least partially removing phosphorus from CMBP, comprising: treating the starting CMBP containing phosphorus with activated charcoal to obtain the CMBP having no phosphorus or less phosphorus than the starting CMBP; and optionally recovering or isolating the CMBP having no phosphorus or less phosphorus than the starting CMBP, e.g., by removing the activated charcoal with filtration or centrifugation, followed by optional precipitation of the CMBP from the filtrate and recovering the CMBP precipitate by filtration or centrifugation. [00036] hi an embodiment, the present invention provides a process for at least partially removing phosphorus from CMHP, comprising: treating the starting CMHP containing phosphorus with activated charcoal to obtain the CMHP having no phosphorus or less phosphorus than the starting CMHP; and optionally recovering or isolating the CMHP having no phosphorus or less phosphorus than the starting CMHP, e.g., by removing the activated charcoal with filtration or centrifugation, followed by optional precipitation of the CMHP from the filtrate and recovering the CMHP precipitate by filtration or centrifugation. [00037] In an embodiment, the present invention provides a process for at least partially removing phosphorus from CMBP, comprising: mixing a solution of the starting CMBP containing phosphorus in an organic solvent with an aqueous solution OfNH4OH to obtain a CMBP precipitate having no phosphorus or less phosphorus than the starting CMBP, wherein the aqueous phase of the mixture preferably has a pH of about 7; and recovering or isolating the CMBP precipitate.
[00038] In an embodiment, the present invention provides a process for at least partially removing phosphorus from CMHP, comprising: mixing a solution of the starting CMHP containing phosphorus in an organic solvent with an aqueous solution OfNH4OH to obtain a CMHP precipitate having no phosphorus or less phosphorus than the starting CMHP, wherein the aqueous phase of the mixture preferably has a pH of about 7; and recovering or isolating the CMHP precipitate.
[00039] In an embodiment, the present invention provides 3-(2-hydroxyethyl)-
2-methyl-9-benzyloxy-4H-pyrido[ 1 ,2-a]pyrimidine-4-one (HMBP). [00040] In an embodiment, the present invention provides recovered or substantially isolated HMBP.
BRIEF DESCRIPTION OF THE DRAWINGS
[00041] Figure 1 illustrates a representative powder X-ray diffraction (PXRD) pattern for CMHTP Form I.
[00042] Figure 2 illustrates a representative powder X-ray diffraction pattern for CMHTP Form II.
DETAILED DESCRIPTION OF THE INVENTION
[00043] CMBP can be contaminated with phosphorus. As used herein, the expression "phosphorus is at least partially removed from the CMBP" means that part or all of the phosphorus is removed from the CMBP contaminated with phosphorus so that the CMBP product contains less than about 26 ppm, preferably less than about 20 ppm, more preferably less than about 15 ppm, further more preferably less than about 10 ppm, even more preferably about 5 ppm or less, and most preferably about 0 ppm, phosphorus, e.g., CMBP free of phosphorus. When the CMBP product having phosphorus at least partially removed is used as an intermediate in preparing CMHTP, the low phosphorus content of the CMBP or the absence of phosphorus in the CMBP results in a high CMHTP yield of at least about 83%, preferably at least about 90% and more preferably at least about 94%, when the CMBP is hydrogenated with about 1% (per weight of 10% Pd/C 50% wet), by weight (based on the weight of the entire reaction mixture, so that the entire reaction mixture is 100% by weight) of 10% palladium/carbon (50% wet) as a catalyst.
[00044] CMHP can be contaminated with phosphorus. As used herein, the expression "phosphorus is at least partially removed from the CMHP" means that part or all of the phosphorus is removed from the CMHP contaminated with phosphorus so that the CMHP product contains less than about 26 ppm, preferably less than about 20 ppm, more preferably less than about 15 ppm, further more preferably less than about 10 ppm, even more preferably about 5 ppm or less, and most preferably about 0 ppm, phosphorus, e.g., CMHP free of phosphorus. When the CMHP product having phosphorus at least partially removed is used as an intermediate in preparing CMHTP,
the low phosphorus content of the CMHP or the absence of phosphorus in the CMHP results in a high CMHTP yield of at least about 83%, preferably at least about 90% and more preferably at least about 94%, when the CMHP is hydrogenated with about
1% (per weight of 10% Pd/C 50% wet), by weight (wherein the weight of the entire reaction mixture is regarded as 100% by weight) of 10% palladium/carbon (50% wet) as a catalyst.
[00045] The present invention is based on a new synthetic route for obtaining
9-hydroxy risperidone (Paliperidone).
[00046] In one embodiment, the present invention provides a process for preparing 3-benzyloxy-2-aminopyridine (BOPA) using a benzyl bromide derivative.
[00047] In one example, the present invention provides a process for preparing
3-benzyloxy-2-aminopyridine (BOPA) via base-promoted alkylation of 2-amino-3- hydroxypyridine (HAP) with benzyl bromide.
[00048] For instance, this benzylation process can be conducted as described in the following scheme:
HAP BOPA
[00049] The starting material, HAP, is commercially available.
[00050] In one embodiment of the present invention of the process for preparing BOPA of the present invention, a mixture of HAP, benzyl bromide, sodium hydroxide, water, dichloromethane and tetrabutylammonium bromide is provided, then maintained at a temperature of about 20° C for about 12 hours to obtain a two phase system. The temperature and time will be dependant on many factors such as the choice of base used, the amount of starting material and the yield desired. The BOPA can them be recovered from the organic phase by any means known in the art. [00051 ] Preferably, HAP is first combined with a solution of sodium hydroxide, water and dichloromethane, and then tetrabutylammonium bromide is combined with the reaction mixture. Preferably, before combining with benzyl bromide, the reaction mixture is maintained for about 15 minutes. BOPA may be recovered from the organic phase by any method known in the art. [00052] The present invention also provides a process for preparing 3-(2- chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[ 1 ,2-a]pyrimidine-4-one (CMBP) by
condensation of BOPA with 3-acetyl-4,5-dihydro-3H-2-furanone (ADHF) to produce 3-(2-hydroxyethyl)-6,7,8,9-tetrahydro-9-benzyloxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one (HMBP) and further chlorinating HMBP to produce CMBP. For instance, the process can be conducted as described in the following scheme.
BOPA ADHF HMBP CMBP
[00053] In one embodiment of the present invention, a process is presented for preparing CMBP from BOPA and ADHF wherein the HMBP is recovered. In the process for this aspect of the invention, BOPA and ADHF are reacted to obtain HMBP, which is then recovered and optionally subsequently converted into CMBP. According to the process of this invention, the HMBP may be produces according to any method known in the art but is then recovered and preferably isolated. For example, HMBP may be prepared by a process comprising: providing a mixture of BOPA, ADHF and one or more water absorbents such as /?-toluenesulfonic acid (TsOH), H2SO4 or a water separator such as a Dean Stark water extraction system as well as one or more aromatic solvents such as xylene or toluene; heating to reflux to obtain crude HMBP. Preferably, the mixture is maintained at room temperature to reflux for about 12 hours to about 30 hours, although the time and temperature necessary are dependant on a number of factors including materials chosen and quantity. Preferably, while bringing the mixture to reflux, water is removed. More preferably, the water removal is done by using a water separator. Preferably, the crude HMBP is further crystallized from one or more polar, aprotic organic solvents such as methyl ether ketone, acetone, nitromethane, acetonitrile, N-methylpyrrolidone, dimethyl formamide or DMSO and preferably acetonitrile.
[00054] Recovery may be by crystallization. Crystallization may be caused by reducing the volume of the solvents and/or by cooling. In one example, the solvents present with the crude HMBP is reduced to induce crystallization. Subsequently, the HMBP may be recrystallized. Specifically, useful solvents in the crystallization process include: organic solvent for example: methyl ether ketone, acetone, nitromethane, acetonitrile, N-methylpyrrolidone, dimethyl formamide or DMSO and preferably acetonitrile.
[00055] In another embodiment of the present invention, the HMBP is solid or isolated.
[00056] In another embodiment of the present invention, the HMBP is substantially pure. Purity may be at least 50% chemically pure, preferably at least 70% chemically pure, more preferably at least 90% chemically pure and most preferably at least 95% chemically pure.
[00057] Once recovered, the HMBP can then be converted into CMBP. In one embodiment, the HMBP is converted by a process comprising: providing a second mixture of HMBP and POCl3; heating the mixture to obtain a reaction residue; combining the reaction residue with ammonium hydroxide to obtain a two phase system having an aqueous and an organic phase, and recovering crude CMBP from the organic phase. Preferably, the mixture is heated to a temperature of greater than 90°C. Preferably, the POCl3 used is distilled. Preferably, prior to combining with ammonium hydroxide, the reaction residue is cooled. Preferably, the crude CMBP is further extracted with toluene. More preferably, extractions are performed with toluene at a temperature of about 9O0C.
[00058] In another embodiment of the present invention solid 3-(2- chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[ 1 ,2-a]- pyrimidin-4- one (herein referred to as "CMHTP") in crystalline or amorpous form is presented. This solid CMHTP can be in crystalline form. In one example, crystalline CMHTP Form I is presented characterized as having PXRD peaks at about 9.7, 19.4, 22.9 and 24.9 +/- 0.2 degrees 2Θ. Additional PXRD peaks may additionally be present at one or more of the following positions: about 22.0, 27.4, 28.1 and 39.4 +/- 0.2 degrees 2Θ. The PXRD pattern of CMHTP Form I can be substantially as the PXRD shown in Figure 1.
[00059] In another embodiment of the invention, the CMHTP Form I has a polymorphic purity of at least about 50%, preferably at least about 90%, more preferably at least about 95% and most preferably at least about 99%. [00060] In another embodiment of the invention, solid CMHTP Form II is presented, having characteristic PXRD peaks at about: 8.5, 11.2, 15.3, 23.8 +/- 0.2 two theta. Preferably, the characteristic PXRD pattern of CMHTP Form II also includes one or more additional peaks of the following: about 17.0, 22.6, 25.6 and 29.7 +/- 0.2 degrees 2Θ. The PXRD pattern of CMHTP form II can be substantially as the PXRD pattern shown in Figure 2.
[00061] In another embodiment of the invention, the CMHTP Form II has a polymorphic purity of at least about 50%, preferably at least about 90%, and more preferably at least about 95% and most preferably at least about 99%. [00062] The powder X-ray diffraction patterns disclosed in this patent application were collected using an X-ray diffractometer with Cu radiation at λ = 1.5418 A.
[00063] In another embodiment of the present invention, the CMHTP described above is converted into paliperidone.
[00064] In another embodiment, the present invention provides a process for preparing 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l, 2- a]- pyrimidin-4-one (CMHTP) from CMBP comprising via hydrogenation using hydrogen, preferably hyperbaric hydrogen, more preferably hydrogen at about 1.5 bar to about 3.5 bar, most preferably hydrogen at 2.5 bar to 3.0 bar, with a catalyst selected from the group of: 10% Pd/C, Pd/C/338, Pd/C/871 , Pd/C/490, Raney-Nickel, platinum oxide, rhodium on carbon and platinum on carbon to form CMHTP, followed by recovery or isolation of the CMHTP formed. Preferably, before the CMBP is used in the process, phosphorus is at least partially removed from the CMBP.
[00065] In another embodiment, the present invention provides a process for preparing 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[ 1 ,2- a]- pyrimidin-4-one (CMHTP) from CMBP comprising removing the benzyl protection from CMBP to produce 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H- pyrido[l,2-a]pyrimidine-4-one (CMHP) and further hydrogenating the condensed pyridine ring in the CMHP using hydrogen with a hydrogenation catalyst to form CMHTP and then recovering the CMHTP. The hydrogenation catalyst can be selected from the group of: 10% Pd/C, Pd/C/338, Pd/C/871 , Pd/C/490, Raney-Nickel, platinum oxide, rhodium on carbon and platinum on carbon. The hydrogen used is preferably hyperbaric hydrogen, more preferably hydrogen at about 1.5 bar to about 3.5 bar, most preferably hydrogen at 2.5 bar to 3.0 bar. Preferably, before the benzyl group is removed from the CMBP, phosphorus is at least partially removed from the CMBP, and/or before the CMHP is hydrogenated in the process, phosphorus is at least partially removed from the CMHP.
[00066] Alternatively, the CMHP may be produced by removing the benzyl protection from HMBP during the chlorination. For instance, the process for
preparing CMHTP can be conducted as described in the following scheme, wherein optionally phosphorus is at least partially removed from the CMBP before the benzyl group is removed from the CMBP and/or phosphorus is at least partially removed from the CMHP after the CMHP is formed and before the hydrogenation of the CMHP to obtain CMHTP at high yield:
[00067] In one embodiment, the present invention provides 3-(2-chloroethyl)-
2-methyl-9-hydroxy-4H-pyrido[l ,2-a]pyrimidine-4-one (CMHP). [00068] hi another embodiment of the present invention a process is provided for preparing CMHTP comprising: providing a mixture of CMBP, HCl and a catalyst such as palladium on charcoal in a solvent such as methanol; treating with hydrogen; and removal of the solvent to obtain CMHTP. Preferably, before the CMBP is used in the process, phosphorus is at least partially removed from the CMBP.
Preferably, the HCl is combined with a solution of CMBP and methanol, and the mixture is then combined with the catalyst. The catalyst can be any hydrogenation catalyst known to a skilled artisan including: 10% Pd/C, 10%Pd/C/338, 10%Pd/C/87L, 10%Pd/C/490, Ra-Ni5, 5%Rh/C/592, PtO, 5%Pt/C/117. Most preferably, the catalyst is 10%Pd/C/338.
[00069] Preferably, after treating with hydrogen, the mixture is heated to a temperature of about 65 °C. Preferably, prior to the removal of the solvent the mixture is cooled to about 20°C. Preferably, the solvent is removed by evaporation, more preferably, under reduced pressure.
[00070] The process may further comprise neutralizing the obtained CMHTP
HCl salt, with an inorganic base, e.g., KHCO3 or, preferably, NaHCO3. CMHTP may then be recovered by any method known in the art.
[00071 ] Treating the mixture with HCl results in lower amounts of the impurities 3-vinyl-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one (MHDP) and 3-ethyl-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l,2-a]- pyrimidin-4-one (MHTP).
[00072] In another embodiment, the present invention provides CMHTP with less than 10%, preferably less than 5%, more preferably less than 4% and most preferably less than 0.5% of MHDP based on area percent as measured by HPLC. The present invention also provides substantially pure CMHTP having less than 17%, preferably less than 13%, more preferably less than 6% and most preferably less than
5% of MHTP as measured by area percent of HPLC.
[00073] In the process of the invention, the intermediate CMHP can also be obtained directly from HMBP. Preferably, phosphorus is at least partially removed from the CMHP obtained.
[00074] In one of the embodiments of the present invention the process for preparing CMHP comprises reacting a mixture of HMBP and POCl3 to form a reaction residue; combining the reaction residue with a solution of methanol and toluene to obtain a precipitate of crude CMHP, and recovering the crude CMHP.
Optionally, phosphorus is at least partially removed from the CMHP obtained.
Preferably, the mixture of HMBP and POCl3 is heated to obtain the reaction residue.
More preferably, the mixture of HMBP and POCl3 is heated to about 70°C to about reflux.
[00075] Preferably, while combining with a solution of methanol and toluene, the reaction residue is maintained at a temperature of about 60°C.
[00076] Preferably, the crude CMHP is recovered by any method known to the skilled in the art. Such methods include, but are not limited to, washing with toluene and further drying the obtained CMHP.
[00077] hi another embodiment, the present invention provides a process for preparing paliperidone by coupling CMHTP with 6-fluoro-3-piperidino-l,2- benisoxazol (FPBI). For instance, the process for preparing paliperidone can be conducted as described in the following scheme:
[00078] In another embodiment of the present invention, the CMHTP is subsequently used to prepare paliperidone. Although the general process for conversion of CMHTP to paliperidone is known in the art, the present invention provides a novel method of converting CMHTP to paliperidone using a recovered or isolated form of CMHTP (e.g., solid such as amorphous or, preferably, crystalline form of CMHTP) as the starting material which differs from the oily or liquid CMHTP residue used as the starting material without isolation in prior art processes for the preparation of paliperidone. In some of the embodiments of the process of the present invention for converting CMHTP to paliperidone, the liquid or oily CMHTP residue used as the starting material in prior art processes is replaced with an isolated form of CMHTP (e.g., solid such as amorphous or preferably crystalline, form of CMHTP) as the starting material. The present invention provides an embodiment of a process for converting CMHTP to paliperidone, wherein a mixture of CMHTP which is isolated,e.g., in a solid such as amorphous or preferably crystalline form, FPBI, sodium carbonate, potassium iodide and dimethylformamide (DMF) is heated to a temperature of about 90° C, then combined with water and extracted with dichloromethane (DCM) to obtain crude paliperidone.
[00079] Both CMHTP and FPBI starting materials can be in the form of a base or hydrogen halide salts. The FPBI starting material is commercially available. Preferably, the crude paliperidone is purified, for example, by recrystallization such as recrystallization from acetonitrile.
[00080] In an embodiment, the present invention provides recovered or substantially isolated CMHTP, e.g., in a solid form such as amorphous or preferably crystalline form.
[00081] The present invention provides processes for the preparation of paliperidone by converting substantially isolated or solid CMHTP to paliperidone.
[00082] In an ambodiment, the present invention also provides recovered or substantially isolated HMBP in a solid form such as amorphous or preferably crystalline form.
[00083] The present invention provides processes for the preparation of paliperidone by using substantially isolated or solid HMBP as an intermediate.
[00084] In the processes disclosed herein for the preparation of paliperidone in the present invention, the processes can use substantially isolated or solid HMBP and substantially isolated or solid CMHTP as intermediates in different steps of the processes.
[00085] The present invention also provides sequential combination of a number of the reaction steps disclosed herein.
[00086] For instance, the present invention includes a process for preparing
CMBP, comprising performing the process for preparing BOPA described above followed by performing the process for preparing CMBP described above using the
BOPA prepared. Preferably, phosphorus is at least partially removed from the CMBP obtained.
[00087] For instance, the present invention includes a process for preparing
CMHTP, comprising performing the process for preparing BOPA described above, followed by performing the process for preparing CMBP described above, and followed by converting the CMBP to CMHTP according to the process described above. Preferably, phosphorus is at least partially removed from the CMBP before its conversion to CMHTP.
[00088] For instance, the present invention includes a process for preparing 9- hydroxy risperidone, comprising performing the process for preparing BOPA described above, followed by performing the process for preparing CMBP described above, followed by converting the CMBP to CMHTP according to the process described above, and followed by performing the process for preparing 9-hydroxy risperidone using the CMHTP according to the process described above. Preferably, phosphorus is at least partially removed from the CMBP before its conversion to
CMHTP.
[00089] For instance, the present invention includes a process for preparing paliperidone, comprising performing a process for preparing CMHTP as described above, followed by performing the process for preparing paliperidone using the
CMHTP according to the process described above, wherein the process for preparing CMHTP can start with CMHTP HCl or CMBP.
[00090] For instance, the present invention includes a process for preparing paliperidone, comprising performing a process for preparing CMBP as described above, followed by converting the CMBP to CMHTP according to the process described above, and followed by performing the process for preparing paliperidone using the CMHTP according to the process described above, wherein the process for preparing the CMBP can start with HMBP or BOPA. Preferably, phosphorus is at least partially removed from the CMBP before its conversion to CMHTP. [00091] For instance, the present invention includes a process for preparing
CMHTP, comprising performing the process for preparing CMBP described above, followed by converting the CMBP to CMHTP according to the process described above, wherein the preparation of CMBP can start with HMBP or BOPA. Preferably, phosphorus is at least partially removed from the CMBP before its conversion to CMHTP.
[00092] Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the synthesis of 9-hydroxy risperidone. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES
Preparation of 3-benzyloxy-2-aminopyridine (BOPA)
[00093] Example 1 : NaOH (40.04 g, 1 mol) was dissolved in water (60 ml) and covered with DCM (100 ml). AHP (20.04 g, 0.178 mol) was added to the reaction mixture in portions, under stirring, followed by the catalyst, TBAB (1.05 g). The reaction mixture was stirred for 15 min at 25-30°C and treated with a solution of benzyl bromide (33.90 g, 0.194 mol) in DCM (80 ml). The reaction mixture was stirred overnight at 20°C and diluted with water (100 ml). The organic phase was separated, and the aqueous phase was extracted with DCM (100 ml). The organic extracts were combined, washed with water (3x100 ml), then washed with brine (100 ml), dried with anhydrous magnesium sulfate, filtered, and evaporated under reduced
pressure to afford 37.8 g of the title product in a purity of 93% (GC), as a solid. Yield 98%.
Preparation of 3-(2-hydroxyethyl)-6,7,8,9-tetrahydro-9-benzyloxy-2-methyl-4H- pyrrido[l,2-a]- pyrimidin-4-one (HMBP)
[00094] Example 2: A mixture of BOPA (28.22 g, 0.131 mol), ADHF (34.3 g,
0.262 mol) and TsOH (2.29 g) in xylene (150 ml) was brought to reflux and stirred overnight, using a water separator (Dean-Stark). Volatiles were removed under reduced pressure to afford 59.65 g of the crude product, which was crystallized from acetonitrile (250 ml). The colored crystals were filtered off, sucked on the sinter and dried in air, to afford 17.53 g of the title product, HMBP, as colored crystals. An additional amount of the title product (4.11 g) was isolated from the filtrate by a repeated crystallization. Total yield 53%, purity 92% (GC).
[00095] Example 3: A mixture of 3-benzyloxy-2-aminopyridine (BOPA)
(1000.5 g), 3-acetyl-4,5-dihydro-2(3H)-furanone (ADHF) (965.0 g), p-toluenesulfonic acid, monohydrate (50.65 g), and toluene (1600 ml) was brought to reflux and stirred for 30 h, using a water separator (Dean-Stark) to collect ~83 g of water, until the level of BOPA was reduced to 3%.
[00096] The solution was cooled for 1.5 h to 65°C, until the crystallization started. The mixture was aged for 0.6 h, cooled to 5°C, and aged overnight, under stirring, to complete the crystallization. The crystalline mass was filtered. The cake was washed with cold toluene (-500 ml) to afford 1631 g of wet product, HMBP, as a pale solid. Purity 95% (HPLC area %), wetness 10%, yield 90%. [00097] The wet product was directly used in the next stage (see Example
4).The mother liquor was evaporated to remove toluene and the residue was distilled under reduced pressure to afford 312 g of 3-acetyl-4,5-dihydro-2(3H)-furanone (ADHF) with a purity of 99%, which could be used for more synthesis of HMBP. Yield of the recovery was 96%.
Preparation of 3-(2-chIoroethyl)-2-methyl-9-benzyIoxy-4H-pyrido[l,2- a]pyrimidine-4-one (CMBP)
[00098] Example 4 [without solvent]: A mixture of HMBP (15.07 g, 0.0461 mol) and freshly distilled POCl3 was heated under reflux for 5.5 h, in a 120°C bath, under stirring, protected by a CaCl2-tube. The excess POCl3 was removed under reduced pressure and the reaction residue was treated with crushed ice (-100 g) and water (75 g), followed by a 24% ammonium hydroxide solution (90 ml). The organic phase was separated, the aqueous phase was extracted with DCM (3x200 ml), and discarded. The organic extracts were combined, washed with water (4x200 ml), dried with anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to afford 14.4 g crude product as a solidifying oil. The residue was extracted with hot toluene (90°C, 150 and 50 ml). The toluene extracts were combined and concentrated to '/--volume, to cause crystallization. The residue was filtered off, washed with cold toluene and dried at 45°C under reduced pressure to afford 7.34 g of the title product, as a pink solid. Additional amounts of the title product (1.92 and 1.0 g) were isolated from the filtrate by repeat crystallization. Total yield 68%, purity 94%.
[00099] Example 5: Diglyme (bis(2-methoxyethyl) ether) (420 ml), wet 3-(2- hydroxyethyl)-2-methyl-9-benzyloxy-4H-pyrido[ 1 ,2-a]-pyrimidine-4-one (HMBP, 351.2 g, assay 90%), and POCl3 (351.5 g) were charged into a reactor, under inert atmosphere. The reaction suspension was heated to 90°C, under stirring, to afford a clear solution. The solution was stirred for 4.5 h at 90-92°C until the level of HMBP reduced to <0.5%.
[000100] The reaction mixture was diluted with toluene (850 ml) allowing the mixture to cool to 40-50°C. Water (800 ml) was carefully fed to the reaction mixture for 15 min, maintaining the temperature below 71°C.
The mixture was stirred allowing the temperature to decrease to 64°C. A 25% NH4OH (550 ml) was gradually fed to the reaction mixture for 10 min to adjust pH 7, maintaining the temperature below 80°C.
The stirrer was stopped to afford two clear phases. The lower aqueous phase (1539 g, colored liquid, pH 7) was separated and discarded. The hot organic phase was washed twice with hot (~50°C) water (205 and 200 ml) at 65-70°C. Lower aqueous phases (205.3 g and 216 g, respectively) were separated and discarded. The mixture was cooled to 5°C for 1.7 h. The crystallization started at 46°C. The crystalline mixture was aged overnight at 5°C and filtered. The cake was washed with cold toluene (50 ml) to afford 371.0 g of the wet crystalline product. The wet product
was dried for 2 h at 75-80°C to afford 289 g of the dry CMBP, as lilac powder. Purity 99.8% (HPLC). Yield 85%.
The mother liquor was evaporated to remove toluene. The filtrate was evaporated to afford 302.1 g of a viscous liquid which was cooled to 50C and stored overnight. The second crop (13.87 g) was collected and dried for 2 h at 7O0C to afford 13.39 g of CMBP, which could be used for more synthesis of CMBP. Purity 98%. Overall recovery yield was 89%.
Example 6: A mixture of 3-(2-hydroxyethyl)-2-methyl-9-benzyloxy-4H-pyrido[l,2- a]-pyrimidine-4-one (HMBP, 60.25 g) and POCl3 (87.29 g) was charged into a 0.5 L reactor. The reaction mixture was brought to reflux (~100-105°C) and stirred for 1.5 h, until the level of the substrate reduced to <0.5%. The remaining POCl3 (33.11 g) was distilled off and the hot residue was dissolved with N,N-dimethylformamide [DMF] (84 ml) at 100°C. The clear solution was cooled to 0°C, under stirring, and quenched with ice water (150 ml), maintaining temperature below 50°C. The mixture was treated with cold (~0°C) 25% NH4OH (150 ml), keeping the temperature below 40°C. The resulting suspension was stirred for 2 h at 40-45°C and filtered. The cake was washed with water (100 g) to afford 59.0 g of wet crude product (wetness 26%. Assay 83% (calibrated HPLC), purity 94%, yield 63%.
The product was crystallized from toluene (270 ml) to afford 42.32 g of the wet product, which was dried for 4 h at 70°C to afford 34.25 g of the crystalline CMBP. Purity 99.8%. Overall yield 56%.
Preparation of 3-(2-chloroethyl)-2-methyl-9-hydroxy-4H-pyrido[l,2- a]pyrimidine-4-one (CMHP)
Example 7: To a solution of 3-(2-hydroxyethyl)-2-methyl-9-hydroxy-4H-pyrido[l,2- a]pyrimidine-4-one (45.08 g) in N,N-dimethylformamide (DMF) (68 ml) POCl3 (72.92 g) was fed, maintaining the temperature below 100°C. The resulting viscous liquid was aged for 2 h and cooled to 30°C, under stirring
The water (~20 ml) was fed for 1 min to the cold reaction mixture to afford the precipitation. The temperature rose to 105°C to afford clear solution. The feeding was stopped to allow the mixture to cool to 650C. The remaining water (100 ml, total 120 ml) was added for 3 min, followed by a 25% NH4OH (134 ml) to adjust pH 7. New precipitation occurred. The mixture was cooled for 0.5 h to 10°C and aged for 1 h,
under stirring, to complete the precipitation. The crystalline mass was filtered and the cake was washed with water (2 x 100 ml) to afford 55.38 g of the wet product which was dried overnight at 75-800C to afford 30.5 g of dry CMHP. Yield 71%.
Example 8: Diglyme (80 ml), 3-(2-hydroxyethyl)-2-methyl-9-hydroxy-4H-pyrido[l,2- a]-pyrimidine-4-one (50.74 g), and POCl3 (75.35 g) were charged into reactor. The reaction mixture was heated to 80-82°C, under stirring. The mixture was converted at 60°C to a heavy paste which was finally transformed into a clear viscous liquid. The mixture was stirred for 4 h at 80-82°C and cooled to 300C. The mixture was carefully quenched with water (120 ml), maintaining the temperature below 85°C. Precipitation occurred. The reaction suspension was treated with a 25% NH4OH (115 ml) for 20 min to adjust pH 7, maintaining the temperature below 65°C (cooling agent 300C). The mixture was cooled to room temperature (20-250C), under stirring, and aged for 1 h to complete the precipitation. The crystalline mass was filtered and the cake was washed with water (2 x 100 ml) to afford 51.70 g of the wet product, which was dried overnight at 75-800C, under reduced pressure to afford 29.0 g of the dry CMHP. Yield 62%.
Example 9: Mixture of 3-(2-hydroxyethyl)-2-methyl-9-benzyloxy-4H-pyrido[l ,2-a]- pyrimidine-4-one (HMBP, 5.03 g) in POCl3 (2.45 ml) was heated to 91-95°C, under stirring, to afford a clear solution. The mixture converted to heavy paste at the end of the reaction. The mixture was heated to 600C and treated with a solution of methanol (10 ml) and toluene (25 ml) to afford the precipitation of the product. The cake was washed with toluene (3 ml) to afford 2.43 g of wet product, which was dried in air for 3 days to afford 1.69 g of the crystalline CMHP. Yield 46%.
Preparation of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H- pyrrido[l,2-a]- pyrimidin-4-one (CMHTP)
Example 10: A mixture of CMBP (10.3 g, 0.031 mol) in methanol (100 ml) was treated with 32% HCl (4.3 g, 0.0376 mol) in an autoclave. The catalyst (10% Pd/C, 0.52 g) was added, the mixture was flushed twice with nitrogen, then hydrogen, finally filled with hydrogen to a pressure of 5 bar, heated to 65°C and stirred over a 6 h period. The mixture was cooled to 200C, the hydrogen was replaced with nitrogen and the mixture was filtered. The residue of the catalyst was washed with a little
methanol. The filtrates were combined and evaporated under reduced pressure to afford 12.11 g of the product, as a crystallizing oil. The product was mixed with water (50 ml) and extracted with ethyl acetate (50 ml). The aqueous phase was neutralized with 10% NaHCO3 solution (50 ml) and the organic products were extracted with DCM (5 x 25 ml). The extracts were washed with 10% NaHCO3 (2 x 25 ml), followed by water (2 x 50 ml), dried overnight over anhydrous magnesium sulfate, filtered and evaporated, to afford 5.80 g of the crude CMHTP product.
Example IQA: Crystallization from ethyl acetate (25 ml) afforded 3.16 g of the title product. Additional amounts of the title product (total 1.35 g) were isolated from the filtrate by repeat crystallization from ethyl acetate to obtain CMHTP Form I having characterizing PXRD peaks at about 9.7, 19.4, 22.9 and 24.9 +/- 0.2 degrees 2Θ and one or more additional PXRD peaks at about 22.0, 27.4, 28.1 and 39.4 +/- 0.2 degrees 2Θ. The total yield of the CMHTP Form I product, in a purity of >93%, was 4.51 g (60%). Optional step:
Example IQB: A slurry of CMHTP Form I (2Og) in 100ml water was stirred at room temperature for 10 minutes. The solid was vacuum filtrated and washed with water (3x60ml), ethyl acetate (60ml) and dried overnight in a vacuum oven at 55°C. The solid was analyzed by XRD to give CMHTP Form II (Figure 2) characterized by PXRD diffraction peaks at about: 8.5, 11.2, 15.3, 23.8 +/- 0.2 two theta. Preferably, this form also includes one or more additional PXRD peaks of the following: 17.0, 22.6, 25.6 and 29.7 +/- 0.2 two theta.
Example 11 : A suspension of 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[l,2- a]pyrimidine-4-one (CMBP, 5.00 g) in methanol (30 ml) was treated with 32% HCl (1.72 g) to afford clear solution with pH 2. The solution was charged into a glass autoclave. The 10% Pd/C (50% wet) catalyst (0.12 g) was added. The mixture was heated to 48°C and hydrogenated under hydrogen pressure of 3 bar over a 7.5-h period, until the level of CMBP reduced to <0.1%.
The reaction mixture was filtered and the used catalyst was washed with methanol (5 ml). The mother liquor and the washing were combined and charged into glass autoclave. Fresh 10% Pd/C (50% wet) catalyst (0.253 g) was added. The mixture was heated to 55°C and hydrogenated under hydrogen pressure of 3 bars over a 24-h period, until the level of CMHP reduced to 0.9%. The reaction mixture was
filtered and the used catalyst was washed with methanol (5 ml). The mother liquor and the washing were combined to afford 17.05 g clear solution (pH 1). The solution was evaporated under reduced pressure to remove volatiles and the viscous residue was dissolved in water (5 ml, pH 1-1.5). The aqueous solution was treated with 10%NaHCO3 (13.2 g) to adjust pH 7-8. The aqueous solution was extracted twice with dichloromethane (2x25 ml) and discarded. Extracts were combined and evaporated to afford 2.8 g of the crude CMHTP product, as solidifying oil. Yield 70%, purity 90.5%.
Preparation of 9-hydroxy risperidone (Paliperidone)
Example 12: A mixture of CMHTP (4.393 g, 0.0168 mol), 6-fluoro-3-piperidino-l,2- benzisoxazol (FPBI, 4.695 g, 0.0203 mol), sodium carbonate (4.968 g, 0.0422 mol) and potassium iodide (0.288 g, 0.0017 mol) in DMF (50 ml) was heated for 8 h at 85°C. The mixture was poured into water (500 ml) and extracted with DCM (4 x 100 ml). The extracts were combined, washed with water (4 x 100 ml), dried with anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to afford the crude title product. Crystallization from acetonitrile (100 ml) afforded 4.63 g of the title product, in a purity of >90%. Yield 58%.
Table 1. Hydrogen ation of CMBP hydrochloride over various catalysts in MeOH at 2.5-3.0 bar
Notes.
1CC stands for the catalyst concentration regarding to the substrate, % w/w.
2T stands for bath temperature in 0C.
3HPLC area %.
4Yield of the crude product.
5ND represents not detected even though the level of the compound was analyzed.
6Free base was taken as HCl reacts with the catalyst
10%Pd/C, type 338 is the best catalyst.
Purification of CMBP
Example 13: A one liter reactor equipped with a mechanical stirrer and a reflux condenser was charged with 41 g CMBP (containing 345 ppm phosphorus) and 600 ml toluene. The mixture was heated to reflux. Five grams of activated charcoal were added to the hot solution, and the resulting mixture was hot filtrated, and cooled to room temperature. The resulting solid was filtered, and dried in a vacuum oven at 50 0C under reduced pressure to give 24 g of CMBP containing 5 ppm of phosphorus.
Purification of CMBP and preparation of CMHTP
Example 14: Purification of CMBP
A one liter reactor equipped with a mechanical stirrer and a reflux condenser was charged with 80 g CMBP (containing 345 ppm phosphorus) and 800 ml toluene. The mixture was heated to 70 °C and washed 4 times with water (200 ml each time). Eight grams of activated charcoal were added to the hot solution, and the resulting mixture was hot filtrated, and cooled to room temperature. The resulting solid was
filtered, and dried in a vacuum oven at 50 0C under reduced pressure to give 68 g of CMBP containing less than 5 ppm of phosphorus.
Preparation of CMHP-HCl
A suspension of 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[ 1 ,2- a]pyrimidine-4-one (CMBP, 60.00 g) in methanol (500 ml) was treated with 32% HCl (20 ml) to afford clear solution with pH 2. The solution was charged into a glass autoclave. The 10% Pd/C (50% wet) catalyst (0.6 g) was added. The mixture was heated to 50 °C and hydrogenated under hydrogen pressure of 2 bar over a 2-h period, until the level of CMBP reduced to <0.1%. The reaction mixture was filtered and the used catalyst was washed with methanol. The mother liquor and the washing were combined.
Preparation of CMHTP-HCl
The previous obtained mother liquor and the washing were charged into glass autoclave.and fresh 10% Pd/C (50% wet) catalyst (0.6 g) was added. The mixture was heated to 80°C and hydrogenated under hydrogen pressure of 2 bars over a 8-h period. The reaction mixture was filtered and the used catalyst was washed with methanol. The mother liquor and the washing were combined, resulting in a solution of CMHTP-HCl in methanol.
Isolation of CMHTP
The solution obtained above was evaporated under reduced pressure to remove volatiles and the viscous residue was dissolved in water and the volatiles evaporated again resulting in a water solution. The aqueous solution was treated with NaOH till pH 7-8 and stirred. After 5 hours the mixture was filtrated, washed and dried in a vacuum oven, resulting in 35 g of crude CMHTP.
Purification of CMHTP
1O g of the solid obtained above was dissolved in 40 ml ethyl acetate and heated to reflux till dissolution. The solution was fitrated with charcoal, cooling to room temperature and stirred. After 4 hours, the mixture was filtrated, washed and dried in a vacuum oven, resulting in 7.7 g of crystalline CMHTP.
Claims
1. A process for preparing 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2-methyl- 4H-pyrrido[l,2-a]- pyrimidin-4-one (CMHTP), comprising:
(A) removing the benzyl group from 3-(2-chloroethyl)-2-methyl-9-benzyloxy- 4H-pyrido[l,2-a]pyrimidine-4-one (CMBP) to form 3-(2-chloroethyl)-2-methyl-9- hydoxy-4H-pyrido[l,2-a]pyrimidine-4-one (CMHP), wherein phosphorus is at least partially removed from the CMBP to obtain CMBP containing less than 26 ppm phosphorus before the benzyl group is removed from the CMBP and/or phosphorus is at least partially removed from the CMHP after the CMHP is formed to obtain CMHP containing less than about 26 ppm phosphorus;
(B) reacting the product of step (A) with hydrogen and a hydrogenation catalyst to form CMHTP; and
(C) recovering or isolating the CMHTP.
2. The process of claim 1, wherein step (A) comprises reacting the CMBP with hydrogen in the presence of a hydrogenation catalyst to convert the CMBP to CMHP.
3. The process of claim 1 or 2, wherein the hydrogenation catalyst in step (A) and/or step (B) is about 1% by weight, with the total weight of the entire reaction mixture treated as 100% by weight, of 10% palladium/carbon.
4. The process of claim 1, wherein in step (A), after phosphorus is at least partially removed from the CMBP, the CMBP contains less than about 15 ppm phosphorus and/or after phosphorus is at least partially removed from the CMHP the CMHP contains less than about 15 ppm phosphorus.
5. The process of claim 4, wherein in step (A), after phosphorus is at least partially removed from the CMBP, the CMBP contains less than about 10 ppm phosphorus and/or after phosphorus is at least partially removed from the CMHP the CMHP contains less than about 10 ppm phosphorus.
6. The process of claim 5, wherein in step (A), after phosphorus is at least partially removed from the CMBP, the CMBP contains less than about 5 ppm phosphorus
and/or after phosphorus is at least partially removed from the CMHP the CMHP contains less than about 5 ppm phosphorus.
7. The process of claim 1, wherein before removing the benzyl group from the CMBP in step (A) phosphorus is at least partially removed from the CMBP by treating the CMBP with NH4OH or activated charcoal.
8. The process of claim 1 , wherein before removing the benzyl group from the CMBP in step (A) the CMBP is dissolved in an organic solvent, phosphorus is at least partially removed from the CMBP by treating the CMBP with aqueous NH4OH to form two phases, and then the benzyl group is removed from the resulting CMBP in the organic phase.
9. The process of claim 8, wherein the pH of the aqueous phase is about 7.
10. The process of claim 1, wherein before removing the benzyl group from the CMBP in step (A), phosphorus is at least partially removed from the CMBP by treating the CMBP with activated charcoal and then separating the activated charcoal from the CMBP to obtain the resulting CMBP.
11. The process of claim 1 , wherein after the CMHP is formed in step (A), phosphorus is at least partially removed from the CMHP by treating the CMHP with NH4OH or activated charcoal before step (B).
12. The process of claim 1, wherein after the CMHP is formed in step (A) the CMHP is dissolved in an organic solvent, phosphorus is at least partially removed from the CMHP by treating the CMHP with aqueous NH4OH before step (B).
13. The process of claim 1, wherein after the CMHP is formed in step (A), phosphorus is at least partially removed from the CMHP by treating the CMHP with activated charcoal and then separating the activated charcoal from the resulting CMHP before step (B).
14. A process for preparing 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-2- methyl-4H-pyrrido[l,2-a]- pyrimidin-4-one (CMHTP), comprising:
(a) mixing 3-(2-hydroxyethyl)-2-methyl-9-benzyloxy-4H-pyrido[l,2- a]pyrimidine-4-one (HMBP) and POCl3 to form a reaction residue;
(b) combining the reaction residue with methanol and toluene to obtain a precipitate of 3-(2-chloroethyl)-2-methyl-9-hydoxy-4H-pyrido[ 1 ,2-a]pyrimidine-4- one (CMHP), wherein phosphorus is at least partially removed from the CMHP to obtain CMHP containing less than about 26 ppm;
(c) reacting the product of step (b) with hydrogen and a hydrogenation catalyst to form CMHTP; and
(d) recovering or isolating the CMHTP.
15. The process of claim 14, wherein the hydrogenation catalyst is about 1% by weight, wherein the total weight of the entire reaction mixture is treated as 100% by weight, of 10% palladium/carbon.
16. The process of claim 15, wherein in step (b), after phosphorus is at least partially removed from the CMHP, the resulting CMHP contains less than about 15 ppm phosphorus.
17. The process of claim 16, wherein in step (b), after phosphorus is at least partially removed from the CMHP, the resulting CMHP contains less than about 10 ppm phosphorus.
18. The process of claim 17, wherein in step (b), after phosphorus is at least partially removed from the CMHP, the resulting CMHP contains less than about 5 ppm phosphorus.
19. The process of claim 14, wherein in step (b) phosphorus is at least partially removed from the CMHP by treating the CMHP with NH4OH or activated charcoal before step (c).
20. The process of claim 14, wherein in step (b) phosphorus is at least partially removed from the CMHP by treating the CMHP with aqueous NH4OH before step
(C).
21. The process of claim 20, wherein the pH of the aqueous phase is about 7.
22. The process of claim 14, wherein in step (b) phosphorus is at least partially removed from the CMHP by treating the CMHP with activated charcoal and then the resulting CMHP is separated from the activated charcoal before step (c).
23. A process for preparing 3-(2-chloroethyl)-2-methyl-9-hydoxy-4H-pyrido[l,2- a]pyrimidine-4-one (CMHP), comprising:
(a) mixing 3-(2-hydroxyethyl)-2-methyl-9-benzyloxy-4H-pyrido[l,2- a]pyrimidine-4-one (HMBP) and POCl3 to form a reaction residue;
(b) combining the reaction residue with methanol and toluene to obtain a precipitate of CMHP, wherein phosphorus is at least partially removed from the CMHP to form CMHP containing less than about 26 ppm phosphorus; and
(c) recovering or isolating the CMHP.
24. The process of claim 23, wherein in step (b), after phosphorus is at least partially removed from the CMHP, the resulting CMHP contains less than about 15 ppm phosphorus.
25. The process of claim 24, wherein in step (b), after phosphorus is at least partially removed from the CMHP, the resulting CMHP contains less than about 10 ppm phosphorus.
26. The process of claim 25, wherein in step (b), after phosphorus is at least partially removed from the CMHP, the resulting CMHP contains less than about 5 ppm phosphorus.
27. The process of claim 23, wherein in step (b) phosphorus is at least partially removed from the CMHP by treating the CMHP with NH4OH or activated charcoal.
28. The process of claim 23, wherein in step (b) phosphorus is at least partially removed from the CMHP by treating the CMHP with aqueous NH4OH.
29. The process of claim 28, wherein the pH of the aqueous phase is about 7.
30. The process of claim 23, wherein in step (b) phosphorus is at least partially removed from the CMHP by treating the CMHP with activated charcoal.
31. A process for preparing 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[ 1 ,2- a]pyrimidine-4-one (CMBP), comprising:
(I) mixing 3-(2-hydroxyethyl)-6,7,8,9-tetrahydro-9-benzyloxy-2-methyl-4H- pyrrido[l,2-a]- pyrimidin-4-one (HMBP) and POCl3 to form a mixture;
(II) heating the mixture from step (I) to obtain 3-(2-chloroethyl)-2-methyl-9- benzyloxy-4H-pyrido[ 1 ,2-a]pyrimidine-4-one (CMBP);
(III) removing phosphorus at least partially from the CMBP to obtain CMBP containing less than about 26 ppm phosphorus; and
(IV) recovering or isolating the CMBP from step (III).
32. The process of claim 31, wherein in step (III) the phosphorus is at least partially removed from the CMBP by treating the CMBP with NH4OH or activated charcoal.
33. The process of claim 31, wherein in step (III) the CMBP is dissolved in an organic solvent to form a solution, and then the phosphorus is at least partially removed from the CMBP by treating the CMBP solution with aqueous NH4OH.
34. The process of claim 33, wherein the pH of the aqueous phase is about 7.
35. The process of claim 31, wherein in step (III) the phosphorus is at least partially removed from the CMBP by treating the CMBP solution with activated charcoal.
36. The process of claim 31, wherein in step (III) after the phosphorus is at least partially removed from the CMBP, the resulting CMBP contains less than about 15 ppm phosphorus.
37. The process of claim 36, wherein in step (III) after the phosphorus is at least partially removed from the CMBP, the resulting CMBP contains less than about 10 ppm phosphorus.
38. The process of claim 37, wherein in step (III) after the phosphorus is at least partially removed from the CMBP, the resulting CMBP contains less than about 5 ppm phosphorus.
39. A process for preparing 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[l,2- a]pyrimidine-4-one (CMBP), comprising:
(A) mixing 3-benzyloxy-2-aminopyridine (BOPA), 3-acetyl-4,5-dihydro-3H- 2-furanone (ADHF), at least one water absorbent and at least one aromatic solvent to form a mixture;
(B) heating the mixture formed in step (A) to obtain 3-(2-hydroxyethyl)- 6,7,8,9-tetrahydro-9-benzyloxy-2-methyl-4H-pyrrido[ 1 ,2-a]- pyrimidin-4-one (HMBP);
(C) recovering or isolating the HMBP;
(D) reacting the HMBP with a chlorinating agent to form the CMBP;
(E) removing phosphorus from the CMBP at least partially to obtain CMBP containing less than about 26 ppm phosphorus; and
(F) isolating or recovering the CMBP from step (E).
40. The process of claim 39, wherein in step (E), after phosphorus is at least partially removed from the CMBP, the resulting CMBP contains less than about 15 ppm phosphorus.
41. The process of claim 40, wherein in step (E), after phosphorus is at least partially removed from the CMBP, the resulting CMBP contains less than about 10 ppm phosphorus.
42. The process of claim 41, wherein in step (E), after phosphorus is at least partially removed from the CMBP, the resulting CMBP contains less than about 5 ppm phosphorus.
43. The process of claim 39, wherein in step (E) phosphorus is at least partially removed from the CMBP by treating the CMBP with NH4OH or activated charcoal.
44. The process of claim 39, wherein in step (E) phosphorus is at least partially removed from the CMBP by treating the CMBP with aqueous NH4OH.
45. The process of claim 44, wherein the pH of the aqueous phase is about 7.
46. The process of claim 39, wherein in step (E) phosphorus is at least partially removed from the CMBP by treating the CMBP with activated charcoal.
47. The process of claim 39, wherein the chlorinating agent is POCl3.
48. A process for preparing paliperidone, comprising the process of claim 1, and further comprising condensing the recovered or isolated CMHTP with 6-fluoro-3- piperidino-l,2-benzisoxazole (FPBI) to form paliperidone.
49. The process of claim 48, wherein the condensing step is conducted in an inorganic base.
50. The process of claim 49, wherein the inorganic base is sodium carbonate.
51. A process for preparing paliperidone, comprising the process of claim 14, and further comprising condensing the recovered or isolated CMHTP with 6-fluoro-3- piperidino-l,2-benzisoxazole (FPBI) to form paliperidone.
52. The process of claim 51, wherein the condensing step is conducted in an inorganic base.
53. The process of claim 52, wherein the inorganic base is sodium carbonate.
54. The process of claim 3, wherein the yield of the CMHTP is at least about 83%.
55. The process of claim 54, wherein the yield of the CMHTP is at least about 94%.
56. The process of claim 15, wherein the yield of the CMHTP is at least about 83%.
57. The process of claim 56, wherein the yield of the CMHTP is at least about 94%.
58. A process for preparing 3-(2-chloroethyl)-2-methyl-9-hydoxy-4H-pyrido[l,2- a]pyrimidine-4-one (CMHP), comprising:
(a) reacting 3-(2-hydroxyethyl)-2-methyl-9-hydoxy-4H-pyrido[l,2- a]pyrimidine-4-one with a chlorination agent to form the CMHP;
(b) mixing the product of step (a) with aqueous NH4OH; and
(c) isolating or recovering the CMHP from step (b).
59. The process of claim 58, wherein the pH of the aqueous phase in step (b) is about
7.
60. The process of claim 58, wherein the chlorinating agent in step (a) is POCl3.
61. The process of claim 58, wherein the reaction in step (a) is conducted in N,N- dimethylformamide.
62. The process of claim 58, wherein the reaction in step (a) is conducted in diglyme.
63. A process for at least partially removing phosphorus from 3-(2-chloroethyl)-2- methyl-9-benzyloxy-4H-pyrido[l ,2-a]pyrimidine-4-one (CMBP), comprising: treating the starting CMBP containing phosphorus with activated charcoal or NH4OH to obtain a CMBP product having no phosphorus or less phosphorus than the starting CMBP; and recovering or isolating the CMBP product.
64. The process of claim 63, wherein the starting CMBP is treated with the activated charcoal.
65. The process of claim 63, wherein the starting CMBP is treated with the aqueous NH4OH.
66. The process of claim 63, wherein the recovered or isolated CMBP product contains less than 26 ppm phosphorus.
67. The process of claim 66, wherein the recovered or isolated CMBP product contains less than 5 ppm phosphorus.
68. A process for at least partially removing phosphorus from 3-(2-chloroethyl)-2- methyl-9-hydroxy-4H-pyrido[l,2-a]pyrimidine-4-one (CMHP), comprising: treating the starting CMHP containing phosphorus with activated charcoal or NH4OH to obtain a CMHP product having no phosphorus or less phosphorus than the starting CMHP; and recovering or isolating the CMHP product.
69. The process of claim 68, wherein the starting CMHP is treated with the activated charcoal.
70. The process of claim 68, wherein the starting CMHP is treated with aqueous NH4OH.
71. The process of claim 68, wherein the recovered or isolated CMHP product contains less than 26 ppm phosphorus.
72. The process of claim 71, wherein the recovered or isolated CMHP product contains less than 5 ppm phosphorus.
73. The process of claim 1, wherein step (A) comprises:
(i) mixing the starting CMBP with an organic solvent to form a mixture; (ii) heating the mixture to obtain a heated mixture; (iii) optionally washing the heated mixture one to five times with water; (iv) mixing the product of step (iii) with activated charcoal; (v) filtrating the product of step (iv);
(vi) cooling the filtrate of step (v) to a temperature below about 25°C to obtain a CMBP precipitate;
(vii) isolating or recovering the CMBP precipitate, wherein the isolated or recovered CMBP contains less than about 15 ppm phosphorus; and
(viii) removing the benzyl group from the isolated or recovered CMBP.
74. The process of claim 73, wherein the isolated or recovered CMBP obtained in step (vii) contains about 5 ppm phosphorus or less.
75. The process of claim 73, wherein the organic solvent in step (i) comprises toluene.
76. The process of claim 73, wherein the heated mixture is washed three to five times with water in step (iii).
77. The process of claim 73, wherein step (viii) comprises:
(a) mixing the isolated or recovered CMBP with an organic solvent and HCl to afford a solution;
(b) hydrogenating the product of step (a) with hydrogen and a hydrogenation catalyst; and
(c) filtering the reaction mixture of step (b) to obtain the CMHP in the filtrate before step (B).
78. The process of claim 77, wherein the organic solvent comprises methanol in step (a).
79. The process of claim 77, wherein the hydrogenation catalyst is 10% P/C in step (b).
80. The process of claim 79, wherein step (B) comprises:
(I) hydrogenating the CMHP with hydrogen and the hydrogenation catalyst to form the CMHTP, wherein the hydrogenation catalyst is 10% Pd/C;
(II) removing volatiles from the reaction mixture of step (T) to obtain a residue;
(III) dissolving the residue in water to form an aqueous solution; and
(IV) treating the aqueous solution with an inorganic base until the pH ranges from about 6 to about 8.
81. The process of claim 80, wherein step (C) comprises:
(1) recovering or isolating the CMHTP from the treated aqueous solution of step (IV) to obtain a solid CMHTP; and
(2) recrystallizing the solid CMHTP from ethyl acetate to obtain purified CMHTP.
82. The process of claim 81, wherein the yield of the CMHTP is at least about 83%.
83. The process of claim 82, wherein the yield of the CMHTP is at least about 90%.
84. The process of claim 83, wherein the yield of the CMHTP is at least about 94%.
85. The process of claim 1, wherein in step (A), after phosphorus is at least partially removed from the CMBP, the CMBP is substantially free of phosphorus and/or after phosphorus is at least partially removed from the CMHP, the CMHP is substantially free of phosphorus.
86. The process of claim 14, wherein in step (b), after phosphorus is at least partially removed from the CMHP, the CMHP is substantially free of phosphorus.
87. The process of claim 23, wherein in step (b), after phosphorus is at least partially removed from the CMHP, the CMHP is substantially free of phosphorus.
88. The process of claim 31, wherein in step (III), after phosphorus is at least partially removed from the CMBP, the CMBP is substantially free of phosphorus.
89. The process of claim 39, wherein in step (E), after phosphorus is at least partially removed from the CMBP, the CMBP is substantially free of phosphorus.
90. The process of claim 58, wherein the isolated or recovered CMHP contains less than about 26 ppm phosphorus.
91. The process of claim 90, wherein the isolated or recovered CMHP contains less than about 10 ppm phosphorus.
92. The process of claim 91, wherein the isolated or recovered CMHP is substantially free of phosphorus.
93. The process of claim 63, wherein the recovered or isolated CMBP product is substantially free of phosphorus.
94. The process of claim 68, wherein the recovered or isolated CMHP product is substantially free of phosphorus.
95. The process of claim 73, wherein the isolated or recovered CMBP is substantially free of phosphorus.
96. Substantially isolated 3-(2-chloroethyl)-2-methyl-9-benzyloxy-4H-pyrido[l,2- a]pyrimidine-4-one (CMBP) containing less than about 26 ppm phosphorus.
97. The CMBP of claim 96 containing less than about 15 ppm phosphorus.
98. The CMBP of claim 97 containing less than about 10 ppm phosphorus.
99. The CMBP of claim 98 containing phosphorus at about 5 ppm or less.
100. The CMBP of claim 96 substantially free of phosphorus.
101. Substantially isolated 3-(2-chloroethyl)-2-methyl-9-hydoxy-4H-pyrido[l,2- a]pyrimidine-4-one (CMHP) containing less than about 26 ppm phosphorus.
102. The CMHP of claim 101 containing less than about 15 ppm phosphorus.
103. The CMHP of claim 102 containing less than about 10 ppm phosphorus.
104. The CMHP of claim 103 containing about 5 ppm or less phosphorus.
105. The CMHP of claim 104 substantially free of phosphorus.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08726227A EP2046790A2 (en) | 2007-05-10 | 2008-02-27 | Process for the synthesis of cmhtp and intermediates thereof |
Applications Claiming Priority (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US92874507P | 2007-05-10 | 2007-05-10 | |
US60/928,745 | 2007-05-10 | ||
US93509307P | 2007-07-26 | 2007-07-26 | |
US60/935,093 | 2007-07-26 | ||
US96301907P | 2007-08-01 | 2007-08-01 | |
US60/963,019 | 2007-08-01 | ||
US11/892,532 | 2007-08-23 | ||
US11/892,532 US7820816B2 (en) | 2006-08-23 | 2007-08-23 | Process for the synthesis of CMHTP and intermediates thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2008140646A2 true WO2008140646A2 (en) | 2008-11-20 |
WO2008140646A3 WO2008140646A3 (en) | 2009-05-28 |
Family
ID=40002832
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2008/002652 WO2008140646A2 (en) | 2007-05-10 | 2008-02-27 | Process for the synthesis of cmhtp and intermediates thereof |
Country Status (3)
Country | Link |
---|---|
US (1) | US7820816B2 (en) |
EP (1) | EP2046790A2 (en) |
WO (1) | WO2008140646A2 (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7820816B2 (en) | 2006-08-23 | 2010-10-26 | Teva Pharmaceutical Industries Ltd. | Process for the synthesis of CMHTP and intermediates thereof |
EP2249649A2 (en) * | 2008-02-05 | 2010-11-17 | Watson Pharma Private Limited | An improved process for preparation of paliperidone |
EP2275423A1 (en) | 2009-07-13 | 2011-01-19 | Krka | Process for the synthesis of paliperidone |
WO2011073997A3 (en) * | 2009-12-14 | 2011-12-22 | Cadila Healthcare Limited | Process for preparing paliperidone and pharmaceutically acceptable salts thereof |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080171876A1 (en) * | 2007-05-10 | 2008-07-17 | Santiago Ini | Pure paliperidone and processes for preparing thereof |
US10350159B2 (en) * | 2010-05-31 | 2019-07-16 | Laboratories Farmacéuticos Rovi, S.A. | Paliperidone implant formulation |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5158952A (en) * | 1988-11-07 | 1992-10-27 | Janssen Pharmaceutica N.V. | 3-[2-[4-(6-fluoro-1,2-benzisoxozol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9 tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a]pyrimidin-4-one, compositions and method of use |
WO2001085731A1 (en) * | 2000-05-05 | 2001-11-15 | Rpg Life Sciences Limited | A PROCESS FOR THE PREPARATION OF ANTI-PSCHOTIC 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2,-a]pyrimidin-4-one |
WO2002012200A1 (en) * | 2000-08-08 | 2002-02-14 | Teva Pharmaceutical Industries Ltd. | Preparation of risperidone |
WO2002014286A1 (en) * | 2000-08-14 | 2002-02-21 | Teva Pharmaceutical Industries Ltd. | Preparation of risperidone |
WO2006005974A1 (en) * | 2004-07-08 | 2006-01-19 | Richter Gedeon Vegyészeti Gyár Rt. | A process for the preparation of risperidone |
Family Cites Families (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2000786C (en) | 1988-11-07 | 1999-01-26 | Cornelus G. M. Janssen | 3-piperidinyl-1,2-benzisoxazoles |
US5254556A (en) | 1988-11-07 | 1993-10-19 | Janssen Pharmaceutica N.V. | 3-piperidinyl-1,2-benzisoxazoles |
SI0730594T1 (en) | 1993-11-23 | 1999-12-31 | Janssen Pharmaceutica N.V. | 9-HYDROXY-PYRIDO (1,2-a)PYRIMIDIN-4-ONE ETHER DERIVATIVES |
TW421649B (en) | 1995-01-31 | 2001-02-11 | Janssen Pharmaceutica Nv | 4-(1H-indol-1yl)-1-piperidinyl derivatives |
US6325826B1 (en) | 1998-01-14 | 2001-12-04 | Advanced Stent Technologies, Inc. | Extendible stent apparatus |
US20050060027A1 (en) | 1999-01-13 | 2005-03-17 | Advanced Stent Technologies, Inc. | Catheter balloon systems and methods |
ES2546268T3 (en) | 2004-09-09 | 2015-09-22 | Janssen Pharmaceutica Nv | Preparation of 9-hydroxy-3- (2-hydroxyethyl) -2-methyl-4H-pyrido [1,2-a] pyrimidin-4-one and its crystals |
JP5249748B2 (en) | 2005-04-25 | 2013-07-31 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | Sterile 3- [2- [4- (6-Fluoro-1,2-benzisoxazol-3-yl) -1-piperidinyl] ethyl] -6,7,8,9-tetrahydro-9-hydroxy-2- Preparation of methyl-4H-pyrido [1,2-a] pyrimidin-4-onepalmitate |
KR100684766B1 (en) * | 2005-07-29 | 2007-02-20 | 삼성에스디아이 주식회사 | Secondary battery module |
US7540881B2 (en) | 2005-12-22 | 2009-06-02 | Boston Scientific Scimed, Inc. | Bifurcation stent pattern |
US7744643B2 (en) | 2006-05-04 | 2010-06-29 | Boston Scientific Scimed, Inc. | Displaceable stent side branch structure |
JP2009524685A (en) | 2006-08-14 | 2009-07-02 | テバ ファーマシューティカル インダストリーズ リミティド | Crystal form of 9-hydroxy-risperidone (paliperidone) |
EP1922319A2 (en) | 2006-08-14 | 2008-05-21 | Teva Pharmaceutical Industries Ltd. | Pure paliperidone and processes for preparing thereof |
WO2008021345A2 (en) | 2006-08-14 | 2008-02-21 | Teva Pharmaceutical Industries Ltd. | Process for the synthesis of 9-hydroxy risperidone (paliperidone) |
WO2008024415A2 (en) * | 2006-08-23 | 2008-02-28 | Teva Pharmaceutical Insustries Ltd. | Process for the synthesis of cmhtp and intermediates thereof |
US7820816B2 (en) | 2006-08-23 | 2010-10-26 | Teva Pharmaceutical Industries Ltd. | Process for the synthesis of CMHTP and intermediates thereof |
US8071767B2 (en) | 2007-01-08 | 2011-12-06 | Actavis Group Ptc Ehf | Process for preparation of 9-hydroxy-3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-A]pyrimidin-4-one hydrochloride |
CN101245065B (en) | 2007-02-14 | 2010-05-19 | 江苏恩华药业股份有限公司 | Method for producing benzo isoxazole derivative and its intermediate |
CA2679807A1 (en) | 2007-03-02 | 2008-09-12 | Schering Corporation | Piperidine derivatives and methods of use thereof |
KR101244185B1 (en) | 2007-04-19 | 2013-03-25 | 유씬 리 | Novel compounds for treatment of psychotic disorders, preparation methods and uses thereof |
US20080171876A1 (en) | 2007-05-10 | 2008-07-17 | Santiago Ini | Pure paliperidone and processes for preparing thereof |
WO2008144073A1 (en) | 2007-05-21 | 2008-11-27 | Teva Pharmaceutical Industries Ltd. | Enzymatic process for the preparation of paliperidone and its intermediate cmhtp |
-
2007
- 2007-08-23 US US11/892,532 patent/US7820816B2/en not_active Expired - Fee Related
-
2008
- 2008-02-27 WO PCT/US2008/002652 patent/WO2008140646A2/en active Application Filing
- 2008-02-27 EP EP08726227A patent/EP2046790A2/en not_active Withdrawn
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5158952A (en) * | 1988-11-07 | 1992-10-27 | Janssen Pharmaceutica N.V. | 3-[2-[4-(6-fluoro-1,2-benzisoxozol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9 tetrahydro-9-hydroxy-2-methyl-4H-pyrido [1,2-a]pyrimidin-4-one, compositions and method of use |
WO2001085731A1 (en) * | 2000-05-05 | 2001-11-15 | Rpg Life Sciences Limited | A PROCESS FOR THE PREPARATION OF ANTI-PSCHOTIC 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2,-a]pyrimidin-4-one |
WO2002012200A1 (en) * | 2000-08-08 | 2002-02-14 | Teva Pharmaceutical Industries Ltd. | Preparation of risperidone |
WO2002014286A1 (en) * | 2000-08-14 | 2002-02-21 | Teva Pharmaceutical Industries Ltd. | Preparation of risperidone |
WO2006005974A1 (en) * | 2004-07-08 | 2006-01-19 | Richter Gedeon Vegyészeti Gyár Rt. | A process for the preparation of risperidone |
Non-Patent Citations (2)
Title |
---|
EL-SAYED BADAWEY AND THOMAS KAPPE: "Synthesis of Some New Imidazo(1,2-a)pyrimidin-5(1H)-ones as Potential Antineoplastic Agents" JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 32, 1995, pages 1003-1006, XP002477350 * |
K. DE SMET ET AL: "Selectivity Control by Use of Near-IR for a Hydrogenation Process" ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 9, no. 3, 2005, pages 344-347, XP002477069 * |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7820816B2 (en) | 2006-08-23 | 2010-10-26 | Teva Pharmaceutical Industries Ltd. | Process for the synthesis of CMHTP and intermediates thereof |
EP2249649A2 (en) * | 2008-02-05 | 2010-11-17 | Watson Pharma Private Limited | An improved process for preparation of paliperidone |
EP2249649A4 (en) * | 2008-02-05 | 2012-09-26 | Watson Pharma Private Ltd | An improved process for preparation of paliperidone |
EP2275423A1 (en) | 2009-07-13 | 2011-01-19 | Krka | Process for the synthesis of paliperidone |
WO2011006638A1 (en) | 2009-07-13 | 2011-01-20 | Krka, D.D., Novo Mesto | Process for the synthesis of paliperidone |
WO2011073997A3 (en) * | 2009-12-14 | 2011-12-22 | Cadila Healthcare Limited | Process for preparing paliperidone and pharmaceutically acceptable salts thereof |
Also Published As
Publication number | Publication date |
---|---|
EP2046790A2 (en) | 2009-04-15 |
US20080200676A1 (en) | 2008-08-21 |
US7820816B2 (en) | 2010-10-26 |
WO2008140646A3 (en) | 2009-05-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20080214809A1 (en) | Process for the synthesis of CMHTP and intermediates thereof | |
CN104159898B (en) | For the preparation of the method for the fluoro-1H-pyrazolo-pyridines of 5-replacing | |
WO2008140646A2 (en) | Process for the synthesis of cmhtp and intermediates thereof | |
WO2017016960A1 (en) | Process for the preparation of (6s)-6-alkyl-10-alkoxy-9-(substituted alkoxy)-2-oxo-6,7-dihydrobenzo[a]quinolizine-3-carboxylic acid analogues | |
JPH0737460B2 (en) | Pyranoindolizine derivative and method for producing the same | |
WO2009010988A1 (en) | An improved, industrially viable process for the preparation of high purity paliperidone | |
JP6081450B2 (en) | Crystalline salt of asenapine | |
JP2019194191A (en) | Methods for producing viloxazine salts and novel polymorphs thereof | |
MXPA03001337A (en) | Preparation of risperidone. | |
US20070260061A1 (en) | Preparation Of 9-Hydroxy -(2-Hydroxyethyl)-2-Methyl-4H-Pyrido[1,2-A]Pryimidin-4-One | |
WO2015124764A1 (en) | Synthesis process of dabigatran etexilate mesylate, intermediates of the process and novel polymorph of dabigatran etexilate | |
JP5819284B2 (en) | Method for producing olopatadine | |
CN103509025A (en) | Preparation method of epinastine hydrochloride and intermediate thereof | |
JP5192707B2 (en) | Manufacturing method of mirtazapine | |
JP2010254692A (en) | Method for purifying paliperidone | |
WO2012070066A1 (en) | Process for the preparation of taurolidine and its intermediates thereof | |
CN111320622A (en) | Method for synthesizing moxifloxacin hydrochloride | |
CN111269211B (en) | Preparation method of benzothiophene derivative | |
JP4461512B2 (en) | Crystals of condensed benzazepine derivatives | |
EP2540717B1 (en) | Lamivudine oxalate and preparation method thereof | |
WO2006100243A1 (en) | Process for the preparation of pantoprazole | |
EP1318146B1 (en) | Process for producing pyrimidine derivative and intermediate thereof | |
JP2004323372A (en) | Benzazepine compound and method for producing the same | |
RU2395488C1 (en) | Method of producing pharmaceutically acceptable dec-glaucine salts | |
JP2017218411A (en) | 1-(3-carboxypyridyl-2-)-2-phenyl-4-methylpiperazine having crystal structure and method for producing the same |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 08726227 Country of ref document: EP Kind code of ref document: A2 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2008726227 Country of ref document: EP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |