CA2368815A1 - Novel synthesis and crystallization of piperazine ring-containing compounds - Google Patents
Novel synthesis and crystallization of piperazine ring-containing compounds Download PDFInfo
- Publication number
- CA2368815A1 CA2368815A1 CA002368815A CA2368815A CA2368815A1 CA 2368815 A1 CA2368815 A1 CA 2368815A1 CA 002368815 A CA002368815 A CA 002368815A CA 2368815 A CA2368815 A CA 2368815A CA 2368815 A1 CA2368815 A1 CA 2368815A1
- Authority
- CA
- Canada
- Prior art keywords
- mirtazapine
- phenyl
- methyl
- piperazine
- cyanopyridyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 23
- 125000004193 piperazinyl group Chemical group 0.000 title abstract description 4
- 238000002425 crystallisation Methods 0.000 title description 4
- 230000008025 crystallization Effects 0.000 title description 4
- 230000015572 biosynthetic process Effects 0.000 title description 3
- 238000003786 synthesis reaction Methods 0.000 title description 3
- RONZAEMNMFQXRA-UHFFFAOYSA-N mirtazapine Chemical compound C1C2=CC=CN=C2N2CCN(C)CC2C2=CC=CC=C21 RONZAEMNMFQXRA-UHFFFAOYSA-N 0.000 claims abstract description 86
- 229960001785 mirtazapine Drugs 0.000 claims abstract description 84
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 60
- 238000000034 method Methods 0.000 claims abstract description 55
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 27
- PYZPABZGIRHQTA-UHFFFAOYSA-N [2-(4-methyl-2-phenylpiperazin-1-yl)pyridin-3-yl]methanol Chemical compound C1N(C)CCN(C=2C(=CC=CN=2)CO)C1C1=CC=CC=C1 PYZPABZGIRHQTA-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- FEIACFYXEWBKHU-UHFFFAOYSA-N (2-aminopyridin-3-yl)methanol Chemical compound NC1=NC=CC=C1CO FEIACFYXEWBKHU-UHFFFAOYSA-N 0.000 claims abstract description 6
- KUSNCWLQRVMIRN-UHFFFAOYSA-N 2-chloro-n-(2-chloroethyl)-n-methyl-2-phenylethanamine Chemical compound ClCCN(C)CC(Cl)C1=CC=CC=C1 KUSNCWLQRVMIRN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 57
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 37
- 239000002904 solvent Substances 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 25
- 239000002585 base Substances 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 8
- 230000007062 hydrolysis Effects 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 8
- -1 iodomethyl Chemical group 0.000 claims description 7
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- XDJWZONZDVNKDU-UHFFFAOYSA-N 1314-24-5 Chemical compound O=POP=O XDJWZONZDVNKDU-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 4
- VSAISIQCTGDGPU-UHFFFAOYSA-N phosphorus trioxide Inorganic materials O1P(O2)OP3OP1OP2O3 VSAISIQCTGDGPU-UHFFFAOYSA-N 0.000 claims description 4
- 229910015900 BF3 Inorganic materials 0.000 claims description 3
- 208000020401 Depressive disease Diseases 0.000 claims description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
- 239000002841 Lewis acid Substances 0.000 claims description 3
- 150000001412 amines Chemical group 0.000 claims description 3
- VMPVEPPRYRXYNP-UHFFFAOYSA-I antimony(5+);pentachloride Chemical compound Cl[Sb](Cl)(Cl)(Cl)Cl VMPVEPPRYRXYNP-UHFFFAOYSA-I 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 125000005997 bromomethyl group Chemical group 0.000 claims description 3
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000002346 iodo group Chemical group I* 0.000 claims description 3
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 238000001556 precipitation Methods 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 3
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical compound Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims 1
- 238000001953 recrystallisation Methods 0.000 abstract description 5
- 238000010992 reflux Methods 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 17
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 230000035484 reaction time Effects 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 6
- 150000002825 nitriles Chemical class 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 238000006798 ring closing metathesis reaction Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 4
- 239000011877 solvent mixture Substances 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical group C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 239000013505 freshwater Substances 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 150000003017 phosphorus Chemical class 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- IRMBVBDXXYXPEW-UHFFFAOYSA-N 1-methyl-3-phenylpiperazine Chemical compound C1N(C)CCNC1C1=CC=CC=C1 IRMBVBDXXYXPEW-UHFFFAOYSA-N 0.000 description 1
- YYXDQRRDNPRJFL-UHFFFAOYSA-N 2-aminopyridine-3-carbonitrile Chemical compound NC1=NC=CC=C1C#N YYXDQRRDNPRJFL-UHFFFAOYSA-N 0.000 description 1
- HTCVSFZWADPKPB-UHFFFAOYSA-N 2-piperazin-1-yl-1h-azepine Chemical group C1CNCCN1C1=CC=CC=CN1 HTCVSFZWADPKPB-UHFFFAOYSA-N 0.000 description 1
- 229940123685 Monoamine oxidase inhibitor Drugs 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 239000011874 heated mixture Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010667 large scale reaction Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002899 monoamine oxidase inhibitor Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 238000000197 pyrolysis Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229940023942 remeron Drugs 0.000 description 1
- 239000012896 selective serotonin reuptake inhibitor Substances 0.000 description 1
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
Abstract
The present invention is directed to methods for the preparation of piperazine ring-containing compounds, particularly mirtazapine. According to the present invention, the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine is made by hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with a base where the base is present in a ratio of up to about 12 moles of the base per one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine. The mirtazapine intermediate 1-(3-carboxypyridly-2)-4-methyl-2-phenyl-piperazine may be made by hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with potassium hydroxide at a temperature of at least about 130 ~C. The method of the present invention also includes reacting 2-amino-3-hydroxymethyl pyridine with N-methyl-1-phenyl-2, 2'-iminodiethyl chloride to form 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl piperazine, and adding sulfuric acid to the 1-(3-hydroxymethylpyridyl-2)-phenyl-4-methylpiperazine to form mirtazapine. The present invention also relates to new processes for recrystallization of mirtazapine form crude mirtazapine.
Description
NOVEL SYNTHESIS AND CRYSTALLIZATION OF PIPERAZINE
RING-CONTAINING COMPOUNDS
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of U.S. Provisional Application No.
60/130,047, filed April 19, 1999.
FIELD OF THE INVENTION
The present invention relates to synthetic organic chemistry, particularly, to synthesis of piperazine ring-containing compounds, such as mirtazapine, and to the crystallization of mirtazapine from different solvents and solvent systems.
BACKGROUND OF THE INVENTION
Mirtazapine, 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino [2,1-a]pyrido[2,3-c][2] benzazepine, having the formula I:
i I \
N N
~N
is approved, under the trademark Remeron~, by the U.S. Food and Drug Administration, for the treatment of depression. Mirtazapine has a tetracyclic chemical structure unrelated to other classes of antidepressants such as selective serotonin reuptake inhibitors, tricyclics or monoamine oxidase inhibitors. Mirtazapine belongs to the piperazinoazepine group of compounds.
Mirtazapine may be made by methods described in U.S. Patent No. 4,062,848.
By a process of U.S. Patent No. 4,062,848 ("the '848 patent"), the mirtazapine intermediate 1-(3-hydroxymethylpyridyl-2-4-methyl-2-phenyl-piperazine is made by a three step process starting with a 2,3-substituted pyridine derivative. Therefore, as shown in Scheme 1, when starting with 2-amino-3-cyano-pyridine, the process of the '848 patent requires four synthetic steps to make mirtazapine. It is desirable to have a process for making mirtazapine that requires fewer steps, and therefore requires less reagent, solvent and time.
Scheme 1 CN CI ~ Step 1 ~ I CN ~ I Step 2 ~ CH ----~ ~N ~N \
N- _NH2 2 CI EtOH
H3C~ ~CH2-CH2 N\
2-amino- N-methyl-I-phenyl- 1-(3-cyanomethylpyridyl-2)-3-cyano-pyridine 2,2'-iminodiethyl chloride 4-methyl-2-phenyl-piperazine Step 3 ~ ( ~ I Step 4 ~N N \ LiAIH4 ~N N \ H2S0~
~N ~N
I-(3-carboxymethylpyridyl-2)- I-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine 4-methyl-2-phenyl-piperazine Mirtazapine By the process of U.S. Patent No. 4,062,848 ("the 848 patent"), the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine is made by the hydrolysis of the nitrile 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine under highly basic conditions of 25 moles of potassium hydroxide (KOH) per mole of nitrile, at high temperature and for long reaction times of 24 hours. These harsh reaction conditions necessitate a great effort in purifying the resulting product as well as creating environmental waste disposal issues associated with neutralizing and disposing of large volumes of concentrated basic solutions. The highly basic conditions and long reaction times make the procedure of the '848 patent very costly, especially in terms of reactor time.
According to the methods of U.S. Patent No. 4,062,848, crude mirtazapine is recrystallized only in ether and petrol ether 40-60. The solvents ether and petrol ether 40-60 are both very difficult to handle in large scale production.
SUMMARY OF THE INVENTION
The present invention is directed to a method for the preparation of R~
mirtazapine, comprising the steps of: reacting a compound of the formula N R2 R3 w ,N
with a compound of the formula H3C ~ to form a compound of the formula R' N N _ ~N
CH3 , and R~
/ /
N N _ ~N
adding a ring closing reagent to the compound of the formula ~H3 to form mirtazapine, wherein R' is selected from the group consisting of hydroxymethyl, chloromethyl, bromomethyl and iodomethyl; Rz is amine; and R3 is selected from the group consisting of chloro, fluoro, bromo and iodo.
In a preferred embodiment of the present invention is directed to a method for the preparation of mirtazapine, comprising the steps of reacting 2-amino-3-hydroxymethyl pyridine with N-methyl-1-phenyl-2,2'-iminodiethyl chloride to form 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl piperazine, and adding sulfuric acid to the 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine to form mirtazapine.
Further, it has now been discovered that the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine may be made by hydrolysis of the nitrile 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine using new more favorable reaction conditions. The new reaction conditions of the present invention include a low mole to mole ratio of potassium hydroxide to nitrite and shorter reaction times.
The present invention relates to a improved process for making 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine by hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine comprising the step of reacting 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with a base wherein the base is present in a ratio of up to about 12 moles of the base per one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine.
In a preferred embodiment of the present invention, the ratio of the base to 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is about 12 moles of base to about one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine to about 9 moles of base to about one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine.
In another preferred embodiment of the present invention, the base is potassium hydroxide or sodium hydroxide.
In another embodiment of the present invention, the mixture of the 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine and the base is heated to at least about 130° C.
In another embodiment of the present invention, the hydrolysis of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is carried out in a mixture water and a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, dimethylformamide, dimethylacetamide and dimethylsulfoxide.
The present invention also relates to improved processes for making mirtazapine from crude mirtazapine comprising the steps of (a) heating a mixture of crude mirtazapine and solvent; and (b) isolating mirtazapine.
In a preferred embodiment of the present invention, water is added to the heated mixture of mirtazapine and solvent to facilitate precipitation of mirtazapine.
In an additional embodiment of the present invention, preferred solvents are methanol, ethanol, isopropanol, acetone, toluene, and hexane and mixtures thereof.
In an additional embodiment of the present invention, preferred solvents are toluene, hexane, and methylene chloride.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel process for preparing piperazine ring-containing compounds, such as mirtazapine, as described in Scheme 2 below. The process of the present invention is advantageous over prior art processes due to, inter alia, the higher yield, smaller number of steps in relation to the alternative methods, and minimized raw material costs.
Scheme 2 / R~ / i / R~ R3 ~ ~ ~ ~ ~ wN~ \
+ N N N
N R I R3 ~N ~N
H3C~N~---~ CH3 CH3 II III IV
Mirtazapine More particularly, the present invention relates to the process of making mirtazapine from compounds of the formulae II, III and IV. In the process of the present invention the compound of formula II in Scheme 2 above, wherein R' denotes hydroxymethyl, chloromethyl, bromomethyl or iodomethyl, and RZ denotes amine, preferably -NHz, is reacted with the compound of formula III in Scheme 2 above, wherein R3 denotes chloro, fluoro, bromo or iodo, to form the compound of formula IV wherein R' is defined as above.
In the process of the present invention, the compound of formula II is dissolved in a solvent such as methylene chloride. The compound of formula III
is added to the solvent mixture and the resulting mixture is heated. Preferably the reaction mixture is heated to the reflux temperature of the solvent. The mixture is heated to form the compound of formula IV. Mirtazapine is then prepared by ring closure of the compound of formula IV.
Ring closure of the compound of formula IV may be performed using a ring-closing reagent.
Suitable ring closing reagents are dehydrating or dehydrohalogenating agents.
Dehydrating or dehydrohalogenating agents that may be added to the reaction mixture for this purpose include acids, such as sulfuric acid, concentrated sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid (PPA), phosphorus oxychloride, phosphorus trioxide, phosphorus pentoxide and Lewis acids, such as aluminum chloride, ferric chloride, zinc chloride, tin chloride, titanium chloride, boron trifluoride, antimony pentachloride and zirconium tetrachloride.
Dehydrating agents that are particularly preferred are sulfuric acid and phosphorus derivatives, such as PPA and phosphorus oxychloride. Concentrated sulfuric acid most preferred. A particularly preferred dehydrohalogenating agent is aluminum chloride.
In a preferred embodiment of the present invention the compounds of the formulae II, III and IV are compounds of the formulae II', III' and IV' respectively as shown in Scheme 3 below. In an embodiment of the present invention, 2-amino-3-hydroxymethyl pyridine is reacted with N-methyl-1-phenyl-2,2'-iminodiethyl chloride to form 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine. In the present invention, 2-amino-3-hydroxymethyl pyridine (II') is added to a solvent. Suitable solvents include 1,2-dichloroethane, methylene chloride, dimethylformamide, dimethylacetamide and dimethylsulfoxide. N-Methyl-1-phenyl-2,2'-imidodiethyl-chloride (III') is added to the solvent mixture and the resulting mixture is heated. Preferably the reaction mixture is heated to the reflux temperature of the solvent. The mixture is heated until 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine is formed and the reaction is complete. A suitable time is about six to about 24 hours. The 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine is then converted to mirtazapine by ring closure.
The ring closure of 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine is performed under strongly dehydrating (R'= OH) conditions, preferably at an elevated temperature. Suitable dehydrating agents, include acids, such as sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid (PPA), phosphorus oxychloride, phosphorus trioxide and phosphorus pentoxide.
Dehydrating agents that are particularly preferred are sulfuric acid and phosphorus derivatives, such as PPA and phosphorus oxychloride. Concentrated sulfuric acid is most preferred.
Scheme 3 / \ ~ _ CH20H CI ~ wN~
+ ~ ~ N
\N- _NH CH2 /CI ~N
H3C~N~ CH3 I I' I I I' IV' 2-amino- N-methyl-1-phenyl- 1-(3-hydroxymethylpyridyl-2)- Mirtazapine 3-hydroxymethyl 2,2'-iminodiethyl chloride 4-methyl-2-phenyl-piperazine pyridine The present invention also provides new processes for making the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine from the nitrite 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine where the nitrite is (I) hydrolyzed by base using a new low mole to mole ratio of base to the nitrite 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine and (ii) hydrolyzed using short reaction times.
Where the present invention provides improved methods for making the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine, the nitrite 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is dissolved in a mixture of water and organic solvent. Preferred organic solvents include polar aprotic solvents and alcohols. Polar aprotic organic solvents such as dimethylformamide, dimethylacetamide and dimethylsulfoxide and the like are preferred. Preferred alcohols are methanol, ethanol, propanol, isopropanol, butanol and the like. A suitable amount of base, such as potassium hydroxide or sodium hydroxide, is added to the reaction mixture. An amount of base, such as potassium hydroxide or sodium hydroxide, of up to about 12 moles of base per mole of nitrite (for example 12:1 KOH:nitrile) is preferred. Amounts of base, such as potassium hydroxide, in the ratio of about 9 moles of potassium hydroxide per one mole of nitrite (9:1 KOH:nitrile), to about 12 moles of potassium hydroxide per mole of nitrite (12:1 KOH:nitrile) are preferred.
In the present invention, the mixture of the nitrite 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine, solvent and base is heated to at least about 130°C. Reaction temperatures of about 130°C to about 150° are preferred. In an embodiment of the present invention, the reaction may be conducted under pressure to facilitate the attainment of high temperatures. A pressure of at least about 3 atmospheres is preferred.
Pressures of at least about 3 atmospheres to about 4 atmospheres are more preferred. The reaction mixture is heated until the reaction is complete. The completion of the reaction may be monitored by HPLC. The amount of time needed for the completion of the hydrolysis of the nitrite vaxies with the temperature of the reaction. Higher reaction temperatures generally require shorter reaction times, while lower reaction temperatures generally requires longer reaction times.
While not limiting the reaction time of the present invention, preferred reaction times of the present invention may be from about 2 hours to about 8 hours. Upon completion of the reaction, the pH of the reaction mixture is lowered, preferably to a pH of about 6 to about 7.
Preferably the pH is lowered with hydrochloric acid. The mirtazapine intermediate,l-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is isolated following washing and filtration of the reaction mixture.
In an additional embodiment of the present invention, the reaction mixture of the nitrite 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine, and potassium hydroxide, is heated while using a minimum amount of water, such as about 0.25-1 mL of water per gram of KOH, and small amounts of an aprotic solvent such as dimethylformamide, dimethylacetamide and dimethylsulfoxide, such as about 0.1 to 0.5 grams of aprotic solvent per gram of nitrite, under very concentrated conditions or almost neat conditions at atmospheric pressure. The mirtazapine intermediate,l-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is isolated following washing and filtration of the reaction mixture.
The new processes of the present invention for making the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine from the nitrite 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine significantly reduce the quantity of potassium hydroxide used, from 25 moles of potassium hydroxide per mole of the nitrite as in the '848 patent, to about 12 moles or less of potassium hydroxide to one mole of the nitrite. The reduction in the amount of base needed considerably simplifies the work-up of the reaction and minimizes environmental problems.
The present invention also provides new methods for making pure mirtazapine by purifying crude mirtazapine by recrystallization. Upon the ring closure of 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine to form mirtazapine, the crude product, mirtazapine, is purified by recrystallization.
It has been discovered that common solvents such as toluene or methylene chloride and solvent systems such as alcohol-water can be used in the recrystallization of crude mirtazapine. According to the present invention, crude mirtazapine is suspended in a suitable solvent. Preferred solvents include methanol, ethanol, isopropanol, and acetone and mixtures thereof, or mixtures of one or more of those solvents with water.
Additional preferred solvents also include toluene, hexane, and methylene chloride.
Solvent mixtures of water and ethanol are more preferred. Solvent mixtures of ratios of about 1:1 to about 1:4 ethanol:water are preferred.
In the present invention, the suspension of crude mirtazapine and solvent is heated to a suitable temperature. Suitable temperatures include, for example, the reflux temperature of the solvent system being used in any particular embodiment of the present invention. For example, in an embodiment of the present invention where toluene is the solvent, a temperature of about 110°C is suitable. Purified mirtazapine precipitates upon cooling of the reaction mixture. Filtration and drying of the resulting precipitate yields purified, recrystallized mirtazapine.
In a further example, crude mirtazapine is suspended in a solvent such as ethanol, and the mixture is heated to reflux. Water is then added dropwise and the solution is cooled to facilitate precipitation of mirtazapine. The precipitate is purified by filtration, washing and drying to yield purified mirtazapine. The crystallized mirtazapine may be a water adduct thereby containing up to 3 % water by weight (3% w/w).
The solvents and solvent systems of the present invention are suitable for large scale reactions, and are more suitable for laxge scale reactions than ether or petrol ether 40-60.
Additionally, the crystallization yield can be substantially improved when using the solvent system of the present invention.
Mirtazapine and mirtazapine intermediates, 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine and 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine each contain an asymmetric carbon atom, as a result of which separate optical isomers may be prepared in addition to a racemic mixtures. Processes of the present invention include these optical isomers just as the racemic mixtures are included in the invention.
In accordance with the present invention, mirtazapine produced by the process of the present invention may be prepared as pharmaceutical compositions that are particularly useful for the treatment of depression. Such compositions comprise a therapeutically effective amount of mirtazapine with pharmaceutically acceptable carriers and/or excipients known to one of skill in the art.
EXAMPLES
The following examples are given for the purpose of illustrating the present invention and shall not be construed as being limitations on the scope or spirit of the invention.
Preparation of 1-(3-Hydroxymethylpyridyl-2)-4-Methyl-2-Phenyl-Piperazine In a 50 mL three-necked flask equipped with a mechanical stirrer, a condenser and a thermometer 1 g (0.008 mole) of 2-amino-3-hydroxymethyl pyridine and 20 mL of 1,2-dichloroethane were charged. The mixing is started and to the suspension 2.8 g (0.012 mole) of N-methyl-1-phenyl-2,2'-iminodiethyl-chloride are added. The reaction mixture is heated to reflux (~80° C) and maintained at this temperature for six hours.
After six hours the reaction mixture is cooled and the solvent (1,2-dichloroethane) is removed by dry distillation. A yellowish powder is obtained which contains 1.8 g 1-(3-hydroxymethyl pyridyl-2)-4-methyl-2-phenyl-piperazine (yield 80%).
This powder can be used without additional purification for the preparation of mirtazapine.
Preparation of Mirtazapine In a 50 mL three-necked flask equipped with a mechanical stirrer, a condenser and a thermometer 1.8 g of 1-(3-hydroxymethyl pyridyl-2)-4-methyl-2-phenyl-piperazine are added to -~-5 mL of concentrated sulfuric acid that was previously cooled to 10°C. The obtained solution is mixed at room temperature for 4 hours, then heated for one hour to about 50° to 60° C. After cooling, the reaction mass is added to 25 g of ice under mixing and neutralized with a concentrated ammonia solution or sodium hydroxide. The formed precipitate is separated by filtration. The mother liquor is evaporated to dryness under vacuum. Both the formed precipitate and the residue from the mother liquor are each suspended in ~ 20 mL of isopropanol. The combined isopropanol extracts are evaporated to dryness. An oil is obtained which contains 1.35 g of mirtazapine (yield 80%).
Example 3 Preparation of Mirtazapine 1-(3-Hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine (1.8 g) is added to ~5 mL of concentrated sulfuric acid. The resulting solution is mixed at 35° C for 6 hours.
After cooling, the reaction mixture is added to 25 g of ice under mixing and basified with a concentrated ammonia solution or sodium hydroxide solution to pH = 10. The separated precipitate is extracted into methylene chloride and the extract is evaporated to dryness; 1.6 g of Mirtazapine is obtained (yield 95%).
Example 4 Preparation of 1-(3-Carboxypyridyl-2-)-4-Methyl-2-Phenyl-Piperazine 1-(3-cyanopyridyl-2-)-4-methyl-2-phenyl-piperazine (54 g) is dissolved in 340 mL of ethanol and 34 mL of water. Potassium hydroxide flakes, 85% (113 g), are added and the reaction mixture is heated in an autoclave to 140° C. The pressure increases to 3-4 atmospheres and the reaction mixture is maintained under pressure with mixing for 5 hours.
After 5 hours, the reaction mixture is cooled, the ethanol is removed from the mixture by vacuum distillation, fresh water and toluene are added and the 2 phases are separated. The water solution is neutralized with hydrochloric acid (HCl) to pH = 6.5-7. At pH = 6.5-7 the water is evaporated and toluene is added. The inorganic salts are filtered and the toluene solution is evaporated to dryness yielding 52 g of 1-(3-carboxypyridyl-2-)-4-methyl- 2-phenyl-piperazine (yield: 90%).
Example 5 Preparation of 1-(3-Carboxypyridyl-2-)-4-Methyl-2-Phenyl-Piperazine Potassium hydroxide (150 g of KOH flakes, 85%) and 75 mL of water and 6.5 g of DMSO are added to 1-(3-cyanopyridyl-2-)-4-methyl-2-phenyl-piperazine (54 g) and the reaction mixture is heated to 145-150° C and mixed for 8 hours. After 8 hours, the inorganic phase containing water and potassium hydroxide (KOH) is separated and the organic phase, containing mainly a product oil, is cooled. Fresh water and toluene are added and the two phases are separated. The aqueous solution is neutralized with HCl to pH = 6.5-7. At pH =
6.5-7, the water is evaporated and toluene is added. The inorganic salts are filtered and the toluene solution is evaporated to dryness yielding 52 g of 1-(3-carboxypyridyl-2-)-4-methyl-2-phenyl-piperazine (yield: 90%).
Examine 6 Recrystallization of Mirtazapine Mirtazapine (20 g), obtained as in Examples 2 and 3, is suspended in 20 mL of ethanol and heated to reflux. At reflux, 40 mL of water is added dropwise to the solution over one hour followed by cooling to 10° C. The resulting filter cake is washed with a solution of water:ethanol (2:1) and dried at 60° C under a vacuum.
Crystallized mirtazapine, 18 g, is obtained in 90% yield.
Table 1 sets forth a summary of additional experiments generally following procedures described above wherein the Yield % is the percent yield of mirtazapine crystals from crude mirtazapine and the Purity % is the percent purity as compared to a mirtazapine standard.
Table 1. Purification of Crude pine by allization Mirtaza Recryst Solvent systemRatio of solventsConditionsYield' ml:ml/g hexane 10 reflux 55 toluene 3 reflux 32 toluene 2 reflux 53 acetone/water 6:25 25 C 65 ethanol/water 7:10 reflux 67 methanol/water2.25:1.5 reflux 67 ethanol/water 1.5:2 reflux 72 isopropyl/water1.65:2 reflux 60 acetone-water 3:2 reflux 53 ethanol/water 1:1.3 reflux 70 ethanol/water 1.3:1.75 reflux 90.3 ethanol/water 1:4 reflux 100 ethanol/water 1.1:1.2 reflux 87.8 ethanol/water 0.8:0.9 reflux 90 ethanol/water 0.8:1 reflux 57 ethanol/water 0.6:0.7 reflux 89.1 ethanol/water 0.35:0.7 reflux 91.5 ethanol/water 0.6:0.69 reflux 87 ethanol/water 2:2.8 reflux 95.6 ' g mirtazapine crystals 100 %/g mirtazapine crude 100 Although certain presently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the described embodiments may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rule of law.
RING-CONTAINING COMPOUNDS
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of U.S. Provisional Application No.
60/130,047, filed April 19, 1999.
FIELD OF THE INVENTION
The present invention relates to synthetic organic chemistry, particularly, to synthesis of piperazine ring-containing compounds, such as mirtazapine, and to the crystallization of mirtazapine from different solvents and solvent systems.
BACKGROUND OF THE INVENTION
Mirtazapine, 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino [2,1-a]pyrido[2,3-c][2] benzazepine, having the formula I:
i I \
N N
~N
is approved, under the trademark Remeron~, by the U.S. Food and Drug Administration, for the treatment of depression. Mirtazapine has a tetracyclic chemical structure unrelated to other classes of antidepressants such as selective serotonin reuptake inhibitors, tricyclics or monoamine oxidase inhibitors. Mirtazapine belongs to the piperazinoazepine group of compounds.
Mirtazapine may be made by methods described in U.S. Patent No. 4,062,848.
By a process of U.S. Patent No. 4,062,848 ("the '848 patent"), the mirtazapine intermediate 1-(3-hydroxymethylpyridyl-2-4-methyl-2-phenyl-piperazine is made by a three step process starting with a 2,3-substituted pyridine derivative. Therefore, as shown in Scheme 1, when starting with 2-amino-3-cyano-pyridine, the process of the '848 patent requires four synthetic steps to make mirtazapine. It is desirable to have a process for making mirtazapine that requires fewer steps, and therefore requires less reagent, solvent and time.
Scheme 1 CN CI ~ Step 1 ~ I CN ~ I Step 2 ~ CH ----~ ~N ~N \
N- _NH2 2 CI EtOH
H3C~ ~CH2-CH2 N\
2-amino- N-methyl-I-phenyl- 1-(3-cyanomethylpyridyl-2)-3-cyano-pyridine 2,2'-iminodiethyl chloride 4-methyl-2-phenyl-piperazine Step 3 ~ ( ~ I Step 4 ~N N \ LiAIH4 ~N N \ H2S0~
~N ~N
I-(3-carboxymethylpyridyl-2)- I-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine 4-methyl-2-phenyl-piperazine Mirtazapine By the process of U.S. Patent No. 4,062,848 ("the 848 patent"), the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine is made by the hydrolysis of the nitrile 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine under highly basic conditions of 25 moles of potassium hydroxide (KOH) per mole of nitrile, at high temperature and for long reaction times of 24 hours. These harsh reaction conditions necessitate a great effort in purifying the resulting product as well as creating environmental waste disposal issues associated with neutralizing and disposing of large volumes of concentrated basic solutions. The highly basic conditions and long reaction times make the procedure of the '848 patent very costly, especially in terms of reactor time.
According to the methods of U.S. Patent No. 4,062,848, crude mirtazapine is recrystallized only in ether and petrol ether 40-60. The solvents ether and petrol ether 40-60 are both very difficult to handle in large scale production.
SUMMARY OF THE INVENTION
The present invention is directed to a method for the preparation of R~
mirtazapine, comprising the steps of: reacting a compound of the formula N R2 R3 w ,N
with a compound of the formula H3C ~ to form a compound of the formula R' N N _ ~N
CH3 , and R~
/ /
N N _ ~N
adding a ring closing reagent to the compound of the formula ~H3 to form mirtazapine, wherein R' is selected from the group consisting of hydroxymethyl, chloromethyl, bromomethyl and iodomethyl; Rz is amine; and R3 is selected from the group consisting of chloro, fluoro, bromo and iodo.
In a preferred embodiment of the present invention is directed to a method for the preparation of mirtazapine, comprising the steps of reacting 2-amino-3-hydroxymethyl pyridine with N-methyl-1-phenyl-2,2'-iminodiethyl chloride to form 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl piperazine, and adding sulfuric acid to the 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine to form mirtazapine.
Further, it has now been discovered that the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine may be made by hydrolysis of the nitrile 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine using new more favorable reaction conditions. The new reaction conditions of the present invention include a low mole to mole ratio of potassium hydroxide to nitrite and shorter reaction times.
The present invention relates to a improved process for making 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine by hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine comprising the step of reacting 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with a base wherein the base is present in a ratio of up to about 12 moles of the base per one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine.
In a preferred embodiment of the present invention, the ratio of the base to 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is about 12 moles of base to about one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine to about 9 moles of base to about one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine.
In another preferred embodiment of the present invention, the base is potassium hydroxide or sodium hydroxide.
In another embodiment of the present invention, the mixture of the 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine and the base is heated to at least about 130° C.
In another embodiment of the present invention, the hydrolysis of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is carried out in a mixture water and a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, dimethylformamide, dimethylacetamide and dimethylsulfoxide.
The present invention also relates to improved processes for making mirtazapine from crude mirtazapine comprising the steps of (a) heating a mixture of crude mirtazapine and solvent; and (b) isolating mirtazapine.
In a preferred embodiment of the present invention, water is added to the heated mixture of mirtazapine and solvent to facilitate precipitation of mirtazapine.
In an additional embodiment of the present invention, preferred solvents are methanol, ethanol, isopropanol, acetone, toluene, and hexane and mixtures thereof.
In an additional embodiment of the present invention, preferred solvents are toluene, hexane, and methylene chloride.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel process for preparing piperazine ring-containing compounds, such as mirtazapine, as described in Scheme 2 below. The process of the present invention is advantageous over prior art processes due to, inter alia, the higher yield, smaller number of steps in relation to the alternative methods, and minimized raw material costs.
Scheme 2 / R~ / i / R~ R3 ~ ~ ~ ~ ~ wN~ \
+ N N N
N R I R3 ~N ~N
H3C~N~---~ CH3 CH3 II III IV
Mirtazapine More particularly, the present invention relates to the process of making mirtazapine from compounds of the formulae II, III and IV. In the process of the present invention the compound of formula II in Scheme 2 above, wherein R' denotes hydroxymethyl, chloromethyl, bromomethyl or iodomethyl, and RZ denotes amine, preferably -NHz, is reacted with the compound of formula III in Scheme 2 above, wherein R3 denotes chloro, fluoro, bromo or iodo, to form the compound of formula IV wherein R' is defined as above.
In the process of the present invention, the compound of formula II is dissolved in a solvent such as methylene chloride. The compound of formula III
is added to the solvent mixture and the resulting mixture is heated. Preferably the reaction mixture is heated to the reflux temperature of the solvent. The mixture is heated to form the compound of formula IV. Mirtazapine is then prepared by ring closure of the compound of formula IV.
Ring closure of the compound of formula IV may be performed using a ring-closing reagent.
Suitable ring closing reagents are dehydrating or dehydrohalogenating agents.
Dehydrating or dehydrohalogenating agents that may be added to the reaction mixture for this purpose include acids, such as sulfuric acid, concentrated sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid (PPA), phosphorus oxychloride, phosphorus trioxide, phosphorus pentoxide and Lewis acids, such as aluminum chloride, ferric chloride, zinc chloride, tin chloride, titanium chloride, boron trifluoride, antimony pentachloride and zirconium tetrachloride.
Dehydrating agents that are particularly preferred are sulfuric acid and phosphorus derivatives, such as PPA and phosphorus oxychloride. Concentrated sulfuric acid most preferred. A particularly preferred dehydrohalogenating agent is aluminum chloride.
In a preferred embodiment of the present invention the compounds of the formulae II, III and IV are compounds of the formulae II', III' and IV' respectively as shown in Scheme 3 below. In an embodiment of the present invention, 2-amino-3-hydroxymethyl pyridine is reacted with N-methyl-1-phenyl-2,2'-iminodiethyl chloride to form 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine. In the present invention, 2-amino-3-hydroxymethyl pyridine (II') is added to a solvent. Suitable solvents include 1,2-dichloroethane, methylene chloride, dimethylformamide, dimethylacetamide and dimethylsulfoxide. N-Methyl-1-phenyl-2,2'-imidodiethyl-chloride (III') is added to the solvent mixture and the resulting mixture is heated. Preferably the reaction mixture is heated to the reflux temperature of the solvent. The mixture is heated until 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine is formed and the reaction is complete. A suitable time is about six to about 24 hours. The 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine is then converted to mirtazapine by ring closure.
The ring closure of 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine is performed under strongly dehydrating (R'= OH) conditions, preferably at an elevated temperature. Suitable dehydrating agents, include acids, such as sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid (PPA), phosphorus oxychloride, phosphorus trioxide and phosphorus pentoxide.
Dehydrating agents that are particularly preferred are sulfuric acid and phosphorus derivatives, such as PPA and phosphorus oxychloride. Concentrated sulfuric acid is most preferred.
Scheme 3 / \ ~ _ CH20H CI ~ wN~
+ ~ ~ N
\N- _NH CH2 /CI ~N
H3C~N~ CH3 I I' I I I' IV' 2-amino- N-methyl-1-phenyl- 1-(3-hydroxymethylpyridyl-2)- Mirtazapine 3-hydroxymethyl 2,2'-iminodiethyl chloride 4-methyl-2-phenyl-piperazine pyridine The present invention also provides new processes for making the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine from the nitrite 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine where the nitrite is (I) hydrolyzed by base using a new low mole to mole ratio of base to the nitrite 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine and (ii) hydrolyzed using short reaction times.
Where the present invention provides improved methods for making the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine, the nitrite 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is dissolved in a mixture of water and organic solvent. Preferred organic solvents include polar aprotic solvents and alcohols. Polar aprotic organic solvents such as dimethylformamide, dimethylacetamide and dimethylsulfoxide and the like are preferred. Preferred alcohols are methanol, ethanol, propanol, isopropanol, butanol and the like. A suitable amount of base, such as potassium hydroxide or sodium hydroxide, is added to the reaction mixture. An amount of base, such as potassium hydroxide or sodium hydroxide, of up to about 12 moles of base per mole of nitrite (for example 12:1 KOH:nitrile) is preferred. Amounts of base, such as potassium hydroxide, in the ratio of about 9 moles of potassium hydroxide per one mole of nitrite (9:1 KOH:nitrile), to about 12 moles of potassium hydroxide per mole of nitrite (12:1 KOH:nitrile) are preferred.
In the present invention, the mixture of the nitrite 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine, solvent and base is heated to at least about 130°C. Reaction temperatures of about 130°C to about 150° are preferred. In an embodiment of the present invention, the reaction may be conducted under pressure to facilitate the attainment of high temperatures. A pressure of at least about 3 atmospheres is preferred.
Pressures of at least about 3 atmospheres to about 4 atmospheres are more preferred. The reaction mixture is heated until the reaction is complete. The completion of the reaction may be monitored by HPLC. The amount of time needed for the completion of the hydrolysis of the nitrite vaxies with the temperature of the reaction. Higher reaction temperatures generally require shorter reaction times, while lower reaction temperatures generally requires longer reaction times.
While not limiting the reaction time of the present invention, preferred reaction times of the present invention may be from about 2 hours to about 8 hours. Upon completion of the reaction, the pH of the reaction mixture is lowered, preferably to a pH of about 6 to about 7.
Preferably the pH is lowered with hydrochloric acid. The mirtazapine intermediate,l-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is isolated following washing and filtration of the reaction mixture.
In an additional embodiment of the present invention, the reaction mixture of the nitrite 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine, and potassium hydroxide, is heated while using a minimum amount of water, such as about 0.25-1 mL of water per gram of KOH, and small amounts of an aprotic solvent such as dimethylformamide, dimethylacetamide and dimethylsulfoxide, such as about 0.1 to 0.5 grams of aprotic solvent per gram of nitrite, under very concentrated conditions or almost neat conditions at atmospheric pressure. The mirtazapine intermediate,l-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is isolated following washing and filtration of the reaction mixture.
The new processes of the present invention for making the mirtazapine intermediate 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine from the nitrite 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine significantly reduce the quantity of potassium hydroxide used, from 25 moles of potassium hydroxide per mole of the nitrite as in the '848 patent, to about 12 moles or less of potassium hydroxide to one mole of the nitrite. The reduction in the amount of base needed considerably simplifies the work-up of the reaction and minimizes environmental problems.
The present invention also provides new methods for making pure mirtazapine by purifying crude mirtazapine by recrystallization. Upon the ring closure of 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine to form mirtazapine, the crude product, mirtazapine, is purified by recrystallization.
It has been discovered that common solvents such as toluene or methylene chloride and solvent systems such as alcohol-water can be used in the recrystallization of crude mirtazapine. According to the present invention, crude mirtazapine is suspended in a suitable solvent. Preferred solvents include methanol, ethanol, isopropanol, and acetone and mixtures thereof, or mixtures of one or more of those solvents with water.
Additional preferred solvents also include toluene, hexane, and methylene chloride.
Solvent mixtures of water and ethanol are more preferred. Solvent mixtures of ratios of about 1:1 to about 1:4 ethanol:water are preferred.
In the present invention, the suspension of crude mirtazapine and solvent is heated to a suitable temperature. Suitable temperatures include, for example, the reflux temperature of the solvent system being used in any particular embodiment of the present invention. For example, in an embodiment of the present invention where toluene is the solvent, a temperature of about 110°C is suitable. Purified mirtazapine precipitates upon cooling of the reaction mixture. Filtration and drying of the resulting precipitate yields purified, recrystallized mirtazapine.
In a further example, crude mirtazapine is suspended in a solvent such as ethanol, and the mixture is heated to reflux. Water is then added dropwise and the solution is cooled to facilitate precipitation of mirtazapine. The precipitate is purified by filtration, washing and drying to yield purified mirtazapine. The crystallized mirtazapine may be a water adduct thereby containing up to 3 % water by weight (3% w/w).
The solvents and solvent systems of the present invention are suitable for large scale reactions, and are more suitable for laxge scale reactions than ether or petrol ether 40-60.
Additionally, the crystallization yield can be substantially improved when using the solvent system of the present invention.
Mirtazapine and mirtazapine intermediates, 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine and 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine each contain an asymmetric carbon atom, as a result of which separate optical isomers may be prepared in addition to a racemic mixtures. Processes of the present invention include these optical isomers just as the racemic mixtures are included in the invention.
In accordance with the present invention, mirtazapine produced by the process of the present invention may be prepared as pharmaceutical compositions that are particularly useful for the treatment of depression. Such compositions comprise a therapeutically effective amount of mirtazapine with pharmaceutically acceptable carriers and/or excipients known to one of skill in the art.
EXAMPLES
The following examples are given for the purpose of illustrating the present invention and shall not be construed as being limitations on the scope or spirit of the invention.
Preparation of 1-(3-Hydroxymethylpyridyl-2)-4-Methyl-2-Phenyl-Piperazine In a 50 mL three-necked flask equipped with a mechanical stirrer, a condenser and a thermometer 1 g (0.008 mole) of 2-amino-3-hydroxymethyl pyridine and 20 mL of 1,2-dichloroethane were charged. The mixing is started and to the suspension 2.8 g (0.012 mole) of N-methyl-1-phenyl-2,2'-iminodiethyl-chloride are added. The reaction mixture is heated to reflux (~80° C) and maintained at this temperature for six hours.
After six hours the reaction mixture is cooled and the solvent (1,2-dichloroethane) is removed by dry distillation. A yellowish powder is obtained which contains 1.8 g 1-(3-hydroxymethyl pyridyl-2)-4-methyl-2-phenyl-piperazine (yield 80%).
This powder can be used without additional purification for the preparation of mirtazapine.
Preparation of Mirtazapine In a 50 mL three-necked flask equipped with a mechanical stirrer, a condenser and a thermometer 1.8 g of 1-(3-hydroxymethyl pyridyl-2)-4-methyl-2-phenyl-piperazine are added to -~-5 mL of concentrated sulfuric acid that was previously cooled to 10°C. The obtained solution is mixed at room temperature for 4 hours, then heated for one hour to about 50° to 60° C. After cooling, the reaction mass is added to 25 g of ice under mixing and neutralized with a concentrated ammonia solution or sodium hydroxide. The formed precipitate is separated by filtration. The mother liquor is evaporated to dryness under vacuum. Both the formed precipitate and the residue from the mother liquor are each suspended in ~ 20 mL of isopropanol. The combined isopropanol extracts are evaporated to dryness. An oil is obtained which contains 1.35 g of mirtazapine (yield 80%).
Example 3 Preparation of Mirtazapine 1-(3-Hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine (1.8 g) is added to ~5 mL of concentrated sulfuric acid. The resulting solution is mixed at 35° C for 6 hours.
After cooling, the reaction mixture is added to 25 g of ice under mixing and basified with a concentrated ammonia solution or sodium hydroxide solution to pH = 10. The separated precipitate is extracted into methylene chloride and the extract is evaporated to dryness; 1.6 g of Mirtazapine is obtained (yield 95%).
Example 4 Preparation of 1-(3-Carboxypyridyl-2-)-4-Methyl-2-Phenyl-Piperazine 1-(3-cyanopyridyl-2-)-4-methyl-2-phenyl-piperazine (54 g) is dissolved in 340 mL of ethanol and 34 mL of water. Potassium hydroxide flakes, 85% (113 g), are added and the reaction mixture is heated in an autoclave to 140° C. The pressure increases to 3-4 atmospheres and the reaction mixture is maintained under pressure with mixing for 5 hours.
After 5 hours, the reaction mixture is cooled, the ethanol is removed from the mixture by vacuum distillation, fresh water and toluene are added and the 2 phases are separated. The water solution is neutralized with hydrochloric acid (HCl) to pH = 6.5-7. At pH = 6.5-7 the water is evaporated and toluene is added. The inorganic salts are filtered and the toluene solution is evaporated to dryness yielding 52 g of 1-(3-carboxypyridyl-2-)-4-methyl- 2-phenyl-piperazine (yield: 90%).
Example 5 Preparation of 1-(3-Carboxypyridyl-2-)-4-Methyl-2-Phenyl-Piperazine Potassium hydroxide (150 g of KOH flakes, 85%) and 75 mL of water and 6.5 g of DMSO are added to 1-(3-cyanopyridyl-2-)-4-methyl-2-phenyl-piperazine (54 g) and the reaction mixture is heated to 145-150° C and mixed for 8 hours. After 8 hours, the inorganic phase containing water and potassium hydroxide (KOH) is separated and the organic phase, containing mainly a product oil, is cooled. Fresh water and toluene are added and the two phases are separated. The aqueous solution is neutralized with HCl to pH = 6.5-7. At pH =
6.5-7, the water is evaporated and toluene is added. The inorganic salts are filtered and the toluene solution is evaporated to dryness yielding 52 g of 1-(3-carboxypyridyl-2-)-4-methyl-2-phenyl-piperazine (yield: 90%).
Examine 6 Recrystallization of Mirtazapine Mirtazapine (20 g), obtained as in Examples 2 and 3, is suspended in 20 mL of ethanol and heated to reflux. At reflux, 40 mL of water is added dropwise to the solution over one hour followed by cooling to 10° C. The resulting filter cake is washed with a solution of water:ethanol (2:1) and dried at 60° C under a vacuum.
Crystallized mirtazapine, 18 g, is obtained in 90% yield.
Table 1 sets forth a summary of additional experiments generally following procedures described above wherein the Yield % is the percent yield of mirtazapine crystals from crude mirtazapine and the Purity % is the percent purity as compared to a mirtazapine standard.
Table 1. Purification of Crude pine by allization Mirtaza Recryst Solvent systemRatio of solventsConditionsYield' ml:ml/g hexane 10 reflux 55 toluene 3 reflux 32 toluene 2 reflux 53 acetone/water 6:25 25 C 65 ethanol/water 7:10 reflux 67 methanol/water2.25:1.5 reflux 67 ethanol/water 1.5:2 reflux 72 isopropyl/water1.65:2 reflux 60 acetone-water 3:2 reflux 53 ethanol/water 1:1.3 reflux 70 ethanol/water 1.3:1.75 reflux 90.3 ethanol/water 1:4 reflux 100 ethanol/water 1.1:1.2 reflux 87.8 ethanol/water 0.8:0.9 reflux 90 ethanol/water 0.8:1 reflux 57 ethanol/water 0.6:0.7 reflux 89.1 ethanol/water 0.35:0.7 reflux 91.5 ethanol/water 0.6:0.69 reflux 87 ethanol/water 2:2.8 reflux 95.6 ' g mirtazapine crystals 100 %/g mirtazapine crude 100 Although certain presently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the described embodiments may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rule of law.
Claims (27)
1. A method for the preparation of mirtazapine, comprising the steps of:
(a) reacting a compound of the formula with a compound of the formula to form a compound of the formula (b) adding a ring closing reagent to the compound of the formula to form mirtazapine wherein R1 is selected from the group consisting of hydroxymethyl, chloromethyl, bromomethyl and iodomethyl; R2 is amine; and R3 is selected from the group consisting of chloro, fluoro, bromo and iodo.
(a) reacting a compound of the formula with a compound of the formula to form a compound of the formula (b) adding a ring closing reagent to the compound of the formula to form mirtazapine wherein R1 is selected from the group consisting of hydroxymethyl, chloromethyl, bromomethyl and iodomethyl; R2 is amine; and R3 is selected from the group consisting of chloro, fluoro, bromo and iodo.
2. The method of claim 1, wherein R1 is hydroxymethyl, R2 is -NH2, and R3 is chloro.
3. The method of claim 1, wherein said a ring closing reagent is selected from the group consisting of sulfuric acid, concentrated sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid, phosphorus oxychloride, phosphorus trioxide, phosphorus pentoxide, Lewis acids, aluminum chloride, ferric chloride, zinc chloride, tin chloride, titanium chloride, boron trifluoride, antimony pentachloride and zirconium tetrachloride.
4. The method of claim 2, wherein said ring closing reagent is sulfuric acid.
5. The method of claim 1 which further comprises the step of heating.
6. A method for the preparation of mirtazapine, comprising the steps of:
(a) reacting 2-amino-3-hydroxymethyl pyridine with N-methyl-1-phenyl-2,2'-iminodiethyl chloride to form 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine, and (b) adding a ring closing reagent to the 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine to form mirtazapine.
(a) reacting 2-amino-3-hydroxymethyl pyridine with N-methyl-1-phenyl-2,2'-iminodiethyl chloride to form 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine, and (b) adding a ring closing reagent to the 1-(3-hydroxymethylpyridyl-2)-4-methyl-2-phenyl-piperazine to form mirtazapine.
7. The method of claim 6, wherein said a ring closing reagent is selected from the group consisting of sulfuric acid, concentrated sulfuric acid, concentrated hydrochloric acid, trifluoroacetic acid, phosphoric acid, polyphosphoric acid, phosphorus oxychloride, phosphorus trioxide, phosphorus pentoxide, Lewis acids, aluminum chloride, ferric chloride, zinc chloride, tin chloride, titanium chloride, boron trifluoride, antimony pentachloride and zirconium tetrachloride.
8. The method of claim 6 wherein the ring closing reagent is sulfuric acid.
9. The method of claim 6 further comprising the step of heating.
10. A process for making 1-(3-carboxypyridyl-2)-4-methyl-2-phenyl-piperazine by hydrolyzing 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine comprising the step of reacting 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine with a base wherein the base is present in a ratio of up to about 12 moles of the base per one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine.
11. The process of claim 10 wherein the ratio of the base to 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine is about 12 moles of base to about one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine to about 9 moles of base to about one mole of 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine.
12. The process of claim 10 wherein the base is potassium hydroxide or sodium hydroxide
13. The process of claim 12 wherein the mixture of the 1-(3-cyanopyridyl-2)-4-methyl-2-phenyl-piperazine and the base is heated to at least about 130°C.
14. The process of claim 13 wherein the mixture is heated to about 130°C to about 150°C.
15. The process of claim 12 wherein the hydrolysis is carried out in water and an aprotic polar solvent.
16. The process of claim 12 wherein the hydrolysis is carried out in a mixture of water and a solvent selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, dimethylformamide, dimethylacetamide and dimethylsulfoxide.
17. The process of claim 12 wherein the hydrolysis is carried out at a pressure of about 3 to about 4 atmospheres pressure.
18. The process of claim 12 wherein the hydrolysis is carried out at almost neat conditions.
19. A process for recrystallized mirtazapine from crude mirtazapine comprising the steps of:
(a) heating a mixture of crude mirtazapine and a solvent;
(b) cooling the mixture such that purified mirtazapine precipitatis; and (c) isolating the recrystallized mirtazapine.
(a) heating a mixture of crude mirtazapine and a solvent;
(b) cooling the mixture such that purified mirtazapine precipitatis; and (c) isolating the recrystallized mirtazapine.
20. The process of claim 19 wherein the solvent is selected from the group consisting of methanol, ethanol, isopropanol, acetone, and mixtures thereof.
21. The process of claim 20 further comprising the step of adding water to the mixture of mirtazapine and solvent to facilitate precipitation of mirtazapine.
22. The process of claim 19 where in the solvent is selected from the group consisting of toluene, hexane, and methylene chloride, and mixtures thereof.
23. The process of claim 20 wherein the solvent is ethanol.
24. The process of claim 19 wherein the recrystallized mirtazapine is a mirtazapine water adduct.
25. The product of the process claim 24.
26. Mirtazapine prepared according to the process of claim 1.
27. A pharmaceutical composition comprising a therapeutically effective amount of mirtazapine of claim 26, and a pharmaceutically acceptable carrier.
28. A method for the treatment of depression, comprising the step of administering to a human subject in need of such treatment the pharmaceutical composition of
27. A pharmaceutical composition comprising a therapeutically effective amount of mirtazapine of claim 26, and a pharmaceutically acceptable carrier.
28. A method for the treatment of depression, comprising the step of administering to a human subject in need of such treatment the pharmaceutical composition of
claim 27.
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WO2001042239A1 (en) * | 1999-12-13 | 2001-06-14 | Sumika Fine Chemicals Co., Ltd. | Process for the preparation of a pyridinemethanol compound |
US6660730B2 (en) * | 2000-11-27 | 2003-12-09 | Sumika Fine Chemicals Co., Ltd. | Anhydrous mirtazapine and process for preparing the same |
UA83666C2 (en) * | 2003-07-10 | 2008-08-11 | Н.В. Органон | Method for the preparation of enantiomerically pure mirtazapine |
ES2246161B1 (en) * | 2004-07-22 | 2007-04-01 | Medichem, S.A. | IMPROVED PROCESS FOR THE MANUFACTURE OF MIRTAZAPINE. |
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