WO2009083258A2 - Solid and crystalline dutasteride and processes for preparation thereof - Google Patents
Solid and crystalline dutasteride and processes for preparation thereof Download PDFInfo
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- WO2009083258A2 WO2009083258A2 PCT/EP2008/011137 EP2008011137W WO2009083258A2 WO 2009083258 A2 WO2009083258 A2 WO 2009083258A2 EP 2008011137 W EP2008011137 W EP 2008011137W WO 2009083258 A2 WO2009083258 A2 WO 2009083258A2
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- 238000000034 method Methods 0.000 title claims abstract description 70
- JWJOTENAMICLJG-QWBYCMEYSA-N dutasteride Chemical compound O=C([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)N[C@@H]4CC3)C)CC[C@@]21C)NC1=CC(C(F)(F)F)=CC=C1C(F)(F)F JWJOTENAMICLJG-QWBYCMEYSA-N 0.000 title claims abstract description 57
- 229960004199 dutasteride Drugs 0.000 title claims abstract description 49
- 239000007787 solid Substances 0.000 title claims description 25
- 230000008569 process Effects 0.000 title abstract description 18
- 238000002360 preparation method Methods 0.000 title description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 51
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- XWMVIJUAZAEWIE-UHFFFAOYSA-N 2,5-bis(trifluoromethyl)aniline Chemical compound NC1=CC(C(F)(F)F)=CC=C1C(F)(F)F XWMVIJUAZAEWIE-UHFFFAOYSA-N 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000002425 crystallisation Methods 0.000 claims abstract description 4
- 230000008025 crystallization Effects 0.000 claims abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 2
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 16
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 239000000725 suspension Substances 0.000 claims description 11
- 239000002841 Lewis acid Substances 0.000 claims description 10
- 150000007517 lewis acids Chemical class 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- 229910015900 BF3 Inorganic materials 0.000 claims description 5
- 150000001266 acyl halides Chemical class 0.000 claims description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 238000002329 infrared spectrum Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000010 aprotic solvent Substances 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 239000012044 organic layer Substances 0.000 claims description 3
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 238000002076 thermal analysis method Methods 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
- 229910015844 BCl3 Inorganic materials 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims 5
- 229910052751 metal Inorganic materials 0.000 claims 3
- 239000002184 metal Substances 0.000 claims 3
- 239000012074 organic phase Substances 0.000 claims 3
- 239000011521 glass Substances 0.000 claims 2
- 239000012535 impurity Substances 0.000 claims 2
- 239000002516 radical scavenger Substances 0.000 claims 2
- 238000005406 washing Methods 0.000 claims 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 claims 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims 1
- 229910003074 TiCl4 Inorganic materials 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 claims 1
- 229960004424 carbon dioxide Drugs 0.000 claims 1
- 235000011089 carbon dioxide Nutrition 0.000 claims 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims 1
- 238000000354 decomposition reaction Methods 0.000 claims 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 claims 1
- 238000004090 dissolution Methods 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 150000004679 hydroxides Chemical class 0.000 claims 1
- 238000010309 melting process Methods 0.000 claims 1
- 150000002739 metals Chemical class 0.000 claims 1
- 150000007522 mineralic acids Chemical class 0.000 claims 1
- 238000001556 precipitation Methods 0.000 claims 1
- 230000007704 transition Effects 0.000 claims 1
- 150000008064 anhydrides Chemical class 0.000 abstract description 20
- 238000000746 purification Methods 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 239000003054 catalyst Substances 0.000 abstract description 5
- 238000002955 isolation Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 125000003368 amide group Chemical group 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 238000007323 disproportionation reaction Methods 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 3
- -1 carboxylic anhydride anhydride Chemical class 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000002411 thermogravimetry Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 241000667653 Duta Species 0.000 description 2
- 238000012369 In process control Methods 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- MUMGGOZAMZWBJJ-DYKIIFRCSA-N Testostosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 MUMGGOZAMZWBJJ-DYKIIFRCSA-N 0.000 description 2
- 229940054749 avodart Drugs 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 238000010965 in-process control Methods 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- DGQOCLATAPFASR-UHFFFAOYSA-N tetrahydroxy-1,4-benzoquinone Chemical compound OC1=C(O)C(=O)C(O)=C(O)C1=O DGQOCLATAPFASR-UHFFFAOYSA-N 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- RZYHXKLKJRGJGP-UHFFFAOYSA-N 2,2,2-trifluoro-n,n-bis(trimethylsilyl)acetamide Chemical compound C[Si](C)(C)N([Si](C)(C)C)C(=O)C(F)(F)F RZYHXKLKJRGJGP-UHFFFAOYSA-N 0.000 description 1
- MKXKZFSAKFUFJP-UHFFFAOYSA-N 2,5-bis(trifluoromethyl)aniline;n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.NC1=CC(C(F)(F)F)=CC=C1C(F)(F)F.NC1=CC(C(F)(F)F)=CC=C1C(F)(F)F MKXKZFSAKFUFJP-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- 108010029908 3-oxo-5-alpha-steroid 4-dehydrogenase Proteins 0.000 description 1
- 102000001779 3-oxo-5-alpha-steroid 4-dehydrogenase Human genes 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WQGJSPDSRUFXPN-UHFFFAOYSA-N CC1=CC=CC=C1.S(=O)(Cl)Cl.S(=O)(Cl)Cl Chemical compound CC1=CC=CC=C1.S(=O)(Cl)Cl.S(=O)(Cl)Cl WQGJSPDSRUFXPN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 206010020112 Hirsutism Diseases 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000004403 Prostatic Hyperplasia Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000007933 aliphatic carboxylic acids Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 206010068168 androgenetic alopecia Diseases 0.000 description 1
- 125000005251 aryl acyl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000002050 international nonproprietary name Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229950004297 lauril Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- NWKYZYGOSPOKDY-UHFFFAOYSA-N n,n-dimethylformamide;pyridine Chemical compound CN(C)C=O.C1=CC=NC=C1 NWKYZYGOSPOKDY-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 238000000399 optical microscopy Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 208000017497 prostate disease Diseases 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
- C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
- C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
Definitions
- the present invention relates to the solid state chemistry of 17 ⁇ -N-[2,5- bis(trifluoromethyl)phenyl] carbamoyl-4-aza-5 - ⁇ -androst- 1 -en-3 -one which international nonproprietary name is Dutasteride (the active ingredient in products marketed as Avodart, Avidart, Avolve, Duagen, Dutas, Dutagen, Duprost) and its process for preparing.
- the synthetic process comprises the mixed anhydride formation, its subsequent reaction with 2,5-bis(trifluoromethyl)phenylamine in the presence of an appropriate Lewis catalyst and its isolation, purification and crystallization from acetonitrile/water.
- the present invention is a novel polymorphic form of Dutasteride called form III, it also relates to methods for preparing Dutasteride in its polymorphic form III.
- Dutasteride is the following:
- Dutasteride is a selective inhibitor of the type 1 and type 2 isoforms of steroid 5 ⁇ - reductase (5 AR), an intracellular enzyme that converts testosterone to 5 ⁇ - dihydrotestoterone (DHT).
- Dutasteride is currently available in the market as Avodart, Avidart, Avolve, Duagen, Dutas, Dutagen, Duprost, etc. as a drug for benign prostatic hyperplasia, and is used for the treatment of prostate diseases such as prostate cancer, acne, male pattern baldness, hirsutism, and prostate gland enlargement.
- Patent US 5565467 shows two different ways to get Dutasteride, one of them includes dehydrogenation of 17 ⁇ -N-[2,5-bis(trifluoromethyl)phenyl]carbamoyl-4-aza-5- ⁇ - androstane-3-one in the presence of catalysts 2,3-dichloro-5,6-dicyano-l,4- benzoquinone (DDQ) and bis(trimethylsilyl) trifluoroacetamide in dioxane as solvent. This process involves several steps.
- the second option is more simple and starts from 4-aza-5 ⁇ -androst-l-ene-3-one-17 ⁇ - carboxylic acid.
- This second way to produce Dutasteride is similar to that disclosed in WO 95/07927.
- Dutasteride The polymorphic forms of Dutasteride are disclosed in US 2004/077673 Al, where two crystalline and one amorphous forms are described.
- the crystalline forms are named I and II and they are characterized by their X-ray powder diffraction pattern and infrared spectra.
- reaction condition developed in the present invention makes it possible to recover the un-reacted starting material (4-aza-5 ⁇ -androst-l-ene-3-one-17 ⁇ - carboxylic acid (H)) with a good quality.
- anhydrides can be formed from two molecules of an ordinary acid only if a dehydrating agent is present.
- Other synthesis of mixed anhydrides involves the reactions of sulfonyl chlorides or acyl halide with carboxylic acid salts. If a metallic salt is used, then Na + , K + or Ag + are the most common cations, but more often, pyridine or another tertiary amine is added to the free acid and the salt thus formed is treated with the acyl halide. This last procedure appeared to be restricted to aryl-acyl chlorides (Justus Liebigs Ann. Chem. 688, 78 (1965)).
- acyl aliphatic chloride or sulfonyl chloride are made react with an aliphatic carboxylic acid in an aprotic solvent like acetonitrile or tetrahydrofuran at low temperature (-30 to O 0 C) and in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (Scheme 3).
- DBU l,8-diazabicyclo[5.4.0]undec-7-ene
- the mixed anhydride Once obtained the mixed anhydride, it can be isolated or not. Although purification by crystallization from different solvents could be performed, we have found recrystallization to be unreliable as a means of purification, effecting partial hydrolysis. In general, mixed anhydrides could be used without further purification because the quality of the obtained anhydride is acceptable to continue with the process.
- Another important aspect of this invention is related to the second step.
- the anhydride group is transformed to amide group by reaction between mixed anhydride and 2,5-bis(trifluoromethyl)phenylamine. This reaction consists in a substitution.
- the amide group generation is performed in the presence of a Lewis acid like boron trifluoride etherate, aluminium trichloride, titanium tetra chloride, boron trichloride, etc. Probably, the Lewis acid lets the formation of a complex with the mixed anhydride (See Scheme 6). This complex suffers the nucleophilic attack from the amine group arising from the 2,5-bis(trifluoromethyl)phenylamine to rend the desired Dutasteride.
- a Lewis acid like boron trifluoride etherate, aluminium trichloride, titanium tetra chloride, boron trichloride, etc.
- reaction (Scheme 6) Due to the reactivity of the anhydride intermediates and the developed conditions (presence of Lewis acid), the reaction (Scheme 6) is finished in around 2 to 4 hours. This is a very important improvement compared with the previous reported synthetic processes.
- Polymorphism can be defined as the ability of the same chemical substance to exist in different crystalline structures.
- the different structures are referred to as polymorphs, polymorphic modifications or forms.
- the present invention provides crystalline Form III of Dutasteride and a process for its preparation.
- the crystalline Form III of Dutasteride is characterized by a Philips equipment X' Pert model with the unit PW3710. Scans were performed over the range of 5°-40° 2 ⁇ , at a 0.02° step size for 2 s per step.
- the melting points result from the curves obtained through DSC (Differential Scanning Calorimetry) in a TA Instruments DSC- equipment at 10 °C/min with a 30 ml/min nitrogen flow.
- the infrared spectra were carried out in a Shimadzu FTIR-8 100 equipment, using a solid substance in the form of pellets with KBr.
- FIG. 1 shows an X-Ray powder diffractogram of crystal- line Form III of Dutasteride.
- FIG. 2 shows an infrared spectrum of crystalline Form III of Dutasteride.
- FIG. 3 shows a thermal profile (DSC and TG) of crystalline Form III of Dutasteride.
- Dutasteride is prepared by a novel and advantageous method because of the global process yield and the quality of the obtained product.
- the first step consists in the reaction of 4-aza-5 ⁇ -androst-l-ene-3-one-17 ⁇ -carboxylic acid (II) with methansulfonyl chloride, p-toluensulfonyl chloride or pivaloyl chloride in the presence of DBU with the selected solvent to produce a mixed anhydride.
- the organic solvent(s) which may be used in the present invention includes at least one solvent selected from the group consisting of tetrahydrofuran, dioxane, acetonitrile, toluene, dimethylacetamide and dimethylformamide, tetrahydrofuran and acetonitrile is most preferred.
- the reaction of the present invention may be carried out at a temperature in the range of -40° to 1O 0 C during 15 - 90 min, preferably -20 to O 0 C during 15-30 min.
- the mixed anhydride obtained could be isolated or not.
- the mixed anhydrides obtained can be used without previous purification in the next step.
- the solution of the mixed anhydride obtained reacts with 2,5-bis(trifiuoromethyl)aniline in the presence of a Lewis acid.
- the Lewis acid which may be employed in the present invention includes a catalyst from the group consisting of boron trifluoride etherate, boron trichloride, aluminium trichloride, titanium tetrachloride, most preferably boron trifluoride etherate.
- the Lewis catalyst is added previous to the addition of the amine compound.
- the reaction of this step may be carried out at a temperature in the range of 20 to 90 0 C, preferably 60-80 0 C.
- the reaction mix concentrates; the residue is taken from an organic solvent, such as methylene dichloride, toluene, ethyl acetate, most preferably ethyl acetate.
- organic solvent such as methylene dichloride, toluene, ethyl acetate, most preferably ethyl acetate.
- the organic layer is treated successively with aqueous solution of sodium bicarbonate and hydrochloric acid.
- the organic solution containing the desired Dutasteride is concentrated in vacuum to rend a solid.
- the process for preparation of polymorphic Form III of Dutasteride includes: a. Dissolving a crude form of Dutasteride in a polar organic solvent, such as acetonitrile, acetone, methanol, tetrahydrofuran, isopropanol, dioxane, preferably acetonitrile
- a polar organic solvent such as acetonitrile, acetone, methanol, tetrahydrofuran, isopropanol, dioxane, preferably acetonitrile
- the crystalline Form III of Dutasteride obtained in the above process is characterized by its X-ray powder diffraction pattern with peaks in angles of 2 ⁇ at the following values: 9.59; 9.90; 14.4; 14.7; 15.6; 19.2; 19.4; 19.8; 20.6; 26.9; 28.5 and 28.9 ⁇ 0.2°.
- the crystalline Form III of Dutasteride has substantially the same X-ray diffraction pattern as shown in Figure 1.
- the crystalline habit of the Form III of dutasteride corresponds to small birrefrigent crystals. It presents homogeneous distribution of sizes.
- the Crystalline Form III of dutasteride presents an intrinsic dissolving speed value (VDI) of the same magnitude of the crystalline forms described in the previous art.
- VDI intrinsic dissolving speed value
- Example 1 Mixed Sulfonic-Carboxylic Anhydrides.
- Example Ia Mixed Sulfonic-Carboxylic Anhydrides.
- Example 2 Mixed Carboxylic Anhydrides.
Abstract
Description
Claims
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EP08868866.8A EP2238152B1 (en) | 2008-01-03 | 2008-12-30 | Processes for preparation of dutasteride |
MX2010007294A MX2010007294A (en) | 2008-01-03 | 2008-12-30 | Solid and crystalline dutasteride and processes for preparation thereof. |
BRPI0821711-4A BRPI0821711A2 (en) | 2008-01-03 | 2008-12-30 | Solid and crystalline dutasteride and processes for its preparation |
CA2709971A CA2709971A1 (en) | 2008-01-03 | 2008-12-30 | Solid and crystalline dutasteride and processes for preparation thereof |
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US1880808P | 2008-01-03 | 2008-01-03 | |
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EP (1) | EP2238152B1 (en) |
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AR (1) | AR070313A1 (en) |
BR (1) | BRPI0821711A2 (en) |
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Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011004242A3 (en) * | 2009-07-09 | 2011-04-21 | Aurobindo Pharma Limited | An improved process for the preparation of dutasteride |
WO2012076516A1 (en) | 2010-12-06 | 2012-06-14 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Pharmaceutical composition comprising dutasteride |
WO2013001322A1 (en) | 2011-06-30 | 2013-01-03 | Richter Gedeon Nyrt. | PROCESS FOR THE SYNTHESIS OF (5α,17β)-N-[(2,5-BIS(TRIFLUOROMETHYL)-PHENYL]-3-OXO-4-AZA-5-ANDROST-1-ENE-17-CARBOXAMIDE |
CN103570796A (en) * | 2012-07-24 | 2014-02-12 | 重庆医药工业研究院有限责任公司 | Preparation method of dutasteride type-I crystal |
CN104292293A (en) * | 2014-09-17 | 2015-01-21 | 广东众生药业股份有限公司 | Preparation method of dutasteride impurity I |
CN106810594A (en) * | 2016-12-30 | 2017-06-09 | 南京生命能科技开发有限公司 | A kind of preparation method of high-purity dutasteride |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102417534B (en) * | 2011-08-31 | 2013-04-10 | 重庆万利康制药有限公司 | Synthesis technology of dutasteride |
US9375433B2 (en) | 2012-09-26 | 2016-06-28 | Tangent Reprofiling Limited | Modulators of androgen synthesis |
WO2014049071A1 (en) * | 2012-09-26 | 2014-04-03 | Tangent Reprofiling Limited | Modulators of androgen synthesis |
KR101251625B1 (en) * | 2012-09-28 | 2013-04-08 | (주)비씨월드제약 | Novel manufacturing method of dutasteride using novel intermediates |
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US5565467A (en) | 1993-09-17 | 1996-10-15 | Glaxo Wellcome Inc. | Androstenone derivative |
US20040077673A1 (en) | 2002-07-17 | 2004-04-22 | Dr. Reddy's Laboratories Limited | Forms of dutasteride and methods for preparation thereof |
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GB0026876D0 (en) * | 2000-11-03 | 2000-12-20 | Glaxo Group Ltd | Process |
KR20050045988A (en) | 2002-07-16 | 2005-05-17 | 지그프리드 리미티드 | Method for introducing a 1,2-double bond into 3-oxo-4-azasteroid compounds |
US20050059692A1 (en) * | 2003-09-09 | 2005-03-17 | Dr. Reddy's Laboratories Limited | Process for the preparation of 17beta-N-[2,5-bis(trifluoromethyl)phenyl] carbamoyl-4-aza-5-alpha-androst-1-en-3-one |
EP1945615A2 (en) * | 2005-11-10 | 2008-07-23 | Dr. Reddy's Laboratories Ltd. | Preparation of dutasteride |
-
2008
- 2008-12-22 AR ARP080105653A patent/AR070313A1/en unknown
- 2008-12-30 EP EP08868866.8A patent/EP2238152B1/en not_active Not-in-force
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- 2008-12-30 MX MX2010007294A patent/MX2010007294A/en active IP Right Grant
- 2008-12-30 CA CA2891751A patent/CA2891751A1/en not_active Abandoned
- 2008-12-30 KR KR1020107014817A patent/KR20110041431A/en not_active Application Discontinuation
- 2008-12-30 BR BRPI0821711-4A patent/BRPI0821711A2/en not_active IP Right Cessation
- 2008-12-30 WO PCT/EP2008/011137 patent/WO2009083258A2/en active Application Filing
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US5565467A (en) | 1993-09-17 | 1996-10-15 | Glaxo Wellcome Inc. | Androstenone derivative |
US20040077673A1 (en) | 2002-07-17 | 2004-04-22 | Dr. Reddy's Laboratories Limited | Forms of dutasteride and methods for preparation thereof |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011004242A3 (en) * | 2009-07-09 | 2011-04-21 | Aurobindo Pharma Limited | An improved process for the preparation of dutasteride |
WO2012076516A1 (en) | 2010-12-06 | 2012-06-14 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Pharmaceutical composition comprising dutasteride |
EP2468262A1 (en) | 2010-12-06 | 2012-06-27 | Krka Tovarna Zdravil, D.D., Novo Mesto | Pharmaceutical composition comprising dutasteride |
WO2013001322A1 (en) | 2011-06-30 | 2013-01-03 | Richter Gedeon Nyrt. | PROCESS FOR THE SYNTHESIS OF (5α,17β)-N-[(2,5-BIS(TRIFLUOROMETHYL)-PHENYL]-3-OXO-4-AZA-5-ANDROST-1-ENE-17-CARBOXAMIDE |
CN103570796A (en) * | 2012-07-24 | 2014-02-12 | 重庆医药工业研究院有限责任公司 | Preparation method of dutasteride type-I crystal |
CN104292293A (en) * | 2014-09-17 | 2015-01-21 | 广东众生药业股份有限公司 | Preparation method of dutasteride impurity I |
CN104292293B (en) * | 2014-09-17 | 2016-04-06 | 广东众生药业股份有限公司 | The preparation method of a kind of dutasteride's impurity I |
CN106810594A (en) * | 2016-12-30 | 2017-06-09 | 南京生命能科技开发有限公司 | A kind of preparation method of high-purity dutasteride |
Also Published As
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US8153648B2 (en) | 2012-04-10 |
CA2709971A1 (en) | 2009-07-09 |
KR20110041431A (en) | 2011-04-21 |
EP2238152A2 (en) | 2010-10-13 |
AR070313A1 (en) | 2010-03-31 |
MX2010007294A (en) | 2010-10-25 |
US20090203724A1 (en) | 2009-08-13 |
WO2009083258A3 (en) | 2009-12-03 |
BRPI0821711A2 (en) | 2015-06-16 |
CA2891751A1 (en) | 2009-07-09 |
EP2238152B1 (en) | 2015-02-18 |
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