ZA200203228B - Resolution of intermediates in the synthesis of substantially pure bicalutamide. - Google Patents

Resolution of intermediates in the synthesis of substantially pure bicalutamide. Download PDF

Info

Publication number: ZA200203228B
Authority: ZA; South Africa
Prior art keywords: formula; substantially pure; percent; pure enantiomer; intermediate compound
Prior art date: 1999-10-27

Application number

ZA200203228A

Other languages

English (en)

Inventor

Nnochiri N Ekwuribe

Kenneth D James

Original Assignee

Nobex Corp

Priority date (The priority date 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 date listed.)

1999-10-27

Filing date

2002-04-23

Publication date

2003-07-23

2002-04-23 Application filed by Nobex Corp filed Critical Nobex Corp

2003-07-23 Publication of ZA200203228B publication Critical patent/ZA200203228B/en

Links

LKJPYSCBVHEWIU-KRWDZBQOSA-N (R)-bicalutamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-KRWDZBQOSA-N 0.000 title claims description 31
229960000997 bicalutamide Drugs 0.000 title claims description 31
239000000543 intermediate Substances 0.000 title description 40
230000015572 biosynthetic process Effects 0.000 title description 8
238000003786 synthesis reaction Methods 0.000 title description 7
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 63
150000001875 compounds Chemical class 0.000 claims description 61
238000000034 method Methods 0.000 claims description 57
-1 nitro, carboxy, carbamoyl Chemical group 0.000 claims description 56
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 52
150000003839 salts Chemical class 0.000 claims description 37
239000000203 mixture Substances 0.000 claims description 34
125000000217 alkyl group Chemical group 0.000 claims description 28
KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 claims description 22
125000004432 carbon atom Chemical group C* 0.000 claims description 21
LKJPYSCBVHEWIU-UHFFFAOYSA-N N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide Chemical compound C=1C=C(C#N)C(C(F)(F)F)=CC=1NC(=O)C(O)(C)CS(=O)(=O)C1=CC=C(F)C=C1 LKJPYSCBVHEWIU-UHFFFAOYSA-N 0.000 claims description 20
229940097647 casodex Drugs 0.000 claims description 19
KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 claims description 19
239000002904 solvent Substances 0.000 claims description 19
229910052739 hydrogen Inorganic materials 0.000 claims description 18
239000001257 hydrogen Substances 0.000 claims description 18
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 17
239000011593 sulfur Chemical group 0.000 claims description 17
229910052717 sulfur Chemical group 0.000 claims description 17
125000005010 perfluoroalkyl group Chemical group 0.000 claims description 15
125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 14
125000004414 alkyl thio group Chemical group 0.000 claims description 14
PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 13
RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 13
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 13
125000001589 carboacyl group Chemical group 0.000 claims description 12
125000004093 cyano group Chemical group *C#N 0.000 claims description 12
229910052736 halogen Inorganic materials 0.000 claims description 12
150000002367 halogens Chemical class 0.000 claims description 12
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
125000003545 alkoxy group Chemical group 0.000 claims description 11
150000002431 hydrogen Chemical class 0.000 claims description 9
125000001424 substituent group Chemical group 0.000 claims description 9
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
125000000623 heterocyclic group Chemical group 0.000 claims description 6
125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
125000005118 N-alkylcarbamoyl group Chemical group 0.000 claims description 5
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
125000001841 imino group Chemical group [H]N=* 0.000 claims description 5
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
229910052799 carbon Inorganic materials 0.000 claims description 4
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 4
229910052760 oxygen Inorganic materials 0.000 claims description 4
239000001301 oxygen Substances 0.000 claims description 4
229920006395 saturated elastomer Polymers 0.000 claims description 4
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
229910014033 C-OH Inorganic materials 0.000 claims description 3
229910014570 C—OH Inorganic materials 0.000 claims description 3
125000001246 bromo group Chemical group Br* 0.000 claims description 3
125000001309 chloro group Chemical group 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
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
125000003342 alkenyl group Chemical group 0.000 claims description 2
125000005277 alkyl imino group Chemical group 0.000 claims description 2
125000000753 cycloalkyl group Chemical group 0.000 claims description 2
125000001188 haloalkyl group Chemical group 0.000 claims description 2
125000005842 heteroatom Chemical group 0.000 claims description 2
125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
125000001624 naphthyl group Chemical group 0.000 claims description 2
229910052757 nitrogen Inorganic materials 0.000 claims description 2
125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 2
125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 4
125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
125000005605 benzo group Chemical group 0.000 claims 1
239000003814 drug Substances 0.000 description 9
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
229940079593 drug Drugs 0.000 description 8
HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 6
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 6
238000002425 crystallisation Methods 0.000 description 5
230000008025 crystallization Effects 0.000 description 5
150000002148 esters Chemical class 0.000 description 5
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
150000001261 hydroxy acids Chemical class 0.000 description 4
239000003956 nonsteroidal anti androgen Substances 0.000 description 4
230000002194 synthesizing effect Effects 0.000 description 4
150000003568 thioethers Chemical class 0.000 description 4
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
206010060862 Prostate cancer Diseases 0.000 description 3
208000000236 Prostatic Neoplasms Diseases 0.000 description 3
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
239000002253 acid Substances 0.000 description 3
150000007513 acids Chemical class 0.000 description 3
238000001640 fractional crystallisation Methods 0.000 description 3
238000004128 high performance liquid chromatography Methods 0.000 description 3
230000007062 hydrolysis Effects 0.000 description 3
238000006460 hydrolysis reaction Methods 0.000 description 3
238000000926 separation method Methods 0.000 description 3
239000007858 starting material Substances 0.000 description 3
239000000126 substance Substances 0.000 description 3
238000005481 NMR spectroscopy Methods 0.000 description 2
KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
150000001412 amines Chemical class 0.000 description 2
230000002280 anti-androgenic effect Effects 0.000 description 2
238000004587 chromatography analysis Methods 0.000 description 2
238000007796 conventional method Methods 0.000 description 2
239000013078 crystal Substances 0.000 description 2
229910052731 fluorine Inorganic materials 0.000 description 2
230000003287 optical effect Effects 0.000 description 2
125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
238000001953 recrystallisation Methods 0.000 description 2
238000001228 spectrum Methods 0.000 description 2
YBMVNSDRBCKPAO-UHFFFAOYSA-N 3-(4-fluorophenyl)-2-hydroxy-2-methylpropanoic acid Chemical compound OC(=O)C(O)(C)CC1=CC=C(F)C=C1 YBMVNSDRBCKPAO-UHFFFAOYSA-N 0.000 description 1
NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
150000001298 alcohols Chemical class 0.000 description 1
239000003098 androgen Substances 0.000 description 1
239000011260 aqueous acid Substances 0.000 description 1
238000011914 asymmetric synthesis Methods 0.000 description 1
RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 1
RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 description 1
150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
238000006243 chemical reaction Methods 0.000 description 1
238000003821 enantio-separation Methods 0.000 description 1
230000032050 esterification Effects 0.000 description 1
238000005886 esterification reaction Methods 0.000 description 1
238000000605 extraction Methods 0.000 description 1
238000003818 flash chromatography Methods 0.000 description 1
239000011737 fluorine Substances 0.000 description 1
230000010354 integration Effects 0.000 description 1
239000007788 liquid Substances 0.000 description 1
238000004811 liquid chromatography Methods 0.000 description 1
238000004519 manufacturing process Methods 0.000 description 1
239000000463 material Substances 0.000 description 1
LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
238000002156 mixing Methods 0.000 description 1
HLZAXMDOWBOHLS-UHFFFAOYSA-N n-(4-cyanophenyl)-4,4,4-trifluoro-3-(4-fluorophenyl)sulfonyl-2-hydroxy-2-methylbutanamide Chemical compound C=1C=C(C#N)C=CC=1NC(=O)C(O)(C)C(C(F)(F)F)S(=O)(=O)C1=CC=C(F)C=C1 HLZAXMDOWBOHLS-UHFFFAOYSA-N 0.000 description 1
150000002894 organic compounds Chemical class 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
239000007800 oxidant agent Substances 0.000 description 1
230000020477 pH reduction Effects 0.000 description 1
230000000144 pharmacologic effect Effects 0.000 description 1
239000002243 precursor Substances 0.000 description 1
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
230000006340 racemization Effects 0.000 description 1
238000002390 rotary evaporation Methods 0.000 description 1
238000010956 selective crystallization Methods 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
229910000104 sodium hydride Inorganic materials 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
150000003457 sulfones Chemical class 0.000 description 1
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
239000006228 supernatant Substances 0.000 description 1
238000010189 synthetic method Methods 0.000 description 1
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 1
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
239000002699 waste material Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/06—Separation; Purification; Stabilisation; Use of additives
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/26—Separation; Purification; Stabilisation; Use of additives
- C07C319/28—Separation; Purification
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers

Landscapes

Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Chemical Kinetics & Catalysis (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

ZA200203228A 1999-10-27 2002-04-23 Resolution of intermediates in the synthesis of substantially pure bicalutamide. ZA200203228B (en)

Applications Claiming Priority (1)

Application Number	Priority Date	Filing Date	Title
US16188499P	1999-10-27	1999-10-27

Publications (1)

Publication Number	Publication Date
ZA200203228B true ZA200203228B (en)	2003-07-23

Family

ID=22583193

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
ZA200203228A ZA200203228B (en)	1999-10-27	2002-04-23	Resolution of intermediates in the synthesis of substantially pure bicalutamide.

Country Status (19)

Country	Link
US (1)	US6593492B1 (de)
EP (1)	EP1224167A1 (de)
JP (1)	JP4778178B2 (de)
KR (1)	KR20020067509A (de)
CN (1)	CN1413188A (de)
AU (1)	AU2619501A (de)
BR (1)	BR0015124A (de)
CA (1)	CA2389100A1 (de)
CZ (1)	CZ20021434A3 (de)
HK (1)	HK1048299A1 (de)
HU (1)	HUP0203186A2 (de)
IL (2)	IL149256A0 (de)
MX (1)	MXPA02004225A (de)
NO (1)	NO20021999L (de)
NZ (1)	NZ518552A (de)
PL (1)	PL360059A1 (de)
TW (1)	TWI271397B (de)
WO (1)	WO2001034563A1 (de)
ZA (1)	ZA200203228B (de)

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EP1669347A1 (de) *	2004-12-10	2006-06-14	Helm AG	Verfahren zur Herstellung von 3-¬(4-Fluorphenyl)sulfonyl\|-2-hydroxy-2-methylpropionsäure
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WO2008013791A2 (en) *	2006-07-24	2008-01-31	University Of Delaware	Pan-antagonists for the androgen receptor and androgen receptor mutants associated with anti-androgen withdrawal
US10010521B2 (en)	2006-08-24	2018-07-03	University Of Tennessee Research Foundation	SARMs and method of use thereof
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WO2011008543A2 (en) *	2009-06-29	2011-01-20	University Of Delaware	Pan-antagonists for the androgen receptor and androgen receptor mutants associated with anti-androgen withdrawal
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CA2389100A1 (en)	2001-05-17
NO20021999L (no)	2002-06-20
MXPA02004225A (es)	2002-10-17
KR20020067509A (ko)	2002-08-22
US6593492B1 (en)	2003-07-15
EP1224167A1 (de)	2002-07-24
PL360059A1 (en)	2004-09-06
JP2003513955A (ja)	2003-04-15
IL149256A0 (en)	2002-11-10
HUP0203186A2 (hu)	2003-01-28
IL149256A (en)	2011-05-31
BR0015124A (pt)	2002-07-02
AU2619501A (en)	2001-06-06
CN1413188A (zh)	2003-04-23
NZ518552A (en)	2003-10-31
NO20021999D0 (no)	2002-04-26
HK1048299A1 (zh)	2003-03-28
WO2001034563A1 (en)	2001-05-17
CZ20021434A3 (cs)	2002-11-13
TWI271397B (en)	2007-01-21
JP4778178B2 (ja)	2011-09-21

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