JP2021527038A - (2r,6r)−ヒドロキシノルケタミンの合成および精製のためのプロセス - Google Patents
(2r,6r)−ヒドロキシノルケタミンの合成および精製のためのプロセス Download PDFInfo
- Publication number
- JP2021527038A JP2021527038A JP2020567577A JP2020567577A JP2021527038A JP 2021527038 A JP2021527038 A JP 2021527038A JP 2020567577 A JP2020567577 A JP 2020567577A JP 2020567577 A JP2020567577 A JP 2020567577A JP 2021527038 A JP2021527038 A JP 2021527038A
- Authority
- JP
- Japan
- Prior art keywords
- compound
- optically active
- adduct
- pyroglutamic acid
- active isomer
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 74
- 230000008569 process Effects 0.000 title claims abstract description 72
- CFBVGSWSOJBYGC-ZYHUDNBSSA-N (2r,6r)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexan-1-one Chemical compound C=1C=CC=C(Cl)C=1[C@]1(N)CCC[C@@H](O)C1=O CFBVGSWSOJBYGC-ZYHUDNBSSA-N 0.000 title abstract description 19
- 230000015572 biosynthetic process Effects 0.000 title description 14
- 238000003786 synthesis reaction Methods 0.000 title description 13
- 238000000746 purification Methods 0.000 title description 6
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 238000011097 chromatography purification Methods 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 160
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 63
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 52
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 claims description 44
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 claims description 42
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 31
- ZQJVHBJDLMIKJK-MHDYBILJSA-N (2R,6R)-2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexan-1-one hydrochloride Chemical compound Cl.N[C@]1(CCC[C@@H](O)C1=O)c1ccccc1Cl ZQJVHBJDLMIKJK-MHDYBILJSA-N 0.000 claims description 26
- 229910021529 ammonia Inorganic materials 0.000 claims description 17
- 238000001953 recrystallisation Methods 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 12
- 239000007800 oxidant agent Substances 0.000 claims description 12
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 10
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical group OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 9
- 230000001590 oxidative effect Effects 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- CFBVGSWSOJBYGC-UHFFFAOYSA-N 2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexan-1-one Chemical compound C=1C=CC=C(Cl)C=1C1(N)CCCC(O)C1=O CFBVGSWSOJBYGC-UHFFFAOYSA-N 0.000 claims 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims 1
- 229940126062 Compound A Drugs 0.000 claims 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 51
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- 239000000543 intermediate Substances 0.000 description 34
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
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- 239000000047 product Substances 0.000 description 11
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
- DDVNLGGCSRULIL-UHFFFAOYSA-N (1-bromocyclopentyl)-(2-chlorophenyl)methanone Chemical compound ClC1=CC=CC=C1C(=O)C1(Br)CCCC1 DDVNLGGCSRULIL-UHFFFAOYSA-N 0.000 description 6
- UJYWUCVWTZEQHO-UHFFFAOYSA-N 1-(2-chlorobenzenecarboximidoyl)cyclopentan-1-ol Chemical compound C=1C=CC=C(Cl)C=1C(=N)C1(O)CCCC1 UJYWUCVWTZEQHO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 230000014759 maintenance of location Effects 0.000 description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 5
- 150000002466 imines Chemical class 0.000 description 5
- 230000002572 peristaltic effect Effects 0.000 description 5
- 229910052573 porcelain Inorganic materials 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- BEQZHFIKTBVCAU-LBPRGKRZSA-N (2s)-2-amino-2-(2-chlorophenyl)cyclohexan-1-one Chemical compound C=1C=CC=C(Cl)C=1[C@@]1(N)CCCCC1=O BEQZHFIKTBVCAU-LBPRGKRZSA-N 0.000 description 4
- BEQZHFIKTBVCAU-UHFFFAOYSA-N 2-amino-2-(2-chlorophenyl)-1-cyclohexanone Chemical compound C=1C=CC=C(Cl)C=1C1(N)CCCCC1=O BEQZHFIKTBVCAU-UHFFFAOYSA-N 0.000 description 4
- LULAYUGMBFYYEX-UHFFFAOYSA-N 3-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000000935 antidepressant agent Substances 0.000 description 4
- 229940005513 antidepressants Drugs 0.000 description 4
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 229910000856 hastalloy Inorganic materials 0.000 description 4
- 238000010949 in-process test method Methods 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VRZJVQFAJVIUAX-QGZVFWFLSA-N tert-butyl N-[(1R)-1-(2-chlorophenyl)-2-oxocyclohexyl]carbamate Chemical compound ClC1=C(C=CC=C1)[C@]1(C(CCCC1)=O)NC(OC(C)(C)C)=O VRZJVQFAJVIUAX-QGZVFWFLSA-N 0.000 description 4
- QIJMMRNZBJHXRI-UHFFFAOYSA-N (2-chlorophenyl)-cyclopentylmethanone Chemical compound ClC1=CC=CC=C1C(=O)C1CCCC1 QIJMMRNZBJHXRI-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- OLXBXJXLFYHQIJ-JTQLQIEISA-N Nc1c([C@H](CCCC2)C2=O)cccc1 Chemical compound Nc1c([C@H](CCCC2)C2=O)cccc1 OLXBXJXLFYHQIJ-JTQLQIEISA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- -1 cyclohexanone (L) -pyroglutamic acid Chemical compound 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
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- CETVQRFGPOGIQJ-UHFFFAOYSA-N lithium;hexane Chemical compound [Li+].CCCCC[CH2-] CETVQRFGPOGIQJ-UHFFFAOYSA-N 0.000 description 3
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- 229910052757 nitrogen Inorganic materials 0.000 description 3
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
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- 238000006946 Rubottom oxidation reaction Methods 0.000 description 2
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- 208000028552 Treatment-Resistant Depressive disease Diseases 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
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- 239000002244 precipitate Substances 0.000 description 2
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- BEQZHFIKTBVCAU-GFCCVEGCSA-N (2r)-2-amino-2-(2-chlorophenyl)cyclohexan-1-one Chemical compound C=1C=CC=C(Cl)C=1[C@]1(N)CCCCC1=O BEQZHFIKTBVCAU-GFCCVEGCSA-N 0.000 description 1
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
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- 206010002091 Anaesthesia Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 0 CC(C)(C)OC(N[C@@]1(C(*)=CCCC1)c1ccccc1Cl)=O Chemical compound CC(C)(C)OC(N[C@@]1(C(*)=CCCC1)c1ccccc1Cl)=O 0.000 description 1
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- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 241000269333 Caudata Species 0.000 description 1
- GIAVYZPYLHJCHT-LBPRGKRZSA-N Cc1ccccc1[C@H](CCCC1)C1=O Chemical compound Cc1ccccc1[C@H](CCCC1)C1=O GIAVYZPYLHJCHT-LBPRGKRZSA-N 0.000 description 1
- 206010011971 Decreased interest Diseases 0.000 description 1
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
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- UQWQCMSYGMAGKF-UHFFFAOYSA-N hexane;lithium Chemical compound [Li].CCCCCC UQWQCMSYGMAGKF-UHFFFAOYSA-N 0.000 description 1
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- 238000011031 large-scale manufacturing process Methods 0.000 description 1
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- 238000001556 precipitation Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
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- KBAHJOGZLVQNBH-UHFFFAOYSA-K rubidium(1+);phosphate Chemical compound [Rb+].[Rb+].[Rb+].[O-]P([O-])([O-])=O KBAHJOGZLVQNBH-UHFFFAOYSA-K 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- UIYOVVYZPVVUMJ-UHFFFAOYSA-N tert-butyl carbamoyl carbonate Chemical compound CC(C)(C)OC(=O)OC(N)=O UIYOVVYZPVVUMJ-UHFFFAOYSA-N 0.000 description 1
- CPWJKGIJFGMVPL-UHFFFAOYSA-K tricesium;phosphate Chemical compound [Cs+].[Cs+].[Cs+].[O-]P([O-])([O-])=O CPWJKGIJFGMVPL-UHFFFAOYSA-K 0.000 description 1
- TWQULNDIKKJZPH-UHFFFAOYSA-K trilithium;phosphate Chemical compound [Li+].[Li+].[Li+].[O-]P([O-])([O-])=O TWQULNDIKKJZPH-UHFFFAOYSA-K 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
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Abstract
Description
本出願は、2018年6月4日に出願された米国仮特許出願第62/680,183号(これによりその全体が参照により組み込まれる)に対する優先権およびその恩典を主張する。
本発明は、治療抵抗性うつ病を治癒させるための治療薬の合成、より特定的には、(2R,6R)−ヒドロキシノルケタミンの合成および精製のための改善されたプロセスに関する。
熱流条件を化合物
に適用し、化合物
を得る工程、および
化合物
を(2R,6R)−ヒドロキシノルケタミン塩酸塩に変換する工程
を含む。
を(2R,6R)−ヒドロキシノルケタミン塩酸塩に変換する工程は、化合物
をピログルタミン酸の光学活性異性体と接触させ、化合物
およびピログルタミン酸の光学活性異性体の付加物を得る工程をさらに含んでもよい。
をピログルタミン酸の光学活性異性体と接触させ、化合物
およびピログルタミン酸の光学活性異性体の付加物を得る工程は、
(i)化合物
をピログルタミン酸の光学活性異性体と接触させ、化合物
およびピログルタミン酸の光学活性異性体の付加物およびその鏡像異性体を得る工程、ならびに
化合物
およびピログルタミン酸の光学活性異性体の付加物をその鏡像異性体から分離する工程を含んでもよい。
およびピログルタミン酸の光学活性異性体の付加物を(2R,6R)−ヒドロキシノルケタミン塩酸塩に変換する工程は、
化合物
およびピログルタミン酸の光学活性異性体の付加物を、Boc−保護基含有剤と反応させ、化合物
を得る工程を含み得る。
およびピログルタミン酸の光学活性異性体の付加物をBoc−保護基含有剤と反応させ、化合物
を得る工程に続いて、
化合物
を塩基およびトリメチルシリルクロリドと接触させ、化合物
を得る工程、ならびに
化合物
を酸化剤、続いて塩酸と接触させて、化合物
を得る工程が実施されてもよい。
工程(a):化合物
をブロム化源と反応させ、化合物
を得る工程、
工程(b):化合物
をアンモニア源と反応させ、化合物
を得る工程、
工程(c):熱流条件を化合物
に適用し、化合物
を得る工程、
工程(d):化合物
をピログルタミン酸の光学活性異性体と接触させ、化合物
およびピログルタミン酸の光学活性異性体の付加物およびその鏡像異性体を得る工程、
工程(e):化合物
およびピログルタミン酸の光学活性異性体の付加物をBoc−保護基含有剤と反応させ、化合物
を得る工程、
工程(f):化合物
を、塩基およびトリメチルシリルクロリドと接触させ、化合物
を得る工程、
工程(g):化合物
を酸化剤、続いて塩酸と接触させ、化合物
を得る工程、ならびに
工程(h):化合物
を再結晶化し、(2R,6R)−ヒドロキシノルケタミン塩酸塩を得る工程を含む。
熱流条件を化合物
に適用し、化合物を得る工程、および
化合物
を(2R,6R)−ヒドロキシノルケタミン塩酸塩に変換する工程
を含む。
を(2R,6R)−ヒドロキシノルケタミン塩酸塩に変換する工程は、化合物
をピログルタミン酸の光学活性異性体と接触させ、化合物
およびピログルタミン酸の光学活性異性体の付加物を得る工程をさらに含んでもよい。
をピログルタミン酸の光学活性異性体と接触させ、化合物
およびピログルタミン酸の光学活性異性体の付加物を得る工程は、
(ii)化合物
をピログルタミン酸の光学活性異性体と接触させ、化合物
およびピログルタミン酸の光学活性異性体の付加物およびその鏡像異性体を得る工程、ならびに
化合物
およびピログルタミン酸の光学活性異性体の付加物をその鏡像異性体から分離する工程を含んでもよい。
およびピログルタミン酸の光学活性異性体の付加物を(2R,6R)−ヒドロキシノルケタミン塩酸塩に変換する工程は、
化合物
およびピログルタミン酸の光学活性異性体の付加物をBoc−保護基含有剤と反応させ、化合物
を得る工程を含んでもよい。
およびピログルタミン酸の光学活性異性体の付加物をBoc−保護基含有剤と反応させ、化合物
を得る工程に続いて、
化合物
を塩基およびトリメチルシリルクロリドと接触させ、化合物
を得る工程、ならびに
化合物
を酸化剤、続いて塩酸と接触させ、化合物
を得る工程が実施されてもよい。
工程(a):化合物
をブロム化源と反応させ、化合物
を得る工程、
工程(b):化合物
をアンモニア源と反応させ、化合物
を得る工程、
工程(c):熱流条件を化合物
に適用し、化合物
を得る工程、
工程(d):化合物
をピログルタミン酸の光学活性異性体と接触させ、化合物
およびピログルタミン酸の光学活性異性体の付加物およびその鏡像異性体を得る工程、
工程(e):化合物
およびピログルタミン酸の光学活性異性体の付加物をBoc−保護基含有剤と反応させ、化合物
を得る工程、
工程(f):化合物
を塩基およびトリメチルシリルクロリドと接触させ、化合物
を得る工程、
工程(g):化合物
を酸化剤、続いて塩酸と接触させ、化合物
を得る工程、ならびに
工程(h):化合物
を再結晶化し、(2R,6R)−ヒドロキシノルケタミン塩酸塩を得る工程を含む。
再結晶化のために、下記機器/条件を使用した:温度制御−90℃から180℃が備えられた20Lガラスジャケット付き反応器ストリーム、10L撹拌ガラスレシーバー、温度制御−40から180℃が備えられた20Lガラスジャケット付き晶析装置、2×6L磁器フィルタ、焼結ガラスフィルタ、5L3つ口フラスコ。
Claims (20)
- 前記酸化剤はメタ−クロロペルオキシ安息香酸である、請求項7に記載のプロセス。
- 前記(2R,6R)−ヒドロキシノルケタミン塩酸塩の純度は97%以上である、請求項1に記載のプロセス。
- 前記アンモニア源は液体アンモニアである、請求項13に記載のプロセス。
- 前記ブロム化源は分子臭素である、請求項15に記載のプロセス。
- (2R,6R)−ヒドロキシノルケタミンの調製のためのプロセスであって、
工程(a):化合物
をブロム化源と反応させ、化合物
を得る工程、
工程(b):前記化合物
をアンモニア源と反応させ、化合物
を得る工程、
工程(c):熱流条件を前記化合物
に適用し、化合物
を得る工程、
工程(d):前記化合物
をピログルタミン酸の光学活性異性体と接触させ、化合物
およびピログルタミン酸の光学活性異性体の付加物およびその鏡像異性体を得る工程、
工程(e):前記化合物
およびピログルタミン酸の前記光学活性異性体の前記付加物をBoc−保護基含有剤と反応させ、化合物
を得る工程、
工程(f):前記化合物
を塩基およびトリメチルシリルクロリドと接触させ、化合物
を得る工程、
工程(g):前記化合物
を酸化剤、続いて塩酸と接触させ、化合物
を得る工程、ならびに
工程(h):前記化合物
を再結晶化し、(2R,6R)−ヒドロキシノルケタミン塩酸塩を得る工程
を含む、プロセス。 - 工程(h)後の前記(2R,6R)−ヒドロキシノルケタミン塩酸塩の純度は97%以上である、請求項17に記載のプロセス。
- 工程(a)から工程(h)のいずれもクロマトグラフィー精製を必要としない、請求項17に記載のプロセス。
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PCT/US2019/035360 WO2019236557A1 (en) | 2018-06-04 | 2019-06-04 | Process for synthesis and purification of (2r,6r)-hydroxynorketamine |
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WO2017165878A1 (en) * | 2016-03-25 | 2017-09-28 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Crystal forms and methods of synthesis of (2r, 6r)-hydroxynorketamine and (2s, 6s)-hydroxynorketamine |
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WO2017165878A1 (en) * | 2016-03-25 | 2017-09-28 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Crystal forms and methods of synthesis of (2r, 6r)-hydroxynorketamine and (2s, 6s)-hydroxynorketamine |
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PATRICK J. MORRIS ET AL.: "Synthesis and N-methyl-D-aspartate (NMDA)eceptor Activity of Ketamine Metabolites", ORGANIC LETTERS, vol. volume 19, issue 17, JPN6023022773, 22 August 2017 (2017-08-22), pages 4572 - 4575, ISSN: 0005210929 * |
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