FI112218B - Menetelmä optisesti puhtaan tai rikastetun piperatsiini-2-tert-butyylikarboksiamidisubstraatin valmistamiseksi - Google Patents

Menetelmä optisesti puhtaan tai rikastetun piperatsiini-2-tert-butyylikarboksiamidisubstraatin valmistamiseksi Download PDF

Info

Publication number: FI112218B
Authority: FI; Finland
Prior art keywords: tert; group; process according; piperazine; potassium
Prior art date: 1994-02-04

Application number

FI963054A

Other languages

English (en)

Finnish (fi)

Swedish (sv)

Other versions

FI963054A0 (fi

FI963054L (fi

Inventor

David Askin

Kai Rossen

Paul Reider

Richard Varsolona

Ralph Volante

Original Assignee

Merck & Co Inc

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.)

1994-02-04

Filing date

1996-08-01

Publication date

2003-11-14

1996-08-01 Application filed by Merck & Co Inc filed Critical Merck & Co Inc

1996-08-01 Publication of FI963054A0 publication Critical patent/FI963054A0/fi

1996-08-01 Publication of FI963054L publication Critical patent/FI963054L/fi

2003-11-14 Application granted granted Critical

2003-11-14 Publication of FI112218B publication Critical patent/FI112218B/fi

Links

238000000034 method Methods 0.000 title claims abstract description 75
230000008569 process Effects 0.000 title claims abstract description 56
-1 -tert-Butyl Carboxamide Chemical class 0.000 title claims abstract description 24
239000000758 substrate Substances 0.000 title claims description 18
238000002360 preparation method Methods 0.000 title abstract description 27
150000003839 salts Chemical class 0.000 claims abstract description 35
239000002904 solvent Substances 0.000 claims abstract description 26
150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 9
229910052751 metal Inorganic materials 0.000 claims abstract description 8
239000002184 metal Substances 0.000 claims abstract description 8
239000003795 chemical substances by application Substances 0.000 claims abstract description 7
BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 98
HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 41
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
239000000203 mixture Substances 0.000 claims description 35
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 25
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 17
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 14
ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical class OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 claims description 13
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 11
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 9
239000001257 hydrogen Substances 0.000 claims description 9
229910052739 hydrogen Inorganic materials 0.000 claims description 9
KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
239000011734 sodium Substances 0.000 claims description 9
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 8
WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
150000004703 alkoxides Chemical class 0.000 claims description 8
125000001072 heteroaryl group Chemical group 0.000 claims description 8
125000003118 aryl group Chemical group 0.000 claims description 7
229910052799 carbon Inorganic materials 0.000 claims description 7
FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 6
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 6
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 6
RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 6
KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 6
229910052744 lithium Inorganic materials 0.000 claims description 6
AWDMDDKZURRKFG-UHFFFAOYSA-N potassium;propan-1-olate Chemical compound [K+].CCC[O-] AWDMDDKZURRKFG-UHFFFAOYSA-N 0.000 claims description 6
MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-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
238000001035 drying Methods 0.000 claims description 5
229910052708 sodium Inorganic materials 0.000 claims description 5
RCOSUMRTSQULBK-UHFFFAOYSA-N sodium;propan-1-olate Chemical compound [Na+].CCC[O-] RCOSUMRTSQULBK-UHFFFAOYSA-N 0.000 claims description 5
MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical class C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 4
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
125000004432 carbon atom Chemical group C* 0.000 claims description 4
238000011065 in-situ storage Methods 0.000 claims description 4
125000001624 naphthyl group Chemical group 0.000 claims description 4
229910021578 Iron(III) chloride Inorganic materials 0.000 claims description 3
150000001335 aliphatic alkanes Chemical class 0.000 claims description 3
125000000217 alkyl group Chemical group 0.000 claims description 3
150000001924 cycloalkanes Chemical class 0.000 claims description 3
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims description 3
LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 3
MXIRPJHGXWFUAE-UHFFFAOYSA-N lithium;propan-1-olate Chemical compound [Li+].CCC[O-] MXIRPJHGXWFUAE-UHFFFAOYSA-N 0.000 claims description 3
OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 3
229910001623 magnesium bromide Inorganic materials 0.000 claims description 3
229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
239000011591 potassium Substances 0.000 claims description 3
229910052700 potassium Inorganic materials 0.000 claims description 3
RPDAUEIUDPHABB-UHFFFAOYSA-N potassium ethoxide Chemical compound [K+].CC[O-] RPDAUEIUDPHABB-UHFFFAOYSA-N 0.000 claims description 3
BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 claims description 3
235000019260 propionic acid Nutrition 0.000 claims description 3
IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 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
150000001491 aromatic compounds Chemical class 0.000 claims description 2
RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 2
125000001033 ether group Chemical group 0.000 claims description 2
IKNCGYCHMGNBCP-UHFFFAOYSA-N propan-1-olate Chemical compound CCC[O-] IKNCGYCHMGNBCP-UHFFFAOYSA-N 0.000 claims description 2
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
150000002431 hydrogen Chemical class 0.000 claims 1
125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
150000001875 compounds Chemical class 0.000 abstract description 52
GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 abstract description 49
230000006340 racemization Effects 0.000 abstract description 26
239000000543 intermediate Substances 0.000 abstract description 18
239000004030 hiv protease inhibitor Substances 0.000 abstract description 10
229940122440 HIV protease inhibitor Drugs 0.000 abstract description 6
IVXQBCUBSIPQGU-UHFFFAOYSA-N piperazine-1-carboxamide Chemical class NC(=O)N1CCNCC1 IVXQBCUBSIPQGU-UHFFFAOYSA-N 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 95
239000000243 solution Substances 0.000 description 58
235000019439 ethyl acetate Nutrition 0.000 description 41
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 24
239000002585 base Substances 0.000 description 19
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
239000000047 product Substances 0.000 description 18
238000006243 chemical reaction Methods 0.000 description 16
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
238000010992 reflux Methods 0.000 description 13
239000007787 solid Substances 0.000 description 13
229910052757 nitrogen Inorganic materials 0.000 description 12
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 11
238000004128 high performance liquid chromatography Methods 0.000 description 11
239000011541 reaction mixture Substances 0.000 description 11
239000012074 organic phase Substances 0.000 description 10
239000002002 slurry Substances 0.000 description 10
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 9
229920006395 saturated elastomer Polymers 0.000 description 9
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
229960000583 acetic acid Drugs 0.000 description 8
239000000463 material Substances 0.000 description 8
UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 8
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
239000002253 acid Substances 0.000 description 7
238000004458 analytical method Methods 0.000 description 7
238000004296 chiral HPLC Methods 0.000 description 7
JSAZTUYNZHDFNH-UHFFFAOYSA-N (7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl)methanesulfonic acid;piperazine Chemical compound C1CNCCN1.C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C JSAZTUYNZHDFNH-UHFFFAOYSA-N 0.000 description 6
208000030507 AIDS Diseases 0.000 description 6
108010010369 HIV Protease Proteins 0.000 description 6
239000003153 chemical reaction reagent Substances 0.000 description 6
230000014759 maintenance of location Effects 0.000 description 6
239000003921 oil Substances 0.000 description 6
239000000126 substance Substances 0.000 description 6
NASIOHFAYPRIAC-JTQLQIEISA-N tert-butyl (3s)-3-(tert-butylcarbamoyl)piperazine-1-carboxylate Chemical compound CC(C)(C)NC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CCN1 NASIOHFAYPRIAC-JTQLQIEISA-N 0.000 description 6
238000004809 thin layer chromatography Methods 0.000 description 6
238000005481 NMR spectroscopy Methods 0.000 description 5
150000001412 amines Chemical class 0.000 description 5
229940125904 compound 1 Drugs 0.000 description 5
238000001816 cooling Methods 0.000 description 5
238000001914 filtration Methods 0.000 description 5
NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 5
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 5
239000002699 waste material Substances 0.000 description 5
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 4
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
208000031886 HIV Infections Diseases 0.000 description 4
208000037357 HIV infectious disease Diseases 0.000 description 4
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
MIOPJNTWMNEORI-OMNKOJBGSA-N [(4s)-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl]methanesulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-OMNKOJBGSA-N 0.000 description 4
150000001408 amides Chemical class 0.000 description 4
238000003556 assay Methods 0.000 description 4
230000015572 biosynthetic process Effects 0.000 description 4
239000007795 chemical reaction product Substances 0.000 description 4
238000004821 distillation Methods 0.000 description 4
238000001704 evaporation Methods 0.000 description 4
230000008020 evaporation Effects 0.000 description 4
239000012065 filter cake Substances 0.000 description 4
125000005842 heteroatom Chemical group 0.000 description 4
208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 4
208000015181 infectious disease Diseases 0.000 description 4
GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 4
150000004682 monohydrates Chemical class 0.000 description 4
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
239000012071 phase Substances 0.000 description 4
150000004885 piperazines Chemical class 0.000 description 4
235000015320 potassium carbonate Nutrition 0.000 description 4
229910000027 potassium carbonate Inorganic materials 0.000 description 4
238000000926 separation method Methods 0.000 description 4
229910052717 sulfur Inorganic materials 0.000 description 4
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 3
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
108091005804 Peptidases Proteins 0.000 description 3
239000004365 Protease Substances 0.000 description 3
102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 3
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
241000700605 Viruses Species 0.000 description 3
150000001298 alcohols Chemical class 0.000 description 3
239000008346 aqueous phase Substances 0.000 description 3
150000001721 carbon Chemical group 0.000 description 3
150000001735 carboxylic acids Chemical class 0.000 description 3
239000003054 catalyst Substances 0.000 description 3
229940125758 compound 15 Drugs 0.000 description 3
239000012467 final product Substances 0.000 description 3
230000005764 inhibitory process Effects 0.000 description 3
230000000670 limiting effect Effects 0.000 description 3
238000004519 manufacturing process Methods 0.000 description 3
150000002924 oxiranes Chemical class 0.000 description 3
239000008194 pharmaceutical composition Substances 0.000 description 3
239000000843 powder Substances 0.000 description 3
230000002265 prevention Effects 0.000 description 3
238000011084 recovery Methods 0.000 description 3
239000011780 sodium chloride Substances 0.000 description 3
YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 3
CTKINSOISVBQLD-VKHMYHEASA-N (S)-Glycidol Chemical compound OC[C@H]1CO1 CTKINSOISVBQLD-VKHMYHEASA-N 0.000 description 2
LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 2
ZAVOOYHGBYKOEQ-UHFFFAOYSA-N 2,2-dimethylpropanamide;piperazine Chemical class C1CNCCN1.CC(C)(C)C(N)=O ZAVOOYHGBYKOEQ-UHFFFAOYSA-N 0.000 description 2
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 2
CNQCWYFDIQSALX-UHFFFAOYSA-N 3-(chloromethyl)pyridine Chemical compound ClCC1=CC=CN=C1 CNQCWYFDIQSALX-UHFFFAOYSA-N 0.000 description 2
YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
206010001513 AIDS related complex Diseases 0.000 description 2
XUGCUHZXYDOYNF-QHTZZOMLSA-N C1CNCCN1.OC(=O)[C@@H]1CCC(=O)N1.OC(=O)[C@@H]1CCC(=O)N1 Chemical compound C1CNCCN1.OC(=O)[C@@H]1CCC(=O)N1.OC(=O)[C@@H]1CCC(=O)N1 XUGCUHZXYDOYNF-QHTZZOMLSA-N 0.000 description 2
102100031780 Endonuclease Human genes 0.000 description 2
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
229910004298 SiO 2 Inorganic materials 0.000 description 2
DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
239000007983 Tris buffer Substances 0.000 description 2
ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 2
230000032683 aging Effects 0.000 description 2
230000000840 anti-viral effect Effects 0.000 description 2
239000008280 blood Substances 0.000 description 2
210000004369 blood Anatomy 0.000 description 2
239000012267 brine Substances 0.000 description 2
229910002091 carbon monoxide Inorganic materials 0.000 description 2
239000013078 crystal Substances 0.000 description 2
230000007812 deficiency Effects 0.000 description 2
238000001514 detection method Methods 0.000 description 2
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
239000003480 eluent Substances 0.000 description 2
150000002170 ethers Chemical class 0.000 description 2
239000002024 ethyl acetate extract Substances 0.000 description 2
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
238000004817 gas chromatography Methods 0.000 description 2
238000010438 heat treatment Methods 0.000 description 2
150000002391 heterocyclic compounds Chemical class 0.000 description 2
150000004679 hydroxides Chemical class 0.000 description 2
230000002458 infectious effect Effects 0.000 description 2
238000002372 labelling Methods 0.000 description 2
JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
238000002844 melting Methods 0.000 description 2
230000008018 melting Effects 0.000 description 2
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 2
230000037361 pathway Effects 0.000 description 2
235000011007 phosphoric acid Nutrition 0.000 description 2
239000002244 precipitate Substances 0.000 description 2
239000002243 precursor Substances 0.000 description 2
102000004196 processed proteins & peptides Human genes 0.000 description 2
108090000765 processed proteins & peptides Proteins 0.000 description 2
230000009467 reduction Effects 0.000 description 2
QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
239000011877 solvent mixture Substances 0.000 description 2
238000006467 substitution reaction Methods 0.000 description 2
238000004448 titration Methods 0.000 description 2
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
LOPKSXMQWBYUOI-BDAKNGLRSA-N (1s,2r)-1-amino-2,3-dihydro-1h-inden-2-ol Chemical compound C1=CC=C2[C@H](N)[C@H](O)CC2=C1 LOPKSXMQWBYUOI-BDAKNGLRSA-N 0.000 description 1
SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical class O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
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 description 1
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
PRMGUPFTRQDBTH-ZETCQYMHSA-N 2,2-dimethyl-1-[(2s)-piperazin-2-yl]propan-1-one Chemical compound CC(C)(C)C(=O)[C@@H]1CNCCN1 PRMGUPFTRQDBTH-ZETCQYMHSA-N 0.000 description 1
KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical class C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 1
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
UZGLOGCJCWBBIV-UHFFFAOYSA-N 3-(chloromethyl)pyridin-1-ium;chloride Chemical compound Cl.ClCC1=CC=CN=C1 UZGLOGCJCWBBIV-UHFFFAOYSA-N 0.000 description 1
KLDLRDSRCMJKGM-UHFFFAOYSA-N 3-[chloro-(2-oxo-1,3-oxazolidin-3-yl)phosphoryl]-1,3-oxazolidin-2-one Chemical compound C1COC(=O)N1P(=O)(Cl)N1CCOC1=O KLDLRDSRCMJKGM-UHFFFAOYSA-N 0.000 description 1
125000006847 BOC protecting group Chemical group 0.000 description 1
QWOJMRHUQHTCJG-UHFFFAOYSA-N CC([CH2-])=O Chemical compound CC([CH2-])=O QWOJMRHUQHTCJG-UHFFFAOYSA-N 0.000 description 1
KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
229940126657 Compound 17 Drugs 0.000 description 1
FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical class OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
108010042407 Endonucleases Proteins 0.000 description 1
102000004190 Enzymes Human genes 0.000 description 1
108090000790 Enzymes Proteins 0.000 description 1
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
239000007836 KH2PO4 Substances 0.000 description 1
VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
108700026244 Open Reading Frames Proteins 0.000 description 1
108010076039 Polyproteins Proteins 0.000 description 1
IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Chemical class OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
229920002807 Thiomer Polymers 0.000 description 1
108010067390 Viral Proteins Proteins 0.000 description 1
AIHIHVZYAAMDPM-QMMMGPOBSA-N [(2s)-oxiran-2-yl]methyl 3-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=CC(S(=O)(=O)OC[C@H]2OC2)=C1 AIHIHVZYAAMDPM-QMMMGPOBSA-N 0.000 description 1
AESUECJLDNUSMZ-UHFFFAOYSA-N [Li]CCCC.C1CCCCC1 Chemical compound [Li]CCCC.C1CCCCC1 AESUECJLDNUSMZ-UHFFFAOYSA-N 0.000 description 1
HHRFWSALGNYPHA-UHFFFAOYSA-N [N].C1CNCCN1 Chemical compound [N].C1CNCCN1 HHRFWSALGNYPHA-UHFFFAOYSA-N 0.000 description 1
125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 1
230000003213 activating effect Effects 0.000 description 1
125000003158 alcohol group Chemical group 0.000 description 1
150000001338 aliphatic hydrocarbons Chemical group 0.000 description 1
125000003545 alkoxy group Chemical group 0.000 description 1
150000001413 amino acids Chemical group 0.000 description 1
150000003863 ammonium salts Chemical class 0.000 description 1
239000003443 antiviral agent Substances 0.000 description 1
239000003125 aqueous solvent Substances 0.000 description 1
238000010936 aqueous wash Methods 0.000 description 1
125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 1
125000002619 bicyclic group Chemical group 0.000 description 1
210000001124 body fluid Anatomy 0.000 description 1
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
230000008859 change Effects 0.000 description 1
230000006957 competitive inhibition Effects 0.000 description 1
229940126543 compound 14 Drugs 0.000 description 1
229940126214 compound 3 Drugs 0.000 description 1
229940125898 compound 5 Drugs 0.000 description 1
239000012141 concentrate Substances 0.000 description 1
230000008878 coupling Effects 0.000 description 1
238000010168 coupling process Methods 0.000 description 1
238000005859 coupling reaction Methods 0.000 description 1
239000010779 crude oil Substances 0.000 description 1
239000012043 crude product Substances 0.000 description 1
230000006378 damage Effects 0.000 description 1
230000003247 decreasing effect Effects 0.000 description 1
230000007850 degeneration Effects 0.000 description 1
230000005595 deprotonation Effects 0.000 description 1
238000010537 deprotonation reaction Methods 0.000 description 1
238000011873 diastereoselective alkylation Methods 0.000 description 1
238000005906 dihydroxylation reaction Methods 0.000 description 1
JMRYOSQOYJBDOI-UHFFFAOYSA-N dilithium;di(propan-2-yl)azanide Chemical compound [Li+].CC(C)[N-]C(C)C.CC(C)N([Li])C(C)C JMRYOSQOYJBDOI-UHFFFAOYSA-N 0.000 description 1
UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
235000019797 dipotassium phosphate Nutrition 0.000 description 1
201000010099 disease Diseases 0.000 description 1
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
239000006185 dispersion Substances 0.000 description 1
239000012153 distilled water Substances 0.000 description 1
UZZWBUYVTBPQIV-UHFFFAOYSA-N dme dimethoxyethane Chemical compound COCCOC.COCCOC UZZWBUYVTBPQIV-UHFFFAOYSA-N 0.000 description 1
230000000694 effects Effects 0.000 description 1
238000010828 elution Methods 0.000 description 1
230000007613 environmental effect Effects 0.000 description 1
LHWWETDBWVTKJO-UHFFFAOYSA-N et3n triethylamine Chemical compound CCN(CC)CC.CCN(CC)CC LHWWETDBWVTKJO-UHFFFAOYSA-N 0.000 description 1
OJCSPXHYDFONPU-UHFFFAOYSA-N etoac etoac Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
238000002474 experimental method Methods 0.000 description 1
239000000284 extract Substances 0.000 description 1
238000000605 extraction Methods 0.000 description 1
239000000706 filtrate Substances 0.000 description 1
238000003818 flash chromatography Methods 0.000 description 1
239000006260 foam Substances 0.000 description 1
239000012458 free base Substances 0.000 description 1
150000002241 furanones Chemical class 0.000 description 1
125000003844 furanonyl group Chemical group 0.000 description 1
230000002068 genetic effect Effects 0.000 description 1
239000012362 glacial acetic acid Substances 0.000 description 1
VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical class O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 1
239000012456 homogeneous solution Substances 0.000 description 1
DLDIDQIZPBIVNQ-UHFFFAOYSA-N hydron;2-methylpropan-2-amine;chloride Chemical compound Cl.CC(C)(C)N DLDIDQIZPBIVNQ-UHFFFAOYSA-N 0.000 description 1
150000001261 hydroxy acids Chemical group 0.000 description 1
210000000987 immune system Anatomy 0.000 description 1
230000002779 inactivation Effects 0.000 description 1
229910052742 iron Inorganic materials 0.000 description 1
XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
229940011051 isopropyl acetate Drugs 0.000 description 1
GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
239000004310 lactic acid Chemical class 0.000 description 1
235000014655 lactic acid Nutrition 0.000 description 1
ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Substances [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 1
UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
229910052749 magnesium Inorganic materials 0.000 description 1
229910052943 magnesium sulfate Inorganic materials 0.000 description 1
235000019341 magnesium sulphate Nutrition 0.000 description 1
229960002510 mandelic acid Drugs 0.000 description 1
DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
230000004048 modification Effects 0.000 description 1
238000012986 modification Methods 0.000 description 1
125000002950 monocyclic group Chemical group 0.000 description 1
239000000178 monomer Substances 0.000 description 1
229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
235000019796 monopotassium phosphate Nutrition 0.000 description 1
LLYKPZOWCPVRPD-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine;n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=CC=N1 LLYKPZOWCPVRPD-UHFFFAOYSA-N 0.000 description 1
GKTNLYAAZKKMTQ-UHFFFAOYSA-N n-[bis(dimethylamino)phosphinimyl]-n-methylmethanamine Chemical compound CN(C)P(=N)(N(C)C)N(C)C GKTNLYAAZKKMTQ-UHFFFAOYSA-N 0.000 description 1
WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
239000012299 nitrogen atmosphere Substances 0.000 description 1
125000001736 nosyl group Chemical group S(=O)(=O)(C1=CC=C([N+](=O)[O-])C=C1)* 0.000 description 1
239000002773 nucleotide Substances 0.000 description 1
125000003729 nucleotide group Chemical group 0.000 description 1
AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
229910052760 oxygen Inorganic materials 0.000 description 1
229910052763 palladium Inorganic materials 0.000 description 1
239000002245 particle Substances 0.000 description 1
230000001575 pathological effect Effects 0.000 description 1
230000002093 peripheral effect Effects 0.000 description 1
NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
125000004193 piperazinyl group Chemical group 0.000 description 1
108700004029 pol Genes Proteins 0.000 description 1
101150088264 pol gene Proteins 0.000 description 1
238000006116 polymerization reaction Methods 0.000 description 1
230000001323 posttranslational effect Effects 0.000 description 1
GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
MCNTVFNKNAAKPJ-UHFFFAOYSA-N potassium;2-methylpropan-2-ol;2-methylpropan-2-olate Chemical compound [K+].CC(C)(C)O.CC(C)(C)[O-] MCNTVFNKNAAKPJ-UHFFFAOYSA-N 0.000 description 1
JIWDQJYCCQFDAF-UHFFFAOYSA-N potassium;2-methylpropan-2-olate;oxolane Chemical compound [K+].CC(C)(C)[O-].C1CCOC1 JIWDQJYCCQFDAF-UHFFFAOYSA-N 0.000 description 1
230000003389 potentiating effect Effects 0.000 description 1
238000012545 processing Methods 0.000 description 1
230000000750 progressive effect Effects 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
125000006239 protecting group Chemical group 0.000 description 1
108090000623 proteins and genes Proteins 0.000 description 1
102000004169 proteins and genes Human genes 0.000 description 1
230000005588 protonation Effects 0.000 description 1
TXJKATOSKLUITR-UHFFFAOYSA-N pyrazine-2-carbonyl chloride Chemical compound ClC(=O)C1=CN=CC=N1 TXJKATOSKLUITR-UHFFFAOYSA-N 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
238000010791 quenching Methods 0.000 description 1
230000000171 quenching effect Effects 0.000 description 1
238000004064 recycling Methods 0.000 description 1
230000002829 reductive effect Effects 0.000 description 1
230000010076 replication Effects 0.000 description 1
230000001177 retroviral effect Effects 0.000 description 1
239000000741 silica gel Substances 0.000 description 1
229910002027 silica gel Inorganic materials 0.000 description 1
239000007790 solid phase Substances 0.000 description 1
230000003595 spectral effect Effects 0.000 description 1
239000007858 starting material Substances 0.000 description 1
125000001424 substituent group Chemical group 0.000 description 1
BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
238000003786 synthesis reaction Methods 0.000 description 1
235000002906 tartaric acid Nutrition 0.000 description 1
239000011975 tartaric acid Substances 0.000 description 1
QQWYQAQQADNEIC-RVDMUPIBSA-N tert-butyl [(z)-[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)O\N=C(/C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-RVDMUPIBSA-N 0.000 description 1
CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
238000010998 test method Methods 0.000 description 1
FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Substances [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
238000002411 thermogravimetry Methods 0.000 description 1
239000010936 titanium Substances 0.000 description 1
229910052719 titanium Inorganic materials 0.000 description 1
125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
238000012546 transfer Methods 0.000 description 1
238000002054 transplantation Methods 0.000 description 1
241001430294 unidentified retrovirus Species 0.000 description 1
231100000925 very toxic Toxicity 0.000 description 1
230000003612 virological effect Effects 0.000 description 1
229910052725 zinc Inorganic materials 0.000 description 1
239000011701 zinc Substances 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
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems

Landscapes

Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
General Health & Medical Sciences (AREA)
Oncology (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmacology & Pharmacy (AREA)
Virology (AREA)
Communicable Diseases (AREA)
Public Health (AREA)
Veterinary Medicine (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Plural Heterocyclic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Peptides Or Proteins (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)
Cephalosporin Compounds (AREA)
Catalysts (AREA)

FI963054A 1994-02-04 1996-08-01 Menetelmä optisesti puhtaan tai rikastetun piperatsiini-2-tert-butyylikarboksiamidisubstraatin valmistamiseksi FI112218B (fi)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date	Title
US19291694A	1994-02-04	1994-02-04
US19291694		1994-02-04
US9501232		1995-01-30
PCT/US1995/001232 WO1995021162A1 (en)	1994-02-04	1995-01-30	Process for making hiv protease inhibitors

Publications (3)

Publication Number	Publication Date
FI963054A0 FI963054A0 (fi)	1996-08-01
FI963054L FI963054L (fi)	1996-08-01
FI112218B true FI112218B (fi)	2003-11-14

Family

ID=22711555

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
FI963054A FI112218B (fi)	1994-02-04	1996-08-01	Menetelmä optisesti puhtaan tai rikastetun piperatsiini-2-tert-butyylikarboksiamidisubstraatin valmistamiseksi

Country Status (20)

Country	Link
US (1)	US5663341A (de)
EP (1)	EP0741712B1 (de)
JP (1)	JPH09508628A (de)
KR (1)	KR100337579B1 (de)
AT (1)	ATE206407T1 (de)
AU (1)	AU691878B2 (de)
BR (1)	BR9506727A (de)
CA (1)	CA2180947A1 (de)
CZ (1)	CZ291774B6 (de)
DE (1)	DE69523038T2 (de)
ES (1)	ES2161863T3 (de)
FI (1)	FI112218B (de)
HU (1)	HUT76303A (de)
NZ (1)	NZ279734A (de)
RO (1)	RO118292B1 (de)
RU (1)	RU2135482C1 (de)
SK (1)	SK281861B6 (de)
TW (1)	TW472047B (de)
UA (1)	UA46730C2 (de)
WO (1)	WO1995021162A1 (de)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
IL110255A (en) *	1993-07-16	1998-12-06	Merck & Co Inc	Formation and resolution of 2-tert-butylcarboxamido-piperazine
US5464788A (en) *	1994-03-24	1995-11-07	Merck & Co., Inc.	Tocolytic oxytocin receptor antagonists
WO1995029170A1 (en) *	1994-04-22	1995-11-02	Koei Chemical Co., Ltd.	Process for producing optically active n-tert-butyl-2-piperazinecarboxamide and method of racemizing the amide
EP0710652B1 (de) *	1994-11-04	1998-03-04	Yamakawa Chemical Industry Co., Ltd.	Verfahren zur Herstellung von optisch aktiven Piperazinderivaten und Zwischenprodukten für ihre Herstellung
US5939549A (en) *	1995-01-23	1999-08-17	Lonza Ag	Process for the production of 1,4,5,6-tetrahydropyrazine-2-carboxylic acid amides
US5618937A (en) *	1995-03-15	1997-04-08	Merck & Co., Inc.	Process to make HIV protease inhibitor from (2S)-4-picolyl-2-piperazine-t-butylcarboxamide
US5612484A (en) *	1995-05-18	1997-03-18	Merck & Co., Inc.	Process for making HIV protease inhibitors
DE19536658C2 (de) *	1995-09-30	1998-02-19	Degussa	Verfahren zur kontinuierlichen Herstellung von basischen, cyclischen, optisch aktiven alpha-Aminosäuren
CA2201218C (en) *	1996-04-23	2004-09-28	Rudolf Fuchs	Process for the preparation of optically active piperazine-2-carboxylic acid derivatives
CA2513716A1 (en)	2003-02-14	2004-08-26	Applied Research Systems Ars Holding N.V.	Piperazine-2-carboxamide derivatives
GB0314260D0 (en) *	2003-06-19	2003-07-23	Astrazeneca Ab	Therapeutic agents

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
GB604185A (en) *	1940-08-08	1948-06-30	Arthur Mandl	Improvements in electric rectifier systems used in power or control systems such as for follow-up systems
US3692775A (en) *	1969-03-17	1972-09-19	Allied Chem	Racemization of d-or l-{60 -amino-caprolactam in the presence of metal ions
US3852351A (en) *	1972-10-02	1974-12-03	Fmc Corp	Chlorination of acetoacetamides
JPH01117869A (ja) *	1987-10-30	1989-05-10	Hokuriku Seiyaku Co Ltd	２−アミノメチルピペラジン誘導体
CA1340588C (en) *	1988-06-13	1999-06-08	Balraj Krishan Handa	Amino acid derivatives
ATE163926T1 (de) *	1991-11-08	1998-03-15	Merck & Co Inc	Hiv-protease-inhibitoren verwendbar in der aids- behandlung
US5413999A (en) *	1991-11-08	1995-05-09	Merck & Co., Inc.	HIV protease inhibitors useful for the treatment of AIDS
MX9308016A (es) *	1992-12-22	1994-08-31	Lilly Co Eli	Compuestos inhibidores de la proteasa del virus de la inmunodeficiencia humana, procedimiento para su preparacion y formulacion farmaceutica que los contiene.

1995
- 1995-01-27 TW TW084100727A patent/TW472047B/zh not_active IP Right Cessation
- 1995-01-30 HU HU9602143A patent/HUT76303A/hu unknown
- 1995-01-30 AU AU16967/95A patent/AU691878B2/en not_active Ceased
- 1995-01-30 JP JP7520686A patent/JPH09508628A/ja not_active Withdrawn
- 1995-01-30 BR BR9506727A patent/BR9506727A/pt active Search and Examination
- 1995-01-30 AT AT95908747T patent/ATE206407T1/de not_active IP Right Cessation
- 1995-01-30 EP EP95908747A patent/EP0741712B1/de not_active Expired - Lifetime
- 1995-01-30 NZ NZ279734A patent/NZ279734A/en unknown
- 1995-01-30 CA CA002180947A patent/CA2180947A1/en not_active Abandoned
- 1995-01-30 RU RU96117468/04A patent/RU2135482C1/ru not_active IP Right Cessation
- 1995-01-30 UA UA96093433A patent/UA46730C2/uk unknown
- 1995-01-30 ES ES95908747T patent/ES2161863T3/es not_active Expired - Lifetime
- 1995-01-30 CZ CZ19962272A patent/CZ291774B6/cs not_active IP Right Cessation
- 1995-01-30 RO RO96-01576A patent/RO118292B1/ro unknown
- 1995-01-30 DE DE69523038T patent/DE69523038T2/de not_active Expired - Fee Related
- 1995-01-30 KR KR1019960704219A patent/KR100337579B1/ko not_active Expired - Fee Related
- 1995-01-30 WO PCT/US1995/001232 patent/WO1995021162A1/en not_active Ceased
- 1995-01-30 SK SK1006-96A patent/SK281861B6/sk unknown
- 1995-06-07 US US08/487,903 patent/US5663341A/en not_active Expired - Fee Related
1996
- 1996-08-01 FI FI963054A patent/FI112218B/fi active

Also Published As

Publication number	Publication date
TW472047B (en)	2002-01-11
CA2180947A1 (en)	1995-08-10
EP0741712B1 (de)	2001-10-04
HUT76303A (en)	1997-07-28
CZ227296A3 (en)	1997-01-15
JPH09508628A (ja)	1997-09-02
CZ291774B6 (cs)	2003-05-14
KR100337579B1 (ko)	2002-11-13
BR9506727A (pt)	1997-09-23
ES2161863T3 (es)	2001-12-16
SK100696A3 (en)	1997-03-05
US5663341A (en)	1997-09-02
AU691878B2 (en)	1998-05-28
HU9602143D0 (en)	1996-09-30
SK281861B6 (sk)	2001-08-06
UA46730C2 (uk)	2002-06-17
DE69523038T2 (de)	2002-06-06
DE69523038D1 (de)	2001-11-08
EP0741712A1 (de)	1996-11-13
RU2135482C1 (ru)	1999-08-27
RO118292B1 (ro)	2003-04-30
ATE206407T1 (de)	2001-10-15
AU1696795A (en)	1995-08-21
MX9603218A (es)	1997-07-31
NZ279734A (en)	1998-05-27
FI963054A0 (fi)	1996-08-01
FI963054L (fi)	1996-08-01
WO1995021162A1 (en)	1995-08-10

Publication	Publication Date	Title
FI112218B (fi)	2003-11-14	Menetelmä optisesti puhtaan tai rikastetun piperatsiini-2-tert-butyylikarboksiamidisubstraatin valmistamiseksi
US20200331883A1 (en)	2020-10-22	Enantiomeric separation of racemic nicotine by addition of an o,o'-disubstituted tartaric acid enantiomer
AU676079B2 (en)	1997-02-27	Process for making HIV protease inhibitors
US5420353A (en)	1995-05-30	Regiospecific process to make cis-1-amino-2-alkanol from epoxide
AU679770B2 (en)	1997-07-10	Process for making HIV protease inhibitors
SK115396A3 (en)	1997-05-07	Regiospecific processes to make cis-1-amino-2-alkanols
US5723615A (en)	1998-03-03	Process for preparing 4-tert-butyloxycarbonyl-(S)-piperazine-2-tert-butylcarboxamide
MXPA96003218A (en)	1997-12-01	Procedure for making inhibitors of human immunodeficiency and composite intermediate virus proteas
US5508404A (en)	1996-04-16	Reductive amination process
GB2333775A (en)	1999-08-04	Process for preparing 4-alkylcarbonyl-(s)-piperazine-2-alkylcarboxamide