DD202546A5

DD202546A5 - Verfahren zur herstellung von neuen benzapetin-2-onen

Verfahren zur herstellung von neuen benzapetin-2-onen Download PDF

Info

Publication number: DD202546A5
Authority: DD; German Democratic Republic
Prior art keywords: compound; alkyl; formula; hydrogen; alkoxy
Prior art date: 1981-08-11

Application number

DD82242400A

Other languages

German (de)

English (en)

Inventor

Jeffrey W H Watthey

Original Assignee

Ciba Geigy

Priority date

1981-08-11

Filing date

1982-08-10

Publication date

1983-09-21

1982-08-10 Application filed by Ciba Geigy filed Critical Ciba Geigy

1983-09-21 Publication of DD202546A5 publication Critical patent/DD202546A5/de

Links

238000000034 method Methods 0.000 title claims description 63
230000008569 process Effects 0.000 title claims description 27
238000002360 preparation method Methods 0.000 title claims description 19
150000001875 compounds Chemical class 0.000 claims abstract description 202
125000003545 alkoxy group Chemical group 0.000 claims abstract description 90
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 86
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 81
239000001257 hydrogen Substances 0.000 claims abstract description 79
125000000217 alkyl group Chemical group 0.000 claims abstract description 78
150000003839 salts Chemical class 0.000 claims abstract description 64
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 40
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 37
125000003118 aryl group Chemical group 0.000 claims abstract description 37
150000002431 hydrogen Chemical class 0.000 claims abstract description 37
125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 37
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 34
229910052736 halogen Inorganic materials 0.000 claims abstract description 25
150000002367 halogens Chemical class 0.000 claims abstract description 25
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 22
125000002837 carbocyclic group Chemical group 0.000 claims abstract description 16
125000004423 acyloxy group Chemical group 0.000 claims abstract description 12
125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 12
125000005530 alkylenedioxy group Chemical group 0.000 claims abstract description 7
-1 carboxy, carbamoyl Chemical group 0.000 claims description 118
230000002829 reductive effect Effects 0.000 claims description 90
239000000203 mixture Substances 0.000 claims description 86
AYQMNFRCBKOMIA-UHFFFAOYSA-N 1-benzazepin-2-one Chemical compound O=C1C=CC=C2C=CC=CC2=N1 AYQMNFRCBKOMIA-UHFFFAOYSA-N 0.000 claims description 56
239000002253 acid Substances 0.000 claims description 46
125000004043 oxo group Chemical group O=* 0.000 claims description 38
238000006243 chemical reaction Methods 0.000 claims description 36
101000588924 Anthopleura elegantissima Delta-actitoxin-Ael1a Proteins 0.000 claims description 30
229910052757 nitrogen Inorganic materials 0.000 claims description 27
230000009467 reduction Effects 0.000 claims description 27
238000006722 reduction reaction Methods 0.000 claims description 27
125000003282 alkyl amino group Chemical group 0.000 claims description 25
238000005804 alkylation reaction Methods 0.000 claims description 24
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
238000009833 condensation Methods 0.000 claims description 20
230000005494 condensation Effects 0.000 claims description 20
230000029936 alkylation Effects 0.000 claims description 19
238000002844 melting Methods 0.000 claims description 19
239000003638 chemical reducing agent Substances 0.000 claims description 15
230000007062 hydrolysis Effects 0.000 claims description 15
238000006460 hydrolysis reaction Methods 0.000 claims description 15
150000007513 acids Chemical class 0.000 claims description 13
125000004432 carbon atom Chemical group C* 0.000 claims description 13
150000002148 esters Chemical class 0.000 claims description 11
229910052799 carbon Inorganic materials 0.000 claims description 10
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
238000005932 reductive alkylation reaction Methods 0.000 claims description 9
125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 6
125000004093 cyano group Chemical group *C#N 0.000 claims description 6
125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
230000003287 optical effect Effects 0.000 claims description 6
125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 6
125000004442 acylamino group Chemical group 0.000 claims description 5
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
150000001721 carbon Chemical group 0.000 claims description 5
238000003797 solvolysis reaction Methods 0.000 claims description 5
125000005843 halogen group Chemical group 0.000 claims description 4
SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 4
238000006555 catalytic reaction Methods 0.000 claims description 3
125000001424 substituent group Chemical group 0.000 claims description 3
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 claims description 3
125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
125000003341 7 membered heterocyclic group Chemical group 0.000 claims description 2
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 claims description 2
CREXVNNSNOKDHW-UHFFFAOYSA-N azaniumylideneazanide Chemical group N[N] CREXVNNSNOKDHW-UHFFFAOYSA-N 0.000 claims description 2
239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 2
ZIIVSQSRUPHYKS-JTQLQIEISA-N (2r)-2-hydroxy-3-iodo-2-methyl-n-[4-nitro-3-(trifluoromethyl)phenyl]propanamide Chemical compound IC[C@@](O)(C)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 ZIIVSQSRUPHYKS-JTQLQIEISA-N 0.000 claims 1
125000005055 alkyl alkoxy group Chemical group 0.000 claims 1
125000003963 dichloro group Chemical group Cl* 0.000 claims 1
238000012423 maintenance Methods 0.000 claims 1
230000001681 protective effect Effects 0.000 claims 1
239000005541 ACE inhibitor Substances 0.000 abstract 1
101100072620 Streptomyces griseus ind2 gene Proteins 0.000 abstract 1
101150091633 psuG gene Proteins 0.000 abstract 1
239000000243 solution Substances 0.000 description 206
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 192
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 168
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 154
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 150
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 132
ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 126
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 117
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 110
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 91
239000002904 solvent Substances 0.000 description 80
235000019441 ethanol Nutrition 0.000 description 75
239000003054 catalyst Substances 0.000 description 59
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 56
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 46
239000011541 reaction mixture Substances 0.000 description 46
239000007858 starting material Substances 0.000 description 43
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 42
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 40
235000011167 hydrochloric acid Nutrition 0.000 description 39
239000000047 product Substances 0.000 description 38
239000000725 suspension Substances 0.000 description 37
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
229960000583 acetic acid Drugs 0.000 description 31
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
235000011054 acetic acid Nutrition 0.000 description 28
229910052943 magnesium sulfate Inorganic materials 0.000 description 27
235000019341 magnesium sulphate Nutrition 0.000 description 27
239000000155 melt Substances 0.000 description 27
239000003921 oil Substances 0.000 description 27
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 26
239000011343 solid material Substances 0.000 description 26
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 22
238000003756 stirring Methods 0.000 description 22
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 21
229910000041 hydrogen chloride Inorganic materials 0.000 description 21
150000003254 radicals Chemical class 0.000 description 21
239000012299 nitrogen atmosphere Substances 0.000 description 20
238000000746 purification Methods 0.000 description 20
239000002585 base Substances 0.000 description 18
239000000284 extract Substances 0.000 description 18
229910052938 sodium sulfate Inorganic materials 0.000 description 18
235000011152 sodium sulphate Nutrition 0.000 description 18
239000007789 gas Substances 0.000 description 17
230000005764 inhibitory process Effects 0.000 description 17
230000015572 biosynthetic process Effects 0.000 description 16
230000008018 melting Effects 0.000 description 16
230000036772 blood pressure Effects 0.000 description 15
239000000706 filtrate Substances 0.000 description 15
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 14
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 13
150000001408 amides Chemical class 0.000 description 13
UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 13
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 13
238000003786 synthesis reaction Methods 0.000 description 13
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
150000001412 amines Chemical class 0.000 description 12
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 12
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
239000012074 organic phase Substances 0.000 description 12
239000000741 silica gel Substances 0.000 description 12
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102400000344 Angiotensin-1 Human genes 0.000 description 11
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ORWYRWWVDCYOMK-HBZPZAIKSA-N angiotensin I Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C1=CC=C(O)C=C1 ORWYRWWVDCYOMK-HBZPZAIKSA-N 0.000 description 11
239000007864 aqueous solution Substances 0.000 description 11
239000000543 intermediate Substances 0.000 description 11
239000002244 precipitate Substances 0.000 description 11
125000006239 protecting group Chemical group 0.000 description 11
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 10
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229920006395 saturated elastomer Polymers 0.000 description 10
UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 9
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 9
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238000001704 evaporation Methods 0.000 description 9
230000008020 evaporation Effects 0.000 description 9
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
238000012360 testing method Methods 0.000 description 9
QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
239000008346 aqueous phase Substances 0.000 description 8
125000004185 ester group Chemical group 0.000 description 8
PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 8
239000000463 material Substances 0.000 description 8
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BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
235000017557 sodium bicarbonate Nutrition 0.000 description 8
229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
229910000104 sodium hydride Inorganic materials 0.000 description 8
229910052717 sulfur Inorganic materials 0.000 description 8
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
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 description 7
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BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 7
239000000376 reactant Substances 0.000 description 7
239000012312 sodium hydride Substances 0.000 description 7
CIVZHVZUMZYFJP-UHFFFAOYSA-N 1h-1-benzazepine-2,5-dione Chemical class N1C(=O)C=CC(=O)C2=CC=CC=C21 CIVZHVZUMZYFJP-UHFFFAOYSA-N 0.000 description 6
OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
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125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
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239000011780 sodium chloride Substances 0.000 description 6
JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 6
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