CS200508B2 - Process for preparing 17alpha-/3-r2-oxypropyl/-17beta-r1-oxy-4,6-gonadien-3-ones - Google Patents
Process for preparing 17alpha-/3-r2-oxypropyl/-17beta-r1-oxy-4,6-gonadien-3-ones Download PDFInfo
- Publication number
- CS200508B2 CS200508B2 CS786763A CS676378A CS200508B2 CS 200508 B2 CS200508 B2 CS 200508B2 CS 786763 A CS786763 A CS 786763A CS 676378 A CS676378 A CS 676378A CS 200508 B2 CS200508 B2 CS 200508B2
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- acid
- hydroxy
- hydroxypropyl
- methyl
- carbon atoms
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 13
- 230000032050 esterification Effects 0.000 claims description 10
- 238000005886 esterification reaction Methods 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 150000007524 organic acids Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 238000006266 etherification reaction Methods 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910000510 noble metal Inorganic materials 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- MSEZLHAVPJYYIQ-VMXHOPILSA-N (8s,9s,10r,13s,14s)-10,13-dimethyl-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CCC[C@@]1(C)CC2 MSEZLHAVPJYYIQ-VMXHOPILSA-N 0.000 claims 1
- 238000006317 isomerization reaction Methods 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 72
- -1 organic acid radical Chemical group 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000002253 acid Substances 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 150000001875 compounds Chemical class 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 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 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 150000008065 acid anhydrides Chemical class 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 229910052786 argon Inorganic materials 0.000 description 5
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 150000003431 steroids Chemical class 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- GPSDUZXPYCFOSQ-UHFFFAOYSA-N m-toluic acid Chemical compound CC1=CC=CC(C(O)=O)=C1 GPSDUZXPYCFOSQ-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 159000000000 sodium salts Chemical class 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 229940014800 succinic anhydride Drugs 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 2
- PQSUYGKTWSAVDQ-ZVIOFETBSA-N Aldosterone Chemical compound C([C@@]1([C@@H](C(=O)CO)CC[C@H]1[C@@H]1CC2)C=O)[C@H](O)[C@@H]1[C@]1(C)C2=CC(=O)CC1 PQSUYGKTWSAVDQ-ZVIOFETBSA-N 0.000 description 2
- PQSUYGKTWSAVDQ-UHFFFAOYSA-N Aldosterone Natural products C1CC2C3CCC(C(=O)CO)C3(C=O)CC(O)C2C2(C)C1=CC(=O)CC2 PQSUYGKTWSAVDQ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 229960002478 aldosterone Drugs 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- QVQLCTNNEUAWMS-UHFFFAOYSA-N barium oxide Chemical compound [Ba]=O QVQLCTNNEUAWMS-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- QEWYKACRFQMRMB-UHFFFAOYSA-N fluoroacetic acid Chemical compound OC(=O)CF QEWYKACRFQMRMB-UHFFFAOYSA-N 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- ZWLPBLYKEWSWPD-UHFFFAOYSA-N o-toluic acid Chemical compound CC1=CC=CC=C1C(O)=O ZWLPBLYKEWSWPD-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 2
- FCOGYPACUCYJOO-UHFFFAOYSA-N (2-ethoxyacetyl) 2-ethoxyacetate Chemical class CCOCC(=O)OC(=O)COCC FCOGYPACUCYJOO-UHFFFAOYSA-N 0.000 description 1
- SEPPVOUBHWNCAW-FNORWQNLSA-N (E)-4-oxonon-2-enal Chemical compound CCCCCC(=O)\C=C\C=O SEPPVOUBHWNCAW-FNORWQNLSA-N 0.000 description 1
- QXQAPNSHUJORMC-UHFFFAOYSA-N 1-chloro-4-propylbenzene Chemical compound CCCC1=CC=C(Cl)C=C1 QXQAPNSHUJORMC-UHFFFAOYSA-N 0.000 description 1
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- ZESRJSPZRDMNHY-YFWFAHHUSA-N 11-deoxycorticosterone Chemical compound O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@H](CC4)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 ZESRJSPZRDMNHY-YFWFAHHUSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- GIAFURWZWWWBQT-UHFFFAOYSA-N 2-(2-aminoethoxy)ethanol Chemical compound NCCOCCO GIAFURWZWWWBQT-UHFFFAOYSA-N 0.000 description 1
- ASDQMECUMYIVBG-UHFFFAOYSA-N 2-[2-(2-aminoethoxy)ethoxy]ethanol Chemical compound NCCOCCOCCO ASDQMECUMYIVBG-UHFFFAOYSA-N 0.000 description 1
- AWLVTQRRKPBQEQ-UHFFFAOYSA-N 2-benzylsulfanylacetic acid Chemical compound OC(=O)CSCC1=CC=CC=C1 AWLVTQRRKPBQEQ-UHFFFAOYSA-N 0.000 description 1
- BUTJLJIPWQEYOC-UHFFFAOYSA-N 2-cyclopropylideneacetic acid Chemical compound OC(=O)C=C1CC1 BUTJLJIPWQEYOC-UHFFFAOYSA-N 0.000 description 1
- CGMMPMYKMDITEA-UHFFFAOYSA-N 2-ethylbenzoic acid Chemical compound CCC1=CC=CC=C1C(O)=O CGMMPMYKMDITEA-UHFFFAOYSA-N 0.000 description 1
- VJIKFWJCVWFZIN-UHFFFAOYSA-N 2-ethylsulfanylacetic acid Chemical compound CCSCC(O)=O VJIKFWJCVWFZIN-UHFFFAOYSA-N 0.000 description 1
- UMVOQQDNEYOJOK-UHFFFAOYSA-N 3,5-dimethylbenzoic acid Chemical compound CC1=CC(C)=CC(C(O)=O)=C1 UMVOQQDNEYOJOK-UHFFFAOYSA-N 0.000 description 1
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 description 1
- LLBZPESJRQGYMB-UHFFFAOYSA-N 4-one Natural products O1C(C(=O)CC)CC(C)C11C2(C)CCC(C3(C)C(C(C)(CO)C(OC4C(C(O)C(O)C(COC5C(C(O)C(O)CO5)OC5C(C(OC6C(C(O)C(O)C(CO)O6)O)C(O)C(CO)O5)OC5C(C(O)C(O)C(C)O5)O)O4)O)CC3)CC3)=C3C2(C)CC1 LLBZPESJRQGYMB-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Natural products OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 229910014033 C-OH Inorganic materials 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 229910014570 C—OH Inorganic materials 0.000 description 1
- RBNPOMFGQQGHHO-UWTATZPHSA-N D-glyceric acid Chemical compound OC[C@@H](O)C(O)=O RBNPOMFGQQGHHO-UWTATZPHSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- APRJFNLVTJWEPP-UHFFFAOYSA-N Diethylcarbamic acid Chemical compound CCN(CC)C(O)=O APRJFNLVTJWEPP-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- GCKMFJBGXUYNAG-HLXURNFRSA-N Methyltestosterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@](C)(O)[C@@]1(C)CC2 GCKMFJBGXUYNAG-HLXURNFRSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SGXDXUYKISDCAZ-UHFFFAOYSA-N N,N-diethylglycine Chemical compound CCN(CC)CC(O)=O SGXDXUYKISDCAZ-UHFFFAOYSA-N 0.000 description 1
- FFDGPVCHZBVARC-UHFFFAOYSA-N N,N-dimethylglycine Chemical compound CN(C)CC(O)=O FFDGPVCHZBVARC-UHFFFAOYSA-N 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- 108010077895 Sarcosine Proteins 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 150000004075 acetic anhydrides Chemical class 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 229960004050 aminobenzoic acid Drugs 0.000 description 1
- 229960004909 aminosalicylic acid Drugs 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 229940040526 anhydrous sodium acetate Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 159000000032 aromatic acids Chemical class 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- WXBLLCUINBKULX-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1.OC(=O)C1=CC=CC=C1 WXBLLCUINBKULX-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 150000003842 bromide salts Chemical class 0.000 description 1
- ZZHGIUCYKGFIPV-UHFFFAOYSA-N butylcarbamic acid Chemical compound CCCCNC(O)=O ZZHGIUCYKGFIPV-UHFFFAOYSA-N 0.000 description 1
- 150000001715 carbamic acids Chemical class 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- ZESRJSPZRDMNHY-UHFFFAOYSA-N de-oxy corticosterone Natural products O=C1CCC2(C)C3CCC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 ZESRJSPZRDMNHY-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229960003654 desoxycortone Drugs 0.000 description 1
- DWLVWMUCHSLGSU-UHFFFAOYSA-N dimethylcarbamic acid Chemical compound CN(C)C(O)=O DWLVWMUCHSLGSU-UHFFFAOYSA-N 0.000 description 1
- 108700003601 dimethylglycine Proteins 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 150000002084 enol ethers Chemical class 0.000 description 1
- USYYTAZBXJZVHZ-UHFFFAOYSA-N ethanesulfonic acid;methane Chemical class C.CCS(O)(=O)=O USYYTAZBXJZVHZ-UHFFFAOYSA-N 0.000 description 1
- KNFXXAGQEUUZAZ-UHFFFAOYSA-N ethyl ethaneperoxoate Chemical compound CCOOC(C)=O KNFXXAGQEUUZAZ-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000008098 formaldehyde solution Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- KDCIHNCMPUBDKT-UHFFFAOYSA-N hexane;propan-2-one Chemical compound CC(C)=O.CCCCCC KDCIHNCMPUBDKT-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940046892 lead acetate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- 229960001566 methyltestosterone Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical class CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- PWXJULSLLONQHY-UHFFFAOYSA-N phenylcarbamic acid Chemical compound OC(=O)NC1=CC=CC=C1 PWXJULSLLONQHY-UHFFFAOYSA-N 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- JTZQCHFUGHIPDF-RYVBEKKQSA-M potassium canrenoate Chemical compound [K+].O=C1CC[C@]2(C)[C@H]3CC[C@](C)([C@](CC4)(O)CCC([O-])=O)[C@@H]4[C@@H]3C=CC2=C1 JTZQCHFUGHIPDF-RYVBEKKQSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Natural products OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- FSYKKLYZXJSNPZ-UHFFFAOYSA-N sarcosine Chemical compound C[NH2+]CC([O-])=O FSYKKLYZXJSNPZ-UHFFFAOYSA-N 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- HSFQBFMEWSTNOW-UHFFFAOYSA-N sodium;carbanide Chemical group [CH3-].[Na+] HSFQBFMEWSTNOW-UHFFFAOYSA-N 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- BPLKQGGAXWRFOE-UHFFFAOYSA-M trimethylsulfoxonium iodide Chemical compound [I-].C[S+](C)(C)=O BPLKQGGAXWRFOE-UHFFFAOYSA-M 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- DGJTZXXNXZVULP-UHFFFAOYSA-N undecanoyl undecanoate Chemical compound CCCCCCCCCCC(=O)OC(=O)CCCCCCCCCC DGJTZXXNXZVULP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Steroid Compounds (AREA)
Description
Ri znamená vodík nebo zbytek organické kyseliny až se 3 atomy uhlíku,R1 is hydrogen or an organic acid radical of up to 3 carbon atoms,
Rž značí vodík, alkylovou skupinu až se 2 atomy uhlíku, aralkylovou skupinu až s 19 atomy uhlíku nebo zbytek organické kyseliny až s 12 atomy uhlíku,R @ 2 denotes hydrogen, an alkyl group of up to 2 carbon atoms, an aralkyl group of up to 19 carbon atoms or an organic acid residue of up to 12 carbon atoms,
R3 představuje methylovou nebo ethylovou skupinu aR 3 represents a methyl or ethyl group and
R4 znamená atom vodíku nebo methylovou skupinu.R4 represents a hydrogen atom or a methyl group.
Jako zbytky kyseliny přicházejí v úvahu zbytky odvozené od netoxických kyselin, které jsou odvozené zvláště od alkanoylových kyselin s 1 až 12 atomy uhlíku, zejména s až 8 atomy uhlíku, například odvozené od jednosytné alkanoylové kyseliny, jako kyseliny mravenčí, octové, propionové, máselné, isomáselné, oí-ethylmáselné, pivalové, valerové, isovalerové, α-ethylvaíerové, trimethyloctové, enanthové nebo kaprylové, nebo odvozené od cyklické kyseliný, zejména cykloalifatické kyseliny, jako kyseliny cyklopropylidenoctové, cyklobutylkarboxylové, cyklopentylkarboxylové, cyklopentyloctové, 3-cyklopentylpropionové, cyklohexylkarboxylové, nebo též odvozené od karbocyklické arylové nebo aralkylové kyseliny, jako kyseliny benzoové, 2-, 3- nebo 4-methylbenzoové.Possible acid residues are those derived from non-toxic acids which are especially derived from alkanoyl acids having 1 to 12 carbon atoms, in particular up to 8 carbon atoms, for example derived from monobasic alkanoylic acids, such as formic, acetic, propionic, butyric, isobutyric, .alpha.-ethylbutyric, pivalic, valeric, isovaleric, .alpha.-ethylviral, trimethylacetic, enanthic or caprylic acids, or derived from a cyclic acid, in particular a cycloaliphatic acid such as cyclopropylideneacetic acid, cyclobutylcarboxylic, cyclopentylcarboxylic, cyclopopentylacetic, derived from a carbocyclic aryl or aralkyl acid such as benzoic, 2-, 3- or 4-methylbenzoic acid.
Protože chemický charakter acylové skupiny není pro sloučeniny vyrobené způsobem podle vynálezu významný, pokud acylová skupina nepůsobí toxicky nebo netvoří s primární hydroxylovou skupinou ester, jsou vhodné též jiné alifatické a aromatické substituované a nesubstituované jedno-, dvoj- a vícesytné karboxylové kyseliny, nasycené nebo nenasycené alifatické, arylalifatické a aromatické karboxylové kyseliny až s 12 atomy uhlíku, zejména však nejvýše s 8 atomy uhlíku.Since the chemical nature of the acyl group is not relevant to the compounds produced by the process of the invention, unless the acyl group is toxic or forms an ester with the primary hydroxyl group, other aliphatic and aromatic substituted and unsubstituted mono-, di- and polybasic carboxylic acids, saturated or unsaturated aliphatic, arylaliphatic and aromatic carboxylic acids having up to 12 carbon atoms, in particular up to 8 carbon atoms.
Je třeba uvést například kyselinu undecylovou, dodekanovou, 3-cyklohe,xypropionovou, 2,3-, 2,4-, 2,6-, 3,4- a 3,5-dimethylbenzoovou, ethylbenzoovou, naftoovou, 3200508Mention may be made, for example, of undecylic acid, dodecanoic acid, 3-cyclohexyl, xypropionic acid, 2,3-, 2,4-, 2,6-, 3,4- and 3,5-dimethylbenzoic acid, ethylbenzoic acid, naphthoic acid, 3200508
-methyl-or-naftoovou, /J-fenylpropionovou, difenyloctovou a «-naftyloctovou nebo dvojsytné alkanoylové kyseliny, například kyselinu šťavelovou, maleinovou, fumarovou, jantarovou, malonovou, glutarovou, os-methylglutarovou, 3-methylglutarovou, /3,/S-dimethylglutarovou, adipovou, pimelovou a sebakovou, dvojsytné aromatické kyseliny schopné tvořit vnitřní anhydridy, jako kyselinu ftalovou, karbamidové kyseliny, jako kyselinu karbamidovou, fenylkarbamidovou, n-butylkarbamidovou, dimethylkarbamidovou, diethylkarbamidovou a alofanovou nebo heterocyklické kyseliny, jako kyselinu /3-furylkarboxylovou, pyrrolkarboxylovou, β-pyrrolidinopropionovou, N-methylpyrrolidino-2-karboxylovou, 6-hydrnxyinrinlyl-3-nctovou, N-methylmorfolino-2-karboxylovou a pyrrol-2-karboxylovou nebo sulfonové kyseliny s 1 až 12 atomy uhlíku, jako kyseliny alkansulfonové, například kyselinu methan- a ethansulfonovou, a arylsulfonové kyseliny, například kyselinu benzensulfonovou a p-toluensulfonovou.-methyl-or-naphthoic, [beta] -phenylpropionic, diphenylacetic and n-naphthylacetic or dibasic alkanoylic acids, for example oxalic, maleic, fumaric, succinic, malonic, glutaric, os-methylglutaric, 3-methylglutaric, [3, (S) - dimethylglutaric, adipic, pimelic and sebacic, dibasic aromatic acids capable of forming internal anhydrides such as phthalic acid, carbamic acids such as carbamic acid, phenylcarbamic acid, n-butylcarbamic acid, dimethylcarbamic acid, diethylcarbamic acid and allophanic or heterocyclic acids such as [3-f] , β-pyrrolidinopropionic, N-methylpyrrolidino-2-carboxylic acid, 6-hydroxyinrinlyl-3-acetic acid, N-methylmorpholino-2-carboxylic acid and pyrrole-2-carboxylic acid or sulfonic acids with 1 to 12 carbon atoms, such as alkanesulfonic acid, e.g. methane- and ethanesulfonic acids, and arylsulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid .
Acylové zbytky podle vynálezu mohou být substituovány jedním nebo několika substituenty.The acyl radicals of the invention may be substituted with one or more substituents.
Jako případné substituenty je třeba uvést například tyto zbytky: hydroxyskupinu, halogen, alkolxyskupinu, acyloxyskupinu, sulfonyloxyskupinu, amidoskupinu, sulfátoskupinu, nitroskupinu, merkaptoskupinu a kyanoskupinu, například zbytky kyseliny glykolové, mléčné, citrónové, vinné, maleinové, glycerové, mannonové, glukonové a salicylové, nebo zbytky aminokyselin, jako glycinu, kyseliny aminopropionové, diglykolaminové a triglykolaminové, methylglycin, dimethylglycin, diethylglycin, kyselinu p-aminosalicylovou, p-aminobenzoovou, ethylmerkaptooctovou, benzylmerkaptooctovou, chloroctovou, fluoroctovou, trichloroctovou, trifluoroctovou, thioglykolovou, m-nitrobenzoovou, 2,3,4-trimethoxybenzoovou, fenoxyoc.tovou a .a-naftyloxyoctovou.Optional substituents include, but are not limited to, hydroxy, halogen, alkoxy, acyloxy, sulfonyloxy, amido, sulfate, nitro, mercapto, and cyano, for example, glycolic, lactic, citric, tartaric, gluconic, maleic, and maleic acid, glyceric, salicylic or amino acid residues such as glycine, aminopropionic acid, diglycolamine and triglycolamine, methylglycine, dimethylglycine, diethylglycine, p-aminosalicylic acid, p-aminobenzoic acid, ethylmercaptoacetic acid, benzylmercaptoacetic acid, chloroacetic acid, fluoroacetic acid, trichloroacetic acid, trifluoroacetic acid, trifluoroacetic acid, trifluoroacetic acid, trifluoroacetic acid, 3,4-trimethoxybenzoic, phenoxyacetic and .alpha.-naphthyloxyacetic.
Zvlášť vhodné, jsou především dvojsytné nasycené a nenasycené karboxylové kyseliny.Particularly suitable are especially dibasic saturated and unsaturated carboxylic acids.
Soli se odvozují od příslušných hemiacylátů těchto dvojsytných kyselin. Jako kationy přicházejí v úvahu zejména alkalické kovy sodík a draslík, jakož i amonium. Vhodné jsou však též dvojmocné kovy alkalických zemin, jako vápník, přičemž na jeden molekvivalent vápníku připadají 2 molekvivalenty hemiacylátu.The salts are derived from the respective hemiacylates of these dibasic acids. Suitable cations are, in particular, the alkali metals sodium and potassium as well as ammonium. However, divalent alkaline earth metals such as calcium are also suitable, with 2 mol equivalents of hemiacylate per mole equivalent of calcium.
Jako alkylové zbytky Rz přicházejí v úvahu methyl a ethyl.Suitable alkyl radicals R2 are methyl and ethyl.
Sloučeniny vyrobitelné způsobem podle vynálezu mají buď samy farmakologicky cenné vlastnosti, nebo jsou meziprodukty pro výrobu uznávaně dobrých léčiv. Tak je například 17 cu- (3-hydr oxypr opy 1) -17/3-hydroxy-7<z-thioacetyl-4-androsten-3-on výhodně použitelný jako meziprodukt pro výrobu známé látky blokující aldosteron spironolaktonu [laktonu kyseliny 3-(17/?-hydro;xy· -7of-thioacetyl-3-oxo-4-androsten-17ai-yljpropionové].The compounds obtainable by the process of the invention either possess pharmacologically valuable properties themselves or are intermediates for the production of well-known drugs. Thus, for example, 17? - (3-hydroxypropyl) -17? -Hydroxy-7? -Thioacetyl-4-androsten-3-one is advantageously useful as an intermediate for the production of the known aldosterone spironolactone blocking agent [3- (17R-Hydroxy-7H-thioacetyl-3-oxo-4-androsten-17a-yl) -propionic acid].
Sloučeniny vyrobitelné způsobem podle vynálezu působí též jako diuretika typu aldosteronových antagonistů, to znamená, že obracejí účinek desoxykortikosteronu na vylučování sodíku a draslíku. Sloučeniny jako 17/?-hydroxy-17«- (3-hydroxypropyl) -7fls-thioacetyl-4-androsten-3-on, 17/3-hydroxy-17«- (3-hydroxypropyl ] -7«-ethylthlo-4-androsten-3-οη·, 17d-aeetoxy-37«f-(3-acethxypropyl)-7«-thioacetyl-4-androsten-3-on, 17/3-hydroxy-17a-(3-acetoxypr opyl)-7oí-thioacetyl-6os-methyl-4-androsten-3-on, draselná sůl íy^-hydroxy-lZoí- (3-hemisukcinyloxypropyl)-6-methyl-4,6-androstadien-3-onu a sodná sůl 17(3-hydroxy-17a-(3-hydrosukcinyloxypropyl)-4,6-androstadien-3-onu vykazují v testovacím modelu podle Hollmanna (G. Hollmann a kol. Tubuláre Wirkungen und renale Elimination von Spirolactonen, Náunyn—Schmiedebergs Arch. Exp. Path. Pharmak. 247 (1964) 419, P. Marx, Renale Wirkungen des d-Aldosterons und seines Antagonisten Spironolacton, Diss. Med. Fak. FU Berlin 1966] překvapivě vyšší účinek než známé obdobné sloučeniny (například Kalium—Canrenoat).The compounds obtainable by the process of the invention also act as aldosterone antagonist-type diuretics, i.e., they reverse the effect of desoxycorticosterone on sodium and potassium excretion. Compounds such as 17β-hydroxy-17β- (3-hydroxypropyl) -7β-thioacetyl-4-androsten-3-one, 17β-hydroxy-17β- (3-hydroxypropyl) -7β-ethylthlo-4 -androsten-3-one, 17d-aethoxy-37α- (3-acethxypropyl) -7'-thioacetyl-4-androsten-3-one, 17β-hydroxy-17α- (3-acetoxypropyl) - 7α-thioacetyl-6α-methyl-4-androsten-3-one, η 4 -hydroxy-1 H- (3-hemisuccinyloxypropyl) -6-methyl-4,6-androstadien-3-one potassium salt and sodium salt 17 (3 -hydroxy-17- (3-hydrosuccinyloxypropyl) -4,6-androstadiene-3-one exhibit in the Hollmann test model (G. Hollmann et al. Tubular Wirkungen and Renale Elimination of Spirolactonen, Nunyn-Schmiedebergs Arch. Exp. Path.). Pharmac., 247 (1964) 419, P. Marx, Renale Wirkungen des d-Aldosterons und Seines Antagonisten Spironolacton, Diss Med Fak FU Berlin 1966] surprisingly higher effect than known similar compounds (for example Kalium-Canrenoat).
Sloučeniny obecného vzorce I se vyrábějí podle vynálezu tím způsobem, že se 4-andro sten-3-ony obecného vzorce II,The compounds of the formula I are prepared according to the invention in that the 4-andro-sten-3-ones of the formula II,
kdewhere
Rs a Rí mají shora uvedený význam, isomerují enaminací nebo enolací na odpovídající Δ3·5—sloučeninu, na Δ5—dvojnou vazbu se aduje formaldehyd, ze získané 6-hydroxymethylenové sloučeniny se odštěpí voda, takto získaný 6-exomethylensteroid se isomeru je cyklohexenem v přítomnosti katalyzátoru na bázi ušlechtilých kovů a potom se popřípadě provede etherifikace, esterifikace a popřípadě se hemiacylát obecného vzorce III,R 5 and R 6 are as defined above, isomerized by enamination or enolation to the corresponding Δ 3 · 5 s compound, Δ 5 voj a formaldehyde is added to the vazbu 5 d double bond from the resulting 6-hydroxymethylene compound, the 6-exomethylene steroid thus obtained is cyclohexene in the presence of a noble metal catalyst and then optionally etherification, esterification and optionally the hemiacylate of formula III,
-ÍCPJrO-C-ÍCHJsC-OH A3 „ A',)-IPCJrO-C-CHI with C-OH A3 (A '),)
O o (lli I kdeO o (lli I where
R3 a Ri mají shora uvedený význam a n znamená 1 až 3, převede na jeho sůl. Zvláštní varianta způsobu podle vynálezu spočívá v tom. že se v případě, kdy R.z znamená zbytek dvojsytné kyseliny, hemiacylát převede na amonnou sůl, sůl alkalického kovu nebo sůl kovu alkalické zeminy.R 3 and R 1 are as defined above and n is 1 to 3, converted to its salt. A particular variant of the process according to the invention consists in this. In the case where R 2 is a dibasic acid residue, the hemiacylate is converted into an ammonium salt, an alkali metal salt or an alkaline earth metal salt.
K enaminaci se výchozí steroid zahřeje například s pyrrolidinem nebo morfolinem, ve vhodném rozpouštědle, jako methanolu, methylenchloridu nebo benzenu, popřípadě za přídavku kyseliny p-toluensulfonové.For enamination, the starting steroid is heated, for example, with pyrrolidine or morpholine, in a suitable solvent such as methanol, methylene chloride or benzene, optionally with the addition of p-toluenesulfonic acid.
K přípravě enoletheru se výchozí steroid účelně zahřeje například s acetondimethylketalem, esterem kyseliny orthomravenčí nebo benzylalkoholem ve vhodném rozpouštědle, jako benzenu, dimethylformamidu nebo dioxanu v přítomnosti kyseliny p-toluensulfonové nebo sírové.To prepare the enol ether, the starting steroid is conveniently heated with, for example, acetone dimethyl ketal, orthoformic acid ester or benzyl alcohol in a suitable solvent such as benzene, dimethylformamide or dioxane in the presence of p-toluenesulfonic acid or sulfuric acid.
Na takto vzniklé 3,5-dienaminy, popřípadě 3-alkoxy-3,5-dieny se aduje formaldehyd. Za tím účelem se přidává formaldehyd při teplotě místnosti pozvolna k Δ3-5—steroidu rozpuštěnému ve vhodném rozpouštědle. Vhodnými rozpouštědly jsou alifatické alkoholy, jako methanol a ethanol, .aromatické uhlovodíky, jako benzen a toluen, jakož i cykloalifatické uhlovodíky, jako cyklohexan.Formaldehyde is added to the 3,5-dienamines or 3-alkoxy-3,5-dienes thus formed. For this purpose, formaldehyde was added slowly at room temperature to a Δ 3-5 -steroids dissolved in a suitable solvent. Suitable solvents are aliphatic alcohols such as methanol and ethanol, aromatic hydrocarbons such as benzene and toluene, as well as cycloaliphatic hydrocarbons such as cyclohexane.
Potom se z takto vzniklé 6-hydro:xymethylenové sloučeniny odštěpí voda. Za tím účelem se působí na 6-hydroxymethylsteroid v protickém rozpouštědle kyselinou. Vhodná je například kombinace dioxanu nebo tetrahydrofuranu a kyseliny chlorovodíkové nebo p-toluensulfonové, popřípadě chloridu kyseliny methansulfonové v pyridinu, popřípadě za přídavku bromidu lithného za působení tepla.Water is then cleaved from the 6-hydroxymethylene compound thus formed. To this end, the 6-hydroxymethylsteroid in a protic solvent is treated with acid. For example, a combination of dioxane or tetrahydrofuran and hydrochloric or p-toluenesulfonic acid or methanesulfonic acid chloride in pyridine, optionally with the addition of lithium bromide under the effect of heat, is suitable.
Takto získaný 6-exomethylensteroid se potom izomeruje na 6-methyl-A6-steroid. Za tím účelem se 6-exomethylensteroíd zahřívá delší dobu například v cyklohexenu v přítomnosti katalyzátoru na bázi ušlechtilého kovu, jako paládia. Za teploty varu je reakce ukončena již po několika hodinách. Přísada octanu sodného nebo draselného zkracuje reakci, která se provádí účelně v protickém rozpouštědle, jako methanolu neethanolu.The 6-exomethylensteroid thus obtained is then isomerized to 6-methyl- 6 6 -steroid. To this end, the 6-exomethylene steroid is heated for a longer time in, for example, cyclohexene in the presence of a noble metal catalyst such as palladium. At the boiling point, the reaction is complete in a few hours. The addition of sodium or potassium acetate shortens the reaction, which is conveniently carried out in a protic solvent such as methanol or ethanol.
Má-li se eterifikovat volná hydroxylová skupina, jako primární hydroxylová skupina na l/oř-propylovém zbytku, lze použít známé metody. Eterifikace se výhodně provádí příslušným alkylhalogenidem. Jako halogenidy jsou vhodné chloridy, bromidy a zejména jodldy. Hydroxysloučenina se například rozpustí v polárním rozpouštědle a zahřeje v přítomnosti báze s alkylačním činidlem na teploty v rozmezí teploty místnosti až 100 °C. Jako báze jsou vhodné například kysličník barnatý, hydrid sodný, uhličitan draselný a alkoholáty alkalických kovů, jako ethylát sodný. Jako! polární rozpouštědla přicházejí v úvahu dimethylformamid, dímethylacetamid, tetrahydrofuran, dioxan, ketony, jako aceton a methylisobutylketon, jakož i alkoholy, jako ethanol, butanol, terč.butanol.If the free hydroxyl group is to be etherified, as the primary hydroxyl group on the 1-n-propyl radical, known methods can be used. The etherification is preferably carried out with an appropriate alkyl halide. Suitable halides are chlorides, bromides and especially iodides. For example, the hydroxy compound is dissolved in a polar solvent and heated in the presence of a base with an alkylating agent to temperatures ranging from room temperature to 100 ° C. Suitable bases are, for example, barium oxide, sodium hydride, potassium carbonate and alkali metal alcoholates such as sodium ethylate. As! polar solvents include dimethylformamide, dimethylacetamide, tetrahydrofuran, dioxane, ketones such as acetone and methyl isobutyl ketone, as well as alcohols such as ethanol, butanol, tert-butanol.
Esterifikace primární hydroxyskupiny, popřípadě hydroxypropylskupiny, se provádí známými metodami. Vhodnou metodou je například reakce s anhydridem kyseliny nebo halogenidem kyseliny v přítomnosti terciárního aminu, například pyridinu, kolidinu, triethylaminu nebo 4-dimethylaminopyridinu alespoň při teplotě místnosti. Primární hydroxyskupinu lze esterifikovat též anhydridem kyseliny v přítomnosti silné kyseliny, jako kyseliny p-toluensulfonové, nebo příslušnou kyselinou a anhydridem kyseliny trifluoroctové při teplotě místnosti.The esterification of the primary hydroxy or hydroxypropyl group is carried out by known methods. A suitable method is, for example, reaction with an acid anhydride or acid halide in the presence of a tertiary amine, for example pyridine, collidine, triethylamine or 4-dimethylaminopyridine at least at room temperature. The primary hydroxy group can also be esterified with an acid anhydride in the presence of a strong acid such as p-toluenesulfonic acid, or the appropriate acid and trifluoroacetic anhydride at room temperature.
Má-li se volná hydroxylová skupina, jako primární hydroxylová skupina na 17«-propylovém zbytku, esterifikovat částečně, pak lze i zde použít známých metod. Zvlášť vhodná je esterifikace solí těžkého kovu příslušné kyseliny, například octanem olovnatým nebo ethoxyoctanem olovnatým, v přítomnosti příslušného anhydridů kyseliny, například anhydridů kyseliny octové, popřípadě anhydridů kyseliny ethoxyoctové, při teplotách kolem teploty místnosti.If the free hydroxyl group, such as the primary hydroxyl group on the 17 ' -propyl moiety, is to be partially esterified, then known methods can also be used here. Especially suitable is the esterification of the heavy metal salts of the corresponding acid, for example lead acetate or lead ethoxyacetate, in the presence of the corresponding acid anhydrides, for example acetic anhydrides or ethoxyacetic anhydrides, at temperatures around room temperature.
Pro výrobu sloučenin obecného vzorce I, v nichž Ri a/nebo Rz znamenají zbytek organické kyseliny, se uvedou v reakci 17(3-hydroxy-17a- (3-hydroxypropyl ]-A4-ketosteroidy již substituované na kruhu B nebo Δ4,6-3 -ketosteroidy s anhydridem alkanokyseliny, přičemž se esterifikuje nejdříve primární hydroxylová skupina a teprve poté terciární 17(3-hydroxylová skupina po prodloužené reakční době, popřípadě při zvýšené teplotě. Za tím účelem se účelně výchozí steroid rozpustí v baziském rozpouštědle, jako pyridinu, piperidinu, kolodinu, triethylaminu nebo lutidinu, a přidá se příslušný anhydrid kyseliny. Příznivý je pro esterifikaci též přídavek esterifikačního ka200508 talyzátoru, jako dimethylaminopyridinu.For the preparation of compounds of the formula I in which R @ 1 and / or R @ 2 represent an organic acid residue, 17 (3-hydroxy-17a- (3-hydroxypropyl) -? 4 -ketosteroids already substituted on ring B or Δ 4 are reacted , 6 -3 -ketosteroidy alkanokyseliny anhydride, wherein the first esterifying the primary hydroxy group and then the tertiary 17 (3-hydroxyl group after extended reaction time, optionally at elevated temperature. For this purpose suitably the starting steroid is dissolved in baziském solvent such as pyridine , piperidine, collodine, triethylamine or lutidine, and the corresponding acid anhydride is added, and the addition of an esterification catalyst such as dimethylaminopyridine is also beneficial for esterification.
Primární hydroxylová skupina se esterifikuje již po krátké době, to znamená po 2 až 5 hodinách, zatímco esterifikace terciární hydroxyskupiny vyžaduje delší esterifikační doby. Reakcí lze přirozeně urychlit zahrátím, například zahřátím až k teplotě varu, přičemž se reakční doba zkrátí na několik hodin.The primary hydroxyl group is esterified after only a short time, i.e. after 2 to 5 hours, while esterification of the tertiary hydroxy group requires longer esterification times. The reaction can naturally be accelerated by heating, for example by heating up to the boiling point, and the reaction time is reduced to several hours.
V případě, že bylo primární 23-hydroxylová skupina esterifikována dvojsytnou kyselinou, může se hemiacylát převést na příslušnou sůl alkalického kovu reakcí například s methylátem sodným nebo draselným v methanolovém roztoku. K přípravě amonné soli se účelně používá roztok amoniaku v methanolu.When the primary 23-hydroxyl group has been esterified with a dibasic acid, the hemiacylate can be converted to the corresponding alkali metal salt by reaction with, for example, sodium or potassium methylate in a methanol solution. Suitably, a solution of ammonia in methanol is used to prepare the ammonium salt.
Reakční produkty obecného vzorce I se známými metodami, jako srážením, filtrací nebo extrakcí, oddělí a například chromatografováním a/nebo překrystalováním vyčistí.The reaction products of formula (I) are separated and purified, for example, by chromatography and / or recrystallization, by known methods such as precipitation, filtration or extraction.
Farmakologicky účinné látky obecného vzorce I lze známými způsoby použít pro léčiva, zejména pro orální aplikaci.The pharmacologically active compounds of the formula I can be used for pharmaceuticals, in particular for oral administration, by known methods.
Dávky sloučenin obecného vzorce I činí u člověka 20 až 500 mg/den.The doses of the compounds of formula I in humans are 20 to 500 mg / day.
Způsob podle vynálezu je blíže objasněn dále v příkladech provedení.The process according to the invention is explained in more detail in the Examples below.
Přikladl ml acetanhydridu se ochladí na —10 stupňů Celsia a přidá se po kapkách 29,5 ml kyseliny dusičné (h — 1,51]; k této směsi se přidá za míchání 10 g 17/3-hydroxy-17 a- (3-hydr oxypr opyl) -4,6-androstadien-3-onu, rozpuštěného ve 200 ml chloroformu, pozvolna po kapkách tak, že teplota nestoupne nad —5 °C. Reakční směs se míchá 20 minut při —5 až —10 °C a poté vlije do ledové vody.Example 1 ml of acetic anhydride was cooled to -10 degrees Celsius and 29.5 ml of nitric acid (h -1.51) was added dropwise, to which 10 g of 17/3-hydroxy-17? - (3- hydroxypropyl) -4,6-androstadiene-3-one, dissolved in 200 ml of chloroform, is slowly added dropwise such that the temperature does not rise above -5 DEG C. The reaction mixture is stirred at -5 DEG to -10 DEG C. for 20 min. then pour into ice water.
Chloroformová fáze se oddělí, vodná fáze se extrahuje methylenchloridem, spojené organické extrakty se promyjí do neutrální reakce a odpaří ve vakuu. Získá se 17/3-nitryloxy-17o·- (3-nitryloxypropyl) -4,6-androstadien-3-on.The chloroform phase is separated, the aqueous phase is extracted with methylene chloride, the combined organic extracts are washed neutral and evaporated in vacuo. There was obtained 17β-nitryloxy-17α- (3-nitryloxypropyl) -4,6-androstadien-3-one.
K 6,5 g 17/3-nitryloxy-17a-( 3-nitryloxypropyl)-4,6-androstadien-3-onu v 65 ml methanolu, 8 ml octanu ethylnatého a 20 ml vody se přidá 5 g kyanidu draselného a zahřívá 6 hodin pod zpětným chladičem. Poté se zahustí ve vakuu, ke zbytku se přidá voda a neutralizuje se zředěnou kyselinou chlorovodíkovou. Vypadlý produkt se odsaje, promyje vodou, vysuší, suspenduje v methylenchloridu a extrahuje několikrát 6 N kyselinou chlorovodíkovou. Chlorovodíkový extrakt se za chlazení ledem neutralizuje hydroxidem sodným, vypadlá sraženina se odsaje, promyje vodou a vysuší.To 6.5 g of 17/3-nitryloxy-17a- (3-nitryloxypropyl) -4,6-androstadiene-3-one in 65 ml of methanol, 8 ml of ethyl acetate and 20 ml of water is added 5 g of potassium cyanide and heated to 6 g. hours under reflux. It is then concentrated in vacuo, water is added to the residue and neutralized with dilute hydrochloric acid. The resulting product is filtered off with suction, washed with water, dried, suspended in methylene chloride and extracted several times with 6 N hydrochloric acid. The HCl extract is neutralized with sodium hydroxide while cooling with ice, and the precipitated precipitate is filtered off with suction, washed with water and dried.
Získá se 3,4 g surového 4,7a-(aminomethylldin) -5-kyano-17/5-nitryloxy-17a- (3-nitryloxypropyl)-5/3-androstan-3-onu.3.4 g of crude 4,7a- (aminomethylldine) -5-cyano-17,5-nitryloxy-17a- (3-nitryloxypropyl) -5,3-androstan-3-one are obtained.
3,4 g surového 4,7a-(aminomethylidin)-5-kyano-17i/3-nitryloxy-17Qř-( 3-nitryloxypropyl )-5/3-androstan-3-onu se zahřívá ve 100 ml 1 N kyseliny chlorovodíkové 6 hodin za míchání na parní lázni. Reakční směs se ochladí, vzniklý 4a,7a-karbonyl-5-kyano-17/3-nitr yloxy-17tó- (3-nitryloxypropyl )-5/3-androstan-3-on se odsaje, promyje vodou a vysuší ve vakuu.3.4 g of crude 4,7- (aminomethylidin) -5-cyano-17 H- (3-nitryloxypropyl) -5 / 3-androstan-3-one are heated in 100 ml of 1 N hydrochloric acid. hours with stirring on a steam bath. The reaction mixture was cooled, and the resulting 4α, 7α-carbonyl-5-cyano-17β-nitroxy-17β- (3-nitryloxypropyl) -5,3-androstan-3-one was filtered off with suction, washed with water and dried in vacuo.
2,1 g sodíku se rozpustí ve 200 ml ethanolu, přidají se 3 g 4a,7a-karbonyl-5-kyano-17/3‘-nitryloxy-17i«- (3-nitryloxypropyl)-5(j3-androstan-3-onu a zahřívá 23 hodin pod zpětným chladičem. Roztok se zahustí ve vakuu, vlije na led a okyselí kyselinou sírovou. Vypadlý produkt se odsaje, promyje vodou, vysuší a překrystaluje z methanolu.Dissolve 2.1 g of sodium in 200 ml of ethanol, add 3 g of 4α, 7α-carbonyl-5-cyano-17β-nitryloxy-17β- (3-nitryloxypropyl) -5 (β-androstane-3- The solution was concentrated in vacuo, poured onto ice and acidified with sulfuric acid, and the product was filtered off with suction, washed with water, dried and recrystallized from methanol.
Získá se 1,7 g ethylesteru kyseliny 17/3-nitryloxy-17,a-(3-mtrvloxypropyl)-3-oxo-4-androsten-7ai-karboxylové o teplotě tání 178 až 180 °C.1.7 g of 17/3-nitryloxy-17, .alpha .- (3-nitro-propyl) -3-oxo-4-androstene-7a-carboxylic acid ethyl ester of melting point 178 DEG-180 DEG C. are obtained.
Za účelem redukce takto získaného esteru se 1,6 g esteru v 10 ml tetrahydroifuranu a 10 ml ledové kyseliny octové míchá se 3,5 g zinkového prachu 10 minut při 0 až 5 °C. Zinkový prach se odfiltruje, filtrát zahustí ve vakuu a vlije do ledové vody. Vypadlý ethylester kyseliny 17/3-hydroxy-17a- (3-hydroxypr opyl) -3-oxo-4-andr osten-7a-karboxylové se odsaje a překrystaluje ze směsi acetonu a hexanu. Teplota tání činí 152 až 153,5 °C.In order to reduce the ester thus obtained, 1.6 g of ester in 10 ml of tetrahydroifuran and 10 ml of glacial acetic acid were stirred with 3.5 g of zinc dust for 10 minutes at 0-5 ° C. The zinc dust is filtered off, the filtrate is concentrated in vacuo and poured into ice water. The precipitated 17β-hydroxy-17α- (3-hydroxypropyl) -3-oxo-4-andrene-7α-carboxylic acid ethyl ester is filtered off with suction and recrystallized from acetone-hexane. Melting point: 152-153.5 ° C.
P ř í k 1 a d 2Example 1 a d 2
4ai,7a-karbonyl-5-kyano-17/S-nltryloxy-17a- (3-nitryloxypropyl) -5/S-androstan-3-on se obdobně, jak je popsáno v předchozím příkladu převede methylátem sodným na methylester kyseliny 17/3-nitryloxy-17,a'-(3-nitryloxypr opyl) -3-oxo-4-andr osten-7a-karboxylové a ochranné skupiny se odstraní redukcí.4α, 7α-Carbonyl-5-cyano-17 (S-n -tryloxy-17α- (3-nitryloxypropyl) -5) -S-androstan-3-one was converted to sodium methyl ester 17 as described in the previous example. The 3-nitryloxy-17, α '- (3-nitryloxypropyl) -3-oxo-4-andrene-7α-carboxylic acid and protecting groups are removed by reduction.
Získá se methylester kyseliny 17/3-hydroxy-17a- (3-hydroxypropyl) -3-oxo-4-androsten-7a-karboxylové o teplotě tání 181 až 183 °C.There was thus obtained 17β-hydroxy-17α- (3-hydroxypropyl) -3-oxo-4-androstene-7α-carboxylic acid methyl ester of melting point 181-183 ° C.
Příklad 3Example 3
15,0 g 17i/?-hydroxy-17o-( 3-hydroxypropyl )-4-androsten-3-onu se zahřívá v 75 ml methanolu a 7,5 ml pyrrolidinu 15 minut pod zpětným chlodičem. Pak se ochladí v ledové lázni, vykrystalovaná sraženina se odsaje a promyje malým množstvím ledového methanolu. Získá se 12,0 g 17oř-( 3-hydroxypropyl ) -3-pyrrolidino-3,5-androstadien-17/3-olu, UV: εΖ76 = 21 300.15.0 g of 17.beta.-hydroxy-17- (3-hydroxypropyl) -4-androsten-3-one was heated in 75 ml of methanol and 7.5 ml of pyrrolidine for 15 minutes under reflux. After cooling in an ice bath, the crystalline precipitate is filtered off with suction and washed with a small amount of ice-cold methanol. 12.0 g of 17α- (3-hydroxypropyl) -3-pyrrolidino-3,5-androstadiene-17/3-ol are obtained, UV: εΖ76 = 21 300.
11,5 g 17«-(3-hydroxypropyl )-3-pyrrolidino-3,5-androstadien-17/S-olu se rozpustí ve 794 ml ethanolu a 397 ml benzenu, pak se přikape 20,8 ml 40% roztoku formaldehydu a míchá se 1 hodinu při teplotě místnosti. Roztok se potom ve vakuu co nejvíce zahustí a zbytek se chromatografuje na silikagelu. Získá se 5,25 g 17i/í-hydroxy-6/3-hydroxymethyl-17a-( 3-hydroxypropyl) -4-androsten-3-onu, UV: smi = 11100.11.5 g of 17- (3-hydroxypropyl) -3-pyrrolidino-3,5-androstadiene-17 / S-ol are dissolved in 794 ml of ethanol and 397 ml of benzene, then 20.8 ml of a 40% formaldehyde solution are added dropwise. and stirred for 1 hour at room temperature. The solution is then concentrated in vacuo as much as possible and the residue is chromatographed on silica gel. 5.25 g of 17 H -hydroxy-6/3-hydroxymethyl-17α- (3-hydroxypropyl) -4-androsten-3-one is obtained, UV: smi = 11100.
5,25 g 17/í-hydroxy’6)á''hydrQxyinethyl-l7o!- (3-hydroxypropyl) -4-androsten-3-onu se míchá ve 260 mí dioxanu a 15,2 ml 5 N kyseliny chlorovodíkové 2,5 hodiny při teplotě místnosti. K reakčnímu roztoku se přidá pak přebytek hydrogenuhličitanu sodného, nerozpuštěný zbytek se odfiltruje a filtrát se odpaří ve vakuu do sucha. Zbytek se chromatografuje na silikagelu. Získá se 3,8 g 17|/3-hydroxy-17cs- (3’hydroxypropyl J-6’ -methylenj4*androsten’3-onu. Z acetonu překrystalovaný vzorek má teplotu tání 178 až5.25 g of 17.alpha.-hydroxy-6 ' -hydroxy-ethyl-17-l- (3-hydroxypropyl) -4-androsten-3-one are stirred in 260 ml of dioxane and 15.2 ml of 5N hydrochloric acid 2, 5 hours at room temperature. Excess sodium bicarbonate was then added to the reaction solution, the insoluble residue was filtered off and the filtrate was evaporated to dryness in vacuo. The residue is chromatographed on silica gel. 3.8 g 17 | / 3-hydroxy-17cs- (3'hydroxypropyl J-6 ' -methylene j * androsten'3 4-one. Sample recrystallized from acetone m.p. 178 DEG
179,5 °C, UV: ε26ΐ = 11 OQQ.179.5 ° C, UV: ε26 ° = 11 ° C.
K 3,5 g 17^-hydroxy-17of-(3’hydroxypropyl)-6-methylen-4’androsťen-3-onu se přidá ve 122 ml ethanolu 1,75 g bezvodého octanu sodného a 257 ml 5% paládiového uhlí a frn forvl niv νουιι hXb om Q Ή on <4 nTo 3.5 g of 17.alpha.-hydroxy-17.beta .- (3 ' hydroxypropyl) -6-methylene-4 ' -androsten-3-one is added 1.75 g of anhydrous sodium acetate and 257 ml of 5% palladium carbon in 122 ml of ethanol; frn forvl niv νουιι hXb om Q Ή on <4 n
V*. «U VUiU v XXVM.4.1X po dávkách 0,7 ml cyklohexenu ve 20 ml ethanolu. Pak se katalyzátor odfiltruje a filtrát ve vakuu co nejvíce zahustí. Zbytek se vyjme methylenchloridem, promyje vodou, vysuší, odpaří a chromatografuje na silikagelu. Získá se 1,9 g 17ij3-hydroxy-17a- (3-·hydrQχyprQpyl·6-methyl'4,6’and^'osta' dien-3'Όnu. Vzorek překrystalovaný z diisopropyletheru a acetonu má teplotu tání 197 až 202 °C, UV: ε29ΐ = 21100,IN*. In VUiU in XXVM.4.1X in portions of 0.7 ml cyclohexene in 20 ml ethanol. Then the catalyst is filtered off and the filtrate is concentrated as much as possible in vacuo. The residue was taken up in methylene chloride, washed with water, dried, evaporated and chromatographed on silica gel. 1.9 g of 17 [beta] -hydroxy-17 [alpha] - (3-hydroxypropyl) 6-methyl-4,6 ' and 4 ' -diene-3 ' is obtained, a sample recrystallized from diisopropyl ether and acetone, m.p. C, UV: ε 29ΐ = 21100,
Příklad 4Example 4
1,8 g trimethylsulfoxoniumjodidu a 2,8 g hydroxidu sodného se míchá 15 minut ve 32 ml dimethylsulfoxidu pod argonovou atmosférou. Potom se přidá 1 g 17,8-hydroxy-17a- (3-hydroxypropyl ]-4,6-androstadien-3-onu a míchá dále 24 hodin při 35 °C, stále pod argonovou amtosférou. Poté se směs vylije do ledové vody okyselené kyselinou octovou, vysrážený produkt se odsaje a rozpustí v methylenchloridu, methylenchloridový extrakt se promyje vodou, vysuší síranem sodným a odpaří ve vakuu. Zbytek se vyčistí chromatografií n’a vrstvě při použití systému chloroform—methanol v poměru 9 : 1. Po překrystalování z acetonu se získá 530 mg 17/3-hydroxy-17a-( 3-hydroxypropyl ] -6^, 7(3-methylen-4-androsten-3-onu o teplotě tání 170 až 172 °C, UV: ¢203 — = 18 300.1.8 g of trimethylsulfoxonium iodide and 2.8 g of sodium hydroxide are stirred for 15 minutes in 32 ml of dimethylsulfoxide under an argon atmosphere. Then 1 g of 17,8-hydroxy-17a- (3-hydroxypropyl) -4,6-androstadiene-3-one is added and stirred for 24 hours at 35 ° C, still under argon amtosphere, then poured into ice water. acidified with acetic acid, the precipitated product is filtered off with suction and dissolved in methylene chloride, the methylene chloride extract is washed with water, dried over sodium sulphate and evaporated in vacuo and the residue is purified by chromatography on a bed of chloroform-methanol 9: 1. acetone gives 530 mg of 17β-hydroxy-17α- (3-hydroxypropyl) -6,7,7 (3-methylene-4-androsten-3-one), m.p. 170-172 ° C, UV: ¢ 203- = 18 300.
P ř í k 1 a d 5Example 1 a d 5
350 mg 17(3-hydroxy-8-inethyW7a-(3-hemisukcinyloxypropyl) -4,6-androstadien-3-onu se uvede v reakci s methanolavým roztokem methylátu sodného a zpracuje. Získá se 310 mg 17/J-hydroxy-6-methyl-17a-(3-hemisu'kcinyloxypropyl)-4,6-androstadien-3-onu ve formě sodné soli, UV: £291 = = 21 000.350 mg of 17 (3-hydroxy-8-methyl-7α- (3-hemisuccinyloxypropyl) -4,6-androstadien-3-one) is reacted with sodium methoxide solution and treated to give 310 mg of 17H-hydroxy-6. methyl-17α- (3-hemisuccinyloxypropyl) -4,6-androstadiene-3-one in the form of the sodium salt, UV: £ 291 = = 21,000.
Příklad 6Example 6
350 mg 17/3-hydroxy-17a-( 3-hydroxypropyl )-6-methyl-4,6-androstadien-3-onu se zahřívá ve 3,5 ml pyridinu a 350 mg anhyd10 ridu kyseliny jantarové 1 hodinu pod zpětným chladičem. Roztok se vylije za míchání do ledové vody, vyloučený olej se odfiltruje, vyjme methylenchloridem, vysuší a odpaří. Zbytek se chromatografuje na silítóagelu. Získá se 420 mg 170-hydroxy-6-methyl-17«s( 3-hemísukcinyloxypropyl )-4,6-androstadien-3-onu ve formě amorfní látky, UV: ε29ΐ = 20 500.350 mg of 17β-hydroxy-17α- (3-hydroxypropyl) -6-methyl-4,6-androstadiene-3-one is heated in refluxing for 3.5 hours in 3.5 ml of pyridine and 350 mg of succinic anhydride. The solution was poured into ice water with stirring, the precipitated oil was filtered off, taken up in methylene chloride, dried and evaporated. The residue is chromatographed on silica gel. 420 mg of 170-hydroxy-6-methyl-17? (3-hemisuccinyloxypropyl) -4,6-androstadiene-3-one are obtained in the form of an amorphous substance, UV: ε29ΐ = 20 500.
Příklad 7Example 7
420 mg 17:j3-hydroxy-6-methyl-17a-(3-hemisukcinyloxypropyl j -4,6-androstadien-3-onu se rozpustí ve 2Q ml absolutního methanolu a uvádí ve reakci s 6,4 ml methanolovéhQ 0,1 N roztoku methylátu draselnobc ov Ho ΉπΗπ ηΐΓΤτ’Τ’οΙηηηη Uml/nnt vorr XJ »-» S-X Cl V X V UlUllMU. JA^U-UVIU J.UX1 tok se vysráží v absolutním etheru, sraženina s odsaje, promyje etherem a vysuší. Získá se 340 mg 17,/3-hydroxy-6-methyl-17-((3-hemiskucinyloxypropyl) -4,6-androstadien-3-onu ve formě draselné soli, tvořící amorfní látku. Teplota tání: 130 °C (za rozkladu), UV: ε29ΐ = 21 300.420 mg of 17: [beta] -hydroxy-6-methyl-17 [alpha] - (3-hemisuccinyloxypropyl) -4,6-androstadien-3-one is dissolved in 20 ml of absolute methanol and reacted with 6.4 ml of methanol 0.1N Potassium methylate solution was dissolved in absolute ether, the precipitate was filtered off with suction, washed with ether and dried. 340 mg of 17β-hydroxy-6-methyl-17 - ((3-hemiscuinyloxypropyl) -4,6-androstadien-3-one in the form of the amorphous potassium salt, m.p. 130 ° C (dec.) , UV: ε29ΐ = 21,300.
PříkladeExample
Jak popsáno v příkladu 6, získá se reakcí 17/3-hydroxy-17<z-( 3-hydroxypropyl)-18-methyl-4,6-estradien-3-onu a anhydridem kyseliny jantarově v pyridinu 17/J-hydroxy-17a- (3-hydroxysukcinylQxypr opyl J-18-methyl-4,6-estradien-3-on ve formě /amorfní látky, UV: £284 = 24 100 (methanol).As described in Example 6, the reaction of 17β-hydroxy-17β- (3-hydroxypropyl) -18-methyl-4,6-estradien-3-one and succinic anhydride in pyridine affords 17β-hydroxy- 17α- (3-hydroxysuccinyl) oxypropyl β-18-methyl-4,6-estradien-3-one in form / amorphous substance, UV: δ 284 = 24 100 (methanol).
Příklad 9Example 9
Jak popsáno v příkladu 7, získá se z i7^-hydroxy’l7a-(3-hydroxysukcinyloxypropyl )-18-methyl-4,6-estradien-3-onu jeho draselná sůl ve formě amorfní látky, UV: £285 = 22 900 (methanol).As described in Example 7, its potassium salt is obtained from N, N-hydroxy-17- (3-hydroxysuccinyloxypropyl) -18-methyl-4,6-estradien-3-one as its amorphous substance, UV: δ 285 = 22 900 (methanol).
Příklad 10Example 10
100 mg 17.0-hydroxy-17a-( 3-hydroxypropyl )-7a-thloacetyl-4-androsten-3-onu se míchá ve 2 ml pyridinu se 2 ml anhydridu kyseliny undecylové za přídavku 30 mg dimethylaminopyridinu 7 hodin při 50 °C. Poté se reakční směs vlije do ledové vody, rozmíchá s pentanem a odsaje, zbytek se extrahuje methylenchloridem, promyje l N kyselinou chlorovodíkovou a vodou a zbytek se zahustí, přičemž se získá 17/i-hydroxy-17iof- (3-undecyloxypropyl) -7a-thioacetyl-4-androsten-3-on ve formě oleje, UV (methanol J £237 — 17 500.100 mg of 17.0-hydroxy-17α- (3-hydroxypropyl) -7α-thloacetyl-4-androsten-3-one is stirred in 2 ml of pyridine with 2 ml of undecylic anhydride with addition of 30 mg of dimethylaminopyridine for 7 hours at 50 ° C. The reaction mixture was then poured into ice water, stirred with pentane and filtered off with suction, the residue was extracted with methylene chloride, washed with 1 N hydrochloric acid and water, and the residue was concentrated to give 17β-hydroxy-17iof- (3-undecyloxypropyl) -7a. thioacetyl-4-androsten-3-one in the form of an oil, UV (methanol J? 237 - 17 500).
P ř í kl a d 11Example 11
1,5 g 17/2-hydrQxy-17a-( 3-hydroxypropyl)-4,6-androstadien-3-onu se rozpustí v 5 ml pyridinu, přidá se 1,5 g anhydridu kyseliny jantarové a zahřívá 1 hodinu pod argonovou atmosférou k varu. Po ochlazení se vmíchá do ledové vody, okyselí kyselinou chlorovodíkovou a extrahuje octanem ethylnatým. Octanový extrakt se promyje vodou do neutrální reakce, vysuší síranem sodným a odpaří ve vakuu. Získají se takto 2 g 17/3-hydroxy-17tf- (3-hydroxysukcinyloxypropyl)-4,6-androstadien-3-onu ve formě amorfní látky, UV: £285 — 23 700.Dissolve 1.5 g of 17/2-hydroxy-17a- (3-hydroxypropyl) -4,6-androstadiene-3-one in 5 ml of pyridine, add 1.5 g of succinic anhydride and heat under argon for 1 hour. to boil. After cooling, it is stirred into ice water, acidified with hydrochloric acid and extracted with ethyl acetate. The acetate extract was washed with water until neutral, dried over sodium sulfate and evaporated in vacuo. 2 g of 17β-hydroxy-17β- (3-hydroxysuccinyloxypropyl) -4,6-androstadiene-3-one are obtained in the form of an amorphous substance, UV: δ 285-23.700.
Příklad 12Example 12
300 mg hemisukcinátu připraveného v příklladu 11 se rozpustí v 15 ml absolutního methanolu a pH se upraví 5,5 ml 0,1 N roztoku methylátu sodného na hodnotu 8. Roztok se zahustí ve vakuu a vysráži ve 200 ml etheru. Vypadlá sůl se odsaje, rozpustí v methanolu a znovu vysráží v etheru. Získá se 210 mg sodné soli 17/í-hydroxy-17a- (3-hydroxysukcinyloxypropyl ] -4,6-androstadien-3-onu o teplotě tání 120 °C (za rozkladu), UV: £285 — 24 100.300 mg of the hemisuccinate prepared in Example 11 were dissolved in 15 ml of absolute methanol and the pH was adjusted to 8 with 5.5 ml of 0.1 N sodium methylate solution. The solution was concentrated in vacuo and precipitated in 200 ml of ether. The resulting salt is filtered off with suction, dissolved in methanol and reprecipitated in ether. 210 mg of 17? -Hydroxy-17? - (3-hydroxysuccinyloxypropyl) -4,6-androstadien-3-one sodium salt, m.p. 120 DEG C. (dec.), UV:? 285-2400, are obtained.
Příklad 13Example 13
400 mg hemisukcinátu vyrobeného v příkladu 11 se rozpustí ve 20 ml absolutního methanolu a pH se upraví 5,4 ml 0,1 N roztoku methylátu draselného na hodnotu 8. Po přesrážení v etheru se získá 285 mg draselné soli 17/3-hydroxy-17a-(3-hydroxysukcinyloxypropyl)-4,6-androstadien-3-onu o teplotě tání 145 °C (za rozkladu).400 mg of the hemisuccinate produced in Example 11 are dissolved in 20 ml of absolute methanol and the pH is adjusted to 8 with 5.4 ml of 0.1 N potassium methylate solution. After precipitation in ether, 285 mg of 17/3-hydroxy-17a potassium salt are obtained. - (3-hydroxysuccinyloxypropyl) -4,6-androstadiene-3-one, m.p. 145 DEG C. (dec.).
P ř í k 1 a d 1 4Example 1 4
Obdobně jako v příkladu 11 se připraví esterifikaci anhydridem kyseliny glutarové v pyridinu a následující reakcí s methylátem draselným draselná sůl 17/3-hydroxy-17a- (3-hydroxyglutaryloxypropyl )-4,6-androstadien-3-onu o teplotě tání 98 °C (za rozkladu).Analogously to Example 11, the esterification of glutaric anhydride in pyridine and subsequent reaction with potassium methylate was prepared by the potassium salt of 17β-hydroxy-17α- (3-hydroxyglutaryloxypropyl) -4,6-androstadien-3-one, m.p. 98 ° C. (with decomposition).
Příklad 15Example 15
Roztok 1 g 17j3-hydroxy-17a-(3-hydroxypropyl)-4,6-estradien-3-onu ve 4 ml pyridinu se zahřívá s 1 g anhydridů kyseliny jantrové 1 hodinu pod argonovou atmosférou k varu. Nechá se vychladnout a vmíchá se do ledové vody, okyselí zředěnou kyselinou chlorovodíkovou a extrahuje octanem éthylnatým. Spojené extrakty se promyjí vodou, vysuší síranem sodným a odpaří do sucha. Získá se 1 g surového 17/3-hydroxy-17a- (3-hydroxysukcinyloxypropyl) -4,6-estradien-3-onu ve formě amorfní látky, UV: £284 — = 26 800 (methanol).A solution of 1 g of 17β-hydroxy-17α- (3-hydroxypropyl) -4,6-estradien-3-one in 4 ml of pyridine was heated to boiling under argon for 1 hour under argon anhydride. Allow to cool and stir in ice water, acidify with dilute hydrochloric acid and extract with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate and evaporated to dryness. 1 g of crude 17β-hydroxy-17α- (3-hydroxysuccinyloxypropyl) -4,6-estradien-3-one is obtained in the form of an amorphous substance, UV: 284 284- = 26 800 (methanol).
Přiklad 16Example 16
Roztok 500 mg 17/3-hydroxy-17«-(3-hydroxysukcinyloxypropyl)-4,6-estradlen-3-onu v 15 ml absolutního methanolu se upraví pomocí pH—metru 0,1 N roztokem methylátu sodného na hodnotu pH 8, zahustí ve vakuu a vysráží 200 ml etheru. Sodná sůl se odsaje, rozpustí v methanolu a opět vysráží etherem. Získá se 350 mg sodné soli 17/3-hydroxy-17a- (3-hydroxysukcinyloxypropyl)-4,6-estradien-3-onu, UV: ε285 = 25 900 (methanol).A solution of 500 mg of 17β-hydroxy-17β- (3-hydroxysuccinyloxypropyl) -4,6-estraden-3-one in 15 mL of absolute methanol is adjusted to pH 8 with 0.1 N sodium methylate solution using a pH meter, It is concentrated in vacuo and precipitated with 200 ml of ether. The sodium salt is filtered off with suction, dissolved in methanol and precipitated again with ether. 350 mg of 17β-hydroxy-17α- (3-hydroxysuccinyloxypropyl) -4,6-estradien-3-one sodium salt are obtained, UV: ε 285 = 25 900 (methanol).
Příkladl7Example 17
Roztok 600 mg 17/3-hydroxy-17a-(3-hydroxysukcinyloxypropyl)-4,6-estradien-3-onu v 30 ml absolutního methanolu se upraví 0,1 N roztokem methylátu draselného na hodnotu pH 8. Po přesrážení v etheru, jak popsáno· v příkladu 12, se získá 320 mg draselné soli 17/í-hydroxy-17a- (3-hydroxysukcinyloxypropyl )-4,6-estradien-3-onu, UV: £284 = 26 300 (methanol).A solution of 600 mg of 17β-hydroxy-17α- (3-hydroxysuccinyloxypropyl) -4,6-estradien-3-one in 30 ml of absolute methanol is adjusted to pH 8 with 0.1 N potassium methylate solution. After precipitation in ether, as described in Example 12, 320 mg of 17? -hydroxy-17? - (3-hydroxysuccinyloxypropyl) -4,6-estradien-3-one potassium salt is obtained, UV:? 284 = 26 300 (methanol).
Příklad 18Example 18
Jak popsáno shora, připraví se esterifikací 17/3-hydroxy-17a- (3-hydr oxypropyl) -4,6-estradien-3-onu anhydridem kyseliny glutarové v pyridinu a následující reakcí s methylátem draselným draselná sůl 17β-hydroxy-17ia- (3-hydroxyglutaryloxypropyl )-4,6-estradien-3-onu ve formě amorfního prášku, UV (methanol): £285 = 24 100. Příklad 19 g 17/3-hydroxy-17a-(3-hydroxypropyl)-4,6-androstadien-3-onu se zahřívá v 350 ml pyridinu se 70 g trifenylmethylchloridu 40 minut na parní lázni. Reakční směs se θ'chladí, nalije pozvolna do 8 1 ledové vody, vysrážená látka se odsaje, promyje vodou a vysuší. Surový produkt se chromatografuje na silikagelu a překrystaluje ze směsi etheru a pentanu. Získá se 61,4 g 17/3-hydroxy-17a- (3-trif enylmethyloxypropyl) -4,6-androstadien-3-onu o teplotě tání 168 až 169 °C.As described above, by esterification of 17β-hydroxy-17α- (3-hydroxypropyl) -4,6-estradien-3-one glutaric anhydride in pyridine and subsequent reaction with potassium methylate, the 17β-hydroxy-17α- potassium salt is prepared. (3-hydroxyglutaryloxypropyl) -4,6-estradien-3-one in the form of an amorphous powder, UV (methanol): δ 285 = 24 100. Example 19 g 17/3-hydroxy-17α- (3-hydroxypropyl) -4, Of 6-androstadiene-3-one was heated in 350 ml of pyridine with 70 g of triphenylmethyl chloride on a steam bath for 40 minutes. The reaction mixture is cooled, poured slowly into 8 l of ice-water, the precipitate is filtered off with suction, washed with water and dried. The crude product is chromatographed on silica gel and recrystallized from ether / pentane. 61.4 g of 17β-hydroxy-17α- (3-triphenylmethyloxypropyl) -4,6-androstadien-3-one, m.p. 168-169 ° C, are obtained.
Příklad 20Example 20
K 1,5 g 17;3-hydroxy-17a-(3-hydroxypropyl )-6(/3,7/?-methylen-4-androsten-3-onu v 5 ml pyridinu se přidá 1,5 ml acetanhydridu a míchá 105 minut při 22 °C. Po zpracování a rozetření s hexanem se získá 1,7 g amorfního 17/3-hydroxy-lTa- (3-acetylpropyl )-6(3, 7(3'-methylen-4-androsten-3-onu. Příklad 21To 1.5 g of 17, 3-hydroxy-17a- (3-hydroxypropyl) -6 ([3,7] p-methylene-4-androsten-3-one) in 5 ml of pyridine was added 1.5 ml of acetic anhydride and stirred 105 min at 22 [deg.] C. After treatment and trituration with hexane, 1.7 g of amorphous 17 [beta] -hydroxy-1H-(3-acetylpropyl) -6 (3,7 (3'-methylene-4-androstene-3)) is obtained. Example 21
500 mg 17/3-hydroxy-17a-(3-hydroxypropyl)-4,6-iandrostadien-3-onu v 15 ml diethylkarbonátu se přidá 10 mg methylátu sódného a zahřívá pod argonem 10 minut na 140 °C. Poté se ochladí, neutralizuje kyselinou octovou a odpaří ve vakuu.500 mg of 17β-hydroxy-17α- (3-hydroxypropyl) -4,6-iandrostadiene-3-one in 15 ml of diethyl carbonate was added with 10 mg of sodium methylate and heated at 140 ° C under argon for 10 minutes. It was then cooled, neutralized with acetic acid and evaporated in vacuo.
Po čištění chromatografií na vrstvě se získá 400 mgl7/3-hydro,xy-17a-(3-e,thoxykarbonyloxypropyl)-4,6-androstadien-3-onu ve formě bezbarvého oleje, UV: ε2«5 = 26 100.After purification by layer chromatography, 400 mg of 17/3-hydroxy, 17- (3-e, thoxycarbonyloxypropyl) -4,6-androstadiene-3-one is obtained in the form of a colorless oil, UV: ε2 = 5 10000.
PŘEDMĚTSUBJECT
Claims (3)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS786763A CS200508B2 (en) | 1976-10-08 | 1978-10-17 | Process for preparing 17alpha-/3-r2-oxypropyl/-17beta-r1-oxy-4,6-gonadien-3-ones |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19762646043 DE2646043C2 (en) | 1976-10-08 | 1976-10-08 | 7α-acetylthio-6α-methyl-4-androsten-3-ones, processes for their preparation and medicaments containing them |
| CS148077A CS200507B2 (en) | 1976-03-05 | 1977-03-04 | Process for preparing 17alpha-/3-r2-oxypropyl/-17beta-r1-oxy-4- genon-3-ones |
| CS786763A CS200508B2 (en) | 1976-10-08 | 1978-10-17 | Process for preparing 17alpha-/3-r2-oxypropyl/-17beta-r1-oxy-4,6-gonadien-3-ones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CS200508B2 true CS200508B2 (en) | 1980-09-15 |
Family
ID=25745443
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS786763A CS200508B2 (en) | 1976-10-08 | 1978-10-17 | Process for preparing 17alpha-/3-r2-oxypropyl/-17beta-r1-oxy-4,6-gonadien-3-ones |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS200508B2 (en) |
-
1978
- 1978-10-17 CS CS786763A patent/CS200508B2/en unknown
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