IT9020275A1 - PROCEDURE FOR THE MANUFACTURE OF 7-DIMETHYLAMINE-6-DEMETYL-6- DEOXYTETRACYCLINE - Google Patents
PROCEDURE FOR THE MANUFACTURE OF 7-DIMETHYLAMINE-6-DEMETYL-6- DEOXYTETRACYCLINEInfo
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- IT9020275A1 IT9020275A1 IT020275A IT2027590A IT9020275A1 IT 9020275 A1 IT9020275 A1 IT 9020275A1 IT 020275 A IT020275 A IT 020275A IT 2027590 A IT2027590 A IT 2027590A IT 9020275 A1 IT9020275 A1 IT 9020275A1
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- 238000000034 method Methods 0.000 title claims description 31
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 22
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 16
- 229960004023 minocycline Drugs 0.000 claims description 11
- 238000005804 alkylation reaction Methods 0.000 claims description 10
- 230000029936 alkylation Effects 0.000 claims description 9
- 238000006396 nitration reaction Methods 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 6
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical group COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 6
- 238000006722 reduction reaction Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 5
- 238000010511 deprotection reaction Methods 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical group 0.000 claims description 4
- 150000002170 ethers Chemical class 0.000 claims description 4
- 238000002955 isolation Methods 0.000 claims description 4
- 229910000510 noble metal Inorganic materials 0.000 claims description 4
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 claims description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- -1 diglima Chemical compound 0.000 claims description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 claims description 3
- 230000000802 nitrating effect Effects 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 2
- 150000001336 alkenes Chemical class 0.000 claims description 2
- 150000001350 alkyl halides Chemical group 0.000 claims description 2
- 238000010531 catalytic reduction reaction Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- 230000011987 methylation Effects 0.000 claims description 2
- 238000007069 methylation reaction Methods 0.000 claims description 2
- QCDYQQDYXPDABM-UHFFFAOYSA-N phloroglucinol Chemical compound OC1=CC(O)=CC(O)=C1 QCDYQQDYXPDABM-UHFFFAOYSA-N 0.000 claims description 2
- 229960001553 phloroglucinol Drugs 0.000 claims description 2
- 230000001681 protective effect Effects 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims 3
- 229940100198 alkylating agent Drugs 0.000 claims 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 2
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 claims 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims 1
- 229940098779 methanesulfonic acid Drugs 0.000 claims 1
- 150000002828 nitro derivatives Chemical class 0.000 claims 1
- 230000003287 optical effect Effects 0.000 claims 1
- 150000003522 tetracyclines Chemical class 0.000 description 22
- 239000000543 intermediate Substances 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 239000004098 Tetracycline Substances 0.000 description 11
- 229960002180 tetracycline Drugs 0.000 description 11
- 229930101283 tetracycline Natural products 0.000 description 11
- 235000019364 tetracycline Nutrition 0.000 description 11
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 3
- MTCQOMXDZUULRV-ADOAZJKMSA-N (4s,4as,5ar,12ar)-4-(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O MTCQOMXDZUULRV-ADOAZJKMSA-N 0.000 description 2
- VFTOHJFKIJLYKN-UHFFFAOYSA-N 7-nitro-9h-fluoren-2-ol Chemical group [O-][N+](=O)C1=CC=C2C3=CC=C(O)C=C3CC2=C1 VFTOHJFKIJLYKN-UHFFFAOYSA-N 0.000 description 2
- 239000000370 acceptor Substances 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000006345 epimerization reaction Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- USVVENVKYJZFMW-ONEGZZNKSA-N (e)-carboxyiminocarbamic acid Chemical compound OC(=O)\N=N\C(O)=O USVVENVKYJZFMW-ONEGZZNKSA-N 0.000 description 1
- WTJXVDPDEQKTCV-UHFFFAOYSA-N 4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide;hydron;chloride Chemical compound Cl.C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2C1CC1C(N(C)C)C(=O)C(C(N)=O)=C(O)C1(O)C2=O WTJXVDPDEQKTCV-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- XMEVHPAGJVLHIG-FMZCEJRJSA-N chembl454950 Chemical compound [Cl-].C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H]([NH+](C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O XMEVHPAGJVLHIG-FMZCEJRJSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000027326 copulation Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 150000008049 diazo compounds Chemical class 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 229960002421 minocycline hydrochloride Drugs 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- ZODDGFAZWTZOSI-UHFFFAOYSA-N nitric acid;sulfuric acid Chemical compound O[N+]([O-])=O.OS(O)(=O)=O ZODDGFAZWTZOSI-UHFFFAOYSA-N 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000006485 reductive methylation reaction Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
DESCRIZIONE DESCRIPTION
dell'invenzione industriale dal titolo:"Procedimento per la fabbricazione di 7-dimetilamino-6-demetil-6-deossitetraciclina" of the industrial invention entitled: "Process for the manufacture of 7-dimethylamino-6-demethyl-6-deoxytetracycline"
Riassunto Summary
Nella fabbricazione di minociclina, ovvero 7-dimetilamino-6-demetil-6-deossitetraciclina, l'intermedio di partenza, 6-demetil-6-deossitetraciclina, prima di essere sottoposto alla nitrazione ed agli altri stadi di trasformazione, viene protetto con un gruppo alchilico tanto nella posizione 9 quanto in corrispondenza della funzione ammidica in posizione 2, che risulta pertanto monoalchilata.Nello stadio finale di deprotezione si procede alla rimozione dei gruppi alchilici di protezione in entrambe le posizioni. In the manufacture of minocycline, or 7-dimethylamino-6-demethyl-6-deoxytetracycline, the starting intermediate, 6-demethyl-6-deoxytetracycline, before being subjected to nitration and the other stages of transformation, is protected with a group alkyl both in position 9 and in correspondence with the amide function in position 2, which is therefore monoalkylated. In the final deprotection stage, the protective alkyl groups are removed in both positions.
Descrizione Description
La presente invenzione riguarda un procedimento per la fabbricazione di 7-dimetilamino-6-demetil-6-deossitetraciclina, avente formula: The present invention relates to a process for the manufacture of 7-dimethylamino-6-demethyl-6-deoxytetracycline, having the formula:
La sostanza in questione nota anche con il nome non chimico di "Minociclina"è un antibiotico ad ampio spettro batterico noto ed utilizzato in terapia da lungo tempo. The substance in question also known by the non-chemical name of "Minocycline" is a broad spectrum bacterial antibiotic known and used in therapy for a long time.
Sono noti diversi procedimenti per la produzione di questa sostanza i quali presentano inconvenienti sia sotto il profilo delle rese sia/oppure sotto il profilo della complessità e delicatezza di almeno alcuni degli stadi di processo. Various processes are known for the production of this substance which have drawbacks both in terms of yields and / or in terms of the complexity and delicacy of at least some of the process stages.
Secondo un primo metodo (J.Org.Chem.,36, 723 (1971); J.Med.Chem.,10, 44(1967); J.Med.Pharm.Chem., £.538(1962)) la 6-demetil-6-deossi- tetraciclina di formula According to a first method (J.Org.Chem., 36, 723 (1971); J.Med.Chem., 10, 44 (1967); J.Med.Pharm.Chem., £ .538 (1962)) the 6-demethyl-6-deoxy-tetracycline of formula
viene sottoposta a nitrazione a dare una miscela di composti 7-nitro e 9-nitro. Dopo separazione degli isomeri il composto 7-nitro viene ridotto e dimetilato a formare la minociclina di formula (I). is subjected to nitration to give a mixture of 7-nitro and 9-nitro compounds. After separation of the isomers, the 7-nitro compound is reduced and dimethylated to form the minocycline of formula (I).
Secondo il procedimento del brevetto USA 3 901 942 la posizione 9 del composto (II) viene protetta con un gruppo alchilico, dopo di che si procede alla nitrazione in posizione 7, riduzione, dimetilazione ed infine rimozione del gruppo protettivo a dare la minociclina (I) desiderata. According to the process of US patent 3 901 942, position 9 of compound (II) is protected with an alkyl group, after which nitration is carried out in position 7, reduction, dimethylation and finally removal of the protective group to give minocycline (I ) desired.
Secondo il brevetto USA 3 403 179 il composto (II) viene fatto reagire con un diestere di un acido azodicarbossilico;il prodotto così ottenuto viene sottoposto ad idrolisi acida o ad idrogenolisi e quindi a dimetilazione riduttiva a dare la minociclina (I) desiderata. According to US patent 3 403 179, compound (II) is reacted with a diester of an azodicarboxylic acid; the product thus obtained is subjected to acid hydrolysis or hydrogenolysis and then to reductive dimethylation to give the desired minocycline (I).
Secondo il brevetto USA 3 239 499 il composto (II) viene protetto in posizione I la e quindi sottoposto a copulazione con un diazocomposto.La successiva idrogenolisi in presenza di un metallo nobile quale catalizzatore seguita da dimetilazione riducente porta alla minociclina (I) desiderata. According to US patent 3 239 499 the compound (II) is protected in position I la and then subjected to copulation with a diazo compound. The subsequent hydrogenolysis in the presence of a noble metal as catalyst followed by reducing dimethylation leads to the desired minocycline (I).
La domanda di brevetto europeo pubblicata 294 762 propone un metodo analogo salvo che nello stadio di idrogenolisi si utilizza sodio ditionito in luogo del metallo nobile abbinato all'idrogeno. The published European patent application 294 762 proposes an analogous method except that in the hydrogenolysis step sodium dithionite is used instead of the noble metal combined with hydrogen.
Gli inconvenienti che si lamentano specificamente per i metodi noti di produzione dell'antibiotico in questione si possono così riassumere: The drawbacks that specifically complain about the known production methods of the antibiotic in question can be summarized as follows:
a) Rese basse specialmente quando siano necessarie operazioni di isolamento di isomeri, come nel primo metodo sopra menzionato. a) Low yields especially when isomer isolation operations are required, as in the first method mentioned above.
b) Instabilità dei prodotti intermedi specialmente per fenomeni di epimerizzazione della posizione 4. b) Instability of the intermediate products especially due to epimerization phenomena of position 4.
c) Difficoltà di isolamento degli intermedi con rese ragionevoli in termini di prodotti puri. c) Difficulty in isolating intermediates with reasonable yields in terms of pure products.
Il procedimento secondo la presente invenzione si caratterizza per gli stadi seguenti: The process according to the present invention is characterized by the following stages:
a) alchilazione selettiva del composto (II) nelle posizioni rispettivamente 9 e sulla funzione ammidica in posizione 2 a formare il composto (III) di formula a) selective alkylation of compound (II) in positions 9 and on the amide function in position 2 respectively to form compound (III) of formula
b) nitrazione dell'intermedio (III) in posizione 7 a formare il composto (IV) di formula b) nitration of the intermediate (III) in position 7 to form the compound (IV) of formula
c) riduzione del gruppo nitro in posizione 7 a formare il composto (V) di formula c) reduction of the nitro group in position 7 to form the compound (V) of formula
d) metilazione in condizioni riducenti del composto (V) a formare il composto (VI) di formula d) methylation under reducing conditions of compound (V) to form compound (VI) of formula
e) deprotezione deirintermedio (VI) con ottenimento della minociclina (I) desiderata. e) deprotection of the intermediate (VI) with obtaining the desired minocycline (I).
Volendo quindi individuare nella sua parte essenziale il procedimento secondo la presente invenzione, esso si caratterizza per il fatto che l'intermediao di partenza oltre ad avere la posizione 9 protetta da un gruppo alchilico è protetto anche in corrispondenza della funzione ammidica in posizione 2, che risulta monoalchilata. Therefore, wishing to identify in its essential part the process according to the present invention, it is characterized by the fact that the starting intermediate in addition to having position 9 protected by an alkyl group is also protected in correspondence with the amide function in position 2, which it is monoalkylated.
Come si potrà constatare dagli esempi che illustrano l'invenzione, i vantaggi che si conseguono con la presente invenzione si possono così riassumere: (i) Le rese sono più elevate; As can be seen from the examples illustrating the invention, the advantages achieved with the present invention can be summarized as follows: (i) The yields are higher;
(ii) nella fase di protezione si può usare acido solforico molto meno costoso rispetto agli acidi necessari nei metodi della tecnica anteriore; (ii) much less expensive sulfuric acid can be used in the protection step than the acids required in prior art methods;
(iii)gli intermedi risultano più stabili rispetto al già menzionato fenomeno di epimerizzazione in posizione 4, probabilmente a causa del maggiore ingombro sterico e quindi della maggiore rigidità della molecola; (iii) the intermediates are more stable than the aforementioned phenomenon of epimerization in position 4, probably due to the greater steric hindrance and therefore to the greater rigidity of the molecule;
(iv) la nitrazione può essere effettuata può agevolmente in fase omogenea con miscela solfonitrica; (iv) the nitration can be easily carried out in the homogeneous phase with a sulphonitic mixture;
(v) la presenza dei due gruppi protettori rende gli intermedi maggiormente idrofobi e quindi il loro isolamento più agevole. (v) the presence of the two protecting groups makes the intermediates more hydrophobic and therefore their isolation easier.
Il procedimento dell'invenzione è illustrato dallo schema che segue: The process of the invention is illustrated by the following diagram:
L'alchilazione del composto (II) può avvenire a temperatura ambiente con un composto appropriato, per esempio un alcohol, un alogenuro alchilico, un composto cicloalchilico oppure con un'olefina in presenza di un acido forte. Come acido forte possono essere usati lacido metansolfonico, etansolfonico, trifluorometansolfonico, fluoridrico o più semplicemente l'acido solforico. L'alchilazione può essere condotta con o senza un appropriato solvente come dimetossietano, diglima, diossano o esametilfosforamide. The alkylation of compound (II) can occur at room temperature with an appropriate compound, for example an alcohol, an alkyl halide, a cycloalkyl compound or with an olefin in the presence of a strong acid. Methanesulfonic, ethanesulfonic, trifluoromethanesulfonic, hydrofluoric acid or more simply sulfuric acid can be used as strong acid. The alkylation can be carried out with or without an appropriate solvent such as dimethoxyethane, diglima, dioxane or hexamethylphosphoramide.
Dopo l'alchilazione il composto (III) risultante può essere isolato e purificato secondo metodi comunemente usati. After the alkylation the resulting compound (III) can be isolated and purified according to commonly used methods.
Preferibilmente si diluisce la miscela di reazione con acqua e si estrae il prodotto con solventi non miscibili con acqua. Preferably the reaction mixture is diluted with water and the product is extracted with solvents not miscible with water.
Dopo concentrazione si tratta con opportuno solvente che rende il prodotto insolubile e quindi filtrabile. L'intermedio (III) in opportune condizioni di reazione può essere direttamente filtrato dalla miscela di reazione come sale o sottoposto alla successiva nitrazione senza isolamento. After concentration, it is treated with a suitable solvent which makes the product insoluble and therefore filterable. The intermediate (III) under suitable reaction conditions can be directly filtered from the reaction mixture as a salt or subjected to subsequent nitration without isolation.
La nitrazione sull'intermedio (ΠΙ), isolato o non, viene condotta in mezzo acido non necessariamente anidro a temperature comprese tra i -15°e i 50C° con i comuni agenti nitranti; in particolare è possibile l'utilizzo della miscela acido solforico acido nitrico industrialmente molto agevole. Il prodotto nitrato (IV) viene agevolmente isolato e purificato mediante cristallizzazione da opportuno solvente. The nitration on the intermediate (ΠΙ), isolated or not, is carried out in an acid medium which is not necessarily anhydrous at temperatures between -15 ° and 50C ° with common nitrating agents; in particular it is possible to use the mixture sulfuric acid nitric acid industrially very easy. The nitrate product (IV) is easily isolated and purified by crystallization from a suitable solvent.
La successiva riduzione del gruppo nitro in posizione 7 seguita dalla metilazione riduttiva viene condotta secondo le note tecniche utilizzano come catalizzatore un metallo nobile puro o supportato. The subsequent reduction of the nitro group in position 7 followed by the reductive methylation is carried out according to the known techniques using a pure or supported noble metal as catalyst.
E' da notare che le due reazioni possono essere condotte separatamente o congiuntamente senza isolare l'intermedio (V). It should be noted that the two reactions can be carried out separately or jointly without isolating the intermediate (V).
Le condizioni durante la riduzione catalitica non sono determinanti: normalmente si opera tra 20 e 50C e pressioni tra 1 e 10 Atm. The conditions during the catalytic reduction are not decisive: normally one operates between 20 and 50C and pressures between 1 and 10 Atm.
L'intermedio (V) può essere isolato o direttamente alchilato nelle stesse condizioni in presenza di formaldeide. The intermediate (V) can be isolated or directly alkylated under the same conditions in the presence of formaldehyde.
L'intermedio finale (VI) viene generalmente isolato molto facilmente per precipitazione da una soluzione acquosa correggendo ad opportuno pH normalmente compreso tra 3 e 5. The final intermediate (VI) is generally isolated very easily by precipitation from an aqueous solution, correcting to a suitable pH normally between 3 and 5.
L'intermedio finale (VI) viene quindi sottoposto a deprotezione mediante trattamento acido in presenza o in assenza di accettore di carbocationi. The final intermediate (VI) is then subjected to deprotection by acid treatment in the presence or absence of a carbocation acceptor.
Come mezzo acido si può utilizzare uno degli acidi già menzionati per l'alchilazione selettiva iniziale e come accettori di carbocationi possono essere usati metilfenil etere, resorcina oppure i suoi eteri, fluoroglucina e i suoi eteri, e cosi' via. One of the acids already mentioned for the initial selective alkylation can be used as the acid medium and methylphenyl ether, resorcinol or its ethers, phloroglucin and its ethers, and so on, can be used as carbocation acceptors.
Al termine della reazione si isola la minociclina (I) mediante estrazione con opportuno solvente organico della base e successiva purificazione del cloridrato oppure precipitando un sale poco solubile che poi viene trasformato in cloridrato e ricristallizzato; un'altra tecnica utilizzabile per la purificazione è l'assorbimento su una colonna contenente una resina macroporosa idonea e successiva eluizione con un opportuno eluente. At the end of the reaction the minocycline (I) is isolated by extraction with a suitable organic solvent of the base and subsequent purification of the hydrochloride or by precipitating a slightly soluble salt which is then transformed into hydrochloride and recrystallized; another technique that can be used for purification is absorption on a column containing a suitable macroporous resin and subsequent elution with a suitable eluent.
Esempio 1 Example 1
9-ter-butil-2(N-tert-butilcarbossamido)-6-demetil-6-deoxi tetraciclina (HI). Ad una miscela di 40 ml di ac. solforico 100 ml di tert-butanolo vengono addizionati, mantenendo la temperatura a circa 5C, 10 g di 6-demetil-6-deoxi tetraciclina. 9-tert-butyl-2 (N-tert-butylcarboxamido) -6-demethyl-6-deoxi tetracycline (HI). To a mixture of 40 ml of ac. sulfuric 100 ml of tert-butanol are added, maintaining the temperature at about 5C, 10 g of 6-demethyl-6-deoxi tetracycline.
Terminata l'aggiunta si addizionano altri 30 ml di tert-butanolo e si lascia reagire a temperatura ambiente per 20-24 ore. At the end of the addition, another 30 ml of tert-butanol are added and it is left to react at room temperature for 20-24 hours.
Lentamente si forma un precipitato che al termine della reazione viene filtrato e lavato con acetone freddo. A precipitate is slowly formed which at the end of the reaction is filtered and washed with cold acetone.
All'analisi, l'intermedio (III) risultante presenta le seguenti caratteristiche: <1>H NMR, ppm =δ (CDCl3) Upon analysis, the resulting intermediate (III) has the following characteristics: <1> H NMR, ppm = δ (CDCl3)
1.38, s, 9H, N-C (CH3)31.38, s, 9H, N-C (CH3) 3
1.41, s, 9H, C-C (CH3)31.41, s, 9H, C-C (CH3) 3
2.41, s, 6H, N (CH3)22.41, s, 6H, N (CH3) 2
6.51, d, 1H, J7 8 = 8Hz, H86.51, d, 1H, J7 8 = 8Hz, H8
7.30, d, 1H H77.30, d, 1H H7
10.05, s, 1H, NHCO 10.05, s, 1H, NHCO
<13>C NMR, ppm =6(CDCl3) <13> C NMR, ppm = 6 (CDCl3)
29.24 - 29.67, C-C (CH3)3 e N-C (CH3)329.24 - 29.67, C-C (CH3) 3 and N-C (CH3) 3
34.65, C-C(CH3)334.65, C-C (CH3) 3
43.66, N(CH3)243.66, N (CH3) 2
52.85, N-C(CH3)352.85, N-C (CH3) 3
Esempio 2: Example 2:
7-nitro-9-ter-butil-2(N-tert-butilcarbossamido)-6-demetil-6-deoxi tetraciclina (IV) 7-nitro-9-tert-butyl-2 (N-tert-butylcarboxamido) -6-demethyl-6-deoxi tetracycline (IV)
Ad una sospensione di 6g di 9-tert-butil-2(N-tert-butil-carbossiamido)-6-demetil-6-deoxi tetraciclina (III) in 18 ml di tert-butanolo viene addizionata lentamente, mantenendo la temperatura a circa 15°C, una miscela di 2,4 ml di acido nitrico 65% più 3,8 ml di acido solforico 96 %. To a suspension of 6g of 9-tert-butyl-2 (N-tert-butyl-carboxyamide) -6-demethyl-6-deoxi tetracycline (III) in 18 ml of tert-butanol is slowly added, keeping the temperature at about 15 ° C, a mixture of 2.4 ml of 65% nitric acid plus 3.8 ml of 96% sulfuric acid.
Dopo due ore si diluisce con 100 ml di acqua e si estrae con 100 ml di metile cloruro. After two hours it is diluted with 100 ml of water and extracted with 100 ml of methyl chloride.
La fase organica viene lavata con acqua a pH 6 e quindi concentrata. The organic phase is washed with water at pH 6 and then concentrated.
Il residuo viene ripreso con 100 ml di acetone e per aggiunta di 23 ml di acqua si provoca la cristallizzazione del prodotto desiderato (IV). The residue is taken up with 100 ml of acetone and by adding 23 ml of water crystallization of the desired product (IV) is caused.
Allanalisi questo intermedio presenta le seguenti caratteristiche: In analysis, this intermediate has the following characteristics:
<1>H NMR, ppm = δ (CDCl3) <1> H NMR, ppm = δ (CDCl3)
1.42, s, 18H, 2 C(CH3)31.42, s, 18H, 2 C (CH3) 3
2.49, s, 6H, N(CH3)22.49, s, 6H, N (CH3) 2
8.05, s, 1H, H88.05, s, 1H, H8
10.10, s, 1H, NHCO 10.10, s, 1H, NHCO
<13>C NMR, ppm = δ (CDCl3) <13> C NMR, ppm = δ (CDCl3)
28.67 - 29.35, C-C(CH3)3 e N - C(CH3)328.67 - 29.35, C-C (CH3) 3 and N - C (CH3) 3
32.17, C-C(CH3)332.17, C-C (CH3) 3
44.84, N(CH3)244.84, N (CH3) 2
52.91, N-C(CH3)352.91, N-C (CH3) 3
Esempio 3: Example 3:
7-nitro-9-tert-butil-2-(N-tert-butil-carbossiamido)-6-demetil-6-deoxi tetraciclina (IV). 7-nitro-9-tert-butyl-2- (N-tert-butyl-carboxyamide) -6-demethyl-6-deoxi tetracycline (IV).
Ad una miscela di 40 ml di ac. solforico 100 ml di tert-butanolo vengono addizionati, mantenendo la temperatura a circa 5C, 10 g di 6-demetil-6-deoxi tetraciclina. To a mixture of 40 ml of ac. sulfuric 100 ml of tert-butanol are added, maintaining the temperature at about 5C, 10 g of 6-demethyl-6-deoxi tetracycline.
Terminata raggiunta si lascia reagire per 20 h a temperatura ambiente quindi si addizionano 20 ml di tert-butanolo e poi mantenendo la temperatura a circa 15C una miscela di 4,7 ml di acido nitrico 65% più 7,6 ml di acido solforico 96%. When reached, it is left to react for 20 h at room temperature, then 20 ml of tert-butanol are added and then, maintaining the temperature at about 15 ° C, a mixture of 4.7 ml of 65% nitric acid plus 7.6 ml of 96% sulfuric acid.
Dopo due ore si -diluisce con 130 ml di acqua e si estrae con 130 ml di metinene cloruro. After two hours it is diluted with 130 ml of water and extracted with 130 ml of methynene chloride.
La fase organica viene quindi lavata con acqua a pH 6 e poi concentrata. Il residuo viene ripreso con 100 ml di acetone e 23 ml di acqua. The organic phase is then washed with water at pH 6 and then concentrated. The residue is taken up with 100 ml of acetone and 23 ml of water.
Lentamente cristallizza il prodotto desirato (IV) che viene filtrato. Slowly crystallizes the desired product (IV) which is filtered.
All'analisi si trovano gli stessi risultati già indicati per il composto intermedio dell'esempio 2. On the analysis the same results are found already indicated for the intermediate compound of Example 2.
Esempio 4: Example 4:
7-ammino-9-tert-butil-2-(N-tert-butilcarbossamido)-6-demetil-6-deoxi tetraciclina (V). 7-amino-9-tert-butyl-2- (N-tert-butylcarboxamido) -6-demethyl-6-deoxi tetracycline (V).
Una soluzione di 3 g di 7-nitro-9-tert-butil-2(N-tert-butil carbossiamido) -6-demetil-6-deoxi tetraciclina in 30 ml di metanolo più 2 ml di ac. solforico 96% viene addizionata di 0.6 g di Pd/C 5% e sottoposta ad idrogenazione a temperatura ambiente e pressione atmosferica per 2 ore. A solution of 3 g of 7-nitro-9-tert-butyl-2 (N-tert-butyl carboxiamido) -6-demethyl-6-deoxi tetracycline in 30 ml of methanol plus 2 ml of ac. 96% sulfuric acid is added with 0.6 g of 5% Pd / C and subjected to hydrogenation at room temperature and atmospheric pressure for 2 hours.
Terminata la reazione si filtra il catalizzatore, si concentra, si riprende con acqua e si estrae a pH neutro con metilene cloruro. At the end of the reaction the catalyst is filtered, concentrated, taken up with water and extracted at neutral pH with methylene chloride.
Addizionando n-esano alla fase organica si ottiene la precipitazione del prodotto desiderato (V). By adding n-hexane to the organic phase, precipitation of the desired product (V) is obtained.
All'analisi il composto intermedio (V) presenta le seguenti caratteristiche: <1>H NMR, ppm =δ(CDCl3) Upon analysis, the intermediate compound (V) has the following characteristics: <1> H NMR, ppm = δ (CDCl3)
1.40, s, 18H, 2 C(CH3)31.40, s, 18H, 2 C (CH3) 3
2.43, s, 6H, N(CH3)22.43, s, 6H, N (CH3) 2
6.81, s, 1H, H86.81, s, 1H, H8
10.20, bs, 1H, NHCO 10.20, bs, 1H, NHCO
<13>H, NMR, ppm = δ (CDCI3) <13> H, NMR, ppm = δ (CDCI3)
29.32 - 29.70, C-C(CH3)3 e N-C(CH3)329.32 - 29.70, C-C (CH3) 3 and N-C (CH3) 3
33.72, C-C(CH3)333.72, C-C (CH3) 3
43.82, N(CH3)243.82, N (CH3) 2
53.22, N-C(CH3)353.22, N-C (CH3) 3
Esempio 5: Example 5:
7-dimetilamino-9-tert-butil-2(N-tert-butilcarbossamido)-6-demetil-6-deoxi tetraciclina (VI) 7-dimethylamino-9-tert-butyl-2 (N-tert-butylcarboxamido) -6-demethyl-6-deoxi tetracycline (VI)
Una soluzione di 3 g di 7-nitro-9-tert-butil-2(N-tert-butil carbossiamido)-6-demetil-6-deoxi tetraciclina (V) in 30 ml di metanolo più 2 ml di acido solforico 96% più 13 ml di formalmeide 40% viene addizionata di 0,6 g di Pd/C 5% e sottoposta ad idrogenazione a 40°C e 75 p.s.i. per 2 ore. Terminata la reazione si filtra il catalizzatore si evapora il solvente, si riprende con 300 ml di acqua, si corregge il pH a circa 4 e si filtra il prodotto. A solution of 3 g of 7-nitro-9-tert-butyl-2 (N-tert-butyl carboxyamide) -6-demethyl-6-deoxi tetracycline (V) in 30 ml of methanol plus 2 ml of 96% sulfuric acid plus 13 ml of 40% formalmeide is added with 0.6 g of 5% Pd / C and subjected to hydrogenation at 40 ° C and 75 p.s.i. for 2 hours. At the end of the reaction the catalyst is filtered, the solvent is evaporated, taken up with 300 ml of water, the pH is corrected to about 4 and the product is filtered.
All'analisi il composto intermedio risultante (VI) presenta le seguenti caratteristiche: Upon analysis, the resulting intermediate compound (VI) exhibits the following characteristics:
<1>H NMR, ppm = δ (CDCl3) <1> H NMR, ppm = δ (CDCl3)
1.38, s, 9H, N-C(CH3)31.38, s, 9H, N-C (CH3) 3
1.41, s, 9H, C-C(CH3)31.41, s, 9H, C-C (CH3) 3
2.47 - 2.52, 2s, 12H, 2N(CH3)22.47 - 2.52, 2s, 12H, 2N (CH3) 2
7.21, s, 1H, H87.21, s, 1H, H8
10.10, s, 1H, NHCO 10.10, s, 1H, NHCO
<13>C NMR, ppm = δ(CDCl3) <13> C NMR, ppm = δ (CDCl3)
28.77 - 29.35, C-C(CH3)3 e N-C(CH3)3 28.77 - 29.35, C-C (CH3) 3 and N-C (CH3) 3
35.11, C-C(CH3)335.11, C-C (CH3) 3
43.78 - 44.84, 2 N (CH3)243.78 - 44.84, 2 N (CH3) 2
52.91, N-C(CH3)352.91, N-C (CH3) 3
Esempio 6 Example 6
7-dimetilamino-6-demetil-6-deoxi tetraciclina cloridrato. 7-dimethylamino-6-demethyl-6-deoxi tetracycline hydrochloride.
Una soluzione di 10 g di 7-dimetilamino-9-tert-butil-2(N-tert-butil carbossamido)-6-demetil-6-deoxi tetraciclina in 50 ml di ac. trifluorometansolfonico 2 ml di anisolo viene mantenuta a temperatura ambiente per 4 ore e poi a 70C per 7 ore. A solution of 10 g of 7-dimethylamino-9-tert-butyl-2 (N-tert-butyl carboxy starch) -6-demethyl-6-deoxi tetracycline in 50 ml of ac. trifluoromethanesulfonic 2 ml of anisole is kept at room temperature for 4 hours and then at 70C for 7 hours.
Terminata la reazione si diluisce con acqua e si estrae con metilene cloruro. La fase acquosa viene quindi concentrata ad un volume opportuno in modo che per raffreddamento precipiti la minociclina ditriflato che viene filtrata e lavata con metil isobutil chetone. At the end of the reaction it is diluted with water and extracted with methylene chloride. The aqueous phase is then concentrated to a suitable volume so that on cooling precipitates the minocycline ditriflate which is filtered and washed with methyl isobutyl ketone.
La minociclina ditriflato viene quindi sciolta in acqua, e dopo neutralizzazione dell'acido triflico si precipita il cloridrato portando a pH 3, 7-4,0 con acido cloridrico. The minocycline ditriflate is then dissolved in water, and after neutralization of the triflic acid the hydrochloride is precipitated, bringing to pH 3.7-4.0 with hydrochloric acid.
Si ottiene la minociclina cloridrato con caratteristiche chimico-fisiche corrispondenti al prodotto standard. Minocycline hydrochloride is obtained with chemical-physical characteristics corresponding to the standard product.
Claims (15)
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