ITMI952097A1 - IMPROVED PROCESS TO PRODUCE EPTASTIGMINE AND NEW INTERMEDIATE USEFUL FOR THE PURPOSE - Google Patents
IMPROVED PROCESS TO PRODUCE EPTASTIGMINE AND NEW INTERMEDIATE USEFUL FOR THE PURPOSE Download PDFInfo
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- ITMI952097A1 ITMI952097A1 IT95MI002097A ITMI952097A ITMI952097A1 IT MI952097 A1 ITMI952097 A1 IT MI952097A1 IT 95MI002097 A IT95MI002097 A IT 95MI002097A IT MI952097 A ITMI952097 A IT MI952097A IT MI952097 A1 ITMI952097 A1 IT MI952097A1
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- hexeroline
- physostigmine
- molar ratio
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- 238000000034 method Methods 0.000 title claims abstract description 38
- RRGMXBQMCUKRLH-CTNGQTDRSA-N [(3ar,8bs)-3,4,8b-trimethyl-2,3a-dihydro-1h-pyrrolo[2,3-b]indol-7-yl] n-heptylcarbamate Chemical compound C12=CC(OC(=O)NCCCCCCC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C RRGMXBQMCUKRLH-CTNGQTDRSA-N 0.000 title claims abstract description 24
- 229950010753 eptastigmine Drugs 0.000 title 1
- 239000003085 diluting agent Substances 0.000 claims abstract description 19
- PIJVFDBKTWXHHD-UHFFFAOYSA-N Physostigmine Natural products C12=CC(OC(=O)NC)=CC=C2N(C)C2C1(C)CCN2C PIJVFDBKTWXHHD-UHFFFAOYSA-N 0.000 claims abstract description 15
- PIJVFDBKTWXHHD-HIFRSBDPSA-N physostigmine Chemical compound C12=CC(OC(=O)NC)=CC=C2N(C)[C@@H]2[C@@]1(C)CCN2C PIJVFDBKTWXHHD-HIFRSBDPSA-N 0.000 claims abstract description 15
- 229960001697 physostigmine Drugs 0.000 claims abstract description 15
- HKGWQUVGHPDEBZ-OLZOCXBDSA-N eseroline Chemical compound C1=C(O)C=C2[C@]3(C)CCN(C)[C@@H]3N(C)C2=C1 HKGWQUVGHPDEBZ-OLZOCXBDSA-N 0.000 claims abstract description 14
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 8
- 150000007524 organic acids Chemical class 0.000 claims abstract description 7
- 235000005985 organic acids Nutrition 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 3
- RFXBSYPBSRSQDU-UHFFFAOYSA-N 1-isocyanatoheptane Chemical compound CCCCCCCN=C=O RFXBSYPBSRSQDU-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 11
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 238000007259 addition reaction Methods 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- -1 glycol ethers Chemical class 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 claims description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- SAMJGBVVQUEMGC-UHFFFAOYSA-N 1-ethenoxy-2-(2-ethenoxyethoxy)ethane Chemical compound C=COCCOCCOC=C SAMJGBVVQUEMGC-UHFFFAOYSA-N 0.000 claims description 2
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- WYUIWUCVZCRTRH-UHFFFAOYSA-N [[[ethenyl(dimethyl)silyl]amino]-dimethylsilyl]ethene Chemical compound C=C[Si](C)(C)N[Si](C)(C)C=C WYUIWUCVZCRTRH-UHFFFAOYSA-N 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 claims description 2
- 229940052303 ethers for general anesthesia Drugs 0.000 claims description 2
- 238000006140 methanolysis reaction Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 claims description 2
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- HIMXYMYMHUAZLW-UHFFFAOYSA-N [[[dimethyl(phenyl)silyl]amino]-dimethylsilyl]benzene Chemical compound C=1C=CC=CC=1[Si](C)(C)N[Si](C)(C)C1=CC=CC=C1 HIMXYMYMHUAZLW-UHFFFAOYSA-N 0.000 claims 1
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 7
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 9
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 229940095064 tartrate Drugs 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 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 2
- XGEGHDBEHXKFPX-UHFFFAOYSA-N N-methyl urea Chemical compound CNC(N)=O XGEGHDBEHXKFPX-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- LSXKDWGTSHCFPP-UHFFFAOYSA-N 1-bromoheptane Chemical compound CCCCCCCBr LSXKDWGTSHCFPP-UHFFFAOYSA-N 0.000 description 1
- 102000012440 Acetylcholinesterase Human genes 0.000 description 1
- 108010022752 Acetylcholinesterase Proteins 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- YFONAHAKNVIHPT-UHFFFAOYSA-N [methyl-[[methyl(diphenyl)silyl]amino]-phenylsilyl]benzene Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C)N[Si](C)(C=1C=CC=CC=1)C1=CC=CC=C1 YFONAHAKNVIHPT-UHFFFAOYSA-N 0.000 description 1
- 229940022698 acetylcholinesterase Drugs 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- AXMPFOXRWZXZFA-UHFFFAOYSA-N heptyl carbamate Chemical compound CCCCCCCOC(N)=O AXMPFOXRWZXZFA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Processo migliorato per produrre eptastigmina e suoi sali di addizione acida con acidi organici in cui il miglioramento consiste nel fatto che la preparazione di eserolina a partire da fisostigmina viene realizzata ponendo a reagire la fisostigmina con un adatto agente sililante e sostituendo poi, nel silit derivato cosi ottenuto, il silil-gruppo con un atomo di idrogeno. Vantaggiosamente, la successiva addizione di eptilisocianato all'eserolina è condotta in presenza di una base e di un diluente polare aprotico.Improved process for producing heptastigmine and its acid addition salts with organic acids wherein the improvement consists in the fact that the preparation of eseroline starting from physostigmine is carried out by reacting physostigmine with a suitable silylating agent and then replacing, in the derived silit thus obtained, the silyl group with a hydrogen atom. Advantageously, the subsequent addition of heptilisocyanate to eseroline is carried out in the presence of a base and an aprotic polar diluent.
Description
DESCRIZIONE DESCRIPTION
dell'invenzione industriale dal titolo: of the industrial invention entitled:
"Processo migliorato per produrre eptastigmina e nuovo intermedio utile allo scopo" "Improved process to produce heptastigmine and new intermediate useful for the purpose"
La presente invenzione riguarda un processo migliorato per produrre eptastigmina ed nuovo intermedio utile allo scopo. Nel corso della presente descrizione e nelle rivendicazioni il termine eptastigmina è utilizzato per contaddistinguere il trimetil-1,3a,8-esaidro-1,2,3,3a,8,8a-pirrol(2,3-b)indol-5(3aS, 8aR) eptil carbammato di formula (I) The present invention relates to an improved process for producing heptastigmine and a new intermediate useful for the purpose. In the course of the present description and in the claims, the term heptastigmine is used to counter-distinguish trimethyl-1,3a, 8-hexahydro-1,2,3,3a, 8,8a-pyrrol (2,3-b) indol-5 ( 3aS, 8aR) heptyl carbamate of formula (I)
L'eptastigmina ed i suoi sali di addizione acida con acidi organici inibiscono l'acetilcolinesterasi e sono particolarmente utili nel trattamento della malattia di Alzheimer. Heptastigmine and its acid addition salts with organic acids inhibit acetylcholinesterase and are particularly useful in the treatment of Alzheimer's disease.
EP-A-0154 864 insegna a preparare l'eptastigmina idrolizzando dapprima la fisostigmina, nota anche come eserina, con un alcossilato alcalino sotto vuoto. Il sale alcalino di eserolina cosi ottenuto viene poi fatto reagire, sempre sotto vuoto, con eptilisocianato in presenza di un solvente idrocarburico medio-polare, preferibilmente benzene. La resa totale varia dal 40 al 70%. EP-A-0154 864 teaches to prepare heptastigmine by first hydrolyzing physostigmine, also known as hexerine, with an alkaline alkoxylate under vacuum. The alkaline hexeroline salt thus obtained is then reacted, still under vacuum, with heptylisocyanate in the presence of a mid-polar hydrocarbon solvent, preferably benzene. The total yield varies from 40 to 70%.
EP-A-0298 202 riguarda principalmente i sali di addizione acida con acidi organici dell'eptastigmina. Però, esso si propone anche di ovviare ad alcuni inconvenienti del procedimento descritto da EP-A-0154 864 (necessità di effettuare l'intera sintesi sotto vuoto e basse rese). A questo proposito, EP-A-0 298 202 insegna ad idrolizzare la fisostigmina in un solvente organico, in particolare un alcool alifatico a basso peso molecolare o un glicole, con alcali in atmosfera di azoto, seguito da trattamento con un acido inorganico forte. Questa idrolisi soffre dell'inconveniente di essere esotermica e difficilmente controllabile su larga scala. L'eserolina grezza cosi ottenuta viene poi purificata per cristallizzazione da una miscela di idrocarburi aromatici ed alitatici, preferibilmente benzene/ etere di petrolio 1:1. La successiva reazione dell'eserolina con eptilisocianato viene effettuata sciogliendo, separatamente, le due materie prime in un solvente organico, preferibilmente etere etilico. Alla soluzione di eserolina viene aggiunta dapprima una quantità catalitica di una sostanza alcalina, preferibilmente sodio metallico, e poi, sotto atmosfera di azoto, la soluzione dell’isocianato. La resa totale varia dal 70 all'80%. EP-A-0298 202 mainly relates to the acid addition salts with organic acids of heptastigmine. However, it also proposes to obviate some drawbacks of the process described by EP-A-0154 864 (need to carry out the entire synthesis under vacuum and low yields). In this regard, EP-A-0 298 202 teaches to hydrolyze physostigmine in an organic solvent, in particular a low molecular weight aliphatic alcohol or a glycol, with alkali in a nitrogen atmosphere, followed by treatment with a strong inorganic acid. This hydrolysis suffers from the drawback of being exothermic and difficult to control on a large scale. The crude hexeroline thus obtained is then purified by crystallization from a mixture of aromatic and alitatic hydrocarbons, preferably benzene / petroleum ether 1: 1. The subsequent reaction of hexeroline with heptylisocyanate is carried out by dissolving the two raw materials separately in an organic solvent, preferably ethyl ether. A catalytic quantity of an alkaline substance, preferably metallic sodium, is first added to the solution of eseroline, and then, under a nitrogen atmosphere, the isocyanate solution. The total yield varies from 70 to 80%.
Per ovviare agli inconvenienti connessi con l'uso dell'etere etilico e del sodio metallico, EP-A-Q 499179 propone di condurre la reazione dell'eserolina con eptilisocianato, eventualmente preparato in situ da 1-bromoeptano e cianato di potassio, in un solvente polare aprotico, preferibilmente acetonitrile o acetato di etile, ed in presenza di quantità catalitiche di un sale di un sale di ammonio quaternario e di un cianato o di un alcolato di un metallo. Anche questa reazione viene preferibilmente condotta in atmosfera di azoto e dura otto ben ore quando si utilizza eptilisocianato o 19 ore, a riflusso, quando quest’ultimo è preparato in situ. To overcome the drawbacks associated with the use of ethyl ether and metallic sodium, EP-A-Q 499179 proposes to carry out the reaction of eseroline with heptylisocyanate, possibly prepared in situ from 1-bromoheptane and potassium cyanate, in a polar solvent aprotic, preferably acetonitrile or ethyl acetate, and in the presence of catalytic quantities of a salt of a quaternary ammonium salt and of a cyanate or an alcoholate of a metal. This reaction is also preferably carried out in a nitrogen atmosphere and lasts eight hours when heptylisocyanate is used or 19 hours, at reflux, when the latter is prepared in situ.
Il processo descritto da questo brevetto soffre principalmente dell'inconveniente di utilizzare eserolina prodotta secondo la tecnica nota: vale a dire, prodotta sotto vuoto secondo l'EP-A-0154 864 o mediante la reazione esotermica dell'EP-A-0 298 202. Inoltre, come già visto, la reazione fra eserolina ed eptilisocianato descritta dall'EP-A-0499 179 richiede tempi piuttosto lunghi. The process described by this patent mainly suffers from the drawback of using eseroline produced according to the known art: that is, produced under vacuum according to EP-A-0154 864 or by the exothermic reaction of EP-A-0 298 202 Moreover, as already seen, the reaction between hexeroline and heptylisocyanate described by EP-A-0499 179 requires rather long times.
Per poter produrre l'eptastigmina ed i suoi sali su larga scale è quindi ancora molto sentita la necessità di un processo in cui l'eserolina possa essere prodotta senza necessità di lavorare sotto vuoto o senza dover controllare una reazione esotermica. Inoltre, è anche molto sentita l'esigenza di ridurre il tempo di reazione fra eserolina ed eptilisocianato. In order to produce heptastigmine and its salts on a large scale, there is therefore still a great need for a process in which eseroline can be produced without the need to work under vacuum or without having to control an exothermic reaction. Furthermore, there is also a strong need to reduce the reaction time between hexeroline and heptylisocyanate.
E' ora stato inaspettatamento trovato che questi inconvenienti possono essere eliminati con la presente invenzione che riguarda un processo migliorato per produrre eptastigmina e suoi sali di addizione acida con acidi organici comprendente It has now been unexpectedly found that these drawbacks can be eliminated with the present invention which relates to an improved process for producing heptastigmine and its acid addition salts with organic acids comprising
1) preparazione di eserolina a partire da fisostigmina, 1) preparation of eseroline from physostigmine,
2) addizione di eptilisocianato all'eserolina a dare eptastigmina, e 2) addition of heptylisocyanate to hexeroline to give heptastigmine, e
3) se lo si desidera, formazione di un sale di addizione acida dell'eptastigmina con un acido organico, 3) if desired, formation of an acid addition salt of heptastigmine with an organic acid,
in cui il miglioramento consiste nel fatto che la fase (1) viene realizzata where the improvement consists in the fact that step (1) is carried out
a) ponendo a reagire la fisostigmina con un adatto agente sililante a dare un Composto di formula a) reacting physostigmine with a suitable silylating agent to give a Compound of formula
in cui R1 , R2 ed R3, uguali o diversi fra loro, sono alchile a basso peso molecolare, alchilene a basso peso molecolare o arile, e wherein R1, R2 and R3, the same or different from each other, are low molecular weight alkyl, low molecular weight alkylene or aryl, and
b) sostituendo poi, nel Composto di formula (II) cosi ottenuto il gruppo SiR1R2R3 con un atomo di idrogeno. b) then replacing the SiR1R2R3 group with a hydrogen atom in the Compound of formula (II) thus obtained.
Esempi di significati preferiti di R1, R2 ed R3 sono metile, etile, propile, butile, vinile e fenile. Ancor più preferibilmente R1, R2 ed R3 sono uguali fra di loro e sono metile. Examples of preferred meanings of R1, R2 and R3 are methyl, ethyl, propyl, butyl, vinyl and phenyl. Even more preferably R1, R2 and R3 are equal to each other and are methyl.
Esempi di adatti agenti sililanti sono i disilazani quali, ad esempio, l'1,3-dimetil-1,1,3,3-tetrafenildisilazano, l'1,3-diferiil-1,1,3,3-tetrametildisilazano, L'1,3-divinil-1,1,3,3-tetrametildisilazano, e L'1,1,1,3,3,3-esametildisilazano (HDMS). L’agente silitante preferito secondo la presente invenzione è L'HDMS (1,1,1,3,3,3-esametildisilazano). Examples of suitable silylating agents are disilazanes such as, for example, 1,3-dimethyl-1,1,3,3-tetraphenyldisilazane, 1,3-diferiil-1,1,3,3-tetramethyldisilazane, L 1,3-divinyl-1,1,3,3-tetramethyldisilazane, and 1,1,1,3,3,3-hexamethyldisilazane (HDMS). The preferred silitating agent according to the present invention is HDMS (1,1,1,3,3,3-hexamethyldisilazane).
Quando L'agente sililante è liquido, la fase 1a viene preferibilmente condotta utilizzando, come diluente, un eccesso dell’agente sililante stesso. Tuttavia, la reazione può anche essere condotta in presenza di un adatto diluente organico od una adatta miscela di diluenti organici la cui natura può essere facilmente predeterminata, di caso in caso, dal tecnico del ramo, a seconda della natura dell'agente sililante usato e mediante semplici prove sperimentali di carattere routinario. La temperatura ed il tempo di reazione della fase 1a variano al variare dell'agente sililante e degli eventuali diluenti usati in funzione di parametri ben noti al tecnico del ramo. Tipicamente, nel caso dell'HDMS, la reazione può essere condotta senza aggiunta di alcun diluente ad una temperatura compresa tra 100° e 125°C, preferibilmente a circa 125°C, per un tempo compreso fra 4 ed 8 ore, preferibilmente 6 ore circa. Alternativamente, la reazione viene condotta in presenza di un diluente scelto fra gli idrocarburi aromatici quali, ad esempio, toluene, xilene e tetraidronaftalene, alla temperatura di riflusso della miscela di reazione. Esempio di diluente preferito è il toluene. When the silylating agent is liquid, step 1a is preferably carried out using, as a diluent, an excess of the silylating agent itself. However, the reaction can also be carried out in the presence of a suitable organic diluent or a suitable mixture of organic diluents, the nature of which can be easily predetermined, case by case, by the person skilled in the art, according to the nature of the silylating agent used and through simple experimental tests of a routine nature. The temperature and the reaction time of step 1a vary as the silylating agent and any diluents used vary as a function of parameters well known to those skilled in the art. Typically, in the case of HDMS, the reaction can be carried out without adding any diluent at a temperature between 100 ° and 125 ° C, preferably at about 125 ° C, for a time between 4 and 8 hours, preferably 6 hours. approximately. Alternatively, the reaction is carried out in the presence of a diluent selected from aromatic hydrocarbons such as, for example, toluene, xylene and tetrahydronaphthalene, at the reflux temperature of the reaction mixture. An example of a preferred diluent is toluene.
IL rapporto molare fisostigmina/HMDS è preferibilmente compreso tra 1:2 e 1:10- Ancor più preferibilmente esso è 1:2,5. La fase 1a porta al Composto (II), che è olio distillabile, con resa pressocchè quantitativa, accanto a N-metil urea. The physostigmine / HMDS molar ratio is preferably between 1: 2 and 1: 10- Even more preferably it is 1: 2.5. Phase 1a leads to Compound (II), which is distillable oil, with almost quantitative yield, alongside N-methyl urea.
II Composto di formula (II) è nuovo derivato stabile e protetto dell'eserolina. Esso costituisce, quindi, un ulteriore oggetto della presente invenzione. The compound of formula (II) is a new stable and protected derivative of eseroline. It therefore constitutes a further object of the present invention.
La fase 1b viene preferibilmente condotta per metanolisi a temperatura ambiente per 1 ora. Dopo allontanamento dei prodotti volatili, L'eserolina grezza cosi ottenuta può essere trasformata in eptastigmina (fase 2) secondo tecniche note quali, ad esempio, quelle descritte nell’EP-A-0499179. Phase 1b is preferably carried out by methanolysis at room temperature for 1 hour. After removal of the volatile products, the crude hexeroline thus obtained can be transformed into heptastigmine (phase 2) according to known techniques such as, for example, those described in EP-A-0499179.
E' però stato sorprendentemete trovato che realizzando la reazione di addizione di eptilisocianato ad eserolina (fase 2) in presenza di una base e di un diluente polare aprotico si abbreviano sensibilmente i tempi di reazione rispetto a quando lo stesso tipo di reazione viene realizzato sempre in un diluente polare aprotico ma in presenza di sistema costituito da (i) quantità catalitiche di un sale d’ammonio quaternario e di un cianato di un metallo o da (ii) quantità catalitiche di un sale d'ammonio quaternario e di un alcolato di un metallo. However, it has been surprisingly found that by carrying out the addition reaction of heptylisocyanate to eseroline (phase 2) in the presence of a base and an aprotic polar diluent, the reaction times are significantly shortened compared to when the same type of reaction is always carried out in an aprotic polar diluent but in the presence of a system consisting of (i) catalytic quantities of a quaternary ammonium salt and a cyanate of a metal or (ii) catalytic quantities of a quaternary ammonium salt and an alcoholate of a metal.
Esempi di adatti diluenti polari aprotici sono l'acetonitrile, il tetraidrofurano e gli eteri di glicoli quali L’1,2-dimetossietano, l'1,2-dietossietano, il diossano, il dietilen glicole dietil etere, il dietilen glicole divinil etere, il dietilen glicole dimetil etere (diglime) ed il trietilen glicole dimetil etere. Il diluente preferito è il diglime. Examples of suitable aprotic polar diluents are acetonitrile, tetrahydrofuran and glycol ethers such as 1,2-dimethoxyethane, 1,2-diethoxyethane, dioxane, diethylene glycol diethyl ether, diethylene glycol divinyl ether, diethylene glycol dimethyl ether (diglime) and triethylene glycol dimethyl ether. The preferred diluent is diglime.
Esempi di adatte basi sono: idruro di sodio, carbonato di sodio, carbonato di potassio, sodio metossido, trietilamina. La base preferita è il carbonato di potassio. Examples of suitable bases are: sodium hydride, sodium carbonate, potassium carbonate, sodium methoxide, triethylamine. The preferred base is potassium carbonate.
Tipicamente, L'eserolina grezza viene ripresa con diglime ed addizionata, in presenza di carbonato di potassio e in corrente di azoto, con eptilisocianato in rapporto molare compreso tra 1:1,05 e 1:2, preferibilmente 1:1,2. Typically, crude hexeroline is taken up with diglime and added, in the presence of potassium carbonate and in a nitrogen stream, with heptylisocyanate in a molar ratio between 1: 1.05 and 1: 2, preferably 1: 1.2.
Il rapporto molare eserolina/base può variare da 1:0,1 a 1:1; preferibilmente esso è di 1:0,1. The molar exeroline / base ratio can vary from 1: 0.1 to 1: 1; preferably it is 1: 0.1.
La reazione può essere condotta ad una temperatura compresa tra 0° e 220°C, preferibilmente tra 20° e 25°C. The reaction can be carried out at a temperature between 0 ° and 220 ° C, preferably between 20 ° and 25 ° C.
Dopo 2 ore circa a temperatura ambiente, la miscela di reazione viene lavorata a dare eptastigmina che può essere trasformata, se lo si desidera,in un suo sale di addizione acida (fase 3), quale il tartrato, secondo tecniche note. After about 2 hours at room temperature, the reaction mixture is worked to give heptastigmine which can be transformed, if desired, into an acid addition salt thereof (phase 3), such as tartrate, according to known techniques.
La facile sostituzione quantitativa del gruppo carbammico (CH3NH-CO) della fisostigmina con un gruppo SiR1R2R3 (dove R1, R2 ed R3 hanno i significati già visti) era del tutto inattesa e costituisce una delle caratteristiche salienti della presente invenzione perché consente di ovviare a tutti gli inconvenienti delle tecniche note per preparare eserolina da fisostigmina. Un'altra caratteristica importante della presente invenzione è la facile trasformazione del silil derivato dell'eserolina (Composto di formula (II)) in eserolina, in condizioni blande e con buone rese. The easy quantitative substitution of the carbamate group (CH3NH-CO) of physostigmine with a SiR1R2R3 group (where R1, R2 and R3 have the meanings already seen) was completely unexpected and constitutes one of the salient features of the present invention because it allows to obviate all the drawbacks of the known techniques for preparing eseroline from physostigmine. Another important feature of the present invention is the easy transformation of the silyl derivative of eseroline (Compound of formula (II)) into eseroline, under mild conditions and with good yields.
Una terza caratteristica importante delta presente invenzione è costituita dal breve tempo richiesto, pur operando a temperatura ambiente, quando l'eserolina grezza viene fatta reagire con eptilisocianato in presenza di una base e di un diluente polare aprotico. A third important feature of the present invention is the short time required, while operating at room temperature, when crude hexeroline is reacted with heptylisocyanate in the presence of a base and an aprotic polar diluent.
Queste ed altre caratteristiche della presente invenzione risulteranno ancora più evidenti dai seguenti esempi che vengono dati a scopo puramente illustrativo e non limitativo. These and other characteristics of the present invention will become even more evident from the following examples which are given for purely illustrative and non-limiting purposes.
Esempio 1 Example 1
Preparazione del trimetil-1,3a,8-esaidro-1,2,3a,8,8a-pirrol (2,3-b)indol-5-(3aS,8aR)trimetilsilil etere (Composto di formula II, R1=R2=R3=CH3) Preparation of trimethyl-1,3a, 8-hexahydro-1,2,3a, 8,8a-pyrrol (2,3-b) indole-5- (3aS, 8aR) trimethylsilyl ether (Compound of formula II, R1 = R2 = R3 = CH3)
Una sospensione di fisostigmina (2g; 7,3 mmoli) in HMDS (3,8 mi; 18 mmoli) è stata scaldata sotto agitazione per 6 ore alla temperatura di riflusso. L’eccesso di HMDS è stato allontanato a pressione ridotta. Dopo aggiunta di etere di petrolio (5 ,ml) la sospensione è stata lasciata sotto agitazione, a temperatura ambiente, per 30 minuti. Dopo filtrazione, la soluzione è stata evaporata a secchezza a dare 2 g (resa: 95 % del teorico) del composto desiderato sotto forma di olio giallo pallido. A suspension of physostigmine (2g; 7.3mmol) in HMDS (3.8ml; 18mmol) was heated under stirring for 6 hours at reflux temperature. The excess of HMDS was removed under reduced pressure. After addition of petroleum ether (5, ml) the suspension was left under stirring, at room temperature, for 30 minutes. After filtration, the solution was evaporated to dryness to give 2 g (yield: 95% of theoretical) of the desired compound in the form of pale yellow oil.
p.e. 124-26°C (0,4 mbar). e.g. 124-26 ° C (0.4 mbar).
Spettro<1>HNMR (CDCl3): delta = 0,22 (s, 9H); 1,40 (s, 3H); 1,92 (t, 2H); 2,67 (m, 2H); 2,88 (s, 3H); 4,00 (s, 1H); 6,28 (d, 1 H) ; 6,52 (s, 1H); 6,74 (d, 1H) . Spectrum <1> HNMR (CDCl3): delta = 0.22 (s, 9H); 1.40 (s, 3H); 1.92 (t, 2H); 2.67 (m, 2H); 2.88 (s, 3H); 4.00 (s, 1H); 6.28 (d, 1H); 6.52 (s, 1H); 6.74 (d, 1H).
Spett ro IR (velo liqui do) : cm<-1 >2958(s), 1493(s) , 1252(s) , 956(s). IR spectrum (liquid veil): cm <-1> 2958 (s), 1493 (s), 1252 (s), 956 (s).
Esempio 2 Example 2
Preparazione del trimetil-1,3a,8-esaidro-1,2,3a,8,8a-pirrol ( 2,3-b)indol-5-(3aS,8aR)trimetilsilil etere (Composto di formula II, <=R>2<=>R3<=C H>3^ Una soluzione di fisostigmina (1g; 3,65 mmoli) e di HDMS (1,9 mi; 9 mmoli) in 5 mi di toluene è stata scaldata a rifluire per 48 ore. La miscela di reazione è stata poi lavorata come descritto nell'Esempio 1. E' stato cosi ottenuto il prodotto desiderato (resa: 95% del teorico). Preparation of trimethyl-1,3a, 8-hexahydro-1,2,3a, 8,8a-pyrrol (2,3-b) indole-5- (3aS, 8aR) trimethylsilyl ether (Compound of formula II, <= R > 2 <=> R3 <= C H> 3 ^ A solution of physostigmine (1g; 3.65mmol) and HDMS (1.9ml; 9mmol) in 5ml of toluene was heated to reflux for 48 hours. The reaction mixture was then worked as described in Example 1. The desired product was thus obtained (yield: 95% of the theoretical).
Esempio 3 Example 3
Preparazione di eptastigmina e del suo tartrato Una soluzione di trimetil-1,3a,8-esaidro-1,2,3a,8,8a-pirrol (2,3-b)indol-5-(3aS,8aR)trimetilsilil etere (1,2 g; 4,1 mmoli) in metanolo (12 ml)è stata lasciata sotto agitazione a temperatura ambiente per 1 ora, in corrente di azoto, e poi evaporata a dare 0,9 g di eserolina. Alla soluzione di eserolina in diglime (18 ml) è stato aggiunto carbonato di potassio (0,09 g) ed in questa miscela è stata gocciolata, in 15 minuti e mantenendo una leggera corrente di azoto, una soluzione di eptilisocianato (0,79 mL; 4,9 mmoli) in diglime (4 ml.) La miscela di reazione è stata lasciata sotto agitazione a temperatura ambiente per 2 ore, filtrata e diluita con acqua (75 ml)e HCl 1:4 (0,1 ml), per allontanare il diglime con distillazione azeotropica a pressione ridotta. Il residuo è stato ripreso con acqua (50ml) ed estratto con diclorometano (2 x 50 ; lamfla)-se organica è stata lavata con acqua (3 x 50 emsle)ccata su solfato di sodio. Dopo allontanamento del solvente a pressione ridotta, il residuo (1,3 g) è stato estratto con esano caldo (3 x 15ml), per rimuovere un'impurezza (Ν,Ν-dieptilurea). Preparation of heptastigmine and its tartrate A solution of trimethyl-1,3a, 8-hexahydro-1,2,3a, 8,8a-pyrrol (2,3-b) indole-5- (3aS, 8aR) trimethylsilyl ether ( 1.2 g; 4.1 mmoles) in methanol (12 ml) was left under stirring at room temperature for 1 hour, in a stream of nitrogen, and then evaporated to give 0.9 g of eseroline. To the solution of eseroline in diglime (18 ml) was added potassium carbonate (0.09 g) and in this mixture a heptylisocyanate solution (0.79 ml ; 4.9 mmol) in diglime (4 ml.) The reaction mixture was left under stirring at room temperature for 2 hours, filtered and diluted with water (75 ml) and HCl 1: 4 (0.1 ml), to remove the diglime with azeotropic distillation at reduced pressure. The residue was taken up with water (50ml) and extracted with dichloromethane (2 x 50; lamfla) - if organic it was washed with water (3 x 50 emsle) clad on sodium sulphate. After removing the solvent under reduced pressure, the residue (1.3 g) was extracted with hot hexane (3 x 15ml), to remove an impurity (Ν, Ν-dieptylurea).
Evaporando il solvente a pressione ridotta, sono stati ottenuti 950 mg di eptastigmina (resa: 64% del teorico) sotto forma di olio che è stato trasformato nel corrispondente tartrato secondo il procedimento descritto nell'EP-A-0298202 (resa: 90% del teorico rispetto all'eptastigmina; p.f. 121-123°C). Evaporating the solvent under reduced pressure, 950 mg of heptastigmine were obtained (yield: 64% of the theoretical) in the form of oil which was transformed into the corresponding tartrate according to the procedure described in EP-A-0298202 (yield: 90% of the theoretical compared to heptastigmine; m.p. 121-123 ° C).
Esempio 4 Example 4
Preparazione di eptastigmina tartrato Operando in modo analogo a quello descritto nell'Esempio 3 ma partendo da 0,5 g di trimetil-1,3a,8-esaidro-1,2,3a,8,8a-pirrol(2,3-b)indol-5-(3aS,8aR)trimetilsilil etere ed utilizzando idruro di sodio (in rapporto molare 1:1 con L'eserolina formatasi nel corso della reazione) in luogo del carbonato di potassio sono stati ottenuti 80 mg di eptastigmina tartrato. Preparation of heptastigmine tartrate Operating in the same way as that described in Example 3 but starting from 0.5 g of trimethyl-1,3a, 8-hexahydro-1,2,3a, 8,8a-pyrrol (2,3-b ) indole-5- (3aS, 8aR) trimethylsilyl ether and using sodium hydride (in molar ratio 1: 1 with the hexeroline formed during the reaction) in place of potassium carbonate 80 mg of heptastigmine tartrate were obtained.
Esempio 5 Example 5
Preparazione di eptastigmina tartrato Una soluzione di trimetil-1,3a,8-esaidro-1,2,3a,8,8a-pirrol (2,3-b)indol-5-(3aS,8aR)trimetilsilil etere (II) (0,6 g; 2,05 mmoli) in metanolo (6 ml)è stata lasciata sotto agitazione a temperatura ambiente ed in corrente di azoto per 1 ora. Dopo evaporazione del metanolo a pressione ridotta, l'eserolina grezza ottenuta (0,45 g) è stata sciolta in 5 mi di acetonitrile. La soluzione, dopo aggiunta di trietilammina (0,29 mi; 2,05 mmoli) è stata lasciata sotto agitazione a temperatura ambiente per 30 minuti. A questa soluzione è stata quindi aggiunta, a goccia a goccia in 10 minuti, una soluzione di eptilisocianato (0,4 mi; 2,5 mmoli) in 2 mi di acetonitrile e la miscela di reazione è stata tenuta sotto agitazione per 2 ore. Preparation of heptastigmine tartrate A solution of trimethyl-1,3a, 8-hexahydro-1,2,3a, 8,8a-pyrrol (2,3-b) indol-5- (3aS, 8aR) trimethylsilyl ether (II) ( 0.6 g; 2.05 mmoles) in methanol (6 ml) was left under stirring at room temperature and in a nitrogen stream for 1 hour. After evaporation of the methanol under reduced pressure, the crude hexeroline obtained (0.45 g) was dissolved in 5 ml of acetonitrile. The solution, after addition of triethylamine (0.29 ml; 2.05 mmoles) was left under stirring at room temperature for 30 minutes. A solution of heptylisocyanate (0.4 ml; 2.5 mmoles) in 2 ml of acetonitrile was then added dropwise over 10 minutes to this solution and the reaction mixture was kept under stirring for 2 hours.
Dopo evaporazione a pressione ridotta. Il residuo è stato lavorato come descritto nell'Esempio 3. Resa: 0,2 g di eptastigmina tartrato. After evaporation under reduced pressure. The residue was processed as described in Example 3. Yield: 0.2 g of heptastigmine tartrate.
Claims (29)
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT95MI002097A IT1276928B1 (en) | 1995-10-13 | 1995-10-13 | IMPROVED PROCESS TO PRODUCE EPTASTIGMINE AND NEW INTERMEDIATE USEFUL FOR THE PURPOSE |
| AU72841/96A AU7284196A (en) | 1995-10-13 | 1996-10-02 | An improved process for producing heptastigmine and a new intermediate compound useful in this process |
| PCT/EP1996/004296 WO1997014694A1 (en) | 1995-10-13 | 1996-10-02 | An improved process for producing heptastigmine and a new intermediate compound useful in this process |
| ZA968284A ZA968284B (en) | 1995-10-13 | 1996-10-02 | Process for producing heptastigmine and a new intermediate compound useful in this process |
| ARP960104662A AR003831A1 (en) | 1995-10-13 | 1996-10-09 | IMPROVED PROCEDURE TO PRODUCE EPTASTIGMINE AND A NEW INTERMEDIATE USEFUL TO THIS END. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT95MI002097A IT1276928B1 (en) | 1995-10-13 | 1995-10-13 | IMPROVED PROCESS TO PRODUCE EPTASTIGMINE AND NEW INTERMEDIATE USEFUL FOR THE PURPOSE |
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| Publication Number | Publication Date |
|---|---|
| ITMI952097A0 ITMI952097A0 (en) | 1995-10-13 |
| ITMI952097A1 true ITMI952097A1 (en) | 1997-04-13 |
| IT1276928B1 IT1276928B1 (en) | 1997-11-03 |
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| Application Number | Title | Priority Date | Filing Date |
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| IT95MI002097A IT1276928B1 (en) | 1995-10-13 | 1995-10-13 | IMPROVED PROCESS TO PRODUCE EPTASTIGMINE AND NEW INTERMEDIATE USEFUL FOR THE PURPOSE |
Country Status (5)
| Country | Link |
|---|---|
| AR (1) | AR003831A1 (en) |
| AU (1) | AU7284196A (en) |
| IT (1) | IT1276928B1 (en) |
| WO (1) | WO1997014694A1 (en) |
| ZA (1) | ZA968284B (en) |
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| EP1689704A2 (en) | 2003-10-21 | 2006-08-16 | CoLucid Pharmaceuticals, Inc. | Carbamoyl esters that inhibit cholinesterase and release pharmacologically active agents |
| EP2125709A2 (en) | 2007-02-02 | 2009-12-02 | Colucid Pharmaceuticals, Inc. | Compounds that inhibit cholinesterase |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1199076B (en) * | 1984-03-01 | 1988-12-30 | Consiglio Nazionale Ricerche | PHYSOSTIGMINE DERIVATIVES WITH PROPERTY OF INHIBITION OF ACETICOLINESTERASI AND RELATED PRODUCTION PROCESS |
| IT1225462B (en) * | 1987-04-03 | 1990-11-14 | Mediolanum Farmaceutici Srl | ORGANIC SALTS OF PHYSOSTIGMIN DERIVATIVES |
| IT1244746B (en) * | 1991-02-14 | 1994-08-08 | Laboratorio Chimico Int Spa | PROCEDURE FOR THE PREPARATION OF 1,3A, 8, -TRIMETHYL-1,2,3,3A, 8, -8A-HEXAIDRO PIRROL (2,3-B) INDOLO-5 (3AS, 8AR) -EPTILCARBAMMATE |
-
1995
- 1995-10-13 IT IT95MI002097A patent/IT1276928B1/en active IP Right Grant
-
1996
- 1996-10-02 WO PCT/EP1996/004296 patent/WO1997014694A1/en active Application Filing
- 1996-10-02 ZA ZA968284A patent/ZA968284B/en unknown
- 1996-10-02 AU AU72841/96A patent/AU7284196A/en not_active Abandoned
- 1996-10-09 AR ARP960104662A patent/AR003831A1/en unknown
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| Publication number | Publication date |
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| IT1276928B1 (en) | 1997-11-03 |
| AR003831A1 (en) | 1998-09-09 |
| ZA968284B (en) | 1997-05-02 |
| WO1997014694A1 (en) | 1997-04-24 |
| ITMI952097A0 (en) | 1995-10-13 |
| AU7284196A (en) | 1997-05-07 |
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