ITRM20110508A1 - PROCESS FOR THE PREPARATION OF SCOPINA'S ESTERS. - Google Patents
PROCESS FOR THE PREPARATION OF SCOPINA'S ESTERS. Download PDFInfo
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- ITRM20110508A1 ITRM20110508A1 IT000508A ITRM20110508A ITRM20110508A1 IT RM20110508 A1 ITRM20110508 A1 IT RM20110508A1 IT 000508 A IT000508 A IT 000508A IT RM20110508 A ITRM20110508 A IT RM20110508A IT RM20110508 A1 ITRM20110508 A1 IT RM20110508A1
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- Prior art keywords
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- ester
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- 238000000034 method Methods 0.000 title claims description 23
- 238000002360 preparation method Methods 0.000 title description 3
- -1 trimethyl-phenyl Chemical group 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 41
- 239000000203 mixture Substances 0.000 claims description 34
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 29
- 150000002148 esters Chemical class 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 22
- 239000002808 molecular sieve Substances 0.000 claims description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 21
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- FIMXSEMBHGTNKT-UHFFFAOYSA-N Scopine Natural products CN1C2CC(O)CC1C1C2O1 FIMXSEMBHGTNKT-UHFFFAOYSA-N 0.000 claims description 17
- 230000015572 biosynthetic process Effects 0.000 claims description 17
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 17
- 238000003786 synthesis reaction Methods 0.000 claims description 17
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 claims description 15
- FIMXSEMBHGTNKT-UPGAHCIJSA-N scopine Chemical compound C([C@@H]1N2C)C(O)C[C@@H]2[C@@H]2[C@H]1O2 FIMXSEMBHGTNKT-UPGAHCIJSA-N 0.000 claims description 15
- 244000007853 Sarothamnus scoparius Species 0.000 claims description 13
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 229960000257 tiotropium bromide Drugs 0.000 claims description 12
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 claims description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 11
- 235000015320 potassium carbonate Nutrition 0.000 claims description 11
- 238000005809 transesterification reaction Methods 0.000 claims description 10
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 9
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 5
- 229940102396 methyl bromide Drugs 0.000 claims description 5
- FVEJUHUCFCAYRP-UHFFFAOYSA-N 2-hydroxy-2,2-dithiophen-2-ylacetic acid Chemical compound C=1C=CSC=1C(O)(C(=O)O)C1=CC=CS1 FVEJUHUCFCAYRP-UHFFFAOYSA-N 0.000 claims description 4
- 229910001914 chlorine tetroxide Inorganic materials 0.000 claims description 4
- 150000002500 ions Chemical class 0.000 claims description 4
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 4
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Chemical compound [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 claims description 4
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 2
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 claims description 2
- 239000007787 solid Substances 0.000 description 33
- 238000004128 high performance liquid chromatography Methods 0.000 description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 17
- 239000000047 product Substances 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000012458 free base Substances 0.000 description 11
- SYHWYWHVEQQDMO-UHFFFAOYSA-N methyl 2-hydroxy-2,2-dithiophen-2-ylacetate Chemical compound C=1C=CSC=1C(O)(C(=O)OC)C1=CC=CS1 SYHWYWHVEQQDMO-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- MEGPURSNXMUDAE-UHFFFAOYSA-N Scopoline Natural products C1C(O2)CC3N(C)C1C2C3O MEGPURSNXMUDAE-UHFFFAOYSA-N 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 239000008346 aqueous phase Substances 0.000 description 5
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 5
- 239000007832 Na2SO4 Substances 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
- 239000002253 acid Substances 0.000 description 4
- 238000005191 phase separation Methods 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 229920002554 vinyl polymer Polymers 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 3
- 230000003197 catalytic effect Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- WBAVLTNIRYDCPM-UHFFFAOYSA-N isoscopolin Natural products COC1=CC=2OC(=O)C=CC=2C=C1OC1OC(CO)C(O)C(O)C1O WBAVLTNIRYDCPM-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- SGTCGCCQZOUMJJ-YMILTQATSA-N scopolin Chemical compound COC1=CC=2C=CC(=O)OC=2C=C1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O SGTCGCCQZOUMJJ-YMILTQATSA-N 0.000 description 3
- SGTCGCCQZOUMJJ-UHFFFAOYSA-N scopolin Natural products COC1=CC=2C=CC(=O)OC=2C=C1OC1OC(CO)C(O)C(O)C1O SGTCGCCQZOUMJJ-UHFFFAOYSA-N 0.000 description 3
- GJECSWIRMFBYOI-UHFFFAOYSA-M 1,3-ditert-butylimidazol-1-ium;chloride Chemical compound [Cl-].CC(C)(C)N1C=C[N+](C(C)(C)C)=C1 GJECSWIRMFBYOI-UHFFFAOYSA-M 0.000 description 2
- WPWZFAUHXAPBFF-UHFFFAOYSA-N 2-hydroxy-2-thiophen-2-ylacetic acid Chemical compound OC(=O)C(O)C1=CC=CS1 WPWZFAUHXAPBFF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 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
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000006286 aqueous extract Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 150000004693 imidazolium salts Chemical class 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- MEGPURSNXMUDAE-RLMOJYMMSA-N scopoline Chemical compound C([C@H](O1)C2)[C@@H]3N(C)[C@H]2[C@H]1[C@H]3O MEGPURSNXMUDAE-RLMOJYMMSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- OHZAHWOAMVVGEL-UHFFFAOYSA-N 2,2'-bithiophene Chemical group C1=CSC(C=2SC=CC=2)=C1 OHZAHWOAMVVGEL-UHFFFAOYSA-N 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- RAXXELZNTBOGNW-UHFFFAOYSA-O Imidazolium Chemical class C1=C[NH+]=CN1 RAXXELZNTBOGNW-UHFFFAOYSA-O 0.000 description 1
- 102000014415 Muscarinic acetylcholine receptor Human genes 0.000 description 1
- 108050003473 Muscarinic acetylcholine receptor Proteins 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- STECJAGHUSJQJN-UHFFFAOYSA-N N-Methyl-scopolamin Natural products C1C(C2C3O2)N(C)C3CC1OC(=O)C(CO)C1=CC=CC=C1 STECJAGHUSJQJN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 229940007550 benzyl acetate Drugs 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 208000007451 chronic bronchitis Diseases 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- SYZWSSNHPZXGML-UHFFFAOYSA-N dichloromethane;oxolane Chemical compound ClCCl.C1CCOC1 SYZWSSNHPZXGML-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000012022 methylating agents Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- MOYZEMOPQDTDHA-UHFFFAOYSA-N norscopolamine Natural products C1C(C2OC22)NC2CC1OC(=O)C(CO)C1=CC=CC=C1 MOYZEMOPQDTDHA-UHFFFAOYSA-N 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical compound [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- CSZLZMBUJPLQQA-UHFFFAOYSA-N thiophen-2-yl 2-hydroxyacetate Chemical compound OCC(=O)OC1=CC=CS1 CSZLZMBUJPLQQA-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
- C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
"Processo per la preparazione degli esteri della scopina†"Process for the preparation of the esters of the broom⠀
DESCRIZIONE DESCRIPTION
CAMPO DELL'INVENZIONE FIELD OF THE INVENTION
Il bromuro di tiotropio (4), descritto in EP418716, à ̈ un potente agente anticolinergico specifico per i recettori muscarinici. Come farmaco à ̈ stato approvato per il trattamento di disordini respiratori, quali l’asma, la COPD, la bronchite cronica e l’enfisema. Tiotropium bromide (4), described in EP418716, is a potent anticholinergic agent specific for muscarinic receptors. As a drug it has been approved for the treatment of respiratory disorders, such as asthma, COPD, chronic bronchitis and emphysema.
Oggetto della presente invenzione à ̈ un nuovo metodo sintetico per la sintesi dell’estere della scopina (3), caratterizzato dall’uso di reagenti di migliore applicabilità industriale e comunque in condizioni basiche non troppo forti che inducano la conversione della scopina in scopolina (Schema 6) che a sua volta può dare luogo, come impurezza, nella successiva reazione di transesterificazione, alla scopolina estere. The object of the present invention is a new synthetic method for the synthesis of the ester of the broom (3), characterized by the use of reagents of better industrial applicability and in any case in not too strong basic conditions that induce the conversion of the broom into a scopoline. (Scheme 6) which in turn can give rise, as an impurity, in the subsequent transesterification reaction, to the ester scopolin.
STATO DELL’ARTE STATE OF THE ART
Un processo per la preparazione del bromuro di tiotropio à ̈ stato riportato in EP418716. In questo metodo il primo passaggio consiste in una transesterificazione della scopina (1) con il metile di(2-tienil)glicolato (2, R = Me) per formare l’estere scopina dell’acido di(2-tienyl)glicolico (3). Questo estere viene poi quaternarizzato con il bromuro di metile per ottenere il tiotropio bromuro (Schema 2). Nella reazione di transesterificazione vengono usati reagenti di non facile impiego industriale, quali il sodio metallico. La resa migliore riportata à ̈ 70% (esempio 3) e non vi sono informazioni sulla purezza HPLC ottenuta. A process for the preparation of tiotropium bromide was reported in EP418716. In this method the first step consists in a transesterification of the scopin (1) with the methyl di (2-thienyl) glycolate (2, R = Me) to form the scopin ester of the (2-thienyl) glycolic acid (3). This ester is then quaternized with methyl bromide to obtain tiotropium bromide (Scheme 2). In the transesterification reaction, reagents that are not easy to use industrial are used, such as metallic sodium. The best yield reported is 70% (example 3) and there is no information on the HPLC purity obtained.
Me Me Me Me Me Me Me Me
N N N Br N N N Br
O O O O O O
O S OR O S OR
OH O O HO S S S OH O O HO S S S
(1) (2) O O (1) (2) O O
scopina HO S HO S (3) tiotropio bromuro (4) brush HO S HO S (3) tiotropium bromide (4)
Schema 2 Scheme 2
Un altro metodo di sintesi à ̈ descritto in US6486321, US656900, US6610849 e US 747153. In questo caso si parte dal tropenolo (5), che viene transesterificato con metile di(2-tienil)glicolato, seguono l’epossidazione e la quaternarizzazione. Questo processo richiede un numero di passaggi più elevato del precedente (Schema 3). Another synthesis method is described in US6486321, US656900, US6610849 and US 747153. In this case we start from tropenol (5), which is transesterified with methyl di (2-thienyl) glycolate, followed by epoxidation and quaternization . This process requires a higher number of steps than the previous one (Scheme 3).
Me Me Me Me
Me Me Me N N N N Br O Me Me Me N N N N Br O
O OR
V2O5, H2O2MeBr O V2O5, H2O2MeBr O
S OR DMF DMF S OR DMF DMF
OH O HO S NaH, toluene O O OH O HO S NaH, toluene O O
S S.
83% S S 83% S S
(5) O O O tropenolo R = H, Et, Me, vinile, HO HO S HO S S (5) O O O tropenol R = H, Et, Me, vinyl, HO HO S HO S S
fenile, succinimidile, phenyl, succinimidyl,
arile. aryl.
Schema 3 Scheme 3
Un processo alternativo à ̈ quello descritto da US6747154 che prevede la reazione di accoppiamento tra il sale della scopina già quaternarizzata (6) e l’acido di(2-tienil)glicolico attivato con il dicarbonil imidazolo ed una quantità stechiometrica di una base forte (il sale litio imidazolile, generato con LiH ed imidazolo) (Schema 4). La parte sperimentale e la resa della sintesi non sono riportate. An alternative process is the one described by US6747154 which involves the coupling reaction between the salt of the already quaternized broom (6) and the (2-thienyl) glycolic acid activated with dicarbonyl imidazole and a stoichiometric quantity of a strong base (the lithium imidazolyl salt, generated with LiH and imidazole) (Scheme 4). The experimental part and the yield of the synthesis are not reported.
Me Me Me Me
Me Me N Br Me Me N Br
N Br O O N Br O O
O S OR O S OR
OH OH
O OR
HO S S HO S S
O OR
(<6>) (<6>)
scopina R = H, Et, Me, vinile, HO S metobromuro fenile, succinimidile, arile broom R = H, Et, Me, vinyl, HO S phenyl metobromide, succinimidyl, aryl
tiotropio bromuro tiotropium bromide
Schema 4 Scheme 4
La domanda di brevetto US 2006/0047120 descrive un altro approccio: la reazione della scopina metobromuro (6) con il sodio ditienil glicolato protetto in situ con trimetilsilile (Schema 5). US patent application 2006/0047120 describes another approach: the reaction of scopin metobromide (6) with sodium dithienyl glycolate protected in situ with trimethylsilyl (Scheme 5).
Me Me Me Me
N O O carbonildiimidazolo Br Me DMF O ONa3SiCl, THF N O O carbonyldiimidazole Br Me DMF O ONa3SiCl, THF
S ONa S ONa
OH OSiMe3Me Me OH OSiMe3Me Me
S S N Br O S S N Br O
S S.
O OR
O OR
Me Me Me Me
N Me3SiO S HO O N Me3SiO S HO O
O S O HO S O S O HO S
Schema 5 Scheme 5
Un problema ricorrente nei processi dell’arte anteriore à ̈ la conversione, indotta da condizioni basiche, della scopina in scopolina (Schema 6) (Tetrahedron Letters, (1967), 14, 1283-1284., Die darstellung von Scopin aus Scopolamin ) che a sua volta può dare luogo come impurezza, nella successiva reazione di transesterificazione, alla scopolina estere. A recurring problem in the processes of the prior art is the conversion, induced by basic conditions, of the broom into a scopolin (Scheme 6) (Tetrahedron Letters, (1967), 14, 1283-1284., Die darstellung von Scopin aus Scopolamin) which in turn can give rise to the ester scopolin as an impurity in the subsequent transesterification reaction.
N N N N
base HO base HO
O O O O
OH OH
scopina (1)scopolinabroom (1) broom
Schema 6 Scheme 6
I metodi di esterificazione diretta risultano di difficile applicabilità a causa dell’instabilità dell’acido di-(2-tienyl) glicolico; infatti un campione di questo acido ottenuto per idrolisi del suo estere metilico à ̈ diventato rapidamente scuro se lasciato a temperatura ambiente indicando una sua evidente degradazione. In letteratura sono noti metodi di transesterificazione mediante uso di N eterociclo carbeni (NHCs). Nolan e collaboratori hanno dimostrato che questi composti sono capaci di catalizzare (usati in percentuale del 2.4 al 5.0% molare) la transesterificazione degli esteri metilici, etilici e vinili con alcoli primari, secondari ed anche terziari (in questo ultimo caso si rendeva necessario l’uso del catalizzatore in percentuale del 20% molare e la resa era solo del 54%)[Journal of Organic Chemistry, (2003), 68, 2812-2819, Efficient Transesterification/Acylation Reactions Mediated by N-Heterocyclic Carbenes Catalysis; Journal of Organic Chemistry (2004), 69, 209-212]. Alcuni NHCs sono disponibili commercialmente, ma possono anche essere convenientemente preparati in situ (Schema 7) per trattamento dei sali di diidroimidazolio o imidazolio di formula (7a) (in cui R’, R’’ e Y hanno i significati riportati in J. Org. Chem. (2004), 69, 209-212) con una base (generalmente il tert butossido di potassio), Direct esterification methods are difficult to apply due to the instability of di- (2-thienyl) glycolic acid; in fact, a sample of this acid obtained by hydrolysis of its methyl ester quickly became dark if left at room temperature, indicating its evident degradation. Transesterification methods using N heterocycle carbenes (NHCs) are known in the literature. Nolan and collaborators have shown that these compounds are capable of catalyzing (used in a percentage of 2.4 to 5.0 mol%) the transesterification of methyl, ethyl and vinyl esters with primary, secondary and even tertiary alcohols (in this last case it was necessary to ™ use of the catalyst in a percentage of 20 mol% and the yield was only 54%) [Journal of Organic Chemistry, (2003), 68, 2812-2819, Efficient Transesterification / Acylation Reactions Mediated by N-Heterocyclic Carbenes Catalysis; Journal of Organic Chemistry (2004), 69, 209-212]. Some NHCs are commercially available, but can also be conveniently prepared in situ (Scheme 7) by treatment of the dihydroimidazolium or imidazolium salts of formula (7a) (in which Râ € ™, Râ € ™ â € ™ and Y have the meanings reported in J. Org. Chem. (2004), 69, 209-212) with a base (generally tert potassium butoxide),
Y Y
<R'>N NR'' base<R'>N NR'' <R '> N NR' 'base <R'> N NR ''
(7a) (8a) (7a) (8a)
Schema 7 Scheme 7
La reazione viene condotta a temperatura ambiente ed in presenza di setacci molecolari (0.5 g/mmole) che catturano l’alcool rilasciato (p.es. setacci molecolari da 4Å per il metanolo e da 5Å per l’etanolo) in modo da spostare la reazione verso l’estere dell’alcol più complesso. Generalmente gli NHCs alchil sostituiti danno risultati migliori (rese del 90-100% sono state riportate per la conversione del metil acetato in benzil acetato) rispetto agli aril sostituiti (rese del 41-49% per la stessa reazione), e quelli generati dai sali di imidazolio danno risultati migliori di quelli generati dai sali di diidroimidazolio. The reaction is carried out at room temperature and in the presence of molecular sieves (0.5 g / mmole) that capture the released alcohol (eg molecular sieves of 4 ... for methanol and 5 ... for ethanol) in in order to shift the reaction towards the ester of the more complex alcohol. Generally alkyl substituted NHCs give better results (yields of 90-100% have been reported for the conversion of methyl acetate to benzyl acetate) than the substituted aryls (yields of 41-49% for the same reaction), and those generated by salts of imidazolium give better results than those generated by the salts of dihydroimidazolium.
SOMMARIO SUMMARY
Scopo della presente invenzione à ̈ un nuovo metodo sintetico per la sintesi dell’estere della scopina, caratterizzato dall’uso di reagenti di migliore applicabilità industriale e comunque in condizioni basiche non troppo forti da indurre la conversione della scopina in scopolina. The purpose of the present invention is a new synthetic method for the synthesis of the ester of the broom, characterized by the use of reagents of better industrial applicability and in any case in basic conditions not too strong as to induce the conversion of the broom into a scopoline.
Si à ̈ sorprendentemente trovato e costituisce oggetto della presente invenzione che la reazione di transesterificazione della scopina (1), con gli esteri dell’acido di-(2-tienil) glicolico (2) in cui R à ̈ scelto nel gruppo metile, etile, propile o vinile, e preferibilmente metile, per ottenere il corrispondente estere (3), può essere efficacemente ottenuta sfruttando la catalisi con NHCs generati da composti di formula di formula (7), per esempio quelli rappresentati a scopo puramente esemplificativo in Tabella I in cui: It has surprisingly been found and the object of the present invention is that the transesterification reaction of scopin (1), with the esters of di- (2-thienyl) glycolic acid (2) in which R is selected in the methyl group, ethyl, propyl or vinyl, and preferably methyl, to obtain the corresponding ester (3), can be effectively obtained by exploiting the catalysis with NHCs generated by compounds of formula (7), for example those represented purely by way of example in Table I in which:
- R<1>ed R<2>sono indipendentemente scelti nel gruppo C1-10alchile, C5-7cicloalchile, adamantile, fenile, fenile sostituito fino a tre gruppi C1-4alchilici, e, preferibilmente, nel gruppo metile, butile, tert-butile, esile, octile, adamantile, cicloesile, trimetil-fenile, diisopropil-fenile, ed ancora più preferibilmente nel gruppo metile, butile, tert-butile, esile, cicloesile. - R <1> and R <2> are independently selected from the C1-10alkyl, C5-7cycloalkyl, adamantyl, phenyl, substituted phenyl groups up to three C1-4alkyl groups, and, preferably, in the methyl, butyl, tert-butyl group , hexyl, octyl, adamantyl, cyclohexyl, trimethyl-phenyl, diisopropyl-phenyl, and even more preferably in the methyl, butyl, tert-butyl, hexyl, cyclohexyl group.
- X rappresenta uno ione scelto nel gruppo Cl, BF4, Br, PF6, I, ClO4, TfO e preferibilmente nel gruppo Cl , BF4 ,- X represents an ion selected in the group Cl, BF4, Br, PF6, I, ClO4, TfO and preferably in the group Cl, BF4,
essendo, fra i composti di formula (7), assolutamente preferiti quelli di Tabella 1 con formula (9), (10), (12) e (14),mediante trattamento con una base scelta nel gruppo NaH, K2CO3, tBuOK (Schema 8), in presenza di setacci molecolari. among the compounds of formula (7), those of Table 1 with formula (9), (10), (12) and (14) being absolutely preferred, by treatment with a base selected from the group NaH, K2CO3, tBuOK (Scheme 8), in the presence of molecular sieves.
S Me X<->Me S Me X <-> Me
N<R1>N <R1>
N N R<2>N N N R <2> N
HO I HAVE
OR O (7) O OR O (7) O
S O S O
Base Base
OH O S O HO S OH O S O HO S
2) (1) (3) 2) (1) (3)
Schema 8 Scheme 8
Questa reazione ha il vantaggio di non usare reagenti potenzialmente pericolosi, né altamente basici in quantità stechiometrica e di usare invece gli NHCs in quantità catalitica. This reaction has the advantage of not using potentially dangerous or highly basic reagents in stoichiometric quantities and of using instead the NHCs in catalytic quantities.
Costituisce altresì parte della presente invenzione il trattamento dell’estere di formula (3) con un agente metilante ad ottenere il tiotropio bromuro di formula (4) secondo metodologie già note nell’arte, come previsto nello schema sintetico 2. Also part of the present invention is the treatment of the ester of formula (3) with a methylating agent to obtain tiotropium bromide of formula (4) according to methods already known in the art, as provided in the synthetic scheme 2.
DESCRIZIONE DETTAGLIATA DELL’INVENZIONE DETAILED DESCRIPTION OF THE INVENTION
Secondo la presente invenzione, l’estere della scopina di formula (3) può venire preparato attraverso una reazione di transesterificazione dell’alcool scopina (1) con un opportuno estere di formula (2), in cui R à ̈ metile, etile, propile, vinile, preferibilmente metile. La reazione à ̈ eseguita in presenza di setacci molecolari, mediante trattamento con N-eterociclocarbeni (NHC) di formula (8), preferibilmente in quantità catalitica, in cui: According to the present invention, the ester of the scopin of formula (3) can be prepared through a transesterification reaction of the alcohol scopin (1) with a suitable ester of the formula (2), in which R is methyl, ethyl , propyl, vinyl, preferably methyl. The reaction is carried out in the presence of molecular sieves, by treatment with N-heterocyclocarbens (NHC) of formula (8), preferably in a catalytic quantity, in which:
- R<1>ed R<2>sono indipendentemente scelti nel gruppo C1-10alchile, C5-7cicloalchile, adamantile, fenile, fenile sostituito fino a tre gruppi C1-4alchilici, e, preferibilmente, nel gruppo metile, butile, tert-butile, esile, octile, adamantile, cicloesile, trimetil-fenile, diisopropil-fenile, ed ancora più preferibilmente nel gruppo metile, butile, tert-butile, esile, cicloesile - R <1> and R <2> are independently selected from the C1-10alkyl, C5-7cycloalkyl, adamantyl, phenyl, substituted phenyl groups up to three C1-4alkyl groups, and, preferably, in the methyl, butyl, tert-butyl group , hexyl, octyl, adamantyl, cyclohexyl, trimethyl-phenyl, diisopropyl-phenyl, and even more preferably in the methyl, butyl, tert-butyl, hexyl, cyclohexyl group
L’alcool (1) e l’estere (2) vengono sciolti in un solvente organico scelto tra toluene, diclorometano, THF, 2-MeTHF (2-metiltetraidrofurano), ciclopentilmetiletere, DMF (dimetilformammide) e DMI (dimetil-2-imidazolidinone) o loro miscela, preferibilmente 2-MeTHF. The alcohol (1) and the ester (2) are dissolved in an organic solvent selected from toluene, dichloromethane, THF, 2-MeTHF (2-methyltetrahydrofuran), cyclopentylmethylether, DMF (dimethylformamide) and DMI (dimethyl-2 -imidazolidinone) or their mixture, preferably 2-MeTHF.
La temperatura viene mantenuta tra 0° e 60°C, preferibilmente tra 20°e 40°C ed ancor più preferibilmente tra 20° e 25°C. The temperature is maintained between 0 ° and 60 ° C, preferably between 20 ° and 40 ° C and even more preferably between 20 ° and 25 ° C.
Il carbene NHC (8) viene formato separatamente per trattamento di un sale di imidazolio di formula (7), [in Tabella I sono riportati una serie di esempi, non limitativi, di composti di formula (7) ], in cui: The carbene NHC (8) is formed separately by treatment of an imidazolium salt of formula (7), [in Table I a series of non-limiting examples of compounds of formula (7) are reported], in which:
- R<1>ed R<2>sono indipendentemente scelti nel gruppo C1-10alchile, C5-7cicloalchile, adamantile, fenile, fenile sostituito fino a tre gruppi C1-4alchilici, e, preferibilmente, nel gruppo metile, butile, tert-butile, esile, octile, adamantile, cicloesile, trimetil-fenile, diisopropil-fenile, ed ancora più preferibilmente nel gruppo metile, butile, tert-butile, esile, cicloesile. - R <1> and R <2> are independently selected from the C1-10alkyl, C5-7cycloalkyl, adamantyl, phenyl, substituted phenyl groups up to three C1-4alkyl groups, and, preferably, in the methyl, butyl, tert-butyl group , hexyl, octyl, adamantyl, cyclohexyl, trimethyl-phenyl, diisopropyl-phenyl, and even more preferably in the methyl, butyl, tert-butyl, hexyl, cyclohexyl group.
- X rappresenta uno ione scelto nel gruppo Cl, BF4, Br, PF6, I, ClO4, TfO e preferibilmente nel gruppo Cl , BF4- X represents an ion selected in the group Cl, BF4, Br, PF6, I, ClO4, TfO and preferably in the group Cl, BF4
sciolto in uno dei solventi organici di cui sopra per aggiunta di una quantità sub-stechiometrica di una base scelta tra NaH, K2CO3, tBuOK, preferenzialmente tBuOK. dissolved in one of the above organic solvents by adding a sub-stoichiometric quantity of a base selected from NaH, K2CO3, tBuOK, preferably tBuOK.
I composti di formula (7) preferiti sono riportati in Tabella 1; tra questi quelli maggiormante preferiti soni i composti con formula (9), (10), (12) e (14), The preferred compounds of formula (7) are reported in Table 1; among these the most preferred are the compounds with formula (9), (10), (12) and (14),
L’impiego degli NHCs, specificamente in quantità catalitica, si à ̈ dimostrato sorprendentemente efficace per la sintesi del composto (3); nell’esempio 10, che ha valore di mero confronto, si riporta una sintesi senza NHCs e le rese ottenute sono state decisamente povere ( intorno al 19%). The use of NHCs, specifically in catalytic quantities, has proved surprisingly effective for the synthesis of compound (3); in example 10, which has the value of mere comparison, a synthesis without NHCs is reported and the yields obtained were decidedly poor (around 19%).
La reazione viene condotta in presenza di setacci molecolari che catturano l’alcol rilasciato (p.es. setacci molecolari da 4Å per il metanolo e da 5Å per l’etanolo) in modo da spostare la reazione verso l’estere dell’alcol più complesso. I setacci molecolari vengono usati in ragione di 1 - 0,1g di setacci per mmole di scopina base (1), preferibilmente in ragione di 0,5 g/mmole. Esempi non limitativi di setacci molecolari adatti possono essere Molecolar Sieves 4Å, Aldrich product number 208604 - beads, 8-12 mesh, e Molecular Sieves 5Å, Fluka product number 69848, rod 1/8 in, o Molecular Sieves 5Å, Aldrich product number 208620, beads, 8-12 mesh. The reaction is carried out in the presence of molecular sieves that capture the released alcohol (eg 4à ... molecular sieves for methanol and 5à ... for ethanol) in order to shift the reaction towards the ester more complex alcohol. Molecular sieves are used in the ratio of 1 - 0.1g of sieves per mmole of basic brush (1), preferably in the ratio of 0.5 g / mmole. Non-limiting examples of suitable molecular sieves can be Molecolar Sieves 4Å, Aldrich product number 208604 - beads, 8-12 mesh, and Molecular Sieves 5Å, Fluka product number 69848, rod 1/8 in, or Molecular Sieves 5Å, Aldrich product number 208620, beads, 8-12 mesh.
L’uso di setacci molecolari à ̈ essenziale per l’ottenimento di alte rese; nell’esempio 9, che ha valore di mero confronto, si riporta una sintesi senza setacci molecolari e le rese ottenute sono state intorno al 7%. The use of molecular sieves is essential for obtaining high yields; in example 9, which has the value of mere comparison, a synthesis without molecular sieves is reported and the yields obtained were around 7%.
I reagenti chimici dell’invenzione ed i setacci molecolari possono essere allestiti, miscelati e posti a reagire tra loro in qualsiasi ordine. Per esempio si prepara una soluzione dell’ alchil di-(2-tienil)glicolato (2) e della scopina base libera (1), si aggiungono alla stessa soluzione i setacci molecolari, si prepara a parte la soluzione dell’N-eterocarbene (8) e la si aggiunge alla prima soluzione. Oppure, si prepara una soluzione del NHC (8) e successivamente si aggiungono alla stessa soluzione i reagenti (1) e (2) più i setacci molecolari in qualsiasi ordine. The chemical reagents of the invention and the molecular sieves can be prepared, mixed and placed to react with each other in any order. For example, a solution of the alkyl di- (2-thienyl) glycolate (2) and of the free base brush (1) is prepared, the molecular sieves are added to the same solution, the N- solution is prepared separately heterocarbene (8) and add it to the first solution. Alternatively, a solution of the NHC (8) is prepared and then reagents (1) and (2) plus the molecular sieves are added to the same solution in any order.
Tabella 1 ESEMPI Table 1 EXAMPLES
Costituiscono esempi non limitativi della presente invenzione i seguenti: The following are non-limiting examples of the present invention:
Sintesi dell’estere scopina (3) usando un NHC derivato dall’1-butil-3-metilimidazolio tetrafluorborato Synthesis of scopin ester (3) using an NHC derived from 1-butyl-3-methylimidazolium tetrafluorborate
Esempio 1: con 7% mol NHC (rispetto al composto (1)) a temperatura ambiente in THF. Example 1: with 7% mol NHC (with respect to compound (1)) at room temperature in THF.
In un pallone anidro contenente circa 7.85 g di setacci molecolari 4Ã… attivati vengono disciolti il metile di-(2-tienil)glicolato (2), (R = Me, 3.97 g, 15.6 mmol) e la scopina base libera (1), (2.61 g, 16.8 mmol), in THF (14 mL). Separatamente, in un pallone vengono mescolati 1-butil-3-metilimidazolio tetrafluoroborato (210 L, 1.12 mmol), KOtBu/THF (960 L, 0.96 mmol) e THF (1.0 mL ) per 15 min a temperatura ambiente. Tale miscela à ̈ quindi trasferita con una siringa nel pallone contenente la soluzione della scopina. La siringa e il pallone vengono lavati con THF (2 x 0.5 mL) e la miscela di reazione viene mescolata a temperatura ambiente per 18 ore. Un controllo HPLC mostra l’86% del prodotto atteso. Dopo 18 ore complessive, la miscela viene filtrata, lavando i setacci con THF (2 x 20.mL). Il filtrato viene concentrato a secchezza e il residuo ripreso con toluene (30 mL) e 1M HCl (30 mL). Durante la separazione delle fasi si osserva precipitazione di un solido e la sospensione risultante viene filtrata, il solido viene lavato con toluene (30 mL) e riunito alla fase acquosa separata. Il pH di tale sospensione acquosa, raffreddata a 0°C, viene portato a valori basici mediante aggiunta di K2CO3solido. Si mantiene la miscela in agitazione a 0°C per circa 30 minuti, dopodiché si filtra il solido ottenuto, si lava con acqua fredda e si secca, dapprima su filtro, e successivamente a 45°C sotto vuoto per 18 ore. Si ottiene un solido bianco (3); 4.30 g, 73%, purezza HPLC 99.89%). In an anhydrous flask containing about 7.85 g of activated molecular sieves 4Ã… the methyl di- (2-thienyl) glycolate (2), (R = Me, 3.97 g, 15.6 mmol) and the free base brush (1) are dissolved, (2.61 g, 16.8 mmol), in THF (14 mL). Separately, 1-butyl-3-methylimidazolium tetrafluoroborate (210 L, 1.12 mmol), KOtBu / THF (960 L, 0.96 mmol) and THF (1.0 mL) are mixed in a flask for 15 min at room temperature. This mixture is then transferred with a syringe into the flask containing the broom solution. The syringe and flask are washed with THF (2 x 0.5 mL) and the reaction mixture is mixed at room temperature for 18 hours. An HPLC check shows 86% of the expected product. After a total of 18 hours, the mixture is filtered, washing the sieves with THF (2 x 20.mL). The filtrate is concentrated to dryness and the residue is taken up with toluene (30 mL) and 1M HCl (30 mL). During phase separation, precipitation of a solid is observed and the resulting suspension is filtered, the solid is washed with toluene (30 mL) and combined with the separated aqueous phase. The pH of this aqueous suspension, cooled to 0 ° C, is brought to basic values by adding solid K2CO3. The mixture is kept under stirring at 0 ° C for about 30 minutes, after which the solid obtained is filtered, washed with cold water and dried, first on a filter, and subsequently at 45 ° C under vacuum for 18 hours. A white solid is obtained (3); 4.30 g, 73%, HPLC purity 99.89%).
Esempio 2: con 6% mol NHC (rispetto al composto (1)) a temperatura ambiente in diclorometano-THF (20:1) Example 2: with 6% mol NHC (with respect to compound (1)) at room temperature in dichloromethane-THF (20: 1)
In un pallone anidro contenente circa 5.0 g di setacci molecolari 4Ã… attivati vengono disciolti il metile di-(2-tienil)glicolato (2), (R = Me; 2.63 g, 10.3 mmol), e la scopina base libera (1), (1.57 g, 10.1 mmol), in CH2Cl2(8 mL). In un pallone separato vengono mescolati 1-butil-3-metilimidazolium tetrafluoroborato (120 L, 0.642 mmol), KOtBu/THF (500 L, 0.500 mmol) e CH2Cl2(1.0 mL ) per 15 min a temperatura ambiente. Tale miscela à ̈ quindi trasferita con una siringa nel pallone contenente la soluzione della scopina. La siringa e il pallone sono lavati con CH2Cl2(1.0 mL) e la miscela di reazione viene mescolata a temperatura ambiente per 16 ore. Un controllo HPLC mostra il 77% del prodotto atteso. La miscela viene filtrata, lavando i setacci con CH2Cl2(2 x 10.mL), ed estratta con 1M HCl (2 x 25 mL). La fase acquosa viene raffreddata a 0°C e il pH portato a valori basici mediante aggiunta di K2CO3solido. La miscela viene estratta con CH2Cl2(2 x 25 mL), la fase organica seccata (Na2SO4), filtrata e il filtrato concentrato in vacuo. Si ottiene un solido (2.69 g, 73%) con purezza HPLC 99.74%. The methyl di- (2-thienyl) glycolate (2), (R = Me; 2.63 g, 10.3 mmol), and the free base brush (1) are dissolved in an anhydrous flask containing about 5.0 g of activated molecular sieves 4à ... , (1.57 g, 10.1 mmol), in CH2Cl2 (8 mL). In a separate flask, 1-butyl-3-methylimidazolium tetrafluoroborate (120 L, 0.642 mmol), KOtBu / THF (500 L, 0.500 mmol) and CH2Cl2 (1.0 mL) are mixed for 15 min at room temperature. This mixture is then transferred with a syringe into the flask containing the broom solution. The syringe and flask are washed with CH2Cl2 (1.0 mL) and the reaction mixture is mixed at room temperature for 16 hours. An HPLC check shows 77% of the expected product. The mixture is filtered, washing the sieves with CH2Cl2 (2 x 10.mL), and extracted with 1M HCl (2 x 25 mL). The aqueous phase is cooled to 0 ° C and the pH brought to basic values by adding solid K2CO3. The mixture is extracted with CH2Cl2 (2 x 25 mL), the dried organic phase (Na2SO4), filtered and the filtrate concentrated in vacuo. A solid is obtained (2.69 g, 73%) with HPLC purity 99.74%.
Esempio 3: con 12% mol NHC (rispetto al composto (1) ) a temperatura ambiente in 2-MeTHF-THF (29:1) In un pallone anidro contenente circa 500 mg di setacci molecolari 4Ã… attivati vengono disciolti il metile di-(2-tienil)glicolato (2), (R = Me; 284 mg, 1.12 mmol), e la scopina base libera (1), (165 mg, 1.06 mmol), in 2-MeTHF (1 mL). In un pallone separato vengono mescolati 1-butil-3-metilimidazolio tetrafluoroborato (24 L, 0.13 mmol), KOtBu/THF (105 L, 0.105 mmol) e 2-MeTHF (1.0 mL ) per 15 min a temperatura ambiente. Tale miscela à ̈ quindi trasferita con una siringa nel pallone contenente la soluzione dell’estere e dell’ammina. La siringa e il pallone vengono lavati con 2-MeTHF (1.0 mL) e la miscela di reazione viene mescolata a temperatura ambiente per 21.5 ore. Un controllo HPLC mostra il 68% del prodotto atteso. La miscela viene filtrata, lavando i setacci con 2-MeTHF (2 x 2.mL), ed estratta con acqua (5 mL) che conteneva 2M HBr (0.8 mL) e successivamente con acqua (4 mL). Gli estratti acquosi vengono combinati e lavati con 2-MeTHF (4 mL), e dopo raffreddamento a 0°C, il pH portato a valori basici mediante aggiunta di K2CO3solido. La miscela viene estratta con CH2Cl2(2 x 6 mL), la fase organica seccata (Na2SO4), filtrato e il filtrato concentrato in vacuo. Si ottiene un solido bianco (296 mg, 74%, purezza HPLC 99.75%). Example 3: with 12% mol NHC (with respect to compound (1)) at room temperature in 2-MeTHF-THF (29: 1) In an anhydrous flask containing about 500 mg of activated molecular sieves 4 ... (2-thienyl) glycolate (2), (R = Me; 284 mg, 1.12 mmol), and free base scopin (1), (165 mg, 1.06 mmol), in 2-MeTHF (1 mL). In a separate flask, 1-butyl-3-methylimidazolium tetrafluoroborate (24 L, 0.13 mmol), KOtBu / THF (105 L, 0.105 mmol) and 2-MeTHF (1.0 mL) are mixed for 15 min at room temperature. This mixture is then transferred with a syringe into the flask containing the solution of the ester and the amine. The syringe and flask are washed with 2-MeTHF (1.0 mL) and the reaction mixture is mixed at room temperature for 21.5 hours. An HPLC check shows 68% of the expected product. The mixture is filtered, washing the sieves with 2-MeTHF (2 x 2.mL), and extracted with water (5 mL) which contained 2M HBr (0.8 mL) and subsequently with water (4 mL). The aqueous extracts are combined and washed with 2-MeTHF (4 mL), and after cooling to 0 ° C, the pH brought to basic values by adding solid K2CO3. The mixture is extracted with CH2Cl2 (2 x 6 mL), the dried organic phase (Na2SO4), filtered and the filtrate concentrated in vacuo. A white solid is obtained (296 mg, 74%, HPLC purity 99.75%).
Esempio 4: con 10% mol NHC (rispetto al composto (1) ) a temperatura ambiente in 2-MeTHF-THF (10:1) In un pallone anidro vengono mescolati 1-butil-3-metilimidazolio tetrafluoroborato (23 L, 0.12 mmol), KOtBu/THF (100 L, 0.100 mmol) e 2-MeTHF (1.0 mL) per 15 min a temperatura ambiente. Dopo sono aggiunti il metile di-(2-tienil)glicolato (2), (R = Me; 288 mg, 1.13 mmol), la scopina base libera (1), (191 mg, 1.23 mmol), e i setacci molecolari 4Ã… attivati (500 mg). Tale miscela viene mescolata a temperatura ambiente per 18 ore. Un controllo HPLC mostra l’89% del prodotto atteso. La miscela viene filtrata, lavando i setacci con 2-MeTHF (2 x 2.mL), e estratta dapprima con acqua (8 mL) che conteneva 2M HBr (0.8 mL) e successivamente con acqua (4 mL). Gli estratti acquosi vengono combinati e lavati con 2-MeTHF (4 mL), e dopo raffreddamento a 0°C , il pH della soluzione viene portato a valori basici mediante aggiunta di K2CO3solido. Si mantiene la miscela in agitazione a 0°C per circa 30 minuti, dopodiché si filtra il solido ottenuto, si lava con acqua fredda (3 x 6 mL) e si secca, dapprima su filtro, e successivamente a 45°C sotto vuoto per 18 ore. Si ottiene un solido bianco (303 mg, 71%, purezza HPLC 99.92%). Example 4: with 10% mol NHC (with respect to compound (1)) at room temperature in 2-MeTHF-THF (10: 1) 1-butyl-3-methylimidazolium tetrafluoroborate (23 L, 0.12 mmol) is mixed in an anhydrous flask ), KOtBu / THF (100 L, 0.100 mmol) and 2-MeTHF (1.0 mL) for 15 min at room temperature. Then methyl di- (2-thienyl) glycolate (2), (R = Me; 288 mg, 1.13 mmol), free base scopin (1), (191 mg, 1.23 mmol), and molecular sieves 4à ... are added. activated (500 mg). This mixture is mixed at room temperature for 18 hours. An HPLC check shows 89% of the expected product. The mixture is filtered, washing the sieves with 2-MeTHF (2 x 2.mL), and extracted first with water (8 mL) which contained 2M HBr (0.8 mL) and then with water (4 mL). The aqueous extracts are combined and washed with 2-MeTHF (4 mL), and after cooling to 0 ° C, the pH of the solution is brought to basic values by adding solid K2CO3. The mixture is kept stirred at 0 ° C for about 30 minutes, after which the solid obtained is filtered, washed with cold water (3 x 6 mL) and dried, first on a filter, and then at 45 ° C under vacuum for 18 hours. A white solid is obtained (303 mg, 71%, HPLC purity 99.92%).
Delle acque madri si recupera per filtrazione un secondo lotto di prodotto (32 mg, 7.5%, purezza HPLC 100%). A second batch of product (32 mg, 7.5%, 100% HPLC purity) is recovered from the mother liquors by filtration.
Esempio 5: con 11% mol NHC (rispetto al composto (1) ) a temperatura ambiente in 2-MeTHF-THF (10:1) In un pallone anidro vengono mescolati 1-butil-3-metilimidazolio tetrafluoroborato (1.00 mL, 5.35 mmol) e KOtBu/THF (4.70 mL, 4.70 mmol) per 15 min a temperatura ambiente. 2-MeTHF (48 mL) viene aggiunto, seguito dal metile di-(2-tienil)glicolato (2), (R = Me; 13.29 g, 1.13 mmol), la scopina base libera (1) (7.42 g, 47.8 mmol), e i setacci molecolari 4Ã… attivati (26.36 g). Tale miscela viene mescolata a temperatura ambiente per 17 ore. Un controllo HPLC mostra l’85% del prodotto atteso. La miscela viene decantata ed i setacci lavati con 2-MeTHF (2 x 50 mL). A tale soluzione organica si aggiunge acqua (100 mL) , la miscela raffreddata e il pH portato a 2 con l’addizione di 2M HBr (5 x 5 mL). Le fasi vengono separate e la fase organica estratta con acqua (100 mL). Le fasi acquose vengono combinate e lavate con 2-MeTHF (100 mL), e dopo raffreddamento, il pH portato a valori basici mediante aggiunta di K2CO3solido. Si mantiene la miscela in agitazione a 0°C per circa 30 minuti, dopodiché si filtra il solido ottenuto, si lava con acqua fredda (3 x 75 mL) e si secca, dapprima su filtro, e successivamente a 40°C sotto vuoto per 18 ore. Si ottiene un solido bianco (14.43 g, 80%, purezza HPLC 99.89%). Example 5: with 11% mol NHC (with respect to compound (1)) at room temperature in 2-MeTHF-THF (10: 1) 1-butyl-3-methylimidazolium tetrafluoroborate (1.00 mL, 5.35 mmol) is mixed in an anhydrous flask ) and KOtBu / THF (4.70 mL, 4.70 mmol) for 15 min at room temperature. 2-MeTHF (48 mL) is added, followed by methyl di- (2-thienyl) glycolate (2), (R = Me; 13.29 g, 1.13 mmol), free base brush (1) (7.42 g, 47.8 mmol ), and the activated molecular sieves 4Ã… (26.36 g). This mixture is mixed at room temperature for 17 hours. An HPLC check shows 85% of the expected product. The mixture is decanted and the sieves washed with 2-MeTHF (2 x 50 mL). To this organic solution is added water (100 mL), the cooled mixture and the pH brought to 2 with the addition of 2M HBr (5 x 5 mL). The phases are separated and the organic phase extracted with water (100 mL). The aqueous phases are combined and washed with 2-MeTHF (100 mL), and after cooling, the pH brought to basic values by adding solid K2CO3. The mixture is kept stirred at 0 ° C for about 30 minutes, after which the solid obtained is filtered, washed with cold water (3 x 75 mL) and dried, first on a filter, and then at 40 ° C under vacuum for 18 hours. A white solid is obtained (14.43 g, 80%, HPLC purity 99.89%).
Esempio 6: Sintesi dell’estere scopina (3) usando un NHC derivato dall’1,3-di-tert-butilimidazolio cloruro con 8% mol NHC (rispetto al composto (1) ) a temperatura ambiente in THF. Example 6: Synthesis of scopin ester (3) using an NHC derived from 1,3-di-tert-butylimidazolium chloride with 8% mol NHC (with respect to compound (1)) at room temperature in THF.
In un pallone anidro contenente circa 500 mg di setacci molecolari 4Ã… attivati vengono dissolti il metile di-(2-tienil)glicolato (2, R = Me; 261 mg, 1.03 mmol) e la scopina base libera (1; 173 mg, 1.12 mmol) in THF (1 mL). In un pallone anidro separato vengono mescolati 1,3-di-tertbutilimidazolio cloruro (20 mg, 0.092 mmol), KOtBu/THF (80 L, 0.080 mmol) e THF (1.0 mL ) per 15 min a temperatura ambiente. Tale miscela à ̈ quindi trasferita con una siringa nel pallone contenente la soluzione dell’estere e dell’ammina. La siringa e il pallone vengono lavati con THF (1.0 mL) e la miscela di reazione viene mescolata a temperatura ambiente per 22 ore. Un controllo HPLC mostra il 70% del prodotto atteso. La miscela viene filtrata, lavando i setacci con THF (2 x 2.mL). Il filtrato viene concentrato a secchezza e il residuo ripreso con toluene (4 mL) e acqua (4 mL), e il pH viene portato a valori acidi (1-2) con 2M HBr. Durante la separazione delle fasi si osserva precipitazione di un solido e la sospensione risultante viene filtrata, il solido viene lavato con toluene (4 mL) e riunito alla fase acquosa separata. Il pH di tale sospensione acquosa, raffreddata a 0°C, viene portato a valori basici mediante aggiunta di K2CO3solido. Si mantiene la miscela in agitazione a 0°C per circa 30 minuti, dopodiché la miscela viene estratta con CH2Cl2(2 x 6 mL), la fase organica lavata con acqua (2 x 4 mL), seccata (Na2SO4), filtrata e il filtrato concentrato in vacuo. Si ottiene un solido biancastro (326 mg, 84%, purezza HPLC 98.45%). The methyl di- (2-thienyl) glycolate (2, R = Me; 261 mg, 1.03 mmol) and the free base scopin (1; 173 mg, 1.12 mmol) in THF (1 mL). In a separate dry flask, 1,3-di-tertbutylimidazolium chloride (20 mg, 0.092 mmol), KOtBu / THF (80 L, 0.080 mmol) and THF (1.0 mL) are mixed for 15 min at room temperature. This mixture is then transferred with a syringe into the flask containing the solution of the ester and the amine. The syringe and flask are washed with THF (1.0 mL) and the reaction mixture is mixed at room temperature for 22 hours. An HPLC check shows 70% of the expected product. The mixture is filtered, washing the sieves with THF (2 x 2.mL). The filtrate is concentrated to dryness and the residue is taken up with toluene (4 mL) and water (4 mL), and the pH is brought to acid values (1-2) with 2M HBr. During phase separation, precipitation of a solid is observed and the resulting suspension is filtered, the solid is washed with toluene (4 mL) and combined with the separated aqueous phase. The pH of this aqueous suspension, cooled to 0 ° C, is brought to basic values by adding solid K2CO3. The mixture is kept under stirring at 0 ° C for about 30 minutes, after which the mixture is extracted with CH2Cl2 (2 x 6 mL), the organic phase washed with water (2 x 4 mL), dried (Na2SO4), filtered and the concentrated filtrate in vacuo. An off-white solid is obtained (326 mg, 84%, HPLC purity 98.45%).
Esempio 7: Sintesi dell’estere scopina (3) usando un NHC derivato dall’1-esil-3-metilimidazolio tetrafluoroborato con 11% mol NHC (rispetto al composto (1) ) a temperatura ambiente in THF. Example 7: Synthesis of the scopin ester (3) using an NHC derived from 1-hexyl-3-methylimidazolium tetrafluoroborate with 11% mol NHC (with respect to compound (1)) at room temperature in THF.
In un pallone anidro contenente circa 500 mg di setacci molecolari 4Ã… attivati vengono dissolti il metile di-(2-tienil)glicolato (2), (R = Me; 256 mg, 1.01 mmol), e la scopina base libera (1), (159 mg, 1.03 mmol), in THF (1 mL). In un pallone separato vengono mescolati 1-esil-3-metilimidazolio tetrafluoroborato (27 L, 0.12 mmol), KOtBu/THF (100 L, 0.100 mmol) e THF (1.0 mL ) per 15 min a temperatura ambiente. Tale miscela à ̈ quindi trasferita con una siringa nel pallone contenente la soluzione dell’estere e dell’ammina. La siringa e il pallone sono lavati con THF (1.0 mL) e la miscela di reazione viene mescolata a temperatura ambiente per 16 ore. Un controllo HPLC mostra il 70% del prodotto atteso. La miscela viene filtrata, lavando i setacci con THF (2 x 2.mL). Il filtrato viene concentrato a secchezza e il residuo ripreso con toluene (4 mL) e acqua (4 mL), e il pH viene portato a valori acidi (1-2) con 2M HBr. Durante la separazione delle fasi si osserva precipitazione di un solido e la sospensione risultante viene filtrata, il solido viene lavato con toluene (4 mL) e riunito alla fase acquosa separata. Il pH di tale sospensione acquosa, raffreddata a 0°C, viene portato a valori basici mediante aggiunta di K2CO3solido. Si mantiene la miscela in agitazione a 0°C per circa 30 minuti, dopodiché la miscela viene estratta con CH2Cl2(2 x 6 mL), la fase organica lavata con acqua (2 x 4 mL), seccata (Na2SO4), filtrato e il filtrato concentrato in vacuo. Si ottiene un solido biancastro (305 mg, 80%, purezza HPLC 99.18%). The methyl di- (2-thienyl) glycolate (2), (R = Me; 256 mg, 1.01 mmol), and the free base brush (1) are dissolved in an anhydrous flask containing about 500 mg of activated molecular sieves 4Ã… , (159 mg, 1.03 mmol), in THF (1 mL). In a separate flask, 1-hexyl-3-methylimidazolium tetrafluoroborate (27 L, 0.12 mmol), KOtBu / THF (100 L, 0.100 mmol) and THF (1.0 mL) are mixed for 15 min at room temperature. This mixture is then transferred with a syringe into the flask containing the solution of the ester and the amine. The syringe and flask are washed with THF (1.0 mL) and the reaction mixture is mixed at room temperature for 16 hours. An HPLC check shows 70% of the expected product. The mixture is filtered, washing the sieves with THF (2 x 2.mL). The filtrate is concentrated to dryness and the residue is taken up with toluene (4 mL) and water (4 mL), and the pH is brought to acid values (1-2) with 2M HBr. During phase separation, precipitation of a solid is observed and the resulting suspension is filtered, the solid is washed with toluene (4 mL) and combined with the separated aqueous phase. The pH of this aqueous suspension, cooled to 0 ° C, is brought to basic values by adding solid K2CO3. The mixture is kept stirred at 0 ° C for about 30 minutes, after which the mixture is extracted with CH2Cl2 (2 x 6 mL), the organic phase washed with water (2 x 4 mL), dried (Na2SO4), filtered and the concentrated filtrate in vacuo. An off-white solid is obtained (305 mg, 80%, HPLC purity 99.18%).
Esempio 8: Sintesi dell’estere scopina (3) usando un NHC derivato dall’1,3-dicicloesilimidazolio tetrafluoroborato con 11% mol NHC (rispetto al composto (1) ) a temperatura ambiente in THF. Example 8: Synthesis of scopin ester (3) using an NHC derived from 1,3-dicyclohexylimidazolium tetrafluoroborate with 11% mol NHC (with respect to compound (1)) at room temperature in THF.
In un pallone anidro contenente circa 500 mg di setacci molecolari 4Ã… attivati vengono dissolti il metile di-(2-tienil)glicolato (2), (R = Me; 295 mg, 1.16 mmol), e la scopina base libera (1), 187 mg, 1.21 mmol) in THF (1 mL). In un pallone anidro separato vengono mescolati 1,3dicicloesilimidazolio tetrafluoroborato (44 mg, 0.14 mmol), KOtBu/THF (115 L, 0.115 mmol) e THF (1.0 mL ) per 15 min a temperatura ambiente. Tale miscela à ̈ quindi trasferita con una siringa nel pallone contenente la soluzione dell’estere e dell’ammina. La siringa e il pallone sono stati lavati con THF (1.0 mL) e la miscela di reazione viene mescolata a temperatura ambiente per 17.5 ore. Un controllo HPLC mostra il 77% del prodotto atteso. La miscela viene filtrata, lavando i setacci con THF (2 x 2.mL). Il filtrato viene concentrato a secchezza e il residuo ripreso con toluene (4 mL) e acqua (4 mL), e il pH viene portato a valori acidi (1-2) con 2M HBr. Durante la separazione delle fasi si osserva precipitazione di un solido e la sospensione risultante viene filtrata, il solido viene lavato con toluene (4 mL) e seccato sul filtro. Si ottiene un solido colore crema (354 mg, 67.5% (come sale HBr), purezza HPLC 98.71%). The methyl di- (2-thienyl) glycolate (2), (R = Me; 295 mg, 1.16 mmol), and the free base brush (1) are dissolved in an anhydrous flask containing about 500 mg of activated molecular sieves 4Ã… , 187 mg, 1.21 mmol) in THF (1 mL). In a separate dry flask, 1,3dicyclohexylimidazolium tetrafluoroborate (44 mg, 0.14 mmol), KOtBu / THF (115 L, 0.115 mmol) and THF (1.0 mL) are mixed for 15 min at room temperature. This mixture is then transferred with a syringe into the flask containing the solution of the ester and the amine. The syringe and flask were washed with THF (1.0 mL) and the reaction mixture was mixed at room temperature for 17.5 hours. An HPLC check shows 77% of the expected product. The mixture is filtered, washing the sieves with THF (2 x 2.mL). The filtrate is concentrated to dryness and the residue is taken up with toluene (4 mL) and water (4 mL), and the pH is brought to acid values (1-2) with 2M HBr. During phase separation, precipitation of a solid is observed and the resulting suspension is filtered, the solid is washed with toluene (4 mL) and dried on the filter. A solid cream color is obtained (354 mg, 67.5% (as HBr salt), HPLC purity 98.71%).
Esempio 9: Sintesi dell’estere scopina (3) usando un NHC derivato dall’1-butil-3-metilimidazolio tetrafluorborato in assenza di setacci molecolari, con 5% mol NHC (rispetto al composto (1) ) a temperatura ambiente in THF. Example 9: Synthesis of the scopin ester (3) using an NHC derived from 1-butyl-3-methylimidazolium tetrafluorborate in the absence of molecular sieves, with 5% mol NHC (with respect to compound (1)) at room temperature in THF.
In un pallone anidro vengono dissolti il metile di-(2-tienil)glicolato (2), (R = Me; 256 mg, 1.01 mmol), e la scopina base libera (1), (180 mg, 1.16 mmol), in THF (1 mL). In un pallone anidro separato vengono mescolati 1-butil-3-metilimidazolio tetrafluoroborato (12 L, 0.064 mmol), KOtBu/THF (52 L, 0.052 mmol) e THF (1.0 mL ) per 15 min a temperatura ambiente. Tale miscela à ̈ quindi trasferita con una siringa nel pallone contenente la soluzione dell’estere e dell’ammina. La siringa e il pallone sono stati lavati con THF (2 x 0.5 mL) e la miscela di reazione viene mescolata a temperatura ambiente per 18 ore. Un controllo HPLC mostra solo il 7% del prodotto atteso. Questa scarsa resa dimostra la necessità di avere i setacci molecolari nell’ambiente di reazione. In an anhydrous flask, methyl di- (2-thienyl) glycolate (2), (R = Me; 256 mg, 1.01 mmol), and the free base scope (1), (180 mg, 1.16 mmol), are dissolved in THF (1 mL). In a separate dry flask, 1-butyl-3-methylimidazolium tetrafluoroborate (12 L, 0.064 mmol), KOtBu / THF (52 L, 0.052 mmol) and THF (1.0 mL) are mixed for 15 min at room temperature. This mixture is then transferred with a syringe into the flask containing the solution of the ester and the amine. The syringe and flask were washed with THF (2 x 0.5 mL) and the reaction mixture is mixed at room temperature for 18 hours. An HPLC check shows only 7% of the expected product. This poor yield demonstrates the need to have molecular sieves in the reaction environment.
Esempio 10: Sintesi dell’estere scopina (3) usando il potassio terbutossido e i setacci molecolari. Example 10: Synthesis of the scopin ester (3) using potassium terbutoxide and molecular sieves.
In un pallone anidro vengono dissolti il metile di-(2-tienil)glicolato (2), (R = Me, 2.54 g, 9.98 mmol), e la scopina base libera (1), (1.59 g, 10.2 mmol), in THF (40 mL). La soluzione viene raffreddata ed i setacci molecolari 4Ã… attivati (7.63 g) aggiunti, in forma di polvere. Il KOtBu/THF (200 L, 0.200 mmol) viene aggiunto e la miscela mescolata per 18 ore a 4 °C. Un controllo HPLC mostra nessun prodotto atteso. La miscela viene portata a temperatura ambiente, KOtBu/THF (200 L, 0.200 mmol) viene aggiunto e la miscela lasciata a riflusso per 23 ore. Un controllo HPLC mostra solo il 19% del prodotto atteso. Questo risultato dimostra la necessità di avere il precursore del carbene nell’ambiente di reazione. In an anhydrous flask are dissolved the methyl di- (2-thienyl) glycolate (2), (R = Me, 2.54 g, 9.98 mmol), and the free base brush (1), (1.59 g, 10.2 mmol), in THF (40 mL). The solution is cooled and the 4Ã… activated molecular sieves (7.63 g) added, in the form of powder. The KOtBu / THF (200 L, 0.200 mmol) is added and the mixture mixed for 18 hours at 4 ° C. An HPLC check shows no expected product. The mixture is brought to room temperature, KOtBu / THF (200 L, 0.200 mmol) is added and the mixture left under reflux for 23 hours. An HPLC check shows only 19% of the expected product. This result demonstrates the need to have the carbene precursor in the reaction environment.
Esempio 11: Sintesi del tiotropio bromuro Example 11: Synthesis of tiotropium bromide
Si prepara una soluzione al 22% di bromuro di metile in acetone facendo gorgogliare il gas in una bottiglia di vetro scuro contenente 1.6 kg di acetone e posizionata su una bilancia fino a ottenere 1.95 kg di soluzione di bromuro di metile in acetone. A 22% solution of methyl bromide in acetone is prepared by bubbling the gas into a dark glass bottle containing 1.6 kg of acetone and placed on a balance until 1.95 kg of methyl bromide in acetone solution is obtained.
In un pallone di reazione, sono caricati nell’ordine: In a reaction flask, the following are loaded in order:
- scopina estere (3): 242.6g (0.6426 moli, 1 eq) - DMF: 388 mL, - ester broom (3): 242.6g (0.6426 moles, 1 eq) - DMF: 388 mL,
- acetone: 1370 mL - acetone: 1370 mL
(Rapporto acetone/DMF circa 3.5:1) (Acetone / DMF ratio about 3.5: 1)
Mantenendo la sospensione sotto agitazione meccanica, si riscalda a 40±5°C fino a ottenere dissoluzione completa del solido. Keeping the suspension under mechanical stirring, it is heated to 40 ± 5 ° C until complete dissolution of the solid is obtained.
Si raffredda fino a 20°C la soluzione limpida (di colore giallo chiaro) e, mantenendo il pallone immerso in bagno ad acqua, sulla soluzione limpida si gocciola rapidamente tramite imbuto gocciolatore una soluzione 22.1% (w/w) di metile bromuro in acetone: 636 mL, pari a circa 1.8 eq. di MeBr. The clear solution (light yellow in color) is cooled down to 20 ° C and, keeping the flask immersed in a water bath, a 22.1% (w / w) solution of methyl bromide in acetone is quickly dropped onto the clear solution through a dropping funnel. : 636 mL, equal to about 1.8 eq. by MeBr.
In poche ore di agitazione a temperatura ambiente, si osserva progressiva precipitazione di solido bianco. La miscela di reazione viene mantenuta in agitazione a temperatura ambiente. Dopo circa 4 giorni (90-100 h) si effettua un campionamento per controllo di reazione. In a few hours of stirring at room temperature, a progressive precipitation of a white solid is observed. The reaction mixture is kept under stirring at room temperature. After about 4 days (90-100 h) a sampling for reaction control is carried out.
La miscela di reazione si presenta come una sospensione eterogenea formata da acque madri limpide e solido granuloso e pesante che tende a depositarsi rapidamente sul fondo del pallone. The reaction mixture appears as a heterogeneous suspension formed by clear mother liquors and a grainy and heavy solid which tends to deposit rapidly on the bottom of the flask.
Si filtra il solido e si lavano pallone e solido su filtro con: 863 mL di miscela acetone/DMF (5:1), 431 mL di miscela acetone/DMF (5:1), 2x431 mL di acetone. Il solido così ottenuto viene seccato sul filtro in corrente di azoto per 2-3h. The solid is filtered and the flask and solid are washed on a filter with: 863 mL of acetone / DMF mixture (5: 1), 431 mL of acetone / DMF mixture (5: 1), 2x431 mL of acetone. The solid thus obtained is dried on the filter in a nitrogen current for 2-3h.
A fine essiccamento il solido si presenta bianco e polveroso. At the end of drying, the solid is white and dusty.
Peso Tiotropio Bromuro grezzo secco: 295.1 g (resa 97.2%). Dry crude Tiotropium Bromide weight: 295.1 g (yield 97.2%).
Claims (6)
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| IT000508A ITRM20110508A1 (en) | 2011-09-27 | 2011-09-27 | PROCESS FOR THE PREPARATION OF SCOPINA'S ESTERS. |
| PCT/IB2012/055138 WO2013046138A1 (en) | 2011-09-27 | 2012-09-27 | Process for the preparation of scopine esters |
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| IT000508A ITRM20110508A1 (en) | 2011-09-27 | 2011-09-27 | PROCESS FOR THE PREPARATION OF SCOPINA'S ESTERS. |
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| CN107827761A (en) * | 2017-11-07 | 2018-03-23 | 宿迁德威化工有限公司 | A kind of preparation method of organic aromatic amine compound |
| CN114890997A (en) * | 2022-04-20 | 2022-08-12 | 江苏联环药业股份有限公司 | Preparation process of anticholinergic drug tiaogelium bromide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0418716A1 (en) * | 1989-09-16 | 1991-03-27 | Boehringer Ingelheim Kg | Thienylcarboxylic acid ester of aminoalcohols, their quaternary products, their preparation and use of the compounds |
| WO2011015884A1 (en) * | 2009-08-07 | 2011-02-10 | Generics [Uk] Limited | Process to prepare scopine esters |
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| US656900A (en) | 1897-09-14 | 1900-08-28 | John A Brill | Car-truck. |
| US747153A (en) | 1903-03-02 | 1903-12-15 | Jesse Austin Dunn | Device for containing and ejecting oil, &c. |
| DE10064816A1 (en) | 2000-12-22 | 2002-06-27 | Boehringer Ingelheim Pharma | Production of tiotropium bromide useful as an anticholinergic comprises oxidation of di-(2-thienyl)-glycolic acid tropenol ester and subsequent quaternisation |
| US6610849B2 (en) | 2001-06-28 | 2003-08-26 | Boehringer Ingelheim Pharma Kg | Process for the manufacture of tropenol |
| DE10200943A1 (en) | 2002-01-12 | 2003-07-24 | Boehringer Ingelheim Pharma | Process for the preparation of scopine esters |
| DE102004041253A1 (en) | 2004-08-26 | 2006-03-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New process for the preparation of tiotropium salts |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0418716A1 (en) * | 1989-09-16 | 1991-03-27 | Boehringer Ingelheim Kg | Thienylcarboxylic acid ester of aminoalcohols, their quaternary products, their preparation and use of the compounds |
| WO2011015884A1 (en) * | 2009-08-07 | 2011-02-10 | Generics [Uk] Limited | Process to prepare scopine esters |
Non-Patent Citations (2)
| Title |
|---|
| GRASA G A ET AL: "EFFICIENT TRANSESTERIFICATION/ACYLATION REACTIONS MEDIATED BY N-HETEROCYCLIC CARBENE CATALYSTS", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, EASTON.; US, vol. 68, 1 January 2003 (2003-01-01), pages 2812 - 2819, XP009061853, ISSN: 0022-3263, DOI: 10.1021/JO0267551 * |
| ROHIT SINGH ET AL: "Transesterification/Acylation of Secondary Alcohols Mediated by N -Heterocyclic Carbene Catalysts", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 69, no. 1, 1 January 2004 (2004-01-01), pages 209 - 212, XP055016169, ISSN: 0022-3263, DOI: 10.1021/jo035431p * |
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