WO2018154596A1 - Procédé de synthèse de bromure de tiotropium monohydraté - Google Patents
Procédé de synthèse de bromure de tiotropium monohydraté Download PDFInfo
- Publication number
- WO2018154596A1 WO2018154596A1 PCT/IN2018/050082 IN2018050082W WO2018154596A1 WO 2018154596 A1 WO2018154596 A1 WO 2018154596A1 IN 2018050082 W IN2018050082 W IN 2018050082W WO 2018154596 A1 WO2018154596 A1 WO 2018154596A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- tiotropium bromide
- methyl
- monohydrate
- synthesis
- bromide monohydrate
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 23
- 230000015572 biosynthetic process Effects 0.000 title abstract description 6
- 238000003786 synthesis reaction Methods 0.000 title abstract description 6
- MQLXPRBEAHBZTK-SEINRUQRSA-M tiotropium bromide hydrate Chemical compound O.[Br-].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 MQLXPRBEAHBZTK-SEINRUQRSA-M 0.000 title description 10
- FIMXSEMBHGTNKT-RZVDLVGDSA-N scopine Chemical compound C([C@@H]1N2C)[C@H](O)C[C@@H]2[C@@H]2[C@H]1O2 FIMXSEMBHGTNKT-RZVDLVGDSA-N 0.000 claims abstract description 18
- FIMXSEMBHGTNKT-UHFFFAOYSA-N Scopine Natural products CN1C2CC(O)CC1C1C2O1 FIMXSEMBHGTNKT-UHFFFAOYSA-N 0.000 claims abstract description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 238000006243 chemical reaction Methods 0.000 claims description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- ZXUQEPZWVQIOJE-UHFFFAOYSA-N methyl 2-chloro-2-oxoacetate Chemical compound COC(=O)C(Cl)=O ZXUQEPZWVQIOJE-UHFFFAOYSA-N 0.000 claims description 9
- TUCRZHGAIRVWTI-UHFFFAOYSA-N 2-bromothiophene Chemical compound BrC1=CC=CS1 TUCRZHGAIRVWTI-UHFFFAOYSA-N 0.000 claims description 8
- -1 methyl halide Chemical class 0.000 claims description 7
- 150000004682 monohydrates Chemical class 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 5
- 238000003747 Grignard reaction Methods 0.000 claims description 4
- MAXKQCIGINCTIC-UHFFFAOYSA-N bromomethane;hydrate Chemical group O.BrC MAXKQCIGINCTIC-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 2
- 101100381997 Danio rerio tbc1d32 gene Proteins 0.000 claims 2
- 101100381999 Mus musculus Tbc1d32 gene Proteins 0.000 claims 2
- 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 abstract description 9
- 229960000257 tiotropium bromide Drugs 0.000 abstract description 6
- 230000008878 coupling Effects 0.000 abstract description 5
- 238000010168 coupling process Methods 0.000 abstract description 5
- 238000005859 coupling reaction Methods 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- CPKISUMKCULUNR-UHFFFAOYSA-N 2-methoxy-2-oxoacetic acid Chemical compound COC(=O)C(O)=O CPKISUMKCULUNR-UHFFFAOYSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- UDHXJZHVNHGCEC-UHFFFAOYSA-N Chlorophacinone Chemical compound C1=CC(Cl)=CC=C1C(C=1C=CC=CC=1)C(=O)C1C(=O)C2=CC=CC=C2C1=O UDHXJZHVNHGCEC-UHFFFAOYSA-N 0.000 description 1
- LOMVENUNSWAXEN-UHFFFAOYSA-N Methyl oxalate Chemical compound COC(=O)C(=O)OC LOMVENUNSWAXEN-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- OWZFULPEVHKEKS-UHFFFAOYSA-N ethyl 2-chloro-2-oxoacetate Chemical compound CCOC(=O)C(Cl)=O OWZFULPEVHKEKS-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 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 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000000414 obstructive effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 235000015096 spirit Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- LERNTVKEWCAPOY-DZZGSBJMSA-N tiotropium Chemical class O([C@H]1C[C@@H]2[N+]([C@H](C1)[C@@H]1[C@H]2O1)(C)C)C(=O)C(O)(C=1SC=CC=1)C1=CC=CS1 LERNTVKEWCAPOY-DZZGSBJMSA-N 0.000 description 1
- 238000005406 washing Methods 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
Definitions
- Tiotropium bromide monohydrate chemically described as (1 ,2 ,4 ,7 )-7-[(hydroxidi-2- thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonane bromide monohydrate, is an anticholinergic bronchodilator used in the management of chronic obstructive pul monary di sease.
- Tiotropium bromide monohydrate has been synthesized via N-demethylated tiotropium which was obtained by a reaction of methyl di(2-thienyl)glycolate and scopine using sodium metal in melt or sodium hydroxide in melt.
- sodium metal melt or sodium hydroxide in melt is not suitable for industrial scale manufacturing.
- Described herein is a process for synthesis of tiotropium bromide monohydrate.
- the process for synthesis of tiotropium bromide monohydrate comprises the steps of:
- Described herein is a process for preparation of tiotropium bromide monohydrate and intermediates thereof.
- a process for coupling of scopine with 2, 2 dithienyl glycolate comprising:
- the reaction of scopine (1) with methyl chlorooxoacetate (2) is conducted at about 0 °C although other possible temperatures are readily apparent to one of skill in the art and are contemplated within the scope of embodiments described herein.
- the reaction is conducted in aprotic solvents such as dichloromethane (DCM), dichloroethane (DCE), chloroform, tetrahydrofuran (TH F) and the like, preferably in DCM.
- DCM dichloromethane
- DCE dichloroethane
- TH F tetrahydrofuran
- Other reagents may be used instead of methyl chlorooxoacetate including and not limited to other alkyl halooxoacetate, (e.g., ethyl chlorooxoacetate and the like).
- the Grignard reaction of the dioxalate intermediate of structure (3) with 2-bromothiophene (4) is initiated at ambient temperature, although other higher or lower temperatures will be readi ly apparent to one of ski 11 in the art and are contempl ated withi n the scope of embodi ments described herein.
- the two steps shown above are conducted under mild conditions while the epoxide remains intact. In other words, an extra step for introduction of the epoxide is not required in the process described herein.
- the process further comprises N-methylation of the intermediate of structure (5) with a methyl halide, preferably methyl bromide monohydrate.
- a methyl halide preferably methyl bromide monohydrate.
- the reaction is conducted in an aprotic solvent such as acetonitrile, THF, chloroform and the like, preferably in a mixture of acetonitrile and chloroform.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
La présente invention concerne un procédé de synthèse de bromure de tiotropium, le couplage de scopine avec du 2,2-dithiényle glycolate étant obtenu par un procédé en deux étapes dans des conditions modérées.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN201741006241 | 2017-02-22 | ||
| IN201741006241 | 2017-02-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2018154596A1 true WO2018154596A1 (fr) | 2018-08-30 |
Family
ID=63254296
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2018/050082 WO2018154596A1 (fr) | 2017-02-22 | 2018-02-19 | Procédé de synthèse de bromure de tiotropium monohydraté |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2018154596A1 (fr) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2814827A1 (fr) * | 2012-02-10 | 2014-12-24 | Hovione International Ltd. | Procédé pour la préparation de bromure de tiotropium |
| EP2825535B1 (fr) * | 2012-03-16 | 2016-04-27 | Zentiva, K.S. | Procédé de préparation de l'ester de scopine de l'acide di-(2- thiényl)glycolique, un intermédiaire dans la synthèse du bromure de tiotropium, et sa nouvelle forme |
-
2018
- 2018-02-19 WO PCT/IN2018/050082 patent/WO2018154596A1/fr active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2814827A1 (fr) * | 2012-02-10 | 2014-12-24 | Hovione International Ltd. | Procédé pour la préparation de bromure de tiotropium |
| EP2825535B1 (fr) * | 2012-03-16 | 2016-04-27 | Zentiva, K.S. | Procédé de préparation de l'ester de scopine de l'acide di-(2- thiényl)glycolique, un intermédiaire dans la synthèse du bromure de tiotropium, et sa nouvelle forme |
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