WO2006038872A1 - Nouveau procede pour la preparation d'acide phosphinique - Google Patents
Nouveau procede pour la preparation d'acide phosphinique Download PDFInfo
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- WO2006038872A1 WO2006038872A1 PCT/SE2005/001472 SE2005001472W WO2006038872A1 WO 2006038872 A1 WO2006038872 A1 WO 2006038872A1 SE 2005001472 W SE2005001472 W SE 2005001472W WO 2006038872 A1 WO2006038872 A1 WO 2006038872A1
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- Prior art keywords
- compound
- formula
- alkyl
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- cyclic
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title description 4
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 14
- 125000003118 aryl group Chemical group 0.000 claims abstract description 12
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
- 125000004122 cyclic group Chemical group 0.000 claims abstract description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 8
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 8
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 7
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 6
- 229910052731 fluorine Inorganic materials 0.000 claims abstract description 6
- 125000004404 heteroalkyl group Chemical group 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 35
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 238000002955 isolation Methods 0.000 claims description 4
- 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 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 3
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- IKGLACJFEHSFNN-UHFFFAOYSA-N hydron;triethylazanium;trifluoride Chemical group F.F.F.CCN(CC)CC IKGLACJFEHSFNN-UHFFFAOYSA-N 0.000 claims description 3
- 239000000543 intermediate Substances 0.000 claims description 3
- 229940086542 triethylamine Drugs 0.000 claims description 3
- SPXOTSHWBDUUMT-UHFFFAOYSA-M 4-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=C(S([O-])(=O)=O)C=C1 SPXOTSHWBDUUMT-UHFFFAOYSA-M 0.000 claims description 2
- 229940093499 ethyl acetate Drugs 0.000 claims description 2
- 235000019439 ethyl acetate Nutrition 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- -1 potassium halide Chemical class 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 23
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000026030 halogenation Effects 0.000 abstract description 6
- 238000005658 halogenation reaction Methods 0.000 abstract description 6
- 125000003158 alcohol group Chemical group 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 8
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000010410 layer Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000000018 receptor agonist Substances 0.000 description 5
- 229940044601 receptor agonist Drugs 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 238000007126 N-alkylation reaction Methods 0.000 description 3
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 3
- 238000003682 fluorination reaction Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 230000000707 stereoselective effect Effects 0.000 description 3
- IAVOOHAFSZKXIS-INIZCTEOSA-N (2s)-2-(dibenzylamino)-3-hydroxypropanoic acid Chemical compound C=1C=CC=CC=1CN([C@@H](CO)C(O)=O)CC1=CC=CC=C1 IAVOOHAFSZKXIS-INIZCTEOSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 210000003169 central nervous system Anatomy 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 208000002551 irritable bowel syndrome Diseases 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- 238000003541 multi-stage reaction Methods 0.000 description 2
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- NHVRIDDXGZPJTJ-UHFFFAOYSA-N skf-97,541 Chemical compound CP(O)(=O)CCCN NHVRIDDXGZPJTJ-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- 230000001131 transforming effect Effects 0.000 description 2
- SOEYCMDWHXVTQC-UHFFFAOYSA-N 3-aminopropylphosphonous acid Chemical class NCCCP(O)O SOEYCMDWHXVTQC-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 0 CN(*)C[C@](*)C(**)=O Chemical compound CN(*)C[C@](*)C(**)=O 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 208000008238 Muscle Spasticity Diseases 0.000 description 1
- 239000005703 Trimethylamine hydrochloride Substances 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical group 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- ZTHNRNOOZGJLRR-UHFFFAOYSA-N chembl112203 Chemical class NCCCP(O)=O ZTHNRNOOZGJLRR-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 150000002148 esters Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical class NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 230000010243 gut motility Effects 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 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 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000003328 mesylation reaction Methods 0.000 description 1
- DUHPPSNWMYHJNC-QGZVFWFLSA-N methyl (2r)-2-chloro-3-(dibenzylamino)propanoate Chemical compound C=1C=CC=CC=1CN(C[C@@H](Cl)C(=O)OC)CC1=CC=CC=C1 DUHPPSNWMYHJNC-QGZVFWFLSA-N 0.000 description 1
- ANSUDRATXSJBLY-VKHMYHEASA-N methyl (2s)-2-amino-3-hydroxypropanoate Chemical compound COC(=O)[C@@H](N)CO ANSUDRATXSJBLY-VKHMYHEASA-N 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 230000036640 muscle relaxation Effects 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002325 prokinetic agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 208000018198 spasticity Diseases 0.000 description 1
- 210000005070 sphincter Anatomy 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- SZYJELPVAFJOGJ-UHFFFAOYSA-N trimethylamine hydrochloride Chemical compound Cl.CN(C)C SZYJELPVAFJOGJ-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/20—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
Definitions
- the present invention is directed to a new process for a regio- and stereoselective synthesis of ⁇ -halo- ⁇ -amino esters and ⁇ -halo- ⁇ -amino amides.
- GABAe-receptor agonists as well as methods of making said compounds are disclosed in WO 98/ 11885 Al and in WO 01/ 42252 Al.
- GABA B receptor agonists are being described as being of use in the treatment of central nervous system (CNS) disorders, such as muscle relaxation in spinal spasticity, cardiovascular disorders, asthma, gut motility disorders such as irritable bowel syndrome (IBS) and as prokinetic and anti-tussive agents.
- CNS central nervous system
- IBS irritable bowel syndrome
- GABA B receptor agonists have also been disclosed as useful in the treatment of emesis (WO 96/11680, A2) and, as mentioned above, in the inhibition of transient lower oesophageal sphincter relaxations, TLOSR (WO 98/11885, Al).
- EP 0356128, Al describes the use of the specific compound (3-aminopropyl) methyl phosphinic acid, as a potent GABA B receptor agonist, in therapy.
- EP 0181833, Al discloses substituted 3-aminopropyl phosphinic acids (or more correctly 3-aminopropyl phosphonous acids having very strong affinities towards GABA B receptor sites.
- EP 0399949, Al discloses derivatives of (3-aminopropyl)methyl phosphinic acid that are described as potent GABA B receptor agonists. These compounds are stated to be useful as muscle relaxants.
- EP 0463969, Al, and FR 2722192, A are both applications related to 4- aminobutanoic acid derivatives having different heterocyclic substituents at the ⁇ -carbon of the butyl chain.
- Synthesis of ⁇ -halo- ⁇ -amino esters has been disclosed by Gani et al. (J. Chem. Soc. Chem. Commun., 16, 1983, 898-900, Gani; Hitchcock, Young).
- the synthesis described herein is a single step reaction performed by reaction between (N-dibenzyl)-(2-amino-3-hydroxy)- propionic acid and (diethylamino)sulphur trifluoride (a compound as hereinafter is called DAST).
- DAST is a thermally unstable compound and has risks when handed in bulk quantities.
- the present invention provides a new process for large-scale halogenation i.e. for large- scale preparation of ⁇ -halo- ⁇ -amino esters or ⁇ -halo- ⁇ -amino amides.
- the reaction is a regioselective synthesis as well as a stereoselective synthesis of the ⁇ -halo- ⁇ -amino ester and ⁇ -halo- ⁇ -amino amide.
- the compound obtained by the process can be further processed to corresponding ⁇ -halo- ⁇ -amino acids.
- One object of the present invention is to provide a process enabling the different reaction steps to be performed in a consecutive order, thus avoiding the time-consuming step of isolation, separation and filtration of the product after each reaction steps. This provides a more environmentally friendly process provided, as less amounts of, for example, solvents are needed for the process.
- a further object of the present invention is to provide a process suitable for full-scale preparation with reactants that are easier and safety to handle, in comparison with DAST as this reactant is a thermally unstable compound.
- the present invention is a step- wise reaction for synthesising a compound of formula I:
- A is O or N
- R is a Ci- C ⁇ alkyl, optionally substituted by an aryl or a heteroaryl;
- R and R are each and independently a C ⁇ - Cio alkyl, optionally substituted or interrupted by an aryl or a heteroaryl; and X is selected from F, Cl, Br, or I.
- the reaction is a halogenation procedure comprising the consecutive sequence of following reactions: a) di-N-alkylation of ⁇ -amino- ⁇ -hydroxy-ester, or of ⁇ -halo- ⁇ -hydroxy-amide; b) formation of a leaving group on the alcohol function; and c) halogenation.
- reaction sequence comprises the following steps: a) reacting compound of formula II
- A represents O or N
- R is as defined above;
- R and R are each and independently C ⁇ - C ⁇ Q alkyl, optionally substituted by aryl, heteroaryl,
- Z is selected from Cl, Br, I; the reaction is hereinafter referred to "di-N-alkylation reaction", a reaction to provide a compound of formula III
- Step b transforming the alcohol to a leaving group Y, to give a compound of formula IV
- A represents O or N;
- R represents a Cj- Cg alkyl, optionally substituted with aryl, heteroaryl;
- R and R each independently represents Cj- Cio alkyl, optionally substituted by aryl, heteroaryl;
- Y represents the leaving group
- Step c reacting compound of formula IV with a halogen source to give the compound of formula I.
- This compound is an intermediate in the process for synthesis of, for example alkyl phospinic acids.
- the starting material to be used for the synthesis of compounds of formula I according to the process provided by the present invention are commercial available, for example from Sigma-Aldrich.
- Ci-C ⁇ o alkyl as used throughout this specification includes linear, branched or cyclic C J-C jo alkyl.
- Examples of C]-C ⁇ Q alkyl include, but are not limited to methyl, ethyl, propyl, n-propyl, isopropyl, cyclopropyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, cyclopentyl, hexyl and cyclohexyl.
- cyclic C3-C6 alkyl as used throughout this specification means a cyclic alkyl having from 3 to 6 carbon atoms in the ring.
- Examples of cyclic C 3 -C 6 alkyl are cyclic propyl, cyclic butyl, cyclic pentyl, and cyclic hexyl.
- cyclic C3-C6 heteroalkyl as used throughout this specification means a cyclic alkyl which one or more of the from 3 to 6 in the ring are elements other than carbon, such as N, S and O.
- aryl as used throughout this specification means an aromatic ring having from 6 to 10 carbon atoms, such as phenyl and naphtyl.
- heteroaryl as used throughout this specification means an aromatic ring in which one or more of the from 5-10 atoms in the ring are elements other than carbon, such as N, S and O.
- the term "leaving group”, denoted Y in the compound of formula IV, can be formed by reaction of III with a reagent suitable for the suitable for the present reaction which can be selected from a group consisting of mesylate (-0802CHs) 5 tosylate - OSO 2 (C 6 H 4 ) CH 3) Inflate (-OSO 2 CF 3 ), nosylate (-OSO 2 (C 6 H 4 ) CH 3 ).
- a reagent suitable for the suitable for the present reaction which can be selected from a group consisting of mesylate (-0802CHs) 5 tosylate - OSO 2 (C 6 H 4 ) CH 3) Inflate (-OSO 2 CF 3 ), nosylate (-OSO 2 (C 6 H 4 ) CH 3 ).
- reagents are commercial available in their respectively chloride or/and anhydride form.
- the invention is not restricted to the leaving groups mentioned above.
- halogene source denotes any compound abel to donate a halide, such compounds can be selected from the group comprising potassium halide, tetraalkyl ammoniumhalide or pyridine hydrohalide.
- the halide used is selected from fluoride, chloride, bromide, and iodide.
- Non-limiting examples of halogene source are triethyl amine trihydrofluoride, potassium fluoride, tetrabutyl arnmoniumfluoride, pyridine hydrofluoride, triethyl amine hydrochloride, trimethyl amine hydrochloride, potassium chloride, tetrabutyl ammoniumchloride, and pyridine hydrochloride.
- the group of halogenating agents is not restricted to these mentioned.
- Suitable solvent for the reaction sequence is selected from the group comprising toluene, methyl ⁇ -o-butylketone, ethylacetate, acetonitrile, or an equivalent solvent, or mixture thereof.
- the reaction is performed as stepwise reaction wherein the different step follows in a consecutive order, thus, without isolation of the intermediates.
- One object of the present invention is to provide a process for the production of ⁇ -halo- ⁇ - amino esters with high enantioselective excess.
- the process of the invention can be stereoselective and more than 98 % enantiomeric excess (%ee) can be achieved. Also when production on larger scale, i.e. of volumes equal or larger than 50 1, high enantiomeric excess is achieved.
- the stereoselectivity of the reaction can be obtained by specific selection of reactants, for example by coupling a sterically hindered group such as benzyl- group to enantiomerically pure (>99 %ee) methyl-(2-amino-3-hydroxy)-propionic acid.
- a further object of the invention is to provide a process for the production of a compound of formula I wherein X represents fluorine or chlorine and Rj represents methyl.
- the procedure is regioselective, it is possible to provide the desired isomer in a ratio of 15- 20: 1.
- the process according to the present invention provides a good yield, i.e. 80 % or higher and reduced production time when performed on larger scale.
- the compound of formula I may be further processed, even without isolation, for example, by reduction of the ester functionality forming the corresponding alcohol.
- This reaction is suitable performed by sodium borohydride using polyethylene glycol 400 (PEG) as solvent (Santaniello, Ferraboschi, Fiecchi, Grisenti, Manzocchi, J.Org. Chem. 1987, 52, pp. 671- 4).
- PEG polyethylene glycol 400
- toluene or tetrahydrofuran
- This also enabled an easy extractive work-up procedure with water.
- Step l Di-N-alkylation 943 g NaHC ⁇ 3 (11.2 mol, 4.5 eq.) and 841 g benzylbromide (4.86 mol, 2 eq.) were dispensed in 2.8 L acetonitrile/water 5:2 mixture and heated to 50 0 C. 400 g of L-Serine- methylester x HCl (2.54 mol, 1.02 eq) was added slowly. The reaction mixture was heated over night (13 hours) and then cooled to 18 0 C. HPLC showed 96 % conversion to methyl N 5 N dibenzylserinate. The inorganic salts were filtered off and washed with 500 mL toluene. IL toluene and 500 mL water were added to the filtrate, the layers were separated after 15 minutes stirring (two clear phases).
- Step 2 Transforming of alcohol to a leaving group - mesylation
- reaction mixture was cooled to 6° C. 280 g triethyl amine (2.74 mol, 1.1 eq) was charged followed by slow addition (Ih 15 min) of 318 g mesyl chloride (2.74 mol, 1.1 eq) diluted in 200 mL toluene. The addition was exothermic, temperature was raised to 15 0 C. +99 % conversion was achieved after 35 minutes (HPLC). 2L water was charged at 10 0 C followed by 150 g Na 2 CC>3 (s) and 300 mL toluene.
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Abstract
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2009286779A (ja) * | 2008-04-28 | 2009-12-10 | Central Glass Co Ltd | α−フルオロ−β−アミノ酸類の製造方法 |
JP2010285350A (ja) * | 2009-06-09 | 2010-12-24 | Central Glass Co Ltd | 2−フルオロアクリル酸エステルの製造方法 |
Citations (1)
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EP1052265A1 (fr) * | 1998-01-30 | 2000-11-15 | Ajinomoto Co., Inc. | Procede servant a preparer des derives de nucleosides |
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2004
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EP1052265A1 (fr) * | 1998-01-30 | 2000-11-15 | Ajinomoto Co., Inc. | Procede servant a preparer des derives de nucleosides |
Non-Patent Citations (6)
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DATABASE CAPLUS [online] SIMONSSON ROGER.: "Synthesis of 14C labelled AZD-3355.", accession no. stn Database accession no. (2004:859374) * |
GANI D ET AL: "Stereochemistry of the Metabolism of the DNA Base Thymine and the Drug 5-Fluorouracil.", J CHEM SOC CHEM COMMUN., 1983, pages 898 - 900, XP002994999 * |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009286779A (ja) * | 2008-04-28 | 2009-12-10 | Central Glass Co Ltd | α−フルオロ−β−アミノ酸類の製造方法 |
EP2246322A4 (fr) * | 2008-04-28 | 2011-09-14 | Central Glass Co Ltd | Procédé de production d acides -fluoro- -aminés |
US8217196B2 (en) | 2008-04-28 | 2012-07-10 | Central Glass Company, Limited | Process for producing α-fluoro-β-amino acids |
JP2010285350A (ja) * | 2009-06-09 | 2010-12-24 | Central Glass Co Ltd | 2−フルオロアクリル酸エステルの製造方法 |
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