WO2000050379A1 - Procede de preparation de (1r, 2s, 4r) -(-) -2 - (2 -dimethylaminoethoxy) -2 -phenyl -1,7,7 - trimethylbicyclo [2.2.1] heptane - Google Patents
Procede de preparation de (1r, 2s, 4r) -(-) -2 - (2 -dimethylaminoethoxy) -2 -phenyl -1,7,7 - trimethylbicyclo [2.2.1] heptane Download PDFInfo
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- WO2000050379A1 WO2000050379A1 PCT/HU2000/000014 HU0000014W WO0050379A1 WO 2000050379 A1 WO2000050379 A1 WO 2000050379A1 HU 0000014 W HU0000014 W HU 0000014W WO 0050379 A1 WO0050379 A1 WO 0050379A1
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- WIPO (PCT)
- Prior art keywords
- formula
- process according
- phenyl
- compound
- trimethylbicyclo
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- QOBGWWQAMAPULA-RLLQIKCJSA-N n,n-dimethyl-2-[[(1r,3s,4r)-4,7,7-trimethyl-3-phenyl-3-bicyclo[2.2.1]heptanyl]oxy]ethanamine Chemical compound C1([C@@]2([C@]3(C)CC[C@@H](C3(C)C)C2)OCCN(C)C)=CC=CC=C1 QOBGWWQAMAPULA-RLLQIKCJSA-N 0.000 title claims abstract 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 150000001447 alkali salts Chemical class 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000002253 acid Substances 0.000 claims abstract description 6
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical class 0.000 claims abstract description 3
- IMQKIJZWVVCZFF-AHRSYUTCSA-N n,n-dimethyl-2-[[(1r,3s,4r)-4,7,7-trimethyl-3-phenyl-3-bicyclo[2.2.1]heptanyl]oxy]acetamide Chemical compound C1([C@@]2([C@]3(C)CC[C@@H](C3(C)C)C2)OCC(=O)N(C)C)=CC=CC=C1 IMQKIJZWVVCZFF-AHRSYUTCSA-N 0.000 claims abstract description 3
- GJOSGKNJWBGNSY-BMFZPTHFSA-N (1r,3s,4r)-4,7,7-trimethyl-3-phenylbicyclo[2.2.1]heptan-3-ol Chemical compound C1([C@]2(O)[C@]3(C)CC[C@@](C3(C)C)(C2)[H])=CC=CC=C1 GJOSGKNJWBGNSY-BMFZPTHFSA-N 0.000 claims abstract 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000011541 reaction mixture Substances 0.000 claims description 10
- 238000009835 boiling Methods 0.000 claims description 7
- 239000012429 reaction media Substances 0.000 claims description 6
- CETWDUZRCINIHU-UHFFFAOYSA-N methyl-n-amyl-carbinol Natural products CCCCCC(C)O CETWDUZRCINIHU-UHFFFAOYSA-N 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 229910052987 metal hydride Inorganic materials 0.000 claims description 4
- 150000004681 metal hydrides Chemical class 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 4
- XBPPLECAZBTMMK-UHFFFAOYSA-N 2-chloro-n,n-dimethylacetamide Chemical compound CN(C)C(=O)CCl XBPPLECAZBTMMK-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 239000003638 chemical reducing agent Substances 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 229910000085 borane Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 150000004678 hydrides Chemical class 0.000 claims description 2
- 150000007517 lewis acids Chemical class 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 239000002249 anxiolytic agent Substances 0.000 abstract description 2
- 230000000949 anxiolytic effect Effects 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract description 2
- 125000003635 2-dimethylaminoethoxy group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])O* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- DSSYKIVIOFKYAU-XCBNKYQSSA-N (R)-camphor Chemical compound C1C[C@@]2(C)C(=O)C[C@@H]1C2(C)C DSSYKIVIOFKYAU-XCBNKYQSSA-N 0.000 description 5
- 241000723346 Cinnamomum camphora Species 0.000 description 5
- 229960000846 camphor Drugs 0.000 description 5
- 229930008380 camphor Natural products 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 239000001530 fumaric acid Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 238000011109 contamination Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 239000011975 tartaric acid Substances 0.000 description 4
- 235000002906 tartaric acid Nutrition 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 150000002736 metal compounds Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZFFBIQMNKOJDJE-UHFFFAOYSA-N 2-bromo-1,2-diphenylethanone Chemical compound C=1C=CC=CC=1C(Br)C(=O)C1=CC=CC=C1 ZFFBIQMNKOJDJE-UHFFFAOYSA-N 0.000 description 1
- WQMAANNAZKNUDL-UHFFFAOYSA-N 2-dimethylaminoethyl chloride Chemical compound CN(C)CCCl WQMAANNAZKNUDL-UHFFFAOYSA-N 0.000 description 1
- KYARBIJYVGJZLB-UHFFFAOYSA-N 7-amino-4-hydroxy-2-naphthalenesulfonic acid Chemical compound OC1=CC(S(O)(=O)=O)=CC2=CC(N)=CC=C21 KYARBIJYVGJZLB-UHFFFAOYSA-N 0.000 description 1
- WWALDFORXVQUGQ-UHFFFAOYSA-N CCC(CC(C1)C2(C)C)C2C1(c1ccccc1)OCC(N(C)C)=O Chemical compound CCC(CC(C1)C2(C)C)C2C1(c1ccccc1)OCC(N(C)C)=O WWALDFORXVQUGQ-UHFFFAOYSA-N 0.000 description 1
- 0 CN(C)C(C*)=O Chemical compound CN(C)C(C*)=O 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 150000003388 sodium compounds Chemical class 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/52—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/18—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the singly-bound oxygen atoms further bound to a carbon atom of a six-membered aromatic ring, e.g. phenoxyacetamides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
- C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
Definitions
- the invention relates to a process for the preparation of (1 R,2S,4R)-(-)-2-(2-dimethy!aminoethoxy)-2-phenyl-1 ,7,7- -trimethylbicyclo[2.2.1]heptane and pharmaceutically acceptable acid addition salts thereof.
- the compound of the Formula I falls under the scope of the Formula I of HU-179,164.
- the compound of the Formula I is prepared by reacting camphor with the corresponding organic metal compound, hydrolyzing the adduct thus obtained and introducing the basic sidechain by etherification of the hydroxy group of the compound thus obtained.
- organic metal compound a Grignard compound or an organic alkali compound - preferably lithium or sodium compound - can be used.
- the preparation of the compound of the Formula I is disclosed in none of the examples of HU-179,164. Following the general disclosure the compound of the Formula I cannot be prepared in a purity which meets the requirements of Pharmacopoeia or only with considerable losses.
- the present invention is based on the recognition that the new compound of the Formula V, never described in prior art, can be readily crystallized and can be easily purified.
- the contaminations and by-products formed in the course of the synthesis can be removed by crystallization of the compound of the Formula V to a very great extent and due to this fact a highly pure compound is used as last intermediate in the synthesis of the desired compound of the Formula I. Details of the invention
- an alkali salt of the compound of the Formula III is reacted with a 2-halogeno-N,N-dimethyl-acetamide of the general Formula IV.
- the compound of the Formula III is known from prior art [Deno et al. J. Amer. Chem. Soc, 77, 3044 (1955)].
- the starting material of the Formula III is converted into an alkali salt, preferably the sodium or potassium salt, particularly advantageously the sodium salt.
- the reaction is carried out by using an alkali hydride or alkali amide, such as sodium hydride, potassium hydride, sodium amide or potassium amide.
- An ether e.g.
- the alkali salt of the compound of the Formula III can be prepared at 10-50°C, preferably at room temperature.
- the alkali salt formed is reacted with a compound of the general Formula IV. It is preferred to use 2-chloro-N,N- -dimethyl-acetamide, i.e. a compound of the general Formula IV, wherein X stands for chlorine. According to a preferred form of realization of the process of the present invention the reaction between the alkali salt of the compound of the Formula III and the 2-halo-N.N-dimethyl-acetamide of the general Formula IV is carried out without isolating the in situ formed alkali salt, i.e. in the reaction mixture obtained by the formation of said alkali salt.
- reaction medium used by the reaction between the alkali salt of the compound of the Formula III and the compound of the general Formula IV is the same as used in the alkali salt formation.
- the reaction between the alkali salt of the compound of the Formula III and the 2-halo-N,N-dimethyl-acetamide of the general Formula IV can be carried out at 10-50°C, preferably at room temperature. The reaction takes place within some hours, the advantageous reaction time being 1-3 hours.
- the formed compound of the Formula V is isolated from the reaction mixture by extraction (preferably with ethyl acetate) and evaporation of the extract.
- the compound of the Formula V is purified by crystallization. Said crystallization can be carried out from a hydrocarbon (e.g. pentane, hexane, heptane, cyclohexane etc.) or a mixture thereof formed with ethyl acetate.
- a hydrocarbon e.g. pentane, hexane, heptane, cyclohexane etc.
- One may work preferably by crystallizing the compound of the Formula V from a mixture of hexane and ethyl acetate.
- the crystalline compound of the Formula V obtained is of high purity, contains only small amounts of contaminations and is suitable for the preparation of the end product of the Formula I meeting the up-to-date requirements of Pharmacopoeia.
- the compound of the Formula V thus obtained is reduced into the desired compound of the Formula I.
- Reduction can be carried out with any metal hydride suitable for the reduction of acid amides, or a complex of a Lewis acid formed with a metal hydride or a borohydride/dimethyl sulfide complex. It is preferred to use lithium aluminium hydride or a borohydride/dimethyl sulfide complex as reducing agent.
- Reduction can be performed in an ether type solvent as reaction medium (e.g. tetrahydrofurane, dimethyl ether, diisopropyl ether etc.). One may work preferably in tetrahydrofurane as medium.
- Reduction can be carried out under heating, advantageously at the boiling point of the reaction mixture. The reaction is complete within some hours, the preferred reaction time being 1-3 hours.
- the product can be isolated from the reaction mixture by extraction with an organic solvent (preferably ethyl acetate), drying and evaporating the extract.
- an organic solvent preferably ethyl acetate
- the crude product of the Formula I obtained after reduction is of high purity, the contamination content determined by HPLC being below 1 %.
- the compound of the Formula I can be converted, if desired, into a pharmaceutically acceptable salt by known methods.
- inorganic acids e.g. hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid
- organic acids e.g. acetic acid, tartaric acid, succinic acid, lactic acid, malic acid, maleic acid, fumaric acid etc.
- the fumarate can be formed in a known manner by adding to the solution of the base of the Formula I and a suitable inert organic solvent a solution of fumaric acid formed with a suitable organic solvent. It is preferred to dissolve the base of the Formula I and fumaric acid in the same solvent.
- reaction medium preferably lower alkanols, particularly ethanol can be used.
- Example 1 Further details of the present invention are to be found in the Examples, without limiting the scope of protection to said Examples.
- Example 1
- the mixture is heated to boiling for an hour, whereupon it is cooled to 25°C and a solution of 14.0 g (0.12 mole) of 2-chloro-N,N-dimethyl- -acetamide and 50 ml of anhydrous tetrahydrofurane is added.
- the reaction mixture is stirred at 25°C for half an hour, whereupon 250 ml of water are added.
- the product is extracted with ethyl acetate, filtered over silica and evaporated. The residue is crystallized from a 4:1 mixture of hexane and ethyl acetate.
- reaction mixture is heated to boiling for 3 hours, cooled to 25°C, at this temperature 40 ml of a saturated ammonium chloride solution are added, the mixture is stirred at 40-50°C for 5 hours and the reaction mixture is made alkaline to pH 10.
- the product is extracted with ethyl acetate, the extract is dried and evaporated to dryness in vacuo. Salt formation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU31823/00A AU3182300A (en) | 1999-02-24 | 2000-02-23 | Process for the preparation of (1r, 2s, 4r) -(-) -2 - (2 -dimethylaminoethoxy) -2 -phenyl -1,7,7 - trimethylbicyclo (2.2.1) heptane |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HUP9900445 | 1999-02-24 | ||
HU9900445A HUP9900445A2 (hu) | 1999-02-24 | 1999-02-24 | Eljárás (1R,2S,4R)-(-)-N,N-(dimetilamino-etoxi)-2-fenil-1,7,7-trimetil-biciklo[2.2.1]heptán előállítására és ennek köztiterméke |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000050379A1 true WO2000050379A1 (fr) | 2000-08-31 |
Family
ID=89997834
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/HU2000/000014 WO2000050379A1 (fr) | 1999-02-24 | 2000-02-23 | Procede de preparation de (1r, 2s, 4r) -(-) -2 - (2 -dimethylaminoethoxy) -2 -phenyl -1,7,7 - trimethylbicyclo [2.2.1] heptane |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU3182300A (fr) |
HU (1) | HUP9900445A2 (fr) |
WO (1) | WO2000050379A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1052245A2 (fr) * | 1999-05-11 | 2000-11-15 | Egis Gyogyszergyar Rt. | (1R, 2S, 4R)-(-)-2-[(2'-(N,N-dimethylamino)-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane à haute pureté, ses sels d'addition d'acides pharmaceutiquement acceptables, leur procédé de préparation et médicaments les contenant |
JP2010501589A (ja) * | 2006-08-24 | 2010-01-21 | ブリストル−マイヤーズ スクイブ カンパニー | 環状11−βヒドロキシステロイドデヒドロゲナーゼI型阻害剤 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4342762A (en) * | 1979-12-14 | 1982-08-03 | Egyt Gyogyszervegyeszeti Gyar | Basic ethers and pharmaceutical compositions containing the same |
-
1999
- 1999-02-24 HU HU9900445A patent/HUP9900445A2/hu unknown
-
2000
- 2000-02-23 AU AU31823/00A patent/AU3182300A/en not_active Abandoned
- 2000-02-23 WO PCT/HU2000/000014 patent/WO2000050379A1/fr active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4342762A (en) * | 1979-12-14 | 1982-08-03 | Egyt Gyogyszervegyeszeti Gyar | Basic ethers and pharmaceutical compositions containing the same |
Non-Patent Citations (1)
Title |
---|
DATABASE WPI Section Ch Week 199302, Derwent World Patents Index; Class B05, AN 1993-011166, XP002142099 * |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1052245A2 (fr) * | 1999-05-11 | 2000-11-15 | Egis Gyogyszergyar Rt. | (1R, 2S, 4R)-(-)-2-[(2'-(N,N-dimethylamino)-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane à haute pureté, ses sels d'addition d'acides pharmaceutiquement acceptables, leur procédé de préparation et médicaments les contenant |
WO2000068183A2 (fr) * | 1999-05-11 | 2000-11-16 | EGIS Gyógyszergyár Rt. | (1r,2s,4r)-(-)-2- [(2'-{n,n-dimethylamino} -ethoxy)] -2-[phenyle] -1,7,7-tri-[methyle]-bicyclo [2.2.1]heptane de grande purete et sels d'addition acides pharmaceutiquement acceptables de ceux-ci et processus de preparation de ces composes ainsi que de medicaments contenant un ou plusieurs de ces composes et leur utilisation |
FR2793489A1 (fr) * | 1999-05-11 | 2000-11-17 | Egyt Gyogyszervegyeszeti Gyar | (1r,2s,4r)-(-)-2-[(2'-{n,n-dimethylamino}-ethoxy)]-2- [phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]-heptane, ses sels d'addition et procede de preparation |
EP1052245A3 (fr) * | 1999-05-11 | 2001-02-28 | Egis Gyogyszergyar Rt. | (1R, 2S, 4R)-(-)-2-[(2'-(N,N-dimethylamino)-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane à haute pureté, ses sels d'addition d'acides pharmaceutiquement acceptables, leur procédé de préparation et médicaments les contenant |
WO2000068183A3 (fr) * | 1999-05-11 | 2001-07-26 | Egyt Gyogyszervegyeszeti Gyar | (1r,2s,4r)-(-)-2- [(2'-{n,n-dimethylamino} -ethoxy)] -2-[phenyle] -1,7,7-tri-[methyle]-bicyclo [2.2.1]heptane de grande purete et sels d'addition acides pharmaceutiquement acceptables de ceux-ci et processus de preparation de ces composes ainsi que de medicaments contenant un ou plusieurs de ces composes et leur utilisation |
US6335469B1 (en) | 1999-05-11 | 2002-01-01 | Orion Corporation | High purity (1R,2S,4R)-(-)-2-[(2′-{N,N-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane and pharmaceutically acceptable acid addition salts thereof |
US6624201B2 (en) | 1999-05-11 | 2003-09-23 | Orion Corporation | High purity (1r,2s,4r)-(−)-2-[(2′-{n,n-dimethylamino}-ethoxy)]-2-[phenyl]-1,7,7 -tri-[methyl]-bicyclo [2.2.1]heptane and pharmaceutically acceptable acid addition salts thereof and a process for the preparation of these compounds as well as medicaments containing 1 or more of these compounds and their use |
JP2010501589A (ja) * | 2006-08-24 | 2010-01-21 | ブリストル−マイヤーズ スクイブ カンパニー | 環状11−βヒドロキシステロイドデヒドロゲナーゼI型阻害剤 |
JP2013173783A (ja) * | 2006-08-24 | 2013-09-05 | Bristol Myers Squibb Co | 環状11−βヒドロキシステロイドデヒドロゲナーゼI型阻害剤 |
Also Published As
Publication number | Publication date |
---|---|
HU9900445D0 (en) | 1999-04-28 |
AU3182300A (en) | 2000-09-14 |
HUP9900445A2 (hu) | 2001-06-28 |
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