SE501162C2 - Process for Preparation of N, N-Dimethylaminomethylaryl Compounds - Google Patents
Process for Preparation of N, N-Dimethylaminomethylaryl CompoundsInfo
- Publication number
- SE501162C2 SE501162C2 SE9002363A SE9002363A SE501162C2 SE 501162 C2 SE501162 C2 SE 501162C2 SE 9002363 A SE9002363 A SE 9002363A SE 9002363 A SE9002363 A SE 9002363A SE 501162 C2 SE501162 C2 SE 501162C2
- Authority
- SE
- Sweden
- Prior art keywords
- formula
- group
- dimethylamine
- mmol
- compound
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 18
- 150000001875 compounds Chemical class 0.000 title claims description 13
- 238000002360 preparation method Methods 0.000 title claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 title claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 32
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims abstract description 29
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 4
- UCBFBQXXPWLTSZ-UHFFFAOYSA-O dimethyl-[1-(methylamino)ethylidene]azanium Chemical class CNC(C)=[N+](C)C UCBFBQXXPWLTSZ-UHFFFAOYSA-O 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 1
- UXKUODQYLDZXDL-UHFFFAOYSA-N fulminic acid Chemical compound [O-][N+]#C UXKUODQYLDZXDL-UHFFFAOYSA-N 0.000 claims 1
- 125000002541 furyl group Chemical group 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 125000004076 pyridyl group Chemical group 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 2
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 abstract 1
- 235000019256 formaldehyde Nutrition 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 9
- 229960000620 ranitidine Drugs 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- -1 aziridine compound Chemical class 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- YECZTTHHUYWDCA-UHFFFAOYSA-N dimethyl-[1-(methylamino)ethylidene]azanium;chloride Chemical compound [Cl-].CNC(C)=[N+](C)C YECZTTHHUYWDCA-UHFFFAOYSA-N 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 3
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 150000003573 thiols Chemical class 0.000 description 3
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- OTXQUGSUXRBUTC-UHFFFAOYSA-N butan-1-ol;toluene Chemical compound CCCCO.CC1=CC=CC=C1 OTXQUGSUXRBUTC-UHFFFAOYSA-N 0.000 description 2
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- MBYQPPXEXWRMQC-UHFFFAOYSA-N (2-chlorophenyl)methanol Chemical compound OCC1=CC=CC=C1Cl MBYQPPXEXWRMQC-UHFFFAOYSA-N 0.000 description 1
- MVQVNTPHUGQQHK-UHFFFAOYSA-N 3-pyridinemethanol Chemical compound OCC1=CC=CN=C1 MVQVNTPHUGQQHK-UHFFFAOYSA-N 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- XKNAIPOKZKWCES-UHFFFAOYSA-N C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.CN(C)CC=1C=NC=CC1 Chemical compound C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.CN(C)CC=1C=NC=CC1 XKNAIPOKZKWCES-UHFFFAOYSA-N 0.000 description 1
- QADXZTLKPDLXFA-UHFFFAOYSA-N C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.CN(C)CC=1OC(=CC1)CN(C)C Chemical compound C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.C1([N+](=O)[O-])=CC([N+](=O)[O-])=CC([N+](=O)[O-])=C1O.CN(C)CC=1OC(=CC1)CN(C)C QADXZTLKPDLXFA-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- BQRQOLQFLNSWNV-UHFFFAOYSA-N [5-[(dimethylamino)methyl]furan-2-yl]methanol Chemical compound CN(C)CC1=CC=C(CO)O1 BQRQOLQFLNSWNV-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004821 distillation 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
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- QSJNAFJALFWFMT-UHFFFAOYSA-N meridine Chemical compound N1C=CC(=O)C2=C1C(=O)C1=NC=CC3=C(C=CC=C4)C4=NC2=C13 QSJNAFJALFWFMT-UHFFFAOYSA-N 0.000 description 1
- 150000003956 methylamines Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 231100000219 mutagenic Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- UGSSAVQQESETEY-UHFFFAOYSA-N n,n-dimethyl-1-phenylethanamine;2,4,6-trinitrophenol Chemical compound CN(C)C(C)C1=CC=CC=C1.OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O UGSSAVQQESETEY-UHFFFAOYSA-N 0.000 description 1
- SLZCOYDOFRTTHF-UHFFFAOYSA-N n,n-dimethyl-1-pyridin-3-ylmethanamine Chemical compound CN(C)CC1=CC=CN=C1 SLZCOYDOFRTTHF-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 238000006053 organic reaction Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- DFWRZHZPJJAJMX-UHFFFAOYSA-N propanimidamide;hydrochloride Chemical compound Cl.CCC(N)=N DFWRZHZPJJAJMX-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- SHNUBALDGXWUJI-UHFFFAOYSA-N pyridin-2-ylmethanol Chemical compound OCC1=CC=CC=N1 SHNUBALDGXWUJI-UHFFFAOYSA-N 0.000 description 1
- GGWBHVILAJZWKJ-KJEVSKRMSA-N ranitidine hydrochloride Chemical compound [H+].[Cl-].[O-][N+](=O)\C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 GGWBHVILAJZWKJ-KJEVSKRMSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/14—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups
- C07C209/16—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of hydroxy groups or of etherified or esterified hydroxy groups with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Furan Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
35 501 162 del. Ett välkänt läkemedel som tillhör denna grupp föreningar är ranitidin, som är ett viktigt medel mot ulcera (magsår och tolvfingertarmsàr) och har formeln CHNO2 (CHa)2NCH2 \<å-Éy/CH2scH=cnzunänncn, IV o En rad förfaranden för framställning av föreningar med den allmänna formeln I genom omvandling av alkoholer till di- se t ex Houben-Weyl, Methoden der orga- 108-235 och ibid. VI/16 (1984), (1985), metylaminer är kända, nischem Chemie, XI/1 (1957); 914-916 (Alkohole III); J. 366, 471; Organic Reactions 29 (1983), JACS 87 (1965), 5261, S.-I) March. Adv. Orgn. Chem. 35 501 162 del. A well-known drug belonging to this group of compounds is ranitidine, which is an important anti-ulcer (gastric ulcer and duodenal ulcer) and has the formula CHNO2 (CH2) 2NCH2 \ <å-Éy / CH2scH = cnzunänncn, IV o with the general formula I by converting alcohols to these, for example, Houben-Weyl, Methoden der orga- 108-235 and ibid. VI / 16 (1984), (1985), methylamines are known, Nischem Chemie, XI / 1 (1957); 914-916 (Alcohols III); J. 366, 471; Organic Reactions 29 (1983), JACS 87 (1965), 5261, S.-I) March. Adv. Orgn. Chem.
Tanigawa et al, Tetrahedron Letters (1975), 1-162; E.H. White et al., 3:e uppl.; Y. samt referenser däri.Tanigawa et al., Tetrahedron Letters (1975), 1-162; E.H. White et al., 3rd ed .; Y. and references therein.
Alla dessa förfaranden är antingen flerstegsreaktioner med isolering av mellanprodukter eller kräver användning av svårtillgängliga reagens, en katalysator och/eller sker under extrema betingelser, t ex hög temperatur eller starkt sur mil- Jo.All of these processes are either multi-step reactions with the isolation of intermediates or require the use of hard-to-reach reagents, a catalyst and / or take place under extreme conditions, eg high temperature or strongly acidic environments.
I den danska patentskriften 148 258 (GB 1 565 966) be- skrives olika analogiförfaranden för framställning av raniti- din. I dessa förfaranden användes lättillgängliga råmaterial men en rad reaktionssteg och besvärliga reningsförlopp ford- ras.Danish patent specification 148 258 (GB 1 565 966) describes various analogous processes for the preparation of ranitidine. In these processes, readily available raw materials are used, but a number of reaction steps and difficult purification processes are required.
I den amerikanska patentskriften 4 497 961 beskrives framställning av ranitidin genom omsättning av en tiol med (ca3)2N\\v,1í;§1\v,,SH v formeln V med ett alkyleringsmedel med den allmänna formeln VI CHNOZ Lcnzcnznfl-CNHCH3 vr 10 15 20 25 30 35 501 162 vari L är en avspjälkbar grupp, företrädesvis en halogenatoms Eftersom utbytena, baserat pa tiolen V, är av storleksordning- en 20-30 %, kommer det totala utbytet baserat pà lättillgäng- liga furanderivat att vara mycket làgt.U.S. Patent No. 4,497,961 discloses the preparation of ranitidine by reacting a thiol of (ca3) 2N \\ v, 1i; §1 \ v ,, SH v formula V with an alkylating agent of the general formula VI CHNOZ Lcnzcnzn CN-CNHCH3 Wherein L is a leaving group, preferably a halogen atom. Since the yields, based on thiol V, are of the order of 20-30%, the total yield based on readily available furan derivatives will be very low. .
I den amerikanska patentskriften 4 440 938 beskrives framställning av ranitidin genom omsättning av tioler V med en aziridinförening (etyleniminförening) med formeln VIII: N02 Å \\ t:N NHCH= och i den brittiska patentskriften 2 075 980 beskrives fram- VIII ställning av ranitidin genom omsättning av V med VIII eller av besläktade föreningar, vari kväveatomen i V och VIII, varvid metylgrupperna är bundna, är substituerad pà annat sätt. I den brittiska patentskriften uppges att höga utbyten erhalles fràn reaktionen, nämligen normalt över 80 % i detta sistnämnda reaktionssteg för framställning av ranitidin. Även om det uppges att de tva utgàngsmaterialen kan ut- vinnas med skäligt goda utbyten är detta förfarande ej lämpat för teknisk användning eftersom aziridin VIII användes däri.U.S. Patent 4,440,938 discloses the preparation of ranitidine by reacting thiols V with an aziridine compound (ethyleneimine compound) of the formula VIII: NO 2 Å \\ t: N NHCH = and British Patent 2,075,980 discloses the preparation of ranitidine by reacting V with VIII or of related compounds, wherein the nitrogen atom of V and VIII, to which the methyl groups are attached, is substituted in another way. The British patent states that high yields are obtained from the reaction, namely normally over 80% in this latter reaction step for the production of ranitidine. Although it is stated that the two starting materials can be recovered in reasonably good yields, this process is not suitable for technical use because aziridine VIII was used therein.
Aziridiner är i allmänhet starkt giftiga, mycket reaktiva sub- stanser som till och med i laga koncentrationer är mutagent och karcinogent aktiva. Teknisk framställning och användning av sådana föreningar skulle vara synnerligen betänkligt och kräva dyrbara säkerhets- och kontrollàtgärder.Aziridines are generally highly toxic, highly reactive substances that are mutagenic and carcinogenically active even at low concentrations. The technical manufacture and use of such compounds would be of great concern and would require costly safety and control measures.
Ett förbättrat förfarande för framställning av ranitidin beskrives i den danska utläggningsskriften 153 758 (EP 219 225). Detta förfarande består däruti att man omsätter N-E2-EE(5-(hydroximetyl)-2-furanyl]-metylJ-tio]-etyl]-N'-metyl -2-nitro-1,1-etendiamin med formeln IX CHNO2 Il Hocnz Wcuzscnzcfiznflcnncn, Ix O 10 15 20 25 30 35 501 162 i ett organiskt lösningsmedel med dimetylamin och en (N,N-di- metylamino)-trifenylfosfoniumhalogenid med formeln X 3P*N2, nal" x vari Hal betecknar brom eller klor.An improved process for the preparation of ranitidine is described in Danish Offenlegungsschrift 153 758 (EP 219 225). This process consists in reacting N-E2-EE (5- (hydroxymethyl) -2-furanyl] -methyl-thio] -ethyl] -N'-methyl-2-nitro-1,1-ethylenediamine of the formula IX CHNO2 Il Hocnz Wcuzscnzc fi zn am cnncn, Ix O 10 15 20 25 30 35 501 162 in an organic solvent with dimethylamine and an (N, N-dimethylamino) -triphenylphosphonium halide of the formula X
Detta förfarande uppvisar emellertid den olägenheten att utgàngsmaterialet trifenylfosfin är dyrbart och eftersom det har hög molekylvikt är priset per mol av detta hjälpämne en belastning för slutproduktens pris.However, this process has the disadvantage that the starting material triphenylphosphine is expensive and since it has a high molecular weight, the price per mole of this excipient is a burden on the price of the final product.
Syftet med uppfinningen är följaktligen tillhandahållan- de av ett förfarande för framställning av de angivna förening- arna med den allmänna formeln I, varigenom man kan omvandla arylmetanoler till motsvarande N,N-dimetylaminometylderivat med formeln I utgående fràn billiga ramaterial, under milda betingelser, nämligen vid svagt basiskt pH-värde, och med goda utbyten (56-88 % isolerad förening), vilket förfarande skulle lämpa sig väl för framställning av ranitidin och övriga före- ningar med formel I i teknisk skala.Accordingly, the object of the invention is to provide a process for the preparation of the indicated compounds of the general formula I, whereby one can convert aryl methanol to the corresponding N, N-dimethylaminomethyl derivative of the formula I starting from inexpensive raw materials, under mild conditions, namely at weakly basic pH, and with good yields (56-88% isolated compound), which procedure would be well suited for the preparation of ranitidine and other compounds of formula I on a technical scale.
Detta syfte uppnås med förfarandet enligt uppfinningen, som kännetecknas därav att man i dimetylformamid, sàsom lös- ningsmedel, omsätter en hydroximetylarylförening med den all- männa formeln R I Arcfioa 11 vari R och Ar har ovan angivna betydelser, med dimetylamin och ett tetrametylformamidiniumsalt med formeln NMe + / 2 x HC \\ NMG2 vari X betecknar en anjon, t ex klor, brom eller tosyl, varef- ter den bildade föreningen eventuellt omvandlas till ett salt därav. 10 15 20 25 30 35 501 162 Enligt uppfinningen hàlles reaktionstemperaturen före- trädesvis vid 80-130°C, och speciellt 90-110°C. Likaledes är det enligt uppfinningen lämpligt att dimetylamin användes i en mängd av 2 mol eller mer för varje mol hydroximetylarylföre- ning II och tetrametylformamidiniumsaltet III i en mängd av 1 mol eller mer för varje mol hydroximetylarylförening II.This object is achieved by the process according to the invention, which is characterized in that dimethylformamide, as solvent, is reacted with a hydroxymethylaryl compound of the general formula RI Arc 2 and 11 wherein R and Ar have the meanings given above, with dimethylamine and a tetramethylformamide NMe salt with the formula + / 2 x HC \\ NMG2 wherein X represents an anion, eg chlorine, bromine or tosyl, after which the compound formed is optionally converted to a salt thereof. According to the invention, the reaction temperature is preferably maintained at 80-130 ° C, and especially 90-110 ° C. Likewise, it is suitable according to the invention that dimethylamine is used in an amount of 2 moles or more for each mole of hydroxymethylaryl compound II and the tetramethylformamidinium salt III in an amount of 1 mole or more for each mole of hydroxymethylaryl compound II.
En speciell fördel med föreliggande förfarande är att det är specifikt i så màtto att eventuellt närvarande mättade alifatiska alkoholer icke kommer att substitueras.A particular advantage of the present process is that it is specific in that any saturated aliphatic alcohols present will not be substituted.
Såsom salter av föreningarna med formeln I framställes lämpligen de konventionellt inom läkemedelsindustrin använda salterna med oorganiska och organiska syror, t ex hydroklori- der, hydrobromider, fosfat, sulfat, pikrat, tosylat eller ben- sensulfonat.As salts of the compounds of formula I, the salts conventionally used in the pharmaceutical industry are suitably prepared with inorganic and organic acids, for example hydrochlorides, hydrobromides, phosphate, sulphate, picrate, tosylate or benzenesulfonate.
Förfarandet enligt uppfinningen lämpar sig speciellt väl för framställning av ranitidin enligt reaktionsschemat + l N02 ïllMez / \ J' Hc-NMe cl' “o\,/lï;ï&\v/S\e/^\N NMe 2 H H No Me NH 2 -->* 7 \§ I om* "e 2"\/Lo \/S\/\1å :Me eller 3-(N,N-dimetylaminometyl)-pyridin enligt schemat CH OH CH NMG \“^f“+*w~e2 “I 22 “§N HC-NMe2Cl DMF \N I praktiken gar man lämpligen tillväga sålunda att alko- holen uppvärmes i en sluten behållare tillsammans med tetrame- tylformamidiniumsaltet, dimetylamin och dimetylformamid till 10 15 20 25 30 35 501 162 80-120°C i 8-64 timmar. Den bildade dimetylaminometylarylföre- ningen upparbetas därefter genom destillation och/eller genom utfällning i form av ett salt.The process according to the invention is particularly well suited for the preparation of ranitidine according to the reaction scheme + 1 NO 2 νll Mez / \ J 'Hc-NMe cl' 'o \, / lï; ï & \ v / S \ e / ^ \ N NMe 2 HH No Me NH 2 -> * 7 \ § I if * "e 2" \ / Lo \ / S \ / \ 1å: Me or 3- (N, N-dimethylaminomethyl) -pyridine according to the scheme CH OH CH NMG \ "^ f“ In practice, it is convenient to proceed so that the alcohol is heated in a closed container together with the tetramethylformamidinium salt, dimethylamine and dimethylformamide to 10 15 20 25 30 35 501 162 80-120 ° C for 8-64 hours. The dimethylaminomethylaryl compound formed is then worked up by distillation and / or by precipitation in the form of a salt.
Förfarandet enligt uppfinningen belyses närmare i det följande med hjälp av nàgra utföringsexempel. Däri visas också reaktionsscheman och i dessa betecknar Me metyl.The method according to the invention is further elucidated in the following by means of some embodiments. It also shows reaction schemes and in these Me denotes methyl.
A. Utgàngsmaterial Tetrametylformamidiniumklorid *NMQ2 ll MezNcÛcl + HCÛNME: -m---> HC-NMe2,Cl_ DMF l20°C, 18 h 83% Dimetylkarbamylklorid (108 g, löstes i dime- 40Û ml) 1,00 mol) tylformamid Efter avkylning till rumstemperatur avfiltrerades de bildade kristallerna, tvättades med DMF och torkades i vakuum vid 110°C. Härvid erhölls 113 g (83 %) Smp 143-14606. tetrametylformamidiniumklo- rid, såsom en vit produkt.A. Starting material Tetramethylformamidinium chloride * NMQ2 11 MezNcCl2 + HCUNME: -m ---> HC-NMe2, Cl_ DMF 120 ° C, 18 h 83% Dimethylcarbamyl chloride (108 g, dissolved in dimethyl- 40Û ml) 1.00 mol) cooling to room temperature, the crystals formed were filtered off, washed with DMF and dried in vacuo at 110 ° C. 113 g (83%) of mp 143-14606 were obtained. tetramethylformamidinium chloride, such as a white product.
Förfarande enliqt uppfinningen Exemgel 1 N.N-dimetvlbensvlamin + “Mez _ ®_cazon + nc-umerci ____> wcgznmez DMF, Me2NH 45 moi se mmol 11o°c,s4 h se: Bensylalkohol (4,86 g, 45 mmol) och tetrametylformamidi- värmdes vid 110°C i 64 timmar i en 200 mmol) och DMF niumklorid (9,3 g, 68 mmol) autoklav tillsammans med dimetylamin (9,0 g, (90 ml). med vatten (90 ml) och extraherades med hexan (2 x 200 ml). De Därefter avkyldes reaktionsblandningen och försattes 10 15 20 25 30 35 S01 162 förenade organiska extrakten tvättades med 25-procentig vat- tenhaltig natriumkloridlösning, torkades över natriumsulfat och indunstades till en olja. Oljan destillerades vid 740 mbar. Den fraktion som destillerades vid 166-170°C tillvara- togs och visade sig bestå av 5,34 g (88 X) N,N-dimetylbensyl- amin. Pärgiös olja nD2° 1,4s9s. HPLC indixerade ca se z ren- het.Process according to the invention Example 1 NN-dimethylbenzylamine + Mez - ®_cazon + nc-umerci ____> wcgznmez DMF, Me2NH 45 moi se mmol 110 ° C, s4 h se: Benzyl alcohol (4.86 g, 45 mmol) at 110 ° C for 64 hours in a 200 mmol) and DMF nium chloride (9.3 g, 68 mmol) autoclave together with dimethylamine (9.0 g, (90 ml) with water (90 ml) and extracted with hexane ( Then the reaction mixture was cooled and added to the combined organic extracts, washed with 25% aqueous sodium chloride solution, dried over sodium sulphate and evaporated to an oil, the oil was distilled at 740 mbar. which was distilled at 166-170 ° C was recovered and found to consist of 5.34 g (88 X) N, N-dimethylbenzylamine.Pergic oil nD2 ° 1.4s9s HPLC indexed approx.
Beräknat för C9H15N (MV 135,2): C 79,95 H 9,69 N 10,36 Funnet; c 00,44 H 10,06 N 10,011 Exemgel 2 2-klor-N.N-dimetvlbensylamin Cl + “eg _ Mezma Cl <::ï;_cu2oa + H -NMe2,c1 __ššš_; 0 cH2NMe2 86% Denna förening framställdes sàsom beskrivits i exempel 1 fràn 2-klorbensylalkohol i 86 % utbyte. Kp./16 mbar 94-98°C.Calculated for C 9 H 15 N (MV 135.2): C 79.95 H 9.69 N 10.36 Found; c 00.44 H 10.06 N 10.011 Example 2 2-chloro-N.N-dimethylbenzylamine Cl + “eg _ Mezma Cl <:: ï; _cu2oa + H -NMe2, c1 __ššš_; 0 cH 2 NMe 2 86% This compound was prepared as described in Example 1 from 2-chlorobenzyl alcohol in 86% yield. Bp./16 mbar 94-98 ° C.
Färgiös olja nD2° 1,5240.Colorful oil nD2 ° 1.5240.
Beräknat för C9H12ClN (MV 169,7): C 63,71 H 7,13 N 8,26 Funnet: C 64,87 H 7,39 N 7,91% Exemgel 3 N.N-dimetvl-1-fenvletvlamin + H Me H fß ïï 2 _ 1 f: @_cuoa + uc-Nmerci _____, Qcuumez DMF, Me2NH 40 mmoi ao mmm 11o°c,s4 h en (píkrat) 1-fenyletanol (4,88 g, 40 mmol) och tetrametylformamidi- 80 mmol) värmdes vid 110°C under 64 h i en 200 mmol) och DMF niumklorid (10,9 g, autoklav tillsammans med dimetylamin (9,0 g, (80 ml). Reaktionsblandningen avkyldes därefter, försattes med 12 N saltsyra till pH 2 och indunstades i vattenstràlevakuum. Återstoden försattes med 6 N natriumhydroxid (100 ml) och 10 15 20 25 30 35 501 162 extraherades därefter med hexan (2 x 200 ml). De förenade or- ganiska extrakten torkades över natriumsulfat och indunstades Den bildade återstoden löstes i etanol och försattes 32 mmol) Den bildade produk- därefter. med pikrinsyra (7,3 g, i etanol.Calculated for C 9 H 12 ClN (MV 169.7): C 63.71 H 7.13 N 8.26 Found: C 64.87 H 7.39 N 7.91% Example gel 3 NN-dimethyl-1-phenylethylamine + H Me H fß ïï 2 _ 1 f: @_cuoa + uc-Nmerci _____, Qcuumez DMF, Me2NH 40 mm ) was heated at 110 ° C for 64 h in 200 mmol) and DMF nium chloride (10.9 g, autoclave together with dimethylamine (9.0 g, (80 ml)) The reaction mixture was then cooled, added with 12 N hydrochloric acid to pH 2 and The residue was added with 6 N sodium hydroxide (100 ml) and then extracted with hexane (2 x 200 ml). The combined organic extracts were dried over sodium sulphate and evaporated. The residue formed was dissolved in ethanol and was added 32 mmol) The product formed - then with picric acid (7.3 g, in ethanol).
Härvid isolerades Smp 137,5- ten avfiltrerades, tvättades och torkades. 9,6 g (64 Z) N,N-dimetyl-1-fenyletylamin-pikrat. -139°C.The mp 137.5 was isolated, filtered off, washed and dried. 9.6 g (64 Z) N, N-dimethyl-1-phenylethylamine picrate. -139 ° C.
Beräknat för C15H18N4O7 (MV 378,3): C 50,79 H 4,79 N 14,81 Funnet: C 50,72 H 4,92 N 14,78%.Calculated for C 15 H 18 N 4 O 7 (MV 378.3): C 50.79 H 4.79 N 14.81 Found: C 50.72 H 4.92 N 14.78%.
Exemgel 4 3-(N,N-dimetvlaminometvl)-pvridin + / cazoa Mez _ / CflzNr-iez \ + flc-Nneycl -----§ l w omr, Mezua \N 30 mmoi so mmol 11o°c.64 h _83 (dipikratl 3-(hydroximetyl)-pyridin (3,27 g, 30 mmol) och tetrame- tylformamidiniumklorid (8,2 g, 60 mol) varmdes vid 110°C under 64 h i en autoklav tillsammans med dimetylamin (6,8 g, 150 mmol) och DMF (60 ml). Reaktionsblandningen kyldes därefter, försattes med 12 N saltsyra till pH 2 och indunstades i vat- tenstralevakuum. Återstoden försattes med 6 N natriumhydroxid (100 ml) och extraherades därefter med t-butylmetyleter (2 x 200 ml). De förenade organiska extrakten tvättades med en 20-procentig vattenhaltig natriumkloridlösning och indunstades därefter till 5 g olja. Oljan löstes i etanol och försattes Den bildade produk- med pikrinsyra (13,7 g, 60 mmol) i etanol. ten avfiltrerades, tvattades och torkades. Härvid isolerades 15,6 g (88 %) 3-(N,N-dimetylaminometyl)~pyridin-dipikrat. Smp 188,5-192°C.Example 4 3- (N, N-dimethylaminomethyl) -pvridine + / cazoa Mez _ / C fl zNr-iez \ + fl c-Nneycl ----- § lw omr, Mezua \ N 30 mmoi so mmol 11o ° c.64 h _83 (dipicratl 3- (hydroxymethyl) -pyridine (3.27 g, 30 mmol) and tetramethylformamidinium chloride (8.2 g, 60 mol) were heated at 110 ° C for 64 h in an autoclave together with dimethylamine (6.8 g, 150 mmol) and DMF (60 ml) The reaction mixture was then cooled, added with 12 N hydrochloric acid to pH 2 and evaporated in a water jet vacuum, the residue was added with 6 N sodium hydroxide (100 ml) and then extracted with t-butyl methyl ether (2 x 200 ml). The combined organic extracts were washed with a 20% aqueous sodium chloride solution and then evaporated to 5 g of oil, the oil was dissolved in ethanol and the product formed with picric acid (13.7 g, 60 mmol) in ethanol was filtered off. was washed and dried to isolate 15.6 g (88%) of 3- (N, N-dimethylaminomethyl) -pyridine dipicrate, mp 188.5-192 ° C.
Beräknat för C20H18N8O13 (MV 594,4): C 40,41 H 3,05 N 18,85 Funnet: C 40,36 H 3,11 N 18,782. 10 15 20 25 30 35 501 162 Exemgel 5 2-(N N-dimet laminomet 1)- ridin *rue - e Û + Hcl: Nå cl" ____Me2NH, / | *ur cflzoa 2' DMF *N cazuuez 74% (dipikrat) framställdes pà liknande sätt sàsom beskrivits i exempel 2 frán 2-(hydroximetyl)-pyridin i 74 Z utbyte. Dipikratet smälte vid 166-168°C.Calculated for C 20 H 18 N 8 O 13 (MW 594.4): C 40.41 H 3.05 N 18.85 Found: C 40.36 H 3.11 N 18.782. 10 15 20 25 30 35 501 162 Exemgel 5 2- (N N-dimet laminomet 1) - ridin * rue - e Û + Hcl: Nå cl "____Me2NH, / | * ur c fl zoa 2 'DMF * N cazuuez 74% (dipikrat ) was prepared in a similar manner to that described in Example 2 from 2- (hydroxymethyl) -pyridine in 74 Z yield, the dipicrate melting at 166-168 ° C.
Exemgel 8 2.5-bis-(N,N-dimetvlaminometvl)-furan + Me 2 Me NH _ 2 __ï>/,\ Me2N,^\lg;§>,^\0H + Hg_NMe2Cl ___š;;ñ Me2N/~\lgo\ NME2 9o°c,2o h 732 (dipikrat) 40 mmol 80 mmol 5-(dimetylaminometyl)-furfurylalkohol <6,20 g, 40 mmol> och tetrametylformamidiniumklorid (10,9 g, 80 mmol) värmdes vid 90°C i 20 h i en autoklav tillsammans med dimetylamin 9,0 g, 200 mmol) och DMF (80 ml). Därefter avkyldes reaktions- blandningen och försattes med 12 N saltsyra till pH 2 och in- dunstades i vattenstrálevakuum Till återstoden sattes 8 N natriumhydroxid (100 ml) och detta extraherades därefter med t-butylmetyleter (2 x 150 ml). De förenade organiska extrakten tvättades med 20-procentig vattenhaltig natriumkloridlösning, torkades över natriumsulfat och indunstades därefter. Den bil- dade återstoden löstes i etanol och pikrinsyra (16 g, 70 mmol) i etanol tillsattes. Den bildade produkten avfiltrerades, tvättades och torkades. Härvid isolerades 18,6 g (73 X) 2,5-bis-(N,N-dimetylaminometyl)-furan~dipikrat_ Smp 199- ~201,5°C. 10 15 20 25 30 35 10 501 162 Beräknat för C22H24N5O15 (MV 640,4>: C 41,26 H 3,77 N 17,50 Funnet: C 41,14 H 3,75 N 17,432.Example 8 2.5-bis- (N, N-dimethylaminomethyl) -furan + Me 2 Me NH _ 2 __ï> /, \ Me2N, ^ \ lg; §>, ^ \ 0H + Hg_NMe2Cl ___ š ;; ñ Me2N / ~ \ lgo NME 2 90 ° C, 20 h 732 (dipicrate) 40 mmol 80 mmol 5- (dimethylaminomethyl) -furfuryl alcohol <6.20 g, 40 mmol> and tetramethylformamidinium chloride (10.9 g, 80 mmol) were heated at 90 ° C for 20 h in an autoclave together with dimethylamine 9.0 g, 200 mmol) and DMF (80 ml). Then the reaction mixture was cooled and added with 12 N hydrochloric acid to pH 2 and evaporated in a water jet vacuum To the residue was added 8 N sodium hydroxide (100 ml) and this was then extracted with t-butyl methyl ether (2 x 150 ml). The combined organic extracts were washed with 20% aqueous sodium chloride solution, dried over sodium sulfate and then evaporated. The resulting residue was dissolved in ethanol and picric acid (16 g, 70 mmol) in ethanol was added. The product formed was filtered off, washed and dried. 18.6 g (73 X) of 2,5-bis- (N, N-dimethylaminomethyl) -furan dipicrate were found, m.p. 199- 201.5 ° C. Calculated for C 22 H 24 N 5 O 15 (MV 640.4>: C 41.26 H 3.77 N 17.50 Found: C 41.14 H 3.75 N 17.432.
Exemgel 7 N-E2-EC(5-E etvl]-N'-metvl-2-nitro-1.1-etendiamin-HCl Cranitidin-HCI) NO I *wmez NHMQ + HC“NMe2,Cl_ 20 mmol 60 mmol NO 2 NHM ,HCl > Me2N 0 S/^\v/H 9 ._EMF__ 90°C,16 h 56% N-(2-CI(5-(hydroximetyl)-2-furanyl]-metyl]-tio]-etyl3- N'-metyl-2~nitro-1,1-etendiamin (5,74 g, 20 mmol) och tetrame- 60 mmol) värmdes under 16 h vid 130 mmol) tylformamidiniumklorid (8,2 g, 90°C i en autoklav tillsammans med dimetylamin (6 g, och DMF (60 ml). Därefter indunstades reaktionsblandningen i vattenstralevakuum och aterstoden löstes i en blandning av 20-procentig vattenhaltig natriumklorid (60 ml) och 1-butanol- -toluen (1:1; 90 ml). Efter justering av pH till 3,5 med 4 N saltsyra separerades faserna. Vattenfasen reglerades till pH 9,5 med 11 N natriumhydroxid och extraherades med 1-butanol~ -toluen (1:1; 2 x 90 ml).Example 7 N-E2-EC (5-E ethyl] -N'-methyl-2-nitro-1,1-ethenediamine-HCl Cranitidine-HCl) NO I * wmez NHMQ + HC „NMe2, Cl_ 20 mmol 60 mmol NO 2 NHM 90 ° C, 16 h 56% N- (2-Cl (5- (hydroxymethyl) -2-furanyl] -methyl] -thio] -ethyl-3-N Methyl-2-nitro-1,1-ethenediamine (5.74 g, 20 mmol) and tetramamine (60 mmol) were heated for 16 h at 130 mmol) of ethyl formamidinium chloride (8.2 g, 90 ° C in an autoclave together with dimethylamine (6 g, and DMF (60 ml), then the reaction mixture was evaporated in a water jet vacuum and the residue was dissolved in a mixture of 20% aqueous sodium chloride (60 ml) and 1-butanol-toluene (1: 1; 90 ml). After adjusting the pH to 3.5 with 4 N hydrochloric acid, the phases were separated, the aqueous phase was adjusted to pH 9.5 with 11 N sodium hydroxide and extracted with 1-butanol-toluene (1: 1; 2 x 90 ml).
De kombinerade organiska extrakten indunstades i vatten- stràlevakuum och löstes i 2-propanol. Denna lösning filtrera- des långsamt genom ett kiselgelskikt (20 g). Filterskiktet ef- tersköljdes med 2-propanol. Filtratet indunstades till ca 50 ml och försattes därefter med 8 N saltsyra till pH 4,5. Den bildade bottenfällningen frànfiltrerades vid 10°C och tvätta- 11 501 162 des med 2-propanol. Torkning gav 3,9 g (56 %) ranitidin-HCl såsom en beigefärgad produkt med smp 135-137°C.The combined organic extracts were evaporated in a water jet vacuum and dissolved in 2-propanol. This solution was slowly filtered through a pad of silica gel (20 g). The filter layer was rinsed with 2-propanol. The filtrate was evaporated to about 50 ml and then added with 8 N hydrochloric acid to pH 4.5. The precipitate formed was filtered off at 10 ° C and washed with 2-propanol. Drying gave 3.9 g (56%) of ranitidine-HCl as a beige product, mp 135-137 ° C.
Beräknat för C13H22N403S,HC1 (MV 350,9): C 44,50 H 6,61 N 15,97 Funnet: C 44,35 H 6,35 N 15,812.Calculated for C 13 H 22 N 4 O 3 S, HCl (MV 350.9): C 44.50 H 6.61 N 15.97 Found: C 44.35 H 6.35 N 15.812.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK340089A DK161513C (en) | 1989-07-10 | 1989-07-10 | PROCEDURE FOR THE PREPARATION OF N, N-DIMETHYLAMINOMETHYLARYL COMPOUNDS |
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| AT (1) | AT398565B (en) |
| DD (1) | DD296481A5 (en) |
| DE (1) | DE4020964A1 (en) |
| DK (1) | DK161513C (en) |
| FI (1) | FI102166B (en) |
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1989
- 1989-07-10 DK DK340089A patent/DK161513C/en not_active IP Right Cessation
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1990
- 1990-06-20 AT AT131390A patent/AT398565B/en not_active IP Right Cessation
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- 1990-07-05 SE SE9002363A patent/SE501162C2/en unknown
- 1990-07-09 FI FI903457A patent/FI102166B/en not_active IP Right Cessation
- 1990-07-09 DD DD34263490A patent/DD296481A5/en not_active IP Right Cessation
- 1990-07-09 HU HU414390A patent/HU206076B/en not_active IP Right Cessation
- 1990-07-09 NO NO903062A patent/NO170578C/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK340089A (en) | 1991-01-11 |
| DD296481A5 (en) | 1991-12-05 |
| NO170578C (en) | 1992-11-04 |
| NO903062D0 (en) | 1990-07-09 |
| HUT54615A (en) | 1991-03-28 |
| FI102166B1 (en) | 1998-10-30 |
| SE9002363D0 (en) | 1990-07-05 |
| DK340089D0 (en) | 1989-07-10 |
| DE4020964A1 (en) | 1991-01-17 |
| HU206076B (en) | 1992-08-28 |
| FI903457A0 (en) | 1990-07-09 |
| ATA131390A (en) | 1994-05-15 |
| SE9002363L (en) | 1991-01-11 |
| NO170578B (en) | 1992-07-27 |
| DK161513C (en) | 1991-12-23 |
| NO903062L (en) | 1991-01-11 |
| FI102166B (en) | 1998-10-30 |
| HU904143D0 (en) | 1990-12-28 |
| AT398565B (en) | 1994-12-27 |
| DK161513B (en) | 1991-07-15 |
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