US2398283A - Bisureas - Google Patents
Bisureas Download PDFInfo
- Publication number
- US2398283A US2398283A US505037A US50503743A US2398283A US 2398283 A US2398283 A US 2398283A US 505037 A US505037 A US 505037A US 50503743 A US50503743 A US 50503743A US 2398283 A US2398283 A US 2398283A
- Authority
- US
- United States
- Prior art keywords
- parts
- bis
- diamine
- solution
- dicarboxylic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 79
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical class [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- 239000000243 solution Substances 0.000 description 35
- -1 heterocyclic secondary amine Chemical class 0.000 description 23
- 229910000027 potassium carbonate Inorganic materials 0.000 description 19
- 229940093956 potassium carbonate Drugs 0.000 description 19
- 235000011181 potassium carbonates Nutrition 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 16
- 125000000217 alkyl group Chemical group 0.000 description 15
- 150000004985 diamines Chemical class 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000004202 carbamide Substances 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 11
- 238000000034 method Methods 0.000 description 11
- 239000007858 starting material Substances 0.000 description 11
- 125000003545 alkoxy group Chemical group 0.000 description 10
- 229920006395 saturated elastomer Polymers 0.000 description 10
- 125000005265 dialkylamine group Chemical group 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 150000003335 secondary amines Chemical class 0.000 description 9
- UZBQIPPOMKBLAS-UHFFFAOYSA-N diethylazanide Chemical compound CC[N-]CC UZBQIPPOMKBLAS-UHFFFAOYSA-N 0.000 description 8
- 230000003993 interaction Effects 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 7
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 7
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- OFCCYDUUBNUJIB-UHFFFAOYSA-N n,n-diethylcarbamoyl chloride Chemical compound CCN(CC)C(Cl)=O OFCCYDUUBNUJIB-UHFFFAOYSA-N 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 4
- VGEMYWDUTPQWBN-UHFFFAOYSA-N n-ethyl-2-methoxyethanamine Chemical compound CCNCCOC VGEMYWDUTPQWBN-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- KJFMBFZCATUALV-UHFFFAOYSA-N phenolphthalein Chemical compound C1=CC(O)=CC=C1C1(C=2C=CC(O)=CC=2)C2=CC=CC=C2C(=O)O1 KJFMBFZCATUALV-UHFFFAOYSA-N 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 4
- DEWLEGDTCGBNGU-UHFFFAOYSA-N 1,3-dichloropropan-2-ol Chemical compound ClCC(O)CCl DEWLEGDTCGBNGU-UHFFFAOYSA-N 0.000 description 3
- KOHBEDRJXKOYHL-UHFFFAOYSA-N 2-methoxy-n-methylethanamine Chemical compound CNCCOC KOHBEDRJXKOYHL-UHFFFAOYSA-N 0.000 description 3
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- XMWFMEYDRNJSOO-UHFFFAOYSA-N morpholine-4-carbonyl chloride Chemical compound ClC(=O)N1CCOCC1 XMWFMEYDRNJSOO-UHFFFAOYSA-N 0.000 description 3
- DBDNQNARCHWMSP-UHFFFAOYSA-N n-(2-chloroethyl)-n-ethylaniline Chemical compound ClCCN(CC)C1=CC=CC=C1 DBDNQNARCHWMSP-UHFFFAOYSA-N 0.000 description 3
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- HDWAEDOMCNQUSW-UHFFFAOYSA-N 2-ethoxy-n-ethylethanamine Chemical compound CCNCCOCC HDWAEDOMCNQUSW-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- OJGMBLNIHDZDGS-UHFFFAOYSA-N N-Ethylaniline Chemical compound CCNC1=CC=CC=C1 OJGMBLNIHDZDGS-UHFFFAOYSA-N 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- JQVDAXLFBXTEQA-UHFFFAOYSA-N dibutylamine Chemical compound CCCCNCCCC JQVDAXLFBXTEQA-UHFFFAOYSA-N 0.000 description 2
- IUNMPGNGSSIWFP-UHFFFAOYSA-N dimethylaminopropylamine Chemical compound CN(C)CCCN IUNMPGNGSSIWFP-UHFFFAOYSA-N 0.000 description 2
- QKIUAMUSENSFQQ-UHFFFAOYSA-N dimethylazanide Chemical compound C[N-]C QKIUAMUSENSFQQ-UHFFFAOYSA-N 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- LIWAQLJGPBVORC-UHFFFAOYSA-N ethylmethylamine Chemical compound CCNC LIWAQLJGPBVORC-UHFFFAOYSA-N 0.000 description 2
- 125000001841 imino group Chemical group [H]N=* 0.000 description 2
- BIFDXOOJPDHKJH-UHFFFAOYSA-N piperidine-1-carbonyl chloride Chemical compound ClC(=O)N1CCCCC1 BIFDXOOJPDHKJH-UHFFFAOYSA-N 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 239000003169 respiratory stimulant agent Substances 0.000 description 2
- 229940066293 respiratory stimulants Drugs 0.000 description 2
- 229910001923 silver oxide Inorganic materials 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- SGRHVVLXEBNBDV-UHFFFAOYSA-N 1,6-dibromohexane Chemical compound BrCCCCCCBr SGRHVVLXEBNBDV-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- RRQHLOZQFPWDCA-UHFFFAOYSA-N 1-n,1-n-dimethylpropane-1,2-diamine Chemical compound CC(N)CN(C)C RRQHLOZQFPWDCA-UHFFFAOYSA-N 0.000 description 1
- QWEJWXUAXUMVFU-UHFFFAOYSA-N 2-ethoxy-n-methylethanamine Chemical compound CCOCCNC QWEJWXUAXUMVFU-UHFFFAOYSA-N 0.000 description 1
- WPYUCWSMVJJWFI-UHFFFAOYSA-N 2-ethoxyacetonitrile Chemical compound CCOCC#N WPYUCWSMVJJWFI-UHFFFAOYSA-N 0.000 description 1
- IBZKBSXREAQDTO-UHFFFAOYSA-N 2-methoxy-n-(2-methoxyethyl)ethanamine Chemical compound COCCNCCOC IBZKBSXREAQDTO-UHFFFAOYSA-N 0.000 description 1
- WZTOGZXZQJFJNS-UHFFFAOYSA-N 2-methoxy-n-methylethanamine;hydrochloride Chemical compound Cl.CNCCOC WZTOGZXZQJFJNS-UHFFFAOYSA-N 0.000 description 1
- ROLMZTIHUMKEAI-UHFFFAOYSA-N 4,5-difluoro-2-hydroxybenzonitrile Chemical compound OC1=CC(F)=C(F)C=C1C#N ROLMZTIHUMKEAI-UHFFFAOYSA-N 0.000 description 1
- HOFGETLODCEHBQ-UHFFFAOYSA-N 4-methyl-n-[2-[(4-methylphenyl)sulfonylamino]ethyl]benzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NCCNS(=O)(=O)C1=CC=C(C)C=C1 HOFGETLODCEHBQ-UHFFFAOYSA-N 0.000 description 1
- ZMGMDXCADSRNCX-UHFFFAOYSA-N 5,6-dihydroxy-1,3-diazepan-2-one Chemical compound OC1CNC(=O)NCC1O ZMGMDXCADSRNCX-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- AFBPFSWMIHJQDM-UHFFFAOYSA-N N-methylaniline Chemical compound CNC1=CC=CC=C1 AFBPFSWMIHJQDM-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- KRALOLGXHLZTCW-UHFFFAOYSA-L calcium;2-acetyloxybenzoate Chemical group [Ca+2].CC(=O)OC1=CC=CC=C1C([O-])=O.CC(=O)OC1=CC=CC=C1C([O-])=O KRALOLGXHLZTCW-UHFFFAOYSA-L 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LJSQFQKUNVCTIA-UHFFFAOYSA-N diethyl sulfide Chemical compound CCSCC LJSQFQKUNVCTIA-UHFFFAOYSA-N 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- VBXOWLZYYQOXBQ-UHFFFAOYSA-N n,n',n'-triethylmethanediamine Chemical compound CCNCN(CC)CC VBXOWLZYYQOXBQ-UHFFFAOYSA-N 0.000 description 1
- UQUPIHHYKUEXQD-UHFFFAOYSA-N n,n′-dimethyl-1,3-propanediamine Chemical compound CNCCCNC UQUPIHHYKUEXQD-UHFFFAOYSA-N 0.000 description 1
- JYRMPDXSENSKDY-UHFFFAOYSA-N n-ethyl-n-(2-methoxyethyl)carbamoyl chloride Chemical compound CCN(C(Cl)=O)CCOC JYRMPDXSENSKDY-UHFFFAOYSA-N 0.000 description 1
- GVWISOJSERXQBM-UHFFFAOYSA-N n-methylpropan-1-amine Chemical compound CCCNC GVWISOJSERXQBM-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- CBPYOHALYYGNOE-UHFFFAOYSA-M potassium;3,5-dinitrobenzoate Chemical compound [K+].[O-]C(=O)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1 CBPYOHALYYGNOE-UHFFFAOYSA-M 0.000 description 1
- AOHJOMMDDJHIJH-UHFFFAOYSA-N propylenediamine Chemical compound CC(N)CN AOHJOMMDDJHIJH-UHFFFAOYSA-N 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- GRVFOGOEDUUMBP-UHFFFAOYSA-N sodium sulfide (anhydrous) Chemical compound [Na+].[Na+].[S-2] GRVFOGOEDUUMBP-UHFFFAOYSA-N 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- XFNJVJPLKCPIBV-UHFFFAOYSA-N trimethylenediamine Natural products NCCCN XFNJVJPLKCPIBV-UHFFFAOYSA-N 0.000 description 1
- 230000001457 vasomotor Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
- C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
- C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/04—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms
- C07C275/06—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
- C07C275/14—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
Definitions
- This invention relates to new bis-ureas which are useful as stimulants of the respiratory and vasomotor centres, having a low, ratio of active ject is to provide such compounds having a low ratio of active dose to toxic dose.
- a further object is to provide processes for the manufacture of the said bis-ureas. Still further objects will appear as the description proceeds.
- A stands for an alkylene chain of 2 to 6 carbon atoms which may be unsubstituted or may bear one or more alkyl, alkoxy or alkoxyalkyl substituents or for a group consisting of two such alkylene chains united by an ether sulphide (-S) or imino (-NH- or N.Alkyl) linkage.
- R and R which are not necessarily alike, stand for alkyl groups which jointly contain not more than 8 carbon atoms or for alkoxyalkyl groups which jointly contain not more than 12 carbon atoms.
- X and Y which also are not necessarily alike, each stands for the secondary amino group corresponding with'an amine XH which is a dialkylamine or heterocyclic secondary amine of molecular weight not exceeding 120, or which is of the form AlkOalk-NH-Alk and has a molecular weight not exceeding 160, or which is of the form (Alk-O-alk) zNH and has a molecular weight not exceeding 220, the terms Alk and alk representing an alkyl and an alkylene radical respectively.
- the new compounds can. be made by two main synthetic methods.
- the carbamyl chloride XCO-Cl (X, it must be remembered, is the radical of a secondary amino group as defined above and is used here as typical ofthe pair X
- the diamine is first combined with phosgene, forming the carbamyl chloride C1CONRA--NR'COC1 which is then caused to react with the secondary amine X-H.
- the reaction may be between one molecular proportion of the diamine and two molecular proportions each of, firstly phosgene, and secondly the; secondary amine, whereby a symmetrical bis-urea results; or alternatively it may be carried out in stages so as to obtain the unsymmetrical compounds.
- the diamine may be combined with one molecular proportion of phosgene, followed by one molecular proportion of the secondary amine X--H, whereby the mono-urea XCO--NR-A--NHR' is formed and this may then be combined with a further proportion of phosgene and then with one molecular proportion of a difierent secondary amine Y-H, whereby the unsymmetricalb'is-urea is produced.
- a definite molal quantity is specified for an amine or a di- .amine, it will be understood that this refers'to the quantity employed for actual condensation, exclusive of any additional quantity added to act as an acid-absorbing agent for HCl liberated in the process.
- the specified molal quantity of the amine or diamine is the minimal, theoretical quantity, to be exceeded in practice by a convenient excess for absorbing the HCl.
- the new compounds are made from the following starting materials. namely, diamines R-NHA-NI-I--R', carbamyl chlorides X-COC1 and the corresponding secondary amines X-H.
- diamines suitable for use in making the new compounds there may be mentioned, for example, N:N'-dimethylethylene diamine, N:N- diethylethylenediamine,N:N'-dimethyltrimeth ylene diamine, N-methyl-N'-ethylethylene diamine, N:N-di-n-propylethylene diamine, N:N'-di-nbutylethylene diamine, N:N'-dimethyl-tetramethylene diamine, N:N-dimethylhexamethylene diamine, N:N'-dimethyl-1:2-propylene diamine, N: N '-dimethyl-1 S-butylene diamine, N N -dimethyl-2-methoxy-trimethylene diamine, B: 3'-di(ethylamino) -diethyl ether, 49:8- di (ethylamino) -diethyl sulphide, ,ezpr-di (eth)
- Example 1 88 parts of diethylcarbamyl chloride dissolved in 120 parts of benzene are added with stirring to a solution of 53 parts of N:N'-dimethy1trimethylenediamine (obtainable from N:N'-dimethyl-N:N-diphenyltrimethylenediamine by the method described-in respect of N:N-climethylethylenediamine-Berichte der' astronom chemischen Deutschen für fürtechnik 1918, vol. 51, p. 738) in 450 parts of benzene.
- N:N'-dimethy1trimethylenediamine obtainable from N:N'-dimethyl-N:N-diphenyltrimethylenediamine by the method described-in respect of N:N-climethylethylenediamine-Berichte der' bmw chemischen Deutschentechnik 1918, vol. 51, p. 738
- N:N-dimethyltrimethylenediamine di- 40 hydrochloride which has M. P.
- N :N-diethylethylenediamine- N:N'-dicarboxylic bis-morpholide (M. P. 98 C.), which is a colourless crystalline solid readily soluble in water, ethanol and benzene and sparingly soluble in light petroleum.
- the morpholine-N-carboxylic chloride used in making this substance has B. P. 137-138 C. at 33 mm. pressure and is obtained by the action of phosgene on morpholine in accordance with the method described in respect of diethylamine in Bulletin de la Socit chimique de Paris, 104, 3rd series, vol. 31, p. 689.
- carboxylic-bis-morpholide (B. P. 229 C. at 0.4 mm. pressure, M. P. 41-42 0.).
- the N:N'-di-nbutylethylene-diamine required has B. P. 226 C., its dihydrochloride melts at 300 C. with decomposition and its di-p-toluene-sulphonyl derivative at 119 C. It is made in a manner analogous-to that used for making N:N'-di-n-propylethylenediamine.
- N:N. dimethyltetramethylene N:N'- dicarboxylic bis-diethylamide B. P. 216 C. at mm. pressure.
- the N:N'-dimethyltetramethylenediamine (B. P. 164 C., dihydrochloride M. P. 275 C.) required is made by condensing 1:4-dibromobutane with sodium p-toluenesulphonyl methylamide in xylene at 140 C. to give di-ptoluenesulphonyl- N: N-dimethyltetramethylene-. diamine of M. P. 129 C. which is hydrolysed in the usual manner.
- N N-dimethylhexamethylenediamine-N N'-dicarboxylic bis-dimethylamide (B. P. 238 C. at 17 mm. pressure). 1
- Example 2 21 parts of N:N-dimethylethylenediamine carbonate is suspended in 250 parts of dry chloroform and the solution is saturated with phosgene at room temperature. After it has stood for hours air is blown through the mixture to remove the excess of phosgene. The mixture is then filtered to remove N:N'-dimethylethylenediamine dihydrochloride and from the filtrate the chloroform is distilled, leaving a pale yellow, mobile somewhatlachrymatory liquid which is the biscarbamyl chloride. This is dissolved in 100 parts of ether. parts of diethylamine are added.
- Example 3 16 parts of N:N-dimethylethylenediamine dihydrochloride are dissolved in 150 parts of water, and sufilcient 32% aqueous caustic soda is then added to make the solution alkaline to phenolphthalein and the whole is cooled to 5 C. parts of dimethylcarbamyl chloride are now added with stirring and cooling at such a rate that the temperature does not exceed 20 C., more caustic soda being added as required to keep the solution just alkaline to phenolphthalein. After stirring for 6 hours sufilcient solid potassium carbonate is added to saturate the solution and the oil which separates out is dissolved up in 100 parts of benzene.
- N:N'-dimethylethylenediamine-N:N'-dicarboxylic bis-dimethylamide (B.P. 193 C. at 20 mm. pressure) is thus obtained. It is a colourless oil which gradually solidifies to a crystalline mass; it is miscible in all proportions with water and the commoner organic solvents.
- Example 4 20 parts of N:N'-dimethyltrimethylenediamine are gradually added with stirring to a cooled solution of 150 parts of phosgene in 500 parts of toluene. the temperature being kept below -10 C. After the addition is complete air is blown through the reaction mixture to remove the excess of phosgene and the mixture is filtered to remove- N:N'-dimethyltrimethylenediamine dihydrcchloride. 34 parts of piperidine are added and after standing one hour the mixture is filtered to remove piperidine hydrochloride. The toluene is then distilled off whereby N:N-dimethyltrimethylenediamine-N:N-dicarboxylic bis-piperidide is obtained. It is a colourless oil of B. P. 205 C. at 0.075 mm. pressure which is readily soluble in ethanol and benzene and only slightly soluble in water. 1
- dimethyltrimethylenediamine-N'-carboxylic diethylamide a colourless. strongly basio'liquid of B. P. 141 C. at 10 mm. which is miscible in'all proportions with water, ethanol, benzene and light petroleum; on further distillation a second fraction consisting of 25 parts of N:Ndimethyltrimethylenediamine-N:N'-dicarboxylic bis-diethylamide of B. P. 210 C./ 10 mm. is obtained.
- Example 6 20 parts of N:N'-dimethyltrimethylenediamine-N' carboxylic diethylamide and 7.5 parts of piperidine-N-carboxylic chloride are mixed together. Reaction occurs with evolution of heat. After the reaction has ended the mixture is dissolved in parts of water and solid potassium carbonate is added until the solution is saturated. The solution is warmed to 100 C. for a short time, then cooled. An oily layer is formed. 100 parts of benzene are added and the oil dissolves therein.
- the benzene solution is separatedand dried over anhydrous potassium carbonate and then distilled whereby there are obtained, as two fractions, 9 parts of unchanged N:N'-dimethyltrimethylenediamine N carboxylic diethylamide and 15 parts of N:N-dimethyltriinethylenediamine N'-carboxylic diethylamide N-carboxyiic piperidide as a colourless liquid of B. P. 245 C. at 17 mm. which is moderately soluble in water and of benzene.
- Example 7 94 parts of diethylcarbamyl chloride dissolved in 300 parts of toluene are added with stirring to a cooled solution of 144 parts of N:N'-dimethylhexamethylene-diamine in 800 parts of toluene at such a rate that the reaction temperature does not rise above C.
- 90 parts of N:N-diethyl-N'-methyl-N'- (G-methylaminohexyl) -urea a strongly basic liquid of B. 'P. 182 C. at 12 mm. pressure which is moderately soluble in water, and 40 parts of N:N-dimethylhexamethylenediamine N:N'-dicarboxylic bis-diethylamide of B. P. 229 C. at 9 mm. pressure.
- Example 8 40 parts of N:N-diethyl-N-methyl-N'-(3- methylaminopropyD-urea dissolved in 150 parts of .dry ether are gradually added, with stirring, to a cooled solution of parts of phosgene in 100 parts of dry ether at such a rate that the temperature does not exceed 10 C.
- the N:N-diethyl-N'-'methyl- N'-(3-methylaminopropyl) -urea hydrochloride which has separated out is filtered off and washed with 50 parts of dry ether. The filtrate and washings are combined and the ether is distilled ofi.
- Example 9 88 parts of diethylcarbamyl chloride dissolved in 120 parts of benzene are added with stirring to a solution of 53 parts (an excess) of N:N'-dimethylpropylene diamine (om-nn-c in-cnr-Nn-om obtainable by reacting propylene diamine with an excess of aqueous methylamine) in 450 parts
- N:N'-dimethylpropylene diamine hydrochloride which separates out is removed by filtration and the filtrate is shaken with 100 parts of a saturated aqueous solution of potassium carbonate.
- the benzene layer is separated off, dried over anhydrous potassium carbonate and distilled, whereby there are obtained 15 parts of N:N'-dimethylpropylene diamine NzN' dicarboxylic bis-diethylamide in the form of a colourless liquid, B. P. 209 C. at 16 mm. pressure. Some 1:3:4-trimethyliminoazolid-2-one is also formed. This distils oif first as it has B. P. 135 C. at 20 mm. pressure.
- N:N'-dimethyl 2 methoxy-trimethylene diamine required as starting material is prepared by condensing glycerol dichlorohydrin with methylaniline to give 1 :3-bis-(methylanilino) -propan-- 2-ol, converting this to its sodium salt and reacting with dimethyl sulphate to give 1:3-bis- (methylanilino) 2 methoxypropane which is then converted into N:N'-dimethyl-2-methoxy trimethylene diamine by the method described, in respect of N:N-dimethylethylene diamine, in Berichte der wholesome Chemischen Deutschenmaschine, 1918, vol. 51, p.
- NzN' di-n-butyl-l-ethoxymethyl-ethylene diamine N:N'-dicarboxylic dimorpholide from NzN' di-n-butyl 1 ethoxymethyl-ethylene diamine (of B. P. 260 C.) itself obtained by interaction of ethyl 2:3-dibromopropyl ether with an excess of aqueous n-butylamine.
- the toluene solution is separated oil, dried with anhydrous potassium carbonate and distilled whereby there is obtained fi-methyl amino-p'- ethylamino-diethyl ether N:N'-dlcarboxylic bisdiethylamide of B. P. 233' C. 'at 15 mm. pressure.
- Example 11 bonate solution, dried over anhydrous potassium carbonate and distilled whereby there is obtained N:N- bis 8 methoxyethyl) -ethylenediamine- N:N'-dicarboxylic acid bis-piperidide of B. P. 285 C./11 mm.
- the N:N'-bis(p-methoxyethyl) -ethylenediamine used as starting material is obtained by reacting ethylene dibromide with an excess of an aqueous solution of p-methoxyethylamine which is conveniently prepared by the catalytic hydrogenation of 'methoxyacetonitrlle in presence of a Raney nickel catalyst.
- Example 12 71 parts of dimethyl carbamyl chloride dissolved in 150 parts of benzene are added eradually, with stirring, to 130 parts of N:N'-bis-(fiethoxyethyl)-hexamethylene diamine in 450 parts of benzene. The whole is then refluxed for one hour, cooled and the precipitated N:N'-bis- (o-ethoxyethyl) -hexamethylene diamine dihydrochloride removed by filtration.
- the benzene solution is shaken with 100 parts of a saturated aqeuous potassium carbonate solution, dried over anhydrous potassium carbonate and distilled, whereby there is obtained N:N'-bis-(p-ethoxyethyl) -hexamethylene diamine-N:N-dicarboxylic bis-dimethylamide of B. P. 268-9 C. at 11 mm.
- N:N'-bis- (p-ethoxyethyl) -hexamethylene diamine used as starting material is obtained by interaction of hexamethylene dibromide with an excess of an aqueous solution of p-ethoxyethylamine, which itself is conveniently prepared by the catalytic hydrogenation of ethoxyacetonitrile.
- Example 13 49 parts of morpholine-N-carboxylic chloride dissolved in '75 parts of benzene are added with stirring to 80 parts of N:N'-bis-(,6-n-butoxyethyl) -2-ethoxy-trimethylene diamine dissolved in 450 parts of benzene.
- the precipitated amine hydrochloride is removed by filtration, the filtrate refluxed for one hour with parts of water and distilled to dryness. The residue is extracted with ether,
- Example 14 175 parts of N:N'-dimethyl-trimethylenediamine dissolved in 500 parts of toluene are added, at -15 C., with stirring, to a solution of 280 parts of phosgene in 1000 parts of toluene. After the addition is complete, air is blown through the reaction mixture to remove the excess of phosgene; N:N'-dimethyl-trimethylene diamine dihydrochloride separates out and is filtered off and washed with dry toluene. The united filtrate and washings are then distilled whereby there is obtained N:N'-dimethyl-trimethylenediamine- N:N-dicarboxylic dichloride of B. P. 163-166 C. at 0.8 mm. pressure, together with some 1:3-dimethyl-2-ketohexahydropyrimidine B. P. C. at 44 mm. pressure.
- N:N'-dimethyl-trlmethylene diamine-N:N'-dicarboxylic dichloride in 50 parts of benzene there is added a solution of 18 parts of methyl methoxyethylamine in 50 parts of benzene.
- Methyl methoxyethylamine hydrochloride separates out and is filtered off and the filtrate is distilled whereby there is obtained NzN-dimethyltrimethylenediamine-N:N dicarboxylic acid bis(methylmethoxyethylamide) of B. P. 253'C. at 16 mm. pressure.
- Example 16 29 parts of di-(B-ethoxyethyl) carbamyl chloride (of B. P. 165 C. at 19 mm. pressure) dissolved in 75 parts of toluene are added with stirring to 17 parts of N:N'-di-n-butyl-ethylene diamine in 50 parts of toluene and the whole is refluxed gently for 6 hours. After cooling, the precipitated amine hydrochloride is removed by filtration, the filtrate refluxed for /2 hour with parts of water and distilled to dryness on the water bath under reduced pressure.
- Example 17 21.5 parts 'of N-methyl-N:N'-diethyl-N-(3- methyl amino 2-methoxypropyl)urea and 7.5' parts of piperidine-N-carboxylic chloride are mixed together. Reaction occurs with the evolution of heat. After the reaction has ended the mixture is dissolved in 100 parts of water and crystalline potassium carbonate is added until the solution is saturated. The solution is warmed to 100 C. for 10 minutes, then cooled and the oily layer is extracted with ether. After drying over anhydrous potassium carbonate the ether solution is distilled whereby there is obtained NzN- dimethyl-2-methoxytrimethylenediamine-N-carboxylic acid diethylamide-N'-carboxylic acid piperidide of B. P. 228 C. at 8 mm. pressure. Its structure corresponds to the formula:
- N-methyl-N:N'-diethyl-N-(3-methylamino-z-methoxypropyl) -urea used as starting material is made as follows. 67 parts of diethyl car- Example 18 31.5 parts of N :N'-di(;8-ethoxye.thyl) -ethy1enediamine-N-carboxylic acid piperidide are mixed with 6- parts of dlmethylcarbamyl chloride and the mixture is heated at 100 C. for 12 hours. The reaction mixture is cooled, shaken with 100 parts of a saturated aqueous solution of potassium car bonate and then extracted with ether.
- the N:N' di (,8 ethoxyethyl)-ethylenediamine-N-carboxylic acid piperidine used as starting material is made as follows. 74 parts of piperidine-N-c'arboxylic chloride dissolved in 150 parts of-benzene are added, with stirring, at a temperature below 10 C. to a solution of 150 parts of NzN' di (,5 ethoxyethyl) -ethylenediamine in 500 parts of benzene. After the addition is complete the Whole is stirred for 5 hours at ordinary temperature.
- N:N'-di-(p-ethoxyethyl) -ethylenediamine hydrochloride separates out and is filtered oil and the filtrate is then distilled whereby there is obtained N:N'-di(,3-ethoxyethyl)-ethylenediamine N carboxylic acid piperidide of B. P. 180 C. at 15 mm. pressure, together with a small proportion of N :N-.di-(pethoxyethyl) -ethylene diamine N:N'-dicarboxylic acid bis piperidide of B. P. 27627'. C. at 15 mm. pressure. 7,
- Example 19 10 parts of ethyl p-ethoxyethyl carbamyl chloride are added to 31.5 parts of N :N'-di-(;3-ethoxyethyl) -ethylenediamine-N-carboxylic acid piperidide (prepared as described in Example 18 above) and the mixture is heated to 120 C. for 8 hours. It is then cooled, shaken with 80 parts of a saturated aqueous solution of potassium carbonate and extracted with ether.
- the ethyl pl-ethoxyethyl carbamyl chloride used as starting material is made from phosgene and ethyl p-ethoxyethyl amine which is itself conveniently made by interaction of ethyl bromide with an excess of aqueous fi-ethoxyethylamine.
- A stands for an alkylene radical having from 2 to 6 carbon atoms and having one of its hydrogen atoms replaced by a radical selected from the group consisting of alkyl and alkoxy; wherein R above 245" i and R are monovalent aliphatic radicals selected from the group consisting of lower alkyl and lower alkoxy-alkyl; and wherein X and Y are the imino radicals of secondar amines selected from the group consisting of lower dialkyl amines.
- A stands for an alkylene radical having from 2 to 6 carbon atoms and having one of its hydrogen atoms replaced by a radical selected from the group consisting of alkyl and alkoxy; wherein R and R are monovalent aliphatic radicals selected from the group consisting of lower alkyl and lower alkoxy-alkyl; and wherein X and Y are the imino radicals of secondary amines selected from the group consisting of lower dialkyl amines, lower alkoxy substituted dialkyl amines and secondary heterocyclic amines, the step which consists of reacting upon a diamine of formula wherein A, R.
- the bis-ureas of the general formula X- -CO-NR--A-NR'-COY wherein A stands for an alkylene radical having from 2 to 6 carbon atoms and having one of its hydrogen atoms replaced by a radical selected from the group consisting of alkyl and alkoxy; R and R are monovalent aliphatic radicals selected from the group consisting of lower alkyl and lower alkoxy-alkyl; and X and Y are the imino radicals of secondary amines selected from the group consisting of lower dialkyl amines, lower alkoxy substituted dialkyl amines and secondary heterocyclic amines.
- N:N'-bis(p-n-butoxyethyl) -2 ethoxy trimethylene-diamine-N:N'-dicarboxylic dimorpholide the same being a compound of the structural formula:
- alk designates an alkylene radical havvalent aliphatic radicals selected from the group consisting of lower alkyl and lower alkoxy-alkyl
- R and R are monovalent aliphatic radicals selected from the group consisting of lower alkyl and lower alkoxy-alkyl: and wherein X, X are the imino radicals of secondary amines selected from the group consisting of lower dialkyl amines, lower alkoxy substituted dialkyl amines and secondar heterocyclic amines, which comprises reacting a carbamyl chloride of formula XCO-'Cl, X having the same meaning as above, in an inert organic solvent, upon an excess of a diamine of the formula R-NHalk-NH--R -alkyl wherein "elk,” R and R have the same meanings as above, removing the precipitated amine-hydrochloride, and recovering the principal reaction product as formulated above.
Description
Patented Apr. 9, 1946 msuanns William Robert Boon, Blackley, Manchester, England, assignor to Imperial Chemical Industries Limited, a corporation of Great Britain No Drawing. Application October 5, 1943, Serial- No. 505,037. In Great Britain January 13,
8 Claims. (Cl. 260-247) This invention relates to new bis-ureas which are useful as stimulants of the respiratory and vasomotor centres, having a low, ratio of active ject is to provide such compounds having a low ratio of active dose to toxic dose. A further object is to provide processes for the manufacture of the said bis-ureas. Still further objects will appear as the description proceeds.
These objects are accomplished by the present invention which. comprises new bis-ureas of the general formulawherein the symbols A, R, R, X and Y have the following meanings, namely:
A stands for an alkylene chain of 2 to 6 carbon atoms which may be unsubstituted or may bear one or more alkyl, alkoxy or alkoxyalkyl substituents or for a group consisting of two such alkylene chains united by an ether sulphide (-S) or imino (-NH- or N.Alkyl) linkage.
R and R, which are not necessarily alike, stand for alkyl groups which jointly contain not more than 8 carbon atoms or for alkoxyalkyl groups which jointly contain not more than 12 carbon atoms.
While X and Y, which also are not necessarily alike, each stands for the secondary amino group corresponding with'an amine XH which is a dialkylamine or heterocyclic secondary amine of molecular weight not exceeding 120, or which is of the form AlkOalk-NH-Alk and has a molecular weight not exceeding 160, or which is of the form (Alk-O-alk) zNH and has a molecular weight not exceeding 220, the terms Alk and alk representing an alkyl and an alkylene radical respectively.
The various alternative values for A, R, R, X and Y and the limitations put upon each of them are not arbitrarily selected. On the contrary. bearing in mind that the preferred compounds are designed to be respiratory stimulants, these limitations are of the essence of the invention. Respiratory stimulants are used, as the name indicates, to stimulate those portions of the central nervous system which control the respiratory mechanism, particularly in cases where breathing has stopped during an operation'under anesthetic. As will be apparent, such compounds must act rapidly and accordingly they are normally administered by intravenous injection. Clearlyadequate solubility in water, or more particularly in physiological saline solution is a prerequisite for suchcompounds. Now other factors being equal, increase in the size and weight of the various radicals A, R, R, X and Y diminishes the'solubility of the bis-urea, and so. limits must be set for the sizes of these variousradicals, but also the limits must vary with any changes in the nature of the radicals. .For instance when A has the form of a simple straight alkylene chain (which is not water-solubilising) then the maxi mum permissible size is a chain of 6 carbon atoms, whereas if the chain is branched 'or; car,- ries alkoxy or alkoxyalkyl substituents -iis broken by an ether, sulphide or imino linkage (an of which modifications tend to enhance-water: solubility), then A maycontairnin total, more than 6 carbon atoms. Similarly if'R and R represent alkyl groups they must not jointly contain more than 8 carbon atoms, whereas if they are alkoxyalkyl groups a greater size and weight (up to 12carbon atoms) can be tolerated because of the enhanced solubilising efi'ect. Again, if X and Y have the alkoxyalkyl-alkylamino or bis-alkoxyalkylamino form it can be of greater size and weight than if it is a simple dialkylamino cheterocyclic secondary amino group. Also the nature and size of the various radicals A. R, R, X and Y aifect the intrinsic chemotherapeutic activity of the compound. Accordingly the particular limitations imposed on the values which can be possessed by these terms have been selected bearing in mind both the intrinsic activ ities and the solubilities of the compounds. All the above limitations may be expressed generically under the single rule that none of the radicals expressed by the symbols A, R, R, X and Y shall contain an uninterrupted chain of more than 6 carbon atoms, and that for each pair of corresponding symbols (that is R and R, X and Y) theaverage carbon content in each uninterrupted alkyl chain shall not exceed 4 atoms. These limitations are of the essence of the invention and must be observed if its object is to be achieved.
The new compounds can. be made by two main synthetic methods.
In the first method the carbamyl chloride XCO-Cl, (X, it must be remembered, is the radical of a secondary amino group as defined above and is used here as typical ofthe pair X In the second method the diamine is first combined with phosgene, forming the carbamyl chloride C1CONRA--NR'COC1 which is then caused to react with the secondary amine X-H. Here also the reaction may be between one molecular proportion of the diamine and two molecular proportions each of, firstly phosgene, and secondly the; secondary amine, whereby a symmetrical bis-urea results; or alternatively it may be carried out in stages so as to obtain the unsymmetrical compounds. Thus the diamine may be combined with one molecular proportion of phosgene, followed by one molecular proportion of the secondary amine X--H, whereby the mono-urea XCO--NR-A--NHR' is formed and this may then be combined with a further proportion of phosgene and then with one molecular proportion of a difierent secondary amine Y-H, whereby the unsymmetricalb'is-urea is produced.
In all the above discussion where a definite molal quantity is specified for an amine or a di- .amine, it will be understood that this refers'to the quantity employed for actual condensation, exclusive of any additional quantity added to act as an acid-absorbing agent for HCl liberated in the process. In other words, the specified molal quantity of the amine or diamine is the minimal, theoretical quantity, to be exceeded in practice by a convenient excess for absorbing the HCl.
As will be seen, therefore, the new compounds are made from the following starting materials. namely, diamines R-NHA-NI-I--R', carbamyl chlorides X-COC1 and the corresponding secondary amines X-H.
Then as diamines suitable for use in making the new compounds there may be mentioned, for example, N:N'-dimethylethylene diamine, N:N- diethylethylenediamine,N:N'-dimethyltrimeth ylene diamine, N-methyl-N'-ethylethylene diamine, N:N-di-n-propylethylene diamine, N:N'-di-nbutylethylene diamine, N:N'-dimethyl-tetramethylene diamine, N:N-dimethylhexamethylene diamine, N:N'-dimethyl-1:2-propylene diamine, N: N '-dimethyl-1 S-butylene diamine, N N -dimethyl-2-methoxy-trimethylene diamine, B: 3'-di(ethylamino) -diethyl ether, 49:8- di (ethylamino) -diethyl sulphide, ,ezpr-di (ethylamino) -diethyl methylamine of the formula N:N-di-n-butyl-l-ethoxymethylethylene diamine of the formula cim-mi-cmcrnoczm) CH2NHC4H9 N N'-bis (fi-methoxyethyl) -ethylene diamine, N:N-bis(p-ethoxyethyl) -ethylene d i a m i n e N:N'-bis(o-isopropyloxyethyl) -ethylene diamine, N:N'-bis(p-ethoxyethyl) -hexamethylene diamine and N:N-bis-(p-n-butyloxyethyl)-2-ethoxy-trimethylene diamine of the formula The following secondary amines and the carbamyl chlorides derived therefrom may be mentioned to exemplify the other classes of starting materials useful for making the new bisureas'of this invention, for instance: dimethylamine, diethylamine, methyl ethylamine, di-npropylamine, di-n-butylamine, methyl-n-propylamine, piperidine, morpholine, methyl methoxyethylamine, ethyl methoxyethylamine, ethyl ethoxyethylamine, di(methoxyethyl)amine and di(fl-ethoxyethyl) amine.
The above starting materials are mentioned only for purposes of illustration and not for limitation of the invention. Obviously other members of the classes indicated by the definitions previously given for the radicals A, R, R, X and Y can be used in the same way. Clearly the number of compounds which can be made by combining together in the manner indicated the various starting materials is very large and the following detailed examples are given by way of illustration only (and not in limitation) of the invention.
Example 1 88 parts of diethylcarbamyl chloride dissolved in 120 parts of benzene are added with stirring to a solution of 53 parts of N:N'-dimethy1trimethylenediamine (obtainable from N:N'-dimethyl-N:N-diphenyltrimethylenediamine by the method described-in respect of N:N-climethylethylenediamine-Berichte der' deutschen chemischen Gesellschaft 1918, vol. 51, p. 738) in 450 parts of benzene. When the reaction is complete the N:N-dimethyltrimethylenediamine di- 40 hydrochloride (which has M. P. 266 c.) is removed by filtration, and the filtrate is shaken with 100 parts of saturated potassium carbonate, dried over anhydrous potassium carbonate and distilled whereby there is obtained 67 parts of N: N-dimethyltrimethylenediamine N: N -dicarboxylic acid bis-diethylamide as a colourless liquid, B. P. 238 C. at 33 mm. pressure which is miscible in all proportions with water and the commoner organic solvents.
In a similar manner there are obtained the following:
(a) N :N'-dimethylethylenediamine N:N'- dicarboxylic bis-piperidide (M. P. C.).
.(b) N-methyl-N-ethylethylenediamine- N:N'- dicarboxylic bis-dimethylamide (B. P. 205 C. at 22 mm. pressure).
(0) N :N-diethylethylenediamine- N:N'-dicarboxylic bis-morpholide (M. P. 98 C.), which is a colourless crystalline solid readily soluble in water, ethanol and benzene and sparingly soluble in light petroleum. The morpholine-N-carboxylic chloride used in making this substance has B. P. 137-138 C. at 33 mm. pressure and is obtained by the action of phosgene on morpholine in accordance with the method described in respect of diethylamine in Bulletin de la Socit chimique de Paris, 104, 3rd series, vol. 31, p. 689.
(d) N:N'- di n-propylethylenediamine-NzN- dicarboxylic bis-dimethylamide (B. P. 208 C. at 18 mm. pressure). TheN:N'-di-n-propylethylenediamine (B. P. 189 (3., dihydrochloride M. P. I
300 C.) required is made by reacting di-p-toluenesulphonylethylenediamine with n-propyl bromide by the method of Berichte, 1895, vol. 28, p.
(e) N:N-di-n-butylethylenedlamine-N:N'-di-.
carboxylic-bis-morpholide (B. P. 229 C. at 0.4 mm. pressure, M. P. 41-42 0.). The N:N'-di-nbutylethylene-diamine required has B. P. 226 C., its dihydrochloride melts at 300 C. with decomposition and its di-p-toluene-sulphonyl derivative at 119 C. It is made in a manner analogous-to that used for making N:N'-di-n-propylethylenediamine.
(j) N:N. dimethyltetramethylene N:N'- dicarboxylic bis-diethylamide (B. P. 216 C. at mm. pressure). The N:N'-dimethyltetramethylenediamine (B. P. 164 C., dihydrochloride M. P. 275 C.) required is made by condensing 1:4-dibromobutane with sodium p-toluenesulphonyl methylamide in xylene at 140 C. to give di-ptoluenesulphonyl- N: N-dimethyltetramethylene-. diamine of M. P. 129 C. which is hydrolysed in the usual manner.
(a) N: N-dimethylhexamethylenediamine-N N'-dicarboxylic bis-dimethylamide (B. P. 238 C. at 17 mm. pressure). 1
Example 2 21 parts of N:N-dimethylethylenediamine carbonate is suspended in 250 parts of dry chloroform and the solution is saturated with phosgene at room temperature. After it has stood for hours air is blown through the mixture to remove the excess of phosgene. The mixture is then filtered to remove N:N'-dimethylethylenediamine dihydrochloride and from the filtrate the chloroform is distilled, leaving a pale yellow, mobile somewhatlachrymatory liquid which is the biscarbamyl chloride. This is dissolved in 100 parts of ether. parts of diethylamine are added. After the reaction is complete the whole is agitated with 150 parts of saturated aqueous sodium carbonate solution, the ethereal layer is separated and dried over anhydrous potassium carbonate. This dry ethereal solution is fractionally distilled to give as one fraction N :N'-dimethylethylenediamine-N:N'-dicarboxylic bis-diethylamide as a colourless liquid, B. P. 339 C. at atmospheric pressure or 224 C. at 13 mm. pressure which is miscible in all proportions with water and the commoner organic solvents.
Example 3 16 parts of N:N-dimethylethylenediamine dihydrochloride are dissolved in 150 parts of water, and sufilcient 32% aqueous caustic soda is then added to make the solution alkaline to phenolphthalein and the whole is cooled to 5 C. parts of dimethylcarbamyl chloride are now added with stirring and cooling at such a rate that the temperature does not exceed 20 C., more caustic soda being added as required to keep the solution just alkaline to phenolphthalein. After stirring for 6 hours sufilcient solid potassium carbonate is added to saturate the solution and the oil which separates out is dissolved up in 100 parts of benzene. The benzene solution is dried over anhydrous potassium carbonate and the hen-- zene is then distilled oil. N:N'-dimethylethylenediamine-N:N'-dicarboxylic bis-dimethylamide (B.P. 193 C. at 20 mm. pressure) is thus obtained. It is a colourless oil which gradually solidifies to a crystalline mass; it is miscible in all proportions with water and the commoner organic solvents.
3 Example 4 20 parts of N:N'-dimethyltrimethylenediamine are gradually added with stirring to a cooled solution of 150 parts of phosgene in 500 parts of toluene. the temperature being kept below -10 C. After the addition is complete air is blown through the reaction mixture to remove the excess of phosgene and the mixture is filtered to remove- N:N'-dimethyltrimethylenediamine dihydrcchloride. 34 parts of piperidine are added and after standing one hour the mixture is filtered to remove piperidine hydrochloride. The toluene is then distilled off whereby N:N-dimethyltrimethylenediamine-N:N-dicarboxylic bis-piperidide is obtained. It is a colourless oil of B. P. 205 C. at 0.075 mm. pressure which is readily soluble in ethanol and benzene and only slightly soluble in water. 1
In a similar manner there can be obtained N:N-dimethyltrimethylenediamine-N:N dicarboxylic bis-(methyl-n-propylamide) and N:N'- dimethyltrimethylenediamine-N:N'- dicarboxylic bis- (ethyl-p-ethoxyethylamide) Example 5 tilled whereby there is obtained 50 parts-of N :N-
dimethyltrimethylenediamine-N'-carboxylic diethylamide, a colourless. strongly basio'liquid of B. P. 141 C. at 10 mm. which is miscible in'all proportions with water, ethanol, benzene and light petroleum; on further distillation a second fraction consisting of 25 parts of N:Ndimethyltrimethylenediamine-N:N'-dicarboxylic bis-diethylamide of B. P. 210 C./ 10 mm. is obtained.
In a similar manner by the interaction of 87 parts of N :N'-diethylethylenediamine z with 67.! parts of diethylcarbamyl chloride there is obtained parts of N:N'-diethylethyleneiiiamine- N-carboxylic diethylamide' as a colourless, strongly basic liquid or B. P. 126 C. at 17 mm. and 31 parts of N:N'-diethylethylenediamine N:N-dicarboxylic bis-diethylamide, acolourless liquid of B. P. 218 C. at 19 mm. which is miscible in all proportions with ethanol and benzene and moderately soluble in "water.
Example 6 20 parts of N:N'-dimethyltrimethylenediamine-N' carboxylic diethylamide and 7.5 parts of piperidine-N-carboxylic chloride are mixed together. Reaction occurs with evolution of heat. After the reaction has ended the mixture is dissolved in parts of water and solid potassium carbonate is added until the solution is saturated. The solution is warmed to 100 C. for a short time, then cooled. An oily layer is formed. 100 parts of benzene are added and the oil dissolves therein. The benzene solution is separatedand dried over anhydrous potassium carbonate and then distilled whereby there are obtained, as two fractions, 9 parts of unchanged N:N'-dimethyltrimethylenediamine N carboxylic diethylamide and 15 parts of N:N-dimethyltriinethylenediamine N'-carboxylic diethylamide N-carboxyiic piperidide as a colourless liquid of B. P. 245 C. at 17 mm. which is moderately soluble in water and of benzene.
is miscible in all proportions with ethanol, benzene and petroleum ether.
In a similar manner by the interaction of 23 parts of N:N'-diethyl ethylene diamine-N'-carboxylic diethylamide and 14 parts of diethylcarbamyl chloride there are obtained 29 parts of NzN' diethylethylenediamine-N:N-dicarboxylic bis-diethylamide of B. P. 218 C. at 19 mm. together with 10 parts of unchanged N:N-diethylethylenediamine-N-carboxylic diethylamide.
Example 7 94 parts of diethylcarbamyl chloride dissolved in 300 parts of toluene are added with stirring to a cooled solution of 144 parts of N:N'-dimethylhexamethylene-diamine in 800 parts of toluene at such a rate that the reaction temperature does not rise above C. By working up the reaction mixture as described in Example there are obtained 90 parts of N:N-diethyl-N'-methyl-N'- (G-methylaminohexyl) -urea, a strongly basic liquid of B. 'P. 182 C. at 12 mm. pressure which is moderately soluble in water, and 40 parts of N:N-dimethylhexamethylenediamine N:N'-dicarboxylic bis-diethylamide of B. P. 229 C. at 9 mm. pressure.
24 parts of N:N-diethyl-N-methyl-N'-(6- methylaminohexyD-urea are mixed with 9 parts of morpholine-N-carboxylic chloride. When the reaction is ended 13 parts of N :N'-dimethylhexamethylenediamine-N-carboxylic diethylamide- N'-carboxylic morpholide of B. P. 248 C. at 9 mm. pressure are isolated as described in Example 6.
Example 8 40 parts of N:N-diethyl-N-methyl-N'-(3- methylaminopropyD-urea dissolved in 150 parts of .dry ether are gradually added, with stirring, to a cooled solution of parts of phosgene in 100 parts of dry ether at such a rate that the temperature does not exceed 10 C. When the reaction is complete the N:N-diethyl-N'-'methyl- N'-(3-methylaminopropyl) -urea hydrochloride which has separated out is filtered off and washed with 50 parts of dry ether. The filtrate and washings are combined and the ether is distilled ofi. The residue is added to a solution of 20 parts of dimethylamine in 80, parts of benzene. Dimethylamine hydrochloride separates out and is filtered off. The benzene solution remaining is distilled whereby there are obtained parts of NzN' dimethyltrimethylenediamine N carboxylic diethylamide N'-carboxylic dimethylamide, which is a colourless oil of B. P. 210 C. at 9 mm. pressure, which is miscible with water.
Example 9 88 parts of diethylcarbamyl chloride dissolved in 120 parts of benzene are added with stirring to a solution of 53 parts (an excess) of N:N'-dimethylpropylene diamine (om-nn-c in-cnr-Nn-om obtainable by reacting propylene diamine with an excess of aqueous methylamine) in 450 parts When the reaction is complete the N: N -dimethylpropylene diamine hydrochloride which separates out is removed by filtration and the filtrate is shaken with 100 parts of a saturated aqueous solution of potassium carbonate. The benzene layer is separated off, dried over anhydrous potassium carbonate and distilled, whereby there are obtained 15 parts of N:N'-dimethylpropylene diamine NzN' dicarboxylic bis-diethylamide in the form of a colourless liquid, B. P. 209 C. at 16 mm. pressure. Some 1:3:4-trimethyliminoazolid-2-one is also formed. This distils oif first as it has B. P. 135 C. at 20 mm. pressure.
In a similar manner there are obtained the following:
(a) N:N'- dimethyl 1:3 butylene diamine- N:N'-dicarboxylic bis-diethylamide, B. P. 217 C. at 19 mm. pressure. No cyclic urea is formed in this case.
(b) N:N'-dimethyl 2 methoxy-trimethylene diamine-N:N'-dicarboxylic bis-piperidide, B. P.
265 C. at 15 mm.; structural formula:
' OER-CH2 CHz-CH2 C 1 N-OO-N-CHz-CH-CHz-N-CO- CHI GHQ-CH1 CH3 CH3 CH3 CHz-CH:
The N:N'-dimethyl 2 methoxy-trimethylene diamine required as starting material is prepared by condensing glycerol dichlorohydrin with methylaniline to give 1 :3-bis-(methylanilino) -propan-- 2-ol, converting this to its sodium salt and reacting with dimethyl sulphate to give 1:3-bis- (methylanilino) 2 methoxypropane which is then converted into N:N'-dimethyl-2-methoxy trimethylene diamine by the method described, in respect of N:N-dimethylethylene diamine, in Berichte der deutschen Chemischen Gesellschaft, 1918, vol. 51, p. 738, or alternatively by interaction of glycerol dichlorohydrin with methyl iodide and silver oxide to give methyl p:p-dichloroisopropyl ether which is then treated with an excess of aqueous 20% methylamine solution.
(c) fl:,B'-di(ethylamino)-diethyl ether N :N- dicarboxylic dimorpholide B. P. 228 C. at 0.3 mm. The 5:5'-di(ethylamino)-diethyl ether is prepared as above from p:p'-di(ethylanilino)-diethyl ether which itself is prepared by reacting ethyl chloroethylaniline with the sodium derivative of ethyl hydroxyethylaniline or less advantageously by reacting pzp'-dichlorodiethyl ether with an excess of ethylaniline.
((1) 49:13 di(ethylamino) diethyl sulphide N :N'-dicarboxylic dimorpholide B. P. 275-276 C. at 21 mm. from ,B:J8'-di(ethy1ani1ino)-diethy1 sulphide, itself obtained by reaction of ethyl chloroethylaniline with sodium sulphide in alcohol or aqueous alcohol.
(e) 3:,8'-di(ethylamino)-diethyl methylamine N :N-dicarboxy1ic dimorpholide from 5: 3-di- (ethylanilino)-diethyl methylamine (B. P. 235- 238 C. at 8 mm.) itself obtained from ethyl chloroethylaniline and aqueous 20% methylamine solution.
(f) NzN' di-n-butyl-l-ethoxymethyl-ethylene diamine N:N'-dicarboxylic dimorpholide from NzN' di-n-butyl 1 ethoxymethyl-ethylene diamine (of B. P. 260 C.) itself obtained by interaction of ethyl 2:3-dibromopropyl ether with an excess of aqueous n-butylamine.
Eaxample 10 73 parts of p-methylamino-fi'-ethylamino-diethyl ether dissolved in 200 parts of dry toluene are added with stirring to a solution of 250 parts of phosgene in 1000 parts of toluene cooled to 25 C. After the addition is completed the excess of phosgene is removed by blowing with air, the amine hydrochloride which separates out is filtered oil and to the filtrate there are added '73 parts of diethylamine. After filtering off the diethylamine hydrochloride which is precipitated the toluene solution is shaken with parts of saturated aqueous potassium carbonate solution. The toluene solution is separated oil, dried with anhydrous potassium carbonate and distilled whereby there is obtained fi-methyl amino-p'- ethylamino-diethyl ether N:N'-dlcarboxylic bisdiethylamide of B. P. 233' C. 'at 15 mm. pressure.
Example 11 bonate solution, dried over anhydrous potassium carbonate and distilled whereby there is obtained N:N- bis 8 methoxyethyl) -ethylenediamine- N:N'-dicarboxylic acid bis-piperidide of B. P. 285 C./11 mm.
The N:N'-bis(p-methoxyethyl) -ethylenediamine used as starting material is obtained by reacting ethylene dibromide with an excess of an aqueous solution of p-methoxyethylamine which is conveniently prepared by the catalytic hydrogenation of 'methoxyacetonitrlle in presence of a Raney nickel catalyst.
In a similar manner there are obtained:
(a) NzN' bisa(,8 methoxyethyl) -ethylenediamine-N:N'-dicarboxylic bis-diethylamide of B. P. 252 C. at 23 mm. v
(b) N:N'-bis(p-ethoxyethyl) -ethylenediamine- N:N'-dicarboxylic bis-piperidide of B. P. 282 C. at 19 mm.
(c) N:N'-bis(isopropyloxyethyl) ethylenediamine-NzN'-dicarboxylic-bis-dimethylamide of B. P. 230 C. at 1 mm.
(d) N:N-bis(isopropyloxyethyl) ethylenediamine-N:N'-dicarboxylic dimorpholide of M. P.
Example 12 71 parts of dimethyl carbamyl chloride dissolved in 150 parts of benzene are added eradually, with stirring, to 130 parts of N:N'-bis-(fiethoxyethyl)-hexamethylene diamine in 450 parts of benzene. The whole is then refluxed for one hour, cooled and the precipitated N:N'-bis- (o-ethoxyethyl) -hexamethylene diamine dihydrochloride removed by filtration. The benzene solution is shaken with 100 parts of a saturated aqeuous potassium carbonate solution, dried over anhydrous potassium carbonate and distilled, whereby there is obtained N:N'-bis-(p-ethoxyethyl) -hexamethylene diamine-N:N-dicarboxylic bis-dimethylamide of B. P. 268-9 C. at 11 mm.
The N:N'-bis- (p-ethoxyethyl) -hexamethylene diamine used as starting material is obtained by interaction of hexamethylene dibromide with an excess of an aqueous solution of p-ethoxyethylamine, which itself is conveniently prepared by the catalytic hydrogenation of ethoxyacetonitrile.
Example 13 49 parts of morpholine-N-carboxylic chloride dissolved in '75 parts of benzene are added with stirring to 80 parts of N:N'-bis-(,6-n-butoxyethyl) -2-ethoxy-trimethylene diamine dissolved in 450 parts of benzene. When the reaction is completed the precipitated amine hydrochloride is removed by filtration, the filtrate refluxed for one hour with parts of water and distilled to dryness. The residue is extracted with ether,
the ether solution dried over anhydrous potas- 7 slum carbonate and fractionated, whereby there is obtained N :N'-bis- (p-n-butoxyethyl) -2-ethoxytrimethylene diamine-N:N'-dicarboxylic dimorpholide of B. P. 258 C. at 0.4 mm. pressure. Its structure corresponds to the formula:
CHr-CH: CHI-CH! N -CO-NCH|-CH-CH r-NCO-N o GHQ-C :Hc (32H: (B2114 v GHQ-C C4Hn CARD The I N:N'-di-(p-n-butoxyethyl) -2-ethoxy-trimethylene diamine used as starting material is obtained by interaction of ethyl-,e:,s'-dichloroisopropyl ether (prepared by interaction of glycerol dichlorohydrin, ethyl iodide and silver oxide) with an excess of aqueous p-n-butoxyethylamine which itself is conveniently obtained by the catalytic hydrogenation of n-butoxyaceto-nitrile in presence of a Raney nickel catalyst.
Example 14 175 parts of N:N'-dimethyl-trimethylenediamine dissolved in 500 parts of toluene are added, at -15 C., with stirring, to a solution of 280 parts of phosgene in 1000 parts of toluene. After the addition is complete, air is blown through the reaction mixture to remove the excess of phosgene; N:N'-dimethyl-trimethylene diamine dihydrochloride separates out and is filtered off and washed with dry toluene. The united filtrate and washings are then distilled whereby there is obtained N:N'-dimethyl-trimethylenediamine- N:N-dicarboxylic dichloride of B. P. 163-166 C. at 0.8 mm. pressure, together with some 1:3-dimethyl-2-ketohexahydropyrimidine B. P. C. at 44 mm. pressure.
To a solution of 11 parts of N:N'-dimethyl-trlmethylene diamine-N:N'-dicarboxylic dichloride in 50 parts of benzene there is added a solution of 18 parts of methyl methoxyethylamine in 50 parts of benzene. Methyl methoxyethylamine hydrochloride separates out and is filtered off and the filtrate is distilled whereby there is obtained NzN-dimethyltrimethylenediamine-N:N dicarboxylic acid bis(methylmethoxyethylamide) of B. P. 253'C. at 16 mm. pressure.
In a similar manner there are obtained:
(a) N:N-diethyl ethylenediamine N:N'-dicarboxylic acid bis(ethyl methoxyethylamide) B. P. 239 C. at 17 mm. pressure.
(b) N: N'-di-n-propyl-ethylenediamine N:N'- dicarboxylic acid bis(methyl ethoxyethylamide) of B. P. 255 C. at 20 mm. pressure.
(c) N:N'-dimethyl-trimethylenediamine-N:N'- dicarboxylic acid bis(ethyl ethoxyethylamide) of B. P. 253 C./14 mm.
Ediample 15 17 parts of ethyl methoxyethyl-carbamyl chloride (made from ethyl methoxyethylamine and phosgene) dissolved in 50 parts of benzene are added with stirring to a solution of 14 parts of N:N'-di-n-propyl ethylenediamine in 50 parts of benzene. N :N-di-n-propylethylenediamine dihydrochloride separates out and is filtered off. The filtrate is shaken with 50 parts of a saturated aqueous solution of potassium carbonate, dried over anhydrous potassium carbonate and distilled whereby there is obtained N:l "-di-n-propyl-ethylene diamine-N:N'-dicarboxylic bis(ethyl methoxyethylamide) of B. P. 265 C. at 25 mm. pressure.
Example 16 29 parts of di-(B-ethoxyethyl) carbamyl chloride (of B. P. 165 C. at 19 mm. pressure) dissolved in 75 parts of toluene are added with stirring to 17 parts of N:N'-di-n-butyl-ethylene diamine in 50 parts of toluene and the whole is refluxed gently for 6 hours. After cooling, the precipitated amine hydrochloride is removed by filtration, the filtrate refluxed for /2 hour with parts of water and distilled to dryness on the water bath under reduced pressure. The residue is extracted with hot 60-80 petroleum ether and the extract fractionally distilled under reduced pressure whereby -N:N-di-n-butyl-ethylene dlamine N :N'-dicar- 7 scribed in respect of N:N'-dimethyl ethylene diamine, in Berichte der deutschen Chemischen Gesellschaft, 1918, vol. 51, p. 738.
Example 17 21.5 parts 'of N-methyl-N:N'-diethyl-N-(3- methyl amino 2-methoxypropyl)urea and 7.5' parts of piperidine-N-carboxylic chloride are mixed together. Reaction occurs with the evolution of heat. After the reaction has ended the mixture is dissolved in 100 parts of water and crystalline potassium carbonate is added until the solution is saturated. The solution is warmed to 100 C. for 10 minutes, then cooled and the oily layer is extracted with ether. After drying over anhydrous potassium carbonate the ether solution is distilled whereby there is obtained NzN- dimethyl-2-methoxytrimethylenediamine-N-carboxylic acid diethylamide-N'-carboxylic acid piperidide of B. P. 228 C. at 8 mm. pressure. Its structure corresponds to the formula:
The N-methyl-N:N'-diethyl-N-(3-methylamino-z-methoxypropyl) -urea used as starting material is made as follows. 67 parts of diethyl car- Example 18 31.5 parts of N :N'-di(;8-ethoxye.thyl) -ethy1enediamine-N-carboxylic acid piperidide are mixed with 6- parts of dlmethylcarbamyl chloride and the mixture is heated at 100 C. for 12 hours. The reaction mixture is cooled, shaken with 100 parts of a saturated aqueous solution of potassium car bonate and then extracted with ether. After drying over anhydrous potassium carbonate the ethereal extract is distilled whereby there is obtained N:N-di- (fl-ethoxyethyl) ethylenediamine- N-carboxylic acid piperidide-N'-carboxylic acid dimethylamide of B. P. 230 C. at 10 mm. pressure.
The N:N' di (,8 ethoxyethyl)-ethylenediamine-N-carboxylic acid piperidine used as starting material is made as follows. 74 parts of piperidine-N-c'arboxylic chloride dissolved in 150 parts of-benzene are added, with stirring, at a temperature below 10 C. to a solution of 150 parts of NzN' di (,5 ethoxyethyl) -ethylenediamine in 500 parts of benzene. After the addition is complete the Whole is stirred for 5 hours at ordinary temperature. N:N'-di-(p-ethoxyethyl) -ethylenediamine hydrochloride separates out and is filtered oil and the filtrate is then distilled whereby there is obtained N:N'-di(,3-ethoxyethyl)-ethylenediamine N carboxylic acid piperidide of B. P. 180 C. at 15 mm. pressure, together with a small proportion of N :N-.di-(pethoxyethyl) -ethylene diamine N:N'-dicarboxylic acid bis piperidide of B. P. 27627'. C. at 15 mm. pressure. 7,
Example 19 10 parts of ethyl p-ethoxyethyl carbamyl chloride are added to 31.5 parts of N :N'-di-(;3-ethoxyethyl) -ethylenediamine-N-carboxylic acid piperidide (prepared as described in Example 18 above) and the mixture is heated to 120 C. for 8 hours. It is then cooled, shaken with 80 parts of a saturated aqueous solution of potassium carbonate and extracted with ether. After drying over anhydrous potassium carbonate the ether solution is distilled, whereby there is obtained NzN' di 3 ethoxyethyl) -ethylenediamine-N- carboxylic acid piperidide-N-carboxylic acid ethyl bamyl chloride dissolved in 150 parts of toluene are added with stirring to a cooled solution of 96 (fl-ethoxyethyl) amide which distils C. at 10 mms. pressure.
The ethyl pl-ethoxyethyl carbamyl chloride used as starting material is made from phosgene and ethyl p-ethoxyethyl amine which is itself conveniently made by interaction of ethyl bromide with an excess of aqueous fi-ethoxyethylamine.
Whereas the above examples illustrate many widely divergent embodiments of the invention it will be apparent to those skilled in the art that many others may be devised without departing from the spirit and scope thereof, and accordingly the invention is not to be regarded as in any way limited thereby but only as defined in the following claims.
In the claims below where a radical such as alkyl, alkylene or alkoxy is preceded by the qualification "lower the latter shall be understood as limiting said radical to a chain length of not more than 6 carbon atoms.
I claim:
1. In the process of producing a bis-urea of the formula XCO--NRA-NR'COY, wherein A stands for an alkylene radical having from 2 to 6 carbon atoms and having one of its hydrogen atoms replaced by a radical selected from the group consisting of alkyl and alkoxy; wherein R above 245" i and R are monovalent aliphatic radicals selected from the group consisting of lower alkyl and lower alkoxy-alkyl; and wherein X and Y are the imino radicals of secondar amines selected from the group consisting of lower dialkyl amines.
lower alkoxy substituted dialkyl amines and.sec-' ondary heterocyclic amines, the step which consists of reacting with a carbamyl chloride of the formula YCOC1, wherein Y has the same meaning as above,. upon a diamine of the group consisting of compounds defined by the formulas HNA-NH and HN-A-N-C t t i I A, R, R and X having the same significance as above, whereby at least one of the imine hydrogens of said diamine is replaced by the radical COY, with elimination of one mole'of HCl.
2. In the process of producing a bis-urea of the formula XCO NRANR'COY, wherein A stands for an alkylene radical having from 2 to 6 carbon atoms and having one of its hydrogen atoms replaced by a radical selected from the group consisting of alkyl and alkoxy; wherein R and R are monovalent aliphatic radicals selected from the group consisting of lower alkyl and lower alkoxy-alkyl; and wherein X and Y are the imino radicals of secondary amines selected from the group consisting of lower dialkyl amines, lower alkoxy substituted dialkyl amines and secondary heterocyclic amines, the step which consists of reacting upon a diamine of formula wherein A, R. and R have the same meaning as above, with a carbamyl chloride of formula XCO-Cl, X having the same meaning as above, whereby at least one of the'imine hydrogens of said diamine is replaced by the radical (JO-X, with elimination of one mole of HCl.
3. As new compounds, the bis-ureas of the general formula X- -CO-NR--A-NR'-COY, wherein A stands for an alkylene radical having from 2 to 6 carbon atoms and having one of its hydrogen atoms replaced by a radical selected from the group consisting of alkyl and alkoxy; R and R are monovalent aliphatic radicals selected from the group consisting of lower alkyl and lower alkoxy-alkyl; and X and Y are the imino radicals of secondary amines selected from the group consisting of lower dialkyl amines, lower alkoxy substituted dialkyl amines and secondary heterocyclic amines.
4. As new compounds, the bis-ureas of the general formula wherein alk designates an alkylene radical having from 2 to 6 carbon atoms; R and R are monobut containing jointly not more than 12 carbon amine-N:N'-dicarboxylic bis-piperidide, the same being a compound of the structural formula:
' CHz-CH; CHz-CH! c z n-oo-N-cm-cn-om-N-co-N crn om-c on; 0 HI on, cal-on,
6. N:N'-bis(p-n-butoxyethyl) -2 ethoxy trimethylene-diamine-N:N'-dicarboxylic dimorpholide, the same being a compound of the structural formula:
7. N:N-dimethyl-2-methoxy-trimethylene-diamine N-carboxylic-diethylamide-N'-carboxy1ic plperidide, the same being a compound of the structural formula:
8. A process of producing a bis-urea oi the formula .wherein "alk designates an alkylene radical havvalent aliphatic radicals selected from the group consisting of lower alkyl and lower alkoxy-alkyl,
ing from 2 to 6 carbon atoms; R and R are monovalent aliphatic radicals selected from the group consisting of lower alkyl and lower alkoxy-alkyl: and wherein X, X are the imino radicals of secondary amines selected from the group consisting of lower dialkyl amines, lower alkoxy substituted dialkyl amines and secondar heterocyclic amines, which comprises reacting a carbamyl chloride of formula XCO-'Cl, X having the same meaning as above, in an inert organic solvent, upon an excess of a diamine of the formula R-NHalk-NH--R -alkyl wherein "elk," R and R have the same meanings as above, removing the precipitated amine-hydrochloride, and recovering the principal reaction product as formulated above.
WILLIAM ROBERT BOON.
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2658056A (en) * | 1948-02-27 | 1953-11-03 | Monsanto Chemicals | Polymeric n-methacrylyl morpholine |
US2816879A (en) * | 1951-11-15 | 1957-12-17 | Du Pont | Process for preparing polyureas utilizing immiscible phases |
US2962530A (en) * | 1957-01-24 | 1960-11-29 | Cilag Chemie | New bis-sulfonyl ureas and process for the production thereof |
US3164571A (en) * | 1959-12-31 | 1965-01-05 | Union Carbide Corp | Polyureas from n-phenyl, phenylene biscarbamyl halide and a diamine |
EP0643043A1 (en) * | 1993-09-09 | 1995-03-15 | Sun Chemical Corporation | Novel bis ureido compositions |
-
1943
- 1943-10-05 US US505037A patent/US2398283A/en not_active Expired - Lifetime
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2658056A (en) * | 1948-02-27 | 1953-11-03 | Monsanto Chemicals | Polymeric n-methacrylyl morpholine |
US2816879A (en) * | 1951-11-15 | 1957-12-17 | Du Pont | Process for preparing polyureas utilizing immiscible phases |
US2962530A (en) * | 1957-01-24 | 1960-11-29 | Cilag Chemie | New bis-sulfonyl ureas and process for the production thereof |
US3164571A (en) * | 1959-12-31 | 1965-01-05 | Union Carbide Corp | Polyureas from n-phenyl, phenylene biscarbamyl halide and a diamine |
EP0643043A1 (en) * | 1993-09-09 | 1995-03-15 | Sun Chemical Corporation | Novel bis ureido compositions |
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