GB2085434A - Furan derivatives - Google Patents

Furan derivatives Download PDF

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GB2085434A
GB2085434A GB8114130A GB8114130A GB2085434A GB 2085434 A GB2085434 A GB 2085434A GB 8114130 A GB8114130 A GB 8114130A GB 8114130 A GB8114130 A GB 8114130A GB 2085434 A GB2085434 A GB 2085434A
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    • 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
    • C07D307/56—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • 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
    • 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
    • C07D307/56—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cooling Or The Like Of Electrical Apparatus (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

1 GB 2 085 434A 1 SP.ECIFICATION Substituted furan compounds This
invention relates to new substituted furan compounds having utility as intermediates in the 5 production of compounds having a selective action on histamine receptors.
Our British Patent Application No. 40125/78 (Publication No. 2006771 A) relates to certain novel aminoalkyl furan derivatives having activity as selective 1-12- antagonists, that is compounds of general formula (1):
R3 R1 1 1 Y D )i 11 R2 NCH2 0 (CH2) n X(CH2)rnN HCNHR4 and physiologically acceptable salts and N-oxides, hydrates and bioprecursors thereof,-in which R, and R2 which may be the same or different each represent hydrogen, Cl, alkyl, C,8 20 cycloalkyl, C3-6 alkeny], aralkyl with 1 to 4 carbon atoms in the alkyl residue or Cl-, alkyl interrupted by an oxygen atom or a group -N-, 25 j RS in which R, represents hydrogen or C,-,alkyl, or R, and R2 may together with the nitrogen atom to which they are attached, form a saturated monocyclic 5 to 7 membered heterocyclic ring which may additionally contain the heterofunction -0- or -N-; i H5 R3 represents straight or branched chain C,-, alkyl, alkoxyalkyl with 1 to 8 carbon atoms in each alkyl residue, C,-, hydroxyalkyl, C,-, alkoxycarbonyl, alkyl thioalkyl with 1 to 8 carbon atoms in each alkyl residue, halogen or aryl; R, represents hydrogen, C,, alkyl, C3-6 alkenyl or alkoxyalkyl with 1 to 8 carbon atoms in each alkyl residue; X represents -0- or -S-; Y represents = S, = 0, = NR6 or = CHNO, where R, represents hydrogen, nitro, cyano, C,-, alkyl aryl, C,, alkylsulphonyl or aryisulphonyl; m represents an integer from 2 to 4 inclusive; and n represents an integer which is 1 or 2, or additionally when X is -S- n may also be zero.
The cycloakyl group preferably has 5 or 6 carbon atoms. The term 'aryi' when applied to aryl groups or the aryl portion of groups means preferably phenyl or substituted phenyl e.g. by one or more C1-4 alky], C1-4 alkoxy or halogen groups. The aralkyl groups preferably have 1 or 2 carbon atoms in the alkyl residue.
The present invention provides compounds of the formula (11) R3 5 R1,,' NCH2 0 (CH2)nX(CH2)mNH2 CV R2 and acid addition salts thereof, in which R, and R2 which may be the same or different each 60 represent hydrogen, C,-, alkyl, C,-, cycloakyl, C3-6 alkenyl, aralkyl with 1 to 4 carbon atoms in the alkyl residue or C1-8 alkyi interrupted by an oxygen atom or a group GB2085434A 2 -N-, 1 MS in which R, represents hydrogen or C,-, alkyl, or R, and R2 may together with the nitrogen atom to which they are attached, form a saturated monocyclic 5 to 7 membered heteracyclic ring which may additionally contain the heterofunction -0- or -N-; i M, R, represents straight or branched chain C,-, alkyl, alkoxyalkyl with 1 to 8 carbon atoms in each alkyl residue, C,-, hydroxyalkyl, C,-, alkoxycarbonyl, alkyl thioalkyl with 1 to 8 carbon 15 atoms in each alkyl residue, halogen or aryi; X represents -0- or -S-; m represents an integer from 2 to 4 inclusive; and n represents an integer which is 1 or 2, or additionally when X is -S n may also be zero.
Preferably, R, represents hydrogen or C, alkyl and R2 represents C, alkyl or R, and R2 together with the nitrogen atom form a pyrrolidine ring; R, represents straight or branched chain C, alkyl, alkoxymethyl with 1 to 4 carbon atoms in the alkyl residue, hydroxymethyl, alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl residue, phenyl or bromine; n is 1; X represents -S- or -0; m is 2 or 3.
The most preferred compounds of formula (11) are those in which n is 1, X is -S- and m is 2 and/or R, and R2 are both methyl or R, and R2 together with the nitrogen atom to which they 30 are attached form a pyrrolidino group.
The compounds of formula (11) are useful as intermediates in the preparation of compounds of formula (1). Thus compounds of formula (1) may be prepared by reacting a compound of formula (H) with a compound capable of converting the group NH, into a group -NHWHIR4 il Y where R4 and Y are as defined in formula (1). This process is described in more detail in Patent 40 Application 40425/78 (Publication No. 2006771 A) referred to above.
Amines of formula (11) wherein n is 1 may be prepared by reacting a compound of formula (111) R3 Rj.,, )U03", NCH2 CH20H R2 where IR, R2 and R, are as defined in formula (11), with an &j- aminaalky[thiot or an &j aminoalkanol, in which the amine group may be protected if desired, under acid conditions, for example in the presence of hydrogen chloride or methane sulphonic acid in a suitable solvent, 55 for example water or tetra hydrofura n. Alternatively, a compound of formula (IV) 3 R3 60 R1 (77) NCH2 CH2 L R2 65 3 GB 2 085 434A 3 in which IR, R2 and R, are as defined in formula (11) and L is a leaving group such as halogen, e.g. chlorine, or acyloxy, e.g. acetoxy may be treated under basic conditions with the co aminoalkyl thiol to give amines of formula (11) wherein X is sulphur and n is 1.
To prepare amines of formula (11) in which R, and R2 are other than hydrogen, R3 is other than hydroxyalkyl or alkoxycarbonyi, n is zero and X is sulphur, a compound of formula (V) 5 R3 1 o R1,.
NCH 0 may be treated with lithium and elemental sulphur followed by reaction with an co-bromoalkyl- 15 phthalimide (V]):
n Br(CH2)mN 20 CM 0 25 The phthalimido protecting group in the resulting product of formula (Vil) R3 0 30 R1 1 1 NCH2::o S (CH2)m N 3 5 R2," 35 may be cleaved by conventional means e.g. with a primary amine or hydrazine, for example methylamine or hydrazine hydrate.
A amine of formula (11) wherein X is an oxygen atom and n is 1 may be obtained by treating a compound of formula (111) with a compound Hal(CH2) NI-12 where Hal represents a halogen atom, preferably chlorine, in the presence of a base, particularly potassium tertiary butoxide, in a suitable solvent such as dimethy1formamide.
Amines of formula (11) in which R, is hydroxymethyl can be prepared from the corresponding 45 compounds in which R3 is alkoxycarbonyl by reduction for example with aluminium hydride in tetrahydrofuran.
Amines of formula (11) wherein X is sulphur and n is 1 and R, and/or R2 is hydrogen may be prepared by reduction of the amide function in a compound of formula (VIII) R3 N C "". 0 CH2 S(CH2)mW2 R2-- II U using, for example, aluminium hydride.
The compounds of formula (Vill) may be prepared by treatment of a compound of formula (IX) 4 GB2085434A 4 R3 1 1 OX) ROOC::, 0 CH2 Hal in which Hal represents a halogen atom, preferably chlorine and R is an alkyl group e.g. methyl, with an w-phthalimidoalkylthiol of formula (X) 0 / s HS(CH2)mN 111!-11 (X) V 0 in which m is as defined in formula (11).
2 1.0 The product of this reaction may then be reacted by conventional means to give a compound of formula (Vill), e.g. with a primary amine R,R2NH in the presence of a base e.g. sodium methoxide.
Where R, and R, are both hydrogen, they may be protected, if desired, in any of the reaction stages, as a phthalimido group. The protecting group may be cleaved, at any suitable stage in 25 the reaction using methods described herein.
The alcohols of formula (lil) may be prepared by a number of processes which are described below.
Alcohols of formula (111) in which R, is alkyl, alkoxyalkyl, aryl or alkylthioalkyl and R, and R2 are other than hydrogen may be made by reacting an ester of formula (XI) R3 1 1 (m) 173 ROOC 0 where COOR is an esterified carboxyl group, e.g. the methyl ester, with an amine of formula R^NH in the presence of a base, for example sodium methoxide to produce a compound of 40 formula (X11) R3 4,5 R1 - 1 1 N-C ""' 0 11 (M) 0 R The compound of formula (X11) is reduced for example with lithium aluminium hydride to produce a compound of formula (V) which is reacted to form the alcohol of formula (111), for example when R, is alkyl with butyl lithium and paraformaidehyde or when R, is alkoxyalkyl with paraformaldehyde acetic acid and hydrogen chloride.
Alcohols of formula (111) in which R. is alkoxy carbonyl and R, and R2 are both methyl may be 55 prepared by reducing an aldehyde of formula (X111) 1 ROOC XO-"'CHO in which COOR is an esterified carboxyl group, e.g. the ethyl ester, with for example, sodium 65 borohydride to an alcohol of formula (M) 1 GB2085434A 5 ROOC 1 1 (XM) 1 3L 0 CH2 OH The alcohol is reacted with the reagent to 9 (E) (CHIN = CH2C1 to produce an alcohol of formula (XV) ROOC CH3 (XZ) :)o NCH2 CH20H CH3 The reagent 9 G (CHIN = CH2C1 can also be used to make alcohols of formula (111) in which R, and R2 are both methyl and R3 'S halogen by reacting it with an alcohol of formula (XVI) 1 1 on CH2 OH Alcohols of formula (111) in which R, and R2 are other than methyl may be prepared from alcohols in which R, and R2 are both methyl by quaternisation of the amino group followed by displacement with the appropriate amine R1R2NW The invention is illustrated by the following Examples.
Preparation 1 (a) NN-Dimethyi-3-(1-methylethyl)-2-furancarboxamide A solution of sodium methoxide (3.3 g) and 3-(1-methylethyi)-2furancarboxylic acid, methyl ester (14 g) in dry methanol (50 m]) was treated with dimethylamine gas during 2 hours. The 45 solvent was removed in vacuo and the residue was dissolved in diethyl ether (150 mi) and washed with water (100 m]). The ethereal extract was dried over anhydrous sodium sulphate and evaporation of the solvent gave the title compound (12 g) as an oil.
UV Xmax (ethanol) 227 nm (sh); 253 nm (c 7,200, 9,250). GLC 15% E.G.S. at 160' retention time 6.8 min.
Similarly prepared from the corresponding esters were:
(b) 1-(3-Methyl-2-furanylcarbonyl)pyrrolidine (23 g) from ester (19.5 g) Found: C, 66.9; H, 7.3; N, 7.9; C,,1-113NO2 requires: C, 67.0; H, 7.3; N, 7.8% c UV Nmax (ethanol) 256 nm (,- 12,400).
(c) 3-Methoxymethyl-N,N-dimethyl-2-furancarboxamide (3 g) from ester (3.7 g) Found:
C,1-113NO3 requires:
59.1; H, 7.1; N, 7.8; 59.0; H, 7.2;N, 7.7% UV Xmax (ethanol) 254 nm (e 9,050).
6 5 Preparation 2 6 Found: C, 48.4; H, 5.0; N, 14.3; C,^,NO.C,1-13N30, requires: C, 48.5; H, 5. 1; N, 14.1 % Similarly prepared from the corresponding carboxamides were:
(b) 1-(3-Methyl-2-furany[methyl)pyrrolidine (15 g) from carboxamide (17 g) picrate salt, m.p. 113'.
Found: C, 48.7; H, 4.6; N, 14.1; C,,Hl,NO.C,H3N307.requires: C, 48.7; H, 4.6; N, 14.2% (c) 3-Methoxymethyl-NN-dimethy]-2-furanmethanamine (1 g) from carboxamide (1.5 g) picrate salt, m.p. 73-74'.
Found: C, 45.3; H, 4.6; N, 14.1; C^,N02.C,1-13N.07 requires: C, 45.2; H, 4.6; N, 14.1% Preparation 3 (a) 4-Bromo-5-(dimethylaminomethyl)-2-furanmethanol. hydrochloride A mixture of 4-bromo-24 uran methanol (3.6 g) and dimethyl (methylene) ammonium chloride (3.0 g) in dry acetonitrile was stirred at ambient temperature for 18 hours. The resulting precipitate was crystallised from acetonitrile affording the title compound (3.0 g) m.p. 190' dec.
Found: C, 35.5; H, 4.9; N, 5.1; C,H12BrNO2.HCI requires: C, 35.5; H, 4.8; N, 5.2% Similarly prepared from the corresponding furanmethanol (14 g) was:
(b) 2-(Dimethoaminomethyl)-5-hydroxymethyl-3-furancarboxylic acid, ethyl ester (18 g) oxalate salt, m.p. 97-99'.
Found: C, 49.0; H, 6.0; N, 4.4; C,1-117NO, requires: C, 49.2; H, 6.0; N, 4.4% Preparation 4 5-(Dimethylaminomethyl)-4-methoxymethyl-2-furanmethanol 45 A mixture of 3-methoxymethyi-N,N-dimethyi-2-furanmethanamine (7 g), acetic acid (60 ml), concentrated hydrochloric acid (30 m[) and paraformaldehyde (3.7 9) was stirred at ambient temperature for 5 hours. The mixture was basified with sodium carbonate, and extracted with diethyl ether (200 mi). The ethereal extract was dried over anhydrous sodium sulphate and the solvent evaporated in vacuo. The residue was distilled affording the title compound (3.5 g) as an 50 off-white waxy solid, b.p. 90./5 X 10-2 mm Hq. The oxalate salt was formed in and recrystallised from ethanol/ethyl acetate m.p. 102-4'.
GB2085434A 6 (a) NN-Dimethyl-3-(1-methylethyl)-2-furanmethanamine A solution of N, N-dimethyl-3-(1 -methylethyi)-2-furancarboxamide (12 9) in dry tetrahydrofuran (250 m[) was treated with lithium aluminium hydride (4.2 g). After 1 hour water (6 mi) was added and the filtered solution evaporated in vacuo. The residue was dissolved in 1 M hydrochloric acid (100 mi) and the solution was washed with diethyl ether (100 m[). The aqueous phase was basified and extracted with diethyl ether (2 X 150 mi), which was dried over anhydrous sodium sulphate. The solvent was removed in vacuo to yield the title compound (7 g) 2i as an oil. The picrate salt was formed in and recrystallised from ethanol, m.p. 111 Found: C, 49.7; H, 6.8; N, 4.8; C,,H17NO3.1---12C204 requires: C, 49.8; H, 6.6; N, 4.8% Preparation 5 (a) 5-(Dimethylaminomethyl)-4-methyl-2-furanmethanol A solution of N,N,3-trimethyl-2-furanmethanamine (10.3 9) in dry tetrahydrofuran (200 mi) under nitrogen was treated over 2 hr with 1.6M n-butyl lithium in hexane (46.2 mi) at - 40' to.
- 45'C. After stirring for 2 hr at room temperature paraformaldehyde (2.3 9) in dry 60 tetrahydrofuran (100 mi) was added and the solution stirred overnight. Water (10 m[) was added and the solvent evaporated. Ethyl acetate (200 m]) and sodium sulphate were added and the organic phase was evaporated giving an oily residue which was distilled (85'/0.1 mm) affording the title compound (8 g).
The oxalate salt was formed and recrystallised from ethanol, m. p. 104106'.
7 GB 2 085 434A 7 Found: C, 49. 1; H, 6.7; N, 5. 1; C,H15NO2.1---12C204.1H20 requires: C, 49-3; H, 6.8; N, 5.2% 2 - Similarly prepared from the corresponding furanmethanamines were:- (b) 4-Methyl-5-(1-pyrrolidinyimethyl)-2-furanmethanol (7.5 g) from the furanmethanamine (12 g) m.p. 86-88' Found: C, 6 7.3; H, 9. 0; N, 7.2; C,1HA02 requires: C, 67.7; H, 8.8; N, 7.2% (b) 5-(Dimethylaminomethyl)-4-(1-methylethyl)-2-furanmethanot (8 g) from the furanmethanamine (6.8 g) m.p. oxalate salt 122-124'.
Found: C, 54.4; H, 7.5; N, 4.9; Cl,H,,N02.H2C204 requires: C, 54.3; H, 7AN, 4.9% EXAMPLE 1 (a) 5-[[2-(Amino)ethyllthiolmethyl-NN-3-trimethyl] furanmethanamine A stirred solution of 2-aminoethanethiol hydrochloride (4.65 g) in concentrated hydrochloric 20 acid (20 mi) was treated with 5-(d i methylam inomethyi)-4-methyi-2-furan methanol (7 g). The mixture was stirred at O'C for 1 hr and kept at 0' overnight. Ethyl acetate (200 mi) and anhydrus sodium carbonate were added, and the friable solid was collected by filtration. The filtrate was evaporated in vacuo and the oily residue which resulted was distilled (1 OW/0. 1 mm) to give the title compound (6.7 g).
The oxalate salt was formed in and recrystallised from ethanol m.p. 175' dec.
Found: C11H20N20S.2H2C204 requires:
43.7; H, 6.0; N, 6.9; 44.1; H, 5.9;N, 6.9% Similarly prepared from 2-aminoethanethiol hydrochloride (A) and the corresponding furan methanol were:
(b) 5-[[2-(Amino)ethyllthiolmethyl-N,N-dimethyl-3-(1-methylethyl)-2furanmethana mine (6.5 g) from the furanmethanol (7 g) and A (4 g) b.p. 125'/10-1 mm Hg, oxalate salt m.p. 186' dec.
Found: C, 46A H, 6.7; N, 6.4; Cl,H24N20S.21-12C20, requires: C, 46.8; H, 6.5;N, 6.4% (c) 5-[[2-(Amino)ethyl]thio]methyl-2-(dimethylaminomethyf)-3furancarboxylic acid, ethyl ester, 40 hydrate (1. 5 g) from the furanmethanol (5 g) and A (2.5 g) 1 R (CHBr,) C = 0 1708 cm - 1.
Found: C, 51.7; H, 7.7; N, 9.2; C,.1---122N203S.1---120requires: C, 51.3; H, 7.9; N, 9.2% 45 (d) 5-[[2(Amino)ethyl]thio]methy]-3-bromo-NN-dimethyi-2-furanmethanamine (1.2 g) from the furanmethanol (2.7 g) and A (1, 1 g) b.p. 120'/2 X 10-2 mm Hg, oxalate salt m.p. 70-72' Found: C, 33.9; H, 4.3; N, 5.2; Cl,Hl,BrN20S.2H2C204.H20 requires: C, 34. 2; H, 4.7; N, 5.7% (e) 5-[[2-(Amino)ethyllthio]methyl-3-methoxymethyl-N.N-dimethyi-2furanmethanami ne (0. 15 g) 5 5 from the furanmethanol (0. 2 g) and A (0. 1 g) b.p. 130-140'/5 X 10-2 mm H9, oxalate salt m.p. 130-133'.
Found: C, 42.5; H, 5.9; N, 6. 1; C12H22N202S.2H2C204.-LH20 requires: C, 42.9; H, 6.1; N, 6.3% 2 (f) 2-[[4-Methyl-5-(l-pyrrolidinyimethyl)-2-furanylmethyl]thio]ethanamine (2.5 g) from the furanmethanol (3.9 g) and A (2.3 g) b.p. 165'/0.06 mm Hg. UV. Xmax (ethanol) 232 nm; 337 nm (e 9.450,460) EXAMPLE 2
8 GB2085434A 8 5-[[2-(Amino)ethyllthiolmethyl-2-(dimethylaminomethyl)-3-furanmethanol A solution of 5-[[2-(amino)ethyi]thio]methyl-2-(dimethylaminomethyl)-3furancarboxyiic acid, ethyl ester (0.75 g) in dry tetrahydrofuran (50 mi) at 0' was treated with a 0.5 molar solution of aluminium hydride in tetrahydrofuran (35 mi). After 2 hours water (6 m]) was added, and the filtered solution evaporated in vacuo. The oily residue was distilled affording the title compound 5 (0.4 g), b.p. 1 7W/ 10 mm Hg.
The oxalate salt was formed in and recrystallised from ethanol, m.p. 140142'.
Found: C, 42.1; H, 5.7; N, 6.6; C,H20N202S.21-12C204 requires: C, 42.5; H, 5.8; N, 6.5% EXAMPLE 3 5-[[2-(Amino)ethyilthiolmethyi-N, 3-dimethyl-2-furanmethanamine (i) 3-Methyl-5-[[2-(1,3-dioxo-2H-isoindol-2-yl)-ethyllthiolmethyl-2furancarboxy lic acid, methyl ester A mixture of 2-(thio)ethyi-1,3-dioxo-2H-indole (8.3 g) and sodium hydride (0.96 9) in dry dimethy[formamide (100 mi) was stirred at 0' for 3 hours. A solution of 5- (chloromethyl)-3 methyl-2-furancarboxylic acid, methyl ester (8 g) in dry dimethylformamide was added and the mixture stirred for 18 hours.
The solvent was evaporated in vacuo and the residue was dissolved in diethyl ether (500 mi) 20 and washed with water (500 mi). The ethereal extract was evaporated and the solid residue was crystallised from methanol yielding the title compound (11 9) m.p. 92-93' Found: C, 6 0.4; H, 5. 0; N, 4. 1; Cl,H1,1\10,S requires: C, 60.2; H, 4.8; N, 3.9% (ii) 5-[[2-(Amino)ethyl]thio]methyl-N,3-dimethyl-2-furancarboxamide Gaseous methylamine was passed into a solution of 3-methyi-5-[[2-(1,3dioxo-2H-isoindol-2yi)ethyi]thio]methyi2-furancarboxylic acid, methyl ester (7.2 9) and sodium methoxide (0.08 g) 30 in dry methanol (20 mi).
After 4 hours 2M hydrochloric acid (100 mi) was added and the solution was extracted with diethyl ether (300 mi). The aqueous fraction was basified with 5M sodium hydroxide (45 mi) and extracted with ethyl acetate (200 mi). The ethyl acetate extract was dried over anhydrous sodium sulphate and evaporation of the solvent gave the title compound (2. 3 g) as a low 35 melting solid.
UV Xmax (ethanol) 264 rim (e 12,600).
Found: C, 52.3; H, 7.5; N, 12.5; C,^^02S requires: C, 52.6; H, 7.1; N, 12. 3% (iii) 5-[[2-(Amino)ethyllthio]methyl-N,3-dimethy]-2-furanmethanamine A solution of 5-[[2-(amino)ethyllthio]methyl-N,3-dimethyi-2furancarboxamide (1.9 9) in dry tetrahydrofuran (20 ml) at 0' was reduced with a 0.5, molar solution of aluminium hydride in tetrahydrofuran (35 mi).
After 4 hours boiling at reflux, water (9 mi) was added and the filtered solution was evaporated in vacuo. The residue was distilled affording the title compound (0.5 g) as a colourless oil, b.p. 1 W/1 0-1 mm Hq.
The oxalate salt was formed in ethanol and recrystallised from methanol/water, m.p. 198' dec.
Found: C, 42.5; H, 5.6; N, 7.0; Cl,H,8N20S.2H2C20, requires: C, 42.6; H, 5.6; N, 7.1 % EXAMPLE 4 5-[2-(Amino)propoxylmethylN, N, 3-trimethy]-2-furanmethanamine A mixture of 5-(d i methyla m inomethyi)-4-methyi-2-f uran methanol (1.35 g) and postassium tertbutoxide (0.9 9) in dry dimethylformamide (3 m]) at 0' was treated with a solution of 2chloropropylamine, hydrochloride (0.4 g) in dry dimethylformamide (2 mi). After 20 minutes at ambient temperature, the mixture was quenched with oxalic acid (2 9) and the solvent removed in vacuo. Excess anhydrous sodium carbonate was added and the product extracted into chloroform. The chloroform extract was purified by filtration and the solvent evaporated in vacuo. The residue was purified by column chromatography (silica, methanol: 0.88 ammonia, 19: 1) affording the title compound (0. 1 g).
The oxalate salt was formed in and recrystallised from ethanol, m.p. 130131 '.
9 GB2085434A 9 Found: C, 45.2; H, 6.5; N, 6.3; C12H22N202S.2H2C204.H20 requires: C, 45.3; H, 6.7; N, 6.6%

Claims (5)

  1. CLAIMS 1. Compounds of the formula (11)
    R3 11.1 NCH2 (CH2)nX(CH2)MNH2 (H) R2 and acid addition salts thereof in which R, and R2 which may be the same or different each represent hydrogen, C,-, alkyl, C4-, cycloakyl, C,-, alkenyl, aralkyl with 1 to 4 carbon atoms in the alkyl residue or C,-, alkyl interrupted by an oxygen atom or a group -N-, i K, in which R, represents hydrogen or C1-8 alkyl, or R, and R2 may together with the to which they are attached, form a saturated monocyclic 5 to 7 membered heterocyclic ring 25 which may additionally contain the heterofunction -0- or -N-; 1 j U fi, nitrogen atom R3 represents straight or branched chain C,,alkyl, alkoxyalkyl with 1 to 8 carbon atoms in each alkyl residue, C,-, hydroxyalkyl, C,-, alkoxycarbonyl, alkyl thioalkyl with 1 to 8 carbon atoms in each alkyl residue, halogen or ary]; X represents -0- or -S-; m represents an integer from
  2. 2 to 4 inclusive, and n represents an integer which is 1 or 2, or additionally when X is -S- n may also be zero. 2. Compounds as claimed in claim 1, in which R, represents hydrogen or C1-4 alkyl and R2 represents C,, alkyl or R, and R2 together with the nitrogen atom form a pyrrolidine ring; R3 represents straight or branched chain C, alkyl, alkoxymethyl with 1 to 4 carbon atoms in the alkyl residue, hydroxymethyl, alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl residue, phenyl or bromine; n is 1; X represents -S- or -0-; m is 2 or
  3. 3. - 3. Compounds as claimed in claim 1 or 2, in which n is 1, X is -S- and m is 2.
  4. 4. Compounds as claimed in any of claims 1 to 3 in which R, and R2 are both methyl or R, and R2 together with the nitrogen atom to which they are attached form a pyrrolidino group.
  5. 5. Compounds as defined in claim 1 substantially as described with particular reference to 50 any of the Examples.
    CLAIMS (31 Dec 1981) 1. Compounds of the formula (11) R3 60.1. NCH2 -, 70 (CH2)nX(CH2)mNH2 (H) R2 and acid addition salts thereof in which R, and R2 which may be the same or different each represent hydrogen, Cl-, alkyl, C,-, cycloalkyl, C3-, alkenyi, aralkyl with 1 to 4 carbon atoms in 65 1 5 R, -N-; 1 K, R, represents straight or branched chain C,-, alkyl, alkoxyalkyl with 1 to 8 carbon atoms in each alkyl residue, C,-, hydroxyalkyl, C,-, alkoxycarbony], alkyl thioalkyl with 1 to 8 carbon atoms in each alkyl residue, halogen or aryl; X represents -0- or -S-; m represents an integer from 2 to 4 inclusive, and GB2085434A 10 the alkyl residue or C,3 alkyl interrupted by an oxygen atom or a group -N-, in which R, represents hydrogen or C,-,, alkyl, or R, and R, may together with the nitrogen atom to which they are attached, form a saturated monocyclic 5 to 7 membered heterocyclic ring which may additionally contain the heterofunction -0- or n represents an integer which is 1 or 2, or additionally when X is -S- n may also be zero. 20 Printed for Her Majesty's Stationery Office by Burgess Et Son (Abingdon) Ltd -1982Published at The Patent Office, 2 5 Southampton Buildings, London. WC2A 1 AY, from which copies may be obtained.
GB8114130A 1977-10-11 1978-10-11 Furan derivatives Expired GB2085434B (en)

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GB4225677 1977-10-11
DE19803039127 DE3039127A1 (en) 1977-10-11 1980-10-16 HEAT RADIATION DEVICE FOR AN ELECTRICAL DEVICE

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GB2085434A true GB2085434A (en) 1982-04-28
GB2085434B GB2085434B (en) 1982-12-08

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DE3916899C2 (en) * 1989-05-24 2003-04-03 Bosch Gmbh Robert Housing for an electronic circuit

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DE3039127A1 (en) 1982-05-13

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