FI86061C - SOM MELLANPRODUKT ANVAENDBARA 3,4-DIHYDRO -4-AMINO-2H-BENZO / B / PYRAN-3-OL-DERIVAT. - Google Patents

Description

The present invention relates to an intermediate which can be used in the preparation of benzopyrans of formula (I) O. The intermediate invention relates to an intermediate which can be used in the preparation of benzopyrans of formula (I) O.

(I) 15 JL. JO> L — r3

Rf ^ Cr \ wherein: one of Ra and R2 is hydrogen and the other is nitro or cyano; R3 is methyl; R 4 is hydrogen or methyl; and the lactam group is in the trans position with respect to the OH group.

· · ’; The compounds of formula I, their preparation and their pharmacological properties are described in parent application 823272 (patent 73675).

The intermediate of the invention is a 3,4-dihydro-4-amino-2H-benzo [b] pyran-3-ol derivative of the formula

HNABL

ä, P0Ck:.: 4b where:

Rx, R2, R3 and R4 are as defined above, 2 86061 one of A and B is CO and the other is (CH2) 3, and L is a leaving group, wherein the substituted amino group is in the trans position with respect to the OH group.

R4 is preferably methyl.

Preferred compounds of formula (II) are those wherein R 1 is nitro or cyano and R 2 is hydrogen.

10

Formula (II) includes the following compounds of formula (III) and (X): HNiCHzbCOIn 20 \ HNCO (CH2) 3L3 * 25 'I II I (X)

Jt-r3 "r Rz 0 \ XRa: 3b wherein R1, R2, R3 and R4 are as defined above and L1 and L3 are leaving groups.

Compounds of formula (I) may be prepared from intermediates (III) and (X) of invention 33 by the following methods A and B.

A. The metal salt of the compound of formula (III) is cyclized.

'40

The leaving group Lj is a group that can be replaced by another aminonucleophile. Preferred examples of such groups are 3,86061 such as hydroxy and especially C 1-4 alkoxy such as ethoxy.

The cyclization is usually carried out by heating the compound of formula 5 (III) under reflux in an inert solvent such as xylene or toluene.

The metal salt of the compound of formula (III) is preferably the sodium salt.

B. Cyclize a compound of formula (X).

The leaving group L3 is a group that can be replaced by a secondary aminonucleophile in addition to the carbonyl function. A preferred example is chlorine.

The cyclization reaction is preferably carried out in a solvent such as dimethylformamide in the presence of a base such as sodium hydride.

20

Compounds of formula (III) may be prepared by reacting a compound of formula (IV): 0 p / f 'Π I (IV) ·; ·· JL Jr-R3:': Rf 0 \ '. % wherein R 1, R 2, R 3 and R 4 are as defined above, to react with a compound of formula (V):: 3S H 2 N- (CH 2) 3 -COL 1 (V) wherein L 1 is as defined above.

4,86061

The reaction is normally carried out in a solvent at low, medium or high temperature. The solvent may be an alcohol such as methanol or ethanol.

When Lx is hydroxy, the reaction proceeds well if carried out in refluxing ethanol in the presence of aqueous sodium carbonate. When Li is C 1 -C 4 alkoxy, the reaction is preferably carried out in the presence of sodium hydroxide in ethanol.

Under certain conditions, a compound of formula (III) cyclizes spontaneously to form a compound of formula (I).

Compounds of formula (IV) may preferably be prepared in situ by reacting a compound of formula (VI):

OH

20

V

Wherein R1r R2, R3 and RA are as defined above and the hydroxy group is in the trans position with respect to the bromine atom, to react with a base such as potassium hydroxide in ether or aqueous dioxane.

'30

Alternatively, compounds of formula (IIIi) may be prepared by reacting a compound of formula (VII): wherein R 1, R 2, R 3 and RA are as defined above and the amino group is in the trans position with respect to a hydroxy group, to react with a compound of formula (VIII): L2 (CH2) 3COLi (VIII) wherein Lj is as defined above and L2 is a leaving group.

The leaving group L2 is a group that can be replaced by 10 primary aminonucleophiles. Preferred examples of such groups are halogen such as chlorine and bromine.

Compounds of formula (VII) may be prepared by reacting a compound of formula (IV) with an ethanolic ammonium hydroxide solution. Alternatively, they can be prepared by reduction of a compound of formula (IX) with zinc and hydrochloric acid: N3

20 I

Wherein Rx, R2, R3 and R4 are as defined above and the azide group is in the trans position with respect to the hydroxy group.

Compounds of formula (IX) may in turn be prepared from a compound of formula (IV) by reaction with sodium azide in the presence of boric acid, for example in dimethylformamide.

Compounds of formula (X) may be prepared by reacting a compound of formula (VII) with a compound of formula (XI): L3 (CH2) 3COLA (XI) 40 6 86061 wherein L3 is as defined above and L4 is an outgoing group.

The leaving group L * is such that when it is adjacent to the carbonyl function, it can be replaced by a primary aminonucleophile.

The reaction is preferably carried out in a solvent such as chloroform or methylene chloride in the presence of an aqueous base such as aqueous sodium hydroxide solution.

10

In reactions with the epoxide of formula (IV), in particular, the trans isomer is formed.

The following Preparation Examples 1-3 illustrate the conversion of intermediates of formula (II) to compounds of formula (I).

Preparation Example 1 6-Cyano-3,4-dihydro-2,2-dimethyl-trans-4- (2-oxo-1-pyrrole-20-dinyl) -2H-benzorbyropyran-3-ol 6-cyano-3,4- dihydro-2,2-dimethyl-trans-4- (1-keto-4-chlorobutylamino) -2H-benzo [b] pyran-3-ol (0.76 g) obtained from Example 1 was added in dry form. in tetrahydrofuran (10 ml) to a suspension of sodium hydride (0.15 g) in tet-2-5: tetrahydrofuran (20 ml) and the reaction mixture was stirred under nitrogen for 3 hours. When adding water and extracting ethyl. ·· *. lacetate gave 540 mg of the title compound.

IR (KBr plate): 3260, 2220, 1651 cm-1.

-3O NMR (CDCl 3) δ 1.28 (3H); 1.55 (3 H); 2.11 (2 H, m); 2.57 (2 H, m); 3.22 (3H; 1 variable H, broad m); 3.64 (1H, d, J = 10); . . 5.26 (1H, d, J = 10); 6.87 (1H, d, J = 9); 7.24 (1H, narrow m); * # «*; ./ 7.45 (1H, q, J = 9, 2).

‘Analysis calculated for C 16 H 13 N 2 O 3: C, 67.12; H 6.34; N 9.78%

Found: C, 66.83; H 6.17; N 9.50%.

7 86061

Preparation Example 2 6-Nitro-3,4-dihydro-2-methyl-trans-4- (2-oxo-1-pyrrolidinyl] -2H-benzorbyrpyran-3-ol (E9) 'CXo

NOa OH

l [(E9) CHa

10 H

The crude ester from Example 2 (0.27 g) was heated to reflux under nitrogen for 72 hours. Evaporation of the solvent and trituration with ethanol and recrystallization from ethyl acetate gave 6-nitro-3,4-dihydro-2-methyl-trans-4- (2-oxo-1-pyrrolidinyl) -2H-benzo [b] pyran. 3-ol as a pale yellow solid (104 mg), m.p. 238-242 ° C.

IR (KBr plate) 1650 cm-1; NMR (DMSOd 6): δ 1.47 (3H, d, J = 7 Hz); 1.80 - 2.23 (2H, m); 2.23-4.00 (5H, m-series); 4.25 (1H, g, J = 10.7 Hz); 5.14 (1H, d, J = 10Hz); 7.02 (1H, d, J = 9Hz); 7.68 (1H, narrow m); 8.06 (1H, q, J = 3Hz).

... ^ 5 Preparation Example 3 •; · 7-Nitro-3,4-dihydro-2,2-dimethyl-trans-4- (2-oxo-1-pyrrolidinyl) -2H -benzorbpyran-3-ol (E10) * -30

Il I (E10) 0 = N o CH3: CH3 35

The resin from Example 3 was heated to reflux under cooling in xylene (30 mL) under nitrogen for 3 days. Evaporation of the solvent gave a complex mixture which was purified using "Cromatro-8 86061 n" (conditions as in Example 3) to give 7-nitro-3,4-dihydro-2,2-dimethyl-trans-4- (2-oxo-1 -pyrrolidinyl) -2H-benzo [b] pyran-3-ol (0.04 g) was then recharged from ethyl acetate, m.p. 211-5 212.5 ° C.

NMR (CDCl 3): δ 1.30 (3H, s); 1.55 (3 H, s); 1.80-3.60 (6H, m-series); 3.80 (1H, d, J = 10Hz); 5.30 (lh, d, J = 10 Hz); 7.00-7. 85 (3H, m).

The following Examples 1-3 illustrate the preparation of intermediates of formula (II).

Example 1 6-Cyano-3,4-dihydro-2,2-dimethyl-trans-4- (1-keto-4-chloro-15-butylamino) -2H-benzorbyropyran-3-ol a) 6-Cyano-3,4- dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo-Cβ-pyran 4-cyanophenol (19.60 g), sodium hydroxide (9.90 g), 40% benzyltrimethylammonium hydroxide in methanol 20 (34.50 g) and 3-methyl-3-chlorobutyne (25.50 g) was stirred in water (150 ml) and dichloromethane (150 ml) for 5.5 days at room temperature. After separation of the layers, the aqueous layer was extracted twice with chloroform, and the combined organic phases were evaporated to leave a resin which was dissolved in ether and washed three times with 10% sodium hydroxide solution and water before drying over magnesium sulfate. Removal of the desiccant and solvent gave a viscous liquid with IR absorptions (membrane) of 2100, 2220 and 3290 cm -1 This liquid (20.91 g) was heated in o-dichlorobenzene (40 ml) at reflux for 1 hour. , 5 hours under a nitrogen atmosphere.

After distilling off the solvent, a fraction having a b.p. was 110-114V0.02 mm Hg (16.57 g) and which on standing formed a low melting solid. 35 substances with an IR absorption of 2230 cm-1. [See M.

Harfenist and E. Thom, J. Org. Chem. 841 (1972), which discloses m.p. 36-37 °].

9 86061

To this 6-cyanochromene (16.50 g) was added N-bromo-succinimide (31.90 g) dissolved in dimethyl sulfoxide (150 ml) and water (3.24 ml), stirring vigorously and cooling, followed by dilution with water and extraction. ethyl acetate, a mixture was obtained which was boiled in acetone (300 ml) and water (100 ml) for 5 hours to hydrolyze a small amount of 3,4-dibromide present. Evaporation of the solvents gave 6-cyano-trans-3-bromo-3,4-dihydro-2,2-dimethyl-2H-benzo [b] pyran-4-ol as white crystals (24.37 g). A small sample of m.p. 128-128.5 ° from 60-80% petroleum ether, nmr (CDCl 3) δ 1.43 (3H), 1.62 (3H), 7.48, (1H, variable), 4.07 (1H, d , J = 9), 4.87 (1H, d, J = 9), 6.80 (1H, d, J = 8), 7.43 (1H, q, J = 8, 2), 7.78 (1H, d, J = 2).

Analysis calculated for C 12 H 12 NO 2 Br: C, 51.07; H 4.26; N 4.96; Br 28.37.

Found: C, 50.95; H 4.38; N 5.03; Br 28.39%.

Bromohydrin (24.30 g) was stirred with sodium hydroxide pellets (5.00 g) in water (250 ml) and dioxane (200 ml) for 3 hours at room temperature. The solvents were removed by distillation under high vacuum and the residue was dissolved in ether and washed with water and brine before drying over magnesium sulfate. Removal of the desiccant and v25 solvent gave crude 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo [b] pyran (16.02 g) as a resin having an absorption at 2230 cm-1. In the IR and NMR spectra (CCl *) δ 1.26 (3H), 1.54 (3H), 3.40 and 3.80 (1H, d, J = 4 each), 6.77 (1H, d , J = 8), 7.43 (1H, q, J = 8, '. 30'), 7.58 (1H, d, J = 2).

b) 6-Cyano-3,4-dihydro-2,2-dimethyl-trans-4-amino-2H-benzo [b] pyrropyran-3-ol

The title compound was prepared by stirring 6-: *. 3 cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-benzo [b] py-: ·; in an ethanolic solution of ammonium hydroxide at room temperature until the end of the epoxide used as a starting material was determined by thin layer chromatography.

_ ..

ίο 86061 (c) 6-Cyano-3,4-dihydro-2,2-dimethyl-trans-4- (1-keto-4-chloro-tert-butylaminol-2H-benzorbyropyran-3-ol)

The aminochromanol (1.40 g) obtained in step b) was stirred in chloroform (20 ml) and water (10 ml) containing sodium hydroxide pyrose (0.26 g) at room temperature. 4-Chlorobutyryl chloride (0.72 ml) was added and the reaction mixture was stirred vigorously for ¼ hours. Separation of the layers and washing of the organic layer with water, then brine, drying over magnesium sulfate, filtration and evaporation gave the title compound as a pale yellow solid.

NMR (CDCl 3) δ 1.23 (3H, s); 1.47 (3 H, s); 1.83-2.67 (5H, m series); 3.50 (1H, d, J 9 Hz) covers 3.54-3.70 (2H, m); 4.97 (1H, t, J = 9Hz); 6.57 (1H, d, J = 9 Hz) covers 6.78 (1H, d, J = 8 Hz); 7.29 (1H, q, J = 8.2 Hz) covers 7.39 (1H, narrow m).

Example 2 6-Nitro-3,4-dihydro-2-methyl-trans-4-ethoxycarbonyl-pyrrolidino-2H-benzo [b] pyran-3-ol a) 6-Nitro-3,4-dihydro-2-methyl-3,4-ol -epoxy-2H-benzorebipyran p-nitrophenol (49.3 g), 3-bromobut-1-yne (39.0 g), potassium carbonate (66 g) and potassium iodide (3.1 g) were heated and stirred under nitrogen for 20 hours. The mixture was cooled, filtered and evaporated and the residue was dissolved in ether and washed with sodium hydroxide solution (10%) before drying over magnesium sulphate. Filtration and evaporation gave phenoxybutynin as a yellow oil (39.03 g). This crude phenoxybutynin (30 g) was heated in o-dichlorobenzene (1 liter) for 24 hours under nitrogen.

. . Removal of the solvent and recrystallization from 60-80 ° petroleum ether gave 2-methyl-6-nitrochromene as an oily solid. This nitrochromene (6.10 g) 3.5 dissolved in dimethyl sulfoxide (50 ml) containing water (1.12 ml) was treated with N-bromosuccinimide (11.40 g) in one portion with vigorous stirring.

After 0.5 h, the reaction mixture was poured into water (500 mL) 11,86061 and extracted with ethyl acetate to give bromohydrin (7.4 g) as a sticky solid. Recrystallization from ethyl acetate-petroleum ether gave a sample, m.p. 159 °. This bromohydrin (2.27 g) was stirred with potassium 5 hydroxy acids (2.2 g) in ether (500 ml) for 48 hours. Filtration gave 3,4-epoxy-2-methylchroman as a yellow crystalline solid (1.05 g).

b) 6-Nitro-3,4-dihydro-2-methyl-trans-4- (ethoxycarbonyl-10-propylamino] -2H-benzo [b] pyran-3-ol

The epoxide from step a) (1.03 g) was boiled with ethyl 4-aminobutyrate hydrochloride (0.84 g) and spheres of sodium hydroxide (0.20 g) in ethanol (50 ml) for 10 hours. Filtration, evaporation and chromatographic purification gave a resin (1.10 g) which was dissolved in 2N hydrochloric acid and extracted three times with ethyl acetate. The base phase was basified and extracted with ethyl acetate to give the crude ester which was used as such in Preparative Example 2.

NMR (CDCl 3) δ 1.24 (3H, t, J = 7 Hz); 1.53 (3H, d, J = 6Hz); 1.88 (1H, broad q, J = 6Hz); 2.20-3.01 (8H, m series; 2H substitutable with D 2 O); 3.57 (1H, d, J = 9Hz); 4.08 (2H, q, J = 7 L). 4.0 »(211, q, J 7 Hz); 6.79 (lii, d, J-3 IIz); 7.94 (1H, q, J = 9.3 Hz); 8.22 (1H, d, J = 3Hz).

"25"

Example 3 7-Nitro-3,4-dihydro-2,2-dimethyl-trans-4- (3-carbethoxypropylamino) -2H-benzorepyran-3-ol 7-nitro-3,4-dihydro-2,2 dimethyl-3,4-epoxy-2H-benzo [b] -. 30 pyrans (0.48 g, preparation described in Example 3 of GB Patent 1,548,221), ethyl 4-aminobutyrate hydrochloride (0.34 g) and sodium hydroxide spheres (0.08 g) were heated to reflux in ethanol (50 ml). hours. Filtration, evaporation and chromatographic treatment with Chromatron (2 mm silica gel HFZVi and gradual elution with pentane-ethyl acetate) gave the epoxide (0.20 g) and trans-4- (3-carbethoxypropylamino) -7 -nitro-2,2-dimethyl-126061 2H-benzo [b] pyran-3-ol (0.21 g) as a resinous substance used as such in Preparative Example 3.

NMR (CDCl 3) δ 1.21 (3H, t, J = 7 Hz); 1.25 (3 H, s); 1.52 (3 H, s); 1.40-2.87 (8H, m series); 3.48 (1H, d, J = 11 Hz); 3.68 δ (1H, d, J = 11 Hz); 4.03 (2H, q, 3 = 1 Hz); 7.13-8.03 (3 H, m).

Mass spectrum (C.I.) MH + at m / z 353; (E.I.) [M-C4H80] (retro-Diels-Alder cleavage) at m / z 281.1127. C 13 H 16 N 2 O 5 requires 281.1117.

Claims (4)

13 86061 An intermediate for the preparation of benzopyrans of formula (I) wherein: one of R 1 and R 2 is hydrogen and the other is nitro or cyano; R3 is methyl; R 1 (is hydrogen Lal methyl; and the lactam group is in the trans position relative to the OH group, characterized in that the intermediate is a 3,4-dihydro-4-amino-2H-benzo [b] pyran-3-ol derivative, of the formula HNABL yyV: wtJto-V ··.-3-0 NRi wherein: R1, R2, R3 and R <are as defined above, one of A and B is CO and the other is (CH2) 3, and .25 L is a leaving group, wherein the substituted amino group is in the trans position with respect to the OH group. Intermediate according to Claim 1, characterized in that it is 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4- (1-keto-4-chlorobutylamino) -2H-benzo [b] pyran-3-ol. 14 86061 Intermediate according to Claim 1, characterized in that it is 6-nitro-3,4-dihydro-2-methyl-trans-4- (ethoxycarbonylpropylamino) -2H-benzo [b] pyran-3-ol. Intermediate according to Claim 1, characterized in that it is 7-nitro-3,4-dihydro-2,2-dimethyl-trans-4- (3-carbethoxypropylamino) -2H-benzo [b] pyran-3-ol .