CS207572B2 - Method of preparation of dibenzo/b,d/pyrane - Google Patents

Description

(54) A process for preparing dlbenzo [b, d] pyranes

The present invention relates to a process for preparing a dibenzopyran of formula (I)

where

R 1 is hydrogen, C 1 -C 5 alkanoyl or -CO- (CH ₂ ) _p -NR 2 R 3, wherein p is 0 or an integer from 1 to 4

R ₂ and R ₃ are each hydrogen or C 1 -C 4 alkyl or together with the nitrogen atom to which they are attached together form a 5- or 6-membered heterocyclic ring selected from the group consisting of piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino C 1 -C 4 alkyl,

R ₄ and R _g are hydrogen, methyl or ethyl,

Z is C 1 -C 9 alkylene or the group - (alkx) _m --X - (alk ₂ ) _n -, wherein each of the substituents (alkj and (alk ₂ ) containing 1 to 9 carbon atoms, the sum of the carbon atoms in the (alkj and (alk ₂ ) j® at most 9, each of m and n is 0 or 1, X is O, S, SO or SO _2, and

W is methyl, phenyl, p-chlorophenyl, p-fluorophenyl, pyridyl, piperidyl, cycloalkyl of 3 to 7 carbon atoms, which is optionally morosubstituted and wherein the substituent is phenyl, p-chlorophenyl or p-fluorophenyl, wherein when W is methyl, is Z— (alkjj _m —X— —- (αΠϊ ₂ ) _η , which is characterized in that the compound of formula II

where

R 1, R 4, R 5, Z and W, as defined above, are reacted with methyl vinyl ketone.

The reaction is carried out in the presence of a base, for example an alkali metal hydroxide or alkoxide or a tertiary organic base such as triethylamine to effect Michael addition, followed by a complete aldol reaction with a alkali metal hydroxide or alkoxide cycling.

The compounds of the formula are novel compounds having analgesic activity and which are also intermediates for the preparation of other analgesic compounds.

The present invention is illustrated by the following examples.

Example 1 dl-6a, 7-Dihydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran-9 (8H) -one

To a solution of 5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (1-methyl-4-phenylbutyl) -4-chromanone (0.916 g) in methanol (4 mL) and methyl vinyl ketone (0.037 mL) was added triethylamine ( 0.09 ml). The reaction mixture was stirred at room temperature for 16 hours and then diluted with ether (50 mL). The resulting ethereal solution was extracted with 10% sodium carbonate solution (4 x 5 mL), dried over sodium sulfate and concentrated in vacuo to give 1.09 g of an oil. The residue was heated to a bath of ethanol (7.3 mL) and 2N potassium hydroxide solution for 16 hours. The reaction mixture was then cooled, acidified with 6 N hydrochloric acid and extracted with dichloromethane (3 x 20 ml). The organic phase was dried over sodium sulfate and evaporated to give 0.99 g of an oil which crystallized from an ether mixture. and hexane (1: 1) to give 0.49 gd1- ^: 6α, 7-dihydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo [b, d] pyran-9 (8H) -one, mp 145-148 ° C, after crystallization from isopropyl ether.

1-2.35 (M, 10, N-methylene, ethylene * remaining protons),

1.55 (S, 6, gem.dimethyl),

2.35-3.0 (M, 5, α-methylene, benzyl methylene, methinyl),

6.1-6.7 (M, 2, ArH),

7-7.35 (M, 5, ArH),

7.9-8.2 (broad S, 1, olefinic proton),

10.8 (S, 1, phenolic OH).

IR (CHCl) C = O 1600 cm ¹

Analysis for C ₂₆ H ₃₀ O ₃ : Calculated:

79.97% C, 7.74% rf; found:

79.91 O / o C, 7.78% H. MS: (molecular ion) 390.

Similarly, dl-6α, 7-dihydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-5-phenylpentyl) -6H-dibenzo [b, d] pyran-9 (8H) -one prepare from

5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (1-methyl-5-phenylpentyl) -4-chromanone, m.p. 204-208 ° C.

1.1, 1.5 (2S, 6, gem.dimethyl),

1,0-3,0 [M, 17, N-methyl, OCH ₂ (CH ₂ ) ₃ -CH (CH ₃ ) -Ar, benzylic residues remaining],

6.2, 6.5 (2D, 2, aromatic protons, J = 2 cps),

7.0-7.4 (M, 5, aromatic protons),

8.05 (D, 1, vinyl protons, J = 2 cps),

10.8 (S, 1, phenolic hydroxyl).

IR: (KBr) C - O 1613 cm ^1st

Analysis for C ₂₇ H ₃₂ O ₃ :

calculated:

% C, 80.16;% H, 7.97; found:

% C, 80.00;% H, 8.29.

dl-6α, 7-Dihydro-1-hydroxy-6,6-dimethyl-3- (2-phenylethyl) -6H-dibenzo [b, d] pyran-9 (8H) -one was prepared from 5-hydroxy- 3-hydroxymethylene-2,2-dimethyl-7- (2-phenylethyl) -4-chromanone, mp 233-235 ° C.

1.0-1.4 (M, 3, 6? -Methynyl, 7-methylene);

1.5 (S, 6, dimethyl dimethyl),

2.35-2.85 (M, 2,8- ' -methylene),

2.9 (S, 4, ethylene),

6.3, 6.55 (2d, 2, aromatic protons),

7.3 (S, 5, aromatic protons),

10.5 (S, 1, hydroxyl-D ₂ O overlap). MS: (molecular ion) 348, and dl-6α, 7-dihydro-1-hydroxy-6,6-dimethyl-3- [1-methyl-3-phenylpropyl) -6H-dibenzo [b, d] pyran-9 (8H) -one from 5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (1-methyl-3-phenylpropyl) -4-chromanone mp 181 ° C.

1.2, 1.3 (d, 2, methyl),

1.55 (S, 6 g of dimethyl),

1.6-3.1 (M, 8, remaining protons),

6.3, 6.55 (2d, 2, ArH),

7.22, 7.25 (2S, 6, ArH, hydroxyl-D ₂ O overcoat),

8.05 (d, 1, oilefin proton).

MS: (molecular ion) 376.

dl-6α-7-Dihydro-1-hydroxy-6α-methyl-3- (1-methyl-4-phenylbutyl) -6H-dibenzo207572 [b, d] pyran-9 (8H) -one is prepared from dl -5-hydroxy-3-hydroxymethyl-en-2-methyl-7- (1-methyl-4-phenylbutyl) -4-chromanone, mp 195-197 ° C.

Roxy-7- [1-methyl-2- (2-phenylethoxy) ethyl] -4-nitroimanone, m.p. 185-187 ° C.

IR (CHC1 ₃₎ C = 0 1613 cm ^1st

NMR: .delta

TMS

CDC13

NMR: δ

TMS

CDC13

1.2 (D, 3, α-imethyl, J = 7 Hz),

1.4 (D, 3,6-methyl, J = 7Hz),

1,3-1,8 (M, 6,7-methylene, allylic prefix),

3.8 (M, 1, methinyl ether,] vicinal - = 11 Hz),

7.0-7.4 (M, 5, ArH),

7.9 (D, 1, vinyl proton, J = 1 Hz),

9.6 (S, 1, phenolic OH),

IR: (KBr) C = 0 1639 cm ^-1 .

Analysis for C ₂₅ H ₂₈ O · ;:

calculated:

% C, 79.75;% H, 7.50; found:

% C, 79.76;% H, 8.33.

UV: λ ^{C21, 5OH} = 226 (ε = 14,400),

324 (ε = 26.600)

MS: (molecular ion) 376.

dl-6α, 7-Dihydro-1-hydroxy-6,6-dlmethyl-3- (1-methyl-4-phenoxybutyl) -6H-dibenzo [b, d] -pyran-9 (8H) -one was prepared from the corresponding M.p. 165-175 ° C.

MS: (molecular ion) 406

Analysis of C ₂₆ H 30 O ₃ :

calculated:

% C, 76.82;% H, 7.44; found:

% C, 76.80;% H, 7.57.

dl-6α, 7-Dihydro-1-hydroxy-6,6-dimethyl-3- [1-methyl-4- (4-pyridyl) butyl] -6H-dibenzo [b, d] pyran-9 (8H) - it is prepared from the corresponding 3-hydroxymethylenderivative as a glassy solid.

MS: (molecular ion) 391.

Analysis for C 25 H 29 NO 3. H ₂ O:

calculated:

% C, 73.32;% H, 7.62;% N, 3.42; found:

% C, 73.22;% H, 7.47;% N, 3.25.

dl-6α, 7-Dihydro-1-hydroxy-6,6-dimethyl-3- [1-methyl-2- (2-phenylethoxy-ethyl)] - 6H-dibenzo [b, d] pyran-9 (8H) 1-OH is prepared from dl-2,2-dimethyl-3-hydroxymethylene-5-hydroxy-1,15 (s, one methyl of gem.dimethyl),

1.20 (d, J = 7Hz, methyl)

1.48 (s, one methyl of g. Dimethyl,

2.0-3.1 (m),

2.85 (t, J = 7Hz, CH ₂ Ph),

3.4-3.8 (m, -CH 2 OCH 2 -),

6.35 (bs, ArH);

6.63 (6s, ArH),

7.30 (s, Ph).

8.10 (d, J = 2 ¹ Hz, C-10 H), and

12.3 (s, phenol).

MS: m / e 406 (M < + >), 391, 376, 363, 315, 302 (100%), 287, 285, and 272.

EXAMPLE 1 d 2, dl-6a, 7-Dihydro-1-hydroxy-6,6-dimethyl-3- (2-heptyloxy) -6 H -dibenzo [b, d] pyran-9 (8 H) -one

To a solution of dl-5-hydroxy-3-hydroxymethylene-2,2-dimethyl-7- (2-heptyloxy) -4-chromanone (5.17 g, 15.4 mmol) and methyl vinyl ketone (2.27 mL, 27 mL), 9 mmol) in methanol (23 mL) was added triethylamine (0.54 mL). The reaction mixture was stirred at room temperature for 16 hours and then diluted with ether (250 mL). The resulting ethereal solution was extracted with 10% sodium carbonate (6 x 30 mL), dried over sodium sulfate and concentrated in vacuo to give 6.11 g of an oil. The residue was heated to boiling in ethanol (45 ml) and 2N potassium hydroxide (45 ml) for 16 hours. The reaction solution was then cooled, acidified with 6 N hydrochloric acid and extracted with dichloromethane (3 x 100 ml). The solid was triturated with hot ether to give 1.0 g of the title compound, mp 185-189 ° C.

1.26 g is obtained by chromatography of the mother liquors on silica gel. The overall yield is 42.3%.

NMR (CDCl 3)? - 11.2 (single proton broad singlet, phenolic OH),

7.9 (single proton wide singlet, vinyl), 6.2, 5.9 (two single proton doublets, J == 3 Hz, aromatic protons),

4.6-4.0 (single proton multiplet, methino ether),

3.0-0.6 (25 protons multiplet, remaining protons).

IR: (KBr) C = 0 1600 cm ^-1

Analysis for C ₂₂ H ₃₀ O:

calculated:

73.71 ° C, 8.44 ° H;

found:

% C, 73.41;% H, 8.37.

UV λ CH 3 CH 2 OH max = 342 mi (ε = 26,800).

In a similar manner, the following compounds were prepared from the appropriate reactants:

dl-6α, 7-dihydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-4-phenylbutoxy) -6H-dibenziol [b, d] pyran-9 (8H) -one, mp 140 up to 168 ° C,

1.3 (D, 2, α-methyl, J = 7 Hz),

1.1- 2.3 [Mi 15, residual protons),

2.3-3.0 (bd, T, 2, benzyl methylene),

4.1- 4.7 (Μ, 1, miethin),

5.95 (D, 1, Ar H, J = 2 Hz),

6.3 (D, 1, Ar H, J = 2 Hz),

7.2-7.4 (M, 5, ArH),

8.0 (D, 1, vinyl proiton, J = 2 Hz).

IR (KBr) C-O 1563 cm ^-1

Analysis for C ₂₆ H ₃₀ O ₄ :

calculated:

C, 76.82; H, 7.44;

found:

% C, 76.74;% H, 7.48.

MS: (molecular ion) 406.

dl-6α, 7-Dihydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenylbutoxy) -6H-dibenzo [b, d] pyran-9 (8H) -one, m.p. 163 ° C.

1.2, 1.3 (d, 3, methyl),

1.45 (s, 6, gem dimethyl),

1.65-2.2 (M, 2, methylene),

2.3-2.95 (M, 4, methylene, benzyl methylene),

4.1- 4.6 (Μ, 1, methinyl),

5.9, 6.15 (2d, 2, ArH),

7.15 (S, 6, ArH, hydrotxyl-D ₂ O overlay), 7.95 (6S, 1, olefinic proton).

MS: (molecular ion) 392.

dl-6α, 7-Dihydro-1-hydroxy-6,6-dimethyl-3-cyclohexyloxy-6H-dibenzo [b, d]) pyran-9 (8H) -one, mp 259-264 ° C.

IR (KBr) C = 0 1590 cm ^-1 , OH 3390 cm),

NMR: δ d 50 1.05-3.0 (M, 15, C ₅ H ₁₀ -cyclohexyl, 6α-methinyl, 7-methylene, 8-α-methylene),

1.45 (S, 6, gem. Dimethyl),

4.0-4.4 (Μ, 1, methinyl),

5.8-6.1 (2d, 2, ArH),

7.1 - 7.25 (d, 1, olefinic proton),

7.3 (S, 1, hydroxyl-D ₂ O overlap).

dl-6α, 7-Dihydro-1-hydroxy-6,6-dimethyl-3- (1-methyl-3-phenoxypropyl) -6H-dibenzolo [b, d] pyran-9 (8H) -one light yellow m.p. 203-206 ° C.

MS: (molecular ion) 392.

Analysis for C ₂₈ H _2S O _4:

calculated:

% C, 76.50;% H, 7.19;

found:

% C, 76.33;% H, 7.12.

Claims (1)

I will invent the object A process for preparing dlbenzo [b, d] pyranium of Formula I wherein R 1 is hydrogen, C 1 -C 5 alkanoyl or -CO- (CH ₂ ) _p -NR ₂ R 5 where p is 0 or is not an integer from 1 to 4, R ₂ and R ₃ are each hydrogen or C 1 -C 4 alkyl or together with the nitrogen atom to which they are attached together form a 5- or 6-membered heterocyclic ring selected from the group consisting of piperidino, pyrrolo, pyrrolidino, morpholino and N- (C 1 -C 4) alkylpiperazino, R ₄ and R ₅ are hydrogen, methyl or ethyl, Z is C 1 -C 9 alkylene or a group (alk _{4 m} -X- (alk ₂ ) _n - wherein each of the substituents (alkj and (alk ₂ ) contains from 1 to 9 carbon atoms, the sum of the carbon atoms) v (alkj and (alk ₂ ) is at most 9, each of man and t is 0 or * 1, X is O, S, SO or SO _2, and W is methyl, phenyl, p-chlorophenyl, p-fluorophenyl, pyridyl, plperidyl, cycloalkyl of 3 to 7 carbon atoms which is optionally monosubstituted and wherein the substituent is phenyl, p-chlorophenyl or p-fluorophenyl, wherein when W is methyl, is Z- (alkimine-X-) (alkyne), characterized in that the compound of formula (II) wherein Ro above, nem. R $, R5, let Z and W have the meaning given to react with methyl vinyl keto-