Method of preparing derivatives of dibenzo-(b,d)-pyran

专利摘要:
9-Hydroxydibenzob,d!pyrans useful as analgesics, hypotansives, immunosuppressants, tranquilizers; as anti-secretory and anti-anxiety drugs; having the formulae: I and II wherein R is hydrogen or alkanoyl having from one to five carbon atoms; R1 is hydrogen, alkanoyl having from one to five carbon atoms or -CO-(CH2)p-NR2R3 wherein p is 0 or an integer from 1 to 4; each of R2 and R3 when taken individually is hydrogen or alkyl having from one to four carbon atoms; R2 and R3 when taken together with the nitrogen to which they are attached form a 5- or 6-membered heterocyclic ring selected from piperidino, pyrrolo, pyrrolidino, morpholino and N-alkylpiperazino having from one to four carbon atoms in the alkyl group; each of R4 and R5 is hydrogen, methyl or ethyl; R0 is oxo or alkylenedioxy having from two to four carbon atoms; Z is (a) alkylene having from one to nine carbon atoms; (b) -(alk1)m-X-(alk2)n- wherein each of (alk1) and (alk2) has from 1 to 9 carbon atoms, with the proviso that the summation of carbon atoms in (alk1) plus (alk2) is not greater than 9; each of m and n is 0 or 1; X is O, S, SO or SO2; and W is methyl, phenyl, p-chlorophenyl, p-fluoro-phenyl, pyridyl, piperidyl, cycloalkyl having from 3 to 7 carbon atoms, or monosubstituted cycloalkyl wherein the substituent is phenyl, p-chlorophenyl or p-fluoro-phenyl; with the proviso that when W is methyl, Z is -(alk1)m-X-(alk2)n-.
公开号:SU843748A3
申请号:SU762416855
申请日:1976-11-03
公开日:1981-06-30
发明作者:Сингх Биндра Джасджит
申请人:Пфайзер Инк (Фирма)；
IPC主号:

专利说明:

(54) METHOD FOR OBTAINING DIBENZO DERIVATIVES (b, d) PIPAHA
-dimethyl-3- (1-methyl-4-fennbutyl - 6H-dibenzo (b, d) pyran-9-beta-ol.
In a solution of 0.25 g d1-6a-beta, 7,10, 10a-alfo1-tetrahydro-1-hydroxy-b, b dimethyl-3- (1-methyl-4-phenylbutyl) -5H-dibenzo (b, d a) nHpaH-a (8H) -oHa in 200 ml of ethanol, which is then stirred at room temperature under a nitrogen atmosphere, 0.5 g of sodium borohydride is added, the reaction mixture is stirred for 30 minutes and acidified with 6 K. hydrochloric acid, and then diluted with 50 ml of water and extracted with three portions of 50 ml of sulfuric ether. The combined ether extracts are dried over sodium sulfate and concentrated in vacuo to give 0.25 g of a mixture of 9-OH-alpha and beta isomers. After treatment in a chromatographic column with silica gel, 0.087 g of d-1-beta, 7.8, 9, 10a-alpha-hexahydro-1-hydroxy-b, b-dimethyl-3- (1-methyl-4- Fanylbutyl) -bH-diben30 (b, d) pyran-9-beta-ol, mp.15b158c (after preliminary crystallization from a mixture of sulfuric ether. with hexane in a 1: 2 ratio).
MS: (mol. Ion) 394.
Calculated,%: C 79.15 j H.8,69 j
-26 e4 3
Found,%: G 78.94; H 8.79.
The following compounds are prepared analogously:
 d-beta-7,8,9,10,10a-alpha - hexahydro-1-hydroxy-b, 6-dimethyl-3- (1-methyl-5-phenylpentyl) -bH-dibenzo (i, d ) pyran-9 beta-ol.
Calculated,%: C 79.37; H 8.88 / - SvHjfoOj
Found,% g With 79.58, H 8.92
d .1 -b-7,8,9,10,10a-hexahydro-1-oxy-b, b-dimethyl-3- (2-phenylethyl) -bH-dibenzo (b, d) pyran-9-beta- ol, so pl. 213-2150C.
Ms: (mol. Ion) 352.
d1-ba-beta-7,8,9,10,10a-alpha-hexahydro-1-hydroxy-b, b-dimethyl-3- (1-methyl-3-phenylpropyl) -bH-dibenzo. {b, d ) piran-9 beta-ol, mp 171-172®С
Calculated,%: C 78.91; n 8.47;
Cgj H 1.2 Oo,
Found,%; C H 8.50.
d 1 -6a-al LA-7, 8,9,10, Yha-goxagidro-1-hydroxy 6-alpha-methyl-3- (1-methyl-4-phenylbutyl) -bH-dibenzo (b, d) T1Iran -9-beta-ol.
This product is obtained as a mixture of diastereoisomeric alcohols. A mixture. The foam product is divided into two components (A and B) by preparative thin-layer chromatographic processing on silk-gel plates using 5% methanol / chloroform solution as elution solvent. The diastereoisomer mixture exhibits an absorption maximum in the infrared range (in chloroform) at 3827 and 3333 cm (it1
From 60 mg of foamy product, 10 mg of component L is isolated, R 0.65
NMR spectrogram: 0-1.5 (M, 5 aromatic), 6.2, 6.3 (20, 2 aromatic) 1.2 (0.3, alpha methyl J 7HZ), 0.8-4 , 5 (M, 22, remaining protons) 4
Component B, 42 Mr, R 0.75 is isolated in a similar manner.
NMR spectrogram rcTj- e, 0-7.5 (M, 5, aromatic), b, 1, 6.3 (2D 2 aromatic) 1.2 (D, 3, alpha-methide O 7HZ), 0.8- 4.5 (M, 22 remaining protons).
d1-ba-beta, 7,8,9,10,10a-alpha-hexahydro-1-hydroxy-6, b-dimethyl-3- (1-methyl - 4-phenoxybutyl) -bH-dibenzo (b, d ) piran-9-beta ol, so pl. 144-14b ° C. R 0.31 (silica gel, 9 parts sulfuric ester: 1 part hexane).
Calculated,%: C 76.06; H 8.35;
Found,%: C 75.85, H 8.22.
dl-6a-beta, 7,8,9,10,10a-alfa-hexahydro-1-oxy-b, b-dimethyl-3- (1-methyl-4-phenoxybutyl) -bH-dibenzo (b, d) pyran-9-alpha-ol (oil).
R 0.37 (silica gel, 9 parts of sulfuric ether: 1 h of hexane).
MS: (mol. Ion) 410.
d 1 ba-beta, 7, 8, 9, 10, 10a-alpha-hexahydro-1-hydroxy-6, b-dimethyl-3-1-methyl-4- (4-pyridyl (, - butyl-bH-dibenzo (B, d) pyran-9-beta-ol, mp: 170-190 ° C.
  Rf 0.19 {silica gel, - 9 parts of benzene and 1 hour of methanol).
d1-6a-beta, 7,10,10a-alpha-tetrahydro-1-hydroxy-b, b-dimethyl-3-1-methyl-2- {2-phenylethoxy) -ethyl-bH-dibenzo (b, d) pyran-9- (8H) -one is converted into d1-ba-beta-7,8,10,9,10a-alfa-hexahydro-l-oxy-6, b-dimethyl-3-1-methyl 2 {2- phenylethoxy) ethyl-bH-dibenzo (b, d) pyran-9-beta-ol (solid).
IR spectrogram (chloroform): OH 3597 and 3333. .
Converts dl-ba-beta ,. 7,10,10a-beta-tetrahydro-1-hydroxy-6, b-dimethyl-3-1 - methyl-2- (2-phenylethoxy-ecyl-6H-dibenzo (b, d) pyran-9 (8H) -one in a1 b-beta, 7,8,9,10,10a-betag8xcahydro-1-oxy-6, b-dimethyl-3-fl-Netil-2- (2-phenylethoxy) ethyl-bH-dibenzo ( B, d) pyran-9-beta-ol, mp 90-105 0..,
IR spectrogram (chloroform): OH 3534 and 3279.
PRI and MER. 2. d1 ba-beta, 7,8, 9, 10, 10a alpha hexahydro-1-hydroxy (s I 6 dimethyl-3- (2-heptylxy) -6H-dibenzo (b, d) pyran-9- beta ol.
In a solution of 0.60 g (1, bb mmol) .d1-bahata, 7, 10,10a-alpha-tetrahydro-1 - OXI-6, 6-dimethyl-3- (2-heptyloxy) 6H- Dibenzo (b, d) pyran-9- (8H) -one in 18 MP of ethanol, stirred at room temperature in the atmosphere
nitrogen, 275 mg sodium borohydride is added. The reaction mixture is stirred for 30 minutes and poured into a mixture of 35 ml of ice, 35 ml of 10% hydrochloric acid and 200 ml of sulfuric ether. The ether layer is separated and the aqueous layer is extracted with an additional two portions of 100 ml of each time. The combined ether extracts are dried over sodium sulfate and evaporated to give an oil-like product. As a result of crystallization from hexane, 305 mg (yield 50.3%) of product are obtained, mp. 102-104s.
NMR spectrogram: (broad singlet of one proton, hydroxyl) 6.1-5.8 (broad singlet of two protons, aromatic) j4, 5-0, 5. (multiplet 31 proton, the remaining protons).
JK Spectrogram (potassium bromide): OH, 3390 cmH
Calculated,%: C, 72.89; H, 9.45;
Cij od
Found%: C 72; 52, H 9.18. : C 72.52,
In a similar way, using the corresponding tetrahydro compounds, the following products are obtained:
d1-ba-beta, 7,8,9,10,20a-alpha-hexahydro-1-hydroxy-6, b-dimethyl-3 (1-methyl-4-phenylbutoxy) -bH-dibenzo (b, d) pyran -9-beta-ol (amorphous solid).
IR spectrogram (potassium bromide): OH, 3390 cm-H
MS: (mol. Ion) 410.
NMR spectrogram dcoM. (P, 3 alpha-methyl) 1.0-4.5 (M, 24, other protons) 5.8-6.0 (M, 2, aromatic) 6.8-7.3 (M, 5, aromatic ).
d 1-ba-beta, 7,8, 9,10, Yha-alpha-hexahydro-1-hydroxy-6, 6-dimethyl-3- (1-methyl-3-phenylpropoxy) -6H-dibenzo (b, d ) piran-9-beta-ol (deep amorphous substance).
MS: (mol. Ion) 396.
d1-ba-beta, 7,8,9,10,10a-alpha-hexahydro-1-hydroxy-6, 6-dimethyl-3-cyclohexyloxy-bN-dibenzo (b, d) pyran-9-beta-ol, mp.214-216 0.
IR spectrogram (potassium bromide): OH, 3365 cmH, 3125 cm-.
MS: (mol. Ion) 346.
dI-ba-beta, 7,8,9,10,10a-alpha0-hexahydro-1-hydroxy-6,6 dimethyl-3- (1-methyl-3-phenoxypropyl) -6H-dibene (b, d) pyran -9-vvta-ol, so pl. 1511520с.
Kf 0.25 (silica gel, 9 parts sulfur ester: - 1 part hexane).
MS: (mol. Ion) 396.
Calculated,%: C 75.72; And 8.14; CfjigHj O / I
Found,%: C 75.79; H 8.39.
d 1-6a-beta, 7,8,9,10,10a-c1Lfa0-hexahydro-1-hydroxy-b, 6-dimethyl-3- (1-methyl-3-phenoxypropyl (-6H-dibenzo (b, d ) pyran-9-alpha-ol (butter-like product).
R 0.35 (silica gel, 9 parts sulfur ester: 1 part hexane).
MS: (mol. Ion) 396.
By performing various techniques, the analgesic activity (ED50 / µm / kg) of several
0 compounds of the formula (). The obtained data, expressed in terms of maximum possible efficiency, are presented in the table.
The following tables are used in the table with the following categories: PB (i - painful cramps caused by phenylbenzoquinone / TF - tail flinching, HP - hot plate, RTC - rat tail squeezing; F3 t sharp jump (jump); T1 - tests with immersion
0 tail.
- (CH)
-CH (CH) - (CHg) -CH (CH3) - (CH,) - CbH5. -CH (CH3) - (CH.j,) 4 -C4, Hjr -CH (CH), - (CHD) -CH (CHi) - (CH.i)
N, t
5.0 10 10 N.T
0.062 0.320.75 1.8
1.33 2.8 3.9, 2
0.94 1.6 5.6 N.T.
Table continuation

权利要求:
Claims (2)
[1]
Claim
1 '
1. The method of obtaining derivatives
dibeneo (b, d) piranha formulas I H 0R fjH ι ^Κ1(I) ηΎπι 1 -Z - w
where R is a hydrogen atom; ’
R. | - a hydrogen atom;
R _a and R ^ are hydrogen or methyl;
Z represents alkylene, containing from 2 to 7 carbon atoms; ' ~ (alk ₍ ) _n -O-Chalko ^ -, where each (alk [) and (alk ^) contains from 2 to 7 carbon atoms, provided that the sum of the carbon atoms in (alk ^) + (alk ^) is not exceeds 7, each of the values of η and η is an integer equal to zero or one;
W is methyl, phenyl, pyridyl, piperidyl or cyclohex, provided that
35 W is methyl, Ζ represents (alk _{ ) _t -0- (alk <2) _p , characterized in that the compound of the formula And where RJ is a hydrogen atom
R „and Rj g have the above g" meanings, they are subjected to reduction with a metal hydride complex compound and the target product is isolated.
[2]
2. The method according to claim 1, characterized in that as
55 metal hydride complex compounds use sodium borohydride.

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