CA1192564A - Process for preparing carboxy-3 keto-4 4h-benzo [4,5]cyclohepta[1,2-b]furan and products thus prepared - Google Patents

Abstract

The present invention relates to compounds of formula: <IMG> in which R represents a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms or an alkoxy radical having from 1 to 6 carbon atoms, and R 'represents a hydrogen atom or an alkyl radical having from 1 to 6 carbon atoms. These compounds are used in particular as intermediates in the synthesis of 4Hbenzo ¢ 4.5 derivatives! cyclohepta ¢ 1,2-b! furan with anti-fibrillating activity.

Description

5 ~ i ~

This is a division of the patent application No 389,724 filed Nov. 9, 1981.
~ a present invention relates to ceto 4H-benzo- / 4,5 / -cyclohepta / 1,2-b / furan acids.
The compounds which are the subject of the present invent.ion have the formula:
COOE ~
~; 3 Rl in which R represents a hydrogen atom, a radical alkyl having 1 to 6 carbon atoms or a radical alkoxy having from 1 to 6 carbon atoms; and Rl represents a hydrogen atom or a radical lS alkyl having from 1 to 6 carbon atoms; as well as their esters or chlorides of acids ~
These compounds are intermediaries obtained during the preparation of described and re ~ endic derivatives in the main application and responding to formula (I):
Rl - N -R2 X

~ ¦ ~ R (I) in which R represents a hydrogen atom, a radical alkyl having 1 to 6 carbon atoms or a radical alkoxy having from 1 to 6 carbon atoms, R 'represents a hydrogen atom or a radical alkyl having from 1 to 6 carbon atoms, X is a hydroxy radical or an oxo radical and Rl and R2, taken separately, independently represent one on the other, a hydrogen atom, an alkyl radical having , ~

5 ~

from 1 to 6 carbon atoms possibly carrying a cyano radical or a radical of formula:

- NOT
~ R5 in which R4 and R5 represent, independently one of the other, a hydrogen atom, an alkyl radical having 1 to 6 carbon atoms or form together and with the a ~ ome 0 of nitrogen on which they are fixed a morpholino radical, and Rl and R2, together, form with the atom nitrogen on which they are fixed, a morpholino radical or piperidino or piperazin ~ possibly relating to the second nitrogen atom an alkyl radical having from 1 to 6 carbon atoms or a phenylalkyl radical, the part of which alkyl has from 1 to 6 carbon atoms, or x is an amino residue ~ Oh ~ -R3 or a radical of formula = M - R3, R3 representing an atom of hydrogen or an xadical alkyl having from 1 to 6 atoms of carbon carrying e ~ entirely a radical of formula-- NOT \

in which R4 and R5 have the same meaning as that given above, Rl is identical to R3 and R2 is a hydrogen atom, or X forms with R2 a bridge = N - and Rl repre-smells of a hydrogen atom or an alkyl radical having 1 has Z carbon atoms possibly carrying a radical of 3.

formula:

- NOT

in which R4 and R5 have the given meaning pxeca-demment.
These compounds of formula (I) can also be present in the form of addition salts with acids ~
The compounds which are the subject of the present inven ~ ion can be prepared according to the reaction scheme following:
~ 7 ~ L CH - ~ ff ~ ~ * ~ C `~ C - C02CH3 II
3 2.; ~

2 ~ III
~ '~

C ~ CH CH 2 ~ ~> IV
R li 3 R

2_ ~ 2 --CH - CH2-- ~ V

R '. ~ 1 ~ 4 C () OH CO () H
- ~ H - ~ i2 ~ Vl Rl R
~ 1.5 CO ~ 1 COC 1 --I ~ CH - C ~ 2-- ~ VII

T ~ ' COOH
~ lJ v, II

R ' VIII

R ' ~ 7b o CO ~ l ll RX

R ' ~ 8c o C ~ ~
~ R XII

In this diagram R represents Ull hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms or a alkoxy radical having from 1 to 6 carbon atoms, and R ' represents a hydrogen atom or an alkyl xadical having from 1 to 6 carbon atoms.
The different stages of synthesis are the following before:
Stage 1: IsYnthese diene condensation is carried out) of a (~ -aryl ~ 2-alkyl furan (IIl with acetylene dicar-methyl boxylate in a solvent such as benzene. We obtains a derivative of oxa-7 bicyclo ~, 2, ~ 7 heptadiene-2,5 (IIII ~ he is not isolated.
Stage 2: Partial hydrogenation of the compound is carried out application of formula (III) in particular in ethanol in pre-sence of 10% palladium on carbon or in acetate 6.

of ethyl in the presence of Raney nickel. We get the consists of formula (IV) ~
Stage 3: This compound of formula (IV) is transformed ~ direct-according to a reaction from Alder Rickert in (~ -aryl) -alk ~ l-5 2 dicarbomethoxy ~ 3.4 furan (V).
St_de 4: By saponification of the diester (V), we obtain the diacid tVI) corresponding.
Stage 5: The diacid is transformed into dichloride (VII) by action of thionyl chloride.
Stage 6: An intramolecular cyclization of the dichloride IVII) in solution in car ~ one sulfide in presence of aluminum chloride. ~ e aqueous treatment of reaction product gives a keto acid of formula IVIII).
In ~ ariante, the keto-acid (VIII) can also be obtained by direct cyclization of the diacid (VI) in polyphosphoric acid between 100 and 130C.
Stage 7b: Treatment of the keto acid (VIII3 by the thionyl chloride leads to acid chloride ~ X).
Stage 8c: I, treatment of the acid chloride (X) with the methanol leads to the ester (XII).
Of course, by continuing the reaction steps -above mentioned according to the following diagram, there is possible to obtain the derivatives of formula I making the subject of the main application, the formula compounds VIII, X or XII being used as intermediaries in the main request process for obtaining said compounds of formula I.
- =
-/

~ 25 ~ i ~
7 ~

~ RVIII

2 1 ~

C ~ n ~ x RI 1 ¦ 2 0 ~ ~~~ 3 ~ j ~
CO ~ XI + H2N ~ C ~

Ib ~ Ri ~ XIII
NH HO l`i- ~ '9c / XII

~, + H2N R
R '\ lOc R ~ R2 'P ~ H

C) ~ 3R C ~ _R

Ibl Ic 8.

In this diagram R and R 'have the same meaning than in formula (I).
R'l, R "l and R" 2 as well as R "'l ~ have the meanings Fications given for Rl, R2 and R3 respectively in the case where X forms with R2 a bridge, X is an oxo group or hydroxyl and X is a group OH
/
= N - R3 or ~

The different stages of synthesis are the following praises Stage 7a ~ Treatment of ceto-acid (VIII3 with a hydxazine ~ IX ~ leads to a compound of formula (I) in which X forms with R2 a bridge = N - (formula Ia ~.
Stage 7b: Treatment of ceto-acid (VIII) with thionyl chloride leads to acid chloride (X).
Stage Bb Treatment of acid chloride (X) with a _.
amine (XI) leads to a compound of formula (I) in which X is an oxo radical (formula lb).
Stage 9b: The reduction of compound (Ib) by BH4K leads to composed of formula (I) in which X is a radical hydroxyl (formula I'b).
Stage 8c: Treatment of the acid chloride (X) with the methanol leads to the ester (XII).
Stage 9c: Treatment of the ester (XII) with an amine (XIII) leads to compound Ic '; this product can be equal-ment obtained by treating the acid chloride (XI) with the amine (XIII) in excess. Derive Ic 'by dehydration leads to the compound of formula (I) in which X is a radical = N - R3 (formula Ic) (stage 10c).
Some of the compounds of formula ~ used as starting material for the synthesis of the compounds of 2 ~
9.

Foxmule VIII, X or XII according to the invention are known (Freund, Immerwahr Ber. 1890, 23, 2847 and RB Woodward J. Amer. Chem. Soc. 1940, 62, 1478).
The preparation processes described have not gives satisfactory results, however. Also these compounds were prepared according to an original process including the reaction scheme is as follows:

10.

CHO ~ CH ~ -C ~ JX ~ V

R

`o` CH - C ~> XV

~ / R ~ 'MgX XVII

~ O ~ CH2 - C ~ XVI 1 ~ 1 / XVI II
R '~ 3 P ~ R

, ~

~ C112 -CH2 ~ L fH ~ CH2 ~
R ~ R
IIa II ~

11.

This process ~ onsiste to condense tQut d ~ ab ~ rd the ~ urural with an arylacétQnitrile ~ XIV ~ in the presence of ethylate sodium.
This gives an aryl-2 (~ -furyl ~ -3 propene-nitrile (XV ~ with good yield.
To prepare the compounds of formula ~ II) in which Rl is a hydrogen atom (formula IIa), we performs a hydrogenation using the borohydxllre of potas-sium in hydro-alcoholic solution. The saturated nitrile obtained ~ 0 (XVI) is then subjected to a reductiYe scission by sodium and ethanol. To prepare the compounds of formula II) in which R 'is different from hydrogen ~ formula IIb) on performs an addition of the organomagnesium (XVII3 on the nitrile (XV ~ and the saturated nitrile obtained is subjected to a scis ~
reductive sion by sodium and ethanol.
The following examples illustrate the preparation c ~ mposes which have object of the invention.
A. - PREPARATION OF STARTING COMPOUNDS
(a3 Phenyl-2 ~~ furyl) -3 ~ ro ~ enenitrile ~ 0 ~ ,, C -~ 9 ~ LC ~ = C ~>

In a six-liter flask fitted with an agitator m ~ canique / of a bulb with bromine and a refrigerant, one intro ~ uit 5 moles of furfural freshly distilled and 5.10 mole ~ of benzyl cyanide. The flask being cooled on ice, with stirring, is added by the bronchial bulb ethanolic sodium eth ~ late solution prepared from 23 9 of sodium and 4 ~ 0 cm3 of pure ethanol. The reaction is exo-thermal. Five minutes after the addition of the ethylate, we add 65 g of acetic acid, 2.5 liters of benzene and 1 liter of water. The gold ~ anic phase is decanted, washed with e ~ u ~ and dried over sodium sulfate. After removing the benzene, the residue is distilled ~ or reduced pressure.
Minimum yield: 95%
E / 15 mm Hg. 190-19SUC
F: 41-42 ~ C

5 ~

Yellowish crystals browning in air.

(b) Phenyl-2 (c ~ -furyl ~ -3 ~ roEanenitrile ~ The In a 2-liter flask with 3 tubes, fitted a mechanical agitator and a coolant, hot 200 g of phenyl-2 ~ -furyl ~ 3 propenenitrile in 300 c: m3 of absolute ethanol. The cooled solution is addi ~
with 30 9 of finely pulverized potassium boruhydride laughed, then 100 cm3 of water. The mixture is brought to reflux for 7 hours, then left for 12 hours at temperature ambient ~ After ~ acidificati ~ n per 50 ~ m3 of acetic acid, the ethanol is distilled. The residue separates into two layers.
~ n benzene extract (500 cm3 ~ The benzene solution is washed with water, dried on ~ sodium ulfate. After elimination benzene, the saturated nitrile is distilled under pressure scaled down.
Yield: 170 g, 85 E / 13 mm Hg: 167-168C
n ~: 1.5444 (c) 2-Phenethyl furan ~ ~ 2 ~ ~ .H ~

In a two-liter flask with three tubes 9 equipped with an agitator, a refri ~ erant and an amp ~ ule bromine, 37 9 of sodium are hot dispersed in 175 cm3 of boiling toluene ~ Heating being stopped and stirring now ~ n adds pa.r ll bulb 0.25 Mole of phenyl-2 I ~ -furyl) 3 propanenitrile mixed at 40 cm3 s ~ '~
13 ~

absolute ethanol. The addition is adjusted so as to nir a self-maintained reflux of the mixture ré ~ ctionnel- On ajsu ~ e hanol ~ drop by drop so as to destroy the sodium by excess. The mixture is then cooled, treated with one liter 5 of water. It separates into two layers. The organic layer is separate; the aqueous layer is sat ~ rée of sodium chloride and extracted with toluene 1400 cm). Organic solutions 50nt mixed, washed with water and dried 5ur sulfate sodium. After distillation of toluene, the residue is rectified under reduced pressure.
Return: 90 ~
E / 10 mm ~ g: 112C
nD19 ~ 1.5 ~ 85 d 19: 1.023 We have gathered below the characteristics compounds of formula ~ II3 prepared by reclective splitting corresponding saturated nitriles.

. 19. _ _.
dd E ~ mm DD d ~ dt gross F Cal. tr. C ~ l. tr.

HH 1121o 1.5385 1.023 sn C12H120 83 ~ 73 83.70 6.97 7.1 H CH3 11hl2 1.5315 1.005 88Cl3H14083.88 83.80 7.52 7, t R C2H5 t2511 l, 5247 0.995 90C14Hl6084.00 83.75 8, a, 3 H n C3H7 13612 1.5200 0.981 85Cl ~; H ~ 80 84.12 83.90 B, 39 8.5 H n-CgHg 146; 2 1.5158 0.966 83C16H200 ~ 4.22 83.90 8.77 9.0 H n-C5 ~ 11,156; 2 1.5123 0.968 85C17H22D 34.31 84.30 9.08 9.1 H C6HS 19114 1.5780 1.074 80C18H16087.10 86.50 6.44 6.4 HC ~ i2-C6H 194; 2 1.5695 1.062 87Cl gHl ~ 0 87.03 87, D0 6.86 7.1 P.OCH3 H 15614 1.5420 1.074 60C13 ~ 142 77.24 77.25 6.92 7.0. _ 1 ~.

B. - PREPARATION OF GOMPOSES ACCORDING TO THE INVENTION
(1) Phenethyl-2 dicarbométh ~ y ~ 3,4 furan CH ~ OCO C00CH ~

H ~ -C ~ l2 - ~ 3 ~ a) Diene synthesis ~ 02C} ~

e ~ + CH ~, OCO-C_C-C02CR ~
(H2 ~ 2 ~ H2 C ~ 2 ~

In a 1 liter flask, 0.5 mole of phenethyl-2 furan, 71 g of acetylenedicarboxylate methyl and 120 cm of benzene. The reaction mixture is brought to reflux for 6 hours. At the end of this time, the tear gas character of dies ~ er acetyl has practically disappeared ~ Benzene is removed under reduced pressure; the 300 cm3 of ethyl acetate are added to the flask residue (b) Partial hydro ~ enation .

2 ~ C0 ~ CH ~
~ Ni ~ ney d ~ ~ H2 ~ ~ \
~ co2c ~ 3 I co ~ c ~ i3 lH2 ~ 1 ~ 2 CH2 ~ 2 at 15.

The ethyl acetate solution obtained in the stage above is hydrogenated in the presence of 10 g of nickel Raney prea ~ ably washed ~ with water (three times3, with ethanol (~ kings ~ sis) e ~ with acetate of ~ hyle (~ kings ~ ois) ~ this washing rigorous allowing better dispersion of the catalyst in sc, lvant used ~ The reaction is exotherm ~ ique, and lasts at most 45 minutes to 1 hour ~ fixing from 11/2 to 11.4 liters hydrogen). The solution is filtered; the iltrate is eYapore under reduced pressure. The viscous and brown residue is introduced into a 2S0 cm3 Vigreux balloon mounted for distillation under reduced pressure (capillary tube, thermo-metre).
(c3 P ~ rolysis ¦ C2 3 200 ~ 2H4 CH2 ~. ~

The previous tank is connected to a refrigerant, a separator and vacuum of an eaU horn; the initial pressure tial is 12 to 15 mm of mercury. During heating, the thermolysis of the partial hydrogenate gives off ethylene which is eliminated in the water pump; there is an increase in internal pressure, this does not return to its initial value only when the pyrolysis is complete. We then distill the residue from the ball, taking care to avoid overheating We have gathered in the table below the characteristics of the compound thus prepared as well as those other compounds of formula (V) prepared analogously Unable to recognize this page.

17.
(2) Pheneth ~ l ~ 2 dicarboxy-3, ~ furan } ~~ C0 ~ C ~ 2 C ~ 2 ~
We bring ~ e reflux for 5 hours a mela ~ e 0 ~ 2 M phenene ~ hyl-2 dicarbomethoxy-3,4 .furan, 56 9 of potash, 200 cm3 of e ~ hanol e ~ 70 cm3 of water ~ Ethanol es ~
then distilled at ambient pressure, the residue is added 200 ~ m3 of water, cooled and poured on 100 cm3 of chlorine acid pure water ~ about 12 N). The precipitate is washed with water, dried. It is recrystallized from the ethanol ~ water mixture, We have gathered in the table below the characteristics of the compound thus prepared as well as those other compounds of formula (VI) prepared in an ana-log ~

_ O Rende- Formula C ~ H ~
FR 'FC m ~ nt ~} ~ t ~ Cal ~ tr. C 1. t, HH 148 98 14 12 5 64.61 65.05 4.61 4.63 H3 207 98 ~ 15H145 65.70 65.35 5.10 4.35 HC2H5 167 98 C16H165 66.66 66.00 5.55 5.25 p.CCH3 H 165 ~ 6 62.07 62.20 4.82 4.73.

1 ~.

(3) Carboxy-3 one ~ 4 4H-benzo ~ 4, ~ J cyclohepta (1,2-b) furan (at) ~ co co211 o 2 2 ~ ~~~~~~~

26 9 of phenethyl-2 dicar ~ oxy-3,4 crude furan and dry are finely pulverized and mixed with 2ao 9 of poly-commercial phosphoric. The mixture is stirred and heated For 30 to 40 minutes between 100 and 130C. At the end of this time, the reaction mixture is poured with stirring into a beaker containing 700 cm3 of water ~ The crystalline precipitate obtained is filtered, washed with water and recrystallized from chloroform after charcoal bleaching ~
Yield: 19.5g, 80%
F. ~ 174DC
b) Yariante HOCO CO H
2 ClCO COCl o \ CH2 - ~ 2 <~.> SOC ~ 12 \ ~ CH2 - C ~

I ~ OCo, f ~ ClCO ~ / lC13 A mixture of D, 25 M of 2-phenethyl-3,4-dicarboxy furan, 120 g of thionyl chloride. The excess of thionyl chloride is removed in vacuo, and the furan acid dichloride residue raw picnic is diluted in 250 cm of carbon sulfide ~

5 ~
19.

In a ~ liter flask with three tubes, provided a mechanical stirrer, a cooler and a light bulb bromine ~ 75 9 of aluminum chloride and 600 cm3 of carbon sulfide. The mixture is brought to reflux for S the dropwise addition of the sulfocarbon solution of furanni acid dichloride. The reflux is maintained for 2 hours after total addition. At the end of this time, the dega-hydrochloric acid is practically finished. At rest, the reaction mixture separates into two layers liquid layer is decanted, washed with water and dried on sodium sulf ~ te. After distillation of the carbon sulphide, about 3 9 expected ketonic acid is collected O The layer solid is decomposed by gl ~ ce (1 kg), the reaction being very lively and accompanied by vapors of sulphide of carbon and hydrochloric acid ~ hydric ~ After decomposition, the alu-mine is soil ~ mobilized by adding 100 cm3 of chlorine acid water ~ The precipitate is filtered ~ washed with water and dried O On recrystallizes it from chloroform after bleaching with coal ~
We have collected in the table below the characteristics of the compound thus prepared as well as those ~ 'other compounds of formula (VIII ~ ana prepared log.

. R FC ¦ R ~ t Fo ~ le ~
. ~ gross Calc. tr. ¦ Calc. I tr.

CH3 ¦ 15 12 4 70 31 70 CO I 4 6 ~ 4 40 1 ¦C2H5 107 50 Cl6H14 ~ 4 71 11 70 40 1 5 18 5 00 ~.

20.

fur ~ nne HOCO ll Cl ~ CO
SOClz ~ ~ ~

The mixture is brought to reflux for 4 hours ~ a mixture of 70 9 of carboxy-3 one-4 ~ -benzo (4, 5 ~ cyclohepta- ~ 1,2-bJ-furan, 90 g of thionyl chloride and 110 cm3 of toluene.
The solvent and excess reagent are evaporated in vacuo. The the residue is taken up hot with 120 cm3 of toluene, and discolours on charcoal. We filter. The filtrate added with 30 cm3 petroleum ether is cooled on ice ~ We collect a first jet of 65 ~ white crystals.
Yield: 86.3%
: 92C
(5) furan ~ 0 C) Q
C 1 CO ~ C, HOCO

Is brought to reflux for 15 hours a melan ~ e of 0.1 M ketonic acid chloride and 200 cm3 of methanol.
(The reaction can be accelerated by adding 15 cm3 of pyridine). The methanol is then distilled. The residue is added 100 cm of benzene, washed with water, to a solution saturated with sodium bicarbonate ~ then back to water.
After drying over sodium sulphate and elimination of ben2ene ~
rectified under reduced pressure.
Yield: 85 to 90 E / 16 mm ~ g: 2 ~ 4C
F: 53C

21.

C) MODE: PREFERRED PREPARATION OF THE COMPOUNDS OF FORMULA (I) OF THE MAIN APPLICATION OR THE COMPONENTS OF THE INVE ~ TIGN
ARE USED AS INTEP ~ REACTIONAL MEDIA
We repeat, as the case may be, steps 1 to 3, 1 a

4 or 1 to 5 ~ above mentioned, then:
(6) Diethylaminoethylcarboxamido-3 diethylamino-ethylamino-4-hydroxy 4 4H ~ benzo (4,5) ~ cyclohepta (1,2-b) fuxanne (dial 1) (C2H5) 2- ~ CH2 2 j C ~ 2-N (C2H5) 2 o HO NH
CH3 (? LO ~ C ~

2 H2N-CE ~ 2-CH2 N (C2U5) 2> ~ ~

25.6 g of ketone ester (10.10 M) are added 35 g of N-diethylethylenediamine co ~ nerciale. The mixture is refluxed for 6 hours. Amine llexces is then remove under vacuum. The viscous residue is taken up per 120 cm3 of ben ~ ene and discoloured with charcoal. The filtrate is cooled and adds 20 cm3 of petroleum ether.
17.5 g of yellowish crystals are collected.
Yield: 40%
F: 133C
Analog: C,% H,% N,%
calculates for C26H40NgO3 68.42 8.77 12.28 finds 68 8.36 12.00 This derivative can also be obtained by reaction acid chloride with excess amine.

5 ~

fl o O = C ~ ~ C2H ~ ;, ~ H2 (CH2) C2H5 / C ~ 5 N - CH2 ~ l ~ 2 CH ~ - CH2 - N

O = C ~ 3 In an erlenmeyer flask placed SOU5 magnetic agitation tick, in a cold water bath, pour 55 ml ~ 0.39 mole) of N, N-diethylethylenediamine and added ~ by small reactions 20.3 g (0 0778 mole) of ~ 3-chloro-carbonyl one-4 4 ~ -benzo ~ l4 / 5J-cyclohepta ~ 1,2-b) furan ~
The mixture is stirred for 10 hours at room temperature. After reaction, 100 ml of ethyl ether are added, ess ~ re and washed with ether. After drying, we obtain 1 ~, 5 9 of cream crystals melting at 125-130C (gross yield: 55%) ~
This crude product is dissolved in 100 ml of ~ hloro-form, passed over Merck activity I alumina, brought to dryness, and recrystallized from acetone. 13.4 9 of crystals are obtained whites f ~ n ~ ant at 133C ~ yield: 37.5 ~).

Analysis: C,% ~, ~ N, ~
theory68.39 8.33 12.27 found 6B, 39 8.81 72.31.
(7) 1 ich] ~ r ~ d ~ of dieth ~ lam_no-ethylcarboxamido-3 aiethylamino 4-ethylamino 4H-benzo l4.5J cyclohepta ~ 1,2-b) -furan * Brand of cor ~ merce 23.

C2H5 \ / C ~ 5 2 NH 1 ~ 2 2 \ C2H5 HCl ~ _ I HO NH
~ Y ~ 3 \ N - (CH) ~ / 2 5 ~ 3 HCl Stirred at room temperature for 4 hours, 4.56 9 of diethylamino-ethylcar ~ oxamido-3 diethylamino-ethyl-4-amino-4-hydroxy 4H ben20 ~ 4.5 ~ cyclohepta ~ 1,2-b) furan (0.01 mole) and 50 ml of 1N HCl (0.05 mole). We get: i ~ nt a clear, light yellow solution. After rection, we cha ~ se solvent under vacuum. The oil is dissolved at room temperature obtained in 150 ml of acetonitrile. We treat this solution per 2 g of black. We filter. We flush 100 ml of ~ olvant under empty and left for 48 hours at 0C.
3.36 9 of cream crystals are wrung ~ product hygroscopic). ~ F = 173 ~ Cj yield = 6115% ~
Analysis after drying C26H33N4O23 HCl = 548 C, ~ H, ~ N, ~
Theory 56.97 7.54 10.22 19.40 Found 56 ~ 85 7.37 10.20 19:38 5 ~ '~
24.

~ 8) Morpholino-eth ~ l-2 oxo-3 dihydro ~ 2? 3 ben20 (6 / 7l cyclo-hepta l1 ~ 2f3-c ~ dJ furo ~ 3 ~ 4-dl pyridazine (compc ~ sé n ~ 2 ~ o A 8 9 of morph ~ lino-é ~ hylhydra ~ ine in 100 cm3 of n-propanol ~ we add ~ ute 12.2 g of keto acid prepared in 3 (R = R '= H ~. The mixture is brought to reflux for 4 hours; propanol is evaporated under reduced pressure. The brown residll is subjected to hot extraction by 50D cm3 of ether. The ether is evaporated. ~ e residue visq ~ them is recris-tallized in ethanol ~ after bleaching on charcoal.
Yield: 45.6%
Weight: ~ g ~: 135C
Analysis: ~ L_ ~ R,% N ~ ~
calculated for ~ 0 ~ 21N33 68.37 5 ~ 9B 11.96 found 5a 5t8 11.6 (9 ~ Oxo-3dihydro-2,3ben ~ o ~, 7Jcyclohe ~ tal1,2,3-c, dJ-furo l3,4-d ~ z ne ~
We bring to reflux for 10 hours ~ a melan ~ e 2 g of this ~ acid prepared in 3, B cm3 hydrated dihydrazine and 40 cm3 of acetic acidO The solution is concentrated to 10 c ~ 3 under vacuum, and pour2e dan ~ a mixture of 30 cm3 of chlorine acid water and 100 cm3 of water. The precipitate is washed with water, dried and recrystallized ~ 3 years chloroform. The constants of products obtained are summarized in the following table (R =
H).

I _, ~ _ C% IH ~ N%
How to posed R 'F ~ C gross CalC tr. Calc. tr. Calc. ~ r.
_. _ __.
3 H 258 14 lON22 70.59 70.53 4.20 4.73 11.76, 5C

4cT._3 186 C15H12 2 2 71.43 71.30 4.76 5.92 ll, lo llloo 5 ~ 173 C16 ~ zO ~ 72,1B 7l, 73 26 ~ i L__ 5 ~
25.

(1D ~ a ~ _arboxamido-3 oxo-4 4H-benzo t4,5 ~ c ~ clohel ~ ta ~
~ -b J furanne (R - R '= ~ 1 ~ R2 = H) (compound n ~ 6).
A 25 9 of chlorule ~ 'crude acid obt ~ nu cn a ~, cooled sllr ice, add carefully 200 cm3 to 'ammo-S niac previously cooled. The precipitate is filtered, washed with water and dried. It is recrystallized from acetic acid.
Quantitative yield ~ White crystals. F ~ 253Co analysis: C,% ~ N,%
calculated for C14H11 ~ 3 69.71 4.56 5.81 ~ found 69970 4.50 5.70 . b) N-alk ~ lcarboxamido-3 oxo-4 4H-benzo (4 ~ 5 ~ -cyclohepta (1,2-b) fura_ne (R = R '= H ~ Icomposés n 7, 8 ~ 9) Acid chloride is prepared from 1 ~ g of keto acid ~ R = R '- H), and diluted in 50 cm3 of toluene.
It is added dropwise to a cold solution of 0.2 M
of amin ~ in 125 cm3 of toluene. After 30 minutes of reflux, the mixture is washed with water ~ dried over ~ ul ~ sodium ate, filtered and concentrated under reduced pressure. By addition of ether, a yellowish precipitate is obtained which is recrystallized read in carbon tetrachlor. The yield is quantitative.
The constants of the amides are summarized ~ on following table (R = R '= ~) Icomposés n 3, 4, S ~

_ ~
C% H ~ ~ ~
Com ~ R, R ~ FC Formula _ _ _.
1 ~ Calc. tr. Calc. tr. Calc.¦ tr ~
gross posed ~ _ ~ _ ~.
7 (C2H5) 2 118 C18H19 ~ 3 72.72 71.80 6.40 6.40 4.71 4.60 8 H, n.C3H7 112 ~ Cl7Hl7 ~ o3 72.08 71.20 6.00 5.90 4.94 4.90 9 ~ C1 ~ 2 ~ 5 147 lcl9Hl9No3l 73 ~ 78 72.95 $ 6.1 6.20 4.53 4.00 .

26.

We prepare other compounds of the same type according to the following operating mode:
In a flat-bottomed Erlenmeyer flask, topped with a refrigerant and a bulb with bromine, we introduce 3 M / 100 ~
cetonic acid chloride (R = R '= ~), 30 cm3 of tetra-anhydrous hydrofuran. The solution is carried on a plate heater with a magnetic stirrer ~ By the bulb to bromine, a mixture of 3 M / 100 of diamine is added and 10 cm3 of tetrahydrofuran; precipitation of chlorhy-drate is instant. After 5 minutes of reflux, it cools on ice; the precipitation is completed by addition of 10 cm3 of anhydrous ether. We filter and recreate mixes in ethanol. The yields are quantitative.
Melting points are determined on a block of Maquenne.
-Unable to recognize this page.

28.
(11) Piperidinocarbonyl-3 hydroxy-4 4H-benzo (4,5) cylohepta (1,2-b) furan (compound n ° 14) A mixture is brought to reflux for 3 hours 10 g of compound No. 9, 3 g of potassium borohydride, 60 cm3 of ethanol and 10 cm3 of water. Solvents are then evaporated under vacuum. The residue, taken up by water, yields 9.5 g of white crystals, which can be recrystallized from the toluene.
Yield: 95%
F: 158 ° C
Analysis: C,% H,% N,%
calculate for C19H21NO3 73.31 6.75 4.50 finds 72.60 6.60 4.45

Claims (2)

The embodiments of the invention, concerning the-what an exclusive property right or lien is claimed, are defined as follows: 1. Process for the preparation of responding compounds to the formula in which R represents a hydrogen atom, a radical alkyl having 1 to 6 carbon atoms or a radical alkoxy having from 1 to 6 carbon atoms, R 'represents a hydrogen atom or a radical alkyl having from 1 to 6 carbon atoms, their esters or acid chlorides, characterized in that (a) a (.beta.-aryl) -alkyl-2- is condensed furan of formula:

(II) in which R and R 'have the above meanings mentioned, with methyl acetylene dicarboxylate in a solvent and an oxa-7 derivative is obtained bicyclo [2,2,1] heptadiene-2,5, (b) a partial hydrogenation of this compound is carried out and we obtain a compound of formula:

(IV) (c) this compound of formula (IV) is directly transformed according to an Alder Rickert reaction in (.beta.-aryl) alkyl-2 dicarbomethoxy-3,4 furan of formula:

(V) (d) saponify this diester (V) and obtain the diacid corresponding;
(e) the diacid is transformed into a corresponding dichloride by action of thionyl chloride;
(f) an intramolecular cyclization of the di-chloride in solution in carbon sulfide in presence of aluminum chloride, and - either the reaction product is treated with water -nel and we obtain a keto acid of formula:

- either the reaction product is treated with water -nel, obtains a keto acid of formula that we react with chloride thionyl and obtains an acid chloride of formula:

- either the reaction product is treated with water -nel and obtains a keto acid of formula reacts this keto acid with chloride thionyl and obtains an acid chloride of formula then reacts this acid chloride with a alcohol to obtain the corresponding ester. 2. Compounds of formula:

in which R represents a hydrogen atom, a radical alkyl having 1 to 6 carbon atoms or a radical alkoxy having from 1 to 6 carbon atoms, and R 'represents a hydrogen atom, an alkyl radical having from 1 to 6 carbon atoms, their esters and acid chlorides, cha-that once they are obtained by a process according to the res indication 1 or its obvious chemical equivalents.