CA1159057A - Process for preparing 7,8-dihydroxy-1- (sulfamylphenyl)-2,3,4,5-tetrahydro-1h-3-benzazepine derivatives - Google Patents

Abstract

PROCESS FOR PREPARING 7,8-DIHYDROXY-1-(SULFAMYLPHENYL)-2,3,4,5-TETRAHYDRO-1H-3-BENZAZEPINE DERIVATIVES

ABSTRACT OF THE DISCLOSURE

A process for preparing new 7,8-dihydroxy-1-(sulfamylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepines having pharmaceutical activity. The lead compound is 6-chloro-7,8-dihydroxy-1-(p-sulfamylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine which has renal dopaminergic together with antihypertensive activity.

Description

-`} I 159057 PROCESS FOR PREPARING 7,8-DIHYDROXY-l-(SULFAMYLPHENYL)-_ _

2,3,4,5-TETRAHYDRO-lH-3-BENZAZEPINE DERIVATIVES

This invention comprises a process for preparing a new group of l-phenyl-2,3,4,5-tetrahydro-lH-3-benzaze-l5 pines whose structures are characterized by having a r~
sulfamyl group (-SO2NH2~ present on the phenyl ring.
The end products have pharmaceutical activity especially as renal dopaminergic and hypotensive agents.
Very few l-phenyl-2,3,4,5-tetrahydro-lH-3-benza-zepines whose structures have a thio containing phenyl substitutent are known in the art. U. S. Patent 4,104,379 describes a series of such benzazepine structures which have a lower alkyl thio, lower alkyl sulfonyl, lower alkyl sulfinyl or dimethylsulfonium halide substituent on the l-phenyl ring. There are no disclosures in the art of either l-phenyl-2,3,~,5-tetrahydro-lH-3-benzazepines with a sulfamyl substituent on the l-phenyl group or a synthetic method readily available for preparîng them.
This invention comprises a chemical process for preparlng compounds of the following structural formula:
'~

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, ", ~ :" " ~ ," :,," `~ ~,"

--`` l 159057 1 ~2 HO ~ ~
~ ~ Rl R3~_ N~4 ` 5 I
in which;
Rl is hydrogen, allyl or lower alkyl such as methyl or ethyl;
R2 is hydrogen, halo such as chloro, bromo, fluoro or iodo or lower alkyl such as methyl, ethyl or propyl;
R3 is hydrogen or, when R2 is other than hydrogen, also halo or lower alkyl; and R4 and R5 are hydrogen or lower alkyl~ or when R4 and R5 are lower alkyl, di-O-Lower alkanoyl esters thereof.
Also included is the optional preparation of O-alkanoyl esters and acid addition salts of the basic compounds of Formula I with pharmaceutically acceptable acids said salts;having the same pharmacodynamic activity 25 of the bases with non-limiting side effects. Exemplary of ;~
such organic or inorganic acids are maleic, malic, fumaric, succinic, methanesulfonic, ethanedisulfonic, salicylic, citric, hydrochloric, sulfamic, phosphoric, nitric, sulfuric or hydrobromic acids. Other~solvates ; 30 such as hydr;ates may also be present. The~salts are prepared by methods known to the art such as reacting the base with an excess of acid in a lower alkyl alcohol or a similar organic solvent.
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1 The term "lower alkyl", whenever used in the definition of the compounds of Formula I, is meant to contain from 1-4 carbon atoms. Also O-alkanoyl esters having from 2-6 carbon atoms in each alkanoyl group may be optionally prepared by methods known to the art, such as reaction with an alkanoyl halide in the presence of a tertiary organic base, with any reactive nitrogen centers such as the 3 ring member or the amino portion of the sulfamyl group protected~ Exemplary of such O-alkanoyl derivatives are acetyl, valeryl, isobutyryl or propionyl.
The new end compounds of Formula I have pharmaceutical activity especially hypotensive activity The compounds of Formula I in which R3 is hydrogen also have pronounced dopaminergic activity as is disclosed more specifically below.
The compounds described above are prepared by the following reaction of this invention:

R2 ~2 R7 ~ ~N Ri ` R5 R7 ~ ! N-Ri -> I

~ 52X ~ 2 `R

II III

The intermediates of Formula II have R2, R3, R4 and R5 as defined for Formula I; X is chloro, bromo or a similar displaceable group; Ri is lower ; alkyl, allyl or a N-protecting group such as trichloroacetyl, benzyloxycarbonyl, trifluoroacetyl or ., '',.:'.

1 ~90~7 1 benzyl; R6 and R7 are lower alkyl of 1-4 carbons especially methyl or, when taken together, ethylene or especially methylene.
The term "N-protecting group" is used to indicate that the 3-substituent is inserted to prevent the chemically reactive hydrogen on the ring nitrogen member of the intermediate (II) from being affected during reaction. It is then removed after the desired chemical reaction by standard reactions to regenerate the secondary amine. Such groups are commonly used in the polypeptide or antibiotic arts. Groups commonly used are tert.-butoxycarbonyl, trichloroethoxycarbonyl, p-methoxybenzylcarbonyl, isobornyloxycarbonyl, trityl, benzhydryl and others suitable for protecting a secondary aminO function-The reaction, II ~ III, is run in an organicsolvent inert to the reactants and in which the reactants are soluble such as dimethylformamide, dimethylacetamide, tetrahydrofuran or dimethylsulfoxide. The amine reactant, HN ~ 6, is usually employed in excess. The reaction is carried out at any convenient temperature until completion. For example a temperature chosen from the range of about 0C to room temperature is most convenient. Compound III may be isolated by methods known to the art or may be reacted further without purification to remove any blocking groups represented by Rl, R6 or R7 by methods known to the art. Exemplary of means to ;~
remove 0-ether protective groups are boron tribromide or trichloride, 48% hydrobromic acidl aluminum chloride or other dealkylating agents. The N-protecting groups at po~ition 2 are more easily removed such as by acid or base treatment. These may also be removed during the dealkylation described above.

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1 The following reaction sequence illustrates the overall series of reactions which is conveniently used to prepare the compounds of this invention:

SEQUENCE A
.
~2 R2 Na~3-N ~ ~ N-R

R~N R3J~3--a4 ~1~ (2) `.
R~2 R2 ~ i ? CN2 ~X~jN Ri R3 R3 1 :

~ OH ~ O-C-N(CH3)2 . (3) (4) `:

R2 R2 , .

j~ N--Rl ~H20 ~ a~J ) : '~/

R3 ~ -CN-NtCE3)2 R ~ 3R

(5) (6) ' `~` ` ' ' ` '` ' '' ' ` '` ` . :'` ~ ` ` ' :' ~ 1590~7 (7) (8 ~ S2 C~2 ~ N-H ~0 ~ ~
~ 0~ ~ 1I N-H
~r ~ EIO- ~-- .

~ ' 4 ~ ~ S02N~
` (10) Formula I, Rl =
In reaction sequence A, Rl is a protective group for a secondary nitrogen as described. In the illustrative sequence, if the starting material (1) has a structure with a 3-allyl or lower alkyl substituent, there ;~
is no need for using such a protective group. R2, R3, R4, R5 and X are as defined above.
The preparation is dependent on a sulfur-oxygen interchange reaction (4 ~5) to introduce the sulfur ~;~
function directly onto the l-phenyl ring.
The protective means for the 7,8-dihydroxy ~roups is conveniently the methylene (-CH2-) link as illustrated above. This system is easily produced in good yield by the selective reaction of a methylene dihalide at the 7,8-position of the appropriate triol (2). The ethylenedioxy system is also conveniently used for this reason by reaction with an ethylene dihalide. `~
7,8-Di-lower-alkoxy-l-(hydroxyphenyl)-~,3,4,5-tetrahydro-lH-

3-benzazepines are less convenient to prepare because of a lack of selectivity in the formation of the ether derivative. They are, however, available in the p}ior art and can be alternatively used.

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1 The second illustrative sequence for preparing the starting materials to illustrate this invention comprises the formation of the 7,8-dialkoxy-1-phenyl-2,3,4,5-tetrahydro-lH-3-benzazepine nucleus with a sulfur function present on the phenyl ring which function may then be converted optionally to the various sulfamyl groups which characterize the structures of the compounds of this invention.
SEQUENCE B

/\ + R60~CH2-CH2-~H2 ~ CH~C6H5 R70 ~
~1) (2) R :

20 R6 ~ C~2 l~2 R60 ~ NH -~

R7 ~ H0~ / H2 R3 CH R3f ~ ~ ~ SCH2C6H

I! ~SCH2C6H5 ~ ,:
(3) (4) .;.

' ~' .. .....
~ .. . : ; .

. '. ~ ~ :' . . ::

-~ ~15~
R2 - 8 ~ R2 l R6O - ~ N-R' R6O
R~O ~ _~ R~O ~ ~

~CH2C6H5 , ' 13--so2x ~5) (6) 10 R60 ~\

~ 2~ ~ R54 ~ SO2N~
(7) (8) I
Reaction sequence B is particularly adaptable to the use of the 7,8-dialkoxy-system of protecting the 7,8-dihydroxy groups however the methylenedioxy or ethylenedioxy derivatives are equally useful for this purpose. Of course the ~inal steps (6-8) are as disclosed above. The symbols are as defined above.
The new compounds of this invention of Formula I
in which R3 is hydrogen are of particular interest in having activity as antihypertensive agents having at least in part a renal dopaminergic mechanism. In a single preliminary screening test the exemplified compound in which R2 and R3 are chloro demonstrated no renal dopaminergic activity.
The active dopaminergic compounds which are part of this invention therefore stimulate peripheral dopamine receptors, for example, they increase renal blood flow and have as an end result antihypertensive activity. This renal vasodilator activity of the designated benzazepine ;; ~ i " ' : , !.

~ . , ~, 1 compounds of Formula I is measured in an anesthetized dog. In this pharmacological procedure, a test compound is administered at progressively increasing (3-fold) infusion rates beginning at 0.1 mcg/kg/min up to 810 mcg/kg/min Eor 5 minutes each to anesthetiæed normotensive dogs and the following parameters are measured: renal artery blood flow, iliac artery blood flow, arterial blood pressure and heart rate. Results are reported as a percent change, increaise or decrease, at time of peak response (from pre-drug controls), and for a significant effect renal blood flow (increase) and renal vascular resistance (decrease) should be approximately 10% or greater. The effect on renal vascular resistance can be calculated from any change in renal blood flow and arterial blood pressure~ To confirm the mechanism of action, representative active renal vasodilator compounds are checked for blockade by bulbocapnine which is known to be a specific blocker of renal dopamine receptors.
Dopamine is run as a positive control in each screening procedure.
A representative compound of this invention, 6-chloro~7,8-dihydroxy-1-(p-sulfamylphenyl)-2,3,4,5-tetra-hydro lH-3-benzazepine hydrobromide, demonstrated the following data:

DE~G DOSE MP;P* ~BF* ~NR* EI:R*
(~g/Xg/min) (ar~erial (renal ~renal (~eart blocd blood vascular ~ate presisure) flcw) resistance) Dop~ne 3 - 4.9 +38.1 -31.6 + O
Test a~und 3 - 3.6 ~17.0 -18.0 - 2.9 - 6.6 ~41.0 -33.7 - 6.3 300 -10.~ ~16.0 -22.7 + 3.3 * % change from control value recorded before each infusion in one dog.

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~ 1~9~57 l In four dogs the EDl5 was 20,ug/kg (dopamine, 3.5 ,ug/kg).
In a phosphate-mannitol dog test the compound demonstrated blood pressure lowering at 5 mg/p.o.
6-Chloro-7,8-dihydroxy-l-(4-N,N-dimethylsulfamyl-phenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine hydrobromide hydrate:
Test ~und 3 0 + ~.7 - 6.2 0 - 1.4 + 6.3 - 6.8 ~ 6.7 300 -15.7 - 6.3 - 9.6 +10.0 6,9-Dichloro-7,8-dihydroxy-l-(p-sulfamylphenyl)-2,3/4,5-tetrahydro-lH-3-benzazepine hydrobromide hydrate.
lS
Test oo~x~d 3 0 0 0 + 5.9 ~ 1.3 0 ~ 1.4 + ~.3 300 1 0.6+ 6.3- 5.1 + 6.3 i The pharmaceutical compositions using the new compounds of this invention having pharmaceutical activity are prepared in conventional dosage unit forms by incorporating a compound of Formula I, an isomer or a pharmaceutically acceptable acid addition salt or ester thereof, with a nontOxJC pharmaceutical carrier according to accepted procedures in a nontoxic amount sufficient to produce the desired pharmaceutical activity in a su~ject, animal or humanO Preferably the compositions will contain the active ingredient in an active but nontoxic amount selected from about 15 mg to about 1000 mg, preferably 25- ~-250 mg, of active ingredient per dosage unit but this quantity depends on the specific biological activity desired and the conditions of the patient.

59~5 ~

1 The following examples are designed solely to illustrate the preparation and use of the compounds of this invention. The temperatures are Centigrade. Other variations of these examples will be obvious to those skilled in the art.
EXAMPLE_l Forty-two grams (0.104 mole) of 6-chloro-7,8-dihydroxy-l-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-lH-3-benza-zepine methane sulfonate (Belgium patent 860,774) was suspended in 1 1. of dry toluene and 30.0 ml of dry acetonitrile then 100 rnl (0.77 mole) of trifluoroacetic anhydride was added rapidly. The mixture was stirred overnight to give a clear solution which was concentrated in vacuo to an oil. This was dissolved in methylene chloride. The solution was then washed twice with water, several times with 5~ sodium bicarbonate solution and then with brine. The dried extract was concentrated to give an oil, ~-chloro-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine trifluoroacetamide (44 g) which was judged to be sufficiently pure by NMR and TLC
for further use.
A solution of 44 g (0.104 mole) of 6-chloro-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetra-hydro-lH-3-benzazepine trifluoroacetamide in 700 ml of dry dimethylformamide was treated with 45.5 g (0.784 mole) of potassium fluoride. After five minutes, 11.2 ml (27.6 g, 0.109 mole) of dibromomethane was added. The mixture was heated at 115 and held at 115 for 6 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed several times with water. The dried, concentrated product was chromatographed over 800 g of silica gel with a 1 to 3 methanol in chloroform gradient. The homogeneous fractions gave 30.4 g (71%) of 6-chloro-7,8-methylenedioxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-1~-3-benzazepine trifluoroacetamide. A sample was crystallized from acetonitrile to give white crystals, m.p. 191-193.

.

"` J 1~90~7 1 Substituting ethylenedibromide for dibromomethane gives the 7,8-ethylenedioxy congener which then is used in the subsequent steps in equimolar quantities. Other reactive dihalomethanes or ethanes are also used similarly.
A solution of 12.6 g (0.031 mole) of 6-chloro-7,8-methylenedioxy 1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine trifluoroacetamide in 100 ml of dry dimethylformamide was treated first with 15~2 g (0.136 mole) of triethylene diamine and then with 6.27 g (0.051 mole) of dimethylthiocarbamoyl chloride. The mixture was stirred at room temperature for four hours, poured onto 500 ml of ice water and the precipitate was filtered and washed well with water. The solid was dissolved in 95% ethanol, treated with charcoal, filtered and diluted with water to the cloud point. Chilling gave a total of 11.3 g (73~) of 6-chloro-7,8-methylenedioxy~
(p-O-dimethylthiocarbamoylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine trifluoroacetamide, m.p. 1~8-131.
Diphenyl-diphenyloxide eutectic (Dowtherm "A'`, 200 ml) was preheated to 200 in an oil bath then 24.0 g (0.048 mole) of 6-chloro-7,3-methylenedioxy-1-(p-O-dimethylthiocarbamoylphenyl)-2,3,4,5-tetrahydro-lH-3-benza-zepine trifluoroacetamide was added in portions to the rapidly stirring mixture. The resulting solution was heated for about ten hours at 205-230. The cooled reaction was poured directly on a column packed with 800 g of silica gel which had been washed with cyclohexane. The column was developed with cyclohexane to remove the heat transfer medium then with a gradient of 3/1, then 5/2 of cyclohexane-ethyl acetate to give the homogeneous product. Crystallization from acetonitrile gave 8.7 g (40%) of 6-chloro-7,8-methylenedioxy-1-(p-S-dimethyl-carbamoylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine trifluoroacetamide, m.p. 194-195.

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~ 1~9~57 1 Ten grams (0.02 mole) of 6-chloro-7,8-methylene-dioxy-l-(_-S-dimethylcarbamoylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine trifluoroacetamide was suspended in 200 ml of 90% formic acid and 35 ml of 30% hydrogen peroxide was added dropwise with stirring at room temperature. The mixture was stirred for 18 hours. The clear solution was evaporated and the residue therefrom was azeotroped several times with 95% ethanol. The crude product was dissolved in ethyl acetate, washed with cold 1%
hydrochloric acid and brine, then concentrated tG about 10 g of crude 6-chloro-7,8-methylenedioxy-1~ sulfophenyl)-2~3,4,5-tetrahydro-lH-3-benzazepine trifluoroacetamide, NMR was consistent with structure and high pressure liquid chromatography on a C-18 reverse phase column with a 60/40/1 water-methanol-acetic acid containing 3 x 10 5M
of sodium hexanesulfonate showed the product to be at least 85% pure.
A mixture of 1.0 g (2.1 mmole) of the crude 6-chloro-7,8-methylenedioxy~ -sulfophenyl)-2,3,4,5-tetrahydro-lH-3-ben~aæepine trifluoroacetamide, 20 ml of thionyl chloride and 0.04 ml of dimethylformamide was heated at 80 for 2 hours. The thionyl chloride was evaporated in vacuo. The residue which is 6-chloro-7,8-methylenedioxy-1-(p-chlorosulfonylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine trifluoroacetamide was dissolved in tetrahydrofuran. The solution was added slowly to 40 ml of iced concentrated ammonium hydroxide.
The mixture was stirred at room temperature for an hour, the pH was adjusted to 8 with hydrochloric acid and the product was extracted into ethyl acetate. The extracts were washed with water, dried, concentrated and applied to a column packed with 50 g of silica gel. The column was developed with a gradient of 24 to 35 percent of ethyl acetate in cyclohexane to give 0.5 g of 6-chloro-7,8-methylenedioxy-1-(~-sulfamylphenyl)-2,3,4,5-tetrahydro-lH-3-.. . . . ~, . ..

- .,, . : . , ' ' . '~ ':::.. ' :, ~
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~ ~59057 1 benzazepine tri~luoroacetamide. Field desorption mass spectroscopy showed an intense m/e at 476 which is consistent with the molecular ion. NMR and I~ were consistent with the structure.
Substituting ethylamine for ammonia gives the (p-N-ethylsulfamylphenyl) derivative. This following alkali hydrolysis and boron tribromide treatment as detailed hereafter gives 6-chloro-7,8-dihydroxy-1-(p-N-ethylcarbamylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine 10 hydrobromide~
A mixture of 0.5 g (1.1 mmole) of 6-chloro-7,8-methylenedioxy-I-(~ sulfamylphenyl)-2,3,4,5-tetrahydro-lX-3-ben2azepine trifluoroacetamide, 0.1 g of sodium hydroxide and 50 ml o~ methanol was stirred at room temperature for 2 hours, poured into water and extracted with ethyl acetate. The combined extracts were washed with brine, dried and concentrated. The residue was chromatographed on 20 g of silica gel with a gradient of 1~ to 5% o~ methanol in chloroform to give 0.35 g of pure 6-chloro-7,8-methylenedioxy-1-(~-sulfamylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine~ This was suspended in 5 ml of dry methylene chloride, cooled to -60 and a solution of 5 ml of boron tribromide in methylene chloride (1 g/ml) was added dropwise with stirring under a nitrogen atmosphere. The mixture was stirred for about an hour at room temperature, recooled to -15 when excess methanol was added cautiously. The solvents were evaporated. The residue was azeotroped several times with methanol. The `
remaining solid was crystallized from me~hanol-acetonitrile ether to give 0.36 g (86%) of 6-chloro-7,8-dihydroxy-1-(p-sulfamylphenyl)-2,3,4,5-tetrabydro-lH-3-benzazepine hydrobromide, m.p. 289-290.
~ he base (1 g) is regenerated using dilute sodium bicarbonate-isopropanol. Aliquots of 100 mg of the base in isopropanol are treated with methane sulfonic or hydrochloric acid to give the methane sulfonic acid or hydrochloride salts.

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A mixture of 5.0 g (0.011 mole) of 6-chloro-7,8-methylenedioxy-l-(p-sulfophenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine trifluoroacetamide/ 70 ml of thionyl chloride and 0.08 ml of dimethylformamide was heated at 80 for 2 hours, the solvents were evaporated in vacuo.
The acid chloride residue was dissolved in tetrahydrofuran. This solution was added slowly to a solution of dimethylamine in tetrahydrofuran at -15.
The reaction was stirred at 0 for an hour then allowed to reach room temperature over 20 minutes. Hydrochloric acid was added to p~ 6.5. The product was extracted into chloroform. The extracts were washed well with water, dried and concentrated to 4.0 g of cr~de product. This was chromatographed on 120 g of silica gel with a gradient of 25~ to 33% of ethyl acetate in cyclohexaneO The homogeneous fractions were crystallized from aqueous ethanol to give 3.1 g (78~) of 6-chloro-7,8-methylenedioxy-l-(p-N,N-dimethylsulfamyl-phenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine trifluoroacetamide, m.p. 143-145.
A solution of 2.3 g (0.00457 mole) of 6-chloro-7,8-methylenedioxy-1-(~-N,N-dimethylsulfamylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine tri~luoroacetamide, 75 ml of methanol and O.S g of sodium hydroxide was stirred at room temperature for 2 hours, diluted with water and extracted several times with ethyl acetate. The extracts were washed with brine, dried and concentrated. The crude residue was chromatographed on 75 g of sllica gel with a gradient of 1~ to 4% of methanol in chloroEorm. The 30 homogeneous cuts were combined and concentrated to give 1.4 g (75~) of 6-chloro-7,8-methylenedioxy-1-(~-N,N,-dimethylsulfamylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine.
A field description mass spectrogram showed an intense peak for m/e of 403 which is consistent with the 35 structure. NMR and IR spectra also agreed with the structure.

. . . , . . , ~ .

j l 11569 5 7 l This product (300 mg) was dissolved in 15 ml of dry methylene chloride, the solution was cooled to -15 under a nitrogen atmosphere. A sol~tion of 3 ml of boron tribromide in methylene chloride (l g/5 ml) was added dropwise. A precipitate formed very quickly. The mixture was then stirred at room temperature for about an hour and recooled in an ice bath. Excess methanol was added carefully. The resulting solution was evaporated. The residue was azeotroped several times with methanol. The solid was crystallized from methanol/acetonitrile to give off white crystals of 6-chloro-7l8-dihydroxy-l-(p-N,N,-dimethylsulfamylphenyl)-2l3l4,5-tetrahydro-lH-3-benzazepine hydrobromide, m.p. 238-240. The NMR and IR spectra are compatible with structure.

A solution of 50 g (0.219 mole) of p-thiobenzyl-benzoic acid in 450 ml of dry tetrahydrofuran was cooled in ice water under a nitrogen atmosphere and a solution of 400 ml of lM diborane in tetrahydrofuran (0.4 mole) was added dropwise. After a half hour, the cooling bath was removed. The mixture was stirred at room temperature for 2 hours. The reaction was recooled in ice water and excess methanol was added cautiously. The solvents were evaporated to give a white solid which was crystallized from aqueous ethanol to give 39.5 g (79~) of ~-thiobenzylbenzyl alcohol, m.p. 87-88.5.
A solution of 38.5 g ~0.167 mole) of ~-thiobenzyl-benzyl alcohol in 400 ml of toluene was treated with 100 g of activated manganese dioxide. The suspension was stirred and heated in an oil bath for 5 hours with a Dean-Stark water separator. The mixture was cooled slightly, filtered through a filter aid with chloroform. `~
The filtrate was concentrated to a pale yellow solid.
This was crystallized from absolute alcohol to give 30.1 g (80~) of p-thiobenzylbenzaldehyde, m.p. 62-63.5.

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l 1~90~'~

1 A solution of 30,0 g (0.132 mole) of p-thio-benzylbenzaldehyde, 37.6 g (0.184 mole) of trimethylsulfonium iodide and 150 ml of dry dimethyl-sulfoxide (held under a nitrogen atmosphere) was added over 15 minutes a solution of 18.6 g (0.17 mole) of potassium t-butoxide in 100 ml of dry dimethylsulfoxide.
The mixture was stirred an additional 45 minutes at room temperature and poured into 3 1. of iced water. The quench was extracted with ethyl acetate (4 x 300 ml), The combined organic extracts were washed with brine and water (4 times) dried over magnesium sulfate. The extracts were concentrated to solid p-thiobenzylstyrene oxide.
This crude epoxide was mixed with 28.5 g (0.13 mole) of 2-chlorohomoveratrylamine and heated at 110 (under nitrogen) for 18 hours. The crude product was dissolved in a little chloroform and applied to a column packed with 900 g of silica gel. ~he column was developed with a gradient of chloroform to 2-1/2% of methanol in chloroform taking 400 ml fractions. The homoyeneous product was crystallized from absolute alcohol to give 15.4 g of ~-~N-2-chloro~3,4-dimethoxyphenethyl-amino methyl~-4'-thiobenzylbenzyl alcohol, m.p. 80-81~5.
A solution of 13.0 g (0.0284 mole) of the benzyl alcohol in 260 ml of dry methylene chloride was treated with 10.4 ml of methanesulfonic acid. The resulting solution was gently refluxed for 3 hours. Ice was added followed by 150 ml of 10% sodium hydroxide solution. The organic layer was separated. The aqueous layer was extracted with methylene chloride and the combined organic extracts were washed with water, dried and concentrated to leave 12.1 g of crude product which was chromatographed on 650 g of silica gel with a gradient of 2% to 4~ of methanol in chloroform. This gave 9.4 g ~75%) of 6-chloro-7,8-dimethoxy-1-(p-thiobenzylphenyl)-2,3,4,5- ~;
tetrahydro-1~-3-ben~azepine. NMR, IR and mass spectra agreed with the structure.

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1 ~590~ 7 1 The benzazepine, 7.7 g (0.017 mole), was dissolved in ~0 ml of acetone and 20 ml of water then a solution of 5.3 g of sodium carbonate in 10 ml of water was added. The mixture was cooled in ice water. A
5 solution of 5.44 g of benzyl chloroformate in 25 ml of acetone was added dropwise. The mixture was stirred at 5 for one hour, then o~ernight at room temperature.
Water was added. The product was extracted into ethyl acetate and washed with brine and water. The concentrated product was chromatographed on 200 g of silica gel with a gradient of chloroform to 0.5~ of methanol in chloroform to give 4.5 g (46%) of 6-chloro-7,8-dimethoxy-1-(p-thiobenzylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine benzylcarbamate as a syrup. The field desorption mass spectroscopy indicated an intense m/e of 573 which is compatible with the structure. The IR and NMR spectra were consistent.
The carbamate (4.5 g, 0.0079 mole) was dissolved in 45 ml of glacial acetic acid and 0.45 ml of water was added. The solution was cooled in water (15).
Chlorine gas was bubbled through the solution for 20 minutes while maintaining the reaction temperature between 25 and 27. Then the mixture was stirred at room temperature for 15 minutes, poured onto 150 ml of ice water and extracted quickly with chloroform. The combined extracts were washed with water and nitrogen was bubbled through the slightly wet solution. The solvent was evaporated at room temperature ln vacuo to give a residue of 6j9-dichloro-7,8-dimethoxy~ -chlorosulfonylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine benzylcarbamate.
The acid chloride residue was dissolved in tetrahydrofuran then added to 75 ml of iced ammonium hydroxide. After being stirred for 2 hours at room temperature, the pH was adjusted to about 8 with hydrochloric acid. The product was extracted into .

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, - . -;

9V~ 7 1 chloroform and washed with water. The dried concentrate was chromatographed on 200 g of silica gel with a gradient of chloroform to 1~ of methanol in chloroorm to give 3.24 9 (75~) of 6,9-dichloro-7,8-dimethoxy-1-(p-sulfamylphenyl)-S 2,3,4,5-tetrahydro-lH-3-benzazepine benzylcarbamate as an oil. The NMR, IR and mass spectra agreed with the structure.
The sulfamyl derivative (2.0 g, 3.56 mmole) was dissolved in 60 ml of dry methylene chloride. The solution was cooled to -15% (under nitrogen). A solu-tion of 17.7 ml of boron tribromide in methylene chloride (1 g/5 ml) was added dropwise. The solution was then stirred at room temperature to produce a precipitate.
After about an hour the mixture was recooled, methanol was added slowly and the solution was concentrated and azeotroped with additional methanol. The~residual product was dissolved in a little acetone and added dropwise to a stirred solution of 3 parts of ether and one part oE ethyl acetate to af~ord an off white powder, 0.586 g (35~), m.p.
210-212 of 6,9-dichloro-7,8-dihydroxy-1-(p-sulfamyl-phenyl~-2,3,4,5-tetrahydro-lH-3-benzazepine hydrobromide.
The crude acid chloride product (200 mg) (obtained by evaporating the chloroform extract prior to treatment with ammonia in the above procedure) is treated with dilute sodium carbonate solution/dimethylformamide.
Evaporation and extraction with methylene chloride is followed by washing and drying the extrac~. Evaporation gives 6,9-dichloro 7,8-dimethoxy-1-(p-sulfophenyl)-2/3,4,5-tetrahydro-lH-3-benzazepine~benzylcarbamate. Alkaline hydrolysis and boron tribromide treatment gives 6,9-dichloro-7,8-dihydroxy-1-(p-sulfophenyl)-2.3,4r5-tetrahydro-lH-3-benzazepine. Alternatively the OjO,N-protected sulfonic acid is treated with phosphorus pentabromide to give the l-(p-bromosulfonylphenyl) - ~o 1 compound which is reacted with ammonium hydroxide.
Hydrolysis and de-etheriication gives 6,9-dichloro-7,8-dihydroxy-l-(p-sulfamylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine hydrobromide.

6-Methyl-7,8-dihydroxy-1-t~-hydroxyphenyl)-2,3,4,5-tetrahydro-lH 3-benzazepine hydrobromide (21 g, German DE-OS 2849766) in toluene-acentronitrile is reacted with 50 ml of trifluoroacetic anhydride. The N-protected product is isolated by concentration in vacuo. This crude material (11 g) is reacted with 12 g of potassium fluoride in dimethylformamide then with 7.2 g of dibromomethane at 100 for 6 hours. The mixture is evaporated and the residue purified as described in ~;
15 Example 1 to give 6-methyl-7,8-methylenedioxy-1 (p-hydroxyphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine trifluoroacetamide.
This material (4 g) is O-acylated using base and dimethylthiocarbamoyl chloride to give the l-(p-O-dimethyl-thiocarbamoylphenyl) compound which (~1.5 9) is heated in diphenyl-diphenyloxide eutectic at 215 to give the 5-dimethylcarbamoyl in~ermediate. Oxidation of this material ~1~2 g) using 5 ml o hydrogen peroxide at room temperature in concentrated formic acid solution for 24 hours gives 6-methyl-7,8-methylenedioxy-1-(~-sulfophenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine trifluoroacetamide.
The sulfonic acid (750 mg) is converted to the sulfonyl chloride using thionyl chloride/dimethylformamide then reacted without purification with an excess of ammonium hydroxide to give 6-methyl-7,8-methylenedioxy-1-(~-sulfamylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine trlfluoroacetamide. Alkaline hydrolysis of the ace~amide (500 mg) and boron tribromide treatment of the residue in the cold gives the desired ~-methyl-7,8 dihydroxy-l-(~-sulfamylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride.

.,, , .. i. ~. . , ~ , ., - . , ~ ::. : ~: ~ . :

1 EXAMPLE_5 6-Chloro-7,8-dimethoxy-1-(p-methoxyphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine (3.47 g, 0.01 mole, m.p. 140-142.5) in 50 ml of acetonitrile r~as mixed wlth 2.8 ml (0.02 mole) of triethylamine and 1.4 ml (0.011 mole) of allyl bromide. The mixture was heated at 85-95 for 2-1/2 hours. The reaction mixture was evaporated. The residue was suspended in water and extracted twice with ethyl acetate. Tbe organic extracts were washed with water, brine and evaporated to give 2.6 g (67.2~) of a yellow oil, 3-allyl-6-chloro-7,8-dimethoxy-1-(p-methoxy-phenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine.
This material (2.6 g, 0.0067 mole) was dissolved in 55 ml of methylene chloride and cooled to -15 at which time 6.0 ml (0.064 m) of boron tribromide in 40 ml of methylene chloride was added slowly over 1/2 hour. The reaction mixture was stirred at room temperature for 3 hours, cooled and treated with an excess of methanol slowly and with cooling. The methanol was evaporated to give a foam. This was dissolved in a minimum amount of methanol and cooled. Some ethyl acetate was added to induce separation of 1.85 g (65~) of 3-allyl-6-chloro-7,8-dihydroxy-1-(p-hydroxyphenyl)-2,3,4,5-tetrahydro~
3-benzazepine hydrobromide, m.p. 195-199 (dec.).
The trihydroxy compound (2~2 g~ is reacted with 2 g of potassium fluoride and 1.4 g of dibromomethane in dimethylformamide with heating. Concentration and purification of the residue gives 3-allyl-6-chloro-7,8-methylenedioxy-1-(~-hydroxyphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine isolated as the hydrobromide salt.
This material ~1.3 g) in dimethylformamide is reacted with an excess of triethylenediamine and dimethyl-thiocarbamoyl chloride at room temperature. After 35 quenching the desired product is separated by extraction ; .;- , :: . ~ .
, - :. : , . . .: . . . , :
" . : .: , .~ . ; . , ~ 1~9057 1 with ethanol to give 3-allyl-6-chloro-7,8-methylenedioxy-1-(~-O-dimethylthiocarbamoylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine which (0.75 g) is heated in diphenyl-diphenyl-oxide at 200 for six hours. Purification by silica gel column gives the desired thio compound which was selectively oxidized in formic acid-hydrogen peroxide to give 3-allyl-6-chloro-7,8-methylenedioxy-1-(p-sulfophenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine as the hydrobromide.
The sulfonic acid (1 g) is reacted with an excess of lQ thionyl chloride with a catalytic amount of dimethyl-formamide at 75. After evaporation, the crude residue is reacted with an excess of iced ammonium hydroxide.
After neutralization, extraction and treatment over a silica gel column 3-allyl-6-chloro-7,8-methylenedioxy-1-(p-sulfamylphenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine is isolated. Treatment with boron tribromide as described above gives 3-allyl-6-chloro-7,8-dihydroxy-1-(~-sulfamyl-phenyl)-2,3,4,5-tetrahydro-lH-3-benzazepine as the hydrochloride.

Claims (6)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. The process of preparing a compound of the formula:

in which;
R1 is hydrogen, lower alkyl of 1-4 carbons or allyl;
R2 is hydrogen, halo or lower alkyl of 1-4 carbons;
R3 is hydrogen, or when R2 is other than hydrogen, halo or lower alkyl of 1-4 carbons; and R4 and R5 are hydrogen or lower alkyl of 1-4 carbons; together with pharmaceutically acceptable acid addition salts thereof or 0-alkanoyl esters thereof, comprising reacting a compound of the formula with a compound of the formula in which:

R2, R3, R4 and R5 are as defined above, X
is chloro, bromo or a similar displaceable group, R6 and R7 are lower alkyl or, together methylene or ethylene and R1 is lower alkyl, allyl or a N-protecting group, optionally deblocking groups at R6, R7 or R1 with a dealkylating agent, acid or base and then optionally forming an acid addition salt or 0-ester of the product.

2. The process of claim 1 in which R1 is trifluoroacetyl, R6 and R7 are methyl,or when taken together, methylene, R2 is chloro, R3 is hydrogen, R4 and R5 are methyl and R1 is hydrogen.

3. The process of claim 1 in which R1 is trifluoroacetyl, R6 and R7 are methyl, or when taken together, methylene, R2 is chloro, R3 is hydrogen, R4 and R5 are hydrogen and R1 is hydrogen.

4. A compound of the formula:

in which:
R1 is hydrogen, lower alkyl of 1-4 carbons or allyl;
R2 is hydrogen, halo or lower alkyl of 1-4 carbons;
R3 is hydrogen, or when R2 is other than hydrogen, halo or lower alkyl of 1-4 carbons; and R4 and R5 are hydrogen or lower alkyl of 1-4 carbons; together with pharmaceutically acceptable acid addition salts thereof or 0-alkanoyl esters thereof, whenever prepared or produced by the process of claim 1 or its obvious chemical equivalent.

5. The compound of claim 4 in which R1 is hydrogen, R2 is chloro, R3 is hydrogen and R4 and R5 are methyl whenever prepared or produced by the process of claim 2 or its obvious chemical equivalent.

6. The compound of claim 4 in which R1 is hydrogen, R2 is chloro, R3 is hydrogen and R4 and R5 are hydrogen whenever prepared or produced by the process of claim 3 or its obvious chemical equivalent.