FI56530C - PROCEDURE FOR FRAMSTAELLNING AV 6-SULFAMYL-1,2,3,4-TETRAHYDRO-4-QUINAZOLINONER - Google Patents

Description

1- -, __ .. 'I Γο, .... ANNOUNCEMENT r CC Π n B 11 UTLÄG GNIN GSSKRI FT 56530 • 3® c (45) 4444; * /' (51) Kv.lk. '/ Int. CI. * C 07 D 239/91 (21) Patent application - Patentansöknlng 170/69 (22) Application mark— AnsBknlngsdag 21.01.69 (23) Initial number — Giltlghetsdag 21.01.69 (41) Has become public - Bllvit ofTentllg 22.07.70

National Board of Patents and Registration N »htävik, .p» non and aud. | U.k .. «in date. -

Patent and Registration Office Ansekan utlagd och utl.skrlften publlcerad 31.10.79 (32) (33) (31) Privilege claimed — Begird prlorltet (71) Wallace & Tiernan Inc., 91 South Harrison Street, East Orange,

New Jersey, USA (72) Bola Vithal Shetty, Rochester, New York, USA (US) (7 * 0 Oy Kolster Ab (μM Method for the preparation of 6-sulfamyl-1,2,3β-tetrahydro-4-quinazolinones) - For the preparation of 6-sulfamyl-1,2,3, U-tetrahydro-U-quinazolinones

The invention relates to a process for the preparation of quinazolinones which are effective urinary secretagogues.

More particularly, the invention relates to a process for the preparation of 6-sulfamyl-1,2,3, H-tetrahydro-1-quinazolinones of the formula

R

C1 N R

y I / T \ ν 's

Ru 2 56530 wherein Y 1 and independently represent hydrogen, methyl or acetyl; R is hydrogen, methyl or benzyl; and R 1 independently of one another is hydrogen, alkyl having 1 to 1 carbon atoms, phenyl or carboxy, or R 1 and R 2 together with the carbon atom to which they are attached form cyclopentyl, cyclohexyl or 1-methylpiperidyl; n is 0 or 1; and R 1, R 2 and R 2. independently of one another hydrogen, methyl, ethyl, nitro, chloro, hydroxy or trifluoromethyl, and for the preparation of their salts.

The invention is characterized in that the anthranilamide of the formula s-5-10Η2> η _ ^ (7 ^ R3 R5

K

wherein Y 1, Y 2, R, R 1, R 2, R 2 and n are as defined above are reacted with an acetal, an aldehyde or a ketone of the formulas respectively

1 H (ORM, R -C-H and R.-C-R

• D ^ '11 1 II ^ 2 0 0 in which R and R2 have the same meaning as above; and R 'is a hydrocarbon group; at room temperature in the presence of acetic acid, and a) when R is benzyl, the resulting compound is optionally hydrogenated to replace the benzyl group with a hydrogen atom; b) when Y1 and Y2 represent a hydrogen atom, the resulting product is reacted with an alkylating or acylating agent to replace at least one hydrogen atom with methyl, respectively; if desired, the product is reacted with an acid or base to form a salt.

From Armarego, W.L.F .: The Chemistry of Heterocyclic Compounds ^ Vol. 24, pp. 392-393 It is known to prepare 1,2,3,4-tetrahydro-4-quinazolinones; however, the reaction is different because the starting material benzamide used in the known process is not substituted in the 4- or 5-position like the anthranilamide starting material of the invention; also, according to the known method, 3 S6S30 quinazoline having an aromatic group in the 3-position is not prepared. FI patent publication 31 * 767 discloses a process for the preparation of 1,2,3,4-tetrahydro-?-Quinazolinones which, according to embodiments, are N-unsubstituted in the 3-position by reacting an anthranilic acid derivative with an aldehyde or ketone. When repeating a suitable embodiment of the FI patent under the conditions of the known process, but using the reagent of the invention toluidine, it is found that the known process is substantially ineffective in preparing the aryl- or aralkyl-substituted benzamide used in the invention to prepare N-substituted quinazolines. Furthermore, in the case of the reaction of benzamide with an aldehyde, ketone or acetal according to the present invention, it should be noted that the reaction takes place without external heat, whereas in the known process the reaction mixture must be heated under reflux. In most embodiments illustrating the present invention, only mixing has been used.

The process according to the invention is preferably carried out in a solvent or suspending medium under acidic conditions and preferably using a molar excess of acetal, aldehyde or ketone. Sometimes it is necessary to carry out the reaction at an elevated temperature to complete the reaction in a suitable time.

Typical Reaction Scheme Synthesis of 2-methyl-3- (o-tolyl) -6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-U-quinazolinone Synthesis procedure: C1-4. NHCO3CH3 | ητ (ch3co) 2ov I T 1. ciso3h ch3 * ch3 27Ίίϊς>

I II

nhcoch3 ^ c1 ^ yNHCO0CH3_ ^ hO_ ^ H2B0, sA ^ icH, (KM ”V ^ H2» ° 2s Δ 111 IV * / ~ \ u

Y Y cocig 'Y I

I ^ I I ov 'H2N02 H0Ac H2N02S ^ s \ ^ Yr / Δ v 0

Ck H H

j | ^ VNH2 CH3CH (OCH3) 2 ^ - CH3

W b ^ h2 »o2sJLyV

“Il o VII 3. VI11 CIf3 56530

It Manufacture of intermediates

Method I

Preparation of 5-chloro-2-methylacetanilide, II

5-Chloro-o-toluidine (i) (1000 g) was added to 9000 ml of water and preheated to 35 ° C in a 17 liter copper vessel. The slurry was stirred vigorously with the careful addition of 1,260 g of acetic anhydride. Stirring was continued for four hours, after which the product was filtered off and air dried. The crude product was recrystallized from 7,500 ml of benzene using 1 + 0 g of charcoal to remove slightly discolored material. The product was air dried.

It weighed 818 g and had a melting point of 13-109 ° C.

Method II

Preparation of 5-chloro-2-methyl-1 + -sulfamylacetanilide III

Chlorosulfonic acid (1,000 g) was placed in a nitrogen purged, 5-liter three-necked round bottom flask equipped with a stirrer and a calcium chloride tube. To chlorosulfonic acid, 5-chloro-2-methylacetanilide (300 g) was carefully added, followed by 88 g of sodium chloride portionwise over one hour. The temperature of the reaction mixture was carefully raised to 80 ° C (foaming occurs). When foaming ceased, the temperature was raised to 92 ° C and maintained for three hours. The hot reaction mixture was added slowly and with good stirring to 3,000 ml of acetone and 1,500 g of ice. The resulting slurry was diluted with water to a total volume of 8,000 ml and the crude sulfonyl chloride was filtered off and washed with water. The wet filter cake was added to 3,000 ml of concentrated ammonium hydroxide, the mixture was stirred at room temperature for one hour, and then the mixture was heated to 50 ° C for 2 hours. The slurry was cooled, filtered, washed with water and air dried. The product weighed 186 g.

Melting point 2i + 8-250 ° C.

Method III

Preparation of N-acetyl-1-chloro-5-sulfamylanthranilic acid IV

To a 12-liter flask were added 8,000 ml of water, 1 1UU of magnesium sulfate heptahydrate and 1 + 00 g of 5-chloro-2-methyl-1 + -sulfamylacetanilide. The mixture was heated to 80 ° C and 710 g and potassium permanganate were added portionwise with good stirring over a period of about four hours at 80-85 ° C. After the addition of potassium permanganate was complete, the mixture was maintained at 80-85 ° C for three hours and filtered hot. The manganese dioxide cake was washed with three 1,000 ml portions of water.

The filtrate was acidified with 200 ml of concentrated hydrochloric acid, filtered, washed with water and air dried. This material was dissolved in 95 # ethanol. The resulting solution was concentrated, the crystallized product was periodically separated from it, and washed with 95% ethanol. The melting point of the purified product was 26U-266 ° C.

5

Method IV S6S30

Preparation of 1 + -chloro-5-sulfamylanthranilic acid V

N-Acetyl-1-chloro-5-sulfamylanthranilic acid (2,500 g) was heated under reflux for 3 hours in 15,000 ml of 3N sodium hydroxide solution and the pH was adjusted to k with concentrated hydrochloric acid. After cooling to 70 ° C, the product was filtered off and washed with water. The moist product was dissolved in 200 liters of boiling water, filtered hot and allowed to cool. Filtered, washed with water and air dried, the product weighed 2,000 g and melted at 275 ~ 2T6 ° C.

Method V

Preparation of 7-chloro-6-sulfamyl-isatoic anhydride VI

1H-Chloro-5-sulfamylanthranilic acid (66 U g) was slurried in 8,000 ml of glacial acetic acid and 800 g of liquid phosgene was added with good stirring. After stirring vigorously for 3 hours at room temperature, the mixture was filtered and washed with 1,000 ml of acetic acid and 2,000 ml of anhydrous ether. After drying in vacuo with phosphorus pentoxide, the weight was 698 g and the melting point was 290-292 ° C.

Method VI

Preparation of 2-amino-1 + -chloro-5-sulfamyl-N- (o-tolyl) -benzamide VII

7-Chloro-6-sulfamyl-isatoic anhydride (720 g) was added to a 12-liter nitrogen purged flask containing 200 ml of o-toluidine and the mixture was stirred for 1/2 hour. It was then heated to 17 ° C (solution temperature 177 ° C) and maintained at about 175 ° C for 10 minutes. It was allowed to cool to 60 ° C by removing the heating mantle and rapidly cooled to 25 ° C with an ice bath. Ether (b 200 mL) was added, the mixture was stirred for a couple of minutes, filtered and washed thoroughly with ether. The crude product was slurried in 9,000 mL of isopropanol, filtered and washed twice with 2,500 mL of 8% aqueous ammonia and once with 2,000 mL of ether. This partially purified amide was recrystallized. The amide was dissolved in dimethylformamide, filtered through Celite and heated to 90 ° C. The resulting solution was added all at once to 95 ° C water. The resulting suspension was allowed to cool with stirring over 20 hours, filtered and washed with dimethylformamide-water 2: 1 methanol and ether. After drying, the product melted at 289-292 ° C with decomposition.

C H N Cl S

Analysis:

Calculated for C 12 H 12 Cl 2 O 2 S i + 9, ^ 8 1 +, 15 12.36 10.1 + 3 9.1 + 1 +

C H N Cl S

Found: 1 + 9.66 1 +, 23 13.1 + 1 10.1 + 3 9.55.

6 56530

Method VII

Preparation of 2,1 + -dichloro-5-carboxybenzenesulfonyl chloride 2'-Dichlorobenzoic acid (200 g) was added over 10 minutes to one kilogram of chlorosulfonic acid. The mixture was stirred for U hours at 160 ° C and added to a mixture of ice and water. The solid was filtered off, washed with water and sucked as dry as possible. The product (2, U-dichloro-5-carboxybenzenesulfonyl chloride) was used in the next step without further purification. '

Method VIII

Preparation of U-dichloro-5- (N-methylsulfamyl) -benzoic acid

The product of Method VII was added to two liters of aqueous Ho - methylamine solution, stirred for three hours and filtered. The filtrate was acidified and the solid was filtered to give 3 g of 2, U-dichloro-5 ** (N-methylsulfuric acid). myl) benzoic acid, mp 185-190 ° C.

Method IX

Preparation of 2-benzylamino-tert-chloro-5- (N-methylsulfamyl) -benzoic acid 2,1-dichloro-5- (N-methylsulfamyl) -benzoic acid (50 g) and 130 ml of benzylamine were heated to room temperature. 160 ° C, maintained at 150 ° C for one hour, 130 ° C for one hour and 90 ° C for one hour. The reaction mixture was added to 100 ml of water and acidified to pH 3-5. The solid was filtered off, heated with U00 ml of alcohol and cooled to give 32 g of 2-benzylarino-U-chloro-5- (N-methylsulfamyl) benzoic acid.

Method X

Preparation of 1-benzyl-.beta.-N-methylsulfamyl-N, N-chloroisatoic anhydride 2-Benzylamino-14-chloro-57 (N-methylsulfamyl) -benzoic acid (UU g), H60 ml of acetic acid and 25 ml of phosgene were stirred overnight. The solid was filtered, washed with isopropanol and ether to give 30 g of 1-benzyl-6- (N-methylsulfamyl) -7-chloroisotoic anhydride, m.p. ^ 23 ~ 236 ° C.

Method XI

To prepare 2-benzylamino-1 + -chloro-5- (N-methylsulfamyl) -N- (o-tolyl) -benzamide, 1-benzyl-6- (N-methylsulfamyl) -7-chloroisatoic anhydride (38 g) and 200 ml of o-toluidine was heated to 170 ° C, kept at 170-1SO ° C for 5 minutes, cooled and 800 ml of ether were added. The solid was filtered off to give 22 g of 2-benzylamino-1'-chloro-5 '(N-methylsulfamyl) -N- (o-tolyl) -benzamide, m.p. 225 ~ 227 ° C.

S6S30 τ

Method XII

Preparation of 2-amino-U-chloro-5-sulfamyl-N- (p-chlorophenyl) benzamide U-chloro-5-sulfamyl-isatoic anhydride (10 g), 10 g of p-chloroaniline and 50 ml of pyridine were heated at 110 for 15 minutes. -112 ° C under nitrogen, cooled for 5 minutes and poured into 500 ml of ice water. The solid was filtered off and recrystallized from a mixture of 350 ml of alcohol and 150 ml of water to give 9 g of 2-amino-k-chloro-5-sulfamyl-N- (p-chlorophenyl) benzamide.

Method XIII

Preparation of 2-amino-1'-chloro-5-sulfamyl-N-phenylbenzamide 7-Chloro-6-sulfamyl-isatoic anhydride (VI) (51 g) and 300 ml of aniline were heated under nitrogen to 175 ° C, maintained at 175 ° C: for 5 minutes and the reaction mixture was cooled to room temperature. Ether (300 mL) was added and the solid was filtered to give * + 0 g of crude product. This and a second crop of 3 g were recrystallized from a mixture of 75 nil of dimethylformamide and 60 ml of water to give 33.5 g of 2-amino-1 + -chloro-5-sulfamyl-N-phenylbenzamide, m.p. 227-230 ° C. An additional 5.7 g was obtained from the mother liquor.

Method XIV

Preparation of 2-amino-1 + -chloro-5-sulfamyl-N- (o-methylbenzyl) -benzamide 6-sulfamyl-7'-chloroisatoic anhydride (20 g) 2-methylbenzylamine (9 g) and 200 ml of pyridine were heated under reflux for 20 minutes. and cooled for one hour and poured into two liters of ice water. The solid was filtered off, sucked dry, heated with one liter of alcohol and filtered to give 19.5 g of (alcohol-insoluble) 2-amino-U-chloro-5-sulfamyl-N- (o-methylbenzyl) benzamide, m.p. 275-278 ° C.

Method XV

Preparation of 2-amino-h-chloro-5-sulfamyl-N-benzylbenzamide 7-Chloro-6-sulfamyl-isatoic anhydride (1.5 g) was added to a solution of 1 ml of benzylamine in 350 ml of water and stirred for two hours. The solid was filtered off, washed and recrystallized from a mixture of 100 ml of dimethylformamide and 80 ml of water to give 31.8 g of 2-amino-1 + -chloro-5-sulfamyl-N-benzylbenzamide.

Method XVI

Preparation of 2'-dichloro-5'-sulfamylbenzoic acid 2'-Dichlorobenzoic acid (800 mg) was added to 4 kg of chlorosulfonic acid, the mixture was heated under reflux for 1 1/2 hours, cooled to 30 ° C, S6S30 and 8 kg of ice was added. The solid was filtered off and washed with water.

The wet solid was added to 8 liters of 28- $ ammonia, which was precooled. .... . ...

to 0 ° C and the solution was clarified by filtration. The solution was allowed to stand

two hours, acidified with hydrochloric acid, cooled and filtered. The solid was filtered off, washed and dried to give 790 g of crude product, which was recrystallized from 5 liters of water to give 2 g of 2'-dichloro-5-sulfamylbenzoic acid, m.p. 225-228 ° C. Method XVII

Preparation of 1+ -chloro-5-sulfamyl-N-methylanthranilic acid 2,1 + -dichloro-5-sulfamylbenzoic acid in 800 ml of a 10 - aqueous methylamine solution was heated at 125-130 ° C for five hours in a pressure reactor.

The reaction mixture was cooled, acidified with hydrochloric acid, filtered and the solid washed with water and air dried. The crude product was heated under reflux with 1,050 mL of 50- $ 5 ethanol, the solution was treated with charcoal and filtered. To the filtrate was added 1 ml of hot water and the mixture was allowed to cool to give 1 * 0 g of h-chloro-5-sulfamyl-N-methylanthranilic acid, m.p. 25 ^ -256 ° C.

Method XVIII

Preparation of 1-methyl-6-sulfamyl-7-chloroisatoic anhydride

A solution of ho ml of phosgene in 160 ml of acetic acid was added to a mixture of 39 g of 4-chloro-5-sulfamyl-N-methylanthranilic acid and 100 ml of acetic acid. The mixture was stirred for four hours and filtered. The solid was washed with a small amount of acetic acid and then ether to give 39 g of 1-methyl-6-sulfamyl-7-chloroisatoic anhydride, m.p. 292-296 ° C.

Method XIX

Preparation of 2-methylamino-U-chloro-5-sulfamyl-N- (o-tolyl) -benzamide 1-methyl-6-sulfamyl-7-chloroisatoic anhydride (7.3 g), 15 g of o-toluene

dine and 50 ml of pyridine were rapidly heated to reflux and heated under reflux for 10 minutes. The reaction mixture was allowed to cool for 1/2 hour and poured into 600 ml of dilute hydrochloric acid and ice. The solid was filtered, washed with water and stirred for one hour with 75 ml of isopropanol and filtered. The solid was washed successively with isopropanol, 8 - ammonia, isopropanol and ether, dried and recrystallized from a mixture of 10 ml of dimethylformamide and 6 ml of water to give 3.5 g of 2-methylamino-U-chloro-5-sulfamyl- N- (o-tolyl) -benzamide, m.p. 27 ^ -275 ° C. Method XX

Preparation of U-chloro-5-sulfamyl-N-benzylanthranilic acid To 500 ml of benzylamine was added 270 g of 2, h-dichloro-5-sulfamylbenzoic acid using a 2-liter three-necked flask. The temperature was rapidly raised to 9,566,330 ° C, held for one hour and cooled to 100 ° C. The reaction mixture was poured into 5 liters of ice water, acidified with 100 ml of HCl, stirred for four hours and filtered. The solid was recrystallized from one liter of 95% ethanol. On cooling, the precipitated solid was filtered and air dried. Weight 192 g, m.p. 2i + 2-2U6 ° C (decomposes).

Method XXI

Preparation of U-benzyl-6-chloro-7-sulfamyl-isatoic anhydride To 100 ml of glacial acetic acid were added 35 50 g of U-chloro-5-sulfamyl-N-benzyl-anthranilic acid and 15 ml of phosgene. The reaction mixture was stirred for 2k hours and then the solid was filtered, washed with ether and air dried. Weight 25.2 g, color white.

Method XXII

Preparation of 2-benzylamino-U-chloro-5-sulfamyl-N- (o-tolyl) -benzamide 25 g of U-benzyl-6-chloro-7-sulfamyl-isatoic anhydride were added to 300 ml of o-toluidine at room temperature. The reaction mixture was heated rapidly to 180 ° C, held for five minutes and allowed to cool. The cooled reaction mixture (50 ° G) was poured into three liters of ether. Upon standing, needles formed which were filtered, washed and dried.

Method XXIII

Preparation of 2-amino-t-chloro-5-sulfamyl-N- (U-hydroxy-2-methylphenyl) -benzamide T-chloro-6-sulfamylisatoic anhydride (39 → 2 g) and U3 g of U-amino-U- methylphenol was added to 1 l + 0 ml of pyridine and the mixture was heated under reflux for 10 minutes, cooled to t0 ° C and poured into 800 ml of hydrochloric acid and 1500 ml of ice. The solid was filtered and washed with water. More solid precipitated from the filtrate after 2k. The solids were mixed separately with the required amount of isopropanol to give a thin paste and filtered and washed to give 15 g, m.p. 283-286 ° C and 21.2 g m.p. 287-289 ° C 2-Amino-H-chloro-5-sulfamyl-N- (1+ -hydroxy-2-methylphenyl) -benzamide a.

Method XXIV

Preparation of 2-amino-U-chloro-5-sulfamyl-N- (o-ethylphenyl) -benzamide 7-Chloro-6-sulfamyl-isatoic anhydride (50 g) and o-ethylaniline (300 ml) were heated rapidly to 155 ° C. , the temperature was maintained there for five minutes and the reaction mixture was allowed to cool to 30 ° C. Ether (300 ml) was added and the reaction mixture was stirred for 30 minutes. The solid was filtered, washed with ether and isopropanol, heated under reflux with 1 + 00 mL of absolute methanol and filtered hot to give 29.5 g of 2-amino-1-chloro-5-sulfamyl-N- (o-ethylphenyl) - benzamidia, m.p. 260-262 ° C.

56530 10

Method XXV

Preparation of 2-amino-1 + -chloro-5-sulfamyl-N- (2,5,5-trimethylphenyl) -benzamide 7-Chloro-6-sulfamyl-isatoic anhydride (50 g) and 5U g of 2,5-trimethyl-anhydride the aniline was suspended in 200 ml of pyridine and heated at 115 ° C for five minutes. The mixture was cooled for 1/2 hour and poured into a mixture of 1,500 ml of ice and water and 200 ml of concentrated hydrochloric acid. The solid was filtered and suspended in one liter of dilute NH 4 OH for half an hour. The solid was filtered off, sucked dry and stirred with 250 ml of absolute methanol, filtered and dried. A second yield of filtrate was obtained. The combined solids were recrystallized from a mixture of 100 ml of dimethylformamide and 100 ml of water to give 23 g of 2-amino-1-chloro-5-sulfamyl-N- (2,1,5-trimethylphenyl) benzamide, m.p. 278-287 ° C.

Method XXVI

Preparation of 2-amino-U-chloro-5-sulfamyl-N- (p-tolyl) -benzamide 7-Chloro-6-sulfamyl-isatoic anhydride (17 g) and 100 g of p-toluidine were heated to 175 ° C. After 5 minutes at 175 ° C, the reaction mixture was allowed to cool to 50 ° C. Ether (100 ml) was added and the solid was filtered, washed and dried to give 16.6 g of crude 2-amino-1-chloro-5-sulfaphyl-N- (p-tolyl) -benzamide. The product was dissolved in 35 ml of dimethylformamide and 29 ml of water were added. The solution was heated to 100 ° C and cooled to give 15.8 g of a solid, m.p. 260.5 to 263.5 ° C.

Method XXVII

Preparation of 2-amino-1 + -chloro-5-sulfamyl-N- (h-methoxy-2-methylphenyl) -benzamide 7-Chloro-6-sulfamyl-isatoic anhydride (27.7 g) g of 4-methoxy-2-methyl- aniline and 100 ml of pyridine were stirred at room temperature and heated under reflux. The mixture was heated under reflux for 10 minutes, cooled to + 0 ° C and poured into a mixture of ice and concentrated hydrochloric acid. The solid was filtered and washed successively with water, 5N ammonia, water, isopropanol and ether. The dried solid was recrystallized from a mixture of 50 ml of dimethylformamide and 32 ml of water to give 17.6 g of 2-amino-4-chloro-5-sulfamyl-N- (1-methoxy-2-methylphenyl) benzamide, mp. 229-230 ° C.

'56530

Method XXVIII

Preparation of U-chloro-5-sulfamyl-N- (p-sulfamylphenyl) anthranilamide T-chloro-5-sulfamylisatoic anhydride (5 g) was added to 30 g of p-aminobenzenesulfonamide at 190-200 ° C. in the ring. After clarification, the reaction mixture was poured into three liters of water at 90 ° C. The solution was cooled and the solid was filtered and purified by chromatography on silica gel to give U-chloro-5-sulfamyl-N- (p-sulfamylphenyl) -anthranilamide, m.p. 30T-308 ° C.

Method XXIX

Preparation of 2-amino-4-chloro-5-sulfamyl-N- (m-tolyl) -benzamide T-chloro-6-sulfamylisatoic anhydride (20 g) and 120 ml of m-toluidine were heated at 165 ° C for three minutes and cooled. 50 ° C. Ether was added and the solid was filtered, washed with alcohol, and ether, and dried in vacuo to give 19> 1 g of 2-amino-U-chloro-5-sulfamyl-N- (m-tolyl) -benzamide, m.p. 27U-277 ° C.

Method XXX

Preparation of 2-benzylamino-U-chloro-U- (N, N-dimethylsulfamyl) -N- (o-tolyl) -benzamide a) 2,1-Dichlorobenzoic acid (200 g) was added over 10 minutes to one kilogram of chlorosulfonic acid. The mixture was stirred for four hours at 160 ° C and added to a mixture of ice and water. The solid was filtered, washed with water and sucked as dry as possible. The product (2, U-dichloro-5 'carboxybenzenesulfonyl chloride) was used in the next step without further purification.

b) 2, U-Dichloro-5-carboxybenzenesulfonyl chloride (112 g) was stirred for four hours with 800 ml of water and 100 g of dimethylamine. The solid was filtered and recrystallized from water to give 6 g of 2,6-dichloro-5- (N, N-dimethylsulfamyl) benzoic acid, m.p. 176-178 ° C.

Cl S

Calculated: 23 »78 10.75

Obtained: 2k, 2k 10.77- c) 2, U-Dichloro-5- (N, N-dimethylsulfamyl) -benzoic acid (70 g) and 100 ml of thionyl chloride were heated under reflux for 11/2 hours and condensed to dryness at U0 ° C. . From residue 2, U-dichloro-5 'dimethylsulfamyl-benzoyl chloride was used without further purification.

d) 2,1 * -Dichloro-5- (N, N-dimethylsulfamyl) -benzoyl chloride (70 g) was added portionwise to 600 ml of o-toluidine. The mixture was stirred for 30 minutes, heated to 120 ° C and poured into two liters of ice water. The mixture was acidified to 12,56530 by the addition of hydrochloric acid and the solid was filtered and washed successively with water, isopropanol, isopropanol ether and ether to give 63.5 g of 2,1 + -dichloro-5- (N, N-dimethylsulfamyl) -N- (o-tolyl) -benzamide, m.p. 182-183 ° C.

e) To 100 ml of benzylamine was added 25.0 g of 2,1 + -dichloro-5- (N, N-dimethylsulfamyl) -N- (o-tolyl) -benzamide. The reaction mixture was gently heated to 120 ° C and held for four hours. The reaction mixture was added to 1 + 00 ml of water and acidified. The solid was filtered off, recrystallized from 200 ml of 95% ethanol. 11 +, 2 g of 2-benzylamino-1 + -chloro-5- (N, N-dimethylsulfamyl) -N- (o-tolyl) -benzamide, m.p. 233 “235 ° C, color white. Method XXXI

Preparation of 2-amino-5-chloro-5- (N, N-dimethylsulfamyl) -N- (o-tolyl) -benzamide 2-Benzylamino-1 + -chloro-5- (N, N-dimethylsulfamyl) -N- (o-tolyl) -benzamide (12 g) in 120 ml of dimethylformamide was catalytically reduced at 2 L +, 2 kg / cm 1 + g of 5% Pd / C. The mixture was diluted with 100 mL of tetrahydrofuran and filtered. The filtrate was concentrated to 70 mL, poured into 600 mL of water, and the solid was filtered and recrystallized from 200 mL of alcohol to give 5.6 g of 2-amino-1 + chloro-5- (N, N-dimethylsulfamyl) - N- (o-tolyl) -benzamide, m.p. 176-177 ° C. Concentration of the filtrate gave a second crop of 3.1 g.

The following examples illustrate the invention in detail.

Example 1 Preparation of 2-methyl-3- (o-tolyl) -6-sulfamyl-7-chloro-1,2,3,1 + -tetrahydro-1 + -quinazolinone 2-Amino-1 + -chloro-5-sulfamyl-N- (o -tolyl) -benzamide (685 g) (Method VI) was slurried in 700 ml of glacial acetic acid. To this slurry were added 2 L + 0 g (280 mL) of dimethyl acetal and 1+ mL of concentrated sulfuric acid. The reaction mixture was stirred for 3 1/2 hours, filtered and washed thoroughly with ether. The yield of the crude substance was 661+ g and its melting point was 252-253 ° C. This was recrystallized from 25 liters of 95% ethanol by dissolving while hot, cooling and evaporating to half volume under reduced pressure and 30 ° C. The weight of the first crop was 685 g, m.p. 2 * * 6-250 ° C (21 + 0-21 + 3 ° C).

C H N Cl S

Analysis:

Calculated for C 18 H 19 ClNO 0 S 52.53 1 +, 1 + 1 11, 1 + 9 9.69 8.76

Found: 52.38 1+, 1 + 5 11, 53 9.70 8.90.

56530

The filtrates from recrystallization were concentrated to half volume to give an additional 251 g of product. Concentration of this filtrate to half volume gave an additional 196 g of product which was recrystallized from 1+ 500 mL of 95- $ ethanol by concentration to half volume in vacuo at 30 ° C to give 151 g of product. This portion was combined with the 251 g portion obtained above. Total weight U02 g, m.p. 21 + 7-252 ° C (227.5-231.5 ° C).

C H N Cl S

Analysis:

Calculated for C 12 H 19 ClN 0 S 52.53 1 +, 1 + 1 11.1 + 9 9.69 8.76

Found: 52.38 1+, 1 + 7 11.7¾ 9.70 9.05.

Example 2 Preparation of 3- (o-tolyl) -6-sulfamyl-7-chloro-1,2,3,1 + -tetrahydro-1 + -quinazolinone

Dimethoxymethane (11.3 ml) was added dropwise over 5 minutes to a mixture of 1 + 0.8 g of 2-amino-1 + -chloro-5-sulfamyl-N- (o-tolyl) -benzamide (Method VI) in 300 ml of acetic acid. and 12 ml of sulfuric acid. The mixture was stirred for 6 hours, poured into 3.5 liters of water, the solid filtered and washed with water. The dried solid was purified by chromatography on silica gel to give 2k, 2 g of product which was crystallized twice from alcohol (800 and 600 ml) to give 15 g of product, m.p. 250 to 253.5 ° C

u n LJ. JM

Calculated: 51.21 U, 01 10.8 11.9¾

Found: 51.27 3.95 9.86 12.21 10.08

Example 3 Preparation of 2-methyl-3-phenyl-6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-U-quinazolinone

To a mixture of 39.2 g of 2-amino-1 + -chloro-5-sulfamyl-N-phenylbenzamide (Method XIII), 1 + 00 ml of acetic acid and 16.2 ml of 1,1-dimethoxyethane was added 0.2 ml of sulfuric acid. . The reaction mixture was stirred for 5 hours at room temperature, the solid was filtered and washed with 75 ml of acetic acid and then with ether to give 1 + 2.2 g of crude product. This was recrystallized twice from alcohol (2 liters and 1.1 liters) and re-dried twice from alcohol (at 110 ° C) to give 22 g of 2-methyl-3-phenyl-6-sulfamyl-7-chloro-1,2 , 3, ¾-tetrahydro-U-quinazolinone, m.p. 21 + 7.5-250 ° C (solvated).

The final product was dried at 130-1l + 0 ° C for 18 hours under P 2 O in vacuo to give the product with a melting point of 2l + 5 → 5l + 9 ° C.

1¾ S6530

C H Cl N S

Calculated: 51 »21 1 +, 01 10.08 11.9 * + 9.11

Found: 51.12 1+, 00 10.35 11.91 9.39.

Example 1+ Preparation of 2-propyl-3 '(o-tolyl) -6-sulfamyl-7-chloro-1,2,3,1 + -tetrahydro-1 + -quinazolinone 2-amino-1 + -chloro-5-sulfamyl -N- (o-Tolyl) -benzamide (Method VI) (10 g), acetic acid (60 ml), butyraldehyde (Θ g) and 8 drops of sulfuric acid were stirred for five minutes. The mixture was poured into one liter of water and filtered. The solid was recrystallized from alcohol to give 8.1 g of product, to which 11.1+ g of a second crop was combined, and recrystallized from alcohol and then acetic acid to give 6.2 g of product, m.p. + 221-22l ° C.

C H N Cl S

Calculated: 57.88 5.12 10.67 9.00 8.11 +

Found 5l +, 7l + 5.22 10.9! + 9.02 8.1U

9.06

Example 5 Preparation of 2-butyl-3- (o-tolyl) -6-sulfamyl-7-chloro-1,2,3,1 + -tetrahydro-U-quinazolinone 2-amino-1 + -chloro-5-sulfamyl- In 250 ml of acetic acid of N- (o-tolyl) -benzamide (Method VI) (23.7 g) was added 13.1 + 6 g of 1,1-diethoxypentane and then 70 drops of sulfuric acid. The mixture was stirred for 6 hours, poured into two liters of water, the solid filtered and dried. The crude material was recrystallized from 300 ml of benzene, twice from isopropanol (200 and 125 ml) and purified by chromatography on silica gel. The solid was then recrystallized from a mixture of tetrahydrofuran (50 ml) and benzene (200 ml) to give 11 +, 7 g of product, m.p. 11 + 5-153 ° C.

C H Cl N

Calculated: 55.95 5.1 + 1 + 8.69 10.30

Found: 56.21 5.1 + 5 8.5! + 10.11 8.1 + 8

Example 6 Preparation of 2-methyl-3-benzyl-6-sulfamyl-7-chloro-1,2,3,1 + -tetrahydro-U-quinazolinone from 2-amino-1 + -chloro-5-sulfamyl-N-benzylbenzamide (Method XV) (3I + g) In 250 ml of acetic acid was added 12.2 ml of 1,1-dimethoxyethane and then 50 drops of sulfuric acid. The mixture was stirred for 1+ hours, poured into three liters of water and 56530 filtered. The solid was heated under reflux with 30 mL of alcohol and filtered to give 25 g of product. This was recrystallized three times from alcohol to give 12.7 g of 2-methyl-3'-benzyl-6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone, m.p. 216-218 ° C.

C H Cl N S

Calculated: 52.53 4.41 9.69 11.49 8.76

Found: 52.25> +, 28 9.64 11.27 8.85-

Example 7 Preparation of 2-phenyl-3 '(o-tolyl) -6-sulfamyl-7' chloro-1,2,3,4-tetrahydro-4-quinazolinone 2-amino-4-chloro-5-sulfamylone N- (o-tolyl) -benzamide, (Method VI) (10 g), benzaldehyde (6 g), acetic acid (120 ml), and 5 drops of sulfuric acid were stirred for two hours at room temperature and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from 600 ml of ethyl acetate-hexane (U: 1) to give 5.9 g of 2-phenyl-3 '(o-tolyl) -6-sulfamyl-7 "chloro-1,2, 3,4-tetrahydro-4-quinazolinone, m.p. 241-243 ° C.

C H N S Cl

Calculated: 58.94 4.24 9.82 7.49 8.29

Found: 58.80 4.24 8.98 7.52 8.40.

Example 8 Preparation of 1,2-dimethyl-3- (o-tolyl) -6-sulfamyl-7 'chloro-1,2,3,4-tetrahydro-4-quinazolinone 2-methylamino-4-chloro-5-sulfamyl- N- (o-tolyl) -benzamide (Method XIX) (18.5 g) was added to 200 ml of acetic acid. To the mixture were added 16 ml of 1,1-dimethoxyethane and 0.5 ml of sulfuric acid. The reaction mixture was stirred for half an hour, filtered and further stirred for 1 1/2 hours. The solid was filtered and washed with acetic acid and ether to give 17.6 g of 1,2-dimethyl-3 '(o-tolyl) -6-sulfamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone , sp. 26L-263 ° C.

C H N Cl S

Calculated: 53.6l 5.03 11.03 9.31 8.42

Found: 53.82 4.92 11.26 9.39 8.18.

Example 9 Preparation of 1-benzyl-3- (o-tolyl) -6-sulfamyl-7'-chloro-1,2,3,4-tetrahydro-4-quinazolinone

To a thick suspension of 5.3 g of 2-benzylamino-4-chloro-5-sulfamyl-N- (o-tolyl) -benzamide (Method XXII) in acetic acid was added 3.0 g of 1,1-dimethoxymethane and 4 g of drops of sulfuric acid over five minutes (one drop after 1-2 minutes). A solution formed and upon stirring overnight solid 16 56530 had precipitated. The solid was filtered off, washed with ether and dried. The product was crystallized twice from glacial acetic acid and the product from the second crystallization was dried at 150 ° C for 72 hours. The product weighed 3.2 g, m.p. 193-195 ° C, color white.

C H N Cl S

Calculated for C 12 H 12 ClN 3 O 3 60.59 U, 86 9.22 7.78 7.03

Found: 60, i + 5 U, 89 9.33 7.62 6.9.

Example 10 Preparation of 2-methyl-3- (1 + -hydroxy-2-methylphenyl) -6-sulfamyl-7-chloro-1,2,3,10-tetrahydro-1-quinazolinone 2-amino-t-chloro-5- sulfamyl-N- (1 + -hydroxy-2-methylphenyl) -benzamide (Method XXIII) (10.7 g) was slurried in 125 ml of acetic acid. 1,1-Dimethoxyethane (9 ml) was added followed by 0.5 ml of sulfuric acid. The mixture was stirred for 30 minutes, filtered and stirred for a further two hours and filtered to give 11.1 g of crude product. From this, 10 g of 10 ml of ethylene glycol were recrystallized and dried at 1 DEG C. to give h, 6 g of 2-methyl-3- (1 + -hydroxy-2-methylphenyl) -6-sulfamyl-7-chloro-1, 2,3,4-tetrahydro-U-quinazolinone, m.p. 305 ~ 306 ° C.

C H N Cl S

Calculated: 50.33 1+, 22 11.00 9.29 8.1 + 0

Found: 50.13 1+, 31 + 10.91 9.36 8.15.

Example 11 Preparation of 3- (o-ethylphenyl) -6-sulfamyl-7-chloro-1,2,3,1 + -tetrahydro-1 + -quinazolinone 2-Amino-1 + -chloro-5-sulfamyl-N- (o-ethylphenyl ) -benzamide (Method XXIV) (25 g) was suspended in 200 ml of acetic acid, 6.1 g of dimethoxymethane and 1.0 ml of sulfuric acid were added and the mixture was stirred for 8 hours. The suspension was poured into water. The solid was filtered and purified by chromatography on silica gel and recrystallized from a mixture of dimethylformamide and water to give 10 g of 3- (o-ethylphenyl) -6-sulfamyl-7-chloro-1,2,3,1 + -tetrahydro-1 + -quinazolinone, m.p. . 278-28it ° C.

C H Cl N S

Calculated: 52.52 1+, 1 + 1 9.69 11.49 8.76

Found: 52.53 1 +, 29 9.78 11.56 8.57-

Example 12 Preparation of 3- (2,2,5-trimethylphenyl) -6-sulfamyl-7-chloro-1,2,3,1 + -tetrahydro-1 + -quinazolinone 2-Amino-4-chloro-5-sulfamyl-N- (2,2,5-Trimethylphenyl) -benzamide (Method XXV) (23 g) was suspended in 200 ml of acetic acid. Dimethoxymethane (6.1 g) was added followed by 1 ml of sulfuric acid. The mixture was stirred for 8 hours, poured into cold water, the solid filtered and purified by chromatography on silica gel. The product was heated under reflux with chloroform, filtered and recrystallized from alcohol to give 2.5 g of 3- (2,1,5-trimethylphenyl) -6-sulfamyl-7-chloro-1,2,3,1-tetrahydro-L- quinazolinone, m.p. 216-230 ° C.

C H H Cl S

Calculated: 53.77 L, 77 11, 07 9.33 8, LL

Found: 53.53 5.06 11.29 9, L7 8.30.

Example 13 Preparation of 2-methyl-3- (p-tolyl) -6-sulfamyl-7-chloro-1,2,3,1-tetrahydro-L-quinazolinone 2-amino-L-chloro-5-sulfamyl N- (p-tolyl) -benzamide (Method XXVI) (36.1 g), 370 ml of acetic acid and 1L of 8 ml of dimethoxymethane were mixed. Sulfuric acid (0.2 ml) was added and the mixture was stirred for L hours. The solid was filtered, washed and crystallized twice from alcohol (3 liters and 2.5 liters) using 30 g of charcoal during the second crystallization to give 28.0 g of 2-methyl-3- (p-tolyl) -6-sulfamyl-7- chloro-1,2,3,L-tetrahydro-L-quinazolinone, m.p.

302 to 303.5 ° C.

C H Cl N S

Calculated: 52.53 L, L1 9.69 11, L9 8.76

Found: 52.67 L, L6 9.61 11.66 9.06.

Example 1L

Preparation of 2-methyl-3- (2-methyl-L-methoxyphenyl) -6-sulfamyl-7-chloro-1,2,3,1-tetrahydro-L-quinazolinone 2-amino-L-chloro-5-sulfamyl- N- (L-methoxy-2-methylphenyl) -benzamide (Method XXVII) (16.5 g) was slurried in 150 ml of acetic acid. Dimethoxyethane (6 mL) and 5 drops of sulfuric acid were added. The mixture was stirred for two hours, filtered and the solid washed with acetic acid and then isopropanol and ether to give 13.5 g of 2-methyl-3 '(2-methyl-L-methoxyphenyl) -6-sulfamyl-7-chloro-1,2 , 3, L-tetrahydro-L-quinazolinone, m.p. 229 ~ 230 ° C.

C H Cl N

Calculated: 51.58 L, 58 8.96 10.6 L

Found: 51.30 L, 62 9.00 10, L8.

56530 18

Example 15 Preparation of 2-methyl-3- (o-tolyl) -6-acetylsulfamyl-7-chloro-1,2,3,k-tetrahydro-k-quinazolinone 2-methyl-3- (o-tolyl) -6- sulfamyl-7-chloro-1,2,3, k-tetrahydro-k-quinazolinone (25 g) was dissolved in 200 ml of pyridine. Acetic anhydride (62.5 ml) was added and the mixture was stirred for 6 hours at room temperature. The solution was poured into 1000 ml of ice water and acidified with concentrated sulfuric acid. After three-quarters of an hour, the solid was filtered, washed with water and recrystallized from a mixture of 50 ml of acetone and 10 ml of water, then dissolved in a mixture of 250 ml of acetone and 100 ml of water, filtered and concentrated to 200 ml to give 17 ml. »1 g of product, m.p. 2k3-2k6 ° C.

C H Cl N S

Calculated: 53.01 U, 1 + 5 8.69 10.30 7.86

Found: 52.71 k, 62 8.88 10.22 7.76.

Example 16 Preparation of 1-benzyl-2-methyl-3 ** (o-tolyl) -6-sulfamyl-7-chloro-1,2,3-k-tetrahydro-k-quinazolinone 2-Benzylamino-k-chloro- To 5-sulfamyl-N- (o-tolyl) -benzamide (Method XXII) (5.6 g) and 3 g of 1,1-dimethoxyethane in 70 ml of acetic acid were added k drops of sulfuric acid over five minutes. The mixture was stirred overnight and filtered. The solid was washed with ether and crystallized from 60 ml of acetic acid to give 3.2 g of product, m.p. 191 ~ 192 ° C.

C H N Cl S

Calculated: 60.59 k, 86 9.22 7.78 7.03

Found: 60, k5 5.99 9.33 7.62 6.9k.

Example 17 Preparation of 2-isopropyl-3- (o-tolyl) -6-sulfamyl-7-chloro-1,2,3,k-tetrahydro-k-quinazolinone 2-amino-k-chloro-5-sulfamyl-N- To (o-tolyl) -benzamide (Method VI) (51 g) in 520 ml of acetic acid was added 30.5 g of isobutyraldehyde diethyl acetal, followed by one drop of sulfuric acid. The mixture was stirred overnight at room temperature. The solid was filtered, washed with acetic acid and then ether and crystallized four times from alcohol. The product was dried at 135 ° C under vacuum under PgO 4 to give 18 g, m.p. 222.5 ~ 236 ° C.

C H Cl N S

Calculated: 5k, 89 5.12 9.00 10.67 8, p

Found: 5k, 83 5.17 9.01 10.62 8.08.

56530 19

Example 18 Preparation of 2,2-dimethyl-3-phenyl-6-sulfamyl-7-chloro-1H-tetrahydro-1-quinazolinone from 2-amino-1 + -chloro-5-sulfamyl-N-phenylbenzamide (Method XIII) 2 g of acetone (2 ml), acetic acid (20 ml) and 2 drops of sulfuric acid were stirred for 1+ hours at room temperature. The solid was filtered, washed with acetic acid and then ether and recrystallized from 1 + 0 ml of methanol to give 1.5 g of product, m.p. 273-278 ° C.

C H N Cl S

Calculated: 52.52 U, i + 1 11.1 + 9 9.69 8.76

Found: 52.26 1.36 11.79 9.87 8.85.

Example 19 Preparation of 1-methyl-3- (o-tolyl) -6-sulfamyl-7-chloro-1,2,3,1-tetrahydro-1-quinazolinone

35.1 g (0.1 mol) of 2-methylamino-1-chloro-5-sulfamyl-N- (o-tolyl) -benzamide (Method XIX) were slurried in 350 ml of glacial acetic acid, 9.9 g (0, 13 moles) of dimethoxymethane followed by 0.5 ml of concentrated sulfuric acid. The resulting mixture was stirred for three hours. The precipitated product was filtered off, washed with glacial acetic acid and then ether and dried in vacuo over P 2 O 3. The dried product (m.p. 202-20 ° C) can be recrystallized by dissolving ethanol and concentrating the solution to about one-third of the original volume.

Example 20 7'-Chloro-1-methyl-6'-sulfamyl-3 '- (o-tolyl) -spiro-N-iperidine-1 +, 2' - (1'-H) -quinazoline-7 + '(3' H) onin preparation tr

Cl “I ^ C1Y" V ”2 + ο / ~ Λ-οη3 k2ho2s Χ ^ Λο-κ„ ^ 3 CH CH3 ^^ 3

To a mixture of 67.9 g (0.2 moles) of 2-amino-1 + -chloro-5-sulfamyl-N- (o-tolyl) -benzamide (Method VI), 900 ml of glacial acetic acid and 30 g (0.265 moles) 1-methyl-3-piperidone, was added dropwise 20 ml of concentrated sulfuric acid. The mixture was stirred vigorously at room temperature for 2b hours. Glacial acetic acid was separated by decantation from 20 S6S30 oil and poured off. The oil was dissolved in one liter of water and after 1 1/2 hours the mixture was filtered and the solid was discarded. The filtrate was treated with saturated sodium carbonate solution until pH 8 was reached. If necessary, water was added to maintain miscibility. The total volume of the mixture was 3.5 liters. The solid was filtered, washed with water and air dried. After crystallization from 95% ethanol three times, 60.0 g of solvated, colorless crystals were obtained. After drying at 131 ° C under vacuum for 18 hours, the dry product was obtained, m.p. 219-222.5 ° C (decomposes).

C H N Cl S

Calculated for C 12 H 14 ClN 2 O 55.23 5.33 12.88 8.15 7.37

Found: 55.11 5.37 12.91 9.28 7.35 7.23.

Example 21 Preparation of 7'-chloro-6'-sulfamyl-3 '- (o-tolyl) -spiro-Cyclopentane-1,2' (1'H-quinazoline) - (') - (3'H) -one - h2no2s CH3

To a mixture of 17 g (0.05 mol) of 2-amino-1-chloro-5-sulfamyl-N- (o-tolyl) -benzamide (Method VI), 175 ml of acetic acid and 10 ml of cyclopentanone were added 25 drops of concentrated sulfuric acid. The mixture was stirred at room temperature. After 2 hours, 10 ml of cyclopentanone were added. After stirring for an additional 15 hours, the solid was filtered, washed with glacial acetic acid and air dried. Yield 16, U g, m.p. 265 '268 ° C. After double crystallization from 95- $ ethanol colorless, the crystalline solid melted at 268-270.5 ° C.

C H N Cl S

Calculated for C 12 H 12 Cl 2 O 3 S 56.22 4.97 10.35 8.73 7.90

Found: 56.38 5.04 10.35 8.44 8.06.

56530 21

Example 22 7, -Chloro-6'-sulfamyl-3,3 '(o-tolyl) -spiro [4-cyclohexane-1,2' - (1'-H) -quinazoline-7 *, (3'-Hi-one preparation ^ X ")

“YY ♦ o = ° -» X X

H2NO2S X) H2NO2S C I

ch3 ch3 2-Amino-1 '' - chloro-5-sulfanyl-N- (o-tolyl) -benzamide (Method VI) (20 g) was slurried in 200 ml of acetic acid. To the slurry were added 7.5 g of cyclohexanone and 6 drops of concentrated sulfuric acid. The mixture was stirred for 5 hours, filtered, washed with ether and dried. The crude product was purified by dissolving in 1 ml of dimethylformamide, heating to 100 ° C and adding 35 ml of water at 100 ° C. After cooling, the product was filtered, washed with 25 ml of a mixture of 3 parts of dimethylformamide and 2 parts of water, then three times with 50 ml of methanol and finally three times with 100 ml of ether, dried in vacuo over phosphorus pentoxide, the product weighed 20. 5 g and melted at 291-293 ° C,

Example 23 Preparation of 2-methyl-3- (3-chloro-2-methylphenyl) -6-sulfamyl-7-chloro-1,2,3,1 * -tetrahydro-1 * -quinazolinone

37.1 * g (0.1 mol) of 2-amino-1 + -chloro-5-sulfamyl-N- (3-chloro-2-methylphenyl) -benzamide were slurried, to about 350 ml of glacial acetic acid, 11.7 g ( 0.13 moles) of 1,1-dimethoxyethane followed by a few drops of concentrated sulfuric acid. The resulting mixture was stirred until the reaction was complete. The precipitated product was filtered off, washed with glacial acetic acid and then ether and dried in vacuo over phosphorus pentoxide. The dry product (m.p. 261 + -267 ° C) can be recrystallized by dissolving in ethanol and concentrating the solution to one third of the original volume.

Example 2k Preparation of 2-methyl-3- (o-trifluoromethylphenyl) -6-sulfamyl-7-chloro-1,2,3,1 * -tetrahydro-1 * quinazone

37.8 g (0.1 mol) of 2-amino-1 * -chloro-5-sulfamyl-N- (o-trifluoromethylphenyl) -benzamide were slurried in 350 ml of glacial acetic acid, 11.7 g (0 mol) of , 13 moles) 56530 1,1-dimethoxyethane followed by 0.5 ml of concentrated sulfuric acid. The resulting mixture was stirred until the reaction was complete. The precipitated product was filtered off, washed with glacial acetic acid and then ether and dried in vacuo over phosphorus pentoxide. The dry product (m.p. 305-307 ° C) can be recrystallized by dissolving in ethanol and evaporating the solution to one third of the original volume. Example 25 Preparation of 2-carboxy-7-chloro-6-sulfamyl-3- (o-tolyl) -1,2,3,1 + -tetrahydro-1-quinazolinone

2-Amino-1 + -chloro-5-sulfsyl-N- (o-tolyl) -benzamide (Method VI) (15 g) was slurried with 9 g of glyoxalic acid monohydrate and 50 ml of glacial acetic acid. 10 drops of concentrated sulfuric acid were added and the mixture was stirred for 2 hours. Water (200 ml) was added and the solid was filtered, dried and recrystallized from one liter of 80% aqueous isopropanol. Weight 1 + -5 g, m.p. 180-195 ° C (decomposes),

C H Cl N

Calculated: 1 + 8.55 3.56 10.62 8.96

Found: 1 + 7.36 3.85 10.07 9.05 1 + 8.19 1 +, 23 9.75

Example 26 Preparation of 1-benzyl-2-methyl-3- (o-tolyl) -6- (N, N-dimethylsulfamyl) -7-chloro-1,2,3,1 + ~ tetrahydro-1 + -quinazolinone

To a suspension of 2-benzylamino-1 + -chloro-5- (N, N-dimethylsulfamyl) -N- (o-tolyl) -benzamide (Method XXXI) (10 g) in 150 ml of glacial acetic acid was added 8.0 g of acetal and then 2 ml of sulfuric acid, The reaction mixture was stirred for one hour, the solid was filtered off and dried. Weight 8.0 g. The solid was recrystallized from isopropanol to give 6.1 g of product, a white solid, m.p. + 183-181 ° C.

C H Cl N S

Calculated for C ^ H ^ CIN ^ S 62.01+ 5.1 + 17.762 8.68 6.62

Found: 62.33 5.1 + 1 6.1 + 6 8.86 6.61 + 62.36 5.66 6.1 + 0 8.77 6.88.

Example 27 Preparation of 7-chloro-6- (N, N-dimethylsulfamyl) -2-methyl-3- (o-tolyl) -1,2,3,1 + -tetrahydro-1 + -quinazolinone

By catalytic debenzylation of 8.0 g of 1-benzyl-2-methyl-3- (o-tolyl) -6- (N, N-dimethylsulfamyl) -7-chloro-1,2,3,1 + -tetrahydro-1 + -quinazolinone 2 6.0 g of 5 - # Pd / C catalyst in 70 ml of methanol at a pressure of 1+, 2 kg / cm were obtained 23 56530

Only partial debenzylation of the rich but recrystallization of the crude product from isopropanol gave pure 7-chloro-6- (Ν, Ν-dimethylsulfamyl) -2-methyl-3- (o-tolyl) -1,2,3,4-tetrahydro-4- quinazolinone, Weight 2.1 g, m.p. 252-254 ° C, color white.

Calculated: S 8.1U

Found: S 8.41,

Example 28 Preparation of 2,2-dimethyl-3- (o-tolyl) -6-sulfamyl-7 "chloro-1,2-Si-2-tetrahydro-1-quinazolinone H / H3 ® v q ru + H3C-O0 ^ J | Ί υπ3

_ CH ^ I

HgNOgS ^ \ ^ CONH H2NO2S5 Cl13 CH3

2-Amino-4-chloro-5-sulfamyl-N- (o-tolyl) -benzamide (18 g) (0.053 mol) was slurried in a solution of acetone (20 ml) and acetic acid (100 ml) at room temperature. P-Toluenesulfonic acid (0.2 g) was added and the reaction mixture was stirred for two hours. The insoluble solids were filtered and washed with acetic acid and diethyl ether, m.p. 259-262 ° C, weight 20 g. The product was recrystallized from 95% ethanol to give the product, m.p. 26 DEG-272 DEG C., weight 12 g,

C H 'N Cl S

Calculated for C17H18ClN3O3S · 53.76 4.77 11.07 9.33 8.44

Found: 53.87 4.85 11.04 9.32 8.6l.

Example 29 Preparation of 2-methyl-3- (o-thiyl) -6- (N, N-dimethylsulfamyl) -7'-chloro-1,2,3,4-tetrahydro-4-quinazolinone

2-Amino-4-chloro-5- (N, N-dimethylsulfamyl) -N- (o-tolyl) -benzamide (Method XXXI) (5.8 g) was slurried in 60 ml of acetic acid and 5 ml of 1.1 ml was added. -dimethoxyethane and 5 drops of sulfuric acid. The mixture was stirred overnight, the solid was filtered, washed with water and dried to give 4.7 g of 2-methyl-3- (o-tolyl) -6- (N, N-dimethylsulfamyl) -7-chloro-1,2, 3,4-tetrahydro-4-quinazolinone, m.p. 252-254 ° C.

Claims (2)

2U 56S30 Claim; Process for the preparation of 6-sulfamyl-1,2,3,4-tetrahydro-1-quinazolinones of the formula ΓΎ 11.2 // \ L o I? -R / VZZ \ TJ R 3 is wherein and independently represent hydrogen, methyl or acetyl; R is hydrogen, methyl or benzyl; R 1 and R 8 independently represent hydrogen, alkyl of 1 to k carbon atoms, phenyl or carboxy, or R 1 and R 2 together with the carbon atom to which they are attached form cyclopentyl, cyclohexyl or 1-methylpiperidyl; N is 0 or 1; and R 1, R 2 and R 2 independently represent hydrogen, methyl, ethyl, methoxy, chlorine, hydroxy or trifluoromethyl, and for the preparation of their salts, characterized in that the anthranilamide of the formula C 1 H 2% SO 2 R 0 -B- (CH 2) n - / N 2 O 5 R 5 wherein Y 1, Y 2, R 2, R 2, R 2, R 2 and n are as defined above are reacted with an acetal, aldehyde or ketone having the formulas are R 1, C 14 OR M, RCH and RC-R 0, respectively, wherein R 1 and R 2 are as defined above; and R 'is a hydrocarbon group; at room temperature in the presence of acetic acid, and a) when R is benzyl, the resulting compound is optionally hydrogenated to replace the benzyl group with a hydrogen atom; b) when Y 1 and Y 2 represent a hydrogen atom, the resulting product is and that the product obtained is, if desired, reacted with an acid or a base to form a salt. 26 56530 Patent: for the production of 6-sulfamyl-1,2f3, ltd-tetrahydro-U-quinazolinones with the formula R Y- „bo2XX c ν 's * ίτ r5 Rlt color Y ^ och betecknar oberoende av varandra väte, methyl or acetyl; R is a prop, methyl or benzyl; R 2 and R 2 are optionally substituted with alkyl of 1-U cholate, phenyl or carboxy or R 2 and R 2 are substituted with cholate of cycloententyl, cyclohexyl or 1-methylpiperidyl; n is 0 or 1; and R 1, R 2 and R 2 are taken up in a variety of compounds, methyl, ethyl, methoxy, chloro, hydroxy or trifluoromethyl, and anhydrous salt, kanyneteck and then anthranilamide in the form of γν 2. R5 * k color Y ^, Y ^, R, R ^ »R ^» R ^ och n bar ovan angiven betydelse, omsättes med en acetal, aldehyd eller keton, vilka har formlerna respektive '^ C (0R') _ , R.-CH and RC-R0 pe 1 II I II <£ n2 0 0 color R1 och har ovan angiven betydelse; and R1 is a piston group; at room temperature and at room temperature, och