SI8310386A8 - Process for obtaining antihypertensive quinzolines - Google Patents

Description

Process for the preparation of antihypertensive quinazolines

FIELD OF THE INVENTION

The invention relates to the synthesis of therapeutically useful heterocyclic compounds.

Technical problem defined

The invention relates to a process for the preparation of therapeutic agents that are derivatives of 4-amino-2- (piperazin-1-yl or homcpiperazin-1-yl) quinazoline. These compounds are useful as regulators of the cardiovascular system and, in particular, in the treatment of hypertension. The state of the art

A different process for the preparation of 4-amino-2- (piperazin-1-yl or homopiperazin-1-yl) quinazoline is described in our pending Yugoslav patent application P-2553/78, the entire description of which is incorporated herein by reference.

A detailed description of the solution to a technical problem with examples of execution

The new compounds obtained by the process of the present invention are compounds of the general formula:

in which (R) represents 6,7-di (lower alkoxy) yl? 6,7,8-tri (lower alkoxy m is 1 or 2; X represents -CHR or -CH CH-j each of R ¹ , which may be the same or different, represents hydrogen or lower alkyl; and R and R, which may be prepared to be the same or Various coils, particularly represents hydrogen, lower alkyl, lower alkoxy, halogen, alkanoyl arrays, arrays alkoxy ^^ rbon or g ^r W ⁱⁿ formulas | -QONR R or -SO NR ⁴ R ^5, Where su R ⁴ and R, which may be the same or different, each individually hydrogen or lower alkyl; and their pharmaceutically acceptable acid addition salts.

In the present description, halogen means fluorine, chlorine, bromine or iodine. The term lower as used for the alkyl and alkoxy groups indicates that such a straight or branched group contains from 1 to 6 C atoms, preferably from 3 to 4 C atoms. The term lower applied to alkanoyl means that such a straight or branched group contains from 2 to 6 C atoms, preferably from 2 to 4 C atoms. The pharmaceutically acceptable acid addition salts of the compounds of the invention are salts formed with acids which give non-toxic addition salts containing pharmaceutically acceptable anions, such as chlorhydrates, bromhydrates, sulfates or bisulphates, phosphates or acid phosphates, acetate, maleate, fumarate, succinate, lactate , tartrate, citrate., gluconate, saccharate, and pt.oluol sulfonate.

One of the preferred groups of compounds obtained by the process of the invention has the formula:

40419

(ΙΑ) α | coke) or 6,7,8-tri (lower alkoxy); R ¹ represents, hydrogen or lower alkyl; and R and R ', which may be the same or different, each individually represent hydrogen, lower alkyl, lower alkoxy, halogen, lower ^ a ^ canoyl or c ^ pu fo ^ mul «^. -C0NR R or "~ where R and R, which may be from where the process is having (R) formula (I)

6,7-dimethoxy, 6,7-diethoxy 6,7, N - trimethoxy; m is 1 or 2; each R 2 is independently H or CH 2; and R and R 'are each independently hydrogen, lower alkyl, lower alkanoyl, or

-SO NR R the same or different represents hydrogen or lower alkyl; and their pharmaceutically acceptable acid addition salts. Another desirable

-C0NH ₂ or SO ₂ N (CH _{3) second}

alkoxy, halogen, lower lower alkoxycarbonyl, / - \

The most appropriate formula:

the compounds of the invention have

2.3 in which R is H or CH.j and R and R are hydrogen, lower alkyl, lower alkoxy, halogen or lower alkanoyl.

The most suitable special compound is 4-amino-2- [4- (1,4-benzodioxane-2-carbonyl) piperazin-1-yl] -6,7-dimethoxyquinazoline.

Compounds of the invention containing one or more asymmetric centers exist in one or more pairs of enantiomers, and these pairs or special isomers can be separated by physical methods, e.g. by fractional crystallization of suitable salts. The invention includes separated pairs as well as mixtures thereof, as racemic mixtures or as separate d- and 1-optically active isomeric forms. When X represents -CHR- where R is lower alkyl then cis- and trans-isomerism is possible, and both isomers (and mixtures thereof) are encompassed by the present invention.

The compounds of the invention are prepared by the reaction of a suitably substituted quinazoline of the formula:

: -..- 4) 0412: ..

with the carboxylic acid of the formula:

'-'χ ₀ ™ «XI,

B ¹ or with its functional equivalent as an acylating agent, e.g. an acid chloride or bromide, an ester activated, or a mixture of the anhydride of a compound of formula (III).

Acid chlorides or bromides can be obtained by conventional methods, e.g. by reacting the free acid with respectively thionyl chloride or bromide.

A preferred activated ester is the succinimido ester of the formula:

which can again be obtained by conventional methods, e.g. by reacting the free acid with N-hydroxysuccinimide in the presence of a dehydrating agent, e.g. dicyclohexylcarbodiimide. Another preferred activated ester is the phthalimido ester.

Suitable mixed anhydride has the formula:

wherein Y is lower alkyl or lower alkoxy, most preferably t-butyl or isobutoxy. They can be obtained by conventional methods, e.g. by reacting the free acid with the corresponding lower alkanoyl chloride or lower alkyl chloroformate, respectively, e.g. pivaloyl chloride or iso-butoxychloroformate, in the presence of a base such as triethylamine. When a compound of formula (III) is used in the form of free acid, the reaction should usually be carried out in the presence of a dehydrating agent such as dicyclohexylcarbodiimide.

Preferably, the compounds of formula (III) are reacted in the form of chloride or acid bromide.

In a typical process using the acid chloride of compound (III), the acid chloride in a suitable solvent, e.g. methylene chloride is added dropwise to a mixed suspension of quinazoline (II) in a suitable solvent, e.g. methylene chloride. The mixture may be stirred for several hours at room temperature, and the resulting solids treated and purified in the usual manner.

When X = -CHR - where r is lower alkyl, then a cis-trans isomer is possible as mentioned in (1).

The intermediates of formula (II) and formula (III) can be obtained by conventional methods.

The pharmaceutically acceptable acid addition salts of the compounds of the invention can be prepared by conventional methods, e.g. by reacting the free base with the appropriate acid in an inert organic solvent, and collecting the resulting salt precipitate by filtration. If necessary, the product can then be recrystallized to make

40419 purified. However, it is often the product obtained in the form of an acid addition salt.

The invention also includes pharmaceutically acceptable bio precursors of the compounds of formula (I) and salts thereof.

The term pharmaceutically acceptable bio precursor requires some explanation. It is, however, common in pharmaceutical practice that certain unwanted physical or chemical properties of a drug are overcome by converting the drug into a chemical derivative that does not possess those unwanted properties but which, after administration to the animal or human, is reconverted to the drug from which it was made. . For example, if the drug is not well absorbed by the oral or animal route when administered to an animal or patient, the drug can be converted to a well-absorbed chemical derivative that is converted back to the original drug in blood or tissue. Again, if the drug is unstable in solution, it is possible to prepare a chemical derivative of the drug which is stable and which can be administered in. solution, but which again translates into the patient's body to obtain the original drug. The pharmaceutical chemist is well aware of the potential to overcome internal deficiencies of the drug through chemical modifications that are only temporary and reversible upon administration to the animal or patient.

In this specification, the term pharmaceutically acceptable bio precursor of a compound of formula (I) means a compound of a structural formula other than a compound of formula (I) but which, after administration to an animal or human, is nevertheless converted into a patient's body into a compound of formula (I).

The antihypertensive effect of the compounds of the invention has been demonstrated by their ability to lower blood pressure in conscious rats with spontaneous hypertension and puppies with renal hypertension when administered orally at cd? Up to 5 mg / kg. The compounds of the invention may be administered alone, but will typically be administered in admixture with a pharmaceutical carrier selected according to the route of administration and standards of pharmaceutical practice. For example, they may be administered orally in the form of tablets containing excipients such as starch or lactose, or capsules or alone or in admixture with excipients, or in the form of elixirs or suspensions containing them. flavoring and bo ying agents. They can be given by injection parenterally, e.g., intramuscularly, intravenously or subcutaneously. For parenteral administration, it is best to use them in the form of sterile aqueous solutions which may contain other solutes, for example, sufficient salt or glucose to produce an isotonic solution.

The compounds of the invention may be administered to a human for treatment with 'hypertension' orally or parenterally, and may be administered orally at limit doses in the range of about 1 to 20 mg / day per average adult patient (O kg), in a single dose, or in up to 3 divided doses. The intravenous dose should be about 1/5 to 1/10 of the daily oral dose. Thus, for the average adult patient, individual oral doses in the form of tablets or capsules will approximately be in the range of 1 to 50 mg of the active compound. Various variations will be required depending on the severity and condition of the patient being treated and especially on the chosen route of administration, as is known to the person skilled in the art.

The invention further provides a method of treating an animal, including a human, suffering from hypertension, comprising administering to the animal an antihypertensive amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof, as given above. The following examples illustrate the invention: Example 1

4-Amino-2- [4- (6-methoxy-3,4-benzodioxane-2-carbonyl) piperazin-1-yl] - ~~

6, 1'-dimethoxyquinazoline

A solution of 6-methoxy-1,4-benzodioxane-2carbonyl chloride (2.17 g) (obtained from chloride) was added dropwise in stirred acid and thionyl dichloromethane (25 ml).

4-amino-2-piperazin-1-yl-6,7-dimethoxy-quinazoline (2.48 g) in methylene chloride (50 ml). After completion, the mixture was stirred for 4 h, treated and the solid suspended in aqueous potassium carbonate and extracted with chloroform. The combined extracts were washed with water, dried (Wa ₂ SO ₄ ) and evaporated in vacuo to give a residue (4.15 g) chromatographed on silica gel (160 g) and eluted with chloroform followed by chloroform-methanol (2/4%) ). Similar fractions (tlc) were combined, evaporated on ethyl acetate and then the residue was collected with ethyl acetatemethanol and treated with ether hydrogen chloride. Adding more ether, and on room? addition at room then cooling gave a solid which was collected and crystallized from methanol to give 4-amino-2- / 4 (6-methoxy-1,4-benzodioxane-2-carbonyl) piperazine-1- yl) -6,7-dimethoxy-quinazoline, hydrate (0.95 g) mp 220 222 ° C.

% Analysis

Found: C, 53.3; H, 5.5; N,] 3.4

Calculated for C ".H.-N.O ^ .HCl.H" O:

27 5 o 2

C, 53.8; H, 5.6; N, 13.1.

Example 2-20

In a similar manner to Example 1, starting from 4-amino-2-piperazin-lyl- (or 2- (3-methyl-piperazin-1-yl) -6,7-dimethoxyquinazoline and the corresponding carbonyl chloride, the following compounds.

Tables

-. : 40419-CH, 0

P

CHjO

/ ~ V

N N. Z \ _! Y o

NH ₂

Primor no. Z s ¹ Isolated shape, etc. (° O) % Analysis (theoretical in parentheses) 0 H N .2 I P and ch_ H Chlorhydrate, hemihydrate 2J8 - 240 ° 56.2 (56.4 5.4 5.7 13.9 13.7) 4 (emeda 8- and 5-isomers) .3 £ ₀ ° X ^ ^{ch <ch} ^ H Chlorhydrate, hemihydrate 225 - 230 ° 58.0 (57.9 6.2 • 6.2 13.3 13.0) (ameAa 8- and 5-ifcomera) 4 H Chlorhydrate, hemihydrate 286-288 ° 57.5 (57.2 5.8 6.0 13.3 13.3) 5 OCH, DO H Chlorhydrate, hemihydrate 268-270 ° 54.1 (54.7 5.5 5.5 13.9 13.3 · ' 6 ID OCH, j H Chlorhydrate, hydrate 230 ° (rapt.) 53.4 (53.8 5.3 5.6 12.8 13.1 7 Jo O ⁰¹ (emeia 6- and 7-isomers) H Chlorhydrate, hydrate 280-281 ° 52.3 (52.0 4.8 4.9 12.8 13.2) 8 01οΧΑ ⁰¹ H hemihydrate 242-243 ° 52.5 (52.2 4.3 4.6 13.2 13.2) 9 H Chlorhydrate 279-280 ° »-99.3 ° ($ 0.4 to DMF) 56.5 (56.6 5.6 5.4 14.1 14.4) 10 ID t \ H Chlorhydrate 284-286 ° n + 95 ° · Nitpl 56.2 (56.6 5.4 5Λ 14.5. 14.4)

Example br * Z R ¹ Isolated form and t.CC.) · Analysis (theoretical in parentheses) C H N 11 ϊ: ό cie, trans emeAa H Chlorhydrate ... hydrate 2J7 - 240 55.0 5.5 13.6 (55.4 5.8 13.5) 12 Ao trana H Chlorhydrate hydrate 242 - 2430 55.8 5.7 13.1 (55.4 5.8 13.5) 13 Sifl. K Chlorhydrate dihydrate 214 - 215 ° 54.0 5.5 12.7 (53.6 6.0 13.0) 14 ΟΗθ H Chlorhydrate hydrate 234 - 237 ° 55.6 5.4 13.3 (55.4 5.8 13.5) 15 H Chlorhydrate hemihydrate 272 ° 55.6 5.2 13.0 (55.7 5.4 13.0) 16 / with · λ ₀ ΑΑ ^σΗ 3 0 H Chlorhydrate hydrate 230 ° 54.4 5.2 12.8 (54.8 5.5 12.8) 17 (emeAa 6- and 7-iomers; H Chlorhydrate Hydrate 232 - 234 ° (Decay) 48.6 5.3 13.5 (49.0 5.4 13.7) 18 H Chlorhydrate, aeakvi-raetano- lat 205 - 207 ° 55.3 6.1 12.9 <55.7 6.2 12.7)

--404-19 -

example no. Z R ^{* 1} Isolated form and m.p. (° C) % Analysis (theoretical in parentheses) OHM 19 ^CH 3 Oxalate seekihydrate, 1 - 6 - 179 ° 53.8 5.4 11.6 (53.6 5.5 12.0) 20 (mixture of 6- and 7-isomers) H Chlorhydrate dihydrate 208 - 210 ° (hydro) 52.2 5.2 11.4 (52.4 5.8 11.8)

Example 21

4-Amino-6,7-dimethoxy-2- / 4- (mixture of 6 N -carbamoyl-1,4-benzodioxane-2-carbamoylpiperazino / quinazoline chloride hydrate

Dicyclohexacarbodiimide (2.06 g) and N-hydroxysuccinimide (1.15 g) were added to a stirred solution of 6- and 7-carbamoyl-1,4-benzodioxane-2 carboxylic acid (2.27 g) in dimethylformamide (70 ml) at 0 ° C. The mixture was stirred at 0 for 1 h, then 4-amino-6,7-dimethoxy-2-piperazino-quinazoline (2.8 g) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was then treated, the filtrate was diluted with ether (5oo ml) and the resulting oily residue was collected. The product was partitioned between: chloroform / isopropanol / sodium bicarbonate solution, the layers were separated, washed with water and evaporated in vacuo. The residue was chromatographed on silica gel eluting with chloroform-methanol (7%) to give a crude product which, after treatment with an ethereal hydrogen chloride solution and recrystallization from methanol / water / ether / dimethylformamide, followed by methanol / water / dimethylformamide of the mixture gave 4-amino-6,7-dimethoxy-2- [4- (6- and 7- (mixture) -carbamoyl-1,4-benzodioxane-2-carbonyl) piperazio / quinazoline hydrochloride. hydrate, m.p. 228-275 ° C (dec.).

Further crystallization gave an analytical sample, m.p. 245 - 248 C.

Analysis%: Found: C, 52.6; H, 5.5; N, 34.6

Calculated for C_.Η., Ν, Ο ^ ΗΟ.H_O:

26 6 6 2

C, 52.5; H, 5.7; N, 15.3.

High-pressure chromatographic analysis showed a mixture of 6- and 7-isomers in a 7: 7 ratio.

The following examples illustrate how to get some of the starting materials:

Preparation 1

6-Methoxy-1,4-benzodioxane-2-carboxylic acid

-40415

The finely divided potassium permanganate (5.02 g) was added in four portions to a stirred suspension of 2-hydroxymethyl-6-methoxy-1,4-benzodioxane (4.52 g) in a solution of potassium hydroxide (1.47 g, in 42 ml of water) at 5 ° C. During the reaction, the temperature was maintained at 5 - 15 ° C and after the addition was complete, stirring was continued at room temperature for another 4 h and then. the reaction mixture was left to stand overnight.

The manganese dioxide was removed by filtration, the solid was washed with water and the combined organic phases. were acidified (pH 1) with concentrated hydrochloric acid, cooled, then extracted with chloroform. The combined chloroform extracts were washed with sodium hydroxide (5N, 2 x 40 ml) and then the base phase was washed again with chloroform, cooled, acidified (pH 1) with concentrated hydrochloric acid and extracted again with chloroform. This last chloroform extract was washed with water, dried (Na2 O4) and evaporated to give the crude residue of 6-methoxy-1,4-benzodioxane-2-carboxylic acid (2.g). The sample was recrystallized from water, m.p. 120 121 ° C.

Analysis%: Found: C, 57.1; H, 4.8

Calculated for C., H 0:

C, 57.1; H, 4.8.

Preparation 2:

8- and 5- (mixture) -Isopropyl-1,4-benzodioxane-2-carboxylic acid (A) A stirred solution of 3-isopropyl catechol (23 g) in acetone (250 ml) was heated under reflux and then added. potassium carbonate (28 g). The heterogeneous mixture was refluxed for a further min. then methyl 2,3-dibromopropionate (10 g) was added dropwise. Three more portions of potassium carbonate (28 g) and methyl 2,3-dibromopropionate (10 g) were similarly added, and the mixture was then refluxed for 12 h. The mixture was then evaporated, the residue diluted with water (700 ml), extracted with chloroform and the combined extracts washed with water, dried (MgSO4) and evaporated. The residual oil was distilled to give 8 (5) -isopropyl-1,4-benzodioxane-2-carboxylate (29.3 9)>

incl. 115-120 ° C / 0.5 mm. C n.m.r. spectroscopy confirmed that the product was in the form of a mixture of 8- (71%) and

5- (29%) isomers.

(B) The above product (29.0 g) in sodium hydroxide solution (160 ml,

2.5 N) was heated to 100 for h and then the resulting solution was cooled and acidified with concentrated hydrochloric acid. The mixture was extracted with chloroform (3 x 200 ml), then the combined extracts were dried (MSO 4) and evaporated in vacuo to give an oil (18 g) which solidified on standing.

Recrystallization from methanol gave a mixture of 8- and 5-isopropyl-1,4-benzodioxane-2-carboxylic acids, m.p. 86 - 88 ° C.

Analysis%: Found: C, 64.7; H, 6.3

Calculated for ^C i2 ^H i4 ° 4 ^:

C, 64.9; H, 6.3.

High-pressure liquid chromatography showed the product to be a mixture of 8- (86%) and 5- (1?%) Isomers. / Spectra Physics 3,500 cs Machine; colomn, 1 'x O.D. in Bondapak C-18; eluent., acetonitrile '(1) /0.15 M potassium hydrogen phosphate buffer pH

3.5 (2); flow rate, 14 ml / min; pressure 600 p.s.i.-a /.

Preparation 3:

Mixture of 8- and 5-Methyl-1,4-benzodioxane

-2-carboxylic acids

Potassium permanganate (23.15 g) was added in three portions to a mixed suspension of a mixture of 8- and 5- methyl-2-hydroxymethyl-1,4,4-benzodioxane (20 g) in a solution of potassium hydroxide (6.5 g 187 ml BO) at 5 ° C.

The reaction temperature was maintained below 15 C and after the addition was complete, the reaction mixture was stirred at room temperature for 4 h. Manganese dioxide was removed by filtration, the filtrate was cooled, acidified with concentrated hydrochloric acid and the oily product which was separated by cooling was extracted with chloroform. Hloroformski extracts su isprani with a 5N solution of sodium hydroxide, the base layer is followed by a ispran hloroformom zakišeljen koncentrovanom with hydrochloric acid to pH 1. The acidic solution was ekstrahovan hloroformom, spliced extracts su isprani brine, dried (MgSO) and evaporated on vacuum at d ^e gave a mixture of 8- and 5-methyl-1,4-benzodioxane-2-carboxylic acid (7.3 g) as a syrupy residue with stable spectroscopic properties. The small sample was esterified with diazomethane and gas chromatography showed that it was a mixture of isomers (5: 2).

6,1-Dimethyl-1,4-benzodioxane-2 carboxylic acid

(A) Mixed solution

4,5-dimethylhetocetol (7.0 g) in dry acetone (45 ml) was refluxed, then potassium carbonate (5 g) was added and then ethyl dibromopropionate (3.5 g) was added dropwise. The addition process was repeated three more times for 1 '/ h and then the reaction was stirred under reflux for another 3' _f h. After cooling, the mixture was graded, the solid was washed thoroughly with acetone and then the combinations and filtrates were concentrated in vacuo. Water (35 ml) was added, the resulting solid was collected, washed with petroleum gas and then treated with ether. Etarski solution is ispran water, dried (Na ^ SO) and evaporated on vacuum at what ^Z was obtained ethyl 6,7-dimethyl-l, 4-benzodioxan-2-carboxylate (17.10 g),

m.p. 70 - 71 ° C.

Found: C, 55.7; H, 6.8

Calculated for C, -H,, .0 .:

! 3 16 4

C, 66.1; H, 6.8.

(B) Hydrolysis of the upper ester (5.0 g) with sodium hydroxide (10%, 13 ml) in ethanol (125 ml) as described for related compounds (J.A.C.S., 7 ?, 6374 (1956) gave the crude

6,7-dimethyl-1,4-benzodioxane-2-carboxylic acid (4.04 g). The sample was recrystallized from water and showed m.p. from 150 - 151 ° C.

Analysis%: Found: C, 63.9; H, 6.0

Calculated for ^ 51 ^ 52 ^ 4 ^:

C, 63.5; H, 5.8

% Analysis

The preparation. 5;

6,7-Dichloro-1,4-benzodioxane-2-carboxylic acid

Hydrolysis of ethyl 6,7-dichloro-1,4-benzodioxane-2-carboxylate (5.0 g) with sodium hydroxide (10%, 10.9 ml) in ethanol (50 ml) gave 6,7-dichloro -1,4- benzodioxane-2-carboxylic acid (3.4 g) mp 155 - 158 ° C with a constant n.m.r. spectrum and an identical Rf value (thin layer chromatography) with an authentic sample.

Preparation 6:

8-Methoxy-1,4-benzodioxane-2-carboxylic acid

8-Methoxy-1,4-benzodioxane-2-carboxamide (2.41 g) in 50% hydrochloric acid (35 ml) was stirred at 100 for 1 h. The resulting solution was cooled, diluted with water (200 ml), extracted with chloroform (3 x 100 ml), then the extracts were dried (MgSC> ₄ ) and evaporated in vacuo. The solid residue (1.8 g) was crystallized from water (mp 75-78) and then from a mixture of ethyl acetate and hexane to give 8-methoxy-1,4-benzodioxane-2-carboxylic acid, mp 131 132 ° C.

Analysis%: Found: C, 56.9; H, 4.8

Calculated for "O _C :

J U 1U □ c, 57.I; H, 4.8.

The preparation. 7;

5-Methoxy-1,4-benzodioxane-2-carboxylic acid

This compound was obtained in the same manner as the preparation. 7, starting from

5-methoxy-1,4-benzodioxane-2-carboxamide. The product is crystallized from water, m.p. 85-87 C, then from a mixture of ethyl acetate and hexane to give 5-methoxy-1,4-benzodioxane -2-carboxylic acid, m.p. 1.39 141 ° C.

Analysis%: Found: C, 56.9; H, 4.8

Calculated for £ ·, ₀ ^Η ηθ ° 5 ^:

C, 57.1; H, 4.8.

Preparation 8:

6-Acetyl-1,4-benzodioxane-2-carboxylic acid

Johnson's reagent (11.6 ml) was added dropwise to a stirred solution

6-acetyl-2-hydroxymethyl-1,4-benzodioxane (4.0 g) in acetone (70 ml) at 10 - 15 C. The reaction was stirred at room temperature for 18 ha then diluted with isopropanol / water / chloroform mixture, organic layers are separated and evaporated in vacuo. The residue was redissolved in chloroform, extracted with saturated sodium carbonate solution (2 x 30 ml) then the basic phase was washed with chloroform, cooled and acidified to pH 1 with concentrated hydrochloric acid.

The acidified solution was extracted with chloroform, the combined extracts were washed with brine, dried (Na2 SO4) and evaporated in vacuo to give 6-acetyl-1,4-benzodioxane-2-carboxylic acid (1.56 g) m.p. 159-162 °. A sample recrystallized from ethanol / ethyl acetate has m.p. 174 - 175 °.

Analysis%: Found; C, 59.0; H, 4.8

Calculated for ^c ^ 2 ^H io ° 5 ^:

C, 59.5; H, 4.5.

Preparation 9:

N-acetyl-1,4-benzodioxane-2-carboxylic acid (A) Methyl solution

2,3-dibromopropionate (13 ml) in acetone (50 ml) was added to the capillary during 1 / g. with a stirred suspension of 3,4-dihydroxy-acetophenic (15.1 g) and: 4041.9- /:: / anhydrous potassium carbonate (28 g) in acetone (100 ml) under reflux. The mixture was stirred at reflux for 4 h, then evaporated in vacuo and the residue partitioned between chloroform and water. The chloroform extracts were washed with water, dried (MgSC> ₄ ) and evaporated to give a mixture (18 g) of 6-

7-acetyl-1,4-benzodioxane

-2-Carboxylic acids in the form of methyl ester in the ratio confirmed by the aid of C 'n.m.r. spectroscopy. A sample of this crude product was recrystallized from isopropanol, m.p. 68 - 80 C.

% Analysis

Found: C, 60.7; H, 4.9

Calculated for ^c -j2 ^H 12 ° 5 ^:

C, 61.0; H, 5.1.

(B) An aqueous solution of sodium hydroxide (1.2 g 5 ml water) was added to a stirred solution of product C ⁷ a) from phase (A) in ethanol (25 ml) at 15. The reaction temperature was maintained below 25 for an hour then the mixture was evaporated in vacuo, the residue triturated with water, acidified with concentrated hydrochloric acid and extracted with chloroform. The combined chloroform extracts were dried (MgSO4), evaporated in vacuo and the residue (1.46 g) was recrystallized from ethyl acetate / methanol to give

7-acetyl-1,4-benzodioxane-2-carboxylic acid, m.p. 167-168 ° C. Analysis%: Found: C, 59.0; H, 4.5

Calculated for CH _and O:

10 5

C, 59.5; H, 4.5.

High Pressure Liquid Chromatography (HPLC) showed an isomer purity of 96% /Spect.ra Physics 3,500 CS Machine; column 3 'x O.D. u-Bondapak C-18; eluent, acetonitrile (D / 0.05M potassium hydrogen phosphate buffer pH 4.5 (2); flow rate 0.6 ml / min .;

pressure 780 p.s.i-a./

The acidic aqueous phase was evaporated in vacuo, the residue was extracted with methanol, the combined extracts were evaporated in vacuo and the product (5.5 g) was recrystallized from ethyl acetate / methanol to give

6-acetyl-1,4-benzodioxane-2-carboxylic acid. HPLC showed only one component corresponding to the authentic sample obtained according to preparation 9.

The preparation. 10:

(A) (+) 1,4-Benzodioxane-2-carboxylic acid

1,4-Benzodioxane-2-carboxylic acid (21.6 g) and (+) dehydroabiethylamine (34.26 g) were mixed in hot industrial methylated spirit (1000 ml) and then allowed to stand at room temperature for 24 h. The precipitate formed was collected (20 g), the filtrate concentrated to 600 ml and allowed to stand for 48 h to give a still solid product (4 g). The combined product (24 gtt 204 -210 °) was industrial crystallized several times from methylated spirit-methanol to constant mp 229 - 230 C (3.0 g), then the mother liquors of the last two crystallizations were combined, their volume was reduced and collected is a solid product (5.6 g). This salt was converted to free carboxylic acid (5.5 g), alpha _D + 60.1 ° (1% in chloroform) in the usual way, then recrystallized twice from toluene to give (+)

1,4-Benzodioxane-2-carboxylic acid (0.23 g), m.p. 98 -99 ° C, alpha ^ - +62.1 (1% solution in chloroform).

Analysis%: Found: C, 60.3; H, 4.4

Calculated for C "H" O,:

8 4

C, 60.0; H, 4.5.

(B) (-) 1,4-Benzodioxane-2-car13

4041?

acetic acid

The initial mother liquor (600 ml) from the previous experiment was evaporated in vacuo and the oily residue was treated with acetone (250 ml) and then left to stand until crystallization was complete. The solid was collected, crystallized from acetone and then the salt (6.0 g) was converted to the free acid in the usual way using dilute sulfuric acid. The crude product was collected by chloroform, chromatographed on silica gel (10 x 50 mm column size) eluted with chloroform, evaporated in vacuo, then crystallized from toluene to give (-)

1.4- Benzodioxane

-2-carboxylic acid (0.90 g), mp 98 - 99 ° C, alpha _D = -66.1 ° (1% solution in chloroform).

% Analysis

Found: C, 59.9; H, 4.5

Calculated for C "H" O,:

8 4

C, 60.0; H, 4.5

Preparation 11:

6- and 7- (mixture) Chloro-1,4-benzodioxane-2-carboxylic acids (A) Gaseous chlorine was passed through an ice-cold solution of methyl

Of 1,4-benzodioxane-2-carboxylate (10

g) in chloroform (100 ml) in the presence of aluminum chloride (0.06 g). The reaction was quenched after 20 minutes, then the solution was purified with nitrogen, washed with water, brine, then again with water, dried (Na2SO4) and evaporated in vacuo to give a mixture (1: 1 by C nmr spectroscopy) of methyl 6- i

7-chloro-1,4-benzodioxane-2-carboxylate (12.0 g).

(B) A sample of the above product (1.4 g) in ethanol (20 ml) was treated with a solution of sodium hydroxide (0.25 g) in water (1 ml) at room temperature to give a black color. After standing at room temperature for 48 h, the mixture was concentrated in vacuo, diluted with water, extracted with chloroform and the chloroform layer discarded. The aqueous phase was acidified with concentrated hydrochloric acid, extracted with chloroform, then the combined extracts were dried (MgSO4) and evaporated in vacuo to give a mixture (1.0 g) of 6-

7-chloro-1. , 4-Benzodioxane-2-carboxylic acids, m.p. 145 - 146 C, with respectable spectroscopic properties.

Preparation 12:

2-Methyl-1,4-benzodioxane-2-carboxylic acid

Johnson's reagent (33.3 ml) was added dropwise to a stirred solution of 2-hydroxymethyl-2-methyl-1,4-benzodioxane (5 g) in acetone (300 ml) at 5 ° C, then the reaction mixture was allowed to reach room temperature. Isopropanol (1.0 ml) was then added followed by water (200 ml), the solution was extracted with chloroform and the extracts were evaporated in vacuo. The residual oil was collected with chloroform (200 ml) and then extracted with dilute sodium bicarbonate solution and the aqueous phase was washed with chloroform. The aqueous phase was then acidified with hydrochloric acid, extracted with chloroform, the combined extracts washed with water, dried (MgSO) and evaporated in vacuo to give 2-methyl-1,4-benzodioxane-2-carboxylic acid (1.7 g). The sample recrystallized from toluene had a m.p. 133-134 ° C.

Analysis%: Found: C, 61.8; H, 5.2

Calculated for C,., Η _ιη Ο,:

4

C, 61.9; H, 5.2.

Preparation 13:

6- and 7- (mixture) N, N-dimethylsulfamoyl-1,4-benzodioxane-2-carboxylic acid

- 40419- (A) Catechol (180 g) was added in portions, stirring, sulfuric acid (138.5 ml) so that the reaction temperature remained below 25 ° C. Upon completion of the addition, the semi-solid mixture was heated at 45 ° C for 60 minutes and then cooled to room temperature and transferred to ice water (700 ml). The solution was neutralized with solid barium carbonate, barium sulfate was collected, the filtrate was acidified to pH 1 with concentrated sulfuric acid and then re-treated. The filtrate was evaporated to leave crude 3,4-dihydroxybenzene-sulfonic acid (182.40 g) which was further used without purification.

(B) The above product (182.40 g) was acetylated in a standard manner using acetic anhydride (300 ml) in pyridine (800 ml) and the crude diacetoxy product (302.49 g) was further used directly.

(C) Phosphorpentachloride (378 g) was added dropwise to a mixed solution of pyridinium salt

3,4-Diacetoxy-benzene sulfonic acid (302.49 g) in chloroform (1000 ml) at 0 C so that the reaction temperature does not increase above 15 C. After the addition is complete, the reaction mixture is stirred at room temperature overnight, then it is treated , the chloroform solution was evaporated in vacuo and the residual oil was transferred over ice water. The aqueous phase was extracted with chloroform, the combined extracts were dried (Na2 SO4) and evaporated in vacuo to give a semi-solid product which was recrystallized from carbon tetrachloride. This product (26.74 g) was treated with aqueous dimethylamine (265 ml, 15% solution) at 20 ° C, the reaction mixture was left at room temperature overnight and then the solution was evaporated in vacuo. The dark residue was diluted with acetone (250 ml), then decanted, the solution evaporated in vacuo and the residue in the form of an oil mixed with the same volume of sodium hydroxide solution at room temperature for 2 h.

The solution was then acidified with concentrated hydrochloric acid and the resulting product crystallized from water to give N, N-dimethyl-3,4-dihydroxybenzene sulfonamide, m.p. 142 ° C.

(D) A solution of sodium hydroxide (0.61 g) in water (5 ml) was added dropwise to a stirred suspension of the above product (3.0 gm) and epichlorohydrin (1.43 ml) in water (15 ml ^ and then the reaction was heated to 80 for 1 ^ After cooling, the reaction was extracted with methylene chloride, the combined extracts were washed with water, dried (Na2SO4) and evaporated to give a mixture of 6 and 7- N, N-dimethylsulfamoyl-2-hydroxymethyl-1,4. -benzodioxane (2.84 g) as a sticky oil with stable spectroscopic properties.

(E) Potassium permanganate (2.15 g) was added in three portions to a mixed suspension of the above alcohol (2.8 g) in a solution of potassium hydroxide (0.59 g ^ in 20 ml of water) and acetone (10 ml) at 5 C so that the reaction temperature was not raised to 10 C. The reaction mixture was left at room temperature for 3 ha then acetone was evaporated and more potassium permanganate (1.5 g) was added and stirring was continued overnight. Finally, more potassium permanganate (3.C g) was added and the reaction mixture was stirred at 35-40C overnight under a nitrogen atmosphere. The resulting manganese dioxide was then collected, washed with water, the combined filtrates were acidified with concentrated hydrochloric acid and extracted with chloroform. The combined extracts were washed with sodium hydroxide solution (5N 2x 40 ml), the alkaline phase acidified with concentrated hydrochloric acid, extracted with chloroform, the combined extracts washed with water, dried (Na2 SO4) and evaporated in vacuo. The crude product (0.46 g) was combined with a similar material (0.21 g) obtained from the re-extraction of the initial manganese dioxide to give a mixture of 6- and 7Ν, Ν-dimethylsulfamoyl-1,4-benzodioxane-2-carboxylic acid (0.67

..4CA1 & -.

g), m.p. 156-162 ° C.

Analysis%: Found: C, 45.5; H, 4.6; N, 4.SO

Calculated for

C, 46.0; H, 4.6; H, 4.3

Preparation 14:

cis and trans Ethyl 3-methyl-1,4-benzodioxane -2-carboxylate.

These compounds were separated from each other by preparative HPLC (high pressure thin layer chromatography) and identified by n.m.r. spectroscopy according to published data (see, e.g., J. Med. Chem., 10, 880, 1967). Each isomer is hydrolyzed to the corresponding acid, which is converted to chloride without further characterization.

Preparation 15:

4-Amino-6,1-dimethoxy-2- (3-methylpiperazin-1-yl) quinazoline

4-Amino-2-chloro-6,7 "dimethoxyquinazoline (8.05 g) and 2-methylpiperazine (10 g) were refluxed in butanol for 15 h. The reaction mixture was then evaporated in vacuo and the residue in the form of an oil was collected by chloroform (200 ml), washed with water (4 x 50 ml), dried (NaSO.) And evaporated in vacuo. The residual oil (13 g) was recrystallized from isopropanol to give 4-amino-6,7-dimethoxy-2 (3-methylpiperazin-1-yl) quinazoline hemihydrate (3.0 g), m.p. 185 - 187 ° C. Analysis% s Found: C, 58.1; H, 6.8; N, 22.8 calculated for C. _H N_0 «z, H„ O:

'3 ZI 3 i i

C, 57.7; H, 7.1; N, 22.4.

The preparation. 16;

A mixture of 6- and 7-carboxy-1, 4-benzodioxane-2-carboxylic acid (A) Sodium hydroxide (1.94 g in 16 ml of water) was added dropwise at room temperature with a mixed suspension of epichlorohydrin (4.6 ml) and ethyl

3,4-dihydroxybenzoic acid (8 g) when all was dissolved. The reaction was heated at 80 C for 1 h, cooled and extracted with dichloromethane, the extracts were washed with water, dried (Na2 SO3 and evaporated in vacuo to give a mixture of 6 and 7-carboxy-2-hydroxymethyl-1,4-benzodioxane (10.87 g) in the form of a sticky oil with stable spectroscopic properties.

(B) The above alcohol (5.0 g) was oxidized with Johnson's reagent (12.3 ml) in acetone (70 ml) as described earlier (Preparation 9) to give a mixture (2: 1 according to HPLC) of 6? -Carbethoxy- 1,4-Benzodioxane-2carboxylic acids (1.78 g) with stable spectroscopic properties.

Preparation 17:

6- and 7-carbamoyl-1,4-benzodioxane-2-carboxylic acid (A) A mixed suspension of potassium carbonate (5.6 g) and 4-cyanocatechol (2.7 g) in acetone (50 ml) was heated under reflux for a while ha then methyl 2,3-dibromopropionate (4.9 g) was added dropwise.

The resulting mixture was refluxed for 48 h, then evaporated in vacuo, the residue was diluted with water and extracted with chloroform. the combined extracts were washed with water, dried (MgSO) and evaporated in vacuo to afford a mixture of methyl 6- and 7-cyano-L *, 4-benzodioxane-2-carboxylate (1.0 g). The sample was recrystallized from isopropanol, m.p. 95 - 96 ° C.

Analysis%: Found: C, 60.2; H, 4.2

Calculated for C, H ^ NO. :

119 4

40419

C, 60.25; H, 4.2.

HPCL analysis of the crude product mixture showed that it was a 5: 2 mixture of two components.

(B) Sodium hydroxide (0.7 ml, 6N) and hydrogen peroxide (1 ml, 30%) were added dropwise to a stirred suspension of the above cyano-ester (0.5 g) in ethanol (4 ml) at 15 C. The mixture was then heated to 40-50 C for 2 h, cooled, acidified with concentrated hydrochloric acid, the product was collected and crystallized from methanol / ethanol / water to give a mixture of 6- and 7-carbamoyl-1,4-benzodioxane-2 carboxylic acids, m.p. 258-260 ° C.

% Analysis: under vacuum and then the residue was collected with ethyl acetatemethanol and treated with ether hydrogen chloride. Adding more ether and then cooling gave it. a solid which was collected and recrystallized from methanol to give 4-amino-2- / 4- (6-methoxy-1,4-benzodioxan-2 carbonyl) piperazin-1-yl] -6,7-dimethoxy-quinazoline hydrochloride, hydrate (0.95 g) mp 220-222 ° C.

Claims (3)

PATENT REQUIREMENTS 1. A process for the preparation of antihypertensive quinazolines of the general formula: Found; C, 53.2; H, 4.1; N, 6.4 You calculate for ^C 10 ^H 9 Ν0 _ζ : C, 53.8; H, 4.1; N, 6.3 In the experience of the Applicant so far, the best way to carry out the process of the present invention is described in Example 1 and can be recapitulated as follows: A solution of 6-methoxy-1,4-benzodioxane-2 carbonyl chloride (2.17 g) (obtained from acid and thionyl chloride) in dichloromethane (25 ml) was added dropwise to a stirred suspension of 4-amino-2-piperazin -] - yl-6 , 7-dimethoxyquinazoline (2.48 g) in methylene chloride (50 ml) at room temperature. After the addition was complete, the mixture was stirred at room temperature for 4 h, then was treated and the solid suspended in aqueous potassium carbonate and extracted with chloroform. The combined extracts were washed with water, dried (Na2SO4) and evaporated in vacuo to give a residue which (4.15 g) was chromatographed on silica gel (160 g) and eluted with chloroform followed by chloroform-raethanol (2 ^i; l% ). Similar fractions (tlc) were combined, evaporated in which (R) was 6,7-dimethoxy; m is 1 or 2; Χρβ CH-CH, or -CH ₂ -CH ₂ -; ^R 2 3 ⁶ or methyl; R and R which may be the same or different represent hydrogen, C -C _? lower alk: ¹ , methoxy, chlorine, acetyl, carbethoxy, carbamoyl or N, N-dimethylsulfonamido group, and their pharmaceutically acceptable acid addition salts, which preserves the reaction of quinazoline of the formula: in which (R) ^, R have the meanings given above, with an acid chloride of the formula: -. .-40419. 12 3 in which X, R, R, R are as defined above, in methylene chloride at room temperature, or with the succinimide acid ester of the above formula (III) in dimethylformamide at room temperature, and, where appropriate, the product of the formula is converted (I) to a pharmaceutically acceptable acid addition salt. 2. The method of claim 1, wherein ^ (R) 6,7-dimethoxy ^ i, 1¾ is 1, each R j is hydrogen and R 1 R 'is hydrogen.