DE3124577A1 - 6-Hydrazonopyrido[2,1-b]quinazolin-11-one derivatives and processes for their preparation - Google Patents

Description

3Ί? 4577

ö-Hydrazono-pyrido ^ J-bJquinazolin-H-one derivatives and processes for their Manufacturing.

The invention relates to new 6-hydrazono-pyrido (2,1-b) quinazolin-11-one derivatives, their salts, their optically active and geometrical isomers and tautomers and processes for their preparation.

The compounds of the present application can be used as starting materials for Manufacture of alkaloids are used.

Some of the pyrido (2,1-b) quinazolin-11-one derivatives are available as alkaloids (Chem. Comm. 1965 , 267; Austral. J. Chem. 1966, 151; Chem. Ber. 1935, 68, 2221; J .Chem.Soc. J956_, 4694; Chem.Ber. 1962, 95_, 2182) are partially known as pharmacologically active compounds (DE-OS 28 12 585; BE-PSs 847.011 and 849 542). The known pyrido (2,1-b) quinazolin-11-one derivatives are in: Moshy, Heterocyclic Systems with bridgehead nitrogen atoms, Volume 2, pp. 1153-1159, Interscience Publishers, Inc., New York, 1961, described.

The connections of the. Invention are new, they correspond to the general Formula I.

I,

1 2
R, R and R, which can be identical or different, _{denote hydrogen, halogen, nitro, carboxyl, nitrile, C 14} -AlkOXy, C ^ -alkoxycarbonyl, C ₁₄ -alkyl, amino or hydroxyl, or

1 2

R and R together form a methylenedioxy group and R is hydrogen, R ^{3 is} hydrogen or C ₁ , -alkyl,

4th
R is hydrogen, C ^ -alkyl, optionally one to three times identically or differently by halogen, C _1-4 -AIlCyI ₁ C _1-4 -AIkOXy, phenyloxy, hydroxy-nitro, amino, cyano, carboxyl, C ^ -alkoxycarbonyl, C ^ -alkanoyl, methylenedioxy, trifluoromethyl, phenyl, C ^ -dialkylamino substituted phenyl, naphthyl or pyridyl and
the dashed line denote any further CC bond that may be present,

'and also include their salts, as well as the optically active and geometrical ones Isomers and tautomers of these compounds.

The compounds of the general formula I in which R, R, R, R, R and the dashed line have the meaning given above, and their salts, their optically active and geometric isomers and tautomers can be prepared in such a way that one
a) for the preparation of compounds of the general formula I, in which

12 3
R, R, R, R and the dashed line have the meaning given above and

R optionally one to three times identical or different by halogen, C ^ -alkyl, C _1-4 -AIkOXy, phenyloxy, hydroxyl, nitro, cyano, amino, carboxyl, C ^ -alkoxycarbonyl, C _1-4 -AIkBnOyI, methylenedioxy, is trifluoromethyl, phenyl, C ₁ _ ₄ dialkylamino substituted phenyl, naphthyl or pyridyl,

Compounds of general form II

wherein

1 ? 3
R, R, R, R and the dashed line have the meaning above and

R is hydrogen or formyl,

with a diazonium salt of the general formula III

₂ in,

wherein

R with the exception of the hydrogen atom and the C., alkyl group die

has the meaning given above, or b) for the preparation of the compounds of general formula I, wherein

12 3
R _s R, R, R and the dotted line has the meaning given above

have and

R is optionally monosubstituted to trisubstituted by identical or different halogen, C ^ _ «- alkyl, C ^ -alkoxy, phenyloxy, hydroxyl, nitro, cyano, amino, carboxyl, C, _ ₄ alkoxycarbonyl, C ^ alkanoyl, methylenedioxy , trifluoromethyl, phenyl, C, _ ₄ dialkylamino substituted phenyl, naphthyl or pyridyl,

Compounds of the general formula IV

H N

wherein

12 3
R, R, R, R and the dashed line have the meaning given above

have and

R ^{7 is} C _1-4 alkYl, with a diazonium salt of the general formula III,

where 4
R has the same meaning as in process variant a),

converts or c) compounds of the general formula V

wherein

1 2 3
R, R, R, R and the dashed line have the meaning given above

to have,

R is hydrogen or halogen and

9
R means halogen, with. a hyclrazine derivative of the general formula Vi

N -HH,

BT,

R has the meaning given above

and, if desired, the compounds of the general formula I obtained, if they contain acidic groups, are reacted with bases to form salts,
if they have basic character, zen with acids to Säureadditionssal- reacting
or else it is liberated from salts formed with acids or bases.

The reaction according to variant a) of the process according to the invention can be carried out in a manner known per se (Parmerter, Urg. Reactions 1959, _ [0, 1-142;
Phillips, Org. Reactions 1959, } Q_, 143-178).

According to an advantageous embodiment, the implementation is carried out under
5O ⁰ C lying temperatures, preferably carried out at -10 to 20 ⁰ C.
Either the compound of the general formula II can be added to the diazonium solution or the reverse procedure can be used. The reaction components are preferably used in an equimolar ratio, but it is also possible to work with a slight excess of one or the other component. The reaction is preferably carried out in an aqueous medium, if desired in the presence of a water-miscible inert inorganic solvent.

Alkanecarboxylic acids (preferably Acetic acid, propionic acid), acid amides (preferably N, N-dimethylformamide), Alcohols (methanol, ethanol, propanol, i-propanol, etc.), ketones (preferably acetone, methyl ethyl ketone), aromatic bases (preferably Pyridine) can be used. The reaction is preferably carried out in the presence of an acid binder. Examples of acid binders are: alkali alkanoates (preferably sodium acetate, potassium acetate), alkali metal Ihydroxides (preferably sodium hydroxide, potassium hydroxide) or alkali carbonates (preferably sodium carbonate, potassium carbonate, sodium hydrogen carbonate etc.).

The advantageous embodiments of variant b) of the invention Process correspond to that of process variant a).

According to process variant c), the compounds of the general Formula I prepared by reacting compounds of general formula V with compounds of general formula VI.

In the compounds of formula VI, the halogen atom is preferably chlorine or bromine. The reaction is preferably carried out in an inert solvent, and alkenols (methanol, ethanol, propanol, i-propanol, etc.), alkanecarboxylic acids (preferably acetic acid, propionic acid ), Acid amides (preferably Ν, Ν-dimethylformamide), aromatic bases (preferably pyridine) can be used. These solvents can optionally be mixed with water. In that case, the reaction is carried out in a mixture of water and a water-miscible organic solvent. If desired, the reaction can be carried out in the presence of an acid binder. The compounds specified in variant a) or excess starting compound VI are preferably used as acid binders. In the reaction, the compounds of the formula VI are used in a molar ratio of from 1 to 8, preferably from 2.5 to 4.5. The reaction is carried out in the temperature range from 0 160 ^° C., preferably at the boiling point of the reaction mixture.

The reaction time depends on the reaction components and can be 30 minutes up to 10 hours.

The compounds of general formula I obtained can in per se can be isolated from the reaction mixture in a known manner. In many cases the product separates out of the reaction mixture and can through Filtration or centrifugation or other common methods can be removed. If the product does not separate from the reaction mixture, the product can optionally be mixed with another solvent, e.g. Water, to be precipitated.

From the compounds of general formula I can with inorganic or organic acids salts are formed, e.g. hydrochlorides, hydrobromides, Sulphates, phosphates, perchlorates, maleates, acetates, etc. ..

From the compounds containing at least one carboxyl group of the general Formula Γ salts can be formed with bases, e.g. alkali metal salts such as the sodium and potassium salts, alkaline earth metal salts such as the calcium and magnesium salts, and also the salts formed with organic amines, such as triethylamine salts, ethanolamine salts, etc.

The invention also relates to the optical and geometric mers and the tautomers of these compounds.

The structure of the geometric isomers is illustrated by the formulas IA and IB:

(IA)

(IB)

and the tautomerism of the compounds of general formula I the formula scheme A)

The compounds of general formula I in which R is not hydrogen contain a center of asymmetry and can exist as optically active compounds or as a racemate.

The compounds of general formula I can be prepared from their with acids salts formed or bases are released in a manner known per se,

If the compounds of the general formula I are basic, they can by reaction with inorganic or organic acids, the acid addition salt are formed. The salt formation takes place in a manner known per se by adding the corresponding compound of the general formula I with the equivalent amount or with excess acid in an inert organic Solvent is reacted.

Compounds of the general formula I which contain carboxyl groups, can be reacted with bases (e.g. alkali metal hydroxides, alkaline earth metal hydroxides, organic amines) are converted into the salts formed with bases.

Some of the compounds used as starting material are known. The compounds of the general formulas II, IV and V are known from the literature (Japanese Kokai No. 78 130 435; BE-PSs 849 542 and 847 011; DE-OSs 28 12 585 and 28 12 586; Mosby, Heterocyclic Systems with bridgehead nitrogen atoms, 2nd volume, pp. 1153-1159, Interscience Publishers, Inc., New York, 1961; Him Heterocycl. Soed. 1976 , 1564-1569; 1979 , 684-691) or can be prepared in an analogous manner.

^w The compounds of general formula I are intermediates for the production of rutecarpine and rutecarpine analogs.

The invention is illustrated, however, by the following examples not limited to these examples.

Examples 1 to 22

0.69 g (0.01 mol.) Of sodium nitrite in 5 ml of water are slowly added dropwise at -5 ° C. to a mixture of 0.01 mol of aniline derivative and 5 ml of 1: 1 dilute 28 misehniger aqueous hydrochloric acid. stir the reaction mixture at -5 / half an hour and then adjust the pH value of the reaction mixture to 4 by adding sodium acetate. The reaction mixture is diluted with glacial acetic acid, then the solution of 2.0 g (0.01 mol) 11-0x0-6,7,8,9-tetrahydro-11H-pyrido (2,1-b) quinazoline in 10 ml 50 Total acetic acid was added dropwise, the reaction mixture obtained was ^{stirred at -5 to 0 °} C. for 3 hours and left to stand in the refrigerator overnight. The precipitated crystals are filtered off and washed with water. The resulting ö-phenylhydrazono-ii-oxo-ö ^ .S ^ -tetrahydro-IIH-pyrido- • (2,1-b) quinazolines can, if necessary, be recrystallized from n-propanol. The compounds thus obtained are shown in Table 1.

links
Formula, I _?
RR ¹ R ^ H H the i
R ³ generally
R ⁴ 1-naphthenyl M.p.
⁰ C Table 1 C ₁₈ H ₁₆ N ₄ O Elemental analysis {%)
calculated found
CHN CH 5.29 18.41 70.97 5.27 N at
game
No. H H H H Ph 2-naphthyl 182-184 Yield molecular formula C ₁₈ H ₁₅ N ₄ OCl 71.03 4.46 16.53 64.01 4.57 18.28 1 H H H H 4-Cl-Ph 4-Ac-Ph 191-192 90 C ₁₉ H ₁₈ N ₄ O 63.81 5.69 17.59 72.13 5.60 16.25 2 H H H H 4-Me-Ph 4-Me-Ph 187-188 94 C ₁₈ H ₁₅ N ₄ OBr 71.67 3.94 14.61 56.24 3.85 17.48 3 H H H H 4-Br-Ph 4-HO-Ph 180-183 88 C ₁₉ H ₁₅ N ₄ OF ₃ 56.41 4.06 15.04 61.89 4.12 14.51 4th H H H H 4-CF ₃ -Ph 4 MeO-Ph 195-197 84 C ₂₄ H ₂₀ N ₄ O ₂ 61.28 5.08 14.13 72.50 4.96 14.86 5 .H H H H 4-PhO-Ph 4-NO ₂ -Ph 178-180 83 C ₁₈ H ₁₅ N ₄ OCl 72.71 4.46 16.53 63.95 4.58 14.07 6th H H H H 3-Cl-Ph 4-F-Ph 181-183 83 C ₁₈ H ₁₅ N ₄ OCl 63.81 4.46 16.53 63.84 4.56 16.65 7th 3-Cl H H H Ph 219-222 89 C ₁₈ H ₁₄ N ₄ OCl ₂ 63.81 3.79 15.05 58.04 3.73 16.71 8th . 3-Cl H H H 4-Cl-Ph 227 65 C ₁₉ H ₁₈ N ₄ O 58.08 5.69 17.59 71.52 5.66 14.72 9 H H H 9-Me Ph 185-186 64 C ₂₂ H ₁₈ N ₄ O 71.67 4.84 14.96 70.55 4.84 17.53 10 H H H H 192-193 75 C ₂₂ H ₁₈ N ₄ O 70.57 4.84 14.96 70.33 4.65 14.40 11 H H H H 220 86 C ₂₀ H ₁₈ N ₄ O ₂ 70.57 5.23 16.17 69.33 5.35 14.87 12th H H H H 255 96 C ₁₉ H ₁₇ N ₄ OCl 69.34 4.65 14.42 58.88 4.78 16.28 13th 3-Cl H H H 231 81 C ₁₈ H ₁₇ N ₄ O ₂ Cl 58.72 4.80 15.70 60.69 4.85 15.18 14th H H H H 225 (b) 64 C ₁₉ H ₁₉ N ₄ O ₂ Cl 60.59 5.16 15.10 62.10 5.23 15.86 15th H H H H 223 84 C ₁₈ H ₁₆ N ₅ O ₃ Cl 61.53 4.18 18.19 56.04 4.19 14.90 16 H H' H H 250 (b) 92 C ₁₈ H ₁₆ N ₄ OFCl '56, 17 4.49 15.61 60.59 4.46 18.89 17th H H 245 92 60.25 15.02 18th 90

Table 1 (continued)

In the case of compounds of the general m.p.

game formula .1 ο r> _Δ calculated found

R ¹

19 H H H

20 H H H

21 H H H

22 2-MeO 3-MeO H

(b) = decomposition

H 4-HOOC-Ph 298 (b) 91 C ₁₉ H ₁₆ N ₄ O ₃ -HC H 3-pyridyl 188 23 C ₁₇ H ₁₅ N ₅ O-HCl H 4-CN-Ph 217 82 C ₁₉ H ₁₅ N ₅ O-HCl H Ph 230 (b) 66 C ₂₀ H ₂₀ N ₄ O ₃

C ₁₉ H ₁₆ N ₄ O ₃ -HCl 59.30 4.45 14.55 59.39 4.60 14.52

59.74 4.72 20.49 59.97 4.65 20.51

62.38 4.41 19.14 62.24 4.50 19.32

65.92 5.53 15.37 65.72 5.26 15.21

Examples 23 to 24

The procedure is as in Examples 1 to 22, but with the difference that instead of H-oxo-6,7,8 _> 9-tetrahydro-11H-pyrido (2 _s 1-b) quin ^ zoline 11-0xo-1, 2,3,4 _J 6,7,8,9-octahydro-11H-pyrido (2,1-b) quinazoline is used. The compounds thus obtained are shown in Table 2.

Table 2

For compounds of the general m.p. yield molecular formula elemental analysis {%)

game formula, 1 _? ~ . calculated found

No. RR ^: R ⁴ R * ³ R ^ ° _C% CHN CHN

70.10 6.53 18.16 69.93 6.51 18.07 70.78 6.87 17.37 70.55 6.91 17.27

23 H H H H Ph 205-208 85 C ₁₈ H ₂₀ N ₄ O 24 H H H 9-Me Ph 190-193 83 C ₁₉ H ₂₂ N ₄ O

M4 ι I

19 ^> \. Ά ^) ι ι

Example 25

10.8 g (0.03 mol) 6,6-dibromo-6,7,8,9-tetrahydro-11-oxo-11H-pyrido (2 ₅ 1-b) -quinazoline and 13.0 g (0, 12 mol) phenyl hydrazine are heated to boiling in 120 ml of ethanol for 4 hours and, after cooling, the precipitated crystals are filtered off. After evaporation of the mother liquor, further crystals separate out, which are filtered off and washed with a little alcohol who the. The combined products are suspended in 150 ml of water with 98.4 g (0.06 mol) of sodium acetate, then filtered and washed with water. 8.4 g (81 %) of 6-phenylhydrazonip> -6,7,8,9-tetrahydro-11-oxo ~ pyrido (2,1-b) quinazoline are obtained, which after recrystallization from i-propanol at 177 179 ° C melts and shows no Sbh'melzpünktsdepressiori with the product obtained according to Example 1.

Example 26

3.74 g (0.01 mol) 6,6-dibromo ^ -methyl ~ 11-oxo-6,7.8 _s 9-tetrahydro-11H-pyrido (2,1-b) quinazoline and 4.32 g ( 0.04 mol) phenyl hydrazine are heated to boiling in 40 ml of ethanol for 10 hours and, after cooling, the precipitated crystals are filtered off. The filtered product is suspended with 2.72 g (0.02 mol) of sodium acetate in 100 ml of water, then filtered and washed with water. 2.4 g (75 %) of δ-phenylhydrazono-g-methyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido (2,1-b) quinazoline are obtained, which after recrystallization from ethanol melts at 185-187 ° C.
Analysis for C ₁₉ H ₁₈ N ₄ O

calculated. (%): C 71.67 H 5.69 N 17.59 found (%): C 71.62 H 5.58 N 17.55.

Example 27

2.79 g (0.01 mole 6-bromo-11-oxo-6,7,8,9-tetrahydro-11H-pyrido (2,1-b) quinazoline and 2.16 g (0.02 mole) phenylhydrazine is heated in 30 ml of ethanol at 8O ⁰ C for 6 hours to boiling, the ethanol is concentrated to one third, the reaction mixture is in one cabinet to crystallize, the precipitated yellow crystals were filtered off and washed with water and ethanol. It will be 2.1 g (69 %) ö-Phenylhydrazono-H-oxo-ö ^ .e ^ -tetrahydro-HH-pyrido (2,1-b) quinazoline obtained, which ^{melts after recrystallization from i-propanol at 179-180 0} C and with the Product produced according to Examples 1 and 25 shows no melting point depression.

Example 28

0.69 g ( 0.01 mol) of sodium nitrite in 5 ml of water is added, the reaction mixture is stirred for half an hour at -5 to - ^.00 C., the pH of the mixture is adjusted to 4 with sodium acetate and the mixture is diluted with 10 ml of acetic acid. To the solution of Diazonuimsalzes dropwise 2.55 g of 6- (dimethylamino-methylene) -11-oxo-6 ₅ 7,8,9-tetrahydro-11H-pyrido (2,1-b) quinazoline is added slowly in 25 ml of dimethylformamide to, the reaction mixture is stirred at 0 ^° C. for 3 hours and then left to stand in the refrigerator overnight. On the next day, the mixture is diluted with water, the precipitated crystals are filtered off and washed with water. 2.61 g (86 %) of 6-phenylhydrazono-e, 7,8,9-tetrahydro-11-oxo-i1H-pyrido (2,1-b) quinazoline are obtained, which after recrystallization from i-propanol at 182 -184 ° C melts and there is no melting point depression with the product obtained according to Example 1.
Analysis for C ₁₃ H ₁₅ N ₄ O

Calculated (%): C 71.03 H 5.29 N 18.41 found (%): C 70.93 H 5.24 N 18.33.

Example 29

0.93 g (0.01 mol) of aniline is dissolved in 5 ml of 1: 1 diluted 38 MischXiger aqueous hydrochloric acid at -5 ⁰ C, then added dropwise with constant stirring and cooling 0.69 g (0.01 mol) of sodium nitrite in 5 ml of water are added, the reaction mixture is stirred for half an hour at -5 to ⁰ ° C., then the pH of the mixture is adjusted to 4 with sodium acetate and the mixture is diluted with 10 ml of acetic acid. The mixture is then slowly and vigorously stirred, the solution of 2.28 g (0.01 mol) of 6-formyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido (2,1-b) quinazoline was added dropwise in 30 ml of acetic acid. The reaction mixture is stirred for one hour at a temperature below 0 ^° C. and then left to stand in the refrigerator overnight. The precipitated crystals are filtered off and washed with water. 3.1 g (91 %) of δ-phenylhydrazono-e ^ .Sg-tetrahydro-H-oxo-HH-pyrido- (2,1-b) quinazoline hydrochloride, which melts at 255 ° C., are obtained. Analysis for C ₁₈ H ₁₇

Calculated (%): C 63.60 H 5.04 N 16.48 Cl 10.16 found [%): C 63.44 H 4.98 N 16.59 Cl 10.11.

Examples 30 to 33

The procedure is as in Examples 1 to 22, but with the difference

that as the starting compound in

Example 30: 2,3,4-Trίmethoxy-11-oxo-6,7,8 _s 9-tetrahydro-11-H-pyrido-

(2,1-b) quinazoline,
Example 31: 11-0xo-6,7,8 _i 9-tetrahydro-11H-pyrido (2,1-b) quinazoline-2-

carboxylic acid,
Example 32: Ethyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido (2,1 -b) quinazoline-

2-carboxylate and in

Example 33: 11-0xo _6,7,8-s 9-tetrahydro-11H-pyrido (2,1-b) quinazoline is used.

The e-phenylhydrazono-H-oxo-ö ^ .S ^ -tetrahydro-HH-pyrido- (2,1-b) quinazoline derivatives obtained are included in Table 3. The products can be recrystallized from n-propanol.

Table 3

For compounds of the general m.p., yield, sum formula, elemental analysis (%)

game formula, 1 _9,. calculated found

No. RR ¹ R ^ RR ⁴ ^ C % CHN CHN

30 2-OMe 3-OMe 4-OMe H Ph 187-189 77 ^C 21 ^H 22 ^N 4 ° 4 ^{63 '94 5} ' ^{62 14 '20 64> 03 5} ' ^{88 14> 28}

31 2-COOH HHH Ph 257 (b) 30 ^C 19 ^H 16 ^N 4 ° 3 ^{65 '51 4} ' ^{62 16 '08 65} ' ^{55 4> 66 16 '01}

32 2-COOEt HHH Ph 201 85 C ₂₁ H ₂₀ N ₄ O ₃ 67.00 5.35 14.88 67.03 5.45 14.85

33 HHHH 4-EtOOC-Ph 214 92 C ₀₁ H _9n NO, 61.09 5.09 13.57 61.25 4.99 13.58, I ₀

HCl,

«· Λ β ff« «

Examples 34 to 44 ■ ■

Procedure is as in Examples 23 to 24, wherein used as starting compounds 11-oxo-1, 2, 3,4,6,7,8,9-octahydro-11H-pyrido (2,1-b) quinazolin-alone derivatives will.

The 6-phenylhydrazono-11-oxo-1,2,3,4-6,7,8,9-octahydro-11H-pyrido (2,1-b) quinazoline derivatives given in Table 4 are obtained.
In Examples 42 'and 43, the precipitated after the diazo bond are
The crystals are suspended in a 5% mixed strength sodium hydroxide solution and then the aqueous solution is extracted by shaking with chloroform. The chloroform solution, dried over calcined sodium sulfate, is evaporated and the residue crystallized.

Table 4

For compounds of the general m.p. yield molecular formula elemental analysis (%)

game formula.I,, . calculated found

No. RR ¹ R ² R ³ R ⁴ ° _C% CHN CHN

34 HHHH 4-Cl-Ph 220 73 C ₁₈ H ₁₉ N ₄ OCl 63.06 5.59 16.34 63.24 5.51 16.32

35 HHH 9-Me 4-Cl-Ph 207-208 70 C ₁₉ H ₂₁ N ₄ OCl 63.95 5.93 15.70 64.14 6.17 15.78

36 HHH 9-Me 4-NO ₂ -Ph 168-170 79 C ₁₉ H ₂₁ N ₅ O ₃ HCl 56.50 5.49 17.34 56.15 5.44 17.00

37 HHHH 4-Me-Ph '203-204 46 C ₁₉ H ₂₂ N ₄ O 70.78 6.88 18.38 70.63 6.56 17.17

38 HHH 9-Me 4-Me-Ph 187-188 74 C ₂₀ H ₂₄ N ₄ O 71.40 7.19 16.65 71.17 6.96 16.72 ν

39 HHH 9-Me 4-Et-Ph 154-155 49 C ₂₁ H ₂₅ N ₄ O 71.97 7.43 15.99 71.58 7.52 16.03 '

40 HHH 9-Me 4-MaO-Ph 161-162 42 C ₂₀ H ₂₄ N ₄ O ₂ 68.16 6.86 15.90 68.43 6.95 15.80

41 HHH 9-Me 2-naphthyl 177-179 11 C ₂₃ H ₂₄ N ₄ O 74.17 6.50 15.04 74.13 6.40 14.72

42 HHH 8-Me Ph 219 59 C ₁₉ H ₂₂ N ₄ O 70.78 6.87 17.37 70.83 6.82 17.40, ·····

43 HHH 9-Me 3,5-DiCl- 227-228 33 C ₁₉ H ₂₀ N ₄ OCl ₂ 58.33 5.15 14.3-1 58.40 5.23 14.27

44 HHH 7-Me Ph 200 59 C ₁₉ H ₂₂ N ₄ O 70.78 6.87 17.37 70.91 6.75 17.45

C t, C «

Example 45

0.46 g (0.005 mol) of aniline in 3 ml of 1: 1 diluted hydrochloric acid 38 MischXiger at -5 ° C, then under constant stirring and cooling, 0.35 g of (O ^-, 005 mol) in 3 ml of water Natriuninitrit added dropwise. The reaction mixture is stirred for half an hour at -5 to 0 ^° C., then the pH of the mixture is adjusted to 4 with sodium acetate and the resulting mixture is then slowly added to the 6-formyl-11-oxo-1,2,3 solution , 4-6,7,8,9octahydro-11H-pyrido (2,1-b) quinazoline in 15 ml of 75% acetic acid was added dropwise. The reaction mixture is stirred for 3 hours at a temperature below 0 ⁰ C, then overnight in one cabinet allowed to stand and finally diluted with 30 ml of water. The precipitated crystals are filtered off and washed with water. This gives 1.3 g (73%) of 6-phenylhydrazono-11-oxo-1 ^ S ^ .e ^ .e ^ -octahydro-II Zolin hydrochloride, melting at 242-244 ⁰ C. Analysis for C ₁₉ H ₂₃ N ₄ OCl

Calculated {%): C 63.59 H 6.46 N 15.61 Cl 9.88 found (%): C 63.21 H 6.28 N 15.75 Cl 9.65

For converting the compounds of the invention to alkaloids such as rutecarpine or rutecarpine derivatives, the compounds of general formula I are

I,

wherein

R, R, R, R, R and the dashed line have the meaning given above to have,

or their acid addition salts in the presence of an acid - preferably an organic, inorganic or Lewis acid - heated. The reaction is optionally carried out in a solvent.

As a solvent, alkanols (methanol, ethanol), water, aromatic Hydrocarbons (frenzene, toluene, xylene), ethers (diethyl ether, DioxdM, tetrahydrofuran), halogenated hydrocarbons (chloroform, carbon chloride, chlorobenzene) etc. can be used.

Hydrogen chloride, hydrogen bromide, Hydrogen iodide, sulfuric acid, phosphoric acid, polyphosphoric acid are used will. Alkanecarboxylic acids (e.g. formic acid, Acetic acid, oxalic acid, propionic acid, caproic acid) or aromatic hydroxy derivatives (e.g. phenol) preferred. Metal halides (e.g. zinc chloride, zinc bromide, aluminum chloride, aluminum bromide, Copper chloride, copper bromide, nickel chloride, platinum chloride, cobalt chloride, tin chloride, beryllium chloride, magnesium chloride, boron trifluoride, etc.) are used will.

The reaction can also be carried out in the presence of amine salts (aniline hydrochloride), Alk.incarboxylic acid halides (acetyl chloride, propionyl chloride), Grignard reagents (Phenyl magnesium chloride, phenyl magnesium bromide, ethyl magnesium bromide, Methyl magnesium iodide), ion exchangers in Η form (Amberlite IR-120) or metal powders (nickel powder, copper powder, cobalt powder) be performed.

The above catalysts can also be used advantageously in combination. For example, the reaction can be carried out in a sulfuric acid-alkanecarboxylic acid mixture (sulfuric acid-acetic acid), hydrogen halide-alkanecarboxylic acid mixture (hydrogen chloride-acetic acid, hydrogen bromide-acetic acid), boron trifluoride-alkanecarboxylic acid mixture (boron trifluoride etherate-acetic acid), Me-Lene 11 - Hydrogen halide mixture (tin chloride-hydrogen chloride) or in Met.dll halide-alkanecarboxylic acid mixture (nickel chloride vinegar see iure) iiuscjefülirl. will.

The reaction temperature hängL on the used catalyst and solvent, and is from 20 to 220 ⁰ C.

_ 27 - "

According to a particularly advantageous embodiment of the method of the invention, the compound of the general formula I or its acid addition salt in polyphosphoric acid at 100-220 ⁰ C, preferably at 140-210 ⁰ C, in particular 160-200 ⁰ C, heated, preferably - calculated on a unit weight of the compound of the formula I - 5-20 units by weight of the polyphosphoric acid can be used. The reaction is preferably carried out within 5-120 minutes.

The compounds of the formula I obtained can be used in a manner known per se can be isolated from the reaction mixture, preferably by dilution with water of the reaction mixture cooled to room temperature and then by removing the product which separated out in crystalline form.

Claims (19)

LICHTENSTEINSTRASSE 3 TELEPHONE; (0611) 555061 TELEGRAMS: LOMOSAPATENT LANDESZENTRALBANK 50007149 POSTSCHECK-ACCOUNT FFM, 1667-809 Chinoin Gyög ^ szer es vegyeszeti Termekek GySra RT H 1045 Budapest, T6 ütca 1-5, Hungary patent claims 1) 6-hydrazono-pyrido (2,1-b) quinazolin-11-one derivatives of the general For mel I wherein R, R and R, which may be the same or different, are hydrogen, halogen, nitro, carboxyl, nitrile, C _1-4 -alkoxy, C | mean _ ₄ alkyl, amino or hydroxyl, or | _ ₄ alkoxycarbonyl, C R and R together form a methylenedioxy group and R is hydrogen, R is hydrogen or C ₁ , -alkyl, 4th
R is hydrogen, c._ ₄ alkyl optionally monosubstituted to trisubstituted by identical or different halogen, C., "alkyl, C. ₄ alkoxy, phenyloxy, hydroxyl, nitro, amino, cyano, carboxyl, C, ₄ alkoxycarbonyl , C ₁₄ alkanoyl, methylenedioxy, trifluoromethyl, phenyl, C ₄ dialkylamino substituted phenyl, naphthyl or pyridyl and the dashed line a possibly present further C-C bond mean, as well as their salts, optically active and geometric isomers and tautomers of these connections. 2) 6-phenylhydrazono-11-oxo-6,7,8 _{9-tetrahydro-s} 11H-pyrido (2,1-b) quinazoline. 3) (+) 6-Phenylhydrazono-9-methyl-11-OXO-6,7,8,9-tetrahydro-11H-pyrido- (2,1-b) quinazoline. 4) 6-phenylhydrazono-11-oxo-1,2,3,4,6,7,8,9-octahydro-11H-pyrido (2,1-b) quinazoline. b) 6-Phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-11H-pyrido (2,1-b) quinazoline-2-carboxylic acid. 6) (+) epyrido (2,1-b) quinazoline. 7) (+) 6-Phenylhydrazono-9-methyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido- (2,1-b) quinazoline-2-carboxylic acid. 8) (+) 6-Phenylhydrazono-9-methyl-11-0X0-6,7,8,9-tetrahydro-11H-pyrido- (2,1-b) quinazoline-3-carboxylic acid. ⁽ J) 6-Phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-11H-pyrido (2,1-b) quinazoline-3-carboxylic acid. 10) Process for the preparation of 6-hydrazono-pyrido (2,1-b) quinazolin-11-one derivatives of the general formula I,
wherein R, R, R, R, R and the dashed line denoted in claim 1 Have meaning as well as their salts, optically active and geometric isomers and tautomers, characterized in that one a) for the preparation of compounds of the general formula I, in which R, R, R, R and the dashed line have the meaning given above have and R optionally one to three times identical or different by halogen, Cj_ ₄ -alkyl, C _1-4 -AlkOXy, phenyloxy, hydroxyl, nitro, cyano, amino, carboxyl, C._ ₄ -alkoxycarbonyl, Cj_ ₄ -alkanoyl, methylenedioxy, Trifluoromethyl, phenyl, C. ^ - Dialkylamino substituted phenyl, naphthyl or pyridyl, compounds of the general formula II wherein R. R, R, R and the dashed line have the meaning given above have and R is hydrogen or formyl, with a diazonium salt of the general formula III ε ⁴ —Ν ₂ ®α ⁹ in, wherein R with the exception of the hydrogen atom and the C. ^ - alkyl group die has the meaning given in claim 1, converts or b) for the preparation of compounds of the general formula I, in which 12 3 R, R, R, R and the dashed line have the meaning given above have and 4th
R is optionally monosubstituted to trisubstituted by identical or different halogen, C ^ -alkyl, C _1-4 -alkoxy, phenyloxy, hydroxyl, nitro, cyano, amino, carboxyl, C, _ ₄ alkoxycarbonyl, Cj ^ alkanoyl, methylenedioxy, Is trifluoromethyl, phenyl, C _{1 4} -dialkylamino substituted phenyl, naphthyl or pyridyl, Compounds of the general formula IV wherein 12 3
R, R, R, R and the dashed line indicated in claim 1 Have meaning and R ^{7 is} C _1-4 -AIk ^ l, with a diazonium salt of the general formula III, wherein R has the same meaning as in process variant a), converts or ι) compounds of the general formula V wherein R, R, R, R and the dashed line indicated in claim 1 Have meaning R is hydrogen or halogen and 9
R mean halogen, with a hydrazine derivative of the general formula VI N -NH ₂ VI, where H R ⁴ that implements R has the meaning given in claim 1, S »O ♦ · · and if desired, the compounds of the general formula I obtained, if they contain acidic groups, are reacted with bases to form salts, if they are basic in character, are reacted with acids to form acid addition salts,
or liberates them from their salts formed with acids or bases. 11) Process according to claim 10, variant a) or b), characterized in that the reaction is carried out at temperatures below 5O ⁰ C, preferably at 0-20 ⁰ C, carries out. 12) Method according to claim 10 and 11, characterized in that one carries out the reaction in a mixture of water and an organic solvent. 13) Method according to claim 12, characterized in that one is as organic Solvent C2 _ «- alkanecarboxylic acid used. 14) Method according to claim 13, characterized in that as Alkanoic acid acetic acid used. 15) Process according to claim 10, variant c), characterized in that the reaction is carried out at temperatures between 0 and 160 ^° C. 16) Method according to claim 10, variant c) and 15, characterized in that that the reaction is carried out in the presence of a solvent. 17) Method according to claim 16, characterized in that one carries out the implementation in the presence of water. 18) Method according to claim 16, characterized in that one is used as organic Solvent C ^ alkanols used. 19) Method according to claim 10, variant c) and 15 to 18, characterized in that that the starting material is compounds of the general formula V used R> R, R, R and the dashed line denotes the description given in claim 1 -D- have meaning, R ⁸ hydrogen or bromine and R means bromine.