HU183173B - Process for producing 6-hydrazono-pyrido-aracket-2,1-b-bracket closed-quinazolin-11-ones - Google Patents

Abstract

Process for the preparation of 6-hydrazone-pyrido (2,1-b) quinazolin-11-one derivatives of the formula I, e.g. 6-phenyl-hydrazono-11-oxo-6,7,8,9-tetrahydro-11H-pyrido (2,1-b) quinazoline. The compounds of the formula I are intermediates for the preparation of rutecarpine and Tutecarpinanalogen.

Description

(57) EXTRAS

The present invention relates to a process for the preparation of 6-hydrazono-pyrido [2,1-b] quinazolin-11-one and its salts having the following formula:

R is hydrogen, halogen, C 1-4 alkoxy, C 2-5 alkoxycarbonyl, carboxy or nitro;

R ¹ is hydrogen or (C1-C4) -alkoxy; R ² is hydrogen or (C1-C4) -alkoxy; R ³ is hydrogen or C 1-4

alkyl;

R ⁴ is hydrogen or phenyl optionally substituted with 1 to 2 identical or different substituents selected from halo, (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy, phenyl, phenoxy, hydroxy, C 4 -C 4 alkanoyl, C 2 -C 5 alkoxycarbonyl, carboxy, cyano, C 2 -C 4 dialkylamino, nitro, trifluoromethyl group, or naphthyl or pyridyl group ;

the dashed line represents the optional double bond - such that

a) For the preparation of compounds of formula I wherein R ⁴ is optionally substituted with 1 to 2 phenyl groups, naphthyl or pyridyl, which may be substituted with one or more substituents, a compound of formula II wherein R, R ¹ , R ² , R ³ and the dashed line are as defined in the parent ring, cs R ⁵ is hydrogen or formyl - is reacted with a diazonium salt of formula III (wherein R ⁴ is other than hydrogen) in the parent ring, or

b) for the preparation of a compound of formula (I) wherein R ⁴ is optionally substituted with 1 to 2 phenyl groups, naphthyl or pyridyl optionally substituted with one or more substituents, a compound of formula (IV) wherein R, R ¹ , R ² , R ³ and the dashed line are as defined in the foregoing and R ⁶ is C 1 -C 4 alkyl) is reacted with a diazonium salt of formula III (wherein R ⁴ is as defined in process a), or

R N

NH /

133 173

R-NH-NH,

VIc) a compound of general formula (V) (wherein R, R ¹ , R ² , R ³ and the dashed line are as defined above, R ⁷ is hydrogen or halogen and R ⁸ is halogen); with a dry derivative of the formula (I) wherein R ⁴ is as defined in the disclosure.

The present invention relates to a process for the preparation of new 6-hydrazonopyridol-2,1-b] quinazolin-11-one and salts thereof.

These new compounds may be useful as starting compounds in the preparation of alkaloids.

Pyrido [2,1b] quinazolin-11-ones are partially as alkaloids (Chem. Comnt. 1965, 267; Austral. J. Chem. 1966, 151; Chem. Bér. 1935, 68, 2221: J. Chem. Soc. 1956, 4694; Chem. Bér. 1962, 95, 2182), in part as compounds with favorable pharmacological properties (Japanese Patent Application Serial No. J5-2O77-O93, Belgian Patent Nos. 2,812,585, 847,011 and 849,542). Compounds of Formula I are new pyrido- [2,1-binazinazolin-11-one derivatives which are unknown in the literature (Moshy, Heterocyclic Systems with Bridgeltead Nitrogen: Volume 2, pages 1153-1159); Interscience Publishers, Inc., New York, 1961).

The present invention provides novel pyrido [2.1-b] quinazolin-11-one and salts thereof having the formula: wherein:

R is hydrogen, halogen, C 1-4 alkoxy, C 2-5 alkoxycarbonyl, carboxy or nitro;

R ¹ is hydrogen, alkoxy, obsession 1-4 -C R ³ is hydrogen, alkoxy, obsession 1-4 -C R ³ is hydrogen obsession 1-4 -C

alkyl,

R ⁴ is hydrogen or phenyl optionally substituted with 1-2 of the same or different substituents selected from halo, C 1-4 alkyl, C 1-4 alkoxy, phenyl, phenoxy, hydroxy, C 4 -C 4 alkanoyl, C 2 -C 5 alkoxycarbonyl, carboxy, cyano, C 2 -C 4 dialkylamino, nitro, trifluoromethyl group (s), naphthyl or pyridyl group, dashed line case is a double bond present - we can produce '

a) phenyl optionally substituted with 1-2 identical or different substituents on R ⁴ - which are halogen (s), (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy, phenyl, phenoxy, hydroxy, C 1 -C 4 alkanoyl, C 2 -C 5 alkoxycarbonyl, carboxy, cyano, C 2 -C 4 dialkylamino, nitro, trifluoromethyl group (s) may be (naphthyl or pyridyl). For the preparation of compounds of formula ¹ , a compound of formula 11 wherein R ¹ , R ¹ , R 6, R ³ and the dashed line are as defined in the preamble, and R ⁵ is hydrogen or phenyl; with a diazonium salt of the formula (wherein R ⁴ is other than hydrogen, as defined in the preamble), or

b) phenyl optionally substituted with 1 to 2 identical or different substituents on R '- which are halogen (s), (C 1 -C 4) -alkyl, (C 14) -alkoxy, phenyl, phenoxy, hydroxy, (C 1 -C 4) alkanoyl, C 2 -C 5 alkoxycarbonyl, carboxy, cyano, C 2 -C 4 dialkylamino, nitro, trifluoromethyl (s), naphthyl or pyridyl (1)

-2183 173, a compound of formula (IV) (wherein R, R ¹ , R ² , R ³ and the dashed line are as defined above and R ⁶ is C 1 -C 4 alkyl). Or a diazonium salt of formula III (wherein R ⁴ is as defined in process a), or

c) a compound of formula (V) (wherein R, R ¹ , R ² , R ³ and the dashed line are as defined above, R ⁷ is hydrogen or halogen and R ⁸ is halogen); with a hydrazine derivative (wherein R ⁴ is as defined herein), optionally converting a compound of formula (I) containing an acidic group thus obtained into a base, converting a compound of formula (I) into an acid addition salt , liberating a compound of formula (I) with an acid or a base thereof.

The diazo coupling reaction of process a) may be carried out in the manner known in the art (Parmerter, Org. Reactions 1959, 10, p-142; Phillips, Org. Reactions 1959, 10, p. 143-178).

In a preferred embodiment of the process, the reaction is carried out at a temperature below 50 ° C, preferably between -10 ° C and 20 ° C. There are two ways of adding the components: adding the compound of formula II to a solution of a given diazonium salt of formula III, or reversing the order. The components may preferably be used in equimolar amounts, but may also be present in minor amounts.

The reaction is preferably carried out in an aqueous medium, optionally in the presence of a water-miscible inert organic solvent. As inert organic solvents, alkanecarboxylic acids (preferably acetic acid, propionic acid), acid amides (preferably Ν, Ν-dimethylformamide), alcohols (preferably methanol, ethanol, propanes, isopropanol) ketones (preferably acetone, methyl ethyl ketone), aromatic bases (e.g. preferably pyridine). The reaction is preferably carried out in the presence of an acid acceptor. As the acid binder, alkali alkanoates (preferably sodium acetate, potassium acetate) or alkali metal hydroxides (preferably sodium hydroxide, potassium hydroxide) or alkaline arbonate (preferably sodium carbonate, potassium carbonate, hydrate) are used.

The preferred embodiment of process b) is the same as described in process a).

In process (c), a representative of a compound of formula (I) wherein R, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and the dashed line are as defined above is a compound of formula (V): by reaction of a hydrazine of formula VI. Preferred compounds of formula (V) are those compounds wherein R ⁸ and R ⁹ are halogen or chlorine or bromine. The compounds of formula (V) and (VI) are preferably reacted in the presence of an inert solvent. Suitable inert solvents include alkanols (preferably methanol, ethanol, propanes, isopropanol, alkanoic carboxylic acids (preferably acetic acid, propionic acid), acid amides (preferably Ν, Ν-dimethylformamide), aromatic bases (preferably pyridine). and then carrying out the reaction in a mixture of water and a water-miscible organic solvent If desired, an acid scavenger may be used in the reaction. However, it is also possible to use an excess of the hydrazine of formula (VI) used as an acid scavenger. In a preferred embodiment of the process, 1-8 moles of hydrazine of general formula VI are used per mole of compound (V), most preferably 2.5-4.5 moles. The reaction is carried out at a temperature of from 0 ° C to 60 ° C, preferably from 60 ° C to> 20 ° C, preferably at the boiling point of the solvent or solvent mixture when using a solvent. Λ reaction time, may vary from 30 minutes to an hour depending on the reactants.

The compounds of formula (I) formed in process (a), (b) or (c) are precipitated from the reaction mixture or are diluted with water and can be recovered from the reaction mixture by filtration, centrifugation or other conventional methods.

The compounds of formula I form salts with organic or inorganic acids (e.g., hydrochloride, hydrobromide, sulfate, phosphate, perchlorate, maleate, acetate).

Compounds of formula (I) containing at least one carboxyl group form salts with bases (e.g., alkali metal salts such as sodium or potassium salts; alkaline earth salts such as calcium or magnesium salts; salts with organic amines such as triethylamine, ethanol salts).

The optical and geometric isomers and tautomers of the compounds of formula (I) of the present invention also exist. Optical isomerism is possible when R ^{3 in} formula (I) is other than hydrogen. The structure of the geometric isomers is represented by the formulas (IA) and (IB). The structure of the possible tautomers is illustrated in Reaction A. The process of the present invention provides a mixture of tautomers and isomers of the compounds of formula (I).

The resulting compound of formula (I) may be liberated from its acid or base salt in a manner known per se.

The resulting compound of formula (I) can be converted into its inorganic or organic acid addition salt. The salt formation can be carried out in a manner known per se by reacting the appropriate compound of formula (I) with a molar equivalent or excess of the appropriate acid in an inert organic solvent.

Compounds of formula (I) containing a carboxyl group may be converted into their base with a suitable base (e.g., an alkali metal hydroxide, an alkaline earth metal hydroxide, an organic amine).

The vast majority of the compounds used as starting materials are known. The starting compounds of formulas II, IV and V are known in the literature. (.15 2077.093, Kokai Tokyo Koho Japanese Patent Nos. 78,130-435; Belgian Patent Nos. 849,542 and 847,011; U.S. Patent Nos. 2,812,585 and 2,812,586, Mosby, Heterocyclic Systems with Bridgehead Nitrogen Afoms; Volume 2). , Pp. 1153-1159; Interscience Publishers, Inc., New York, 1961; Hint. Geterocycl. Soed.

-3183 173

1976, 1564-1569; 1979, 684-691) or in the manner described in the references cited above.

The compounds of formula (I) are intermediates for the preparation of Rutecarpiu alkaloid and Rutecarpin analogs.

The following examples further illustrate the process without limiting the invention to the examples.

-22. The pH was adjusted to pH 4 by the addition of Example 1B. The mixture was diluted with glacial acetic acid (5 mL) and a dropwise portion of 2.0 g (0.01 mol) of 1-oxo-6,7,8,9-tetrahydro-1H-pyrido [2,1-b] quina7.olin in 10 mL of 50% acetic acid.

After the dropwise addition, the reaction mixture was stirred at -5 ° C to 0 ° C for 3 hours. Leave to cool in the refrigerator the next day. The precipitated crystals are filtered off and washed with water. The resulting 6-phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-11H-pyrido [2,1-b] quinazolines are purified, if necessary, by recrystallization from 10% propanol. See Table 1 for the compounds prepared.

0.01 mol of an aromatic or aromatic heterocyclic primary amine derivative corresponding to R is mixed with 5 ml of a 1: 1 dilute solution of 28% hydrochloric acid and brought to -5 ° C. While stirring and cooling, a solution of sodium nitrite (0.69 g, 0.01 mol) in water (5 ml) was slowly added dropwise, the reaction mixture was stirred for half an hour at -5 ° C to 0 ° C, and then the mixture was stirred at room temperature for 20 minutes.

23-24. example

1 to 22. Example 1, but starting from 11-oxo-1,2,3,4,6,7,8 instead of 1-oxo-6,7,8,9-telhydro-1H-pyrido [2,1-h] quinazoline 9-octahydro-1H-pyrido [2,1-b] quinazoline is used.

See Table 2 for the compounds prepared.

Table 1

Prepared Example compound of formula (I)

RR ¹ R ^J R ³ R ⁴

Yield formula ° C%

ANALYSIS (%) Calculated Found

C Η N C II N

First H H H H Ph 182-184 90 c _I8 h ₁₆ n ₄ o 71.03 5.29 18.41 70.97 5:27 18.28 11 H 11 11 4-C1 Ph 191-192 94 Ci 8 Hj 5 N ₄ OC1 63.81 4:46 16.53 64.0! 5.5 7 16.2-5 Third H H H H 4-Me-Ph 187-188 88 c ₁₉ h ₁₈ n ₄ o 71.67 5.69 17.59 72.13 5.60 17.48 4th H H H H 4-Br-Ph 180-183 84 C ₁₈ H ₁₅ N ₄ 0Br 56.4 i 3.94 14.61 56.24 3.85 14.51 5th H H H H 4-CF ₃ -Ph 195-197 83 C ₁₉ H _1S N ₄ OF ₃ 61.28 4.06 15.04 61.89 4.12 14.86 6th H H H H 4-Ph-Ph O 178-180 83 Cj ₄ H ₀ N ₄ Oi 72.71 5.08 14,13 72.50 4.96 14.07 7th 11 11 11 II 3-Cl-Ph 181 183 89 C «H ₅ N ₄ OCl 63.81 4:46 16.53 63.53 4.58 16.65 8th 3-Cl H H H Ph 219-222 65 C ₁₈ H _is N ₄ 0 C ₁ 63.81 4:46 16.53 63.84 4.56 16.71 9th 3-Cl H H H 4-Cl-Ph 227 64 C _I8 H ₁₄ N ₄ 0C1i 58.08 3.79 15.05 58.04 3.73 14.72 10th H H H 9-Me Ph 185-186 75 C ₁₉ H ₁₈ N ₄ 0 71.67 5.69 17.59 71.52 5.66 17:53 ll. H H H H 1-naphthyl 192 193 86 C22 HigN ₄ 0 70.57 4.84 14.96 70.55 4.84 14.40 12th H H H H 2-naphthyl 220 96 C 11 H ₈ N ₄ O 70.57 4.84 14.96 70.33 4.65 14.87 13th H H H H 4-Ph-Ac 255 81 C ₁₀ H, ₈ N ₄ 0 ₂ 69.34 5.23 16.17 69.33 5.35 16:28 14th 3-Cl H H H 4-Me-Ph 231 64 c ₁₉ h ₁₇ n ₄ oci 58.72 4.65 14.42 58.88 4.78 15:18 15th H H H H 4-HO-Ph 225 (B) 84 C, ₈ H ₁₇ N ₄ 0iCl 60.59 4.80 15.70 60.69 4.85 15.86 16th H H H H 4-MeO-Ph 223 92 C ₁₉ H ₁₉ N ₄ 0iC1 61.53 5.16 15,10 62.10 5.23 14.90 17th H H H H 4-NO 3 -Ph 250 (b) 92 c _í8 h ₁₆ n ₅ 0 ₃ ci 56.17 4.18 18.19 56.04 4.19 18.89 18th H H H H 4-F-Ph 245 90 c ₁₈ h ₁₆ n ₄ ofci 60.25 4:49 15.61 60.59 4.46 15.02 19th H H H H 4-H00C- Ph 298 (b) 91 c „h ₁₆ n ₄ o ₃ .hci 59.30 4.45 14.55 59.39 4.60 14:52 20th II H H H 3-pyridyl 188 23 c, ₇ h _is n ₅ o.hci 59.74 4.72 20.49 59.97 4.65 20.51 21st 11 11 11 11 4-CN-Ph 217 82 C, ₉ H ₁₅ N ₅ O.Hd 62.38 4.4 1 19,14 62.24 1:50 19:32 2? 2-MeO 3-What SHE H 11 230 (b) 66 C in H, N.) O ₃ 65.92 5.53 15:37 (55.72 5:26 15:21

-4183 173

Table 2

Example Produced in general (I) Op. C Yield % Molecular formula c calculated H Analysis (%) Found H N R compound of formula R ⁴ N C R ¹ R ² R ³ 23rd H H Η H Pli 205-208 85 C | ₈ H ₂₀ N ₄ O 70,10 6.53 18.16 69.93 6.51 18.07 24th H H H 9 -Me Ph 190-193 83 c „h _2J n ₄ o 70.78 6.87 17.37 70.55 6.91 17.27

Example 25 ¹

10.8 g (0.03 mole) of 6, o-dibromo-6,7,8,9-tetrahydro-11-oxo-1H-pyrido [2'-b] quinazoline and 13.0 g (0.12 mole) of phenyl -hydrazine is boiled in 120 ml of ethanol for 4 hours. After cooling, the precipitated crystals are filtered off. On evaporation of the nuts ^zu when another kristályleválás happens, filtered and washed with a little alcohol. The combined filtered product was suspended in 150 ml of water containing 8.4 g (0.06 mol) of sodium acetate, filtered and washed with water. 8.4 g (81%) of 6-phenylhydrazono-6,7,8,9-tetrahydro-11-oxo-1H-pyrido [2,1b] quinazoline are obtained, m.p. 177-179 ° C by recrystallization from isopropanol. , and when mixed with the product of Example 1, gives no melting point reduction.

Example 26

3.74 g (0.01 mol) of 6.6 dichloro-9-methyl-11-oxo-6,7,8,9-tetrahydro-1 H -pyrido [2,1-b] quinazoline cs 4.32 g (0.04 mol) ) phenylenedrazine was boiled in 40 ml of ethanol for 10 hours. After cooling, the precipitated crystals are filtered off. The filtered product was suspended in 100 ml of water containing 2.72 g (0.02 mol) of sodium acetate, filtered and washed with water.

4 g (75%) of orange o-phenylhydrazono-9-methyl- ⁴⁰ -l-oxo-6,7,8,9-tetrahydro-11H-pyrido [2,1b] quinazoline are obtained, which is recrystallized from ethanol to give 185 187 ° C melting.

Analysis for C ₉ H | _{8 according to} N ₄ O;

Calculated: C, 71%; H, 5.69%; N, 17.59%;

Found: C, 7162%; II, 5.58%; N, 17.59%.

Example 27

2.79 g (0.01 mol) of 6-bromo-11-oxo-6,7,8,9-tetrahydro-1H-pyrido [2,1b] quinazoline and 2.16 g (0.02 mol) of phenylhydrazine. of ethanol was heated at 80 ° C for 6 hours. 55 Then ethanol is reduced to one third. Allow to crystallize in the refrigerator. The separated yellow crystals are filtered off, washed with water and ethanol. 2.1 g (69%) of 6-phenylhydrazonol oxo-6,7,8,9-tetrahydropyrido [2,1-b] quinazoline are obtained, m.p. 179-180 ° C and recrystallized from isopropanol, and when mixed with the product of Example I) or Example 25), the aunt gives a decrease in the melting point.

Calcd for C _I8 H ₁₆ N ₄ O Calc'd: 65

Calculated: C, 71.03; H, 5.29%; N, 18.41%; Found; C, 70.88%; H5.25%; N, 18.38%.

Example 28

Aniline (0.93 g, 0.9 mL, 0.01 mol) was dissolved in 5 mL of 1: 1 dilute hydrochloric acid (38%) and cooled to 5 ° C. Under constant cooling and stirring, a solution of sodium nitrite (0.69 g, 0.01 mol) in water (5 ml) was added dropwise. The reaction mixture was stirred for half an hour at -5 ° C to 0 ° C, then the pH of the solution was adjusted to pH 4 by the addition of sodium acetate and diluted with 10 ml of acetic acid. To the solution of the diazonium salt is slowly added dropwise to -5 DEG C. 2.55 g of 6- (dimethylaminomethylcn) -1-oxo-6,7,8,9-tetrahydro-11,11-pyrido [2'-b] quinazoline. 25 ml of dimethylformamide solution. The reaction mixture was stirred for 3 hours at 0 ° C and allowed to stand in the refrigerator overnight. The next day, it is diluted with water and the precipitated crystals are filtered off and washed with water. 2.61 g (86%) of 6-phenylhydrazo, ono-6,7,8,9-tetralidro11oxo-11H-pyrido [2,1-b] quinazoline are obtained, m.p. 182-184 ° C by recrystallization from iso-propanol. when mixed with the product prepared according to pclda I, it does not give a melting point reduction.

Analysis based on the formula Ci ₈ H ₁₆ N ₄ 0:

Calculated: C, 71.03; H, 5.29%; N, 18.41%; Found: C, 70.93%; H5,24%; N, 18.33%.

Example 29

Aniline (0.93 g, 0.01 mol) was dissolved in 5 mL of 1: 1 dilute hydrochloric acid (38) and cooled to -5 ° C. Under constant cooling and stirring, a solution of 0.69 g (0.01 mol) of sodium nitrite in 5 ml of water is added dropwise. The reaction mixture was stirred for half an hour at 5 ° C to 0 ° C, then the pH of the solution was adjusted to pH 4 by addition of sodium acetate and diluted with 10 ml of acetic acid. To the reaction mixture was added 2.28 g (0.01 mol)

A solution of 6-formyl-11-oxo-6,7,8,8,9 tetrahydro-11H-pyrido [2,1-b] quinazoline in 30 ml of acetic acid was added slowly dropwise. Stir for 1 hour (below 0 ° C) then leave to stand in the refrigerator overnight. The precipitated crystals are filtered off and washed with water. 3.1 g (91%) of 6-phenylhydiazono-6,7,8,9-tetrahydio-11-oxo-11H-pyrido [2,1-b] quinazoline hydrochloride are obtained, m.p.

183,173

Analysis of C | Based on the formula ₈ H ₁₇ N ₄ OC1:

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%.

30-33. example

1 to 22. In the same manner as in Example 30, the starting pindo [2,1b] quinazoline derivative in Example 30 is 2,3,4-trimethoxy-11-oxo-6,7,8,9-tetrahydro-1H-pyrido [2,1b]. ] quinazoline, 11-oxo-6,7,8,9-tetrahydro-11H-pyrido [2,1b] quinazoline-2-carboxylic acid in Example 31, ethyl 11-oxo-6,7,8 in Example 32, 9-Tetrahydro-11-yl-pyrido [2,1b] quinazoline-2-carboxylate, using the 1-oxo-6,7,8,9-tetralidro-11H-pyrido [2,1-b] quinazoline in Example 33, in Example 3. 6-Phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-1H-pyrido [2,1b] quinazolines as shown in Table II. Recrystallization from n-propanol.

- Example 44

23-24. Using the procedures described in Examples 1 to 4 using IIoxo-1,2,3,4,6,7,8,9-octahydro-1 H -pyrido [2,1-b] quinazolones, the 6-phenylhydrazo-4-oxo -1,2,3,4,6,7,8,9-octahydro-1H-pyrido [2,1b] quinazolines were prepared.

In Examples 42 and 43, the crystals precipitated from the diazo coupling reaction mixture were suspended in 5% sodium hydroxide solution and extracted with chloroform. The chloroform solution dried over anhydrous sodium sulfate was evaporated and the residue crystallized.

Table 3

Example Prepared by the general formula (I) Yield formula % Analysis (%) R Compound R ¹ R ² R ³ R ⁴ Op. C calculated Found C 11 N C H N 30th 2-OMe 3-OMe 4 OMe H pb 187-9 77 C ₂₁ H ₂₂ N ₄ O ₄ 63.94 5.62 14.20 64.03 5.88 14.28 31st 2 COOII Η H H Ph 257 (b) 30 C, ₉ H _I6 N ₄ O ₃ 65.51 4.62 16:08 65,55 4.66 16:01 32nd 2-COOEt Η H Ή Ph 201 85 C ₂₁ H ₂₀ N ₄ O ₃ 67.00 5.35 14.88 67.03 5.45 14.85 33rd H Η H H 4-EtOOC Ph 214 92 C ₂₁ H ₂₀ N ₄ O ₃ HCl 61.09 5.09 13.57 61.25 4.99 13.58

Table 4

Analysis (%)

Example R R ¹ R ² R ³ R ⁴ Op. C Hozan % Molecular formula Calculated C 11 N C Found H N 34th H H H H 4 Cl-Pli 220 73 C _1B H _I9 N ₄ CI 63.06 5.59 16.34 63.24 5.51 16.32 35th II H H 9-Me 4-ClPh 207-208 70 c ₁₉ h ₂₁ n ₄ oci 63.95 5.93 15.70 64.14 6.17 15.78 36th H H H 9-Me 4-NO ₂ -Ph 168-170 79 C ₁₉ H ₂ , N _s O ₃ HC 156.50 5.49 17:34 56.15 5.44 17,00 37th H H H H 4-Me-Ph 203-204 46 0j9 h ₂₂ n ₄ 0 70.78 6.88 17.38 70.63 6:56 17:17 38th H H H 9-Me 4-Me-Ph 187-188 74 C ₂ oh ₂₄ n ₄ 0 71.40 7J9 16.65 71.17 6.96 16.72 39th II H H 9-Me 4-Et-Ph 154-155 49 C _{2 (} H ₂₆ N ₄ O 71.97 7.48 15.99 71.58 7.52 16.03 40th II H H 9-Me 4-MeO-Ph 161-162 42 c ₂₀ h ₂₄ n ₄ o ₂ 68.16 6.86 15.90 68.43 6.95 15.80 41st H H H 9-Me 2-naphthyl . 177-179 11 c ₂₃ h ₂₄ n ₄ 0 74.17 6.50 15:04 74.13 6.40 14.72 42nd H H II 8-Me Ph 219 59 c ₁₉ h ₂₂ n ₄ o 70.78 6.87 17.37 70.83 6.82 17:40 43rd H H H 9-Me Ph-3,5-dicle 227-228 33 C ₁₉ H ₂₀ N ₄ OC! ₂ 58.33 5.15 14.31 58.40 5.23 14:27 44th H H H 7-Me Ph 200 59 c ₁₉ h ₂₂ n ₄ o 70.78 6.87 17.37 70.9] 6.75 17.45

-6, 183 1 73 2

Example 45 Example 50

Aniline (0.46 g, 0.005 mol) was dissolved in 3 ml of 1: 1 dilute 38% hydrochloric acid and bound to -5 ° C. A solution of 0.35 g (0.005 mol) of sodium nitrite in 3 ml of water is added dropwise with constant cooling and stirring.

The reaction mixture was stirred for half an hour at -5 ° C to 0 ° C, then the pH of the solution was adjusted to pH 4 by addition of sodium acetate. To the reaction mixture was added 1.23 g (0.005 mol) of 6-formyl-11-oxo-1,2,3,10,6,6,8,8,9-octahydro-11H-pyrido [2,1b] quinazoline in 15 ml. A solution of 75% (v / v) acetic acid was added dropwise with stirring at a temperature below 0 ° C for 3 hours, then allowed to stand overnight in a refrigerator and diluted with 30 ml of water. The precipitated crystals were filtered and washed with water. 1.3 g (73%) of 6-phenylhydrazono-11-oxo-1,2,3,4,6,7,8,9-octahydro-1H-pyrido [2,1-b] quinazoline hydrochloride are obtained, m.p. Mp 242-244 ° C.

Analysis based on the formula 0 _Ι9 Η ₂ 3Ν ₄ 00:

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%.

1.21 g (0.01 mol) of 2,6-dimethylaniline are dissolved in 5 ml of a 1: 1 dilution of 18% hydrochloric acid and cooled to -5 ° C. Under constant cooling and stirring, a solution of 0.69 g (0.01 mol) of sodium nitrite in 5 ml of water is added dropwise. The reaction mixture was stirred for half an hour at -5 ° C to 0 ° C. The solution was then adjusted to pH 4 by addition of sodium acetate and diluted with acetic acid (10 mL). To a solution of the diazonium salt is added dropwise a solution of 1-oxo-6,7,8,9-tetrahydro-1H-pyrido [2,1-b] quinazoline (2.0 g, 0.01 mol) in 50 ml of 50% acetic acid (5 ml). ° C to 0 ° C. The reaction mixture was stirred for 3 hours at 0 C and allowed to stand in the refrigerator overnight. The next day, the reaction mixture was diluted with water and the precipitated crystals were filtered and washed with water. After drying, the filtered product is purified by recrystallization from isopropanol. 1.5 g (35%) of 6- (2,6-dimethylenylhydrazono) -1-oxo-6,7,8,9-tetrahydro-11H-pyrido [2,1-b] quinazoline are obtained, m.p. -149 C's are.

Analysis for C ₂₀ H ₂₀ N ₄ O:

Calculated: C, 72.26%; H, 6.06%; N, 16.85%; Found: C, 72.22%; H6,00%; N, 16.81%.

46-48. example

1-22. Example 1, except that the starting pyrido [2,1-b] quinazoline in Example 46 was 11-oxo-6,7,8,9-tetrahydro-1 H -pyrido [2,1b] quinazoline and the aromatic amine 4-aminobiphenyl; in Example 47, the starting pyrido [2,1-b] quinazoline is methyl 11-oxo-6,7,8,9-tetrahydro-1H-pyrido [2,1-b] quinazoline-2-carboxylate; and Example 48 uses 2-nitro-11-oxo-6,7,8,8,9-tetrahydro-11H-pyrido [2,1-b] quinazoline. (Table 5)

Example 49 ¹ 40

Working as in Example 28, except that p-dimethylaminoaniline was used instead of aniline. 6- (4-Dimethylaminophenyl-lidrazono) -6,7,8,9-tetrahydro-11-oxo-1H-pyrido [2,1-b] quinazoline is obtained in a yield of 27%.

Analysis using the formula C ₂₀ H ₂ ] Ν ₅ Ο ₃ :

Calculated: C, 69.14; H, 6.09%; N, 20.15%;

Found: C, 69.08%; H6,12%; N, 20.25%. ₅₀

Example 51 6-Phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-1H-pyrido [2,1-b] quinazoline hydrochloride (g) is dissolved in 30 ml of dimethylformamide and 1 g of sodium acetate is added. After stirring for 1 hour, the solution was diluted with water (50 mL) and the precipitate was filtered off and washed with water. After drying the product is decomposed with ethanol phosphorus! purified. 0.5 g (56%) of 6-phenylhydrazono-11-oxo-6,7,8,9-tetrahydro-1H-pyrido [2.1-b] quinazoline are obtained, m.p.

Analysis for C, _s H, 1% O:

Calculated: C, 71.03; H, 5.29%; N, 18.41%; Found: C, 70.98%; H, 5.34%; N, 18.37%.

Claims (9)

Patent claims A process for the preparation of 6-hydrazono-pyrido [2,1-b] quinazolin-11-one and its salts represented by the following formula: Table 5 Example R R ¹ R ² R ³ R ⁴ Op. C Yield Molecular formula Analysis Calculated Found C Η N C Η N 46th H H H H Ph-Ph 198-199 89 C ₂₄ H ₂₀ N ₄ O 75.77 5.29 14.72 75.82 5.31 14.66 47th 2 COOCHj H H II Ph 230-232 92 C ₂ « H, _r N ₄ 0 ₃ 66.28 5.00 15:46 66.34 5.05 15:40 48th NC-2); H II 11 Ph 247-248 81 C, H H, <N ₅ O ₃ 61.88 4:32 20.04 62.00 4:40 19.89 183,173 R is hydrogen, halogen, C14-alkoxy, C2-C5-alkoxycarbonyl, carboxy or nitro; R ¹ is hydrogen or alkoxy; C 1-4 R ² is hydrogen or alkoxy; C 1-4 R ³ is hydrogen or alkyl; C 1-4 R ⁴ is hydrogen or optionally 1-2 phenyl substituted with the same or different substituents selected from halo (s), (C 1 -C 4) -alkyl, (C 1 -C 4) -alkanoyl, phenyl, phenoxy, hydroxy, (C 1 -C 4) -alkanoyl, (C 2 -C 5) -alkoxycarbonyl - carboxy, cyano, C2-4 dialkylamino, nitro, trifluoromethyl and naphthyl or pyridyl; the dashed line represents an optional double bond, characterized in that: a) phenyl optionally substituted on R ⁴ with 1 to 2 identical or different substituents selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, phenyl, phenoxy, hydroxy, C 1-4 alkanoyl, C 2-5 alkoxycarbonyl, carboxy, cyano, C 2-4 dialkylamino, nitro, trifluoromethyl group - either naphthyl or pyridyl; a compound of formula II wherein R, R ¹ , R ² , R ³ and the dashed line are as defined above and R ⁵ is hydrogen or formyl; with a diazonium salt of the general formula (wherein R ⁴ , except hydrogen, is as defined herein), or b) phenyl optionally substituted with 1-2 identical or different substituents on R ⁴ - which substituents are halogen (s), (C 1 -C 4) -alkyl, (C 1 -C 4) -alkoxy, phenyl, phenoxy, hydroxy, (C 1 -C 4) -alkanoyl, (C 2 -C 5) -alkoxycarbonyl, carboxy, a cyano, C2-C4 dialkylamino, nitro, trifluoromethyl group, or a naphthyl or pyridyl group, to form a compound of formula I; wherein R ¹ , R ¹ , R ² , R ³ and the dashed line are defined as Cs (R ⁶ is C 1 -C 4 alkyl) in one of the diazonium salts of formula (III) Wherein R ⁴ is as defined in process a), or c) a compound of formula (V) (wherein R, R ', R ² , R ³ and the dotted line are as defined herein, R ⁷ is hydrogen or O and R ⁸ is halo); with a hydrazine derivative of the Formula (wherein R ⁴ is as defined herein) and optionally converting a compound of formula (I) containing an acidic group thus obtained with a base to an acid addition salt with an acid addition salt. liberating a compound of formula (I) with an acid or a base thereof. Process for carrying out process a) and b) according to claim 1, characterized in that the reaction is carried out at a temperature lower than 50 ° C, preferably between -10 ° C and 20 ° C. Process according to claim 1 or 2, characterized in that the reaction is carried out in a mixture of water and an organic solvent. 4. The process of claim 3 wherein the organic solvent is a C 2 -C 4 alkane carboxylic acid. 5. A process according to claim 4 wherein the alkali carboxylic acid is acetic acid. 6. A process according to claim 1, wherein the reaction is carried out at a temperature between 60 ° C and 120 ° C. 7. A process according to claim 1, wherein the reaction is carried out in the presence of a solvent. 8. The process according to claim 7, wherein the organic solvent is C 1-4 alkanoyl. 9. The process of Claim 1 wherein R ⁷ is hydrogen or bromine, R ⁸ is bromine, wherein R, R ', R ² , R are the starting materials. ³ and the dashed line has the meaning given above). 2 pieces of figure Published by the National Office of Inventions Λ responsible for publication: Zoltán Himer Head of Department Published by: Technical Publisher COPYl.UX -8183 173