HK1037368B - Process for the synthesis of (1h)-benzo[c]quinolizin-3-ones derivatives - Google Patents

Description

(1H) Synthesis method of (E) -benzo [ c ] quinolizin-3-one derivative

Technical Field

The present invention relates to a method for synthesizing a (1H) -benzo [ c ] quinolizin-3-one derivative represented by the general formula (I). The method comprises only three steps and takes a compound which is commercially available or easy to prepare as a raw material. The compounds of formula (I) are useful as 5 alpha-reductase inhibitors.

Background

The compounds of general formula (I) above are known inhibitors of 5 α -reductase and can be used for the treatment of pathologies modulated by this enzyme (for example acne in men, baldness, prostate cancer and prostatic hypertrophy, and hirsutism in women) (see international application N ° PCT/EP 97/00552). They are also useful as plant growth regulators.

As described in the above-mentioned patent applications, the compounds of formula (I) have hitherto been prepared by a multistep process starting from compounds of formula II.

According to this process, the amide group of compound II is protected as N-Boc derivative, the compound obtained is reduced, reacted with a siloxy diene obtained "in situ", hydrolyzed to give the compound of general formula III

Finally, a double bond is introduced in the b position by reaction of dichlorodicyanoquinone with the corresponding silyleneglycolether (silylenolether) or by oxidation with mercuric acetate.

It follows that the above-described process involves a number of steps which adversely affect the final yield of the desired compound.

Given the importance of these compounds as 5 α -reductase inhibitors, there is a clear need to create new methods to more efficiently produce the desired compounds.

Disclosure of Invention

The present invention relates to (1H) -benzo [ c ] s represented by the general formula (I)]Synthesis method of quinolizin-3-one derivative and pharmaceutically acceptable salt or ester thereofIn the formula:

R₁、R₂、R₃、R₄、R₅identical or different, selected from: h, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, cycloalkyl, aryl, heterocycle, halogen, CN, nitrogenCompounds, NRR', C_1-8Alkylamino, arylamino, C_1-8Alkoxy, aryloxy, COOR, CONRR ', wherein R and R', which are identical or different, are selected from: h, C_1-8Alkyl, cycloalkyl, aryl, heterocycle, aryl C_1-8An alkyl group;

q is selected from: a single bond, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, cycloalkyl, CO, CONR, NR, wherein R is as described above;

w is selected from: h, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, cycloalkyl, trifluoromethyl, C_1-8Alkoxy radical, C_1-8alkoxy-C_1-8Alkyl, aryl C_1-8Alkyl, aryl, aryloxy, arylamino, C_1-8Alkylcarbonyl, arylcarbonyl, arylcarboxyl, arylcarboxyamide, halogen, CN, NRR', C_1-8Alkylamino, heterocyclic, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic may be substituted;

n is an integer from 1 to 4;

the method uses a compound which is sold or easily prepared as a raw material and only comprises three steps, namely

Thioamides 3 in organic solvents in the presence of strong but non-nucleophilic bases

N-alkylated by vinyl ketones of the general formula 2:

to give the corresponding compound 4:

the compound is methylated at the sulfur atom to produce salt 5:

the compound is reacted directly with a strong but non-nucleophilic base in an organic solvent to yield the desired compound I.

Detailed Description

The present invention can solve the above problems by a synthesis method comprising only three steps and using a compound which is easy to synthesize or commercially available as a starting material.

In the compounds of the general formula I according to the invention, C_1-8Alkyl radical, C_2-8Alkenyl and C_2-8Alkynyl represents a straight or branched hydrocarbon group, for example: methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, ethenyl, propenyl, butenyl, isobutenyl, ethynyl, propynyl, butynyl, and the like.

The term cycloalkyl denotes: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, norbornane, camphane (canphane), adamantane.

The term aryl denotes: phenyl and naphthyl.

The term heterocycle specifically denotes: saturated or aromatic heterocycles containing one or more N atoms, more particularly: pyridine, imidazole, pyrrole, indole, triazole, pyrrolidine, piperidine.

Halogen means: fluorine, chlorine, bromine, iodine.

The substituents for W hereinbefore are preferably: halogen, OR, phenyl, NRR ', CN, COOR, CONRR', C_1-18Alkyl (R and R' are as described above).

In particular, the process of the invention makes it possible to prepare compounds of general formula (I) in which:

q ═ single bond, CO, CONR, NR (wherein R is as described above). W ═ H, F, Cl, Br, Me, tert-butyl, C_1-18Alkoxy, 2, 5-dimethylhexyl, trifluoromethyl, 2, 5-bis (trifluoromethyl) phenyl, 4-methoxyphenyl, 4-fluorophenyl, phenyl-C_1-8Alkyl radical, C_1-8Alkylcarbonyl, phenylcarbonyl.

n is 1 and 2.

R₁、R₂、R₃、R₄、R₅H, Me, CN, phenyl, COOR, CONRR '(R and R' are as described above).

The pharmaceutically acceptable esters and salts of the present invention include: hydrochloride, sulfate, citrate, formate, phosphate.

The specific compounds prepared by the method of the invention are:

2, 3, 5, 6-tetrahydro- (1H) -benzo [ c ] quinolizin-3-one;

8-chloro-2, 3, 5, 6-tetrahydro- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-8-methyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-4-methyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-1-methyl- (1H) -benzo [ c ] quinolizin-3-one;

8-chloro-2, 3, 5, 6-tetrahydro-4-methyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-4, 8-dimethyl- (1H) -benzo [ c ] quinolizin-3-one;

8-chloro-2, 3, 5, 6-tetrahydro-1-methyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-1, 4-dimethyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-6-methyl- (1H) -benzo [ c ] quinolizin-3-one;

8-chloro-2, 3, 5, 6-tetrahydro-6-methyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-6, 8-dimethyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-4, 6-dimethyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-1, 6-dimethyl- (1H) -benzo [ c ] quinolizin-3-one;

8-chloro-2, 3, 5, 6-tetrahydro-4, 6-dimethyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-4, 6, 8-trimethyl- (1H) -benzo [ c ] quinolizin-3-one;

8-chloro-2, 3, 5, 6-tetrahydro-1, 6-dimethyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-1, 4, 6-trimethyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-5-methyl- (1H) -benzo [ c ] quinolizin-3-one;

8-chloro-2, 3, 5, 6-tetrahydro-5-methyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-5, 8-dimethyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-4, 5-dimethyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-1, 5-dimethyl- (1H) -benzo [ c ] quinolizin-3-one;

8-chloro-2, 3, 5, 6-tetrahydro-4, 5-dimethyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-4, 5, 8-trimethyl- (1H) -benzo [ c ] quinolizin-3-one;

8-chloro-2, 3, 5, 6-tetrahydro-1, 5-dimethyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-1, 4, 5-trimethyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-5, 6-dimethyl- (1H) -benzo [ c ] quinolizin-3-one;

8-chloro-2, 3, 5, 6-tetrahydro-5, 6-dimethyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-5, 6, 8-trimethyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-4, 5, 6-trimethyl- (1H) -benzo [ c ] quinolizin-3-one;

8-chloro-2, 3, 5, 6-tetrahydro-4, 5, 6-trimethyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-1, 5, 6-trimethyl- (1H) -benzo [ c ] quinolizin-3-one;

8-chloro-2, 3, 5, 6-tetrahydro-1, 5, 6-trimethyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-4, 5, 6, 8-tetramethyl- (1H) -benzo [ c ] quinolizin-3-one.

According to the present invention, the above-mentioned compounds of formula (I) can be prepared from compounds of formulae 2 and 3:in the formula R₁、R₂、R₃、R₄、R₅W, Q and m are as defined above.

Formulas 2 and 3 are commercially available or can be prepared according to known techniques.

As can be seen from scheme 1, the preparation process of the present invention for the preparation of compounds of general formula I comprises N-alkylation of thioamides 3 with vinyl ketones 2 in the presence of strong but not nucleophilic bases to give N-alkylated thioamides 4. The reaction is preferably carried out in an organic solvent such as THF, at a temperature of preferably 0-30 deg.C for a reaction time of preferably 2-4 hours. It is better to add the vinyl ketone intermittently to the thioamide.

The nature of the base is critical to the efficiency of the reaction: the strong nucleophilic bases do cause polymerization of the vinyl ketone, while the weak bases do not allow the reaction to proceed. A preferred base having the above properties is K₂CO₃18-crown-6 or Diazabicycloundecene (DBU). The N-alkylated thioamide is then methylated at the sulfur atom to produce salt 5. Such salts are not normally isolated but are reacted with bases to give the final compoundAn object I. The reaction conditions (temperature and time) and the type of base of this step are also important.

The best results are obtained with the following conditions: dimethyl sulfate is used as a methylating agent and a strong but non-nucleophilic base (e.g., DBU) is used to carry out the reaction at reflux temperature of an organic solvent (e.g., toluene) for half an hour to 1 hour.

To illustrate the present invention in more detail, two synthetic methods of the compounds of formula (I) are described in the following examples.

Example 1

Preparation of 6-chloro-1- (3-oxo-1-pentyl) - (1H) -3, 4-dihydroquinoline-2-thione [ Compound 4, formula (QW)_n＝Cl，R₁＝R₃＝R₄＝R₅＝H，R₂＝Me]

Ethylvinyl ketone (Compound 2, wherein R is₁＝R₅＝H，R₂Me) (340 ml, 3.42 mmol) was added to a solution containing 6-chloro- (1H) -3, 4-dihydroquinoline-2-thione (compound 3, formula (QW) therein)_n＝Cl，R₃＝R₄H) (450 mg, 2.28 mmol), anhydrous K₂CO₃(692 mg, 5.01 mmol) and 18-crown-6 (60 mg, 0.23 mmol) in dry THF (41 mL) were stirred into suspension. The suspension was then allowed to warm to room temperature and after stirring for 30 minutes, the suspension was cooled to 0 ℃ and ethyl vinyl ketone (3.42 mmol) was added. After 1 hour at room temperature, the suspension was cooled to 0 ℃ and the final ethyl vinyl ketone (3.42 mmol) was added. After 1 hour at room temperature, the reaction had gone to completion. With a short anhydrous Na₂SO₄The reaction mixture was column filtered and then the solvent was evaporated. The residual oil was chromatographed (ethyl acetate: ligroin 1: 9, R)_f0.29) to yield pure 6-chloro-1- (3-oxo-1-pentyl) - (1H) -3, 4-dihydroquinoline-2-thione [ compound 4, formula (QW)_n＝Cl，R₁＝R₃＝R₄＝R₅＝H，R₂＝Me](277 mM)G, 45%) as a pale yellow solid (melting point 68-70 ℃).

The other method is as follows: thioamide 3(450 mg, 2.28 mmol) was dissolved in 5 ml anhydrous THF, DBU (69 ml, 0.46 mmol) was added, and then ethyl vinyl ketone 2(275 ml, 2.76 mmol) was added dropwise with stirring and under nitrogen, with cooling at 0 ℃. After 2.5 h at 0 ℃ ethyl vinyl ketone (113 ml, 1.38 mmol) was added and allowed to react for a further 1h at 0 ℃ and the solvent was evaporated using CH₂Cl₂The residual oil was diluted (30 ml) with 5% citric acid, NaHCO₃(saturation) and water washing. Na for organic layer₂SO₄Drying, filtering and evaporating to obtain crude oil which can be chromatographed by the above method. This gives compound 4 in the form of a 1.6: 1 mixture with unreacted thioamide 3. The calculated yield was 4: 35%.

Example 2

Preparation of 8-chloro-2, 3, 5, 6-tetrahydro-4-methyl- (1H) -benzo [ c ]]Quinolizin-3-one [ Compound 1, formula (QW)_n＝Cl，R₁＝R₃＝R₄＝R₅＝H，R₂＝Me]

To 6-chloro-1- (3-oxo-1-pentyl) - (1H) -3, 4-dihydroquinoline-2-thione [ Compound 4, formula (QW) under stirring and nitrogen atmosphere_n＝Cl，R₁＝R₃＝R₄＝R₅＝H，R₂＝Me]Me was added to a solution of (250 mg, 0.93 mmol) in dry toluene (3 mL)₂SO₄(149 ml, 1.57 mmol). The solution was heated to reflux and after 5 minutes a red oil began to separate. After a further 10 minutes, DBU (235 ml, 1.57 ml) was added dropwise to the refluxing biphasic reaction mixture, and after a further few minutes the mixture was darkened. Reflux was continued for 20 min, then the solution was cooled to room temperature, diluted with dichloromethane (50 ml), washed with water (50 ml), and finally Na₂SO₄And (5) drying. After filtration and evaporation of the solvent, the dark residual oil was chromatographedIonization (ethyl acetate: ligroin ═ 1: 1, Rf ═ 0.28) gave pure 8-chloro-2, 3, 5, 6-tetrahydro-4-methyl- (1H) -benzo [ c ═ e]Quinolizin-3-one [ Compound 1, formula (QW)_n＝Cl，R₁＝R₃＝R₄＝R₅＝H，R₂＝Me](90 mg, 41%) which is an oil that solidifies on standing (melting point 112 ℃ C. and 114 ℃ C.).

Example 3

Preparation of 6-methyl-1- (3-oxo-1-pentyl) - (1H) -3, 4-dihydroquinoline-2-thione [ Compound 4, formula (QW)_nMethyl, R₁＝R₃＝R₄＝R₅＝H，R₂＝Me]

Ethylvinyl ketone (Compound 2, wherein R is₁＝R₅＝H，R₂Me) (380 ml, 3.81 mmol) was added to a solution containing 6-methyl- (1H) -3, 4-dihydroquinoline-2-thione (compound 3, formula (QW) therein)_nMethyl, R₃＝R₄H) (500 mg, 2.82 mmol), anhydrous K₂CO₃(900 mg, 6.5 mmol) and 18-crown-6 (89 mg, 0.28 mmol) in anhydrous THF (47 mL) were stirred into suspension. The suspension was then allowed to warm to room temperature and after stirring for 60 minutes, the suspension was cooled to 0 ℃ and ethyl vinyl ketone 2(3.81 mmol) was added. After 2 hours at room temperature, the reaction had gone to completion. With a short anhydrous Na₂SO₄The reaction mixture was column filtered and then the solvent was evaporated. The residual oil was chromatographed (ethyl acetate: ligroin 1: 9, R)_f0.23) to yield pure 6-methyl-1- (3-oxo-1-pentyl) - (1H) -3, 4-dihydroquinoline-2-thione [ compound 4, formula (QW)_nMethyl, R₁＝R₃＝R₄＝R₅＝H，R₂＝Me](500 mg, 68%) as a white solid (melting point 70-71 ℃ C.).

Example 4

Preparation of 8-methyl-2, 3, 5, 6-tetrahydro-4-methyl- (1H) -benzo [ c ]]Quinazin-3-one [ compounds1, formula (QW)_nMethyl, R₁＝R₃＝R₄＝R₅＝H，R₂＝Me]

To 6-methyl-1- (3-oxo-1-pentyl) - (1H) -3, 4-dihydroquinoline-2-thione [ Compound 4, formula (QW) under stirring and nitrogen atmosphere_nMethyl, R₁＝R₃＝R₄＝R₅＝H，R₂＝Me]Me was added to a solution of (350 mg, 1.40 mmol) in dry toluene (4 mL)₂SO₄(227 ml, 2.40 mmol). The solution was heated to reflux and after 5 minutes a red oil began to separate. After a further 15 minutes, DBU (365 ml, 2.40 ml) was added dropwise to the refluxing biphasic reaction mixture and after a further few minutes the mixture was darkened. Reflux was continued for 20 min, then the solution was cooled to room temperature, diluted with dichloromethane (50 ml), washed with water (50 ml), and finally Na₂SO₄And (5) drying. After filtration and evaporation of the solvent, the dark residual oil is chromatographed (ethyl acetate: ligroin ═ 1: 1, R_f0.29) to yield pure 8-methyl-2, 3, 5, 6-tetrahydro-4-methyl- (1H) -benzo [ c)]Quinolizin-3-one [ Compound 1, formula (QW)_nMethyl, R₁＝R₃＝R₄＝R₅＝H，R₂＝Me](152 mg, 50%) which is an oil that becomes solid on standing (melting point 143. ang. 145 ℃ C.). Scheme 1

Claims (6)

1. (1H) -benzo [ c ] represented by the formula (I)]Synthesis method of quinolizin-3-one derivative and pharmaceutically acceptable salt or ester thereofIn the formula:

R₁、R₂、R₅identical or different, selected from: h, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, halogen, CN, nitride, NRR', C_1-8Alkylamino, arylamino, C_1-8Alkoxy, aryloxy, COOR, CONRR', R₃、R₄Identical or different, selected from: h, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, cycloalkyl, aryl, heterocycle, halogen, CN, nitride, NRR', C_1-8Alkylamino, arylamino, C_1-8Alkoxy, aryloxy, COOR, CONRR ', wherein R and R', which are identical or different, are selected from: h, C_1-8Alkyl, cycloalkyl, aryl, heterocycle, aryl C_1-8An alkyl group;

q is selected from: a single bond, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, cycloalkyl, CO, CONR, NR, wherein R is as described above;

w is selected from: h, C_1-8Alkyl radical, C_2-8Alkenyl radical, C_2-8Alkynyl, cycloalkyl, trifluoromethyl, C_1-8Alkoxy radical, C_1-8alkoxy-C_1-8Alkyl, aryl C_1-8Alkyl, aryl, aryloxy, arylamino, C_1-8Alkylcarbonyl, arylcarbonyl, arylcarboxyl, arylcarboxyamide, halogen, CN, NRR', C_1-8Alkylamino, heterocyclic, wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclic may be substituted;

n is an integer from 1 to 4;

the method is characterized in that:

in an organic solvent, at K₂CO₃Thioamides 3 in the Presence of/18-crown-6-or diazabicycloundecenes

N-alkylated by vinyl ketones of the general formula 2:

to give the corresponding compound 4:

the compound is methylated at the sulfur atom to produce salt 5:

the compound is reacted with K in an organic solvent₂CO₃18-crown-6Or diazabicycloundecene to yield the desired compound I.

2. A method according to claim 1, characterised in that it uses diazabicycloundecene.

3. The process of claim 1 wherein the solvent is tetrahydrofuran.

4. The process of any of claims 1-2, wherein the methylating agent is dimethyl sulfate and the solvent is toluene at reflux temperature.

5. The process of claim 4, wherein the total reaction time is from half an hour to 1 hour.

6. The method of claim 1, wherein the compound of formula (I) is:

8-chloro-2, 3, 5, 6-tetrahydro-4-methyl- (1H) -benzo [ c ] quinolizin-3-one;

2, 3, 5, 6-tetrahydro-4, 8-dimethyl- (1H) -benzo [ c ] quinolizin-3-one.