ES2347630B1 - SYNTHESIS AND USES OF 4-CIANOPENTANOATOS AND 4-CIANOPENTENOATS SUBSTITUTED. - Google Patents

Abstract

Synthesis and uses of 4-cyanopentanoates and Substituted 4-cyanopentenoates.

The present invention relates to substituted 4-clanopentanoates of general formula 1 and 4-cyanopentenoates
substitutes of general formula 2 and a procedure for obtaining it.

Description

Synthesis and uses of 4-cyanopentanoates and Substituted 4-cyanopentenoates.

Preparation and use as precursors of compounds 5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-one replaced.

Technical field

The present invention relates to 4-substituted cyanopentanoates of general formula 1 and substituted 4-cyanopentenoates of the general formula 2 and a procedure for obtaining it. The invention relates also to the use of 4-cyanopentanoates substituted of general formula 1 and 4-substituted cyanopentenoates of general formula 2 as synthesis intermediates in obtaining compounds 5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-one replaced.

one

State of the art

Protein kinases (PKs) are involved in processes as diverse as angiogenesis, restenosis, arteriosclerosis and, in particular, in the growth processes tumor. Consequently, the development of selective inhibitors of PKs has become a very active area of research. The compounds 5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-one substituted 3 and its pharmaceutically acceptable salts have proven to be selective inhibitors of various protein kinases. Specifically KDR (kinase insert domaincontainig receiver) and FGFR (fibroblast growth factor receptor) kinases (US709833B2). This fact makes these dihydropyridinonic compounds 3 have antiproliferative activity and therefore be useful in the cancer treatment or control, specifically in the case of solid tumors

2

These compounds of general formula 3 where R 4 may be H, alkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkenyl or alkynyl substituted or not and R 3 and Ar they can be substituted aryl or heteroaryl or are not obtained in the actuality from uracil in a minimum of six stages synthetic (US709833B2).

In this environment Borrell and collaborators (Nuria Mont, Jordi Teixidó, C. Oliver Kappe, José I. Borrell, Molecular Diversily 2003 7 , 153-159) previously developed a synthetic route for obtaining referrable pyridopyrimidine systems 11 for treatment of an ester α, β-unsaturated 8 with an acetonitrile with an acceptor substituent G (7a and 7b) and subsequently with a substituted guanidine or amidine 10.

3

These pyridopyrimidine systems 11 have an amine or alcohol group in position 4 of the pyrimidine ring. To obtain pyridopyrimidines 3 with an H in position 4 instead of alcohol or amine it is necessary to use an acetonitrile in which G was an aldehyde group. Therefore the compound to be used would be cyanoacetaldehyde, a compound not synthetically accessible. An alternative to the use of cyanoacetaldehyde is 3,3-dimethoxypropanonitrile 5 where R2 is Me, which has the protected aldehyde group in the form of acetal. The acetal group is not an acceptor in contrast to the aldehyde, so the acidity of the H of the methylene present in the 3,3-dimethoxypropanonitrile decreases dramatically with respect to the acetonitriles used by Borrell et al. This fact makes it necessary to find a stronger base than the NaOMe used by Borrell and collaborators. 3,3-Dimethoxypropanonitrile gives an elimination reaction by treatment with strong bases or under acid catalysis generating 3-methoxyacrylonitrile (US 2002028962 (A1)). Surprisingly, the use of concrete bases such as NaOH / DMF or t -BOKOK / THF allow the ionization of 3,3-dimethoxypropanonitrile without the said removal taking place. This allows its use to obtain substituted 4-cyanopentanoates of general formula 1 and substituted 4-cyanopentenoates of general formula 2 on which the present invention relates.

In view of the above, there is in the state of the art the need to provide a route simpler synthetic for obtaining systems 5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-one replaced 3. This synthetic route goes through obtaining 4-substituted cyanopentanoates of general formula 1 or substituted 4-cyanopentenoates of the general formula 2, compounds of general formula 3 can be obtained in two stages synthetic

Object of the invention

In one aspect the invention therefore relates to substituted 4-cyanopentanoates of the general formula 1 where

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4

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R_ {1} can be a C 1-6 alkyl radical and where

R2 can be a C 1-6 alkyl radical and where

Ar can be aryl, optionally substituted with one or more substituents independently selected from alkyl C 1-6, C 1-6 alkoxy, halide;

a naphthyl, optionally substituted with one or more substituents independently selected from alkyl C 1-6, C 1-6 alkoxy, halide;

a heteroaryl, optionally substituted with one or more substituents independently selected from alkyl C 1-6, C 1-6 alkoxy, halide

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In another aspect the invention is referred to by both substituted 4-cyanopentenoates of formula general 2 where

5

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R_ {1} can be a C 1-6 alkyl radical and where

R2 can be a C 1-6 alkyl radical and where

Ar can be aryl, optionally substituted with one or more substituents independently selected from alkyl C 1-6, C 1-6 alkoxy, halide;

a naphthyl, optionally substituted with one or more substituents independently selected from alkyl C 1-6, C 1-6 alkoxy, halide;

a heteroaryl, optionally substituted with one or more substituents independently selected from alkyl C 1-6, C 1-6 alkoxy, halide

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In a preferred embodiment the compound of Formula 1 is selected from the group consisting of:

[one] 2- (2,6-dichlorophenyl) -4-cyano-5,5-dimethoxypentanoate of methyl

[2] 4-cyano-5,5-dimethoxy-2-o-tolylpentanoate of ethyl

[3] 4-cyano-5,5-dimethoxy-2- (2-methoxyphenyl) pentanoate of methyl

[4] 4-cyano-5,5-dimethoxy-2- (naphthalen-1-yl) pentanoate of methyl

[5] 4-cyano-5,5-dimethoxy-3-phenylpentanoate of methyl

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In a preferred embodiment the compound of Formula 2 is selected from the group consisting of:

[6] 2- (2,6-dichlorophenyl) -4-cyano-5-methoxipent-4-enoate of methyl

[7] 4-cyano-5-methoxy-2-o-tolylpent-4-enoate of ethyl

[8] 4-cyano-5-methoxy-2- (2-methoxyphenyl) pent-4-enoate of methyl

[9] 4-cyano-5-methoxy-2- (naphthalen-1-yl) pent-4-enoate of methyl

[10] 4-cyano-5-methoxy-3-phenylpent-4-enoate of methyl

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In another aspect the invention relates to a procedure for obtaining 4-cyanopentanoates substituted 1 and 4-substituted cyanopentenoates 2 of general formula of the invention. Said procedure, hereinafter method of the invention comprises treating an ester α, β-unsaturated of general formula 4 with a propionitrile of general formula 5 in the presence of a base in a inert solvent. When the reaction is carried out at low temperatures (-78ºC) the majority is obtained 4-substituted cyanopentanoate of general formula 1 while if the reaction is done at higher temperatures (60ºC) the Majority compound is 4-cyanopentenoate replaced by general formula 2. Obtaining 4-substituted cyanopentenoates of general formula 2 It is also possible by heating the 4-substituted cyanopentanoates of general formula 1 in the presence of a base. The conjugate addition reaction is represented in Scheme 1, where R 1, R 2 and Ar have the previously defined meaning.

Scheme one

6

In a particular embodiment of the procedure of invention the base used is an alkali alkoxide as per example potassium tert-butoxide or a hydroxide alkaline such as sodium hydroxide. The inert solvent is a solvent that does not interfere with the reaction and can be selected of a large group of conventional organic solvents. In a particular embodiment an ether type solvent is used, preferably tetrahydrofuran or other types of solvents such as dimethylformamide

4-cyanopentanoates substituted of general formula 1 and the 4-substituted cyanopentenoates of general formula 2 obtained can be purified and / or isolated from the reaction medium according to procedures known to those skilled in the art, by example chromatographic procedures or distillation.

If the compounds of general formula 1 or 2 are obtained in the form of a mixture of stereoisomers, particularly diastereoisomers, said mixtures can be separated by conventional procedures that those skilled in the art They know, for example, chromatographic procedures.

In another aspect of the invention the use of the compounds of general formula 1 and 2 as precursors in the synthesis of compounds 5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-one substituted 3. In this sense the present invention relates therefore with a system preparation procedure substituted dihydropyrimidinonics 3 comprising the passage through of a compound of general formula 1 or 2 and which according to a particular embodiment thereof comprises the following steps of reaction (Scheme 2):

a) cyclization of 1-substituted cyanopentanoate 1 or Substituted 4-cyanopentenoate by reaction with a guanidine or substituted guanidine salt of general formula 6, where R 3 may be H, C 1-6 alkyl, aryl, substituted or not, and heteroaryl, substituted or not, obtaining a compound of general formula 3 with R 4 = H.

b) if desired, nitrogen can be derivatized lactam in position 8. This can be arylated by treatment with aryl halides in the presence of CuI, a ligand 1,2-diamine and an alkali carbonate base or alkylated by reaction with an alkyl halide in the presence of a base as sodium hydride. Thus compounds are obtained 5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-one replaced 3.

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Scheme 2

7

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In a particular embodiment, the procedure to obtain compounds 5,8-dihydro-6H-pyrido [2,3-d] pyrimidin-7-one substituted 3 where R 4 is H is carried out without isolating intermediate of general formula 1 or 2 as represented in the Scheme 3. According to this particular embodiment it is done react an α, β-unsaturated ester of general formula 4 with a propionitrile of general formula 5 in presence of potassium tert-butoxide. Neutralizes with acetic acid, the solvent is removed under reduced pressure and add guanidine 6 salt in the presence of pyridine or Na 2 CO 3. If guanidine salt is a carbonate it is not You need to add no base. It is allowed to react at 150 ° C - 180 ° C under stirring obtaining the compound of general formula 3 with a higher performance

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Scheme 3

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8

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In a preferred embodiment R 3 is a C 1-6 alkyl group, aryl, preferably phenyl or H.

Next, for a better understanding of the present invention, without it being construed as limitations to it, the following examples are set forth.

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Examples Obtaining the 2- (2,6-dichlorophenyl) -4-cyano-5-methoxipent-4-enoate of methyl (2, R1 = Me, R2 = Me, Ar = 2,6-dichlorophenyl)

At a solution of 1.15 g (5 mmol) of 4 (R 1 = Me Ar = 2,6-dichlorophenyl) in 0.85 mL (7.5 mmol) of 5 (R 2 = Me) 50 mL of 0.1M solution of t-ButOK in THF was added. It was stirred at 60 ° C for 5 min. It was neutralized with glacial AcOH. The solvent was removed at reduced P. The residue was purified by flash chromatography and subsequently by distillation. 0.96 g (3 mmol, 61%) of yellow oil corresponding to the mixture of diastereoisomers of the desired product were obtained. It is described spectroscopically as a major isomer (E). IR (KBr) ν max: 2949, 2209, 17.39, 1645, 1437, 1266, 1222, 783. 1 H-NMR (400 MHz, CDCl 3): δ = 7.32 ( d, J = 8.0 Hz, 2H), 7.17 (t, J = 8.0 Hz),
6.69 (s), 4.68 (dd, J3 = 10.0 Hz, J3 = 5.5 Hz), 3.71 (s, 3H), 3.66 (s, 3H), 3.12 (dd, J3 } = 5.5 Hz, J ^ {2} = 4.14), 2.92 (dd, J ^ {3} = 10.0 Hz, J ^ {2} = 4.14). 13 C-NMR (100 MHz, CDCl 3): δ = 171.7, 161.1, 134.4, 129.0, 128.6, 119.3, 89.3, 61.6, 52.5, 45.4, 25.5. HRMS (EI +) m / z calculated for C 14 H 13 Cl 2 NO 3 313.0272. Obtained 313.0271.

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Obtaining the 6- (2,6-Dichlorophenyl) -5,6-dihydro-2- (phenylamino) pyrido [2,3-d] pyrimidin-7 (8H) -one (3, R 3 = Ph, R 4 = H, Ar = 2.6-dichlorophenyl)

To a solution of 0.46 g (2 mmol) of 4 (R1 = Me Ar = 2,6-dichlorophenyl) in 0.35 mL (3 mmol) of 5 (R2 = Me) was added 20 mL of 0.1M solution of t-ButOK in THF. It was stirred at T amb for 5 min. It was neutralized with glacial AcOH. Chromatographic filtering was performed using silica gel as stationary phase and 200 mL of AcOEt / Hexane 1: 1 mixture as the mobile phase. The solvent was removed at reduced P. 1.07 g (6 mmol) of phenylguanidine 6 carbonate (R 3 = Ph) was added to the residue and the mixture was heated at 150 ° C under stirring overnight. The solid residue was suspended in MeOH, filtered and washed with water and then with MeOH. 0.28 g (0.7 mmol, 36%) of white solid were obtained. IR (KBr) ν max: 3289, 3204, 3145, 1685, 16.02, 1579, 1498, 1446, 1241, 756. 1 H-NMR (400 MHz, CDCl 3): delta = 10.96 (s), 9.41 (s), 8.19 (s), 7.82 (d, J = 7.8 Hz, 2H), 7.56 (d, J = 8.2 Hz), 7.52 (d, J = 7.9 Hz), 7.39 (t, J = 8.1 Hz), 7.24 (t, J = 7.9 Hz, 2H), 6.91 (t, J = 7.3 Hz), 4.76 (dd, J3 = 13.8 Hz, J ^ {2} = 8.0 Hz), 3.23 (m), 2.99 (dd, J ^ {3} = 15.8 Hz, J ^ {2} = 8.0 Hz). 13 C-NMR (100 MHz, CDCl 3): δ = 169.8, 158.8, 157.4, 155.6, 140.7, 135.3, 134.9, 134.8, 129.9, 129.8, 128.4 (2C), 121.0, 118.6 (2C ), 104.3, 43.3, 25.0. HRMS (FAB +) m / z calculated for C 19 H 14 Cl 2 N 4 O 385.0623. Obtained 385.0622.

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Obtaining the 2-amino-5.6-dihydro-6- (naphthalen-1-yl) pyrido [2,3-d] pyrimidin-7 (8H) -one (3, R 3 = H, R 4 = H, Ar = naphthyl)

To a solution of 0.45 g (2 mmol) of 4 (R1 = Me, Ar = naphthyl) in 0.35 mL (3 mmol) of 5 (R2 = Me) was added 20 mL of solution 0 , 1M of t-ButOK in THF. It was stirred at T amb for 5 min. It was neutralized with glacial AcOH. Chromatographic filtering was performed using silica gel as stationary phase and 200 mL of AcOEt / Hexane 1: 1 mixture as the mobile phase. The solvent was removed at reduced P. 0.54 g (6 mmol) of guanidine carbonate 6 (R 3 = H) and 4 mL of pyridine were added to the residue and the mixture was heated in microwave 1 h at 180 ° C. Water was added to the solution, the precipitate obtained was filtered and this was washed with water and then with MeOH. 0.26 g (0.9 mmol, 44%) of white solid were obtained. IR (KBr) ν max: 3368, 3331, 3161, 2895, 1682, 1630, 1573, 1497, 1231, 776. 1 H-NMR (400 MHz, CDCl 3): δ = 10.80 (s), 8.10 (m), 7.95 (m), 7.90 (s), 7.85 (d, J = 8.1 Hz), 7.54 (m, 2H), 7.45 (t, J = 11 Hz), 7.35 (d , J = 7.1 Hz), 6.40 (s, 2H), 4.70 (t, J = 8.5 Hz), 3.08 (d, J = 8.5 Hz). 13 C-NMR (100 MHz, CDCl 3): δ = 172.3, 162.5, 158.0, 155.6, 135.3, 133.6, 131.2, 128.7, 127.5, 126.1, 125.6, 125.4, 125.2, 124.0, 103.5, 42.9, 27.9. HRMS (FAB +) m / z calculated for C 17 H 14 N 4 O 291.1246. Obtained 291.1247.

Claims (20)

1. Compound of general formula 1,

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9 where, R1 may be an alkyl radical C_ {1-6} and where R2 can be an alkyl radical C_ {1-6} and where Ar may be aryl, optionally substituted with one or more substituents independently selected from alkyl C 1-6, C 1-6 alkoxy, halide; a naphthyl, optionally substituted with one or more independently selected substituents of alkyl C 1-6, C 1-6 alkoxy, halide; a heteroaryl, optionally substituted with one or more substituents independently selected from alkyl C 1-6, C 1-6 alkoxy, halide

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2. Compound of general formula 2,

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10 where, R1 may be an alkyl radical C_ {1-6} and where R2 can be an alkyl radical C_ {1-6} and where Ar may be aryl, optionally substituted with one or more substituents independently selected from alkyl C 1-6, C 1-6 alkoxy, halide; a naphthyl, optionally substituted with one or more independently selected substituents of alkyl C 1-6, C 1-6 alkoxy, halide; a heteroaryl, optionally substituted with one or more substituents independently selected from alkyl C 1-6, C 1-6 alkoxy, halide

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3. Compound according to claim 1, in the that Ar is aryl preferably naphthyl or phenyl, optionally substituted by one or more substituents selected from alkyl C 1-6, C 1-6 alkoxy and halide 4. Compound according to claim 2, in the that Ar is aryl preferably naphthyl or phenyl, optionally substituted by one or more substituents selected from alkyl C 1-6, C 1-6 alkoxy and halide

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5. A compound according to claim 1 selected from the group consisting of: [one] 2- (2,6-dichlorophenyl) -4-cyano-5,5-dimethoxypentanoate of methyl [2] 4-cyano-5,5-dimethoxy-2-o-tolylpentanoate of ethyl [3] 4-cyano-5,5-dimethoxy-2- (2-methoxyphenyl) pentanoate of methyl [4] 4-cyano-5,5-dimethoxy-2- (naphthalen-1-yl) pentanoate of methyl [5] 4-cyano-5,5-dimethoxy-3-phenylpentanoate of methyl

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6. A compound according to claim 2 selected from the group consisting of: [6] 2- (2,6-dichlorophenyl) -4-cyano-5-methoxipent-4-enoate of methyl [7] 4-cyano-5-methoxy-2-o-tolylpent-4-enoate of ethyl [8] 4-cyano-5-methoxy-2- (2-methoxyphenyl) pent-4-enoate of methyl [9] 4-cyano-5-methoxy-2- (naphthalen-1-yl) pent-4-enoate of methyl [10] 4-cyano-5-methoxy-3-phenylpent-4-enoate of methyl

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7. A procedure for the preparation of a compound of formula 1 comprising reacting a compound of general formula 4 with a compound of general formula 5 in presence of a base. eleven 8. A procedure for the preparation of a compound of formula 1 according to claim 7, wherein the base is selects between an alkali alkoxide and an alkali hydroxide. 9. A procedure for the preparation of a compound of formula 1 according to claim 7 or 8, wherein the alkaline alkoxide is potassium tert-butoxide and the alkaline hydroxide is NaOH. 10. A procedure for the preparation of a compound of formula 2 comprising reacting a compound of general formula 4 with a compound of general formula 5 in presence of a base. 12 11. A procedure for the preparation of a compound of formula 2 according to claim 10, wherein the base is selects between an alkali alkoxide and an alkali hydroxide. 12. A procedure for the preparation of a compound of formula 2 according to claim 10 or 11, wherein the alkaline alkoxide is potassium tert-butoxide and the alkaline hydroxide is NaOH.

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13. A procedure for the preparation of a compound of general formula 3 where R 4 is H, which comprises reacting a compound of general formula 1 or 2 with a compound of general formula 6 or a salt thereof in the presence of a base. 13 14. A procedure for the preparation of a compound of formula 3 wherein R 4 is H according to claim 13, where the base is selected from an alkali alkoxide, a carbonate or an amine. 15. A procedure for the preparation of a compound of formula 3 wherein R 4 is H according to claim 13 or 14, where the alkali alkoxide is NaOMe, the carbonate is Na 2 CO 3 and the amine is pyridine. 16. A one-pot procedure for the preparation of a compound of formula 3 where R 4 is H which comprises reacting a compound of general formula 4 with a compound of general formula 5 in the presence of a base. 17. A one-pot procedure for the preparation of a compound of formula 3 where R 4 is H according to claim 16 comprising reacting a compound of general formula 4 with a compound of general formula 5 in the presence of a base and then with a compound of general formula 6 in the presence of a second base. 18. A one-pot procedure for the preparation of a compound of formula 3 where R 4 is H according to claims 16 and 17 wherein the first base is selects between an alkali alkoxide and an alkali hydroxide and the second base is selected from an alkali alkoxide, a carbonate or an amine. 19. A one-pot procedure for the preparation of a compound of formula 3 where R 4 is H according to any of claims 16 to 18 wherein the alkaline alkoxide is NaOMe or potassium tert-butoxide, the alkali hydroxide is NaOH, the carbonate is Na2CO3 and the Amine is pyridine. 20. Use of a compound of general formula 3 where R 4 is H as synthesis intermediate in the preparation of a compound of general formula 3 where R 4 can be alkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkenyl or alkynyl replaced or not. 14