CA1038870A - Pyrimidine derivatives - Google Patents
Pyrimidine derivativesInfo
- Publication number
- CA1038870A CA1038870A CA222,321A CA222321A CA1038870A CA 1038870 A CA1038870 A CA 1038870A CA 222321 A CA222321 A CA 222321A CA 1038870 A CA1038870 A CA 1038870A
- Authority
- CA
- Canada
- Prior art keywords
- oxo
- pyrimidine
- dihydro pyrido
- substituted
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
ABSTRACT OF THE DISCLOSURE
Method for the preparation of 8-substituted 2-amino-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine 6-carboxylic acids:
(IIIa) wherein R2 is a lower alkyl radical comprising 1 to 5 carbon atoms, and R and R' taken separately, may be identical or different and represent atoms of hydrogen or lower alkyl radicals comprising 1 to 5 carbon atoms or may together constitute, with the nitrogen atom to which they are attached, a 5 or 6-membered haterocyclic ring, optionally containing a second heteroatom, selected from the group consisting of pyrrolidino, piperidino, p-hydroxypiperidino, morpholino, piperazino or N4- substituted piperazino, comprising reacting an 8-substituted 2-alkylsulfonyl-6-carbalkoxy-5-oxo-5, 8-dihydro pyrido [2,3-d] pyrimidine of formula (I) (I) wherein R2 is as defined above and R1 and R3 may be identical or different and represent lower alkyl groups comprising 1 to 5 car-bon atoms with an amine of formula:
in which R and R' are defined as above so as to obtain an 8-substituted 2-amino-6-carbalkoxy-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine of formula (III):
(III)
Method for the preparation of 8-substituted 2-amino-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine 6-carboxylic acids:
(IIIa) wherein R2 is a lower alkyl radical comprising 1 to 5 carbon atoms, and R and R' taken separately, may be identical or different and represent atoms of hydrogen or lower alkyl radicals comprising 1 to 5 carbon atoms or may together constitute, with the nitrogen atom to which they are attached, a 5 or 6-membered haterocyclic ring, optionally containing a second heteroatom, selected from the group consisting of pyrrolidino, piperidino, p-hydroxypiperidino, morpholino, piperazino or N4- substituted piperazino, comprising reacting an 8-substituted 2-alkylsulfonyl-6-carbalkoxy-5-oxo-5, 8-dihydro pyrido [2,3-d] pyrimidine of formula (I) (I) wherein R2 is as defined above and R1 and R3 may be identical or different and represent lower alkyl groups comprising 1 to 5 car-bon atoms with an amine of formula:
in which R and R' are defined as above so as to obtain an 8-substituted 2-amino-6-carbalkoxy-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine of formula (III):
(III)
Description
~(~3~870 The present invention relates to a new method for the preparation of 8-substituted 2-amino-5-oxo-5,8-dihyaro pyrido [2,3-d~ pyrimidine 6-carboxylic acids of the formula:
il COOH
~_R R
which are remarkable antibacterial agents.
In this formula:
- R2 is a lower alkyl radical comprislng 1 to 5 carbon atoms, preferably 1 to 2 carbon atoms, - R, R', taken separately, may be identical or different and represent atoms of hydrogen or lower alkyl radicals comprising 1 to 5 carbon atoms, or taken together, R, R' may constitute, with the nitrogen atom to which they ., .
are attached, a 5 or 6-membered heterocyclic ring, such as pyrrolidino or piperidino, p-hydroxypiperidino, this hetero-cyclic ring may equally comprise a second heteroatom N or O, such as morpholino, piperazinyl, N4-substituted piperazinyl.
A method of this type consists of a) reacting an 8-substituted 2-alkylsulfonyl-6-carbalkoxy-5-oxo-5,8-dihydro pyrido [2,3-d ] pyrimidine of the formula (I): -N~ ~ (I) in which:
il COOH
~_R R
which are remarkable antibacterial agents.
In this formula:
- R2 is a lower alkyl radical comprislng 1 to 5 carbon atoms, preferably 1 to 2 carbon atoms, - R, R', taken separately, may be identical or different and represent atoms of hydrogen or lower alkyl radicals comprising 1 to 5 carbon atoms, or taken together, R, R' may constitute, with the nitrogen atom to which they ., .
are attached, a 5 or 6-membered heterocyclic ring, such as pyrrolidino or piperidino, p-hydroxypiperidino, this hetero-cyclic ring may equally comprise a second heteroatom N or O, such as morpholino, piperazinyl, N4-substituted piperazinyl.
A method of this type consists of a) reacting an 8-substituted 2-alkylsulfonyl-6-carbalkoxy-5-oxo-5,8-dihydro pyrido [2,3-d ] pyrimidine of the formula (I): -N~ ~ (I) in which:
- 2 - ~ i~
- Rl, R2, R3 may be identical or different and represent lower alkyl groups comprising 1 to 5 carbon atoms, preferably 1 to 2 carbon atoms, with an amine of the formula:
,-R
H
"-R' in which R and R' are defined as above to obtain an 8-substituted 2-amino-6-carbalkoxy-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine of formula III:
o ~R
in which R, R', R2 and R3 are defined as above, and b) of saponifying the ester (III) thus obtained in the corresponding acid: Q
( / ~ ~ ~ (IIIa) -R' 12 The initial products 8-substituted 2-alkylsulfonyl-6-carbalkoxy-5-oxo-5,8-dihydro pyrido [2,3-d~ pyrimidines of formuia (I) are characterised by their high reactivity resulting : from the attracting effect of the alkylsulfonyl group~ Due to this, they are able to take part in numerous nucleophilic re-actions. In particular, they react with ammonia and primary and secondary aliphatic or heterocyclic amines to produce, with 20 very good yields, 8-substituted 2-amino-6-carbalkoxy-5,8-dihydro pyrido [2,3-d~ pyrimidines and their 2-monoalkylamino or 2-` dialkylamino derivatives (III) according to the diagram:
- Rl, R2, R3 may be identical or different and represent lower alkyl groups comprising 1 to 5 carbon atoms, preferably 1 to 2 carbon atoms, with an amine of the formula:
,-R
H
"-R' in which R and R' are defined as above to obtain an 8-substituted 2-amino-6-carbalkoxy-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine of formula III:
o ~R
in which R, R', R2 and R3 are defined as above, and b) of saponifying the ester (III) thus obtained in the corresponding acid: Q
( / ~ ~ ~ (IIIa) -R' 12 The initial products 8-substituted 2-alkylsulfonyl-6-carbalkoxy-5-oxo-5,8-dihydro pyrido [2,3-d~ pyrimidines of formuia (I) are characterised by their high reactivity resulting : from the attracting effect of the alkylsulfonyl group~ Due to this, they are able to take part in numerous nucleophilic re-actions. In particular, they react with ammonia and primary and secondary aliphatic or heterocyclic amines to produce, with 20 very good yields, 8-substituted 2-amino-6-carbalkoxy-5,8-dihydro pyrido [2,3-d~ pyrimidines and their 2-monoalkylamino or 2-` dialkylamino derivatives (III) according to the diagram:
- 3 -3887a~
+RlS2~ ~ R~ ~N~ ~COOR3 (I) (III) In these formulae, Rl, R2, R3 and R, R' correspond ; to the definitions given above in the description~
The esters (III), when saponified, provide the cor-responding acids (IIIa), certain of which are valuable anti-bacterial agents for the treatment of infections by gram negative bacteria and are already described in the published French Patent No. 2,194,420 of August 2nd 1972~
The reaction of the sulfones (I) with ammonia and the amines may be carried out at temperatures between 60 and 120C, but, in general, a temperature of 80C ensures an adequate reaction speed.
Preferably, the reaction is conducted with a solvent having a suitable boiling point, the lower alcohols, comprising 1 to 5 carbon atoms, are most suitable.
The reaction is carried out by using the amine in excess with respect to the sulfone; for example two moles of amine per mole of sulfone. It is also equally possible to use equimolecular proportions of the two reactants in the presence of at least one mole of a basic agent, for example a tertiary aliphatic amine such as triethylamine~
The amount of solvent used is such that the reactants are present at a concentration of between lO and 25%.
In general, the reaction is completed after a period of l to 5 hours heating. The amine derivatives (III) are isolated, ~(~3b~870 according to their solubility characteristics, by utilising the general procedures described in the following examples~
In the cases where ammonia or amines of lower boiling point than the temperature necessary for t:he reaction are used, the operation may be carried out in an autoclave with an excess of amine. However, it is possible and particularly interesting to effect this operation at ordinary pressure, by bubbling a gaseous stream of ammonia or amine into the solution, maintained under reflux, of the sulfone in the chosen solvent, A particularly interesting application of this procedure resides in the direct preparation of 6-carbethoxy-8-ethyl-5-oxo-2-piperazinyl-5,8-dihydro pyrido 12,3-d] pyrimidine (IV) by simple reaction of 6-carbethoxy-8-ethyl-2-methylsulphonyl-5-oxo- .
5,8-dihydro pyrido ~2,3-d] pyrimidine (V) with piperazine used as its hexahydrate: .
COOC2~15 ~_~:00C2~5 ~
~N NH -~ H3CSO2 ~ ~ N ~ ~
C2H5 ~2H5 (V) (IV) : The ester (IV) is an important intermediate for the preparation of the corresponding acid which has excelle.nt anti-bacterial properties.
It is well known that the ester (IV) cannot be obl-ained . directly by the action of 6-carbethoxy-2-chloro-8-ethyl-5-oxo-5,8-dihydro pyrido [2,3,-d} pyrimidine on piperazine under normal conditions. In effect, the high reactivity of the halogen atom does not allow a sufficiently selective reaction and the main reaction product is the N,Nl - disubstituted piperazine de-rivative ~IVa); the preparation of the ester (IV) thus necessi-tates the synthesis of the N-formylated piperazine derivative as described in the application referred to above.
O O
~5czoCo ~ ~ cooc2l~s C2H5 ~ J C2H5 (IVa) On the other hand, it is possible to obtain the ester (IV) with excellent yields, directly by the action of the methylsulone (V) on piper~ælne hexahydrate, Preerably the procedure is carried out with an excess (1.5 to 2 moles~ of piperazine with respect to the sulfone (1 mole?
and in the presence of an excess (2 to 5 moles) of a tertiary aliphatic base, such as triethylamine; the piperazine and the tertiary base, in solution (concentration of reactants : 10 to 20%) in a lower aliphatic alcohol, e.g. ethanol, are stirred and warmed to reflux. There is added dropwise over a period of about 1 hour, a solution of the sulfone (V) (1 mole) in 3 to 5 volumes of a suitable solvent, e.g. dimethylformamide (D.M.F.). The addition finished, the reaction is completed by continuing reflux for 30 mins. to 1 hr. The solvents are evaporated under vacuum.
The residue is dissolved in a di~ute solution of a mineral or strong organic acid (e.g. methanesulphonic acid). A light in-soluble substance is separated by filtration. The solution is made alkaline by the addition of an alkali metal carbonate and the reaction product extracted by a suitable solvent, e.g. chloro-form. Evaporation of the solvent leaves the ester (IV) as residue.
Purified by recrystallisation in benzene, it is obtained with yields of about 80%.
1038~
It is known that the amination reaction in position 2 on the nucleus of pyrido ~2,3-d] pyrimidine derivatives may be realised by the action of the amines on the 2-methylmercapto or 2-chloro derivatives.
The use of the alkylsulfonyl derivatives of the inven-tion represents an appreciable technical progress. In effect, the alkylsulfonyl radicals have a reactivity intermediate be-tween that of the alkylmercapto radicals (the least reactive) and halogen (the most reactive).
With respect to the 2-alkylmercapto dérivatives, the alkylsulfonyl derivatives allow amination reactions to be carried out at much lower temperatures and avoid work under pressure. In addition, the reactions effected with the former emit toxic mercaptons and disagreeable odours; the reactions of the latter are odourless, which, from the pollution point of view, is a further advantage.
With respect to the 2-halogen compounds, the least mobility of the sulfonyl radical allows work to be carried out in a greater range of solvents and abo~e all, as shown in the piperazine example, a greater selectivity in the case of complex reactions is obtained.
The initial products are new compounds corresponding to the general formula tI) hereafter:
~l ~ S ~ ~ COOR3 (I) ~l .
`: ~ R2 in which Rl, R2 and R3 may be identical or different and represent lower alkyl groups, comprising l to 5 carbon atoms, preferably 1 to 2 carbon atoms. il~ 38 87 These products may be obtained according to the inven-tion from a corresponding 8-suhstituted 2-alkylmercapto-6-carbal-koxy-5-oxo-5,8-dihydro pyrido ~2,3-d] pyrimidine, of formula (II)-~ COOR3 in particular a 2-alkylmercapto-6-carbethoxy-8-ethyl-5-oxo-5,8-dihydro pyrido [2,3-d) pyrimidine (IIa), by oxidation by means of mild oxidising agents normally used for this purpose, such as potassium permanganate, potassium bichromate or hydrogen peroxide.
However, it is preferable to use a halogen, in particular chlorine, acting in aqueous media. In the last case, the reaction may be represented as follows:
Rl-S ~ + 2 C12 + 2 H20----~Rl 52 ~ ~ ~ OOC2H5 (IIa) 2 5 C2H5 The reaction is carried out by passing a stream of chlorine gas into a vigorously stirred suspension of the 2-alkyl-mercapto derivative (II), at a temperature from 0 to 2SC, until the increase in weight of the reaction mixture corresponds to 90 -105% of the theoretical weight of halogen such as may be calculated according to the above equation, i.e. 2 moles of halogen for 1 mole of alkylmercapto derivative (II).
When this increase in weight has been obtained, the flow of halogen is stopped and the reaciton is allowed to proceed, with stirring at a temperature from 0 to 25C until the starting ~3~7~
material is completely converted, which takes about 10 min. to 1 hr. according to the conditions.
After possible dilution with water, the solid reaction product is dried without heat, washed and recrystallized in an appropriate solvent.
In the course of this oxidation, it is necessary to avoid the use of a large excess of halogen which, while favouring the formation of by-products, risks bringing about a reduction of yields generally comprised between 80 and 90~.
The evolution of the reaction depends on the nature of the media: in water the reaction is slow, probably due to the very low solubility of the alkylmercapto derivatives (II). This is why it is preferable to use dilute aqueous solutions of water-soluble organic solvents, such as lower alcohols, most preferably methanol, or even acetic acid. These solubilisation adjuvants may be used at concentrations varying between 5 and 50~.
For concentrations of adjuvants greater than 20%, there is observed in the course of the oxidation reaction a definitive or transient dissolution of the alkylmercapto derivative. At lower concentrations (5 to 10~ the evolution of the reaction is expressed by a modification of the appearance of the solid in suspension, and which may be estimated, on samples of the latter, by the determination of an appropriate physical constant, for example the melting point.
In the place of chlorine gas, it is possible to use all other procedures permitting the liberation of halogen in the native state in the reactlon medium, for example alkali metal hypo-chlorites or hydrogen peroxide acting on a suspension of ~3815t7~
compounds (II) in hydrochloric acid, in the presence of solubilisation adjuvants.
The following non-limiting examples are given to illu-- strate the invention.
The products of examples 2 to 5 and example -7 have already been described in the French patent application cited above as well as the acids resulting from their saponification.
Example 1 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydro-pyrido [2,3-d] pyrimidine (formula I Rl = -CH3, R~ = C2H5)~
In a 500 cm3 flask, provided with a mechanical stirrer and a thermometer and lmmersed in an ice bath, there is vigorously ; stirred 29.3g (0.1 mole) of 6-carbethoxy-8-ethyl-2-methylmercapto-5-oxo-5,8-dihydro pyrido [2,3-dl pyrimidine in a solution of acetic acid (15 cm3) in water (285 cm3). A stream of chlorine is passed into the solution at such a rate that the temperature remains between 10 and 15C. The flask and its contents, weighed before the introduction of gas, are weighed again at regular intervals.
When an increase in weight of 13g is attained (theory for 2 moles of chlorine = 14.2g), after approximately 1 hour, the gas stream is stopped and the mixture stirred for 30 min. at 10C.
After adding 100 cm3 of water, the precipitate is filtered, washed with water then with ethanol (2 x 35 cm3) and dried under vacuum. There is obtained 26.6g (81.8~ yield) of 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine (m.pt.= 176C). A sample recrystallised from ~3~870 isopropanol gave the same melting point.
Analysis for C13 H15 N3 O5 S tM.w~ = 325.27) C H N S
% Calculated 48.00 4.65 12.92 9.82 % Found 47.83 4.74 13.20 9.65 In examples 2 to 7, the product of example 1 is used as an intermediate in the preparation of 8-substituted 2-amino-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine 6-carboxylic acids which are known for their antibacterial activity.
Example 2 A solution of 3.9g piperazine hexahydrate (0.02 mole) and 2.02 g of triethylamine (0.02 mole) in 50 cm3 ethanol are heated to re~lux. There is added dropwise, over a period of about 1 hour, 3.25g (0.002 mole) of 6-carbethoxy-8-ethyl-2-methylsulfonyl-S-oxo-5,8-dihydro pyrido 12,3-di pyrimidine of example 1 in solution in 15 cm3 of D.M.F.
The solvents are evaporated under vacuum~and the residue - taken up i~ 20 cm of l.S N HCl; an insoluble substance is eliminated by extraction with chloroform. The aqueous solution is made alkaline by addition of Na2CO3 and the reaation product `~ extracted with chloroform (5 x 10 cm3). The organic extracts are combined and the solution decolourised by agitation with animal black is filtered. Evaporation leaves 2.65g (yield 80%) of 6-carbethoxy-8-ethyl-2-piperazinyl-5-oxo-5,8-dihydro pyrido t2,3-d] pyrimidine C m. pt. = 156C).
Analysis for C16 H21 N5 O3 (M.W. - 331.37) 1~38~370 C H N
Calcaulted (~) 57.99 6.39 21.14 Found (%) 57.98 6.23 21.39 The saponification of this ester leads to the corresp-onding acid; 2.65 g of this ester in suspension in 30 cm3 of 75%
ethanol are treated with 22 cm3 of N soda and the mixture is stirred for 2 2- hours at ambient temperature. The solution is acidified by 1.26 cm3 o glacial acetic acid. After keeping in the refrigerator the precipitate is filtered, washed with alcohol 10 then dried under vacuum. There is obtained 2.29g of 8-ethyl-2-piperazinyl-5-oxo-5,8-dihydro pyrido [2,3~d] pyrimidine l 6-carboxylic acid; m.pt. 260-262C (Kofler block) with j decomposition.
AnalysiS for C14 H17 N5 O3 tM-W- = 303-32) ., C H N
Calculated (%) 55.43 5.65 23.09 Found (%) 55.68 5.67 23.25 Example 3 1.6 g of 6-carbethoxy-8-ethyl-2-methylsulonyl-5-oxo-20 5,8-dihydro pyrido [2,3-d] pyrimidine of example 1 and lg ; of l-methylpiperazine, in 20 cm3 of isopropanol, are heated at reflux for 1 hour. The solvent is evaporated under vacuum, the i residue is taken up by 40 cm3 of a saturated solution of Na2CO3 ; and the mixture extracted by 4 x 10 cm3 of chloroform. The organic phases are combined and the solvent evaporatedv The residue recrystallised from a mixture of isopropyl oxide and benzene (1:1) gives 1.36g (79% yield) of 6-carbethoxy-8-ethyl-L0381!37~
5-oxo-2-(4'-methylpiperazinyl) -5,8-dihydro pyrido 12,3-d]
pyrimidine melting at two temperatures; 146C, solidification, then 158C.
Analysis for C17 H23 N5 O3 (M.W. = 345.39) C H N
Calculated % S9.11 6.71 20.~8 Found % 59.23 6.68 20.42 ~ he saponification of this esterr by addition of a solution of lN NaOH, with stirring at 50 - 60C for 2 hours 10 to ambient temperature and acidification to pH6 by acetic acid, gives 8-ethyl-5-oxo-2-~4'-methylpiperazinyl)-5,8-dihydro pyrido [2,3-d] pyrimidine 6-carboxylic acid ~M.P. = 227C).
r Analysis or C15 Hlg N5 O3 ~M.W. = 317.34) C H N
Calculated %56.77 6.04 22.07 Found % 56.69 6.23 22.35 ,~ Example 4 13g of6-carbethoxy-8-ethyl-2-methylsulphonyl-5-oxo-5, 8-dihydro pyrido [2,3-d] pyrimidine of example }, Sg of l-formyl 20 piperazine and 5.6g of triethylamine in 100 cm3 of isopropanol 5 ~ are stirred and heated for 2 hours at reflux during which the product of the reaction partially precipitates. After cooling~
the precipitate is filtered, washed with isopropanol and dried.
There is obtained 11.36g (80% yield) of 6-carbethoxy-8-ethyl-5-oxo-2-(4'formyl piperazinyl) -5,8-dihydro pyrido [2,3-d]
pyrimidine having two melting points, 198C, solidification, then 204C.
1~38~37~
Analysis for C17 H21 N5 O4 (M-W- = 359-38) C H N
Calculated (%) 56.81 5.89 19.49 Found (~) 56.97 5.95 19.58 3.6g of the formyl derivative are suspended in 25 cm3 of a 5% alcoholic solution of HCl. The dichlorohydrate of the formyl derivative precipitates after 8 hours of standing at ordinary temperature. It is taken up by 100 cm3 ether, then filtered, placed back in suspension in 40 cm3 of water, made alkaline by addition of Na2 CO3 then extracted with chloroform.
After evaporation of the solvent and crystallisation in 40 cm3 of a 1:1 mixture of isopropyl oxide-benzene, there is obtained 2.8g of 6-carbethoxy-8-ethyl-5-oxo-2-piperazinyl-5,8-dihydro pyrido ~2,3-d] pyrimidine, m.pt. = 156C, identical to the product of example 2.
Example 5 10.7g of 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydro pyrido [2,3-d~ pyrimidine (0.03 mole) described in example 1, 7.8g of ~ -hydroxyethylpiperazine ~0.06 mole) and 100 cm3 of isopropanol are heated to reflux for 2 hours. After cooling, the mixture is mixed with 50 cm of isopropyl oxide;
the precipitate is filtered, washed with 50 cm3 of a mixture of isopropanol (30 volumes)-isopropyl oxide (70 volumes). There i8 obtained 10.2g (91% yield) of 6-carbethoxy-8~ethyl-5-oxo~-2-t4'-( ~-hydroxyethyl) piperazinyl)-5,8-dihydro pyrido [2~3-d]
pyrimidine (m.pt. = 172C).
~38870 Analysis for C1~3 H25 N5 O4 (M.W. = 375.42).
C H N
Calculated % 57.586.71 18.60 Found 9~ 57.536.57 18.80 The saponification of this ester yields the corresponding acid; 10.2g of this ester and 40 cm3 of N ethanolic soda are stirred for 2 hours at ordinary temperature; the solution is neutralised by 2 cm3 of glacial acetic acid. The precipitate : ~ .
is filtered, washed with water and recrystallised from ethanol.
10 There is obtained 8.6g o~ 8-ethyl-5-oxo-2-(4~ hydroxyethyl) piperazinyl-5,8-dihydro pyrido [2,3-d] pyrimidine 6-carboxylic " .
acid (m.pt. = 222C).
Analysis for C16 H21 N5 04 (M.W. = 347.37) C H N
Calculated % 55.32 6.09 20.16 Found % 54.96 6.04 19~92 Example 6 .~
In a single-necked flask, provided with a reflux con-denser and an ammonia delivery tube, a suspension of 6.5g (0.02 20 mole~ of 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydro pyrido ~2,3-d] pyrimidine of example 1 in 40 cm3 of ethanol is heated to reflux under a rapid stream of NH3. The operation is continued until the melting point of the solid (initially 176C) reaches 265C, which takes about 4 hours.
The mixture is c ~d~ 8an7d mixed with 100 cm3 water.
The precipitate is filtered, washed with water and dried. There is obtained 3.04 g (57.5%) of 2-amino-6-carbethoxy-8-ethyl-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine, purified by recrystallisation in ethanol (m.pt. - 266C).
Analysis for C12 H14 N4 O3 (M.W. = 262.26) C H N
Calculated % 54.95 5.38 21.37 Found % 55 35 5'5~ 21.17 The saponification of this ester yields 2-am:Lno-8-ethyl-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine 6-carboxylic acid (m.pt. = 292C).
Example 7 1.6g of 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine and 1.6g of pyrrolidine in 20 cm3 of isopropanol are stlrred and heated to reflux.
After dissolution of the sulfone the reaction product precipitates rapidly. The heating is conti~ued for 1 hour, the mixture is cooled and the solid filtered and washed with 2 x 5 cm3 ethanol.
There is obtained 1.38g (92% yield) of 6-carbethoxy-8-ethyl-5-oxo-2-pyrrolidino-5,8-dihydro pyrido ~2,3-d] pyrimidine (m.pt =
202C~. -The saponification of this ester yields 8-ethyl-5-oxo-2-pyrrolidino-5,8-dihydro pyrido 12,3-d] pyrimidine 6-carboxylic acid (m.pt. = 314C).
+RlS2~ ~ R~ ~N~ ~COOR3 (I) (III) In these formulae, Rl, R2, R3 and R, R' correspond ; to the definitions given above in the description~
The esters (III), when saponified, provide the cor-responding acids (IIIa), certain of which are valuable anti-bacterial agents for the treatment of infections by gram negative bacteria and are already described in the published French Patent No. 2,194,420 of August 2nd 1972~
The reaction of the sulfones (I) with ammonia and the amines may be carried out at temperatures between 60 and 120C, but, in general, a temperature of 80C ensures an adequate reaction speed.
Preferably, the reaction is conducted with a solvent having a suitable boiling point, the lower alcohols, comprising 1 to 5 carbon atoms, are most suitable.
The reaction is carried out by using the amine in excess with respect to the sulfone; for example two moles of amine per mole of sulfone. It is also equally possible to use equimolecular proportions of the two reactants in the presence of at least one mole of a basic agent, for example a tertiary aliphatic amine such as triethylamine~
The amount of solvent used is such that the reactants are present at a concentration of between lO and 25%.
In general, the reaction is completed after a period of l to 5 hours heating. The amine derivatives (III) are isolated, ~(~3b~870 according to their solubility characteristics, by utilising the general procedures described in the following examples~
In the cases where ammonia or amines of lower boiling point than the temperature necessary for t:he reaction are used, the operation may be carried out in an autoclave with an excess of amine. However, it is possible and particularly interesting to effect this operation at ordinary pressure, by bubbling a gaseous stream of ammonia or amine into the solution, maintained under reflux, of the sulfone in the chosen solvent, A particularly interesting application of this procedure resides in the direct preparation of 6-carbethoxy-8-ethyl-5-oxo-2-piperazinyl-5,8-dihydro pyrido 12,3-d] pyrimidine (IV) by simple reaction of 6-carbethoxy-8-ethyl-2-methylsulphonyl-5-oxo- .
5,8-dihydro pyrido ~2,3-d] pyrimidine (V) with piperazine used as its hexahydrate: .
COOC2~15 ~_~:00C2~5 ~
~N NH -~ H3CSO2 ~ ~ N ~ ~
C2H5 ~2H5 (V) (IV) : The ester (IV) is an important intermediate for the preparation of the corresponding acid which has excelle.nt anti-bacterial properties.
It is well known that the ester (IV) cannot be obl-ained . directly by the action of 6-carbethoxy-2-chloro-8-ethyl-5-oxo-5,8-dihydro pyrido [2,3,-d} pyrimidine on piperazine under normal conditions. In effect, the high reactivity of the halogen atom does not allow a sufficiently selective reaction and the main reaction product is the N,Nl - disubstituted piperazine de-rivative ~IVa); the preparation of the ester (IV) thus necessi-tates the synthesis of the N-formylated piperazine derivative as described in the application referred to above.
O O
~5czoCo ~ ~ cooc2l~s C2H5 ~ J C2H5 (IVa) On the other hand, it is possible to obtain the ester (IV) with excellent yields, directly by the action of the methylsulone (V) on piper~ælne hexahydrate, Preerably the procedure is carried out with an excess (1.5 to 2 moles~ of piperazine with respect to the sulfone (1 mole?
and in the presence of an excess (2 to 5 moles) of a tertiary aliphatic base, such as triethylamine; the piperazine and the tertiary base, in solution (concentration of reactants : 10 to 20%) in a lower aliphatic alcohol, e.g. ethanol, are stirred and warmed to reflux. There is added dropwise over a period of about 1 hour, a solution of the sulfone (V) (1 mole) in 3 to 5 volumes of a suitable solvent, e.g. dimethylformamide (D.M.F.). The addition finished, the reaction is completed by continuing reflux for 30 mins. to 1 hr. The solvents are evaporated under vacuum.
The residue is dissolved in a di~ute solution of a mineral or strong organic acid (e.g. methanesulphonic acid). A light in-soluble substance is separated by filtration. The solution is made alkaline by the addition of an alkali metal carbonate and the reaction product extracted by a suitable solvent, e.g. chloro-form. Evaporation of the solvent leaves the ester (IV) as residue.
Purified by recrystallisation in benzene, it is obtained with yields of about 80%.
1038~
It is known that the amination reaction in position 2 on the nucleus of pyrido ~2,3-d] pyrimidine derivatives may be realised by the action of the amines on the 2-methylmercapto or 2-chloro derivatives.
The use of the alkylsulfonyl derivatives of the inven-tion represents an appreciable technical progress. In effect, the alkylsulfonyl radicals have a reactivity intermediate be-tween that of the alkylmercapto radicals (the least reactive) and halogen (the most reactive).
With respect to the 2-alkylmercapto dérivatives, the alkylsulfonyl derivatives allow amination reactions to be carried out at much lower temperatures and avoid work under pressure. In addition, the reactions effected with the former emit toxic mercaptons and disagreeable odours; the reactions of the latter are odourless, which, from the pollution point of view, is a further advantage.
With respect to the 2-halogen compounds, the least mobility of the sulfonyl radical allows work to be carried out in a greater range of solvents and abo~e all, as shown in the piperazine example, a greater selectivity in the case of complex reactions is obtained.
The initial products are new compounds corresponding to the general formula tI) hereafter:
~l ~ S ~ ~ COOR3 (I) ~l .
`: ~ R2 in which Rl, R2 and R3 may be identical or different and represent lower alkyl groups, comprising l to 5 carbon atoms, preferably 1 to 2 carbon atoms. il~ 38 87 These products may be obtained according to the inven-tion from a corresponding 8-suhstituted 2-alkylmercapto-6-carbal-koxy-5-oxo-5,8-dihydro pyrido ~2,3-d] pyrimidine, of formula (II)-~ COOR3 in particular a 2-alkylmercapto-6-carbethoxy-8-ethyl-5-oxo-5,8-dihydro pyrido [2,3-d) pyrimidine (IIa), by oxidation by means of mild oxidising agents normally used for this purpose, such as potassium permanganate, potassium bichromate or hydrogen peroxide.
However, it is preferable to use a halogen, in particular chlorine, acting in aqueous media. In the last case, the reaction may be represented as follows:
Rl-S ~ + 2 C12 + 2 H20----~Rl 52 ~ ~ ~ OOC2H5 (IIa) 2 5 C2H5 The reaction is carried out by passing a stream of chlorine gas into a vigorously stirred suspension of the 2-alkyl-mercapto derivative (II), at a temperature from 0 to 2SC, until the increase in weight of the reaction mixture corresponds to 90 -105% of the theoretical weight of halogen such as may be calculated according to the above equation, i.e. 2 moles of halogen for 1 mole of alkylmercapto derivative (II).
When this increase in weight has been obtained, the flow of halogen is stopped and the reaciton is allowed to proceed, with stirring at a temperature from 0 to 25C until the starting ~3~7~
material is completely converted, which takes about 10 min. to 1 hr. according to the conditions.
After possible dilution with water, the solid reaction product is dried without heat, washed and recrystallized in an appropriate solvent.
In the course of this oxidation, it is necessary to avoid the use of a large excess of halogen which, while favouring the formation of by-products, risks bringing about a reduction of yields generally comprised between 80 and 90~.
The evolution of the reaction depends on the nature of the media: in water the reaction is slow, probably due to the very low solubility of the alkylmercapto derivatives (II). This is why it is preferable to use dilute aqueous solutions of water-soluble organic solvents, such as lower alcohols, most preferably methanol, or even acetic acid. These solubilisation adjuvants may be used at concentrations varying between 5 and 50~.
For concentrations of adjuvants greater than 20%, there is observed in the course of the oxidation reaction a definitive or transient dissolution of the alkylmercapto derivative. At lower concentrations (5 to 10~ the evolution of the reaction is expressed by a modification of the appearance of the solid in suspension, and which may be estimated, on samples of the latter, by the determination of an appropriate physical constant, for example the melting point.
In the place of chlorine gas, it is possible to use all other procedures permitting the liberation of halogen in the native state in the reactlon medium, for example alkali metal hypo-chlorites or hydrogen peroxide acting on a suspension of ~3815t7~
compounds (II) in hydrochloric acid, in the presence of solubilisation adjuvants.
The following non-limiting examples are given to illu-- strate the invention.
The products of examples 2 to 5 and example -7 have already been described in the French patent application cited above as well as the acids resulting from their saponification.
Example 1 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydro-pyrido [2,3-d] pyrimidine (formula I Rl = -CH3, R~ = C2H5)~
In a 500 cm3 flask, provided with a mechanical stirrer and a thermometer and lmmersed in an ice bath, there is vigorously ; stirred 29.3g (0.1 mole) of 6-carbethoxy-8-ethyl-2-methylmercapto-5-oxo-5,8-dihydro pyrido [2,3-dl pyrimidine in a solution of acetic acid (15 cm3) in water (285 cm3). A stream of chlorine is passed into the solution at such a rate that the temperature remains between 10 and 15C. The flask and its contents, weighed before the introduction of gas, are weighed again at regular intervals.
When an increase in weight of 13g is attained (theory for 2 moles of chlorine = 14.2g), after approximately 1 hour, the gas stream is stopped and the mixture stirred for 30 min. at 10C.
After adding 100 cm3 of water, the precipitate is filtered, washed with water then with ethanol (2 x 35 cm3) and dried under vacuum. There is obtained 26.6g (81.8~ yield) of 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine (m.pt.= 176C). A sample recrystallised from ~3~870 isopropanol gave the same melting point.
Analysis for C13 H15 N3 O5 S tM.w~ = 325.27) C H N S
% Calculated 48.00 4.65 12.92 9.82 % Found 47.83 4.74 13.20 9.65 In examples 2 to 7, the product of example 1 is used as an intermediate in the preparation of 8-substituted 2-amino-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine 6-carboxylic acids which are known for their antibacterial activity.
Example 2 A solution of 3.9g piperazine hexahydrate (0.02 mole) and 2.02 g of triethylamine (0.02 mole) in 50 cm3 ethanol are heated to re~lux. There is added dropwise, over a period of about 1 hour, 3.25g (0.002 mole) of 6-carbethoxy-8-ethyl-2-methylsulfonyl-S-oxo-5,8-dihydro pyrido 12,3-di pyrimidine of example 1 in solution in 15 cm3 of D.M.F.
The solvents are evaporated under vacuum~and the residue - taken up i~ 20 cm of l.S N HCl; an insoluble substance is eliminated by extraction with chloroform. The aqueous solution is made alkaline by addition of Na2CO3 and the reaation product `~ extracted with chloroform (5 x 10 cm3). The organic extracts are combined and the solution decolourised by agitation with animal black is filtered. Evaporation leaves 2.65g (yield 80%) of 6-carbethoxy-8-ethyl-2-piperazinyl-5-oxo-5,8-dihydro pyrido t2,3-d] pyrimidine C m. pt. = 156C).
Analysis for C16 H21 N5 O3 (M.W. - 331.37) 1~38~370 C H N
Calcaulted (~) 57.99 6.39 21.14 Found (%) 57.98 6.23 21.39 The saponification of this ester leads to the corresp-onding acid; 2.65 g of this ester in suspension in 30 cm3 of 75%
ethanol are treated with 22 cm3 of N soda and the mixture is stirred for 2 2- hours at ambient temperature. The solution is acidified by 1.26 cm3 o glacial acetic acid. After keeping in the refrigerator the precipitate is filtered, washed with alcohol 10 then dried under vacuum. There is obtained 2.29g of 8-ethyl-2-piperazinyl-5-oxo-5,8-dihydro pyrido [2,3~d] pyrimidine l 6-carboxylic acid; m.pt. 260-262C (Kofler block) with j decomposition.
AnalysiS for C14 H17 N5 O3 tM-W- = 303-32) ., C H N
Calculated (%) 55.43 5.65 23.09 Found (%) 55.68 5.67 23.25 Example 3 1.6 g of 6-carbethoxy-8-ethyl-2-methylsulonyl-5-oxo-20 5,8-dihydro pyrido [2,3-d] pyrimidine of example 1 and lg ; of l-methylpiperazine, in 20 cm3 of isopropanol, are heated at reflux for 1 hour. The solvent is evaporated under vacuum, the i residue is taken up by 40 cm3 of a saturated solution of Na2CO3 ; and the mixture extracted by 4 x 10 cm3 of chloroform. The organic phases are combined and the solvent evaporatedv The residue recrystallised from a mixture of isopropyl oxide and benzene (1:1) gives 1.36g (79% yield) of 6-carbethoxy-8-ethyl-L0381!37~
5-oxo-2-(4'-methylpiperazinyl) -5,8-dihydro pyrido 12,3-d]
pyrimidine melting at two temperatures; 146C, solidification, then 158C.
Analysis for C17 H23 N5 O3 (M.W. = 345.39) C H N
Calculated % S9.11 6.71 20.~8 Found % 59.23 6.68 20.42 ~ he saponification of this esterr by addition of a solution of lN NaOH, with stirring at 50 - 60C for 2 hours 10 to ambient temperature and acidification to pH6 by acetic acid, gives 8-ethyl-5-oxo-2-~4'-methylpiperazinyl)-5,8-dihydro pyrido [2,3-d] pyrimidine 6-carboxylic acid ~M.P. = 227C).
r Analysis or C15 Hlg N5 O3 ~M.W. = 317.34) C H N
Calculated %56.77 6.04 22.07 Found % 56.69 6.23 22.35 ,~ Example 4 13g of6-carbethoxy-8-ethyl-2-methylsulphonyl-5-oxo-5, 8-dihydro pyrido [2,3-d] pyrimidine of example }, Sg of l-formyl 20 piperazine and 5.6g of triethylamine in 100 cm3 of isopropanol 5 ~ are stirred and heated for 2 hours at reflux during which the product of the reaction partially precipitates. After cooling~
the precipitate is filtered, washed with isopropanol and dried.
There is obtained 11.36g (80% yield) of 6-carbethoxy-8-ethyl-5-oxo-2-(4'formyl piperazinyl) -5,8-dihydro pyrido [2,3-d]
pyrimidine having two melting points, 198C, solidification, then 204C.
1~38~37~
Analysis for C17 H21 N5 O4 (M-W- = 359-38) C H N
Calculated (%) 56.81 5.89 19.49 Found (~) 56.97 5.95 19.58 3.6g of the formyl derivative are suspended in 25 cm3 of a 5% alcoholic solution of HCl. The dichlorohydrate of the formyl derivative precipitates after 8 hours of standing at ordinary temperature. It is taken up by 100 cm3 ether, then filtered, placed back in suspension in 40 cm3 of water, made alkaline by addition of Na2 CO3 then extracted with chloroform.
After evaporation of the solvent and crystallisation in 40 cm3 of a 1:1 mixture of isopropyl oxide-benzene, there is obtained 2.8g of 6-carbethoxy-8-ethyl-5-oxo-2-piperazinyl-5,8-dihydro pyrido ~2,3-d] pyrimidine, m.pt. = 156C, identical to the product of example 2.
Example 5 10.7g of 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydro pyrido [2,3-d~ pyrimidine (0.03 mole) described in example 1, 7.8g of ~ -hydroxyethylpiperazine ~0.06 mole) and 100 cm3 of isopropanol are heated to reflux for 2 hours. After cooling, the mixture is mixed with 50 cm of isopropyl oxide;
the precipitate is filtered, washed with 50 cm3 of a mixture of isopropanol (30 volumes)-isopropyl oxide (70 volumes). There i8 obtained 10.2g (91% yield) of 6-carbethoxy-8~ethyl-5-oxo~-2-t4'-( ~-hydroxyethyl) piperazinyl)-5,8-dihydro pyrido [2~3-d]
pyrimidine (m.pt. = 172C).
~38870 Analysis for C1~3 H25 N5 O4 (M.W. = 375.42).
C H N
Calculated % 57.586.71 18.60 Found 9~ 57.536.57 18.80 The saponification of this ester yields the corresponding acid; 10.2g of this ester and 40 cm3 of N ethanolic soda are stirred for 2 hours at ordinary temperature; the solution is neutralised by 2 cm3 of glacial acetic acid. The precipitate : ~ .
is filtered, washed with water and recrystallised from ethanol.
10 There is obtained 8.6g o~ 8-ethyl-5-oxo-2-(4~ hydroxyethyl) piperazinyl-5,8-dihydro pyrido [2,3-d] pyrimidine 6-carboxylic " .
acid (m.pt. = 222C).
Analysis for C16 H21 N5 04 (M.W. = 347.37) C H N
Calculated % 55.32 6.09 20.16 Found % 54.96 6.04 19~92 Example 6 .~
In a single-necked flask, provided with a reflux con-denser and an ammonia delivery tube, a suspension of 6.5g (0.02 20 mole~ of 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydro pyrido ~2,3-d] pyrimidine of example 1 in 40 cm3 of ethanol is heated to reflux under a rapid stream of NH3. The operation is continued until the melting point of the solid (initially 176C) reaches 265C, which takes about 4 hours.
The mixture is c ~d~ 8an7d mixed with 100 cm3 water.
The precipitate is filtered, washed with water and dried. There is obtained 3.04 g (57.5%) of 2-amino-6-carbethoxy-8-ethyl-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine, purified by recrystallisation in ethanol (m.pt. - 266C).
Analysis for C12 H14 N4 O3 (M.W. = 262.26) C H N
Calculated % 54.95 5.38 21.37 Found % 55 35 5'5~ 21.17 The saponification of this ester yields 2-am:Lno-8-ethyl-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine 6-carboxylic acid (m.pt. = 292C).
Example 7 1.6g of 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine and 1.6g of pyrrolidine in 20 cm3 of isopropanol are stlrred and heated to reflux.
After dissolution of the sulfone the reaction product precipitates rapidly. The heating is conti~ued for 1 hour, the mixture is cooled and the solid filtered and washed with 2 x 5 cm3 ethanol.
There is obtained 1.38g (92% yield) of 6-carbethoxy-8-ethyl-5-oxo-2-pyrrolidino-5,8-dihydro pyrido ~2,3-d] pyrimidine (m.pt =
202C~. -The saponification of this ester yields 8-ethyl-5-oxo-2-pyrrolidino-5,8-dihydro pyrido 12,3-d] pyrimidine 6-carboxylic acid (m.pt. = 314C).
Claims (16)
1. Method for the preparation of 8-substituted 2-amino-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine 6-carboxylic acids:
(IIIa) wherein R2 is a lower alkyl radical comprising 1 to 5 carbon atoms, and R and R', taken separately, may be identical or different and represent atoms of hydrogen or lower alkyl radicals comprising 1 to 5 carbon atoms or may together consistitute, with the nitrogen atom to which they are attached, a 5 or 6-membered heterocyclic ring, optionally containing a second heteroatom, selected from the group consisting of pyrrolidino, piperidino, p-hydroxypiperidino, morpholino, piperazino or N4-substituted piperazino, comprising reacting an 8-substituted 2-alkylsulfonyl-6-carbalkoxy-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine of formula (I):
(I) wherein R2 is as defined above and R1 and R3 may be identical or different and represent lower alkyl groups comprising l to 5 carbon atoms with an amine of formula:
in which R and R' are defined as above so as to obtain an 8-substituted 2-amino-6-carbalkoxy-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine of formula (III):
(III) and saponifying the ester (III) to obtain the corresponding acid (IIIa).
(IIIa) wherein R2 is a lower alkyl radical comprising 1 to 5 carbon atoms, and R and R', taken separately, may be identical or different and represent atoms of hydrogen or lower alkyl radicals comprising 1 to 5 carbon atoms or may together consistitute, with the nitrogen atom to which they are attached, a 5 or 6-membered heterocyclic ring, optionally containing a second heteroatom, selected from the group consisting of pyrrolidino, piperidino, p-hydroxypiperidino, morpholino, piperazino or N4-substituted piperazino, comprising reacting an 8-substituted 2-alkylsulfonyl-6-carbalkoxy-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine of formula (I):
(I) wherein R2 is as defined above and R1 and R3 may be identical or different and represent lower alkyl groups comprising l to 5 carbon atoms with an amine of formula:
in which R and R' are defined as above so as to obtain an 8-substituted 2-amino-6-carbalkoxy-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine of formula (III):
(III) and saponifying the ester (III) to obtain the corresponding acid (IIIa).
2. A method according to claim 1 wherein at least one of R1, R2 and R3 is an alkyl group of 1 or 2 carbon atoms.
3. Method according to claim 1 wherein the reaction between the alkylsulfonyl derivative (I) and the amine is carried out at a temperature between 60 and 120°C.
4. Method according to claim 1 wherein the reaction is carried out in a solvent having a suitable boiling point.
5. Method according to claim 4 wherein the solvent is a lower aliphatic alcohol having 1 to 5 carbon atoms.
6. Method according to claim 1 wherein the reaction is carried out using an excess of amine of 1.5 to 2 moles of the latter per mole of alkylsulfonyl derivative.
7. Method according to claim 1 wherein the reaction is carried out in the presence of a basic agent, such as a teriary aliphatic amine, in particular triethylamine.
8. Method according to claim 7 wherein the basic agent is a tertiary aliphatic amine.
9. Method according to claim 8 wherein the amine is triethylamine.
10. Method according to claim 1 wherein the 6-carbethoxy-8-ethyl-2-methylsulfonyl-5-oxo-5,8-dihydro pyrido [2,3-d] pyrimidine is reacted with piperazine in the form of a hexahydrate to obtain 6-carbethoxy-8-ethyl-5-oxo-2-piperazinyl-5,8-dihydro pyrido [2,3-d] pyrimidine which is saponified to obtain the corresponding acid.
11. Method according to claim 1 wherein the 8-substituted 2-alkylsulfonyl-6-carbalkoxy-5-oxo-5,8-dihydro pyrido [2,3-d] pyri-midine of formula (I) is prepared by the oxidation of an 8-substituted 2-alkylmercapto-6-carbalkoxy-5-oxo-5,8-dihydro pyrido [2,3-d] pyri-midine of formula (II):
(II) in which R1, R2, R3 are defined as above, by means of a mild oxidizing agent or a halogen or a compound able to liberate the halogen in the reaction medium.
(II) in which R1, R2, R3 are defined as above, by means of a mild oxidizing agent or a halogen or a compound able to liberate the halogen in the reaction medium.
12. Method according to claim 11 wherein the mild oxidizing agent is chosen from the group comprising potassium permanganate, potassium bichromate, hydrogen peroxide.
13. Method according to claim 11, wherein the halogen is chlorine acting in an aqueous medium.
14. Method according to claim 13, wherein the aqueous medium contains a solubilisation adjuvant constituted by a water-soluble organic solvent, such as a lower alcohol, in particular methanol or acetic acid, used at a concentration of 5 to 50%.
15. Method according to claim 11, wherein the compound able to liberate a halogen is an alkali metal hypochlorite or hydrogen peroxide acting on a hydrochloric acid.
16. Method according to claim 9, wherein the reaction is carried out at a temperature of between 0 and 25°C.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB11538/74A GB1484138A (en) | 1974-03-14 | 1974-03-14 | Pyrido pyrimidine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1038870A true CA1038870A (en) | 1978-09-19 |
Family
ID=9988077
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA222,321A Expired CA1038870A (en) | 1974-03-14 | 1975-03-14 | Pyrimidine derivatives |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS5929595B2 (en) |
| CA (1) | CA1038870A (en) |
| CH (1) | CH603642A5 (en) |
| CS (1) | CS193510B2 (en) |
| DD (2) | DD123606A5 (en) |
| DK (1) | DK152497C (en) |
| FR (2) | FR2299336A1 (en) |
| GB (1) | GB1484138A (en) |
| IN (1) | IN141366B (en) |
| NL (1) | NL7503113A (en) |
| RO (1) | RO65404A (en) |
| SE (1) | SE7502845L (en) |
| YU (1) | YU39114B (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3326118A1 (en) | 1982-08-02 | 1984-02-09 | Byk Gulden Lomberg Chemische Fabrik Gmbh, 7750 Konstanz | Pyridopyrimidinetriones, processes for their preparation, their use and medicaments containing them |
| NZ210847A (en) * | 1984-01-26 | 1988-02-29 | Abbott Lab | Naphthyridine and pyridopyrimidine derivatives and pharmaceutical compositions |
| US4851535A (en) * | 1985-01-23 | 1989-07-25 | Toyama Chemical Co., Ltd. | Nicotinic acid derivatives |
| JP2000232222A (en) * | 1999-02-10 | 2000-08-22 | Nec Corp | Manufacture of semiconductor device |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2194420B1 (en) * | 1972-08-02 | 1975-10-17 | Bellon Labor Sa Roger | |
| GB1451911A (en) * | 1972-08-14 | 1976-10-06 | Dainippon Pharmaceutical Co | 2-1-piperazino-5-oxopyrido-2,3,d-pyrimidine-6-carboxylic acids their preparation and pharmaceutical compositions thereof |
-
1974
- 1974-03-14 GB GB11538/74A patent/GB1484138A/en not_active Expired
-
1975
- 1975-02-27 FR FR7506182A patent/FR2299336A1/en active Granted
- 1975-03-12 RO RO7581614A patent/RO65404A/en unknown
- 1975-03-12 DK DK100275A patent/DK152497C/en not_active IP Right Cessation
- 1975-03-12 YU YU00600/75A patent/YU39114B/en unknown
- 1975-03-12 IN IN482/CAL/75A patent/IN141366B/en unknown
- 1975-03-13 SE SE7502845A patent/SE7502845L/xx unknown
- 1975-03-14 DD DD191319A patent/DD123606A5/xx unknown
- 1975-03-14 CH CH330175A patent/CH603642A5/xx not_active IP Right Cessation
- 1975-03-14 CA CA222,321A patent/CA1038870A/en not_active Expired
- 1975-03-14 NL NL7503113A patent/NL7503113A/en active Search and Examination
- 1975-03-14 DD DD184793A patent/DD120021A5/xx unknown
- 1975-03-14 CS CS751747A patent/CS193510B2/en unknown
- 1975-03-14 JP JP50030976A patent/JPS5929595B2/en not_active Expired
-
1976
- 1976-01-12 FR FR7600593A patent/FR2289507A1/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| SE7502845L (en) | 1975-09-15 |
| FR2299336B1 (en) | 1979-03-30 |
| JPS50129596A (en) | 1975-10-13 |
| YU39114B (en) | 1984-06-30 |
| IN141366B (en) | 1977-02-19 |
| CH603642A5 (en) | 1978-08-31 |
| CS193510B2 (en) | 1979-10-31 |
| GB1484138A (en) | 1977-08-24 |
| FR2299336A1 (en) | 1976-08-27 |
| NL7503113A (en) | 1975-09-16 |
| RO65404A (en) | 1980-06-15 |
| DD120021A5 (en) | 1976-05-20 |
| YU60075A (en) | 1982-02-28 |
| DD123606A5 (en) | 1977-01-05 |
| DK100275A (en) | 1975-09-15 |
| DK152497C (en) | 1988-08-01 |
| FR2289507A1 (en) | 1976-05-28 |
| JPS5929595B2 (en) | 1984-07-21 |
| DK152497B (en) | 1988-03-07 |
| FR2289507B1 (en) | 1978-11-10 |
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