DE2061430A1 - 4 mercaptopyrazolo square bracket on 3.4 square bracket to pyrimidine and method of making the same ben - Google Patents

Description

DR. HANS ULRICH MAY

D 8 MUNICH 2, OTTOSTRASSEIa

TELEGRAMS: MAYPATENT MUNICH

bd / lh Munich, 14. December 1970

———- Dr.M./m

S-21-P-6/917

Sapchim-Fournier-Cimag S.A. in Paris / France

4-Mfercaptopyrazoio- ^ "3f4-d_7 ^> -pyrimidines and Process for their Preparation

. The invention relates to 4-Mercaptopyraaolo _i / ~ 3 _t 4-dJ7pyriraidine ^s and in particular those corresponding to 'which of the following general formula:

SR ₃

(I)

before in R ₁ , R ₂ both an alkyl, aryl, aralkyl, cycloalkyl, acyl,. Arylsulfonyl or heterocyclic radical and R _{3 is} an alkyl, aryl, aralkyl, cycloalkyl or heterocyclic radical. Several synthesis routes for the preparation of 4-mercapto-pyrazolo-3, 4-d 7-pyriidiaes are already known.

These Synthesevege must include the cyclization and sulfidation of the non-sulphurized 3 and 4-position disubstituted pyra25ols guarantee. All of these procedures have in common that the

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_2 ^ 206U30

Sulfurization is not the first stage of the synthesis and <3aaa they are generally carried out by OCE cyclization or a in the course of the sulfurization cycliaierenden Vy razol intermediate ,,

As a result, these synthetic routes usually lead to relatively "moderately complicated manufacturing processes, which involve intermediate products which must preferably be isolated9 in order to eliminate by-products and 4-Mereaptopyrazo-Io {3e4 <~ 4 / pyrimdine of sufficient purity to produce with acceptable yield on an industrial scale »

The invention aims at a process which enables a simplified preparation of any 4-mercaptopyrazolo- £ 3 _s 4-dJpyrimdine corresponding to the general formula (I) given above.

The inventive method is characterized in that in a first stage a 3-amino-4 '~ cyano-pyrazole general formula:

(II)

by means of a definition of the general formula:

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206U30

R ₃ SH (III)

is sulfurized, where in the general formulas R ^ »Rg and R_ have the same meanings as above to get a 3-amino-4 thioatnido-pyrazole of the general formula:

to produce, and that in a second stage the cyclization this 3-amino-4-thioamido-pyrazole by means of a suitable Cyclisierungamittela is carried out «

In this process according to the invention, "in which the suIfurierung takes place before the cyclization »can be the required Carry out operations relatively easily "

In particular, the two stages of this process can be and the same reaction medium without isolation of the intermediate product 3-atninc-4-thioamido-pyra formed on the spot: zols are carried out, which is another advantage of the invent in accordance with. Procedural means.

For this purpose and according to a preferred embodiment the process is the sulfurization of the i-amino ^ -cyano-pyrazole, that is, the action of a sulfur compound of the general formula R, SH, such as hydrogen sulfide or a

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SAD 0RI6WAL

OQ Q. Γ21

aliphatic, aromatic, cycloaliphatic or arylaliphatic Mercaptan, on said pyrazole in the presence carried out by sodium methyl glycolate dissolved in methyl glycol,

This alcoholate and this solvent, which have the purpose to fix the required for the reaction sulfur compound temporarily, have the advantage of a subsequent work in aitu at fairly high! Temperature, for example, 120 to 125 ⁰ C, allow au as to admissible rapid cyclization of the 3-amino-4-thioamido-pyrazole formed as an intermediate is required »

Although it is known to use alcoholates and in particular sodium ethylate and methylate to fix a sulfur compound which is used in any reaction, for example in a reaction with a nitrile, the alcohol in which it is dissolved must then be removed in order to be able to increase the temperature of the reaction mixture ₀

The use according to the invention of dissolved in methyl glycol Sodium methyl glycolate avoids this disadvantage.,

In summary, the first stage of the process according to the invention takes place Process, that is, the one necessary for sulfurization Bonding of the hydrogen sulfide or a thiol to the nitrile function in the 4-position of the pyraeol nucleus according to the following Reaction scheme

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B: »G
H

(D

SH

HN

H ₂ R.

Civ)

.R,

Bie second Bfcufe of the inventive method, the heisat the cyclization of the 3 ~ amino "4 ~ thioäinido ~ pyra2ols _y can by any Cyclisierungsmittela, in particular with the aid of üthylorthoformiat be made as described by BoC A ₀ Uq Killoi" and S _P Vromon in Tetrahedron 196? » 2 ^. ( ² ) t described

According to a preferred embodiment of the invention The JPormamid is used as an oiling agent for the process Gyeliaierung dea i'-Aminö-i-bhloassiido-pyrazols used ^

This second process purchase then proceeds according to the following Heaction scheme ί

HK * QlH ■ J JIl lll'l - | - lip

αι. — I »I l ·

H

- I I

HCOKH

(ν)

H ₂ O + NH ₅

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_fi 206H30

β> ö »

In this reaction scheme, the formamide is represented by the formula (V) reproduced. "

It has been found da8S formamide, which has been never vorgesehlagen as Oyclisierungsmittel of '5-amino "4 thioamiäo-pyrazole, compared to other known Cyclisierungsmitteln and especially the numerous benefits Äthylorthoformiat has ₀

Above all, it enables work to be carried out without isolating any intermediate products, while the use of ethyl orthoformate, for example, first requires the preparation of the ethoxyraethylene amine and preferably its isolation from the reaction mixture _{or the like}

In addition, the use of formamide does not lead to the same as that of the Äthylorthoforraiafcs z, u side reactions, and the final product obtained therefore contains fewer impurities and is easier to clean

Finally, the final yield of pure product is considerably higher if formamide is used as the cyclizing agent instead of ethyl orthoformate _a

The process according to the invention is of course suitable for the production of any ^ mercapto-pyrazolone ^ -ajpyrimidines, which correspond to the formula (I) given above, and particularly advantageously leads to the production of previously unknown and isolated 4-foercapto-pyrazolo t, 3i4 "» cQpyrimidiQen _e

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The invention therefore also relates as new substances to the i-heptyl-3-ben8yl-4-mercapto «pyrezolo-C3 _i 4-dJpyrimidine (for which in the formula (I)

R ₁ »n - C 1 H ₁ C;

R ₂ * C ₆ H ₅ -CH ₂ ;

R ₃ »Η,

as well as the 1-paratoluenesulfonyl «3-isobutyl ~ 4-mercapto-pyraeolo- £ 3f4-d] pyriraidin, for which in the formula (I)

R ₂ * -CH ₂ -CH- (CH ₃ ) ₂ and R ₃ * H
mean ₀

Like the other well-known 4-mercaptopyrazolo-i.3 »4-4 / Py ^r i ^m i ^ö i ^ne, these new products have an analgesic and diuretic effect and have the property of inhibiting the formation of uric acid. They can therefore be used for treatment of gout and general rheumatic diseases c

The two new products can thus individually or in recipes as a drug for the specified purposes _P and the invention also includes such drugs "

The inventive method is illustrated by the following examples ",

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m » O -

example 1

Manufacture of 4 "mercapto-pyrazolo- £ 3f4 ~ dJpyrimiaift

(R ₁ s R ₂ β R ₃ = H)

In a clean and dry 1 1 reaction vessel 147j) O g of methyl glycol given *

The mixture is warmed with stirring and 14.0 g of methylglycol are slowly distilled ab »This distillation is used to dry the methyl glycol by removing the water in the azeotrope mixed in order to be able to import sodium later "

It is allowed to cool to 40 ° and 11 »1 g of sodium are added and refluxed for 30 min,

It is then cooled to 60 ° C. and 47 * 5 g of 3-amino-4i-eyano-pyraaol are added. The apparatus is flushed with nitrogen in order to work in an atmosphere niehtexploeiven _s and are initiated by a dipping Rohree 22.4 g of hydrogen sulfide into the reaction mixture and absorbed there "

The reaction mixture is stirred for 1 hour and then flushed with nitrogen to avoid the malodorous and completely expel toxic hydrogen sulfide »

100 g of formamide are then added and the mixture is <Ue heated with stirring and reflux for 4 hours and let down Poured into 300 g of deionized (purified) water.

The product obtained is then cleaned «

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According to a preferred embodiment, this cleaning is carried out by passing the product over decolorizing carbon, which, however, requires a previous complete solution of the product * "This dissolution is preferably carried out by a treatment with sodium hydroxide, which the respective 4-mercaptopyrazolor3 _P 4" dJpyrimidine is converted into the completely soluble corresponding motrium mercaptide,

As a modification, the dissolution can be achieved by recrystallization in a suitable organic solvent «

Is so add to the obtained Realctionsgeraisch a AUB 16 g of sodium hydroxide and 100 g of water solution of caustic soda produced "until a fluid and homogeneous mixture is obtained, 'then be 3 ₈ 5 g of decolorizing carbon (CMCA5O3) added The mixture is stirred for 2 hours at 20 ⁰ C, whereupon the decolorizing carbon is filtered off »

The filtrate is acidified with 385 g of 10% sulfuric acid to a pH between 2 and 3 in order to bind the alkali and thus separate out the 4 "mercapto" pyraaolo "/ 3 ₉ 4-dJpyrimidine. Centrifuging or filtered off at room temperature, the separated product is washed with 25Og salt-free water to the still retained free sulfuric acid to remove, and dried at 80 ⁰ C ₀

The product is obtained as a solid white substance in an amount of 63 »5 to 66.8 g (95 to 100 % yield)«

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206H30 - ίο -

Analysis values of the product;
Sulfur content: 2O _s 95 # (theoretical 21 acid titre: 99.8%
Melting point:> 36O ⁰ C (with decomposition)

Example 2

Production of 1 ~ propyl-4-mercapto-pyrazolo ~ f3f4- & fpyrimidine (R ₁ * nC * H «; R ₂ - R ^« H)

^ In a 2 1 Reatctionsgefäs.s 300 g methyl glycol are added and dried by azeotropic distillation "22.2 g of sodium at 35 ⁰ C is then added for 30 minutes at 60 ° C heated to reflux, whereupon 132 g of 2-propyl 3-amino-4 ~ eyanopyrazole can be added «

The reaction vessel is flushed with nitrogen, and 44 _f Ö g of hydrogen sulfide are introduced into the reaction device and absorbed there. "It is stirred for 1 hour and then flushed again with nitrogen",

200 g of formamide are added and the mixture is heated under reflux with stirring for 4 hours. Then the reaction mixture placed in 600 g of deionized water and one made of 32 g of sodium hydroxide and 200 g of water prepared alkali solution was added to convert the mercaptan to form the sodium mercaptide in to dissolve in an aqueous medium ^

T ₉ O g Entfa'rbungekohle be zugeeetst, and it is stirred for 2 hours at 20 C ^p. The decolorizing carbon is filtered off

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The filter was then acidified by adding 790 g of 10% sulfuric acid to pH 2 to 3. Bsn separates aas product. Room temperature by centrifugation or filtration, it was washed with 500 g of salt-free water and dried at 75 to 85 ⁰ O ₀

The product obtained in this way is 165> 6 g of a solid, white, yellow « shimmering fabric (yield 97 #) ο

Analysis values of the product:
Sulfur content: 16 _f 50 % (theoretical 16.49 %>) acid titer. I 99 ₉ 7 %
Melting point: 210 to 212 ⁰ C *

Example 5 Production of l-Hgptyl-3 "bengyl ~ 4 ~ meroapto-pyragolo« »C5,4-fll

pyrimidine

(R ₁ * nC ™ H ₁₅ ? H ₂ * OgHc - OH ₂ ~ j H ~ »H)

90 g of methyl glycol are dried by distilling off the azeotrope * 5 »6 g of sodium are added and the mixture is heated under reflux for 30 minutes * The reaction mixture is ^{cooled to 60 0} O, and 65.1 g of 2-heptyl-3-amino-4 -cyano-5-benayl-pyrazoi are added.

After flushing the apparatus with nitrogen, 11.2 g of hydrogen sulfide are obtained initiated and absorbed "This is followed by an hour. Then "flushed with nitrogen, and 50 g of formamide are added * It is under for 4 hours Stir and reflux,

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The reaction mixture is poured into 200 g of salt-free water, and an aqueous alkali solution, which is prepared from 8.8 g of sodium hydroxide and 70 g of water, is added Dareaf with stirring for 3 hours at room temperature with 2 g of decolorizing charcoal (C £ CA 50 S) treated «The decolorizing carbon is filtered off, and it is acidified to pH 2.5 with 190 g of 10 # sulfuric acid. The precipitated product is separated off, washed with 200 g of water and ^{dried at 80 °} C. *

The product obtained is 70.3 g of a pale yellow, solid substance (yield 94%) or the like

Of the product's analysis values?

Sulfur content: 9 _r 35 $ (theoretically 9 * 41 $) Acid titer: 99.1? Ό

Melting point:> 305 to 307 ⁰ C (with decomposition) «

Example 4

Production of the l-p-toluene-sulfonyl-3-iBobutyl-4-mercapto- «- ^> 4-d? pyrimidine »

(R ₁ = P-CH ₅ -C ₆ H ₄ -SO ₂ -; R ₂ «CH ₂ -CH- (CH ₃ ) ₂ ; R ₅ = H)

300 g of methyl glycol are dried by distilling off the first runnings, and 11.2 g of sodium are added. The mixture is then heated under reflux for 30 minutes. After cooling the mixture to 6O ⁰ C 140 g 2 ~ p ".Toluol8ulfonyl-3 'amino-4-oyano-5 added to ~ 1-isobuty py.razol -

It is flushed with nitrogen while stirring, and then 22 _E i> g öohwftfei.w / iotte.vst.off are introduced and absorbed »

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BAD ORfQJNAL

After completion of the introduction of the hydrogen sulfide is further stirred for 1 hour. and 100 g of formamide are added »with stirring, and reflux is heated for 5 hours

The reaction mixture is poured into 600 g of deionized water, and an aqueous alkali solution ₉ made from 18 g of sodium hydroxide and 150 g of water is added. With stirring for 2 Gtunden is treated at 40 ⁰ C with 5 g of decolorizing carbon (50 CBCA SL) long., The mixture is then filtered and the decolorizing carbon g 390! The above sulfuric acid to pH <2.5 to 3E0 acidified, the product is separated off "with Water blown until the washing water is neutral, and dried at 70 ° C

The product obtained is 152 "9 g of a white, pale greenish powder (yield 96?") _{Or similar}

Analysis values of the product;

Sulfur content: 17 _S T55 & (theoretically 17> 68 #) Acid titer: 99 _S 6 ^

Schmelzpunkti y 305 to 3O7 ° C (with decomposition)

Example 5

Manufacture, from 4-Ithjrl ^ mercapbo> »p _t yra ^ olpp ^ -djpyrimldin (H ₁ * Hg« H i H ₅ s C ₂ H ₅ -)

In a 1 1 Reaktlonsgeffiaa 150 g methyl glycol warden added and dried "by azeotropic Deotlllation After cooling to 30 ⁰ C 1I I ₃ g of sodium is added and it is ^ 30 for minutes

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-14- 206U30

th refluxed

After cooling to 6O ⁰ C 47 _S 5 g of 3-amino "4 ~ cyano ~ pyraaol added * Next 27 ₉ 3 g of ethylmercaptan was added, and the mixture is heated for 2 hours with stirring at 65 to 7O ⁰ C,

Then 100 g of formamide are added, and it is under Stir and Rüokfluss heated for 7 hours "

The reaction mixture is poured into 500 g of deionized water, separated off and washed with v / aaser. The product obtained is recrystallized from a Yvasser-ethanol mixture (weight ratio 60/40) or another organic solvent and treated with decolorizing charcoal. It is then filtered off and dried at 70 ⁰ C

The product obtained is 75-2 g of white crystal pieces (yield

Analysis values of the product;
Sulfur content: 17 ₉ 92 £ (theoretically 17.775 ") Melting point: 161 to 163 ° C _O

In Examples 1 to 5 given above, formamide was used as Used cyclizing agents

In the following example, ethyl · - ^: orthoformate is used as the cyclizing agent

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2061 A 30 «· 15 <=

Example 6

Production of 4-mercapto-pyragolof5 «4-äJpyrimiain (H ₁ - H ₂ = R ₅ = H)

In a 3 1 Reaktionsgefäae 441 g methyl glycol are given sub HUhren slowly 42 _f O g Hethylglykol are distilled off * It is cooled to 40 to 5O ⁰ C, 33.3 sodium g asugefügt, and it is heated for 30 minutes' refluxing, after cooling to 60 ⁰ C. 142.5 g of 3-amino-4-eyanc-pyra2ol added

The apparatus is flushed with nitrogen, and with the help of a 67s2 S hydrogen sulfide is introduced into the reaction mixture and absorbed there »

The mixture is then stirred for 1 hour, flushed with nitrogen, and 1000 g of ethyl orthoformate are added

The mixture is heated for 6 hours with stirring and reflux, and the excess reagents are distilled off under reduced pressure. The distillation residue is poured into 900 g of distilled water. An alkali solution is then added, which is prepared from 48 g of sodium hydroxide and 300 g of water is to obtain a homogeneous liquid mixture. The solution obtained is stirred at 20 ° 0 for 3 hours treated with 10 g decolorizing carbon (CECA 50 S)

The decolorizing carbon was then filtered off and the _P Piltrat is 1155 g lO ^ sulfuric acid to a pH between

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2 and 3 acidified. At room temperature, the product filtered off washed with 750 g of distilled water at 80 ⁰ C of the product is abfiltrlerit, dried, yielding 150 g is obtained, "

Bieses product is still strongly colored yellow and must be purified again by dissolution in an alkali solution and treatment with a decolorizing "Dos carried out by dissolving in an aqueous alkaline solution of 45 g of sodium hydroxide and 280 g of distilled Wassere is then for 3 hours at 25 to 30 ⁰ C treated with 10 g decolorizing carbon (CJCA 50 S). The decolorization charcoal is filtered off and the piltrate is acidified with 10% sulfuric acid to a pH between 2 and 3. The product is filtered off at room temperature, 'ater washed with 750 g of distilled "and dried at 80 ⁰ C.

The product obtained is 130 g of an amorphous, pale yellow powder (yield 65 $) having a melting point ^ 36O ⁰ C (with decomposition) "

SAD ORiGINAL
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Claims (1)

ι · ■■■ i: .. ^ p: ij »T" n "'! i:! ii !: ¹ ! li | H | ■. · ■■! ■■ # ■■■ '■■ . 17-206U30 Claims Process acid production of ^ "Mercapto-pyrazolo - ^^ - dy pyrimidines of the general formula: where R ^ and Rg alkyl · », aryl, aralkyl, cycloalkyl, Acyl, arylsulfonyl or heterocyclic radicals, and R, an alkyl, _s aryl, aralkyl, »cycloalkyl or heterocyclic radical, characterized in that in a first stage a 3-amino-4-eyano ~ pyras5ol of the general formula : N ■ »C» «^ ~ -> ~ - ™ .R ₂ H ₂ N «-J 1 R ₁ wherein Rj and Rg have the meanings given above, by treatment with a sulfur compound of the general formula R ^ SH, where R- * has the meaning given above, is sulfurized to obtain a 3-amino ~ 4-thioamidopyrazole, and in one the second stage of this 3-amino-4-thloamido-pyrazole is cyclized with the aid of a cyclization agent _D 109826/1928 SAD ' 206U30 Method according to claim 1, characterized in that Isolation of its two stages is carried out in the same reaction family without / of the 3-amino-4- thioamido-pyrazoleB formed in this as an intermediate product 3a Method according to one of claims 1 or 2, characterized in that the sulfidation of the 3-amino-4-cyanpyrazola is carried out in the presence of sodium methyl glycolate dissolved in methyl glycol « ο Method according to one of Claims 1 to 3, characterized in that daas as a cyclizing agent for the cyclization of the 3-amino-4-thioamido-pyrazole formamide is used ο 5ο method according to one of claims 1 to 3 »characterized in that that as a cyclizing agent aur cyclization of 3-amino-4-thioamido-pyrazole ethyl orthoformate is used· 6ο Method according to one of claims 1 to 5 »characterized in that the product obtained is purified by dissolving it by adding a base, treating with decolorizing charcoal, acidifying the solution, separating and washing the product obtained, or by recrystallization in an organic solvent and treatment with decolorizing charcoal« , 109826/1928 J ₁₉ . 206U30 7.1-heptyl 3-benzyl 4-mercapto pyrazolo / "3,4-d_J7pyr iraidin. 8.1 "p-Toluenesulfonyl-3-isobutyl-4-mercaptopyrimidine. 9 «Medicinal products with a content of or consisting of one the pyrimidines according to claim 7 or 8. 109826/1928 tJFHOlNAL INSPECTED