CH496673A - Purazoles and pyrazolo-3 4-d-pyrimidines xanthine - Google Patents
Purazoles and pyrazolo-3 4-d-pyrimidines xanthineInfo
- Publication number
- CH496673A CH496673A CH13370A CH13370A CH496673A CH 496673 A CH496673 A CH 496673A CH 13370 A CH13370 A CH 13370A CH 13370 A CH13370 A CH 13370A CH 496673 A CH496673 A CH 496673A
- Authority
- CH
- Switzerland
- Prior art keywords
- amino
- product
- formula
- allopurinol
- reaction
- Prior art date
Links
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 title 2
- 229940075420 xanthine Drugs 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- FRBZBJHKHSVFNK-UHFFFAOYSA-N 3-amino-2-cyanoprop-2-enamide Chemical compound NC=C(C#N)C(N)=O FRBZBJHKHSVFNK-UHFFFAOYSA-N 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 3
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 2
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 abstract description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 abstract description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 201000005569 Gout Diseases 0.000 abstract description 3
- 108010093894 Xanthine oxidase Proteins 0.000 abstract description 3
- 102100033220 Xanthine oxidase Human genes 0.000 abstract description 3
- 238000001727 in vivo Methods 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 3
- QUKPALAWEPMWOS-UHFFFAOYSA-N 1h-pyrazolo[3,4-d]pyrimidine Chemical compound C1=NC=C2C=NNC2=N1 QUKPALAWEPMWOS-UHFFFAOYSA-N 0.000 abstract description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 abstract description 2
- 239000004202 carbamide Substances 0.000 abstract description 2
- 230000003647 oxidation Effects 0.000 abstract description 2
- 238000007254 oxidation reaction Methods 0.000 abstract description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 abstract 2
- 238000002955 isolation Methods 0.000 abstract 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 239000002798 polar solvent Substances 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 229960003459 allopurinol Drugs 0.000 description 5
- -1 ethoxymethylene Chemical group 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000013067 intermediate product Substances 0.000 description 3
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
- FFNKBQRKZRMYCL-UHFFFAOYSA-N 5-amino-1h-pyrazole-4-carbonitrile Chemical compound NC1=NNC=C1C#N FFNKBQRKZRMYCL-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- NMVVJCLUYUWBSZ-UHFFFAOYSA-N aminomethylideneazanium;chloride Chemical compound Cl.NC=N NMVVJCLUYUWBSZ-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- YPXGHKWOJXQLQU-UHFFFAOYSA-N ethyl 5-amino-1h-pyrazole-4-carboxylate Chemical compound CCOC(=O)C=1C=NNC=1N YPXGHKWOJXQLQU-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Process 3-Amino-4-carboxamidopyrazole (V) is used in the synthesis of pyrazolo (3,4-d)-pyrimidine derivs. such as Allopurinol (I). These compounds inhibit xanthine oxidase in vivo and are active in the treatment of gout and other conditions where the decrease of purine oxidation is desirable. The new process is more economical and gives a purer product even without isolation of (V). The first reaction between (II) and (III) is usually carried out in a polar solvent such as water or preferably lower alcohol, at room temperature. The product (IV) may be isolated but the preferred method is to react (IV) direct with hydrazine without isolation. Product (V) is isolated in very pure form and may be reacted with formamide to give Allopurinol (I) or with urea to give (VI).
Description
Verfahren zur Herstellung von 3-Amino-2-cyanacrylamid
Die Verbindung SHydroxypyrazolo-[3,4-d]pyrimi- din der Formel
EMI1.1
auch unter der Kurzbezeichnung Allopurinol bekannt, ist in der britischen Patentschrift Nr. 798 646 beschrieben, und ihre Wirksamkeit als Inhibitor der Oxydase von Xanthin in vivo, sowie ihr daraus folgender Wert für die Behandlung von Gicht und anderer Kankheiten, wo die Oxydation von Purinen zurückgedrängt werden soll, wurden aus der britischen Patentschrift Nummer 975 850 bekannt.
Allopurinol wurde bisher mit Hilfe verschiedener Verfahren hergestellt, von denen die folgenden wichtig sind: a) Ein Dreistufenverfahren, bei welchem erst aus Äthoxymethylenmalondinitril und Hydrozin gemäss folgender Gleichung 3 -Amino-4-cyanpyrazol gewonnen wird:
EMI1.2
Die Verbindung der Formel IV wird zu 3-Amino4-carboxamido-pyrazol der Formel
EMI1.3
partiell hydrolysiert und durch die Umsetzung der Verbindung der Formel II mit Formamid wird das Allopurinol gewonnen; b) Ein Zweistufenverfahren, bei welchem man erst Äthoxymethylencyanessigs äureäthyl- ester mit Hydrazin zu 3-Amino-4-carbäthoxypyrazol gemäss der Gleichung
EMI1.4
umsetzt, worauf man durch die Umsetzung der Verbindung der Formel III mit Formamid das Allopurinol erhält.
Die Verbindung der Formel II ist auch wertvoll als Ausgangsstoff für die Herstellung anderer Derivate von Pyrazolo-[3,4-d]pyrimidin. Man kann z. B. durch die Umsetzung von 3-Amino-4-carboxamido-pyrazol der Formel II mit Harnstoff 4,6-Dihydroxypyrazol > [3,4-d]- pyrimidin der Formel
EMI1.5
herstellen. Diese Verbindung ist, in ähnlicher Weise wie das Allopurinol, ein Inhibitor der Oxydase von Xanthin in vivo, kann also zur Behandlung der Gicht verwendet werden.
Man kann das 3-Amino-4-carboxamidopyrazol nach einem Verfahren herstellen, welches aus zwei Stufen besteht, indem man (A) Formamidin (V) mit Cyanacetamid (VI) gemäss folgender Gleichung
EMI2.1
zu 3-Amino-3-cyanacrylamid (VII) umsetzt und (B) das 3-Amino-2-cyanacrylamid der Formel VII mit Hydrazin gemäss der Gleichung
EMI2.2
umsetzt.
Es wurde aber gefunden, dass die Umsetzung (A) unerwarteterweise schon bei Zimmertemperatur oder gar bei noch tieferen Temperaturen sehr rasch vor sich geht. Dies war nicht zu erwarten, da bei den bekannten, formell analogen Verfahren die Umsetzung nur bei die Zimmertemperatur um etwa 1000 C übersteigenden Temperaturen schnell vor sich geht. Unter Zimmertemperaturen versteht man die zwischen 16 und 250 C liegende Temperatur.
Bei der Durchführung der Umsetzung (A) verwendet man zweckmässig ein Lösungsmittel, vorzugsweise eine polare Flüssigkeit, wie Wasser oder einen niederen Alkohol, z. B. Athanol. Die Reaktion verläuft in Wasser etwas schneller, aber bei Verwendung von Äthanol gewinnt man ein reineres Produkt.
Die Umsetzung (B) kann man mit dem isolierten Zwischenprodukt der Formel VII durchführen oder man kann die beiden Verfahrensschritte (A) und (B) zusammenfassen, ohne das Zwischenprodukt der Formel VII zu isolieren, und diese zweite Variante ist empfehlenswert. Man erhält bei dieser das 3-Amino-4 carboxamidopyrazol der Formel II in sehr reiner Form mit einer Ausbeute von etwa 80 % der Theorie. Der Umstand, dass man das Zwischenprodukt nicht zu isolieren braucht, verleiht den Verfahren A) und B) eine Überlegenheit über die eingangs erwähnten bekannten Herstellungsverfahren a) und b). Beim bekannten Verfahren a) erhält man ohne Isolierung der Zwischenprodukte ein sehr unreines 3-Amino-4-carboxamidopyrazol. Beim Verfahren b) ist die Ausbeute an 3-Amino Scarbäthoxypyrazol sehr schlecht, wenn man das Zwischenprodukt nicht isoliert.
Die vorliegende Erfindung schafft ein Verfahren, das im Vergleich zu den bekannten Verfahren wirtschaftlicher ist und ein reineres Produkt liefert. Die Verbindung der Formel I muss in sehr reiner Form gewonnen werden, da sie an Kranke verabfolgt wird, die chronische Leiden haben. Die Herstellungskosten und die Ausbeute an den Zwischenprodukten sind von geringerer Bedeutung als die Anwesenheit von Verunreinigungen, die man aus dem Endprodukt sehr schwer entfernen kann.
Bekannte Verfahren zur Herstellung von 3-Amino Scarboxamidopyrazol der Formel II liefern gute Ausbeuten, aber das Produkt ist mit Spuren von Fremdstoffen verunreinigt. Diese verbleiben nach der Über- führung des 3-Amino-4-carboxamidopyrazols in das Allopurinol (I), das von diesen nur sehr schwer befreit werden kann. Demgegenüber liefert das erfindungsgemässe Verfahren zur Herstellung von 3-Amino-2-cyanacrylamid, welches oben als Verfahren (A) bezeichnet ist, ein Produkt in sehr grosser Reinheit, das auch ohne isoliert zu werden, zur Herstellung der Formel II verwendet werden kann.
Beispiel 3 -Amino-2-cyanacrylamid
Zu einer Lösung von 5,94 g Natriummethoxyd in 50 ml Äthanol gibt man 10,0 g Formamidinhydrochlorid und rührt das Gemisch 15 Minuten bei Zimmertemperatur. Es wird dann filtriert, bis es salzfrei ist.
Zu dem Filtrat werden 8,4 g Cyanoacetamid zugesetzt und das Reaktionsgemisch 1 Stunde bei Zimmertemperatur gerührt. Das 3-Amino-2-cyanacrylamid, welches sich absetzt, wird gesammelt und mit 25 ml Äthanol gewaschen. Gewicht 7,6 g. Das Filtrat liefert nach Kühlen auf 50 C 1 weiteres Gramm des Produkts.
Gesamtgewicht 8,6 g (77,5 %ige Ausbeute), Schmelzpunkt 185-1860C.
Process for the preparation of 3-amino-2-cyanoacrylamide
The compound SHydroxypyrazolo- [3,4-d] pyrimidine of the formula
EMI1.1
Also known under the abbreviation Allopurinol, is described in British Patent No. 798 646, and its effectiveness as an inhibitor of xanthine oxidase in vivo, and its consequent value in the treatment of gout and other diseases where the oxidation of purines is suppressed are known from British patent specification number 975,850.
Allopurinol has so far been produced with the help of various processes, of which the following are important: a) A three-stage process in which 3-amino-4-cyanpyrazole is first obtained from ethoxymethylene malondinitrile and hydrozine according to the following equation:
EMI1.2
The compound of formula IV becomes 3-amino4-carboxamido-pyrazole of formula
EMI1.3
partially hydrolyzed and the reaction of the compound of formula II with formamide gives the allopurinol; b) A two-stage process in which ethyl ethoxymethylene cyanetate is first converted with hydrazine to give 3-amino-4-carbethoxypyrazole according to the equation
EMI1.4
reacted, whereupon the allopurinol is obtained by reacting the compound of formula III with formamide.
The compound of formula II is also valuable as a starting material for the preparation of other derivatives of pyrazolo- [3,4-d] pyrimidine. You can z. B. by reacting 3-amino-4-carboxamido-pyrazole of the formula II with urea 4,6-dihydroxypyrazole> [3,4-d] - pyrimidine of the formula
EMI1.5
produce. Similar to allopurinol, this compound is an inhibitor of xanthine oxidase in vivo, so it can be used to treat gout.
The 3-amino-4-carboxamidopyrazole can be prepared by a process which consists of two stages by converting (A) formamidine (V) with cyanoacetamide (VI) according to the following equation
EMI2.1
to 3-amino-3-cyanoacrylamide (VII) and (B) the 3-amino-2-cyanoacrylamide of the formula VII with hydrazine according to the equation
EMI2.2
implements.
However, it has been found that the reaction (A) unexpectedly takes place very quickly even at room temperature or even at even lower temperatures. This was not to be expected, since in the known, formally analogous processes, the reaction only proceeds rapidly at temperatures exceeding room temperature by about 1000 ° C. Room temperature is understood to mean the temperature between 16 and 250 C.
When carrying out reaction (A), a solvent is advantageously used, preferably a polar liquid such as water or a lower alcohol, e.g. B. Ethanol. The reaction is a little faster in water, but using ethanol you get a purer product.
The reaction (B) can be carried out with the isolated intermediate of the formula VII or the two process steps (A) and (B) can be combined without isolating the intermediate of the formula VII, and this second variant is recommended. This gives the 3-amino-4-carboxamidopyrazole of the formula II in very pure form with a yield of about 80% of theory. The fact that the intermediate product does not need to be isolated gives processes A) and B) a superiority over the known production processes a) and b) mentioned at the outset. In the known process a), a very impure 3-amino-4-carboxamidopyrazole is obtained without isolating the intermediate products. In process b) the yield of 3-amino-scarbethoxypyrazole is very poor if the intermediate is not isolated.
The present invention provides a process which, compared to the known processes, is more economical and provides a purer product. The compound of the formula I must be obtained in a very pure form, since it is administered to sick people who have chronic ailments. The manufacturing costs and the yield of the intermediate products are of less importance than the presence of impurities which are very difficult to remove from the final product.
Known processes for the preparation of 3-amino scarboxamidopyrazole of the formula II give good yields, but the product is contaminated with traces of foreign substances. These remain after the conversion of the 3-amino-4-carboxamidopyrazole into the allopurinol (I), which can only be freed from them with great difficulty. In contrast, the process according to the invention for the preparation of 3-amino-2-cyanoacrylamide, which is referred to above as process (A), provides a product in very high purity which can also be used to prepare the formula II without being isolated.
Example 3 - Amino-2-cyanoacrylamide
10.0 g of formamidine hydrochloride are added to a solution of 5.94 g of sodium methoxide in 50 ml of ethanol and the mixture is stirred for 15 minutes at room temperature. It is then filtered until it is free of salt.
8.4 g of cyanoacetamide are added to the filtrate and the reaction mixture is stirred for 1 hour at room temperature. The 3-amino-2-cyanoacrylamide which settles out is collected and washed with 25 ml of ethanol. Weight 7.6 g. After cooling to 50 ° C., the filtrate yields 1 more gram of product.
Total weight 8.6 g (77.5% yield), melting point 185-1860C.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB31690/66A GB1200444A (en) | 1966-07-14 | 1966-07-14 | The preparation of pyrazoles and pyrazolopyrimidines |
| CH976767A CH485731A (en) | 1966-07-14 | 1967-07-10 | Process for the preparation of 3-amino-4-carboxamidopyrazole |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH496673A true CH496673A (en) | 1970-09-30 |
Family
ID=25705290
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH13370A CH496673A (en) | 1966-07-14 | 1967-07-10 | Purazoles and pyrazolo-3 4-d-pyrimidines xanthine |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH496673A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1985000598A1 (en) * | 1983-07-29 | 1985-02-14 | Commonwealth Scientific And Industrial Research Or | Herbicidal crotonic acid derivatives, their preparation and compositions containing them |
-
1967
- 1967-07-10 CH CH13370A patent/CH496673A/en not_active IP Right Cessation
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1985000598A1 (en) * | 1983-07-29 | 1985-02-14 | Commonwealth Scientific And Industrial Research Or | Herbicidal crotonic acid derivatives, their preparation and compositions containing them |
| GB2156811A (en) * | 1983-07-29 | 1985-10-16 | Commw Scient Ind Res Org | Herbicidal crotonic acid derivatives their preparation and compositions containing them |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |