CS273780B1 - Method of 2, 3-0 -isopropyliden -9-/rs/2,3-dihydroxypropyl/adenine preparation - Google Patents
Method of 2, 3-0 -isopropyliden -9-/rs/2,3-dihydroxypropyl/adenine preparation Download PDFInfo
- Publication number
- CS273780B1 CS273780B1 CS821088A CS821088A CS273780B1 CS 273780 B1 CS273780 B1 CS 273780B1 CS 821088 A CS821088 A CS 821088A CS 821088 A CS821088 A CS 821088A CS 273780 B1 CS273780 B1 CS 273780B1
- Authority
- CS
- Czechoslovakia
- Prior art keywords
- adenine
- dihydroxypropyl
- preparation
- isopropylidene
- isopropyliden
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 5
- 238000000034 method Methods 0.000 title claims description 7
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 title abstract description 11
- 229930024421 Adenine Natural products 0.000 title abstract description 11
- 229960000643 adenine Drugs 0.000 title abstract description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims abstract description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 7
- 238000009835 boiling Methods 0.000 claims abstract description 5
- BNPOTXLWPZOESZ-UHFFFAOYSA-N 4-(chloromethyl)-2,2-dimethyl-1,3-dioxolane Chemical compound CC1(C)OCC(CCl)O1 BNPOTXLWPZOESZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 3
- 238000005804 alkylation reaction Methods 0.000 claims description 7
- 230000029936 alkylation Effects 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 2
- 239000003054 catalyst Substances 0.000 claims 2
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 238000000746 purification Methods 0.000 claims 1
- 238000004809 thin layer chromatography Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- 208000009889 Herpes Simplex Diseases 0.000 abstract 1
- 239000013067 intermediate product Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- -1 isopropylidene-p-toluenesulfonyloxy-dihydroxypropane Chemical compound 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
1 CS 273700 01
2',3'-0-Isoprapyliden-9-(RS)-(2,3~dihydroxypropyl)adenin strukturního vzorce I
II II
C CH
CH-- CH —CH 0 o\ / c / \
je klíčovým meziproduktem přípravy 9-(RS)-(2,3-dihydroxypropyl)adeninu. Tato látka se|irm?(vrt vo farmacii vn formě gólu k léěení horpeo simplex, V literatuře je popsána příprava žádané látky několika způsoby. Tak v práci A. Ho-lého: Coll. Czech. Chem. Com,· 43, 3, 103 (1978) se zahřívá sodná sůl adeninuy vznikláreakcí adeninu s hydridem sodným, s isopropyliden-p-toluensulíonyloxy-dihydroxypropanernv dimethylformamidu při 100 °C a 15 h zahřívání. Tento postup, který pracuje s hydridemsodným Je z bezpečnostní ho hledisku pro výrobu nepoužitelný.
Další postup je popsán v sovětské práci A. M. Kritsina, L.I. KolobuSkina, S.N. Michej-leva a V.L. Florentěva: Chimija Geterocikl. Soediňon. 1975, 125-131. Podle tohoto postupuse alkylace adeninu provádí 2,2-dimethyl-4-chlormethyl-l,3-dioxolanem ve vroucím dimethyl -íormamidu za katalýzy bezvodého uhličitanu draselného po dobu 50 až 60,h a výtěžku 90 % th.Při reprodukci popsané práce nebylo dosaženo nikdy 90 % th, výtěžku, ale pouze 50 až 60 %th žádané alkylované látky. Nevýhodou uvedeného postupu Je dlouhá.doba alkylace.
Postupem podle tohoto vynálezu který spočívá v tom, že se alkylace adeninu provádí2,2-dimethyl-4-clilormethyl-1,3-dloxolanem ve vroucím dlmethylformamidu za přítomnosti práš-kovaného hydroxidu sodného nebo draselného, se zkracuje doba alkylace za zachování výtěž-nosti žádaného produktu (55 až 60 % th) na 12 hodin. Zkrácením reakční doby alkylace najednu čtvrtinu původní doby alkylace, se tento postup stal realizovatelný v žádaném vý-robním měřítku. Přikladl 100 g adeninu se nechá reagovat v 600 ml dlmethylformamidu za varu rozpouštědlase 167 g 2,2-dimethyl-4-chlormethyl-l,3-dioxolanu za přítomnosti 37,1 g mletého hydroxidusodného po dobu 12 hodin. Po této době se reakční směs za horka zfiltruje a z filtrátu seprodukt isoluje krystalizací. Výtěžek produktu je 103 g (55,7 % th). P ř í k 1 a d 2 100 g adeninu se nechá reagovat za stejných podmínek jako v příkladu 1 za přítom-nosti 52 g mletého hydroxidu draselného. Zpracování je stejné jako v příkladu 1. Výtěžekproduktu je 110 g, tj. 59,6 % th. r
1 CS 273700 01
2 ', 3'-O-Isoprapylidene-9- (RS) - (2,3-dihydroxypropyl) adenine of structural formula I
II II
C CH
CH-- CH — CH 0 o \ t
is a key intermediate for the preparation of 9- (RS) - (2,3-dihydroxypropyl) adenine. This substance has been produced in a pharmacy in the form of a goal for the treatment of horpeo simplex. The preparation of the desired substance in the literature is described in several ways. Thus, in A. Hoell: Coll. 103 (1978), the sodium salt of adenine is heated by reaction of adenine with sodium hydride, isopropylidene-p-toluenesulfonyloxy-dihydroxypropane in dimethylformamide at 100 ° C and heating for 15 hours.
The next procedure is described in the Soviet work of AM Kritsin, LI KolobuSkin, SN Michej-lev and VL Florenteva: Chimija Geterocikl. Soediňon. 1975, 125-131. According to this process, the alkylation of adenine is carried out with 2,2-dimethyl-4-chloromethyl-1,3-dioxolane in boiling dimethylformamide under the catalysis of anhydrous potassium carbonate for 50-60 hours and a yield of 90% th. 90% th, yield but only 50-60% th of the desired alkylated substance. The disadvantage of this process is the long duration of alkylation.
According to the process of the present invention, the alkylation of the adenine is carried out with 2,2-dimethyl-4-chloromethyl-1,3-dloxolan in boiling dlmethylformamide in the presence of powdered sodium or potassium hydroxide, the alkylation time is reduced while maintaining the yield. the desired product (55-60% th) for 12 hours. By reducing the alkylation reaction time to one quarter of the original alkylation time, this process has become feasible at the desired manufacturing scale. EXAMPLE 1 100 g of adenine are reacted in 600 ml of dimethylformamide at a boiling point of 167 g of 2,2-dimethyl-4-chloromethyl-1,3-dioxolane in the presence of 37.1 g of ground hydroxide sodium for 12 hours. After this time, the reaction mixture was filtered while hot and the product was isolated by crystallization from the filtrate. The product yield was 103 g (55.7% th). EXAMPLE 2 100 g of adenine are reacted under the same conditions as in Example 1 in the presence of 52 g of ground potassium hydroxide. The work-up is the same as in Example 1. The yield of the product is 110 g, i.e. 59.6% th. r
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS821088A CS273780B1 (en) | 1988-12-13 | 1988-12-13 | Method of 2, 3-0 -isopropyliden -9-/rs/2,3-dihydroxypropyl/adenine preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS821088A CS273780B1 (en) | 1988-12-13 | 1988-12-13 | Method of 2, 3-0 -isopropyliden -9-/rs/2,3-dihydroxypropyl/adenine preparation |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CS821088A1 CS821088A1 (en) | 1990-08-14 |
| CS273780B1 true CS273780B1 (en) | 1991-04-11 |
Family
ID=5432374
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CS821088A CS273780B1 (en) | 1988-12-13 | 1988-12-13 | Method of 2, 3-0 -isopropyliden -9-/rs/2,3-dihydroxypropyl/adenine preparation |
Country Status (1)
| Country | Link |
|---|---|
| CS (1) | CS273780B1 (en) |
-
1988
- 1988-12-13 CS CS821088A patent/CS273780B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CS821088A1 (en) | 1990-08-14 |
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