GB753567A - Synthesis of nucleoside esters of pyrophosphoric acid - Google Patents
Synthesis of nucleoside esters of pyrophosphoric acidInfo
- Publication number
- GB753567A GB753567A GB29015/52A GB2901552A GB753567A GB 753567 A GB753567 A GB 753567A GB 29015/52 A GB29015/52 A GB 29015/52A GB 2901552 A GB2901552 A GB 2901552A GB 753567 A GB753567 A GB 753567A
- Authority
- GB
- United Kingdom
- Prior art keywords
- uridine
- isopropylidene
- salt
- nucleoside
- phosphate
- 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.)
- Expired
Links
- 239000002777 nucleoside Substances 0.000 title abstract 5
- -1 nucleoside esters Chemical class 0.000 title abstract 4
- 230000015572 biosynthetic process Effects 0.000 title abstract 2
- 238000003786 synthesis reaction Methods 0.000 title abstract 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 title 1
- 229940005657 pyrophosphoric acid Drugs 0.000 title 1
- 229910019142 PO4 Inorganic materials 0.000 abstract 4
- 239000002253 acid Substances 0.000 abstract 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 abstract 4
- 239000010452 phosphate Substances 0.000 abstract 4
- 125000006239 protecting group Chemical group 0.000 abstract 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 abstract 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 abstract 3
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 abstract 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract 3
- DRTQHJPVMGBUCF-XVFCMESISA-N Uridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-XVFCMESISA-N 0.000 abstract 3
- 150000003863 ammonium salts Chemical class 0.000 abstract 3
- 150000008064 anhydrides Chemical class 0.000 abstract 3
- 235000011180 diphosphates Nutrition 0.000 abstract 3
- 230000007062 hydrolysis Effects 0.000 abstract 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract 3
- 150000003833 nucleoside derivatives Chemical class 0.000 abstract 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 abstract 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 abstract 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract 2
- 125000003710 aryl alkyl group Chemical group 0.000 abstract 2
- 159000000009 barium salts Chemical class 0.000 abstract 2
- 239000002585 base Substances 0.000 abstract 2
- DRTQHJPVMGBUCF-PSQAKQOGSA-N beta-L-uridine Natural products O[C@H]1[C@@H](O)[C@H](CO)O[C@@H]1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-PSQAKQOGSA-N 0.000 abstract 2
- 125000001369 canonical nucleoside group Chemical group 0.000 abstract 2
- 239000003795 chemical substances by application Substances 0.000 abstract 2
- VWWQXMAJTJZDQX-UYBVJOGSSA-N flavin adenine dinucleotide Chemical compound C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1CO[P@](O)(=O)O[P@@](O)(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C2=NC(=O)NC(=O)C2=NC2=C1C=C(C)C(C)=C2 VWWQXMAJTJZDQX-UYBVJOGSSA-N 0.000 abstract 2
- 235000019162 flavin adenine dinucleotide Nutrition 0.000 abstract 2
- 239000011714 flavin adenine dinucleotide Substances 0.000 abstract 2
- 229940093632 flavin-adenine dinucleotide Drugs 0.000 abstract 2
- 230000002140 halogenating effect Effects 0.000 abstract 2
- 229910003002 lithium salt Inorganic materials 0.000 abstract 2
- 159000000002 lithium salts Chemical class 0.000 abstract 2
- 201000006652 primary hypertrophic osteoarthropathy Diseases 0.000 abstract 2
- 239000000047 product Substances 0.000 abstract 2
- 239000002904 solvent Substances 0.000 abstract 2
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 abstract 2
- 229940045145 uridine Drugs 0.000 abstract 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 abstract 1
- 102000053602 DNA Human genes 0.000 abstract 1
- 108020004414 DNA Proteins 0.000 abstract 1
- FNDXFUBHPXBGMD-UHFFFAOYSA-N OP(O)O.OP(O)(O)=O Chemical compound OP(O)O.OP(O)(O)=O FNDXFUBHPXBGMD-UHFFFAOYSA-N 0.000 abstract 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 abstract 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 abstract 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 abstract 1
- BHIIGRBMZRSDRI-UHFFFAOYSA-N [chloro(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(Cl)OC1=CC=CC=C1 BHIIGRBMZRSDRI-UHFFFAOYSA-N 0.000 abstract 1
- 238000005903 acid hydrolysis reaction Methods 0.000 abstract 1
- 150000007513 acids Chemical class 0.000 abstract 1
- 239000003513 alkali Substances 0.000 abstract 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 abstract 1
- 150000001412 amines Chemical class 0.000 abstract 1
- 229910021529 ammonia Inorganic materials 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 abstract 1
- 235000019445 benzyl alcohol Nutrition 0.000 abstract 1
- PELLYVDRZIFQRF-UHFFFAOYSA-N benzyl dihydrogen phosphite Chemical compound OP(O)OCC1=CC=CC=C1 PELLYVDRZIFQRF-UHFFFAOYSA-N 0.000 abstract 1
- GWAOFSOXGNJTAQ-UHFFFAOYSA-N benzyl phosphono hydrogen phosphate Chemical compound OP(O)(=O)OP(O)(=O)OCC1=CC=CC=C1 GWAOFSOXGNJTAQ-UHFFFAOYSA-N 0.000 abstract 1
- 239000006227 byproduct Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 abstract 1
- ITVPBBDAZKBMRP-UHFFFAOYSA-N chloro-dioxido-oxo-$l^{5}-phosphane;hydron Chemical class OP(O)(Cl)=O ITVPBBDAZKBMRP-UHFFFAOYSA-N 0.000 abstract 1
- TXZVKSNFCZUARP-UHFFFAOYSA-N dibenzyl phosphate triethylazanium Chemical compound P(=O)(OCC1=CC=CC=C1)(OCC1=CC=CC=C1)[O-].C(C)[NH+](CC)CC TXZVKSNFCZUARP-UHFFFAOYSA-N 0.000 abstract 1
- UQSHIDHNLKIYGN-UHFFFAOYSA-N diphenoxyphosphoryl diphenyl phosphate Chemical compound C=1C=CC=CC=1OP(OP(=O)(OC=1C=CC=CC=1)OC=1C=CC=CC=1)(=O)OC1=CC=CC=C1 UQSHIDHNLKIYGN-UHFFFAOYSA-N 0.000 abstract 1
- 150000002148 esters Chemical class 0.000 abstract 1
- 239000012467 final product Substances 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 abstract 1
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 abstract 1
- 238000007327 hydrogenolysis reaction Methods 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- HSNUXDIQZKIQRR-UHFFFAOYSA-N hydroxy-imino-bis(phenylmethoxy)-$l^{5}-phosphane Chemical compound C=1C=CC=CC=1COP(=O)(N)OCC1=CC=CC=C1 HSNUXDIQZKIQRR-UHFFFAOYSA-N 0.000 abstract 1
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 abstract 1
- 238000000034 method Methods 0.000 abstract 1
- 125000003729 nucleotide group Chemical group 0.000 abstract 1
- 230000020477 pH reduction Effects 0.000 abstract 1
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical class NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 abstract 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 abstract 1
- ZNNZYHKDIALBAK-UHFFFAOYSA-M potassium thiocyanate Chemical compound [K+].[S-]C#N ZNNZYHKDIALBAK-UHFFFAOYSA-M 0.000 abstract 1
- 229940116357 potassium thiocyanate Drugs 0.000 abstract 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 abstract 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/02—Phosphorylation
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
The invention comprises nucleoside esters of phosphorous and halophosphonic acids, and the synthesis of nucleoside pyrophosphates therefrom as set out below, in which R1 and/or R2 is a nucleoside residue, the other being a monovalent hydrocarbon residue as also are R3 and R4. A phosphite mono-ester (R3O)(HO) PHO is treated with ZPO(OR4)2 in the presence of a tertiary base to give a phosphite-phosphate "mixed anhydride" (R3O)(PHO)O(PO)(OR4)2. Treatment of the latter with a nucleoside R1OH (protected if necessary) with a halogenating agent in an indifferent solvent in the presence of a tertiary base gives a halophosphonate ester (R1O)(R3O)(PO)X. This is reacted with an orthophosphate mono-salt in which the other two hydrogen atoms may be replaced, one by a group R2 and the other by a protecting group where necessary, and the resulting pyrophosphate ester hydrolysed to split off the group R3 and any protecting groups in the phosphate or nucleoside portions of the molecule. The final product is (R1O)(HO)(PO)O(PO)(OH) (OR2). Preferably R3 is aralkyl, R4 is aryl and Z is halogen or (R4O)2(PO)-O-. The halogenating agent is preferably an N-chloro secondary amide such as N-chloro-succinimide or N : 2 : 4-trichloracetanilide. The chlorophosphonates so obtained may be characterized by hydrolysis to nucleotide esters or by treatment with amines to give aminophosphonates. The orthophosphate may be used as a metallic, ammonium or substituted ammonium salt such as that of triethylamine. Aralkyl protecting groups may be removed by treatment with a metallic or substituted ammonium salt (e.g. lithium chloride), or an alkali thiocyanate in a cyanoalkane, or by a phenol which has been used as solvent in the previous stage, or else by hydrogenolysis. Protecting groups on the nucleoside residue (e.g. O-acyl or isopropylidene) can be split off by careful acid or alkaline hydrolysis. In the examples: (1) monobenzyl phosphite (by acidification of its ammonium salt) is treated with diphenyl chlorophosphate or tetraphenyl pyrophosphate to give a mixed anhydride (characterized by reaction with ammonia and benzyl alcohol to form dibenzyl aminophosphonate); this with 21 : 31-isopropylidene-uridine yields 21 : 31 - isopropylidene - uridine - 51 - benzyl phosphite, converted by N-chlorsuccinimide into the 51-benzylchlorophosphonate (characterized by hydrolysis to 21 : 31-isopropylideneuridine - 51 - benzylhydrogenphosphate); this is reacted with triethylammonium 21 : 31-isopropylidene-51-benzylphosphate and the product debenzylated with potassium thiocyanate in acetonitrile; hydrolysis with hydrochloric acid gives di - (uridine - 51) - pyrophosphate, obtained as barium salt and converted via the free acid into the lithium salt; uridine-51-phosphate is a by-product; (2) 21 : 31-isopropylidene - uridine - 51 - benzylchlorophosphonate and triethylammonium dibenzyl phosphate give 21 : 31-isopropylidene-uridine-51-tri benzylpyrophosphate, converted by heating with lithium chloride into the lithium salt of 21 : 31 - isopropylidene - uridine - 51 - benzyl pyrophosphate; this is acidified and hydrogenated to uridine-51-pyrophosphate (obtained as barium salt) together with its 21 : 31-isopropylidene derivative and uridine-51-phosphate; (3) the mixed anhydride of (1) is reacted with 21 : 31 - diacetyl - uridine to give 21 : 31-diacetyl - uridine - 51 - benzylphosphite and halogenated to 21 : 31-diacetyluridine-51-benzylchlorophosphonate; (4) similarly to (3) there are prepared 21 : 31 - isopropylidene - adenosine - 51 - benzylphosphite and 51 - benzylchlorophosphonate; the latter is reacted with mono-silver riboflavin-51-phosphate (from the di-silver salt and the free acid) and the product hydrolysed to P-(riboflavin-51)-P1-(adenosine51) - dihydrogenpyrophosphate (purified via silver salt); this is identical with the natural flavin - adenine - dinucleotide (FAD). The process is applicable to any purine or pyrimidine nycleoside obtained by hydrolysing ribonucleic and deoxyribonucleic acids. Specifications 621,094 and 697,473 are referred to.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB29015/52A GB753567A (en) | 1952-11-17 | 1952-11-17 | Synthesis of nucleoside esters of pyrophosphoric acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB29015/52A GB753567A (en) | 1952-11-17 | 1952-11-17 | Synthesis of nucleoside esters of pyrophosphoric acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB753567A true GB753567A (en) | 1956-07-25 |
Family
ID=10284890
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB29015/52A Expired GB753567A (en) | 1952-11-17 | 1952-11-17 | Synthesis of nucleoside esters of pyrophosphoric acid |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB753567A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1983002616A1 (en) * | 1982-02-01 | 1983-08-04 | Innovax Lab Ltd | COMPOSITION AND METHOD FOR FORMING A5'p5'pn3'p (AppNp) |
-
1952
- 1952-11-17 GB GB29015/52A patent/GB753567A/en not_active Expired
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1983002616A1 (en) * | 1982-02-01 | 1983-08-04 | Innovax Lab Ltd | COMPOSITION AND METHOD FOR FORMING A5'p5'pn3'p (AppNp) |
| FR2521147A1 (en) * | 1982-02-01 | 1983-08-12 | Innovax Lab Ltd | COMPOSITION AND METHOD FOR FORMING A5'P5'PN3'P (APPNP) |
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