CN115322236A - Novel method for synthesizing ribavirin - Google Patents
Novel method for synthesizing ribavirin Download PDFInfo
- Publication number
- CN115322236A CN115322236A CN202211083023.4A CN202211083023A CN115322236A CN 115322236 A CN115322236 A CN 115322236A CN 202211083023 A CN202211083023 A CN 202211083023A CN 115322236 A CN115322236 A CN 115322236A
- Authority
- CN
- China
- Prior art keywords
- ribavirin
- acetyl
- ribofuranosyl
- triazole
- beta
- 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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- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 23
- 229960000329 ribavirin Drugs 0.000 title claims abstract description 21
- HZCAHMRRMINHDJ-DBRKOABJSA-N ribavirin Natural products O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1N=CN=C1 HZCAHMRRMINHDJ-DBRKOABJSA-N 0.000 title claims abstract description 21
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- -1 2, 3, 5-tri-O-acetyl-beta-D-ribofuranosyl Chemical group 0.000 claims abstract description 8
- 238000001914 filtration Methods 0.000 claims abstract description 7
- 239000011347 resin Substances 0.000 claims abstract description 7
- 229920005989 resin Polymers 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 5
- 238000007112 amidation reaction Methods 0.000 claims abstract description 4
- OLQDKJGHMNCLOH-HKUMRIAESA-N methyl 1-[(2r,3r,4r,5r)-3,4-diacetyloxy-5-(acetyloxymethyl)oxolan-2-yl]-1,2,4-triazole-3-carboxylate Chemical compound N1=C(C(=O)OC)N=CN1[C@H]1[C@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O1 OLQDKJGHMNCLOH-HKUMRIAESA-N 0.000 claims abstract description 4
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910001413 alkali metal ion Inorganic materials 0.000 claims abstract description 3
- 230000009435 amidation Effects 0.000 claims abstract description 3
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 3
- 239000003729 cation exchange resin Substances 0.000 claims abstract description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical group [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000758 substrate Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims 3
- 239000011734 sodium Substances 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 abstract 1
- 239000002585 base Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000006196 deacetylation Effects 0.000 description 4
- 238000003381 deacetylation reaction Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005576 amination reaction Methods 0.000 description 3
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 125000002091 cationic group Chemical group 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/056—Triazole or tetrazole radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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 discloses a new method for synthesizing ribavirin, which comprises the following steps: removing acetyl from 1- (2, 3, 5-tri-O-acetyl-beta-D-ribofuranosyl) -1H-1,2, 4-triazole-3-carboxylic acid methyl ester in an alcohol solvent under the catalysis of a base catalyst; adding cation exchange resin into the solution to remove alkali metal ions, filtering to remove the resin, and concentrating under reduced pressure to obtain 1- (2, 3, 5-tri-O-acetyl-beta-D-ribofuranosyl) -1H-1,2, 4-triazole-3-methyl carboxylate; then adding methanol and introducing ammonia gas for amidation to obtain ribavirin. The invention adopts a two-step method to synthesize ribavirin. The consumption of ammonia gas is greatly reduced, the amount of three wastes is reduced, and the process is safer and more environment-friendly; the product yield in the process is improved to 98 percent, the production cost is reduced, and the industrialized production is convenient to implement.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing ribavirin.
Background
Ribavirin, chemical name: 1-beta-D-ribofuranosyl-1H-1, 2, 4-triazole-3-carboxamide, which is a broad-spectrum strong antiviral drug and belongs to the synthetic nucleoside drug structure as follows:
the synthesis method of ribavirin is reported in both literature and patents, and the main method is a chemical synthesis method, wherein the final synthesis step is the amidation reaction of 1- (2,3,5-tri-O-acetyl-beta-D-ribofuranosyl) -1H-1,2,4-triazole-3-methyl carboxylate directly in an ammonia solution. This process has 2 major drawbacks, one is the consumption of large amounts of ammonia (at least 4 equivalents), and the other is the production of 3 molecules of acetamide, which solubilizes ribavirin and affects the crystallization of the product, so that the amination reaction yield does not exceed 88%. Although patents (such as CN 109336937) report that the amination reaction yield reaches 97%, actually, tests are carried out for many times according to the patent report method, the highest yield is 88%, and more ribavirin residues are detected in the mother liquor.
Disclosure of Invention
The invention aims to provide a novel method for synthesizing ribavirin, which is safe and environment-friendly and has high yield.
The technical solution of the invention is as follows:
a novel method for synthesizing ribavirin is characterized in that: the method comprises the following steps: 1- (2, 3, 5-tri-O-acetyl-beta-D-ribofuranosyl) -1H-1,2, 4-triazole-3-carboxylic acid methyl ester is deacetylated in an alcohol solvent under the catalysis of an alkali catalyst; adding cation exchange resin into the solution to remove alkali metal ions, filtering to remove the resin, and concentrating under reduced pressure to obtain 1- (2, 3, 5-tri-O-acetyl-beta-D-ribofuranosyl) -1H-1,2, 4-triazole-3-methyl carboxylate; then adding methanol and introducing ammonia gas for amidation to obtain ribavirin.
The reaction principle is as follows:
(1) Deacetylation of
(2) Synthesis of ribavirin
The catalyst used for the deacetylation is preferably sodium methoxide and sodium ethoxide;
the solvent used for the deacetylation is preferably methanol or ethanol;
the dosage of the deacetylation catalyst is 0.1-0.5wt% of the substrate;
in the amination process, the dosage of ammonia is 1-2 times (mol/mol) of the substrate.
The invention adopts a two-step method to synthesize ribavirin. The consumption of ammonia gas is greatly reduced, the amount of three wastes is reduced, and the process is safer and more environment-friendly; the product yield in the process is improved to 98 percent, the production cost is reduced, and the industrialized production is convenient to implement.
The present invention will be further described with reference to the following examples.
Detailed Description
Example 1:
adding 100mL of methanol into a reaction kettle, adding 0.04 g of sodium methoxide, adding 20g of 1- (2, 3, 5-tri-O-acetyl-beta-D-ribofuranosyl) -1H-1,2, 4-triazole-3-carboxylic acid methyl ester, keeping the temperature at 25-30 ℃, stirring for 3H, adding 0.1g of D61 type cationic resin, stirring for half an hour, filtering to remove the resin, decompressing and concentrating the filtrate to be dry, adding 100mL of methanol, introducing 1.32 g of ammonia gas, keeping the temperature for reaction for 22H, cooling to 0-5 ℃, keeping the temperature for 1H, and filtering to obtain 12.5 g of ribavirin with the yield of 98.6%.
Example 2:
adding 100mL of ethanol into a reaction kettle, adding 0.04 g of sodium ethoxide, adding 20g of 1- (2, 3, 5-tri-O-acetyl-beta-D-ribofuranosyl) -1H-1,2, 4-triazole-3-methyl carboxylate, preserving heat and stirring for 3H at the temperature of 25-30 ℃, adding 0.1g of D61 type cationic resin, stirring for half an hour, filtering to remove the resin, decompressing and concentrating the filtrate to be dry, adding 100mL of methanol, introducing 1.06 g of ammonia gas, preserving heat and reacting for 22H, cooling to 0-5 ℃, preserving heat for 1H, and filtering to obtain 12.4 g of ribavirin, wherein the yield is 98.2%.
Claims (4)
1. A novel method for synthesizing ribavirin is characterized in that: the method comprises the following steps: 1- (2, 3, 5-tri-O-acetyl-beta-D-ribofuranosyl) -1H-1,2, 4-triazole-3-carboxylic acid methyl ester is deacetylated in an alcohol solvent under the catalysis of an alkali catalyst; then adding cation exchange resin into the solution to remove alkali metal ions, filtering to remove the resin, and then concentrating under reduced pressure to obtain 1- (2, 3, 5-tri-O-acetyl-beta-D-ribofuranosyl) -1H-1,2, 4-triazole-3-methyl carboxylate; then adding methanol and introducing ammonia gas for amidation to obtain ribavirin.
2. The novel process for the synthesis of ribavirin according to claim 1 characterized in that: the alkali catalyst is sodium alkoxide.
3. The novel process for the synthesis of ribavirin according to claim 2 characterized in that: the sodium alkoxide is sodium methoxide or sodium ethoxide, and the dosage of the sodium alkoxide is 0.1-0.5wt% of the substrate.
4. The novel process for the synthesis of ribavirin according to claim 1,2 or 3, characterized in that: the alcohol solvent is methanol or ethanol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211083023.4A CN115322236A (en) | 2022-09-06 | 2022-09-06 | Novel method for synthesizing ribavirin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211083023.4A CN115322236A (en) | 2022-09-06 | 2022-09-06 | Novel method for synthesizing ribavirin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115322236A true CN115322236A (en) | 2022-11-11 |
Family
ID=83930153
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211083023.4A Pending CN115322236A (en) | 2022-09-06 | 2022-09-06 | Novel method for synthesizing ribavirin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115322236A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1535277A (en) * | 2001-07-30 | 2004-10-06 | �����ﰲ�ط���������ѧ(�����)�ɷ��� | Process for preparation of L-ribavirin |
| JP2009078982A (en) * | 2007-09-25 | 2009-04-16 | Kao Corp | Branched alkyl galactoside |
-
2022
- 2022-09-06 CN CN202211083023.4A patent/CN115322236A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1535277A (en) * | 2001-07-30 | 2004-10-06 | �����ﰲ�ط���������ѧ(�����)�ɷ��� | Process for preparation of L-ribavirin |
| JP2009078982A (en) * | 2007-09-25 | 2009-04-16 | Kao Corp | Branched alkyl galactoside |
Non-Patent Citations (1)
| Title |
|---|
| 张逸伟 等: "新型利巴韦林衍生物的合成", 合成化学, vol. 18, no. 6, 31 December 2010 (2010-12-31), pages 712 - 714 * |
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