CN112457304B - Preparation method of nifuratel - Google Patents
Preparation method of nifuratel Download PDFInfo
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- CN112457304B CN112457304B CN202011429685.3A CN202011429685A CN112457304B CN 112457304 B CN112457304 B CN 112457304B CN 202011429685 A CN202011429685 A CN 202011429685A CN 112457304 B CN112457304 B CN 112457304B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention relates to a preparation method of Nifuratel (Nifuratel). The method comprises the following steps: (1) reacting a compound 1 (with the chemical name of epoxy chloropropane) with a compound 10 (with the chemical name of tert-butyl carbazate) to obtain an intermediate 11; (2) the intermediate 11 reacts with CDI (chemical name: carbonyl diimidazole) to obtain an intermediate 12; (3) carrying out substitution reaction on the compound 12 and sodium methyl mercaptide to obtain an intermediate 13; (4) under the action of acid, removing Boc group in the structure from the intermediate 13 to obtain an intermediate 4; (5) and reacting the intermediate 4 with 5-nitrofurfural to obtain nifuratel. The process route provided by the invention has the advantages that: the method has the advantages of short route, cheap and easily-obtained raw materials, simple and convenient operation, high reaction yield, no generation of sulfur-containing intermediate with low boiling point, environmental friendliness and easy industrial production.
Description
Technical Field
The invention relates to the technical field of medicine manufacturing, in particular to a novel method for preparing nifuratel.
Background
Nifuratel (Nifuratel) is a spectral antibiotic that can be used to treat vulvar and vaginal infections and leukorrhagia and urinary infections caused by bacteria, trichomonad, mold and Candida, alimentary canal amebiasis and Giardia disease. Its chemical name is 5- [ (methylthio) methyl ] -3- [ (5-nitrofurylidene) amino ] -2-oxazolidinone, CAS registry number 4936-47-4, and its structural formula is shown below.
There are currently three routes reported for the total synthesis of nifuratel. The first route is shown as Scheme 1, epoxy chloropropane is used as a raw material, and the epoxy chloropropane reacts with methyl mercaptan to obtain an intermediate 2; the intermediate 2 reacts with hydrazine hydrate to prepare an intermediate 3, and then the intermediate 3 is cyclized with diethyl carbonate to obtain an intermediate 4; hydrolyzing the compound 5 by acid to obtain 5-nitrofurfural, and reacting with the compound 4 to obtain nifuratel. The methyl mercaptan used in the route has foul smell and pollutes the environment; the used hydrazine hydrate is excessive by more than 3 times, and the hydrazine hydrate which does not participate in the reaction also causes environmental pollution.
The second route is shown in Scheme 2, which is similar to the method shown in Scheme 1, replacing methyl mercaptan with sodium methyl mercaptide alone. The intermediate 7 synthesized in the route has low boiling point, high volatility, bad smell and environmental pollution, and the excessive use of hydrazine hydrate also causes environmental pollution.
The third route is shown as Scheme 3, thiourea is used as a reaction starting material and reacts with dimethyl sulfate to obtain an intermediate 9; reacting the intermediate with epoxy chloropropane to obtain an intermediate 7; the subsequent routes were the same as Scheme 1 and Scheme 2. The synthesis also produces low boiling point compound 7, while using excess hydrazine hydrate and highly toxic dimethyl sulfate.
Disclosure of Invention
In order to overcome the defects of the technical route, the invention provides a new method for synthesizing nifuratel, which adopts the following technical route:
the method comprises the following operation steps:
s1 Synthesis of Compound 11
Dissolving the compound 1 in an organic solvent, adding the compound 10, then stirring the reaction at 25 ℃, and detecting by TLC until the compound 10 disappears; adding water to the reaction solution, separating and extracting, drying the organic layer by using anhydrous sodium sulfate, filtering, and removing the solvent under reduced pressure to obtain the compound 11.
Wherein the organic solvent is one or more of dichloromethane, chloroform, tetrahydrofuran, 1, 4-dioxane and methyl tert-butyl ether, preferably tetrahydrofuran.
Wherein the molar ratio of the compound 1 to the compound 10 is 1: 1-1.5, preferably, the molar ratio of the compound 1 to the compound 10 is 1: 1-1.1.
S2: synthesis of Compound 12
Dissolving the compound 11 in an organic solvent, adding CDI, then reacting in a certain temperature range, and detecting by TLC until the compound 11 disappears; adding water into the reaction solution, separating and extracting, drying the organic layer by using anhydrous sodium sulfate, filtering, and removing the solvent under reduced pressure to obtain the compound 12.
Wherein the organic solvent is one or more of tetrahydrofuran, acetonitrile, acetone and toluene, and tetrahydrofuran is preferred.
Wherein the molar ratio of the compound 11 to the CDI is 1: 1-2; preferably, the molar ratio of the compound 11 to the CDI is 1: 1-1.2.
Wherein the reaction temperature is 20-100 ℃, and preferably 60-65 ℃.
S3: synthesis of Compound 13
Dissolving compound 12 in organic solvent, and dripping 20% sodium methanethiol aqueous solution at 0 deg.C; the reaction was then stirred at 25 ℃ and checked by TLC until compound 12 disappeared; the solvent was removed under reduced pressure, dichloromethane and water were added, liquid separation extraction was performed, the organic layer was dried over anhydrous sodium sulfate, suction filtration was performed, the solvent was removed under reduced pressure, and recrystallization was performed with methyl tert-butyl ether to obtain compound 13.
Wherein the organic solvent is one or more of methanol, ethanol, tetrahydrofuran, acetonitrile, dichloromethane, chloroform and toluene, preferably ethanol.
Wherein the molar ratio of the compound 12 to the sodium methyl mercaptide is 1: 1-2, and preferably, the molar ratio of the compound 13 to the sodium methyl mercaptide is 1: 1-1.2.
S4: synthesis of Compound 4
Dissolving compound 13 in an organic solvent, and adding an acid at 0 ℃; the reaction was then stirred at 25 ℃ and checked by TLC until compound 13 disappeared; removing the solvent under reduced pressure, adding a saturated sodium bicarbonate aqueous solution into a reaction bottle, adjusting the pH of the system to 7-8, adding dichloromethane, performing liquid separation extraction, drying an organic layer by using anhydrous sodium sulfate, performing suction filtration, and removing the solvent under reduced pressure to obtain a compound 4;
wherein the organic solvent is one or more of dichloromethane, chloroform, tetrahydrofuran and toluene, preferably dichloromethane.
Wherein, the acid is hydrochloric acid or trifluoroacetic acid, preferably trifluoroacetic acid.
Wherein the volume ratio of the trifluoroacetic acid to the organic solvent is 1: 4-1: 1, and preferably, the volume ratio of the trifluoroacetic acid to the organic solvent is 1: 4-1: 2.
S5: synthesis of nifuratel
Dissolving a compound 4 in an organic solvent, adding 5-nitrofurfural at 0 ℃, then stirring and reacting at 20 ℃, and detecting by TLC until the compound 4 disappears; and (4) carrying out suction filtration, drying a filter cake, and recrystallizing by using ethanol to obtain a pure nifuratel product.
Wherein the organic solvent is one or more of methanol, ethanol, acetonitrile, tetrahydrofuran and dichloromethane, preferably ethanol.
Wherein the molar ratio of the compound 4 to the 5-nitrofurfural is 1: 1-1.5, preferably, the molar ratio of the compound 4 to the 5-nitrofurfural is 1: 1-1.2
Compared with the prior art, the invention has the beneficial effects that:
1. the invention provides a new method for synthesizing nifuratel, which uses a new synthetic raw material of tert-butyl carbazate, avoids the use of excessive hydrazine hydrate, does not generate volatile sulfur-containing intermediate with low boiling point, and is environment-friendly.
2. The method has the advantages of short route, cheap and easily available raw materials, high yield and high purity, and is suitable for industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following embodiments further describe the present invention in detail. The experimental methods in the present invention are conventional methods unless otherwise specified. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The progress of the reaction of the present invention can be monitored by conventional monitoring methods in the art (e.g., TLC, HPLC or NMR), typically at the end of the reaction when starting material is lost.
The compound 1, the compound 10, the CDI and the 5-nitrofurfural of the invention are purchased from Shanghai Bide medicine science and technology company, and other chemical reagents and raw materials are purchased from Saen chemical technology (Shanghai) company.
Example 1:
embodiment 1 of the present invention provides a preparation method of intermediate 11, and the synthetic route thereof is as follows:
the preparation method specifically comprises the following steps:
compound 1(120g, 1.3mol) was dissolved in tetrahydrofuran (1.5L), compound 10(171.4g, 1.3mmol) was added, followed by stirring at 25 ℃ for 24h, and disappearance of Compound 1 was detected by TLC; water (500mL) was added to the reaction mixture, followed by liquid separation and extraction, drying of the organic layer with anhydrous sodium sulfate, suction filtration, and removal of the solvent under reduced pressure to obtain Compound 11.
282g of light yellow oily matter is prepared by the method, and the yield is 96.8%.
The identification of intermediate 11 produced in this example gave the following results:
ESI-MS(m/z):225.6；
1H NMR(400MHz,CDCl3)δ7.06(d,J＝5.7Hz,1H),4.01-4.04(m,1H),3.54(dd,J＝2.1,1.4Hz,2H),3.46(d,J＝4.2Hz,1H),2.78(m,2H),1.39(s,9H).
example 2:
embodiment 2 of the present invention provides a preparation method of intermediate 12, and the synthetic route thereof is as follows:
the preparation method specifically comprises the following steps:
compound 11(280g, 1.25mol) was dissolved in tetrahydrofuran (2L), CDI (202g, 1.25mol) was added, followed by reaction at 60 ℃ for 12h, disappearance of compound 11 was detected by TLC, water (0.6L) was added to the reaction solution, liquid separation extraction was performed, the organic layer was dried with anhydrous sodium sulfate, suction filtration was performed, and the solvent was removed under reduced pressure to obtain compound 12.
296g of white solid obtained by the method has the yield of 94.8 percent.
The identification of intermediate 12 prepared in this example gave the following results:
ESI-MS(m/z):251.7；
1H NMR(400MHz,CDCl3)δ7.76(s,1H),5.12–5.14(m,1H),3.79(d,J＝0.9Hz,2H),3.66(m,2H),1.42(s,9H).
example 3:
example 3 of the present invention provides a method for preparing intermediate 12:
compound 11(200g, 0.9mol) was dissolved in acetonitrile (1.4L), CDI (144g, 0.9mol) was added, followed by reaction at 60 ℃ for 12h, disappearance of compound 11 was detected by TLC, water (0.4L) and ethyl acetate (1L) were added to the reaction solution, liquid separation extraction was performed, the organic layer was dried using anhydrous sodium sulfate, suction filtration was performed, and the solvent was removed under reduced pressure to obtain compound 12.
191g of white solid obtained by the method is obtained, and the yield is 85.6%.
Example 4:
embodiment 4 of the present invention provides a preparation method of intermediate 13, and the synthetic route thereof is as follows:
the preparation method specifically comprises the following steps:
compound 12(260g, 1.04mol) was dissolved in ethanol (1.5L), 20% sodium thiomethoxide solution (363.5mL, 1.04mol) was added dropwise at 0 deg.C, followed by stirring at 25 deg.C for 8h, and disappearance of Compound 12 was detected by TLC; ethanol was removed under reduced pressure, methylene chloride (2L) and water (1.0L) were added to the system, followed by liquid-separation extraction, drying of the organic layer over anhydrous sodium sulfate, suction filtration, removal of the solvent under reduced pressure, and recrystallization from methyl tert-butyl ether (1.2L) to give compound 13.
259g of pale yellow solid obtained by the method has the yield of 95.2 percent.
Compound 13 prepared in this example was identified with the following results:
ESI-MS(m/z):263.2；
1H NMR(400MHz,CDCl3)δ7.80(s,1H),5.05–5.09(m,1H),3.71(m,2H),3.06(m,2H),1.41(s,9H).
example 5:
embodiment 5 of the present invention provides a preparation method of intermediate 4, and the synthetic route is as follows:
the preparation method specifically comprises the following steps:
compound 13(240g, 0.91mol) was dissolved in dichloromethane (0.85L), trifluoroacetic acid (272mL, 3.66mol) was added at 0 deg.C, the reaction was stirred at 25 deg.C for 5h, and disappearance of compound 13 was detected by TLC; removing the solvent under reduced pressure, adding a saturated sodium bicarbonate aqueous solution into a reaction bottle, adjusting the pH of the system to 7-8, adding dichloromethane (0.5L), carrying out liquid separation extraction, drying an organic layer by using anhydrous sodium sulfate, carrying out suction filtration, and removing the solvent under reduced pressure to obtain a compound 4.
138g of white solid obtained by the method has the yield of 93.0 percent.
Compound 4 prepared in this example was identified with the following results:
ESI-MS(m/z):163.3；
1H NMR(400MHz,CDCl3)δ4.65–4.70(m,1H),3.99(dd,J＝12.5,2.4Hz,1H),3.81(dd,J＝12.4,2.3Hz,1H),3.00–3.09(m,2H),2.12(s,3H).
example 6:
example 6 of the present invention provides a method for preparing intermediate 4:
compound 13(240g, 0.91mol) was dissolved in tetrahydrofuran (0.9L), and hydrochloric acid solution (4mol/L, 0.92L, 3.66mol) was added dropwise at 0 deg.C, followed by stirring at 25 deg.C for 2h, and disappearance of Compound 13 was detected by TLC; removing the solvent under reduced pressure, adding a saturated sodium bicarbonate aqueous solution into a reaction bottle, adjusting the pH of the system to 7-8, adding dichloromethane (0.5L), carrying out liquid separation extraction, drying an organic layer by using anhydrous sodium sulfate, carrying out suction filtration, and removing the solvent under reduced pressure to obtain a compound 4.
127g of white solid is obtained by the method, and the yield is 85.6%.
Example 7:
embodiment 7 of the present invention provides a preparation method of nifuratel, which comprises the following synthetic route:
the preparation method specifically comprises the following steps:
dissolving compound 4(130g, 0.8mol) in ethanol (1.0L), adding 5-nitrofurfural (124g, 0.88mol) at 0 ℃, stirring and reacting at 20 ℃ for 14h, and detecting the disappearance of compound 4 by TLC; and (4) carrying out suction filtration, drying a filter cake, and recrystallizing by using ethanol to obtain a pure nifuratel product.
The method is adopted to obtain 212g of yellow crystalline solid, the yield is 92.7 percent, and the purity is 99.8 percent.
The nifuratel obtained in this example was identified as follows:
ESI-MS(m/z):286.3；
1H NMR(400MHz,DMSO-d6)δδ7.91(s,1H),7.76(d,J＝4.9Hz,1H),7.15(d,J＝4.7Hz,1H),4.80-5.10(m,1H),4.08–4.12(m,1H),3.82(dd,J＝12.4,2.7Hz,1H),2.80-3.05(m,2H),2.15(s,3H).
example 8:
embodiment 8 of the present invention provides a method for preparing nifuratel:
compound 8(128g, 0.79mol) was dissolved in acetonitrile (0.8L), 5-nitrofurfural (122g, 0.87mol) was added at 0 ℃, followed by stirring at 20 ℃ for 10h, and compound 4 was detected by TLC to disappear; and (4) carrying out suction filtration, drying a filter cake, and recrystallizing by using ethanol to obtain a pure nifuratel product. The method is adopted to obtain 196g of yellow crystalline solid, the yield is 87.1 percent, and the purity is 99.8 percent.
The above-described embodiments of the present invention should not be construed as limiting the scope of the present invention. Any other corresponding changes and modifications made according to the technical idea of the present invention should be included in the protection scope of the claims of the present invention.
Claims (6)
1. A synthetic method of nifuratel is characterized by comprising the following steps:
s1 Synthesis of Compound 11
Dissolving the compound 1 in an organic solvent, adding the compound 10, stirring for reaction, adding water into reaction liquid, extracting, treating an organic phase, and removing the solvent to obtain a compound 11;
s2: synthesis of Compound 12
Dissolving the compound 11 in an organic solvent, adding CDI for reaction, adding water into reaction liquid, extracting, treating an organic phase, and removing the solvent to obtain a compound 12;
s3: synthesis of Compound 13
Dissolving the compound 12 in an organic solvent, dropwise adding a sodium methyl mercaptide aqueous solution at 0 ℃, stirring for reaction, removing the solvent, adding dichloromethane and water, extracting, and removing the solvent to obtain a compound 13;
s4: synthesis of Compound 4
Dissolving the compound 13 in an organic solvent, adding acid at 0 ℃, stirring for reaction, removing the solvent, adjusting the pH to 7-8, adding dichloromethane, extracting, and removing the solvent to obtain a compound 4;
s5: synthesis of nifuratel
Dissolving the compound 4 in an organic solvent, and adding 5-nitrofurfural at 0 ℃; and after the addition, stirring for reaction to obtain nifuratel.
2. A nifuratel synthesis method according to claim 1, characterized in that the organic solvent used in the synthesis of compound 11 in step S1 is one or more of dichloromethane, chloroform, tetrahydrofuran, 1, 4-dioxane and methyl tert-butyl ether; the molar ratio of the compound 1 to the compound 10 is 1: 1-1.5.
3. A nifuratel synthesis method according to claim 1, characterized in that, in step S2, the organic solvent used in the synthesis of compound 12 is one or more of tetrahydrofuran, acetonitrile, acetone and toluene; the molar ratio of the compound 11 to the CDI is 1: 1-2; the reaction temperature is 20-100 ℃.
4. A nifuratel synthesis method according to claim 1, characterized in that, the organic solvent used in the synthesis of compound 13 in step S3 is one or more of methanol, ethanol, tetrahydrofuran, acetonitrile, dichloromethane, chloroform and toluene; the molar ratio of the compound 12 to the sodium methyl mercaptide is 1: 1-2.
5. A nifuratel synthesis method according to claim 1, characterized in that, the organic solvent used in the synthesis of compound 4 in step S4 is one or more of dichloromethane, chloroform, tetrahydrofuran and toluene; the acid is hydrochloric acid or trifluoroacetic acid; the volume ratio of the acid to the organic solvent is 1: 4-1: 1.
6. A method for synthesizing nifuratel according to claim 1, wherein the organic solvent used in the synthesis of nifuratel in step S5 is one or more of methanol, ethanol, acetonitrile, tetrahydrofuran and dichloromethane; the molar ratio of the compound 4 to the 5-nitrofurfural is 1: 1-1.5.
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| CN103396413A (en) * | 2013-08-14 | 2013-11-20 | 盐城凯利药业有限公司 | Preparation method of nifuratel |
| CN103664923A (en) * | 2013-12-23 | 2014-03-26 | 湖南方盛制药股份有限公司 | Preparation method for nifuratel |
| CN104379580A (en) * | 2012-05-11 | 2015-02-25 | 波利化学公司 | (R) -nifuratel, its use for the treatment of infections and synthesis of (R) and (S) -nifuratel |
| CN105693709A (en) * | 2016-01-15 | 2016-06-22 | 安徽悦康凯悦制药有限公司 | Technology for producing nifuratel |
| CN105820145A (en) * | 2015-01-07 | 2016-08-03 | 成都青山利康药业有限公司 | Method for preparing 5-nitro-2-furaldehyde and nifuratel |
| CN108084174A (en) * | 2017-11-28 | 2018-05-29 | 北京朗依制药有限公司 | The preparation method of Nifuratel |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104379580A (en) * | 2012-05-11 | 2015-02-25 | 波利化学公司 | (R) -nifuratel, its use for the treatment of infections and synthesis of (R) and (S) -nifuratel |
| CN103396413A (en) * | 2013-08-14 | 2013-11-20 | 盐城凯利药业有限公司 | Preparation method of nifuratel |
| CN103664923A (en) * | 2013-12-23 | 2014-03-26 | 湖南方盛制药股份有限公司 | Preparation method for nifuratel |
| CN105820145A (en) * | 2015-01-07 | 2016-08-03 | 成都青山利康药业有限公司 | Method for preparing 5-nitro-2-furaldehyde and nifuratel |
| CN105693709A (en) * | 2016-01-15 | 2016-06-22 | 安徽悦康凯悦制药有限公司 | Technology for producing nifuratel |
| CN108084174A (en) * | 2017-11-28 | 2018-05-29 | 北京朗依制药有限公司 | The preparation method of Nifuratel |
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