CN112457304A - Preparation method of nifuratel - Google Patents
Preparation method of nifuratel Download PDFInfo
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- CN112457304A CN112457304A CN202011429685.3A CN202011429685A CN112457304A CN 112457304 A CN112457304 A CN 112457304A CN 202011429685 A CN202011429685 A CN 202011429685A CN 112457304 A CN112457304 A CN 112457304A
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- nifuratel
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- SRQKTCXJCCHINN-NYYWCZLTSA-N nifuratel Chemical compound O=C1OC(CSC)CN1\N=C\C1=CC=C([N+]([O-])=O)O1 SRQKTCXJCCHINN-NYYWCZLTSA-N 0.000 title claims abstract description 27
- 229960002136 nifuratel Drugs 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 25
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims abstract description 15
- 229940125797 compound 12 Drugs 0.000 claims abstract description 15
- SXINBFXPADXIEY-UHFFFAOYSA-N 5-Nitrofurfural Chemical compound [O-][N+](=O)C1=CC=C(C=O)O1 SXINBFXPADXIEY-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229940125904 compound 1 Drugs 0.000 claims abstract description 9
- 229940125773 compound 10 Drugs 0.000 claims abstract description 9
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 7
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 239000003960 organic solvent Substances 0.000 claims description 23
- 150000001875 compounds Chemical class 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 16
- 230000015572 biosynthetic process Effects 0.000 claims description 16
- 238000003786 synthesis reaction Methods 0.000 claims description 16
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 238000000605 extraction Methods 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- XHXXWWGGXFUMAJ-UHFFFAOYSA-N methanethiol;sodium Chemical compound [Na].SC XHXXWWGGXFUMAJ-UHFFFAOYSA-N 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 6
- 239000012074 organic phase Substances 0.000 claims 2
- 238000000034 method Methods 0.000 abstract description 20
- 239000002994 raw material Substances 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 5
- 238000009835 boiling Methods 0.000 abstract description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000011593 sulfur Substances 0.000 abstract description 2
- 229910052717 sulfur Inorganic materials 0.000 abstract description 2
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 8
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 abstract 2
- -1 Boc group Chemical group 0.000 abstract 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- 238000000967 suction filtration Methods 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 238000001035 drying Methods 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 10
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000000926 separation method Methods 0.000 description 8
- 230000008034 disappearance Effects 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 6
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 238000003912 environmental pollution Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 208000004881 Amebiasis Diseases 0.000 description 1
- 206010001980 Amoebiasis Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- QIQPRTHUKJMOBE-UHFFFAOYSA-N CSCC(CN1N=C2OC([N+]([O-])=O)=CC2)OC1=O Chemical group CSCC(CN1N=C2OC([N+]([O-])=O)=CC2)OC1=O QIQPRTHUKJMOBE-UHFFFAOYSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- 241000224466 Giardia Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 241001502500 Trichomonadida Species 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 206010046914 Vaginal infection Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种硝呋太尔（Nifuratel）的制备方法。该方法包括如下步骤：（1）化合物1（化学名为：环氧氯丙烷）与化合物10（化学名为：肼基甲酸叔丁酯）反应，得到中间体11；（2）中间体11与CDI（化学名为：羰基二咪唑）反应，得到中间体12；（3）化合物12与甲硫醇钠发生取代反应，得到中间体13；（4）在酸的作用下，中间体13脱去结构中的Boc基团，得到中间体4；（5）中间体4与5‑硝基糠醛反应，得到硝呋太尔。本发明提供的工艺路线的优点：路线简短，原料廉价易得，操作简便，反应收率高，避免产生低沸点的含硫中间体，环境友好，易于工业化生产。The present invention relates to a preparation method of nifuratel. The method includes the following steps: (1) compound 1 (chemical name: epichlorohydrin) reacts with compound 10 (chemical name: tert-butylcarbazate) to obtain intermediate 11; (2) intermediate 11 is reacted with CDI (chemical name: carbonyldiimidazole) reacts to obtain intermediate 12; (3) compound 12 undergoes substitution reaction with sodium methanethiolate to obtain intermediate 13; (4) under the action of acid, intermediate 13 is removed The Boc group in the structure obtains the intermediate 4; (5) the intermediate 4 is reacted with 5-nitrofurfural to obtain nifuratel. The advantages of the process route provided by the invention are as follows: the route is short, the raw materials are cheap and easy to obtain, the operation is simple, the reaction yield is high, the generation of low-boiling sulfur-containing intermediates is avoided, the environment is friendly, and the industrial production is easy.
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.
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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 |
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| 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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| 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 |
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