CN116655527A - Preparation method and application of 2-methylamino-3-formylpyridine - Google Patents
Preparation method and application of 2-methylamino-3-formylpyridine Download PDFInfo
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- CN116655527A CN116655527A CN202310634207.3A CN202310634207A CN116655527A CN 116655527 A CN116655527 A CN 116655527A CN 202310634207 A CN202310634207 A CN 202310634207A CN 116655527 A CN116655527 A CN 116655527A
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- methylamino
- formylpyridine
- preparation
- cyanopyridine
- reaction
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- HLHGWWKGIQXCKA-UHFFFAOYSA-N 2-(methylamino)pyridine-3-carbaldehyde Chemical compound CNC1=NC=CC=C1C=O HLHGWWKGIQXCKA-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- VYPMWCUNCNMNOM-UHFFFAOYSA-N [2-(methylamino)pyridin-3-yl]methanol Chemical compound CNC1=NC=CC=C1CO VYPMWCUNCNMNOM-UHFFFAOYSA-N 0.000 claims abstract description 24
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims abstract description 23
- GZPHSAQLYPIAIN-UHFFFAOYSA-N 3-pyridinecarbonitrile Chemical compound N#CC1=CC=CN=C1 GZPHSAQLYPIAIN-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000010992 reflux Methods 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 238000010438 heat treatment Methods 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 18
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 9
- 239000013067 intermediate product Substances 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000001953 recrystallisation Methods 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 239000012279 sodium borohydride Substances 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 1
- 238000002156 mixing Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 13
- 238000007086 side reaction Methods 0.000 abstract description 3
- 238000000605 extraction Methods 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 238000002425 crystallisation Methods 0.000 abstract 1
- 230000008025 crystallization Effects 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 238000009835 boiling Methods 0.000 description 8
- -1 lithium aluminum hydride Chemical compound 0.000 description 7
- 239000012467 final product Substances 0.000 description 5
- 239000012280 lithium aluminium hydride Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000008901 benefit Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- KPIVDNYJNOPGBE-UHFFFAOYSA-N 2-aminonicotinic acid Chemical compound NC1=NC=CC=C1C(O)=O KPIVDNYJNOPGBE-UHFFFAOYSA-N 0.000 description 3
- IBRSSZOHCGUTHI-UHFFFAOYSA-N 2-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Cl IBRSSZOHCGUTHI-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 125000003172 aldehyde group Chemical group 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 125000004185 ester group Chemical group 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- SMYTUBMIBZOXTH-UHFFFAOYSA-N 2-(methylamino)pyridine-3-carboxylic acid Chemical compound CNC1=NC=CC=C1C(O)=O SMYTUBMIBZOXTH-UHFFFAOYSA-N 0.000 description 1
- RXTRRIFWCJEMEL-UHFFFAOYSA-N 2-chloropyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1Cl RXTRRIFWCJEMEL-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003674 animal food additive Substances 0.000 description 1
- 229910010277 boron hydride Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000007697 cis-trans-isomerization reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229960002715 nicotine Drugs 0.000 description 1
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ONMWRJQIJQAPQD-UHFFFAOYSA-N tert-butyl 2-(methylamino)pyridine-3-carboxylate Chemical compound CNC1=NC=CC=C1C(=O)OC(C)(C)C ONMWRJQIJQAPQD-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical compound CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention relates to a preparation method of 2-methylamino-3-formylpyridine, which comprises the following steps: and (3) heating and refluxing the 3-cyanopyridine and dimethyl sulfate in an organic solvent I, adding alkali, and continuing to react under the condition of heating and refluxing to obtain an intermediate 2-methylamino-3-formylpyridine. The raw materials used in the preparation method are cheap and easy to obtain, the preparation process has few side reactions and easy purification, and the higher purity can be achieved only by the steps of extraction and heavy crystallization, and the anhydrous reaction condition is not required to be strictly controlled; the yield and purity are high, and the prepared 2-methylamino-3-formylpyridine is suitable for industrial mass production of 2-methylamino-3-hydroxymethylpyridine, thereby preparing isaconazole hydrochloride and/or isaconazole onium sulfate.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of 2-methylamino-3-formylpyridine.
Background
2-methylamino-3-hydroxymethylpyridine (CAS No. 32399-12-5) is an intermediate in the synthesis of isaconazole hydrochloride and isaconazole sulfate.
The synthesis process mainly comprises the following steps:
method 1:
WO2001032652 reports the preparation of 2-methylamino-3-hydroxymethylpyridine from 2-chloronicotinic acid by a 4-step reaction, wherein the final step is the reduction of tert-butyl 2-methylamino-3-picolinate with lithium aluminum hydride to give the product 2-methylamino-3-hydroxymethylpyridine. Methylamine reacts with not only 2-chloronicotinyl chloride but also tert-butyl formate, and the byproducts are more. The synthetic route is as follows:
method 2:
WO2001032652 also discloses another synthetic route:
method 3: WO2010089993 discloses a process for preparing 2-methylamino-3-picolinic acid from 2-chloronicotinic acid as raw material and methylamine hydrochloride, followed by hydrogenation reduction to obtain the product 2-methylamino-3-hydroxymethylpyridine. Wherein, DMF with high boiling point and strong polarity solvent is used, the post-treatment is troublesome, the yield is not high, and the synthetic route is as follows:
method 4:
US68212238 uses 2-aminonicotinic acid as raw material, and the product is obtained through 3 steps of reaction. The raw material 2-amino nicotinic acid is expensive and is not suitable for industrialized large-scale preparation. The synthetic route is as follows:
in the synthetic methods of the patents, lithium aluminum hydride is used as a hydrogenation reducing agent, the reagent is expensive and easy to explode, and the process is required to strictly achieve an anhydrous environment, so that the industrial production is not facilitated.
Method 5:
CN110317165 discloses a process for preparing 2-methylamino-3-hydroxymethylpyridine from compound a in the presence of lewis acid and metal borohydride, which has large steric hindrance and low reactivity of tert-butyl carboxylate, and the synthetic route is as follows:
method 6:
CN108822027 discloses a preparation method of 2-methylamino-3-hydroxymethylpyridine, which is prepared from an intermediate in the synthetic route of WO2010089993 as raw material, and the reaction formula is as follows:
in the method 5 and the method 6, potassium borohydride/sodium is adopted to replace lithium aluminum hydride, but the impurities are more, and the yield is lower.
Method 7:
CN115872926a discloses a preparation method of 2-methylamino-3-hydroxymethyl pyridine, which avoids using lithium aluminum hydride or metal boron hydride compound, but has the advantages of numerous steps, long synthesis time and low yield, and the synthetic route is as follows:
however, the preparation of 2-methylamino-3-hydroxymethylpyridine by the above-mentioned patent method has the disadvantages of low yield, high raw material cost or limited purchase and complicated post-treatment.
Disclosure of Invention
In order to solve the problems that the synthesis method of the intermediate 2-methylamino-3-hydroxymethyl pyridine for preparing the isaconazole hydrochloride and the isaconazole onium sulfate in the prior art is not suitable for industrial operation, such as using a high boiling point solvent, and is not easy to post-treat; the inflammable and explosive substances are used, and the reaction is required to be carried out strictly under anhydrous conditions; the invention provides a method for preparing 2-methylamino-3-formyl, which is suitable for industrialized production of 2-methylamino-3-formyl, and is a preparation process for industrially producing 2-methylamino-3-formyl with low cost and easily available raw materials, and the method is used for preparing 2-methylamino-3-formyl with high purity and high yield.
The present invention provides the following technical solution to solve the above problems.
A method for preparing 2-methylamino-3-formyl, comprising the following steps:
and (3) heating and refluxing the 3-cyanopyridine and dimethyl sulfate in an organic solvent I, adding alkali, and continuing to react under the condition of heating and refluxing to obtain an intermediate 2-methylamino-3-formylpyridine.
The invention takes 3-cyanopyridine (also called as nicotinonitrile and nicotine nitrile) as raw materials, is mainly used as intermediates of medicines, feed additives and pesticides, has lower price than the prior art which takes 2-chloronicotinic acid or 2-aminonicotinic acid as raw materials, and has the cost advantage of industrialized production. And the 3-cyanopyridine and the dimethyl sulfate are subjected to reflux reaction under alkaline conditions, an intermediate product 2-methylamino-3-formylpyridine is prepared by a one-pot method, and the preparation process and the post-treatment are simple.
Further, the molar ratio of 3-cyanopyridine to dimethyl sulfate is 1:1-2, preferably 1:1.1-1.3. Such as 1:1.1, 1:1.2, 1:1.3, etc.
Further, the reaction of the 3-cyanopyridine and the dimethyl sulfate is a heating reaction for 1-5h, then alkali is added for continuing the heating reaction for 1-5h, and the heating reaction is to 60-85 ℃; the alkali is one or the combination of two of sodium hydroxide and potassium hydroxide, and the dosage of the alkali is 2-3 times of the molar quantity of the 3-cyanopyridine.
Further, the reaction solvent of 3-cyanopyridine and dimethyl sulfate is one or two of tetrahydrofuran and 2-methyltetrahydrofuran. Tetrahydrofuran has a boiling point of about 66℃and 2-methyltetrahydrofuran has a boiling point of about 78℃and a high reflux temperature, and thus 2-methyltetrahydrofuran is preferable. However, it is not preferable to select a solvent having a boiling point too high, such as toluene, and the reflux temperature is too high, which is unfavorable for the reaction and even does not allow a smooth production of the product.
Further, the metal borohydride is selected from one or two of sodium borohydride and potassium borohydride, and the dosage of the metal borohydride is 1-1.5 times of the dosage of the intermediate 2-methylamino-3-formylpyridine.
The invention contributes to the prior art in that the intermediate product 2-methylamino-3-formylpyridine is obtained by reacting the raw material 3-cyanopyridine which is cheap and easy to obtain with dimethyl sulfate in one step. The inventors speculate that the following intermediate state reaction occurs in step (S1):
the 3-cyanopyridine is subjected to methylation reaction with dimethyl sulfate, then added with sodium hydroxide or potassium hydroxide, the pyridine ring is opened by a process product, and 2-methylamino-3-formylpyridine is obtained through cis-trans isomerization, ring closing and methyl migration.
Further, the organic solvent I is at least one selected from tetrahydrofuran and 2-methyltetrahydrofuran; the post-reaction treatment is as follows: after the reaction is finished, cooling to room temperature, adding water, standing for layering, taking an organic phase, extracting a water layer by using an organic solvent I, merging the organic phases, washing, drying, recrystallizing a crude product, and obtaining an intermediate product of 2-methylamino-3-formylpyridine. The recrystallization uses at least one of petroleum ether, n-hexane and n-heptane as the solvent; the amount of the recrystallization solvent is not particularly limited, and is generally 3 to 6 times the mass of the product.
The invention also provides a preparation method of the 2-methylamino-3-hydroxymethylpyridine, which comprises the following steps:
(S1) heating and refluxing 3-cyanopyridine and dimethyl sulfate in an organic solvent I, then adding alkali, and continuing to react under the condition of heating and refluxing to obtain an intermediate 2-methylamino-3-formylpyridine;
(S2) reacting the intermediate product 2-methylamino-3-formylpyridine with sodium metal borohydride in an organic solvent II, and then adding water to continue the reaction to prepare the product 2-methylamino-3-hydroxymethyl pyridine.
The invention takes 3-cyano pyridine and dimethyl sulfate as raw materials, firstly prepares 2-methylamino-3-formylpyridine, and then prepares 2-methylamino-3-hydroxymethyl pyridine by reduction under the action of metal borohydride, and the synthetic route is as follows:
further, in the step (S2), the organic solvent II is at least one selected from methanol, ethanol, isopropanol, acetone, and diethyl ether. The post treatment of the step (S2) is concentration, extraction is carried out for 1 to 3 times by using ethyl acetate, the organic phases are combined, concentration and drying are carried out, and the crude product is recrystallized to obtain the product 2-methylamino-3-hydroxymethyl pyridine. The recrystallization solvent is at least one selected from petroleum ether, n-hexane, n-heptane and ethyl acetate, preferably a mixed solvent of n-heptane and ethyl acetate according to the volume ratio of 1-2:1-2.
The invention also provides the use of 2-methylamino-3-formylpyridine for the synthesis of isaconazole hydrochloride and/or isaconazole onium sulfate.
Compared with the prior art, the invention has the following excellent effects:
1. the raw materials used in the invention are cheap and easy to obtain, and the whole reaction process can obtain the product 2-methylamino-3-hydroxymethyl pyridine with high purity and high yield by only two steps.
2. The preparation process has less side reaction, easy purification and high product purity.
3. The functional group of the intermediate product of the invention which needs to be reduced is an aldehyde group, and most of the prior art is an ester group, and the hydrogenation reduction condition of the aldehyde group is milder than that of the ester group, so that the intermediate product does not need to use a reducing reagent such as lithium aluminum hydride and the like, and the reaction does not need anhydrous operation.
4. The preparation method has the advantages of simple steps, low cost and easy obtainment of raw materials, no need of strict control of reaction conditions, high yield and high purity, and is a preparation method which is very suitable for industrial mass production of 2-methylamino-3-hydroxymethylpyridine.
Drawings
FIG. 1 is an HPLC chart of intermediate 2-methylamino-3-formylpyridine obtained in example 1.
FIG. 2 is an HPLC chart of 2-methylamino-3-hydroxymethylpyridine as the product of example 7.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. The following examples facilitate a better understanding of the present invention, but are not intended to limit the same. The experimental methods in the following examples are conventional methods unless otherwise specified.
Example 1
3-cyanopyridine (104.1 g,1 mol), 800g of solvent 2-methyltetrahydrofuran and dimethyl sulfate (138.7 g,1.1 mol) are added into a reaction bottle, reflux reaction is carried out for 3 hours, 50% concentration sodium hydroxide solution (NaOH is 2 mol) is dropwise added under the reflux condition, reflux reaction is continued for 2 hours, the temperature is reduced to 20-25 ℃, water is added, standing and layering are carried out, the water layer is extracted once by 2-methyltetrahydrofuran, the organic phases are combined, the organic phases are washed for 2 times by saturated saline, drying and concentration are carried out, and the crude product is added into n-heptane for recrystallization, thus obtaining an intermediate product 2-methylamino-3-formylpyridine with the purity of 93.8% and the molar yield of 67.4%.
FIG. 1 is an HPLC chart of 2-methylamino-3-formylpyridine as the product of example 1.
The hydrogen spectrum of the intermediate 2-methylamino-3-formylpyridine is as follows: 1 H-NMR(CDCl 3 ):δ3.11(3H,d),6.63-6.66(1H,m),7.76(1H,d),8.37(1H,d),9.80(1H,s)。
example 2
Other conditions and operations were the same as in example 1 except that dimethyl sulfate was used in an amount of 1.3mol. The final product 2-methylamino-3-formylpyridine was 93.5% pure and 71.6% molar yield.
Example 3
Other conditions and operations were the same as in example 1 except that dimethyl sulfate was used in an amount of 1.5mol. The final product 2-methylamino-3-formylpyridine was 93.0% pure and 68.2% molar yield.
Example 4
Other conditions and operations were the same as in example 1 except that dimethyl sulfate was used in an amount of 1.8mol. The final product 2-methylamino-3-formylpyridine was 91.2% pure and 57.9% molar yield.
By comparison of examples 1 to 4, it was found that dimethyl sulfate is preferably 1.1 to 1.3 times that of 3-cyanopyridine, and in this range, the yield can be improved by increasing the amount of dimethyl sulfate. The purity and yield are reduced by continuously increasing the dosage of the dimethyl sulfate, and the reason is probably that the excessive dimethyl sulfate of the hydrogen base solution is methylated.
Example 5
Other conditions and operations were the same as in example 2 except that NaOH was replaced with equimolar amount of KOH. The final product 2-methylamino-3-formylpyridine was 93.7% pure and 70.8% molar yield. It is demonstrated that the use of NaOH and KOH has substantially no effect on the reaction.
Example 6
Other conditions and operations were the same as in example 2 except that the solvent 2-methyltetrahydrofuran was replaced with equal mass of tetrahydrofuran. The final product 2-methylamino-3-formylpyridine was 93.4% pure and 74.5% molar yield. The boiling point of tetrahydrofuran is about 66 ℃, the boiling point of 2-methyltetrahydrofuran is about 78 ℃, and the reflux temperature is high, so that the reaction is facilitated.
Example 7
2-methylamino-3-formylpyridine (68.1 g,0.5 mol), 500g ethanol, and sodium borohydride (18.9 g,0.5 mol) were added to the flask in three portions at 18-25℃with the same amount, and the reaction was continued at 18-25℃for 3 hours after the completion of the addition. Stirring was continued for 5 hours with water. Concentrating to remove ethanol, extracting the water phase with ethyl acetate for 2 times, combining organic phases, drying, concentrating, recrystallizing the crude product with ethyl acetate and n-heptane (v/v=1:1) to obtain the product 2-methylamino-3-hydroxymethylpyridine with a purity of 97.2% and a molar yield of 92.1%.
FIG. 2 is an HPLC chart of 2-methylamino-3-hydroxymethylpyridine as the product of example 7.
The hydrogen spectrum of the product 2-methylamino-3-hydroxymethylpyridine is as follows: 1 H NMR(CDCl 3 ):3.01(d,3H),4.58(s,2H),6.49-6.52(m,1H),7.21(d,1H),8.04(d,1H)。
comparative example 1
Other conditions and operations were the same as in example 2 except that the solvent 2-methyltetrahydrofuran was replaced with equal mass of toluene. The product 2-methylamino-3-formylpyridine was not obtained. Toluene has a boiling point of 110.6 ℃ and a temperature too high, which results in uncontrollable side reactions.
Comparative example 2
Other conditions and operations were the same as in example 1 except that the solvent 2-methyltetrahydrofuran was replaced with equal mass of water. No 2-methylamino-3-formylpyridine was obtained. The presence of water may cause decomposition of dimethyl sulfate at high temperatures.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (10)
1. A method for preparing 2-methylamino-3-formylpyridine, comprising the following steps:
and (3) heating and refluxing the 3-cyanopyridine and dimethyl sulfate in an organic solvent I, adding alkali, and continuing to react under the condition of heating and refluxing to obtain the product 2-methylamino-3-formylpyridine, wherein the organic solvent I is selected from one or two of tetrahydrofuran and 2-methyltetrahydrofuran.
2. The process according to claim 1, wherein the molar ratio of 3-cyanopyridine to dimethyl sulfate is 1:1-2.
3. The process according to claim 1, wherein the molar ratio of 3-cyanopyridine to dimethyl sulfate is 1:1.1-1.3.
4. The preparation method according to claim 1, wherein the reaction of 3-cyanopyridine and dimethyl sulfate is a heat reflux reaction for 1-5 hours, followed by adding a base to continue the heat reflux reaction for 1-5 hours.
5. The preparation method according to claim 1, wherein the alkali is one or a combination of sodium hydroxide and potassium hydroxide, and the amount of the alkali is 2-3 times of the molar amount of the 3-cyanopyridine.
6. The method of manufacturing according to claim 1, further comprising the step of post-treatment: after the reaction is finished, cooling to room temperature, adding water, standing for layering, taking an organic phase, extracting a water layer by using an organic solvent I, merging the organic phases, washing, drying, recrystallizing a crude product, and obtaining an intermediate product of 2-methylamino-3-formylpyridine.
7. The method according to claim 6, wherein the solvent used for recrystallization is one or a combination of two or more of petroleum ether, n-hexane and n-heptane.
8. The preparation method of the 2-methylamino-3-hydroxymethylpyridine is characterized by comprising the following steps of:
(S1) preparing a 2-methylamino-3-formylpyridine according to the method of any one of claims 1-7;
(S2) reacting the 2-methylamino-3-formylpyridine obtained in the step (S1) with sodium metal borohydride in an organic solvent II, and then adding water to continue the reaction to obtain the product 2-methylamino-3-hydroxymethylpyridine.
9. The method according to claim 8, wherein in the step (S2), the metal borohydride is selected from one or a combination of sodium borohydride and potassium borohydride, and the amount of the metal borohydride is 1 to 1.5 times the amount of the intermediate 2-methylamino-3-formylpyridine material; and/or
The organic solvent II is selected from one or more of methanol, ethanol, isopropanol, acetone and diethyl ether; and/or;
step (S2) is followed by a post-treatment comprising the steps of: concentrating, extracting with ethyl acetate for 1-3 times, mixing organic phases, concentrating, drying, and recrystallizing crude product to obtain 2-methylamino-3-hydroxymethyl pyridine; the recrystallization solvent is one or more of petroleum ether, n-hexane, n-heptane and ethyl acetate, preferably a mixed solvent of n-heptane and ethyl acetate according to the volume ratio of 1-2:1-2.
Use of 2-methylamino-3-formylpyridine for the preparation of isaconazole hydrochloride and/or isaconazole onium sulfate.
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