CN115626893B - Synthesis method of 2-hydroxy-5-hydroxymethylpyridine - Google Patents
Synthesis method of 2-hydroxy-5-hydroxymethylpyridine Download PDFInfo
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- CN115626893B CN115626893B CN202211232824.2A CN202211232824A CN115626893B CN 115626893 B CN115626893 B CN 115626893B CN 202211232824 A CN202211232824 A CN 202211232824A CN 115626893 B CN115626893 B CN 115626893B
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- JLPOBAADYFDVAV-UHFFFAOYSA-N 5-(hydroxymethyl)-1h-pyridin-2-one Chemical compound OCC1=CC=C(O)N=C1 JLPOBAADYFDVAV-UHFFFAOYSA-N 0.000 title claims abstract description 37
- 238000001308 synthesis method Methods 0.000 title claims abstract description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- RHOUZEYZPPQSLE-UHFFFAOYSA-N 2-methoxy-5-(methoxymethyl)pyridine Chemical compound COCC1=CC=C(OC)N=C1 RHOUZEYZPPQSLE-UHFFFAOYSA-N 0.000 claims abstract description 25
- 239000002904 solvent Substances 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 16
- SKCNYHLTRZIINA-UHFFFAOYSA-N 2-chloro-5-(chloromethyl)pyridine Chemical compound ClCC1=CC=C(Cl)N=C1 SKCNYHLTRZIINA-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 4
- 230000007062 hydrolysis Effects 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 12
- 238000001704 evaporation Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 9
- 239000005457 ice water Substances 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000003756 stirring Methods 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 238000000605 extraction Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 230000001276 controlling effect Effects 0.000 description 9
- 239000000047 product Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 5
- 238000007792 addition Methods 0.000 description 4
- 239000000575 pesticide Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 102000004157 Hydrolases Human genes 0.000 description 2
- 108090000604 Hydrolases Proteins 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- YYNSXKLGLKOLQZ-UHFFFAOYSA-N ethyl 6-oxo-1h-pyridine-3-carboxylate Chemical compound CCOC(=O)C1=CC=C(O)N=C1 YYNSXKLGLKOLQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002917 insecticide Substances 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- HOKKPVIRMVDYPB-UVTDQMKNSA-N (Z)-thiacloprid Chemical compound C1=NC(Cl)=CC=C1CN1C(=N/C#N)/SCC1 HOKKPVIRMVDYPB-UVTDQMKNSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- HQQTZCPKNZVLFF-UHFFFAOYSA-N 4h-1,2-benzoxazin-3-one Chemical class C1=CC=C2ONC(=O)CC2=C1 HQQTZCPKNZVLFF-UHFFFAOYSA-N 0.000 description 1
- -1 6-difluoromethoxy-pyridin-3-yl-methyl moieties Chemical group 0.000 description 1
- BLHCMGRVFXRYRN-UHFFFAOYSA-N 6-hydroxynicotinic acid Chemical compound OC(=O)C1=CC=C(O)N=C1 BLHCMGRVFXRYRN-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 239000005906 Imidacloprid Substances 0.000 description 1
- 239000005940 Thiacloprid Substances 0.000 description 1
- JFBZPFYRPYOZCQ-UHFFFAOYSA-N [Li].[Al] Chemical compound [Li].[Al] JFBZPFYRPYOZCQ-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- YWTYJOPNNQFBPC-UHFFFAOYSA-N imidacloprid Chemical compound [O-][N+](=O)\N=C1/NCCN1CC1=CC=C(Cl)N=C1 YWTYJOPNNQFBPC-UHFFFAOYSA-N 0.000 description 1
- 229940056881 imidacloprid Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
Abstract
The invention discloses a synthesis method of 2-hydroxy-5-hydroxymethylpyridine, which is characterized by comprising the following steps: (1) Sodium methoxide is added into a solvent, then 2-chloro-5-chloromethylpyridine is added, and methoxy is carried out to obtain 2-methoxy-5- (methoxymethyl) pyridine, wherein the mass ratio of the 2-chloro-5-chloromethylpyridine to sodium methoxide is 1: (2-5); (2) 2-methoxy-5- (methoxymethyl) pyridine reacts with dilute acid, and 2-hydroxy-5-hydroxymethyl pyridine is obtained through hydrolysis, and the method has the advantages of simple process line, mild and safe reaction conditions, high extraction efficiency and lower production cost, and is suitable for large-scale production.
Description
Technical Field
The invention relates to the field of synthesis of medical and pesticide intermediates, in particular to a synthesis method of 2-hydroxy-5-hydroxymethylpyridine.
Background
2-hydroxy-5-hydroxymethyl pyridine is an important intermediate of medicines and pesticides, and has wide application in medicines and pesticides: as reported in patent WO2011012622A1, 2-hydroxy-5-hydroxymethylpyridine is an important intermediate for the synthesis of benzoxazinone derivatives for the treatment of GLYTL-mediated diseases; as also reported in patent US2002049330A1, novel pyridones and their use as serine hydrolase modulators, which modulate serine hydrolase activity and are useful in the treatment of alzheimer's disease, 2-hydroxy-5-hydroxymethylpyridine is a key intermediate in the synthesis of novel pyridones; document Journal of Fluorine Chemistry (2017) 155-165 reports that the pyridine neonicotinoid insecticides imidacloprid (compound 15 below) and thiacloprid (compound 16 below) containing 6-trifluoromethoxy-or 6-difluoromethoxy-pyridin-3-yl-methyl moieties, 2-hydroxy-5-hydroxymethylpyridine, are important intermediates for the synthesis of such novel insecticides.
The traditional synthesis of 2-hydroxy-5-hydroxymethyl pyridine is to take 6-hydroxy nicotinic acid as a starting material, reflux react for more than 48 hours in ethanol with sulfuric acid as a catalyst to obtain 6-hydroxy nicotinic acid ethyl ester, then the 6-hydroxy nicotinic acid ethyl ester is dissolved in tetrahydrofuran, and reduced by lithium aluminum tetrahydroide to obtain a crude 2-hydroxy-5-hydroxymethyl pyridine product, and the crude product is subjected to column purification to obtain the 2-hydroxy-5-hydroxymethyl pyridine; because the traditional process for synthesizing the 2-hydroxy-5-hydroxymethylpyridine is complex in operation, difficult to purify and high in price of initial raw materials, the cost price is high, the price of the 2-hydroxy-5-hydroxymethylpyridine is high, and the cost burden is increased for popularization and application of downstream products of the 2-hydroxy-5-hydroxymethylpyridine.
Disclosure of Invention
The invention aims to solve the technical problem of providing a synthesis method of 2-hydroxy-5-hydroxymethylpyridine, which has the advantages of simple process line, mild and safe reaction conditions and lower production cost and is suitable for large-scale production.
The technical scheme adopted for solving the technical problems is as follows: a synthetic method of 2-hydroxy-5-hydroxymethylpyridine comprises the following steps:
(1) Sodium methoxide is added into a solvent, then 2-chloro-5-chloromethylpyridine is added, and methoxy is carried out to obtain 2-methoxy-5- (methoxymethyl) pyridine;
(2) 2-methoxy-5- (methoxymethyl) pyridine reacts with acid, and 2-hydroxy-5-hydroxymethyl pyridine is obtained through hydrolysis.
Further, the specific process of the step (1) is as follows: adding sodium methoxide into solvent, controlling the temperature not higher than T1, stirring and dissolving, and slowly adding 2-chloro-5-chloromethylpyridine; then heating to T2 until the reaction is completed, evaporating the solvent under reduced pressure, pouring the residue into cold water, extracting with dichloromethane, washing an organic phase twice with saturated salt water, drying with anhydrous sodium sulfate, decolorizing with active carbon, filtering, and evaporating the dichloromethane under reduced pressure to obtain colorless liquid 2-methoxy-5- (methoxymethyl) pyridine, wherein the control temperature of T1 is more than or equal to 0 ℃ and less than or equal to 50 ℃; t2 is controlled at a temperature of 20 ℃ to 140 ℃.
Further, the mass ratio of the 2-chloro-5-chloromethylpyridine to the sodium methoxide is 1: (2-5).
Further, the solvent is methanol, N-Dimethylformamide (DMF), 1, 4-dioxane or tetrahydrofuran.
Further, the specific process of the step (2) is as follows: adding 2-methoxy-5- (methoxymethyl) pyridine into dilute acid, heating to T3 until the reaction is completed, cooling to below room temperature by using an ice water bath, adjusting pH to be between 5 and 6 by using a 50wt% sodium hydroxide aqueous solution, and controlling the temperature to be not higher than T4; evaporating the reaction mixed solution under reduced pressure, extracting the product twice by using ethanol, drying by using anhydrous sodium sulfate, and evaporating the solvent under reduced pressure to obtain white-like solid 2-hydroxy-5-hydroxymethylpyridine, wherein the temperature of T3 is controlled to be more than or equal to 50 ℃ and less than or equal to 150 ℃; t4 is controlled at a temperature of-10 ℃ to-40 ℃.
Further, the dilute acid is dilute sulfuric acid, dilute hydrobromic acid, dilute nitric acid, trifluoroacetic acid or dilute phosphoric acid.
Compared with the prior art, the invention has the advantages that: the invention relates to a method for synthesizing 2-hydroxy-5-hydroxymethyl pyridine, which comprises the steps of firstly synthesizing 2-methoxy-5- (methoxymethyl) pyridine with sodium methoxide, and hydrolyzing the synthesized 2-methoxy-5- (methoxymethyl) pyridine under an acidic condition to obtain the 2-hydroxy-5-hydroxymethyl pyridine. The preparation method uses the 2-chloro-5-chloromethylpyridine with wide raw material sources and low price as the initial raw material, has simple synthesis process, few steps, mild reaction conditions and high total yield up to 88 percent, effectively reduces the production cost, has considerable social and economic benefits and has high industrial application value.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of 2-hydroxy-5-hydroxymethylpyridine synthesized in example 1 of the present invention.
Detailed Description
The invention is described in further detail below with reference to the embodiments of the drawings.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
A synthetic method of 2-hydroxy-5-hydroxymethylpyridine comprises the following steps:
(1) Sodium methoxide is added into a solvent, then 2-chloro-5-chloromethylpyridine is added, and methoxy is carried out to obtain 2-methoxy-5- (methoxymethyl) pyridine;
(2) 2-methoxy-5- (methoxymethyl) pyridine reacts with dilute acid, and is hydrolyzed to obtain 2-hydroxy-5-hydroxymethylpyridine, wherein the synthetic route is as follows:
the specific process of the step (1) is as follows: adding sodium methoxide into solvent, controlling the temperature not higher than T1, stirring and dissolving, and slowly adding 2-chloro-5-chloromethylpyridine; then heating to T2 until the reaction is completed, evaporating the solvent under reduced pressure, pouring the residue into cold water, extracting with dichloromethane, washing an organic phase twice with saturated salt water, drying with anhydrous sodium sulfate, decolorizing with active carbon, filtering, and evaporating the dichloromethane under reduced pressure to obtain colorless liquid 2-methoxy-5- (methoxymethyl) pyridine, wherein the control temperature of T1 is more than or equal to 0 ℃ and less than or equal to 50 ℃; t2 is controlled at a temperature of between 20 and 140 ℃, and the mass ratio of the 2-chloro-5-chloromethylpyridine to sodium methoxide is 1: (2-5), wherein the solvent is methanol, N-Dimethylformamide (DMF), 1, 4-dioxane or tetrahydrofuran.
The specific process of the step (2) is as follows: adding 2-methoxy-5- (methoxymethyl) pyridine into dilute acid, heating to T3 until the reaction is completed, cooling to below room temperature by using an ice water bath, adjusting pH to be between 5 and 6 by using a 50wt% sodium hydroxide aqueous solution, and controlling the temperature to be not higher than T4; evaporating the reaction mixed solution under reduced pressure, extracting the product twice by using ethanol, drying by using anhydrous sodium sulfate, and evaporating the solvent under reduced pressure to obtain white-like solid 2-hydroxy-5-hydroxymethylpyridine, wherein the temperature of T3 is controlled to be more than or equal to 50 ℃ and less than or equal to 150 ℃; t4 is controlled at the temperature of minus 10 ℃ to minus 40 ℃, and the dilute acid is dilute sulfuric acid, dilute hydrobromic acid, dilute nitric acid, trifluoroacetic acid or dilute phosphoric acid, and the concentration is generally 6N.
Example 1
1. Synthesis of 2-methoxy-5- (methoxymethyl) pyridine
Adding 1.5L of absolute methanol into a 3L reaction bottle, slowly adding sodium methoxide (167 g,3.1 mol) under ice water bath, and controlling the temperature to be not higher than 35 ℃; then, 2-chloro-5-chloromethylpyridine (200 g,1.2 mol) was added, and after the addition was completed, the reaction was carried out under stirring at room temperature for 1 hour, the temperature was raised to reflux (about 62 ℃ C.) and the reaction was carried out for 1 hour again; after the reaction was completed, sodium methoxide was evaporated under reduced pressure, the residue was poured into cold water, extracted with methylene chloride, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, decolorized with activated carbon, filtered, and the methylene chloride was evaporated under reduced pressure to give 180g of 2-methoxy-5- (methoxymethyl) pyridine as a colorless liquid in 95% yield.
2. Synthesis of 2-hydroxy-5-hydroxymethylpyridine
In a 500mL reaction bottle, 180mL of water is firstly added into the reaction bottle at normal temperature, stirring is started, 180mL of concentrated hydrochloric acid is added, 50g of 2-methoxy-5- (methoxymethyl) pyridine is finally added, then, the temperature is kept at 100 ℃ for overnight, TLC is sampled the next day, the reaction is complete, the heating is stopped, the oil bath is removed, the ice water bath is used for cooling to below room temperature, the pH value is regulated to 5-6 by using 50% sodium hydroxide aqueous solution, and the temperature is controlled to be lower than 20 ℃; the reaction mixture was evaporated under reduced pressure, the product was extracted twice with ethanol, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 38g of 2-hydroxy-5-hydroxymethylpyridine as an off-white solid in 93% yield. The nuclear magnetic resonance spectrum is shown in figure 1.
Example 2
1. Synthesis of 2-methoxy-5- (methoxymethyl) pyridine
Adding 1.5L of absolute methanol into a 3L reaction bottle, slowly adding sodium methoxide (167 g,3.1 mol) under ice water bath, and controlling the temperature to be not higher than 35 ℃; then, 2-chloro-5-chloromethylpyridine (200 g,1.2 mol) was added thereto, and after the addition was completed, the reaction was stirred at room temperature for 1 hour, the temperature was raised to 50℃and further the reaction was carried out for 1 hour. After the reaction was completed, methanol was distilled off under reduced pressure, the residue was poured into cold water, extracted with methylene chloride, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, decolorized with activated carbon, filtered, and distilled off under reduced pressure to give 169g of 2-methoxy-5- (methoxymethyl) pyridine as a colorless liquid, with a yield of 89%.
2. Synthesis of 2-hydroxy-5-hydroxymethylpyridine
In a 500mL reaction bottle, 180mL of water is firstly added into the reaction bottle at normal temperature, stirring is started, 180mL of concentrated hydrochloric acid is added, and finally 50g of 2-methoxy-5- (methoxymethyl) pyridine is added. Then, the temperature is kept at 75 ℃ overnight; sampling TLC the next day, indicating that the reaction is complete, turning off the heating, removing the oil bath, cooling to below room temperature with ice water bath, adjusting pH to be 5-6 with 50% sodium hydroxide aqueous solution, and controlling the temperature to be lower than 20deg.C; the reaction mixture was evaporated under reduced pressure, the product was extracted twice with ethanol, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 31g of 2-hydroxy-5-hydroxymethylpyridine as an off-white solid in a yield of 76%.
Example 3
1. Synthesis of 2-methoxy-5- (methoxymethyl) pyridine
Adding 1.5L of absolute methanol into a 3L reaction bottle, slowly adding sodium methoxide (167 g,3.1 mol) under ice water bath, and controlling the temperature to be not higher than 25 ℃; then, 2-chloro-5-chloromethylpyridine (200 g,1.2 mol) was added thereto, and the reaction was stirred at room temperature overnight after the addition. After completion of TLC detection, methanol was distilled off under reduced pressure, the residue was poured into cold water, extracted with methylene chloride, the organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, decolorized with active carbon, filtered, and distilled off under reduced pressure to give 120g of 2-methoxy-5- (methoxymethyl) pyridine as a colorless liquid in 63% yield.
2. Synthesis of 2-hydroxy-5-hydroxymethylpyridine
In a 500mL reaction bottle, 180mL of water is firstly added into the reaction bottle at normal temperature, stirring is started, 180mL of concentrated hydrochloric acid is added, and finally 50g of 2-methoxy-5- (methoxymethyl) pyridine is added. Then, the mixture was incubated at 50℃overnight. Sampling TLC the next day, indicating that the reaction is complete, turning off the heating, removing the oil bath, cooling to below room temperature with ice water bath, adjusting pH to be 5-6 with 50% sodium hydroxide aqueous solution, and controlling the temperature to be lower than 20deg.C; the reaction mixture was evaporated under reduced pressure, the product was extracted twice with ethanol, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 26g of 2-hydroxy-5-hydroxymethylpyridine as an off-white solid in a yield of 64%.
The above description is not intended to limit the invention, nor is the invention limited to the examples described above. Variations, modifications, additions, or substitutions will occur to those skilled in the art and are therefore within the spirit and scope of the invention.
Claims (4)
1. The synthesis method of the 2-hydroxy-5-hydroxymethylpyridine is characterized by comprising the following steps of:
(1) Sodium methoxide is added into a solvent, then 2-chloro-5-chloromethylpyridine is added, and methoxy is carried out to obtain 2-methoxy-5- (methoxymethyl) pyridine;
(2) 2-methoxy-5- (methoxymethyl) pyridine reacts with acid, and 2-hydroxy-5-hydroxymethyl pyridine is obtained through hydrolysis;
the specific process of the step (1) is as follows: adding sodium methoxide into solvent, controlling the temperature not higher than T1, stirring and dissolving, and slowly adding 2-chloro-5-chloromethylpyridine; then heating to T2 until the reaction is completed, evaporating the solvent under reduced pressure, pouring the residue into cold water, extracting with dichloromethane, washing an organic phase twice with saturated salt water, drying with anhydrous sodium sulfate, decolorizing with active carbon, filtering, and evaporating the dichloromethane under reduced pressure to obtain colorless liquid 2-methoxy-5- (methoxymethyl) pyridine, wherein the control temperature of T1 is more than or equal to 0 ℃ and less than or equal to 50 ℃; t2 is controlled at a temperature of between 20 and 140 ℃ and T2 is controlled at a temperature of between 140 and 20 ℃;
the solvent is methanol, N-dimethylformamide, 1, 4-dioxane or tetrahydrofuran.
2. The method for synthesizing 2-hydroxy-5-hydroxymethylpyridine according to claim 1, wherein the method comprises the steps of: the mass ratio of the 2-chloro-5-chloromethylpyridine to the sodium methoxide is 1: (2-5).
3. The method for synthesizing 2-hydroxy-5-hydroxymethylpyridine according to claim 1, wherein the specific process of step (2) comprises the following steps: adding 2-methoxy-5- (methoxymethyl) pyridine into dilute acid, heating to T3 until the reaction is completed, cooling to below room temperature by using an ice water bath, adjusting pH to be between 5 and 6 by using a 50wt% sodium hydroxide aqueous solution, and controlling the temperature to be not higher than T4; evaporating the reaction mixed solution under reduced pressure, extracting the product twice by using ethanol, drying by using anhydrous sodium sulfate, and evaporating the solvent under reduced pressure to obtain white-like solid 2-hydroxy-5-hydroxymethylpyridine, wherein the temperature of T3 is controlled to be more than or equal to 50 ℃ and less than or equal to 150 ℃; t4 is controlled at a temperature of-10 ℃ to-40 ℃.
4. A method for synthesizing 2-hydroxy-5-hydroxymethylpyridine according to claim 3, wherein: the dilute acid is dilute sulfuric acid, dilute hydrobromic acid, dilute nitric acid, trifluoroacetic acid or dilute phosphoric acid.
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| US5726315A (en) * | 1993-06-25 | 1998-03-10 | Smithkline Beecham Plc | Certain 3-hydroxy-6-hydroxymethyl-pyridine intermediates |
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| WO2011012622A1 (en) * | 2009-07-30 | 2011-02-03 | Glaxo Group Limited | Benzoxazinone derivatives for the treatment of glytl mediated disorders |
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| KR20140008471A (en) * | 2004-10-21 | 2014-01-21 | 다우 아그로사이언시즈 엘엘씨 | Thieno-pyrimidine compounds having fungicidal activity |
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| US6169183B1 (en) * | 1996-07-23 | 2001-01-02 | Lonza, Ltd. | Process for preparing pyridinecarboxylic esters |
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