CN118271239B - A method for synthesizing 3-(6-methoxy-2-pyridine)-propionic acid - Google Patents
A method for synthesizing 3-(6-methoxy-2-pyridine)-propionic acid Download PDFInfo
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- CN118271239B CN118271239B CN202410376976.2A CN202410376976A CN118271239B CN 118271239 B CN118271239 B CN 118271239B CN 202410376976 A CN202410376976 A CN 202410376976A CN 118271239 B CN118271239 B CN 118271239B
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 9
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 36
- XHWDFGQAXHSIMH-UHFFFAOYSA-N 2-(bromomethyl)-6-methoxypyridine Chemical compound COC1=CC=CC(CBr)=N1 XHWDFGQAXHSIMH-UHFFFAOYSA-N 0.000 claims abstract description 19
- OPXGBIUWGAUTER-UHFFFAOYSA-N (6-methoxypyridin-2-yl)methanol Chemical compound COC1=CC=CC(CO)=N1 OPXGBIUWGAUTER-UHFFFAOYSA-N 0.000 claims abstract description 17
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims abstract description 14
- 150000003842 bromide salts Chemical class 0.000 claims abstract description 13
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 230000007062 hydrolysis Effects 0.000 claims abstract description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 10
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 8
- 230000009471 action Effects 0.000 claims abstract description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 18
- 238000001308 synthesis method Methods 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 12
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 5
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 5
- 230000035484 reaction time Effects 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 238000000605 extraction Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 7
- 239000002585 base Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000001105 regulatory effect Effects 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YDNWTNODZDSPNZ-UHFFFAOYSA-N 6-methoxypyridine-2-carbaldehyde Chemical compound COC1=CC=CC(C=O)=N1 YDNWTNODZDSPNZ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- VVSWASODHNAKRZ-UHFFFAOYSA-N pyridin-2-yl prop-2-enoate Chemical class C=CC(=O)OC1=CC=CC=N1 VVSWASODHNAKRZ-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 108091006082 receptor inhibitors Proteins 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000002699 waste material Substances 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明属于医药合成领域，具体涉及一种3‑(6‑甲氧基‑2‑吡啶)‑丙酸的合成方法。合成方法包括以下步骤：6‑甲氧基‑2‑吡啶甲醇和对甲苯磺酰氯反应得到对甲苯磺酸酯中间体，然后对甲苯磺酸酯中间体和溴化盐反应得到2‑(溴甲基)‑6‑甲氧基吡啶；2‑(溴甲基)‑6‑甲氧基吡啶在碱作用下与丙二酸二乙酯反应生成3‑(6‑甲氧基‑2‑吡啶甲基)‑丙二酸二乙酯，3‑(6‑甲氧基‑2‑吡啶甲基)‑丙二酸二乙酯水解脱羧后得到3‑(6‑甲氧基‑2‑吡啶)‑丙酸。本发明以6‑甲氧基‑2‑吡啶甲醇为起始原料，经三步取代反应后水解脱羧即可得到3‑(6‑甲氧基‑2‑吡啶)‑丙酸，该方法具有反应步骤少、所用试剂经济廉价、反应条件温和以及产品纯度高的优势，适于工业化生产。
The present invention belongs to the field of pharmaceutical synthesis, and specifically relates to a method for synthesizing 3-(6-methoxy-2-pyridine)-propionic acid. The method comprises the following steps: 6-methoxy-2-pyridinemethanol reacts with p-toluenesulfonyl chloride to obtain a p-toluenesulfonate intermediate, and then the p-toluenesulfonate intermediate reacts with a bromide salt to obtain 2-(bromomethyl)-6-methoxypyridine; 2-(bromomethyl)-6-methoxypyridine reacts with diethyl malonate under the action of a base to generate 3-(6-methoxy-2-pyridylmethyl)-diethyl malonate, and 3-(6-methoxy-2-pyridylmethyl)-diethyl malonate is hydrolyzed and decarboxylated to obtain 3-(6-methoxy-2-pyridine)-propionic acid. The invention uses 6-methoxy-2-pyridinemethanol as a starting material, and performs hydrolysis and decarboxylation after three-step substitution reaction to obtain 3-(6-methoxy-2-pyridine)-propionic acid. The method has the advantages of fewer reaction steps, economical and cheap reagents, mild reaction conditions and high product purity, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of medicine synthesis, and particularly relates to a synthesis method of 3- (6-methoxy-2-pyridine) -propionic acid.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
The 3- (6-methoxy-2-pyridine) -propionic acid can be used as a medical intermediate for synthesizing pyridine and To 11-like receptor inhibitor medicines (CN 114591339B) the current synthesis method of the 3- (6-methoxy-2-pyridine) -propionic acid mainly takes 6-methoxy pyridine-2-formaldehyde as a raw material, and phosphorus ylide undergoes a Witting reaction To obtain substituted pyridylacrylate, and then undergoes Pd/C-H 2 hydrogenation reduction and hydrolysis To obtain the 3- (6-methoxy-2-pyridine) -propionic acid (Angew.chem.int.ed., 2019,58,18513-18518). The problems of the route are that 1.witting reagent is high in price and increases production cost, 2. The reaction generates a large amount of triphenylphosphine oxide, which increases the difficulty of purification and post-treatment of the product, has a large molecular weight, and finally is not in line with the principle of atom economy when being removed as waste, 3. The reduction of double bonds requires Pd/C with high price as a catalyst, which is not beneficial to cost control, and the inflammability and explosiveness of hydrogen gas serving as a reducing agent also increases the potential safety hazard of the production process.
Disclosure of Invention
In order to solve the defects in the prior art, the invention aims to provide a synthesis method of 3- (6-methoxy-2-pyridine) -propionic acid. The method takes the 6-methoxy-2-pyridine methanol as the initial raw material, and the 3- (6-methoxy-2-pyridine) -propionic acid can be obtained through hydrolysis and decarboxylation after three-step substitution reaction.
In order to achieve the above object, the present invention is realized by the following technical scheme:
in a first aspect, a method for synthesizing 3- (6-methoxy-2-pyridine) -propionic acid comprises the following steps:
S1, reacting 6-methoxy-2-pyridine methanol with p-toluenesulfonyl chloride to obtain a p-toluenesulfonate intermediate, and then reacting the p-toluenesulfonate intermediate with bromide salt to obtain 2- (bromomethyl) -6-methoxypyridine;
S2, 2- (bromomethyl) -6-methoxypyridine reacts with diethyl malonate under the action of alkali to generate diethyl 3- (6-methoxy-2-picolyl) -malonate, and the diethyl 3- (6-methoxy-2-picolyl) -malonate is hydrolyzed and decarboxylated to obtain 3- (6-methoxy-2-pyridine) -propionic acid.
Preferably, in the step S1, triethylamine is used as a base in the reaction of 6-methoxy-2-pyridine methanol and p-toluenesulfonyl chloride, and the molar ratio of 6-methoxy-2-pyridine methanol, triethylamine and p-toluenesulfonyl chloride is 1 (0.9-1.1): 0.9-1.1.
Preferably, in the step S1, the reaction temperature of the 6-methoxy-2-pyridine methanol and the p-toluenesulfonyl chloride is 27-30 ℃ and the reaction time is 5-7 h.
Preferably, in step S1, the bromide salt includes at least one of sodium bromide, potassium bromide and lithium bromide.
Preferably, in the step S1, the molar ratio of the 6-methoxy-2-pyridine methanol to the bromide salt is 1 (1-2.5).
Preferably, in step S1, acetone is used as a solvent in the reaction of the p-toluenesulfonate intermediate and the bromide salt, and the mixture is heated and refluxed for 7-9 hours.
Preferably, in step S2, the base includes at least one of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium tert-butoxide, and sodium tert-butoxide.
Preferably, in the step S2, the molar ratio of the 6-methoxy-2-pyridine methanol to the alkali to the diethyl malonate is 1 (1.5-2.5) (0.9-1.1).
Preferably, in the step S2, the temperature of the reaction of the 2- (bromomethyl) -6-methoxypyridine and diethyl malonate under the action of alkali is 15-30 ℃ and the time is 10-14 h.
Preferably, in the step S2, the reaction temperature of hydrolysis is 40-80 ℃ and the reaction time is 3-5 h.
The beneficial effects obtained by one or more of the technical schemes of the invention are as follows:
According to the invention, 6-methoxy-2-pyridine methanol is used as a starting material, nucleophilic substitution reaction is carried out with p-toluenesulfonyl chloride, bromide and diethyl malonate in sequence, and the obtained intermediate is subjected to hydrolytic decarboxylation to obtain 3- (6-methoxy-2-pyridine) -propionic acid, wherein the reactions in all steps can be carried out under normal pressure, the reaction conditions are mild, and high-cost catalysts and reagents are not required.
The total yield of the 3- (6-methoxy-2-pyridine) -propionic acid obtained by the synthesis method is higher than 50%, and byproducts which are difficult to separate are not produced in the reaction process, so that the method is favorable for obtaining a high-purity product.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 shows the nuclear magnetic resonance spectrum of 3- (6-methoxy-2-pyridine) -propionic acid obtained by the synthesis of the present invention.
Detailed Description
The existing 3- (6-methoxy-2-pyridine) -propionic acid synthesis path needs to use expensive Witting reagent and Pd/C catalyst, and by-product triphenylphosphine oxide is difficult to separate, so that the inflammability and the explosiveness of hydrogen in the reaction process increase potential safety hazard.
To solve the above technical problems, a first exemplary embodiment of the present invention provides a method for synthesizing 3- (6-methoxy-2-pyridine) -propionic acid, comprising the steps of:
S1, reacting 6-methoxy-2-pyridine methanol with p-toluenesulfonyl chloride to obtain a p-toluenesulfonate intermediate, and then reacting the p-toluenesulfonate intermediate with bromide salt to obtain 2- (bromomethyl) -6-methoxypyridine;
S2, 2- (bromomethyl) -6-methoxypyridine reacts with diethyl malonate under the action of alkali to generate diethyl 3- (6-methoxy-2-picolyl) -malonate, and the diethyl 3- (6-methoxy-2-picolyl) -malonate is hydrolyzed and decarboxylated to obtain 3- (6-methoxy-2-pyridine) -propionic acid.
In one or more examples of this embodiment, in step S1, triethylamine is used as a base in the reaction of 6-methoxy-2-pyridinemethanol and p-toluenesulfonyl chloride, and the molar ratio of 6-methoxy-2-pyridinemethanol, triethylamine and p-toluenesulfonyl chloride is 1 (0.9 to 1.1): 0.9 to 1.1.
In one or more examples of this embodiment, in step S1, the reaction temperature of 6-methoxy-2-pyridinemethanol and p-toluenesulfonyl chloride is 27 to 30 ℃ for 5 to 7 hours.
In one or more embodiments of this embodiment, in step S1, the bromide salt includes at least one of sodium bromide, potassium bromide, and lithium bromide.
In one or more embodiments of this embodiment, in step S1, the molar ratio of 6-methoxy-2-pyridinemethanol to bromide salt is 1 (1 to 2.5).
In one or more examples of this embodiment, in step S1, acetone is used as a solvent in the reaction of the mesylate intermediate and the bromide salt, and the mixture is heated and refluxed for 7 to 9 hours.
In one or more embodiments of this embodiment, in step S2, the base includes at least one of sodium methoxide, sodium ethoxide, sodium hydroxide, potassium tert-butoxide, and sodium tert-butoxide.
In one or more embodiments of the present invention, in step S2, the molar ratio of 6-methoxy-2-pyridinemethanol to the base is 1 (1.5 to 2.5).
In one or more examples of this embodiment, in step S2, the 2- (bromomethyl) -6-methoxypyridine is reacted with diethyl malonate at a temperature of 15 to 30 ℃ for a time of 10 to 14 hours under the action of a base.
In one or more embodiments of this embodiment, in step S2, the reaction temperature of the hydrolysis is 40 to 80 ℃ and the reaction time is 3 to 5 hours.
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail below with reference to specific examples and comparative examples.
Example 1
700ML of methylene chloride, 6-methoxy-2-pyridinemethanol (139 g,1.0 mol) and triethylamine (101 g,1.0 mol) were mixed as a reaction system, and p-toluenesulfonyl chloride (190 g,1.0 mol) was slowly added to the reaction system at 0℃and stirred rapidly at 27℃for 6 hours after the completion of the dropwise addition. After the reaction was completed, 500mL of cold water was added to the reaction system, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a methanesulfonate intermediate.
The resulting methanesulfonate intermediate was dissolved with 700mL of acetone, lithium bromide solid (174 g,2.0 mol) was added, heated under reflux for 8 hours, the reaction was completed, the acetone solvent was distilled off under reduced pressure, 600mL of methylene chloride and 400mL of water were added to conduct extraction and separation, the organic phase was collected, and the solvent was distilled off under reduced pressure to obtain a crude 2- (bromomethyl) -6-methoxypyridine product.
Diethyl malonate (176 g,1.1 mol) was added to 600mL of ethanol at0 ℃, then sodium hydroxide (80 g,2.0 mol) was slowly added to the solution, stirred for 15min, and the 2- (bromomethyl) -6-methoxypyridine obtained above was slowly added in portions and reacted at room temperature for 12h. 200mL of ice water is added into the reaction system at0 ℃, the temperature is raised to 60 ℃ and the mixture is stirred for 4 hours, the hydrolysis decarboxylation is carried out, the ethanol is removed by rotary evaporation, the pH value is regulated to 6-7 by using a 3M AcOH aqueous solution, 300mL of dichloromethane is added, the liquid is separated by extraction, the collected organic phase is distilled off under reduced pressure, the solvent is removed by reduced pressure, and the crude product is recrystallized to obtain 110g of 3- (6-methoxy-2-pyridine) -propionic acid, and the total yield of three steps is 61%.
The nuclear magnetic hydrogen spectrum of 3- (6-methoxy-2-pyridine) -propionic acid is shown in figure 1 ,1H NMR(500MHz,DMSO)δ12.09(s,1H),7.58(dd,J＝8.2,7.3Hz,1H),6.84(d,J＝7.2Hz,1H),6.61(d,J＝8.2Hz,1H),3.82(s,3H),2.91(t,J＝7.3Hz,2H),2.64(t,J＝7.3Hz,2H).
Example 2
700ML of methylene chloride, 6-methoxy-2-pyridinemethanol (139 g,1.0 mol) and triethylamine (101 g,1.0 mol) were mixed as a reaction system, and p-toluenesulfonyl chloride (190 g,1.0 mol) was slowly added to the reaction system at 0℃and stirred rapidly at 30℃for 6 hours after the completion of the dropwise addition. After the reaction was completed, 500mL of cold water was added to the reaction system, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a p-toluenesulfonate intermediate.
The obtained p-toluenesulfonate intermediate was dissolved with 700mL of acetone, lithium bromide solid (174 g,2.0 mol) was added, heated under reflux for 8h, the reaction was completed, the acetone solvent was distilled off under reduced pressure, 600mL of methylene chloride and 400mL of water were added for extraction and separation, and the organic phase was collected and the solvent was distilled off under reduced pressure to obtain a crude 2- (bromomethyl) -6-methoxypyridine product.
Diethyl malonate (176 g,1.1 mol) was added to 600mL of ethanol at 5 ℃, then sodium ethoxide (136 g,2.0 mol) was slowly added to the solution, stirred for 15min, and the 2- (bromomethyl) -6-methoxypyridine obtained above was slowly added in portions and reacted at room temperature for 12h. 200mL of ice water is slowly added into the reaction system at 0 ℃, the temperature is raised to 60 ℃ and the reaction system is stirred for 4 hours, the hydrolysis decarboxylation is carried out, the ethanol is removed by rotary evaporation, the pH value is regulated to 6-7 by using a 3M AcOH aqueous solution, 300mL of dichloromethane is added, the liquid is separated by extraction, the collected organic phase is removed by reduced pressure distillation, the crude product is recrystallized to obtain 148g of 3- (6-methoxy-2-pyridine) -propionic acid, and the total three-step yield is 82%.
Example 3
700ML of methylene chloride, 6-methoxy-2-pyridinemethanol (139 g,1.0 mol) and triethylamine (101 g,1.0 mol) were mixed as a reaction system, and p-toluenesulfonyl chloride (190 g,1.0 mol) was slowly added to the reaction system at 0℃and stirred rapidly at 27℃for 6 hours after the completion of the dropwise addition. After the reaction was completed, 500mL of cold water was added to the reaction system, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a methanesulfonate intermediate.
The resulting methanesulfonate intermediate was dissolved with 700mL of acetone, lithium bromide solid (174 g,2.0 mol) was added, heated under reflux for 8 hours, the reaction was completed, the acetone solvent was distilled off under reduced pressure, 600mL of methylene chloride and 400mL of water were added to conduct extraction and separation, the organic phase was collected, and the solvent was distilled off under reduced pressure to obtain a crude 2- (bromomethyl) -6-methoxypyridine product.
Diethyl malonate (176 g,1.1 mol) was added to 600mL of ethanol at 5 ℃, then potassium hydroxide (124 g,2.0 mol) was slowly added to the solution, stirred for 15min, and the 2- (bromomethyl) -6-methoxypyridine obtained above was slowly added in portions and reacted at room temperature for 12h. 200mL of ice water is added into the reaction system at0 ℃, the temperature is raised to 60 ℃ and the mixture is stirred for 4 hours, the hydrolysis decarboxylation is carried out, the ethanol is removed by rotary evaporation, the pH value is regulated to 6-7 by using a 3M AcOH aqueous solution, 300mL of dichloromethane is added, the liquid is separated by extraction, the collected organic phase is distilled off under reduced pressure, the solvent is removed by reduced pressure, the crude product is recrystallized to obtain 96g of 3- (6-methoxy-2-pyridine) -propionic acid, and the total yield of three steps is 53 percent.
Example 4
700ML of methylene chloride, 6-methoxy-2-pyridinemethanol (139 g,1.0 mol) and triethylamine (101 g,1.0 mol) were mixed as a reaction system, and p-toluenesulfonyl chloride (190 g,1.0 mol) was slowly added to the reaction system at 0℃and stirred rapidly at 30℃for 6 hours after the completion of the dropwise addition. After the reaction was completed, 500mL of cold water was added to the reaction system, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain a methanesulfonate intermediate.
The resulting methanesulfonate intermediate was dissolved with 700mL of acetone, sodium bromide solid (206 g,2.0 mol) was added, heated under reflux for 8 hours, the reaction was completed, the acetone solvent was distilled off under reduced pressure, 600mL of methylene chloride and 400mL of water were added to conduct extraction and separation, the organic phase was collected, and the solvent was distilled off under reduced pressure to obtain a crude 2- (bromomethyl) -6-methoxypyridine product.
Diethyl malonate (176 g,1.1 mol) was added to 600mL of ethanol at0 ℃, then sodium ethoxide (136 g,2.0 mol) was slowly added to the solution, stirred for 15min, and the 2- (bromomethyl) -6-methoxypyridine obtained above was slowly added in portions and reacted at room temperature for 12h. 200mL of ice water is added into the reaction system at0 ℃, the temperature is raised to 60 ℃ and the mixture is stirred for 4 hours, the hydrolysis decarboxylation is carried out, the ethanol is removed by rotary evaporation, the pH value is regulated to 6-7 by using a 3M AcOH aqueous solution, 300mL of dichloromethane is added, the liquid is separated by extraction, the collected organic phase is distilled off under reduced pressure, the solvent is removed by reduced pressure, and the crude product is recrystallized to obtain 136g of 3- (6-methoxy-2-pyridine) -propionic acid, and the total yield of three steps is 75%.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
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