CN102476983A - Synthetic method of 6-methoxy-2-naphthaldehyde - Google Patents
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- VZBLASFLFFMMCM-UHFFFAOYSA-N 6-methoxynaphthalene-2-carbaldehyde Chemical compound C1=C(C=O)C=CC2=CC(OC)=CC=C21 VZBLASFLFFMMCM-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000010189 synthetic method Methods 0.000 title claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 30
- AYFJBMBVXWNYLT-UHFFFAOYSA-N 2-bromo-6-methoxynaphthalene Chemical compound C1=C(Br)C=CC2=CC(OC)=CC=C21 AYFJBMBVXWNYLT-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000005893 bromination reaction Methods 0.000 claims abstract description 12
- LUZDYPLAQQGJEA-UHFFFAOYSA-N 2-Methoxynaphthalene Chemical compound C1=CC=CC2=CC(OC)=CC=C21 LUZDYPLAQQGJEA-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006722 reduction reaction Methods 0.000 claims abstract description 9
- 239000000243 solution Substances 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 229960000583 acetic acid Drugs 0.000 claims description 6
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 238000010907 mechanical stirring Methods 0.000 claims description 3
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims 2
- 238000001308 synthesis method Methods 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 4
- 238000009776 industrial production Methods 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- YZBILXXOZFORFE-UHFFFAOYSA-N 6-Methoxy-2-naphthoic acid Chemical compound C1=C(C(O)=O)C=CC2=CC(OC)=CC=C21 YZBILXXOZFORFE-UHFFFAOYSA-N 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 229960004270 nabumetone Drugs 0.000 description 2
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- -1 filter Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- XZBIXDPGRMLSTC-UHFFFAOYSA-N formohydrazide Chemical compound NNC=O XZBIXDPGRMLSTC-UHFFFAOYSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
技术领域 technical field
本发明涉及化工领域，具体涉及一种6-甲氧基-2-萘甲醛的合成方法。The invention relates to the field of chemical industry, in particular to a method for synthesizing 6-methoxy-2-naphthaldehyde.
背景技术 Background technique
6-甲氧基-2-萘甲醛是非甾体抗炎药-萘丁美酮的关键中间体。萘丁美酮又名瑞力芬，是在上世纪80年代初上市的非甾体抗炎药，用于治疗类风湿性关节炎、骨关节炎等，以及其他需抗炎治疗的类似症状。其独特的药代动力学特征和良好的安全性，使其成为目前世界上应用最广泛的非甾体抗炎药之一。6-Methoxy-2-naphthaldehyde is a key intermediate of non-steroidal anti-inflammatory drug-nabumetone. Nabumetone, also known as Relifine, is a non-steroidal anti-inflammatory drug that was launched in the early 1980s. It is used to treat rheumatoid arthritis, osteoarthritis, etc., and other similar symptoms that require anti-inflammatory treatment. Its unique pharmacokinetic characteristics and good safety make it one of the most widely used non-steroidal anti-inflammatory drugs in the world.
近年来，合成6-甲氧基-2-萘甲醛的方法主要有：In recent years, the methods for synthesizing 6-methoxy-2-naphthaldehyde mainly include:
1)由6-甲氧基-2-萘甲酸与硫酸二甲酯发生酯化反应制得6-甲氧基-2-萘甲酸，再与水合肼反应得到6-甲氧基-2-萘甲酰肼，最后通过McFadyen-Stevens还原反应得到化合物6-甲氧基-2-萘甲醛，此方法的缺点是硫酸二甲酯毒性大，水合肼对环境污染较强，另外原料6-甲氧基-2-萘甲酸价格较贵，而且路线较长，收率低，不利于工业化生产。1) 6-methoxy-2-naphthoic acid is obtained by the esterification reaction of 6-methoxy-2-naphthoic acid and dimethyl sulfate, and then reacted with hydrazine hydrate to obtain 6-methoxy-2-naphthalene Formic hydrazide, and finally obtain the compound 6-methoxy-2-naphthaldehyde through the McFadyen-Stevens reduction reaction. The disadvantage of this method is that dimethyl sulfate is highly toxic, and hydrazine hydrate is relatively polluting to the environment. In addition, the raw material 6-methoxy Base-2-naphthoic acid is more expensive, and the route is longer and the yield is low, which is not conducive to industrial production.
2)以2-甲氧基萘为中间体，通过溴代、还原、格氏反应，制得化合物6-甲氧基-2-萘甲醛，在格氏反应一步，产物分离困难，后处理应用了柱层析的方法，难以进行工业化生产。2) Using 2-methoxynaphthalene as an intermediate, the compound 6-methoxy-2-naphthaldehyde is obtained through bromination, reduction, and Grignard reaction. In one step of the Grignard reaction, the product is difficult to separate, and the post-treatment application The method of column chromatography is difficult to carry out industrial production.
发明内容 Contents of the invention
为克服现有技术中的不足，本发明的目的在于提供一种制得率高、纯度好、适合工业化生产应用的双稠吡咯啶-9-乙酸盐酸盐的制备方法。In order to overcome the deficiencies in the prior art, the object of the present invention is to provide a method for preparing double-condensed pyrrolidine-9-acetic acid hydrochloride with high yield, good purity and suitable for industrial production.
为解决上述技术问题，实现上述技术效果，本发明采用了以下技术方案：In order to solve the above-mentioned technical problems and realize the above-mentioned technical effects, the present invention adopts the following technical solutions:
一种6-甲氧基-2-萘甲醛的合成方法，将2-甲氧基萘经过溴代反应和还原反应生成6-溴-2-甲氧基萘，其特征在于，将所述6-溴-2-甲氧基萘与N，N-二甲基甲酰胺反应合成所述6-甲氧基-2-萘甲醛。A kind of synthetic method of 6-methoxy-2-naphthalene formaldehyde, 2-methoxynaphthalene generates 6-bromo-2-methoxynaphthalene through bromination reaction and reduction reaction, it is characterized in that, described 6 -Bromo-2-methoxynaphthalene reacts with N,N-dimethylformamide to synthesize said 6-methoxy-2-naphthylcarbaldehyde.
进一步的，所述6-溴-2-甲氧基萘与N，N-二甲基甲酰胺反应生成6-甲氧基-2-萘甲醛的具体过程包括以下步骤：Further, the specific process that the 6-bromo-2-methoxynaphthalene reacts with N, N-dimethylformamide to generate 6-methoxy-2-naphthaldehyde comprises the following steps:
步骤1)在氮气的保护下，在一反应容器中分别加入6-溴-2-甲氧基萘溶液和无水四氢呋喃溶液，充分搅拌一段时间；Step 1) under the protection of nitrogen, respectively add 6-bromo-2-methoxynaphthalene solution and anhydrous tetrahydrofuran solution into a reaction vessel, and fully stir for a period of time;
步骤2)将所述反应容器冷却一段时间后，逐步滴加正丁基锂溶液，充分搅拌一段时间；Step 2) After cooling the reaction vessel for a period of time, gradually add n-butyllithium solution dropwise, and fully stir for a period of time;
步骤3)再往所述反应容器中逐步滴加N，N-二甲基甲酰胺溶液，控制反应温度、充分搅拌一段时间；Step 3) adding N,N-dimethylformamide solution gradually dropwise to the reaction vessel, controlling the reaction temperature and fully stirring for a period of time;
步骤4)再往所述反应容器中加入饱和的氯化铵溶液，充分搅拌一段时间；Step 4) add saturated ammonium chloride solution to the reaction vessel again, fully stir for a period of time;
步骤5)将上述反应液用乙酸乙酯萃取，合并有机相，得到萃取物；Step 5) extracting the above reaction solution with ethyl acetate, combining the organic phases to obtain the extract;
步骤6)所述萃取物用无水硫酸钠干燥、旋干，得到油状液体；Step 6) the extract is dried with anhydrous sodium sulfate and spin-dried to obtain an oily liquid;
步骤7)所述油状液体用乙酸乙酯重结晶，得到黄色固体，所述黄色固体即为本发明的6-甲氧基-2-萘甲醛。Step 7) The oily liquid is recrystallized with ethyl acetate to obtain a yellow solid, which is 6-methoxy-2-naphthaldehyde of the present invention.
进一步的，所述溴代反应包括以下具体过程：首选，在冰醋酸溶液中、机械搅拌下，加入2-甲氧基萘，冰浴冷却，控制反应温度在30℃以下，然后，将溴素和冰醋酸的混合液慢慢滴加至反应液中，滴加完毕后，室温、充分搅拌，得到溴代反应液。Further, the bromination reaction includes the following specific process: firstly, in glacial acetic acid solution, under mechanical stirring, add 2-methoxynaphthalene, cool in an ice bath, control the reaction temperature below 30°C, and then, the bromine The mixed solution with glacial acetic acid was slowly added dropwise to the reaction solution, and after the dropwise addition was completed, it was fully stirred at room temperature to obtain a bromination reaction solution.
进一步的，所述还原反应包括以下具体过程：往所述溴代反应液中加入水溶液，缓慢加热至回流，分批加入锡粉后继续回流，冷却至室温，再加入水溶液，过滤，所得滤饼用乙酸乙酯重结晶Further, the reduction reaction includes the following specific process: adding an aqueous solution to the bromination reaction solution, slowly heating to reflux, adding tin powder in batches and continuing to reflux, cooling to room temperature, adding an aqueous solution, and filtering to obtain a filter cake Recrystallized from ethyl acetate
本发明以化合物2-甲氧基萘为原料，通过溴代反应及经锡粉还原制得化合物6-溴-2-甲氧基萘，所述6-溴-2-甲氧基萘与N，N-二甲基甲酰胺作用，不需柱色谱纯化，即制得高纯度的6-甲氧基-2-萘甲醛，并使收率有所提高。The present invention uses compound 2-methoxynaphthalene as a raw material, and obtains compound 6-bromo-2-methoxynaphthalene through bromination reaction and tin powder reduction, and described 6-bromo-2-methoxynaphthalene and N , N-dimethylformamide, without column chromatography purification, that is, the preparation of high-purity 6-methoxy-2-naphthaldehyde, and the yield has increased.
具体实施方式 Detailed ways
一种6-甲氧基-2-萘甲醛的合成方法，将2-甲氧基萘经过溴代反应和还原反应生成6-溴-2-甲氧基萘，其特征在于，将所述6-溴-2-甲氧基萘与N，N-二甲基甲酰胺反应合成所述6-甲氧基-2-萘甲醛。A kind of synthetic method of 6-methoxy-2-naphthalene formaldehyde, 2-methoxynaphthalene generates 6-bromo-2-methoxynaphthalene through bromination reaction and reduction reaction, it is characterized in that, described 6 -Bromo-2-methoxynaphthalene reacts with N,N-dimethylformamide to synthesize said 6-methoxy-2-naphthylcarbaldehyde.
(1)6-溴-2-甲氧基萘(4)的合成(1) Synthesis of 6-bromo-2-methoxynaphthalene (4)
在200mL三颈瓶中加入20mL冰醋酸，机械搅拌下，加入2-甲氧基萘5g(31.6mmol)。冰浴冷却，控制反应温度在30℃以下，将溴素10g(63.2mmol)和10mL冰醋酸的混合液慢慢滴加至反应液中，滴加完毕后，室温搅拌1h。Add 20 mL of glacial acetic acid into a 200 mL three-necked flask, and add 5 g (31.6 mmol) of 2-methoxynaphthalene under mechanical stirring. Cool in an ice bath, control the reaction temperature below 30°C, slowly add a mixture of 10 g (63.2 mmol) of bromine (63.2 mmol) and 10 mL of glacial acetic acid to the reaction solution dropwise, and stir at room temperature for 1 h after the addition is complete.
往上述反应液中加入15mL水，开始缓慢加热至回流，分批加入5.5g锡粉(46.2mmol)，后继续回流2-3h，冷却至室温，加入100mL水，过滤，滤饼用乙酸乙酯重结晶，得到白色固体6.7g，收率89.4％，mp103-105℃。Add 15mL of water to the above reaction solution, start to slowly heat to reflux, add 5.5g of tin powder (46.2mmol) in batches, then continue to reflux for 2-3h, cool to room temperature, add 100mL of water, filter, filter cake with ethyl acetate Recrystallization gave 6.7 g of white solid, yield 89.4%, mp 103-105°C.
(2)6-甲氧基-2-萘甲醛(1)的合成(2) Synthesis of 6-methoxy-2-naphthaldehyde (1)
在氮气保护、搅拌的条件下，于200mL三颈瓶中加入6-溴-2-甲氧基萘6.7g(28.3mmol)和50mL无水四氢呋喃，冷却至-78℃，将20mL(31.9mmol)正丁基锂缓慢滴加到反应液中，继续搅拌1h，然后将6.2g(85.0mmol)N，N-二甲基甲酰胺溶液滴加到反应液中，控制反应液温度在-70℃左右，继续搅拌1h。Under the condition of nitrogen protection and stirring, 6.7g (28.3mmol) of 6-bromo-2-methoxynaphthalene and 50mL of anhydrous tetrahydrofuran were added to a 200mL three-necked flask, cooled to -78°C, and 20mL (31.9mmol) Slowly add n-butyl lithium dropwise into the reaction solution, continue stirring for 1 hour, then add 6.2g (85.0mmol) N,N-dimethylformamide solution dropwise into the reaction solution, and control the temperature of the reaction solution at about -70°C , continue stirring for 1h.
反应液加入40mL饱和氯化铵，继续搅拌10min后，用乙酸乙酯(3×20mL)萃取，合并有机相，无水硫酸钠干燥，旋干，得到油状液体，乙酸乙酯重结晶，得到黄色固体4.2g，收率80.3％，mp76-77℃。Add 40 mL of saturated ammonium chloride to the reaction solution, continue stirring for 10 min, extract with ethyl acetate (3×20 mL), combine the organic phases, dry over anhydrous sodium sulfate, and spin dry to obtain an oily liquid, which is recrystallized from ethyl acetate to obtain a yellow Solid 4.2g, yield 80.3%, mp76-77°C.
上述实施例只是为了说明本发明的技术构思及特点，其目的是在于让本领域内的普通技术人员能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡是根据本发明内容的实质所作出的等效的变化或修饰，都应涵盖在本发明的保护范围内。The above-mentioned embodiments are only to illustrate the technical concept and characteristics of the present invention, and its purpose is to enable those of ordinary skill in the art to understand the content of the present invention and implement it accordingly, and cannot limit the protection scope of the present invention. All equivalent changes or modifications made according to the essence of the present invention shall fall within the protection scope of the present invention.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103664542A (en) * | 2013-11-26 | 2014-03-26 | 南京工业大学 | Method for preparing 2-bromo-6-methoxynaphthalene by using microchannel modular reaction device |
| CN104418716A (en) * | 2013-08-20 | 2015-03-18 | 福建省力菲克生物技术有限公司 | Preparation method of nabumetone intermediate 2-methoxyl-6-naphthaldehyde |
-
2010
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| 《Bioorganic & Medicinal Chemistry》 20040707 Nobuyuki Matsunaga et al. C17,20-lyase inhibitors. Part 2: Design, synthesis and structure-activity relationships of (2-naphthylmethyl)-1H-imidazoles as novel C17,20-lyase inhibitors 4313-4336 1-4 第12卷, * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104418716A (en) * | 2013-08-20 | 2015-03-18 | 福建省力菲克生物技术有限公司 | Preparation method of nabumetone intermediate 2-methoxyl-6-naphthaldehyde |
| CN103664542A (en) * | 2013-11-26 | 2014-03-26 | 南京工业大学 | Method for preparing 2-bromo-6-methoxynaphthalene by using microchannel modular reaction device |
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Application publication date: 20120530 |