CN104418716A - Preparation method of nabumetone intermediate 2-methoxyl-6-naphthaldehyde - Google Patents
Preparation method of nabumetone intermediate 2-methoxyl-6-naphthaldehyde Download PDFInfo
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- CN104418716A CN104418716A CN201310363798.1A CN201310363798A CN104418716A CN 104418716 A CN104418716 A CN 104418716A CN 201310363798 A CN201310363798 A CN 201310363798A CN 104418716 A CN104418716 A CN 104418716A
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- naphthaldehyde
- nabumetone
- preparation
- methoxynaphthalene
- bromo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
- C07C41/24—Preparation of ethers by reactions not forming ether-oxygen bonds by elimination of halogens, e.g. elimination of HCl
Abstract
The invention discloses a preparation method of a nabumetone intermediate 2-methoxyl-6-naphthaldehyde. The preparation method comprises following steps: with 2-methoxylnaphthalene as an initial raw material, performing bromination to obtain 1,6-dibromo-2-methoxylnaphthalene; performing metal reduction to prepare 6-bromo-2-methoxylnaphthalene with a zinc-copper alloy as a reducing agent in a solvent, wherein a mass fraction of zinc is 50-100%; and further carrying out a Grignard reaction to prepare the 2-methoxyl-6-naphthaldehyde. The method is low in cost, is mild in reaction conditions and is good in selectivity.
Description
Technical field
The invention belongs to biomedicine field, specifically relate to a kind of synthetic method of intermediate of nabumetone 2-methoxyl group-6-naphthaldehyde.
Background technology
Nabumetone (Nabumetone) has another name called Maxicom, Relafen, Nai Bumeitong, chemistry 4-by name (6-methoxyl group-2-how base)-2-butanone, be Beecham company of Britain exploitation non_steroidal anti_inflammatory drug of new generation, 1985 first in love orchid sell with trade(brand)name RELIFEX.Nabumetone belongs to the prodrug of ketone type structure, have antipyretic, analgesia and anti-inflammatory action, it can be metabolised in liver has bioactive 6-methoxyl-2-naphthylacetic acid (6-MAN), and metabolite without hepato-enteric circulation, but excretes through urine.Nabumetone is non-acid type antiphlogiston, to gastrointestinal mucosa without direct hormesis, long-term taking better tolerance, the long half-lift of having comparatively, be one to all kinds of inflammation and pain all have good therapeutic effect first-line treatment medicine (Chen little Quan, Zuo Zhili, Chou Yuqin etc. nabumetone synthesis improvement. organic chemistry, 2010,30 (7): 1069-1071.).
From the people such as Chatterjee in 1972 publish thesis report nabumetone synthetic method so far (Chatterjee J N et al. Indian J Chem 1973,11:214), the synthesis of this medicine relevant is existing much to be reported.Wherein, the route being intermediate and then synthesis nabumetone with 2-methoxyl group-6-naphthaldehyde, the advantage such as be easy to get because it has raw material, easy and simple to handle, production cost is low, quite by the concern of medical personal.Therefore, the synthesising process research of 2-methoxyl group-6-naphthaldehyde is just seemed particularly important.At present, the existing reported in literature synthesized about this intermediate is starting raw material mainly with beta naphthal, and through methylating, bromination, metallic reducing obtain the bromo-6-methoxynaphthalene of 2-, then prepare 2-methoxyl group-6-naphthaldehyde through grignard reaction.In reduction step, metallic reducing agent common be at present metallic tin (Chen Wanjie. Survey of Synthetic Routes For Nabumetone. medicine industry, 1987,18 (10): 477-478), but the shortcoming such as at the bottom of there is expensive, poor selectivity, yied of redution, limits the development and application of this technique.Therefore, the application intends improving the metallic reducing step of preparation 2-methoxyl group-6-naphthaldehyde intermediate, namely substitutes existing reductive agent metallic tin with platina cheap and easy to get, thus improves reaction preference, cost-saving, improves economic benefits.
Summary of the invention
The object of the invention is to provide a kind of preparation method of Intermediate of Nabumetone, 6-Methoxy-2-naphthaldehyde, there is the defects such as expensive, poor selectivity to overcome in prior art.
To achieve these goals, solution of the present invention is:
The preparation method of intermediate of nabumetone 2-methoxyl group-6-naphthaldehyde, comprise the following steps: with 2-methoxynaphthalene for initial feed, 1 is obtained through bromination, the bromo-2-methoxynaphthalene of 6-bis-, adopt platina as reductive agent in a solvent, wherein the massfraction of zinc is 50% ~ 100%, obtains after the bromo-2-methoxynaphthalene of 6-through metallic reducing, then prepares 2-methoxyl group-6-naphthaldehyde through grignard reaction further.
Reaction scheme of the present invention is as follows:
During metal reduction reaction, temperature and the yield of reaction times on product all have impact, and temperature is too high, and the reaction times is long, easily cause two bromines of the bromo-2-methoxynaphthalene of 1,6-bis-to be all reduced, and generate by product; If but temperature of reaction is too low, the time is too short, speed of response can be caused slow, and reaction time is long.
Described metal reduction reaction temperature is 40 ~ 120
oc, the reaction times is 0.5 ~ 20 hour, and the mol ratio of metallic reducing agent consumption and the bromo-2-methoxynaphthalene of reaction substrate 1,6-bis-is 1:0.01 ~ 1.Preferred: metal reduction reaction temperature is 60 ~ 120
oc, the reaction times is 0.5 ~ 10 hour, and the mol ratio of metallic reducing agent consumption and the bromo-2-methoxynaphthalene of reaction substrate 1,6-bis-is 1:0.1 ~ 0.5.
Described metal reduction reaction solvent for use is the mixing solutions of acetic acid and water, and mass ratio is acetic acid: water=1 ~ 50: 1.Preferred: metal reduction reaction solvent for use is the mixing solutions of acetic acid and water, mass ratio is acetic acid: water=1 ~ 10: 1.
Feature of the present invention is to improve metallic reducing step in existing preparation method, when metallic reducing prepares 6-bromo-2-methoxynaphthalene, adopts platina to replace metallic tin to be reductive agent.
After adopting such scheme, utilize the method for the invention to prepare Intermediate of Nabumetone, 6-Methoxy-2-naphthaldehyde, there is productive rate high (more than 75%), product purity advantages of higher.
The metallic reducing agent that the inventive method adopts is with low cost, wide material sources, and selectivity is good, and the method operating procedure is simple, and reaction conditions is gentle, is beneficial to industrialization and commercially produces and have production cost advantage.
Accompanying drawing explanation
Fig. 1 is the nuclear magnetic spectrogram of the bromo-2-methoxynaphthalene of 6-in embodiment 1;
Fig. 2 is the infrared spectrum of the bromo-2-methoxynaphthalene of 6-in embodiment 1;
Fig. 3 is the high-efficient liquid phase chromatogram of the bromo-2-methoxynaphthalene of 6-in embodiment 2.
Embodiment
Below in conjunction with embodiment, the inventive method is further elaborated, but is not limited to following examples.
embodiment 1
the preparation of the bromo-2-methoxynaphthalene of 6-
In the reactor of 1 L, add 8 g 2-methoxynaphthalenes, 24 g bromines, 24 g platinas (in platina, Zn content is 50%) and 50 mL massfractions are in the aqueous acetic acid of 50%, 80
oreact 15 hours under C.Filter, add 200 mL water in filtrate, suction filtration, dry, obtain the bromo-2-methoxynaphthalene of 10.1 g 6-, purity 98.91%, productive rate 88%.Fig. 1 is the nuclear magnetic spectrogram of the bromo-2-methoxynaphthalene of 6-of this embodiment 1, wherein,
1h NMR (400 MHz, CDCl
3) δ 7.92 (d,
j=1.6 Hz, 1H), 7.62 (dd,
j=15.8,8.9 Hz, 2H), 7.50 (dd,
j=8.7,1.9 Hz, 1H), 7.16 (dd,
j=9.0,2.5 Hz, 1H), 7.10 (d,
j=2.3 Hz, 1H), 3.92 (s, 3H).Fig. 2 is the infrared spectrum of the bromo-2-methoxynaphthalene of 6-of this embodiment 1.
the preparation of 2-methoxyl group-6-naphthaldehyde
In the reactor of 1L, add 200 mL anhydrous tetrahydro furans, 30 g magnesium powder, 0.5 gram of monobromethane, 60
oCunder add the 300 mL anhydrous tetrahydrofuran solutions and 50 mL anhydrous dimethyl formamides that are dissolved with the bromo-2-methoxynaphthalene of 150 g 6-, back flow reaction 8 hours.Remove solvent under reduced pressure, obtain clear yellow viscous thing, adding 200 mL massfractions is the aqueous acetic acid of 40%, suction filtration, obtains 9.8 g 2-methoxyl group-6-naphthaldehydes, purity 99.5%, productive rate 82%.
embodiment 2
the preparation of the bromo-2-methoxynaphthalene of 6-
In the reactor of 1 L, add 8 g 2-methoxynaphthalenes, 24 g bromines, 19.2 g platinas (in platina, Zn content is 75%) and 15 mL massfractions are in the aqueous acetic acid of 50%, 80
oreact 6 hours under C.Filter, add 100 mL water in filtrate, suction filtration, dry, obtain the bromo-2-methoxynaphthalene of 9.5 g 6-, purity 96.5%, productive rate 82.5%.
Fig. 3 is the high-efficient liquid phase chromatogram of the bromo-2-methoxynaphthalene of 6-of this embodiment 2.Adopt Shimadzu LC-20AD to analyze sample, detect that the appearance time of the bromo-2-methoxynaphthalene of 6-is 8.015 minutes.Peak area according to peak each in original spectrogram is normalized, and sample purity is 97.39%.
Step again according to embodiment 1 prepares intermediate of nabumetone 2-methoxyl group-6-naphthaldehyde, purity 98.5%, productive rate 80%.
Claims (5)
1. the preparation method of intermediate of nabumetone 2-methoxyl group-6-naphthaldehyde, it is characterized in that comprising the following steps: with 2-methoxynaphthalene for initial feed, 1 is obtained through bromination, the bromo-2-methoxynaphthalene of 6-bis-, adopt platina as reductive agent in a solvent, wherein the massfraction of zinc is 50% ~ 100%, obtains after the bromo-2-methoxynaphthalene of 6-through metallic reducing, then prepares 2-methoxyl group-6-naphthaldehyde through grignard reaction further.
2. the preparation method of intermediate of nabumetone 2-methoxyl group-6-naphthaldehyde according to claim 1, is characterized in that: described metal reduction reaction temperature is 40 ~ 120
oc, the reaction times is 0.5 ~ 20 hour, and the mol ratio of metallic reducing agent consumption and the bromo-2-methoxynaphthalene of reaction substrate 1,6-bis-is 1:0.01 ~ 1.
3. the preparation method of intermediate of nabumetone 2-methoxyl group-6-naphthaldehyde according to claim 2, is characterized in that: described metal reduction reaction temperature is 60 ~ 120
oc, the reaction times is 0.5 ~ 10 hour, and the mol ratio of metallic reducing agent consumption and the bromo-2-methoxynaphthalene of reaction substrate 1,6-bis-is 1:0.1 ~ 0.5.
4. the preparation method of intermediate of nabumetone 2-methoxyl group-6-naphthaldehyde according to claim 1, is characterized in that: described metal reduction reaction solvent for use is the mixing solutions of acetic acid and water, and mass ratio is acetic acid: water=1 ~ 50: 1.
5. the preparation method of intermediate of nabumetone 2-methoxyl group-6-naphthaldehyde according to claim 4, is characterized in that: described metal reduction reaction solvent for use is the mixing solutions of acetic acid and water, and mass ratio is acetic acid: water=1 ~ 10: 1.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926633A (en) * | 2015-05-06 | 2015-09-23 | 江西力田维康科技有限公司 | Preparation method for 3-alkoxybenzaldehyde |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5840996A (en) * | 1997-05-08 | 1998-11-24 | Albemarle Corporation | Production of brominated methoxynaphthalene compounds |
| CN101870636A (en) * | 2010-04-01 | 2010-10-27 | 大唐(杭州)医药化工有限公司 | Preparation method of 2-bromo-6-fluoronaphthalene |
| CN102476983A (en) * | 2010-11-25 | 2012-05-30 | 苏州卫生职业技术学院 | Method for synthesizing 6-methoxy-2-naphthaldehyde |
-
2013
- 2013-08-20 CN CN201310363798.1A patent/CN104418716A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5840996A (en) * | 1997-05-08 | 1998-11-24 | Albemarle Corporation | Production of brominated methoxynaphthalene compounds |
| CN101870636A (en) * | 2010-04-01 | 2010-10-27 | 大唐(杭州)医药化工有限公司 | Preparation method of 2-bromo-6-fluoronaphthalene |
| CN102476983A (en) * | 2010-11-25 | 2012-05-30 | 苏州卫生职业技术学院 | Method for synthesizing 6-methoxy-2-naphthaldehyde |
Non-Patent Citations (1)
| Title |
|---|
| 陈万杰: "萘普酮合成路线概述", 《中国医药工业杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104926633A (en) * | 2015-05-06 | 2015-09-23 | 江西力田维康科技有限公司 | Preparation method for 3-alkoxybenzaldehyde |
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Application publication date: 20150318 |