CN101367762A - Preparation method of midbody 7-chloroquinaldine - Google Patents
Preparation method of midbody 7-chloroquinaldine Download PDFInfo
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Abstract
The present invention provides a preparation method of medicine intermediate 7-chlorine quinaldine. M-chloroaniline salt of inorganic acid and crotonaldehyde have a closed loop reaction in mixed solvent of alcohol and arene to prepare the salt of 7-chlorine quinaldine; alkaline is added for neutralization; and the 7-chlorine quinaldine can be prepared. The present invention has the advantages that the production of a large quantity of isomers is inhibited, the operation is simple, the production period is obviously shortened, no large amount of acid, alkaline or expensive solvent is used in the post-processing, and the product is more conducive to the environmental protection; a large amount of energy is saved; simultaneously, the reaction conditions are simplified, the reaction process is safer and more reliable, the quality and yield rate of the product are ensured, and the present invention is more suitable for industrial production.
Description
Technical field
The present invention relates to the medicine intermediate field, more specifically to the preparation method of 7-chlorine quinaldine red.
Background technology
7-chlorine quinaldine red has another name called 7-chloro-2-toluquinoline, and as the important intermediate of synthetic Menglusitena (Montelu-kast), LTRA MK-0679, its synthetic method receives much concern.
U.S. Pat 5126456, among the US5066806, Zhiguo Song, people such as Emmerich Pastorek adopt m-chloro aniline and crotonic aldehyde to react under acidic conditions, can make 7-chloro-2-toluquinoline, wherein adopt the chloranil to make oxygenant, use zinc chloride, tartrate etc. carry out complexing with product and carry out separating with isomer 5-chloro-2-toluquinoline, the chloranil, tartrate is all very expensive, and last handling process is quite loaded down with trivial details, carry out complexing, filter, obtain the complex compound of product, product again with complex compound with separate, crystallization, filter, it is comparatively complicated to obtain its operating process of product at last, temperature of reaction is at 110 degree, and temperature is higher, security is relatively poor, is not suitable for the suitability for industrialized production operation.
Among the hungarian patent HU200401607, people such as Salamon Zolt á n Debrecen are by m-chloro aniline and methyl aceto acetate, N, obtain 7-chloro-2-toluquinoline after dinethylformamide cyclisation, chlorination and hydrolysis, the decarboxylation, this reactions steps is many, total recovery is less than 25%, the raw materials cost height.
Document Chemical ﹠amp; Pharmaceutical Bulletin, 34 (2), 463-70; In 1986, people such as Machiko Ono adopt paraldehyde and m-chloro aniline reaction can obtain 7-chlorine quinaldine red (yield 34%) and 5-chlorine quinaldine red (yield 3.78%), but, cause to obtain the higher 7-chlorine quinaldine red that gets of purity because this mixture is difficult to separate.
Document J.Heterocyclic Chem.30, in 17 (1993), people such as Zhiguo Song use the reaction of m-chloro aniline and crotonic aldehyde to use chloranil are done the yield 81% that oxygenant has improved product 7-chloro-2-toluquinoline, also provided and made solvent with tetrahydrofuran (THF), method of purification with the zinc chloride complexing, but the process trouble, cost is higher.
Ganesabaskaran Sivaprasad, people such as Rengasamy Rajesh and ParamasivanT.perumal also use synthetic 7-chlorine quinaldine red under m-chloro aniline and the condition of crotonic aldehyde at microwave in Tetrahedron Letters 47 (2006) 1783-1785, this method yield has improved, but do not have actual application value, and do not solve product separation, the method for purification.
Summary of the invention
Purpose of the present invention makes whole technological process be more suitable for suitability for industrialized production for the preparation method of a kind of yield height, purity height, safe 7-chlorine quinaldine red is provided.
The technical solution adopted in the present invention is as follows:
The m-chloro aniline inorganic acid salt carries out ring-closure reaction with crotonic aldehyde in the mixed solvent of alcohols-aromatic hydrocarbons, obtain the salt of 7-chlorine quinaldine red, add in the alkali and after obtain 7-chlorine quinaldine red, reaction formula is as follows
In the technique scheme, described m-chloro aniline inorganic acid salt can be hydrobromate, hydrochloride, vitriol or nitrate, preferred hydrobromate;
Raw material crotonic aldehyde cis of the present invention still is transly all can adopt, but considers from economic angle, preferably adopts trans crotonic aldehyde;
Alcoholic solvent of the present invention can be methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol etc., described aromatic hydrocarbon solvent is pure benzene,toluene,xylene, chlorobenzene, oil of mirbane, Ortho Nitro Toluene, m-chloro-nitrobenzene etc., alcoholic solvent particular methanol wherein, the preferred Ortho Nitro Toluene of aromatic solvents;
In the mixed solvent of the present invention, the proportional range of alcohols and aromatics be from 1:1 (volume ratio) to 5:1 (volume ratio), optimum proportion is 3:1 (volume ratio);
Among the above-mentioned preparation method, m-chloro aniline salt: crotonic aldehyde: the molar ratio scope of mixed solvent adopts 1:1～1.5:10～50, and optimum proportion is 1:1.2:30;
Among the preparation method of the present invention, temperature of reaction is 25～110 degree, and optimum temps is 65 degree (methanol eddy temperature);
The reaction times that the present invention relates to can be from 30 minutes to 5 hours, and preferably the reaction times is 1 hour.The dropping time can be from 10 minutes to 1 hour, preferably 20 minutes;
The alkali that the present invention relates to can be the aqueous solution of yellow soda ash, sodium bicarbonate, sodium hydroxide, potassium hydroxide, salt of wormwood, saleratus etc., preferred sodium bicarbonate;
The concentration of the alkali that the present invention relates to can be 5%-40% (mass percent), preferably uses 10% alkali lye;
The present invention adopts the doebner-miller method, m-chloro aniline salt reacts in the mixed solvent based on methyl alcohol, by carrying out ring-closure reaction with crotonic aldehyde, directly obtain the salt of corresponding high purity 7-chlorine quinaldine red, obtain 7-chlorine quinaldine red by neutralization, this method has effectively suppressed the generation of a large amount of isomer.Technology with other is compared, and has saved other method to complicated operations processes such as product separation, purifications, makes operation very simple, and the production cycle obviously shortens; Saved a large amount of acid, alkali and the expensive solvent used in other method last handling process, made and produce environmental protection more; A large amount of energy that other method aftertreatment will consume have also been saved; Reduced reaction conditions simultaneously, reaction process is more safe and reliable, and has guaranteed quality product and yield, under the contrast, is to be more suitable for industrialized production method.
Embodiment
Below by embodiment the present invention is further specified, but embodiment does not limit protection scope of the present invention.
Embodiment 1
The preparation of m-chloro aniline hydrobromate:
In the four-hole boiling flask that 1000 milliliters have mechanical stirring, thermometer, prolong, an addition funnel, add Hydrogen bromide (500 grams, 40%, 2.5mol, commercially available technical grade), cool off with water-bath, begin to drip m-chloro aniline 292 grams, 99%, 2.273mol, commercially available technical grade), controlled temperature is no more than 50 degree, about 30 minutes of dropping time, after cooling to room temperature, begin to filter the m-chloro aniline hydrobromate, dry 454 the gram, content 99%, yield 95%.
In the four-hole boiling flask that 2000 milliliters have mechanical stirring, thermometer, prolong, an addition funnel, hydrobromate (the 211g that adds m-chloro aniline, 1mol), 1000 milliliters of methyl alcohol, 300 milliliters of Ortho Nitro Toluenes, temperature rising reflux, drip crotonic aldehyde (trans commercially available 85g, 98%, 1.2mol) time is about 20 minutes, refluxes 40 minutes, cools to 15 degree-25 degree, the adularescent solid is separated out, filter, 2 * 200 milliliters of washings of methyl alcohol get 7-chlorine quinaldine red hydrobromate 195 grams, content 99.3%, yield 74.7%.Hydrobromate 195 gram (0.75mol) joined in 10% yellow soda ash 410 ml solns, stirred 30 minutes, filter, white solid 7-chlorine quinaldine red is dried to such an extent that 134 restrain, content 99.5%, yield 100%,
1HNMR data 2.90 (s, 3H), 8.91 (d, J=8.6,2H), 7.7-8.1 (m, 2H), 8.2-8.4 (M, 2H), filtrated stock adds 2000 milliliters in water, tells organic layer and descends secondary response for 280 milliliters, and water layer directly distills methyl alcohol recovery set and uses.
HLPC day island proper body fluid spectrum analysis; Chromatographic column: ODS-C
18/ 4.6mm * 150mm; Moving phase: acetonitrile: 0.1%H
3PO
4The aqueous solution=2:8; Wavelength=225nm; Flow velocity: 1ml/min; About 6.0 minutes of product, content, 99.5%; About 6.5 minutes of isomer; Content 0.01%;
Embodiment 2
In the four-hole boiling flask that 2000 milliliters have mechanical stirring, thermometer, prolong, an addition funnel, hydrobromate (the 211g that adds m-chloro aniline, 1mol), 1000 milliliters of methyl alcohol, 300 milliliters of toluene, 100 milliliters of Ortho Nitro Toluenes, temperature rising reflux, the dropping crotonic aldehyde (trans commercially available 85g, 98%, 1.2mol) time is about 20 minutes, refluxed 40 minutes, cool to 15 degree-25 degree, the adularescent solid is separated out, and filters, 2 * 200 milliliters of washings of methyl alcohol, get 7-chlorine quinaldine red hydrobromate 201 grams, content 99.6%, yield 77.0%.Hydrobromate 201 gram (0.77mol) joined in 10% yellow soda ash 410 ml solns, stirred 30 minutes, filter, white solid 7-chlorine quinaldine red dry 136.8 the gram, content 99.5%, yield 100%, filtrated stock add 2000 milliliters in water, tell organic layer and descend secondary response for 390 milliliters, water layer directly distills methyl alcohol recovery set and uses.
Embodiment 3
In the four-hole boiling flask that 2000 milliliters have mechanical stirring, thermometer, prolong, an addition funnel, hydrobromate (the 211g that adds m-chloro aniline, 1mol), 1000 milliliters of methyl alcohol, 200 milliliters of toluene, 200 milliliters of Ortho Nitro Toluenes, temperature rising reflux, the dropping crotonic aldehyde (trans commercially available 85g, 98%, 1.2mol) time is about 20 minutes, refluxed 40 minutes, cool to 15 degree-25 degree, the adularescent solid is separated out, and filters, 2 * 200 milliliters of washings of methyl alcohol, get 7-chlorine quinaldine red hydrobromate 198 grams, content 99.6%, yield 76.3.0%.Hydrobromate 198 gram (0.76mol) joined in 10% yellow soda ash 410 ml solns, stirred 30 minutes, filter, white solid 7-chlorine quinaldine red dry 135 the gram, content 99.4%, yield 100%, filtrated stock add 2000 milliliters in water, tell organic layer and descend secondary response for 385 milliliters, water layer directly distills methyl alcohol recovery set and uses.
In the four-hole boiling flask that 2000 milliliters have mechanical stirring, thermometer, prolong, an addition funnel, the hydrochloride that adds m-chloro aniline is (commercially available, Milan, Nanjing chemical industry company limited, 166g, 99%, 1mol), 1000 milliliters of methyl alcohol, 300 milliliters of Ortho Nitro Toluenes, temperature rising reflux, the dropping crotonic aldehyde (trans commercially available 85g, 98%, 1.2mol) time is about 20 minutes, refluxed 40 minutes, cool to the 0-10 degree, the adularescent solid is separated out, and filters, 2 * 200 milliliters of washings of methyl alcohol, must get 7-chloroquine any thiamine hydrochloride 123 grams, content 98.5%, yield 56.7%.Hydrochloride 123 gram (0.567mol) joined in 10% yellow soda ash 310 ml solns, stirred 30 minutes, filter, white solid 7-chlorine quinaldine red dry 102 the gram, content 99.1%, yield 100%, filtrated stock add 2000 milliliters in water, tell organic layer and descend secondary response for 274 milliliters, water layer directly distills methyl alcohol recovery set and uses.Analyze identical with example 1.
Embodiment 4
The preparation of m-chloro aniline nitrate
In the four-hole boiling flask that 1000 milliliters have mechanical stirring, thermometer, prolong, an addition funnel, add ethylene dichloride (commercially available technical grade) 500 milliliters, m-chloro aniline 260 grams, 99%, 2.0mol, commercially available technical grade) cool off with ice-water bath, begin to drip nitrosonitric acid (commercially available, technical grade) 128.5 grams, 98%, 2.0mol, be controlled under the chambers temp about 30 minutes of dropping time, after at room temperature stirring 30 minutes, filter m-chloro aniline nitrate, dry 381 the gram, content 99%, yield 99%.
In the four-hole boiling flask that 2000 milliliters have mechanical stirring, thermometer, prolong, an addition funnel, nitrate (the 192.5g that adds m-chloro aniline, 99%, 1mol), 1000 milliliters of methyl alcohol, 300 milliliters of Ortho Nitro Toluenes, temperature rising reflux, the dropping crotonic aldehyde (trans commercially available 85g, 98%, 1.2mol) time is about 20 minutes, refluxed 40 minutes, cool to-the 5-5 degree, the adularescent solid is separated out, and filters, 2 * 200 milliliters of washings of methyl alcohol, get 7-chlorine quinaldine red nitrate 152 grams, content 98.3%, yield 62.1%.Nitrate 152 gram (0.621mol) joined in 10% yellow soda ash 340 ml solns, stirred 30 minutes, filter, white solid 7-chlorine quinaldine red dry 112 the gram, content 98.3% yield 100%, filtrated stock adds 2000 milliliters in water, tells organic layer and descends secondary response for 278 milliliters, and water layer directly distills methyl alcohol recovery set and uses.Analyze identical with example 1.
Embodiment 4
The preparation of m-chloro aniline vitriol
In the four-hole boiling flask that 1000 milliliters have mechanical stirring, thermometer, prolong, an addition funnel, add ethylene dichloride (commercially available technical grade) 500 milliliters, m-chloro aniline 260 grams, 99%, 2.0mol, commercially available technical grade) cool off with ice-water bath, begin to drip the vitriol oil (commercially available, technical grade) 200 grams, 98%, 2.0mol, be controlled under the chambers temp about 30 minutes of dropping time, after at room temperature stirring 30 minutes, filter m-chloro aniline nitrate, dry 251 the gram, content 99%, yield 99%.
In the four-hole boiling flask that 2000 milliliters have mechanical stirring, thermometer, prolong, an addition funnel, vitriol (the 278.5g that adds m-chloro aniline, 99%, 1mol), 1000 milliliters of methyl alcohol, 300 milliliters of Ortho Nitro Toluenes, temperature rising reflux, the dropping crotonic aldehyde (trans commercially available 85g, 98%, 1.2mol) time is about 20 minutes, refluxed 40 minutes, cool to-the 10-0 degree, the adularescent solid is separated out, and filters, 2 * 200 milliliters of washings of methyl alcohol, get 7-chlorine quinaldine red vitriol 175 grams, content 97.4%, yield 61.8%.Vitriol 175 gram (0.62mol) joined in 10% yellow soda ash 660 ml solns, stirred 30 minutes, filter, white solid 7-chlorine quinaldine red dry 110 the gram, content 98.1%, yield 100%, filtrated stock add 2000 milliliters in water, tell organic layer and descend secondary response for 274 milliliters, water layer directly distills methyl alcohol recovery set and uses.Analyze identical with example 1.
Claims (10)
1. the preparation method of a pharmaceutical intermediate 7-chlorine quinaldine red comprises the steps:
The m-chloro aniline inorganic acid salt carries out ring-closure reaction with crotonic aldehyde in the mixed solvent of alcohols-aromatic hydrocarbons, be cooled to the salt of separating out 7-chlorine quinaldine red, add in the alkali and after obtain 7-chlorine quinaldine red.
2. preparation method according to claim 1 is characterized in that, described m-chloro aniline inorganic acid salt is hydrobromate, hydrochloride, vitriol or nitrate.
3. preparation method according to claim 1 is characterized in that, described crotonic aldehyde is a cis or trans.
4. preparation method according to claim 1 is characterized in that, described alcoholic solvent is methyl alcohol, ethanol, n-propyl alcohol, Virahol or propyl carbinol; Described aromatic hydrocarbon solvent is pure benzene,toluene,xylene, chlorobenzene, oil of mirbane, Ortho Nitro Toluene or m-chloro-nitrobenzene.
5. preparation method according to claim 1 is characterized in that, the volume ratio of alcohols and aromatic hydrocarbons is 1～5:1 in the described mixed solvent, preferred 3:1.
6. preparation method according to claim 1 is characterized in that, the mol ratio of described m-chloro aniline salt, crotonic aldehyde and mixed solvent is 1:1～1.5:10～50, preferred 1:1.2:30.
7. preparation method according to claim 1 is characterized in that, temperature of reaction is 25～110 ℃, preferred 65 ℃.
8. preparation method according to claim 1 is characterized in that, the reaction times is 0.5～5 hour, preferred 1 hour; The dropping time is 10～60 minutes, preferred 20 minutes.
9. preparation method according to claim 1 is characterized in that, described alkali is the aqueous solution of yellow soda ash, sodium bicarbonate, sodium hydroxide, potassium hydroxide, salt of wormwood or saleratus.
10. preparation method according to claim 9 is characterized in that, the mass percent concentration of the described aqueous solution is 5～40%, preferred 10%.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102134219A (en) * | 2010-12-31 | 2011-07-27 | 华东理工大学 | Preparation method of quinoline derivative |
| CN110845405A (en) * | 2019-11-26 | 2020-02-28 | 江西盛伟科技股份有限公司 | Synthesis method of 7-chloroquinaldine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102134219A (en) * | 2010-12-31 | 2011-07-27 | 华东理工大学 | Preparation method of quinoline derivative |
| CN110845405A (en) * | 2019-11-26 | 2020-02-28 | 江西盛伟科技股份有限公司 | Synthesis method of 7-chloroquinaldine |
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Assignee: Zhejiang Keyuan Chemicals Co., Ltd. Assignor: Jiaxing Institute of Applied Chemistry and Engineering, Chinese Academy of Sciences Contract record no.: 2010330002289 Denomination of invention: Preparation method of midbody 7-chloroquinaldine Granted publication date: 20101201 License type: Exclusive License Open date: 20090218 Record date: 20101229 |
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