CN104003903A - Synthetic method of 2-cyano-4'-methylbiphenyl - Google Patents
Synthetic method of 2-cyano-4'-methylbiphenyl Download PDFInfo
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- CN104003903A CN104003903A CN201410201677.1A CN201410201677A CN104003903A CN 104003903 A CN104003903 A CN 104003903A CN 201410201677 A CN201410201677 A CN 201410201677A CN 104003903 A CN104003903 A CN 104003903A
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Abstract
The invention discloses a synthetic method of 2-cyano-4'-methylbiphenyl, which adopts paratoluidine and benzoyl chloride as raw materials; a Friedel-Crafts acylation reaction is carried out under a Lewis acid catalysis condition; then a ring-closure reaction of a diazonium salt and a benzene ring is carried out in the presence of sodium nitrite; ring opening is carried out under an alkaline condition to generate a main product as shown in formula VI and a byproduct as shown in formula VII, and the ring-opening products are prepared into salts which are then subjected to separation; and finally, carboxyl groups are converted into cyan groups to obtain 2-cyano-4'-methylbiphenyl. The synthetic method of the invention has the advantages of easily available raw materials, safety, convenience for production management, low cost, reduction in 'three wastes' pollution, byproduct recyclability, and improved atom utilization rate.
Description
Technical field
The present invention relates to a kind of synthetic method of sartanbiphenyl.
Background technology
2-Cyano-4 '-methylbiphenyl (sartanbiphenyl, I) is the key intermediate of synthetic vessel Angiotensin Ⅱ antagonism class medicine, as losartan, telmisartan, valsartan, Irb etc.The features such as this type of medicine has efficiently, safety, better tolerance, target-organ protection, growth momentum is powerful, has a extensive future.Therefore, the improvement of sartanbiphenyl synthesis technique all has very important significance to the study on the synthesis of whole sandy beach class medicine and production.
At present, synthetic to prepare the method that sartanbiphenyl is conventional more, mainly contains following several: (1) Meyer o-anisic acid method, adopt Whitfield's ointment or o-anisic acid as raw material, the synthetic sartanbiphenyl of application Meyer reaction ， Jing oxazoline, but its synthetic route is long, and overall yield of reaction is lower.(2) Suzuki coupling method, the synthetic sartanbiphenyl of 4-methylphenylboronic acid and 2-bromoxynil coupling under the catalysis of palladium, due to expensive raw material price, this synthetic route can only rest on laboratory stage, and the method for there is no is carried out industrialized production.(3) Negishi coupling method, first by grignard reaction, prepare p-methylphenyl magnesium halide, then organic zinc reagent is prepared in reaction with ZnCl2, the synthetic sartanbiphenyl of last and adjacent bromoxynil cross-coupling, this synthetic method need to be prepared a large amount of organic zinc reagents, and anhydrous ZnCl2 very easily absorbs water and causes operation easier larger, a large amount of metal reagents add the difficulty that also can strengthen separating-purifying.(4) catalytic reduction method, prepares sartanbiphenyl by 4 '-bis-brooethyls-2-cyanobiphenyl or the debrominate of 4 '-brooethyl-2-cyanobiphenyl shortening, and this method raw material is that after sartanbiphenyl synthesizes, bromination is synthetic again, synthetic obviously unreasonable conversely.
Summary of the invention
The object of the present invention is to provide the synthetic method of a kind of safe, high yield, highly purified sartanbiphenyl.
Technical solution of the present invention is:
It is raw material that para-totuidine (II) is take in the present invention, under Louis acid catalysis condition, friedel-crafts acylation occurs with Benzoyl chloride (III); Then under Sodium Nitrite participates in through diazonium salt and phenyl ring generation closed loop; Then open loop under alkaline condition, generates principal product (VI) and by product (VII), open-loop products is made to salt and carry out separation; Finally carboxyl is converted into cyano group and makes sartanbiphenyl (I).Its synthetic route is as follows:
In the present invention, the catalyzer that friedel-crafts acylation is used is Lewis acid, as AlCl
3, ZnCl
2, or FeCl
3deng, temperature of reaction is 160 ℃.
In the present invention, diazotization reaction acid used is sulfuric acid, and solvent used is water.
In the present invention, it is copper powder, cupric chloride that diazonium salt closes ring catalyzer used, or copper sulfate etc.
In the present invention, the alkali that alkaline open loop is used is sodium hydroxide, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium hydroxide, potassium methylate, potassium ethylate, or potassium tert.-butoxide, and potassium tert.-butoxide is optimal selection.
In the present invention, open-loop products is made salt, and to carry out separated alkali used be magnesium hydroxide, hydrated barta or calcium hydroxide etc.After purifying, discarded open-loop products can carry out cyclization and gets back to raw material in the vitriol oil.
The dewatering agent that forms cyano group in the present invention is sulfur oxychloride, phosphorus trichloride, or Vanadium Pentoxide in FLAKES.
Reaction conditions of the present invention is gentle, easy and simple to handle, is applicable to suitability for industrialized production.
Advantage of the present invention: raw material is easy to get, safety, is convenient to production management; Cost is lower, reduces three-waste pollution; By product recoverable, improves atom utilization.
Below in conjunction with embodiment, the invention will be further described.
Embodiment
The preparation (IV) of amino-5 methyldiphenyl ketones of 2-
Benzoyl chloride (133.6mL, 1.15mol) is placed in to reaction flask, stirs, be warming up to 120 ℃, slowly add para-totuidine (50.00g, 0.46mol), after adding, be warming up to 140 ℃, after 2 hours, add anhydrous ZnCl2 (79.06g, 0.58mol), temperature rises to 160 ℃ of reactions 3 hours, be cooled to 100 ℃, add 200mL water, stir, water layer is poured out after cooling.Toward the sulfuric acid 150mL that adds 70% in the residuum in reaction flask, 140 ℃ are stirred 2 hours, after cooling, reaction solution is poured in large water gaging, use ammonia neutralization reaction solution, ethyl acetate extraction, revolves to steam and removes ethyl acetate, solid 95% ethyl alcohol recrystallization, obtain yellow solid (79.70g, productive rate 82.2%).
1H?NMR(400MHz,CDCl3,ppm)δ:7.64(d,1H),7.54(t,1H),7.47(t,2H),7.23(s,1H),7.13(d,1H),5.91(s,2H),2.18(s,3H)。
The preparation (V) of 2-methyl Fluorenone
The sulfuric acid of the acetic acid of the water of 120mL, 120mL and 37.8g is placed in to reaction flask, add 2-amino-5-methyldiphenyl ketone (40.00g, 0.19mol), stirring makes molten clear, is cooled to subsequently 0 ℃, be added dropwise to Sodium Nitrite (13.25g, 0.19mol) aqueous solution 25mL, dripped after 1 hour, added 4g copper powder, be warming up to 80 ℃, react 2 hours.Be cooled to room temperature, with dichloromethane extraction, revolve and steam except desolventizing, 90% ethyl alcohol recrystallization for solid, obtains yellow solid (30.04g, 82.4%).
1H?NMR(400MHz,DMSO,ppm)δ:7.74(d,1H),7.68(d,1H),7.59(t,2H),7.42(d,2H),7.34(t,1H),2.35(s,3H)。
The preparation of 2-carboxyl-4 '-methyl diphenyl (VI)
(1) 2-methyl Fluorenone open loop under alkaline condition
(a) 2-methyl Fluorenone open loop under potassium hydroxide condition
Potassium hydroxide (11.71g, 0.21mol) is placed in to reaction flask, adds 25mL toluene, be heated with stirring to 110 ℃, be added dropwise in the toluene solution of the 40mL that is dissolved with 2-methyl Fluorenone (10.00g, 0.051mol), drip rear continuation stirring reaction 2h.Cool to room temperature, adds 50mL water, fully stirs, and mixture is transferred in separating funnel, divides and goes organic phase, and water extracts with toluene, hydrochloric acid tune pH to 4-6 for water, and filtration under diminished pressure, dries, and obtains white solid (6.51g, productive rate 60.2%).(the shared ratio of principal product in product (VI) is 50%, and the shared ratio of by product (VII) is 50%.)
(b) 2-methyl Fluorenone open loop under potassium tert.-butoxide condition
Potassium tert.-butoxide (67.02g, 0.60mol) is placed in to reaction flask, adds 800mL tetrahydrofuran (THF), stirring makes molten clear, adds 2-methyl Fluorenone (29.00g, 0.15mol), continue stirring reaction after 1 hour, add 400mL water, stir and make dissolution of solid, revolve to steam and remove tetrahydrofuran (THF), water dichloromethane extraction, water is adjusted pH to 4-6 with hydrochloric acid, filtration under diminished pressure, dry, obtain white solid (29.21g, productive rate 91.8%).(the shared ratio of principal product in product (VI) is 60%, and the shared ratio of by product (VII) is 40%.)
(2) separation of open-loop products
Open-loop products (21.22g, 0.10mol) under potassium tert.-butoxide condition and magnesium hydroxide (2.92g, 0.05mol) are placed in to reaction flask, add 200mL water, heated and stirred, to molten clear, then distills part water to make to separate out a small amount of solid, then be cooled to 0 ℃, filter, filter cake is soluble in water again, add hydrochloric acid and adjust PH to 4-6, separate out solid, filter, dry, obtain 2-carboxyl-4 '-methyl diphenyl (8.06g, productive rate 38.0%), purity reaches 99%.
1H?NMR(400MHz,CDCl3,ppm)δ:7.95(d,1H),7.57(t,1H),7.38-7.45(m,2H),7.29(s,2H),7.23(d,2H),2.42(s,3H)。
(3) by product (VII) reclaims and obtains 2-methyl Fluorenone
Above-mentioned separating obtained filtrate being adjusted to pH to 4-6 with hydrochloric acid, separate out therefore body is dried, obtain white solid (13.09g), is the mixture of principal product (VI) and by product (VII).
This mixture (13.09g, 0.062mol) is placed in to reaction flask, adds the 50mL vitriol oil, stir, be warming up to 40 ℃, after 6 hours, add 200mL water, separate out yellow solid, filter, dry, obtain 2-methyl Fluorenone (11.86g, productive rate 98.1%).
The preparation of 2-Cyano-4 '-methylbiphenyl (I)
By 2-carboxyl-4 '-methyl diphenyl (8.48g, 0.040mol) be placed in reaction flask, add 150mL1,2-ethylene dichloride, stirs, and then adds pyridine (3.21g, 0.040mol) with 15mL sulfur oxychloride, reflux, revolves after 8 hours to steam and removes 1,2-ethylene dichloride and unreacted sulfur oxychloride.80mL toluene is joined in residuum, be stirred to dissolve, drip 50mL strong aqua, stirring at normal temperature 8 hours, filters, and dries.This is dried to thing and be again placed in reaction flask, add 100mL1,2-ethylene dichloride and 25mL sulfur oxychloride, heated and stirred is to refluxing, after 4 hours, revolve to steam and remove 1,2-ethylene dichloride and unreacted sulfur oxychloride, 80% ethyl alcohol recrystallization for residuum, obtain white solid (6.48g, productive rate 83.8%).
1H?NMR(400MHz,CDCl3,ppm)δ:7.75(d,1H),7.63(t,1H),7.40-7.51(m,4H),7.30(d,2H)，2.42(s,3H)。
Claims (7)
1. a synthetic method for sartanbiphenyl, is characterized in that: take para-totuidine and Benzoyl chloride as raw material, under Louis acid catalysis condition, friedel-crafts acylation occurs; Then under Sodium Nitrite participates in through diazonium salt and phenyl ring generation closed loop; Then open loop under alkaline condition, the by product of the principal product of production VI and formula VII, makes salt by open-loop products and carries out separation; Finally carboxyl is converted into cyano group and makes sartanbiphenyl.
2. the synthetic method of sartanbiphenyl according to claim 1, is characterized in that: the catalyzer that friedel-crafts acylation is used is Lewis acid, and temperature of reaction is 160 ℃.
3. the synthetic method of sartanbiphenyl according to claim 2, is characterized in that: described Lewis acid is AlCl
3, ZnCl
2or FeCl
3.
4. according to the synthetic method of the sartanbiphenyl described in claim 1,2 or 3, it is characterized in that: diazonium salt and phenyl ring generation closed loop catalyzer used is copper powder, cupric chloride or copper sulfate.
5. according to the synthetic method of the sartanbiphenyl described in claim 1,2 or 3, it is characterized in that: the alkali that under alkaline condition, open loop is used is sodium hydroxide, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium hydroxide, potassium methylate, potassium ethylate or potassium tert.-butoxide.
6. according to the synthetic method of the sartanbiphenyl described in claim 1,2 or 3, it is characterized in that: when open-loop products is made salt and carried out separation, alkali used is magnesium hydroxide, hydrated barta or calcium hydroxide; After purifying, discarded open-loop products carries out cyclization and gets back to raw material in the vitriol oil.
7. according to the synthetic method of the sartanbiphenyl described in claim 1,2 or 3, it is characterized in that: the dewatering agent that carboxyl is converted into cyano group is sulfur oxychloride, phosphorus trichloride or Vanadium Pentoxide in FLAKES.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037134A (en) * | 2015-05-21 | 2015-11-11 | 启东东岳药业有限公司 | Asymmetric diphenic acid isomeride separation method |
| CN113773266A (en) * | 2021-09-28 | 2021-12-10 | 公安部物证鉴定中心 | clonazepam-D2 and preparation method thereof |
Citations (3)
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| JPS63275548A (en) * | 1987-05-02 | 1988-11-14 | Res Inst For Prod Dev | Production of o-aminobenzoyl compound |
| US20040058977A1 (en) * | 2002-09-16 | 2004-03-25 | Zongru Guo | Sulfonyl-containing 2,3-diarylindole compounds, methods for making same, and methods of use thereof |
| CN101955415B (en) * | 2010-08-20 | 2013-06-19 | 绍兴文理学院 | Method for preparing 2-hydroxyl biphenyl compound |
-
2014
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS63275548A (en) * | 1987-05-02 | 1988-11-14 | Res Inst For Prod Dev | Production of o-aminobenzoyl compound |
| US20040058977A1 (en) * | 2002-09-16 | 2004-03-25 | Zongru Guo | Sulfonyl-containing 2,3-diarylindole compounds, methods for making same, and methods of use thereof |
| CN101955415B (en) * | 2010-08-20 | 2013-06-19 | 绍兴文理学院 | Method for preparing 2-hydroxyl biphenyl compound |
Non-Patent Citations (4)
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| E.RITHCHIE: "Derivatives of 2, 3-diphenylindole", 《JOURNAL AND PROCEEDINGS OF THE ROYAL SOCIETY OF NEW SOUTH WALES》, vol. 80, 31 December 1946 (1946-12-31), pages 39 * |
| ROGER BOLTON等: "Competition in intramolecular arylation of triphenylmethanols", 《JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 2》, no. 3, 31 December 1986 (1986-12-31), pages 407 - 406 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105037134A (en) * | 2015-05-21 | 2015-11-11 | 启东东岳药业有限公司 | Asymmetric diphenic acid isomeride separation method |
| CN113773266A (en) * | 2021-09-28 | 2021-12-10 | 公安部物证鉴定中心 | clonazepam-D2 and preparation method thereof |
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