CN103483254A - Method for synthesizing 3-methylquinoline-8-sulfonyl chloride - Google Patents
Method for synthesizing 3-methylquinoline-8-sulfonyl chloride Download PDFInfo
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- CN103483254A CN103483254A CN201210193268.2A CN201210193268A CN103483254A CN 103483254 A CN103483254 A CN 103483254A CN 201210193268 A CN201210193268 A CN 201210193268A CN 103483254 A CN103483254 A CN 103483254A
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- toluquinoline
- sulphuryl chloride
- chloro
- phenylpropionamide
- synthetic method
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- 238000000034 method Methods 0.000 title claims abstract description 26
- XCMAYGDQKTWICK-UHFFFAOYSA-N 3-methylquinoline-8-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC2=CC(C)=CN=C21 XCMAYGDQKTWICK-UHFFFAOYSA-N 0.000 title abstract 4
- 230000002194 synthesizing effect Effects 0.000 title description 10
- ZTHRQJQJODGZHV-UHFFFAOYSA-N n-phenylpropanamide Chemical compound CCC(=O)NC1=CC=CC=C1 ZTHRQJQJODGZHV-UHFFFAOYSA-N 0.000 claims abstract description 58
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 26
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims abstract description 18
- 235000019260 propionic acid Nutrition 0.000 claims abstract description 9
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims abstract description 9
- 239000007787 solid Substances 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- 238000010189 synthetic method Methods 0.000 claims description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 239000012752 auxiliary agent Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 239000002994 raw material Substances 0.000 claims description 9
- 238000006277 sulfonation reaction Methods 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 8
- 239000012044 organic layer Substances 0.000 claims description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 7
- 239000012047 saturated solution Substances 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 5
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical group [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 claims description 5
- 235000019270 ammonium chloride Nutrition 0.000 claims description 5
- 230000008034 disappearance Effects 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 238000007711 solidification Methods 0.000 claims description 5
- 230000008023 solidification Effects 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 238000013019 agitation Methods 0.000 claims description 4
- 238000010009 beating Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 3
- DTBDAFLSBDGPEA-UHFFFAOYSA-N 3-methylquinoline Chemical compound C1=CC=CC2=CC(C)=CN=C21 DTBDAFLSBDGPEA-UHFFFAOYSA-N 0.000 abstract 2
- UMYPPRQNLXTIEQ-UHFFFAOYSA-N 2-chloro-3-methylquinoline Chemical compound C1=CC=C2N=C(Cl)C(C)=CC2=C1 UMYPPRQNLXTIEQ-UHFFFAOYSA-N 0.000 abstract 1
- 150000008282 halocarbons Chemical class 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 238000001308 synthesis method Methods 0.000 abstract 1
- 239000000047 product Substances 0.000 description 14
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 229960003856 argatroban Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/36—Sulfur atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
本发明公开了一种3-甲基喹啉-8-磺酰氯的合成方法，以苯胺为起始原料经与丙酸反应得到N-苯基丙酰胺，然后再成环得到2-氯-3-甲基喹啉，再经过卤代烃还原得到3-甲基喹啉，再经氯磺化得到产物3-甲基喹啉-8-磺酰氯。本发明方法成本低廉，操作简便，经济效益好，产率高，适合工业化生产。利用本发明方法可高产率得到3-甲基喹啉-8-磺酰氯。The invention discloses a synthesis method of 3-methylquinoline-8-sulfonyl chloride, which uses aniline as a starting material to react with propionic acid to obtain N-phenylpropanamide, and then forms a ring to obtain 2-chloro-3 -Methylquinoline, and then obtain 3-methylquinoline through halogenated hydrocarbon reduction, and then obtain product 3-methylquinoline-8-sulfonyl chloride through chlorosulfonation. The method of the invention has the advantages of low cost, simple and convenient operation, good economic benefit and high yield, and is suitable for industrialized production. The method of the present invention can obtain 3-methylquinoline-8-sulfonyl chloride in high yield.
Description
Technical field
The present invention relates to the synthetic method of a kind of 3-toluquinoline-8-SULPHURYL CHLORIDE, belong to chemical technology field.
Background technology
At existing patent (US4201863, EP8746, US4258192, CN200610046254) introduced a kind of chemosynthesis process of the newtype drug-argatroban (Argatrban) for the acute ischemic cerebral apoplexy treatment in, and 3-toluquinoline-8-SULPHURYL CHLORIDE is applied to this process as a kind of intermediate.3-toluquinoline-8-SULPHURYL CHLORIDE has as shown in the formula the chemical structure shown in (5).
Disclose the method for a kind of 3-of preparation toluquinoline-8-SULPHURYL CHLORIDE as existing process patent (US6235778, CN200610046254), but be only to be confined to prepare this step reaction of 3-toluquinoline-8-SULPHURYL CHLORIDE from the 3-toluquinoline.Only just in this one-step method for synthesizing, still exist some problems not to be resolved, containing a large amount of hydrogenchloride in product is yellow to making product, and, due to complex operation, the aftertreatment imperfection causes the method productive rate not high simultaneously.
Summary of the invention
The present invention relates to a kind of synthesis technique of novel thrombin inhibitors argatroban intermediate, the method for a kind of synthetic 3-toluquinoline-8-SULPHURYL CHLORIDE specifically, 3-toluquinoline-8-SULPHURYL CHLORIDE is the important chemical for the synthesis of medicine, agricultural chemicals.The purpose of this invention is to provide a kind of high yield, purity is good, prepares the synthetic method of 3-toluquinoline-8-SULPHURYL CHLORIDE from aniline, and raw material cheaply is easy to get, simple to operate, is applicable to suitability for industrialized production, and products obtained therefrom contains hydrogenchloride can meet the requirement of medical production field less.It is a kind of simple to operate that purpose of the present invention provides, and raw material is easy to get, with low cost, is conducive to the high yield of suitability for industrialized production, the synthesis technique of high purity 3-toluquinoline-8-SULPHURYL CHLORIDE.
The present invention proposes the synthetic method of a kind of 3-toluquinoline-8-SULPHURYL CHLORIDE, the aniline of take obtains the N-Phenylpropionamide as the raw material warp reacts with propionic acid, and then Cheng Huan obtains the chloro-3-toluquinoline of 2-, through halohydrocarbon, reduction obtains the 3-toluquinoline again, then obtains product 3-toluquinoline-8-SULPHURYL CHLORIDE through chlorosulphonation.
The present invention proposes the synthetic method of a kind of 3-toluquinoline-8-SULPHURYL CHLORIDE, comprise the following steps:
The first step, the aniline of take prepares the N-Phenylpropionamide as raw material
Add aniline, propionic acid and VITMAIN B1, be heated to 120 ℃, reacts 10 hours, stop heating, cool to room temperature, under agitation slowly pour reaction system in frozen water, stirs, filter, wash the solid of separating out with water twice, then water making beating filtration, by the gained solid, dry to such an extent that faint yellow solid is the N-Phenylpropionamide.
Second step, the N-Phenylpropionamide is through becoming ring to obtain the chloro-3-toluquinoline of 2-
In DMF, slowly drip chlorizating agent under ice bath, after solidification phenomenon occurring, continue dropping until solidify disappearance, then add the N-Phenylpropionamide to be reacted, then be heated to 78 ℃, react 12 hours, stop heating, cool to room temperature, slowly carefully pour the ice-cold 5%NaOH solution that contains ice cube into, the product of separating out is carried out to suction filtration, and through washing, oven dry, obtaining white solid is the chloro-3-toluquinoline of 2-.
Wherein, above-mentioned chlorizating agent is thionyl chloride or oxalyl chloride.
Above-mentioned feed ratio N-Phenylpropionamide: DMF: chlorizating agent=1: 1.5～2.5: 5～7.
The 3rd step, the chloro-3-toluquinoline of 2-obtains the 3-toluquinoline through reduction
By the chloro-3-toluquinoline of 2-, zinc powder, water, the hydrogen source agent is heated to 80 ℃, reacts 10 hours, stop heating, be cooled to room temperature, regulate PH=7, add ethyl acetate, stir 10min, obtain organic layer after separatory, use anhydrous magnesium sulfate drying, be spin-dried for solvent, obtaining weak yellow liquid is the 3-toluquinoline.
Wherein, above-mentioned hydrogen source agent is ammonium chloride or hydrochloric acid.
The chloro-3-toluquinoline of above-mentioned feed ratio 2-: zinc powder: hydrogen source agent=1: 1.2～2: 30～70.
The 4th step, the 3-toluquinoline obtains product 3-toluquinoline-8-SULPHURYL CHLORIDE through chlorosulphonation
The 3-toluquinoline is reacted with chlorsulfonic acid, then be cooled to 80 ℃ and add the sulfonation auxiliary agent, continue to react half an hour.Be cooled to 50 ℃, add methylene dichloride, under-10 ℃ of conditions, slowly drip water 100mL, then the saturated solution that drips sodium bicarbonate obtains organic layer to PH=7 after separatory, use anhydrous sodium sulfate drying, be spin-dried for, obtaining faint yellow solid is 3-toluquinoline-8-SULPHURYL CHLORIDE.
Wherein, above-mentioned sulfonation auxiliary agent is sodium-chlor or Repone K.
The feed ratio of 3-toluquinoline and sulfonation auxiliary agent 1: 0.2～0.8.
The present invention has following advantage compared with the prior art:
1) raw material of the present invention is all that market is buied, wide material sources, and cheap, production cost is low.
2) (p.4186) relatively, by improving temperature of reaction, the increase reaction times has been improved the yield of product for Tetrahedron Letters, 2010, vol.51 for the first step of the present invention and existing document.
3) second step of the present invention has been selected this kind of less reagent of phosphorus oxychloride toxicity used with respect to existing patent of thionyl chloride, and the simultaneous reactions aftertreatment adds in aqueous sodium hydroxide solution without any waste gas generation, protection of the environment.
4) the present invention's the 3rd step has selected zinc powder and sour agent reduction that reaction is reacted under normal pressure, makes reaction have more security, also avoids having used high-tension apparatus, has improved security.
5) the present invention's the 4th step has selected saturated solution of sodium bicarbonate to go down an anti-reaction that the unnecessary chlorsulfonic acid of neutralization makes in the situation that high yield has also kept colourity and the high purity of product at dichloromethane solvent when processing reaction.
6) the short method of synthetic route of the present invention is simple, easy to operate, has higher suitability for industrialized production practical value, and product meets the requirement of chemical industry and medicine and other fields fully.
The inventive method is with low cost, easy and simple to handle, without column chromatography purification, middle through neutralization, washing, and extraction, can obtain the finished product, and good in economic efficiency, productive rate is high, is applicable to suitability for industrialized production.But utilize the inventive method high yield to obtain 3-toluquinoline-8-SULPHURYL CHLORIDE.
The accompanying drawing explanation
Figure 1 shows that the nuclear magnetic spectrogram of the N-Phenylpropionamide that embodiment 1 is prepared.
Figure 2 shows that the nuclear magnetic spectrogram of the chloro-3-toluquinoline of the prepared 2-of embodiment 1.
Figure 3 shows that the nuclear magnetic spectrogram of the 3-toluquinoline that embodiment 1 is prepared.
Figure 4 shows that the nuclear magnetic spectrogram of the prepared 3-toluquinoline of embodiment 1-8-SULPHURYL CHLORIDE.
Figure 5 shows that the nuclear magnetic spectrogram of the prepared 3-toluquinoline of embodiment 2-8-SULPHURYL CHLORIDE.
Embodiment
Further set forth the present invention below in conjunction with specific embodiments and the drawings.Below implement process of the present invention and method, except the following content of mentioning specially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.
The synthetic method of 3-toluquinoline of the present invention-8-SULPHURYL CHLORIDE, the aniline of take obtains the N-Phenylpropionamide as the raw material warp reacts with propionic acid, and then Cheng Huan obtains the chloro-3-toluquinoline of 2-, then reduction obtains the 3-toluquinoline through halohydrocarbon, then obtains product 3-toluquinoline-8-SULPHURYL CHLORIDE through chlorosulphonation.The inventive method specifically comprises the following steps:
The first step, prepare N-Phenylpropionamide (as with as shown in following formula (2)) with aniline (as take as shown in following formula (1)) as starting raw material
Aniline, propionic acid and VITMAIN B1 reaction, be heated to 120 ℃, react 10 hours, stop heating, cool to room temperature, under agitation by reaction system, slowly pour in frozen water, stir 15min, filter the solid of separating out, wash with water twice, the water making beating is filtered again, 60 ℃ of solids are dried to obtain faint yellow solid, i.e. N-Phenylpropionamide, yield 90%.
Second step, the N-Phenylpropionamide is through becoming ring to obtain the chloro-3-toluquinoline of 2-(as with as shown in following formula (3))
In DMF, slowly drip thionyl chloride under ice bath, in the dropping process, there will be solidification phenomenon, continue to drip and solidify disappearance, then add the N-Phenylpropionamide, add rear maintenance thermotonus 10min, then be heated to 78 ℃, react 12 hours, stop heating, cool to room temperature, slowly carefully pour the ice-cold 5%NaOH solution that contains ice cube into, and product is separated out, suction filtration, wash twice with water, and solid is dried, white solid, i.e. the chloro-3-toluquinoline of 2-, yield 85%.
Above-mentioned chlorizating agent is thionyl chloride or oxalyl chloride.
Above-mentioned feed ratio N-Phenylpropionamide: DMF: chlorizating agent=1: 1.5～2.5: 5～7.
The 3rd step, the chloro-3-toluquinoline of 2-obtains 3-toluquinoline (as with as shown in following formula (4)) through reduction
The chloro-3-toluquinoline of 2-, zinc powder, water, the hydrogen source agent is disposable to add in reaction flask, is heated to 80 ℃, reacts 10 hours, stop heating, be cooled to room temperature, add ethyl acetate, stir 10min, separatory, organic layer, anhydrous magnesium sulfate drying, be spin-dried for solvent, obtains weak yellow liquid, be the 3-toluquinoline, productive rate 87%.
The hydrochloric acid that above-mentioned hydrogen source agent is ammonium chloride or 1mol/L.
The chloro-3-toluquinoline of above-mentioned feed ratio 2-: zinc powder: hydrogen source agent=1: 1.2～2: 30～70.
The 4th step, the 3-toluquinoline obtains final product 3-toluquinoline-8-SULPHURYL CHLORIDE (as with as shown in following formula (5)) through chlorosulphonation
The 3-toluquinoline reacts with chlorsulfonic acid, reacts 3 hours, is cooled to 80 ℃ and adds the sulfonation auxiliary agent, continues to react half an hour.Be cooled to 50 ℃, add the 200mL methylene dichloride, in the time of-10 ℃, slowly drip water 100mL, then the saturated solution that drips sodium bicarbonate is to PH=7, separatory, organic layer, anhydrous sodium sulfate drying, be spin-dried for.Faint yellow solid, i.e. 3-toluquinoline-8-SULPHURYL CHLORIDE, productive rate 96%.
Above-mentioned sulfonation auxiliary agent is sodium-chlor or Repone K.
The feed ratio of 3-toluquinoline and sulfonation auxiliary agent 1: 0.2～0.8.
Synthesizing of N-Phenylpropionamide
Connect thermometer in the there-necked flask of 500mL, reflux condensing tube, the disposable aniline (100g, 1.07mol) that adds, propionic acid (90mL, 1.2mol), VITMAIN B1 (10g, 34mmol), heat 120 ℃, reacts 10 hours.Reaction is under agitation slowly poured reaction system in the 500mL frozen water after finishing, and stirs 15min, filters the solid of separating out, and with the washing twice of 2x100mL, making beating refilters, 60 ℃ of oven dry of solid, faint yellow solid N-Phenylpropionamide, productive rate 90%.
The nuclear magnetic spectrogram of N-Phenylpropionamide prepared by the present embodiment as shown in Figure 1.
1HNMR(400MHz，CDCl
3)7.5(d，2H)，7.3(t，2H)，7.1(s，1H)，7.08～7.1(t，1H)，2.36～2.42(m，2H)，1.2(t，3H)。
Synthesizing of the chloro-3-toluquinoline of 2-
There-necked flask at 250mL connects thermometer, reflux condensing tube, and conduit, conduit one end passes into tank, adds people's DMF (12.2mL, 0.15mol) under 0 ℃ of stirring, slowly drip thionyl chloride (50.8mL, 0.7mol) under ice bath, there will be solidification phenomenon in the dropping process, continue to drip and solidify disappearance, then add N-Phenylpropionamide (15g, 0.1mol), add rear storage temperature reaction 5min, then be heated to 78 ℃, reaction is spent the night.After completion of the reaction, slowly carefully pour the ice-cold 5%NaOH solution (300mL) that contains ice cube into, product is separated out, and suction filtration washes with water one time, and solid is dried, and obtains the chloro-3-toluquinoline of white solid 2-, productive rate 85%.
In the present embodiment, feed ratio N-Phenylpropionamide: DMF: thionyl chloride=1: 1.5: 7
The nuclear magnetic spectrogram of the chloro-3-toluquinoline of 2-prepared by the present embodiment as shown in Figure 2.
1HNMR(500MHz，CDCl
3)8.0～7.9(d，2H)，7.7(d，1H)，7.6(t，1H)，7.5(t，1H)，2.5(s，3H)。
Synthesizing of 3-toluquinoline (4)
In the there-necked flask of 500mL, connect thermometer, once add the chloro-3-toluquinoline of 2-(10g, 0.056mol), zinc powder (6.3g, 0.097mol), 1N HCl (2.8ml, 2.8mol), H
2o (100mL).After adding, be warmed up to 80 ℃, react 2 hours.After reaction finishes, the reaction flask ice bath is cooling after, slowly add the NaOH solid in batches, in adition process, do not make system temperature surpass 10 ℃, when PH=7, add ethyl acetate (200mL), stir 10min, separatory, anhydrous sodium sulfate drying, filter, and is spin-dried for, obtain weak yellow liquid 3-toluquinoline, productive rate 87%.
In the present embodiment, the chloro-3-toluquinoline of feed ratio 2-: zinc powder: HCl=1: 1.7: 50.
The nuclear magnetic spectrogram of 3-toluquinoline prepared by the present embodiment as shown in Figure 3.
1HNMR(500MHz，CDCl
3)8.7(s，1H)，8.0(d，1H)，7.8(s，1H)，7.69～7.67(d，1H)，7.62～7.59(t，1H)，7.48～7.45(t，1H)，2.45(t，3H)。
Synthesizing of 3-toluquinoline-8-SULPHURYL CHLORIDE
In the there-necked flask of 250mL, connect thermometer, reflux condensing tube, add chlorsulfonic acid (73g, 0.63mol), slowly drips 3-toluquinoline (15g, 0.1mol) under ice bath, in the dropping process, can produce a large amount of hydrogen chloride gas.After dropwising, wait until and be warming up to 135 ℃ when temperature-resistant, react 3 hours.Then add sodium-chlor (3g, 0.05mol), add fashionable attention conduit and enter tank, then react half an hour.Be cooled to 50 ℃, add the 200mL methylene dichloride, in the time of-10 ℃, slowly drip water 100mL, drip again the saturated solution of sodium bicarbonate to PH=7, separatory, organic layer, anhydrous sodium sulfate drying, be spin-dried for, obtain faint yellow solid 3-toluquinoline-8-SULPHURYL CHLORIDE, productive rate 96%.
In the present embodiment, feed ratio 3-toluquinoline: sodium-chlor=1: 0.5.
The nuclear magnetic spectrogram of 3-toluquinoline prepared by the present embodiment-8-SULPHURYL CHLORIDE as shown in Figure 4.
1HNMR(500MHz，CDCl
3)9.0(s，1H)，8.4(d，1H)，8.1(d，1H)，8.0(s，1H)，7.6(t，1H)，2.6(t，3H)。
Embodiment 2
Synthesizing of N-Phenylpropionamide
Connect thermometer in the there-necked flask of 500mL, reflux condensing tube, the disposable aniline (100g, 1.07mol) that adds, propionic acid (110mL, 1.5mol), VITMAIN B1 (10g, 34mmol), heat 100 ℃, reacts 10 hours.Reaction is poured reaction system in 500mL water into after finishing, and stirs 15min, filters the solid of separating out, with the washing twice of 2x100mL, 60 ℃ of oven dry of solid, yellow solid N-Phenylpropionamide, productive rate 85%.
Synthesizing of the chloro-3-toluquinoline of 2-
There-necked flask at 250mL connects thermometer, reflux condensing tube, and conduit, conduit one end passes into tank, adds people's DMF (12.20mL, 0.15mol) under 0 ℃ of stirring, slowly drip oxalyl chloride (57mL, 0.6mol) under ice bath, there will be solidification phenomenon in the dropping process, continue to drip and solidify disappearance, then add N-Phenylpropionamide (15g, 0.1mol), add rear storage temperature reaction 5min, then be heated to 78 ℃, reaction is spent the night.After completion of the reaction, slowly carefully pour the ice-cold 5%NaOH solution (300mL) that contains ice cube into, product is separated out, and suction filtration washes with water one time, and solid is dried, and obtains the chloro-3-toluquinoline of white solid 2-, productive rate 80%.
In the present embodiment, feed ratio N-Phenylpropionamide: DMF: oxalyl chloride=1: 1.5: 6.
Synthesizing of 3-toluquinoline
In the there-necked flask of 1000mL, connect thermometer, once add the chloro-3-toluquinoline of 2-(10g, 0.056mol), zinc powder (6.3g, 0.097mol), ammonium chloride (180g, 3.36mol), water (250mL).After adding, be warmed up to 80 ℃, react 12 hours.After reaction finishes, the reaction flask ice bath is cooling after, slowly add the NaOH solid in batches, in adition process, do not make system temperature surpass 10 ℃, when PH=7, add ethyl acetate (200mL), stir 10min, separatory, anhydrous sodium sulfate drying, filter, and is spin-dried for, obtain weak yellow liquid 3-toluquinoline, productive rate 60%.
In the present embodiment, the chloro-3-toluquinoline of feed ratio 2-: zinc powder: ammonium chloride=1: 1.7: 60.
Synthesizing of 3-toluquinoline-8-SULPHURYL CHLORIDE
In the there-necked flask of 250mL, connect thermometer, reflux condensing tube, add chlorsulfonic acid (73g, 0.63mol), slowly drips 3-toluquinoline (15g, 0.1mol) under ice bath, in the dropping process, can produce a large amount of hydrogen chloride gas.After dropwising, wait until and be warming up to 135 ℃ when temperature-resistant, react 3 hours.Then add Repone K (3.5g, 0.05mol), add fashionable attention conduit and enter tank, then react half an hour.Be cooled to 50 ℃, add the 200mL methylene dichloride, in the time of-10 ℃, slowly drip water 100mL, drip again the saturated solution of sodium bicarbonate to PH=7, separatory, organic layer, anhydrous sodium sulfate drying, be spin-dried for, obtain faint yellow solid 3-toluquinoline-8-SULPHURYL CHLORIDE, productive rate 93%.
In the present embodiment, feed ratio 3-toluquinoline: Repone K=1: 0.5.
The nuclear magnetic spectrogram of 3-toluquinoline prepared by the present embodiment-8-SULPHURYL CHLORIDE as shown in Figure 5.
1HNMR(500MHz，CDCl3)9.0(s，1H)，8.4(d，1H)，8.1(d，1H)，8.0(s，1H)，7.6(t，1H)，2.6(t，3H)。
Claims (8)
1. the synthetic method of 3-toluquinoline-8-SULPHURYL CHLORIDE, it is characterized in that, described method be take aniline and is obtained the N-Phenylpropionamide as raw material through reacting with propionic acid, and then Cheng Huan obtains the chloro-3-toluquinoline of 2-, through halohydrocarbon, reduction obtains the 3-toluquinoline again, then obtains product 3-toluquinoline-8-SULPHURYL CHLORIDE through chlorosulphonation.
2. the synthetic method of 3-toluquinoline as claimed in claim 1-8-SULPHURYL CHLORIDE, is characterized in that, comprises the following steps:
The first step, the aniline of take prepares the N-Phenylpropionamide as raw material
Add aniline, propionic acid and VITMAIN B1, be heated to 120 ℃, react cool to room temperature 10 hours, under agitation by reaction system, slowly pour in frozen water, stir, filter, the solid of separating out is washed with water twice, the water making beating is filtered again, by the gained solid, dries to such an extent that faint yellow solid is the N-Phenylpropionamide;
Second step, the N-Phenylpropionamide is through becoming ring to obtain the chloro-3-toluquinoline of 2-
In DMF, slowly drip chlorizating agent under ice bath, after solidification phenomenon occurring, continue dropping until solidify disappearance, then add the N-Phenylpropionamide to be reacted, then be heated to 78 ℃, react 12 hours, stop heating, cool to room temperature, slowly carefully pour the ice-cold 5%NaOH solution that contains ice cube into, the product of separating out is carried out to suction filtration, and through washing, oven dry, obtaining white solid is the chloro-3-toluquinoline of 2-;
The 3rd step, the chloro-3-toluquinoline of 2-obtains the 3-toluquinoline through reduction
By the chloro-3-toluquinoline of 2-, zinc powder, water, the hydrogen source agent is heated to 80 ℃, reacts 10 hours, stop heating, be cooled to room temperature, regulate PH=7, add ethyl acetate, stir, obtain organic layer after separatory, use anhydrous magnesium sulfate drying, be spin-dried for solvent, obtaining weak yellow liquid is the 3-toluquinoline;
The 4th step, the 3-toluquinoline obtains product 3-toluquinoline-8-SULPHURYL CHLORIDE through chlorosulphonation
The 3-toluquinoline is reacted with chlorsulfonic acid, then be cooled to 80 ℃ and add the sulfonation auxiliary agent, continue to react half an hour; Be cooled to 50 ℃, add methylene dichloride, under-10 ℃ of conditions, slowly drip water, then the saturated solution that drips sodium bicarbonate obtains organic layer to PH=7 after separatory, use anhydrous sodium sulfate drying, be spin-dried for, obtaining faint yellow solid is 3-toluquinoline-8-SULPHURYL CHLORIDE.
3. the synthetic method of 3-toluquinoline as claimed in claim 2-8-SULPHURYL CHLORIDE, is characterized in that, chlorizating agent described in second step is thionyl chloride or oxalyl chloride.
4. the synthetic method of 3-toluquinoline as claimed in claim 2-8-SULPHURYL CHLORIDE, is characterized in that, feed ratio N-Phenylpropionamide: DMF in second step: chlorizating agent=1: 1.5～2.5: 5～7.
5. the synthetic method of 3-toluquinoline as claimed in claim 2-8-SULPHURYL CHLORIDE, is characterized in that, hydrogen source agent described in the 3rd step is ammonium chloride or hydrochloric acid.
6. the synthetic method of 3-toluquinoline as claimed in claim 2-8-SULPHURYL CHLORIDE, is characterized in that, the chloro-3-toluquinoline of feed ratio 2-in the 3rd step: zinc powder: hydrogen source agent=1: 1.2～2: 30～70.
7. the synthetic method of 3-toluquinoline as claimed in claim 2-8-SULPHURYL CHLORIDE, is characterized in that, described in the 4th step, the sulfonation auxiliary agent is sodium-chlor or Repone K.
8. the synthetic method of 3-toluquinoline as claimed in claim 2-8-SULPHURYL CHLORIDE, is characterized in that, the feed ratio 1: 0.2～0.8 of 3-toluquinoline and sulfonation auxiliary agent in the 4th step.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6307050B1 (en) * | 2000-08-29 | 2001-10-23 | R. T. Alamo Venture I Llc | Method of synthesizing flosequinan from 4-fluoroanthranilic acid |
| CN1935791A (en) * | 2006-04-07 | 2007-03-28 | 北京成宇化工有限公司 | Method for preparing 3-methyl quinolines-8-sulfochlorides |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6307050B1 (en) * | 2000-08-29 | 2001-10-23 | R. T. Alamo Venture I Llc | Method of synthesizing flosequinan from 4-fluoroanthranilic acid |
| WO2002018343A1 (en) * | 2000-08-29 | 2002-03-07 | R.T. Alamo Ventures I, Llc | Method for synthesizing flosequinan from 4-fluoroanthranilic acid |
| CN1935791A (en) * | 2006-04-07 | 2007-03-28 | 北京成宇化工有限公司 | Method for preparing 3-methyl quinolines-8-sulfochlorides |
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| OTTO METH-COHN，等: "A Versatile New Synthesis of Quinolines and Related Fused Pyridines. Part 8." Conversion of Anilides into 3-Substituted Quinolines and into Quinoxalines", 《JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1: ORGANIC AND BIO-ORGANIC CHEMISTRY》 * |
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