CN1762984A - Purification method for amide and sulfonylamine compound synthesized from liquid phase - Google Patents
Purification method for amide and sulfonylamine compound synthesized from liquid phase Download PDFInfo
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- CN1762984A CN1762984A CN 200510060979 CN200510060979A CN1762984A CN 1762984 A CN1762984 A CN 1762984A CN 200510060979 CN200510060979 CN 200510060979 CN 200510060979 A CN200510060979 A CN 200510060979A CN 1762984 A CN1762984 A CN 1762984A
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- -1 sulfonylamine compound Chemical class 0.000 title claims abstract description 25
- 150000001408 amides Chemical class 0.000 title claims abstract description 13
- 238000000746 purification Methods 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title claims description 5
- 239000007791 liquid phase Substances 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 67
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 66
- 238000003756 stirring Methods 0.000 claims abstract description 63
- LETZPVMNOGITER-UHFFFAOYSA-N 2-pyridin-1-ium-1-ylethanamine Chemical compound NCC[N+]1=CC=CC=C1 LETZPVMNOGITER-UHFFFAOYSA-N 0.000 claims abstract description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 41
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 36
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 238000005406 washing Methods 0.000 claims abstract description 23
- 238000001035 drying Methods 0.000 claims abstract description 22
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims abstract description 21
- 239000012074 organic phase Substances 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 21
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims abstract description 15
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 14
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- 239000002516 radical scavenger Substances 0.000 claims description 47
- 230000031709 bromination Effects 0.000 claims description 40
- 238000005893 bromination reaction Methods 0.000 claims description 40
- 239000012141 concentrate Substances 0.000 claims description 21
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 20
- 238000004817 gas chromatography Methods 0.000 claims description 20
- 238000002156 mixing Methods 0.000 claims description 20
- 229910002027 silica gel Inorganic materials 0.000 claims description 20
- 239000000741 silica gel Substances 0.000 claims description 20
- 229960001866 silicon dioxide Drugs 0.000 claims description 20
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 16
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 16
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 12
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- 229960005181 morphine Drugs 0.000 claims description 8
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- JRBPAEWTRLWTQC-UHFFFAOYSA-N dodecylamine Chemical compound CCCCCCCCCCCCN JRBPAEWTRLWTQC-UHFFFAOYSA-N 0.000 claims description 6
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 claims description 6
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 claims description 4
- 230000000694 effects Effects 0.000 abstract description 2
- 150000008040 ionic compounds Chemical class 0.000 abstract description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 238000004587 chromatography analysis Methods 0.000 abstract 1
- 239000007788 liquid Substances 0.000 abstract 1
- 230000000269 nucleophilic effect Effects 0.000 abstract 1
- 230000000149 penetrating effect Effects 0.000 abstract 1
- 239000012071 phase Substances 0.000 abstract 1
- 229910052710 silicon Inorganic materials 0.000 abstract 1
- 239000010703 silicon Substances 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 49
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 18
- 239000000047 product Substances 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OJGMBLNIHDZDGS-UHFFFAOYSA-N N-Ethylaniline Chemical compound CCNC1=CC=CC=C1 OJGMBLNIHDZDGS-UHFFFAOYSA-N 0.000 description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- XWBDWHCCBGMXKG-UHFFFAOYSA-N ethanamine;hydron;chloride Chemical compound Cl.CCN XWBDWHCCBGMXKG-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- LKQUCICFTHBFAL-UHFFFAOYSA-N n-benzylbenzamide Chemical compound C=1C=CC=CC=1C(=O)NCC1=CC=CC=C1 LKQUCICFTHBFAL-UHFFFAOYSA-N 0.000 description 2
- DKYVVNLWACXMDW-UHFFFAOYSA-N n-cyclohexyl-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC1CCCCC1 DKYVVNLWACXMDW-UHFFFAOYSA-N 0.000 description 2
- 229920005989 resin Polymers 0.000 description 2
- 239000011347 resin Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- WTHKAJZQYNKTCJ-UHFFFAOYSA-N 4-methyl-N-(phenylmethyl)benzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NCC1=CC=CC=C1 WTHKAJZQYNKTCJ-UHFFFAOYSA-N 0.000 description 1
- 229920002536 Scavenger resin Polymers 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000006757 chemical reactions by type Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- USAFAYBLWJSOFY-UHFFFAOYSA-N n-dodecyl-4-methylbenzenesulfonamide Chemical compound CCCCCCCCCCCCNS(=O)(=O)C1=CC=C(C)C=C1 USAFAYBLWJSOFY-UHFFFAOYSA-N 0.000 description 1
- PZYZDSMNHHDRHM-UHFFFAOYSA-N n-dodecylbenzamide Chemical compound CCCCCCCCCCCCNC(=O)C1=CC=CC=C1 PZYZDSMNHHDRHM-UHFFFAOYSA-N 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 238000003746 solid phase reaction Methods 0.000 description 1
- 238000010671 solid-state reaction Methods 0.000 description 1
- 238000010530 solution phase reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The purification process of amide and sulfamide compound synthesized in solution phase includes the following steps: 1. dissolving 1 mmol amine compound in 3-5 ml methane dichloride via stirring, adding 2-2.5 mmol benzoyl chloride or 4-tolylsulfonyl chloride, adding 2-3 mmol triethylamine or pyridine, stirring under room temperature, and tracing the reaction process via vapor chromatographic method until finishing reaction; and 2. adding 1.2-2.0 mmol water soluble N-aminoethyl pyridinium as nucleophilic amino eliminator via stirring at room temperature, adding 10-15 ml ethyl acetate to dilute reacted liquid, washing with 10-15 ml salt water, penetrating the organic phase through silicon gel column, drying with anhydrous sodium sulfate and drying. The present invention adopts water soluble ionic compound as eliminator carrier and water to wash reaction product to reach the aim of purification. The eliminator is easy to prepare and purify, low in cost, high in reaction activity, high in purifying efficiency and suitable for mass synthesis.
Description
Technical field
The present invention relates to the purification process of combined synthesizing amide of a kind of solution and sulfamide compound.
Background technology
In recent years, combinatorial chemistry has greatly promoted the development of pharmaceutical chemistry and materials chemistry, provides very effective means for seeking the new drug lead compound and preparing the material with specific function.Compare with the solid phase combination is synthetic, combined synthesizing of solution has plurality of advantages: (1) reaction type is many, and it is combined synthetic that existing reaction all can be used for solution; (2) need not to design synthetic link molecule and cleaved products; (3) the easy tracking and the detection reaction process; (4) need not many times of excessive reagent and a large amount of cleaning solvents, cost is low, is easy to realize a large amount of synthetic.But, how to realize that fast separating and purifying target compound storehouse is the key issue that the combined chemistry of solution will solve.In the combined synthetic separating and purifying technology of solution, it is the method for widespread use that polymkeric substance load scavenging agent (polymer-supported scavenger) is assisted separation and purification.This method uses close electricity such as isocyanic ester excessive in the resin of functionalization and the solution-phase reaction, carboxylic acid halides, amine or nucleophilic reagent to react, and reaches the purpose of purifies and separates by removing by filter the product resin.Though it is simple to operate, the charge capacity of scavenger resin is low, the cost height, be unsuitable for a large amount of synthetic, and the efficient of purifies and separates that had disadvantages affect such as " solid state reaction effects ".
Summary of the invention
The purification process that the purpose of this invention is to provide combined synthesizing amide of a kind of solution and sulfamide compound.
The step of method is as follows:
1) the 1mmol aminated compounds is dissolved in 3～5ml methylene dichloride under stirring, slowly add 2～3mmol triethylamine or pyridine after adding 2～2.5mmol Benzoyl chloride or 4-toluene sulfonyl chloride, mixing solutions at room temperature stirs, and follows the tracks of reaction process with gas-chromatography, and reaction finishes;
2) add the water miscible amino nucleophilicity scavenging agent bromination N-aminoethyl pyridinium salt of 1.2～2.0mmol, stirring at room 6～12 hours, add 10～15ml ethyl acetate dilute reaction solution also with 10～15ml salt water washing 2～3 times, after organic phase is passed 0.5～1cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain amides or sulfamide compound.
Described aminated compounds is aromatic amine compounds, fat amine compound.Aromatic amine compounds is aniline, 4-anisidine, 2-aminotoluene or N-ethylphenyl amine.Fat amine compound is benzylamine, morphine quinoline, amino dodecane, hexahydroaniline or hexahydropyridine.
The present invention adopts micromolecular water dissolubility ionic compound as the scavenging agent carrier, and the product of scavenging agent and cleaning reaction can separate with target compound by liquid-liquid phase extraction, reaches the purpose of purifying.This class scavenging agent is a raw material with pyridine and 2-bromine ethylamine hydrochloride, preparation and purifying easily, and cost is low, reactive behavior height, purification efficiency height (product purity height, yield height) and be suitable for a large amount of synthetic.
Embodiment
The present invention adopts water miscible combined synthetic acid amides of amino nucleophilicity scavenging agent purification solution and sulfamide compound, this class scavenging agent and excessive electrophilic reagent (acyl chlorides, SULPHURYL CHLORIDE) react, removing product that generates and excessive scavenging agent are removed (liquid-liquid phase extracting and separating) by washing, thereby reach the purpose of purified product, reaction formula is as follows:
The acid amides of the synthetic gained of the present invention and the yield of sulfamide compound and purity see Table 1 and table 2.
The combined synthesizing amide compounds of table 1 solution
| No | Amine | Product | Yield (%) | Purity (%) | Molecular weight (EI) (M +，m/z) |
| 1 | aniline | 5a | 87 | 97 | 197 |
| 2 | benzylamine | 5b | 84 | 92 | 211 |
| 3 | 4-methoxylaniline | 5c | 88 | 99 | 227 |
| 4 | 2-toluidine | 5d | 85 | 97 | 211 |
| 5 | morpholine | 5e | 88 | 98 | 191 |
| 6 | hexahydropyridine | 5f | 87 | 99 | 189 |
| 7 | cyclohexylamine | 5g | 86 | 99 | 203 |
| 8 | dodecylamine | 5h | 88 | 97 | 289 |
| 9 | N-ethylaniline | 5i | 83 | 99 | 225 |
The combined synthetic sulfamide compound of table 2 solution
| No | Amine | Product | Yield (%) | Purity (%) | Molecular weight (EI) (M +，m/z) |
| 1 | aniline | 7a | 83 | 95 | 247 |
| 2 | benzylamine | 7b | 85 | 99 | 261 |
| 3 | 4-methoxylaniline | 7c | 86 | 96 | 277 |
| 4 | cyclohexylamine | 7d | 84 | 99 | 253 |
| 5 | hexahydropyridine | 7e | 87 | 93 | 239 |
| 6 | morpholine | 7f | 88 | 99 | 241 |
| 7 | dodecylamine | 7g | 85 | 96 | 339 |
| 8 | 3-toluidine | 7h | 83 | 94 | 261 |
| 9 | N-ethylaniline | 7i | 82 | 97 | 275 |
Following examples will help to understand the present invention, but be not limited to content of the present invention:
Synthesizing of embodiment 1 water-soluble scavenging agent bromination N-aminoethyl pyridinium salt (1)
20.5g after (0.1mol) the pyridine Hybrid Heating of 2-bromine ethylamine hydrochloride and 50ml steaming newly refluxed 24 hours, pyridine was removed in underpressure distillation, portioning adding solid potassium hydroxide adjusting pH=8 after the adding 10ml water dissolution in the gained solid.The aqueous solution extracts product (30ml * 2) with ethyl acetate washing (30ml * 2), solid concentrated, dry gained with acetonitrile, merges the acetonitrile extracting solution, concentrates and obtains bromination N-aminoethyl pyridinium salt 18.3g, yield 90%.
mp：227.9～229.6℃
1H NMR(500MHz，D
2O)：δ3.43(t，2H，J＝6.0Hz)，4.80(t，2H，J＝6.0Hz)，8.10(m，2H)，8.58(m，1H)，8.89(m，2H)；
13C NMR(125MHz，D
2O)：δ40.89，61.43，128.98，145.00，146.76；
IR(KBr)：3555，3481，3418，1637，1618，1079，1036cm
-1.
MS(ESI)：m/z 123([M-Br]
+).
Embodiment 2 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic N-phenylbenzamaide
93mg (1mmol) aniline is dissolved in the 3ml methylene dichloride under stirring, slowly add 303mg (3mmol) triethylamine after adding 280mg (2mmol) Benzoyl chloride, mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 244mg (1.2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 6 hours, add 10ml ethyl acetate dilute reaction solution and use 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 171mg N-phenylbenzamaide, yield is 87%.It is 97% that GC/MS analyzes its purity.Molecular weight is 197.
Embodiment 3 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic N-benzyl benzamide
107mg (1mmol) benzylamine is dissolved in the 3ml methylene dichloride under stirring, slowly add 303mg (3mmol) triethylamine after adding 280mg (2mmol) Benzoyl chloride, mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 244mg (1.2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 10 hours, add 10ml ethyl acetate dilute reaction solution and use 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 177mg N-benzyl benzamide, yield is 84%.It is 92% that GC/MS analyzes its purity.Molecular weight is 211.
Embodiment 4 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic N-4-anisole yl-benzamide
123mg (1mmol) 4-anisidine is dissolved in the 3ml methylene dichloride under stirring, slowly add 303mg (3mmol) triethylamine after adding 280mg (2mmol) Benzoyl chloride, mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 244mg (1.2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 6 hours, add 10ml ethyl acetate dilute reaction solution and use 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 200mgN-4-anisole yl-benzamide, yield is 88%.It is 99% that GC/MS analyzes its purity.Molecular weight is 227.
Embodiment 5 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic N-2-aminomethyl phenyl benzamide
107mg (1mmol) 2-aminotoluene is dissolved in the 3ml methylene dichloride under stirring, slowly add 303mg (3mmol) triethylamine after adding 280mg (2mmol) Benzoyl chloride, mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 244mg (1.2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 12 hours, add 10ml ethyl acetate dilute reaction solution and use 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 179mgN-2-aminomethyl phenyl benzamide, yield is 85%.It is 97% that GC/MS analyzes its purity.Molecular weight is 211.
Embodiment 6 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic morphine quinoline yl-benzamide
87mg (1mmol) morphine quinoline is dissolved in the 3ml methylene dichloride under stirring, slowly add 303mg (3mmol) triethylamine after adding 280mg (2mmol) Benzoyl chloride, mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 244mg (1.2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 6 hours, add 10ml ethyl acetate dilute reaction solution and use 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 168mg morphine quinoline yl-benzamide, yield is 88%.It is 98% that GC/MS analyzes its purity.Molecular weight is 191.
Embodiment 7 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic hexahydropyridine yl-benzamide
85mg (1mmol) hexahydropyridine is dissolved in the 3ml methylene dichloride under stirring, slowly add 303mg (3mmol) triethylamine after adding 280mg (2mmo1) Benzoyl chloride, mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 244mg (1.2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 6 hours, add 10ml ethyl acetate dilute reaction solution and use 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 164mg hexahydropyridine yl-benzamide, yield is 87%.It is 99% that GC/MS analyzes its purity.Molecular weight is 189.
Embodiment 8 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic N-phenylcyclohexane methane amide
99mg (1mmol) hexahydroaniline is dissolved in the 3ml methylene dichloride under stirring, slowly add 303mg (3mmol) triethylamine after adding 280mg (2mmol) Benzoyl chloride, mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 244mg (1.2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 6 hours, add 10ml ethyl acetate dilute reaction solution and use 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 175mg N-phenylcyclohexane methane amide, yield is 86%.It is 99% that GC/MS analyzes its purity.Molecular weight is 203.
Embodiment 9 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic N-dodecyl benzamide
185mg (1mmol) lauryl amine is dissolved in the 3ml methylene dichloride under stirring, slowly add 303mg (3mmol) triethylamine after adding 280mg (2mmol) Benzoyl chloride, mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 244mg (1.2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 6 hours, add 10ml ethyl acetate dilute reaction solution and use 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 254mgN-dodecyl benzamide, yield is 88%.It is 97% that GC/MS analyzes its purity.Molecular weight is 289.
Embodiment 10 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic N-ethylphenyl benzamide
121mg (1mmol) N-ethylphenyl amine is dissolved in the 3ml methylene dichloride under stirring, slowly add 303mg (3mmol) triethylamine after adding 280mg (2mmol) Benzoyl chloride, mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 407mg (2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 6 hours, add 10ml ethyl acetate dilute reaction solution and use 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 187mg N-ethylphenyl benzamide, yield is 83%.It is 99% that GC/MS analyzes its purity.Molecular weight is 225.
Embodiment 11 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic N-phenyl-4-methyl benzenesulfonamide
93mg (1mmol) aniline is dissolved in the 3ml methylene dichloride under stirring, and slowly adds 237mg (3mmol) pyridine behind adding 382mg (2mmol) the 4-Methyl benzenesulfonyl chlorine.Mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 244mg (1.2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 6 hours adds 10ml ethyl acetate dilute reaction solution and uses 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 205mg N-phenyl-4-methyl benzenesulfonamide, yield is 83%.It is 95% that GC/MS analyzes its purity.Molecular weight is 247.
Embodiment 12 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic N-benzyl-4-methyl benzenesulfonamide
107mg (1mmol) benzylamine is dissolved in the 3ml methylene dichloride under stirring, and slowly adds 237mg (3mmol) pyridine behind adding 382mg (2mmol) the 4-Methyl benzenesulfonyl chlorine.Mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 244mg (1.2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 6 hours adds 10ml ethyl acetate dilute reaction solution and uses 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 222mg N-phenyl-4-methyl benzenesulfonamide, yield is 85%.It is 99% that GC/MS analyzes its purity.Molecular weight is 261.
Embodiment 13 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic N-4-p-methoxy-phenyl-4-methyl benzenesulfonamide
123mg (1mmol) 4-anisidine is dissolved in the 3ml methylene dichloride under stirring, and slowly adds 237mg (3mmol) pyridine behind adding 382mg (2mmol) the 4-Methyl benzenesulfonyl chlorine.Mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 244mg (1.2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 6 hours adds 10ml ethyl acetate dilute reaction solution and uses 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 238mgN-4-p-methoxy-phenyl-4-methyl benzenesulfonamide, yield is 86%.It is 96% that GC/MS analyzes its purity.Molecular weight is 277.
Embodiment 14 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic N-cyclohexyl-4-methyl benzenesulfonamide
99mg (1mmol) hexahydroaniline is dissolved in the 3ml methylene dichloride under stirring, and slowly adds 237mg (3mmol) pyridine behind adding 382mg (2mmol) the 4-Methyl benzenesulfonyl chlorine.Mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 244mg (1.2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 6 hours adds 10ml ethyl acetate dilute reaction solution and uses 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 213mg N-cyclohexyl-4-methyl benzenesulfonamide, yield is 84%.It is 99% that GC/MS analyzes its purity.Molecular weight is 253.
Embodiment 15 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic hexahydropyridine base-4-methyl benzenesulfonamide
85mg (1mmol) hexahydropyridine is dissolved in the 3ml methylene dichloride under stirring, and slowly adds 237mg (3mmol) pyridine behind adding 382mg (2mmol) the 4-Methyl benzenesulfonyl chlorine.Mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 244mg (1.2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 6 hours adds 10ml ethyl acetate dilute reaction solution and uses 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 208mg hexahydropyridine base-4-methyl benzenesulfonamide, yield is 87%.It is 93% that GC/MS analyzes its purity.Molecular weight is 239.
Embodiment 16 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic morphine quinoline base-4-methyl benzenesulfonamide
87mg (1mmol) morphine quinoline is dissolved in the 3ml methylene dichloride under stirring, and slowly adds 237mg (3mmol) pyridine behind adding 382mg (2mmol) the 4-Methyl benzenesulfonyl chlorine.Mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 407mg (2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 12 hours adds 10ml ethyl acetate dilute reaction solution and uses 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 212mg morphine quinoline base-4-methyl benzenesulfonamide, yield is 88%.It is 99% that GC/MS analyzes its purity.Molecular weight is 241.
Embodiment 17 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic N-dodecyl-4-methyl benzenesulfonamide
185mg (1mmol) lauryl amine is dissolved in the 3ml methylene dichloride under stirring, and slowly adds 237mg (3mmol) pyridine behind adding 382mg (2mmol) the 4-Methyl benzenesulfonyl chlorine.Mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 244mg (1.2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 6 hours adds 10ml ethyl acetate dilute reaction solution and uses 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 288mgN-dodecyl-4-methyl benzenesulfonamide, yield is 85%.It is 96% that GC/MS analyzes its purity.Molecular weight is 339.
Embodiment 18 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic N-3-aminomethyl phenyl-4-methyl benzenesulfonamide
107mg (1mmol) 3-monomethylaniline is dissolved in the 3ml methylene dichloride under stirring, and slowly adds 237mg (3mmol) pyridine behind adding 382mg (2mmol) the 4-Methyl benzenesulfonyl chlorine.Mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 244mg (1.2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 6 hours adds 10ml ethyl acetate dilute reaction solution and uses 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 217mgN-3-aminomethyl phenyl-4-methyl benzenesulfonamide, yield is 83%.It is 94% that GC/MS analyzes its purity.Molecular weight is 261.
Embodiment 19 water-soluble scavenging agent bromination N-aminoethyl pyridinium salts are used for synthetic N-ethylphenyl-4-methyl benzenesulfonamide
121mg (1mmol) N-ethylaniline is dissolved in the 3ml methylene dichloride under stirring, and slowly adds 237mg (3mmol) pyridine behind adding 382mg (2mmol) the 4-Methyl benzenesulfonyl chlorine.Mixing solutions at room temperature stirs, follow the tracks of reaction process with gas-chromatography, reaction finishes, add 407mg (2mmol) scavenging agent bromination N-aminoethyl pyridinium salt, stirring at room 12 hours adds 10ml ethyl acetate dilute reaction solution and uses 10ml salt water washing 2 times, after organic phase is passed the 0.5cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain 226mgN-ethylphenyl-4-methyl benzenesulfonamide, yield is 82%.It is 97% that GC/MS analyzes its purity.Molecular weight is 275.
Claims (4)
1. the purification process of combined synthesizing amide of solution and sulfamide compound is characterized in that the step of method is as follows:
1) the 1mmol aminated compounds is dissolved in 3～5ml methylene dichloride under stirring, slowly add 2～3mmol triethylamine or pyridine after adding 2～2.5mmol Benzoyl chloride or 4-toluene sulfonyl chloride, mixing solutions at room temperature stirs, and follows the tracks of reaction process with gas-chromatography, and reaction finishes;
2) add the water miscible amino nucleophilicity scavenging agent bromination N-aminoethyl pyridinium salt of 1.2～2.0mmol, stirring at room 6～12 hours, add 10～15ml ethyl acetate dilute reaction solution also with 10～15ml salt water washing 2～3 times, after organic phase is passed 0.5～1cm silicagel column, use anhydrous sodium sulfate drying, concentrate and obtain amides or sulfamide compound.
2. the purification process of combined synthesizing amide of a kind of solution according to claim 1 and sulfamide compound is characterized in that described aminated compounds is aromatic amine compounds, fat amine compound.
3. the purification process of combined synthesizing amide of a kind of solution according to claim 2 and sulfamide compound is characterized in that described aromatic amine compounds is aniline, 4-anisidine, 2-aminotoluene or N-ethylphenyl amine.
4. the purification process of combined synthesizing amide of a kind of solution according to claim 2 and sulfamide compound is characterized in that described fat amine compound is benzylamine, morphine quinoline, amino dodecane, hexahydroaniline or hexahydropyridine.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103265505A (en) * | 2013-05-24 | 2013-08-28 | 浙江工业大学 | Preparation method of N-p-toluenesulfonyl piperidine |
| CN104130165A (en) * | 2014-06-30 | 2014-11-05 | 江苏瑞克医药科技有限公司 | Post-processing method for moclobemide intermediate |
| CN110950783A (en) * | 2019-11-23 | 2020-04-03 | 苏州华道生物药业股份有限公司 | Solid phase synthesis method of N-butyl benzene sulfonamide |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103265505A (en) * | 2013-05-24 | 2013-08-28 | 浙江工业大学 | Preparation method of N-p-toluenesulfonyl piperidine |
| CN103265505B (en) * | 2013-05-24 | 2016-03-09 | 浙江工业大学 | A kind of preparation method of N-tosylpiperidine |
| CN104130165A (en) * | 2014-06-30 | 2014-11-05 | 江苏瑞克医药科技有限公司 | Post-processing method for moclobemide intermediate |
| CN104130165B (en) * | 2014-06-30 | 2016-02-03 | 江苏瑞克医药科技有限公司 | A kind of moclobemide intermediate post-treating method |
| CN110950783A (en) * | 2019-11-23 | 2020-04-03 | 苏州华道生物药业股份有限公司 | Solid phase synthesis method of N-butyl benzene sulfonamide |
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