CN101585782B - Method for synthesizing N-methyl-N-methoxy-2- (4-cyclopropylcarbonylphenyl) -2-methylpropanamide - Google Patents
Method for synthesizing N-methyl-N-methoxy-2- (4-cyclopropylcarbonylphenyl) -2-methylpropanamide Download PDFInfo
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- CN101585782B CN101585782B CN2009100994228A CN200910099422A CN101585782B CN 101585782 B CN101585782 B CN 101585782B CN 2009100994228 A CN2009100994228 A CN 2009100994228A CN 200910099422 A CN200910099422 A CN 200910099422A CN 101585782 B CN101585782 B CN 101585782B
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- methyl
- methoxyl group
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- propanamide
- alcoholic solvent
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- 238000000034 method Methods 0.000 title claims abstract description 14
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- XJTVYCIRQPXEGB-UHFFFAOYSA-N 2-[4-(cyclopropanecarbonyl)phenyl]-n-methoxy-n,2-dimethylpropanamide Chemical compound C1=CC(C(C)(C)C(=O)N(C)OC)=CC=C1C(=O)C1CC1 XJTVYCIRQPXEGB-UHFFFAOYSA-N 0.000 title 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 46
- 238000006243 chemical reaction Methods 0.000 claims abstract description 24
- 238000003756 stirring Methods 0.000 claims abstract description 21
- 239000002904 solvent Substances 0.000 claims abstract description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 230000001476 alcoholic effect Effects 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 238000000605 extraction Methods 0.000 claims description 9
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 7
- -1 N-methyl-N-methoxyl-2- (4-cyclopropoxycarbonylphenyl) -2-methylpropanamide Chemical compound 0.000 abstract description 4
- 238000001914 filtration Methods 0.000 abstract description 2
- JQYUZWWZADSJFE-UHFFFAOYSA-N 2-[4-(4-chlorobutanoyl)phenyl]-n-methoxy-n,2-dimethylpropanamide Chemical compound CON(C)C(=O)C(C)(C)C1=CC=C(C(=O)CCCCl)C=C1 JQYUZWWZADSJFE-UHFFFAOYSA-N 0.000 abstract 2
- 238000001704 evaporation Methods 0.000 abstract 1
- 229910052760 oxygen Inorganic materials 0.000 description 12
- 239000001301 oxygen Substances 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000003643 water by type Substances 0.000 description 4
- RRJFVPUCXDGFJB-UHFFFAOYSA-N Fexofenadine hydrochloride Chemical compound Cl.C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RRJFVPUCXDGFJB-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 229960000354 fexofenadine hydrochloride Drugs 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- LSBDFXRDZJMBSC-UHFFFAOYSA-N Amide-Phenylacetic acid Natural products NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 125000005909 ethyl alcohol group Chemical group 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- CDIIZULDSLKBKV-UHFFFAOYSA-N 4-chlorobutanoyl chloride Chemical class ClCCCC(Cl)=O CDIIZULDSLKBKV-UHFFFAOYSA-N 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 206010039085 Rhinitis allergic Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 241001425575 Vagrans Species 0.000 description 1
- WXIUBYCJAAEOFL-UHFFFAOYSA-N [S].ClOCl Chemical class [S].ClOCl WXIUBYCJAAEOFL-UHFFFAOYSA-N 0.000 description 1
- 201000010105 allergic rhinitis Diseases 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical class Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000002052 anaphylactic effect Effects 0.000 description 1
- 229960004754 astemizole Drugs 0.000 description 1
- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940088529 claritin Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 238000000199 molecular distillation Methods 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 201000005404 rubella Diseases 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for synthesizing N-methyl-N-methoxyl-2- (4-cyclopropoxycarbonylphenyl) -2-methylpropanamide, which comprises the following steps: adding alkali metal hydroxide into an alcohol solvent, uniformly stirring, then dropwise adding the alcohol solvent of N-methyl-N-methoxy-2- [4- (4-chlorobutyryl) phenyl ] -2-methylpropanamide into the alcohol solvent, wherein the molar ratio of the alkali metal hydroxide to the N-methyl-N-methoxy-2- [4- (4-chlorobutyryl) phenyl ] -2-methylpropanamide is 6-10: 1, and then reacting at 20-50 ℃ for 10-30 h, evaporating the alcohol solvent after the reaction is finished, adding water into the residue, extracting with dichloromethane, drying, filtering, and removing the dichloromethane to obtain the product N-methyl-N-methoxy-2- (4-cyclopropoxycarbonylphenyl) -2-methacrylamide. The preparation process and the post-treatment of the invention are simple, and the product yield is high.
Description
Technical field
The present invention relates to the method for a kind of synthetic N-methyl-N-methoxyl group-2-(4-encircles the third oxygen carbonyl phenyl)-2-methyl propanamide.
Background technology
Anaphylactic disease is human common disease, like allergic rhinitis, chronic sudden rubella, spring fever etc.Fexofenadine hydrochloride is a Claritin of new generation; With like product Vagran (astemizole; Owing to be prone to cause cardiac toxic; Cancelled from American market in 1999), cetirizine, LT etc. compare, fexofenadine hydrochloride has the advantage that effect is fast, curative effect is high, toxic side effect is little.N-methyl-N-methoxyl group-2-(4-encircles the third oxygen carbonyl phenyl)-2-methyl propanamide is the important intermediate of synthetic fexofenadine hydrochloride; U.S. Pat 006242606B1 discloses its compound method; But the N-of method for preparing methyl-N-methoxyl group-2-(4-encircles the third oxygen carbonyl phenyl)-2-methyl propanamide productive rate lower (about overall yield 28%); And product must be purified through recrystallize after the molecular distillation, and aftertreatment is trouble, and production cost is higher.
Summary of the invention
The technical problem that the present invention will solve is the deficiency to above-mentioned prior art, provides a kind of productive rate high, the method for synthetic N-methyl-N-methoxyl group-2-(4-encircles the third oxygen carbonyl phenyl)-2-methyl propanamide that product postprocessing is simple and production cost is low.
Synthetic N-methyl of the present invention-N-methoxyl group-2-(4-encircles the third oxygen carbonyl phenyl)-the 2-methyl propanamide is the compound with following structure:
In order to solve the problems of the technologies described above, technical scheme of the present invention is: the method for a kind of synthetic N-methyl-N-methoxyl group-2-(4-encircles the third oxygen carbonyl phenyl)-2-methyl propanamide, and preparation process is following:
(1) alkali metal hydroxide is joined in the alcoholic solvent, stir, make that the volumetric molar concentration of alkali metal hydroxide in this alcoholic solvent is 2～3.4mol/L;
(2) N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamide is joined in the alcoholic solvent; Stir, make that [4-(4-chlorobutyryl) phenyl]-volumetric molar concentration of 2-methyl propanamide in this alcoholic solvent is 1mol/L to N-methyl-N-methoxyl group-2-;
(3) then step (2) gained mixture is added drop-wise in step (1) the gained mixture, wherein the mol ratio of alkali metal hydroxide and N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamide is 6～10: 1;
(4) be 20～50 ℃ of following stirring reactions 10～30 hours in temperature of reaction then; Evaporate to dryness alcoholic solvent after reaction finishes; In residue, add entry, use dichloromethane extraction, drying; Filter, remove behind the methylene dichloride product N-methyl-N-methoxyl group-2-(4-encircles the third oxygen carbonyl phenyl)-2-methyl propanamide.
Alkali metal hydroxide in the above-mentioned steps (1) is sodium hydroxide or Pottasium Hydroxide, is preferably sodium hydroxide.
Alcoholic solvent in above-mentioned steps (1) and (2) is a kind of in methyl alcohol, the ethanol or the mixed solvent be made up of them.
Temperature of reaction in the above-mentioned steps (4) is preferably 30 ℃.
Reaction times in the above-mentioned steps (4) is preferably 18 hours.
Raw material N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl] that the present invention uses-2-methyl propanamide adopts prior art for preparing to obtain.
Advantage of the present invention and beneficial effect: the method that the present invention synthesizes N-methyl-N-methoxyl group-2-(4-encircles the third oxygen carbonyl phenyl)-2-methyl propanamide has the productive rate height; Preparation technology is simple, and product only needs simple aftertreatment such as conventional extraction, washing, drying, solvent evaporated and the low advantage of production cost.
Embodiment
The invention is further illustrated by the following examples, but the present invention not only is confined to following examples.
Embodiment 1
In 250 milliliters of there-necked flasks, adding 16.00 gram (0.40mol) sodium hydroxide and 150 milliliters of anhydrous methanols stirs; Then; While stirring 15.50 gram (0.05mol) N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamides are dissolved in the drips of solution that stirs that 50 milliliters of anhydrous methanols form and are added in the there-necked flask, dropwise the back 30 ℃ of following stirring reactions 18 hours.Remove anhydrous methanol under reduced pressure after reaction finishes, add 100 ml waters and 100 milliliters of methylene dichloride in the residue, separatory, water layer are used twice of 100 milliliters of dichloromethane extraction respectively.Merge the extraction liquid that contains dichloromethane layer, use anhydrous sodium sulfate drying again, filter, remove methylene dichloride under reduced pressure and get product N-methyl-N-methoxyl group-2-(4-encircles the third oxygen carbonyl phenyl)-2-methyl propanamide 13.00 grams (0.047mol), productive rate 95%.
Above-mentioned reaction raw materials N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamide adopts the art methods preparation: (1) with 98.4 gram (0.6mol) α, alpha-alpha-dimethyl phenyl acetic acid is dissolved in 400 milliliters of toluene, and 0 ℃ drips 131 milliliters of sulfur oxychlorides down; 100 milliliters of toluene and excessive sulfur oxychloride are removed in the back underpressure distillation that finishes of stirring at room reaction back flow reaction 2 hours again after 15 hours, reaction, add 184.6 gram (1.34mol) salt of wormwood; 58.5 gram (0.6mol) N, O-dimethyl hydroxylamine hydrochloride and 300 ml waters, stirring at room reaction 4 hours; After finishing, reaction in reaction mixture, drips 200 milliliters of 2N hydrochloric acid; Separatory, organic phase are used 2N hydrochloric acid, saturated sodium bicarbonate, saturated common salt water washing, anhydrous sodium sulfate drying after-filtration successively; Toluene is removed in underpressure distillation; Residuum distill N-methyl-N-methoxyl group-α, alpha-alpha-dimethyl phenylacetamide 111.8 gram (0.54mol), productive rate 90%;
(2) 64 gram (0.48mol) aluminum chlorides are dissolved in 200 milliliters of ethylene dichloride, drip 34 gram (0.24mol) 4-chlorobutanoylchlorides under the room temperature and be dissolved in the solution that 60 milliliters of ethylene dichloride form, room temperature reaction drips 41.4 gram (0.20mol) N-methyl-N-methoxyl group-α again after 1 hour; The alpha-alpha-dimethyl phenylacetamide is dissolved in the solution that 50 milliliters of ethylene dichloride form, and dropwises the back room temperature reaction 16 hours, after reaction finishes reaction mixture is slowly poured in 200 milliliters of 2N hydrochloric acid of frozen water refrigerative; Separatory; Water layer extracts with ethylene dichloride, merges organic phase, washes and washes with saturated sodium bicarbonate solution respectively; Dry; Filter, remove solvent and get product N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamide 66.3 grams (purity 80%), productive rate 85%; Embodiment 2～3 also together.
Embodiment 2
In 250 milliliters of there-necked flasks, add 20.50 grams (82%; 0.30mol) Pottasium Hydroxide and 150 milliliters of anhydrous methanols stir; Then; While stirring 15.50 gram (0.05mol) N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamides are dissolved in the drips of solution that stirs that 50 milliliters of anhydrous methanols form and are added in the there-necked flask, after dropwising, 20 ℃ of following stirring reactions 30 hours.Remove anhydrous methanol under reduced pressure after reaction finishes, add 100 ml waters and 100 milliliters of methylene dichloride in the residue, separatory, water layer are used twice of 100 milliliters of dichloromethane extraction respectively.Merge the extraction liquid that contains dichloromethane layer, use anhydrous sodium sulfate drying again, filter, remove methylene dichloride under reduced pressure and get product N-methyl-N-methoxyl group-2-(4-encircles the third oxygen carbonyl phenyl)-2-methyl propanamide 12.38 grams (0.045mol), productive rate 90%.
Embodiment 3
In 250 milliliters of there-necked flasks, add 20.00 gram (0.50mol) sodium hydroxide and 150 milliliters of absolute ethyl alcohols; Stir; Then; While stirring 15.50 gram (0.05mol) N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamides are dissolved in the drips of solution that stirs that 50 milliliters of absolute ethyl alcohols form and are added in the there-necked flask, after dropwising, 50 ℃ of following stirring reactions 30 hours.Remove absolute ethyl alcohol under reduced pressure after reaction finishes, add 100 ml waters and 100 milliliters of methylene dichloride in the residue, separatory, water layer are used twice of 100 milliliters of dichloromethane extraction respectively.Merge the extraction liquid that contains dichloromethane layer, anhydrous sodium sulfate drying filters, and removes methylene dichloride under reduced pressure and gets product N-methyl-N-methoxyl group-2-(4-encircles the third oxygen carbonyl phenyl)-2-methyl propanamide 12.65 grams (0.046mol), productive rate 92%.
Can know that to sum up the present invention synthesizes the method for N-methyl-N-methoxyl group-2-(4-encircles the third oxygen carbonyl phenyl)-2-methyl propanamide, preparation were established is simple, and the aftertreatment of product is also simple, and productive rate is higher.
Claims (3)
1. the method for synthetic N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide, it is characterized in that: preparation process is following:
(1) alkali metal hydroxide is joined in the alcoholic solvent, stir, make that the volumetric molar concentration of alkali metal hydroxide in this alcoholic solvent is 2～3.4mol/L;
(2) N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamide is joined in the alcoholic solvent; Stir, make that [4-(4-chlorobutyryl) phenyl]-volumetric molar concentration of 2-methyl propanamide in this alcoholic solvent is 1mol/L to N-methyl-N-methoxyl group-2-;
(3) then step (2) gained mixture is added drop-wise in step (1) the gained mixture, wherein the mol ratio of alkali metal hydroxide and N-methyl-N-methoxyl group-2-[4-(4-chlorobutyryl) phenyl]-2-methyl propanamide is 6～10: 1;
(4) be 20～50 ℃ of following stirring reactions 10～30 hours in temperature of reaction then; Evaporate to dryness alcoholic solvent after reaction finishes; In residue, add entry, use dichloromethane extraction, drying; Filter, remove behind the methylene dichloride product N-methyl-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide;
Alkali metal hydroxide in the said step (1) is sodium hydroxide or Pottasium Hydroxide;
Alcoholic solvent in said step (1) and (2) is methyl alcohol or ethanol or by the two mixed solvent of forming.
2. the method for synthetic N-methyl according to claim 1-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide, it is characterized in that: the temperature of reaction in the said step (4) is 30 ℃.
3. the method for synthetic N-methyl according to claim 1-N-methoxyl group-2-(4-cyclopropyl carbonyl phenyl)-2-methyl propanamide, it is characterized in that: the reaction times in the said step (4) is 18 hours.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100994228A CN101585782B (en) | 2009-06-06 | 2009-06-06 | Method for synthesizing N-methyl-N-methoxy-2- (4-cyclopropylcarbonylphenyl) -2-methylpropanamide |
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|---|---|---|---|
| CN2009100994228A CN101585782B (en) | 2009-06-06 | 2009-06-06 | Method for synthesizing N-methyl-N-methoxy-2- (4-cyclopropylcarbonylphenyl) -2-methylpropanamide |
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| CN101585782B true CN101585782B (en) | 2012-04-25 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1128987A (en) * | 1993-06-25 | 1996-08-14 | 默里尔多药物公司 | New intermediates for the preparation of antihistamine piperidine derivatives |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1128987A (en) * | 1993-06-25 | 1996-08-14 | 默里尔多药物公司 | New intermediates for the preparation of antihistamine piperidine derivatives |
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