CN103396334A - New synthesis method of 2-ethoxy-4-amino-5-chlorobenzoic acid and intermediate thereof - Google Patents
New synthesis method of 2-ethoxy-4-amino-5-chlorobenzoic acid and intermediate thereof Download PDFInfo
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- XWGYOMHQGQZRLC-UHFFFAOYSA-N 4-amino-5-chloro-2-ethoxybenzoic acid Chemical compound CCOC1=CC(N)=C(Cl)C=C1C(O)=O XWGYOMHQGQZRLC-UHFFFAOYSA-N 0.000 title abstract 2
- 238000001308 synthesis method Methods 0.000 title 1
- 238000002360 preparation method Methods 0.000 claims abstract description 42
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 239000002994 raw material Substances 0.000 claims abstract description 12
- WUBBRNOQWQTFEX-UHFFFAOYSA-N 4-aminosalicylic acid Chemical compound NC1=CC=C(C(O)=O)C(O)=C1 WUBBRNOQWQTFEX-UHFFFAOYSA-N 0.000 claims abstract description 10
- 229960004909 aminosalicylic acid Drugs 0.000 claims abstract description 10
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 8
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 8
- 230000007062 hydrolysis Effects 0.000 claims abstract description 7
- 238000006200 ethylation reaction Methods 0.000 claims abstract description 5
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 18
- -1 potassium salt compound Chemical class 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000000543 intermediate Substances 0.000 claims description 12
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 11
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- KIWBPDUYBMNFTB-UHFFFAOYSA-N Ethyl hydrogen sulfate Chemical compound CCOS(O)(=O)=O KIWBPDUYBMNFTB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 9
- YPELFRMCRYSPKZ-UHFFFAOYSA-N 4-amino-5-chloro-2-ethoxy-N-({4-[(4-fluorophenyl)methyl]morpholin-2-yl}methyl)benzamide Chemical compound CCOC1=CC(N)=C(Cl)C=C1C(=O)NCC1OCCN(CC=2C=CC(F)=CC=2)C1 YPELFRMCRYSPKZ-UHFFFAOYSA-N 0.000 abstract description 6
- 229960004085 mosapride Drugs 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000021736 acetylation Effects 0.000 abstract 1
- 238000006640 acetylation reaction Methods 0.000 abstract 1
- 159000000001 potassium salts Chemical class 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 22
- 239000002253 acid Substances 0.000 description 19
- 238000001035 drying Methods 0.000 description 18
- 238000005406 washing Methods 0.000 description 18
- 238000010438 heat treatment Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 12
- 125000004494 ethyl ester group Chemical group 0.000 description 11
- ZGIBSKHPEMBBCT-UHFFFAOYSA-N 2-acetamidooxybenzoic acid Chemical compound CC(=O)NOC1=CC=CC=C1C(O)=O ZGIBSKHPEMBBCT-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 235000015320 potassium carbonate Nutrition 0.000 description 8
- 239000011734 sodium Substances 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- 229940113720 aminosalicylate Drugs 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000370 acceptor Substances 0.000 description 3
- 238000005265 energy consumption Methods 0.000 description 3
- PRZJIMSXCLZGLT-UHFFFAOYSA-M potassium;4-amino-2-hydroxybenzoate Chemical compound [K+].NC1=CC=C(C([O-])=O)C(O)=C1 PRZJIMSXCLZGLT-UHFFFAOYSA-M 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 238000004896 high resolution mass spectrometry Methods 0.000 description 2
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 2
- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- GGRLKHMFMUXIOG-UHFFFAOYSA-M 2-acetyloxyethyl(trimethyl)azanium;hydroxide Chemical compound [OH-].CC(=O)OCC[N+](C)(C)C GGRLKHMFMUXIOG-UHFFFAOYSA-M 0.000 description 1
- ANQWOEYKZJYUFB-UHFFFAOYSA-N [Na].NOC1=CC=CC=C1C(O)=O Chemical compound [Na].NOC1=CC=CC=C1C(O)=O ANQWOEYKZJYUFB-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000012320 chlorinating reagent Substances 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 201000006549 dyspepsia Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000010931 ester hydrolysis Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- HAHZTTVTUIYEKH-UHFFFAOYSA-N methyl 2-acetamidooxybenzoate Chemical class COC(C=1C(ONC(C)=O)=CC=CC=1)=O HAHZTTVTUIYEKH-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical group OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000002182 synaptic membrane Anatomy 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of an important intermediate, namely 2-ethoxy-4-amino-5-chlorobenzoic acid for synthesis of mosapride. According to the method, a product is obtained by four-step reaction of acetylation, di-ethylation, chlorination and hydrolysis of p-aminosalicylic acid or corresponding sodium salt and potassium salt compounds thereof. The method has the advantages of cheap price, easiness in obtainment of raw materials, short synthesis steps, mild reaction conditions, easiness in control, simplicity in operation, little pollution, high total yield, low cost, good product quality, stability and easiness in implementation of large-scale industrial production.
Description
Technical field
The invention provides the preparation method of a kind of important intermediate 2-oxyethyl group of synthetic Mosapride Citrate-4-amino-5-chloro-benzoic acid, belong to the synthetic field of medicine.
Background technology
Mosapride Citrate is selective serotonin 4 (5-HT4) receptor stimulant, 5-HT4 acceptor by excited gi tract cholinergic relay cell and myenteric nerve plexus, promote the release of vagusstoff, thereby enhancing gastrointestinal movement, improve functional dyspepsia patient's gastrointestinal symptom, do not affect the secretion of hydrochloric acid in gastric juice.Dopamine D 2 on Mosapride Citrate and brain synaptic membrane, 5-HT1,5-HT2 acceptor are without avidity, thereby there is no the side effect of the caused extrapyramidal system of these acceptors retardance, the advantage such as have that receptor-selective is strong, pharmacokinetics is good, selectively acting digestive tube, dosage are little.Because its clinical efficacy is good, side effect is low at home and abroad to be widely used.
There is more deficiency in existing Mosapride Citrate synthesis technique, (structure is suc as formula shown in (I) to be mainly manifested in intermediate 2-oxyethyl group-4-acetylaminohydroxyphenylarsonic acid 5-chloro-benzoic acid, hereinafter to be referred as " formula (I) compound ") preparation cost higher, account for the large percentage of whole Mosapride Citrate raw materials cost.Document J.Med.Chem., 1991,34 (2), describe its preparation method in 616-624 and be take to the acetaminosalicylic acid methyl esters as starting raw material, through iodoethane ethylization, chlorosuccinimide chloro and ester hydrolysis, amido linkage basic hydrolysis four-step reaction altogether obtains product.This method starting raw material price, be not easy to obtain, ethylization reagent iodoethane is expensive, and cost is high.The open its preparation method of CN1226295C be take to amino salicylic acid sodium as raw material, through hcl acidifying, methanol esterification, diacetyl oxide acetylize, monobromethane ethylize, chlorosuccinimide chloro and basic hydrolysis six-step process obtain product.This method reactions steps is long, and total recovery is low, pollutes greatlyr, and energy consumption is high, and cost is high.
Through research, the contriver has invented the new synthetic method of a kind of preparation formula (I) compound.The method, take para-aminosalicylic acid or its corresponding sodium salt, potassium salt compound as raw material, obtains product through acetylize, two ethylization, chloro and hydrolysis four-step reaction.The method cost of material is cheap, be easy to get, and synthesis step is short, reaction conditions is gentle, be easy to control, and simple to operate, less pollution, total recovery is high, cost is low, good product quality and stable, is easy to large-scale industrial production.
Summary of the invention
, for solving the problem that prior art preparation formula (I) raw materials of compound cost is high, preparation process long, pollution is high, energy consumption is large, the invention provides new preparation process and two kinds of new intermediates thereof of a kind of formula (I) compound.
As technical scheme of the present invention, one aspect of the present invention provides the preparation method of formula (I) compound.Its employing para-aminosalicylic acid or its corresponding sodium salt, potassium salt compound are starting raw material, through acetylize, two ethylization, chloro, hydrolysis four, go on foot and obtain product.Synthetic route of the present invention is:
As technical scheme of the present invention, the present invention provides two kinds of new intermediates of preparation formula (I) compound on the other hand.Its Chinese style (II) compound is 2-oxyethyl group-4-acetamido-5-chloro-benzoic acid ethyl ester, and its structural formula is:
Formula (III) compound is 2-oxyethyl group-4-acetaminobenzoic acid ethyl ester, and its structural formula is:
As the preparation method of formula of the present invention (I) compound, the starting raw material that uses is sodium para-aminosalicylate or its hydrate, potassium p-aminosalicylate and para-aminosalicylic acid.
Described acetylization reaction, take diacetyl oxide as acylating agent, reacts in solvent, the solvent of selecting is water, ethyl acetate, ethanol or acetone, and temperature of reaction is that room temperature extremely refluxes, and the reaction times is 2-4 hour.Wherein preferably water is as solvent, and temperature of reaction is 50 ℃, and the reaction times is 2 hours, has reacted rear extremely acid with acid for adjusting pH value, filter, and washing, drying obtains acetaminosalicylic acid.
The described pair of ethylation reaction is take monobromethane or ethyl sulfate as ethylization reagent, the solvent of selecting is DMF (N, dinethylformamide), dimethyl sulfoxide (DMSO) or acetonitrile isopolarity non-protonic solvent, temperature of reaction is 80-120 ℃, the reaction times is 5-10 hour.Wherein preferred monobromethane is ethylization reagent, and DMF is solvent, take salt of wormwood as alkali,, in 100 ℃ of reactions 8 hours, adds the elutriation crystalline substance after having reacted, filter, and washing, drying obtains 2-oxyethyl group-4-acetaminobenzoic acid ethyl ester.
Described chlorination is take NCS (N-chlorosuccinimide) as chlorinating agent, and DMF is solvent, salt of wormwood is alkali in 60-80 ℃ of reaction 1-4 hour, adds the elutriation crystalline substance after react, filtration, washing, drying obtains 2-oxyethyl group-4-acetamido-5-chloro-benzoic acid ethyl ester.
Described hydrolysis reaction adopts the aqueous sodium hydroxide solution back hydrolysis, has reacted rear extremely acid with acid for adjusting pH value, filter, and washing, drying obtains 2-oxyethyl group-4-amino-5-chloro-benzoic acid.
As the preparation method of formula of the present invention (I) compound, concrete steps are:
Step 1, take para-aminosalicylic acid or its corresponding sodium salt, potassium salt compound as starting raw material, take water as solvent, diacetyl oxide is that acylating agent carries out acetylization reaction;
Step 2, carry out two ethylation reactions take monobromethane or ethyl sulfate as ethylization reagent;
Step 3, carry out chlorination take chlorosuccinimide as chlorination reagent;
Step 4,, with the aqueous sodium hydroxide solution reaction that is hydrolyzed that refluxes, obtain formula (I) compound.
Beneficial effect of the present invention shows:
(1) preparation process total recovery of the present invention is high, can reach 71.7%, and according to its yield of method preparation formula (I) compound that Chinese patent CN1226295C provides, can only reach 55%.The preparation method who describes with CN1226295C compares, and has shortened reactions steps, effectively raises the total recovery of 2-oxyethyl group-4-amino-5-chloro-benzoic acid, reduce cost, reduced pollution, and simple to operate, having reduced energy consumption, is a synthetic route that industrial application value is arranged very much.
(2) with document J.Med.Chem., 1991,34 (2), the preparation method that 616-624 describes compares, and raw material of the present invention is cheap, be easy to get, and the ethylization reagent low price of employing greatly reduces the cost of product.
Embodiment
Embodiment 1
The preparation of step 1 to acetaminosalicylic acid: sodium para-aminosalicylate (52.54g, 0.3mol), water (260mL) and diacetyl oxide (30.6g, 0.3mol) add reaction flask, stirring heating, 50 ℃ were reacted 2 hours, had reacted rear accent pH to acid, filter, washing, drying obtains white solid to acetaminosalicylic acid (47.73g, 81.5%).mp232℃。
1H-NMR(400MHz，d
6-DMSO)：δ2.07(s，3H)，7.02(dd，J
1＝8.4Hz，J
2＝8.4Hz，1H)，7.34(d，J＝1.6Hz，1H)，7.69(d，J＝4.8Hz，1H)，10.20(s，1H)，11.35(br，1H)，13.67(br，1H).
The preparation of step 2 2-oxyethyl group-4-acetaminobenzoic acid ethyl ester: to acetaminosalicylic acid (46.84g, 0.24mol), DMF (500mL), salt of wormwood (66.34g, 0.48mol) and monobromethane (65.38g, 0.6mol) input reaction flask, stirring heating, 100 ℃ were reacted 8 hours, be poured into water stirring and crystallizing, filter, washing, drying obtains white solid 2-oxyethyl group-4-acetaminobenzoic acid ethyl ester (56.87g, 94.3%).mp141℃。
1H-NMR(400MHz，CDCl
3)：δ1.35(t，J
1＝7.2，J
2＝7.2Hz，3H)，1.43(t，J
1＝7.2Hz，J
2＝6.8Hz，3H)，2.19(s，3H，CH
3)，4.07(dd，J
1＝7.2Hz，J
2＝7.2Hz，2H)，4.30(dd，J
1＝7.2Hz，J
2＝7.2Hz，2H)，6.82(dd，J
1＝7.2Hz，J
2＝7.2Hz，1H)，7.53(dd，J
1＝7.2Hz，J
2＝7.2Hz，1H)，7.58(dd，J
1＝7.2Hz，J
2＝7.2Hz，1H)，7.77(dd，J
1＝7.2Hz，J
2＝7.2Hz，1H).HR-MS(ESI
+)：C
13H
17NO
4(M+Na
+)，274.1050，calcl274.1052.
The preparation of step 3 2-oxyethyl group-4-acetamido-5-chloro-benzoic acid ethyl ester: 2-oxyethyl group-4-acetaminobenzoic acid ethyl ester (55.28g, 22mol), DMF (280ml), NCS (29.38g, 0.22mol) the input reaction flask, stirring heating, 70 ℃ were reacted 1 hour, and were poured into water stirring and crystallizing, filter, washing, drying obtains white solid 2-oxyethyl group-4-acetamido-5-chloro-benzoic acid ethyl ester (60.66g, 96.5%).mp115℃。
1H-NMR(400MHz，CDCl
3)：δ1.36(t，J
1＝7.2Hz，J
2＝7.2Hz，3H)，1.45(t，J
1＝6.8Hz，J
2＝6.8Hz，3H)，2.27(s，3H)，4.12(dd，J
1＝7.2Hz，J
2＝6.8Hz，2H)，4.31(dd，J
1＝7.2Hz，J
2＝7.2Hz，2H)，7.74(m，1H)，7.86(s，1H)，8.28(s，1H).HR-MS(ESI
+)：C
13H
16ClNO
4(M+Na
+)，308.660，calcl308.674.
The preparation of step 4 2-oxyethyl group-4-amino-5-chloro-benzoic acid: 2-oxyethyl group-4-acetamido-5-chloro-benzoic acid ethyl ester (60.00g, 0.21mol), sodium hydroxide (67.2g, 1.68mol) solution, ethanol (300mL) drops into reaction flask, heat temperature raising back flow reaction 6-8 hour, cooling, regulate pH to acid, filter, washing, drying obtains white solid 2-oxyethyl group-4-amino-5-chloro-benzoic acid (43.78g, 96.7%).mp160。
1H-NMR(400MHz，CDCl
3)：δ1.53(t，J
1＝6.8Hz，J
2＝7.2Hz，3H)，4.21(dd，J
1＝7.2Hz，J
2＝6.8Hz，2H)，4.63(br，2H)，6.32(s，1H)，8.07(s，1H)，10.61(br，1H).
Embodiment 2
Preparation to acetaminosalicylic acid: para-aminosalicylic acid (4.60g, 0.03mol), water (46mL) and diacetyl oxide (3.07g, 0.03mol) add reaction flask, stirring heating, 60 ℃ were reacted 4 hours, cooling, filter, washing, drying obtains white solid to acetaminosalicylic acid (4.70g, 80.2%).
Embodiment 3
Preparation to acetaminosalicylic acid: potassium p-aminosalicylate (5.74g, 0.03mol), water (29mL) and diacetyl oxide (3.07g, 0.03mol) add reaction flask, stirring heating, 50 ℃ were reacted 2 hours, cooling, transfer pH to acid, filter washing, drying obtains white solid to acetaminosalicylic acid (4.76g, 81.3%).
Embodiment 4
Preparation to acetaminosalicylic acid sodium: sodium para-aminosalicylate (5.25g, 0.03mol), dehydrated alcohol (53mL) and diacetyl oxide (3.07g, 0.03mol) add reaction flask, stirring heating, back flow reaction 3 hours, after having reacted, filter, washing, drying obtains white solid to acetaminosalicylic acid sodium (5.03g, 77.3%).
Embodiment 5
Preparation to acetaminosalicylic acid potassium: potassium p-aminosalicylate (5.74g, 0.03mol)., dehydrated alcohol (57mL) and diacetyl oxide (3.07g, 0.03mol) add reaction flask, stirring heating, 50 ℃ were reacted 4 hours, after having reacted, filter, washing, drying obtains white solid to acetaminosalicylic acid potassium (5.29g, 75.6%).
Embodiment 6
Preparation to acetaminosalicylic acid sodium: sodium para-aminosalicylate (5.25g, 0.03mol), ethyl acetate (26mL) and diacetyl oxide (3.07g, 0.03mol) add reaction flask, stirring heating, back flow reaction 4 hours, after having reacted, filter, washing, drying obtains white solid to acetaminosalicylic acid sodium (5.12g, 78.6%).
Embodiment 7
The preparation of 2-oxyethyl group-4-acetaminobenzoic acid ethyl ester: to acetaminosalicylic acid sodium (5.00g, 0.023mol), DMF (25mL), salt of wormwood (6.36g, 0.046mol) and ethyl sulfate (8.94g, 0.058mol) input reaction flask, stirring heating, 120 ℃ were reacted 10 hours, be poured into water stirring and crystallizing, filter, washing, drying obtains white solid 2-oxyethyl group-4-acetaminobenzoic acid ethyl ester (4.78g, 82.6%).
Embodiment 8
The preparation of 2-oxyethyl group-4-acetaminobenzoic acid ethyl ester: to acetaminosalicylic acid sodium (5.00g, 0.023mol), DMF (25mL), salt of wormwood (6.36g, 0.046mol) and monobromethane (6.32g, 0.058mol) input reaction flask, stirring heating, 100 ℃ were reacted 8 hours, be poured into water stirring and crystallizing, filter, washing, drying obtains white solid 2-oxyethyl group-4-acetaminobenzoic acid ethyl ester (5.43g, 93.9%).
Embodiment 9
The preparation of 2-oxyethyl group-4-acetaminobenzoic acid ethyl ester: to acetaminosalicylic acid potassium (5.00g, 0.021mol), DMF (25mL), salt of wormwood (5.80g, 0.042mol) and monobromethane (5.72g, 0.053mol) input reaction flask, stirring heating, 100 ℃ were reacted 8 hours, be poured into water stirring and crystallizing, filter, washing, drying obtains white solid 2-oxyethyl group-4-acetaminobenzoic acid ethyl ester (5.08g, 94.4%).
Embodiment 10
The preparation of 2-oxyethyl group-4-acetamido-5-chloro-benzoic acid ethyl ester: to acetaminosalicylic acid (4.49g, 0.023mol), DMF (25mL), salt of wormwood (6.36g, 0.046mol) and ethyl sulfate (8.94g, 0.058mol) the input reaction flask, stirring heating, 120 ℃ were reacted 10 hours, had reacted rear cooling, added NCS (3.07g, 0.023mol), stirring heating, 70 ℃ were reacted 2 hours, and were poured into water stirring and crystallizing, filter, washing, drying obtains white solid 2-oxyethyl group-4-acetamido-5-chloro-benzoic acid ethyl ester (4.70g, 71.5%).
Embodiment 11
The preparation of 2-oxyethyl group-4-acetamido-5-chloro-benzoic acid ethyl ester: to acetaminosalicylic acid (4.68g, 0.024mol), DMF (50mL), salt of wormwood (6.63g, 0.048mol) and monobromethane (6.54g, 0.06mol) the input reaction flask, stirring heating, 100 ℃ were reacted 8 hours, had reacted rear cooling, added NCS (3.20g, 0.024mol), stirring heating, 70 ℃ were reacted 2 hours, and were poured into water stirring and crystallizing, filter, washing, drying obtains white solid 2-oxyethyl group-4-acetamido-5-chloro-benzoic acid ethyl ester (5.31g, 77.5%).
Claims (7)
1. intermediate for the preparation of 2-oxyethyl group-4-amino-5-chloro-benzoic acid, its structural formula is:
Wherein R is Cl or H.
2. the intermediate for the preparation of 2-oxyethyl group-4-amino-5-chloro-benzoic acid according to claim 1; it is characterized in that its preparation method comprises following steps;, by para-aminosalicylic acid or its corresponding sodium salt, potassium salt compound, react through acetylize, two steps of two ethylization
3. the intermediate for the preparation of 2-oxyethyl group-4-amino-5-chloro-benzoic acid according to claim 1; it is characterized in that; its preparation method comprises following steps,, by para-aminosalicylic acid or its corresponding sodium salt, potassium salt compound, through acetylize, two ethylization and chlorination, obtains
According to claim 1 in the described intermediate for the preparation of 2-oxyethyl group-4-amino-5-chloro-benzoic acid of any one; the preparation method who it is characterized in that described 2-oxyethyl group-4-amino-5-chloro-benzoic acid comprises following steps: para-aminosalicylic acid or its corresponding sodium salt, potassium salt compound obtain through acetylize, two ethylization, chloro and hydrolysis four-step reaction.
5. the described intermediate for the preparation of 2-oxyethyl group-4-amino-5-chloro-benzoic acid of any one according to claim 1-4, it is characterized in that, described acetylization reaction take water, ethyl acetate or ethanol any one or arbitrarily two or more mixture as solvent, take diacetyl oxide as acylating agent; The described pair of ethylation reaction is take monobromethane or ethyl sulfate as ethylization reagent.
6. according to claim 3 or 4 described intermediates for the preparation of 2-oxyethyl group-4-amino-5-chloro-benzoic acid, is characterized in that described chlorination is take chlorosuccinimide as the chlorination agent.
7. the intermediate for the preparation of 2-oxyethyl group-4-amino-5-chloro-benzoic acid according to claim 4 is characterized in that the preparation method of described 2-oxyethyl group-4-amino-5-chloro-benzoic acid is as follows:
Step 1, take para-aminosalicylic acid or its corresponding sodium salt, potassium salt compound as starting raw material, take water as solvent, diacetyl oxide is that acylating agent carries out acetylization reaction;
Step 2, obtain as ethylization reagent carries out two ethylation reactions take monobromethane or ethyl sulfate
Step 3, obtain as chlorination reagent carries out chlorination take chlorosuccinimide
Step 4, refluxing to be hydrolyzed to react with aqueous sodium hydroxide solution obtains.
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