CN103613521A - Water-phase synthetic method of probenecid - Google Patents
Water-phase synthetic method of probenecid Download PDFInfo
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- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 229960003081 probenecid Drugs 0.000 title claims abstract description 39
- 238000010189 synthetic method Methods 0.000 title abstract 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 58
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000006193 diazotization reaction Methods 0.000 claims abstract description 34
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 32
- BDRLPYKWEDAQMB-UHFFFAOYSA-N benzoic acid;sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O.OC(=O)C1=CC=CC=C1 BDRLPYKWEDAQMB-UHFFFAOYSA-N 0.000 claims abstract description 27
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims abstract description 20
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- 239000007788 liquid Substances 0.000 claims description 13
- 238000001308 synthesis method Methods 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 11
- 239000000463 material Substances 0.000 claims description 5
- 238000010930 lactamization Methods 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 238000005304 joining Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 15
- 239000000047 product Substances 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000005516 engineering process Methods 0.000 abstract description 5
- 239000003960 organic solvent Substances 0.000 abstract description 5
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 239000006227 byproduct Substances 0.000 abstract description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract 2
- 229960004050 aminobenzoic acid Drugs 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 15
- 239000012295 chemical reaction liquid Substances 0.000 description 10
- 239000012320 chlorinating reagent Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- 239000005457 ice water Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000012286 potassium permanganate Substances 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- UCAGLBKTLXCODC-UHFFFAOYSA-N carzenide Chemical compound NS(=O)(=O)C1=CC=C(C(O)=O)C=C1 UCAGLBKTLXCODC-UHFFFAOYSA-N 0.000 description 2
- 229950000188 halopropane Drugs 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- SVDVKEBISAOWJT-UHFFFAOYSA-N n-methylbenzenesulfonamide Chemical compound CNS(=O)(=O)C1=CC=CC=C1 SVDVKEBISAOWJT-UHFFFAOYSA-N 0.000 description 2
- KMUONIBRACKNSN-UHFFFAOYSA-N potassium dichromate Chemical compound [K+].[K+].[O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O KMUONIBRACKNSN-UHFFFAOYSA-N 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- JHWIEAWILPSRMU-UHFFFAOYSA-N 2-methyl-3-pyrimidin-4-ylpropanoic acid Chemical compound OC(=O)C(C)CC1=CC=NC=N1 JHWIEAWILPSRMU-UHFFFAOYSA-N 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- 206010011906 Death Diseases 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940059260 amidate Drugs 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 229960002708 antigout preparations Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 235000019636 bitter flavor Nutrition 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 description 1
- YVWGMAFXEJHFRO-UHFFFAOYSA-N halopropane Chemical compound FC(F)C(F)(F)CBr YVWGMAFXEJHFRO-UHFFFAOYSA-N 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000002696 manganese Chemical class 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000003595 mist Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the technical field of organic chemical synthesis and specifically discloses a water-phase synthetic method of probenecid. The water-phase synthetic method comprises the following steps: firstly, preparing diazotization reaction liquor by reacting aminobenzoic acid, hydrochloric acid and sodium nitrite; secondly, feeding liquid-state sulfur dioxide into diluted hydrochloric acid aqueous liquor to obtain a sulfonyl chlorinazation reagent; thirdly, enabling the two reaction liquor to generate sulfonyl chlorinazation reaction to obtain p-carboxyl benzene sulfonyl chloride; and finally, preparing a probenecid pure product by reacting the p-carboxyl benzene sulfonyl chloride with dipropyl amine through acidifying. The synthetic process adopts a water-phase synthetic technology, changes a reaction path, reduces production of byproducts, and avoids use of an organic solvent and a virulent agent; and product yield is ideal (91%, in terms of para aminobenzoic acid), and purity is high (98%). The novel synthetic process is developed for being beneficial to enlarged implementation of industrialization.
Description
Technical field
The invention belongs to the technical field of organic chemical synthesis, be specially a kind of water phase synthesis method of probenecid, take para-amino benzoic acid as raw material, using water as reaction media, first through diazotization, sulfonating chlorinating reaction, prepare carboxyl benzene sulfonyl chloride, then react and make probenecid with dipropyl amine.
Background technology
Probenecid, chemical name: p-(dipropyl dithiocarbamic acid) phenylformic acid, English name: Probenecid; 4-[(Dipropylamino) sulfonyl] benzoic acid, molecular formula: C
13h
19nO
4s, molecular weight: 285.36, white crystalline powder.Fusing point 194-196 ℃.Be dissolved in acetone, be slightly dissolved in ethanol or chloroform, water-soluble hardly.Be dissolved in diluted sodium hydroxide solution, almost insoluble in diluted acid.Odorless, mildly bitter flavor.It is the adjuvant drug of a kind of anti-gout drugs and antibiotic therapy.
At present, the production technique of probenecid mainly contains two kinds:
(1) p-methyl benzenesulfonic acid-dipropyl amine method
Take p-methyl benzenesulfonic acid as raw material, through potassium bichromate or potassium permanganate oxidation, then react generation with chlorsulfonic acid generation sulfonating chlorinating to carboxyl benzene sulfonyl chloride, amidate action occurs then in organic solvent and obtain the finished product probenecid.Reaction process route is as follows:
This technique in a large number with an organic solvent, seriously polluted; Heavy metal recovery and treatment cost are high; Chlorsulfonic acid transportation, storage and use are dangerous large, and acid mist is obvious.Along with the increasing of environmental protection pressure, people increase severely day by day to the concern of environment, and this route is substantially in end-of-life state.
(2) to methyl benzenesulfonamide-Halopropane method
To methyl benzenesulfonamide, through potassium bichromate or potassium permanganate oxidation, be P―Carboxybenzenesulfonamide, under the effect of alkali, with Halopropane generation alkylated reaction, after acidifying, obtain probenecid.Reaction process route is as follows:
This process using sodium dichromate 99 or potassium permanganate oxidation are to methyl benzenesulfonamide, and yield is on the low side (lower than 50%).In addition, the waste water that contains chromium or manganese is difficult to dispose, and these have all seriously restricted further developing of this technique.
Summary of the invention
The object of the invention is to the problem for above-mentioned existence, a kind of water phase synthesis method of probenecid is provided.First, para-amino benzoic acid, hydrochloric acid, Sodium Nitrite reaction make diazotization reaction liquid; Then, liquid sulfur dioxide is passed into diluted hydrochloric acid aqueous solution and obtain sulfonating chlorinating reagent; Then, above-mentioned two kinds of reaction solution generation sulfonating chlorinatings reaction obtains carboxyl benzene sulfonyl chloride; Finally, carboxyl benzene sulfonyl chloride is reacted with dipropyl amine, through acidifying, obtain probenecid sterling.This synthesis technique adopts water synthetic technology, has changed response path, reduced the generation of by product, has avoided the use of organic solvent, poisonous reagent; Product yield desirable (91%, in para-amino benzoic acid), purity high (98%).The exploitation of this new synthesis process, is conducive to industrialized amplification and implements.Technical scheme of the present invention is:
The water phase synthesis method of probenecid, its step is as follows:
(1) diazotization reaction
Para-amino benzoic acid, hydrochloric acid are added in reactor, after be down to-20-20 ℃, slowly drip sodium nitrite solution, obtain diazotization product;
(2) sulfonating chlorinating reaction
At-20-20 ℃, in sulfonating chlorinating reactor, add water, hydrochloric acid and liquid sulfur dioxide successively, and the diazotization product that before slowly adding at this temperature, step makes, add rear normal-temperature reaction 5-24h, solid-liquid separation, solid is to carboxyl benzene sulfonyl chloride;
(3) synthetic probenecid reaction
Dipropyl amine and water are joined in Lactamization reactor, at 15-100 ℃, add carboxyl benzene sulfonyl chloride in batches, after reaction 2-4h, add hcl acidifying, filtration to obtain probenecid sterling.
In the present invention, the raw material that slowly adds or add in batches of mentioning adds mode, is and take reacting balance as object, is the routine techniques term of chemical industry.
The water phase synthesis method of probenecid, its step is as follows:
(1) diazotization reaction
Para-amino benzoic acid, hydrochloric acid are added in reactor, after be down to-20-20 ℃, slowly drip sodium nitrite solution, time for adding is controlled as 3-5 hour, obtains diazotization product;
(2) sulfonating chlorinating reaction
At-20-20 ℃, in sulfonating chlorinating reactor, add water, hydrochloric acid and liquid sulfur dioxide successively, and the diazotization product that before adding at this temperature, step makes, joining day is controlled as 3-5 hour, add rear normal-temperature reaction 5-24h, solid-liquid separation, solid is to carboxyl benzene sulfonyl chloride;
(3) synthetic probenecid reaction
Dipropyl amine and water are joined in Lactamization reactor, at 15-100 ℃, add carboxyl benzene sulfonyl chloride in batches, to being divided into 30-40 adding of carboxyl benzene sulfonyl chloride, criticize, after reaction 2-4h, add hcl acidifying, filtration to obtain probenecid sterling.
Wherein, the mol ratio of material used is as follows: para-amino benzoic acid: Sodium Nitrite: sulfurous gas: diazotization hydrochloric acid used: sulfonating chlorinating hydrochloric acid used: dipropyl amine=1:(1-1.1): (2-5): (2-4): (15-20): (3-4).
Preferred molar ratio of material is as follows: para-amino benzoic acid: Sodium Nitrite: sulfurous gas: diazotization hydrochloric acid used: sulfonating chlorinating hydrochloric acid used: dipropyl amine=1:1.04:3.5:3:17.5:3.8.
Wherein, be preferably-10-10 ℃ of diazotization reaction temperature.
Be preferably-5-15 ℃ of sulfonating chlorinating temperature of reaction.
Carboxyl benzene sulfonyl chloride and dipropyl amine temperature of reaction are preferably to 30-50 ℃.
Reaction scheme of the present invention is as follows:
Beneficial effect of the present invention is:
This synthetic route has been abandoned the thinking of traditional oxidation electron-deficient aromatic ring methyl, adopt water organic synthesis technology completely, take para-amino benzoic acid as starting raw material, using water as reaction media, through processes such as diazotization, sulfonating chlorinating, amidations, produce probenecid, avoid heavy metallic salt in conventional oxidation process as the use of manganese salt or chromic salts, organic solvent, greatly reduced the treatment cost of waste water, also stopped the risk of Heavy-metal Polluted Environment simultaneously.In addition, adopt liquid sulfur dioxide and hydrochloric acid preparation sulfonating chlorinating reagent, not only effectively avoided hypertoxic, perishable, volatile reagent--a large amount of uses of sulfur oxychloride, and shortened operating time of sulfonating chlorinating step, improve the service temperature of sulfonating chlorinating step, simplified the operation of sulfonating chlorinating step.Add mode and addition sequence to material are optimized, and have greatly improved the utilization ratio of raw material and the purity of product, and in a word, this technological operation is simple, and atom utilization high (total recovery is up to 91%), is significantly improved compared with traditional technology.
The present invention, by changing initial action raw material, has developed the water synthesis technique of a probenecid, and product yield reaches 85～91%, and apparently higher than existing technique, purity is greater than 98%, meets Chinese Pharmacopoeia standard.
Embodiment
Followingly by specific embodiment, technical scheme of the present invention is described in detail, is not construed as limiting the invention.
embodiment 1
(1) diazotization reaction
Get 68.6g para-amino benzoic acid (0.5mol), 250g water and 127.4ml hydrochloric acid (31%, 1.25mol) join in 2000ml there-necked flask, in ice-water bath, stir, be cooled to 0-5 ℃, drip sodium nitrite solution (34.5g Sodium Nitrite, 0.5mol, be dissolved in 190g water), control temperature at 10-20 ℃, it is 4 hours that time for adding is controlled, after dropping finishes, at this temperature, continue reaction 1 hour, obtain diazotization reaction liquid.
(2) sulfonating chlorinating reaction
In 5000ml there-necked flask, add 250g water, 765ml hydrochloric acid (31%, 7.5mol), in ice-water bath, stir, be cooled to-5 ℃, start to pass into liquid sulfur dioxide, control temperature at-3--1 ℃, when passing into 64g sulfurous gas (1mol), sulfurous gas absorbs complete, obtains sulfonating chlorinating reagent.
In sulfonating chlorinating reagent, add diazotization reaction liquid, adding the time control of diazotization reaction liquid is 5 hours, is warming up to gradually 5-10 ℃, continues reaction 8 hours at this temperature; Filtration obtains 121g to carboxyl benzene sulfonyl chloride.
(3) synthetic probenecid reaction
In 1000ml there-necked flask, add 350g water, 152g dipropyl amine (1.5mol), open and stir, when temperature is greater than 15 ℃, start to divide gradually 40 batches add step (2) gained to carboxyl benzene sulfonyl chloride, temperature control 40-50 ℃, adds and at this temperature, stirs 3 hours continuing after carboxyl benzene sulfonyl chloride.Drip hydrochloric acid (31%), regulate pH value to 2-3, continue to stir 1 hour.Filter, obtain 135g probenecid crude product, put in 500ml pure water, agitator treating 1 hour, heavy 122.8g after filtering, being dried, yield 86.2%(is in para-amino benzoic acid), purity 98.2%.
embodiment 2
(1) diazotization reaction
Get 68.6g para-amino benzoic acid (0.5mol), 250g water and 152.9ml hydrochloric acid (31%, 1.5mol) join in 2000ml there-necked flask, in ice-water bath, stir, be cooled to 0-5 ℃, drip sodium nitrite solution (36.0g Sodium Nitrite, 0.52mol, be dissolved in 190g water), control temperature at 0-10 ℃, it is 3 hours that time for adding is controlled, after dropping finishes, at this temperature, continue reaction 1 hour, obtain diazotization reaction liquid.
(2) sulfonating chlorinating reaction
In 5000ml there-necked flask, add 250g water, 887ml hydrochloric acid (31%, 8.7mol), in ice-water bath, stir, be cooled to-5 ℃, start to pass into liquid sulfur dioxide, control temperature at 0-5 ℃, when passing into 112g sulfurous gas (1.75mol), sulfurous gas absorbs complete, obtains sulfonating chlorinating reagent.
In sulfonating chlorinating reagent, add diazotization reaction liquid, adding the time control of diazotization reaction liquid is 4 hours, is warming up to gradually 5-15 ℃, continues reaction 5 hours at this temperature; Filtration obtains 150g to carboxyl benzene sulfonyl chloride.
(3) synthetic probenecid reaction
In 1000ml there-necked flask, add 350g water, 192g dipropyl amine (1.9mol), open and stir, when temperature is greater than 15 ℃, start to divide gradually 35 batches add step (2) gained to carboxyl benzene sulfonyl chloride, temperature control 40-50 ℃, adds and at this temperature, stirs 2 hours continuing after carboxyl benzene sulfonyl chloride.Drip hydrochloric acid (31%), regulate pH value to 2-3, continue to stir 1 hour.Filter, obtain 155.4g probenecid crude product, put in 500ml pure water, agitator treating 1 hour, heavy 129.5g after filtering, being dried, yield 90.9%(is in para-amino benzoic acid), purity 98.7%.
embodiment 3
(1) diazotization reaction
Get 68.6g para-amino benzoic acid (0.5mol), 250g water and 203.9ml hydrochloric acid (31%, 2mol) join in 2000ml there-necked flask, in ice-water bath, stir, be cooled to-10--5 ℃, drip sodium nitrite solution (38.0g Sodium Nitrite, 0.55mol, be dissolved in 190g water), control temperature at 0-10 ℃, it is 5 hours that time for adding is controlled, after dropping finishes, at this temperature, continue reaction 1 hour, obtain diazotization reaction liquid.
(2) sulfonating chlorinating reaction
In 5000ml there-necked flask, add 250g water, 968ml hydrochloric acid (31%, 9.5mol), in ice-water bath, stir, be cooled to-5 ℃, start to pass into liquid sulfur dioxide, control temperature at 5-10 ℃, when passing into 160g sulfurous gas (2.5mol), sulfurous gas absorbs complete, obtains sulfonating chlorinating reagent.
In sulfonating chlorinating reagent, add diazotization reaction liquid, adding the time control of diazotization reaction liquid is 3 hours, is warming up to gradually 10-15 ℃, continues reaction 20 hours at this temperature; Filtration obtains 146.7g to carboxyl benzene sulfonyl chloride, needn't be dried, and directly enters next step reaction.
(3) synthetic probenecid reaction
In 1000ml there-necked flask, add 350g water, 202g dipropyl amine (2mol), open to stir, when temperature is greater than 30 ℃, start to divide gradually 30 batches add step (2) gained to carboxyl benzene sulfonyl chloride, temperature control 40-50 ℃, adds and at this temperature, stirs 4 hours continuing after carboxyl benzene sulfonyl chloride.Drip hydrochloric acid (31%), regulate pH value to 2-3, continue to stir 1 hour.Filtration obtains 151.7g probenecid crude product, puts in 500ml pure water, and agitator treating 1 hour, heavy 128.5g after filtering, being dried, yield 90.2%(is in para-amino benzoic acid), purity 98.8%.
Claims (8)
1. the water phase synthesis method of probenecid, its step is as follows:
(1) diazotization reaction
Para-amino benzoic acid, hydrochloric acid are added in reactor, after be down to-20-20 ℃, slowly drip sodium nitrite solution, obtain diazotization product;
(2) sulfonating chlorinating reaction
At-20-20 ℃, in sulfonating chlorinating reactor, add water, hydrochloric acid and liquid sulfur dioxide successively, and the diazotization product that before slowly adding at this temperature, step makes, add rear normal-temperature reaction 5-24h, solid-liquid separation, solid is to carboxyl benzene sulfonyl chloride;
(3) synthetic probenecid reaction
Dipropyl amine and water are joined in Lactamization reactor, at 15-100 ℃, add carboxyl benzene sulfonyl chloride in batches, after reaction 2-4h, add hcl acidifying, filtration to obtain probenecid sterling.
2. the water phase synthesis method of probenecid according to claim 1, its step is as follows:
(1) diazotization reaction
Para-amino benzoic acid, hydrochloric acid are added in reactor, after be down to-20-20 ℃, slowly drip sodium nitrite solution, time for adding is controlled as 3-5 hour, obtains diazotization product;
(2) sulfonating chlorinating reaction
At-20-20 ℃, in sulfonating chlorinating reactor, add water, hydrochloric acid and liquid sulfur dioxide successively, and the diazotization product that before adding at this temperature, step makes, joining day is controlled as 3-5 hour, add rear normal-temperature reaction 5-24h, solid-liquid separation, solid is to carboxyl benzene sulfonyl chloride;
(3) synthetic probenecid reaction
Dipropyl amine and water are joined in Lactamization reactor, at 15-100 ℃, add carboxyl benzene sulfonyl chloride in batches, to being divided into 30-40 adding of carboxyl benzene sulfonyl chloride, criticize, after reaction 2-4h, add hcl acidifying, filtration to obtain probenecid sterling.
3. the water phase synthesis method of probenecid according to claim 1 and 2, it is characterized in that, the mol ratio of material used is as follows: para-amino benzoic acid: Sodium Nitrite: sulfurous gas: diazotization hydrochloric acid used: sulfonating chlorinating hydrochloric acid used: dipropyl amine=1:(1-1.1): (2-5): (2-4): (15-20): (3-4).
4. the water phase synthesis method of probenecid according to claim 3, it is characterized in that, the mol ratio of material used is as follows: para-amino benzoic acid: Sodium Nitrite: sulfurous gas: diazotization hydrochloric acid used: sulfonating chlorinating hydrochloric acid used: dipropyl amine=1:1.04:3.5:3:17.5:3.8.
5. the water phase synthesis method of probenecid according to claim 1 and 2, is characterized in that, diazotization reaction temperature is-10-10 ℃.
6. the water phase synthesis method of probenecid according to claim 1 and 2, is characterized in that, sulfonating chlorinating temperature of reaction is-5-15 ℃.
7. the water phase synthesis method of probenecid according to claim 1 and 2, is characterized in that, to carboxyl benzene sulfonyl chloride and dipropyl amine temperature of reaction, is 30-50 ℃.
8. the water phase synthesis method of probenecid according to claim 2, is characterized in that, it is 4 hours that described time for adding is controlled.
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| CN104502513A (en) * | 2015-01-14 | 2015-04-08 | 中国矿业大学连云港徐圩新区高新技术研究院 | Carzenide high performance liquid chromatography measuring method |
| CN107033038A (en) * | 2017-05-03 | 2017-08-11 | 北京康正康仁生物科技有限公司 | The preparation method of probenecid |
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| ROBERT L.ELLSWORTH，ET AL: "Synthesis of p-（di-n-propylsulfamyl）benzoic-1-(ring)-14C acid and p-（di-n-propylsulfamyl）benzoic-acid-14C(probenecid-14C)", 《JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS》, vol. 15, 31 December 1978 (1978-12-31) * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104502513A (en) * | 2015-01-14 | 2015-04-08 | 中国矿业大学连云港徐圩新区高新技术研究院 | Carzenide high performance liquid chromatography measuring method |
| CN104502513B (en) * | 2015-01-14 | 2016-04-06 | 中国矿业大学连云港徐圩新区高新技术研究院 | A kind of high performance liquid chromatography determination method of p-carboxybenzenesulfonamide |
| CN107033038A (en) * | 2017-05-03 | 2017-08-11 | 北京康正康仁生物科技有限公司 | The preparation method of probenecid |
| CN107033038B (en) * | 2017-05-03 | 2019-03-22 | 北京康正康仁生物科技有限公司 | The preparation method of probenecid |
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| Publication number | Publication date |
|---|---|
| CN103613521B (en) | 2015-10-21 |
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