CN116199605A - Synthesis method of 5-chloro-2-hydroxy-dimethylbenzenesulfonamide - Google Patents
Synthesis method of 5-chloro-2-hydroxy-dimethylbenzenesulfonamide Download PDFInfo
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- -1 5-chloro-2-hydroxy-dimethylbenzenesulfonamide Chemical compound 0.000 title claims abstract description 17
- 238000001308 synthesis method Methods 0.000 title abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 19
- 239000000010 aprotic solvent Substances 0.000 claims abstract description 10
- 229940124530 sulfonamide Drugs 0.000 claims abstract description 9
- 150000003456 sulfonamides Chemical class 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- YRGAYAGBVIXNAQ-UHFFFAOYSA-N 1-chloro-4-methoxybenzene Chemical compound COC1=CC=C(Cl)C=C1 YRGAYAGBVIXNAQ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000010520 demethylation reaction Methods 0.000 claims abstract description 6
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002841 Lewis acid Substances 0.000 claims abstract description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 5
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 5
- 238000005694 sulfonylation reaction Methods 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 239000007858 starting material Substances 0.000 claims abstract description 3
- 239000000376 reactant Substances 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000003786 synthesis reaction Methods 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 claims description 2
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 claims description 2
- GSJRUEBQWPLHSN-UHFFFAOYSA-N n-methylmethanamine;oxolane Chemical compound CNC.C1CCOC1 GSJRUEBQWPLHSN-UHFFFAOYSA-N 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 5
- 238000010189 synthetic method Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000004440 column chromatography Methods 0.000 abstract description 2
- 239000012043 crude product Substances 0.000 abstract description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000012295 chemical reaction liquid Substances 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 3
- OVLWZBXWQUKLPT-UHFFFAOYSA-N (4-chlorophenyl) n,n-dimethylsulfamate Chemical compound CN(C)S(=O)(=O)OC1=CC=C(Cl)C=C1 OVLWZBXWQUKLPT-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- VWYKSJIPZHRLNO-UHFFFAOYSA-N 4-chloro-2,6-dimethylphenol Chemical compound CC1=CC(Cl)=CC(C)=C1O VWYKSJIPZHRLNO-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000024799 Thyroid disease Diseases 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 239000013064 chemical raw material Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
- C07C303/04—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups
- C07C303/08—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof by substitution of hydrogen atoms by sulfo or halosulfonyl groups by reaction with halogenosulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/38—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reaction of ammonia or amines with sulfonic acids, or with esters, anhydrides, or halides thereof
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a synthesis method of 5-chloro-2-hydroxy-dimethylbenzenesulfonamide, which takes p-chloroanisole as a starting material and comprises the following steps of: chlorosulfonic acid is used as a reaction reagent, and the sulfonylation reaction is carried out in an aprotic solvent 1 or in a solvent-free state; step II, sulfonamide reaction: dimethylamine is used as a reaction reagent, and the sulfonamide reaction is carried out in the presence of alkali and a reaction solvent; step III, demethylation reaction: the demethylation reaction is carried out in aprotic solvent 2 using lewis acid as a reactant. The method has the advantages that the selected initial raw material p-anisole is supplied in a large quantity in the market, the method is low in cost and easy to obtain, the reaction condition is mild, the operation is simple and safe, the post-treatment process is simple and convenient, the crude product is easy to purify without complex modes such as column chromatography, the average yield is more than 80%, the purity is more than 99.0%, and the method is low in cost and suitable for large-scale industrial production.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of 5-chloro-2-hydroxy-dimethylbenzenesulfonamide.
Background
5-chloro-2-hydroxy-dimethylbenzenesulfonamide having the structural formula
As an important pharmaceutical and chemical raw material, widely used for synthesis of pharmaceutical intermediates, such documents report more, for example, patent document WO2010/000031 reports that it can be used for synthesis of aids drugs, and US2002006946A1 reports that it can be used for synthesis of drugs for treating thyroid diseases. Whereas few reports have been made regarding the synthesis of 5-chloro-2-hydroxy-dimethylbenzenesulfonamide, the synthesis method is reported in Tetrahedron Letters,2001, vol.42, #49, p.8729-8731, and the specific synthetic route is as follows:
however, the existing literature synthesis method has more severe reaction process conditions, the reaction parameters are reported to be required to obtain target compounds in the presence of aluminum trichloride at a temperature of more than 140 ℃, the yield is less than 70%, the industrialization prospect of the route is poor, the equipment requirement is high, and the pollution and the energy consumption are high.
Disclosure of Invention
The invention aims to provide a synthesis method of 5-chloro-2-hydroxy-dimethyl benzene sulfonamide, which adopts p-anisole as a raw material, is low in cost and easy to obtain, has a simple process, is simple and convenient to post-treat and operate, has mild conditions, low reaction cost, high yield and good purity, and is suitable for industrial production.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the invention provides a synthesis method of 5-chloro-2-hydroxy-dimethylbenzenesulfonamide, which comprises the following synthesis routes:
the method takes p-chloroanisole as a starting material and comprises the following three synthesis steps: i is a sulfonylation reaction; II is amidation reaction; III is a demethylation reaction; specifically comprising:
in the step I, the sulfonylation reaction is carried out in an aprotic solvent 1 or in a solvent-free state by taking chlorosulfonic acid as a reaction reagent;
in the step II, sulfonamide reaction, dimethylamine is used as a reaction reagent, and sulfonamide reaction is carried out in the presence of alkali and a reaction solvent;
in the step III, the demethylation reaction is carried out in an aprotic solvent 2 by taking Lewis acid as a reaction reagent.
Preferably, in step I, the aprotic solvent 1 is selected from one of dichloromethane, toluene, and dichloroethane.
Preferably, in step I, the feed temperature is from-5 to 25℃and preferably from 0 to 10 ℃.
Preferably, in step II, the dimethylamine is selected from one form of dimethylamine hydrochloride, dimethylamine aqueous solution, dimethylamine alcohol solution or dimethylamine tetrahydrofuran solution.
Preferably, in step II, the reaction solvent is selected from one of dichloromethane, toluene, tetrahydrofuran, and water.
Preferably, in step II, the feed temperature is from-5 to 25℃and preferably from 0 to 10 ℃.
Preferably, in step III, the lewis acid is selected from one of aluminum trichloride, boron tribromide, hydrobromic acid.
Preferably, in step III, the aprotic solvent 2 is selected from one of dichloromethane, toluene, tetrahydrofuran, and acetic acid.
Preferably, in step III, the feed temperature is from-5 to 25℃and preferably from 0 to 10 ℃.
Compared with the prior art, the invention has the beneficial effects that: the synthetic route has the advantages of mass supply of the initial raw material p-chloroanisole in the market, low cost, easy acquisition, mild reaction conditions, simple and safe operation, simple post-treatment process, easy purification of crude products, no need of complex modes such as column chromatography and the like, average yield of over 80 percent, purity of over 99.0 percent, low cost and suitability for large-scale industrial production.
Drawings
FIG. 1 is the target product of example 1 1 H-NMR chart.
FIG. 2 is an HPLC chart of the target product in example 1.
FIG. 3 is the target product of example 2 1 H-NMR chart.
FIG. 4 is an HPLC chart of the target product in example 2.
Detailed Description
The invention is further illustrated below in connection with specific examples which are provided solely for the purpose of illustration and are not intended to limit the scope of the invention.
The experimental procedure, in which specific conditions are not noted in the examples below, is generally followed by conventional conditions.
Comparative example 1
The object is prepared in this comparative example reference Tetrahedron Letters,2001, vol.42, #49, p.8729-8731
The technical route is as follows: />
The method comprises the following steps:
at room temperature (20-30 ℃), add 4-chlorophenyl dimethylsulfamate (CAS number 1135-05-3, 10g,1.0 eq) to 250mL three-necked flask, add aluminum trichloride (10 g,1.0 eq), heat up to 140-145 ℃ in oil bath, keep the temperature for 2 hours, control the raw materials to disappear in TLC, slowly drop the reaction liquid to 100mL diluted hydrochloric acid for quenching, control the temperature to 10-20 ℃, stir for 30 minutes, extract with dichloromethane, dry, concentrate to obtain 7g of yellow solid, recrystallize the solid with about 300mL (PE: EA=2:1) mixed solvent to obtain 5.7g pale yellow solid with purity of 95.7%, yield: 57%.
The following examples were carried out to prepare the target by the synthesis method of the present invention
The technical route is as follows:
example 1
Step I: chlorosulfonic acid (100 mL, 2.5V/W), N, was added to a 250mL three-necked flask at room temperature (20-30 ℃ C.), and the mixture was stirred at room temperature 2 3, replacing three times, controlling the temperature of an ice salt bath to be 0-5 ℃, slowly dropwise adding p-chloroanisole (40 g), naturally heating to room temperature after adding, reacting for 2 hours, controlling the raw materials to disappear in TLC, slowly dropwise adding the reaction liquid into 200mL of ice water, controlling the temperature to be 10-20 ℃, stirring for 30 minutes, filtering to obtain 73.5g of white solid, baking the material in a 50 ℃ oven for 16 hours to obtain 63g of white solid with the purity of 97.2 percent, and obtaining the yield: 93.3 percent, 1 H-NMR(DMSO):δ(ppm)7.63(d,7H),7.34(dd,1H),6.99(d,1H),3.74(s,3H)。
step II: THF (200 mL, 5V/W) is added into a 500mL three-necked flask at room temperature (20-30 ℃), the sulfonyl chloride compound (40 g,1.0 eq) is stirred and dissolved, and the temperature of the ice salt bath is controlled to be 0+/-5 ℃; t-in = 0 ℃, slowly dropwise adding dimethylamine aqueous solution (77.3 g,2.5 eq), and controlling the temperature to react at 0±5 ℃; incubation for 2 hours, TLC control: ending the reaction; the reaction solution is concentrated under reduced pressure to remove most THF, the rest reaction solution is slowly added into 400g of ice water in a dropwise manner, stirred for 30 minutes, filtered to obtain white solid, and baked for 16 hours at 50 ℃ in an oven to obtain 39.6g of white solid with the purity of 100 percent and the yield: 95.7 percent, 1 H-NMR(DMSO):δ(ppm)7.78-7.63(m,2H),7.30(d,1H),3.90(s,3H),2.74(s,6H)。
step III: DCM (300 mL, 10V/W) is added into a 500mL three-necked flask at room temperature (20-30 ℃), the sulfonamide (30 g,1.0 eq) is stirred and dissolved, and dry ice acetone is cooled to an internal temperature of 0-10 ℃; BBr is slowly dripped by controlling the internal temperature to be between 0 and 10 DEG C 3 (75.3 g,2.5 eq) and slowly returned to room temperature for 2 hours after the end of the dropwise addition; TLC control of reaction junctionsBundling, namely, cooling the reaction liquid to an internal temperature of less than 5 ℃, slowly dropwise adding the reaction liquid into 150mL of ice methanol, and controlling the internal temperature to be less than or equal to 20 ℃; stirring for 30 minutes after the dripping is finished, concentrating under reduced pressure to remove DCM, steaming twice with methanol, pouring a small amount of solvent into 200mL of ice water, stirring for 30 minutes, filtering, and drying to obtain 36.2g of off-white solid; recrystallisation of the solid with about 600mL (PE: ea=2:1) of mixed solvent gives 26.4g of a white solid, purity: 99.6%, yield: 93.4 percent, 1 H-NMR(DMSO):δ(ppm)11.00(s,1H),7.62(d,1H),7.53(dd,1H),7.07(d,1H),2.78(s,6H)。
example 2
Step I: chlorosulfonic acid (12.5L, 2.5V/W) and N are added into a 20L glass reaction kettle at room temperature (20-30 ℃), and then 2 Replacing three times, controlling the temperature of an ice salt bath to be 0-5 ℃, slowly dropwise adding p-chloroanisole (5.0 kg), naturally heating to room temperature for reaction for 2 hours after adding, enabling TLC central control raw materials to disappear, slowly dropwise adding the reaction liquid into 50L ice water, controlling the temperature to be 10-20 ℃, stirring for 30 minutes, filtering to obtain 8.3kg of white solid, and drying the material in a 50 ℃ oven for 16 hours to obtain 7.88kg of white solid with the purity of 91.3 percent and yield: 93.3 percent, 1 H-NMR(DMSO):δ(ppm)7.63(d,7H),7.34(dd,1H),6.99(d,1H),3.74(s,3H)。
step II: THF (39.4L, 5V/W) is added into a 50L reaction kettle at room temperature (20-30 ℃), the sulfonyl chloride compound (7.88 kg,1.0 eq) is stirred and dissolved, and the temperature is controlled to be 0+/-5 ℃; t-in = 0 ℃, slowly dropwise adding dimethylamine aqueous solution (9.2 kg,2.5 eq), and controlling the temperature to react at 0±5 ℃; incubation for 2 hours, TLC control: ending the reaction; the reaction solution is concentrated under reduced pressure to remove most THF, the rest reaction solution is slowly added into 63kg ice water in a dropwise manner, stirred for 30 minutes, filtered to obtain white solid, and baked for 16 hours at 50 ℃ in an oven to obtain 7.8kg white solid with purity: 86.3%, yield: 95.7 percent, 1 H-NMR(DMSO):δ(ppm)7.78-7.63(m,2H),7.30(d,1H),3.90(s,3H),2.74(s,6H)。
step III: under the room temperature condition (20-30 ℃), DCM (70L, 10V/W) is added into a 100L reaction kettle, the sulfonamide (7.8 kg,1.0 eq) is stirred and dissolved, and the temperature is reduced to 0-10 ℃ at the inner temperature; BBr is slowly dripped by controlling the internal temperature to be between 0 and 10 DEG C 3 (19.57 kg,2.5 eq) and slowly returned to room temperature after the end of the dropwise additionReacting for 2 hours; after TLC central control reaction is finished, the reaction liquid is cooled to the internal temperature of less than 5 ℃, and is slowly dripped into 39L of ice methanol, and the internal temperature is controlled to be less than or equal to 20 ℃; stirring for 30 min after the dripping, concentrating under reduced pressure to remove DCM, steaming twice with methanol, adding a small amount of solvent, stirring for 30 min in 54.6L ice water, filtering, and oven drying to obtain white solid; the solid was recrystallized from about 156L (PE: ea=2:1) of mixed solvent to give 6.88kg of white solid with purity: 99.6%, yield: 93.47 percent, 1 H-NMR(DMSO):δ(ppm)8.82(s,1H),7.50(d,1H),7.43(dd,1H),7.02(d,1H),2.79(s,6H)。
table 1: yield of different synthetic processes
| Project | Feeding amount | Yield is good | Color of the product |
| Comparative example 1 | 10g | 57.0％ | Yellowish light yellow |
| Example 1 | 40g | 82.1％ | White-like color |
| Example 2 | 5.0kg | 83.2％ | White color |
As can be seen from Table 1, the three-step average yield of the products obtained by the synthesis of examples 1-2 is about 80%, which is higher than that of comparative example 1 in the prior art, and the purification process is simple, the production and amplification process is stable, and the color quality of the obtained target product is good.
The previous description of the embodiments is provided to facilitate a person of ordinary skill in the art in order to make and use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above-described embodiments, and those skilled in the art, based on the principle of the present invention, should make improvements and modifications without departing from the scope of the present invention.
Claims (9)
1. A synthetic method of 5-chloro-2-hydroxy-dimethylbenzenesulfonamide comprises the following synthetic route:
the method takes p-chloroanisole as a starting material and comprises the following steps:
step I, sulfonylation reaction: chlorosulfonic acid is used as a reaction reagent, and the sulfonylation reaction is carried out in an aprotic solvent 1 or in a solvent-free state;
step II, sulfonamide reaction: dimethylamine is used as a reaction reagent, and the sulfonamide reaction is carried out in the presence of alkali and a reaction solvent;
step III, demethylation reaction: the demethylation reaction is carried out in aprotic solvent 2 using lewis acid as a reactant.
2. The method for synthesizing 5-chloro-2-hydroxy-dimethylbenzenesulfonamide according to claim 1, wherein in step I, the aprotic solvent 1 is selected from one of dichloromethane, toluene, and dichloroethane.
3. The process for the synthesis of 5-chloro-2-hydroxy-dimethylbenzenesulfonamide according to claim 1, wherein in step I the feed temperature is from-5 to 25 ℃.
4. The method for synthesizing 5-chloro-2-hydroxy-dimethylbenzenesulfonamide according to claim 1, wherein in step II, the dimethylamine is selected from one form of dimethylamine hydrochloride, dimethylamine aqueous solution, dimethylamine alcohol solution, and dimethylamine tetrahydrofuran solution.
5. The method for synthesizing 5-chloro-2-hydroxy-dimethylbenzenesulfonamide according to claim 1, wherein in step II, the reaction solvent is selected from one of dichloromethane, toluene, tetrahydrofuran, and water.
6. The process for the synthesis of 5-chloro-2-hydroxy-dimethylbenzenesulfonamide according to claim 1, wherein in step II the feed temperature is from-5 to 25 ℃.
7. The method for synthesizing 5-chloro-2-hydroxy-dimethylbenzenesulfonamide according to claim 1, wherein in step III, the lewis acid is selected from one of aluminum trichloride, boron tribromide, hydrobromic acid.
8. The method for synthesizing 5-chloro-2-hydroxy-dimethylbenzenesulfonamide according to claim 1, wherein in step III, the aprotic solvent 2 is selected from one of dichloromethane, toluene, tetrahydrofuran, and acetic acid.
9. The process for the synthesis of 5-chloro-2-hydroxy-dimethylbenzenesulfonamide according to claim 1, wherein in step III, the addition temperature is from-5 to 25 ℃.
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