CN117865859A - Preparation method of enantiomerically pure p-toluenesulfonamide - Google Patents
Preparation method of enantiomerically pure p-toluenesulfonamide Download PDFInfo
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- CN117865859A CN117865859A CN202211670042.7A CN202211670042A CN117865859A CN 117865859 A CN117865859 A CN 117865859A CN 202211670042 A CN202211670042 A CN 202211670042A CN 117865859 A CN117865859 A CN 117865859A
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- toluenesulfonamide
- enantiomerically pure
- acyl
- ethyl
- benzyl
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- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 24
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 22
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 22
- -1 acyl p-toluenesulfonamide Chemical compound 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 17
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims abstract description 17
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 15
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 15
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 8
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 7
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 238000010511 deprotection reaction Methods 0.000 claims abstract description 6
- 150000008065 acid anhydrides Chemical class 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000012046 mixed solvent Substances 0.000 claims description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- YNJDSRPIGAUCEE-JTQLQIEISA-N 4-methylbenzenesulfinamide Chemical class CC1=CC=C([S@@](N)=O)C=C1 YNJDSRPIGAUCEE-JTQLQIEISA-N 0.000 claims description 6
- YNJDSRPIGAUCEE-UHFFFAOYSA-N 4-methylbenzenesulfinamide Chemical class CC1=CC=C(S(N)=O)C=C1 YNJDSRPIGAUCEE-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- NOGFHTGYPKWWRX-UHFFFAOYSA-N 2,2,6,6-tetramethyloxan-4-one Chemical compound CC1(C)CC(=O)CC(C)(C)O1 NOGFHTGYPKWWRX-UHFFFAOYSA-N 0.000 claims description 2
- FXJVNINSOKCNJP-UHFFFAOYSA-N 4-methylbenzenesulfinic acid Chemical compound CC1=CC=C(S(O)=O)C=C1 FXJVNINSOKCNJP-UHFFFAOYSA-N 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- KHDBMTLGTSGEEG-UHFFFAOYSA-M sodium;2-methylbenzenesulfinate Chemical compound [Na+].CC1=CC=CC=C1S([O-])=O KHDBMTLGTSGEEG-UHFFFAOYSA-M 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims 1
- KVCGISUBCHHTDD-UHFFFAOYSA-M sodium;4-methylbenzenesulfonate Chemical compound [Na+].CC1=CC=C(S([O-])(=O)=O)C=C1 KVCGISUBCHHTDD-UHFFFAOYSA-M 0.000 abstract description 6
- 230000009471 action Effects 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 150000001263 acyl chlorides Chemical class 0.000 abstract description 2
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000007788 liquid Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 4
- BVJCFOOIOSGZFW-UHFFFAOYSA-N n-(4-methylphenyl)sulfonylacetamide Chemical compound CC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 BVJCFOOIOSGZFW-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940080701 chymosin Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000003287 optical effect Effects 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- YNJDSRPIGAUCEE-SNVBAGLBSA-N 4-methylbenzenesulfinamide Chemical compound CC1=CC=C([S@](N)=O)C=C1 YNJDSRPIGAUCEE-SNVBAGLBSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 238000005915 ammonolysis reaction Methods 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- ZYZHMSJNPCYUTB-CYBMUJFWSA-N (1r)-n-benzyl-1-phenylethanamine Chemical compound N([C@H](C)C=1C=CC=CC=1)CC1=CC=CC=C1 ZYZHMSJNPCYUTB-CYBMUJFWSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N p-toluenesulfonic acid Substances CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- QAZLUNIWYYOJPC-UHFFFAOYSA-M sulfenamide Chemical compound [Cl-].COC1=C(C)C=[N+]2C3=NC4=CC=C(OC)C=C4N3SCC2=C1C QAZLUNIWYYOJPC-UHFFFAOYSA-M 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Classifications
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- 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
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of enantiomerically pure p-toluenesulfonamide, belonging to the technical field of organic synthesis. The method comprises the steps of taking sodium p-toluenesulfonate as a raw material, firstly reacting with thionyl chloride to generate acyl chloride, then reacting with ammonia water to generate p-toluenesulfonamide, then reacting with acid anhydride under the action of strong alkali to obtain N- (ethyl or benzyl) acyl p-toluenesulfonamide, then resolving with chiral 1, 2-dimethylcyclohexanediamine, dissociating to obtain corresponding chiral N- (ethyl or benzyl) acyl p-toluenesulfonamide, then reacting with sulfuric acid/methanol to generate Vilsmeier reagent by deprotection or oxalyl chloride/DMF, and then reacting with hydrazine hydrate to obtain the enantiomerically pure p-toluenesulfonamide. The method has the advantages of easily available raw materials, low cost, continuous operation, low equipment requirement, recoverable resolving agent, and suitability for industrial mass production.
Description
Technical Field
The invention relates to a preparation method of enantiomerically pure p-toluenesulfonamide, belonging to the technical field of organic synthesis.
Background
Enantiomerically pure p-toluene sulfinamides include two configurations: (R) -p-toluene sulfinamide, CAS:247089-85-6, english name: (R) -4-Methyl bezenesulfinamide; (S) -p-toluene sulfinamide, CAS:188447-91-8, english name: (S) -4-Methyl bezene sulfinamide.
The chiral sulfoxide amide is an effective chiral auxiliary agent, can induce related asymmetric transformation, can activate C-N double bond for addition, has excellent fluorescence, can rapidly monitor the residual condition, can rapidly obtain a target product in chiral drug synthesis, and is convenient for large-scale production, research and development and application.
There are many reports of the synthetic routes of the enantiomerically pure p-toluenesulfonamide, wherein the large-scale production method of the (S) -p-toluenesulfonamide with the kilogram level is mainly referred to [ Journal of Organic Chemistry,1999, vol.64, #4, p.1403-1406], the reports are that firstly, sodium p-toluenesulfonate and thionyl chloride form acid chloride, then (1R, 2S, 5R) - (-) -menthol (S) -p-toluenesulfonate is obtained by the action of an acid binding agent and L-menthol, then (S) -p-toluenesulfonamide is obtained by the ultralow-temperature ammonolysis reaction with LiHMDS and ammonium chloride, the route for producing menthol (S) -p-toluenesulfonate needs acid and long-time crystallization to obtain an intermediate with relatively high yield, finally the intermediate is subjected to the ultralow-temperature ammonolysis of LiHMDS, the route has higher requirements on equipment, and the expensive reagent of LiHMDS and a large amount of tetrahydrofuran are used, so that the cost is further increased, and the large-scale production is not favored. The reaction equation is as follows:
for a more novel route reference [ Advanced Synthesis and Catalysis,2006, vol.348, #10-11, p.1183-1192], reports that sodium p-toluenesulfonate forms an acid chloride with oxalyl chloride, then sulfenamide is reacted with ammonia, followed by reaction with acid anhydride under sodium hydride strong base to give N-3- (3-pyridine) -propionyl-p-toluenesulfonamide, followed by partial deacylation under the action of a-chymosin (corresponding to acyl hydrolase) to give (R) -p-toluenesulfonamide, and partial treatment with hydrazine hydrate to give (S) -p-toluenesulfonamide. The enantiomer pure p-toluene sulfinamide ee obtained by the route is more than 98 percent, and the chiral requirement is relatively low for the optical purity; the method has high atom utilization rate, but (3-pyridine) -propionic anhydride is not easy to purchase, and the price of the a-chymosin is high, so that the industrialized mass production of the a-chymosin is influenced. The reaction equation is as follows:
document [ Tetrahedron Asymmetry,2011, vol.22, #4, p.387-393] reports that p-toluenesulfonic acid sodium salt and oxalyl chloride form acid chloride, which is then reacted with (R) - (+) -N-benzyl-1-phenethylamine under the action of triethylamine acid binding agent to give (R/S) -N-benzyl-N- (1-phenylethyl) benzenesulfonamide (40%), which is then reacted with methanol and boron trifluoride diethyl etherate to give (R/S) -methyl p-toluenesulfonate, which is finally reacted with LiHMDS and ammonium chloride at ultra-low temperature to give (R/S) -p-toluenesulfonic acid amide, with a total yield of about 32%. The reaction equation is as follows:
aiming at the defects of the method, the invention adopts the preparation method with simple and convenient flow, high atomic utilization rate, mild reaction condition and low equipment requirement, and the optical purity of the obtained product is more than 99.5 percent, thereby being suitable for industrial scale production and meeting the increasing market demand.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a preparation method of the enantiomerically pure p-toluenesulfonamide. The method comprises the steps of taking sodium p-toluenesulfonate as a raw material, firstly reacting with thionyl chloride to generate acyl chloride, then reacting with ammonia water to generate p-toluenesulfonamide, then reacting with acid anhydride under the action of strong alkali to obtain N- (ethyl or benzyl) acyl p-toluenesulfonamide, then resolving with chiral 1, 2-dimethylcyclohexanediamine, then dissociating to obtain corresponding chiral N- (ethyl or benzyl) acyl p-toluenesulfonamide, then reacting with sulfuric acid/methanol to generate Vilsmeier reagent by deprotection or oxalyl chloride/DMF, and then reacting with hydrazine hydrate to obtain the enantiomerically pure p-toluenesulfonamide. The method has the advantages of easily available raw materials, low cost, continuous operation, low equipment requirement, recoverable resolving agent, and suitability for industrial mass production.
The preparation method of the enantiomerically pure p-toluenesulfonamide comprises the following steps:
the first step: the sodium salt of the paratoluenesulfinic acid, thionyl chloride, a catalyst and toluene are reacted to generate the paratoluenesulfinyl chloride, and then the paratoluenesulfinyl chloride reacts with ammonia water;
and a second step of: mixing and reacting p-toluenesulfonamide, strong alkali, anhydride and tetrahydrofuran/dimethyl sulfoxide mixed solvent to obtain N- (ethyl or benzyl) acyl p-toluenesulfonamide;
and a third step of: heating and refluxing N- (ethyl or benzyl) acyl p-toluenesulfonamide and chiral 1, 2-dimethylcyclohexanediamine serving as a resolving agent in a mixed solvent, cooling and crystallizing to obtain resolved salt of the N- (ethyl or benzyl) acyl p-toluenesulfonamide, and dissociating to obtain chiral N- (ethyl or benzyl) acyl p-toluenesulfonamide;
fourth step: mixing chiral N- (ethyl or benzyl) acyl p-toluenesulfonamide, methanol and concentrated sulfuric acid for deprotection to obtain enantiomerically pure p-toluenesulfonamide; or chiral N- (ethyl or benzyl) acyl-p-toluenesulfonamide is reacted with oxalyl chloride/DMF and then reacted with hydrazine hydrate to obtain the enantiomerically pure p-toluenesulfonamide.
Further, in the above technical scheme, in the first step, the catalyst is selected from pyridine or N, N-dimethylformamide.
Further, in the above technical scheme, in the first step, the molar ratio of the toluene sulfinic acid sodium salt, the thionyl chloride, the catalyst and the ammonia water is 1:1.15-1.25:0.001-0.02:10-15.
Further, in the above technical scheme, in the second step, the strong base is selected from potassium tert-butoxide or sodium tert-butoxide; the acid anhydride is selected from acetic anhydride or benzoic anhydride; the ratio of the tetrahydrofuran/dimethyl sulfoxide mixed solvent is 16:1.
further, in the above technical scheme, in the second step, the molar ratio of the p-toluene sulfinamide, the strong base and the anhydride is 1:1.20-1.25:1.15-1.20.
Further, in the above technical scheme, in the third step, the mixed solvent is selected from ethyl acetate and isopropyl alcohol mixed solvents.
Further, in the above technical scheme, in the third step, the molar ratio of the N- (ethyl or benzyl) acyl p-toluenesulfonamide to the resolving agent is 1:0.49-0.50.
Further, in the above technical scheme, in the fourth step, when the methanol/sulfuric acid is used for deprotection, the molar ratio of chiral N- (ethyl or benzyl) acyl-p-toluenesulfonamide to concentrated sulfuric acid is 1:0.85-0.95.
Further, in the above technical scheme, in the fourth step, the molar ratio of the chiral N- (ethyl or benzyl) acyl p-toluenesulfonamide, oxalyl chloride, DMF and hydrazine hydrate is 1:2.0-2.5:1.5-2.5:8.0-10.0.
Advantageous effects of the invention
1. The acidamide is further strengthened through double acylation, and the acidamide is subjected to salification and resolution with the enantiomerically pure 1, 2-dimethylcyclohexanediamine, so that the optical purity of the obtained product can reach more than 99.5%, and the product quality is better.
2. The process has the advantages of easily available raw materials, low cost, low equipment requirement and recoverable resolving agent.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples should be construed as merely illustrative of the present invention and not limiting the scope of the present invention. Various changes and modifications to the present invention may be made by one skilled in the art after reading the description herein, and such equivalent changes and modifications are intended to fall within the scope of the present invention as defined in the appended claims. Synthesis of enantiomerically pure (R) -and (S) -p-toluene sulfinamides
Example 1
178.2g (1 mol) of sodium p-toluenesulfonate, 1.6 (0.02 mol) of pyridine and 900mL of toluene are put into a four-port reaction flask for mixing, 142.8g (1.2 mol) of thionyl chloride is added dropwise at room temperature, the temperature is raised to 80 ℃ for reaction for 8 hours, reduced pressure distillation is carried out at 40-50 ℃ until no liquid flows, 1L of toluene is added each time during the period, and the total addition is 2 times; then 600mL of dichloromethane is added, the temperature is reduced to 5-10 ℃, the mixture is slowly added into 680g (10 mol) of 25 percent ammonia water which is reduced to 0-5 ℃ in advance, the mixture is reacted for 2 hours at 5-10 ℃, the mixture is heated to room temperature for 1 hour, the mixture is distilled to a non-flowing liquid under reduced pressure at 30-35 ℃, n-heptane is added to extract impurities, 500mL of dichloromethane is added for extraction, an organic phase is dried by anhydrous sodium sulfate, and the organic phase is distilled to the residual volume of 2-3 under reduced pressure130.2g of p-toluenesulfonamide was obtained by beating with the addition of n-heptane, yield 83.9% and HPLC 98.6%. 1 HNMR(400MHz,CDCl 3 )δ:7.63-7.59(m,2H),7.31-7.27(m,2H),4.56(s,2H),2.38(s,3H).
Example 2
Under the protection of argon, 93.1g (0.6 mol) of p-toluenesulfonamide and 850mL of anhydrous tetrahydrofuran/dimethyl sulfoxide mixed solvent are put into a four-port reaction bottle to be mixed, the temperature is reduced to 0-5 ℃, 70.4g (0.69 mol) of acetic anhydride is added, 80.8g (0.72 mol) of potassium tert-butoxide is added in batches, the reaction is carried out for 2 hours at 0-5 ℃, aqueous acetic acid solution is added dropwise at 0 ℃ to quench, 300mL of dichloromethane are used for extraction, the organic phases are combined, water washing is carried out, the organic phases are distilled to 2-3 volumes under reduced pressure, N-heptane is added to obtain 104.3g of N-acetyl-p-toluenesulfonamide, the yield is 88.1%, and HPLC is 97.4%. 1 HNMR(400MHz,CDCl 3 )δ:8.24(s,1H),7.60-7.56(m,2H),7.35-7.29(m,2H),2.45(s,3H),2.21(s,3H).
Example 3
Under the protection of argon, 93.1g (0.6 mol) of p-toluenesulfonamide and 850mL of anhydrous tetrahydrofuran/dimethyl sulfoxide mixed solvent are put into a four-port reaction bottle to be mixed, the temperature is reduced to 0-5 ℃, 70.4g (0.69 mol) of acetic anhydride is added, 69.2g (0.72 mol) of sodium tert-butoxide is added in batches, the reaction is carried out for 2 hours at 0-5 ℃, aqueous acetic acid solution is added dropwise at 0 ℃ to quench, 300mL of dichloromethane is used for extraction, the organic phases are combined, water washing is carried out, the organic phases are distilled to 2-3 volumes under reduced pressure, and N-heptane is added to obtain 99.5g of N-acetyl-p-toluenesulfonamide, the yield is 84.1%, and HPLC is 98.7%.
Example 4
78.9g (0.4 mol) of N-acetyl-p-toluenesulfonamide and 150mL of isopropanol are put into a four-port reaction bottle to be mixed, the temperature is raised to 35-40 ℃, 28.4g (0.2 mol) of mixed solution of (1R, 2R) -1, 2-dimethyl cyclohexanediamine and 390mL of ethyl acetate are added, the temperature is raised and refluxed for 6 hours, the slow gradient is cooled to 5-10 ℃, filtration is carried out, the filter cake is leached by ethyl acetate, the filter cake is put into the four-port reaction bottle again, 500mL of methyl tertiary butyl ether is added, 3% dilute sulfuric acid is dripped to adjust the pH=3.5-4.5, the mixture is stood for layering, the aqueous layer is extracted by methyl tertiary butyl ether, the organic layer is combined, washed to be neutral by saturated sodium chloride aqueous solution, the mixture is dried by anhydrous sodium sulfate, the organic phase is decompressed and distilled until no flow liquid is obtained, and 29.0g of (R) -N-acetyl-p-toluenesulfonamide is obtained, the yield is 36.8%, and the HPLC is 99.3%, and 99.5%ee.
Example 5
78.9g (0.4 mol) of N-acetyl-p-toluenesulfonamide and 100mL of isopropanol are put into a four-port reaction bottle to be mixed, the temperature is raised to 35-40 ℃, 27.8g (0.196 mol) of (1S, 2S) -1, 2-dimethyl cyclohexanediamine and 360mL of ethyl acetate are added, the temperature is raised and refluxed for 8 hours, the temperature is slowly reduced to 5-10 ℃, filtration is carried out, the filter cake is leached by ethyl acetate, the filter cake is put into the four-port reaction bottle again, 500mL of dichloromethane is added, 2M hydrochloric acid is dropwise added to adjust the pH to 3.5-4.5, the mixture is stood for layering, the aqueous layer is extracted by dichloromethane, the organic layer is combined, the mixture is washed to be neutral by saturated sodium chloride aqueous solution, anhydrous sodium sulfate is dried, the organic phase is decompressed and distilled until no liquid is flowed to obtain 32.0g of (S) -N-acetyl-p-toluenesulfonamide, the yield is 40.6%, HPLC is 99.6%, and ee=99.8%.
Example 6
29.0g (0.1472 mol) of (R) -N-acetyl-p-toluenesulfonamide of example 4 and 300mL of methanol are put into a four-port reaction bottle, cooled to 10-15 ℃, 13.3g (0.133 mol) of 98% concentrated sulfuric acid is added dropwise, the mixture is reacted overnight at room temperature, distilled to a non-flowing liquid under reduced pressure at 25-30 ℃, 300mL of methyl tertiary butyl ether is added for mixing, saturated sodium bicarbonate is respectively added for washing, saturated saline solution is respectively added for washing, anhydrous sodium sulfate of an organic phase is dried, distilled to the rest 2 volumes under reduced pressure, N-heptane is added for thermal recrystallization, 20.6g of (R) -p-toluenesulfonamide is obtained after cooling, the yield is 90.1%, HPLC is 99.8%, and 99.5% ee is obtained after filtration.
Example 7
29.2g (0.4 mol) of N, N-dimethylformamide is put into a four-port reaction bottle, cooled to 10 ℃, 50.8g (0.4 mol) of oxalyl chloride is added dropwise, the mixture is reacted for 30min at room temperature, a mixed solution of 32g (0.1624 mol) of (S) -N-acetyl-p-toluenesulfonamide in example 5 and 200mL of dichloromethane is added dropwise, the mixture is reacted for 3 h at room temperature, cooled to 0-5 ℃, water quenching is added, layering is carried out, an organic phase is washed with saturated sodium bicarbonate and saturated sodium chloride aqueous solution, distilled to a non-flowing liquid at 30-35 ℃ under reduced pressure, 300mL of ethanol is added, 320.5g (4 mol) of 40% hydrazine hydrate is added dropwise at room temperature, the ethanol is distilled to be removed at 35-40 ℃ under reduced pressure, the temperature is reduced to 5-10 ℃, the pH=5.0-6.0 is adjusted by dropwise adding an acetic acid aqueous solution, dichloromethane extraction is carried out, an organic phase is washed with 10% potassium bicarbonate aqueous solution and washed once with water, anhydrous sodium sulfate is dried, the organic phase is distilled to remove dichloromethane under reduced pressure, ethyl acetate and N-heptane mixed solvent is added to be recrystallized to obtain the mixed solvent (S) -p-toluenesulfonamide of 99.8.99.99% by HPLC (99.8%).
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should be covered by the protection scope of the present invention by making equivalents and modifications to the technical solution and the inventive concept thereof.
Claims (9)
1. A process for the preparation of enantiomerically pure p-toluenesulfinamides comprising the steps of:
the first step: the sodium salt of the paratoluenesulfinic acid, thionyl chloride, a catalyst and toluene are reacted to generate the paratoluenesulfinyl chloride, and then the paratoluenesulfinyl chloride reacts with ammonia water;
and a second step of: mixing and reacting p-toluenesulfonamide, strong alkali, anhydride and tetrahydrofuran/dimethyl sulfoxide mixed solvent to obtain N- (ethyl or benzyl) acyl p-toluenesulfonamide;
and a third step of: heating and refluxing N- (ethyl or benzyl) acyl p-toluenesulfonamide and chiral 1, 2-dimethylcyclohexanediamine serving as a resolving agent in a mixed solvent, cooling and crystallizing to obtain resolved salt of the N- (ethyl or benzyl) acyl p-toluenesulfonamide, and dissociating to obtain chiral N- (ethyl or benzyl) acyl p-toluenesulfonamide;
fourth step: mixing chiral N- (ethyl or benzyl) acyl p-toluenesulfonamide, methanol and concentrated sulfuric acid for deprotection to obtain enantiomerically pure p-toluenesulfonamide; or chiral N- (ethyl or benzyl) acyl-p-toluenesulfonamide is reacted with oxalyl chloride/DMF and then reacted with hydrazine hydrate to obtain the enantiomerically pure p-toluenesulfonamide.
2. The process for the preparation of enantiomerically pure p-toluenesulfonamide according to claim 1 characterized in that: in the first step, the catalyst is selected from pyridine or N, N-dimethylformamide.
3. The process for the preparation of enantiomerically pure p-toluenesulfonamide according to claim 1 characterized in that: in the first step, the molar ratio of the toluene sulfinic acid sodium salt, the thionyl chloride, the catalyst and the ammonia water is 1:1.15-1.25:0.001-0.02:10-15.
4. The process for the preparation of enantiomerically pure p-toluenesulfonamide according to claim 1 characterized in that: in the second step, the strong base is selected from potassium tert-butoxide or sodium tert-butoxide; the acid anhydride is selected from acetic anhydride or benzoic anhydride; the ratio of the tetrahydrofuran/dimethyl sulfoxide mixed solvent is 16:1.
5. the process for the preparation of enantiomerically pure p-toluenesulfonamide according to claim 1 characterized in that: in the second step, the molar ratio of the p-toluene sulfinamide, the strong base and the anhydride is 1:1.20-1.25:1.15-1.20.
6. The process for the preparation of enantiomerically pure (R) -and (S) -p-toluenesulfinamides according to claim 1, characterized in that: in the third step, the mixed solvent is ethyl acetate and isopropanol solvent.
7. The process for the preparation of enantiomerically pure (R) -and (S) -p-toluenesulfinamides according to claim 1, characterized in that: in the third step, the molar ratio of the N- (ethyl or benzyl) acyl-p-toluenesulfonamide to the resolving agent is 1:0.49-0.50.
8. The process for the preparation of enantiomerically pure p-toluenesulfonamide according to claim 1 characterized in that: in the fourth step, when the methanol/sulfuric acid is adopted for deprotection, the molar ratio of chiral N- (ethyl or benzyl) acyl-p-toluenesulfonamide to concentrated sulfuric acid is 1:0.85-0.95.
9. The process for the preparation of enantiomerically pure p-toluenesulfonamide according to claim 1 characterized in that: in the fourth step, the molar ratio of the chiral N- (ethyl or benzyl) acyl p-toluenesulfonamide, oxalyl chloride, DMF and hydrazine hydrate is 1:2.0-2.5:1.5-2.5:8.0-10.0.
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