CN116410128A - Method for preparing tosylate Ai Duosha class intermediate by one-pot method - Google Patents
Method for preparing tosylate Ai Duosha class intermediate by one-pot method Download PDFInfo
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- CN116410128A CN116410128A CN202310296440.5A CN202310296440A CN116410128A CN 116410128 A CN116410128 A CN 116410128A CN 202310296440 A CN202310296440 A CN 202310296440A CN 116410128 A CN116410128 A CN 116410128A
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- duosha
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- tosylate
- toluene sulfonic
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- 238000000034 method Methods 0.000 title claims abstract description 22
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000005580 one pot reaction Methods 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- -1 oxalyl chloride monomethyl ester Chemical class 0.000 claims abstract description 16
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 claims abstract description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000001914 filtration Methods 0.000 claims abstract description 8
- 238000001035 drying Methods 0.000 claims abstract description 7
- 238000010992 reflux Methods 0.000 claims abstract description 6
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 5
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 4
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- 239000000543 intermediate Substances 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 229940126214 compound 3 Drugs 0.000 claims description 14
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 13
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 229940125904 compound 1 Drugs 0.000 claims description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 235000006408 oxalic acid Nutrition 0.000 claims description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical class OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims 1
- 230000005494 condensation Effects 0.000 claims 1
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Substances ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 abstract description 7
- MAXBVGJEFDMHNV-UHFFFAOYSA-N 5-chloropyridin-2-amine Chemical compound NC1=CC=C(Cl)C=N1 MAXBVGJEFDMHNV-UHFFFAOYSA-N 0.000 abstract description 6
- 239000000654 additive Substances 0.000 abstract description 2
- 230000000996 additive effect Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000010438 heat treatment Methods 0.000 abstract 2
- 239000000243 solution Substances 0.000 description 11
- 229940125898 compound 5 Drugs 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 206010014522 Embolism venous Diseases 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- 206010020100 Hip fracture Diseases 0.000 description 1
- VBBOSXYNZFIQBE-UHFFFAOYSA-N O.CC1=CC=C(C=C1)S(=O)(=O)O.C(C(=O)N)(=O)N Chemical compound O.CC1=CC=C(C=C1)S(=O)(=O)O.C(C(=O)N)(=O)N VBBOSXYNZFIQBE-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229940127217 antithrombotic drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 150000004985 diamines Chemical class 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000004394 hip joint Anatomy 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- QXJJODRMMDQBKV-UHFFFAOYSA-N methyl 2-[(5-chloropyridin-2-yl)amino]-2-oxoacetate Chemical compound COC(=O)C(=O)NC1=CC=C(Cl)C=N1 QXJJODRMMDQBKV-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 208000004043 venous thromboembolism Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- 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
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- 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
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for preparing a Ai Duosha class intermediate of toluenesulfonic acid by a one-pot method, which belongs to the field of drug synthesis, and is characterized in that 2-amino-5-chloropyridine and oxalyl chloride monomethyl ester are used as raw materials, heating is carried out for 1-5 hours, then alkali, an additive and a compound 4 are directly added into reaction liquid, heating reflux is carried out for 6-18 hours, water is added, filtering, separating and drying are carried out, and the intermediate is obtained. This intermediate can be used to prepare tosylate Ai Duosha class.
Description
Technical Field
The invention relates to a preparation method of an intermediate of an antithrombotic drug toluene sulfonic acid Ai Duosha class, which adopts a one-pot preparation method.
Background
The Ai Duosha class tosylate is a small molecular oral anticoagulant developed by Japanese first Co-product, and the active ingredient toluene sulfonic acid Ai Duosha class is a selective factor Xa inhibitor and is clinically used for treating venous thromboembolism of patients with total knee joint replacement, total hip joint replacement and hip fracture operation. The chemical name of toluene sulfonic acid Ai Duosha class is: n- (5-chloro-2-pyridinyl) -N' - [ (1S, 2R, 4S) -4- [ (dimethylamino) formyl ] -2- [ [ (4, 5,6, 7-tetrahydro-5-methylthiazol [5,4-c ] pyridin-2-yl) formyl ] amino ] cyclohexyl ] ethanediamide p-toluenesulfonate monohydrate of the formula:
international application WO 2007/032388A (CN 103214414B, comparative document 1) describes a process for synthesizing optically active diamines as an important intermediate (compound 5) in the synthesis of the drug toluene sulfonic acid Ai Duosha class, which is liable to cause a decrease in yield due to the difficulty in stirring because the reaction system becomes hard and solidifies after neutralization of the oxalate with a tertiary amine.
Aiming at the problems, WO 2010/104078 (CN 102348688B, comparison document 2) proposes a new material adding sequence to effectively solve the problem of curing of a reaction system.
However, there are problems that the amount of oxalyl chloride monoethyl ester used in the process of preparing the compound 10 is large, the production efficiency is low, the amount of the organic solvent used is large, and environmental pollution is required to be overcome.
Disclosure of Invention
In order to overcome the technical problems, the invention aims to provide a method for preparing a Ai Duosha class intermediate of toluene sulfonic acid by a one-pot method, which has the advantages of simple process and high product yield and is suitable for industrial production.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
tosylate Ai Duosha class intermediate (compound 5), chemical name: [ (1 r,2s,5 s) -2- [ [2- [ (5-chloropyridin-2-yl) amino ] -2-oxoacetyl ] amino ] -5- (dimethylaminocarbonyl) cyclohexyl ] carbamic acid tert-butyl ester:
the synthesis process of the intermediate is as follows:
wherein Boc represents t-butoxycarbonyl and R represents methyl or ethyl.
Specifically, the reaction process of the above reaction formula is as follows:
step (a), reacting the compound 1 with the compound 2 in an organic solvent at a temperature of between 40 ℃ and a reflux temperature for 1 to 5 hours to generate a compound 3;
the organic solvent is acetonitrile or dichloromethane;
the molar ratio of the compound 1 to the compound 2 is 1.0-1.2:1.0.
and (b) directly adding alkali, an additive (oxalic acid or acetic acid) and a compound 4 into the reaction liquid without separating the compound 3, continuously reacting for 6-18 hours at 58 ℃ to reflux temperature, desolventizing, adding water, filtering, separating and drying to obtain an intermediate (compound 5).
The base is triethylamine or diisopropylethylamine, and the molar ratio of the compound 3 to the base is 1.0:3.5-5.2.
The molar ratio of the compound 3 to the compound 4 is 1.0-1.2:1.0.
the invention also discloses the use of the obtained intermediate (compound 5) for preparing Ai Duosha class (compound 6) of toluene sulfonic acid:
the specific process is as follows: deprotection of compound 5 under acidic conditions gives compound 7, which is then condensed with compound 8 under basic conditions to give compound 9, which has the following reaction scheme:
then salifying the compound 9 and p-toluenesulfonic acid monohydrate to obtain a compound 6, wherein the reaction formula is as follows:
compared with the prior art, the invention has the following beneficial effects:
1. according to the invention, 2-amino-5-chloropyridine and oxalyl chloride monomethyl ester are used as raw materials, the compound 3 is prepared first, a separation step is not needed, the compound 4 is directly added to generate a Ai Duosha class intermediate of toluenesulfonic acid, the processes of separating, cleaning and the like after the compound 3 is prepared in the prior art are omitted, and the consumption of oxalyl chloride monomethyl ester and an organic solvent acetonitrile is reduced.
2. According to the method, the intermediate of the Ai Duosha class toluene sulfonic acid is prepared by adopting a one-pot method, and tertiary amine is not required to be added in parts to avoid the decomposition of the compound 2 in a free form as in the comparison document 2, so that the operation process is simplified, the lengthy separation process and the purification process of the intermediate compound in the post-treatment process are avoided, the time and resources are saved, the yield is improved, and the production efficiency is greatly improved.
The specific embodiment is as follows:
the present invention is described in more detail by the following examples, which should not be construed as limiting the present invention.
The chemical names of the compounds referred to in this application are listed below:
compound 1: 2-amino-5-chloropyridine;
compound 2: oxalyl chloride monomethyl ester;
compound 3:2- [ (5-chloropyridin-2-yl) amino ] -2-oxoacetic acid methyl ester;
compound 4: (1 r,2s,5 s) -2-amino-5- [ (dimethylamino) carbonyl ] cyclohexyl ] carbamic acid tert-butyl ester;
compound 5: [ (1 r,2s,5 s) -2- [ [2- [ (5-chloropyridin-2-yl) amino ] -2-oxoacetyl ] amino ] -5- (dimethylaminocarbonyl) cyclohexyl ] carbamic acid tert-butyl ester;
compound 6: tosylate Ai Duosha shift;
compound 9: n- (5-chloro-2-pyridinyl) -N' - [ (1S, 2R, 4S) -4- [ (dimethylamino) formyl ] -2- [ [ (4, 5,6, 7-tetrahydro-5-methylthiazolo [5,4-c ] pyridin-2-yl) formyl ] amino ] cyclohexyl ] ethanediamide.
Comparative example 1
The comparative example is an intermediate prepared by a separation method, and the process flow is as follows:
step one, preparation of methyl 2- [ (5-chloropyridin-2-yl) amino ] -2-oxoacetate (compound 3): to a constant pressure dropping funnel was added acetonitrile solution (80 mL) to 2-amino-5-chloropyridine (10 g), and the mixture was preheated and shaken until completely dissolved. To an acetonitrile solution (80 mL) of oxalyl chloride monomethyl ester (11.44 g) was added an acetonitrile solution (80 mL) of 2-amino-5-chloropyridine (10 g) kept as a preheated solution at 70℃and stirred at this temperature for 1 hour. Then, methanol (12.4 mL) was added for quenching, the internal temperature was lowered to 10℃for filtration, and the resultant was rinsed with acetonitrile solution (20 mL) and dried to obtain the title compound 3, a total of 18.10g.
Nuclear magnetic data: 1 H-NMR(CDCL3)δ:8.31-8.32(d,1H，J＝2.4Hz),7.73-7.75(dd,1H，J＝8.9，2.5Hz),8.22-8.24(d,1H，J＝8.9Hz),9.48(s,1H),3.99(s,1H)。
step two, preparation of tosylate Ai Duosha class intermediate (compound 5):
7.35g of the compound 3 obtained in the step one was taken and dissolved in 55mL of acetonitrile at room temperature, then 12.13g of triethylamine, 7.6g of the compound 4,2.4g of oxalic acid were added, and after stirring at 70℃for 6 hours, the solvent was concentrated under reduced pressure, and then cooled to room temperature, water (30 mL) was added to the reaction solution, and stirring at room temperature was carried out for 2 hours. Filtration and rinsing with acetonitrile, water mixture (15 mL) and drying gave the title compound 11.46g in 90% purity 98.2%.
Example 1
Tert-butyl [ (1R, 2S, 5S) -2- [ [2- [ (5-chloropyridin-2-yl) amino ] -2-oxoacetyl ] amino ] -5- (dimethylaminocarbonyl) cyclohexyl ] carbamate (compound 5) was prepared using a one-pot method:
to an acetonitrile solution (73 ml) of 2-amino-5-chloropyridine (compound 1,5.05 g) at 70℃was added oxalyl chloride monomethyl ester (compound 2,4.72 g), and stirred at this temperature for 1 hour. After cooling to 20℃15.96g of triethylamine, 10g of compound 4 and 3.15g of oxalic acid are added. After the temperature was raised to 70℃and stirred for 8 hours, the reaction solution was cooled to room temperature, 40mL of water was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. Filtration and rinsing with 20mL of acetonitrile/water mixture, and drying gave 14.93g of intermediate (compound 5) in 92% yield and 99.0% purity.
Nuclear magnetic data: 1 H-NMR(DMSO-d6)δ:8.45-8.46(d,1H，J＝2.3Hz),8.01-8.03(dd,1H，J＝8.8，2.4Hz),8.05-8.07(d,1H，J＝8.9Hz),10.21(s,1H),8.64-8.66(d,1H，J＝7.7Hz),3.94-3.96(dd,1H，J＝7.0，3.4Hz),1.76-1.90(m,2H),1.70-2.57(m,2H),2.93-2.97(t,1H，J＝12.5Hz),1.43-1.55(m,2H),3.83-3.84(d,1H，J＝3.0Hz),7.02-7.04(d,1H，J＝6.5Hz),2.81(s,3H),3.01(s,3H),1.40(s,9H)。
comparing the comparative example with example 1, it can be seen that the present application uses a one-pot process to perform a continuous chemical reaction in one reactor, avoiding the time consuming quenching of the reaction, isolation of intermediates, extraction and purification processes in organic synthesis, and purifying intermediate compounds to save time and resources.
Example 2
Use of the intermediate obtained in example 1 for the preparation of tosylate Ai Duosha class
Step 1, preparation of compound 9:
to an acetonitrile solution (mass volume ratio: 12g:204 mL) of the compound 5 prepared in example 1 was added 7.4g of methanesulfonic acid at room temperature, stirred at 40℃for 4 hours and then deprotected to give compound 7, 8.4g of compound 8 was added, 14.9g of triethylamine was added, and stirred at this temperature for 1 hour, and the compound 7 and the compound 8 were condensed to give compound 9. 408mL of water was added to the reaction system, and the mixture was filtered, and the cake was slurried with 72mL of acetonitrile under reflux for 6 hours. Cooling to room temperature, filtering, eluting with 24mL of ethanol, and drying to obtain 12.7g of compound 9.
Step 2, preparation of toluene sulfonic acid Ai Duosha class:
to an ethanol solution of compound 9 (mass volume ratio: 10g:49 mL) was added an aqueous solution of p-toluenesulfonic acid (mass volume ratio: 3.47g:21 mL) at 50 ℃. The temperature was raised to 70℃and 0.1g of activated carbon was added thereto, followed by stirring at this temperature for 0.5 hours. The activated carbon was filtered and rinsed with a mixture of ethanol and water (17 mL:3mL by volume). Cooling to 10 ℃ for 3-5 hours, and continuously stirring for 2 hours. Filtration, rinsing with a mixture of ethanol and water (volume ratio: 19mL:1 mL) and drying to obtain Ai Duosha class of toluene sulfonic acid, the total amount of which is 12.36g, the yield is 91.8% and the purity is 99.6%.
Nuclear magnetic data: 1 H-NMR(DMSO-d6)δ:8.44-8.45(d,1H，J＝1.8Hz)，7.98-7.99(d,1H，J＝2.4Hz)，8.00-8.05(dd,1H，J＝16.8，8.9Hz)，10.25(s,1H)，9.19-9.21(d,1H，J＝7.1Hz)，4.45-4.46(d,1H，J＝3.1Hz)，1.68-1.71(dd,2H，J＝14.5，10.7Hz)，1.47-1.69(m,2H)，2.98(s,1H)，2.04-2.13(dd,2H，J＝28.9，12.5Hz)，4.00-4.06(m,1H)，8.73-8.75(d,1H，J＝7.3Hz)，4.62(s,2H)，3.67(s,2H)，3.20(s,2H)，2.27(s,3H)，2.94(s,3H)，2.79(s,3H)，7.09-7.11(d,2H，J＝7.9Hz)，7.45-7.47(d,2H，J＝8.0Hz)，3.01(s,3H)，10.15(s,1H)。
Claims (7)
1. the preparation method of the intermediate of Ai Duosha class toluene sulfonic acid is characterized by comprising the following synthesis process:
r represents methyl or ethyl.
2. The process for the preparation of the intermediate Ai Duosha class of toluene sulfonic acid according to claim 1, wherein step (a), compound 1 and compound 2 are reacted in an organic solvent at a temperature ranging from 40 ℃ to reflux temperature for 1-5 hours to form compound 3;
and (b) directly adding alkali, oxalic acid or acetic acid and the compound 4 into the reaction liquid without separating the compound 3, continuously reacting for 6-18 hours at 58 ℃ to reflux temperature, desolventizing, adding water, filtering, separating and drying to obtain the intermediate of the toluene sulfonic acid Ai Duosha class.
3. The process for preparing Ai Duosha class of intermediate toluene sulfonic acid according to claim 2, wherein in step (a), the organic solvent is acetonitrile or dichloromethane; the molar ratio of the compound 1 to the compound 2 is 1.0-1.2:1.0.
4. the process for preparing Ai Duosha class of tosylate intermediates according to claim 2 wherein in step (b) the base is triethylamine or diisopropylethylamine;
the molar ratio of the compound 3 to the base is 1.0:3.5-5.2.
The molar ratio of the compound 3 to the compound 4 is 1.0-1.2:1.0.
5. use of the intermediate of Ai Duosha shift tosylate of claim 1 for the preparation of Ai Duosha shift tosylate.
6. The use according to claim 5, wherein the reaction scheme is as follows:
step (1)
Step (2)
7. Use according to claim 6, characterized by the following steps:
(1) Deprotection of the intermediate toluene sulfonic acid Ai Duosha class under acidic conditions gives compound 7 with t-butoxycarbonyl removed, followed by condensation with compound 8 under basic conditions to give compound 9;
(2) Salifying compound 9 and p-toluenesulfonic acid monohydrate gives toluenesulfonic acid Ai Duosha shift.
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