CN117326953A - Preparation method of lisdexamphetamine dimesylate intermediate - Google Patents
Preparation method of lisdexamphetamine dimesylate intermediate Download PDFInfo
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- 229960001451 lisdexamfetamine Drugs 0.000 title claims abstract description 12
- VOBHXZCDAVEXEY-JSGCOSHPSA-N lisdexamfetamine Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](C)CC1=CC=CC=C1 VOBHXZCDAVEXEY-JSGCOSHPSA-N 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 52
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 30
- PYHRZPFZZDCOPH-QXGOIDDHSA-N (S)-amphetamine sulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.C[C@H](N)CC1=CC=CC=C1.C[C@H](N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-QXGOIDDHSA-N 0.000 claims abstract description 25
- 229940119751 dextroamphetamine sulfate Drugs 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 7
- 229910052751 metal Inorganic materials 0.000 claims abstract description 7
- 239000002184 metal Substances 0.000 claims abstract description 7
- 229940126062 Compound A Drugs 0.000 claims abstract description 5
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000009471 action Effects 0.000 claims abstract description 5
- 150000001450 anions Chemical class 0.000 claims abstract description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 36
- 239000000243 solution Substances 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 239000007864 aqueous solution Substances 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 239000011780 sodium chloride Substances 0.000 claims description 9
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims description 8
- 238000000967 suction filtration Methods 0.000 claims description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-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
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 239000008346 aqueous phase Substances 0.000 claims description 2
- 229910052793 cadmium Inorganic materials 0.000 claims description 2
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229910052804 chromium Inorganic materials 0.000 claims description 2
- 239000011651 chromium Substances 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 239000003350 kerosene Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 229910052725 zinc Inorganic materials 0.000 claims description 2
- 239000011701 zinc Substances 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- 239000010410 layer Substances 0.000 description 13
- 239000012065 filter cake Substances 0.000 description 12
- 239000008213 purified water Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- -1 amine dimethyl sulfonate Chemical class 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000002386 leaching Methods 0.000 description 6
- 239000011259 mixed solution Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000013078 crystal Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 description 2
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 description 2
- 229960000632 dexamfetamine Drugs 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 208000013403 hyperactivity Diseases 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- KRIOVPPHQSLHCZ-UHFFFAOYSA-N propiophenone Chemical compound CCC(=O)C1=CC=CC=C1 KRIOVPPHQSLHCZ-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 208000014679 binge eating disease Diseases 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a lisdexamphetamine dimesylate intermediate. The preparation method of the invention comprises the following steps: step 1, reacting a compound A with an active metal under the action of acid to obtain a reaction solution; step 2, adding concentrated hydrochloric acid into the reaction liquid, reacting, and separating to obtain a compound B; and 3, carrying out anion replacement reaction on the compound B and sulfuric acid to obtain the dextroamphetamine sulfate. The invention realizes the synthesis of the high-purity dextroamphetamine sulfate, has simple and safe reaction process and has good application prospect.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a lisdexamphetamine dimesylate intermediate.
Background
Leisha amphetamine dimesylate, chemical name (2S) -2, 6-amino-N- [ (1S) -1-methyl-2-phenethyl]Caproic acid amine dimethyl sulfonate, molecular formula C 17 H 33 N 3 O 7 S 2 Molecular weight 455.58982, CAS registry number 608137-33-3, is an amphetamine derivative developed by the United kingdom Hitachi (Shire) biopharmaceutical company in cooperation with New River Pharma company. The structure of the lisdexamphetamine dimesylate is shown as follows:
the drug was first marketed in the united states at month 2 of 2007 for the treatment of attention deficit and hyperactivity disorder in children (attention-deficits/hyperactivity disorder ADHD). Currently, lisdexamphetamine dimesylate is the only agonist approved for maintenance therapy in all ADHD patients older than 6 years. The FDA was approved again as a first and only one example of a treatment for moderate to severe binge eating disorder in adults at month 1 of 2015. Therefore, the application prospect of the lisdexamphetamine dimesylate is very wide.
The current synthesis route of the lisdexamphetamine dimesylate is as follows:
the method adopts D-amphetamine as the starting material, and has wide commercial sources, simple process and high production efficiency. Therefore, the synthetic route is the most commonly used synthetic route in the industrial production of the lisdexamphetamine dimesylate at present. In the route, the dextroamphetamine sulfate is an indispensable intermediate substance, so that the improvement of the purity of the dextroamphetamine sulfate can reduce the quality risk of introducing impurities of the dextroamphetamine dimesylate, and improve the safety of finished products; meanwhile, dangerous hydrogenation reduction reaction is avoided in the preparation process of the dextroamphetamine sulfate, and improvement of the safety of the production process is also important for the production of medicines.
Therefore, it is necessary to develop a process for preparing dextroamphetamine sulfate with high purity and low safety risk. The current method for synthesizing the dextroamphetamine sulfate takes propiophenone as a main raw material to synthesize (Li Yongqing, development [ C ] of dextroamphetamine sulfate, paper assembly, fifth edition, 210-218), which has the problems that distillation and purification operation are needed in the process of preparing the intermediate 1 (propiophenone), the operation is troublesome, the control is poor, and the product is easy to degrade, which has adverse effects on the yield and purity of the product, and the yield is only 28.2-31.7%.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of dextroamphetamine sulfate with high purity and low safety risk.
A preparation method of a dimesylate lisdexamphetamine intermediate comprises the following steps:
step 1, reacting a compound A with an active metal under the action of acid to obtain a reaction solution;
step 2, adding concentrated hydrochloric acid into the reaction liquid, reacting, and separating to obtain a compound B;
and 3, carrying out anion replacement reaction on the compound B and sulfuric acid to obtain the dextroamphetamine sulfate.
Preferably, in step 1, the active metal is selected from one or a mixture of two or more of zinc, cadmium, iron, copper, aluminum and chromium; and/or the dosage ratio of the compound A to the active metal is 1: (1-3); and/or the acid is selected from one or a mixture of more than two of acetic acid, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, citric acid, fumaric acid, maleic acid, succinic acid and methanesulfonic acid; and/or, the reaction is carried out under the action of activated carbon; and/or, the temperature of the reaction is 25-60 ℃; and/or the reaction time is 2-6h.
Preferably, the acid is a mixture of concentrated hydrochloric acid and acetic acid, wherein the molar ratio of hydrochloric acid to acetic acid in the mixture is (0.5-5): 10, preferably (0.5-2): 10.
preferably, the solvent of the concentrated hydrochloric acid and acetic acid is selected from one or two or more of tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, toluene, acetonitrile and acetone, preferably at least one of tetrahydrofuran and ethyl acetate, more preferably ethyl acetate.
Preferably, in step 1, the reaction is performed in a solvent a, wherein the solvent a is selected from one or a mixture of two or more of tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, toluene, acetonitrile and acetone.
Preferably, in step 1, the solvent a is at least one of tetrahydrofuran or ethyl acetate or a mixture of two.
Preferably, in step 2, the reaction solution is washed with an aqueous sodium chloride solution before adding concentrated hydrochloric acid.
Preferably, the aqueous sodium chloride solution is prepared by mixing water and saturated sodium chloride solution according to a volume ratio of 1-3:1.
Preferably, in step 2, the specific steps of the separation are as follows: removing the solvent a, adding water for dissolution, adding an organic solvent, adding alkali to adjust the pH of a water layer to 10-14, and concentrating an organic phase to obtain the aqueous phase; the organic solvent is selected from one or more of dichloromethane, dichloroethane, chloroform, toluene, xylene, heptane, octane or sulfonated kerosene, preferably dichloromethane.
Preferably, in the step 2, the temperature of the reaction is 20-40 ℃; and/or the reaction time is 3-7h.
Preferably, in step 3, the specific steps of the anion exchange reaction are as follows: dissolving the compound B in a solvent B, adding sulfuric acid to adjust the pH to be acidic, and separating to obtain a product dextroamphetamine sulfate;
the solvent b is selected from one or a mixture of two or more of absolute ethyl alcohol, ethanol water solution, methanol or methanol water solution; the concentration of the ethanol aqueous solution and the concentration of the methanol aqueous solution are respectively 45-95% in volume fraction.
Preferably, in step 3, the condition of adding sulfuric acid to adjust the pH to an acidic reaction is as follows: the pH is regulated to 5.0-6.0; and/or, the temperature of the reaction is 0-10 ℃; and/or the reaction time is 1-5h.
Preferably, in the step 3, the separation process comprises suction filtration, washing and drying; the washing agent used in the washing process is ethanol, and the drying mode is that the drying is carried out under reduced pressure at 30-50 ℃.
In the invention, the concentration of the concentrated hydrochloric acid is 36-38% (the concentration of substances is 12mol/L; the density is 1.179 g/cm) 3 ) Is an aqueous solution of hydrochloric acid.
The invention provides a new synthetic route of dextroamphetamine sulfate, the yield of the synthesized product can reach 88.94-93.84%, and the purity of the product can reach 99.2-99.8%. Compared with the yield of 28.2-31.7% in the existing synthesis method, the synthesis method has the advantage that the yield is greatly improved. In addition, the dextroamphetamine sulfate obtained by the method has high purity, and the high purity of the intermediate ensures the safety of the finished drug of the lisdexamphetamine dimesylate to a great extent. Meanwhile, the preparation method avoids dangerous hydrogenation reduction reaction and improves the safety of medicine production. Therefore, the invention has good application prospect.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present invention is limited to the following examples only. All techniques implemented based on the above description of the invention are within the scope of the invention.
Drawings
FIG. 1 is a schematic diagram showing the crystal structure calculated after detection of the product prepared in example 1 of the present invention by an Xcalibur Eos diffractometer.
Detailed Description
In the following examples, reagents and materials not specifically described are commercially available.
Example 1
27.00g of tert-butyl (R) -1-iodomethyl-2-phenylpropyl carbamate (0.059 mol) was weighed out, 108ml of ethyl acetate and 27ml of tetrahydrofuran were added, and after stirring and dissolution at room temperature, 0.88g of activated carbon and 8.80g of zinc powder (0.135 mol) were added. A solution of 8.95g acetic acid (0.149 mol) and 1.36g concentrated hydrochloric acid (36% -38% strength aqueous solution, 0.0138 mol) in 27ml ethyl acetate was cooled and stirred for 240min at 50 ℃. Suction filtration, filtrate is washed continuously with a mixed solution of purified water/saturated sodium chloride aqueous solution (2/1). Then, 27ml of concentrated hydrochloric acid was added thereto, and the reaction was stirred at an internal temperature of 30℃for 300 minutes. The reaction solution is decompressed and concentrated at 50 ℃ to remove solvent, purified water is added to be stirred and dissolved, dichloromethane is added to the water layer to be stirred at room temperature, 40 percent sodium hydroxide solution is added dropwise to adjust the pH of the water layer to 10-14. Standing for separating, concentrating the organic layer under reduced pressure to remove dichloromethane, adding absolute ethanol, adding sulfuric acid to adjust pH to 5.0-6.0, and stirring at room temperature for 30min. Cooling to 5deg.C, stirring for 60min, filtering, leaching the filter cake with a small amount of anhydrous ethanol, and draining. The filter cake is transferred into a baking oven, and is dried under reduced pressure at 40 ℃ to obtain 12.40g of dextroamphetamine sulfate with purity of 99.5% and yield of 89.59%.
The product prepared in this example was examined using an Xcalibur Eos diffractometer and its crystallographic parameters were calculated as follows:
β＝95.027(6)°，
Z＝4,
T＝293.15K,
μ(MoKa)＝0.178mm -1 ，
Dcalc＝1.177g/cm 3 。
the crystal structure was solved in Olex2 using the ShelXT program and the package optimized structure was optimized using ShelXL. The results of the crystal structure obtained are shown in FIG. 1.
The calculation result of the structure is consistent with the structural formula of the dextroamphetamine sulfate, which shows that the product synthesized by the embodiment is actually dextroamphetamine sulfate.
Example 2
30.20g of tert-butyl (R) -1-iodomethyl-2-phenylpropyl carbamate (0.066 mol) was weighed out, 150ml of methylene chloride was added, and after stirring and dissolution at room temperature, 0.99g of activated carbon and 9.86g of zinc powder (0.151 mol) were added. A solution of 10.04g of acetic acid (0.167 mol) and 1.51g of concentrated hydrochloric acid (36 to 38% strength aqueous solution, 0.0153 mol) in 30ml of dichloromethane was cooled and added dropwise, and the mixture was stirred at 50℃for 240 minutes. Suction filtration, filtrate is washed continuously with a mixed solution of purified water/saturated sodium chloride aqueous solution (2/1). Then, 30ml of concentrated hydrochloric acid was added thereto, and the reaction was stirred at an internal temperature of 30℃for 300 minutes. The reaction solution is decompressed and concentrated at 50 ℃ to remove solvent, purified water is added to be stirred and dissolved, dichloromethane is added to the water layer to be stirred at room temperature, 40 percent sodium hydroxide solution is added dropwise to adjust the pH of the water layer to 10-14. Standing for separating, concentrating the organic layer under reduced pressure to remove dichloromethane, adding 95% ethanol water solution, adding sulfuric acid to adjust pH to 5.0-6.0, and stirring at room temperature for 30min. Cooling to 5deg.C, stirring for 60min, filtering, leaching the filter cake with a small amount of anhydrous ethanol, and draining. The filter cake is transferred into a baking oven, and is dried under reduced pressure at 40 ℃ to obtain 13.72g of dextroamphetamine sulfate with purity of 99.8% and yield of 88.94%.
Example 3
29.50g of tert-butyl (R) -1-iodomethyl-2-phenylpropyl carbamate (0.065 mol) was weighed out, 120ml of ethyl acetate and 30ml of acetone were added, and after stirring and dissolution at room temperature, 0.45g of activated carbon and 8.91g of zinc powder (0.136 mol) were added. A solution of 8.86g acetic acid (0.148 mol) and 1.35g concentrated hydrochloric acid (36% -38% strength aqueous solution, 0.0137 mol) in 30ml ethyl acetate was cooled and added dropwise, and the mixture was stirred at 45℃for 300min. Suction filtration, filtrate is washed continuously with a mixed solution of purified water/saturated sodium chloride aqueous solution (2/1). Then, 30ml of concentrated hydrochloric acid was added thereto, and the reaction was stirred at an internal temperature of 20℃for 400 minutes. The reaction solution is decompressed and concentrated at 50 ℃ to remove solvent, purified water is added to be stirred and dissolved, dichloromethane is added to the water layer to be stirred at room temperature, 40 percent sodium hydroxide solution is added dropwise to adjust the pH of the water layer to 10-14. Standing for separating, concentrating the organic layer under reduced pressure to remove dichloromethane, adding absolute ethanol, adding sulfuric acid to adjust pH to 5.0-6.0, cooling to 0deg.C, maintaining the temperature and stirring for 300min, vacuum filtering, leaching the filter cake with a small amount of absolute ethanol, and vacuum drying. The filter cake is transferred into a baking oven, and is dried under reduced pressure at 40 ℃ to obtain 13.89g of dextroamphetamine sulfate with purity of 99.4% and yield of 91.77%.
Example 4
31.20g of tert-butyl (R) -1-iodomethyl-2-phenylpropyl carbamate (0.068 mol) was weighed out, 150ml of toluene was added, and after stirring and dissolution at room temperature, 5.72g of activated carbon and 11.45g of zinc powder (0.175 mol) were added. A solution of 11.50g of acetic acid (0.192 mol) and 1.70g of concentrated hydrochloric acid (36-38% strength aqueous solution, 0.0173 mol) in 30ml of toluene was cooled and added dropwise, and the mixture was stirred at 60℃for 360 minutes. Suction filtration, filtrate is washed continuously with a mixed solution of purified water/saturated sodium chloride aqueous solution (2/1). Then, 30ml of concentrated hydrochloric acid was added thereto, and the reaction was stirred at an internal temperature of 40℃for 180 minutes. The reaction solution is decompressed and concentrated at 50 ℃ to remove solvent, purified water is added to be stirred and dissolved, dichloromethane is added to the water layer to be stirred at room temperature, 40 percent potassium hydroxide solution is added dropwise to adjust the pH of the water layer to 10-14. Standing for separating, concentrating the organic layer under reduced pressure to remove dichloromethane, adding anhydrous methanol, adding sulfuric acid to adjust pH to 5.0-6.0, and stirring at room temperature for 30min. Reducing the internal temperature to 5 ℃, preserving heat, stirring for 60min, filtering, leaching the filter cake with a small amount of absolute methanol, and drying. The filter cake is transferred into a baking oven, and is dried under reduced pressure at 40 ℃ to obtain 14.82g of dextroamphetamine sulfate with purity of 99.4% and yield of 92.56%.
Example 5
33.10g of tert-butyl (R) -1-iodomethyl-2-phenylpropyl carbamate (0.073 mol) were weighed out, 170ml of ethyl acetate were added, and after stirring at room temperature for dissolution, 1.32g of activated carbon and 13.22g of zinc powder (0.202 mol) were added. A solution of 13.25g acetic acid (0.221 mol) and 1.88g concentrated hydrochloric acid (36% -38% strength aqueous solution, 0.0191 mol) in 30ml ethyl acetate was added dropwise at an internal temperature, and stirred for 240min at 55 ℃. Suction filtration, filtrate is washed continuously with a mixed solution of purified water/saturated sodium chloride aqueous solution (2/1). Then, 30ml of concentrated hydrochloric acid was added thereto, and the reaction was stirred at an internal temperature of 35℃for 300 minutes. The reaction solution is decompressed and concentrated at 50 ℃ to remove solvent, purified water is added to be stirred and dissolved, dichloromethane is added to the water layer to be stirred at room temperature, 40 percent sodium hydroxide solution is added dropwise to adjust the pH of the water layer to 10-14. Standing for separating, concentrating the organic layer under reduced pressure to remove dichloromethane, adding 45% ethanol water solution, adding sulfuric acid to adjust pH to 5.0-6.0, cooling to 10deg.C, stirring at room temperature for 180min, suction filtering, leaching the filter cake with a small amount of absolute ethanol, and suction drying. The filter cake is transferred into a baking oven, and is dried under reduced pressure at 40 ℃ to obtain 15.28g of dextroamphetamine sulfate with purity of 99.6% and yield of 90.14%.
Example 6
30.91g of tert-butyl (R) -1-iodomethyl-2-phenylpropyl carbamate (0.068 mol) was weighed out, 150ml of acetonitrile was added thereto, and after stirring and dissolution at room temperature, 0.82g of activated carbon and 8.25g of zinc powder (0.126 mol) were further added thereto. A solution of 8.30g acetic acid (0.138 mol) and 1.25g concentrated hydrochloric acid (36% -38% strength aqueous solution, 0.0127 mol) in 30ml acetonitrile was cooled and added dropwise, and the mixture was stirred at 25℃for 360min. Suction filtration, filtrate is washed continuously with a mixed solution of purified water/saturated sodium chloride aqueous solution (2/1). Then, 30ml of concentrated hydrochloric acid was added thereto, and the reaction was stirred at an internal temperature of 25℃for 420 minutes. The reaction solution is decompressed and concentrated at 50 ℃ to remove solvent, purified water is added to be stirred and dissolved, dichloromethane is added to the water layer to be stirred at room temperature, 40 percent sodium hydroxide solution is added dropwise to adjust the pH of the water layer to 10-14. Standing for separating, concentrating the organic layer under reduced pressure to remove dichloromethane, adding absolute ethanol, adding sulfuric acid to adjust pH to 5.0-6.0, cooling to 5deg.C, maintaining the temperature and stirring for 180min, suction filtering, leaching the filter cake with a small amount of absolute ethanol, and suction drying. Transferring the filter cake into a baking oven, drying under reduced pressure at 40 ℃ to obtain 14.91g of dextroamphetamine sulfate with purity of 99.2% and yield of 93.84%.
As can be seen from the above examples, the method provided by the invention can be used for preparing the dextroamphetamine sulfate, the yield can reach 88.94-93.84%, and the product purity can reach 99.2-99.8%. Therefore, the invention realizes the synthesis of the high-purity dextroamphetamine sulfate, and the reaction process is simple and safe, so the invention has good application prospect.
Claims (10)
1. The preparation method of the lisdexamphetamine dimesylate intermediate is characterized by comprising the following steps of:
step 1, reacting a compound A with an active metal under the action of acid to obtain a reaction solution;
step 2, adding concentrated hydrochloric acid into the reaction liquid, reacting, and separating to obtain a compound B;
and 3, carrying out anion replacement reaction on the compound B and sulfuric acid to obtain the dextroamphetamine sulfate.
2. The method of manufacturing according to claim 1, wherein: in the step 1, the active metal is selected from one or a mixture of more than two of zinc, cadmium, iron, copper, aluminum and chromium; and/or the dosage ratio of the compound A to the active metal is 1: (1-3); and/or the acid is selected from one or a mixture of more than two of acetic acid, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, formic acid, citric acid, fumaric acid, maleic acid, succinic acid and methanesulfonic acid; and/or, the reaction is carried out under the action of activated carbon; and/or, the temperature of the reaction is 25-60 ℃; and/or the reaction time is 2-6h.
3. The method of manufacturing according to claim 2, wherein: the acid is a mixture of concentrated hydrochloric acid and acetic acid, wherein the molar ratio of the hydrochloric acid to the acetic acid in the mixture is (0.5-5): 10.
4. the method of manufacturing according to claim 1, wherein: in the step 1, the reaction is carried out in a solvent a, wherein the solvent a is selected from one or a mixture of two or more of tetrahydrofuran, ethyl acetate, dichloromethane, chloroform, toluene, acetonitrile and acetone.
5. The method of manufacturing according to claim 4, wherein: in step 2, the reaction mixture was washed with an aqueous sodium chloride solution before adding concentrated hydrochloric acid.
6. The method of manufacture of claim 5, wherein: in step 2, the specific steps of the separation are as follows: removing the solvent a, adding water for dissolution, adding an organic solvent, adding alkali to adjust the pH of a water layer to 10-14, and concentrating an organic phase to obtain the aqueous phase;
the organic solvent is selected from one or more of dichloromethane, dichloroethane, chloroform, toluene, xylene, heptane, octane or sulfonated kerosene.
7. The method of manufacturing according to claim 1, wherein: in the step 2, the temperature of the reaction is 20-40 ℃; and/or the reaction time is 3-7h.
8. The method of manufacturing according to claim 1, wherein: in the step 3, the specific steps of the anion replacement reaction are as follows: dissolving the compound B in a solvent B, adding sulfuric acid to adjust the pH to be acidic, and separating to obtain a product dextroamphetamine sulfate;
the solvent b is selected from one or a mixture of two or more of absolute ethyl alcohol, ethanol water solution, methanol or methanol water solution; the concentration of the ethanol aqueous solution and the concentration of the methanol aqueous solution are respectively 45-95% in volume fraction.
9. The method of preparing as claimed in claim 8, wherein: in the step 3, the condition of adding sulfuric acid to adjust the pH to be acidic is as follows: the pH is regulated to 5.0-6.0; and/or, the temperature of the reaction is 0-10 ℃; and/or the reaction time is 1-5h.
10. The method of preparing as claimed in claim 8, wherein: in the step 3, the separation process comprises suction filtration, washing and drying; the washing agent used in the washing process is ethanol, and the drying mode is that the drying is carried out under reduced pressure at 30-50 ℃.
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