CN117776955A - Synthetic method of mugwort Fu Nibu and intermediate thereof - Google Patents
Synthetic method of mugwort Fu Nibu and intermediate thereof Download PDFInfo
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- 240000006891 Artemisia vulgaris Species 0.000 title claims abstract description 14
- 235000003261 Artemisia vulgaris Nutrition 0.000 title claims abstract description 14
- 238000010189 synthetic method Methods 0.000 title claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 60
- 238000000034 method Methods 0.000 claims abstract description 21
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 239000004744 fabric Substances 0.000 claims abstract description 14
- YEZADZMMVHWFIY-UHFFFAOYSA-N 4-tert-butylbenzenesulfonyl chloride Chemical compound CC(C)(C)C1=CC=C(S(Cl)(=O)=O)C=C1 YEZADZMMVHWFIY-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 9
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 238000002360 preparation method Methods 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 29
- 238000001914 filtration Methods 0.000 claims description 17
- 238000010992 reflux Methods 0.000 claims description 17
- 238000005406 washing Methods 0.000 claims description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000012065 filter cake Substances 0.000 claims description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000000706 filtrate Substances 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 9
- 230000002194 synthesizing effect Effects 0.000 claims description 9
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 8
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 7
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 7
- LZQMCUIWYRQLOG-UHFFFAOYSA-N 4-tert-butylbenzenesulfonic acid Chemical group CC(C)(C)C1=CC=C(S(O)(=O)=O)C=C1 LZQMCUIWYRQLOG-UHFFFAOYSA-N 0.000 claims description 6
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical group OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical group OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 239000000243 solution Substances 0.000 claims description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 238000001308 synthesis method Methods 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000000543 intermediate Substances 0.000 description 30
- -1 (2R) -2- (2-chlorophenyl) -N- (3, 3-difluoro-cyclobutyl) -2-chloroacetamide Chemical compound 0.000 description 8
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 8
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 8
- 101000960234 Homo sapiens Isocitrate dehydrogenase [NADP] cytoplasmic Proteins 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 230000035772 mutation Effects 0.000 description 5
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- 101001042041 Bos taurus Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial Proteins 0.000 description 4
- 102100039905 Isocitrate dehydrogenase [NADP] cytoplasmic Human genes 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 3
- FKKYFULJVMGLID-SNVBAGLBSA-N ClC1=C(C=CC=C1)[C@H](C(=O)NC1CC(C1)(F)F)O Chemical compound ClC1=C(C=CC=C1)[C@H](C(=O)NC1CC(C1)(F)F)O FKKYFULJVMGLID-SNVBAGLBSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 2
- 206010000830 Acute leukaemia Diseases 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- VLJNHYLEOZPXFW-UHFFFAOYSA-N pyrrolidine-2-carboxamide Chemical compound NC(=O)C1CCCN1 VLJNHYLEOZPXFW-UHFFFAOYSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000306 recurrent effect Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- RWOLDZZTBNYTMS-SSDOTTSWSA-N (2r)-2-(2-chlorophenyl)-2-hydroxyacetic acid Chemical compound OC(=O)[C@H](O)C1=CC=CC=C1Cl RWOLDZZTBNYTMS-SSDOTTSWSA-N 0.000 description 1
- RKATWUBDSJHPEV-UHFFFAOYSA-N 3,3-difluorocyclobutan-1-amine Chemical compound NC1CC(F)(F)C1 RKATWUBDSJHPEV-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- 101000960235 Dictyostelium discoideum Isocitrate dehydrogenase [NADP] cytoplasmic Proteins 0.000 description 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000006990 cholangiocarcinoma Diseases 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- ODBLHEXUDAPZAU-UHFFFAOYSA-N isocitric acid Chemical compound OC(=O)C(O)C(C(O)=O)CC(O)=O ODBLHEXUDAPZAU-UHFFFAOYSA-N 0.000 description 1
- WIJZXSAJMHAVGX-DHLKQENFSA-N ivosidenib Chemical compound FC1=CN=CC(N([C@H](C(=O)NC2CC(F)(F)C2)C=2C(=CC=CC=2)Cl)C(=O)[C@H]2N(C(=O)CC2)C=2N=CC=C(C=2)C#N)=C1 WIJZXSAJMHAVGX-DHLKQENFSA-N 0.000 description 1
- 229950010738 ivosidenib Drugs 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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 synthetic method of mugwort Fu Nibu and an intermediate thereof; the synthesis method of the Ai Funi cloth intermediate comprises the following steps: taking a compound shown in a formula I as a raw material, and reacting with any one of p-tert-butylbenzenesulfonyl chloride, benzenesulfonyl chloride and trifluoro-sulfonic anhydride in a solvent in the presence of alkali to obtain an intermediate compound shown in a formula II; the synthetic route is as follows:the method has the advantages of milder reaction conditions during the preparation of the intermediate, simple and convenient post-treatment and high production efficiency, can effectively control the generation of S-type isomer, and provides great convenience for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a synthetic method of mugwort Fu Nibu and an intermediate thereof.
Background
Acute Myelogenous Leukemia (AML) is the most common acute leukemia in adults, with poor post-healing R/R AML, with five-year survival rates of about 27%. For 6-10% of AM L patients, IDH1 enzyme mutations block normal blood stem cell differentiation, leading to the development of acute leukemia.
On 7 and 20 2018, cancer biopharmaceutical company Agios Pharmaceuticals announced that its anticancer drug Ivosidenib (trade name tibsosov (Ai Funi cloth)) was approved by the us FDA for recurrent or refractory acute myeloid leukemia (R/R AML) adult patients with the presence of a susceptible isocitrate dehydrogenase-1 (IDH 1) mutation. Tibsosov is an oral targeted inhibitor against IDH1 enzyme, and is the first and only drug to be approved by the FDA for the treatment of IDH1 mutant R/R AML.
Ai Funi is a revolutionary targeted drug that has been approved by the FDA in the united states for three indications:
is used for treating adult recurrent or refractory acute myeloid leukemia patients carrying IDH1 susceptible mutation by single drug;
acute myelogenous leukemia with a susceptible IDH1 mutation for use in combination with azacitidine in new diagnosis, detected by FDA approved assays in adults 75 years old or older, or patients with complications excluding the use of intensive induction chemotherapy;
is used for the adult patients with the locally advanced or metastatic cholangiocarcinoma, which have been treated in the past and carry IDH1 mutation detected by the FDA batch detection method.
Currently, the synthetic route for Ai Funi cloth is as follows:
in the route, R- (-) -o-chloromandelic acid is reacted with 3, 3-difluoro-cyclobutylamine to obtain a compound (2R) -2- (2-chlorophenyl) -N- (3, 3-difluoro-cyclobutyl) -2-hydroxyacetamide, and then the compound is reacted with thionyl chloride to generate (2R) -2- (2-chlorophenyl) -N- (3, 3-difluoro-cyclobutyl) -2-chloroacetamide, and then the compound is used for preparing Ai Funi cloth; however, thionyl chloride restricts industrial mass production, and a certain amount of S-type isomer is also generated in the product.
Therefore, there is a need to develop other more optimal synthetic methods to produce Ai Funi cloths and their intermediates.
Disclosure of Invention
In order to solve the technical problems, the invention aims to provide a synthesis method of mugwort Fu Nibu and an intermediate thereof, which has milder reaction conditions when preparing the intermediate, simple and convenient post-treatment and high production efficiency, can effectively control the generation of S-type isomer and provides great convenience for industrial production.
In order to achieve the technical purpose and the technical effect, the invention is realized by the following technical scheme:
the invention provides a synthesis method of a mugwort Fu Nibu intermediate, which comprises the steps of taking a compound shown in a formula I as a raw material, and reacting the compound with any one of p-tert-butylbenzenesulfonyl chloride, benzenesulfonyl chloride and trifluoro-sulfonic anhydride in a solvent in the presence of alkali to obtain an intermediate compound shown in a formula II;
the synthetic route is as follows:
wherein, in the formula II, R is one of trifluoromethyl sulfonic acid group, benzene sulfonic acid group and p-tert-butyl benzene sulfonic acid group.
Further, the feeding mole ratio of the compound shown in the formula I to any one of p-tert-butylbenzenesulfonyl chloride, benzenesulfonyl chloride and trifluoro-sulfonic anhydride is 1: (1.5-1.8); the molar ratio of the alkali to the compound shown in the formula I is 3:1.
further, the base is triethylamine.
Further, the solvent is at least one of dichloromethane, tetrahydrofuran and 2-methyltetrahydrofuran.
Further, in the above synthesis method, the reaction is carried out at room temperature for 16 to 20 hours.
Another aspect of the present invention provides a method for synthesizing mugwort Fu Nibu, comprising the steps of
(1) Taking a compound shown in a formula I as a raw material, and reacting with any one of p-tert-butylbenzenesulfonyl chloride, benzenesulfonyl chloride and trifluoro-sulfonic anhydride in a solvent in the presence of alkali to obtain an intermediate compound shown in a formula II;
(2) Reacting an intermediate compound shown in a formula II with a compound shown in a formula III in the presence of cesium carbonate to prepare Ai Funi cloth shown in a formula IV;
the synthetic route is as follows:
wherein, in the formula II, R is one of trifluoromethyl sulfonic acid group, benzene sulfonic acid group and p-tert-butyl benzene sulfonic acid group.
Further, the molar ratio of the intermediate compound represented by formula II to the compound represented by formula III is (1.3-1.5): 1.
further, the molar ratio of the intermediate compound shown in the formula II to cesium carbonate is 1: (1.5-1.6).
Further, in the above method, the compound represented by formula III is added to the intermediate compound represented by formula II and then heated to reflux for 14 to 18 hours.
Further, after the reaction of the intermediate compound shown in the formula II and the compound shown in the formula III is finished, the following post-treatment process is carried out: filtering the reacted materials, washing a filter cake, concentrating the filtrate to dryness to obtain an oily crude product, dissolving the oily crude product, adding sodium bicarbonate solution, stirring, separating liquid, washing with saturated brine, adding active carbon, heating for refluxing, filtering, washing a filter cake cleanly, concentrating the filtrate, heating to reflux, adding an organic solvent to separate out solid, cooling, stirring, filtering, washing the filter cake again, and drying to obtain the Ai Funi cloth intermediate.
The beneficial effects of the invention are as follows:
the invention synthesizes the intermediate compound shown in the formula II which is different from the traditional method by adopting a novel synthesis method, the synthesis method of the intermediate compound has milder reaction conditions, simple and convenient post-treatment, can effectively control the generation of S-type isomer, and provides great convenience for industrial production.
The synthesis method disclosed by the invention is simple to operate, low in production cost, high in production efficiency, high in purity of the obtained product, suitable for mass production and capable of meeting market demands.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of the product obtained in example 1 of the present invention.
Detailed Description
The following description of the embodiments of the present invention will be made more apparent and fully by reference to the accompanying drawings, in which it is shown, by way of illustration, only some, but not all embodiments of the invention. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention provides a synthesis method of a mugwort Fu Nibu intermediate, which takes a compound shown in a formula I as a raw material to react with any one of p-tert-butylbenzenesulfonyl chloride, benzenesulfonyl chloride and trifluoro-sulfonic anhydride in a solvent in the presence of alkali to obtain an intermediate compound shown in a formula II;
the synthetic route is as follows:
wherein, in the formula II, R is one of trifluoromethyl sulfonic acid group, benzene sulfonic acid group and p-tert-butyl benzene sulfonic acid group.
In the method, the feeding mole ratio of the compound shown in the formula I to any one of p-tert-butylbenzenesulfonyl chloride, benzenesulfonyl chloride and trifluoro-sulfonic anhydride is 1: (1.5-1.8); the molar ratio of the alkali to the compound shown in the formula I is 3:1.
in the above method, the base is preferably triethylamine.
In the above method, the solvent is preferably at least one of dichloromethane, tetrahydrofuran, and 2-methyltetrahydrofuran.
In the above synthesis method, the reaction is carried out at room temperature for 16-20 hours.
The invention further provides a synthesis method of the mugwort Fu Nibu, which comprises the following steps of
(1) The intermediate compound shown in the formula II is synthesized by adopting the synthesis method of the Ai Funi cloth intermediate, and specifically comprises the following steps: taking a compound shown in a formula I as a raw material, and reacting with any one of p-tert-butylbenzenesulfonyl chloride, benzenesulfonyl chloride and trifluoro-sulfonic anhydride in a solvent in the presence of alkali to obtain a compound shown in a formula II;
(2) Reacting an intermediate compound shown in a formula II with a compound shown in a formula III in the presence of cesium carbonate to prepare Ai Funi cloth shown in a formula IV;
the synthetic route is as follows:
wherein, in the formula II, R is one of trifluoromethyl sulfonic acid group, benzene sulfonic acid group and p-tert-butyl benzene sulfonic acid group.
In the above method, the molar ratio of the intermediate compound represented by formula II to the compound represented by formula III is (1.3-1.5): 1.
the feeding mole ratio of the intermediate compound shown in the formula II to cesium carbonate is 1: (1.5-1.6).
In the above method, the compound of formula III is added to the intermediate compound of formula II and then heated to reflux for 14-18 hours.
After the reaction of the intermediate compound shown in the formula II and the compound shown in the formula III is finished, the following post-treatment process is carried out: filtering the reacted materials, washing a filter cake, concentrating the filtrate to dryness to obtain an oily crude product, dissolving the oily crude product, adding sodium bicarbonate solution, stirring, separating liquid, washing with saturated brine, adding active carbon, heating for refluxing, filtering, washing a filter cake cleanly, concentrating the filtrate, heating to reflux, adding an organic solvent to separate out solid, cooling, stirring, filtering, washing the filter cake again, and drying to obtain the Ai Funi cloth intermediate.
The invention is further illustrated by the following examples.
Example 1
Step (1): a1000 ml dry three-neck flask was charged with 55.1g (0.2 mol) of the compound (2R) -2- (2-chlorophenyl) -N- (3, 3-difluorocyclobutyl) -2-hydroxyacetamide represented by formula I, 60.7g (0.6 mol) of triethylamine, 440ml of methylene chloride, stirring at room temperature for 15 minutes, adding ice-salt bath to cool down to about 10℃to begin to drop 69.9g (0.3 mol) of p-tert-butylbenzenesulfonyl chloride, controlling the temperature to 10-25℃to complete the system without raising the temperature, removing ice-salt bath after the system is completed to raise the temperature to 16-20 hours, TLC monitoring the completion of the reaction (DCM: 30:1), cooling down again to 0℃with ice-salt bath, adding 500ml of aqueous sodium bicarbonate (mass fraction 3%) to quench the reaction, stirring for 15 minutes, separating the aqueous layer, extracting 1-2 times with DCM, combining the organic layers, washing 1 time with saturated brine, adding anhydrous magnesium sulfate to the organic layer, filtering, concentrating the filtrate to obtain 85.3g (intermediate compound represented by formula II), 96.3%, purity of 98.6% EE, purity of which is 90.90%.
Step (2): a1000 ml three-necked flask was charged with 42.3g (0.13 mol) of an intermediate compound (2S) -1- (4-cyanopyridin-2-yl) -N- (5-fluoropyridin-3-yl) -5-oxosubunit tetrahydropyrrole-2-carboxamide of formula II, 65.2g (0.2 mol) of cesium carbonate was added, 400ml of THF was added, the mixture was replaced with 3 times of nitrogen gas, slightly bubbled, the temperature was raised to 45℃and stirred for 1 hour, a solution (47.2 g/100 ml) of a compound (2R) -2- (2-chlorophenyl) -N- (3, 3-difluorocyclobutyl) -2- ({ dimethyl [4- (2-methylpropan-2-yl) phenyl ] - λ6-thio } oxy) acetamide of formula III (0.1 mol) was added dropwise at 40-45℃and the completion of the dropwise addition was raised to 66℃under reflux, reflux reaction for 14-18 hours, sampling HPLC monitoring, reaction completion, cooling to room temperature, filtering, washing a filter cake with THF, concentrating the filtrate to dryness to obtain 50g of oily crude product, dissolving in 400ml of dichloromethane, adding 400ml of sodium bicarbonate aqueous solution (mass fraction 10%), stirring for 30 minutes, separating liquid, washing an organic layer with saturated brine, adding 5g of active carbon, heating and refluxing for 1 hour, filtering, washing the filter cake cleanly, concentrating the filtrate to 100ml, heating to reflux, adding 100ml of N-heptane, precipitating solid, cooling, stirring at 15 ℃ for 8 hours, filtering, washing the filter cake with N-heptane, drying to obtain Ai Funi cloth compound shown in formula IV, which is 37.2g in total, purity 99.3% and yield 63.8%. The nuclear magnetic pattern of the Ai Funi cloth compound of example 1 is shown in fig. 1, and the data are as follows:
H NMR(400MHz,DMSO):
δ8.91(m,1H)，8.68-8.52(m,4H)，7.66-7.55(m,2H)，7.34-7.14(m,4H)，6.88-6.91(m,1H)，6.37(m,1H)，4.67(m,1H)，4.06(m,1H)，2.93-2.03(m,8H)。
example 2
Step (1): 3kg (10.9 mol) of the compound (2R) -2- (2-chlorophenyl) -N- (3, 3-difluorocyclobutyl) -2-hydroxyacetamide shown in the formula I and 3.33kg (32.6 mol) of triethylamine are added into a 50L clean reaction kettle, 24L of dichloromethane is stirred at room temperature for 30 minutes, an ice maker is cooled to about 10 ℃, 3.80kg (16.3 mol) of p-tert-butylbenzenesulfonyl chloride is started to be dropwise added, the temperature is controlled to be 10-25 ℃, the system is not warmed up, the temperature is closed and reduced after the dropwise addition is completed, the reaction is heated to the room temperature for 16-20 hours, TLC monitors the completion of the reaction (DCM: meOH=30:1), the reaction is cooled to 0 ℃ again, 20L of sodium bicarbonate aqueous solution (mass fraction 3%) is added for quenching the reaction, the reaction is stirred for 30 minutes, a water layer is extracted for 1-2 times by DCM, an organic layer is combined, saturated brine is washed for 1 time, anhydrous magnesium sulfate is added into the organic layer, filtration is filtered, and filtrate is concentrated to obtain 4.75kg of oily substance shown in the formula II, the intermediate compound with the purity value of 98.1%, and the EE value of 92.5%.
Step (2): 2.24kg (6.89 mol) of the intermediate compound (2S) -1- (4-cyanopyridin-2-yl) -N- (5-fluoropyridin-3-yl) -5-oxosubunit tetrahydropyrrole-2-carboxamide of formula II, 3.45kg (10.60 mol) of cesium carbonate, 22L of THF were added, the mixture was replaced 3 times with nitrogen, slightly bubbled, heated to 45℃and stirred for 1 hour, a solution (2.5 kg/10L) of the compound (2R) -2- (2-chlorophenyl) -N- (3, 3-difluorocyclobutyl) -2- ({ dimethyl-idene [4- (2-methylpropan-2-yl) phenyl ] - λ6-thio } oxy) acetamide (5.30 mol) of formula III was added dropwise, after the dripping is finished, the mixture is heated to 66 ℃ (reflux), reflux reaction is carried out for 14-18 hours, sampling HPLC monitoring is carried out, the mixture is cooled to room temperature, filtration is carried out, a filter cake is washed by THF, the filtrate is concentrated to dryness, 3kg of oily crude product is obtained, the oily crude product is dissolved in 20L of dichloromethane, 20L of sodium bicarbonate aqueous solution (mass fraction 10%) is added, stirring is carried out for 30 minutes, liquid separation is carried out, an organic layer is washed by saturated brine, 200g of active carbon is added, heating reflux is carried out for 1 hour, filtration is carried out, the filter cake is washed cleanly, the filtrate is concentrated to 5L, heating reflux is carried out, 5L of N-heptane is added, solid is separated, cooling is carried out, stirring is carried out for 16 hours at 15 ℃, filtration is carried out, the filter cake is washed by N-heptane, and drying is carried out to obtain Ai Funi cloth compound shown in IV, 2.03kg, purity 99.4% and yield 65.7%.
The foregoing description is only illustrative of the present invention and is not intended to limit the scope of the invention, and all modifications or equivalent arrangements using the teachings of this invention, or direct or indirect application in other related arts, are included within the scope of this invention.
Claims (10)
1. A synthetic method of a mugwort Fu Nibu intermediate is characterized in that a compound shown in a formula I is taken as a raw material to react with any one of p-tert-butylbenzenesulfonyl chloride, benzenesulfonyl chloride and trifluoro-sulfonic anhydride in a solvent in the presence of alkali to obtain an intermediate compound shown in a formula II;
the synthetic route is as follows:
wherein, in the formula II, R is one of trifluoromethyl sulfonic acid group, benzene sulfonic acid group and p-tert-butyl benzene sulfonic acid group.
2. The method for synthesizing the moxa Fu Nibu intermediate according to claim 1, wherein the molar ratio of the compound represented by the formula i to any one of p-tert-butylbenzenesulfonyl chloride, benzenesulfonyl chloride and trifluoro-sulfonic anhydride is 1: (1.5-1.8); the molar ratio of the alkali to the compound shown in the formula I is 3:1.
3. the method for synthesizing an intermediate of mugwort Fu Nibu according to claim 1, wherein said base is triethylamine.
4. The method for synthesizing an intermediate of moxa Fu Nibu according to claim 1, wherein the solvent is at least one of dichloromethane, tetrahydrofuran and 2-methyltetrahydrofuran.
5. The method for synthesizing an intermediate of mugwort Fu Nibu according to claim 1, wherein the reaction is performed at room temperature for 16-20 hours.
6. A process for the synthesis of mugwort Fu Nibu, characterized in that an intermediate compound of formula ii is prepared according to the preparation process of any one of claims 1 to 5; reacting an intermediate compound shown in a formula II with a compound shown in a formula III in the presence of cesium carbonate to prepare Ai Funi cloth shown in a formula IV;
the synthetic route is as follows:
wherein, in the formula II, R is one of trifluoromethyl sulfonic acid group, benzene sulfonic acid group and p-tert-butyl benzene sulfonic acid group.
7. The method for synthesizing moxa Fu Nibu according to claim 6, wherein the molar ratio of the intermediate compound represented by formula ii to the compound represented by formula iii is (1.3-1.5): 1.
8. the method for synthesizing mugwort Fu Nibu according to claim 6, wherein the molar ratio of the intermediate compound of formula II to cesium carbonate is 1: (1.5-1.6).
9. The method for synthesizing moxa Fu Nibu according to claim 6, wherein the intermediate compound of formula II is added with the compound of formula III and then heated to reflux for 14 to 18 hours.
10. The method for synthesizing an intermediate of moxa Fu Nibu according to claim 6, wherein the reaction of the intermediate compound represented by formula ii with the compound represented by formula iii is completed by the following post-treatment process: filtering the reacted materials, washing a filter cake, concentrating the filtrate to dryness to obtain an oily crude product, dissolving the oily crude product, adding sodium bicarbonate solution, stirring, separating liquid, washing with saturated brine, adding active carbon, heating for refluxing, filtering, washing a filter cake cleanly, concentrating the filtrate, heating to reflux, adding an organic solvent to separate out solid, cooling, stirring, filtering, washing the filter cake again, and drying to obtain the Ai Funi cloth intermediate.
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