CN119060059A - A preparation process of rituximab tosylate - Google Patents
A preparation process of rituximab tosylate Download PDFInfo
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- 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 47
- 229960004641 rituximab Drugs 0.000 title claims abstract 5
- 238000002360 preparation method Methods 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 138
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- 238000000034 method Methods 0.000 claims abstract description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 69
- 239000000243 solution Substances 0.000 claims description 56
- 238000003756 stirring Methods 0.000 claims description 48
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 32
- 239000007787 solid Substances 0.000 claims description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- 239000012065 filter cake Substances 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 239000012074 organic phase Substances 0.000 claims description 21
- 238000005406 washing Methods 0.000 claims description 21
- 238000010438 heat treatment Methods 0.000 claims description 20
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 16
- 229960000583 acetic acid Drugs 0.000 claims description 16
- 239000012362 glacial acetic acid Substances 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000012046 mixed solvent Substances 0.000 claims description 14
- 239000003208 petroleum Substances 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 238000001914 filtration Methods 0.000 claims description 11
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 9
- 238000010791 quenching Methods 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- -1 sodium triacetoxyborohydride Chemical compound 0.000 claims description 8
- 239000012141 concentrate Substances 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YONLFQNRGZXBBF-ZIAGYGMSSA-N (2r,3r)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@@H](C(=O)O)[C@@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-ZIAGYGMSSA-N 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 238000010898 silica gel chromatography Methods 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 3
- ZDGGJQMSELMHLK-UHFFFAOYSA-N m-Trifluoromethylhippuric acid Chemical compound OC(=O)CNC(=O)C1=CC=CC(C(F)(F)F)=C1 ZDGGJQMSELMHLK-UHFFFAOYSA-N 0.000 claims description 3
- 230000001376 precipitating effect Effects 0.000 claims description 3
- 239000012321 sodium triacetoxyborohydride Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 4
- 238000010828 elution Methods 0.000 claims 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 2
- 235000017550 sodium carbonate Nutrition 0.000 claims 2
- 239000002244 precipitate Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 15
- 238000003786 synthesis reaction Methods 0.000 abstract description 15
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 238000007112 amidation reaction Methods 0.000 abstract description 3
- 150000001408 amides Chemical class 0.000 abstract description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 abstract description 3
- 238000004440 column chromatography Methods 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 125000003277 amino group Chemical group 0.000 abstract 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 17
- 230000000171 quenching effect Effects 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 230000036632 reaction speed Effects 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 208000004631 alopecia areata Diseases 0.000 description 4
- 238000002386 leaching Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- YOZLVAFWYLSRRN-VZXYPILPSA-N C[C@H]1CC[C@H](CN1C(=O)C=C)NC2=NC=NC3=C2C=CN3.CC1=CC=C(C=C1)S(=O)(=O)O Chemical compound C[C@H]1CC[C@H](CN1C(=O)C=C)NC2=NC=NC3=C2C=CN3.CC1=CC=C(C=C1)S(=O)(=O)O YOZLVAFWYLSRRN-VZXYPILPSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 1
- 102000042838 JAK family Human genes 0.000 description 1
- 102000006500 Janus Kinase 3 Human genes 0.000 description 1
- 108010019421 Janus Kinase 3 Proteins 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940042040 innovative drug Drugs 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及一种甲苯磺酸利特昔替尼的制备工艺。本发明所述制备工艺的原料经过羰基与氨基的酰胺化反应，酰胺被还原后经过L‑DBTA拆分需要的手性化合物，最后与对甲基磺酸成盐得到目标化合物。本发明所述的制备工艺，其使用可获得的一个手性异构体的原料进行合成，避免了现有技术方法中的两次手性色谱柱拆分，具有更好的经济性，另外，使用的拆分剂L‑DBTA价格低廉、试剂易得，避免昂贵试剂；反应温和、操作安全、拆分安全性高；避免柱层析纯化，利于工业化生产。The present invention relates to a preparation process of rituximab tosylate. The raw materials of the preparation process of the present invention are subjected to an amidation reaction of a carbonyl group and an amino group, and the amide is reduced and then subjected to L-DBTA splitting of the required chiral compound, and finally the target compound is obtained by salification with p-toluenesulfonic acid. The preparation process of the present invention uses an available raw material of a chiral isomer for synthesis, avoiding the two chiral chromatographic column splitting in the prior art method, and has better economy. In addition, the splitting agent L-DBTA used is low in price and the reagent is easy to obtain, avoiding expensive reagents; the reaction is mild, the operation is safe, and the splitting safety is high; column chromatography purification is avoided, which is conducive to industrial production.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to a preparation process of Li Texi tenib tosylate.
Background
Toluene sulfonic acid Li Texi tinib (Ritlecitinib Tosylate) is a novel oral targeted Janus kinase 3 (JAK 3) inhibitor, and can effectively block the activity of signal molecules and immune cells, and the signal molecules and the immune cells are considered to be the causes of alopecia areata. The American-type FDA approval innovative drug, namely, li Texi Tenib capsule (trade name: LITFULO), was marketed by the American-type Buddha company, month 6, 2023, 23, and was used for treating severe alopecia areata in people 12 years old and older. In the area of alopecia areata treatment, this is the second FDA approved targeted immunosuppressant and is the only treatment for adolescents with severe alopecia areata.
The chemical name of the toluene sulfonic acid Li Texi tenib is 1- { (2S, 5R) -2-methyl-5- [ (7H-pyrrolo [2,3-d ] pyrimidine-4-yl) amino ] piperidin-1-yl } prop-2-en-1-one 4-methylbenzene-1-sulfonic acid, and the chemical structural formula is shown in formula I:
however, the current preparation process for toluene sulfonic acid Li Texi tinib still needs to be improved.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the related art to some extent. Therefore, an object of the present invention is to provide a process for preparing the compound toluene sulfonic acid Li Texi tinib shown in formula I. Compared with the prior art, the method has the advantages that the steps of the route are shortened, and the reaction is 3 steps. The method comprises the steps of carrying out amidation reaction on carbonyl and amino on raw materials, carrying out L-DBTA resolution on amide after amide is reduced, and finally salifying with p-methylsulfonic acid to obtain a target compound.
In one aspect of the invention, the invention provides a preparation process of a compound toluene sulfonic acid Li Texi tinib shown in formula I. According to an embodiment of the invention, the preparation process comprises:
(1) Contacting a compound represented by formula 1 with a compound represented by formula 2, glacial acetic acid, naBH (OAc) 3 to obtain a compound represented by formula 3;
(2) Contacting a compound represented by formula 3 with L-DBTA to obtain a compound represented by formula 4;
(3) Contacting the compound shown in the formula 4 with p-toluenesulfonic acid to obtain the compound toluene sulfonic acid Li Texi tinib shown in the formula I,
The inventor discovers that the target product toluene sulfonic acid Li Texi tinib can be successfully synthesized and prepared by taking the compound shown in the formula 1 and the compound shown in the formula 2 as starting materials through 3 steps of reactions.
The term "contacting" as used herein is to be understood in a broad sense and may be any manner that enables at least two reactants to react chemically, for example by mixing the two reactants under appropriate conditions. The reactants to be contacted may be mixed under stirring as needed, and thus the type of stirring is not particularly limited, and for example, mechanical stirring, that is, stirring under the action of mechanical force, may be used.
The terms "first," "second," and the like herein are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. In the description of the present invention, the meaning of "a plurality" is two or more, unless explicitly defined otherwise.
According to embodiments of the present invention, the above-described method for preparing the compound represented by formula 3, the compound represented by formula 4, and the compound represented by formula I may further have at least one of the following additional technical features:
According to embodiments of the present invention, the chemical reactions described herein may be performed according to any method known in the art. The source of the starting materials for the compound of formula 3, the compound of formula 4, and the compound of formula I is not particularly limited, and may be prepared by any known method or commercially available.
According to an embodiment of the present invention, in the step (1), the contact manner of the compound represented by formula 1 with the compound represented by formula 2, glacial acetic acid, naBH (OAc) 3 is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 1 with the compound shown in the formula 2, glacial acetic acid and NaBH (OAc) 3 can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 3 by using the method is further improved.
According to the embodiment of the invention, in the step (1), the method comprises the steps of maintaining the temperature at 5-12 ℃, adding a compound shown in a formula 1, a compound shown in a formula 2 and glacial acetic acid into 1, 2-dichloroethane, stirring the mixture for 10 hours at the temperature of 8-10 ℃, then adding sodium triacetoxyborohydride (NaBH (OAc) 3) into the reaction solution, heating the mixture to 32-40 ℃ for 4 hours, cooling the reaction solution to room temperature, quenching the reaction solution, adding a saturated ammonium chloride solution, adding a 1M aqueous solution of NaOH for washing, adding ethyl acetate for extraction for 2 times, mixing the organic phases, adding saturated brine for washing, drying the organic phases, concentrating the organic phases under reduced pressure, purifying the concentrate by using a petroleum ether/ethyl acetate mixed solvent through silica gel column chromatography, and obtaining the compound shown in the formula 3. Therefore, the efficiency of the contact reaction of the compound shown in the formula 1 with the compound shown in the formula 2, glacial acetic acid and NaBH (OAc) 3 can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 3 by using the method is further improved.
According to the embodiment of the invention, in the step (1), the molar ratio of the compound shown in the formula 1 to the compound shown in the formula 2, glacial acetic acid and NaBH (OAc) 3 is 1 (1.0-1.15): 1.0 (1.3-1.6), and the molar ratio of the compound shown in the formula 1 to the compound shown in the formula 2, glacial acetic acid and NaBH (OAc) 3 is 1:1.05:1.0:1.4. Thereby, the efficiency of preparing the compound represented by formula 3 using this method can be further improved.
According to an embodiment of the present invention, in step (1), the reaction is preferably carried out at 36℃for 4 hours.
According to the embodiment of the invention, in the step (1), the volume ratio of the petroleum ether/ethyl acetate mixed solvent is 1 (6-10), and preferably the volume ratio of the petroleum ether/ethyl acetate mixed solvent is 1:8.
According to one embodiment of the present invention, in step (1), comprising the steps of maintaining at 5 ℃ to 12 ℃ and heating to 36 ℃ for 4 hours, quenching the reaction solution to room temperature, adding saturated ammonium chloride solution (20 mL), then adding 1M aqueous NaOH solution (150 mL) for washing, adding ethyl acetate for extraction 2 times (150 mL each time), adding 150mL of saturated brine after combining organic phases, drying anhydrous sodium sulfate, concentrating the organic phases under reduced pressure, using petroleum ether/ethyl acetate mixed solvent with volume ratio of 1:8, and purifying the mixture to obtain the silica gel of the formula 21.80%, wherein the temperature is maintained at 5 ℃ to 12 ℃, the compound of formula 1 (16.72 g,0.10 mol), the glacial acetic acid (6.0.10 mL) is added to 1, 2-dichloroethane (200 mL), the temperature is maintained at 8 ℃ to 10 hours, naBH (OAc) 3:35 (29.67 g,0.14 mol) is added to the reaction solution, the reaction solution is cooled to room temperature, saturated ammonium chloride solution (20 mL) is added, then 1M aqueous NaOH solution (150 mL) is added, ethyl acetate is extracted 2 times (150 mL each time), 150mL of saturated brine is added, anhydrous sodium sulfate is dried, the organic phase is concentrated under reduced pressure, the petroleum ether/ethyl acetate is mixed solvent with volume ratio of ethyl acetate, and the silica gel is purified, and the yield of the compound of the formula 21.80.80% is obtained.
According to an embodiment of the present invention, in the step (2), the contact manner of the compound represented by formula 3 with L-DBTA is not particularly limited. Therefore, the contact reaction efficiency of the compound shown in the formula 3 and the L-DBTA can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 4 by using the method is further improved.
According to the embodiment of the invention, in the step (2), the method comprises the steps of adding methanol into a reaction bottle filled with a compound shown in a formula 3 and (-) -dibenzoyl-L-tartaric acid (L-DBTA), stirring and dissolving, heating and heating to reflux state, stirring and reacting for 10-12 hours, observing that a large amount of solids are separated out from the solution, cooling the reaction solution to the room temperature, crystallizing and stirring for 2 hours, filtering, adding methanol into a filter cake for leaching, adding dichloromethane and 5% Na 2CO3 solution, stirring and dissolving, separating the solution, adding saturated saline water into an organic phase for washing, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a solid, namely the compound shown in the formula 4. Therefore, the contact reaction efficiency of the compound shown in the formula 3 and the L-DBTA can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula 4 by using the method is further improved.
According to the embodiment of the invention, in the step (2), the molar ratio of the compound shown in the formula 3 to the L-DBTA is 1 (0.6-0.7), and preferably the molar ratio of the compound shown in the formula 3 to the L-DBTA is 1:0.65. Thereby, the efficiency of preparing the compound represented by formula 4 using this method can be further improved.
According to an embodiment of the present invention, in step (2), it is preferable that the reaction time is 11 hours when heated to a reflux state and stirred.
According to one embodiment of the present invention, in the step (2), the method comprises the steps of adding 200mL of methanol to a reaction flask containing the compound represented by formula 3 (18.90 g,66.24 mmol) and (-) -dibenzoyl-L-tartaric acid (L-DBTA) (15.43 g,43.06 mmol) at room temperature, stirring and dissolving, heating to reflux, stirring and reacting for 11 hours, observing that a large amount of solids are precipitated in the solution, cooling the reaction solution to room temperature, crystallizing and stirring for 2 hours, filtering, adding 20mL of methanol to the filter cake, eluting, adding 150mL of dichloromethane and 150mL of 5% Na 2CO3 solution, stirring and dissolving, separating the solution, adding 150mL of saturated saline water to the organic phase, drying over anhydrous sodium sulfate, concentrating under reduced pressure, and obtaining the solid, namely the compound represented by formula 4, wherein the amount of 8.30g, purity of 98.4%, ee >98.5%, and yield of 43.9% are obtained.
According to an embodiment of the present invention, in step (3), the manner of contacting the compound represented by formula 4 with p-toluenesulfonic acid is not particularly limited. Therefore, the efficiency of the contact reaction of the compound shown in the formula 4 and the p-toluenesulfonic acid can be improved, the reaction speed is increased, and the efficiency of preparing the compound shown in the formula I by using the method is further improved.
According to the embodiment of the invention, in the step (3), the method comprises the steps of dissolving a compound shown in a formula 4 in an organic solvent C at room temperature, slowly dropwise adding p-toluenesulfonic acid, keeping the room temperature and stirring for 1 hour, precipitating a large amount of solid, filtering the solid, washing a filter cake with a proper amount of ethylene glycol dimethyl ether, recrystallizing with methanol, and drying the filtered filter cake in vacuum to obtain the compound shown in the formula I, namely the toluenesulfonic acid Li Texi tinib. Therefore, the contact reaction efficiency of the compound shown in the formula 4 and the p-toluenesulfonic acid can be improved, the reaction speed is increased, and the preparation efficiency of the compound shown in the formula I, namely the toluenesulfonic acid Li Texi tinib by using the method is further improved.
According to the embodiment of the invention, in the step (3), the molar ratio of the compound shown in the formula 4 to the p-toluenesulfonic acid is 1 (1.05-1.2), and preferably the molar ratio of the compound shown in the formula 4 to the p-toluenesulfonic acid is 1:1.1. Thus, the efficiency of preparing the compound of formula I using this method can be further improved.
According to an embodiment of the present invention, in step (3), the organic solvent C is at least one selected from ethanol, acetone, or tetrahydrofuran.
According to one embodiment of the present invention, in the step (3), there is included the steps of dissolving the compound represented by the formula 4 (2.9 g,10.16 mmol) in 30mL of ethanol at room temperature, slowly dropping p-toluenesulfonic acid (1.93 g,11.20 mmol), stirring at room temperature for 1 hour, precipitating a large amount of solid, filtering the solid, washing the filter cake with an appropriate amount of ethylene glycol dimethyl ether, then recrystallizing with 10mL of methanol, and vacuum drying the filter cake after filtration to obtain the compound toluene sulfonic acid Li Texi tinib represented by the formula I, yield 3.96g, yield 85.2%, HPLC purity 99.8%.
According to a specific embodiment of the present invention, the synthetic route for the compound toluene sulfonic acid Li Texi tinib of formula I can be as follows:
Compared with the prior art, the preparation process of the Li Texi tinib tosylate has at least the following beneficial effects:
1. According to the method, the raw materials undergo amidation reaction of carbonyl and amino, amide is reduced and then undergoes L-DBTA to split a chiral compound required, and finally the chiral compound is salified with p-methanesulfonic acid to obtain a target compound toluene sulfonic acid Li Texi tinib.
2. Compared with the prior art, the method has the remarkable advantages that (1) the chemical substances used in the synthetic route are all commercial products, and the operation method, the operation steps, the reaction conditions, the intermediates and the like adopted in the reaction have good operability. In addition, the reaction route of the design method has short steps, short experimental period and easy mass synthesis. (2) The method uses the available raw material of one chiral isomer to synthesize, avoids twice chiral chromatographic column resolution in the prior art method, has better economy, and (3) uses (R) -N-3, 5-dinitrobenzoyl phenylglycine as resolving agent in the prior art, and has high price. The resolving agent (L-DBTA) used in the preparation method has low price, easily obtained reagent, avoids expensive reagent, has mild reaction, safe operation and high resolving safety, avoids column chromatography purification, and is beneficial to industrial production. (4) The invention has the advantages of easily available raw materials, simple and convenient operation method and higher product yield.
Detailed Description
Embodiments of the present invention are described in detail below. The following examples are illustrative only and are not to be construed as limiting the invention. The examples are not to be construed as limiting the specific techniques or conditions described in the literature in this field or as per the specifications of the product. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
EXAMPLE 1 Synthesis of Compound of formula 3
Maintaining at 5-12 ℃, adding a compound (16.72 g,0.10 mol) shown in formula 1 and a compound (14.08 g,0.105 mol) shown in formula 2 and glacial acetic acid (6.0 g,0.10 mol) into 1, 2-dichloroethane (200 mL), stirring at 8-10 ℃ for 10 hours, adding sodium triacetoxyborohydride (NaBH (OAc) 3) (29.67 g,0.14 mol) into the reaction solution, heating to 36 ℃ for 4 hours, cooling the reaction solution to room temperature, adding a saturated ammonium chloride solution (20 mL), quenching, adding a 1M aqueous NaOH solution (150 mL), adding ethyl acetate for extraction for 2 times (150 mL each time), adding 150mL of saturated brine for washing, drying the anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, using a petroleum ether/ethyl acetate mixed solvent with a volume ratio of 1:8, purifying by silica gel column chromatography to obtain a compound shown in formula 3, wherein the yield is 21.80 g.
LC-MS(APCI):m/z=286.2(M+1)+。
EXAMPLE 2 Synthesis of Compound of formula 3
Maintaining at 5-12 ℃, adding a compound (16.72 g,0.10 mol) shown in a formula 1 and a compound (13.41 g,0.10 mol) shown in a formula 2 into 1, 2-dichloroethane (200 mL), stirring at 8-10 ℃ for 10 hours, adding NaBH (OAc) 3 (27.55 g,0.13 mol) and heating to 32 ℃ for 4 hours, cooling the reaction solution to room temperature, adding a saturated ammonium chloride solution (20 mL), quenching, adding a 1M aqueous NaOH solution (150 mL) for washing, adding ethyl acetate for extraction 2 times (150 mL each), adding 150mL of saturated brine for washing, drying anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, purifying the concentrate by using a petroleum ether/ethyl acetate mixed solvent with a volume ratio of 1:6 by a silica gel column, and obtaining the compound shown in the formula 3, wherein the yield is 21.23g and 74.4%.
EXAMPLE 3 Synthesis of Compound of formula 3
Maintaining at 5-12 ℃, adding a compound (16.72 g,0.10 mol) shown in a formula 1 and a compound (15.43 g,0.115 mol) shown in a formula 2 into 1, 2-dichloroethane (200 mL), stirring at 8-10 ℃ for 10 hours, adding NaBH (OAc) 3 (33.91 g,0.16 mol) and heating to 40 ℃ for reaction for 4 hours, cooling the reaction solution to room temperature, adding a saturated ammonium chloride solution (20 mL), quenching, adding a 1M aqueous NaOH solution (150 mL) for washing, adding ethyl acetate for extraction 2 times (150 mL each), adding 150mL of saturated brine for washing, drying anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, purifying the concentrate by using a petroleum ether/ethyl acetate mixed solvent with a volume ratio of 1:10 by a silica gel column, and obtaining the compound shown in the formula 3, wherein the yield is 21.63g and 75%.
Comparative example 1 Synthesis of Compound of formula 3
The molar ratio of the compound shown in the formula 1 to the compound shown in the formula 2, glacial acetic acid and NaBH (OAc) 3 is adjusted to be 1:0.98:1.2:1.1, and the temperature is kept at 8-10 ℃ and the stirring time is adjusted to be 9 hours.
Maintaining at 5-12 ℃, adding a compound (16.72 g,0.10 mol) shown in a formula 1 and a compound (13.14 g,0.098 mol) shown in a formula 2 into 1, 2-dichloroethane (200 mL), stirring at 8-10 ℃ for 9 hours, adding NaBH (OAc) 3 (23.31 g,0.11 mol) and heating to 36 ℃ to react for 4 hours, cooling the reaction solution to room temperature, adding a saturated ammonium chloride solution (20 mL), quenching, then adding a 1M aqueous NaOH solution (150 mL), extracting 2 times (150 mL each time), adding 150mL saturated brine after adding ethyl acetate, washing, drying anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, purifying the concentrate by using a petroleum ether/ethyl acetate mixed solvent with a volume ratio of 1:8 by a silica gel column, and obtaining the compound shown in the formula 3, wherein the yield is 21.55g and 72.0%.
Comparative example 2 Synthesis of Compound of formula 3
The molar ratio of the compound of formula 1 to the compound of formula 2, glacial acetic acid, naBH (OAc) 3 was adjusted to 1:1.3:1.0:1.8.
Maintaining at 5-12 ℃, adding a compound (16.72 g,0.10 mol) shown in a formula 1 and a compound (17.44 g,0.13 mol) shown in a formula 2 into 1, 2-dichloroethane (200 mL), stirring at 8-10 ℃ for 10 hours, adding NaBH (OAc) 3 (38.15 g,0.18 mol) and heating to 40 ℃ for reaction for 4 hours, cooling the reaction solution to room temperature, adding a saturated ammonium chloride solution (20 mL), quenching, then adding a 1M aqueous NaOH solution (150 mL) for washing, adding ethyl acetate for extraction 2 times (150 mL each time), adding 150mL of saturated brine for washing, drying anhydrous sodium sulfate, concentrating the organic phase under reduced pressure, purifying the concentrate by using a petroleum ether/ethyl acetate mixed solvent with a volume ratio of 1:8 by a silica gel column, and obtaining the compound shown in the formula 3, wherein the yield is 21.11g and 74.0%.
EXAMPLE 4 Synthesis of Compound of formula 4
200ML of methanol is added into a reaction bottle containing a compound shown in a formula 3 (18.90 g,66.24 mmol) and (-) -dibenzoyl-L-tartaric acid (L-DBTA) (15.43 g,43.06 mmol) and stirred for dissolution, heating and heating to reflux, stirring and reacting for 11 hours, a large amount of solid is observed to be separated out of the solution, the reaction solution is cooled to the room temperature, crystallization and stirring are carried out for 2 hours, 20mL of methanol is added into a filter cake for leaching, 150mL of dichloromethane and 150mL of 5% Na 2CO3 solution are added, stirring and dissolution are carried out, the separated liquid is added into 150mL of saturated saline for water washing, anhydrous sodium sulfate is dried, and decompression and concentration are carried out, thus obtaining the solid, namely the compound shown in the formula 4, the yield is 8.30g, the purity is 98.4%, and the ee is more than 98.5%, and the yield is 43.9%.
LC-MS(APCI):m/z=286.2(M+1)+。
IH-NMR(400MHz,DMSO-d6):δppm 11.52(s,1H),8.11(d,1H),7.44-7.20(m,1H),7.09(s,1H),6.81(dd,J＝30.9,17.3Hz,1H),6.54(dd,1H),6.09(dd,J＝16.7,2.0Hz,1H),5.66(dd J＝10.5,1.9Hz,1Η),4.81(s,0.5H),4.55(d,J＝13.2Hz,0.5H),4.36(s,0.5H),4.11-4.04(m,1.5H),2.96(t,0.5H),2.58(t,0.5H),1.94-1.54(m,4H),1.16-1.26(m,3H).
EXAMPLE 5 Synthesis of Compound of formula 4
200ML of methanol is added into a reaction bottle containing a compound (18.90 g,66.24 mmol) shown in a formula 3 and L-DBTA (14.24 g,39.74 mmol) at room temperature, stirring and dissolving are carried out, heating and heating are carried out until a reflux state is achieved, stirring and reacting are carried out for 10 hours, a large amount of solids are observed to be precipitated in the solution, the reaction solution is cooled to room temperature, crystallization and stirring are carried out for 2 hours, filtration is carried out, 20mL of methanol is added into a filter cake for leaching, 150mL of dichloromethane and 150mL of 5% Na 2CO3 solution are added, stirring and dissolving are carried out, liquid separation is carried out, 150mL of saturated saline water is added into an organic phase for washing, anhydrous sodium sulfate is dried, and after decompression and concentration, the solid is obtained, namely the compound shown in a formula 4, 7.77g is obtained, the purity is 98.1%, ee is more than 98.5%, and the yield is 41.1%.
EXAMPLE 6 Synthesis of Compound of formula 4
200ML of methanol is added into a reaction bottle containing a compound (18.90 g,66.24 mmol) shown in a formula 3 and L-DBTA (16.61 g,46.37 mmol) at room temperature, stirring and dissolving are carried out, heating and heating are carried out until a reflux state is achieved, stirring and reacting are carried out for 12 hours, a large amount of solids are observed to be separated out in the solution, the reaction solution is cooled to room temperature, crystallization and stirring are carried out for 2 hours, filtration is carried out, 20mL of methanol is added into a filter cake for leaching, 150mL of dichloromethane and 150mL of 5% Na 2CO3 solution are added, stirring and dissolving are carried out, the separated liquid is carried out, 150mL of saturated saline water is added into an organic phase for washing, anhydrous sodium sulfate is dried, and after decompression and concentration, the solid is obtained, namely the compound shown in a formula 4, 8.18g is obtained, the purity is 98.3%, ee is more than 98.5%, and the yield is 43.3%.
EXAMPLE 7 Synthesis of the Compound tosylate Li Texi tinib of formula I
The compound shown in formula 4 (2.9 g,10.16 mmol) is dissolved in 30mL of ethanol at room temperature, p-toluenesulfonic acid (1.93 g,11.20 mmol) is slowly added dropwise, stirring is carried out at room temperature for 1 hour, a large amount of solid is separated out, the solid is filtered, a filter cake is washed by a proper amount of ethylene glycol dimethyl ether, then 10mL of methanol is used for recrystallization, and the filtered filter cake is dried in vacuum to obtain the compound shown in formula I, namely, the toluenesulfonic acid Li Texi tinib, the yield is 3.96g, the yield is 85.2%, and the HPLC purity is 99.8%.
LC-MS(APCI):m/z=286.2(M+1)+。
1H NMR(400MHz,DMSO-d6):δppm 12.69(brs,1H),9.24(brs,1H),8.42(s,1H),7.52(d,J＝8.1Hz,2H),7.47(m,1H),7.14(d,J＝8.3Hz,2H),6.95(d,J＝1.2Hz,1H),6.88(m,1H),6.15(m,1H),5.75(m,1H),4.82(m,0.5H),4.58(m,0.5H),4.43(m,0.5H),4.13(m,0.5H),3.98(m,1H),3.14(m,0.5H),2.84(m,0.5H),2.28(s,3H),1.90-1.75(m,4H),1.28-1.19(m,3H).
EXAMPLE 8 Synthesis of the Compound tosylate Li Texi tinib of formula I
At room temperature, the compound shown in the formula 4 (2.9 g,10.16 mmol) is dissolved in 30mL of ethanol, p-toluenesulfonic acid (1.84 g,10.67 mmol) is slowly added dropwise, stirring is carried out for 1 hour at 20-25 ℃, a large amount of solids are separated out, the solids are filtered, a filter cake is washed by a proper amount of ethylene glycol dimethyl ether, then 10mL of methanol is used for recrystallization, and the filtered filter cake is dried in vacuum, thus obtaining the compound shown in the formula I, namely toluene sulfonic acid Li Texi tinib, the yield is 3.81g, the yield is 81.9%, and the HPLC purity is 99.6%.
EXAMPLE 9 Synthesis of the Compound tosylate Li Texi tinib of formula I
At room temperature, the compound shown in the formula 4 (2.9 g,10.16 mmol) is dissolved in 30mL of ethanol, p-toluenesulfonic acid (2.10 g,12.19 mmol) is slowly added dropwise, stirring is carried out for 1 hour at 20-25 ℃, a large amount of solids are separated out, the solids are filtered, a filter cake is washed by a proper amount of ethylene glycol dimethyl ether, then 10mL of methanol is used for recrystallization, and the filter cake after filtration is dried in vacuum, thus obtaining the compound toluene sulfonic acid Li Texi tinib shown in the formula I, the yield is 3.92g, the yield is 84.3%, and the HPLC purity is 99.5%.
EXAMPLE 10 Synthesis of the Compound tosylate Li Texi tinib of formula I
At room temperature, the compound shown in the formula 4 (2.9 g,10.16 mmol) is dissolved in 30mL of acetone, p-toluenesulfonic acid (1.93 g,11.20 mmol) is slowly added dropwise, stirring is carried out for 1 hour at 20-25 ℃, a large amount of solids are separated out, the solids are filtered, a filter cake is washed by a proper amount of ethylene glycol dimethyl ether, then 10mL of methanol is used for recrystallization, and the filtered filter cake is dried in vacuum, so that the compound toluene sulfonic acid Li Texi tinib shown in the formula I is obtained, the yield is 3.73g, the yield is 80.2%, and the HPLC purity is 99.4%.
EXAMPLE 11 Synthesis of the Compound tosylate Li Texi tinib of formula I
At room temperature, the compound shown in the formula 4 (2.9 g,10.16 mmol) is dissolved in 30mL of tetrahydrofuran, p-toluenesulfonic acid (1.93 g,11.20 mmol) is slowly added dropwise, stirring is carried out for 1 hour at 20-25 ℃, a large amount of solids are separated out, the solids are filtered, a filter cake is washed by a proper amount of ethylene glycol dimethyl ether, then 10mL of methanol is used for recrystallization, and the filtered filter cake is dried in vacuum, thus obtaining the compound toluene sulfonic acid Li Texi tinib shown in the formula I, the yield is 81.0%, and the HPLC purity is 99.9%.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
While embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and not to be construed as limiting the invention, and that variations, modifications, alternatives and variations may be made to the above embodiments by one of ordinary skill in the art within the scope of the invention.
Claims (10)
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