CN115991682A - Preparation method and application of culture Ma Beite-D4 - Google Patents
Preparation method and application of culture Ma Beite-D4 Download PDFInfo
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- CN115991682A CN115991682A CN202310272156.4A CN202310272156A CN115991682A CN 115991682 A CN115991682 A CN 115991682A CN 202310272156 A CN202310272156 A CN 202310272156A CN 115991682 A CN115991682 A CN 115991682A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 150000001875 compounds Chemical class 0.000 claims abstract description 158
- 239000002904 solvent Substances 0.000 claims abstract description 34
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims abstract description 26
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 claims abstract description 22
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims abstract description 10
- 229910000024 caesium carbonate Inorganic materials 0.000 claims abstract description 10
- 238000003756 stirring Methods 0.000 claims abstract description 10
- 239000002253 acid Substances 0.000 claims abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 66
- 238000006243 chemical reaction Methods 0.000 claims description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 239000000243 solution Substances 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- 239000007864 aqueous solution Substances 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical group [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical group [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 7
- 239000012071 phase Substances 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- 239000012535 impurity Substances 0.000 claims description 5
- 238000010791 quenching Methods 0.000 claims description 5
- 230000000171 quenching effect Effects 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000008346 aqueous phase Substances 0.000 claims description 2
- 238000010790 dilution Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000002994 raw material Substances 0.000 abstract description 5
- 238000012544 monitoring process Methods 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 238000001816 cooling Methods 0.000 description 8
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 8
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 6
- 125000005605 benzo group Chemical group 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 5
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- -1 oxazol-2-yl (3- (4-methoxyphenoxy) propyl) amino Chemical group 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 102000023984 PPAR alpha Human genes 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 description 3
- 108091008725 peroxisome proliferator-activated receptors alpha Proteins 0.000 description 3
- 239000013558 reference substance Substances 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 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 description 3
- ZHKNLJLMDFQVHJ-RUZDIDTESA-N (2r)-2-[3-[[1,3-benzoxazol-2-yl-[3-(4-methoxyphenoxy)propyl]amino]methyl]phenoxy]butanoic acid Chemical compound CC[C@H](C(O)=O)OC1=CC=CC(CN(CCCOC=2C=CC(OC)=CC=2)C=2OC3=CC=CC=C3N=2)=C1 ZHKNLJLMDFQVHJ-RUZDIDTESA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000003908 quality control method Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000556 agonist Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- FERIUCNNQQJTOY-DYCDLGHISA-N deuterio butanoate Chemical compound C(CCC)(=O)O[2H] FERIUCNNQQJTOY-DYCDLGHISA-N 0.000 description 1
- 230000003028 elevating effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 1
- 229960002297 fenofibrate Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000009437 off-target effect Effects 0.000 description 1
- 229950009401 pemafibrate Drugs 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method and application of a culture Ma Beite-D4, wherein the preparation method comprises the following steps: dissolving a structural compound shown in a formula I in a first solvent, adding acid and p-benzoquinone, and reacting at room temperature to obtain a structural compound shown in a formula II; dissolving a structural compound shown in a formula III in a second solvent, adding boron tribromide at low temperature, and reacting at room temperature to obtain a structural compound shown in a formula IV; dissolving a structural compound shown in a formula IV in a third solvent, adding the structural compound shown in a formula II and cesium carbonate, and reacting at room temperature to obtain the structural compound shown in a formula V; dissolving the structural compound shown in the formula V in a fourth solvent, stirring at room temperature, and concentrating to dry the fourth solvent to obtain the structural compound shown in the formula VI, namely the Peup Ma Beite-D4. The invention provides a new synthetic route, which has the advantages of easily available raw materials, few steps, high yield and low cost, and fills the technical blank of the preparation of the culture Ma Beite-D4.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method and application of a culture Ma Beite-D4.
Background
Pepper Ma Beite (Pemafibrate) is a selective peroxisome proliferator-activated receptor alpha (PPARα) modulator, and phase 2 studies have shown that Peup Ma Beite has greater triglyceride lowering and HDL cholesterol elevating effects and less off-target effects than PPARα agonists such as fenofibrate.
The target compound of the invention is PEGylated Ma Beite-D4, and the chemical name is (R) -2- (3- ((benzo [ D)]Oxazol-2-yl (3- (4- (methoxy-d 3) phenoxy) propyl) amino) methyl) phenoxy) butanoic acid-d is an important impurity for peg Ma Beite.
。
The synthesis and preparation of the compound are not reported in the related literature at present, and an impurity reference substance with low cost, easy obtainment and high quality can not be provided for the related research of the quality control of the culture Ma Beite.
Disclosure of Invention
The invention aims to provide a preparation method and application of a culture Ma Beite-D4, and solves the problems that the preparation technology of the culture Ma Beite-D4 is blank and a simple route cannot be provided for synthesis of the culture Ma Beite-D4 in the prior art.
In order to achieve the above purpose, the present invention adopts the following technical scheme:
in a first aspect, the present invention provides a method for preparing a culture Ma Beite-D4, comprising the steps of:
(1) Dissolving a structural compound shown in a formula I in a first solvent, adding acid and p-benzoquinone, and reacting for 2-4 hours at room temperature to obtain a structural compound shown in a formula II;
(2) Dissolving a structural compound shown in a formula III in a second solvent, adding boron tribromide at low temperature, and reacting for 1-3 hours at room temperature to obtain a structural compound shown in a formula IV;
(3) Dissolving a structural compound shown in a formula IV in a third solvent, adding the structural compound shown in a formula II and cesium carbonate, and reacting for 2-4 hours at room temperature to obtain the structural compound shown in the formula V;
(4) Dissolving a structural compound shown in a formula V in a fourth solvent, stirring for 0.2-1 hour at room temperature, and concentrating to dry the fourth solvent to obtain a structural compound shown in a formula VI, namely, a culture Ma Beite-D4;
wherein, the structural compound shown in formula I, the structural compound shown in formula II, the structural compound shown in formula III, the structural compound shown in formula IV, the structural compound shown in formula V and the structural compound shown in formula VI are as follows:
。
further, the preparation method of the culture Ma Beite-D4 comprises the following steps:
(1) Dissolving a structural compound shown in a formula I in a first solvent, adding acid and p-benzoquinone to react for 2-4 hours at room temperature, adding sodium hydroxide aqueous solution to adjust the pH value after the reaction is finished, extracting with ethyl acetate, and purifying by column chromatography to obtain the structural compound shown in a formula II;
(2) Dissolving a structural compound shown in a formula III in a second solvent, adding boron tribromide at low temperature, reacting for 1-3 hours at room temperature, adding a dilute hydrochloric acid aqueous solution for quenching, and extracting with ethyl acetate to obtain the structural compound shown in a formula IV;
(3) Dissolving a structural compound shown in a formula IV in a third solvent, adding the structural compound shown in a formula II and cesium carbonate, reacting for 2-4 hours at room temperature, adding water for dilution, extracting with dichloromethane, adding a dilute acetic acid aqueous solution for adjusting the pH of an aqueous phase, and extracting with ethyl acetate to obtain the structural compound shown in a formula V;
(4) And (3) dissolving the structural compound shown in the formula V in a fourth solvent, stirring for 0.2-1 hour at room temperature, and concentrating to dry the fourth solvent to obtain the structural compound shown in the formula VI.
In some embodiments, in step (1), the first solvent is deuterated methanol.
In some specific technical schemes, in the step (1), the reaction concentration of the dissolved structural compound shown in the formula I is 0.5-1.5 mol/L.
In some specific technical schemes, in the step (1), the added acid is any one of p-toluenesulfonic acid and concentrated sulfuric acid, and the use amount of the acid is 1.0-1.5 equivalents of the molar amount of the structural compound shown in the formula I.
In some specific technical schemes, in the step (1), the dosage of the p-benzoquinone is 0.05-0.2 equivalent of the molar quantity of the structural compound shown in the formula I.
In some specific embodiments, in step (1), the reaction temperature is 0 to 25 ℃.
In some embodiments, in step (1), the concentration of the aqueous sodium hydroxide solution is 2 mol/l, and the adjusted ph=6.
In some specific embodiments, in step (1), the column chromatography uses a mixed mobile phase of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 1:0.1 to 0.3.
In some specific embodiments, in step (2), the second solvent is any one of dichloromethane, tetrahydrofuran, and diethyl ether.
Preferably, in step (2), the second solvent is dichloromethane.
In some specific embodiments, in the step (2), the reaction concentration of the dissolved structural compound represented by formula III is 0.1 to 0.5 mol/l.
In some specific embodiments, in the step (2), the boron tribromide is used in an amount of 2 to 4 equivalents based on the molar amount of the structural compound represented by formula III.
In some specific embodiments, in step (2), the boron tribromide is added at a temperature of 0 ℃.
In some specific embodiments, in step (2), the reaction temperature is 0 to 25 ℃.
In some specific embodiments, in step (2), the concentration of the diluted aqueous hydrochloric acid solution is 1 mol/l, and the adjusted ph=6.
In some specific embodiments, in step (3), the third solvent is any one of N, N-dimethylformamide solution and dichloromethane.
In some specific technical schemes, in the step (3), the reaction concentration of the dissolved structural compound shown in the formula IV is 0.05-0.2 mol/L.
In some specific embodiments, in the step (3), the amount of the structural compound represented by formula II is 1.2 to 1.8 equivalents of the molar amount of the structural compound represented by formula IV.
In some specific embodiments, in the step (3), the amount of cesium carbonate is 1.5 to 3 equivalents of the molar amount of the structural compound represented by formula IV.
In some specific technical schemes, in the step (3), the reaction temperature is 20-25 ℃.
In some specific embodiments, in step (3), the concentration of the diluted aqueous acetic acid solution is 1 mol/l, and the adjusted ph=4.
In some embodiments, in step (4), the fourth solvent is heavy water.
In some specific technical schemes, in the step (4), the reaction temperature is 20-25 ℃.
In a second aspect, the invention also provides an application of the culture Ma Beite-D4 obtained by the preparation method in preparation of a culture Ma Beite impurity reference substance.
Compared with the prior art, the invention provides a preparation method and application of the culture Ma Beite-D4, and the preparation method has the following beneficial effects:
the invention provides a new synthetic route, hydroquinone and (R) -2- (3- ((benzo [ D ] oxazol-2-yl (3- (4-methoxyphenoxy) propyl) amino) methyl) phenoxy) butyric acid are taken as raw materials, and the (R) -2- (3- ((benzo [ D ] oxazol-2-yl (3- (4- (methoxy-D3) phenoxy) propyl) amino) methyl) phenoxy) butyric acid-D is obtained through four steps of substitution, bromination, substitution and deuteration; the preparation method has the advantages of easily available raw materials, few steps, high yield and low cost, fills the technical blank of the preparation of the culture Ma Beite-D4, has important significance for the synthesis of the culture Ma Beite-D4, and can provide an impurity reference substance with low cost, easy obtainment and high quality for the quality control related research of the culture Ma Beite.
Drawings
In order to more clearly illustrate the embodiments of the invention or the technical solutions of the prior art, the drawings which are used in the description of the embodiments or the prior art will be briefly described, it being obvious that the drawings in the description below are only some embodiments of the invention, and that other drawings can be obtained according to these drawings without inventive faculty for a person skilled in the art.
FIG. 1 is a one-dimensional nuclear magnetic hydrogen spectrum of the product synthesized in example 1 of the present invention;
FIG. 2 is a mass spectrum of the product synthesized in example 1 of the present invention;
FIG. 3 is a high performance liquid chromatography of the product synthesized in example 1 of the present invention.
Detailed Description
The technical solutions of the present invention will be clearly and completely described below by means of detailed embodiments in conjunction with the accompanying drawings, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. 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 preparation method of a culture Ma Beite-D4, which takes a structural compound shown in a formula I and a structural compound shown in a formula III as starting materials, wherein the structural compound shown in the formula I is substituted to synthesize an intermediate product shown in a formula II, the structural compound shown in the formula III is brominated to synthesize a structural compound shown in a formula IV, the structural compound shown in a formula V is substituted to synthesize a structural compound shown in a formula V, and finally the structural compound shown in a formula VI is deuterated to synthesize the structural compound shown in a formula VI. As not explicitly indicated, the reagents used in the present invention are all commercially available reagents and the operating temperatures involved, unless otherwise indicated, are all room temperature at 25 ℃.
Wherein the structural compound shown in formula I, the structural compound shown in formula II, the structural compound shown in formula IIIThe structural compound shown in IV, the structural compound shown in formula V and the structural compound shown in formula VI are as follows:
。
the structural compound shown in the formula I is hydroquinone, and is a commercially available raw material;
other raw materials including p-benzoquinone and concentrated sulfuric acid are commercially available;
the chemical name of the structural compound shown in the formula II is 4- (methoxy-d 3) phenol, the structural compound is synthesized autonomously, and the synthetic route of the structural compound shown in the formula II is shown as follows:
the structural compound of formula III is (R) -2- (3- ((benzo [ d ] oxazol-2-yl (3- (4-methoxyphenoxy) propyl) amino) methyl) phenoxy) butanoic acid, which is commercially available as a starting material;
other starting materials including boron tribromide are commercially available;
the chemical name of the structural compound shown in the formula IV is (R) -2- (3- ((benzo [ d ] oxazol-2-yl (3-bromopropyl) amino) methyl) phenoxy) butyric acid, which is synthesized autonomously, and the synthetic route of the structural compound shown in the formula IV is shown as follows:
a compound of the formula V, which is autonomously synthesized under the chemical name (R) -2- (3- ((benzo [ d ] oxazol-2-yl) (3- (4- (methoxy-d 3) phenoxy) propyl) amino) methyl) phenoxy) butyric acid, has the synthetic route shown in the following formula V:
a compound of the formula VI is PEGy Ma Beite-D4, which is chemically named (R) -2- (3- ((benzo [ D ] oxazol-2-yl) (3- (4- (methoxy-D3) phenoxy) propyl) amino) methyl) phenoxy) butanoic acid-D.
The synthetic reaction process of the invention is as follows:
example 1 this example provides the preparation of culture Ma Beite-D4, specifically:
(1) 1 equivalent of a structural compound shown in a formula I is taken and dissolved in deuterated methanol with the mass of 2 times of the volume of the structural compound shown in the formula I, and the reaction concentration of the structural compound shown in the formula I is 0.5 mol/liter; adding 0.1 equivalent of p-benzoquinone, cooling to 0 ℃, dropwise adding 1.3 equivalent of concentrated sulfuric acid, heating to room temperature, stirring for reaction for 3 hours, monitoring the completion of the reaction, and stopping the reaction. The reaction solution ph=6 was adjusted with 2M aqueous sodium hydroxide, extraction was performed using ethyl acetate 20 times the mass of the structural compound represented by formula I, the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness, the organic solvent was evaporated to dryness by spin-drying, and the mobile phase was petroleum ether: ethyl acetate=1:0.2 to give white crystals, which are the structural compound of formula II in 90% yield.
(2) 1 equivalent of a structural compound shown in a formula III is taken and dissolved in a dichloromethane solution with the mass of 10 times of the volume of the structural compound shown in the formula III, and the reaction concentration of the structural compound shown in the formula III is 0.1 mol/liter; cooling to 0 ℃, adding 3 equivalents of boron tribromide, heating to room temperature, stirring and reacting for 1 hour, and stopping the reaction after monitoring the completion of the reaction. Cooling to 0 ℃, pouring the reaction solution into 1M dilute hydrochloric acid aqueous solution for quenching, extracting by using ethyl acetate with the mass of 20 times of the volume of the structural compound shown in the formula III, drying an organic layer by using anhydrous sodium sulfate, and concentrating to dryness to obtain yellow oily liquid, namely the structural compound shown in the formula IV, wherein the yield is 70%.
(3) 1 equivalent of the structural compound shown in the formula IV is taken and dissolved in N, N-dimethylformamide solution with the mass of 20 times of the volume of the structural compound shown in the formula IV, the reaction concentration of the structural compound shown in the formula IV is 0.05 mol/liter, 2 equivalents of cesium carbonate is added, 1.5 equivalents of the structural compound shown in the formula II is added, the reaction is stirred at room temperature for 2 hours, and after monitoring the completion of the reaction, the reaction is stopped. Pouring the reaction solution into water with the mass of 10 times of the volume of the structural compound shown in the formula IV, extracting by using dichloromethane with the mass of 20 times of the volume of the structural compound shown in the formula IV, regulating the pH value of a water layer by using 1M dilute acetic acid aqueous solution to be=4, extracting by using ethyl acetate with the mass of 10 times of the volume of the structural compound shown in the formula IV, drying by using anhydrous sodium sulfate, and concentrating to obtain a white solid, namely the structural compound shown in the formula V, wherein the yield is 80%.
(4) 1 equivalent of the structural compound shown in the formula V is taken and dissolved in heavy water with the mass of 5 times of the structural compound shown in the formula IV, the reaction is stirred at room temperature for 0.2 hour, and after the completion of monitoring the reaction, the reaction is stopped. Concentrated to dryness to give a white solid, namely, peban Ma Beite-D4, in 95% yield.
FIG. 1 shows one-dimensional nuclear magnetic hydrogen spectra of the synthesized products. Figure 2 shows a mass spectrum of the synthesized product with a peak value of 494.4. Figure 3 shows a high performance liquid spectrum of the synthesized product.
Example 2 this example provides the preparation of culture Ma Beite-D4, specifically:
(1) 1 equivalent of a structural compound shown in a formula I is taken and dissolved in deuterated methanol with the mass 1 times of the volume of the structural compound shown in the formula I, and the reaction concentration of the structural compound shown in the formula I is 1 mol/liter; adding 0.2 equivalent of p-benzoquinone, cooling to 0 ℃, dropwise adding 1.2 equivalent of concentrated sulfuric acid, heating to room temperature, stirring for 2 hours, monitoring the reaction, and stopping the reaction. The reaction solution ph=6 was adjusted with 2M aqueous sodium hydroxide, extraction was performed using ethyl acetate 20 times the mass of the structural compound represented by formula I, the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness, the organic solvent was evaporated to dryness by spin-drying, and the mobile phase was petroleum ether: ethyl acetate=1:0.2 to give white crystals, which are the structural compound of formula II in 80% yield.
(2) 1 equivalent of a structural compound shown in a formula III is taken and dissolved in tetrahydrofuran solution with the mass of 4 times of the volume of the structural compound shown in the formula III, and the reaction concentration of the structural compound shown in the formula III is 0.25 mol/liter; cooling to 0 ℃, adding 2 equivalents of boron tribromide, heating to room temperature, stirring and reacting for 1 hour, and stopping the reaction after monitoring the completion of the reaction. Cooling to 0 ℃, pouring the reaction solution into 1M dilute hydrochloric acid aqueous solution for quenching, extracting by using ethyl acetate with the mass of 20 times of the volume of the structural compound shown in the formula III, drying an organic layer by using anhydrous sodium sulfate, and concentrating to dryness to obtain yellow oily liquid, namely the structural compound shown in the formula IV, wherein the yield is 60%.
(3) 1 equivalent of the structural compound shown in the formula IV is taken and dissolved in N, N-dimethylformamide solution with the mass of 10 times of the volume of the structural compound shown in the formula IV, the reaction concentration of the structural compound shown in the formula IV is 0.1 mol/liter, 1.5 equivalent of cesium carbonate is added, 1.2 equivalent of the structural compound shown in the formula II is added, the reaction is stirred at room temperature for 2 hours, and after monitoring the completion of the reaction, the reaction is stopped. Pouring the reaction solution into water with the mass of 10 times of the volume of the structural compound shown in the formula IV, extracting by using dichloromethane with the mass of 20 times of the volume of the structural compound shown in the formula IV, regulating the pH value of a water layer by using 1M dilute acetic acid aqueous solution to be=4, extracting by using ethyl acetate with the mass of 10 times of the volume of the structural compound shown in the formula IV, drying by using anhydrous sodium sulfate, and concentrating to obtain a white solid, namely the structural compound shown in the formula V, wherein the yield is 65%.
(4) 1 equivalent of the structural compound shown in the formula V is taken and dissolved in heavy water with the mass of 5 times of the structural compound shown in the formula IV, the reaction is stirred at room temperature for 0.2 hour, and after the completion of monitoring the reaction, the reaction is stopped. Concentrated to dryness to give a white solid, namely, peban Ma Beite-D4, in 85% yield.
Example 3 this example provides the preparation of culture Ma Beite-D4, specifically:
(1) 1 equivalent of a structural compound shown in a formula I is taken and dissolved in deuterated methanol with the mass 0.7 times of the volume of the structural compound shown in the formula I, and the reaction concentration of the structural compound shown in the formula I is 1.5 mol/L; 0.15 equivalent of p-benzoquinone is added, the temperature is reduced to 0 ℃, 1.4 equivalent of p-toluenesulfonic acid is added, the temperature is raised to room temperature, the reaction is stirred for 4 hours, and after the completion of the monitoring reaction, the reaction is terminated. The reaction solution ph=6 was adjusted with 2M aqueous sodium hydroxide, extraction was performed using ethyl acetate 20 times the mass of the structural compound represented by formula I, the organic layer was dried over anhydrous sodium sulfate and concentrated to dryness, the organic solvent was evaporated to dryness by spin-drying, and the mobile phase was petroleum ether: ethyl acetate=1:0.2 to give white crystals, which are the structural compound of formula II in 70% yield.
(2) 1 equivalent of the structural compound shown in the formula III is taken and dissolved in a dichloromethane solution with the mass of 2 times of the volume of the structural compound shown in the formula III, and the reaction concentration of the structural compound shown in the formula III is 0.5 mol/liter; cooling to 0 ℃, adding 4 equivalents of boron tribromide, heating to room temperature, stirring and reacting for 1 hour, and stopping the reaction after monitoring the completion of the reaction. Cooling to 0 ℃, pouring the reaction solution into 1M dilute hydrochloric acid aqueous solution for quenching, extracting by using ethyl acetate with the mass of 20 times of the volume of the structural compound shown in the formula III, drying an organic layer by using anhydrous sodium sulfate, and concentrating to dryness to obtain yellow oily liquid, namely the structural compound shown in the formula IV, wherein the yield is 55%.
(3) 1 equivalent of the structural compound shown in the formula IV is taken and dissolved in a dichloromethane solution with the mass of 5 times of the volume of the structural compound shown in the formula IV, the reaction concentration of the structural compound shown in the formula IV is 0.2 mol/liter, 3 equivalents of cesium carbonate and 1.8 equivalents of the structural compound shown in the formula II are added, the reaction is stirred at room temperature for 2 hours, and after the completion of the monitoring reaction, the reaction is stopped. Pouring the reaction solution into water with the mass of 10 times of the volume of the structural compound shown in the formula IV, extracting by using dichloromethane with the mass of 20 times of the volume of the structural compound shown in the formula IV, regulating the pH value of a water layer to be=4 by using 1M dilute acetic acid aqueous solution, extracting by using ethyl acetate with the mass of 10 times of the volume of the structural compound shown in the formula IV, drying by using anhydrous sodium sulfate, and concentrating to obtain a white solid, namely the structural compound shown in the formula V, wherein the yield is 60%.
(4) 1 equivalent of the structural compound shown in the formula V is taken and dissolved in heavy water with the mass of 5 times of the structural compound shown in the formula IV, the reaction is stirred at room temperature for 1 hour, and the reaction is terminated after the completion of monitoring. Concentrated to dryness to give a white solid, namely, peban Ma Beite-D4, in 80% yield.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Furthermore, it should be understood that although the present disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.
Claims (10)
1. A method for preparing a culture Ma Beite-D4, comprising the steps of:
(1) Dissolving a structural compound shown in a formula I in a first solvent, adding acid and p-benzoquinone, and reacting for 2-4 hours at room temperature to obtain a structural compound shown in a formula II;
(2) Dissolving a structural compound shown in a formula III in a second solvent, adding boron tribromide at low temperature, and reacting for 1-3 hours at room temperature to obtain a structural compound shown in a formula IV;
(3) Dissolving a structural compound shown in a formula IV in a third solvent, adding the structural compound shown in a formula II and cesium carbonate, and reacting for 2-4 hours at room temperature to obtain the structural compound shown in the formula V;
(4) Dissolving a structural compound shown in a formula V in a fourth solvent, stirring for 0.2-1 hour at room temperature, and concentrating to dry the fourth solvent to obtain a structural compound shown in a formula VI, namely, a culture Ma Beite-D4;
wherein, the structural compound shown in formula I, the structural compound shown in formula II, the structural compound shown in formula III, the structural compound shown in formula IV, the structural compound shown in formula V and the structural compound shown in formula VI are as follows:
2. the method for preparing a culture Ma Beite-D4 as claimed in claim 1, comprising the steps of:
(1) Dissolving a structural compound shown in a formula I in a first solvent, adding acid and p-benzoquinone to react for 2-4 hours at room temperature, adding sodium hydroxide aqueous solution to adjust the pH value after the reaction is finished, extracting with ethyl acetate, and purifying by column chromatography to obtain the structural compound shown in a formula II;
(2) Dissolving a structural compound shown in a formula III in a second solvent, adding boron tribromide at low temperature, reacting for 1-3 hours at room temperature, adding a dilute hydrochloric acid aqueous solution for quenching, and extracting with ethyl acetate to obtain the structural compound shown in a formula IV;
(3) Dissolving a structural compound shown in a formula IV in a third solvent, adding the structural compound shown in a formula II and cesium carbonate, reacting for 2-4 hours at room temperature, adding water for dilution, extracting with dichloromethane, adding a dilute acetic acid aqueous solution for adjusting the pH of an aqueous phase, and extracting with ethyl acetate to obtain the structural compound shown in a formula V;
(4) And (3) dissolving the structural compound shown in the formula V in a fourth solvent, stirring for 0.2-1 hour at room temperature, and concentrating to dry the fourth solvent to obtain the structural compound shown in the formula VI.
3. A method of preparing a culture Ma Beite-D4 according to claim 1 or 2, wherein: in step (1), the first solvent is deuterated methanol; in the step (2), the second solvent is any one of dichloromethane, tetrahydrofuran and diethyl ether; in the step (3), the third solvent is any one of N, N-dimethylformamide solution and dichloromethane; in step (4), the fourth solvent is heavy water.
4. A method of preparing a culture Ma Beite-D4 according to claim 1 or 2, wherein: in the step (1), the reaction concentration of the dissolved structural compound shown in the formula I is 0.5-1.5 mol/L; in the step (2), the reaction concentration of the dissolved structural compound shown in the formula III is 0.1-0.5 mol/L; in the step (3), the reaction concentration of the dissolved structural compound shown in the formula IV is 0.05-0.2 mol/L.
5. A method of preparing a culture Ma Beite-D4 according to claim 1 or 2, wherein: in the step (1), the added acid is any one of p-toluenesulfonic acid and concentrated sulfuric acid, and the use amount of the acid is 1.0-1.5 equivalents of the molar amount of the structural compound shown in the formula I.
6. A method of preparing a culture Ma Beite-D4 according to claim 1 or 2, wherein: in the step (1), the dosage of the p-benzoquinone is 0.05-0.2 equivalent of the molar quantity of the structural compound shown in the formula I; in the step (2), the usage amount of the boron tribromide is 2-4 equivalents of the molar amount of the structural compound shown in the formula III; in the step (3), the amount of the structural compound shown in the formula II is 1.2-1.8 equivalents of the molar amount of the structural compound shown in the formula IV, and the amount of cesium carbonate is 1.5-3 equivalents of the molar amount of the structural compound shown in the formula IV.
7. A method of preparing a culture Ma Beite-D4 according to claim 1 or 2, wherein: in the step (1), the reaction temperature is 0-25 ℃; in the step (2), the adding temperature of the boron tribromide is 0 ℃, and the reaction temperature is 0-25 ℃; in the step (3), the reaction temperature is 20-25 ℃; in the step (4), the reaction temperature is 20-25 ℃.
8. The method for producing a culture Ma Beite-D4 as claimed in claim 2, wherein: in step (1), the concentration of the aqueous sodium hydroxide solution is 2 mol/l, and the adjusted ph=6; in step (2), the concentration of the diluted hydrochloric acid aqueous solution is 1 mol/liter, and the adjusted ph=6; in step (3), the concentration of the diluted acetic acid aqueous solution was 1 mol/liter, and the adjusted ph=4.
9. The method for producing a culture Ma Beite-D4 as claimed in claim 2, wherein: in the step (1), the mobile phase used in the column chromatography is a mixed mobile phase of petroleum ether and ethyl acetate, wherein the volume ratio of petroleum ether to ethyl acetate is 1:0.1 to 0.3.
10. Use of a culture Ma Beite-D4 obtained by a preparation method according to any one of claims 1-9 in the preparation of a culture Ma Beite impurity control.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JP2010006767A (en) * | 2008-06-27 | 2010-01-14 | Kowa Co | Highly pure deuterated derivative and its production method |
| CN105102415A (en) * | 2013-03-29 | 2015-11-25 | 兴和株式会社 | Method for improving optical purity of 2-hydroxycarboxylic acid or derivative thereof |
| WO2022249071A1 (en) * | 2021-05-27 | 2022-12-01 | Kowa Company, Ltd | Pemafibrate and/or tofogliflozin for use in treating liver disease |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2010006767A (en) * | 2008-06-27 | 2010-01-14 | Kowa Co | Highly pure deuterated derivative and its production method |
| CN105102415A (en) * | 2013-03-29 | 2015-11-25 | 兴和株式会社 | Method for improving optical purity of 2-hydroxycarboxylic acid or derivative thereof |
| WO2022249071A1 (en) * | 2021-05-27 | 2022-12-01 | Kowa Company, Ltd | Pemafibrate and/or tofogliflozin for use in treating liver disease |
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| YUKIYOSHI YAMAZAKI等: "Synthesis of highly deuterium-labeled (R)-K-13675, PPAR a agonist, for use as an internal standard for low-level quantification of drugs in plasma", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
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