CN110655517A - Preparation method of doriravir open-loop impurities and impurities thereof - Google Patents

Preparation method of doriravir open-loop impurities and impurities thereof Download PDF

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CN110655517A
CN110655517A CN201910601389.8A CN201910601389A CN110655517A CN 110655517 A CN110655517 A CN 110655517A CN 201910601389 A CN201910601389 A CN 201910601389A CN 110655517 A CN110655517 A CN 110655517A
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impurity
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王志邦
徐靖坤
田磊
张祖良
廖洁海
邹慧
王尧
刘洋
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ANHUI BIOCHEM BIO-PHARMACEUTICAL Co Ltd
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    • C07ORGANIC CHEMISTRY
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    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses a preparation method of a dortavir open-loop impurity, which comprises the preparation of an impurity A and an impurity B, and specifically comprises the steps of taking a compound 1 as an initial raw material, condensing with a compound 2 to generate a compound 3, hydrolyzing under an alkaline condition to generate a compound 4, reacting with a compound 5 to generate a compound 6, obtaining the impurity A from the compound 6 by adopting a protection-ring closing-deprotection method, and further reacting to obtain the impurity B; the impurities are also disclosed; compared with the prior art, the preparation method disclosed by the invention has the advantages that a new and unprecedented synthesis route is adopted, and the preparation of the impurity A and the impurity B of the bulk drug of the Lepisorus durissima is completed; the designed impurity synthesis route has the advantages of simple and mild reaction conditions, good yield and safe reaction operation, and solves the dilemma that the impurities A and B for degrading the doramevir are small in amount and cannot be separated in an acid-base damage test; the characterization work of the impurity A and the impurity B is also completed, and the subsequent further research on the impurity A and the impurity B is facilitated.

Description

Preparation method of doriravir open-loop impurities and impurities thereof
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a preparation method of a doramevir open-loop impurity and an impurity thereof.
Background
HIV (human immunodeficiency virus) integrase inhibitor dolutegravir sodium, developed by the company grignard, was approved by the FDA in the united states for marketing in 2013 at 8 months. The Chinese chemical name is (4R,12aS) -9- { [ (2, 4-difluorophenyl) methyl ] carbamoyl } -4-methyl-6, 8-dioxo-3, 4,6,8,12,12 a-hexahydro-2H-pyrido [1 ', 2': 4,5] pyrazine [2,1-b ] [1,3] oxazine-7-enol sodium, and the structural formula is aS follows:
Figure BDA0002118168120000011
doltiravir is a human immunodeficiency virus type 1(HIV-1) integrase chain transfer inhibitor (INSTI) suitable for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and children over 12 years of age and weighing at least 40 kg. Patent US9120817 discloses a preparation method thereof, specifically: the starting material, 1- [2, 2-bis (methyloxy) ethyl ] -5-methoxycarbonyl-4-oxo-3-methoxy-1, 4-dihydro-2-pyridinecarboxylic acid methyl ester, is hydrolyzed to carboxylic acid by the action of lithium hydroxide, the ester group having small steric hindrance. The compound 1- [2, 2-bis (methyloxy) ethyl ] -5-carboxylic acid-4-oxo-3-methoxy-1, 4-dihydro-2-pyridinecarboxylic acid methyl ester is deprotected in acetal in acetic acid and methanesulfonic acid to form aldehyde groups. The aldehyde group-containing compound reacts with (R) -3-aminon-butanol to generate a ring-fused compound. The heterocyclic compound and 2, 4-difluorobenzylamine are condensed by CDI (N, N-dicarbonylimidazole) to generate amide. Finally, demethylating by lithium chloride to generate the doriravir raw material, wherein the synthetic route is as follows:
Figure BDA0002118168120000021
the application tries to adopt the Lepisavir bulk drug synthesized by the reaction of the route, and the LC-MS detection shows that the main peak 420([ M + H ] is removed]+) In addition to the molecular ion peak of (a), there is a molecular weight of 420([ M + H) ([ M + H ]) which is the same as the molecular weight of the product]+) Small impurity peaks (mainly including impurity a and impurity B) which are inferred to be due to the instability of the side ring and the degradation of the partial ring opening of dolabravir under acidic conditions and during the heating step.
Figure BDA0002118168120000022
Because the impurity A is supposed to be generated by heating under an acidic condition, the application attempts to degrade the doramevir by refluxing in a 6N hydrochloric acid aqueous solution, after the reaction is carried out for 6 hours, the reaction liquid is identified by LC-MS, only a trace amount of the impurity A is generated, and the impurity A is mixed with other impurities and is difficult to separate and extract; and the prior art does not disclose a method for preparing impurity a and impurity B. Because the research on impurities is beneficial to the research on the quality of medicines, and the CFDA has higher requirements on the research on the impurities in the medicine declaration, the acquisition of the impurity reference substance has important significance on the medicine declaration and the quality control of the medicines, and therefore, the field urgently needs to provide a brand-new synthetic route of the impurities A and the impurities B which are not reported in similar articles.
Disclosure of Invention
The invention aims to provide a preparation method of doramevir open-loop impurities, which aims to solve the problems in the background technology.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of doriravir ring-opening impurities comprises the preparation of impurities A and impurities B, and specifically comprises the following steps: the compound 1 is used as a starting material and condensed with a compound 2 to generate a compound 3, the compound 3 is hydrolyzed to a compound 4 under an alkaline condition and then reacts with a compound 5 to generate a compound 6, the compound 6 adopts a protection-ring closure-deprotection method to obtain an impurity A, and the impurity A is further reacted to obtain an impurity B, and the synthetic route is as follows:
Figure BDA0002118168120000031
wherein R is1Is methyl, ethyl or benzyl; r2Is methyl or ethyl; r3Is benzoyl, acetyl, tert-butyl dimethyl silicon baseTert-butyldiphenylsilyl, benzyl or allyl.
As a further scheme of the invention, the preparation method of the dorzolavir ring-opening impurity mainly comprises the following steps:
(1) under the conditions that dichloromethane is used as a solvent and N, N' -carbonyldiimidazole is used as a condensation reagent, the compound 1 and the compound 2 react at room temperature, and after the reaction is finished, the obtained material is washed, evaporated to dryness and refined to obtain a compound 3;
(2) hydrolyzing the compound 3 obtained in the step (1) under an alkaline condition, adjusting the pH of the obtained material to 3-4 after the reaction is finished, and performing spin drying and extraction to obtain a compound 4;
(3) under the condition that dichloromethane is used as a solvent, the compound 4 obtained in the step (2) and the compound 5 are subjected to condensation reaction at room temperature, and after the reaction is finished, the obtained material is washed by water, dried by spinning and recrystallized to obtain a compound 6;
(4) protection: taking dichloromethane as a solvent for the compound 6 obtained in the step (3), and adding a protecting group reagent R under the alkaline condition3Reacting with Cl, pouring the materials into ice water after the reaction is finished, separating liquid, washing with water, and spin-drying the solvent to obtain a compound 7;
(5) closing the ring: taking acetonitrile as a solvent for the compound 7 obtained in the step (4), closing a ring under the action of acid, spin-drying the solvent, and then pretreating to obtain a compound 8;
(6) deprotection: hydrolyzing the compound 8 obtained in the step (5) under an alkaline condition to obtain an impurity A;
(7) removing protecting group R from impurity A at 70-80 deg.C with acetonitrile as solvent1Then, the reaction material is subjected to acid washing, spin-drying, extraction, spin-drying and ethanol recrystallization to obtain impurity B.
As a further scheme of the invention, after the reaction in the step (1) is finished, washing the obtained material with 0.5-1.5N hydrochloric acid aqueous solution, 4-6% sodium carbonate aqueous solution and saturated saline solution in sequence, evaporating the organic phase under reduced pressure, and refining to obtain a compound 3; the obtained compound 3 was purified by silica gel column chromatography, and the eluent was n-hexane/ethyl acetate (5: 1) - (1: 1).
As a further embodiment of the present invention, the hydrolysis reaction in step (2) is performed in an organic solvent, wherein the organic solvent is any one of methanol, ethanol and isopropanol; the alkali solution is any one of 1-2N aqueous solutions of lithium hydroxide, sodium hydroxide and potassium hydroxide; adding water and an extracting agent for extraction, wherein the extracting agent is dichloromethane.
As a further embodiment of the present invention, the condensation reaction in step (3) is carried out using a condensation reagent which is a compound of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and dicyclohexylcarbodiimide or a compound of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole, and the present invention preferably uses a compound of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole as the condensation reagent; the molar ratio of the condensation reagent to the compound 4 is (1.1: 1) - (2.0: 1); and (3) washing the materials obtained after the reaction, washing with saturated salt water, spin-drying and recrystallizing in sequence, wherein the recrystallization comprises the following specific steps: after the obtained material is dried by spinning, dichloromethane is added for dissolution, n-hexane is added dropwise under stirring, then stirring is carried out at room temperature, and solid is slowly separated out; or adding dichloromethane and n-hexane for reflux dissolution, slowly cooling to room temperature, stirring and crystallizing.
As a further embodiment of the present invention, the protecting group reagent R in the step (4)3Protecting group R in Cl3Is any one of benzoyl, acetyl, tert-butyl dimethyl silicon base, tert-butyl diphenyl silicon base, benzyl and allyl; the protecting group reagent R3The mol ratio of the Cl to the compound 6 is (1.1: 1) - (2.0: 1); the base used in the reaction is any one of triethylamine, pyridine and N, N' -diisopropylethylamine, and the molar ratio of the base to the compound 6 is (1.1: 1) - (2.0: 1).
As a further scheme of the invention, the acid used for ring closure in the step (5) is one or more of sulfuric acid, p-toluenesulfonic acid, acetic acid and methanesulfonic acid, and the invention prefers mixed acid of acetic acid and methanesulfonic acid, wherein the addition amount of the methanesulfonic acid is 0.2-0.5 equivalent, and the addition amount of the acetic acid is 4-10 equivalent; the pretreatment method comprises the following steps: after the reaction, the obtained compound 7 is added into dichloromethane, stirred and dissolved, washed by 0.8-1N hydrochloric acid aqueous solution, and dried by spinning under reduced pressure to obtain a compound 8.
As a further embodiment of the present invention, the hydrolysis reaction in step (6) is performed in an organic solvent, wherein the organic solvent is any one of methanol, ethanol and isopropanol; the reaction alkali is any one of lithium hydroxide, sodium hydroxide and potassium hydroxide.
As a further embodiment of the present invention, the protecting group R is removed in said step (7)1The reagent of (2) is magnesium chloride or magnesium bromide, and the molar ratio of the magnesium chloride or magnesium bromide to the impurity A is (1.1: 1) - (2.0: 1); the pickling solution is 5-7N hydrochloric acid aqueous solution.
As a further scheme of the invention, the invention also discloses the dortavir open-loop impurity prepared by the method, preferably, the structure of the impurity a is as follows:
the nuclear magnetic hydrogen spectrum related data of the impurity A are as follows:1HNMR(400MHz,CDCl3)δ:10.55(t,J=5.9Hz,1H),8.64(s,1H),7.37(td,J=8.6,6.4Hz,1H),6.87~6.77(m,3H),6.42(d,J=6.3Hz,1H),5.20~5.08(m,1H),4.65(d,J=5.9Hz,2H),4.05(s,3H),3.71~3.59(m,1H),3.57~3.47(m,1H),2.55(s,1H),2.00~1.90(m,1H),1.84~1.73(m,1H),1.40(d,J=6.9Hz,3H);LC-MS(m/z):434[M+H]+
preferably, the impurity B has the following structure:
Figure BDA0002118168120000061
the nuclear magnetic hydrogen spectrum related data of the impurity B are as follows:1H NMR(400MHz,DMSO-d6)δ:12.28(s,1H),10.60(t,J=5.9Hz,1H),8.80(s,1H),7.55(d,J=6.4Hz,1H),7.43(td,J=8.7,6.6Hz,1H),7.25(ddd,J=10.6,9.3,2.6Hz,1H),7.07(tdd,J=8.5,2.6,1.0Hz,1H),7.01(d,J=6.4Hz,1H),4.89(dt,J=8.2,6.5Hz,1H),4.57(d,J=5.9Hz,2H),4.53(t,J=4.9Hz,1H),3.43~3.35(m,2H),1.94~1.71(m,2H),1.29(d,J=6.8Hz,3H);LC-MS(m/z):420[M+H]+
compared with the prior art, the invention has the beneficial effects that:
(1) the invention uses a new and unprecedented synthesis route to finish the preparation of the impurities A and B of the bulk drug of the Lepisorus dortalus;
(2) the impurity synthesis route designed by the invention has the advantages of simple and mild reaction conditions, good yield and safe reaction operation, and solves the dilemma that the impurities A and B degraded by the tipranavir are small in amount and cannot be separated in an acid-base damage test;
(3) the invention also completes the characterization work of the impurity A and the impurity B, and the analysis of mass spectrum and nuclear magnetic spectrum data of the impurity A and the impurity B shows that the purity of the impurity prepared by reaction is higher, so that the impurity analysis work in the preparation of the crude drugs of the Levoviru can be met, and the subsequent further research on the impurity A and the impurity B is convenient.
Drawings
FIG. 1 is a synthesis scheme of an open-loop impurity of dorzolavir according to an embodiment of the present invention;
FIG. 2 is a nuclear magnetic hydrogen spectrum of Compound 3 prepared in an example of the present invention;
FIG. 3 is a nuclear magnetic hydrogen spectrum of Compound 6 prepared in an example of the present invention;
FIG. 4 is a nuclear magnetic hydrogen spectrum of impurity A prepared in an example of the present invention;
FIG. 5 is a nuclear magnetic hydrogen spectrum of impurity B prepared in an example of the present invention;
FIG. 6 is a nuclear magnetic carbon spectrum of impurity B prepared in an example of the present invention;
FIG. 7 is a GC-MS report of impurity A prepared in accordance with an example of the present invention;
FIG. 8 is a GC-MS report of impurity B prepared in accordance with the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Referring to fig. 1, the synthesis of the dortavir open-loop impurity a and the impurity B from the preferred raw materials is taken as an example, and the synthesis principle is as follows:
the first step is as follows: reacting compound 1 with compound 2 to produce compound 3
Using dichloromethane as a solvent, using N, N-dicarbonyl imidazole (CDI) as a condensation reagent, carrying out condensation reaction on a compound 1 and a compound 2 at room temperature, washing the obtained material after the reaction is finished with a 1N hydrochloric acid aqueous solution, a 5% sodium carbonate aqueous solution and saturated salt water in sequence, evaporating an organic phase under reduced pressure, and refining to obtain a compound 3, wherein the refining adopts a silica gel column chromatography method, and an eluent adopts N-hexane and ethyl acetate which are 3: 1; the reaction equation is as follows:
Figure BDA0002118168120000071
the second step is that: hydrolysis of Compound 3 to Compound 4
Stirring and uniformly mixing ethanol and the compound 3, adding a 2N sodium hydroxide aqueous solution for hydrolysis reaction, adjusting the pH to 3-4 by using a 6N hydrochloric acid aqueous solution after the reaction is finished, spin-drying, and adding water and dichloromethane for extraction to obtain a compound 4; the reaction equation is as follows:
Figure BDA0002118168120000081
the third step: reacting compound 4 with compound 5 to produce compound 6
Under the conditions that dichloromethane is used as a solvent and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride and 1-hydroxybenzotriazole are used as condensation reagents, a compound 4 and a compound 5 are stirred for 2 hours at room temperature, reaction liquid is sequentially washed by water, washed by saturated salt solution and dried in a spinning mode, dichloromethane is added for stirring and dissolving, normal hexane is added for stirring for 20-24 hours at room temperature, a product is separated out, and the compound 6 is obtained through suction filtration and vacuum drying; wherein the optimal ratio of the condensation reagent to the compound 4 is 1.5: 1; the reaction equation is as follows:
Figure BDA0002118168120000082
the fourth step: protecting compound 6 with protecting group reagent to obtain compound 7
Taking dichloromethane as a solvent, adding a compound 6, triethylamine and a protecting group reagent benzoyl chloride for reaction, pouring a reaction solution into ice water after the reaction is finished, separating the solution, washing with water, and spin-drying the solvent to obtain a compound 7, wherein the optimal ratio of the protecting group reagent benzoyl chloride to the compound 6 is 1.5: 1; the molar ratio of the triethylamine to the compound 6 is 1.8: 1; the reaction equation is as follows:
Figure BDA0002118168120000083
the fifth step: ring closure reaction
The compound 7 is prepared by using acetonitrile as a solvent, closing a ring under the action of 6 equivalents of acetic acid and 0.3 equivalent of methanesulfonic acid, then spin-drying the solvent, adding dichloromethane, then carrying out acid washing by using 1N hydrochloric acid aqueous solution, and carrying out reduced pressure spin-drying to obtain a compound 8; the reaction equation is:
Figure BDA0002118168120000091
and a sixth step: deprotection to obtain impurity A
Adding methanol and sodium hydroxide into the compound 8, stirring for 1h at room temperature, and hydrolyzing to remove benzoyl to obtain an impurity A; the reaction equation is:
Figure BDA0002118168120000092
the seventh step: the impurity A further reacts to obtain an impurity B
Impurity A uses acetonitrile as solvent, and removes R from magnesium chloride at 75 DEG C1Adding 6N hydrochloric acid aqueous solution to the protecting group, spin-drying, adding water to the residue, extracting with dichloromethane, spin-drying, and recrystallizing with ethanol to obtain impurity B, wherein the magnesium chloride and the impurity are magnesium chlorideThe optimal ratio of the component A is 1.5: 1; the reaction equation is:
Figure BDA0002118168120000093
example 2
And (3) carrying out condensation reaction on the compound 1 and the compound 2 to generate a compound 3:
Figure BDA0002118168120000094
compound 1(20.0g, 63.4mmol) and methylene chloride (150mL) were added to the reaction flask and dissolved with stirring at room temperature. The temperature is reduced to 15 to 20 ℃, N-carbonyl diimidazole (13.9g, 85.7mmol) is added, and the reaction is kept for 2 hours under the protection of nitrogen. Compound 2(10.0g, 69.9mmol) was added dropwise thereto, and the mixture was allowed to warm to room temperature for 2 hours. The reaction mixture was washed with 1N aqueous HCl (100mL), 5% aqueous sodium carbonate (130mL) and saturated brine (100mL) in this order. The organic phase was concentrated to dryness and the resulting oil was isolated by column chromatography [ mobile phase: n-hexane: ethyl acetate (2: 1) ], to give compound 3(18.9g, 68%) as a white solid powder.
The nuclear magnetic hydrogen spectrum of the prepared compound 3 is shown in figure 2, and the related data of the nuclear magnetic hydrogen spectrum and the mass spectrum are as follows:1H NMR(400MHz,CDCl3)δ:10.39(s,1H),8.42(s,1H),7.38(td,J=8.4,6.4Hz,1H),6.87~6.76(m,2H),4.63(d,2H),4.50(t,J=4.8Hz,1H),4.04(d,J=4.8Hz,2H),3.98(d,J=10.6Hz,6H),3.39(s,6H);LC-MS(m/z):441[M+H]+
example 3
Hydrolyzing the compound 3 prepared in the embodiment 2 of the invention under alkaline conditions to generate a compound 4, and carrying out a condensation reaction on the compound 4 and a compound 5 to generate a compound 6:
Figure BDA0002118168120000101
compound 3(18.9g, 42.9mmol) and ethanol (190mL) were added to the reaction flask and dissolved with stirring. 2N NaOH aqueous solution (95mL) was added, the reaction was stirred at room temperature for 1 hour, and TLC identified the disappearance of starting material. The pH was adjusted to 3-4 with 6N HCl aqueous solution. The reaction was concentrated to dryness, water (50mL), dichloromethane (100m L X3) was added to the residue and the combined organic phases were concentrated to dryness to give compound 4 as a white solid to which dichloromethane (180mL), 1-hydroxybenzotriazole (8.7g, 64.4mmol), 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (12.3g, 64.4mmol), compound 5(7.7g, 85.8mmol) were added directly. After stirring at room temperature for 2 hours, the reaction mixture was washed with water (180mL) and saturated brine (100mL), and the organic phase was concentrated to dryness. To the residue was added methylene chloride (40mL), and the mixture was dissolved with stirring and n-hexane (120mL) was added. After stirring at room temperature for 24 hours, a solid precipitated, which was filtered off and the filter cake was dried under vacuum to give Compound 6(16.2g, 76%) as pale yellow solid particles.
The nuclear magnetic hydrogen spectrum of the prepared compound 6 is shown in figure 3, and the related data of the nuclear magnetic hydrogen spectrum and the mass spectrum are as follows:1H NMR(400MHz,CDCl3)δ:10.33(t,J=5.9Hz,1H),8.35(s,1H),7.39(td,J=8.5,6.4Hz,1H),7.12(d,J=8.4Hz,1H),6.88~6.77(m,2H),4.63~4.59(m,3H),4.41~4.32(m,1H),4.03(d,J=5.0Hz,2H),3.90(s,3H),3.84~3.72(m,2H),3.39(d,J=4.3Hz,6H),1.99~1.89(m,1H),1.66~1.56(m,1H),1.33(d,J=6.7Hz,3H);LC-MS(m/z):498[M+H]+
example 4
Preparation of impurity A
Figure BDA0002118168120000111
To a reaction flask was added compound 6(16.0g, 32.2mmol), dichloromethane (160mL), triethylamine (4.9g, 48.3 mmol). The temperature was reduced to 0-5 ℃ and a solution of benzoyl chloride (5.4g, 38.6mmol) in dichloromethane (40mL) was slowly added dropwise. After dropping, the reaction was stirred at room temperature for 5 hours. The reaction solution was slowly poured into ice water, separated, washed with organic phase water (100mL), and the organic phase was concentrated to dryness to give compound 7 as an oil. To the remaining oily compound 7 were added acetonitrile (200mL), methanesulfonic acid (0.9g, 9.7mmol), and glacial acetic acid (9.3g, 154.6 mmol). And raising the temperature to reflux reaction for 7 hours under the protection of nitrogen, reducing the temperature, and removing the solvent by a water pump under reduced pressure. The residue was washed with dichloromethane (120mL), 1N HCl (120mL) and the organic phase was spin dried under reduced pressure to give compound 8 as a yellow oil. Methanol (150mL) and sodium hydroxide (7.2g, 178.8mmol) were added to the resulting compound 8, and the reaction was stirred at room temperature for 1 hour. The solvent was removed by suction under reduced pressure, and the residue was extracted with water (150mL), methylene chloride (150mL), and the solvent was removed by suction under reduced pressure to give impurity A (9.0g, 65%) as a white powder as a solid.
The nuclear magnetic hydrogen spectrum of the impurity A is shown in figure 4, and the related data of the nuclear magnetic hydrogen spectrum and the mass spectrum are as follows:1H NMR(400MHz,CDCl3)δ:10.55(t,J=5.9Hz,1H),8.64(s,1H),7.37(td,J=8.6,6.4Hz,1H),6.87~6.77(m,3H),6.42(d,J=6.3Hz,1H),5.20~5.08(m,1H),4.65(d,J=5.9Hz,2H),4.05(s,3H),3.71~3.59(m,1H),3.57~3.47(m,1H),2.55(s,1H),2.00~1.90(m,1H),1.84~1.73(m,1H),1.40(d,J=6.9Hz,3H);LC-MS(m/z):434[M+H]+
the LC-MS report spectrum of the impurity A is shown in FIG. 7, and it can be seen from FIG. 7 that: the molecular weight of the synthesized impurity A is consistent with that of the impurity A, and corresponding mass spectrum peaks and liquid phase spectrograms in LC-MS prove that the synthesized impurity A has higher purity and is suitable for the research of impurity reference substances.
Example 5
Synthesis of impurity B
Figure BDA0002118168120000121
The reaction flask was charged with impurity A (9.0g, 20.8mmol), acetonitrile (100mL) was added, the mixture was stirred to dissolve, then the temperature was raised to 70-80 ℃ under nitrogen protection, magnesium chloride (2.8g, 29.8mmol) was added, and the reaction was maintained for 5 hours. After cooling to room temperature, 6N HCl aqueous solution (20mL) was added, the reaction was concentrated to dryness, water (100mL) was added to the residue, dichloromethane (100 mL. times.2) was extracted, the organic phases were combined, and the solvent was spun off with a water pump under reduced pressure. Adding ethanol (60mL), heating to 75-80 deg.C, refluxing and stirring for 1 hr, cooling to room temperature, vacuum filtering, washing filter cake with ethanol, and drying at 45 deg.C under normal pressure to obtain white solid powder product impurity B (7.3g, 84%).
The nuclear magnetic hydrogen spectrum and the carbon spectrum of the impurity B are shown in figures 5 and 6, and the related data of the nuclear magnetic hydrogen spectrum and the mass spectrum are as follows:1HNMR(400MHz,DMSO-d6)δ:12.28(s,1H),10.60(t,J=5.9Hz,1H),8.80(s,1H),7.55(d,J=6.4Hz,1H),7.43(td,J=8.7,6.6Hz,1H),7.25(ddd,J=10.6,9.3,2.6Hz,1H),7.07(tdd,J=8.5,2.6,1.0Hz,1H),7.01(d,J=6.4Hz,1H),4.89(dt,J=8.2,6.5Hz,1H),4.57(d,J=5.9Hz,2H),4.53(t,J=4.9Hz,1H),3.43~3.35(m,2H),1.94~1.71(m,2H),1.29(d,J=6.8Hz,3H);LC-MS(m/z):420[M+H]+
the LC-MS report spectrum of impurity B is shown in FIG. 8, and it can be seen from FIG. 7 that: the molecular weight of the mass spectrum is consistent with that of the impurity B, and corresponding mass spectrum peaks and liquid phase spectrograms in the LC-MS prove that the synthesized impurity B has higher purity and is suitable for the research of impurity reference substances.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.

Claims (11)

1. A preparation method of doriravir ring-opening impurities is characterized by comprising the preparation of impurities A and impurities B, and specifically comprises the following steps: the compound 1 is used as a starting material and condensed with a compound 2 to generate a compound 3, the compound 3 is hydrolyzed to a compound 4 under an alkaline condition and then reacts with a compound 5 to generate a compound 6, the compound 6 adopts a protection-ring closure-deprotection method to obtain an impurity A, and the impurity A is further reacted to obtain an impurity B, and the synthetic route is as follows:
Figure FDA0002118168110000011
wherein R is1Is methyl, ethyl or benzyl; r2Is methyl or ethyl; r3Is benzoyl, acetyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, benzyl or allyl.
2. The method for preparing doramevir open-loop impurities according to claim 1, which is characterized by mainly comprising the following steps:
(1) under the conditions that dichloromethane is used as a solvent and N, N' -carbonyldiimidazole is used as a condensation reagent, the compound 1 and the compound 2 react at room temperature, and after the reaction is finished, the obtained material is washed, evaporated to dryness and refined to obtain a compound 3;
(2) hydrolyzing the compound 3 obtained in the step (1) under an alkaline condition, adjusting the pH of the obtained material to 3-4 after the reaction is finished, and performing spin drying and extraction to obtain a compound 4;
(3) under the condition that dichloromethane is used as a solvent, the compound 4 obtained in the step (2) and the compound 5 are subjected to condensation reaction at room temperature, and after the reaction is finished, the obtained material is washed by water, dried by spinning and recrystallized to obtain a compound 6;
(4) protection: taking dichloromethane as a solvent for the compound 6 obtained in the step (3), and adding a protecting group reagent R under the alkaline condition3Reacting with Cl, pouring the materials into ice water after the reaction is finished, separating liquid, washing with water, and spin-drying the solvent to obtain a compound 7;
(5) closing the ring: taking acetonitrile as a solvent for the compound 7 obtained in the step (4), closing a ring under the action of acid, spin-drying the solvent, and then pretreating to obtain a compound 8;
(6) deprotection: hydrolyzing the compound 8 obtained in the step (5) under an alkaline condition to obtain an impurity A;
(7) removing protecting group R from impurity A at 70-80 deg.C with acetonitrile as solvent1Then, the reaction material is subjected to acid washing, spin-drying, extraction, spin-drying and ethanol recrystallization to obtain impurity B.
3. The method for preparing doramevir open-loop impurities according to claim 2, wherein after the reaction in the step (1) is finished, the obtained material is washed with 0.5-1.5N hydrochloric acid aqueous solution, 4-6% sodium carbonate aqueous solution and saturated saline solution in sequence, and the organic phase is evaporated to dryness under reduced pressure and refined to obtain a compound 3; the obtained compound 3 was purified by silica gel column chromatography, and the eluent was n-hexane/ethyl acetate (5: 1) - (1: 1).
4. The method for preparing doramevir open loop impurities according to claim 2, wherein the hydrolysis reaction in the step (2) is carried out in an organic solvent, wherein the organic solvent is any one of methanol, ethanol and isopropanol; the alkali solution is any one of 1-2N aqueous solutions of lithium hydroxide, sodium hydroxide and potassium hydroxide; adding water and an extracting agent for extraction, wherein the extracting agent is dichloromethane.
5. The method for preparing the doramevir ring-opening impurities according to claim 2, wherein the condensation reagent used in the condensation reaction in the step (3) is a compound of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and dicyclohexylcarbodiimide or a compound of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole, and the compound of 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole is preferably used as the condensation reagent; the molar ratio of the condensation reagent to the compound 4 is (1.1: 1) - (2.0: 1); and (3) washing the materials obtained after the reaction, washing with saturated salt water, spin-drying and recrystallizing in sequence, wherein the recrystallization comprises the following specific steps: after the obtained material is dried by spinning, dichloromethane is added for dissolution, n-hexane is added dropwise under stirring, then stirring is carried out at room temperature, and solid is slowly separated out; or adding dichloromethane and n-hexane for reflux dissolution, slowly cooling to room temperature, stirring and crystallizing.
6. The method for preparing dortavir open-loop impurities according to claim 2,the protecting group reagent R in the step (4)3Protecting group R in Cl3Is any one of benzoyl, acetyl, tert-butyl dimethyl silicon base, tert-butyl diphenyl silicon base, benzyl and allyl; the protecting group reagent R3The mol ratio of the Cl to the compound 6 is (1.1: 1) - (2.0: 1); the base used in the reaction is any one of triethylamine, pyridine and N, N' -diisopropylethylamine, and the molar ratio of the base to the compound 6 is (1.1: 1) - (2.0: 1).
7. The method for preparing dortavir open-loop impurities according to claim 2, wherein the acid used for closing the loop in step (5) is one or more of sulfuric acid, p-toluenesulfonic acid, acetic acid and methanesulfonic acid, and the invention prefers a mixed acid of acetic acid and methanesulfonic acid, wherein the addition amount of the methanesulfonic acid is 0.2-0.5 equivalent, and the addition amount of the acetic acid is 4-10 equivalent; the pretreatment method comprises the following steps: after the reaction, the obtained compound 7 is added into dichloromethane, stirred and dissolved, washed by 0.8-1N hydrochloric acid aqueous solution, and dried by spinning under reduced pressure to obtain a compound 8.
8. The method for preparing doramevir open loop impurities according to claim 2, wherein the hydrolysis reaction in the step (6) is carried out in an organic solvent, wherein the organic solvent is any one of methanol, ethanol and isopropanol; the reaction alkali is any one of lithium hydroxide, sodium hydroxide and potassium hydroxide.
9. The process for preparing doriravir open-loop impurities according to claim 2, wherein the protecting group R is removed in the step (7)1The reagent of (2) is magnesium chloride or magnesium bromide, and the molar ratio of the magnesium chloride or magnesium bromide to the impurity A is (1.1: 1) - (2.0: 1); the pickling solution is 5-7N hydrochloric acid aqueous solution.
10. An impurity of dortavir ring opening prepared by the method of any one of claims 1-9, wherein the structure of the impurity a is as follows:
the nuclear magnetic hydrogen spectrum related data of the impurity A are as follows:1H NMR(400MHz,CDCl3)δ:10.55(t,J=5.9Hz,1H),8.64(s,1H),7.37(td,J=8.6,6.4Hz,1H),6.87~6.77(m,3H),6.42(d,J=6.3Hz,1H),5.20~5.08(m,1H),4.65(d,J=5.9Hz,2H),4.05(s,3H),3.71~3.59(m,1H),3.57~3.47(m,1H),2.55(s,1H),2.00~1.90(m,1H),1.84~1.73(m,1H),1.40(d,J=6.9Hz,3H);LC-MS(m/z):434[M+H]+
11. an impurity of dortavir ring opening prepared by the method of any one of claims 1-9, wherein the impurity B has the structure:
Figure FDA0002118168110000041
the nuclear magnetic hydrogen spectrum related data of the impurity B are as follows:1H NMR(400MHz,DMSO-d6)δ:12.28(s,1H),10.60(t,J=5.9Hz,1H),8.80(s,1H),7.55(d,J=6.4Hz,1H),7.43(td,J=8.7,6.6Hz,1H),7.25(ddd,J=10.6,9.3,2.6Hz,1H),7.07(tdd,J=8.5,2.6,1.0Hz,1H),7.01(d,J=6.4Hz,1H),4.89(dt,J=8.2,6.5Hz,1H),4.57(d,J=5.9Hz,2H),4.53(t,J=4.9Hz,1H),3.43~3.35(m,2H),1.94~1.71(m,2H),1.29(d,J=6.8Hz,3H);LC-MS(m/z):420[M+H]+
CN201910601389.8A 2019-07-04 2019-07-04 Preparation method of doriravir open-loop impurities and impurities thereof Pending CN110655517A (en)

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