CN108101838B - Synthesis method of dolutegravir intermediate and related substance detection method thereof - Google Patents
Synthesis method of dolutegravir intermediate and related substance detection method thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/89—Inverse chromatography
Abstract
The invention discloses a synthesis method of a dolutegravir intermediate and a related substance detection method thereof, wherein 4-chloroacetoacetic acid methyl ester and benzyl alcohol are used as starting materials, a dolutegravir intermediate i is obtained only by four-step reaction, the reaction conditions are simple, only one toluene is used as a solvent in the reaction, the raw materials are easy to obtain, the obtained product is subjected to post-treatment and purification by a column chromatography method, the yield of the product obtained in each step is up to more than 90%, and the method is suitable for industrial production; the method for detecting the related substances of the intermediate i of dolutegravir adopts a high performance liquid chromatography, and the content of the related substances of the intermediate i of dolutegravir is 99.6 percent through detection, the separation degree of each impurity is greater than 3.0, and the separation degree is better.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a synthesis method of a dolutegravir intermediate and a related substance detection method thereof.
Background
Dolutegravir (Dolutegravir), whose chemical name is (4R,12aS) -N- [ (2, 4-difluorophenyl) methyl ] -3,4,6,8,12,12 a-hexahydro-7-hydroxy-4-methyl-6, 8-dioxo-2H-pyrido [1 ', 2': 4,5] pyrazino [2,1-b ] [1,3] oxazine-9-carboxamide, CAS registry number 1051375-16-6, the dolutegravir is a new anti-HIV drug under the flag of British pharmaceutical megalobemin Sterk (GSK), and is approved by Food and Drug Administration (FDA) of China, 8 months and 12 months in 2013 to be used for treating or primarily treating HIV-1 adults and children infected persons of 12 years and more and with the weight of at least 40 kg.
Dolutegravir is a once daily drug that achieves efficacy in phase III clinical trials comparable to the molassadon HIV/AIDS drug Raltegravir (Raltegravir, Isentress). Letegravir was administered 2 times daily, and 2 were inhibitors of HIV integrase. FDA officials indicate that aids infected people need targeted treatment according to individual specifications, and Tivicay will provide new options for patients. In a study conducted one year ago, 88% of patients received Tivicay for 48 weeks, with a significant improvement over the Atripla from Gilead. Analysts expect Dolutegravir to be a heavy pound drug sold annually in the billions of dollars, and will be a strong competitor of the best-selling HIV composite drug, Atripla, in the world by gillided Sciences.
2, 5-pyridinedicarboxylic acid, 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-4-oxo-3-benzyloxy-2, 5-dimethyl ester is a basic and key intermediate in dolutegravir synthesis, the method has important significance for the synthesis research of finished products of dolutegravir, the existing synthesis intermediate 2, 5-pyridinedicarboxylic acid, 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-4-oxo-3-benzyloxy-2, 5-dimethyl ester takes maltol [ formula (2) ] as a starting material, the synthesis route is longer, the steps are more complicated, the types and raw materials of related solvents are more, the large-scale production is not facilitated, the related detection methods are more, and the development and actual detection of the detection methods are not facilitated.
Disclosure of Invention
The invention aims to provide a dolutegravir intermediate synthesis method and a related substance detection method thereof, wherein the dolutegravir intermediate 2, 5-pyridinedicarboxylic acid, 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-4-oxo-3-benzyloxy-2, 5-dimethyl ester is obtained by four-step reaction, the reaction conditions are simple, only one toluene solvent is used in the reaction, the raw materials are easy to obtain, and the method is suitable for industrial production.
The purpose of the invention can be realized by the following technical scheme:
a synthetic method of a dolutegravir intermediate is disclosed, wherein the synthetic route of the dolutegravir intermediate i is as follows:
the specific synthesis steps are as follows:
s1, reacting the compound a and the compound b with toluene as a solvent under the action of cesium carbonate, and purifying to obtain a compound c;
s2, carrying out condensation reaction on the compound c and the compound d under the action of sodium methoxide by taking toluene as a solvent, and purifying to obtain a compound e;
s3, performing cyclization reaction on the compound e and the compound f under the action of sodium tert-butoxide by taking toluene as a solvent, and purifying to obtain a compound g;
and S4, dropwise adding the compound g and a solvent toluene into the mixture under heating reflux, and purifying after substitution to obtain the dolutegravir intermediate i.
Further, the equivalent ratio of the compound a, the compound b and the cesium carbonate in the step S1 is: 1:1.0-1.5: 2-5; the reaction temperature is 105-110 ℃, and the reaction time is 8-12 h.
Further, the equivalent ratio of the compound c, the compound d and sodium methoxide in step S2 is: 1:2-3.5: 1-1.5; the reaction temperature is 100-110 ℃, and the reaction time is 3-5 h.
Further, the equivalent ratio of the compound e, the compound f and the sodium tert-butoxide in the step S3 is: 1:1.2-1.6: 0.5-0.8; the reaction temperature is 105-110 ℃, and the reaction time is 6-8 h.
Further, the equivalent ratio of the compound g to the compound h in the step S4 is: 1: 1.1-1.3; the reaction temperature is 95-105 ℃, and the reaction time is 2-3 h.
Further, the crude products of the compound c, the compound e, the compound g and the compound i obtained by the reaction are purified by column chromatography, and the crude product of the compound c is purified by petroleum ether: dichloromethane is 10:3 as eluent; the column chromatography of the crude product of the compound e adopts petroleum ether and methanol as 5:1 as eluent; the column chromatography of the crude compound g adopts n-hexane, ethyl acetate 9:4 as eluent; the column chromatography of the crude product of the compound i adopts n-hexane to ethyl acetate: methanol 12:3: 2as eluent.
A method for detecting related substances of a dolutegravir intermediate adopts high performance liquid chromatography for detecting related substances of a dolutegravir intermediate i, a used chromatographic column is a reversed-phase chromatographic column, and a filler of the reversed-phase chromatographic column is octadecylsilane chemically bonded silica or octylsilane chemically bonded silica; the method comprises the following steps of (1) dissolving a dolutegravir intermediate i by using a diluent at the wavelength of 210nm and the column temperature of 30 ℃, injecting the dissolved dolutegravir intermediate i into a high performance liquid chromatograph, wherein the sample amount is 10ul, and adopting a gradient elution method, wherein a 0.1% phosphoric acid aqueous solution is used as a water phase, and acetonitrile is used as an organic phase, wherein the elution gradient is as follows:
wherein the flow rate is 0.8-1.2 ml/min.
Furthermore, the reverse phase chromatographic column adopts a waters Xbridge C185 μm, 4.6X 150mm type chromatographic column.
Further, the diluent is methanol, and the concentration of the dolutegravir intermediate is 0.3-0.8 mg/ml.
Further, the flow rate was 1.0 ml/min.
The invention has the beneficial effects that:
the invention provides a synthesis method of a dolutegravir intermediate and a related substance detection method thereof, wherein 4-chloroacetoacetic acid methyl ester and benzyl alcohol are used as starting materials, the dolutegravir intermediate 2, 5-pyridinedicarboxylic acid, 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-4-oxo-3-benzyloxy-2, 5-dimethyl ester can be obtained by four-step reaction, the reaction conditions are simple, only one toluene is used as a solvent in the reaction, the raw materials are easy to obtain, column chromatography is adopted for post-treatment and purification of the obtained product, the yield of the product obtained in each step is up to more than 90%, and the method is suitable for industrial production; the detection method of the related substances of the dolutegravir intermediate i adopts high performance liquid chromatography, the analysis method is simple, the conditions are relatively common, the operation is easy, the content of the related substances of the 2, 5-pyridinedicarboxylic acid, 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-4-oxo-3-benzyloxy-2, 5-dimethyl ester is 99.6 percent through detection, the separation degree of each impurity is more than 3.0, and the separation degree is better.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all 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
Synthesis of methyl 4- (benzyloxy) -3-oxobutyrate
Adding 50mol of 4-methyl chloroacetoacetate, 60mol of benzyl alcohol, 20mol of cesium carbonate and 500ml of toluene into a reaction bottle, putting the reaction bottle into an oil bath pot, heating to 110 ℃, refluxing for 12h, cooling to room temperature after the reaction is finished, filtering, performing rotary evaporation to remove a toluene solvent, separating a crude product by using a column chromatography, wherein an eluent is petroleum ether, and dichloromethane is 10:3, so that 4- (benzyloxy) -3-oxobutyric acid methyl ester is obtained, and the yield is 92%;
example 2
Synthesis of methyl 4-benzyloxy-2- ((dimethylamino) methylene) -3-acetoacetate
Putting 40mol of methyl 4- (benzyloxy) -3-oxobutyrate obtained in example 1, 120mol of N, N-dimethylformamide dimethyl acetal, 40mol of sodium methoxide and 400ml of toluene into a reaction bottle, putting the reaction bottle into an oil bath kettle, heating to 100 ℃, refluxing for 5 hours, cooling to room temperature after the reaction is finished, adding a saturated sodium chloride solution and 3% hydrochloric acid into the reaction bottle, shaking for 10 minutes, layering, pouring out an organic layer, removing the solvent by using a rotary evaporator to obtain a crude product, and then separating the crude product by using column chromatography, wherein an eluent is petroleum ether, namely methanol is 5:1, so that methyl 4-benzyloxy-2- ((dimethylamino) methylene) -3-acetoacetate is obtained with the yield of 95%;
example 3
Synthesis of 4-oxo-3-benzyloxy-4H-pyran-2, 5-dicarboxylic acid dimethyl ester
Putting 30mol of 4-benzyloxy-2- ((dimethylamino) methylene) -3-methyl acetoacetate obtained in example 2, 45mol of dimethyl oxalate, 15mol of sodium tert-butoxide and 300ml of toluene into a reaction bottle, putting the reaction bottle into an oil bath, heating to 105 ℃, refluxing for 6H, cooling to room temperature after the reaction is finished, filtering, performing rotary evaporation to remove a toluene solvent, separating a crude product by column chromatography, wherein an eluant is n-hexane and ethyl acetate is 9:4, so that 4-oxo-3-benzyloxy-4H-pyran-2, 5-dicarboxylic acid dimethyl ester is obtained, and the yield is 90%;
example 4
Synthesis of 2, 5-pyridinedicarboxylic acid, 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-4-oxo-3-benzyloxy-2, 5-dimethyl ester
Adding 10mol of 4-oxo-3-benzyloxy-4H-pyran-2, 5-dicarboxylic acid dimethyl ester obtained in example 3 and 100ml of toluene into a reaction bottle, then putting the reaction bottle into an oil bath kettle, heating to 100 ℃, dropwise adding 12mol of aminoacetaldehyde dimethyl acetal when refluxing, continuing refluxing for 3 hours after the addition is finished, cooling to room temperature after the reaction is finished, removing the toluene solvent by rotary evaporation, and then separating a crude product by column chromatography, wherein an eluent is n-hexane: methanol-12: 3:2 gave 2, 5-pyridinedicarboxylic acid, 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-4-oxo-3-benzyloxy-2, 5-dimethyl ester in a yield of 91%;
example 5
Detection of related substances of 2, 5-pyridinedicarboxylic acid, 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-4-oxo-3-benzyloxy-2, 5-dimethyl ester: the related substances are detected by high performance liquid chromatography, a chromatographic column adopts waters XBridge C185 μm and 4.6 × 150mm, the wavelength is 210nm, the column temperature is 30 ℃, the concentration of a detected substance is 0.5mg/ml, methanol is used as a diluent, the sample injection amount is 10ul, the flow rate is 1ml/min, 0.1% phosphoric acid aqueous solution is used as an aqueous phase, acetonitrile is used as an organic phase, and the elution gradient is as follows:
through related substance detection, the content of the 2, 5-pyridinedicarboxylic acid, 1- (2, 2-dimethoxyethyl) -1, 4-dihydro-4-oxo-3-benzyloxy-2, 5-dimethyl ester is 99.6%, the separation degree of each impurity is more than 3.0, and the separation degree is better.
The foregoing is merely exemplary and illustrative of the principles of the present invention and various modifications, additions and substitutions of the specific embodiments described herein may be made by those skilled in the art without departing from the principles of the present invention or exceeding the scope of the claims set forth herein.
Claims (5)
1. A method for synthesizing a dolutegravir intermediate is characterized by comprising the following steps: the synthetic route of the dolutegravir intermediate i is as follows:
the specific synthesis steps are as follows:
s1, reacting the compound a and the compound b with toluene as a solvent under the action of cesium carbonate, and purifying to obtain a compound c;
the equivalent ratio of the compound a, the compound b and the cesium carbonate in the step S1 is as follows: 1:1.0-1.5: 2-5; the reaction temperature is 105-110 ℃, and the reaction time is 12 h;
s2, carrying out condensation reaction on the compound c and the compound d under the action of sodium methoxide by taking toluene as a solvent, and purifying to obtain a compound e;
the equivalent ratio of the compound c, the compound d and the sodium methoxide in the step S2 is as follows: 1:2-3.5: 1-1.5; the reaction temperature is 100-110 ℃, and the reaction time is 5 h;
s3, performing cyclization reaction on the compound e and the compound f under the action of sodium tert-butoxide by taking toluene as a solvent, and purifying to obtain a compound g;
the equivalent ratio of the compound e, the compound f and the sodium tert-butoxide in the step S3 is as follows: 1:1.2-1.6: 0.5-0.8; the reaction temperature is 105-110 ℃, and the reaction time is 6 h;
s4, dropwise adding a compound h into the mixture of the compound g and a solvent toluene under heating reflux, and purifying after substitution to obtain a dolutegravir intermediate i;
the equivalent ratio of the compound g to the compound h in the step S4 is as follows: 1: 1.1-1.3; the reaction temperature is 95-105 ℃, and the reaction time is 3 h;
the crude products of the compound c, the compound e, the compound g and the compound i obtained by the reaction are purified by adopting a column chromatography, and the crude product of the compound c is purified by adopting petroleum ether: dichloromethane is 10:3 as eluent; the column chromatography of the crude product of the compound e adopts petroleum ether and methanol as 5:1 as eluent; the column chromatography of the crude compound g adopts n-hexane, ethyl acetate 9:4 as eluent; the column chromatography of the crude product of the compound i adopts n-hexane to ethyl acetate: methanol is 12:3: 2as eluent;
the method for detecting the related substances of the dolutegravir intermediate i comprises the following steps:
the detection of related substances of the dolutegravir intermediate i adopts high performance liquid chromatography, the used chromatographic column is a reversed-phase chromatographic column, and a filler of the reversed-phase chromatographic column is octadecylsilane chemically bonded silica or octylsilane chemically bonded silica; the method comprises the following steps of dissolving a dolutegravir intermediate i by using a diluent at the wavelength of 210nm and the column temperature of 30 ℃, injecting the dissolved dolutegravir intermediate i into a high performance liquid chromatograph, wherein the sample amount is 10ul, and adopting a gradient elution method, wherein a 0.1% phosphoric acid aqueous solution is used as a water phase, and acetonitrile is used as an organic phase, wherein the elution gradient is as follows:
wherein the flow rate is 0.8-1.2 ml/min;
the content of the dolutegravir intermediate i prepared in the step S4 is 99.6%.
2. A method for detecting related substances of a dolutegravir intermediate is characterized by comprising the following steps: the detection of related substances of the dolutegravir intermediate i adopts high performance liquid chromatography, the used chromatographic column is a reversed-phase chromatographic column, and a filler of the reversed-phase chromatographic column is octadecylsilane chemically bonded silica or octylsilane chemically bonded silica; the method comprises the following steps of dissolving a dolutegravir intermediate i by using a diluent at the wavelength of 210nm and the column temperature of 30 ℃, injecting the dissolved dolutegravir intermediate i into a high performance liquid chromatograph, wherein the sample amount is 10ul, and adopting a gradient elution method, wherein a 0.1% phosphoric acid aqueous solution is used as a water phase, and acetonitrile is used as an organic phase, wherein the elution gradient is as follows:
wherein the flow rate is 0.8-1.2 ml/min;
the structural formula of the dolutegravir intermediate i is shown as follows
3. The method for detecting the related substances of the dolutegravir intermediate according to claim 2, characterized in that: the reverse phase chromatographic column adopts waters Xbridge C185 μm, 4.6X 150mm type chromatographic column.
4. The method for detecting the related substances of the dolutegravir intermediate according to claim 2, characterized in that: the diluent is methanol, and the concentration of the dolutegravir intermediate is 0.3-0.8 mg/ml.
5. The method for detecting the related substances of the dolutegravir intermediate according to claim 2, characterized in that: the flow rate was 1.0 ml/min.
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