CN110396099A - The synthetic method of diastereoisomer impurity in a kind of Du Lutewei raw material - Google Patents
The synthetic method of diastereoisomer impurity in a kind of Du Lutewei raw material Download PDFInfo
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- CN110396099A CN110396099A CN201910430917.8A CN201910430917A CN110396099A CN 110396099 A CN110396099 A CN 110396099A CN 201910430917 A CN201910430917 A CN 201910430917A CN 110396099 A CN110396099 A CN 110396099A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
Invention provides a kind of synthetic method of diastereoisomer impurity in Du Lutewei raw material, and the synthetic method of the impurity includes: step 1: using SM1 as raw material, condensation reaction occurs with 2,4- difluorobenzylamine, generates compound I；Step 2: compound I reacts with alkali in reaction dissolvent and generates compound II；Step 3: compound II is hydrolyzed in acid condition generates compound III；Step 4: compound III and R- amino butanol generate compound IV using acid catalyzed reaction in reaction dissolvent；Step 5: compound IV generates compound V under conditions of condensing agent catalysis in reaction dissolvent；Step 6: for compound V under the action of alkali metal salt, demethylation generates impurity VI.The synthetic method of diastereoisomer impurity in the Du Lutewei raw material being easy to get the present invention provides a kind of simple process, raw material, new impurity, which is prepared, to provide reference substance for the quality analysis of Du Lutewei, to promote the quality standard of Du Lutewei.
Description
Technical field
The invention belongs to field of medicinal chemistry, in particular to the conjunction of diastereoisomer impurity in a kind of Du Lutewei raw material
At method.
Background technique
Du Lutewei (dolutegravir, DTG) is to be used to treat in one kind of the research and development listing of in August, 2013 by GSK
The antiviral drugs of HIV-1.It is a kind of human immunodeficiency virus Class1 (HIV-1) integrase chain tra nsfer inhibitor, with
The combination treatment HIV-1 infection of other antiretroviral agents.DTG is by blocking reverse transcription disease with integrating in conjunction with zymophore
The chain tra nsfer step of malicious DNA (DNA) integration, to inhibit hiv integrase；At present Du Lutewei can individually or with
Other medicines combination, for treating adult and 12 years old or more teenager and weight is more than that 40 kilograms of the HIV-1 of child patient feels
Dye；Therefore research is carried out to Du Lutewei to be of great significance.
The miscellaneous Quality Research of Du Lutewei can be used for impurity quantification and quantitative analysis in Du Lutewei production, so as to
To improve the quality standard of Du Lutewei, important directive significance is provided for people's masses'safety medication；And existing research is very
In terms of being mentioned to Du Lutewei impurity less, thus found that the quality for further improving Du Lutewei has very big difficulty.
Summary of the invention
In view of the above-mentioned problems, the present invention provides a kind of synthetic method of diastereoisomer impurity in Du Lutewei raw material,
The impurity has the structure such as following formula (VI):
The synthetic method of formula (VI) impurity includes:
Step 1: with 1- (2,2- dimethoxy-ethyl) -5- methoxyl group -6- (methoxycarbonyl) -4- oxo-Isosorbide-5-Nitrae-two
Pyridinium hydroxide -3- formic acid is raw material, and condensation reaction occurs with 2,4- difluorobenzylamine, generates compound I；
Step 2: compound I reacts with alkali in reaction dissolvent and generates compound II；
Step 3: compound II is hydrolyzed in acid condition generates compound III；
Step 4: compound III and R- amino butanol generate compound IV using acid catalyzed reaction in reaction dissolvent；
Step 5: under conditions of condensing agent catalysis intramolecular cyclization generationization occurs for compound IV in reaction dissolvent
Close object V；
Step 6: for compound V under the action of alkali metal salt, demethylation generates impurity VI.
Further, the condensing agent of condensation reaction is CDI in the step 1, and the solvent of the condensation reaction is dichloromethane
One of alkane, acetone, tetrahydrofuran, dioxane are a variety of, and the temperature of the condensation reaction is 30~65 DEG C, the condensation
The time of reaction is 1~5h.
Further, the solvent of the condensation reaction is methylene chloride.
Further, the alkali in the step 2 be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide,
One of cesium carbonate, triethylamine are a variety of, and the reaction dissolvent is methanol, ethyl alcohol, isopropanol, n-butanol, one in acetone
Kind is a variety of.
Further, the alkali in the step 2 is sodium hydroxide and potassium hydroxide.
Further, the acid in the step 3 is one of formic acid, acetic acid, trifluoroacetic acid, p-methyl benzenesulfonic acid or more
Kind.
Further, reaction dissolvent is acetonitrile, tetrahydrofuran, ethyl acetate, one in dioxane in the step 4
Kind is a variety of；The acid is one of formic acid, acetic acid, hydrochloric acid, phosphoric acid, sulfuric acid, p-methyl benzenesulfonic acid, methanesulfonic acid or a variety of.
Further, reaction dissolvent is acetonitrile in the step 4, and the acid is formic acid.
Further, the reaction dissolvent in the step 5 is N, N- dimethylformamide, dimethyl sulfoxide, N, N- diformazan
One of base acetyl ammonia is a variety of；The condensing agent includes one of HATU, HBTU, CDI, and the reaction temperature is 0~
40℃。
Further, the reaction dissolvent of demethylation is one of tetrahydrofuran, dioxane, acetone in the step 6
Or it is a variety of；The alkali metal salt is one of lithium bromide, sodium bromide, potassium bromide, lithium iodide, sodium iodide, potassium iodide.
The conjunction of diastereoisomer impurity in the Du Lutewei raw material being easy to get the present invention provides a kind of simple process, raw material
At method, new impurity is prepared, reference substance can be provided for the quality analysis of Du Lutewei, to promote the matter of Du Lutewei
Amount standard.Other features and advantages of the present invention will be illustrated in the following description, also, partly becomes from specification
It is clear that understand through the implementation of the invention.The objectives and other advantages of the invention can be by wanting in specification, right
Pointed structure is sought in book and attached drawing to be achieved and obtained.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described, it should be apparent that, the accompanying drawings in the following description is this hair
Bright some embodiments for those of ordinary skill in the art without creative efforts, can be with root
Other attached drawings are obtained according to these attached drawings.
Fig. 1 shows the synthetic schemes of the diastereoisomer impurity in the Du Lutewei raw material of the embodiment of the present invention；
Fig. 2 shows the synthetic schemes of the raw material of the embodiment of the present invention.
Specific embodiment
In order to make the object, technical scheme and advantages of the embodiment of the invention clearer, below in conjunction with the embodiment of the present invention
In attached drawing, technical solution in the embodiment of the present invention clearly and completely illustrated, it is clear that described embodiment is
A part of the embodiment of the present invention, instead of all the embodiments.Based on the embodiments of the present invention, those of ordinary skill in the art
Every other embodiment obtained without making creative work, shall fall within the protection scope of the present invention.
Fig. 1 shows the synthetic schemes of the diastereoisomer impurity in the Du Lutewei raw material of the embodiment of the present invention.
As shown in Figure 1, in a kind of Du Lutewei raw material diastereoisomer impurity synthetic method, wherein the impurity synthesized has
Such as the structure of following formula (VI):
The synthetic method of formula (VI) impurity includes:
Step 1: with SM1 (oxo -1 1- (2,2- dimethoxy-ethyl) -5- methoxyl group -6- (methoxycarbonyl) -4-,
4- dihydropyridine -3- formic acid) it is raw material, condensation reaction occurs with SM3 (2,4- difluorobenzylamine), generates compound I；
Wherein, the condensing agent of condensation reaction selects CDI (N, N'- carbonyl dimidazoles)；Reaction dissolvent selects methylene chloride, third
One of ketone, tetrahydrofuran, dioxane are a variety of, it is preferred that reaction dissolvent selects methylene chloride (DCM), selects dichloro
Methane is easily removed, and good to the dissolubility of raw material and product, side reaction is less because it is low boiling point solvent；Condensation reaction
Temperature be 30~65 DEG C；The time of condensation reaction is 1~5h；Since temperature too low reaction speed is too slow, raw material reaction is endless
Entirely, yield is lower, brings bigger difficulty to post-processing and purifying.When reaction temperature reaches 40 DEG C or more, reaction speed is bright
It is aobvious to accelerate, it improves work efficiency.
Specifically, the synthetic method of compound I are as follows: under room temperature, the raw material of 50.0g is added into dry there-necked flask
The CDI of SM1,33.4g add the reaction solution DCM of 500.0mL；Nitrogen displacement then is carried out to there-necked flask inside；It is exemplary
, nitrogen displacement is extracted out the air in container using nitrogen replaceable equipment, is realized and is carried out nitrogen displacement, main purpose is to keep away
Exempt from the oxygen in container in fuel gas and air and form flammable mixtures, and then may cause internal combustion or explosion；Nitrogen is set
Exchange device includes: nitrogen linking is received and affiliated accessory, liquefied petroleum gas linking receipts, nitrogen cylinder and tank-truck for liquefied petroleum gas.
After the completion of nitrogen displacement 40 DEG C at a temperature of make above-mentioned mixed liquor reaction 3h, be then down to room temperature, 27.2g be added
SM3, be allowed to react 2~3h after mixing is rocked in room temperature；The water of 300.0mL is then added into reaction solution, is steamed by decompression
The mode evaporated removes major part DCM, residue is filtered, and makes filtrate layered by standing, takes organic phase, and remaining water phase
It is extracted twice again with the extract liquor DCM of 200.0mL；Then the organic phase obtained after extraction is obtained with filtrate layered organic
Mutually merge, it is dry with anhydrous sodium sulfate after merging.Organic phase is refiltered afterwards, the silica gel that 70.0g is added in filtrate after filtering carries out
Sample is mixed, solvent is evaporated off in back spin, then carries out column chromatography for separation, and mobile phase utilizes methylene chloride when column chromatography for separation: methanol=
100:1 (volume ratio) is eluted, and the component after collecting elution, evaporated under reduced pressure obtains grease 52.20g, as compound I.
Illustratively, revolving, which removes solvent, is carried out by rotary evaporator, and continuous still under reduced pressure is mainly used for
Volatile solvents, rotary evaporator are usually made of the part such as motor, cucurbit, heating kettle, condenser pipe；Carrying out DCM's
When removal, 40 DEG C (boiling points of DCM) can be heated to, DCM evaporation can be made to achieve the effect that remove DCM.Column chromatography for separation method is
According to adsorption capacity of the substance in stationary phase be different and is separated, the big substance of polarity is easily fixed phase under normal circumstances
Absorption, the small substance of polarity, which is not easy to be fixed, mutually to be adsorbed, and column chromatography procedure is Adsorption and desorption, the mistake adsorbing and desorb again again
Journey；Silica gel is as stationary phase in column chromatography for separation, to the separation of complex organic compound efficiency with higher, the leaching of mobile phase
Lotion selection has a significant impact to column chromatography separating effect tool, and the component big to polarity selects highly polar leaching in column chromatography
Lotion, the component weak to polarity then select the eluent of low pole to elute, and the eluent of above-mentioned column chromatography for separation uses two
Chloromethanes: methanol=100:1 (volume ratio) is eluted.
Step 2: compound I reacts with alkali in reaction dissolvent and generates compound II；
Wherein, alkali selection sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide, cesium carbonate, in triethylamine
It is one or more, it is preferred that alkali selects the aqueous solution of sodium hydroxide and potassium hydroxide, and reaction dissolvent selects methanol, ethyl alcohol, isopropyl
One of alcohol, n-butanol, acetone are a variety of.
Specifically, the generation method of compound II are as follows: EtOH (ethyl alcohol) 500ml is taken, by the change of the 52.20g in step 1
It closes object I to be dissolved in EtOH, the 2N sodium hydrate aqueous solution of 177.8ml is added under room temperature；Wherein the sodium hydroxide of 2N is water-soluble
Liquid is 2mol/l sodium hydrate aqueous solution；Preparation method is marked by the way that the sodium hydrate solid of 80g to be dissolved in distilled water
Surely the solution for obtaining 1L takes 177.8ml to carry out aforesaid operations from the solution of 1L.
The mixed solution that sodium hydroxide is added is stirred into 1~2h at room temperature；Concentrated hydrochloric acid tune pH to 1.0 is added, adds
The water and 300mL methylene chloride for entering 100mL, are layered solution left standstill after being sufficiently mixed, take organic phase；Again for isolated water phase
It is extracted one time with 300.0mL methylene chloride, takes organic phase extracted, merge the organic phase obtained twice；Then by organic phase
It is dry by anhydrous sodium sulfate, it is then filtered, filtrate is spin-dried for obtaining grease 55.0g, as compound II.
Wherein, filtrate is spin-dried for referring to that removal solvent obtains crystal, is spin-dried for filtrate and needs with revolving instrument.
It should be noted that organic phase and inorganic phase are mainly two kinds of different compounds of density, when standing, will appear point
Liquid can be convenient for extracting, and general organic phase is organic matter, and inorganic phase is inorganic matter.Illustratively, the mixing of water and oil
Liquid, after standing water oil can because density difference and be layered, oil because density is small and be in water top, the two be layered
Afterwards convenient for the separation of the two；Oil is organic matter, as organic phase in this example；Water is that inorganic matter is inorganic phase.
Step 3: compound II is hydrolyzed in acid condition generates compound III；
Wherein, one of acid selection formic acid, acetic acid, trifluoroacetic acid, p-methyl benzenesulfonic acid or a variety of, it is preferred that acid selection
Formic acid.
Specifically, the generation method of compound III are as follows: 55.0g compound II obtained in step 2 to be dissolved in
In 550.0mL formic acid, 3~4h being reacted under conditions of 90 DEG C, solvent is evaporated off, obtain off-white powder, weigh 49.03g, as changes
Close object III.
Step 4: compound III and R- amino butanol generate compound IV using acid catalyzed reaction in reaction dissolvent；
Wherein, one of reaction dissolvent selection acetonitrile, tetrahydrofuran, ethyl acetate, dioxane or a variety of, preferably
, reaction dissolvent selects acetonitrile；One of acid selection formic acid, acetic acid, hydrochloric acid, phosphoric acid, sulfuric acid, p-methyl benzenesulfonic acid, methanesulfonic acid
It is or a variety of, it is preferred that acid selection formic acid.
Specifically, the synthetic method of compound IV are as follows: the 49.03g compound III in step 3 is dissolved in 500.0mL second
In nitrile, the SM2 (R- amino butanol) of 17.2g, the formic acid of 3.87g are added under stirring condition, reacts mixed solution in 62 DEG C
13~14h.Reaction solution is removed under reduced pressure, 100.0mL acetonitrile is added into residue, continues to be evaporated under reduced pressure, obtains grease 60.0g,
As compound IV.
Step 5: under conditions of condensing agent catalysis intramolecular cyclization generationization occurs for compound IV in reaction dissolvent
Close object V；
Wherein, reaction dissolvent selects N, N- dimethylformamide, dimethyl sulfoxide, N, one of N- dimethylacetamide ammonia
It is or a variety of, it is preferred that reaction dissolvent selects N, N- dimethylformamide；Condensing agent selects HATU, and ((7- aoxidizes three nitrogen of benzo to 2-
Azoles)-N, N, N', N'- tetramethylurea hexafluorophosphate), HBTU (2- (7- aoxidize benzotriazole)-N, N, N', N'- tetramethyl
Urea hexafluorophosphate), one of CDI (N, N'- carbonyl dimidazoles), it is preferred that condensing agent selects HATU, reaction temperature selection
0~40 DEG C.
Specifically, the synthetic method of compound V are as follows: compound IV obtained in step 4 is taken 20.0g, is dissolved in 200ml
DMF (n,N-Dimethylformamide) in, be added the DIEA (n,N-diisopropylethylamine) of HATU, 23.0mL of 25.0g, 25
It is allowed to react 2~3h, end of reaction under conditions of DEG C, revolving removes major part DMF, and the 1N of 500.0mL is added into residue
Aqueous hydrochloric acid solution (1mol/l aqueous hydrochloric acid solution), 300.0mL ethyl acetate stand after mixing, then take organic phase；For surplus
Remaining water phase uses 100.0mL ethyl acetate to extract five times again, and the organic phase being obtained by extraction merges with the organic phase obtained is stood.It is past
It is slowly added to saturated sodium bicarbonate aqueous solution tune pH to 7~8 in organic phase, concussion a period of time, is allowed to be sufficiently mixed, then take
Organic phase, organic phase is washed twice with 300.0mL saturated sodium-chloride water solution extraction again, dry with anhydrous sodium sulfate.Having after drying
Solvent is mutually removed by distillation in machine, and gained grease column chromatographic purifying uses methylene chloride: methanol=100:1 (volume ratio) first
Eluted, then with methylene chloride: methanol=50:1 (volume ratio) elutes, and collects same component, is spin-dried for, obtains white solid
4.5g, purity 99.942%；As compound V.
Illustratively, configure 1N aqueous hydrochloric acid solution aqueous solution method are as follows: if selection 36-38% concentrated hydrochloric acid solution into
Row configuration calculates the volume of used concentrated hydrochloric acid: according to molar concentration (1mol) × molecular weight (36.46) ÷ content first
It is about 90mL that volume, which can be obtained, in (36~38% can calculate by 37) ÷ density (1.18)；Then pass through (36~38%) of 90ml
Hydrochloric acid, which adds water to be settled to 1000mL, can be obtained the aqueous hydrochloric acid solution of 1N.
Step 6: for compound V under the action of alkali metal salt, demethylation generates compound VI.
Wherein, one of the reaction dissolvent selection tetrahydrofuran of demethylating reaction, dioxane, acetone or a variety of, it is excellent
Choosing, reaction dissolvent selects tetrahydrofuran；Alkali metal salt selects lithium bromide, sodium bromide, potassium bromide, lithium iodide, sodium iodide, iodate
One of potassium, it is preferred that alkali metal salt selects lithium bromide.
The synthesis of compound VI: it by IM3-ZC (compound V) 2.0g in step 5, is dissolved in 16.0mL and obtains THF (tetrahydro
Furans) in, the LiBr (lithium bromide) of 1.0g is added, is heated to flowing back, reacts 3 hours, is down to room temperature, the 1N of 10.0ml is added
(1mol/l) aqueous hydrochloric acid solution quenching reaction, is removed under reduced pressure most of THF, adds the methylene chloride of 20.0mL, and concussion is layered,
Take organic phase；It uses the methylene chloride of 20.0mL to extract again one time wherein remaining water phase, merges the organic phase that two sides obtain, subtract
Pressure is spin-dried for, and is obtained the isopropanol that 20.0mL is added in off-white powder, is then beaten, is filtered；Obtained filter cake is in 40.0 DEG C of drums
It air-dries dry, obtains off-white powder 1.45g, purity 98.652%, the diastereo-isomerism in compound VI, that is, Du Lutewei raw material
Body impurity.
The present invention be with SM1 (oxo -1 1- (2,2- dimethoxy-ethyl) -5- methoxyl group -6- (methoxycarbonyl) -4-,
4- dihydropyridine -3- formic acid) it is raw material；Illustratively, Fig. 2 shows the flow charts of SM1 synthesis；As shown in Figure 2；SM1 raw material
Synthetic method are as follows:
With compound a (4- chloro methyl acetoacetate) and compound b (benzyl alcohol) for raw material, under the action of cesium carbonate,
Purifying obtains compound c after using toluene as solvent reaction；Illustratively, the equivalent proportion of compound a, compound b and cesium carbonate are as follows:
1:(1.0~1.5): (2~5)；Reaction temperature is 105~110 DEG C, and the reaction time is 8~12h.
Under the action of sodium methoxide, purifying obtains compound after being reacted using toluene as solvent condensation by compound c and compound d
e；Illustratively, the equivalent proportion of compound c, compound d and sodium methoxide are as follows: 1:(2~3.5): (1~1.5)；Reaction temperature is
100~110 DEG C, the reaction time is 3~5h.
Compound e and compound f under the action of sodium tert-butoxide, using toluene as solvent annulation after purify and obtain chemical combination
Object g；Illustratively, the equivalent proportion of compound e, compound f and sodium tert-butoxide are as follows: 1:(1.2~1.6): (0.5~0.8)；Instead
Answering temperature is 105~110 DEG C, and the reaction time is 6~8h.
Compound h is added dropwise in the case where being heated to reflux in compound g and solvent toluene, and purifying obtains compound i after substitution；
Illustratively, the equivalent proportion of compound g and compound h are as follows: 1:(1.1~1.3)；Reaction temperature is 95~105 DEG C, the reaction time
For 2~3h.
Compound i is reacted with alkali metal salt generates j, and wherein j is SM1 (1- (2,2- dimethoxy-ethyl) -5- methoxy
Base -6- (methoxycarbonyl) -4- oxo-Isosorbide-5-Nitrae-dihydropyridine -3- formic acid).
The impurity that the present invention is prepared can provide reference substance for the quality analysis of Du Lutewei, to promote Du Lutewei
Quality standard.
It needs, what the OMe in diagram was indicated is methoxyl group；What Bn was indicated is benzyl；Et indicates ethyl.
Although the present invention is described in detail referring to the foregoing embodiments, those skilled in the art should manage
Solution: it is still possible to modify the technical solutions described in the foregoing embodiments, or to part of technical characteristic into
Row equivalent replacement；And these are modified or replaceed, various embodiments of the present invention technology that it does not separate the essence of the corresponding technical solution
The spirit and scope of scheme.
Claims (10)
1. the synthetic method of diastereoisomer impurity in a kind of Du Lutewei raw material, it is characterised in that: the impurity has such as
The structure of lower formula (VI):
The synthetic method of formula (VI) impurity includes:
Step 1: with 1- (2,2- dimethoxy-ethyl) -5- methoxyl group -6- (methoxycarbonyl) -4- oxo-Isosorbide-5-Nitrae-dihydro pyrrole
Pyridine -3- formic acid is raw material, and condensation reaction occurs with 2,4- difluorobenzylamine, generates compound I；
Step 2: compound I reacts with alkali in reaction dissolvent and generates compound II；
Step 3: compound II is hydrolyzed in acid condition generates compound III；
Step 4: compound III and R- amino butanol generate compound IV using acid catalyzed reaction in reaction dissolvent；
Step 5: compound IV occurs intramolecular cyclization under conditions of condensing agent catalysis and generates compound in reaction dissolvent
V；
Step 6: for compound V under the action of alkali metal salt, demethylation generates impurity VI.
2. according to claim 1 in Du Lutewei raw material diastereoisomer impurity synthetic method, it is characterised in that: institute
The condensing agent for stating condensation reaction in step 1 is CDI, and the solvent of the condensation reaction is methylene chloride, acetone, tetrahydrofuran, two
One of six ring of oxygen is a variety of, and the temperature of the condensation reaction is 30~65 DEG C, and the time of the condensation reaction is 1~5h.
3. according to claim 2 in Du Lutewei raw material diastereoisomer impurity synthetic method, it is characterised in that: institute
The solvent for stating condensation reaction is methylene chloride.
4. according to claim 1 to 3 in Du Lutewei raw material diastereoisomer impurity synthetic method,
Be characterized in that: the alkali in the step 2 is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium hydroxide, cesium carbonate, three
One of ethamine is a variety of, and the reaction dissolvent is one of methanol, ethyl alcohol, isopropanol, n-butanol, acetone or a variety of.
5. according to claim 4 in Du Lutewei raw material diastereoisomer impurity synthetic method, it is characterised in that: institute
Stating the alkali in step 2 is sodium hydroxide and potassium hydroxide.
6. according to claim 1 to 3 in Du Lutewei raw material diastereoisomer impurity synthetic method,
Be characterized in that: the acid in the step 3 is one of formic acid, acetic acid, trifluoroacetic acid, p-methyl benzenesulfonic acid or a variety of.
7. according to claim 1 to 3 in Du Lutewei raw material diastereoisomer impurity synthetic method,
Be characterized in that: reaction dissolvent is one of acetonitrile, tetrahydrofuran, ethyl acetate, dioxane or a variety of in the step 4；
The acid is one of formic acid, acetic acid, hydrochloric acid, phosphoric acid, sulfuric acid, p-methyl benzenesulfonic acid, methanesulfonic acid or a variety of.
8. according to claim 7 in Du Lutewei raw material diastereoisomer impurity synthetic method, it is characterised in that: institute
Stating reaction dissolvent in step 4 is acetonitrile, and the acid is formic acid.
9. according to claim 1 to 3 in Du Lutewei raw material diastereoisomer impurity synthetic method,
Be characterized in that: the reaction dissolvent in the step 5 is N, N- dimethylformamide, dimethyl sulfoxide, N, N- dimethylacetamide ammonia
One of or it is a variety of；The condensing agent includes one of HATU, HBTU, CDI, and the reaction temperature is 0~40 DEG C.
10. according to claim 1 to 3 in Du Lutewei raw material diastereoisomer impurity synthetic method,
Be characterized in that: the reaction dissolvent of demethylation is one of tetrahydrofuran, dioxane, acetone or a variety of in the step 6；
The alkali metal salt is one of lithium bromide, sodium bromide, potassium bromide, lithium iodide, sodium iodide, potassium iodide.
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| CN114213432A (en) * | 2021-12-31 | 2022-03-22 | 瑞孚信江苏药业股份有限公司 | Preparation method of dolutegravir |
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| CN103154004A (en) * | 2010-08-05 | 2013-06-12 | 盐野义制药株式会社 | Process for preparing compound having HIV integrase inhibitory activity |
| WO2014128545A2 (en) * | 2013-02-19 | 2014-08-28 | Aurobindo Pharma Limited | An improved process for the preparation of dolutegravir |
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- 2019-05-22 CN CN201910430917.8A patent/CN110396099A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103154004A (en) * | 2010-08-05 | 2013-06-12 | 盐野义制药株式会社 | Process for preparing compound having HIV integrase inhibitory activity |
| WO2014128545A2 (en) * | 2013-02-19 | 2014-08-28 | Aurobindo Pharma Limited | An improved process for the preparation of dolutegravir |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114213432A (en) * | 2021-12-31 | 2022-03-22 | 瑞孚信江苏药业股份有限公司 | Preparation method of dolutegravir |
| CN114213432B (en) * | 2021-12-31 | 2023-02-17 | 瑞孚信江苏药业股份有限公司 | Preparation method of dolutegravir |
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Application publication date: 20191101 |