CN110229174A - The synthetic method of Bictegravir bulk pharmaceutical chemicals genotoxicity impurity - Google Patents
The synthetic method of Bictegravir bulk pharmaceutical chemicals genotoxicity impurity Download PDFInfo
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- CN110229174A CN110229174A CN201910430937.5A CN201910430937A CN110229174A CN 110229174 A CN110229174 A CN 110229174A CN 201910430937 A CN201910430937 A CN 201910430937A CN 110229174 A CN110229174 A CN 110229174A
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- 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
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Abstract
The present invention provides the synthetic methods of Bictegravir bulk pharmaceutical chemicals genotoxicity impurity, specifically include the synthetic method for preparing genotoxicity impurity A and B, first using three fluorin benzyl amines as raw material, reaction obtains three fluorin benzyl amine dimers under alkaline condition, then the three fluorin benzyl amines dimer and compound C are condensed to yield genotoxicity impurity A, the genotoxicity impurity A carries out demethylation and handles to obtain genotoxicity impurity B.
Description
Technical field
The invention belongs to impurity of the drug to synthesize field, in particular to genotoxicity is miscellaneous in a kind of Bictegravir bulk pharmaceutical chemicals
The synthetic method of matter A and genotoxicity impurity B.
Background technique
Biketarvy is the treatment human immunodeficiency virus type 1 (Human researched and developed by Ji Leadd B.V, the U.S.
Immunodeficiency Virus-1, hereinafter referred to as HIV-1) infection drug, on 2 7th, 2018 by U.S.'s food and medicine
Surveillance Authority (Food and Drug Administration, abbreviation FDA) approval listing, significant in efficacy, market manifestation
Well, clinical data shows that Biketarvy and conventional inverase do not find side effect and resistance to during treating within 3 months at present
Pharmacological property.Biketarvy is by Bictegravir (50mg), emtricitabine (Emtricitabine, 200mg), tenofovir Chinese mugwort
Three kinds of drawing phenol amine fumarate (Tenofovir Alafenamide, 25mg) is at the compound preparation being grouped as.Wherein, grace it is bent he
It is the active drug treated HIV-1 and infect clinical application many years that shore and tenofovir Chinese mugwort, which draw phenol amine fumarate all, and
Bictegravir is then main new chemical molecular entity in drug Biketarvy, is a kind of chain tra nsfer of HIV-1 integrase
Inhibitor (Integrase Strand Transfer Inhibitor, abbreviation INSTI), and integrase is a kind of HIV-1 coding
Virus replication necessary to a kind of enzyme, Bictegravir can inhibit integrase activity, prevent HIV-1 be integrated into place
Main DNA, and then prevent conversion and the virus progression of HIV-1 virus.
Biketarvy is developed to first have to that the active constituent Bictegravir to conform to quality requirements is prepared；And
In Bictegravir preparation process, the preparation work of impurity reference substance is also even more important, and researcher needs in preparation process
The various impurity generated are studied in detail, and the impurity reference substance of acquisition is to active medicaments object ingredient (Active
Pharmaceutical Ingredient, hereinafter referred to as API) production technology exploitation, analysis method exploitation and quality standard formulation
There are significant impacts.And in all impurity reference substances, genotoxicity impurity (including latent gene toxic impurities) is even more important,
International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (International Council for Harmonization, with
Lower abbreviation ICH) guideline in, the metering of the permission daily ingestion of genotoxicity impurity (including latent gene toxic impurities) is
1.5 micrograms/day.During the technique research and development of drug, research staff needs to pay close attention to genotoxicity impurity, understands synthesis base
Because of the method for toxic impurities, genotoxicity impurity and the suitable analysis method of exploitation are removed to develop suitable preparation process
Genotoxicity impurity is detected, genotoxicity impurity is no more than limit specified in ICH guideline in final control API；However,
In the prior art for type, structure or the synthesis side of related gene toxic impurities in Bictegravir bulk pharmaceutical chemicals preparation process
Method is short in understanding.
Summary of the invention
In order to solve Bictegravir bulk pharmaceutical chemicals in the prior art genotoxicity impurity type and synthesis be short in understanding
The technical issues of, the invention discloses genotoxicity impurity A in a kind of Bictegravir bulk pharmaceutical chemicals and genotoxicity impurity Bs
Synthetic method and its synthetic product.
The synthetic method of genotoxicity impurity A in a kind of Bictegravir bulk pharmaceutical chemicals, which comprises 2,4,6- tri-
Fluorin benzyl amine reacts under alkaline condition obtains three fluorin benzyl amine dimers；The three fluorin benzyl amines dimer and compound C are dissolved in two
One of chloromethanes, tetrahydrofuran or ethyl acetate or multi-solvents obtain mixed liquor I；Contracting is added in the mixed liquor I
Mixture and alkali, and it is heated to 20-40 DEG C of reaction 7-8 hours, obtain mixed liquor II；Decompression is carried out to the mixed liquor II to be spin-dried for obtaining
Residue, add the mixture of methylene chloride and methanol as eluant, eluent to residue column chromatography for separation, collection is isolated
Main component, the solvent being spin-dried in the main component obtains genotoxicity impurity A.
Further, described 2,4,6- tri- fluorin benzyl amines react under alkaline condition obtain three fluorin benzyl amine dimers include: by
Described 2,4,6- tri- fluorin benzyl amines are dissolved in one or more solvents in tetrahydrofuran or methylene chloride, obtain mixed liquor III；Described
It is added in hexamethyldisilazide lithium, hexamethyldisilane amine base sodium or potassium hexamethyldisilazide at least in mixed liquor III
A kind of alkali obtains mixed liquor IV；The mixed liquor IV is heated to 25-40 DEG C and is reacted 14 hours, 10% chlorine is added after reaction
Change aqueous ammonium and carry out quenching reaction, vacuum rotary steam removes solvent, obtains mixed liquor V；Dichloromethane is added in the mixed liquor V
Alkane aqueous phase extracted, and organic phase is collected, after carrying out evaporated under reduced pressure to the organic phase, obtain residue；To the residue into
Row column chromatographic purifying is added methylene chloride as eluant, eluent, collects primary product, be spin-dried for solvent, obtain three fluorin benzyl amine dimers.
Further, the three fluorin benzyl amines dimeric structure are as follows:
Further, the compound C-structure are as follows:
Wherein, R, S respectively indicate the chiral configuration of compound.
Further, the condensing agent is 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid
One of salt, dicyclohexylcarbodiimide or 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride are a variety of.
Further, the alkali is one of n,N-diisopropylethylamine or triethylamine or a variety of.
A kind of genotoxicity impurity A of the synthesis of synthetic method described in any one of -6 according to claim 1, feature exist
In the structure of the genotoxicity impurity A are as follows:
Wherein, R, S respectively indicate the chiral configuration of compound.
A kind of synthetic method of genotoxicity impurity B in Bictegravir bulk pharmaceutical chemicals, which is characterized in that the method packet
Include: genotoxicity impurity A being obtained with synthetic method described in any one of claim 1-6 or as claimed in claim 7 is original
Material, is dissolved in one of acetonitrile or dioxane or multi-solvents for the genotoxicity impurity A, obtains mixed liquor VI；Institute
The demethylation reagent that 2.0-4.0 molar equivalent is added in mixed liquor VI is stated, and is heated to 40-50 DEG C of reaction 4-6 hours, obtains base
Because of toxic impurities B.
Further, the demethylation reagent is one of magnesium bromide or lithium bromide or a variety of.
A kind of genotoxicity impurity B of the synthesis of the synthetic method according to any one of claim 8-9, feature exist
In the structure of the genotoxicity impurity B are as follows:
Wherein, R, S respectively indicate the chiral configuration of compound.
The present invention is using three fluorin benzyl amines as raw material, and reaction obtains three fluorin benzyl amine dimers under alkaline condition, then will be described
Three fluorin benzyl amine dimers and compound C are condensed to yield genotoxicity impurity A, and the genotoxicity impurity A carries out demethylation processing
Obtain genotoxicity impurity B.The genotoxicity impurity synthetic method of Bictegravir bulk pharmaceutical chemicals of the present invention, not only can be with
The genotoxicity impurity A and B of purity is high are prepared, and synthesis route is simple and convenient to operate, selectivity is good；Synthesis obtains
Genotoxicity impurity A and B can be used for the quality research of Bictegravir bulk pharmaceutical chemicals and quality control experiment, control
The purity of Bictegravir bulk pharmaceutical chemicals or its preparation.Other features and advantages of the present invention will be explained in the following description
It states, also, partly as will become apparent from the description, or understand through the implementation of the invention.The purpose of the present invention and
Other advantages can be achieved and obtained by structure pointed in the specification, claims and drawings.
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 process of genotoxicity impurity A in synthesis Bictegravir bulk pharmaceutical chemicals according to an embodiment of the present invention
Schematic diagram；
Fig. 2 shows the processes of genotoxicity impurity B in synthesis Bictegravir bulk pharmaceutical chemicals according to an embodiment of the present invention
Schematic diagram.
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 process of genotoxicity impurity A in synthesis Bictegravir bulk pharmaceutical chemicals according to an embodiment of the present invention
Schematic diagram.As shown, first 2,4,6- tri- fluorin benzyl amines react under alkaline condition obtains three fluorin benzyl amine dimers, described in preparation
It is raw material, using tetrahydrofuran, methylene chloride as solvent that three fluorin benzyl amine dimer steps, which include: with 2,4,6- tri- fluorin benzyl amines, then plus
Enter hexamethyldisilazide lithium (Lithium Hexamethyldisilazide, hereinafter referred to as LiHMDS), two silicon of hexamethyl
Base amido sodium (Na Hexamethyldisilazide, hereinafter referred to as NaHMDS), potassium hexamethyldisilazide (K
Hexamethyldisilazide, hereinafter referred to as KHMDS) alkali is done, it is heated to 25~40 DEG C and reacts 14 hours；After completion of the reaction,
10% aqueous ammonium chloride solution is added and carries out quenching reaction, vacuum rotary steam removes solvent, adds methylene chloride aqueous phase extracted, collects
Organic phase after organic phase carries out evaporated under reduced pressure, obtains residue；Column chromatographic purifying, eluant, eluent two are carried out to the residue
Chloromethanes collects primary product, is spin-dried for solvent, obtains yellow solid, as three fluorin benzyl amine dimers.Wherein, described 2,4,6- tri-
The solvent of fluorin benzyl amine is preferably tetrahydrofuran, the three fluorin benzyl amines dimeric structure being prepared are as follows:
Then, using the three fluorin benzyl amines dimer and compound C as raw material, with methylene chloride, tetrahydrofuran or acetic acid second
Ester is solvent, with 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphate (HATU), dicyclohexyl carbon
Diimine (Dicyclohexylcarbodiimide, abbreviation DCC) or 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide salt
Hydrochlorate (EDCI) is condensing agent, with n,N-diisopropylethylamine (DIEA) or triethylamine does alkali, be heated to 20~40 DEG C of reactions 7~
8 hours, obtain mixed liquor II；After the reaction was completed, decompression is carried out to the mixed liquor II to be spin-dried for obtaining residue, add dichloro
The mixture of methane and methanol carries out column chromatography for separation to residue as eluant, eluent, collects the main component isolated, is spin-dried for
Solvent in the main component obtains faint yellow solid, as genotoxicity impurity A.Wherein, the three fluorin benzyl amines dimer
Solvent with compound C is preferably tetrahydrofuran；The condensing agent is preferably that 1- (3- dimethylamino-propyl) -3- ethyl carbon two is sub-
Amine hydrochlorate (EDCI)；The alkali is preferably N, N- diisopropylethylamine (DIEA)；Reaction temperature described in synthetic method is preferably
30~40 DEG C；The eluant, eluent for synthesizing the genotoxicity impurity A is preferably methylene chloride: methanol=50:1 mixture；
The compound C-structure are as follows:
R, S respectively indicates the chiral configuration of compound；
The structure of the genotoxicity impurity A are as follows:
R, S respectively indicates the chiral configuration of compound；The genotoxicity impurity A is a kind of new compound, has no text
Report is offered, can be used for the experiment of the quality research of Bictegravir bulk pharmaceutical chemicals and quality control, to control Bictegravir original
Expect medicine or the purity of its preparation；Meanwhile the genotoxicity impurity A is analysed in depth, convenient also can be research and development people
Member improves Bictegravir bulk pharmaceutical chemicals preparation process and provides relevant technical motivation.
Illustratively, 2,4,6- tri- fluorin benzyl amine 6.4g, tetrahydrofuran 10mL are added in 100mL reaction flask, are added
LiHMDS 20mL is heated to 25~40 DEG C and reacts 14 hours；10% aqueous ammonium chloride solution 15mL is added, stirs 10 minutes, subtracts
Pressure is evaporated off tetrahydrofuran, methylene chloride 20mL aqueous phase extracted is added simultaneously carries out liquid separation and collect organic phase, to organic phase evaporated under reduced pressure,
Again to residue column chromatographic purifying, methylene chloride is added as solvent is spin-dried for after eluant, eluent, obtains yellow solid 4.0g, as three
Fluorin benzyl amine dimer；Then, compound C2.0g, tetrahydrofuran 14mL and three fluorin benzyl amines two are added in 100ml reaction flask
Aggressiveness 2.2g, 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (EDCI) 4g, N, N- diisopropylethylamine
(DIEA) 1.2g is heated to 30~40 DEG C of 7~8h of reaction, then is spin-dried for reaction product, methylene chloride is added later: methanol
The eluant, eluent of=50:1 obtains faint yellow solid, i.e. genotoxicity impurity A 1.2g, purity to residue column chromatography for separation is spin-dried for
It is 98%, mass spectrum (Mass Spectrum, hereinafter referred to as MS): [M+H]+=605.
Fig. 2 shows the processes of genotoxicity impurity B in synthesis Bictegravir bulk pharmaceutical chemicals according to an embodiment of the present invention
Schematic diagram.As shown, genotoxicity impurity B using the genotoxicity impurity A as raw material, carries out demethylation processing, to close
At obtaining genotoxicity impurity B, comprising: using the genotoxicity impurity A as raw material, with acetonitrile, dioxane is solvent, and is added
Entering magnesium bromide or lithium bromide is demethylation reagent, and demethylation reagent dosage is 2.0~4.0 molar equivalents, it is then heated to 40~
50 DEG C are reacted 4~6 hours；To which appropriate hydrochloric acid is added after completion of the reaction, in reaction product and stirs 30 minutes, then it is spin-dried for mixing
Liquid carries out residue column chromatographic purifying, the mixture of methylene chloride and methanol is added as eluant, eluent, synthesis obtains pale yellow colored solid
Body, as genotoxicity impurity B.Wherein, the solvent of the genotoxicity impurity A is preferably 2- methyltetrahydrofuran；It is described de-
Methylating reagent is preferably magnesium bromide；And the demethylation reagent dosage is preferably 3.0 molar equivalents；It is miscellaneous to synthesize the genotoxicity
The eluant, eluent of matter B is preferably methylene chloride: methanol=20:1 mixture；The structure of the genotoxicity impurity B are as follows:
R, S respectively indicates the chiral configuration of compound；The genotoxicity impurity B is also a kind of new compound, has no
Document report can be used for the experiment of the quality research of Bictegravir bulk pharmaceutical chemicals and quality control, to control Bictegravir
The purity of bulk pharmaceutical chemicals or its preparation；Meanwhile the genotoxicity impurity B is analysed in depth, convenient also can be research and development
Personnel improve Bictegravir bulk pharmaceutical chemicals preparation process and provide relevant technical motivation.
Illustratively, genotoxicity impurity A 1.0g, magnesium bromide 0.52g and acetonitrile are added in 50mL reaction flask
10mL, heating mixed liquor to 40~50 DEG C react 4~6 hours；To which the hydrochloric acid that concentration is 2 mol/Ls after completion of the reaction, is added
2mL is simultaneously stirred 30 minutes；Then, be spin-dried for reaction solution, add using methylene chloride: methanol=20:1 mixture is as eluant, eluent
Column chromatographic purifying is carried out to residue, collects the main component that purifying obtains, the solvent being spin-dried in the main component obtains light
Yellow solid 0.7g, as impurity B, purity 98%, mass spectrum MS:[M+H]+=591.
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 genotoxicity impurity A in a kind of Bictegravir bulk pharmaceutical chemicals, which is characterized in that the described method includes:
Tri- fluorin benzyl amine of 2,4,6- reacts under alkaline condition obtains three fluorin benzyl amine dimers；
The three fluorin benzyl amines dimer and compound C are dissolved in one of methylene chloride, tetrahydrofuran or ethyl acetate or more
Kind solvent, obtains mixed liquor I；
Condensing agent and alkali are added in the mixed liquor I, and is heated to 20-40 DEG C of reaction 7-8 hours, obtains mixed liquor II；
Decompression is carried out to the mixed liquor II to be spin-dried for obtaining residue, adds the mixture of methylene chloride and methanol as elution
Agent collects the main component isolated to residue column chromatography for separation, the solvent being spin-dried in the main component, obtains gene poison
Property impurity A.
2. synthetic method according to claim 1, which is characterized in that described 2,4,6- tri- fluorin benzyl amines are anti-under alkaline condition
Should obtain three fluorin benzyl amine dimers includes:
Described 2,4,6- tri- fluorin benzyl amines are dissolved in one or more solvents in tetrahydrofuran or methylene chloride, obtain mixed liquor III；
Hexamethyldisilazide lithium, two silicon substrate amine of hexamethyldisilane amine base sodium or hexamethyl are added in the mixed liquor III
At least one of base potassium alkali, obtains mixed liquor IV；
The mixed liquor IV is heated to 25-40 DEG C and is reacted 14 hours, 10% aqueous ammonium chloride solution is added after reaction and quenches
It goes out reaction, vacuum rotary steam removes solvent, obtains mixed liquor V；
Methylene chloride aqueous phase extracted is added in the mixed liquor V, and collects organic phase, evaporated under reduced pressure is carried out to the organic phase
Afterwards, residue is obtained；
Column chromatographic purifying is carried out to the residue, methylene chloride is added as eluant, eluent, collects primary product, is spin-dried for solvent,
Obtain three fluorin benzyl amine dimers.
3. synthetic method according to claim 1 or 2, which is characterized in that the three fluorin benzyl amines dimeric structure are as follows:
4. synthetic method according to claim 1, which is characterized in that the compound C-structure are as follows:
Wherein, R, S respectively indicate the chiral configuration of compound.
5. synthetic method according to claim 1, which is characterized in that the condensing agent is that (7- aoxidizes three nitrogen of benzo to 2-
Azoles)-N, N, N', N'- tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide or 1- (3- dimethylamino-propyl) -3- ethyl
One of carbodiimide hydrochloride is a variety of.
6. synthetic method according to claim 1, which is characterized in that the alkali is n,N-diisopropylethylamine or triethylamine
One of or it is a variety of.
7. a kind of genotoxicity impurity A of the synthesis of synthetic method described in any one of -6 according to claim 1, which is characterized in that
The structure of the genotoxicity impurity A are as follows:
Wherein, R, S respectively indicate the chiral configuration of compound.
8. the synthetic method of genotoxicity impurity B in a kind of Bictegravir bulk pharmaceutical chemicals, which is characterized in that the described method includes:
Genotoxicity impurity A being obtained with synthetic method described in any one of claim 1-6 or as claimed in claim 7 is original
Material, is dissolved in one of acetonitrile or dioxane or multi-solvents for the genotoxicity impurity A, obtains mixed liquor VI；
The demethylation reagent of 2.0-4.0 molar equivalent is added in the mixed liquor VI, and it is small to be heated to 40-50 DEG C of reaction 4-6
When, obtain genotoxicity impurity B.
9. synthetic method according to claim 8, which is characterized in that the demethylation reagent is in magnesium bromide or lithium bromide
It is one or more.
10. a kind of genotoxicity impurity B of the synthesis of the synthetic method according to any one of claim 8-9, which is characterized in that
The structure of the genotoxicity impurity B are as follows:
Wherein, R, S respectively indicate the chiral configuration of compound.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104995198A (en) * | 2012-12-21 | 2015-10-21 | 吉里德科学公司 | Polycyclic-carbamoylpyridone compounds and their pharmaceutical use |
| WO2018005328A1 (en) * | 2016-06-27 | 2018-01-04 | Concert Pharmaceuticals, Inc. | Deuterated bictegravir |
-
2019
- 2019-05-22 CN CN201910430937.5A patent/CN110229174A/en not_active Withdrawn
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104995198A (en) * | 2012-12-21 | 2015-10-21 | 吉里德科学公司 | Polycyclic-carbamoylpyridone compounds and their pharmaceutical use |
| WO2018005328A1 (en) * | 2016-06-27 | 2018-01-04 | Concert Pharmaceuticals, Inc. | Deuterated bictegravir |
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