CN106565747A - Novel method for preparing dolutegravir - Google Patents
Novel method for preparing dolutegravir Download PDFInfo
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- CN106565747A CN106565747A CN201610988625.2A CN201610988625A CN106565747A CN 106565747 A CN106565747 A CN 106565747A CN 201610988625 A CN201610988625 A CN 201610988625A CN 106565747 A CN106565747 A CN 106565747A
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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
- 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
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention discloses a novel method for preparing dolutegravir (E) defined in the description, and relates to the field of medicinal chemistry. The method comprises the following steps of 1) performing a condensation reaction of a compound (A) and 2,4-difluorobenzylamine to prepare a compound (B) defined in the description; 2) performing aldehyde group protecting group removal on the compound (B) to obtain a compound (C) defined in the description; 3) performing a cyclization reaction of the compound (C) and R-3-amino-1-butanol to prepare a compound (D) defined in the description; and 4) performing a demethylation reaction of the compound (D) to obtain the dolutegravir (E). According to the method, a novel route is adopted, and reaction conditions are continuously optimized, so that the total yield is greatly increased; and the total yield calculated by taking the compound (A) as a starting material is 75% or more, and the yields of single reactions are all 90% or more.
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a kind of new method for preparing Du Lutewei.
Background technology
Du Lutewei, its chemical name is (4R, 12aS)-N- [(2,4- difluorophenyl) methyl] -3,4,6,8,12,12a-
Hexahydro -7- hydroxy-4-methyl -6,8- dioxo -2H- pyridos [1 ', 2 ':4,5] pyrazine simultaneously [2,1-b] [1,3] oxazine -9- first
Acid amides, CAS.NO：1051375-16-6, molecular formula：C20H19F2N3O5, shown in its structural formula such as formula (E)(E), Du Lutewei is resisted under Britain's pharmacy giant's GlaxoSmithKline PLC (GSK)
HIV new drugs, 2013 Nian8Yue12 food and drug administrations (FDA) ratify to have treated or just controlled HIV- for the past
1 adult and 12 years old and at least 40 kilograms childhood infection persons of above body weight.Du Lutewei (Dolutegravir)
It is the medicine for taking once day, has reached in III clinical trial phases and silent sand east HIV/AIDS medicine Mercks
The curative effect that (Raltegravir, Isentress) is mutually equal to.The official of FDA represents that HIV infection crowd is needed according to personal
Concrete condition is targetedly treated, and Du Lutewei will provide new selection for patient.Grind in for carrying out the year before
In studying carefully, patient receives after the Du Lutewei treatments of 48 weeks, and the conditions of patients for having 88% has clear improvement, better than Gilead companies
Atripla.Analyst, it is expected that Du Lutewei is expected to become annual sales amount up to the heavy pound medicine of multi-million dollar, while will become
The strong competitor of lucky moral biotech firm (Gilead Sciences) world most situation of selling well HIV combination drugs Atripla.
Compound structure of the first public Du Lutewei of PCT application WO 2006116764 and preparation method thereof, subsequent PCT
Apply for the also improved synthesis technique of degrees of overtness Lu Tewei such as WO 2015019310, PCT application WO 2015009927, but report at present
The Du Lutewei preparation methods in road have the disadvantage that：The total recovery of PCT application WO 2015019310 only 20.76%, and adopt
Starting material carry borate, unstable, explosive；PCT application WO2015009927, the material adopted in building-up process is held high
It is expensive, cause high cost, wherein an one-step hydrolysis reaction yield only 43.6%.
The content of the invention
It is an object of the invention to provide a kind of new method for preparing Du Lutewei, the new method product for preparing Du Lutewei
Rate and purity are high, and low cost, reaction condition is gentle.
In order to realize the purpose of the present invention, the present invention provides following technical scheme：
One kind prepares the new method of Du Lutewei (E)
(E), it is comprised the following steps：
Step 1) there is the prepared compound (B) of condensation reaction by compound (A) and 2,4- difluorobenzylamines
Step 2) compound (B) removing aldehyde radical protection group obtain compound (C)
Step 3) compound (C) and R-3- amino-n-butyl alcohol carry out annulation and compound (D) be obtained
Step 4) compound (D) occur demethylation after obtain Du Lutewei (E).
In step 1) in, wherein, R is alkyl, methyl, ethyl, isopropyl, benzyl etc., in certain embodiments, institute
R is stated for methyl；The condensation reaction is carried out in the presence of condensing agent, the condensing agent be selected from N, N'- carbonyl dimidazoles (CDI),
1- (3- dimethylamino-propyls) -3- ethyl carbodiimides (EDC), dicyclohexylcarbodiimide (DCC), DIC
(DIC), 1,8- diazabicyclos [5.4.0] -7- endecatylenes (DBU) etc.；In one embodiment, the condensing agent is N,
N'- carbonyl dimidazoles (CDI), the consumption of the condensing agent is 1.0 equivalent～2.0 equivalents of compound (A),
The condensation reaction is carried out in ether solvent, and the ether solvent is selected from tetrahydrofuran, 2- methylfurans, dioxy
One or more in penta ring, Isosorbide-5-Nitrae-dioxane, oxirane, ether, dipropyl ether, ethyl-butyl ether etc..
In one embodiment, the operation of the condensation reaction includes：Toward ether solvent put into 1 equivalents of compound (A) and
The condensing agent of 1.0～1.5 equivalents, is warming up to backflow, after 1.0～5.0h of stirring, then put into the condensing agent of 0.1～0.5 equivalent after
It is continuous to be refluxed after 1.0～5.0h, 20～25 DEG C are cooled to, 2,4- difluorobenzylamines are put into, maintain 20～25 DEG C and stir to reaction
Finish.
In step 2) in, wherein, R is alkyl, methyl, ethyl, isopropyl, benzyl etc., in certain embodiments, institute
R is stated for methyl；The reaction of the removing aldehyde radical protection group is carried out in the presence of organic acid, and the organic acid is selected from formic acid, acetic acid
Or its combination, the consumption of the organic acid is 2～5 times of compound (B) weight, remove the reaction of aldehyde radical protection group about 40～
Carry out at about 80 DEG C, in one embodiment, the reaction of the removing aldehyde radical protection group is carried out at about 60 DEG C.
In step 3) in, wherein, R is alkyl, methyl, ethyl, isopropyl, benzyl etc., in certain embodiments, institute
R is stated for methyl；The annulation is carried out in nitrile solvents, such as acetonitrile, acrylonitrile or its combination, the annulation
Reaction temperature is for about 55～about 70 DEG C, preferably from about 60～about 65 DEG C.In one embodiment, the operation bag of the annulation
Include：Compound (C) mixes with nitrile solvents, puts into acetic acid after stirring and being warming up to about 50 DEG C, then is warming up to about 55～about 70 DEG C
The nitrile solution of R-3- amino-n-butyl alcohol is added dropwise afterwards, is maintained about 55～about 70 DEG C to stir to reaction and is finished.
In step 4) in, the demethylation is carried out in the presence of a lewis acid, the lewis acid be aluminium chloride,
Aluminium bromide, magnesium bromide etc., the lewis acidic consumption for compound (D) 2.0eq～4.0eq, the demethylation
At 70～90 DEG C, preferably 80 DEG C.
Raw materials used and reaction reagent of the invention can be prepared in accordance with known methods, it is also possible to commercially；Such as
The preparation method that compound (A) can be reported according to PCT application WO2015009927 is obtained.
It should be noted that in the context of the present invention, regardless of whether using " about " or the wording such as " about ", Suo You
The numeral of the displosure is approximation.Each digital numerical value is possible to occur 1%, 2%, 5%, 7%, 8%,
10%th, the difference such as 15% or 20%.Whenever disclose one have N values it is digital when, it is any with N+/- 1%, N+/- 2%, N
The numeral of +/- 3%, N+/- 5%, N+/- 7%, N+/- 8%, N+/- 10%, N+/- 15%or N+/- 20% value can be by clearly
It is open, wherein " +/- " refers to and adds deduct.Whenever disclosing a lower limit in a number range, RL, and a upper limit, RU,
When, any numerical value within the scope of the disclosed can be specifically disclosed.Particularly, contain following in the range of this
Numerical value：R=RL+K* (RU-RL), wherein K be one by 1% increment increase from 1% to 100% variable.Such as：1%th,
2%th, 3%, 4%, 5%, 50%, 51%, 52%, 95%, 96%, 97%, 98%, 99% or 100%.In addition, also especially wrapping
The above-mentioned number range with two R definitions being disclosed that is contained.
Advantages of the present invention：
1st, the present invention adopts new route, and reaction condition is constantly optimized so that total recovery is significantly carried
Height, total recovery is calculated more than 75% by starting material of compound (A), and single reaction yield is more than 90%；
2nd, the new method for preparing Du Lutewei of the present invention avoids using inflammable and explosive and corrosive reagents, reaction condition
Gently, it is easy to operate, it is adapted to industrialized production；
3rd, the new method for preparing Du Lutewei of the present invention, it puts the higher raw material R-3- amino-n-butyl alcohol of price
In final reaction step, increase operation rate, reduces cost, preparing per kilogram Du Lutewei can save 500～1000 yuan.
Specific embodiment
In order that those skilled in the art more fully understands technical scheme, some are disclosed further below non-
The present invention is described in further detail to limit embodiment.
The 1- of embodiment 1 (2,2- dimethoxy-ethyls) -1,4- dihydro -3- methoxyl group -4- oxo -5- (2,4 difluorobenzene first
Aminoacyl) pyridine -2- methyl esters (compound B) preparation
Toward reaction bulb input tetrahydrofuran (700g), compound A (80g, 0.254mol) and CDI (49.4g, 1.2eq)；Rise
Temperature stirs 2.5h to backflow (70 DEG C)；Input CDI (12.4g, 0.3eq), continues to be refluxed 2.0h；20～25 DEG C are cooled to,
Input 2,4- difluorobenzylamines (40.0g, 1.1eq)；Maintain 20～25 DEG C of stirring reactions 5h；After the completion of reaction, methyl- tert fourth is put into
Base ether (600g) and 3% hydrochloric acid (600g)；Stirring 10 minutes, stands 10 minutes；Layering, organic layer puts into 3% sodium hydroxid
(600g)；Stirring 10 minutes, stands 10 minutes；Layering, organic layer input water (600g)；Stirring 10 minutes, stands 10 minutes；Point
Layer, organic phase is concentrated to dryness, and directly carries out the next step.
The 1- of embodiment 2 (2- oxoethyls) -1,4- dihydro -3- methoxyl group -4- oxo -5- (2,4 difluorobenzene carbamyls
Base) pyridine -2- methyl esters (compound C) preparation
It is obtained in concentrate toward embodiment 1 and puts into formic acid (240g)；60 DEG C are warming up to, stirring reaction 3h；Decompression is steamed
Formic acid, 10% sodium dihydrogen phosphate of input (600g) and dichloromethane (800g)；Stirring 10 minutes, stands 10 minutes；Layering, water layer
Extracted once with dichloromethane (400g)；Layering, merges organic layer, after steaming solvent, puts into methyl tertiary butyl ether(MTBE) (240g)；Room
Temperature stirring 3h, filters, and collects compound C, white solid, yield 92%.
The preparation of the Du Lutewei of embodiment 3
Acetonitrile (700g) and compound C (90g, 0.228mol) are put into toward reaction bulb；Stirring is warming up to 50 DEG C, puts into vinegar
Sour (13.7g, 1eq)；60～65 DEG C are warming up to, R-3- amino-n-butyl alcohol (22.3g, 1.1eq) and acetonitrile (100g) is added dropwise；Protect
The HPLC purity of warm stirring reaction 15h to compound in liquid phase (D) be 98.0% after input six be hydrated magnesium bromides (199.7g,
3eq), 80 DEG C are warming up to, stirring reaction 2h；After the completion of reaction, 3% hydrochloric acid (830g) and dichloromethane (1200g) are put into；Point
Layer, water layer input dichloromethane (600g；Layering, merges organic layer and is concentrated to dryness, and puts into ethanol, is again concentrated to do, degree of obtaining
Lu Tewei (yield 90.9%).
The preparation of the compound B of embodiment 4
Past reaction bulb input methyltetrahydrofuran (700g), compound A (80g, 0.254mol) and CDI (49.4g,
1.2eq)；Backflow (70 DEG C) is warming up to, 2.5h is stirred；Input DBU (0.3eq), continues to be refluxed 2.0h；It is cooled to 20～25
DEG C, input 2,4- difluorobenzylamines (40.0g, 1.1eq)；Maintain 20～25 DEG C of stirring reactions 5h；After the completion of reaction, methyl- tert is put into
Butyl ether (600g) and 3% hydrochloric acid (600g)；Stirring 10 minutes, stands 10 minutes；Layering, organic layer puts into 3% sodium hydroxid
(600g)；Stirring 10 minutes, stands 10 minutes；Layering, organic layer input water (600g)；Stirring 10 minutes, stands 10 minutes；Point
Layer, organic phase is concentrated to dryness, and directly carries out the next step.
The preparation of the compound C of embodiment 5
It is obtained in concentrate toward embodiment 1 and puts into formic acid (300g)；70 DEG C are warming up to, stirring reaction 3h；Decompression is steamed
Formic acid, 10% sodium dihydrogen phosphate of input (600g) and dichloromethane (800g)；Stirring 10 minutes, stands 10 minutes；Layering, water layer
Extracted once with dichloromethane (400g)；Layering, merges organic layer, after steaming solvent, puts into methyl tertiary butyl ether(MTBE) (240g)；Room
Temperature stirring 3h, filters, and collects compound C, white solid, yield 95%.
The preparation of the Du Lutewei sodium salts of embodiment 6
Acetonitrile (700g) and compound C (90g, 0.228mol) are put into toward reaction bulb；Stirring is warming up to 50 DEG C, puts into vinegar
Sour (13.7g, 1eq)；70 DEG C are warming up to, R-3- amino-n-butyl alcohol (22.3g, 1.1eq) and acetonitrile (100g) is added dropwise；Insulation is stirred
Mix reaction 15h；Compound (D) in liquid phase if HPLC purity be greater than 95.0%, input six be hydrated magnesium bromides (199.7g,
3eq), 80 DEG C are warming up to, stirring reaction 2h；After the completion of reaction, 3% hydrochloric acid (830g) and dichloromethane (1200g) are put into；Point
Layer, water layer input dichloromethane (600g；Layering, merges organic layer and is concentrated to dryness, and puts into ethanol, is again concentrated to do；Input second
Alcohol (1000g) and 10% sodium hydroxid (100g), are warming up to 80 DEG C, are cooled to room temperature, are stirred for 1h, filter, and collect Du Lute
Wei sodium salt, white solid (yield 90.7%), HPLC purity 99.7%.
The preferred embodiments of the present invention are the foregoing is only, the present invention is not limited to, for the skill of this area
For art personnel, the present invention can have various modifications and variations.It is all within the spirit and principles in the present invention, made any repair
Change, equivalent, improvement etc., should be included within the scope of the present invention.
Claims (10)
1. one kind prepares the new method of Du Lutewei (E)
It is comprised the following steps：
Step 1) there is the prepared compound (B) of condensation reaction by compound (A) and 2,4- difluorobenzylamines
Step 2) compound (B) removing aldehyde radical protection group obtain compound (C)
Step 3) compound (C) and R-3- amino-n-butyl alcohol carry out annulation and compound (D) be obtained
Step 4) compound (D) occur demethylation after obtain Du Lutewei (E), wherein, R be alkyl, methyl, second
Base, isopropyl, benzyl.
2. the new method of Du Lutewei (E) is prepared as claimed in claim 1, in step 1) in, the condensation reaction is in condensing agent
In the presence of carry out, the condensing agent be selected from N, N'- carbonyl dimidazoles, 1- (3- dimethylamino-propyls) -3- ethyl carbodiimides, two
Cyclohexyl carbodiimide, DIC or 1,8- diazabicyclos [5.4.0] -7- endecatylenes；The condensing agent
Consumption for compound (A) 1.0 equivalent～2.0 equivalents.
3. the new method of Du Lutewei (E) is prepared as claimed in claim 1, in step 1) in, the condensation reaction is molten in ethers
Carry out in agent, the ether solvent selected from tetrahydrofuran, 2- methylfurans, dioxolanes, Isosorbide-5-Nitrae-dioxane, oxirane,
One or more in ether, dipropyl ether, ethyl-butyl ether.
4. the new method of Du Lutewei (E) is prepared as claimed in claim 1, in step 1) in, the operation bag of the condensation reaction
Include：The condensing agent of 1 equivalents of compound (A) and 1.0～1.5 equivalents is put into toward ether solvent, backflow is warming up to, stir 1.0～
After 5.0h, then put into the condensing agent of 0.1～0.5 equivalent and continue to be refluxed after 1.0～5.0h, be cooled to 20～25 DEG C, input
2,4- difluorobenzylamines, maintain 20～25 DEG C to stir to reaction and finish.
5. the new method of Du Lutewei (E) is prepared as claimed in claim 1, in step 2) in, the removing aldehyde radical protection group
Reaction is carried out in the presence of organic acid, and selected from formic acid, acetic acid or its combination, the consumption of the organic acid is chemical combination to the organic acid
2～5 times of thing (B) weight.
6. the new method of Du Lutewei (E) is prepared as claimed in claim 1, in step 2) in, remove the reaction of aldehyde radical protection group
Carry out at 40～80 DEG C or carry out at 60 DEG C.
7. the new method of Du Lutewei (E) is prepared as claimed in claim 1, in step 3) in, the annulation is molten in nitrile
Carry out in agent, the nitrile solvents are acetonitrile, acrylonitrile or its combination, and the reaction temperature of the annulation is 55～70 DEG C,
Or for 60～65 DEG C.
8. the new method of Du Lutewei (E) is prepared as claimed in claim 1, in step 3) in, the operation bag of the annulation
Include：Compound (C) mixes with nitrile solvents, and acetic acid is put into after stirring and being warming up to 50 DEG C, then is added dropwise after being warming up to 55～70 DEG C
The nitrile solution of R-3- amino-n-butyl alcohol, maintains about 55～70 DEG C to stir to reaction and finishes.
9. the new method of Du Lutewei (E) is prepared as claimed in claim 1, in step 4) in, the demethylation is on road
Carry out in the presence of Lewis acid, the lewis acid is aluminium chloride, aluminium bromide, magnesium bromide, the lewis acidic consumption is chemical combination
2.0 equivalent～4.0 equivalents of thing (D).
10. the new method of Du Lutewei (E) is prepared as claimed in claim 1, in step 4) in, the demethylation is 70
Carry out at～90 DEG C, or carry out at 80 DEG C.
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| CN201610988625.2A CN106565747A (en) | 2016-11-10 | 2016-11-10 | Novel method for preparing dolutegravir |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108752218A (en) * | 2018-07-18 | 2018-11-06 | 浙江沙星科技有限公司 | A kind of variation route prepared by Du Lutewei key intermediates 2,4- difluorobenzylamines |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108752218A (en) * | 2018-07-18 | 2018-11-06 | 浙江沙星科技有限公司 | A kind of variation route prepared by Du Lutewei key intermediates 2,4- difluorobenzylamines |
| CN108752218B (en) * | 2018-07-18 | 2021-03-19 | 浙江沙星科技有限公司 | Route for preparing dolutegravir key intermediate 2, 4-difluorobenzylamine |
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