CN107722056A - The preparation method of Tedizolid Phosphate - Google Patents
The preparation method of Tedizolid Phosphate Download PDFInfo
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- CN107722056A CN107722056A CN201711045478.6A CN201711045478A CN107722056A CN 107722056 A CN107722056 A CN 107722056A CN 201711045478 A CN201711045478 A CN 201711045478A CN 107722056 A CN107722056 A CN 107722056A
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- 0 C[n]1nnc(-c(cc2)ncc2-c(c(F)c2)ccc2N(C[C@](CO*(*)O)O2)C2=O)n1 Chemical compound C[n]1nnc(-c(cc2)ncc2-c(c(F)c2)ccc2N(C[C@](CO*(*)O)O2)C2=O)n1 0.000 description 1
- HRICXMAWVXGGPT-UHFFFAOYSA-N C[n]1nnc(-c(cc2)ncc2-c(c(F)c2)ccc2NC(OCC2=CCCC=C2)=O)n1 Chemical compound C[n]1nnc(-c(cc2)ncc2-c(c(F)c2)ccc2NC(OCC2=CCCC=C2)=O)n1 HRICXMAWVXGGPT-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to field of medicine and chemical technology, and in particular to a kind of preparation method of Tedizolid Phosphate.Compound shown in formula Z1 is the precursor of Tedizolid Phosphate, and ring-closure reaction, which occurs, through catalyst as raw material using X3 obtains, and the preparation method of compound is shown in formula Z1：With formula R compounds ring-closure reaction occurs in the presence of catalysts and solvents for the compound of Formula X 3, obtains compound shown in formula Z1；The phosphorylated reaction of compound shown in formula Z1, obtains Tedizolid Phosphate.The preparation method of the present invention is avoided using this higher-boiling compounds of DMPU as catalyst, and the use of mixed solvent adds the dissolubility of reaction system, substantially reduces the reaction time, is adapted to industrialized production.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of preparation method of Tedizolid Phosphate.
Background technology
Tedizolid Phosphate (tedizolid phosphate), (R) -3- (4- (2- (2- methyl tetrazolium -5- bases) pyridine -
5- yls) 3- fluorophenyls) -5- hydroxyl first base oxazolidine -2- ketone dihydrogen phosphoric acid esters (formula I), structural formula is as follows, and the medicine is used to treat leather orchid
Family name's positive bacterial infection, such as infection and pulmonary infection etc. caused by acute bacterial skin infection, MRSA.
Tedizolid Phosphate is a kind of oxazolidone antibiotics, suitable for treatment staphylococcus aureus (including resistance to first
Oxygen XiLin bacterial strain and methicillin sensitive strain), the adult acute caused by gram-positive bacteria such as various streptococcus and enterococcus
Bacterial cutaneous tissue infection.Tedizolid Phosphate is a kind of prodrug, can be quickly converted to have biology by phosphatase in vivo
The specially azoles amine of activity.
The preparation method of presently disclosed Tedizolid Phosphate mainly has following two：
(1) route in CN1894242, first step reaction use poisonous organotin reagent, prepared by second step condensation reaction
Key intermediate (R) -3- (4- (2- (2- methyl tetrazolium -5- bases) pyridine -5- bases) 3- fluorophenyls) -5- Qiang Jia Ji oxazolidines -2-
The yield of ketone as little as 26%, three-step reaction prepare (R)-[3- (4- (2- (2- methyl tetrazolium -5- bases) pyridine -5- bases) -3- fluorine
Phenyl) -2- oxygen -5- oxazolidinyls] methyl acid phosphate double (tetrabutyl esters) needs to carry out at -78 DEG C, and the reaction time is grown.Therefore, the road
Line total recovery is low, and production cost is high, severe reaction conditions, generation cycle length, is not suitable for industrialized production.
(2) route is grown by starting material synthetic reaction route of the fluoro- 4- bromanilines of 3- in CN102177156, wherein second
Step boronation, which is reacted, to be only in the yield of -72 DEG C of low temperature progress and obtained product 4- (benzyloxycarbonyl amino) -2- fluorobenzoic boric acids
66% and very impure, the 4th step annulation need to use expensive reagent and make catalyst, and cost is higher, and be passed through after cyclization
Post processing gained Tedizolid Phosphate precursor purity is relatively low, the Tedizolid Phosphate purity for causing final step phosphorylation to obtain
It is relatively low.Therefore, the route is also not suitable with industrialization large-scale production.
There is many defects in the synthetic method of Tedizolid Phosphate disclosed in prior art, therefore still need to prepare phosphoric acid specially
The new method of azoles amine.
The content of the invention
In view of this, it is an object of the invention to provide a kind of preparation method of Tedizolid Phosphate, preparation of the invention
Method is avoided using this higher-boiling compounds of DMPU as catalyst, and the use of mixed solvent adds the molten of reaction system
Xie Xing, the reaction time is substantially reduced, be adapted to industrialized production.
To achieve the above object, the technical scheme is that：
Compound shown in formula Z1 is the precursor of Tedizolid Phosphate, is anti-through catalyst generation cyclization by raw material of X3
It should obtain, when preparing Tedizolid Phosphate, compound yield and purity directly affect Tedizolid Phosphate shown in formula Z1
Yield and purity.
The preparation method of compound shown in formula Z1, the compound of Formula X 3 is with formula R compounds in the presence of catalysts and solvents
Generation ring-closure reaction, compound shown in formula Z1 is obtained,
The catalyst is the one or more of tert-butyl alcohol lithium, sodium tert-butoxide and potassium tert-butoxide.
The silicon substrate amine of hexamethyl two is substituted as catalyst using the less expensive tert-butyl alcohol lithium being easy to get, sodium tert-butoxide, potassium tert-butoxide
Base lithium (LiHMDS) and 1,3- dimethyl -3,4,5,6- tetrahydrochysene -2- pyrimidones (DMPU), reduce cost, and avoid use
This higher boilings of DMPU (246 DEG C) compound.
As a preferred embodiment, the catalyst is tert-butyl alcohol lithium.
Further, the solvent is the mixed solvent of tetrahydrofuran and acetonitrile.
The single solvent of tetrahydrofuran is substituted with the mixed solvent of tetrahydrofuran and acetonitrile, adds the dissolving of reaction system
Property, reaction time were foreshortened to 3 hours by 15 hours.
Further, the volume ratio of the tetrahydrofuran and acetonitrile is 1：2~2：1.
As a preferred embodiment, the volume ratio of the tetrahydrofuran and acetonitrile is 1：1.
The second object of the present invention is to provide a kind of preparation method of Tedizolid Phosphate, using compound shown in Z1 in
Mesosome, comprise the following steps：
1) with formula R compounds ring-closure reaction occurs in the presence of catalysts and solvents for the compound of Formula X 3, obtains shown in formula Z1
Compound；
2) with pyrophosphoryl chloride or POCl3 esterification occurs for compound shown in formula Z1, obtains Tedizolid Phosphate；
The catalyst is the one or more of tert-butyl alcohol lithium, sodium tert-butoxide and potassium tert-butoxide；The solvent is tetrahydrochysene furan
Mutter and acetonitrile mixed solvent, the volume ratio of the tetrahydrofuran and acetonitrile is 1：2~2：1.
Specific reaction equation is in step 2)：
The single solvent of tetrahydrofuran is substituted with the mixed solvent of tetrahydrofuran and acetonitrile, adds the dissolving of reaction system
Property, reaction time were foreshortened to 3 hours by 15 hours.
Further, the mol ratio of X3 compounds, formula R compounds and catalyst is respectively 1 in step 1)：1~1.5 and 1：
1.5~3.
As a preferred embodiment, the mol ratio of X3 compounds, formula R compounds and catalyst is respectively 1 in step 1)：1.1~
1.5 and 1：2~3.
As a preferred embodiment, the mol ratio of X3 compounds, formula R compounds and catalyst is respectively 1 in step 1)：1.3 and
1：2.2.
As a preferred embodiment, the mol ratio of X3 compounds, formula R compounds and catalyst is respectively 1 in step 1)：1.1 and
1：2.
As a preferred embodiment, the volume ratio of the tetrahydrofuran and acetonitrile is 1：1.
Further, reaction is carried out under an inert gas in step 1), as preferably nitrogen；The temperature of reaction in step 1)
For 20~35 DEG C.
Using tert-butyl alcohol lithium, sodium tert-butoxide, potassium tert-butoxide be catalyst occur ring-closure reaction temperature far below DMPU this
Kind higher boiling (246 DEG C) compound is as temperature required for catalyst, and reaction condition is gentle, while reducing catalyst cost
Also reduce energy consumption.
Further, compound shown in Z1 made from step 1) carries out step again after absolute ethyl alcohol and/or DMF recrystallizations
2) reaction.
Further, the purification process is：Compound shown in Z1 made from step 1) adds absolute ethyl alcohol and/or DMF enters
Row recrystallization, obtains Z1 after purification.
The third object of the present invention is to provide the Tedizolid Phosphate that a kind of above-mentioned preparation method is prepared.Above-mentioned system
Tedizolid Phosphate yield and purity that Preparation Method is prepared are high, purity can reach 99.5% and more than.
The present invention also aims to provide a kind of purification process of compound shown in Z1, comprise the following steps：
1) compound is added in absolute ethyl alcohol shown in Z1, is beaten at 70~90 DEG C；
2) material after step 1) mashing is after filtering, scrubbed, after 65~85 DEG C of DMF of addition is completely dissolved, obtains molten
Liquid；
3) step 2) resulting solution is added to absolute ethyl alcohol after decolourizing, filtering and carries out crystallization, obtains Z1 products.
As a preferred embodiment, the mass volume ratio of compound shown in Z1 and absolute ethyl alcohol is 0.1g/mL.
As a preferred embodiment, compound shown in Z1 and DMF mass volume ratio are 0.125g/mL.
The purification process of compound, comprises the following steps shown in a kind of specific Z1：
1) compound is added in absolute ethyl alcohol shown in Z1, mashing is heated to reflux at 70~90 DEG C 25~40 minutes；
2) material after step 1) mashing filters after naturally cooling to room temperature, and filter cake washs 3 times with a small amount of absolute ethyl alcohol and taken out
65~85 DEG C of DMF is added after dry to be completely dissolved, and obtains solution；
3) step 2) resulting solution is added to absolute ethyl alcohol after decolourizing, filtering and carries out crystallization, is filtered after crystallization, filter cake is used
A small amount of absolute ethyl alcohol is drained after washing 3 times, is placed in 40~55 DEG C of temperature, vacuum -0.08MPa~-0.1MPa vacuum drying chambers
Dry 2~3.5 hours, obtain Z1 products.
With DMF and/or absolute ethyl alcohol recrystallization substitute methanol/water mashing purification process, by the purity of Z1 compounds by
98.4% is promoted to more than 99.5%.
The beneficial effects of the present invention are：
1) with less expensive tert-butyl alcohol lithium, the tert-butyl alcohol being easy to get in the method for compound shown in formula Z1 provided by the invention
Sodium, potassium tert-butoxide as catalyst substitute LHMDS (LiHMDS) and 1,3- dimethyl -3,4,5,6- tetrahydrochysenes -
2- pyrimidones (DMPU), and avoid using this higher boilings of DMPU (246 DEG C) compound, the temperature that ring-closure reaction occurs is far low
In DMPU, reaction condition is gentle, and energy consumption is also reduced while reducing catalyst cost.
2) in the preparation method of Tedizolid Phosphate of the present invention compound shown in formula Z1 with tetrahydrofuran and acetonitrile
Mixed solvent substitutes the single solvent of tetrahydrofuran, adds the dissolubility of reaction system, and it is small that the reaction time by 15 foreshortens to 3
When.
3) present invention also offers the purification process of compound shown in Z1, before compound shown in Z1 is Tedizolid Phosphate
Body, when preparing Tedizolid Phosphate, compound yield and purity shown in formula Z1 directly affect Tedizolid Phosphate yield and
Purity, the purification process of methanol/water mashing is substituted with DMF and/or absolute ethyl alcohol recrystallization in purification process, by Z1 compounds
Purity be promoted to more than 99.5% by 98.4%.
Embodiment
It detailed description of a preferred embodiment of the present invention will be given below.The reality of unreceipted actual conditions in preferred embodiment
Proved recipe method, generally according to normal condition, illustrated embodiment is to preferably be illustrated to present disclosure, but is not
Present disclosure is only limitted to illustrated embodiment.So those skilled in the art according to foregoing invention content to embodiment party
Case carries out nonessential modifications and adaptations, still falls within protection scope of the present invention.
The preparation method of compound shown in the formula Z1 of embodiment 1
The compound of 50g Formula X 3 is added in 1L there-necked flasks, tetrahydrofuran 400ml, acetonitrile 400ml, is passed through nitrogen, temperature control 25
DEG C, solids is insoluble, adds tert-butyl alcohol lithium 19.8g, solids dissolving, reaction solution is changed into yellow from colourless, after stirring 2 hours
R- (-)-glycidol butyric acid and formula R compound 19.7g are added dropwise into reaction solution, rear insulation reaction is added dropwise 3 hours, samples
Middle control TLC (solvents：Chloroform/methanol=10/1), after the spot of the compound of Formula X 3 disappears, it is added dropwise by concentrated hydrochloric acid and water
The watery hydrochloric acid of preparation, pH to 8 is adjusted, after being sufficiently stirred 30 minutes, 35 DEG C~55 DEG C of bath temperature, vacuum -0.07MPa~-
0.1MPa is concentrated under reduced pressure into cutout, obtains compound shown in formula Z1.
The preparation method of compound shown in the formula Z1 of embodiment 2
The compound of 50g Formula X 3 is added in 1L there-necked flasks, tetrahydrofuran 400ml, acetonitrile 400ml, is passed through nitrogen, temperature control 25
DEG C, solids is insoluble, adds sodium tert-butoxide 23.8g, solids dissolving, reaction solution is changed into yellow from colourless, after stirring 2 hours
R- (-)-glycidol butyric acid and formula R compound 19.7g are added dropwise into reaction solution, rear insulation reaction is added dropwise 3 hours, samples
Middle control TLC (solvents：Chloroform/methanol=10/1), after the spot of the compound of Formula X 3 disappears, it is added dropwise by concentrated hydrochloric acid and water
The watery hydrochloric acid of preparation, pH to 8 is adjusted, after being sufficiently stirred 30 minutes, 35 DEG C~55 DEG C of bath temperature, vacuum -0.07MPa~-
0.1MPa is concentrated under reduced pressure into cutout, obtains compound shown in formula Z1.
The preparation method of compound shown in the formula Z1 of embodiment 3
The compound of 50g Formula X 3 is added in 1L there-necked flasks, tetrahydrofuran 400ml, acetonitrile 400ml, is passed through nitrogen, temperature control 25
DEG C, solids is insoluble, adds potassium tert-butoxide 27.8g, solids dissolving, reaction solution is changed into yellow from colourless, after stirring 2 hours
R- (-)-glycidol butyric acid and formula R compound 19.7g are added dropwise into reaction solution, rear insulation reaction is added dropwise 3 hours, samples
Middle control TLC (solvents：Chloroform/methanol=10/1), after the spot of the compound of Formula X 3 disappears, it is added dropwise by concentrated hydrochloric acid and water
The watery hydrochloric acid of preparation, pH to 8 is adjusted, after being sufficiently stirred 30 minutes, 35 DEG C~55 DEG C of bath temperature, vacuum -0.07MPa~-
0.1MPa is concentrated under reduced pressure into cutout, obtains compound shown in formula Z1.
The preparation method of compound shown in the formula Z1 of embodiment 4
The compound of 50g Formula X 3 is added in 1L there-necked flasks, tetrahydrofuran 400ml, acetonitrile 400ml, is passed through nitrogen, temperature control 25
DEG C, solids is insoluble, adds tert-butyl alcohol lithium 9.9g and potassium tert-butoxide 13.9g, solids dissolving, and reaction solution is changed into yellow from colourless
Color, stir and R- (-)-glycidol butyric acid and formula R compound 19.7g are added dropwise in 2 hours backward reaction solutions, be incubated after being added dropwise
Reaction 3 hours, TLC (solvents are controlled in sampling：Chloroform/methanol=10/1), after the spot of the compound of Formula X 3 disappears, drop
Add the watery hydrochloric acid by concentrated hydrochloric acid and water preparation, adjust pH to 8, after being sufficiently stirred 30 minutes, 35 DEG C~55 DEG C of bath temperature, vacuum
Degree -0.07MPa~-0.1MPa is concentrated under reduced pressure into cutout, obtains compound shown in formula Z1.
The purification process of compound shown in the formula Z1 of embodiment 5
Concentrated to embodiment 1~4 and absolute ethyl alcohol 500ml is added in gained solid, 85 DEG C are heated to reflux mashing 30 minutes, from
So be cooled to room temperature after filter, filter cake wash 3 times with a small amount of absolute ethyl alcohol drain after go in 1L there-necked flasks, addition
DMF400ml, 75 DEG C of heating are allowed to be completely dissolved, and activated carbon decolorizing are added after dissolved clarification 15 minutes, and filtering, filtrate goes to 1L tri-
In mouth bottle, lower addition absolute ethyl alcohol 500ml is stirred, separates out a large amount of solids, stirring and crystallizing is filtered after 4 hours at room temperature, and filter cake is used
A small amount of absolute ethyl alcohol is drained after washing 3 times, is placed in temperature 50 C.Vacuum -0.08MPa~-0.1MPa vacuum drying chambers dry 3
Hour obtains formula Z1 products.Following table is the yield and HPLC purity of the formula Z1 products of embodiment 1~4.
The yield and HPLC purity of the formula Z1 products of 1 embodiment of table 1~4
| Yield | HPLC purity | |
| Embodiment 1 | 85.7% | 99.80% |
| Embodiment 2 | 85.0% | 99.73% |
| Embodiment 3 | 85.2% | 99.69% |
| Embodiment 4 | 86.7% | 99.83% |
The preparation method of the Tedizolid Phosphate of embodiment 6
Will the Z1 products 35g of embodiment 2 after purification with add in tetrahydrofuran 700mL, add triethylamine 29.8g, 0 DEG C
Slurry stirs, then the POCl3 43.5g for being dissolved in 35mL tetrahydrofurans is added dropwise, and is stirred 3 hours at 1-2 DEG C, solution is filtered again,
With washes of absolute alcohol, product is dried to constant weight, the yield of gained Tedizolid Phosphate in vacuum tank at room temperature is
84.8%, HPLC analyze its purity as 95.5%.
Finally illustrate, the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although with reference to compared with
The present invention is described in detail good embodiment, it will be understood by those within the art that, can be to the skill of the present invention
Art scheme is modified or equivalent substitution, and without departing from the objective and scope of technical solution of the present invention, it all should cover at this
Among the right of invention.
Claims (10)
1. the preparation method of compound shown in formula Z1, it is characterised in that the compound of Formula X 3 is with formula R compounds in catalysts and solvents
In the presence of ring-closure reaction occurs, obtain compound shown in formula Z1,
The catalyst is the one or more of tert-butyl alcohol lithium, sodium tert-butoxide and potassium tert-butoxide.
2. preparation method according to claim 1, it is characterised in that the solvent is molten for the mixing of tetrahydrofuran and acetonitrile
Agent.
3. preparation method according to claim 2, it is characterised in that the volume ratio of the tetrahydrofuran and acetonitrile is 1：2
~2：1.
4. the preparation method of Tedizolid Phosphate, it is characterised in that using compound shown in Z1 as intermediate, comprise the following steps：
1) with formula R compounds ring-closure reaction occurs in the presence of catalysts and solvents for the compound of Formula X 3, obtains chemical combination shown in formula Z1
Thing；
2) with pyrophosphoryl chloride or POCl3 esterification occurs for compound shown in formula Z1, obtains Tedizolid Phosphate；
The catalyst is the one or more of tert-butyl alcohol lithium, sodium tert-butoxide and potassium tert-butoxide；The solvent be tetrahydrofuran and
The volume ratio of acetonitrile mixed solvent, tetrahydrofuran and acetonitrile is 1：2~2：1.
5. preparation method according to claim 4, it is characterised in that X3 compounds, formula R compounds and catalysis in step 1)
The mol ratio of agent is respectively 1：1~1.5 and 1：1.5~3.
6. preparation method according to claim 4, it is characterised in that reaction is carried out under an inert gas in step 1), is made
To be preferably nitrogen；The temperature of reaction is 20~35 DEG C in step 1).
7. preparation method according to claim 4, it is characterised in that compound shown in Z1 made from step 1) is by anhydrous
The reaction of step 2) is carried out after ethanol and/or DMF recrystallizations again.
8. preparation method according to claim 7, it is characterised in that the purification process is：Z1 institutes made from step 1)
Show that compound adds absolute ethyl alcohol and/or DMF is recrystallized, obtain Z1 after purification.
9. the Tedizolid Phosphate that the preparation method described in claim any one of 4-8 is prepared.
The purification process of compound shown in 10.Z1, it is characterised in that comprise the following steps：
1) compound is added in absolute ethyl alcohol shown in Z1, is beaten at 70~90 DEG C；
2) material after step 1) mashing is after filtering, scrubbed, after 65~85 DEG C of DMF of addition is completely dissolved, obtains solution；
3) step 2) resulting solution is added to absolute ethyl alcohol after decolourizing, filtering and carries out crystallization, obtains Z1 products.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114105968A (en) * | 2020-08-28 | 2022-03-01 | 河北明吉化工科技有限公司 | Method for removing palladium residue of tedizolid |
| WO2022166022A1 (en) * | 2021-02-04 | 2022-08-11 | 海南通用康力制药有限公司 | Purification method for tedizolid phosphate |
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| WO2022166022A1 (en) * | 2021-02-04 | 2022-08-11 | 海南通用康力制药有限公司 | Purification method for tedizolid phosphate |
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Application publication date: 20180223 |