CN107266373A - A kind of bulk drug Da Shabuwei preparation method - Google Patents
A kind of bulk drug Da Shabuwei preparation method Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
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Abstract
The invention discloses a kind of bulk drug Da Shabuwei preparation method, comprise the following steps preparation N (base of 6 (base of 4,4,5,51,3,2 dioxaborolan of tetramethyl 2) naphthalene 2) methane sulfanilamide (SN)：S1：Using A0 as raw material, deprotection reaction is carried out to amino and prepares A1；S2：Amidatioon, get Da Shabuwei intermediates N (base of 6 (base of 4,4,5,51,3,2 dioxaborolan of tetramethyl 2) naphthalene 2) methane sulfanilamide (SN) are carried out to A1.Bulk drug Da Shabuwei of the present invention preparation method is deprotected the refined synthetic route of deamination substitution using amido protecting boronation amino; step is simple; reaction condition is gentle; intermediate product stability is high; reaction is quenched to be separated easily with intermediate, and above-mentioned factor is conducive to industrialization to mass produce.
Description
Technical field
The present invention relates to medical synthesis field, and in particular to a kind of bulk drug Da Shabuwei preparation method.
Background technology
N- (6- (the 3- tert-butyl groups -5- ((the 2H)-yl of 2,4- dioxo -3,4- dihydro-pyrimidin -1) -2- methoxyphenyls) naphthalene -
2- yls) methane sulfanilamide (SN), molecular formula：C26H27N3O5S；Non-nucleoside AG14361, trade name Da Shabuwei is ABT tri-
Join one of main component in anti-hepatitis medicine, it has following structure：
The synthesis of the uracil or thymine derivative for the treatment of hepatitis C is disclosed in patent (CN102746239A)
The synthetic route of method, wherein Da Shabuwei comprises the following steps：
Step A：Prepare the iodo- 4- nitrophenols of the 2- tert-butyl groups -6-；
Step B：With trimethyl silyl diazomethane reaction system under the iodo- 4- nitrophenols pressurized conditions of the 2- tert-butyl groups -6-
The iodo- 2- methoxyl groups -5- nitrobenzene of the standby 1- tert-butyl groups -3-；
Step C：Step B product prepares the iodo- 4- aminoanisoles of the 3- tert-butyl groups -5- with iron reaction；
Step D：Under cryogenic conditions (- 20 DEG C) step C product in DMF with (E) -3- methoxy propyl enoyl- isocyanic acids
Ester reaction prepares (E)-N- (the iodo- 4- Methoxyphenylaminos formoxyls of the 3- tert-butyl groups -5-) -3- methoxy propyl acrylamides；
Step E：Prepare 1- (the iodo- 4- methoxyphenyls of the 3- tert-butyl groups -5-) dihydro-pyrimidin -2,4 (1H, 3H)-diketone；
Step F：In microwave tube, step E product, N- (6- (4,4,5,5- tetramethyls -1,3,2- are made by nitrogen jet
Dioxaborolan -2- bases) naphthalene -2- bases) methane sulfanilamide (SN) and sodium carbonate liquor 1：1 ethanol-toluene (1.7mL) solution deaerates
15min；Addition 1,1 '-bis- (diphenylphosphino) ferrocene palladium bichloride (II) dichloromethane complex, degassing is further continued for carrying out
5min.Seal pipe heats 1h in microwave at 100 DEG C, with dchloromethane, with citric acid solution and salt water washing, organic layer with
(3- mercaptopropyis) silica gel stirs 1h.Filtered by Celite, be concentrated in vacuo, obtain target product Da Shabuwei.
In above-mentioned processing step, the key intermediate N- (6- (4,4,5,5- of Da Shabuwei final step substitution reactions are synthesized
Tetramethyl -1,3,2- dioxaborolan -2- bases) naphthalene -2- bases) preparation process of methane sulfanilamide (SN) is：
Step A '：Prepare 6- bromonaphthalene -2- amine；
Step B '：The pyridine solution of 6- bromonaphthalene -2- amine is handled with the methane sulfonyl chloride of dropwise addition, N- (6- bromonaphthalenes -2- are prepared
Base) methane sulfanilamide (SN)；
Step C '：By N- (6- bromonaphthalene -2- bases) methane sulfanilamide (SN), double (pinacol base) two boron, potassium acetate and Combiphos
Pd6 toluene mixture heated at reflux 3h.Cooling, is diluted with ethyl acetate and water, post-treated to obtain N- (6- (4,4,5,5-
Tetramethyl -1,3,2- dioxaborolan -2- bases) naphthalene -2- bases) methane sulfanilamide (SN).
Above-mentioned intermediate synthetic route is complicated, cost is high, is unfavorable for industrial mass production.For example methane sulfonyl chloride is handled
Alkalescence condition and reaction dissolvent are necessary for pyridine needed for the amidatioon of 6- bromonaphthalene -2- amine, are made with dichloromethane, tetrahydrofuran, DMF
For solvent, combine do not react with potassium carbonate, pyridine, DIPEA respectively；Synthesize Da Shabuwei reaction
Condition is high, and microwave heating is not popularized fully in current large-scale production, and silica gel chromatographic column purifying consumptive material is more,
Substitution reaction step yield disclosed in CN102746239A is 41%.Therefore, to solve problem present in prior art, capture
The technology barriers of external drugmaker, suddenly wait to find that a technique is simple, with low cost, are adapted to the Da Shabuwei of large-scale production
Synthetic route.
The content of the invention
An object of the present invention is to overcome defect present in prior art, and there is provided a kind of bulk drug Da Shabuwei's
Preparation method, the problem of to solve cost in the prior art high, complex process.
To achieve the above object, the technical scheme is that：A kind of bulk drug Da Shabuwei preparation method, its feature
It is, comprises the following steps preparation N- (6- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan -2- bases) naphthalene -2- bases) first
Alkane sulfanilamide (SN)：
S1：Using A0 as raw material, deprotection reaction is carried out to amino and prepares A1；
A0 has following structure：
R1Selected from the tert-butyl group, benzyl and tablet held before the breast by officials methoxyl group.
S2：Amidatioon, get Da Shabuwei intermediate Ns (6- (4,4,5,5- tetramethyls -1,3,2- dioxas penta are carried out to A1
Borine -2- bases) naphthalene -2- bases) methane sulfanilamide (SN).
Further, in addition to using S2 products and B0 the S3 of substitution reaction occurs as reactant, prepares Da Shabuwei thick
The S3 reaction equations of product are：
Further, R1 is to be reacted in the dichloromethane of A0 at normal temperatures with trifluoroacetic acid in the tert-butyl group, S1, dichloromethane
Volume ratio with trifluoroacetic acid is (4.9~5.2):1, A0 and trifluoroacetic acid mol ratio be 1：(9.5~10).By each raw material
Consumption is controlled in above range, on the basis of production cost is reduced compound A1 can be made to keep higher yield.R1 also may be used
Think the amido protecting group such as benzyl and tablet held before the breast by officials methoxyl group, corresponding deprotection reaction process conditions and above-mentioned difference.
Further, A1 dichloromethane solution in the presence of organic base, reacts, A1 with mesyl chloride at room temperature in S2
Mol ratio with mesyl chloride is 1：The mol ratio of (1.2~1.4), A1 and organic base is 1：(1.7~2.1).Above-mentioned organic base,
The raw materials such as carbonate may each be the conventional raw material in pharmaceutical synthesis field.The amount ratio of each raw material is controlled in above range,
Significant loss can be being reduced, while reduction production cost, make reaction that there is higher conversion ratio.
Further, organic base is selected from least one of triethylamine, diisopropylethylamine.Wherein it is preferably three second
Amine, can further reduce production cost, it is more suitable for commercial Application.
Further, in the presence of carbonate, S2 products and B0 in S3 are dissolved in the mixed of Isosorbide-5-Nitrae-dioxane and water
Close in solution, substitution reaction temperature is 85~90 DEG C.The optional one of catalyst：Pd(PPh3)4、Pd(OAc)2、Pd(dppb)Cl2
Further, carbonate is selected from least one of sodium carbonate and potassium carbonate.
Further, in addition to S3 obtained by Da Shabuwei crude products purification step S4, Da Shabuwei crude product recrystallization it is molten
Liquid is by tetrahydrofuran and methanol with volume ratio 1：(3~3.4) are mixed, and the solution temperature of Da Shabuwei crude products is 68~71
℃。
Further, reaction is quenched using frozen water in S1 and S2 steps.
The second object of the present invention is to overcome defect present in prior art, and there is provided a kind of system of Da Shabuwei tablets
Preparation Method, it is characterised in that include above-mentioned bulk drug Da Shabuwei preparation method, in addition to by active ingredient Da Shabuwei
Tabletted processing step is mixed with auxiliary material.
The advantages of the present invention are：
Bulk drug Da Shabuwei of the present invention preparation method uses amido protecting-boronation-amino deprotection-amino amides
The synthetic route of change-substitution-refined, step is simple, and reaction condition is gentle, and intermediate product stability is high, and reaction is quenched and middle
Body separation is easy, and above-mentioned factor is conducive to industrialization to mass produce.
Embodiment
With reference to embodiment, the embodiment to the present invention is further described.Following examples are only used for more
Plus technical scheme is clearly demonstrated, and can not be limited the scope of the invention with this.
Da Shabuwei production process is：
S1：Prepare A1
Dichloromethane, A0, stirring and dissolving are added into reactor；Room temperature is slowly added to TFA trifluoroacetic acids, then reaction solution
18h is stirred at room temperature；Thin-layered chromatography monitoring reaction；Processing, Ran Houyou are quenched with frozen water for reactant mixture after the completion of reaction
Machine layer separation；Institute's organic layer is fully washed with saturated sodium bicarbonate solution, and organic layer is filtered and used dichloromethane by diatomite
Diatomite is washed, then with salt water washing organic phase.Anhydrous sodium sulfate drying organic layer is used, vacuum distillation crude product is directly used in
Next step is reacted, and obtains end-product A1.
Reaction equation is so that R1 is the tert-butyl group as an example：
S2：Prepare N- (6- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan -2- bases) naphthalene -2- bases) methane sulfanilamide (SN)
A1 is added in dichloromethane and stirred, organic base is then added, 10min is stirred；Mesyl chloride is added dropwise；Then react
3h is stirred at room temperature in liquid, and TLC tracking and monitorings are to reacting complete, and after reaction terminates, reaction solution, which is transferred in frozen water, to be stirred 30min, has
Machine is mutually layered, and salt water washing, anhydrous sodium sulfate drying, organic phase is concentrated under reduced pressure；Finally, crude product adds petroleum ether and stirring
30min, filtering, with petroleum ether, is dried below 50 DEG C, obtains intermediate methane sulfanilamide (SN).
Reaction equation is：
S3：Prepare Da Shabuwei crude products
Nitrogen, which is protected, adds Isosorbide-5-Nitrae dioxane and water into reactor, adds S2 products, palladium catalyst and 1- (the tertiary fourths of 3-
The iodo- 4- methoxyphenyls of base -5-) dihydro-pyrimidin -2,4 (1H, 3H)-diketone, stirring, addition carbonate；Reaction solution is heated to 85
~90 DEG C of insulation reaction 4-6h, reaction solution TLC tracking and monitoring are complete to reaction；Reaction solution is cooled to 40 DEG C and then uses ethyl acetate
Dilution, layering, aqueous phase is extracted with ethyl acetate 2 times again, merges organic phase and is washed with water, organic phase salt water washing；At 50 DEG C
Organic phase vacuum distillation, crude product adds ethyl acetate and stirs 30min, suction filtration get Da Shabuwei crude products at 50-60 DEG C.
S4：Refined Da Shabuwei
Crude product and activated carbon are added to the mixed liquor (volume ratio 1 of recrystallization solvent tetrahydrofuran and methanol：(3~3.4)),
68~71 DEG C are heated to, suction filtration removes activated carbon, insulation crystallization 40min；Filter solid is crossed, solid is washed with methanol, it is dry at 60 DEG C
It is dry 3-4 hours, obtain refined Da Shabuwei.
Reaction equation is：
Embodiment 1
S1：Prepare A1
Dichloromethane, A0 (47kg), stirring and dissolving are added into reactor；Room temperature is slowly added to TFA trifluoroacetic acids
(141.37kg, 92.1L), then 18h is stirred at room temperature in reaction solution；Thin-layered chromatography monitoring reaction；Reaction after the completion of reaction
Processing is quenched with frozen water (616L) in mixture, and then organic layer is separated；Institute organic layer saturated sodium bicarbonate solution (462L) fills
Divide washing, organic layer is filtered by diatomite and washs diatomite with dichloromethane (226L), then washed with salt solution (205L)
Wash organic phase.Organic layer is dried with anhydrous sodium sulfate (20.5kg), vacuum distillation crude product is directly used in next step reaction, obtains whole production
Thing A0 30.8kg.
S2：Prepare N- (6- (4,4,5,5- tetramethyls -1,3,2- dioxaborolan -2- bases) naphthalene -2- bases) methane sulfanilamide (SN)
The product (30.78kg) of previous step is added in dichloromethane (308L) and stirred, triethylamine is then added
(22.8kg), stirs 10min；Mesyl chloride (1.3kg) is added dropwise；Then reaction solution is stirred at room temperature 3h, and TLC tracking and monitorings are to anti-
Should be complete, after reaction terminates, reaction solution, which is transferred in frozen water (308L), stirs 30min, organic phase layering, salt solution (205L) washing,
Anhydrous sodium sulfate (1kg) is dried, and organic phase is concentrated under reduced pressure；Finally, crude product adds petroleum ether (154L) stirring 30min, filters,
Washed with petroleum ether (30.8L), dried below 50 DEG C, obtain end-product 23.6kg (67.96mol), yield is 60%.
S3：According to the technique described in CN102746239 1488-1489 sections, with 1- (the iodo- 4- methoxyl groups of the 3- tert-butyl groups -5-
Phenyl) dihydro-pyrimidin -2,4 (1H, 3H)-diketone and S2 products therefroms prepare Da Shabuwei crude products, and sampling carries out silica gel to crude product
Column chromatography is purified.
Embodiment 2
The difference of embodiment 2 and embodiment 1 is that S3 reaction process is different from embodiment 1, is specially：
S3：Isosorbide-5-Nitrae dioxane (141.4L), palladium catalyst Pd (PPh are added into reactor under nitrogen protection3)4
(3.9kg) and water (70.68L), adds S2 products (23.56kg) and 1- (the iodo- 4- methoxyphenyls of the 3- tert-butyl groups -5-) dihydro phonetic
Pyridine -2,4 (1H, 3H)-diketone (27.13kg), stirring adds sodium carbonate (8.63kg)；Reaction solution is incubated 4-6h, reaction solution TLC
Tracking and monitoring is complete to reaction；Reaction solution is cooled to 40 DEG C and then with ethyl acetate (235.6L) dilution, is layered, aqueous phase uses second again
Acetoacetic ester (235.6L) is extracted 2 times, is merged organic phase and is washed with water (47.12L), organic phase is washed with salt solution (117.8L)；
50 DEG C of organic phase vacuum distillations, crude product adds ethyl acetate (94.24L) and stirs 30min, suction filtration, get Da Shabu at 50-60 DEG C
Wei crude product (29.45kg), sampling carries out silica gel chromatography to crude product.The substitution reaction single step yield 76.5%.
Embodiment 3
The difference of embodiment 3 and embodiment 2 is that the purification process of Da Shabuwei crude products is different, is specially：
S4：By crude product (29.44kg, Da Shabuwei percentage by weight are 86%, 51.29mol) and activated carbon (0.3kg)
Tetrahydrofuran (88.3L) and methanol (265L) are added, 68~71 DEG C are heated to, suction filtration removes activated carbon, insulation crystallization 40min；
Filter solid is crossed, solid is washed with methanol (14.72L), it is dry 3-4 hours at 60 DEG C, obtain refined Da Shabuwei 18.84kg
(38.17mol), yield 74%.
The volume ratio of dichloromethane and trifluoroacetic acid determines the acidity of S1 reaction systems.
Embodiment 4
The volume ratio of S1 dichloromethane and trifluoroacetic acid is 5.1 in embodiment 3:1, A0 and trifluoroacetic acid mol ratio be 1：
9.7；The mol ratio of A1 and mesyl chloride is 1 in S2：1.3, A1 and organic base mol ratio be 1：2；Organic base is triethylamine, carbon
Hydrochlorate is sodium carbonate, and the recrystallization solutions of S4 Da Shabuwei crude products is by tetrahydrofuran and methanol with volume ratio 1：3 mix.
The volume ratio of S1 dichloromethane and trifluoroacetic acid is 4.9 in embodiment 4:1, A0 and trifluoroacetic acid mol ratio be 1：
9.5；The mol ratio of A1 and mesyl chloride is 1 in S2：1.2, A1 and organic base mol ratio be 1：1.7；Organic base is diisopropyl
Base ethamine, carbonate is sodium carbonate, and the recrystallization solutions of S4 Da Shabuwei crude products is by tetrahydrofuran and methanol with volume ratio 1：3.4
Mix.
Embodiment 5
The volume ratio of S1 dichloromethane and trifluoroacetic acid is (5.2) in embodiment 5:1, A0 and the mol ratio of trifluoroacetic acid be
1：10；The mol ratio of A1 and mesyl chloride is 1 in S2：1.4, A1 and organic base mol ratio be 1：2.1；Organic base is pyridine,
Carbonate is potassium carbonate, and the recrystallization solutions of S4 Da Shabuwei crude products is by tetrahydrofuran and methanol with volume ratio 1：3.2 mixing and
Into.
The S1 yields of embodiment 3,4,5 are between 60~65%.Embodiment is that amplification test is compared, and is implemented
The yield of each step of example is of a relatively high.
Amido protecting-boronation-refined the synthetic route of amino deprotection-deamination-substitution-, and in the prior art
Amidatioon-boronation-substituted synthetic route compare, beneficial effect is：Each step is respectively provided with higher yield, and each step
Product purity it is higher.At the same time, the separating-purifying in each step for intermediate product is relatively simple.In addition, of the invention
In the preparation method of use, each raw material is the common reagent in this area, and raw material is relatively inexpensive.In summary each factor, this hair
The preparation method of bright use is more suitable for industrializing large-scale application.
Only it is the preferred embodiment of the present invention described in upper, it is noted that for those skilled in the art
For, without departing from the technical principles of the invention, some improvements and modifications can also be made, these improvements and modifications
It should be regarded as protection scope of the present invention.
Claims (10)
1. a kind of bulk drug Da Shabuwei preparation method, it is characterised in that comprise the following steps preparation N- (6- (4,4,5,5-
Tetramethyl -1,3,2- dioxaborolan -2- bases) naphthalene -2- bases) methane sulfanilamide (SN)：
S1：Using A0 as raw material, deprotection reaction is carried out to amino and prepares A1；
A0 has following structure：
R1Selected from the tert-butyl group, benzyl and tablet held before the breast by officials methoxyl group.
S2：Amidatioon, get Da Shabuwei intermediate Ns (6- (4,4,5,5- tetramethyls -1,3, the boron of 2- dioxas penta are carried out to A1
Alkane -2- bases) naphthalene -2- bases) methane sulfanilamide (SN).
2. bulk drug Da Shabuwei according to claim 1 preparation method, it is characterised in that also including by S2 products and
The S3 of substitution reaction occurs as reactant for B0, and the S3 reaction equations for preparing Da Shabuwei crude products are：
3. bulk drug Da Shabuwei according to claim 1 preparation method, it is characterised in that during R1 is the tert-butyl group, S1
Reacted in the dichloromethane of A0 at normal temperatures with trifluoroacetic acid, the volume ratio of dichloromethane and trifluoroacetic acid is (4.9~5.2):
1, A0 and trifluoroacetic acid mol ratio be 1：(9.5~10).
4. bulk drug Da Shabuwei according to claim 1 preparation method, it is characterised in that A1 dichloromethane in S2
Solution reacts with mesyl chloride at room temperature in the presence of organic base, and the mol ratio of A1 and mesyl chloride is 1：(1.2~1.4),
The mol ratio of A1 and organic base is 1：(1.7~2.1).
5. bulk drug Da Shabuwei according to claim 4 preparation method, it is characterised in that organic base is selected from three second
At least one of amine, diisopropylethylamine.
6. bulk drug Da Shabuwei according to claim 2 preparation method, it is characterised in that in carbonate and palladium chtalyst
In the presence of agent, S2 products and B0 in S3 are dissolved in the mixed solution of Isosorbide-5-Nitrae-dioxane and water, under inert gas shielding
Substitution reaction temperature is 85~90 DEG C.
7. bulk drug Da Shabuwei according to claim 6 preparation method, it is characterised in that carbonate is selected from carbonic acid
At least one of sodium and potassium carbonate.
8. bulk drug Da Shabuwei according to claim 1 preparation method, it is characterised in that also including reaching sand obtained by S3
The recrystallization solution of purification step S4, the Da Shabuwei crude product of cloth Wei crude product is by tetrahydrofuran and methanol with volume ratio 1：(3~
3.4) mix, the solution temperature of Da Shabuwei crude products is 68~71 DEG C.
9. bulk drug Da Shabuwei according to claim 1 preparation method, it is characterised in that S1 and S2 steps are used
Reaction is quenched in frozen water.
10. a kind of preparation method of Da Shabuwei tablets, it is characterised in that comprising described in any one in claim 1-9
Bulk drug Da Shabuwei preparation method, in addition to active ingredient Da Shabuwei is mixed into tabletted technique with auxiliary material walked
Suddenly.
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| CN112168826A (en) * | 2020-09-30 | 2021-01-05 | 郑州大学 | Application of daresbuvir in preparation of anti-esophageal cancer and gastric cancer tumor medicines |
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| CN112168826A (en) * | 2020-09-30 | 2021-01-05 | 郑州大学 | Application of daresbuvir in preparation of anti-esophageal cancer and gastric cancer tumor medicines |
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