CN108117523A - The preparation method of halo uracil class compound - Google Patents
The preparation method of halo uracil class compound Download PDFInfo
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- CN108117523A CN108117523A CN201611073880.0A CN201611073880A CN108117523A CN 108117523 A CN108117523 A CN 108117523A CN 201611073880 A CN201611073880 A CN 201611073880A CN 108117523 A CN108117523 A CN 108117523A
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- 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
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Abstract
The invention discloses a kind of preparation methods of compound as shown in Equation 2, comprise the steps of, in solvent, by compound 1 and PCl5Carry out chlorination reaction, you can；Wherein, X F, Cl, Br or I；The solvent is selected from SOCl2, carbon tetrachloride, 1,2 dichloroethanes, 1,1,1 trichloroethanes, the one or more in trichloro ethylene and 1,1,2 trichloroethanes；The preparation method is using 5 halo uracils as starting material, simple process, and yield is higher and environmentally friendly, may be adapted to industrialized production.
Description
Technical field
The present invention relates to the preparation methods of halo uracil class compound.
Background technology
Pa wins former times cloth (Palbociclib), be by Pfizer Inc. (Pfizer) research and develop, as using endocrine therapy as
The initial scheme on basis, shares with Letrozole in the estrogen receptor positive, the hEGF that did not received systematic treating
2 feminine gender (ER of receptor+/HER2-) postmenopausal women treat advanced breast cancer.
The synthetic route that the rich former times cloth of pa is reported in patent WO2014128588A1 is as follows：
The route, for starting material, is occurred ammonification with cyclopentamine and obtains the chloro- 6- rings of the bromo- 2- of 5- with 2,4-, bis- chloro- 5- Bromopyrimidines
With crotonic acid Heck reactions occur for amyl pyrimidine, then through lactamize cyclic the chloro- 8- cyclopenta -5- picolines of 2- simultaneously [2,
3-d] pyrimidine -7 (8H) -one, the chloro- 8- cyclopenta -5- picolines of 6- bromines 2- simultaneously [2,3-d] pyrimidine -7 (8H) -one is obtained through bromination,
Ammonification occurs with 2- amino -5- (4-N- tert-butoxycarbonyl -1-N- piperazinyls) pyridine again and obtains 8- cyclopenta -5- methyl -2-
{ [5- (piperazine -1- bases) pyridine -2- bases] amino } pyrido [2,3-d] pyrimidine -7 (8H) -one reacts generation 6- (1- through Heck
N-butoxy-vinyl) -8- cyclopenta -5- methyl -2- { [5- (piperazine -1- bases) pyridine -2- bases] amino } pyrido [2,3-
D] pyrimidine -7 (8H) -one, most afterwards through 6 acetylations of acidic hydrolysis, piperazine takes off Boc and protects to obtain the rich former times cloth of pa.2 in the route,
Bis- chloro- 5- Bromopyrimidines of 4- are important intermediate.
That reports at present prepares raw material 2, and in the method for bis- chloro- 5- Bromopyrimidines of 4-, mainly the carbonyl of uracil is carried out
Chlorination, chlorination reagent mainly use phosphorus oxychloride, and reaction yield is generally 90% or so.But phosphorus oxychloride is extremely toxic substance, right
Actual bodily harm is big；
In addition, having recorded 2 in WO2011076419A1, the preparation method of bis- fluoro- 5- Bromopyrimidines of 4- employs PCl5As
Chlorination reagent, but still use of the poisonous reagent phosphorus oxychloride as solvent can not be got rid of, reaction temperature is high, at 100 DEG C or more, and
Yield less than 90%,
The content of the invention
The technical problems to be solved by the invention are in order to which the preparation method of existing bis- chloro- 5- Bromopyrimidines of 2,4- is overcome to deposit
Chlorination reagent or solvent toxicity it is big, yield is low, reaction temperature is high the defects of, and provide a kind of halo uracil class chemical combination
The preparation method of object.The preparation method is using 5- halo uracils as starting material, simple process, and yield is higher and to environment friend
It is good, it may be adapted to industrialized production.
The present invention provides a kind of preparation methods of compound as shown in Equation 2, comprise the steps of, in solvent, by chemical combination
Object 1 and PCl5Carry out chlorination reaction, you can,
Wherein, one kind in X F, Cl, Br or I；The solvent is selected from SOCl2, carbon tetrachloride, 1,2- dichloroethanes, 1,
One or more in 1,1- trichloroethanes, trichloro ethylene and 1,1,2- trichloroethanes.
Wherein, in the chlorination reaction, the PCl5Mole dosage ratio with the compound 1 can be the normal of this field
Rule ratio, specifically preferred according to the invention (2.3:1)~(3:1), further preferably (2.5:1)~(2.8:1).
Wherein, in the chlorination reaction, the usage ratio of the compound 1 and the solvent can be that such is anti-for this field
Conventional amount used in answering, 0.5mol/L~2mol/L specifically preferred according to the invention, further preferred 0.6mol/L~1.8mol/L.
Wherein, the temperature of the chlorination reaction can be the ordinary temperature of such reaction of this field, specifically preferred according to the invention
It can make the temperature of the solvent refluxing.
Wherein, the time of the chlorination reaction can according to reaction solution from suspension become settled solution determine reaction eventually
Point, and be monitored using the common detection methods (such as HPLC, TLC or NMR) in this field, TLC specifically preferred according to the invention
Detection.
Wherein, when X is Br in compound shown in the formula 1, the preparation method of the compound as indicated with 2, compared with
Good, it can also comprise the steps of, under the action of acid or acid/acid anhydrides, uracil and bromide reagent are reacted, you can；
The bromide reagent is bis- bromo- 5,5- dimethyl hydantoins (DBH) of 1,3-；Acid/the acid anhydrides refers to the mixing of acid and acid anhydrides
Object；Acid in described sour or described acid/acid anhydrides is organic acid；The acid anhydrides is organic acid acid anhydrides；
Wherein, in the preparation method, the acid had not only made catalyst but also had made solvent use in the present invention, and described has
Machine acid can be the organic acid suitable for such reaction, acetic acid and/or propionic acid specifically preferred according to the invention, the acetic acid and the propionic acid
For acetic anhydride and anhydrous propionic acid；
In the preparation method, acid anhydrides in the acid/acid anhydrides can be to have for moisture during absorbing reaction
Machine acid acid anhydrides, acetic anhydride and/or propionic andydride specifically preferred according to the invention；
Wherein, in the preparation method, the amount ratio or the uracil of the uracil and the acid with it is described
The amount ratio of acid/acid anhydrides can be this field such reaction conventional amount used ratio, 0.8mol/L~1mol/L specifically preferred according to the invention,
Further preferred 0.811mol/L.
In the acid/acid anhydrides, the mole dosage ratio of described sour and described acid anhydrides is 1/18~1/8, preferably 1/15~1/
10.Wherein, in the preparation method, the temperature of the reaction can be the ordinary temperature of such reaction of this field, and the present invention is special
Not preferably 25 DEG C~70 DEG C, further preferred 50 DEG C~60 DEG C.
Wherein, in the preparation method, the mole dosage of the bromide reagent can be the normal of such reaction of this field
Dosage is advised, it is specifically preferred according to the invention for 0.4~1.5, preferably the 0.6~1.2 of uracil dosage.
Wherein, in the preparation method, the reaction time can be used in this field common detection methods (such as
HPLC, TLC or NMR) it is monitored, the present invention preferably TLC methods are monitored.
Wherein, it is described also to be post-processed after reaction in the preparation method；The post processing is preferably dilute
It releases, filter, dry.Wherein, it is described to dilute the conventional dilution mode that this field can be used, preferably it is diluted with ethyl acetate；
The suction filtration, the dry ordinary operation mode that this field can be used.
Wherein, in the preparation method, the reaction can also carry out under catalyst action, and the catalyst can be should
The conventional catalyst of class reaction, Trimethylsilyl trifluoromethanesulfonate (TMSOTf) specifically preferred according to the invention；The catalyst rubs
Your dosage and the mole dosage ratio of bromide reagent can be the conventional amount used of such reaction of this field, specifically preferred according to the invention 0.8
~1.2, more preferable 1:1.
Wherein, compounds process for production thereof as shown in Equation 2 of the present invention, preferably, may also include following post processing：
Reaction mixture after the chlorination reaction is extracted, dry, concentration.Preferably by the reaction mixture during extraction
It is mixed with ice water；Extractant preferred dichloromethane during the extraction；
This field routine operation can be used in the drying；
The concentration is using this field routine operation；
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition can be combined each preferably to get the present invention
Example.
The reagents and materials used in the present invention are commercially available.
The positive effect of the present invention is：
(1) present invention uses PCl5As chlorination reagent, and avoid using the phosphorus oxychloride of severe toxicity as solvent, reaction
Terminal easily judges and control；Yield is higher, and post processing is simple；
(2) back flow reaction temperature of the present invention is relatively low, reduces hazard index；
(3) can be recycled after the drying of this reaction solvent for use, it is environmentally protective.
Specific embodiment
It is further illustrated the present invention below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a scope.The experimental method of actual conditions is not specified in the following example, according to conventional methods and conditions or according to business
Product specification selects.
Embodiment 1
5-bromouracil (6.0g, 31.4mmol) and PCl5(16.4g, 78.5mmol) is mixed in reaction bulb, addition 1,
Reaction mixture is heated to flowing back by 2- dichloroethanes (50mL).Mixture becomes faint yellow from suspension in reaction process
Settled solution, the reaction was complete for the raw material of TLC displays at this time, is down to room temperature.Reaction mixture is poured slowly into the ice water of stirring, is stirred
1h is mixed, addition DCM (3 × 50mL) is extracted, and organic layer adds anhydrous MgSO4Dry, solvent evaporated obtains light yellow transparent liquid.
Silicagel column is further purified, and obtains colourless transparent liquid, i.e. compound 2 (yield 99%, purity 97.5%).
Embodiment 2
5-bromouracil (6.0g, 31.4mmol) and PCl5(19.68g, 94.2mmol) is mixed in reaction bulb, addition
SOCl2Reaction mixture is heated to flowing back by (50mL).In reaction process mixture from suspension become it is faint yellow clarification it is molten
Liquid, the reaction was complete for the raw material of TLC displays at this time, is down to room temperature.Reaction mixture is poured slowly into the ice water of stirring, stirs 1h,
It adds DCM (3 × 50mL) to extract, organic layer adds anhydrous MgSO4Dry, solvent evaporated obtains light yellow transparent liquid.Silicagel column
It is further purified, obtains colourless transparent liquid, i.e. compound 2 (yield 99%, purity 97.2%).
Embodiment 3
5-bromouracil (6.0g, 31.4mmol) and PCl5(16.4g, 78.5mmol) is mixed in reaction bulb, addition four
Reaction mixture is heated to flowing back by chlorination carbon (50mL).Mixture becomes faint yellow clarification from suspension in reaction process
Solution, the reaction was complete for the raw material of TLC displays at this time, is down to room temperature.Reaction mixture is poured slowly into the ice water of stirring, is stirred
1h, addition DCM (3 × 50mL) are extracted, and organic layer adds anhydrous MgSO4Dry, solvent evaporated obtains light yellow transparent liquid.Silicon
Rubber column gel column is further purified, and obtains colourless transparent liquid, i.e. compound 2 (yield 99%, purity 97%).
Embodiment 4
5-bromouracil (6.0g, 31.4mmol) and PCl5(16.4g, 87.9mmol) is mixed in reaction bulb, addition 1,
Reaction mixture is heated to flowing back by 1,2- trichloroethanes (50mL).Mixture becomes yellowish from suspension in reaction process
Color settled solution, the reaction was complete for the raw material of TLC displays at this time, is down to room temperature.Reaction mixture is poured slowly into the ice water of stirring,
1h is stirred, addition DCM (3 × 50mL) is extracted, and organic layer adds anhydrous MgSO4Dry, solvent evaporated obtains pale yellow transparent liquid
Body.Silicagel column is further purified, and obtains colourless transparent liquid, i.e. compound 2 (yield 99.5%, purity 97%).
Embodiment 5
Uracil (100g, 892.1mmol), solvent (glacial acetic acid (1L), acetic anhydride (100mL)) are mixed in reaction bulb
(white suspension), 50 DEG C are stirred to react, addition 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 153g,
535.3mmol), it is stirred to react.After 1.5h, white suspension becomes bean curd scoriform, and (sampling is a little, addition for TLC contact plates at this time
THF dilutes, DCM/MeOH, and 4:1 expansion), the reaction was complete for display.Post processing：By reaction mixture addition EA dilutions, filter, very
Sky is dry, obtains white solid, i.e. 5-bromouracil, i.e. compound 2 (168.8, yield 99.9%, purity 99.3%).
Embodiment 6~12
With reference to the operation of embodiment 5, change solvent, temperature, reaction time, carry out embodiment 2~8 as follows, as a result
It is as shown in the table：
Embodiment 13
Uracil (1mol), solvent (glacial acetic acid (937.5mL), acetic anhydride (62.5mL)) are mixed in reaction bulb (white
Suspension), 50 DEG C are stirred to react, and addition 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 1.2mol) is stirred to react.
After 1.5h, white suspension becomes bean curd scoriform, and TLC contact plates (sample a little, addition THF dilutions, DCM/MeOH, 4 at this time:1 exhibition
Open), the reaction was complete for display.Post processing：By reaction mixture addition EA dilutions, filter, filter cake is washed with EA, is dried in vacuo, is obtained
To white solid, i.e. 5-bromouracil (yield 99.0%, purity 99.4%).
Embodiment 14
Uracil (0.8mol), solvent (glacial acetic acid (889ml), acetic anhydride (111ml)) are mixed in reaction bulb (white mixed
Suspension), 60 DEG C are stirred to react, and addition 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 1.5mol) is stirred to react.
After 1.5h, white suspension becomes bean curd scoriform, and TLC contact plates (sample a little, addition THF dilutions, DCM/MeOH, 4 at this time:1 exhibition
Open), the reaction was complete for display.Post processing：By reaction mixture addition EA dilutions, filter, filter cake is washed with EA, is dried in vacuo, is obtained
To white solid, i.e. 5-bromouracil (yield 99.0%, purity 98.9%).
Embodiment 15
Uracil (0.9mol), solvent (glacial acetic acid (889ml), acetic anhydride (111ml)) are mixed in reaction bulb (white mixed
Suspension), 50 DEG C are stirred to react, and addition 1,3-dibromo-5,5-dimethylhydantoin (DBDMH, 0.45mol) is stirred to react.
After 1.5h, white suspension becomes bean curd scoriform, and TLC contact plates (sample a little, addition THF dilutions, DCM/MeOH, 4 at this time:1 exhibition
Open), the reaction was complete for display.Post processing：By reaction mixture addition EA dilutions, filter, vacuum drying obtains white solid, i.e.,
5-bromouracil (yield 99.0%, purity 98.6%).
Comparative example 1
Reference literature Synthesis, molecular docking and ADME prediction of some
pyridine and pyrimidine derivatives as anti-colorectal cancer drugs.Journal
Of Chemical and Pharmaceutical Research, 2 (5), 60-66, recorded content carries out as follows in 2010
Operation：5-bromouracil (250g), n,N-Dimethylaniline (300mL) are mixed in the reaction bulb of 2L, and SOCl is added dropwise at 40 DEG C2
(600mL), back flow reaction 5h, does not react.
Comparative example 2
5-bromouracil (6.0g, 31.4mmol) and PCl5(16.4g, 78.5mmol) is mixed in reaction bulb, addition two
Reaction mixture is heated to flowing back, not reacted by chloromethanes (50mL).
Comparative example 3
5-bromouracil (6.0g, 31.4mmol) and PCl5(16.4g, 78.5mmol) is mixed in reaction bulb, adds chlorine
Imitative (50mL), reaction mixture is heated to flowing back, is not reacted.
Comparative example 2~7
Reference literature Bromination at C-5 of pyrimidine and C-8 of purine
nucleosides with 1,3-dibromo-5,5-dimethylhydantoinTetrahedron Letters,53(26),
3333-3336；Experiment content and data recorded in 2012 select 5 higher reactions of yield, as shown in the table.
| Substrate | DBH(eq.) | TMSOTf(eq.) | Solvent/temperature (DEG C) | Yield (%) |
| 1a | 0.55 | 0.55 | DCM/40 | 98 |
| 1a | 0.55 | 0.55 | DMF/25 | 98 |
| 1a | 0.55 | 0.55 | MeCN/25 | 90 |
| 1a | 0.55 | — | DMF/25 | 95 |
| 1a | 0.55 | — | MeCN/25 | 86 |
Reaction substrate in upper table is replaced with into uracil, carries out repetition Experimental comparison example 1~6 as follows：
Comparative example 2
DBH (1.4g, 4.9mmol) is added to the CH of uracil (1g, 8.9mmol)2Cl2In the suspension of (15mL).Reaction
Mixture stirs 6h at 40 DEG C, and the reaction was complete for TLC detections raw material, and solvent evaporated, addition ethyl acetate (20mL) is beaten, and is taken out
It filters, is dried in vacuo 4h at 55 DEG C, obtains white solid product 0.41g, i.e., -5-bromouracil (24.1%)
Comparative example 3
DBH (1.4g, 4.9mmol) is added in the suspension of the DMF (15mL) of uracil (1g, 8.9mmol).Reaction is mixed
It closing object and 6h is stirred under room temperature (25 DEG C), the reaction was complete for TLC detections raw material, and solvent evaporated, addition ethyl acetate (20mL) is beaten,
It filters, is dried in vacuo 4h at 55 DEG C, obtains white solid product 0.77g, i.e., -5-bromouracil (45.3%).
Comparative example 4
DBH (1.4g, 4.9mmol) is added in the suspension of the acetonitrile (15mL) of uracil (1g, 8.9mmol).Reaction
Mixture stirs 6h under room temperature (25 DEG C), and the reaction was complete for TLC detections raw material, and solvent evaporated, addition ethyl acetate (20mL) is beaten
Slurry filters, and is dried in vacuo 4h at 55 DEG C, obtains white solid product 0.51g (30.0%), i.e., -5-bromouracil.
Comparative example 5
DBH (1.4g, 4.9mmol), TMSOTf (1.1g, 4.9mmol) are added to the CH of uracil (1g, 8.9mmol)2Cl2
In the suspension of (15mL).Reaction mixture stirs 6h at 40 DEG C, and the reaction was complete for TLC detections raw material, and solvent evaporated adds second
Acetoacetic ester (20mL) is beaten, and is filtered, and is dried in vacuo 4h at 55 DEG C, is obtained white solid product 0.82g, i.e., -5-bromouracil
(48.2%)
Comparative example 6
DBH (1.4g, 4.9mmol), TMSOTf (1.1g, 4.9mmol) are added to the DMF of uracil (1g, 8.9mmol)
In the suspension of (15mL).Reaction mixture stirs 6h under room temperature (25 DEG C), and the reaction was complete for TLC detections raw material, solvent evaporated,
It adds ethyl acetate (20mL) to be beaten, filter, 4h is dried in vacuo at 55 DEG C, obtain white solid product 0.77g, is i.e. -5- bromines are urinated
Pyrimidine (45.3%)
Comparative example 7
DBH (1.4g, 4.9mmol), TMSOTf (1.1g, 4.9mmol) are added to the acetonitrile of uracil (1g, 8.9mmol)
In the suspension of (15mL).6h is stirred at room temperature in reaction mixture, and the reaction was complete for TLC detections raw material, and solvent evaporated adds second
Acetoacetic ester (20mL) is beaten, and is filtered, and is dried in vacuo 4h at 55 DEG C, is obtained white solid product 1.10g, i.e., -5-bromouracil
(64.7%)
Comparative example 8~19
With reference to the operation of embodiment 5, change solvent, temperature, reaction time, carry out comparative example 7~18 as follows, as a result
It is as shown in the table：
Claims (10)
1. a kind of preparation method of compound as shown in Equation 2, which is characterized in that comprise the steps of, in solvent, by compound 1
And PCl5Carry out chlorination reaction, you can,
Wherein, X F, Cl, Br or I；The solvent is selected from SOCl2, carbon tetrachloride, 1,2- dichloroethanes, 1,1,1- trichloroethanes,
One or more in trichloro ethylene and 1,1,2- trichloroethanes.
2. preparation method as described in claim 1, which is characterized in that the PCl5Mole dosage ratio with the compound 1 is
(2.3:1)~(3:1), preferably (2.5:1)~(2.8:1).
3. preparation method as described in claim 1, which is characterized in that the compound 1 and the usage ratio of the solvent are
0.5mol/L~2mol/L, preferably 0.6mol/L~1.8mol/L.
4. preparation method as described in claim 1, which is characterized in that the X is Br.
5. preparation method as claimed in claim 4, which is characterized in that also comprise the steps of, in the effect of acid or acid/acid anhydrides
Under, uracil and bromide reagent are reacted, you can；The bromide reagent is bis- bromo- 5,5- dimethyl hydantoins of 1,3-；
Acid/the acid anhydrides refers to the mixture of acid and acid anhydrides；Acid in described sour or described acid/acid anhydrides is organic acid；The acid anhydrides
For organic acid acid anhydrides；
6. preparation method as claimed in claim 5, which is characterized in that the organic acid for acetic acid and/or propionic acid and/or,
Acid anhydrides in the acid/acid anhydrides is acetic anhydride and/or propionic andydride.
7. preparation method as claimed in claim 4, which is characterized in that the amount ratio 0.8mol/L of the uracil and the acid
~1mol/L, preferably 0.811mol/L；Or amount ratio 0.8mol/L~1mol/L of the uracil and the acid/acid anhydrides, it is excellent
Select 0.811mol/L.
8. preparation method as claimed in claim 4, the mole dosage ratio of the described sour and described acid anhydrides in the acid/acid anhydrides
For 1/18~1/8, preferably 1/15~1/10；And/or the temperature of the reaction is 25 DEG C~70 DEG C, preferably 50 DEG C~60 DEG C.
9. preparation method as claimed in claim 4, which is characterized in that the mole dosage of the bromide reagent is uracil mole
The 0.5~1.5 of dosage, preferably 0.6~1.2.
10. preparation method as claimed in claim 4, which is characterized in that also comprising catalyst, the catalyst is for the reaction
Trimethylsilyl trifluoromethanesulfonate；And/or the mole dosage of the catalyst and the mole dosage ratio of bromide reagent are 0.8
~1.2, preferably 1:1.
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| CN108117523B (en) | 2021-05-07 |
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