CN110156699A - A kind of preparation method of 4- ethyoxyl -1H- pyrimid-2-one - Google Patents
A kind of preparation method of 4- ethyoxyl -1H- pyrimid-2-one Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 238000006243 chemical reaction Methods 0.000 claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 13
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 claims abstract description 8
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000007062 hydrolysis Effects 0.000 claims abstract description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 9
- 235000019441 ethanol Nutrition 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 4
- 239000000460 chlorine Substances 0.000 abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000002341 toxic gas Substances 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000007039 two-step reaction Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 239000012071 phase Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 238000010189 synthetic method Methods 0.000 description 3
- 238000010792 warming Methods 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- -1 Sodium alkoxide Chemical class 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 1
- REZCUNDZKVUACL-UHFFFAOYSA-N 2,4-diethoxypyrimidine Chemical compound CCOC1=CC=NC(OCC)=N1 REZCUNDZKVUACL-UHFFFAOYSA-N 0.000 description 1
- HHGBVPMMOSVISH-UHFFFAOYSA-N 2-ethylsulfonylpyrimidine Chemical class CCS(=O)(=O)C1=NC=CC=N1 HHGBVPMMOSVISH-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 102000004073 Dopamine D3 Receptors Human genes 0.000 description 1
- 108090000525 Dopamine D3 Receptors Proteins 0.000 description 1
- 229940088353 Dopamine D3 receptor antagonist Drugs 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- 208000012661 Dyskinesia Diseases 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000019771 cognition Effects 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002300 dopamine 3 receptor blocking agent Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008451 emotion Effects 0.000 description 1
- QPUSANCBJDDXSA-UHFFFAOYSA-N ethanethiol;sodium Chemical compound [Na].CCS QPUSANCBJDDXSA-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 239000012495 reaction gas Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- 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
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
-
- C—CHEMISTRY; METALLURGY
- 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
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of preparation methods of 4- ethyoxyl -1H- pyrimid-2-one, comprising the following steps: 2,4- Dichloro-pyrimidin is dissolved in solvent, sodium ethoxide is added, reaction obtains the chloro- 4- ethyoxyl-pyrimidine of 2-；The chloro- 4- ethyoxyl-pyrimidine of 2- is dissolved in solvent, hydrolysis obtains 4- ethyoxyl -1H- pyrimid-2-one under alkaline condition.A kind of preparation method of 4- ethyoxyl -1H- pyrimid-2-one of the invention, may be implemented that preparation method is simple, raw material is easy to get, product is easily isolated, and reaction condition is mild, easily controllable, is suitable for large-scale production；Meanwhile this toxic gas of chlorine is not used in two-step reaction, it increases so that preparing the upper feature of environmental protection.
Description
Technical field
The present invention relates to a kind of preparation methods of 4- ethyoxyl -1H- pyrimid-2-one, belong among fine chemistry industry and medicine
Body synthesizes field.
Background technique
4- ethyoxyl-1H- pyrimid-2-one (I) is important medicinal intermediate, for synthesizing a kind of dopamine D 3-receptor
Antagonist.Dopamine receptor is divided into 5 hypotypes, including D1, D2, D3, D4 and D5.Wherein, dopamine D 3 receptor (D3R) is main
Be distributed in emotion, the closely related edge brain area of cognition, be schizophrenia, Parkinson's disease, dyskinesia and drug at
The potential treatment target spot of the related diseases such as addiction.The research of highly selective D3R receptor antagonist is one of research hotspot of drug.This
Outside, 4- ethyoxyl -1H- pyrimid-2-one (I) is also used to the synthesis of one antiviral and antitumor nucleosides.Therefore, 4- ethyoxyl-
The market prospects of 1H- pyrimid-2-one are more wide.Exploitation one is easy to operate, and route is short, high income, suitable for scale production
Synthetic method be of great significance.
Document " Action of Alkali on 2,4-Diethoxypyrimidine and the Application
of the Reaction to a New Synthesis of Cytosine. J.Am.Chem.Soc.1935,57,552-
554 " report a kind of 4- ethyoxyl -1H- pyrimid-2-one (I) report synthetic method it is as follows:
Reagent and condition: a) NaOEt, EtOH; b) NaOEt, EtOH, H2O
In the route III hydrolysis to I when can generate the compound IV of equivalent, cause the difficulty isolated and purified.
Document " Researches on Pyrimidines. CXLIX. Reactions of Some 2-
Ethylsulfonylpyrimidines. J.Am.Chem.Soc.1936,58,5423-426 " reports another middle synthesis I's
Method hydrolyzes preparation I by compound V:
Raw material compound V used in reaction need to prepare from compound II by 3 step reactions (J.Am.Chem.Soc.1935,
57,2252-2255):
Reagent and condition: a) EtSNa; b) EtONa; c)Cl2,H2O
Wherein, need to use ethyl mercaptan sodium when II prepares VI, and VII preparation V needs to use chlorine.The chlorine for needing to use in reaction
Gas is the chemical reagent with overpowering odor and severe toxicity.
Above-mentioned 2 kinds of report methods are all unsuitable for large scale preparation 4- ethyoxyl -1H- pyrimid-2-one (I).The market prospects of I
It is more wide.Exploitation one is easy to operate, and route is short, high income, and synthetic method suitable for scale production is of great significance.
Summary of the invention
The technical problem to be solved by the present invention is to overcome the 4- ethyoxyl -1H- pyrimid-2-one of the prior art to be difficult to scale
The defect that metaplasia produces, provides a kind of preparation method of 4- ethyoxyl -1H- pyrimid-2-one, and it is simple, former that preparation method may be implemented
Material is easy to get, product is easily isolated, and is suitable for large-scale production.
Above-mentioned technical purpose of the invention has the technical scheme that
A kind of preparation method of 4- ethyoxyl -1H- pyrimid-2-one, comprising the following steps:
(1) 2,4- Dichloro-pyrimidin is dissolved in solvent, sodium ethoxide is added, reaction obtains the chloro- 4- ethyoxyl-pyrimidine of 2-；
(2) the chloro- 4- ethyoxyl-pyrimidine of 2- is dissolved in solvent, hydrolysis obtains 4- ethyoxyl -1H- pyrimidine -2- under alkaline condition
Ketone；
Reaction process are as follows:
。
By using above-mentioned technical proposal, 4- ethyoxyl -1H- pyrimid-2-one is prepared by two steps, method is simple,
It does not need to be suitable for large-scale production using toxic gas.
Preferably, the solvent in the step (1) is ethyl alcohol.
It is cheap and easy to get using ethyl alcohol as solvent by using above-mentioned technical proposal, so that cost reduces, it is suitable for extensive raw
It produces.
Preferably, the reaction temperature of the step (1) is -5 DEG C ~ 5 DEG C, and the reaction time is 0.5 ~ 2h.
By using above-mentioned technical proposal, it is phonetic that the chloro- 4- ethyoxyl-of 2- is obtained using reasonable reaction temperature and reaction time
Pyridine, the obtained intermediate product yield are high.
Preferably, the solvent in the step (2) is one of THF/ water or Isosorbide-5-Nitrae-dioxane/water.
By using above-mentioned technical proposal, make the dissolubility of compound good using mixed solvent, promote the progress of reaction,
And the 4- ethyoxyl -1H- pyrimid-2-one made is easily isolated.
Preferably, the volume ratio of the THF or Isosorbide-5-Nitrae-dioxane and water is 1.0:0.5 ~ 1.0:2.
Preferably, the alkali in step (2) the neutral and alkali condition is Li2CO3, K2CO3, Na2CO3, Cs2CO3, LiOH,
At least one of NaOH, KOH, CsOH.
It by using above-mentioned technical proposal, is dissolved in the water to obtain alkaline solution using above-mentioned common alkali, at low cost, effect
Fruit is good.
Preferably, the molar ratio of the chloro- 4- ethyoxyl-pyrimidine of 2- and alkali is 1.0:1.2 ~ 1.0 in the step (2):
2.0。
By using above-mentioned technical proposal, using the chloro- 4- ethyoxyl-pyrimidine of the 2- of certain mol proportion and alkali, be conducive to anti-
The progress and post-processing answered, and yield is high.
Preferably, the reaction temperature in the step (2) is 70 DEG C ~ 100 DEG C.
In conclusion the invention has the following advantages:
A kind of preparation method of 4- ethyoxyl -1H- pyrimid-2-one of the invention, may be implemented that preparation method is simple, raw material is easy
, product be easily isolated, be suitable for large-scale production；Meanwhile a kind of preparation side of 4- ethyoxyl -1H- pyrimid-2-one of the invention
Method does not use this toxic gas of chlorine in two-step reaction, increases so that preparing the upper feature of environmental protection；A kind of 4- second of the invention
The preparation method reaction condition of Oxy-1 H- pyrimid-2-one is mild, easily controllable, obtained 4- ethyoxyl -1H- pyrimid-2-one
Yield is high, is suitable for large-scale production.
Detailed description of the invention
Fig. 1 is 4- ethyoxyl -1H- pyrimid-2-one of the invention1HNMR figure.
Specific embodiment
The invention will be further described below.Following embodiment is only used for clearly illustrating technical side of the invention
Case, and not intended to limit the protection scope of the present invention.
A kind of preparation method of 4- ethyoxyl -1H- pyrimid-2-one, comprising the following steps:
(1) 2,4- Dichloro-pyrimidin is dissolved in solvent, sodium ethoxide is added, reaction obtains the chloro- 4- ethyoxyl-pyrimidine of 2-；
(2) the chloro- 4- ethyoxyl-pyrimidine of 2- is dissolved in solvent, hydrolysis obtains 4- ethyoxyl -1H- pyrimidine -2- under alkaline condition
Ketone；
Reaction process are as follows:
。
4- ethyoxyl -1H- the pyrimid-2-one being prepared1HNMR figure is as shown in Figure 1.
Embodiment 1
(1) synthesis of the chloro- 4- ethyoxyl-pyrimidine of 2-:
2,4- Dichloro-pyrimidin (100 g, 671 mmol, 1.0 equiv.) is dissolved in 400 ml ethyl alcohol, is cooled to 0 DEG C, second is added
Sodium alkoxide (48.0 g, 705 mmol, 1.05 equiv.) reacts 1 hour, and TLC display reaction terminates, and 2L water, water phase EA is added
Extraction, organic phase anhydrous Na2SO4Concentration is dried, filtered, PE is beaten to obtain the chloro- 4- ethyoxyl-pyrimidine 85.10 of faint yellow solid 2-
G, yield 80%.
(2) synthesis of 4- ethyoxyl -1H- pyrimid-2-one:
The chloro- 4- ethyoxyl-pyrimidine of 2- (75.0 g, 473 mmol, 1.0 equiv.) is dissolved in 400 ml of Isosorbide-5-Nitrae-dioxane
In the mixed liquor of 400 ml of water, it is added potassium carbonate (117.8 g, 851 mmol, 1.8 equiv.), is warming up to 100 DEG C of reactions
5 hours, TLC showed end of reaction.It is cooled to room temperature, is concentrated, methanol, filtering is added in water phase, and filter cake is washed with a small amount of methanol.Filter
Liquid is concentrated under reduced pressure, and mixes silica gel, column chromatographs to obtain 44.9 g of white solid 4- ethyoxyl -1H- pyrimid-2-one, yield 67.7%.
1H NMR(400 MHz, DMSO-D6) δ(ppm): 11.26(s, 1H), 7.68(d,J =7.00 Hz, 1H)
5.84(dJ =6.96 Hz, 1H), 4.26(dd,J=14.12,7.04 Hz, 1H), 1.27(t,J = 7.08 Hz,
3H).
LC-MS (ESI-): m/z 139.1 (M-H)。
Embodiment 2
(1) synthesis of the chloro- 4- ethyoxyl-pyrimidine of 2-:
2,4- Dichloro-pyrimidin (100 g, 671 mmol, 1.0 equiv.) is dissolved in 400 ml ethyl alcohol, is cooled to -5 DEG C, is added
Sodium ethoxide (48.0 g, 705 mmol, 1.05 equiv.) reacts 0.5 hour, and TLC display reaction terminates, and 2L water, water phase is added
It is extracted with EA, organic phase anhydrous Na2SO4Concentration is dried, filtered, PE is beaten to obtain the chloro- 4- ethyoxyl-pyrimidine of faint yellow solid 2-
80.15 g, yield 76%.
(2) synthesis of 4- ethyoxyl -1H- pyrimid-2-one:
2,4- Dichloro-pyrimidin (10.0 g, 63.05 mmol, 1.0 equiv.) is dissolved in the mixed of 100 ml of THF 100ml and water
Close in liquid, NaOH(3.78 g, 94.58 mmol, 1.5 equiv. be added), it is warming up to 70 DEG C and reacts 10 hours, TLC is shown
End of reaction is cooled to room temperature.Methanol, filtering is added in liquid separation, concentration, water phase, and mother liquor mixes silica gel, and column chromatographs to obtain white solid
6.16 g, yield 69.7%.
1H NMR(400 MHz, DMSO-D6) δ(ppm): 11.26(s, 1H), 7.68(d,J =7.00 Hz, 1H)
5.84(dJ =6.96 Hz, 1H), 4.26(dd,J=14.12,7.04 Hz, 1H), 1.27(t,J = 7.08 Hz,
3H).
LC-MS (ESI-): m/z 139.1 (M-H)。
Embodiment 3
(1) synthesis of the chloro- 4- ethyoxyl-pyrimidine of 2-:
2,4- Dichloro-pyrimidin (100 g, 671 mmol, 1.0 equiv.) is dissolved in 400 ml ethyl alcohol, is cooled to 5 DEG C, second is added
Sodium alkoxide (48.0 g, 705 mmol, 1.05 equiv.) reacts 2 hours, and TLC display reaction terminates, and 2L water, water phase EA is added
Extraction, organic phase anhydrous Na2SO4Concentration is dried, filtered, PE is beaten to obtain the chloro- 4- ethyoxyl-pyrimidine 88.23 of faint yellow solid 2-
G, yield 83%.
(2) synthesis of 4- ethyoxyl -1H- pyrimid-2-one:
The chloro- 4- ethyoxyl-pyrimidine of 2- (10.0 g, 63.05 mmol, 1.0 equiv.) is dissolved in THF 100ml and water 100
In the mixed liquor of ml, Na is added2CO3(13.37 g, 126.1 mmol, 2.0 equiv.) are warming up to 85 DEG C of reactions overnight, TLC
It shows end of reaction, is cooled to room temperature.Methanol, filtering is added in liquid separation, concentration, water phase, and mother liquor mixes silica gel, and column chromatographs white solid
6.36 g of body, yield 72.0%.
1H NMR(400 MHz, DMSO-D6) δ(ppm): 11.26(s, 1H), 7.68(d,J =7.00 Hz, 1H)
5.84(dJ =6.96 Hz, 1H), 4.26(dd,J=14.12,7.04 Hz, 1H), 1.27(t,J = 7.08 Hz,
3H).
LC-MS (ESI-): m/z 139.1 (M-H)。
The above is only a preferred embodiment of the present invention, protection scope of the present invention is not limited merely to above-mentioned implementation
Example, all technical solutions belonged under thinking of the present invention all belong to the scope of protection of the present invention.It should be pointed out that for the art
Those of ordinary skill for, several improvements and modifications without departing from the principles of the present invention, these improvements and modifications
It should be regarded as protection scope of the present invention.
Claims (8)
1. a kind of preparation method of 4- ethyoxyl -1H- pyrimid-2-one, characterized in that the following steps are included:
(1) 2,4- Dichloro-pyrimidin is dissolved in solvent, sodium ethoxide is added, reaction obtains the chloro- 4- ethyoxyl-pyrimidine of 2-；
(2) the chloro- 4- ethyoxyl-pyrimidine of 2- is dissolved in solvent, hydrolysis obtains 4- ethyoxyl -1H- pyrimidine -2- under alkaline condition
Ketone；
Reaction process are as follows:
。
2. a kind of preparation method of 4- ethyoxyl -1H- pyrimid-2-one according to claim 1, characterized in that the step
Suddenly the solvent in (1) is ethyl alcohol.
3. a kind of preparation method of 4- ethyoxyl -1H- pyrimid-2-one according to claim 1, characterized in that the step
Suddenly the reaction temperature of (1) is -5 DEG C ~ 5 DEG C, and the reaction time is 0.5 ~ 2h.
4. a kind of preparation method of 4- ethyoxyl -1H- pyrimid-2-one according to claim 1, characterized in that the step
Suddenly the solvent in (2) is one of THF/ water or Isosorbide-5-Nitrae-dioxane/water.
5. a kind of preparation method of 4- ethyoxyl -1H- pyrimid-2-one according to claim 4, characterized in that the THF
Or the volume ratio of Isosorbide-5-Nitrae-dioxane and water is 1.0:0.5 ~ 1.0:2.
6. a kind of preparation method of 4- ethyoxyl -1H- pyrimid-2-one according to claim 1, characterized in that the step
Suddenly the alkali in (2) neutral and alkali condition is Li2CO3, K2CO3, Na2CO3, Cs2CO3, LiOH, NaOH, at least one in KOH, CsOH
Kind.
7. a kind of preparation method of 4- ethyoxyl -1H- pyrimid-2-one according to claim 1, characterized in that the step
Suddenly the molar ratio of the chloro- 4- ethyoxyl-pyrimidine of 2- and alkali is 1.0:1.2 ~ 1.0:2.0 in (2).
8. a kind of preparation method of 4- ethyoxyl -1H- pyrimid-2-one according to claim 1, characterized in that the step
Suddenly the reaction temperature in (2) is 70 DEG C ~ 100 DEG C.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1180356A (en) * | 1995-03-31 | 1998-04-29 | 惠尔康基金会集团公司 | Method for synthesizing nucleoside analogs |
| WO2016130652A1 (en) * | 2015-02-10 | 2016-08-18 | Vanderbilt University | Negative allosteric modulators of metabotropic glutamate receptor 3 |
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2019
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1180356A (en) * | 1995-03-31 | 1998-04-29 | 惠尔康基金会集团公司 | Method for synthesizing nucleoside analogs |
| WO2016130652A1 (en) * | 2015-02-10 | 2016-08-18 | Vanderbilt University | Negative allosteric modulators of metabotropic glutamate receptor 3 |
Non-Patent Citations (1)
| Title |
|---|
| KOHFUKU KOHDA ET AL.: "SYNTHESIS AND PROPERTIES OF N-AMINOPYRIMIDINES", 《TETRAHEDRON》 * |
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