CN111333586A - Preparation method of compound containing 6-methyl uracil structure - Google Patents
Preparation method of compound containing 6-methyl uracil structure Download PDFInfo
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- CN111333586A CN111333586A CN202010101608.9A CN202010101608A CN111333586A CN 111333586 A CN111333586 A CN 111333586A CN 202010101608 A CN202010101608 A CN 202010101608A CN 111333586 A CN111333586 A CN 111333586A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 40
- SHVCSCWHWMSGTE-UHFFFAOYSA-N 6-methyluracil Chemical group CC1=CC(=O)NC(=O)N1 SHVCSCWHWMSGTE-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 229940126214 compound 3 Drugs 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- 229940125904 compound 1 Drugs 0.000 claims description 16
- 229940125782 compound 2 Drugs 0.000 claims description 16
- 229940125898 compound 5 Drugs 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 13
- 238000010438 heat treatment Methods 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 10
- 239000008096 xylene Substances 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 6
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 6
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 claims description 6
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 6
- ZOIORXHNWRGPMV-UHFFFAOYSA-N acetic acid;zinc Chemical compound [Zn].CC(O)=O.CC(O)=O ZOIORXHNWRGPMV-UHFFFAOYSA-N 0.000 claims description 5
- 239000004246 zinc acetate Substances 0.000 claims description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 239000011592 zinc chloride Substances 0.000 claims description 3
- 235000005074 zinc chloride Nutrition 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 2
- 239000001639 calcium acetate Substances 0.000 claims description 2
- 229960005147 calcium acetate Drugs 0.000 claims description 2
- 235000011092 calcium acetate Nutrition 0.000 claims description 2
- PNOXNTGLSKTMQO-UHFFFAOYSA-L diacetyloxytin Chemical compound CC(=O)O[Sn]OC(C)=O PNOXNTGLSKTMQO-UHFFFAOYSA-L 0.000 claims description 2
- PVFSDGKDKFSOTB-UHFFFAOYSA-K iron(3+);triacetate Chemical compound [Fe+3].CC([O-])=O.CC([O-])=O.CC([O-])=O PVFSDGKDKFSOTB-UHFFFAOYSA-K 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 238000009776 industrial production Methods 0.000 abstract description 6
- 239000000543 intermediate Substances 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract 2
- 239000002994 raw material Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
- 230000006872 improvement Effects 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 201000009273 Endometriosis Diseases 0.000 description 4
- 238000012790 confirmation Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 3
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 3
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 229940125797 compound 12 Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 3
- XLXSAKCOAKORKW-AQJXLSMYSA-N gonadorelin Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)NCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H]1NC(=O)CC1)C1=CC=C(O)C=C1 XLXSAKCOAKORKW-AQJXLSMYSA-N 0.000 description 3
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 3
- 235000009518 sodium iodide Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- LMYRWZFENFIFIT-UHFFFAOYSA-N toluene-4-sulfonamide Chemical compound CC1=CC=C(S(N)(=O)=O)C=C1 LMYRWZFENFIFIT-UHFFFAOYSA-N 0.000 description 3
- 239000005051 trimethylchlorosilane Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000012612 commercial material Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000006185 dispersion Substances 0.000 description 2
- 210000005168 endometrial cell Anatomy 0.000 description 2
- 229940011871 estrogen Drugs 0.000 description 2
- 239000000262 estrogen Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000001672 ovary Anatomy 0.000 description 2
- 210000003101 oviduct Anatomy 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- JKUYRAMKJLMYLO-UHFFFAOYSA-N tert-butyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OC(C)(C)C JKUYRAMKJLMYLO-UHFFFAOYSA-N 0.000 description 2
- -1 6-methyl uracil structure compound Chemical class 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000002474 gonadorelin antagonist Substances 0.000 description 1
- 229940121381 gonadotrophin releasing hormone (gnrh) antagonists Drugs 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000002974 pharmacogenomic effect Effects 0.000 description 1
- 230000001817 pituitary effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000006561 solvent free reaction Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 210000004291 uterus Anatomy 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
- C07D239/46—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
Abstract
The invention discloses a preparation method of a compound containing a 6-methyl uracil structure, which relates to the technical field of synthesis of medical intermediates and organic chemical intermediates, and comprises the following synthesis steps: (1) the synthesis method is applicable to industrial production, low in cost, high in purity of prepared products and high in yield, and the synthesis method is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of synthesis of medical intermediates and organic chemical intermediates, and relates to a preparation method of a 6-methyl uracil derivative.
Background
Endometriosis (EMS) is a common gynecological disease in women, an estrogen-related disease, formed by intimal cells planted in abnormal locations. The endometrial cells should grow in the uterine cavity, but because the uterine cavity is communicated with the ovary and the pelvic cavity through the oviduct, the endometrial cells can grow in an ectopic mode through the oviduct, the ovary, the pelvic cavity and the adjacent area of the uterus.
Loragol (orilisa) is used for the treatment of severe to severe pain associated with Endometriosis (EMs) in female patients. The pharmacogenetic research is Abbvie, is a novel GnRH antagonist, changes the influence on the estrogen level by changing the GnRH inhibition level of the pituitary, is approved by the FDA in U.S. 7 months in 2018, and is the first and only one fasting gonadotropin releasing hormone (GnRH) receptor antagonist which is approved to specially treat Ems-related moderate and severe pain.
The published synthetic methods can be seen in patents CN100424078C and US8765948B2, an important intermediate in this route is compound 4. Refluxing and reacting the compound 4 with urea by using hydrochloric acid/water as a solvent for 6 hours, and performing post-treatment to obtain a compound 6; there are two methods for preparing compound 5 from compound 6: the method 1 comprises the steps of dissolving a compound 6 in acetonitrile, reacting with diketene, adding trimethylchlorosilane and sodium iodide, stirring at room temperature for 20 hours until the raw materials disappear, and carrying out post-treatment to obtain a compound 5. Dissolving a compound 6 and tert-butyl acetoacetate in toluene, adding a catalytic amount of p-toluenesulfonamide, and refluxing to separate water to obtain a compound 5; the compound 5 is used as an initial raw material, and a target product, namely the oxagoril, is obtained through multi-step substitution, coupling and hydrolysis reactions.
The specific synthetic route is as follows:
in the two existing methods for preparing the compound 5, the compound 4 is taken as a starting material, and the preparation of the compound 5 can be realized only by two steps of reaction, in the first method, the compound 4 reacts with urea to obtain the compound 6, the yield is 73%, the compound 6 reacts with diketene, trimethylchlorosilane and sodium iodide need to be added, wherein the usage amounts of the diketene, the trimethylchlorosilane and the sodium iodide need to be 15 equivalents, the reaction yield is 79%, the total yield of the two steps is 58%, and the atom economy is poor; the second method comprises the steps of reacting the compound 4 with urea to obtain a compound 6, wherein the yield is 73%, reacting the compound 6 with tert-butyl acetoacetate, and performing reflux dehydration in toluene by using p-toluenesulfonamide (PTSA) as a dehydrating agent, wherein the reaction yield is 63%, and the total yield of the two steps is 46%;
the method comprises the following steps:
the method 2 comprises the following steps:
there is a method for preparing compound 12, reference: the 6-methyl-uracil and its N-substituted derivative are synthesized in the university of northwest (Nature science edition), 2009: 63-66. In the literature, compound 1 and compound 2 are used as starting materials, and compound 12 is synthesized through 2 steps, wherein the specific synthetic route is as follows:
the method comprises the steps of taking ethyl acetoacetate and ethyl carbamate as initial raw materials, zinc acetate as a catalyst, and dimethylbenzene as a solvent, carrying out reflux reaction at 140 ℃ for 6 hours to obtain a compound 3, and carrying out solvent-free reaction on the compound 3 and substituted amine at 150-160 ℃ to obtain a compound 12.
The existing synthesis routes have the defects that the steps are long, expensive reagents and catalysts are needed, the post-treatment is complicated due to environmental pollution, and particularly, the purification difficulty is high due to the long steps, the purity of the obtained product is poor, the yield is low, and the large-scale industrial production is not facilitated.
In order to overcome the defects of the existing synthetic steps of the compound containing the 6-methyl uracil structure, the invention designs the preparation method of the compound containing the 6-methyl uracil structure, which is simple to operate and high in yield.
Disclosure of Invention
The invention provides a preparation method of a compound containing a 6-methyl uracil structure, which has high product yield and high purity and is suitable for industrial production.
A preparation method of a compound containing a 6-methyl uracil structure comprises the following steps:
(1) reacting compound 1 ethyl carbamate with compound 2 ethyl acetoacetate under the heating condition and the action of an organic solvent and a catalyst to generate compound 3 oxazine diketone, wherein the reaction temperature is 50-200 ℃; the molar equivalent range of the compound 1 is 1-10, and the molar equivalent of the compound 2 is 1-10; the catalyst is any one or more of zinc acetate, stannous acetate, calcium acetate, ferric acetate, zinc chloride, phosphorus trichloride and boron trifluoride diethyl etherate; the organic solvent is any one or more of toluene, xylene, benzene, DMF, carbon tetrachloride, dioxane and dimethyl sulfoxide,
the reaction formula of the step (1) is as follows:
(2) reacting the compound 3 with a compound 42-fluoro-6- (trifluoromethyl) phenyl) methylamine under the conditions of heating and organic solvent or solvent-free to generate a compound 5, namely a 6-methyl-uracil substituted derivative,
the reaction formula of the step (2) is as follows:
as a further improvement of the scheme, the use mole equivalent of the compound 1 in the step (1) is 1-3.
As a further improvement of the scheme, in the step (1), the compound 1 and the compound 2 react under the heating condition to obtain the compound 3, and the reaction temperature is 110-160 ℃.
As a further improvement of the scheme, in the step (1), the compound 1 and the compound 2 react in an organic solvent under the condition of a catalyst to obtain a compound 3, and the catalyst is zinc acetate.
As a further improvement of this embodiment, in step (1), compound 1 and compound 2 are in an organic solvent, and the organic solvent is xylene.
As a further improvement of the scheme, the compound 1 is reacted with the compound 2 to prepare a compound 3 shown in the formula, and the using molar equivalent of the compound 2 is 1-3.
As a further improvement of the scheme, in the step (2), the compound 3 and the compound 4 react under the heating condition to obtain the compound 5, and the reaction temperature is 140-170 ℃.
As a further improvement of the scheme, in the step (2), the compound 3 and the compound 4 are reacted under the condition of an organic solvent to obtain the compound 5, wherein the organic solvent is any one or more of dimethylbenzene, DMF and N-methylpyrrolidone.
Compared with the prior art, the preparation method of the compound containing the 6-methyl uracil structure has the following advantages:
1) the route of the invention is relatively simple, the used raw materials are commercial materials, and the raw materials are relatively cheap, have no complex special operation, and are suitable for industrial production;
2) the prepared 6-methyl uracil structure compound medical intermediate has high yield and good quality;
3) the post-treatment is simple, the impurity removal capability is strong, and the obtained product has high purity;
4) after the reaction is finished, adding DMF/water solution for dispersion, separating out a solid product, and purifying once to obtain the solid product, wherein the yield reaches 84.1%, the product purity reaches 98.8%, the reaction yield is high, and the compound 4 is high in price and high in raw material cost ratio, so that the yield is improved, and the cost for synthesizing the loragoid is effectively reduced.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more clear, the present invention is further described with reference to the following embodiments:
example 1
The general synthetic route equation is as follows:
step 1) reaction of Compound 1 with Compound 2 to produce Compound 3
The synthetic route equation is as follows:
adding 8.91g of ethyl carbamate and 14.31g of ethyl acetoacetate into a reaction bottle, adding 40mL of xylene, heating to 140 ℃, stirring for 6h, performing TLC plate chromatography until the raw material is completely converted, distilling off the xylene, and performing column chromatography separation (n-heptane: ethyl acetate: 5:1) to obtain the compound 3, wherein the yield is 78% and the purity is 97.3%.
Compound 3 nuclear magnetic data are as follows:
1H-NMR(400MHz,Chloroform-d)δ10.63(s,1H),4.90(t,J＝1.1Hz,1H), 2.34(d,J＝1.0Hz,3H).
step 2) reacting compound 3 with compound 4 to produce compound 5
The synthetic route equation is as follows:
adding 12.71g of the compound 3 and 38.62g of the compound 4 into a reaction bottle, heating to 150 ℃, stirring for 2h, performing TLC plate counting until the raw materials are completely converted, slowly cooling to room temperature, adding a DMF/water solution, stirring for dispersion, filtering to obtain a crude product, purifying the crude product with ethanol, and filtering to obtain a light yellow solid, wherein the yield is 84.1% and the purity is 98.8%.
Compound 5 nuclear magnetic data are as follows:
1H-NMR(400MHz,CDCl3)δ9.03(s,1H),7.56(d,J＝7.8Hz,1H), 7.46-7.41(m,1H),7.30-7.25(m,1H),5.61(s,1H),5.38(s,2H),2.17(s, 3H)。
m + H molecular ion peak 303.1.
Example 2
Step 1) adding 17.8g of ethyl carbamate and 26.0g of ethyl acetoacetate into a reaction bottle, adding 1.36g of zinc chloride, adding 80mL of toluene, heating, refluxing and stirring for 25h, performing TLC (thin layer chromatography) on a plate until the raw materials are completely converted, evaporating the toluene, and performing column chromatography (n-heptane: ethyl acetate: 5:1) to obtain the compound 3, wherein the yield is 71.6% and the purity is 97.4%.
Nuclear magnetic confirmation of compound 3:
1H-NMR(400MHz,Chloroform-d)δ10.63(s,1H),4.90(t,J＝1.1Hz,1H), 2.34(d,J＝1.0Hz,3H)。
step 2) adding 10.0g of the compound 3 and 34.4g of the compound 4 into a reaction bottle, adding 100ml of DMF, heating and refluxing, performing TLC plate counting until the raw materials are completely converted, slowly cooling to room temperature, stirring and dispersing the aqueous solution, filtering to obtain a crude product, purifying the crude product with ethanol, and filtering to obtain a light yellow solid, wherein the yield is 78.7% and the purity is 99.4%.
Nuclear magnetic confirmation of compound 5: 1H-NMR (400MHz, CDCl3) δ 9.03(s,1H),7.56(d, J ═ 7.8Hz,1H),7.46-7.41(m,1H),7.30-7.25(m,1H),5.61(s,1H),5.38(s, 2H),2.17(s, 3H).
Example 3
Step 1) 17.77g of ethyl carbamate and 28.6g of ethyl acetoacetate are added into a reaction flask, 9.7g of boron trifluoride diethyl etherate is added, 180mL of xylene is added into the mixture, the mixture is heated to 140 ℃ and stirred for 25 hours, TLC (thin layer chromatography) is carried out until the raw materials are completely converted, the xylene is distilled off, and the compound 3 is obtained through column chromatography (n-heptane: ethyl acetate: 5:1), the yield is 62.3%, and the purity is 98.5%.
Nuclear magnetic confirmation of compound 3:
1H-NMR(400MHz,Chloroform-d)δ10.63(s,1H),4.90(t,J＝1.1Hz,1H), 2.34(d,J＝1.0Hz,3H)。
step 2) adding 10.0g of the compound 3 and 30.4g of the compound 4 into a reaction bottle, adding 100ml of N-methylpyrrolidone, heating to 150 ℃, reacting for 22 hours, performing TLC plate counting until the raw materials are completely converted, slowly cooling to room temperature, stirring and dispersing the aqueous solution, filtering to obtain a crude product, purifying the crude product with ethanol, and filtering to obtain a light yellow solid, wherein the yield is 62.8% and the purity is 98.3%.
Nuclear magnetic confirmation of compound 5: 1H-NMR (400MHz, CDCl3) δ 9.03(s,1H),7.56(d, J ═ 7.8Hz,1H),7.46-7.41(m,1H),7.30-7.25(m,1H),5.61(s,1H),5.38(s, 2H),2.17(s, 3H).
From the above examples 1 to 3, it is understood that the yield of example 1 is 84.1%, the purity is 98.8%, the route of the present invention is divided into two steps, which is relatively simple, the raw materials are all commercial materials, and the raw materials are relatively cheap, and no complicated special operation is required, so that the present invention is suitable for industrial production.
The above description is only for the preferred embodiment of the present invention, and not intended to limit the scope of the present invention, and all equivalent modifications made by the present invention are within the scope of the present invention.
Claims (8)
1. A preparation method of a compound containing a 6-methyl uracil structure is characterized by comprising the following steps:
(1) reacting compound 1 ethyl carbamate with compound 2 ethyl acetoacetate under the heating condition and the action of an organic solvent and a catalyst to generate compound 3 oxazine diketone, wherein the reaction temperature is 50-200 ℃; the molar equivalent range of the compound 1 is 1-10, and the molar equivalent of the compound 2 is 1-10; the catalyst is any one or more of zinc acetate, stannous acetate, calcium acetate, ferric acetate, zinc chloride, phosphorus trichloride and boron trifluoride diethyl etherate; the organic solvent is any one or more of toluene, xylene, benzene, DMF, carbon tetrachloride, dioxane and dimethyl sulfoxide,
the reaction formula of the step (1) is as follows:
(2) reacting the compound 3 with a compound 42-fluoro-6- (trifluoromethyl) phenyl) methylamine under the conditions of heating and organic solvent or solvent-free to generate a compound 5, namely a 6-methyl-uracil substituted derivative,
the reaction formula of the step (2) is as follows:
2. the method for preparing a compound containing a 6-methyluracil structure according to claim 1, wherein compound 1 is used in step (1) in a molar equivalent of 1 to 3.
3. The method for preparing a compound containing a 6-methyl uracil structure according to claim 1, wherein in the step (1), the compound 1 and the compound 2 are reacted under heating to obtain the compound 3, and the reaction temperature is 110-160 ℃.
4. The method for preparing the compound containing the 6-methyluracil structure according to claim 1, wherein the compound 1 and the compound 2 in the step (1) are reacted in an organic solvent under the condition of a catalyst to obtain the compound 3, and the catalyst is zinc acetate.
5. The method for preparing the compound containing the 6-methyluracil structure according to claim 1, wherein the compound 1 and the compound 2 in the step (1) are in an organic solvent, and the organic solvent is xylene.
6. The method for preparing a compound having a 6-methyl uracil structure according to claim 1, wherein compound 1 is reacted with compound 2 to prepare compound 3, and the molar equivalent of compound 2 is 1 to 3.
7. The method for preparing a compound containing a 6-methyl uracil structure according to claim 1, wherein in the step (2), the compound 3 and the compound 4 are reacted under heating to obtain the compound 5, and the reaction temperature is 140-170 ℃.
8. The method for preparing a compound containing a 6-methyl uracil structure according to claim 1, wherein in the step (2), the compound 3 is reacted with the compound 4 in the presence of an organic solvent to obtain the compound 5, wherein the organic solvent is any one or more of xylene, DMF, and N-methylpyrrolidone.
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