CN102952086B - Preparation method of 2-morpholinyl-substituted pyrimidine compounds - Google Patents
Preparation method of 2-morpholinyl-substituted pyrimidine compounds Download PDFInfo
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- CN102952086B CN102952086B CN 201210369583 CN201210369583A CN102952086B CN 102952086 B CN102952086 B CN 102952086B CN 201210369583 CN201210369583 CN 201210369583 CN 201210369583 A CN201210369583 A CN 201210369583A CN 102952086 B CN102952086 B CN 102952086B
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- Prior art keywords
- morpholinyl
- preparation
- moroxydine
- reaction
- morpholine
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- 238000002360 preparation method Methods 0.000 title abstract description 7
- -1 2-morpholinyl-substituted pyrimidine compounds Chemical class 0.000 title abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- KJHOZAZQWVKILO-UHFFFAOYSA-N N-(diaminomethylidene)-4-morpholinecarboximidamide Chemical compound NC(N)=NC(=N)N1CCOCC1 KJHOZAZQWVKILO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229960005389 moroxydine Drugs 0.000 claims abstract description 12
- 150000003230 pyrimidines Chemical class 0.000 claims abstract description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 17
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 claims description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 6
- 238000000967 suction filtration Methods 0.000 claims description 3
- XHTYQFMRBQUCPX-UHFFFAOYSA-N 1,1,3,3-tetramethoxypropane Chemical compound COC(OC)CC(OC)OC XHTYQFMRBQUCPX-UHFFFAOYSA-N 0.000 claims description 2
- DUIMWXDLDBNUFD-UHFFFAOYSA-N 4-pyrimidin-2-ylmorpholine Chemical compound C1COCCN1C1=NC=CC=N1 DUIMWXDLDBNUFD-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 230000001105 regulatory effect Effects 0.000 claims description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 abstract description 16
- 239000002994 raw material Substances 0.000 abstract description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 abstract description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 abstract 2
- NNBBQNFHCVVQHZ-UHFFFAOYSA-N methyl carbamimidothioate;sulfuric acid Chemical compound CSC(N)=N.OS(O)(=O)=O NNBBQNFHCVVQHZ-UHFFFAOYSA-N 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 description 5
- 239000000243 solution Substances 0.000 description 3
- XCHQPQVLYGBMFD-UHFFFAOYSA-N 4-hydroxy-2-morpholin-4-yl-1h-pyrimidin-6-one Chemical compound OC1=CC(=O)NC(N2CCOCC2)=N1 XCHQPQVLYGBMFD-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of 2-morpholinyl-substituted pyrimidine compounds, comprising the following steps of: carrying out reaction on morpholine and S-methyl-iso-thiourea sulfate, which are taken as raw materials, to obtain moroxydine sulfate, and carrying out reaction on moroxydine sulfate which is taken as a synthon and different 1, 3-dicarbonyl compounds respectively to obtain a series of 2-morpholinyl-subsitiuated pyrimidine compounds. The preparation method is simple in operation technology, and the problem of poor selectivity due to the fact that the pyrimidine ring is firstly synthesized, and is substituted by morpholine can be avoided.
Description
Technical field
The present invention relates to a kind of preparation method, specifically relate to the preparation of 2-morpholinyl substituted pyrimidines compounds.
Background technology
Pyrimidines is the important heterogeneous ring compound of a class in the organic chemistry, is used widely in fields such as chemical pharmacy, fine chemistry industries in recent years.The pyrimidines that the 2-morpholinyl replaces has certain activity, is the important intermediate of pharmacy field.
Traditional synthetic method generally is earlier synthetic pyrimidine ring, and then replaces with morpholine.When other being arranged can be with the functional group of morpholine radical reaction the time on pyrimidine ring, selectivity is relatively poor, and yield is lower, therefore reaction substrate is had certain requirement.
Summary of the invention
The objective of the invention is when solving synthetic 2-morpholinyl substituted pyrimidines compounds and since exist on the substrate different can be with the functional group of morpholinyl reaction the time selectivity relatively poor, be difficult to be fixed the compound of structure.And entire operation technology is simple, and the Moroxydine vitriol that makes is as an important synthon, can with the corresponding pyrimidines of a series of dicarbonyl compound prepared in reaction.
Realize that above-mentioned purpose technical scheme of the present invention is, a kind of synthetic method of brand-new preparation 2-morpholinyl substituted pyrimidines compounds, described reaction is raw material with morpholine and S-methyl-isourea, at first reaction makes Moroxydine vitriol, and then prepare pyrimidines with the cyclization of 1,3-dicarbonyl compound.
This reaction may further comprise the steps:
(1) be raw material with morpholine and S-methyl-isourea, reaction obtains Moroxydine vitriol in the aqueous solution;
(2) Moroxydine vitriol is with different 1, and the reaction of 3-dicarbonyl compound obtains the pyrimidines that a series of 2-morpholinyls replace.
Wherein, whether fully reaction is to determine by liquid chromatography.
The present invention compared with prior art has following beneficial effect: (1) the present invention is raw material with morpholine and S-methyl-isourea, can obtain an important synthon Moroxydine vitriol; (2) Moroxydine and a series of 1, the reaction of 3-dicarbonyl compound obtains corresponding pyrimidines, has avoided the yield that causes owing to reason optionally low, can synthesize the pyrimidine compound of ad hoc structure.
Embodiment
For ease of the understanding of technical solution of the present invention, be introduced below in conjunction with concrete embodiment.
Embodiment 1:
In the 1L there-necked flask, add 80gS-methyl-isourea, 50g morpholine, 300mL water, backflow stirring reaction 4h.Distill out 150mL water, residuum is cooled to 10 degree, with gained white solid suction filtration, dries, and gets Moroxydine vitriol 72g, yield 74%.
Embodiment 2:
Add 200mL ethanol in the 1L there-necked flask, add 11g sodium then in batches, disposable adding 60g Moroxydine vitriol after reaction finishes drips the 45g diethyl malonate, then back flow reaction 5h.The after-filtration that finishes is removed inorganic salt, filtrate be spin-dried for yellow solid, ethyl alcohol recrystallization obtains white solid product 2-morpholinyl-4,6-dihydroxy-pyrimidine 46g, yield 88%.
Embodiment 3:
In the 1L there-necked flask, add 200mL ethanol, 60g Moroxydine vitriol, refluxing drips 43g tetramethoxy propane, back flow reaction 4h then down.Revolve after finishing to steam and remove ethanol, gained is regulated pH=10 with body and function 10% sodium hydroxide solution, separates out white solid.Suction filtration, the oven dry, get 2-morpholinyl pyrimidine and remove by filter inorganic salt, filtrate be spin-dried for yellow solid, ethyl alcohol recrystallization obtains white solid product 2-morpholinyl-4,6-dihydroxy-pyrimidine 32g, yield 74%.
Technique scheme has only embodied the optimal technical scheme of technical solution of the present invention, those skilled in the art to some part wherein some changes that may make all embodied principle of the present invention, belong within protection scope of the present invention.
Claims (1)
1. method for preparing 2-morpholinyl substituted pyrimidines compounds, it is characterized in that in the 1L there-necked flask, adding 200mL ethanol, 60g Moroxydine vitriol, refluxing drips 43g tetramethoxy propane, back flow reaction 4h then down, revolve after finishing to steam and remove ethanol, the gained solid is regulated pH=10 with 10% sodium hydroxide solution, separates out white solid, suction filtration, oven dry gets 2-morpholinyl pyrimidine.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201210369583 CN102952086B (en) | 2012-09-28 | 2012-09-28 | Preparation method of 2-morpholinyl-substituted pyrimidine compounds |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 201210369583 CN102952086B (en) | 2012-09-28 | 2012-09-28 | Preparation method of 2-morpholinyl-substituted pyrimidine compounds |
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| CN102952086A CN102952086A (en) | 2013-03-06 |
| CN102952086B true CN102952086B (en) | 2013-08-28 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1823048A (en) * | 2003-07-15 | 2006-08-23 | 神经能质公司 | Substituted pyrimidin-4-ylamina analogues as vanilloid receptor ligands |
| WO2008109599A1 (en) * | 2007-03-05 | 2008-09-12 | Wyeth | Pyrimido [5,4-c] quinoline-2, 4-diamine derivatives and methods of use thereof |
| CN101389622A (en) * | 2006-01-20 | 2009-03-18 | 诺瓦提斯公司 | Pyrimidine derivatives used as pi-3 kinase inhibitors |
| WO2010118367A2 (en) * | 2009-04-10 | 2010-10-14 | Progenics Pharmaceuticals, Inc. | Antiviral pyrimidines |
-
2012
- 2012-09-28 CN CN 201210369583 patent/CN102952086B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1823048A (en) * | 2003-07-15 | 2006-08-23 | 神经能质公司 | Substituted pyrimidin-4-ylamina analogues as vanilloid receptor ligands |
| CN101389622A (en) * | 2006-01-20 | 2009-03-18 | 诺瓦提斯公司 | Pyrimidine derivatives used as pi-3 kinase inhibitors |
| WO2008109599A1 (en) * | 2007-03-05 | 2008-09-12 | Wyeth | Pyrimido [5,4-c] quinoline-2, 4-diamine derivatives and methods of use thereof |
| WO2010118367A2 (en) * | 2009-04-10 | 2010-10-14 | Progenics Pharmaceuticals, Inc. | Antiviral pyrimidines |
Non-Patent Citations (5)
| Title |
|---|
| Fan Zhang.Synthesis and cytotoxic activity of 2,5-disubstituted pyrimido[5,4-c]quinoline derivatives.《Chinese Chemical Letters》.2011,第22卷1278. |
| Medicinal Chemistry》.2009,第17卷第4452页. * |
| Sabine Linz.Design, synthesis and dopamine D4 receptor binding activities of new N-heteroaromatic 5/6-ring Mannich bases.《Bioorganic & * |
| SabineLinz.Design synthesis and dopamine D4 receptor binding activities of new N-heteroaromatic 5/6-ring Mannich bases.《Bioorganic & Medicinal Chemistry》.2009 |
| Synthesis and cytotoxic activity of 2,5-disubstituted pyrimido[5,4-c]quinoline derivatives;Fan Zhang;《Chinese Chemical Letters》;20110729;第22卷;第1277页倒数第2行到第1278页第5行，式1 * |
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| CN102952086A (en) | 2013-03-06 |
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Effective date of registration: 20240206 Address after: No. 4 Xi'an Road, South District, Jinghai Economic Development Zone, Jinghai District, Tianjin City, 301699 Patentee after: TIANJIN HESHENG MEDICAL TECHNOLOGY DEVELOPMENT Co.,Ltd. Country or region after: China Address before: Room 501, Building F, Green Industry Base, No. 6 Haitai Development Road, Huayuan Industrial Park (Outer Ring), Xiqing District, Tianjin, 300381 Patentee before: TIANJIN SCIPHARMACN Ltd. Country or region before: China |