CN104098562A - Synthetic method of 5,6-dihydropyrimidine[2,3-d]pyrimidine-4,7(3H,8H)-dione - Google Patents
Synthetic method of 5,6-dihydropyrimidine[2,3-d]pyrimidine-4,7(3H,8H)-dione Download PDFInfo
- Publication number
- CN104098562A CN104098562A CN201310125810.5A CN201310125810A CN104098562A CN 104098562 A CN104098562 A CN 104098562A CN 201310125810 A CN201310125810 A CN 201310125810A CN 104098562 A CN104098562 A CN 104098562A
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- CN
- China
- Prior art keywords
- pyrimidine
- diketone
- sodium
- synthetic method
- dihydro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000010189 synthetic method Methods 0.000 title claims abstract description 8
- BBZZGDLNBVRFFI-UHFFFAOYSA-N 4,5-dihydropyrimidine Chemical compound C1CN=CN=C1 BBZZGDLNBVRFFI-UHFFFAOYSA-N 0.000 title 1
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims abstract description 11
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 8
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 claims abstract description 6
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- NZHIIDNOLFOHSG-UHFFFAOYSA-N 2,3-dihydropyridine Chemical compound C1CN=CC=C1 NZHIIDNOLFOHSG-UHFFFAOYSA-N 0.000 claims description 10
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- WOLZUEKAOVDISP-UHFFFAOYSA-N 2,3-dihydro-1h-pyridine-6-thione Chemical compound S=C1NCCC=C1 WOLZUEKAOVDISP-UHFFFAOYSA-N 0.000 claims description 5
- 239000011734 sodium Substances 0.000 claims description 5
- 229910052708 sodium Inorganic materials 0.000 claims description 5
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
- -1 sodium alkoxide Chemical class 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 229960000935 dehydrated alcohol Drugs 0.000 claims description 2
- LMHHRCOWPQNFTF-UHFFFAOYSA-N s-propan-2-yl azepane-1-carbothioate Chemical compound CC(C)SC(=O)N1CCCCCC1 LMHHRCOWPQNFTF-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 abstract 1
- 238000005580 one pot reaction Methods 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 abstract 1
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 4
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an important intermediate 5,6-dihydro-2-mercaptopyrimidine[2,3-d]pyrimidine-4,7(3H,8H)-dione obtained through one pot process by using easily available raw materials comprising methyl acrylate, ethyl cyanoacetate and thiourea. The intermediate is reduced by Raney-Ni to obtain 5,6-dihydro-2-mercaptopyrimidine[2,3-d]pyrimidine-4,7(3H,8H)-dione. A synthetic method of 5,6-dihydro-2-mercaptopyrimidine[2,3-d]pyrimidine-4,7(3H,8H)-dione has the advantages of low cost, mild reaction conditions, simple operation and easy mass preparation.
Description
Technical field
The present invention relates to a kind of 5,6-dihydropyridine [2,3-d] pyrimidine-4, the synthesis technique of 7 (3H, 8H)-diketone, belongs to medicine, chemical technology field.
Background technology
As important natural product pyrimidine base (uridylic, thymus pyrimidine and cytosine(Cyt)), they have formed nucleic acid.Pyrimidine and derivative thereof are the important intermediate of forming a connecting link between chemical industry and medicinal industry, are widely used in the fields such as medicine, agricultural chemicals.
In pyrimidine derivatives, some compound has good antitumor action, has good antiviral activity; Also some compound has anti-inflammatory, analgesia and the biological activity such as antibacterial.
Summary of the invention
The present invention seeks to select a new synthetic route to prepare 5,6-dihydropyridine [2,3-d] pyrimidine-4,7 (3H, 8H)-diketone, this route raw material is easy to get, inexpensive, and productive rate is high, reaction conditions is gentle, is suitable for industrial production, has extremely strong economic implications.
Reaction scheme is as follows:
Of the present invention 5,6-dihydropyridine [2,3-d] pyrimidine-4, the synthetic method of 7 (3H, 8H)-diketone, synthetic 5,6-dihydro-2-mercaptopyridine [2,3-d] pyrimidine-4,7 (3H, in 8H)-diketone (compound 4): methyl acrylate, ethyl cyanoacetate and thiocarbamide one kettle way obtain important intermediate sodium alkoxide used, including but not limited to sodium methylate, sodium ethylate, sodium isopropylate and sodium tert-butoxide etc.; Reaction solvent can be anhydrous methanol, can be also dehydrated alcohol, Virahol and the trimethyl carbinol etc.; Temperature of reaction is at 65 to 100 ℃.
Of the present invention 5,6-dihydropyridine [2,3-d] pyrimidine-4, the synthetic method of 7 (3H, 8H)-diketone, in synthetic 5,6-dihydropyridine [2,3-d] pyrimidine-4, in 7 (3H, 8H)-diketone (compound 5): temperature of reaction is at 100 to 105 ℃.
Embodiment
Embodiment 1: synthetic 5,6-dihydro-2-mercaptopyridine [2,3-d] pyrimidine-4,7 (3H, 8H)-diketone (compound 4)
In reaction flask, add methyl acrylate (1) (34.5g, 0.4 mole), ethyl cyanoacetate (2) (45.3g, 0.4 mole), thiocarbamide (3) (30.5g, 0.4 mole), sodium methylate (71.4g, 1.32 moles) and methyl alcohol (1.7 liters), stir reflux 40 hours.Be cooled to room temperature, suction filtration, gained solid recrystallizing methanol, obtains white solid (4) 32.4g, yield: 40.5%.
Embodiment 2: synthetic 5,6-dihydropyridine [2,3-d] pyrimidine-4,7 (3H, 8H)-diketone (compound 5)
Raney-Ni (65g) carefully joins 5,6-dihydro-2-mercaptopyridine [2,3-d] pyrimidine-4 in batches, in the suspension of 7 (3H, 8H)-diketone (32.4g, 0.16 mole) and water (25 milliliters), and reflux 3 hours.Be cooled to room temperature, suction filtration, filtrate concentrates to obtain white solid (5) 29.2g, yield: 85%.
Claims (3)
1. the present invention discloses a kind of 5,6-dihydropyridine [2,3-d] pyrimidine-4, the synthetic method of 7 (3H, 8H)-diketone, comprises following steps: (1) methyl acrylate, ethyl cyanoacetate and thiocarbamide one kettle way under the effect of sodium alkoxide obtains important intermediate 5,6-dihydro-2-mercaptopyridine [2,3-d] pyrimidine-4,7 (3H, 8H)-diketone; (2) 5,6-dihydro-2-mercaptopyridine [2,3-d] pyrimidine-4,7 (3H, 8H)-diketone obtains target compound through Raney-Ni reduction.
2. as claimed in claim 5,6-dihydropyridine [2,3-d] pyrimidine-4,7 (3H, the synthetic method the first step of 8H)-diketone, it is characterized in that: methyl acrylate, ethyl cyanoacetate and thiocarbamide one kettle way obtain important intermediate sodium alkoxide used, including but not limited to sodium methylate, sodium ethylate, sodium isopropylate and sodium tert-butoxide etc.; Reaction solvent can be anhydrous methanol, can be also dehydrated alcohol, Virahol and the trimethyl carbinol etc.; Temperature of reaction is at 65 to 100 ℃.
3. as claimed in claim 5,6-dihydropyridine [2,3-d] pyrimidine-4, the synthetic method second step of 7 (3H, 8H)-diketone, is characterized in that: the first step gained intermediate obtains target compound through Raney-Ni reduction, and temperature of reaction is at 100 to 105 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310125810.5A CN104098562A (en) | 2013-04-12 | 2013-04-12 | Synthetic method of 5,6-dihydropyrimidine[2,3-d]pyrimidine-4,7(3H,8H)-dione |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310125810.5A CN104098562A (en) | 2013-04-12 | 2013-04-12 | Synthetic method of 5,6-dihydropyrimidine[2,3-d]pyrimidine-4,7(3H,8H)-dione |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104098562A true CN104098562A (en) | 2014-10-15 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310125810.5A Pending CN104098562A (en) | 2013-04-12 | 2013-04-12 | Synthetic method of 5,6-dihydropyrimidine[2,3-d]pyrimidine-4,7(3H,8H)-dione |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104098562A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002006245A1 (en) * | 2000-07-05 | 2002-01-24 | Synaptic Pharmarceutical Corporation | Selective melanin concentrating hormone-1 (mch1) receptor antagonists and uses thereof |
| US6720324B2 (en) * | 2000-07-05 | 2004-04-13 | Synaptic Pharmaceutical Corporation | Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof |
-
2013
- 2013-04-12 CN CN201310125810.5A patent/CN104098562A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002006245A1 (en) * | 2000-07-05 | 2002-01-24 | Synaptic Pharmarceutical Corporation | Selective melanin concentrating hormone-1 (mch1) receptor antagonists and uses thereof |
| US6720324B2 (en) * | 2000-07-05 | 2004-04-13 | Synaptic Pharmaceutical Corporation | Selective melanin concentrating hormone-1 (MCH1) receptor antagonists and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| 任青云等: "《吡啶并嘧啶类化合物的合成研究进展》", 《有机化学》 * |
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| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20141015 |