CN115677598A - Preparation method for synthesizing pyrimidinedione compound - Google Patents
Preparation method for synthesizing pyrimidinedione compound Download PDFInfo
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- CN115677598A CN115677598A CN202211414763.1A CN202211414763A CN115677598A CN 115677598 A CN115677598 A CN 115677598A CN 202211414763 A CN202211414763 A CN 202211414763A CN 115677598 A CN115677598 A CN 115677598A
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- -1 pyrimidinedione compound Chemical class 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 238000006243 chemical reaction Methods 0.000 claims abstract description 52
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract description 23
- 239000002253 acid Substances 0.000 claims abstract description 22
- 238000000034 method Methods 0.000 claims abstract description 20
- 238000006722 reduction reaction Methods 0.000 claims abstract description 20
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 17
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 14
- 239000002184 metal Substances 0.000 claims abstract description 12
- 229910052751 metal Inorganic materials 0.000 claims abstract description 12
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- 150000008512 pyrimidinediones Chemical class 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 29
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 239000007805 chemical reaction reactant Substances 0.000 claims description 12
- 238000005406 washing Methods 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- 239000003638 chemical reducing agent Substances 0.000 claims description 10
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000007810 chemical reaction solvent Substances 0.000 claims description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 238000004537 pulping Methods 0.000 claims description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 238000007670 refining Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 238000005809 transesterification reaction Methods 0.000 claims description 5
- YOYAIZYFCNQIRF-UHFFFAOYSA-N 2,6-dichlorobenzonitrile Chemical compound ClC1=CC=CC(Cl)=C1C#N YOYAIZYFCNQIRF-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical group [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-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
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- XPTAYRHLHAFUOS-UHFFFAOYSA-N 2-chloro-6-fluorobenzonitrile Chemical compound FC1=CC=CC(Cl)=C1C#N XPTAYRHLHAFUOS-UHFFFAOYSA-N 0.000 claims description 2
- VCZNNAKNUVJVGX-UHFFFAOYSA-N 4-methylbenzonitrile Chemical compound CC1=CC=C(C#N)C=C1 VCZNNAKNUVJVGX-UHFFFAOYSA-N 0.000 claims description 2
- UWFOIFNWYIOWKH-UHFFFAOYSA-N C(N)(OCCCC(C)=O)=O Chemical compound C(N)(OCCCC(C)=O)=O UWFOIFNWYIOWKH-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 125000004802 cyanophenyl group Chemical group 0.000 claims 1
- 239000008096 xylene Substances 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 9
- 238000009776 industrial production Methods 0.000 abstract description 6
- 238000000746 purification Methods 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 11
- OGQYJDHTHFAPRN-UHFFFAOYSA-N 2-fluoro-6-(trifluoromethyl)benzonitrile Chemical compound FC1=CC=CC(C(F)(F)F)=C1C#N OGQYJDHTHFAPRN-UHFFFAOYSA-N 0.000 description 10
- 239000001257 hydrogen Substances 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- 238000001914 filtration Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- 239000000579 Gonadotropin-Releasing Hormone Substances 0.000 description 4
- 101000857870 Squalus acanthias Gonadoliberin Proteins 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 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 4
- 229940035638 gonadotropin-releasing hormone Drugs 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- 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 3
- 239000007868 Raney catalyst Substances 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- 239000004202 carbamide Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 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 2
- 201000009273 Endometriosis Diseases 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- FCYVKQRWNQRCFE-UHFFFAOYSA-N [2-fluoro-6-(trifluoromethyl)phenyl]methanamine Chemical compound NCC1=C(F)C=CC=C1C(F)(F)F FCYVKQRWNQRCFE-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- GBOWGKOVMBDPJF-UHFFFAOYSA-N 1-fluoro-3-(trifluoromethyl)benzene Chemical compound FC1=CC=CC(C(F)(F)F)=C1 GBOWGKOVMBDPJF-UHFFFAOYSA-N 0.000 description 1
- FAKUGVHRTLCKHB-UHFFFAOYSA-N 2-fluoro-6-(trifluoromethyl)benzaldehyde Chemical compound FC1=CC=CC(C(F)(F)F)=C1C=O FAKUGVHRTLCKHB-UHFFFAOYSA-N 0.000 description 1
- XYVAUHKIIHYPAX-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)benzonitrile Chemical compound FC(F)(F)OC1=CC=C(Br)C=C1C#N XYVAUHKIIHYPAX-UHFFFAOYSA-N 0.000 description 1
- HEAUOKZIVMZVQL-VWLOTQADSA-N Elagolix Chemical compound COC1=CC=CC(C=2C(N(C[C@H](NCCCC(O)=O)C=3C=CC=CC=3)C(=O)N(CC=3C(=CC=CC=3F)C(F)(F)F)C=2C)=O)=C1F HEAUOKZIVMZVQL-VWLOTQADSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004310 Ion Channels Human genes 0.000 description 1
- 102000008238 LHRH Receptors Human genes 0.000 description 1
- 108010021290 LHRH Receptors Proteins 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000755 effect on ion Effects 0.000 description 1
- 229950004823 elagolix Drugs 0.000 description 1
- 229940011871 estrogen Drugs 0.000 description 1
- 239000000262 estrogen Substances 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 230000035558 fertility Effects 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- DQYGXRQUFSRDCH-UQIIZPHYSA-M sodium;4-[[(1r)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]amino]butanoate Chemical compound [Na+].COC1=CC=CC(C=2C(N(C[C@H](NCCCC([O-])=O)C=3C=CC=CC=3)C(=O)N(CC=3C(=CC=CC=3F)C(F)(F)F)C=2C)=O)=C1F DQYGXRQUFSRDCH-UQIIZPHYSA-M 0.000 description 1
- JKUYRAMKJLMYLO-UHFFFAOYSA-N tert-butyl 3-oxobutanoate Chemical compound CC(=O)CC(=O)OC(C)(C)C JKUYRAMKJLMYLO-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method for synthesizing pyrimidinedione compounds, which belongs to the technical field of chemical pharmacy and comprises the following three steps: 1) Carrying out hydrogenation reduction reaction on a compound I serving as a raw material under the action of a metal catalyst to obtain an intermediate II; 2) Carrying out amine ester exchange reaction on the intermediate II and the compound III to realize the preparation of an intermediate IV; 3) And (3) carrying out cyclization reaction on the intermediate IV under the condition of anhydrous acid to realize the preparation of the target compound V. The method simplifies the synthesis process of the pyrimidinedione compound, greatly shortens the circuit for synthesizing the pyrimidinedione compound V, reduces the cost, inhibits the generation of V-impuity impurities, reduces the generation of reaction byproducts, ensures the purification of the pyrimidinedione compound V, improves the yield, ensures that the preparation process of the pyrimidinedione compound V is more environment-friendly, and meets the requirement of industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to a preparation method for synthesizing pyrimidinedione compounds.
Background
The production process of chemicals is made up by using raw materialsThe production of the raw materials and the preparation of the medicine. The synthesized pyrimidinedione compound is widely applied to an elargol sodium key intermediate as a pharmaceutical preparation, namely elargol sodium (Elagolix Soidum), a CAS registry number: 832720-36-2, structural formula:
it is a novel potent, selective, orally active gonadotropin releasing hormone receptor GnRHR nonpeptide antagonist with a Kd value of 54pM. At a concentration of 10. Mu.M, there was no significant active effect on ion channels, enzymes and transporters.
Globally, as many as two hundred million women suffer from endometriosis, and have a significantly rising trend, with the age of onset mostly between 30 and 49 years. The morbidity of women of childbearing age is up to 15 percent, accounts for about 70 to 80 percent of infertility patients, seriously affects the physical and mental health, work and fertility of the women, has uncertain etiology, and is reported to be possibly related to factors such as immunity, heredity, blood vessels, estrogen and receptors thereof. The current treatment for this disease is primarily an orally active non-peptide gonadotropin releasing hormone (GnRHR) antagonist for the treatment of endometriosis. And the compound is used as a key intermediate 1- [ 2-fluoro-6- (trifluoromethyl) benzyl group of the sodium elargol]-6-methylpyrimidine-2,4 (1H, 3H) -dione (Compound V, structure: formula
The CAS registry number: 830346-47-9), the synthetic process of compound v is now reported as follows: for example, WO2019/112968, WO2021214318 and the like utilize 3-fluorobenzotrifluoride as a raw material, firstly use an n-butyllithium/DMF system to obtain 2-fluoro-6-trifluoromethylbenzaldehyde, and then obtain a product through a series of reactions such as oximation reaction, reduction and the like, wherein the specific synthetic route is as follows:
although the initial raw materials are simple and easy to obtain, the synthetic route has long reaction steps, needs column purification, has complex process and low overall yield, and is not suitable for industrial production.
The literature on the preparation of compound v is reported at this stage as follows: for example, patent WO2005/7164, US7056927, US7419983B2, CN1819829a, etc. report that 2-fluoro-6-trifluoromethylbenzonitrile is used as a starting material, cyano is reduced by borane, and then the cyano is reacted with urea and hydrochloric acid to prepare a urea compound, and then urea and diketene are cyclized under the condition of sodium iodide to obtain a key intermediate of the GnRHR drug, wherein the published route is as follows:
the route uses an explosive and toxic tube product diketene, and uses borane as a reducing agent of cyano group, so that the route has high toxicity, is inflammable, is not friendly to the environment, has high danger and high production safety risk, and is not suitable for industrial production;
another route is reported in patents WO2009/62087, WO2018198086A1, WO2021/130776, etc., and the specific synthetic route is as follows:
the method uses tert-butyl acetoacetate to replace diketene in the previous method for carrying out ring closing reaction, but the method has long reaction time and high temperature, generates a large amount of compound IV, and IV-impurity impurities which are difficult to purify in the compound IV, so that the obtained product contains a large amount of V-impurity impurities, is difficult to purify and has the yield of about 50 percent.
In summary, the preparation method of the compound v at the present stage has a long synthetic route, a complex synthetic process, difficult obtainment of starting materials, high cost, generation of a large amount of reaction byproducts, incapability of ensuring the purification of the compound v, low yield and incapability of meeting the requirements of industrial production.
Disclosure of Invention
The invention aims to provide a preparation method for synthesizing pyrimidinedione compounds, which aims to solve the problems that the preparation method for synthesizing the compound V in the prior art has long synthesis route, complex synthesis process, difficult obtainment of initial raw materials, high cost, generation of a large amount of reaction byproducts, incapability of ensuring the purification of the compound V, low yield and incapability of meeting the requirements of industrial production.
In order to achieve the purpose, the invention provides the following technical scheme: a preparation method for synthesizing pyrimidinedione compounds comprises the following specific synthetic route:
the preparation method comprises the following steps of carrying out hydrogenation reduction reaction on a compound I serving as a raw material under the action of a metal catalyst to obtain an intermediate II, carrying out amine ester exchange reaction on the intermediate II and a compound III to realize the preparation of an intermediate IV, and carrying out cyclization reaction on the intermediate IV under the condition of anhydrous acid to realize the preparation of a target compound V.
The specific synthetic procedure for compound v prepared according to the above synthetic route is as follows:
s1, preparation of an intermediate II: taking a compound I as a reaction starting material, directly putting the compound I into a hydrogenation kettle, carrying out hydrogenation reduction reaction at 20-100 ℃ in the atmosphere of an organic solvent and a reducing agent with the pressure of 0.1-2 MPa under the action of 0.1-20% of the metal catalyst of the compound I and ammonia water, and carrying out treatment and concentration to obtain an intermediate II, wherein the metal catalyst is Ranney-Ni, the compound I is one of benzonitrile, 2,4,6-trifluorophenylnitrile, 2-fluoro-6- (trifluoromethyl) benzonitrile, 2-fluoro-6-chlorobenzonitrile, p-cyanotoluene, 2,6-dichlorobenzonitrile and 5-bromo-2- (trifluoromethoxy) benzonitrile, and the organic solvent is one or a mixture of methanol, ethanol, tetrahydrofuran, N-dimethylacetamide, acetone, acetonitrile, ethylene glycol, dimethyl sulfoxide and 1,4-dioxane; the reducing agent is one of H2, naBH4, naBH3CN, zn or HCL;
s2, preparing an intermediate IV: and (3) mixing the intermediate II obtained in the S1 with the compound III according to a molar ratio of 1: 1.0-6.0, adding strong base and weak acid salt organic base at room temperature to perform amine ester exchange reaction at 0-70 ℃, concentrating, washing, and pulping with ethanol to obtain an intermediate IV, wherein the compound III is one of (3-oxobutyl) -ethyl carbamate, (3-oxobutyl) -methyl carbamate and 2,4-dioxopiperidine-1-benzyl formate, the furan solvent is one or a mixture of dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, 1,4-dioxane and dimethylacetamide, and the strong base and weak acid salt organic base is one of sodium methoxide, sodium ethoxide and sodium hydride;
s3, preparation of a compound V: stirring the intermediate IV obtained in the S2 in a reaction solvent, refluxing and carrying water under the condition of anhydrous acid, performing cyclization reaction at the temperature of 20-150 ℃ for 1-10 hours, and refining with isopropanol to obtain a target compound V, wherein the molar ratio of the intermediate IV to the anhydrous acid is 1:0.1 to 3.0, the anhydrous acid is one or a mixture of more of thionyl chloride, glacial acetic acid, nitric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid and methanesulfonic acid, and the reaction solvent is one or a mixture of more of dimethylbenzene, methylbenzene, chlorobenzene, carbon tetrachloride, N-dimethylformamide and dimethyl sulfoxide.
Compared with the prior art, the invention has the beneficial effects that:
1. the compound V is prepared by adopting a three-step synthesis process of hydrogenation reduction reaction-amine ester exchange reaction-cyclization reaction, so that the synthesis process of the pyrimidinedione compound can be effectively simplified, the circuit for synthesizing the pyrimidinedione compound V is greatly shortened, and then, benzonitrile (namely the compound I) which is low in price and easy to obtain is used as a starting raw material, so that the preparation cost is effectively reduced.
2. According to the invention, the compound I which is easy to obtain and low in price is adopted for carrying out hydrogenation reduction reaction, so that the preparation of the intermediate II is more convenient and faster, the intermediate II and the compound III are used for carrying out amine ester exchange reaction, so that the intermediate IV is effectively refined, the generation of IV-impurity impurities is effectively avoided, and the intermediate IV is subjected to cyclization reaction under the acidic action by utilizing the acidic action of anhydrous acid, so that the generation of V-impurity impurities is effectively inhibited, the generation of reaction byproducts is effectively reduced, the purification of the pyrimidinedione compound V is ensured, the yield is also effectively improved, the preparation process of the pyrimidinedione compound V is more environment-friendly, and the requirement of industrial production is met.
3. The method utilizes a mutual synthesis mode among the compound I, the intermediate II, the compound III and the intermediate IV to ensure that the synthesis route of the pyrimidinedione compound V is simpler, and effectively simplifies the synthesis process of the pyrimidinedione compound V, thereby effectively reducing the cost for preparing the pyrimidinedione compound V.
Detailed Description
The following examples are intended to further illustrate the invention and are not intended to limit the application of the invention.
Example 1
Step one, (preparation of intermediate II):
firstly, taking 2-fluoro-6- (trifluoromethyl) benzonitrile as a compound I as an initial reaction raw material, taking Ranney-Ni (Raney nickel) as a metal catalyst, and taking hydrogen as a reducing agent; simultaneously selecting ethanol as an organic solvent;
then adding the compound I (20g, 106mmol), ethanol (100 mL), ranney-Ni (2 g) and ammonia water (4 g) into a miniature hydrogenation kettle provided with a thermometer, a stirrer and a pressure gauge, stirring and dissolving, replacing by using hydrogen, simultaneously raising the temperature to 45-55 ℃, starting adjusting the pressure of the hydrogen to 0.1-0.5 MPa, carrying out hydrogenation reduction reaction for 7-8 hours, tracking the reaction of the compound I according to HPLC (high performance liquid chromatography) until the reaction is completed, filtering and filtering the Ranney-Ni, and concentrating the filtrate to obtain 2-fluoro-6-trifluoromethylbenzylamine (intermediate II) (21 g, the molar yield is 100%, and the purity is 97%).
Step two, (preparation of intermediate IV):
firstly, 2-fluoro-6- (trifluoromethyl) benzonitrile (an intermediate II) which is obtained by carrying out hydrogenation reduction reaction by taking 2-fluoro-6- (trifluoromethyl) benzonitrile as a compound I is taken as a reaction starting material of an intermediate IV, meanwhile, (3-oxobutyl) -ethyl carbamate is taken as a compound III and taken as a reaction raw material, tetrahydrofuran is taken as a furan solvent, and sodium ethoxide is taken as a strong alkali and weak acid salt organic base;
adding the intermediate II (21 g, 108 mmol), tetrahydrofuran (200 ml) and the compound III (21g, 122 mmol) into a four-mouth reaction bottle with a thermometer and a stirrer, stirring for dissolving, adding sodium ethoxide (6 g, 88mmol) at 25-30 ℃, then heating to 60-70 ℃ for amine transesterification reaction for 5-8 hours, tracking the reaction of the intermediate II according to HPLC (high performance liquid chromatography) until complete reaction, finishing the reaction, washing with water, concentrating, and pulping with ethanol to obtain N- ((2-fluoro-6-trifluoromethylphenyl) carbamoyl) -3-oxobutanamide (intermediate IV) (30 g, the molar yield is 88%, and the purity is 98%).
Step three, (preparation of compound v):
firstly, taking N- ((2-fluoro-6-trifluoromethylphenyl) carbamoyl) -3-oxobutanamide (intermediate IV) obtained in the second step as a reaction starting material of a compound V, simultaneously selecting p-toluenesulfonic acid as anhydrous acid, and selecting toluene as a reaction solvent;
and stirring and dissolving the intermediate IV (30 g, 95 mmol) and toluene (200 ml) in a four-mouth reaction bottle provided with a thermometer and a stirrer, adding p-toluenesulfonic acid (31g, 180mmol) into the four-mouth reaction bottle, stirring, refluxing and carrying water, heating to 80-100 ℃ for cyclization reaction for 2-3 hours, cooling to room temperature after the reaction is finished, washing with 2M sodium hydroxide and water to neutrality, concentrating, and refining with isopropanol to obtain the target compound 1- [ 2-fluoro-6- (trifluoromethyl) benzyl ] -6-methylpyrimidine-2,4 (1H, 3H) -diketone (compound V) (25.5 g, the molar yield is 91%, and the purity is 99.8%).
Example 2:
step one, (preparation of intermediate II):
firstly, 2,4,6-trifluorophenylnitrile is taken as a compound I as an initial reaction raw material, ranney-Ni (Raney nickel) is taken as a metal catalyst, and hydrogen is taken as a reducing agent; simultaneously selecting ethanol as an organic solvent;
then adding the compound I (20g, 127mmol), ethanol (100 mL), ranney-Ni (2 g) and ammonia water (4 g) into a miniature hydrogenation kettle provided with a thermometer, a stirrer and a pressure gauge, stirring and dissolving, replacing by using hydrogen, simultaneously raising the temperature to 45-55 ℃, starting adjusting the pressure of the hydrogen to 0.1-0.5 MPa, carrying out hydrogenation reduction reaction for 7-8 hours, tracking the reaction of the compound I according to HPLC (high performance liquid chromatography) until the reaction is completed, filtering and filtering the Ranney-Ni, and concentrating the filtrate to obtain 2,4,6-trifluoromethylbenzylamine (intermediate II) (20.5 g, the molar yield is 100%, and the purity is 95%).
Step two, (preparation of intermediate IV):
firstly, using 2,4,6-trifluorophenylnitrile as a compound I to carry out hydrogenation reduction reaction to obtain 2,4,6-trifluoromethylbenzylamine (an intermediate II) as a reaction starting material of an intermediate IV, simultaneously using (3-oxobutyl) -ethyl carbamate as a compound III as a reaction starting material, selecting tetrahydrofuran as a furan solvent, and using sodium ethoxide as a strong base and a weak acid salt organic base;
adding the intermediate II (20.5 g,127 mmol), tetrahydrofuran (200 ml) and the compound III (21g, 122 mmol) into a four-mouth reaction bottle with a thermometer and a stirrer, stirring for dissolving, adding sodium ethoxide (6 g, 88mmol) at 25-30 ℃, then heating to 60-70 ℃ for amine transesterification reaction for 5-8 hours, tracking the reaction of the intermediate II according to HPLC (high performance liquid chromatography) until complete reaction, washing with water, concentrating, and pulping with ethanol to obtain N- ((2,4,6-trifluoromethylphenyl) carbamoyl) -3-oxobutanamide (intermediate IV) (31 g, 85% of molar yield and 98% of purity).
Step three, (preparation of compound v):
firstly, taking N- ((2,4,6-trifluoromethylphenyl) carbamoyl) -3-oxobutanamide (intermediate IV) obtained in the second step as a reaction starting material of a compound V, simultaneously selecting p-toluenesulfonic acid as an anhydrous acid, and selecting toluene as a reaction solvent;
stirring and dissolving the intermediate IV (31 g, 108 mmol) and toluene (200 ml) in a four-mouth reaction bottle provided with a thermometer and a stirrer, adding p-toluenesulfonic acid (31g, 180mmol) into the four-mouth reaction bottle, stirring, refluxing and carrying out water carrying, heating to 80-100 ℃ for carrying out cyclization reaction for 2-3 hours, cooling to room temperature after the reaction is finished, washing with 2M sodium hydroxide and washing with water to neutrality, concentrating, and refining with isopropanol to obtain the target compound 1- (2,4,6-trifluoromethylbenzyl) -6-methylpyrimidine-2,4 (1H, 3H) -diketone (compound V) (25 g, the molar yield is 88%, and the purity is 99.8%).
Example 3:
step one, (preparation of intermediate II):
firstly, 2,6-dichlorobenzonitrile is taken as a compound I as an initial reaction raw material, ranney-Ni (Raney nickel) is taken as a metal catalyst, and hydrogen is taken as a reducing agent; simultaneously selecting ethanol as an organic solvent;
then adding the compound I (20g, 116mmol), ethanol (100 mL), ranney-Ni (2 g) and ammonia water (4 g) into a miniature hydrogenation kettle provided with a thermometer, a stirrer and a pressure gauge, stirring and dissolving, replacing by using hydrogen, simultaneously raising the temperature to 45-55 ℃, starting adjusting the pressure of the hydrogen to 0.1-0.5 MPa, carrying out hydrogenation reduction reaction for 7-8 hours, tracking the reaction of the compound I according to HPLC (high performance liquid chromatography) until the reaction is completed, filtering and filtering the Ranney-Ni, and concentrating the filtrate to obtain 2,6-dichloromethylbenzylamine (an intermediate II) (20.5 g, the molar yield is 100%, and the purity is 95%).
Step two, (preparation of intermediate IV):
firstly, using 2,6-dichlorobenzonitrile as a compound I to carry out hydrogenation reduction reaction to obtain 2,6-dichloromethylbenzylamine (an intermediate II) as a reaction starting material of an intermediate IV, simultaneously using (3-oxobutyl) -ethyl carbamate as a compound III as a reaction starting material, selecting tetrahydrofuran as a furan solvent, and using sodium ethoxide as a strong base and weak acid salt organic base;
adding the intermediate II (20.5 g,116 mmol), tetrahydrofuran (200 ml) and the compound III (21g, 122 mmol) into a four-mouth reaction bottle with a thermometer and a stirrer, stirring for dissolving, adding sodium ethoxide (6 g, 88mmol) at 25-30 ℃, then heating to 60-70 ℃ for 5-8 hours of amine transesterification, tracking the reaction of the intermediate II according to HPLC (high performance liquid chromatography) until complete reaction, washing with water, concentrating, and pulping with ethanol to obtain N- ((2,6-dichloromethylphenyl) carbamoyl) -3-oxobutanamide (intermediate IV) (30 g, the molar yield is 83%, and the purity is 96%).
Step three, (preparation of compound v):
firstly, taking N- ((2,6-dichloromethylphenyl) carbamoyl) -3-oxobutanamide (intermediate IV) obtained in the second step as a reaction starting material of a compound V, simultaneously selecting p-toluenesulfonic acid as anhydrous acid, and selecting toluene as a reaction solvent;
and stirring and dissolving the intermediate IV (30 g, 99 mmol) and toluene (200 ml) in a four-mouth reaction bottle provided with a thermometer and a stirrer, adding p-toluenesulfonic acid (31g, 180mmol) into the four-mouth reaction bottle, stirring, refluxing and carrying out water carrying, heating to 80-100 ℃ for carrying out cyclization reaction for 2-3 hours, cooling to room temperature after the reaction is finished, washing with 2M sodium hydroxide and washing with water to be neutral, concentrating, and refining with isopropanol to obtain the target compound 1- (2,6-dichloromethylbenzyl) -6-methylpyrimidine-2,4 (1H, 3H) -diketone (compound V) (23 g, the molar yield is 84%, and the purity is 99.7%).
Comparative example 1:
step one, (preparation of intermediate II):
firstly, taking 2-fluoro-6- (trifluoromethyl) benzonitrile as a compound I as an initial reaction raw material, taking concentrated hydrochloric acid as a common catalyst, and taking Zn (zinc) or HCL (hydrogen chloride) as a reducing agent; simultaneously, 1,4-dioxane is selected as an organic solvent;
then adding the compound I (20g, 106mmol), 1,4-dioxane (100 mL) and concentrated hydrochloric acid (20 mL) into a miniature hydrogenation kettle provided with a thermometer, a stirrer and a pressure gauge, stirring and dissolving, adding Zn powder or HCL in batches at 10-20 ℃, heating to 45-55 ℃ after adding, carrying out hydrogenation reduction reaction for 7-8 hours, tracking the reaction of the compound I according to HPLC (high performance liquid chromatography), till complete reaction, filtering and filtering Ranney-Ni, and concentrating the filtrate to obtain 2-fluoro-6-trifluoromethylbenzylamine (intermediate II) (16 g, the molar yield is 80%, and the purity is 92%).
Step two, (preparation of intermediate IV):
firstly, 2-fluoro-6- (trifluoromethyl) benzonitrile (an intermediate II) which is obtained by carrying out hydrogenation reduction reaction by taking 2-fluoro-6- (trifluoromethyl) benzonitrile as a compound I is taken as a reaction starting material of an intermediate IV, meanwhile, (3-oxobutyl) -ethyl carbamate is taken as a compound III and taken as a reaction raw material, tetrahydrofuran is taken as a furan solvent, and sodium ethoxide is taken as a strong alkali and weak acid salt organic base;
adding the intermediate II (16 g, 84 mmol), tetrahydrofuran (200 ml) and the compound III (1lg, 92 mmol) into a four-mouth reaction bottle with a thermometer and a stirrer, stirring for dissolving, adding sodium ethoxide (6 g, 88mmol) at 25-30 ℃, then heating to 60-70 ℃ for amine transesterification reaction for 5-8 hours, tracking the reaction of the intermediate II according to HPLC (high performance liquid chromatography) until complete reaction, finishing the reaction, washing with water, concentrating, and pulping with ethanol to obtain N- ((2-fluoro-6-trifluoromethylphenyl) carbamoyl) -3-oxobutanamide (intermediate IV) (23 g, the molar yield is 88%, and the purity is 95%).
Step three, (preparation of compound v):
firstly, taking N- ((2-fluoro-6-trifluoromethylphenyl) carbamoyl) -3-oxobutanamide (intermediate IV) obtained in the second step as a reaction starting material of a compound V, simultaneously selecting p-toluenesulfonic acid as an anhydrous acid, and selecting toluene as a reaction solvent;
then 23g of intermediate IV, 73 mmol) and toluene (200 ml) are stirred and dissolved in a four-mouth reaction bottle provided with a thermometer and a stirrer, then p-toluenesulfonic acid (23g, 133mmol) is added into the four-mouth reaction bottle to be stirred, refluxed and charged with water, the temperature is increased to 80-100 ℃ to carry out cyclization reaction for 2-3 hours, after the reaction is finished, the temperature is reduced to room temperature, the reaction product is washed by 2M sodium hydroxide and water to be neutral, and after concentration, the reaction product is refined by isopropanol to obtain the target compound 1- [ 2-fluoro-6- (trifluoromethyl) benzyl ] -6-methylpyrimidine-2,4 (1H, 3H) -diketone (compound V) (15 g, the molar yield is 66%, and the purity is 97%).
The following are tables comparing the parameters of the compounds V prepared in examples 1 to 3 with those of the compound V prepared in comparative example 1:
from the above table, it can be known that the compound i is a compound V synthesized by 2-fluoro-6- (trifluoromethyl) benzonitrile and 2,4,6-trifluorophenylnitrile under the reduction of a metal catalyst and hydrogen, the content of V-inpurity is relatively high, the total yield of the former is higher than that of the latter, and the compound V synthesized by 2-fluoro-6- (trifluoromethyl) benzonitrile under the reduction of a common catalyst and Zn powder or HCL is relatively low, the content of V-inpurity is relatively high, the total yield is relatively low, so that the content of the compound V, the content of V-inpurity and the total yield are related to the selection of the catalyst and the reducing agent.
Claims (10)
1. A preparation method for synthesizing pyrimidinedione compounds is characterized in that the specific synthetic route is as follows:
the preparation method comprises the following steps of carrying out hydrogenation reduction reaction on a compound I serving as a raw material under the action of a metal catalyst to obtain an intermediate II, carrying out amine ester exchange reaction on the intermediate II and a compound III to realize the preparation of an intermediate IV, and carrying out cyclization reaction on the intermediate IV under the condition of anhydrous acid to realize the preparation of a target compound V.
2. The preparation method of the pyrimidinedione compound according to claim 1, wherein the specific synthesis steps are as follows:
s1, preparation of an intermediate II: taking a compound I as a reaction starting material, directly putting the compound I into a hydrogenation kettle, carrying out hydrogenation reduction reaction under the action of a metal catalyst and ammonia water in the atmosphere of an organic solvent and a reducing agent, and carrying out treatment and concentration to obtain an intermediate II;
s2, preparation of an intermediate IV: mixing the intermediate II obtained in the S1 and a compound III in a furan solvent, adding strong base and weak acid salt organic base at room temperature to perform amine ester exchange reaction, concentrating, washing with water, and pulping with ethanol to obtain an intermediate IV;
s3, preparation of a compound V: stirring the intermediate IV obtained in the S2 in a reaction solvent, refluxing under the condition of anhydrous acid and carrying out cyclization reaction with water, and refining with isopropanol to obtain a target compound V.
3. The preparation method of the pyrimidinedione compound as claimed in claim 2, wherein in S1, the amount of the metal catalyst is 0.1-20% of the weight of the compound i, wherein the metal catalyst is raney-Ni; the compound I is one of cyanophenyl, 2,4,6-trifluorophenylnitrile, 2-fluoro-6- (trifluoromethyl) cyanophenyl, 2-fluoro-6-chlorobenzonitrile, p-cyanotoluene, 2,6-dichlorobenzonitrile and 5-bromo-2- (trifluoromethoxy) cyanophenyl.
4. The method according to claim 2, wherein the organic solvent in S1 is one or more selected from methanol, ethanol, tetrahydrofuran, N-dimethylacetamide, acetone, acetonitrile, ethylene glycol, dimethyl sulfoxide, and 1,4-dioxane; the reducing agent is one of H2, naBH4, naBH3CN, zn or HCL.
5. The process according to claim 2, wherein the temperature of the hydrogenation reduction reaction in S1 is 20 to 100 ℃ and the pressure of the hydrogenation reduction reaction is 0.1 to 2MPa.
6. The method according to claim 2, wherein the molar ratio of intermediate ii to compound iii in S2 is 1: 1.0-6.0, wherein the compound III is one of (3-oxobutyl) -ethyl carbamate, (3-oxobutyl) -methyl carbamate and 2,4-dioxopiperidine-1-benzyl formate.
7. The method according to claim 2, wherein in S2, the furan solvent is one or more selected from dimethylformamide, dimethylsulfoxide, tetrahydrofuran, acetonitrile, 1,4-dioxane and dimethylacetamide, the strong and weak acid salt organic base is one selected from sodium methoxide, sodium ethoxide and sodium hydride, and the amine transesterification reaction temperature is 0-70 ℃.
8. The preparation method of pyrimidinedione compounds according to claim 2, wherein in S3, the molar ratio of intermediate iv to anhydrous acid is 1:0.1 to 3.0, wherein the anhydrous acid is one or a mixture of more of thionyl chloride, glacial acetic acid, nitric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid and methanesulfonic acid.
9. The process according to claim 2, wherein the solvent used in S3 is one or more selected from the group consisting of xylene, toluene, chlorobenzene, carbon tetrachloride, N-dimethylformamide, and dimethylsulfoxide.
10. The process according to claim 2, wherein the temperature of the cyclization reaction in S3 is 20-150 ℃ and the time of the cyclization reaction is 1-10 hours.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008151510A1 (en) * | 2007-06-11 | 2008-12-18 | Anhui Qingyun Pharmaceutical And Chemical Co., Ltd. | Preparation of 4-(fluorophenyl)-6-isopropyl-2-(n-methyl-n-methylsulfonylamino)- 5-formyl-pyrimidine |
| CN109970663A (en) * | 2017-12-27 | 2019-07-05 | 上海科胜药物研发有限公司 | A method of it prepares and dislikes La Geli intermediate |
| CN111333548A (en) * | 2020-04-10 | 2020-06-26 | 江苏海悦康医药科技有限公司 | Preparation method of 1- (2-fluoro-6- (trifluoromethyl) benzyl) urea |
| CN112159358A (en) * | 2020-10-26 | 2021-01-01 | 上海朴颐化学科技有限公司 | Preparation method of oxalagogri intermediate |
| CN113453679A (en) * | 2018-12-20 | 2021-09-28 | C4医药公司 | Targeted protein degradation |
-
2022
- 2022-11-11 CN CN202211414763.1A patent/CN115677598A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008151510A1 (en) * | 2007-06-11 | 2008-12-18 | Anhui Qingyun Pharmaceutical And Chemical Co., Ltd. | Preparation of 4-(fluorophenyl)-6-isopropyl-2-(n-methyl-n-methylsulfonylamino)- 5-formyl-pyrimidine |
| CN109970663A (en) * | 2017-12-27 | 2019-07-05 | 上海科胜药物研发有限公司 | A method of it prepares and dislikes La Geli intermediate |
| CN113453679A (en) * | 2018-12-20 | 2021-09-28 | C4医药公司 | Targeted protein degradation |
| CN111333548A (en) * | 2020-04-10 | 2020-06-26 | 江苏海悦康医药科技有限公司 | Preparation method of 1- (2-fluoro-6- (trifluoromethyl) benzyl) urea |
| CN112159358A (en) * | 2020-10-26 | 2021-01-01 | 上海朴颐化学科技有限公司 | Preparation method of oxalagogri intermediate |
Non-Patent Citations (1)
| Title |
|---|
| 车峰峰;谢晓强;许挺俊;: "噁拉戈利关键中间体的合成工艺优化", 精细与专用化学品, no. 10, 21 October 2020 (2020-10-21), pages 330 - 334 * |
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