CN110256360B - Preparation method of 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine - Google Patents
Preparation method of 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine Download PDFInfo
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- CN110256360B CN110256360B CN201910530373.2A CN201910530373A CN110256360B CN 110256360 B CN110256360 B CN 110256360B CN 201910530373 A CN201910530373 A CN 201910530373A CN 110256360 B CN110256360 B CN 110256360B
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- propylmercapto
- nitro
- pyrimidine
- dichloro
- toluene
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- DDEDQHVHVPJFAC-UHFFFAOYSA-N 4,6-dichloro-5-nitro-2-propylsulfanylpyrimidine Chemical compound CCCSC1=NC(Cl)=C([N+]([O-])=O)C(Cl)=N1 DDEDQHVHVPJFAC-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 69
- 238000006243 chemical reaction Methods 0.000 claims abstract description 14
- PHMVMACIFWKESN-UHFFFAOYSA-N 4-hydroxy-5-nitro-2-propylsulfanyl-1h-pyrimidin-6-one Chemical compound CCCSC1=NC(O)=C([N+]([O-])=O)C(O)=N1 PHMVMACIFWKESN-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000001816 cooling Methods 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 239000000706 filtrate Substances 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 239000005457 ice water Substances 0.000 claims abstract description 6
- 230000007935 neutral effect Effects 0.000 claims abstract description 6
- 239000000741 silica gel Substances 0.000 claims abstract description 6
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims abstract description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical group NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 5
- 238000002390 rotary evaporation Methods 0.000 claims description 5
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 4
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 claims description 3
- XPPKVPWEQAFLFU-UHFFFAOYSA-N diphosphoric acid Chemical compound OP(O)(=O)OP(O)(O)=O XPPKVPWEQAFLFU-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 229940005657 pyrophosphoric acid Drugs 0.000 claims 1
- CNTIXUGILVWVHR-UHFFFAOYSA-N diphosphoryl chloride Chemical compound ClP(Cl)(=O)OP(Cl)(Cl)=O CNTIXUGILVWVHR-UHFFFAOYSA-N 0.000 abstract description 4
- 238000001704 evaporation Methods 0.000 abstract description 3
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 14
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012320 chlorinating reagent Substances 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 244000245420 ail Species 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 231100000481 chemical toxicant Toxicity 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 235000004611 garlic Nutrition 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910001392 phosphorus oxide Inorganic materials 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- VSAISIQCTGDGPU-UHFFFAOYSA-N tetraphosphorus hexaoxide Chemical compound O1P(O2)OP3OP1OP2O3 VSAISIQCTGDGPU-UHFFFAOYSA-N 0.000 description 1
- OEKWJQXRCDYSHL-FNOIDJSQSA-N ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 description 1
- 229960002528 ticagrelor Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/38—One sulfur atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Abstract
The invention discloses a preparation method of 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine. Dissolving 6-hydroxy-5-nitro-2- (propylmercapto) -4(3H) -pyrimidone in toluene, cooling, slowly dropwise adding pyrophosphoryl chloride, heating, adding a catalyst, reacting for 10-40 hours, cooling after the reaction is finished, pouring into ice water, stirring, layering, adding 60-120 mesh neutral silica gel into the upper toluene layer, stirring, filtering, and rotationally evaporating the filtrate to recover toluene to obtain the oily 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine. The method has the advantages of mild reaction conditions, high reaction yield and little environmental pollution.
Description
Technical Field
The invention relates to the technical field of chemical industry, in particular to a preparation method of 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine.
Background
4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine is a key intermediate in the synthesis of the novel anticoagulant ticagrelor developed by the company AstraZeneca (AstraZeneca).
WO9905142 takes phosphorus oxychloride as a chlorinating agent and a solvent, N, N-diethylaniline as an acid-binding agent, and 6-hydroxy-5-nitro-2- (propylmercapto) -4(3H) -pyrimidone (alias: 4, 6-dihydroxy-5-nitro-2- (propylmercapto) pyrimidine, and the two are the same substance) is chlorinated to prepare the 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine.
WO2011017108 employs the same process, 1.8 grams of 6-hydroxy-5-nitro-2- (propylmercapto) -4(3H) -pyrimidinone, 15mL of phosphorus oxychloride and 2mL of N, N-diethylaniline are refluxed for three hours to prepare 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine. WO2011101740, CN103787984, CN103896857 and CN104003943 use N, N-diisopropylethylamine as an acid-binding agent, CN102250097 and CN103923020 use N, N-dimethylaniline as the acid-binding agent, CN10292445, IN2011CH 034127 use N, N-diethylaniline as the acid-binding agent, and CN103288748 use triethylamine as the acid-binding agent. CN104230818 by Bu4N+·Br-The phosphorus oxychloride is a better chlorinating agent as a catalyst, but the phosphorus oxychloride is liquid with pungent odor and garlic smell, is vigorously fuming in humid air, reacts with water, is hydrolyzed into phosphoric acid and hydrogen chloride, and is heated to explode when meeting water, and toxic chloride and phosphorus oxide gases are emitted. Belonging to the catalog of highly toxic chemicals (2002 edition).
CN102659691 uses phosphorus pentachloride as a chlorination reagent, Wu, Qianqian and the like (China journal of medical industry, 44(6),557 559; 2013 uses solid phosgene as a chlorination reagent, and WO2019016111 uses phosgene as a chlorination reagent, wherein the aim is to avoid the use of phosphorus oxychloride.
Disclosure of Invention
The invention aims to overcome the problems of harsh reaction conditions, low reaction yield and large environmental pollution in the existing preparation of 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine, and provides a preparation method of 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine.
The technical scheme of the invention is as follows:
the preparation method of the 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine comprises the following steps: dissolving 6-hydroxy-5-nitro-2- (propylmercapto) -4(3H) -pyrimidone in toluene, cooling to 0-20 ℃, dropwise adding 0.5-1.0 molar equivalent of pyrophosphoryl chloride within 2-8 hours, heating to 80-110 ℃, adding a catalyst, reacting for 10-40 hours, cooling after the reaction is finished, pouring into ice water, stirring for 1-2 hours, layering, adding 60-120 mesh neutral silica gel into the upper toluene layer, stirring for 0.5-1 hour, filtering, and rotationally evaporating the filtrate to recover toluene to obtain the oily 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine.
Preferably, the catalyst is ethanolamine, diethanolamine or triethanolamine.
Preferably, the molar ratio of the catalyst to the 6-hydroxy-5-nitro-2- (propylmercapto) -4(3H) -pyrimidone is 0.01-0.1.
Preferably, the temperature is reduced to 0-30 ℃ after the reaction is finished.
Preferably, the temperature for recovering the toluene by rotary evaporation of the filtrate is 50-70 ℃.
Expressed as the following reaction formula:
compared with the prior art, the invention has the beneficial effects that:
1) the raw materials in the preparation process are all safe and easy to obtain, and the risk that combustible, explosive and highly toxic compounds such as phosphorus oxychloride and phosgene need to be used in the prior art is solved; the solvent in the reaction process can be recycled; the actual operation cost is low.
3) The method has high conversion rate and selectivity of over 90 percent, overcomes the problem that the phosphorus oxychloride is used as both a chlorinating agent and a solvent in the prior art by using the catalyst, and obtains remarkable progress compared with the prior art.
Drawings
FIG. 1 is a chromatogram of the product of example 1.
Detailed Description
Example 1
Adding 250 ml of toluene into a 500 ml three-neck flask, adding 50.0 g of 6-hydroxy-5-nitro-2- (propylmercapto) -4(3H) -pyrimidinone (purity: 98 +%, CAS number: 145783-12-6, alias: 4, 6-dihydroxy-5-nitro-2- (propylmercapto) pyrimidine), dissolving in toluene, cooling to 0 ℃, dropwise adding 27.0 g of pyrophosphorol chloride within 2 hours, heating to 80 ℃, adding 0.13 g of monoethanolamine, reacting for 10 hours, cooling to 0 ℃, pouring into ice water, stirring for 1 hour, demixing, adding 60-120 mesh neutral silica gel into the upper toluene layer, stirring for 0.5 hour, filtering, carrying out rotary evaporation on the filtrate at 50 ℃ to recover toluene to obtain 45.8 g of oily 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine, the content was 97.5% by gas chromatography (FIG. 1). Gas chromatograph: SHIMADZU GC-2014C. Analysis conditions were as follows: HP-1 capillary column, 15m 0.53mm, 0.15 μm, initial temperature 120 deg.C, 20 deg.C/min heating to 300 deg.C, and keeping for 1 min. Injector temperature 250 ℃ and detector temperature 300 ℃.
MS-ESI(m/z)：268[M+H]+；1H NMR(300MHz,CDCl3):1.07(t,J＝8.0Hz,3H)，1.74-1.85(m,2H)，3.15(t,J＝8.0Hz，2H)；13C NMR(300MHz,CDCl3):13.5，22.0，29.9，34.0，152.1(2C)，174.5
Example 2
Adding 250 ml of toluene into a 500 ml three-neck flask, adding 50.0 g of 6-hydroxy-5-nitro-2- (propylmercapto) -4(3H) -pyrimidone, dissolving in the toluene, cooling to 20 ℃, dropwise adding 54 g of pyrophosphoryl chloride within 8 hours, heating to 110 ℃, adding 2.27 g of diethanolamine, reacting for 40 hours, cooling to 30 ℃ after the reaction is finished, pouring into ice water, stirring for 2 hours, layering, adding 60-120 mesh neutral silica gel into the upper toluene layer, stirring for 1 hour, filtering, and performing rotary evaporation on the filtrate at 70 ℃ to recover toluene to obtain 49.2 g of oily 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine with the content of 98.1%.
Example 3
Adding 250 ml of toluene into a 500 ml three-neck flask, adding 50.0 g of 6-hydroxy-5-nitro-2- (propylmercapto) -4(3H) -pyrimidone, dissolving in the toluene, cooling to 0 ℃, dropwise adding 40.0 g of pyrophosphoryl chloride within 2 hours, heating to 80 ℃, adding 3.20 g of triethanolamine, reacting for 10 hours, cooling to 0 ℃ after the reaction is finished, pouring into ice water, stirring for 1 hour, layering, adding 60-120 mesh neutral silica gel into the upper toluene layer, stirring for 0.5 hour, filtering, and rotationally evaporating the filtrate at 50 ℃ to recover toluene to obtain 50.5 g of oily 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine with the content of 98.5%.
Claims (4)
1. A preparation method of 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine is characterized by comprising the following steps:
dissolving 6-hydroxy-5-nitro-2- (propylmercapto) -4(3H) -pyrimidone in toluene, cooling to 0-20 ℃, dropwise adding 0.5-1.0 molar equivalent of pyrophosphoric acid chloride within 2-8 hours, heating to 80-110 ℃, and adding a catalyst, wherein the catalyst is ethanolamine, diethanolamine or triethanolamine; the molar ratio of the catalyst to the 6-hydroxy-5-nitro-2- (propylmercapto) -4(3H) -pyrimidone is 0.01-0.1; reacting for 10-40 hours, after the reaction is finished, cooling, pouring into ice water, stirring for 1-2 hours, layering, adding 60-120 mesh neutral silica gel into the upper toluene layer, stirring for 0.5-1 hour, filtering, and performing rotary evaporation on the filtrate to recover toluene to obtain the oily 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine.
2. The process of claim 1 wherein the catalyst is triethanolamine.
3. The process for preparing 4, 6-dichloro-5-nitro-2- (propylmercapto) -pyrimidine according to claim 1, wherein the temperature is lowered to 0-30 ℃ after the reaction is completed.
4. The process according to claim 1, wherein the temperature for recovering toluene by rotary evaporation of the filtrate is 50-70 ℃.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5502187A (en) * | 1992-04-03 | 1996-03-26 | The Upjohn Company | Pharmaceutically active bicyclic-heterocyclic amines |
| CN103787984A (en) * | 2014-01-26 | 2014-05-14 | 苏州特瑞药业有限公司 | Preparation method of Ticagrelor intermediate 4, 6-dichloro-5-nitro-2-(propylthio) pyrimidine |
| CN104003943A (en) * | 2014-05-06 | 2014-08-27 | 南通常佑药业科技有限公司 | Preparation method for ticagrelor intermediate |
| CN105884694A (en) * | 2014-12-30 | 2016-08-24 | 上海复星医药产业发展有限公司 | Preparing method for ticagrelor intermediate 4,6-dichloro-2-tri-sulfydryl-5-aminopyrimidine |
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- 2019-06-19 CN CN201910530373.2A patent/CN110256360B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5502187A (en) * | 1992-04-03 | 1996-03-26 | The Upjohn Company | Pharmaceutically active bicyclic-heterocyclic amines |
| CN103787984A (en) * | 2014-01-26 | 2014-05-14 | 苏州特瑞药业有限公司 | Preparation method of Ticagrelor intermediate 4, 6-dichloro-5-nitro-2-(propylthio) pyrimidine |
| CN104003943A (en) * | 2014-05-06 | 2014-08-27 | 南通常佑药业科技有限公司 | Preparation method for ticagrelor intermediate |
| CN105884694A (en) * | 2014-12-30 | 2016-08-24 | 上海复星医药产业发展有限公司 | Preparing method for ticagrelor intermediate 4,6-dichloro-2-tri-sulfydryl-5-aminopyrimidine |
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