US20200207722A1 - Method for preparation of chlorinated s-propylthiobarbituric acid - Google Patents
Method for preparation of chlorinated s-propylthiobarbituric acid Download PDFInfo
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- US20200207722A1 US20200207722A1 US16/621,222 US201816621222A US2020207722A1 US 20200207722 A1 US20200207722 A1 US 20200207722A1 US 201816621222 A US201816621222 A US 201816621222A US 2020207722 A1 US2020207722 A1 US 2020207722A1
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- 238000000034 method Methods 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- QWVRNSPNBZGMRZ-UHFFFAOYSA-N 5-propan-2-yl-2-sulfanylidene-1,3-diazinane-4,6-dione Chemical class CC(C)C1C(=O)NC(=S)NC1=O QWVRNSPNBZGMRZ-UHFFFAOYSA-N 0.000 title 1
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 51
- 150000001875 compounds Chemical class 0.000 claims description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 101100203596 Caenorhabditis elegans sol-1 gene Proteins 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 7
- 239000011541 reaction mixture Substances 0.000 claims description 6
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 2
- 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 abstract description 7
- 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 abstract description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 14
- 239000003054 catalyst Substances 0.000 description 10
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 8
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- -1 polydimethylsiloxane Polymers 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004817 gas chromatography Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000002699 waste material Substances 0.000 description 3
- TYUGYHWJJDAURE-UHFFFAOYSA-N CCCSC1=NC(N(C)C)=C([N+](=O)[O-])C(Cl)=N1 Chemical compound CCCSC1=NC(N(C)C)=C([N+](=O)[O-])C(Cl)=N1 TYUGYHWJJDAURE-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- UKVQBONVSSLJBB-UHFFFAOYSA-N 2-pyridin-2-ylacetonitrile Chemical compound N#CCC1=CC=CC=N1 UKVQBONVSSLJBB-UHFFFAOYSA-N 0.000 description 1
- UKLBKPMUSFVCDB-UHFFFAOYSA-N 3-methylpyridine;toluene Chemical compound CC1=CC=CC=C1.CC1=CC=CN=C1 UKLBKPMUSFVCDB-UHFFFAOYSA-N 0.000 description 1
- NTSLROIKFLNUIJ-UHFFFAOYSA-N 5-Ethyl-2-methylpyridine Chemical compound CCC1=CC=C(C)N=C1 NTSLROIKFLNUIJ-UHFFFAOYSA-N 0.000 description 1
- KNCHDRLWPAKSII-UHFFFAOYSA-N 5-ethyl-2-methylpyridine Natural products CCC1=CC=NC(C)=C1 KNCHDRLWPAKSII-UHFFFAOYSA-N 0.000 description 1
- BFIPORBEVPESRH-UHFFFAOYSA-N CCCSC1=NC(Cl)=C(Cl)C(Cl)=N1 Chemical compound CCCSC1=NC(Cl)=C(Cl)C(Cl)=N1 BFIPORBEVPESRH-UHFFFAOYSA-N 0.000 description 1
- OTFPBEGMQXEJJG-UHFFFAOYSA-N CCCSC1=NC(Cl)=NC(Cl)=N1 Chemical compound CCCSC1=NC(Cl)=NC(Cl)=N1 OTFPBEGMQXEJJG-UHFFFAOYSA-N 0.000 description 1
- FWCXQLAABAQTMM-UHFFFAOYSA-N S1(=O)(=O)CCCC1.N1=CC=CC=C1 Chemical compound S1(=O)(=O)CCCC1.N1=CC=CC=C1 FWCXQLAABAQTMM-UHFFFAOYSA-N 0.000 description 1
- FIEGIJQGYXOMBZ-UHFFFAOYSA-N acetonitrile;3-methylpyridine Chemical compound CC#N.CC1=CC=CN=C1 FIEGIJQGYXOMBZ-UHFFFAOYSA-N 0.000 description 1
- 229940090047 auto-injector Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- DZCMOEVPIMXJES-UHFFFAOYSA-N chlorobenzene;pyridine Chemical compound C1=CC=NC=C1.ClC1=CC=CC=C1 DZCMOEVPIMXJES-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- DAKIDYQCFJQMDF-UHFFFAOYSA-N dichloromethane;pyridine Chemical compound ClCCl.C1=CC=NC=C1 DAKIDYQCFJQMDF-UHFFFAOYSA-N 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide dmf Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004508 fractional distillation Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- GGZRVXCSRWTOME-UHFFFAOYSA-N pyridine;toluene Chemical compound C1=CC=NC=C1.CC1=CC=CC=C1 GGZRVXCSRWTOME-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000758 substrate Substances 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
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- 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
- C07D239/30—Halogen atoms or nitro radicals
Definitions
- the invention discloses a method for preparation of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine by conversion of 5-nitro-2-propylthiopyrimidine-4,6-diol with phosgene in the presence of DMF.
- US 2013/0030176 A1 discloses of method for preparation of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine and its use as intermediate for the preparation of ticagrelor.
- Example 10 discloses a yield of 233.5 g of the 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (MW 266 g/mol) with a purity of 99.45% is disclosed; with a MW of 229 g/mol for the substrate 5-nitro-2-propylthiopyrimidine-4,6-diol and a starting amount of 200 g the yield is 99.9%, which is admittedly very high.
- the method has the advantage of comparably high yields without the problem of generation of H 3 PO 4 as waste.
- Subject of the invention is a method for the preparation of compound of formula (2)
- PHOS is selected from the group consisting of phosgene, diphosgene, triphosgene and mixtures thereof.
- Compound of formula (1) is a known compound and can be produced by known methods.
- PHOS is phosgene.
- the molar amount of PHOS is from 2 to 5 times, more preferably from 2 to 4 times, even more preferably from 2 to 3 times, of the molar amount of compound of formula (1).
- the amount of DMF is from 10 to 100 times, more preferably from 15 to 75 times, even more preferably from 15 to 50 times, especially from 15 to 40 times, more specially from 20 to 30 times, of the weight of PHOS.
- the reaction temperature TEMP1 of REAC1 is from ⁇ 10 to 50° C., more preferably from ⁇ 5 to 40° C., even more preferably from ⁇ 5 to 30° C., especially from ⁇ 2.5 to 25° C.
- reaction time TIME1 of REAC1 is from 5 h to 48 h, more preferably from 10 h to 24 h, even more preferably of from 12 h to 20 h.
- REAC1 is in the beginning of TIME1 done at a lower temperature than at the end of TIME1;
- REAC1 is done at first for 4.5 h to 41 h at ⁇ 10 to 9° C. and thereafter for 30 min to 7 h at 10 to 50° C.;
- REAC1 is done at first for 9 h to 21 h at ⁇ 5 to 7° C. and thereafter for 1 h to 3 h at 12 to 40° C.;
- REAC1 is done at first for 10.5 h to 19.5 h at ⁇ 5 to 50° C. and thereafter for 1.5 h to 2.5 h at 15 to 30° C.;
- the DMF acts also as solvent in REAC1.
- compound of formula (1) is dissolved in DMF to provide a solution SOL-1
- PHOS is dissolved in DMF to provide a solution SOL-PHOS
- SOL-1 and SOL-PHOS are mixed with each other to provide for REAC1; preferably, for the mixing of SOL-1 with SOL-PHOS, SOL-1 is added to SOL-PHOS.
- the amount of DMF for preparation of SOL-1 is from 1 to 10 times, more preferably from 1.5 to 7.5 times, even more preferably from 2.5 to 7.5 times, of the weight of compound of formula (1);
- the amount of DMF for preparation of SOL-PHOS is from 10 to 90 times, more preferably from 10 to 50 times, even more preferably from 15 to 40 times, especially from 15 to 30 times, of the weight of PHOS.
- compound of formula (2) can be isolated and purified by conventional methods, which are known to those skilled in the art. These conventional methods include quenching the reaction mixture from REAC1 with water, with a solvent or with both water and a solvent, extraction, distillation, preferably fractional distillation, which can be done under reduced pressure, crystallization, chromatography, filtration, washing or any combination of these methods.
- the solvent that is used for quenching the reaction mixture is preferably an organic solvent, more preferably toluene; preferably, the quenching is done with water and toluene, thereby two phases are generated; then the phases are separated and the organic phase is evaporated to provide compound of formula (2).
- the amount of water is from 5 to 15 times, more preferably from 7.5 to 12.5 times, of the weight of compound of formula (1).
- the amount of toluene is from 4 to 14 times, more preferably from 6.5 to 11 times, of the weight of compound of formula (1).
- the addition of toluene and water is done at a temperature of from ⁇ 10 to 30° C., more preferably of from ⁇ 5 to 20° C., even more preferably of from ⁇ 5 to 15° C., especially of from ⁇ 5 to 10° C., more especially of from ⁇ 5 to 5° C., even more especially of from ⁇ 2.5 to 2.5° C.
- HP-1 (SIMDIST), 15 m ⁇ 0.53 mm, 0.15 micrometer film-thickness, polydimethylsiloxane (or an equivalent column).
- the GC results are given in area %.
Abstract
The invention discloses a method for preparation of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine by conversion of 5-nitro-2-propylthiopyrimidine-4,6-diol with phosgene in the presence of DMF.
Description
- The invention discloses a method for preparation of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine by conversion of 5-nitro-2-propylthiopyrimidine-4,6-diol with phosgene in the presence of DMF.
- US 2013/0030176 A1 discloses of method for preparation of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine and its use as intermediate for the preparation of ticagrelor.
- Example 10 discloses a yield of 233.5 g of the 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (MW 266 g/mol) with a purity of 99.45% is disclosed; with a MW of 229 g/mol for the substrate 5-nitro-2-propylthiopyrimidine-4,6-diol and a starting amount of 200 g the yield is 99.9%, which is admittedly very high.
- Nevertheless the method uses phosphorous oxychloride (MW 153 g/mol) as Cl source for the exchange of the OH residues against Cl. The given 425.6 g of phosphorous oxychloride are converted by the reaction ultimately to 271 g phosphoric acid H3PO4 (MW 100). So 1.16 times, of the weight of the product, of phosphoric acid needs to be disposed of. This waste is a serious environmental challenge as well as a cost factor.
- There was a need for a process that does not pose the mentioned waste problem in form of H3PO4.
- An extensive screening of phosgene as alternative Cl source without catalyst, with various catalysts and with various solvents was not successful but showing yields of not more than 32%, instead showing significant amounts of undesired by products, as documented herein under Comparative Examples 1 to 60. Only one combination, the combination of phosgene with DMF, surprisingly showed satisfying yields.
- The method has the advantage of comparably high yields without the problem of generation of H3PO4 as waste.
- The following abbreviations are used, if not otherwise stated:
- compound of formula (1) 5-nitro-2-propylthiopyrimidine-4,6-diol, also called 5-nitro-2-propylsulfanyl-pyrimidine-4,6-diol
- compound of formula (2) 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine
- DMF dimethyl formamide
- eq equivalent
- RT room temperature
- MW molecular weight
- Subject of the invention is a method for the preparation of compound of formula (2)
- by a reaction REAC1 of compound of formula (1)
- with a compound PHOS in the presence of DMF;
- PHOS is selected from the group consisting of phosgene, diphosgene, triphosgene and mixtures thereof.
- Compound of formula (1) is a known compound and can be produced by known methods.
- Preferably, PHOS is phosgene.
- Preferably, the molar amount of PHOS is from 2 to 5 times, more preferably from 2 to 4 times, even more preferably from 2 to 3 times, of the molar amount of compound of formula (1).
- Preferably, the amount of DMF is from 10 to 100 times, more preferably from 15 to 75 times, even more preferably from 15 to 50 times, especially from 15 to 40 times, more specially from 20 to 30 times, of the weight of PHOS.
- Preferably, the reaction temperature TEMP1 of REAC1 is from −10 to 50° C., more preferably from −5 to 40° C., even more preferably from −5 to 30° C., especially from −2.5 to 25° C.
- Preferably, the reaction time TIME1 of REAC1 is from 5 h to 48 h, more preferably from 10 h to 24 h, even more preferably of from 12 h to 20 h.
- In one embodiment, REAC1 is in the beginning of TIME1 done at a lower temperature than at the end of TIME1;
- preferably, REAC1 is done at first for 4.5 h to 41 h at −10 to 9° C. and thereafter for 30 min to 7 h at 10 to 50° C.;
- more preferably, REAC1 is done at first for 9 h to 21 h at −5 to 7° C. and thereafter for 1 h to 3 h at 12 to 40° C.;
- even more preferably, REAC1 is done at first for 10.5 h to 19.5 h at −5 to 50° C. and thereafter for 1.5 h to 2.5 h at 15 to 30° C.;
- Preferably, the DMF acts also as solvent in REAC1.
- More preferably, compound of formula (1) is dissolved in DMF to provide a solution SOL-1, and PHOS is dissolved in DMF to provide a solution SOL-PHOS; and SOL-1 and SOL-PHOS are mixed with each other to provide for REAC1; preferably, for the mixing of SOL-1 with SOL-PHOS, SOL-1 is added to SOL-PHOS.
- Therefore in one embodiment, the amount of DMF for preparation of SOL-1 is from 1 to 10 times, more preferably from 1.5 to 7.5 times, even more preferably from 2.5 to 7.5 times, of the weight of compound of formula (1); and
- the amount of DMF for preparation of SOL-PHOS is from 10 to 90 times, more preferably from 10 to 50 times, even more preferably from 15 to 40 times, especially from 15 to 30 times, of the weight of PHOS.
- After REAC1, compound of formula (2) can be isolated and purified by conventional methods, which are known to those skilled in the art. These conventional methods include quenching the reaction mixture from REAC1 with water, with a solvent or with both water and a solvent, extraction, distillation, preferably fractional distillation, which can be done under reduced pressure, crystallization, chromatography, filtration, washing or any combination of these methods.
- Preferably, the solvent that is used for quenching the reaction mixture is preferably an organic solvent, more preferably toluene; preferably, the quenching is done with water and toluene, thereby two phases are generated; then the phases are separated and the organic phase is evaporated to provide compound of formula (2).
- Preferably, after REAC1 toluene and water is added to the reaction mixture.
- Preferably, the amount of water is from 5 to 15 times, more preferably from 7.5 to 12.5 times, of the weight of compound of formula (1).
- Preferably, the amount of toluene is from 4 to 14 times, more preferably from 6.5 to 11 times, of the weight of compound of formula (1).
- Preferably, the addition of toluene and water is done at a temperature of from −10 to 30° C., more preferably of from −5 to 20° C., even more preferably of from −5 to 15° C., especially of from −5 to 10° C., more especially of from −5 to 5° C., even more especially of from −2.5 to 2.5° C.
- Compound of formula (3):
- Compound of formula (4):
- Compound of formula (5):
- GC Method
- Instrument:
- Hewlett Packard gas chromatograph 6890 with a split injector and a flame ionisation detector or an instrument with corresponding performance and quality.
- Column:
- HP-1 (SIMDIST), 15 m×0.53 mm, 0.15 micrometer film-thickness, polydimethylsiloxane (or an equivalent column).
- Instrument. Settings:
- Oven:
-
INITIAL TEMP 50° C. HOLD 2 min RAMP 1 20° C./min NEXT TEMP 320° C. HOLD 10 min - Injector:
-
Injection volume 1 microliter Check the auto-injector parameters - Inlets:
-
INJ. MODE Split INJ TEMP 250° C. SPLIT FLOW 200 ml/min SPLIT RATIO 25:1 MODE constant flow 8.0 ml/min - Detectors:
-
DET TEMP 300° C. Check the FID gas flow rates - The GC results are given in area %.
- 5.0 g (21.62 mmol, 1 eq) of compound of formula (1) were dissolved in 25 mL of solvent SOLV and base was added. 100 mL of SOLV were mixed with 4.7 g of phosgene (47.56 mmol. 2.2 eq) at 0° C. The solution of compound of formula (1) and base was added at 0° C. to the mixture of SOLV with phosgene. After stirring for 5 h at 0° C. and then for 2 h at RT, a sample from the reaction mixture was taken and analysed with GC. Result are shown in Table 1 with the following abbreviations:
- CE Comparative Example
- DPA-2.2 Diisopropylamine, 2.2 eq
- DPA-2.5 Diisopropylamine, 2.5 eq
- EMP-2.2 5-Ethyl-2-methylpyridine, 2.2 eq
- NMM-2.2 N-Methylmorpholine, 2.2 eq
- TEA-2.2 Triethylamine (2.2 eq.)
- (2) compound of formula (2)
- (3) compound of formula (2)
- (4) compound of formula (4)
-
TABLE 1 GC Results CE Base SOLV (2) (3) (4) 1 DPA-2.2 Dichloromethane 20% 15% 10% 2 DPA-2.2 Toluene 25% 12% 8% 3 DPA-2.2 Acetonitrile 30% 17% 12% 4 DPA-2.2 Chlorobenzene 10% 18% 9% 5 DPA-2.2 Sulfolane 32% 12% 14% 6 DPA-2.2 Dimethyl carbonate 12% 19% 5% 7 DPA-2.5 Dichloromethane 20% 15% 10% 8 DPA-2.5 Toluene 25% 12% 8% 9 DPA-2.5 Acetonitrile 30% 17% 12% 10 DPA-2.5 Chlorobenzene 10% 18% 9% 11 DPA-2.5 Sulfolane 32% 12% 14% 12 DPA-2.5 Dimethyl carbonate 12% 19% 5% 13 3-Picoline Dichloromethane 21% 18% 11% (2.2 eq.) 14 3-Picoline Toluene 28% 13% 8% (2.2 eq.) 15 3-Picoline Acetonitrile 31% 12% 7% (2.2 eq.) 16 3-Picoline Chlorobenzene 17% 22% 15% (2.2 eq.) 17 3-Picoline Sulfolane 22% 18% 10% (2.2 eq.) 18 3-Picoline Dimethyl carbonate 28% 11% 15% (2.2 eq.) 19 TEA-2.2 Dichloromethane 20% 14% 8% 20 TEA-2.2 Toluene 25% 12% 8% 21 TEA-2.2 Acetonitrile 30% 17% 12% 22 TEA-2.2 Chlorobenzene 10% 18% 9% 23 TEA-2.2 Sulfolane 32% 12% 14% 24 TEA-2.2 Dimethyl carbonate 12% 19% 5% 25 Pyridine Dichloromethane 20% 15% 10% (2.2 eq.) 26 Pyridine Toluene 25% 12% 8% (2.2 eq.) 27 Pyridine Acetonitrile 30% 17% 12% (2.2 eq.) 28 Pyridine Chlorobenzene 12% 19% 5% (2.2 eq.) 29 Pyridine Sulfolane 20% 15% 10% (2.2 eq.) 30 Pyridine Dimethyl carbonate 25% 12% 8% (2.2 eq.) 31 EMP-2.2 Dichloromethane 30% 17% 12% 32 EMP-2.2 Toluene 10% 18% 9% 33 EMP-2.2 Acetonitrile 32% 12% 14% 34 EMP-2.2 Chlorobenzene 12% 19% 5% 35 EMP-2.2 Sulfolane 21% 18% 11% 36 EMP-2.2 Dimethyl carbonate 28% 13% 8% 37 NMM-2.2 Dichloromethane 16% 15% 8% 38 NMM-2.2 Toluene 20% 15% 15% 39 NMM-2.2 Acetonitrile 18% 15% 5% 40 NMM-2.2 Chlorobenzene 20% 18% 10% 41 NMM-2.2 Sulfolane 22% 18% 10% 42 NMM-2.2 Dimethyl carbonate 28% 15% 8% - 5.0 g (21.62 mmol, 1 eq) of compound of formula (1) were dissolved in 125 mL of solvent SOLV and Catalyst was added. 4.7 g of phosgene (47.56 mmol, 2.2 eq) were added at 0° C. After 5 h at 0° C., then 2 h at RT and then 2 h at 40° C., a sample from the reaction mixture was taken and analysed with GC.
- Result are shown in Table 2 with the following abbreviations:
- (2) compound of formula (2)
- CE Comparative Example
- TPP-0.1 Triphenylphosphine, 0.1 eq
- TPP-0.3 Triphenylphosphine, 0.3 eq
-
TABLE 2 CE Catalyst SOLV Remarks 43 TPP-0.1 Dichloromethane less than 0.5% of (2) 44 TPP-0.1 Toluene less than 0.5% of (2) 45 TPP-0.1 Acetonitrile less than 0.5% of (2) 46 TPP-0.1 Chlorobenzene less than 0.5% of (2) 47 TPP-0.1 Sulfolane less than 0.5% of (2) 48 TPP-0.1 Dimethyl carbonate less than 0.5% of (2) 49 TPP-0.3 Dichloromethane less than 0.5% of (2) 50 TPP-0.3 Toluene less than 0.5% of (2) 51 TPP-0.3 Acetonitrile less than 0.5% of (2) 52 TPP-0.3 Chlorobenzene less than 0.5% of (2) 53 TPP-0.3 Sulfolane less than 0.5% of (2) 54 TPP-0.3 Dimethyl carbonate less than 0.5% of (2) 55 no catalyst Dichloromethane less than 0.5% of (2) 56 no catalyst Toluene less than 0.5% of (2) 57 no catalyst Acetonitrile less than 0.5% of (2) 58 no catalyst Chlorobenzene less than 0.5% of (2) 59 no catalyst Sulfolane less than 0.5% of (2) 60 no catalyst Dimethyl carbonate less than 0.5% of 2 - 5.0 g (21.62 mmol, 1 eq) compound of formula (1) were dissolved in 25 mL of DMF. 100 mL of DMF were mixed with 4.7 g of phosgene (47.56 mmol, 2.2 eq) at 0° C. The solution of compound of formula (1) was added to the mixture of DMF with phosgene at 0° C. After 14 h stirring at 0° C. and then 2 h at RT, 50 mL of water and 50 mL of toluene were added at 0° C. The mixture was stirred 15 min and the phases were separated. The organic phase was evaporated under vacuum. 5 g of compound of formula (2) were isolated (83% yield, 98.2% purity, GC analysis showed 1.1% of compound of formula (3), 0.32% of compound of formula (4) and 0.35% of compound of formula (5)).
- 50 g (216.2 mmol, 1 eq) of compound of formula (1) were dissolved in 250 mL of DMF. 1000 mL of DMF were mixed with 47 g of phosgene (475.6 mmol, 2.2 eq) at 0° C. The solution of compound of formula (1) was added to the mixture of DMF with phosgene at 0° C. After 14 h stirring at 0° C. and then 2 h at RT, 500 mL of water and 500 mL of toluene were added at 0° C. The mixture was stirred 30 min and the phases were separated. The organic phase was evaporated under vacuum. 54 g of compound of formula (2) were isolated (93% yield, 98.4% purity, GC analysis showed 1.1% of compound of formula (3), 0.26% of compound of formula (4) and 0.24% of compound of formula (5)).
Claims (10)
2. Method according to claim 1 , wherein
PHOS is phosgene.
3. Method according to claim 1 , wherein
the molar amount of PHOS is from 2 to 5 times of the molar amount of compound of formula (1).
4. Method according to claim 1 , wherein
the amount of DMF is from 10 to 100 times of the weight of PHOS.
5. Method according to claim 1 , wherein the reaction temperature TEMP1 of REAC1 is from −10 to 50° C.
6. Method according to claim 1 , wherein the reaction time TIME1 of REAC1 is from 5 h to 48 h.
7. Method according to claim 1 , wherein compound of formula (1) is dissolved in DMF to provide a solution SOL-1, and PHOS is dissolved in DMF to provide a solution SOL-PHOS; and SOL-1 and SOL-PHOS are mixed with each other to provide for REAC1.
8. Method according to claim 7 , wherein for the mixing of SOL-1 with SOL-PHOS, SOL-1 is added to SOL-PHOS.
9. Method according to claim 1 , wherein after REAC1 toluene and water is added to the reaction mixture.
10. Method according to claim 1 , wherein the addition of toluene and water is done at a temperature of from −10 to 30° C.
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US16/621,222 US10689350B1 (en) | 2017-07-18 | 2018-07-16 | Method for preparation of chlorinated s-propylthiobarbituric acid |
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