WO2022042549A1 - 一种磷酸特地唑胺中间体及其制备方法 - Google Patents
一种磷酸特地唑胺中间体及其制备方法 Download PDFInfo
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- WO2022042549A1 WO2022042549A1 PCT/CN2021/114308 CN2021114308W WO2022042549A1 WO 2022042549 A1 WO2022042549 A1 WO 2022042549A1 CN 2021114308 W CN2021114308 W CN 2021114308W WO 2022042549 A1 WO2022042549 A1 WO 2022042549A1
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- tedizolid phosphate
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- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- QCGUSIANLFXSGE-GFCCVEGCSA-N tedizolid phosphate Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](COP(O)(O)=O)C2)=O)F)=N1 QCGUSIANLFXSGE-GFCCVEGCSA-N 0.000 title claims abstract description 20
- 229960003947 tedizolid phosphate Drugs 0.000 title claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims abstract description 75
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 229960003879 tedizolid Drugs 0.000 claims description 4
- XFALPSLJIHVRKE-GFCCVEGCSA-N tedizolid Chemical compound CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](CO)C2)=O)F)=N1 XFALPSLJIHVRKE-GFCCVEGCSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- 125000003118 aryl group Chemical group 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- YTMVYYAKOPIJCZ-UHFFFAOYSA-N 4-bromo-3-fluoroaniline Chemical compound NC1=CC=C(Br)C(F)=C1 YTMVYYAKOPIJCZ-UHFFFAOYSA-N 0.000 abstract description 10
- 238000000034 method Methods 0.000 abstract description 8
- 150000001412 amines Chemical class 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 50
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- 239000000243 solution Substances 0.000 description 23
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 23
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 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 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- 239000011259 mixed solution Substances 0.000 description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
- JANKGNBDRWYWSN-UHFFFAOYSA-N 5-bromo-2-(2-methyltetrazol-5-yl)pyridine Chemical compound CN1N=NC(C=2N=CC(Br)=CC=2)=N1 JANKGNBDRWYWSN-UHFFFAOYSA-N 0.000 description 9
- 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 description 9
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 7
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 7
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 6
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical group CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 5
- 238000010626 work up procedure Methods 0.000 description 5
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 3
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 3
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- 0 C[n]1nnc(-c(nc2)ccc2-c(ccc(*C(*=O)N(*)*)c2)c2F)n1 Chemical compound C[n]1nnc(-c(nc2)ccc2-c(ccc(*C(*=O)N(*)*)c2)c2F)n1 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000012805 post-processing Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- AJSTXXYNEIHPMD-UHFFFAOYSA-N triethyl borate Chemical compound CCOB(OCC)OCC AJSTXXYNEIHPMD-UHFFFAOYSA-N 0.000 description 2
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 2
- SJHPCNCNNSSLPL-CSKARUKUSA-N (4e)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)\N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-CSKARUKUSA-N 0.000 description 1
- UAXDUQWXEJLTSR-UTONKHPSSA-N (5r)-3-[3-fluoro-4-[6-(2-methyltetrazol-5-yl)pyridin-3-yl]phenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one;phosphoric acid Chemical group OP(O)(O)=O.CN1N=NC(C=2N=CC(=CC=2)C=2C(=CC(=CC=2)N2C(O[C@@H](CO)C2)=O)F)=N1 UAXDUQWXEJLTSR-UTONKHPSSA-N 0.000 description 1
- RBRWAYCOVWVMHS-UHFFFAOYSA-N 1-methylpiperazine;oxolane Chemical compound C1CCOC1.CN1CCNCC1 RBRWAYCOVWVMHS-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- PUJDIJCNWFYVJX-UHFFFAOYSA-N NC(OCc1ccccc1)=O Chemical compound NC(OCc1ccccc1)=O PUJDIJCNWFYVJX-UHFFFAOYSA-N 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- MPXQYNYBUZHTMR-UHFFFAOYSA-N [2-fluoro-4-(phenylmethoxycarbonylamino)phenyl]boronic acid Chemical compound C1=C(F)C(B(O)O)=CC=C1NC(=O)OCC1=CC=CC=C1 MPXQYNYBUZHTMR-UHFFFAOYSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- -1 dibenzylamine tetrahydrofuran Chemical compound 0.000 description 1
- XVLKGNGMTHJRLV-UHFFFAOYSA-N dichloromethane;n-ethylethanamine Chemical compound ClCCl.CCNCC XVLKGNGMTHJRLV-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 description 1
- 229960003907 linezolid Drugs 0.000 description 1
- NEIQCPNEJSEGAQ-UHFFFAOYSA-N morpholine;oxolane Chemical compound C1CCOC1.C1COCCN1 NEIQCPNEJSEGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- GSJRUEBQWPLHSN-UHFFFAOYSA-N n-methylmethanamine;oxolane Chemical compound CNC.C1CCOC1 GSJRUEBQWPLHSN-UHFFFAOYSA-N 0.000 description 1
- VIWWLVBTPJWYOP-UHFFFAOYSA-N oxolane;n-propan-2-ylpropan-2-amine Chemical compound C1CCOC1.CC(C)NC(C)C VIWWLVBTPJWYOP-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
- C07F3/06—Zinc compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/653—Five-membered rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
Definitions
- the present disclosure belongs to the field of medicinal chemistry, and in particular relates to an intermediate for preparing tedizolid phosphate and a preparation method thereof.
- Tedizolid phosphate chemical name is (R)-3-(4-(2-(2-methyltetrazol-5-yl)pyridin-5-yl)3-fluorophenyl)-5-hydroxymethyl Oxazolidin-2-one dihydrogen phosphate, English name Tedizolid Phosphate, trade name (CAS No: 856867-55-5).
- Tedizolid phosphate is a second-generation oxazolone antibiotic developed by Cubist, and was approved by the US FDA in June 2014. It is mainly used for the treatment of gram-positive bacteria such as Staphylococcus aureus and various streptococci. Skin or tissue infections caused by bacteria. Tedizolid has high activity and broad antibacterial spectrum, and its dosage is one-third of the first-generation linezolid. It is expected to replace the latter and create a market of nearly 1.5 billion US dollars.
- TRIUS THERAPEUTICS discloses a method for preparing tedizolid phosphate in patent CN102177156, and the route is shown in Scheme 1.
- This route uses 3-fluoro-4-bromoaniline and benzyl chloroformate as starting materials to synthesize tedizolid phosphate, wherein the product obtained in the second step boronation reaction is 4-(benzyloxycarbonylamino)-2-fluorophenylboronic acid
- the yield is only 66%, the purity is 89.8%, the bromine impurity cannot be removed in the post-processing process, the palladium catalyst residue is relatively high in the third step reaction, and the palladium catalyst recovery rate is only 18%.
- the total yield of this route is low, only about 40%, with low efficiency and high cost.
- the purpose of the present disclosure is to provide a new intermediate of tedizolid phosphate, a preparation method thereof, and a method for preparing tedizolid phosphate in view of the deficiencies of the prior art.
- the present disclosure provides a new intermediate, the structure is the compound shown in formula I, or a pharmaceutically acceptable salt thereof,
- R 1 and R 2 are each independently selected from C 1-12 alkyl, C 3-8 cycloalkyl, aryl or substituted aryl; or R 1 and R 2 and the attached N atom form a 3-8 membered ring.
- R 1 and R 2 are each independently selected from C 1-6 alkyl, benzyl; or R 1 and R 2 form a 5- or 6-membered heterocycle with the attached N atom.
- R 1 and R 2 are each independently selected from methyl, ethyl, isopropyl, benzyl; R 1 and R 2 and the attached N atom form morpholine, N- Methylpiperazine, etc.
- the present disclosure provides a preparation method of an intermediate (compound I) of tedizolid phosphate, which comprises the following steps:
- Step (1) 4-bromo-3-fluoroaniline (compound II) and disubstituted amine (compound III) are used as raw materials to react to generate compound IV;
- Step (3) compound V and compound VI carry out a coupling reaction to obtain compound I;
- step (1) compound IV is prepared by using 4-bromo-3-fluoroaniline (compound II), bis(trichloromethyl)carbonate and disubstituted amine (compound III) as raw materials.
- step (2) compound III is subjected to boronation reaction with a boronating reagent to obtain compound V, and the boronating reagent is triisopropyl borate, trimethyl borate, triethyl borate, preferably triisopropyl borate.
- step (3) compound V is coupled with 5-bromo-2-(2-methyl-2H-tetrazol-5-yl)-pyridine under palladium catalysis to obtain compound I.
- step (3) the reaction is carried out at 50-80° C. for 12 hours.
- the beneficial effect of the present disclosure is that the present disclosure provides an intermediate (compound I) of tedizolid phosphate and a preparation method thereof.
- the reaction yield of the second step can reach 85%, and the purity is 97%.
- the impurities in this step process are significantly reduced, and the yield and purity are greatly improved.
- compound I can be directly precipitated after the reaction in the third step is completed, the post-processing process is simplified, and the operation of removing palladium by recrystallization is reduced, the product yield is improved, and the recovery of palladium in the mother liquor is facilitated.
- the method disclosed by the invention is simple in operation, high in yield, high in purity and low in cost, and is suitable for industrial production.
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Abstract
本公开提供了一种磷酸特地唑胺的中间体及其制备方法。本公开以3-氟-4-溴苯胺和二取代胺为起始原料合成磷酸特地唑胺中间体(化合物I),进而制备磷酸特地唑胺。本公开提供的方法操作简单,收率高,纯度高,适合工业化生产。
Description
相关申请的交叉引用
本公开要求于2020年8月26日提交中国专利局的申请号为CN202010867695.9、名称为“一种磷酸特地唑胺中间体及其制备方法”的中国专利申请的优先权,其全部内容通过引用结合在本公开中。
本公开属于药物化学领域,具体涉及一种用于制备磷酸特地唑胺的中间体及其制备方法。
磷酸特地唑胺,化学名为(R)-3-(4-(2-(2-甲基四唑-5-基)吡啶-5-基)3-氟苯基)-5-羟甲基恶唑烷-2-酮二氢磷酸酯,英文名为Tedizolid Phosphate,商品名为
(CAS No:856867-55-5)。磷酸特地唑胺是由Cubist公司所开发的第二代噁唑酮类抗生素,并于2014年6月获得美国FDA批准上市,主要用于治疗金黄色葡萄球菌及各种链球菌等革兰氏阳性菌引起的皮肤或组织等感染。特地唑胺活性高,抗菌谱广,用量是第一代利奈唑胺的三分之一,有望取代后者打下近15亿美元规模的市场。
TRIUS THERAPEUTICS公司在专利CN102177156中公开了一种制备磷酸特地唑胺的方法,路线如Scheme 1所示。
该路线以3-氟-4-溴苯胺和氯甲酸苄酯为起始原料合成磷酸特地唑胺,其中第二步硼化反应得到的产物4-(苄氧羰基氨基)-2-氟苯硼酸的收率仅为66%,纯度为89.8%,后处理过程无法除去掉溴杂质,第三步反应中钯催化残留量较高,钯催化剂回收率只有18%。另外,该路线总收率较低,仅为40%左右,效率低,成本高。
因此,我们需要寻找新的制备路线或者新的中间体用于制备磷酸特地唑胺。
发明内容
本公开的目的在于针对现有技术的不足,提供一种新的磷酸特地唑胺的中间体及其制备方法及用于制备磷酸特地唑胺的方法。
一方面,本公开提供一种新的中间体,结构为式I所示的化合物,或其药学上可接受的盐,
其中,R
1和R
2各自独立地选自C
1-12烷基、C
3-8环烷基、芳基或取代芳基;或者R
1和R
2与相连的N原子形成3-8元环。
进一步,在某些优选实施例中,R
1和R
2各自独立地选自C
1-6烷基、苄基;或者R
1和R
2与相连的N原子形成5元或6元杂环。
更进一步,在某些优选实施例中,R
1和R
2各自独立地选自甲基、乙基、异丙基、苄基;R
1和R
2与相连的N原子形成吗啡啉、N-甲基哌嗪等。
另一方面,本公开提供一种磷酸特地唑胺的中间体(化合物I)的制备方法,其包括以下步骤:
步骤(1):4-溴-3-氟苯胺(化合物II)与二取代胺(化合物III)为原料,反应生成化合物IV;
步骤(2):化合物IV经硼化反应得到化合物V;
步骤(3):化合物V与化合物VI进行偶联反应,得到化合物I;
进一步,步骤(1)以4-溴-3-氟苯胺(化合物II)、二(三氯甲基)碳酸酯和二取代胺(化合物III)为原料,制得化合物IV。
进一步,步骤(2)中化合物III与硼化试剂进行硼化反应得到化合物V,所述硼化试剂为硼酸三异丙酯,硼酸三甲酯,硼酸三乙酯,优选硼酸三异丙酯。
进一步,步骤(3)中化合物V与5-溴-2-(2-甲基-2H-四唑-5-基)-吡啶在钯催化下偶联反应制得化合物I。
更进一步,步骤(3)在50~80℃条件下反应12小时。
另一方面,式I所示的化合物可以用于制备特地唑胺或者磷酸特地唑胺,具体方案如下:
化合物I脱保护得到化合物VII;再与氯甲酸苄酯反应得到化合物VIII;然后与化合物IX环化反应,得到特地唑胺,最后磷酸化得到化合物X。
本公开的有益效果在于,本公开提供了一种磷酸特地唑胺的中间体(化合物I)及其制备方法。其中第二步反应收率可达85%,纯度为97%,相比原研公司的技术路线相比,此步过程杂质明显减少,且收率和纯度有大幅度提高。本公开中第三步反应结束后可以直接析出得到化合物I,后处理过程得到简化,并且减少了重结晶除钯的操作,提高了产物收率且有利于母液中钯的回收。本公开的方法操作简单,收率高,纯度高,成本低,适合工业化生产。
图1为本公开提供的实施例1中化合物IV(R
1=甲基,R
2=甲基)的
1H NMR
图2为本公开提供的实施例2中化合物V(R
1=甲基,R
2=甲基)的
1H NMR
图3为本公开提供的实施例3中化合物I(R
1=甲基,R
2=甲基)的
1H NMR
下面结合实施例对本公开的技术内容作进一步的阐述,其目的是为了更好的理解本公开的内容,但本公开的保护范围不限于此。
实施例1 化合物IV的制备(R
1=甲基,R
2=甲基)
在100mL三口瓶内加入5.0g 4-溴-3-氟苯胺和3.12g二(三氯甲基)碳酸酯和30mL四氢呋喃混合溶清;将5.87g三乙胺和30mL四氢呋喃混合,滴加到反应液中,控制温度为0~5℃,反应3小时,然后将14.5mL 2.0M二甲胺四氢呋喃溶液加到反应液中,在0~5℃ 条件下反应1小时,经后处理,得到标题化合物,收率96%,纯度99.5%。
1H NMR谱图见图1。
实施例2 化合物V的制备(R
1=甲基,R
2=甲基)
在25mL三口瓶内加入0.5g实施例1得到的化合物IV和0.72g硼酸三异丙酯和5mL四氢呋喃混合溶清,降温到-78℃,再向其中加入1.5mL 2.5M正丁基锂,反应2小时,反应结束,经后处理,得到标题化合物,收率85%;纯度97%。
1H NMR谱图见图2。
实施例3 化合物I的制备(R
1=甲基,R
2=甲基)
在25mL三口瓶内加入0.2g实施例2得到的化合物V和0.106g 5-溴-2-(2-甲基-2H-四唑-5-基)-吡啶(化合物VI)和3mL四氢呋喃混合溶清;氮气保护下加入0.025g四三苯基膦钯及0.122g碳酸钾和0.5L水,将反应温度升温至60℃反应12小时,反应结束后,经后处理,得到标题化合物,收率97%,纯度98%。
1H NMR谱图见图3。
实施例4 化合物VII的制备
在25mL三口瓶内加入0.5g实施例3得到的化合物I和10mL二氧六环和2.5mL去离子水混合,加入0.1g氢氧化锂,升温到90℃反应20小时,经后处理,得到标题化合物,收率99%,纯度98%。
实施例5 化合物IV的制备(R
1=乙基,R
2=乙基)
在100mL三口瓶内加入5.0g 4-溴-3-氟苯胺和3.12g二(三氯甲基)碳酸酯和30mL二氯甲烷混合溶清;将5.87g三乙胺和30mL四氢呋喃混合,滴加到反应液中,控制温度为0~5℃,反应3小时,然后将15mL 2.0M二乙胺二氯甲烷溶液加到反应液中,在0~5℃条件下反应1小时,经后处理,得到标题化合物。
实施例6 化合物V的制备(R
1=乙基,R
2=乙基)
在25mL三口瓶内加入0.5g实施例5得到的化合物IV和0.72g硼酸三甲酯和5mL二氯甲烷混合溶清,降温到-78℃,再向其中加入1.5mL 2.5M正丁基锂,反应2小时,TLC监测,反应结束,经后处理,得到标题化合物。
实施例7 化合物I的制备(R
1=乙基,R
2=乙基)
在25mL三口瓶内加入0.2g实施例6得到的化合物V和0.106g 5-溴-2-(2-甲基-2H-四唑-5-基)-吡啶和3mL四氢呋喃混合溶清;氮气保护下加入0.025g四三苯基膦钯及0.122 g碳酸钾和0.5mL水,将反应温度升温至60℃反应12小时,反应结束后,经后处理,得到标题化合物。
实施例8 化合物VII的制备
在25mL三口瓶内加入0.5g实施例7得到的化合物I和10mL二氧六环和2.5mL去离子水混合,加入0.1g氢氧化锂,升温到90℃反应20小时,经后处理,得到标题化合物。
实施例9 化合物IV的制备(R
1=异丙基,R
2=异丙基)
在100mL三口瓶内加入5.0g 4-溴-3-氟苯胺和3.2g二(三氯甲基)碳酸酯和30mL四氢呋喃混合溶清;将6g三乙胺和30mL四氢呋喃混合,滴加到反应液中,控制温度为0~5℃,反应3小时,然后将17mL 2.0M二异丙胺四氢呋喃溶液加到反应液中,在0~5℃条件下反应1小时,经后处理,得到标题化合物。
实施例10 化合物V的制备(R
1=异丙基,R
2=异丙基)
在25mL三口瓶内加入0.5g实施例9得到的化合物IV和0.8g硼酸三乙酯和5mL四氢呋喃混合溶清,降温到-78℃,再向其中加入1.5mL 2.5M正丁基锂,反应2小时,TLC监测,反应结束,经后处理,得到标题化合物。
实施例11 化合物I的制备(R
1=异丙基,R
2=异丙基)
在25mL三口瓶内加入0.2g实施例10得到的化合物V和0.15g 5-溴-2-(2-甲基-2H-四唑-5-基)-吡啶和3mL四氢呋喃混合溶清;氮气保护下加入0.03g四三苯基膦钯及0.13g碳酸钾和0.5mL水,将反应温度升温至60℃反应12小时,反应结束后,经后处理,得到标题化合物。
实施例12 化合物VII的制备
在25mL三口瓶内加入0.5g实施例11得到的化合物I和10mL二氧六环和2.5mL去离子水混合,加入0.1g氢氧化锂,升温到90℃反应20小时,经后处理,得到标题化合物。
实施例13 化合物IV的制备(R
1=苯甲基,R
2=苯甲基)
在100mL三口瓶内加入5.0g 4-溴-3-氟苯胺和3.12g二(三氯甲基)碳酸酯和30mL四氢呋喃混合溶清;将5.87g三乙胺和30mL四氢呋喃混合,滴加到反应液中,控制温度为0~5℃,反应3小时,然后将19mL 2.0M二苄胺四氢呋喃溶液加到反应液中,在0~5℃条 件下反应1小时,经后处理,得到标题化合物。
实施例14 化合物V的制备(R
1=苯甲基,R
2=苯甲基)
在25mL三口瓶内加入0.5g实施例13得到的化合物IV和0.8g硼酸三异丙酯和5mL四氢呋喃混合溶清,降温到-78℃,再向其中加入1.5mL 2.5M正丁基锂,反应2小时,TLC监测,反应结束,经后处理,得到标题化合物。
实施例15 化合物I的制备(R
1=苯甲基,R
2=苯甲基)
在25mL三口瓶内加入0.2g实施例14得到的化合物V和0.2g 5-溴-2-(2-甲基-2H-四唑-5-基)-吡啶和3mL四氢呋喃混合溶清;氮气保护下加入0.03g四三苯基膦钯及0.15g碳酸钾和0.5mL水,将反应温度升温至60℃反应12小时,反应结束后,经后处理,得到标题化合物。
实施例16 化合物VII的制备
在25mL三口瓶内加入0.5g实施例15得到的化合物I和10mL二氧六环和2.5mL去离子水混合,加入0.1g氢氧化锂,升温到90℃反应20小时,经后处理,得到标题化合物。
实施例17 化合物IV的制备(化合物III为吗啡啉)
在100mL三口瓶内加入5.0g 4-溴-3-氟苯胺和3.2g二(三氯甲基)碳酸酯和30mL四氢呋喃混合溶清;将5.8g三乙胺和30mL四氢呋喃混合,滴加到反应液中,控制温度为0~5℃,反应3小时,然后将20mL 2.0M吗啡啉四氢呋喃溶液加到反应液中,在0~5℃条件下反应1小时,经后处理,得到标题化合物。
实施例18 化合物V的制备(化合物III为吗啡啉)
在25mL三口瓶内加入0.5g实施例17得到的化合物IV和0.72g硼酸三异丙酯和5mL四氢呋喃混合溶清,降温到-78℃,再向其中加入1.5mL 2.5M正丁基锂,反应2小时,TLC监测,反应结束,经后处理,得到标题化合物。
实施例19 化合物I的制备(化合物III为吗啡啉)
在25mL三口瓶内加入0.2g实施例18得到的化合物V和0.2g 5-溴-2-(2-甲基-2H-四唑-5-基)-吡啶和3mL四氢呋喃混合溶清;氮气保护下加入0.03g四三苯基膦钯及0.15g碳酸钾和0.5mL水,将反应温度升温至60℃反应12小时,反应结束后,经后处理,得到标 题化合物。
实施例20 化合物VII的制备
在25mL三口瓶内加入0.5g实施例19得到的化合物I和10mL二氧六环和2.5mL去离子水混合,加入0.1g氢氧化锂,升温到90℃反应20小时,经后处理,得到标题化合物。
实施例21 化合物IV的制备(化合物III为N-甲基哌嗪)
在100mL三口瓶内加入5.0g 4-溴-3-氟苯胺和3.12g二(三氯甲基)碳酸酯和30mL四氢呋喃混合溶清;将5.87g三乙胺和30mL四氢呋喃混合,滴加到反应液中,控制温度为0~5℃,反应3小时,然后将20mL 2.0M N-甲基哌嗪四氢呋喃溶液加到反应液中,在0~5℃条件下反应2小时,经后处理,得到标题化合物。
实施例22 化合物V的制备(化合物III为N-甲基哌嗪)
在25mL三口瓶内加入0.5g实施例21得到的化合物IV和0.72g硼酸三异丙酯和5mL四氢呋喃混合溶清,降温到-78℃,再向其中加入2mL 2.5M正丁基锂,反应3小时,TLC监测,反应结束,经后处理,得到标题化合物。
实施例23 化合物I的制备(化合物III为N-甲基哌嗪)
在25mL三口瓶内加入0.2g实施例22得到的化合物V和0.12g 5-溴-2-(2-甲基-2H-四唑-5-基)-吡啶和3mL四氢呋喃混合溶清;氮气保护下加入0.03g四三苯基膦钯及0.15g碳酸钾和0.5mL水,将反应温度升温至60℃反应12小时,反应结束后,经后处理,得到标题化合物。
实施例24 化合物VII的制备
在25mL三口瓶内加入0.5g实施例23得到的化合物I和10mL二氧六环和2.5mL去离子水混合,加入0.1g氢氧化锂,升温到90℃反应20小时,经后处理,得到标题化合物。
实施例25 化合物VIII的制备
在25mL三口瓶内加入0.5g实施例4得到的化合物VII和10mL四氢呋喃混合,加入碳酸钠;降温至0~5℃,将0.4g氯甲酸苄酯滴加到反应液中反应2小时,经后处理,得到标题化合物。
实施例26 化合物X的制备
同专利CN102177156(B)实施例6。
实施例27 化合物I的制备
同专利CN102177156(B)实施例7。
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