JP4422183B2 - ジイソプロピル((1−(ヒドロキシメチル)−シクロプロピル)オキシ)メチルホスホネートの製造方法 - Google Patents
ジイソプロピル((1−(ヒドロキシメチル)−シクロプロピル)オキシ)メチルホスホネートの製造方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims description 24
- HHZZOQSDZBZQFK-UHFFFAOYSA-N [1-[di(propan-2-yloxy)phosphorylmethoxy]cyclopropyl]methanol Chemical compound CC(C)OP(=O)(OC(C)C)COC1(CO)CC1 HHZZOQSDZBZQFK-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 123
- 238000006243 chemical reaction Methods 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- QJTROUHNWPQATP-UHFFFAOYSA-N 1-(trityloxymethyl)cyclopropan-1-ol Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)OCC1(O)CC1 QJTROUHNWPQATP-UHFFFAOYSA-N 0.000 claims description 13
- -1 ethyl magnesium halide Chemical class 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims description 11
- 239000007787 solid Substances 0.000 claims description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 8
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 8
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 claims description 8
- KOMSQTMQKWSQDW-UHFFFAOYSA-N ethyl 5-methyl-1,2-oxazole-4-carboxylate Chemical compound CCOC(=O)C=1C=NOC=1C KOMSQTMQKWSQDW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 5
- 239000000460 chlorine Chemical group 0.000 claims description 4
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 claims description 4
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- GPVOTFQILZVCFP-UHFFFAOYSA-N 2-trityloxyacetic acid Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(OCC(=O)O)C1=CC=CC=C1 GPVOTFQILZVCFP-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- ABLZXFCXXLZCGV-UHFFFAOYSA-N phosphonic acid group Chemical group P(O)(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 claims description 3
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- YCCXQARVHOPWFJ-UHFFFAOYSA-M magnesium;ethane;chloride Chemical group [Mg+2].[Cl-].[CH2-]C YCCXQARVHOPWFJ-UHFFFAOYSA-M 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 239000000047 product Substances 0.000 claims 1
- 239000000543 intermediate Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 230000002194 synthesizing effect Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- ZANNOFHADGWOLI-UHFFFAOYSA-N ethyl 2-hydroxyacetate Chemical compound CCOC(=O)CO ZANNOFHADGWOLI-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 239000003443 antiviral agent Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000002777 nucleoside Substances 0.000 description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 125000006267 biphenyl group Chemical group 0.000 description 2
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000011630 iodine Chemical group 0.000 description 2
- 229910052740 iodine Chemical group 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- DDFHBQSCUXNBSA-UHFFFAOYSA-N 5-(5-carboxythiophen-2-yl)thiophene-2-carboxylic acid Chemical compound S1C(C(=O)O)=CC=C1C1=CC=C(C(O)=O)S1 DDFHBQSCUXNBSA-UHFFFAOYSA-N 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 238000006129 Kulinkovich cyclopropane synthesis reaction Methods 0.000 description 1
- KLPTYUXPTXPKDQ-UHFFFAOYSA-N [[1-[di(propan-2-yloxy)phosphorylmethoxy]cyclopropyl]methoxy-diphenylmethyl]benzene Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)OCC1(OCP(=O)(OC(C)C)OC(C)C)CC1 KLPTYUXPTXPKDQ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 210000000692 cap cell Anatomy 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- YOXHCYXIAVIFCZ-UHFFFAOYSA-N cyclopropanol Chemical compound OC1CC1 YOXHCYXIAVIFCZ-UHFFFAOYSA-N 0.000 description 1
- 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 208000002672 hepatitis B Diseases 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 229940083251 peripheral vasodilators purine derivative Drugs 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000005292 vacuum distillation Methods 0.000 description 1
Classifications
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/54—Quaternary phosphonium 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
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
Description
従って、化合物(2)の純度を向上し、一般式(7)の化合物の合成するとき、一般式(6)の化合物の安全性を改善することが当業界に求められてきた。
一般式(4)の化合物をトリチルクロリドと反応させて下記一般式(8)のトリチルオキシ−酢酸エチルエステルを製造し、
まず、本明細書の全般にわたって使われた略語は次の通り定義される。
Tr:トリチル
Et:エチル
EDC:1,2−ダイクロロエタン
THF:テトラヒドロフラン
EA:エチルアセテート
iPr:イソプロピル
LTB:リチウムt−ブトキシド
NMP:N−メチルピロリドン
DBMP:ジイソプロピルブロモメチルホスホネート
MTBE:メチルt-ブチルエーテル
TFA:トリフルオロ酢酸
MDC:メチレンクロリド
AN:アセトニトリル
min:分
本発明の方法は98〜100%に達する高純度の化合物(2)を製造する。
一般式(2)の化合物に離脱基を導入させて下記一般式(11)の化合物を製造し、
一般式(11)の化合物を前記一般式(3)の化合物とカップリング反応させて下記一般式(12)の化合物を製造し、
一般式(12)の化合物を加水分解して下記一般式(13)の化合物を製造し、
一般式(13)の化合物から基Xを除去すると同時に、ホスホン酸部位にt−ブチルカルボニルオキシメチル基を導入させることを含む方法で製造できる。
下記実施例で、反応の完結を判断するためのHPLC条件は次の通りである。
[HPLC条件]
カラム:Capcell pak C18(Type:MG5μm;Size:4.6mm I.D×250mm)
波長(λ):254nm
流速:1.0mL/min
勾配条件:初期:20/80(H2O/AN、0.1%TFA)、5分:20/80、7分:0/100、10分:0/100、12分:20/80
実施例1
トリチルオキシ−酢酸エチルエステル(8)の製造
トリチルクロリド 279g(1.0mol)をEDC 680mL(5mL/g、グルコール酸エチル基準)に溶かし、グルコール酸エチル 135g(1.3mol)を反応溶液に加えた。ここにピリジン 99g(1.25mol)を投入した後、40℃で、19時間攪拌した。HPLCで反応が完結されたことを確認した後、0.5N 塩酸水溶液 270mL(2mL/g、グルコール酸エチル基準)を反応溶液に投入し、2相(two-phase)を作った後、抽出した。抽出過程を再度繰り返した後、EDCを減圧蒸留した。化合物(8)を固体として得るために、680mLのヘキサンを濃縮された化合物に投入し、温度を0℃に下げた後、混合物を約3時間攪拌し、濾過した。
1−トリチルオキシメチル-シクロプロパノール(9)の製造
実施例1で得られた化合物(8)(実施例1の収率が100%と仮定する)にテトラヒドロフラン 1040mL(3mL/g、化合物(8)基準)を投入し、温度を0℃に下げた。ここにチタニウムテトライソプロポキシド 113.8グラム(0.4mol)を投入した後、エチルマグネシウムブロマイド 1500mL(3.0mol、1モル濃度)を5〜15℃で3〜6時間かけて滴下した。HPLCで反応完結を確認した後、20%のクエン酸水溶液1790mL(5mL/g、化合物(8)基準)を35℃が越えない条件下で、反応溶液に投入し、約1時間攪拌した。攪拌後、テトラヒドロフランを減圧蒸留と酢酸エチル 1390mL(4mL/g、化合物(8)基準)と690mL(2mL/g、化合物(8)基準)で2回抽出した。有機層を飽和されたNaHCO3水溶液 690mL(2mL/g、化合物(8)基準)で洗浄し後、減圧濃縮して表題化合物(9)を得た。
(1−トリチルオキシメチル−シクロプロポキシメチル)−ホスホン酸ジイソプロピルエステル(10)の製造
実施例2で減圧濃縮して得られた化合物(9) 261.25g(0.79mol)(HPLCで78.54%のピーク面積を有したので、実施例1からはじめて、0.79%の収率)化合物(9)が得られたと仮定する)にNMP 1050mL(4mL/g、化合者(9)基準)とDBMP 307g(1.2mol)を投入した。反応混合物にLTB 107g(1.3mol)を投入し、反応溶液の温度が45℃を越えないように調節しながら攪拌した。約6〜19時間後、HPLCで反応完結を確認し、14%のNH4Cl水溶液 1830mL(7mL/g、化合物(9)基準)を投入して反応を中断させた。ここに、MTBE 1050mL(4mL/g、化合物(9)基準)と520mL(2mL/g、化合物(9)基準)を投入して2回層分離した。有機層を回収して、21%のNaCl水溶液 1650mL(6.3mL/g、化合物(9)基準)で洗浄した。残っている有機層を減圧濃縮した後、ヘプタン 1300mL(5mL/g、化合物(8)基準)を投入し、温度を−10℃に下げ、約3時間後に濾過し、固体の表題化合物(10)を586g(純度 96.23%、収率 71.3%)得た。
[NMR]化合物(10)の外に他のピークは観察されなかった。
ジイソプロピル[1−(ヒドロキシメチル)−シクロプロピル]オキシメチルホスホネート(2)の製造
実施例3で得られた化合物(10) 59.15g(116.3mmol)をアセトン 59.2mL(1mL/g、化合物(10)基準)に溶かし、ここにH2O 5.9mL(327.8mmol)とTFA 26.52g(232.6mmol)を投入した後、室温で攪拌した。HPLC上で化合物(10)が7%以下であることを確認した後、3N NaOH 水溶液を75mL(2.6mL/g、化合物(10)基準)投入し、アセトンを減圧蒸留して除去した。反応中に生成された固体を濾過し、その濾液をメチレンクロリドで118.3mL(2mL/g、化合物(10)基準)づつ2回抽出した。有機層を減圧濃縮して表題化合物(2)を31.71g(純度98%、化合物(10)を基準にした収率 102.4%)得た。
[NMR]前記一般式(2)の化合物の外に、溶媒であるメチレンクロリドのピークのみ観察される。
Claims (9)
- 下記一般式(2)の化合物の製造方法であって、
- 一般式(9)の化合物を反応させて一般式(10)の化合物を製造する段階で用いられる溶媒がN−メチルピロリドンである請求項1に記載の方法。
- 一般式(9)の化合物を反応させて一般式(10)の化合物を製造する段階で用いられる塩基がリチウムt−ブトキシドである請求項1又は2に記載の方法。
- エチルマグネシウムハライドがエチルマグネシウムクロリドまたはエチルマグネシウムブロマイドである請求項1又は2に記載の方法。
- エチルマグネシウムハライドをチタニウムテトライソプロポキシドの存在下に、一般式(8)の化合物と反応させる請求項1又は2に記載の方法。
- 一般式(10)の化合物のトリチル基をヒドロキシル基に転換させた後、得られた生成物を水酸化ナトリウムで処理し、生成した固体を濾過し、濾液をメチレンクロリドで抽出して一般式(2)の化合物を得る請求項1又は2に記載の方法。
- 下記一般式(1)の化合物の製造方法であって、
前記一般式(11)の化合物を下記一般式(3)の化合物とカップリング反応させて、
下記一般式(12)の化合物を収得し、
一般式(12)の化合物を加水分解して下記一般式(13)の化合物を製造し、
前記一般式(13)の化合物から基Xを除去すると同時に、ホスホン酸部位にt−ブチルカルボニルオキシメチル基を導入することを特徴とする一般式(1)の化合物の製造方法。
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KR1020040051558A KR101033290B1 (ko) | 2004-07-02 | 2004-07-02 | 다이아이소프로필((1-(하이드록시메틸)-사이클로프로필)옥시)메틸포스포네이트의 새로운 제조 방법 |
PCT/KR2005/002007 WO2006004330A1 (en) | 2004-07-02 | 2005-06-27 | Process for preparing di-isopropyl ((1(hydroxymethyl)-cyclopropyl)oxy) methylphosphonate |
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CN106432330B (zh) * | 2015-08-11 | 2019-02-01 | 天津科伦药物研究有限公司 | Lb80380药物的中间体化合物及其制备方法和用途 |
KR20180014903A (ko) | 2016-08-01 | 2018-02-12 | 삼성디스플레이 주식회사 | 전자 소자, 이의 실장 방법 및 이를 포함하는 표시 장치의 제조 방법 |
CN108997429B (zh) * | 2018-07-27 | 2020-10-30 | 广州粤美医药科技有限公司 | 一种制备贝西福韦的方法 |
CN115181013B (zh) * | 2022-07-22 | 2023-08-08 | 北京先通国际医药科技股份有限公司 | 修饰脂肪酸型pet试剂前体关键中间体的制备方法及其用途 |
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US5817647A (en) * | 1993-04-01 | 1998-10-06 | Merrell Pharmaceuticals Inc. | Unsaturated acetylene phosphonate derivatives of purines |
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TW200606170A (en) | 2006-02-16 |
RU2007104036A (ru) | 2008-08-10 |
CA2571592A1 (en) | 2006-01-12 |
AU2005260375A1 (en) | 2006-01-12 |
CN101061128B (zh) | 2010-10-06 |
US20090187019A1 (en) | 2009-07-23 |
US7795463B2 (en) | 2010-09-14 |
TWI326685B (en) | 2010-07-01 |
NZ552246A (en) | 2009-07-31 |
ZA200610744B (en) | 2008-05-28 |
EP1765838A1 (en) | 2007-03-28 |
MXPA06015262A (es) | 2007-03-21 |
US20100305364A1 (en) | 2010-12-02 |
CA2571592C (en) | 2010-02-09 |
KR101033290B1 (ko) | 2011-05-09 |
AU2005260375B8 (en) | 2011-01-20 |
BRPI0512886A (pt) | 2008-04-15 |
JP2008505066A (ja) | 2008-02-21 |
CN101061128A (zh) | 2007-10-24 |
AU2005260375B2 (en) | 2010-12-09 |
AR049566A1 (es) | 2006-08-16 |
KR20060002501A (ko) | 2006-01-09 |
WO2006004330A1 (en) | 2006-01-12 |
EP1765838A4 (en) | 2009-05-27 |
RU2326885C1 (ru) | 2008-06-20 |
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