CN103755617A - 一种制备依折麦布关键杂质的方法 - Google Patents
一种制备依折麦布关键杂质的方法 Download PDFInfo
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- 238000000034 method Methods 0.000 title claims description 16
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 title abstract description 15
- 229960000815 ezetimibe Drugs 0.000 title abstract description 14
- 239000012535 impurity Substances 0.000 title abstract description 6
- 239000003054 catalyst Substances 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- WHUOJOBYLUYPHQ-QMMMGPOBSA-N C1(=CC=CC=C1)[C@H]1C(N=[C-]O1)=O Chemical compound C1(=CC=CC=C1)[C@H]1C(N=[C-]O1)=O WHUOJOBYLUYPHQ-QMMMGPOBSA-N 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 3
- 229940125782 compound 2 Drugs 0.000 claims description 3
- 229940126214 compound 3 Drugs 0.000 claims description 3
- 229940125898 compound 5 Drugs 0.000 claims description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 2
- GPGSMLXOBVGHQH-DHIUTWEWSA-N (3r,4s)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)propyl]-4-(4-hydroxyphenyl)azetidin-2-one Chemical compound C1=CC(O)=CC=C1[C@H]1N(C=2C=CC(F)=CC=2)C(=O)[C@@H]1CCCC1=CC=C(F)C=C1 GPGSMLXOBVGHQH-DHIUTWEWSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
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- 238000002360 preparation method Methods 0.000 abstract description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 abstract 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 239000006096 absorbing agent Substances 0.000 abstract 1
- 235000012000 cholesterol Nutrition 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 abstract 1
- 125000004433 nitrogen atom Chemical group N* 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 16
- 238000003756 stirring Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000000967 suction filtration Methods 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
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- 239000012043 crude product Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
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- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
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- 235000002639 sodium chloride Nutrition 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- AITNMTXHTIIIBB-UHFFFAOYSA-N 1-bromo-4-fluorobenzene Chemical class FC1=CC=C(Br)C=C1 AITNMTXHTIIIBB-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical class CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 235000001018 Hibiscus sabdariffa Nutrition 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 208000000563 Hyperlipoproteinemia Type II Diseases 0.000 description 1
- 102100024640 Low-density lipoprotein receptor Human genes 0.000 description 1
- 206010063985 Phytosterolaemia Diseases 0.000 description 1
- 235000005291 Rumex acetosa Nutrition 0.000 description 1
- 240000007001 Rumex acetosella Species 0.000 description 1
- 208000002227 Sitosterolemia Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 206010045261 Type IIa hyperlipidaemia Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000009098 adjuvant therapy Methods 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 201000001386 familial hypercholesterolemia Diseases 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000005220 pharmaceutical analysis Methods 0.000 description 1
- 235000002378 plant sterols Nutrition 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000003513 sheep sorrel Nutrition 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical class Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
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- 229940051223 zetia Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于药物化学领域，涉及一种1-苯基-(3R)-[3-(4-氟苯基)-(3S)-羟基丙基]-(4S)-(4-羟基苯基)-2-丙内酰胺的制备，其为抑制胆固醇吸收剂药物——依折麦布中的关键杂质，其与依折麦布不同在于1位氮原子取代基为苯基而非4-氟苯基，以1-(5-甲氧基-1,5-二氧代戊基)-4(S)-苯基-2-恶唑烷酮为原料，采用合适的原料及催化剂，经过七步合成得到。
Description
技术领域
本发明属于药物化学领域，涉及一种1-苯基-(3R)-[3-(4-氟苯基)-(3S)-羟基丙基]-(4S)-(4-羟基苯基)-2-丙内酰胺制备方法。
背景技术
依折麦布又译名为依折替米贝，依替米贝等，适用于治疗原发性高胆固醇血症、纯合子家族性高胆固醇血症、纯合子谷甾醇血症（或植物甾醇血症），是一种饮食控制以外的辅助治疗药品。将其与他汀类药物联合应用，可作为其他将血脂治疗的辅助疗法，具有很好的治疗效果。该药由Schering-Plough研制，于2002年在美国和德国上市，2008年进入中国市场，其具有用量少、毒副作用小、疗效确切等优点。
目前，对于依折麦布已经有了十分稳定的合成工艺。专利US5767115以简单的物料，经七步反应制备得到光学纯度较高的依折麦布，但其操作较为复杂，产品存在不好纯化的问题。专利US19980206931提供了一种改进的简单的使用中性条件高产率地合成依折麦布的方法，只需5步反应，收率可达50%左右。以上均是较早，且较成熟的依折麦布的合成工艺。
对于本发明的目标化合物，其与依折麦布在结构上十分的相近，但其药物活性却与之有着较大的区别，研究发现其与依折麦布有着不同的治疗效果，影响着药物的活性以及稳定性，在药物的检测中具有重要的地位，是依折麦布的关键性杂质。但目前并没有涉及合成目标化合物的文献报道，我们通过全合成制备出该杂质，该方法原料易得，操作简单，可实施性强，对于依折麦布的药物分析研究，以及药物活性成分研究具有重要的意义。
发明内容
本发明提供一种1-苯基-(3R)-[3-(4-氟苯基)-(3S)-羟基丙基]-(4S)-(4-羟基苯基)-2-丙内酰胺制备方法，其步骤在于，以1-(5-甲氧基-1,5-二氧代戊基)-4(S)-苯基-2-恶唑烷酮为原料，采用合适的原料及催化剂，经过七步合成得到。该方法具有操作简单，反应条件温和，构型稳定等特点。
其所述由化合物2合成化合物3采用的TBAF为四氢呋喃溶液，其浓度为0.5~1.5 mol/L，该步反应温度为40 ~ 60 ℃；由化合物3合成化合物4所采用的碱为强碱烯溶液，包括NaOH溶液、KOH溶液，其中优选NaOH溶液；由化合物4合成化合物5所采用的酰化试剂为草酰氯；化合物5与格氏试剂反应合成化合物6，并加入了ZnCl2以降低格氏试剂活性，及四三苯基磷钯催化反应进行；化合物6通过硼氢化还原为化合物7，采用R-CBS作为手性催化剂，反应温度为0 ~ -25 ℃，优选-15 ℃；化合物7通过Pd/C催化脱苄基得到目标产物，其中的氢化试剂为氢气、甲酸铵，其中优选甲酸铵。
具体实施方式
以下通过实施例进一步说明本发明，但不作为对本发明的限制。
实施例：
步骤一：向250 mL三口瓶中加入100 mL二氯甲烷和3.3 mL四氯化钛，氮气保护。搅拌冷却至0 ℃，滴加2.97 mL四异丙醇钛，搅拌15 min后，加入8.8 g 1-(5-甲氧基-1,5-二氧代戊基)-4(S)-苯基-2-恶唑烷酮的20 mL二氯甲烷溶液，然后缓慢滴加二异丙基乙胺(DIPEA)11.7mL，保持0 ℃搅拌1 h。冷却至-20 ℃，加入化合物1-01 20.7 g，保持-20 ℃反应4 h。待反应结束滴加8.8 mL冰醋酸和18 mL二氯甲烷溶液。反应液升温至0 ℃，加入36 mL 2 mol/L硫酸，保持0~5 ℃反应1 h。抽滤，滤液分液，有机相用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得黄色固体。粗品用100 mL异丙醇加热打浆，冷却抽滤，得白色固体，真空干燥，得化合物2干燥产物13.5 g，收率74.7%。
步骤二：向250 mL三口烧瓶中加入10.0 g化合物2和115 mL甲苯、0.4 mL 1 mol/L的TBAF的四氢呋喃溶液，氮气保护，控温30 ℃。量取10 mL BSA滴加如反应体系，滴完后升温至50 ℃。TLC点板，待反应结束，停止加热，滴加28 mL甲醇，反应液依次用50 mL 1N盐酸、70 mL饱和碳酸氢钠、70 mL去离子水洗涤，无水硫酸钠干燥，减压浓缩得黄褐色油状物。将油状物溶于40 mL甲醇，加冰浴析晶，抽滤，得白色固体，真空干燥。得6.1 g干燥化合物3，收率84.9%。
步骤三：向100 mL三口烧瓶中加入6.0 g化合物3和10 mL丙酮，水浴控温20 ℃。缓慢滴加20 mL 0.83 mol/L的NaOH溶液，于20 ℃反应2 h。TLC点板监测，反应结束后，加入20 mL去离子水和35 mL乙酸乙酯，搅拌0.5 h。水相用40 mL乙酸乙酯萃取两次，取水相用12 mL 1mol/L盐酸缓慢滴加，有大量白色固体析出，酸化至pH=3，用50 mL乙酸乙酯萃取两次，无水硫酸钠干燥。抽滤，滤液减压浓缩至干，得油状产物5.8 g，冷却固化，得5.6 g化合物4，收率96.5%。
步骤四：用30 mL二氯甲烷溶解步骤三中5.6 g化合物4，加入100 mL三口烧瓶，搅拌，氮气保护，控温20 ℃。取2 mL草酰氯溶于14 mL二氯甲烷中，滴加入反应体系，并滴加3滴N,N-二甲基甲酰胺。反应6 h，TLC点板，待反应结束，将反应液浓缩至干，得油状物5.8 g，即为化合物5，产品粗收率99.0%。
步骤五：向100 mL三口烧瓶中加入0.5 g镁屑，几粒碘和30 mL 无水四氢呋喃，氮气保护，搅拌，升温至40 ℃。将2.4 mL对氟溴苯缓慢滴加如反应体系，反应2 h，待镁屑消失，降温至0 ℃，称量2.9 g无水ZnCl2加入反应体系，搅拌0.5 h，取0.5 g Pd(PPh3)4加入体系。用20 mL无水四氢呋喃溶步骤四中5.8 g化合物5，缓慢滴加如反应体系，于0 ℃反应1 h。TLC点板，待反应基本结束，升温至20 ℃反应1 h，抽滤，滤液减压浓缩，得红褐色油状物7.5 g，TLC显示不纯，含两个杂质点，得化合物6的粗品。
步骤六：向250 mL三口瓶中加入100 mL二氯甲烷，0 ℃搅拌下加入2 mL硼烷二甲硫醚和2.2 mLR-CBS，反应1 h。将7.5 g步骤五中化合物6的粗品溶于15 mL二氯甲烷中，缓慢滴加如反应体系，0 ℃反应10 h。待反应结束，将18 mL浓度5%的双氧水滴加如反应体系，分液，有机相用75 mL 1mol/L的盐酸及75 mL饱和食盐水各洗涤两次，无水硫酸钠干燥。抽滤，滤液减压浓缩至干，得褐色油状物5.2 g，TLC含四个杂质点，通过柱层析分离，得TLC单点的化合物7，质量为3.6 g。
步骤七：向100 mL三口瓶中加入3.6 g化合物7和35 mL甲醇，搅拌溶解，分别加入5.7 g甲酸铵、18 mL甲酸和0.4 g Pd/C于反应体系，搅拌反应2 h。点板，待反应结束，将反应液抽滤，滤液减压浓缩至干，的白色固体4.6 g，TLC显示含两个小杂质点。通过柱层析分离，得TCL单点的化合物8，即最终目标化合物，质量为2.4 g。
1HNMR（DMSO,400MHz）δ:1.720-1.828 (4H,m), 2.506(1H,d), 4.799(1H,d), 5.309(1H,d), 6.737-7.354(13H,m), 9.537(1H,s)。
Claims (8)
1.一种制备依折麦布杂质的方法，以1-(5-甲氧基-1,5-二氧代戊基)-4(S)-苯基-2-恶唑烷酮为原料，经以下步骤制备1-苯基-(3R)-[3-(4-氟苯基)-(3S)-羟基丙基]-(4S)-(4-羟基苯基)-2-丙内酰胺
2.根据权利要求1的方法，其特征在于，由化合物2合成化合物3采用的TBAF为四氢呋喃溶液，其浓度为0.5~1.5 mol/L，该步反应温度为40~60℃。
3. 根据权利要求1的方法，其特征在于，由化合物3合成化合物4所采用的碱为强碱稀溶液。
4. 根据权利要求3的方法，其特征在于，所采用的碱为1 mol/L的NaOH溶液或0.5 mol/L的KOH溶液。
5. 根据权利要求1的方法，其特征在于，由化合物4合成化合物5所采用的酰化试剂为草酰氯。
6. 根据权利要求1的方法，其特征在于，化合物5与格氏试剂反应合成化合物6的过程中加入ZnCl2，催化剂为四三苯基磷钯。
7. 根据权利要求1方法，其特征在于，化合物6通过硼氢化还原为化合物7，采用R-CBS作为手性催化剂，反应温度为0 ~ -25 ℃。
8. 根据权利要求1方法，其特征在于，由化合物7合成化合物8的步骤中，催化剂为Pd/C，氢化试剂为氢气或甲酸铵。
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