CN117402085A - 一种合成d-n-boc-联苯丙胺醇的新方法 - Google Patents
一种合成d-n-boc-联苯丙胺醇的新方法 Download PDFInfo
- Publication number
- CN117402085A CN117402085A CN202311329984.3A CN202311329984A CN117402085A CN 117402085 A CN117402085 A CN 117402085A CN 202311329984 A CN202311329984 A CN 202311329984A CN 117402085 A CN117402085 A CN 117402085A
- Authority
- CN
- China
- Prior art keywords
- boc
- reaction
- added
- methyl
- oxo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 15
- 230000002194 synthesizing effect Effects 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- -1 (R) - (2-oxo-oxazolidine-4-yl) methyl biphenyl Chemical group 0.000 claims abstract description 7
- 239000007858 starting material Substances 0.000 claims abstract description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 230000008569 process Effects 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 10
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 9
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 8
- XZXRYNVWWTZADH-VIFPVBQESA-N [(4s)-2-oxo-1,3-oxazolidin-4-yl]methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC[C@H]1NC(=O)OC1 XZXRYNVWWTZADH-VIFPVBQESA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 5
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 5
- MEXGFDVEUOGVFI-GSVOUGTGSA-N (4r)-4-(hydroxymethyl)-1,3-oxazolidin-2-one Chemical compound OC[C@@H]1COC(=O)N1 MEXGFDVEUOGVFI-GSVOUGTGSA-N 0.000 claims description 4
- 229940025084 amphetamine Drugs 0.000 claims description 4
- HYGVRONUWGXDLF-UHFFFAOYSA-L magnesium;1,1'-biphenyl;dibromide Chemical compound [Mg+2].[Br-].[Br-].C1=CC=CC=C1C1=CC=CC=C1 HYGVRONUWGXDLF-UHFFFAOYSA-L 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 239000000413 hydrolysate Substances 0.000 claims 1
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 6
- 238000011112 process operation Methods 0.000 abstract description 2
- XLOVYLFWBKRFFD-JTQLQIEISA-N CC1=C(C=CC(=C1)C)S(=O)(=O)O[C@@H]1NC(OC1)=O Chemical compound CC1=C(C=CC(=C1)C)S(=O)(=O)O[C@@H]1NC(OC1)=O XLOVYLFWBKRFFD-JTQLQIEISA-N 0.000 abstract 1
- 239000007818 Grignard reagent Substances 0.000 abstract 1
- 150000004795 grignard reagents Chemical class 0.000 abstract 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000007787 solid Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 8
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000003054 catalyst Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- PKJBWOWQJHHAHG-UHFFFAOYSA-N 1-bromo-4-phenylbenzene Chemical group C1=CC(Br)=CC=C1C1=CC=CC=C1 PKJBWOWQJHHAHG-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 2
- 229940122586 Enkephalinase inhibitor Drugs 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- CBQJSKKFNMDLON-SNVBAGLBSA-N N-acetyl-D-phenylalanine Chemical compound CC(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 CBQJSKKFNMDLON-SNVBAGLBSA-N 0.000 description 2
- CBQJSKKFNMDLON-JTQLQIEISA-N N-acetyl-L-phenylalanine Chemical compound CC(=O)N[C@H](C(O)=O)CC1=CC=CC=C1 CBQJSKKFNMDLON-JTQLQIEISA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000002792 enkephalinase inhibitor Substances 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 150000002690 malonic acid derivatives Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 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 description 2
- SJSNUMAYCRRIOM-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SJSNUMAYCRRIOM-QFIPXVFZSA-N 0.000 description 2
- 229960004699 valsartan Drugs 0.000 description 2
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 1
- NELFDUVDACTLRD-UHFFFAOYSA-N 3-(2-phenylphenyl)propan-1-amine Chemical compound C1(=CC=CC=C1)C1=C(C=CC=C1)CCCN NELFDUVDACTLRD-UHFFFAOYSA-N 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OUYCCCASQSFEME-MRVPVSSYSA-N D-tyrosine Chemical compound OC(=O)[C@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-MRVPVSSYSA-N 0.000 description 1
- 229930195709 D-tyrosine Natural products 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
- MICFYWRTIGKAPQ-UHFFFAOYSA-N benzaldehyde;1,1'-biphenyl Chemical compound O=CC1=CC=CC=C1.C1=CC=CC=C1C1=CC=CC=C1 MICFYWRTIGKAPQ-UHFFFAOYSA-N 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 239000003777 experimental drug Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000005555 hypertensive agent Substances 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 150000004712 monophosphates Chemical class 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N n,n-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- PYNXFZCZUAOOQC-UTKZUKDTSA-N sacubitril Chemical compound C1=CC(C[C@H](C[C@@H](C)C(=O)OCC)NC(=O)CCC(O)=O)=CC=C1C1=CC=CC=C1 PYNXFZCZUAOOQC-UTKZUKDTSA-N 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
本发明公开了一种沙库巴曲中间体的制备方法,属于药物制药领域。通过(R)‑4‑(羟甲基)恶唑烷‑2‑酮与磺酰氯反应生成(S)‑(2‑氧代恶唑烷‑4‑基)甲基‑4‑甲基苯磺酸酯,产物再与格氏试剂反应得到(R)‑(2‑氧代噁唑烷‑4‑基)甲基联苯,再经水解,氨基上BOC得到D‑N‑BOC‑联苯丙胺醇。该制备方法路线短,反应条件温和,工艺操作简便,适合工业化生产。
Description
技术领域
本发明涉及一种沙库巴曲中间体联苯丙胺醇的制备方法,属于药物合成技术领域。
背景技术
治疗心衰目前可选的药物仍然比较少,患病人员仍面临着高死亡风险且生活质量差的状况。LCZ696(商品名Entresto)是一种双效血管紧张素受体脑啡肽酶抑制剂,由诺华研发,具有独特的作用模式,结合了诺华的高血压药物缬沙坦和实验性药物脑啡肽酶抑制剂沙库巴曲(Sacubitril,AHU-377),被认为能够减少心衰的应变。其中,沙库巴曲可阻断威胁负责降低血压的2种多肽的作用机制,缬沙坦则可改善血管舒张,刺激身体排泄钠和水。目前LCZ696已批准用于射血分数降低的心力衰竭患者的治疗,疗效显著而副作用低,具有广阔的市场前景。
D-N-BOC-联苯丙胺醇是合成沙库巴曲缬沙坦钠的关键起始原料,目前文献报道的合成方法存在合成路线长,或者需要昂贵的手性催化剂,或者用到易燃易爆物料等问题,成本高,不利于工业化生产等问题。
文献,(J.Med.Chem,1995,38,1689-1700)公开了一种D-N-BOC-联苯丙胺醇的制备方法,其合成路线如下:
该路线的原料D-酪氨酸价格昂贵,反应过程中用的三氟甲磺酸酐,不仅价格昂贵,而且腐蚀性很强,对生产操作要求较高,Suzuki偶联反应步骤用的钯催化剂价格也较昂贵。整个合成路线比较长,总收率低,成本高。
专利WO2014032627公开了一种沙库巴曲中间体(D-N-BOC-联苯丙胺醇)的制备方法,其合成路线如下:
虽然该路线较短,但Mitsunobu反应用到三苯基膦,其不产物三苯基氧膦不易去除。偶氮二甲酸二烷基酯对光、热和震动敏感,存在一定的安全风险。
专利WO2013026773公开了一种沙库巴曲中间体(D-N-BOC-联苯丙胺醇)的制备方法,首先联苯苯甲醛和N-苯甲酰基甘氨酸为原料,在醋酸酐的条件下制备的中间体在经甲醇开环,所得到的的中间体经过钌催化剂与手性单磷配体催化不对称氢化还原双键,得到对映中间体,在经过催化氢化还原和Boc保护得到最终产物。其合成路线如下:
该路线使用铑催化剂和手性配体催化还原构建手性中心,该催化剂和手性配体价格昂贵不易获得,使D-N-BOC-联苯丙胺醇的合成成本较高,且该反应需要在无水无氧的条件下进行,反应条件苛刻,那一实现产业化。
专利CN101774941A与CN102482202B公开首先合成N-乙酰基苯丙氨酸的消旋体,再经手性拆分制备得到(R)-N-乙酰基苯丙氨酸,该中间体可后续通过一系列化学反应制备得到N-[(1R)-2-[1,1′-联苯]-4-基-1-(羟基基)乙基]氨基甲酸叔丁酯。合成路线如下所示:
该方法采用丙二酸衍生物经加热脱羧反应,制备得到N-乙酰基苯丙氨酸的消旋体,采用手性拆分剂(S)-1-苯乙胺进行拆分,制备得到(R)-N-乙酰基苯丙氨酸。该工艺起始原料丙二酸衍生物不易制备,拆分反应收率低,拆分工艺通常使另外一个构型的产物不能利用,或者不能完全消旋再加以利用,导致该中间体原料成本增加,不适合工业化生产。
发明内容
技术问题:针对目前现有技术合成方法存在合成路线长,或者需要昂贵的手性催化剂,或者用到易燃易爆物料,或者成本高,不利于工业化生产,或者使用手性拆分剂造成成本升高等问题,本发明提出了以下解决的技术方案。
技术方案
本发明D-N-BOC-联苯丙胺醇的合成方法如下:
i (R)-4-(羟甲基)恶唑烷-2-酮与对甲苯磺酰氯反应生成(S)-(2-氧代恶唑烷-4-基)甲基- 4-甲基苯磺酸酯;
ii 第i步产物与联苯溴化镁反应得到(R)-(2-氧代噁唑烷-4-基)甲基联苯;
iii第ii步产物再经水解,氨基上BOC得到D-N-BOC-联苯丙胺醇;
该制备方法路线短,反应条件温和,工艺操作简便,适合工业化生产。
进一步,第一步反应 (R)-4-(羟甲基)恶唑烷-2-酮和对甲苯磺酰氯反应过程中加入碱性试剂 DMAP和 TEA;
进一步,联苯溴化镁的制备方法通过氮气保护下,将镁粉THF溶液加热至不超过60℃,加入4-溴联苯的THF溶液,反应引发后,再加入剩余的4-溴联苯的THF溶液反应;
更进一步,反应引发时,反应体系中加入碘。
进一步,第二步反应将(S)-(2-氧代恶唑烷-4-基)甲基- 4-甲基苯磺酸酯的 THF溶液加入到联苯溴化镁的THF溶液中;
更进一步,反应温度在低温条件下进行,反应温度-10~-20℃;
更进一步,反应体系中加入碘化亚铜;
进一步,第三步反应将第二步所得产物中加入乙醇溶解,再加入盐酸回流。稍后体系降至室温,加入NaOH溶液和 BOC酸酐;
更进一步,加入NaOH溶液和 BOC酸酐后,将体系加热至35~45℃保温,再加入水于40~45℃保温,然后将至20~25℃保温。
技术效果:通过本发明的技术方案得到的沙库巴曲中间体联苯丙氨醇,路线简单,条件温和,没有使用强腐蚀性的试剂,并且在手性中间体的合成中没有使用手性拆分剂,最终得到产物的收率达到了90%以上,并且在最终产物中并无对映异构体检出,节省了成本,优化了工艺,适合工业化生产。
实施方式
用到溶剂名称简写说明
DCM 二氯甲烷;DMAP 4-二甲氨基吡啶;MTBE 甲基叔丁基醚
THF 四氢呋喃;Boc 叔丁氧羰基; (Boc)2O Boc酸酐
步骤1:(S)-(2-氧代恶唑烷-4-基)甲基- 4-甲基苯磺酸酯的合成
向500mLDCM中加入25g (R)-4-(羟甲基)恶唑烷-2-酮(0.21mol)和42.7g对甲苯磺酰氯(0.22mol,1.05eq), 加入 DMAP (1.3g,10.5 mmol,0.05 eq)和 TEA (19.2g,0.19mol,1.1 eq)。将反应混合物加热至室温并搅拌过夜。用水淬灭反应,用150mlDCM 萃取两遍。将有机层用 1 N盐酸洗涤两次,将有机相浓缩干DCM。残余物用MTBE结晶,过滤后真空干燥,得到55.3 g白色固体。收率97%,纯度99.6%。
步骤2:(R)-(2-氧代噁唑烷-4-基)甲基联苯的合成
实施例
向三口瓶中加入100ml THF和5.2g(1.2eq)镁粉,同时将49.0g对溴联苯溶于100ml THF中。氮气保护下将镁粉体系加热至35~50℃,在35~50℃加入少量碘和30ml 4-溴联苯的THF溶液,反应引发后,在35~50℃加入剩余的4-溴联苯的THF溶液,加毕,保温4h。然后将体系将至室温,加入4.2g碘化亚铜。再将体系冷却至-10~-20℃,加入含50.0g (S)-(2-氧代恶唑烷-4-基)甲基- 4-甲基苯磺酸酯(0.18mol)的200ml THF溶液,加毕,保温反应2h。将反应体系倒入150.0g 4M盐酸中,搅拌,静置,分液。保留有机相。将有机相在30~40℃减压浓缩溶剂,得类白色固体,直接投下一步。
实施例
向三口瓶中加入100ml THF和5.6g(1.3eq)镁粉,同时将49.0g对溴联苯溶于100mlTHF中。氮气保护下将镁粉体系加热至50~60℃,在50~60℃加入少量碘和30ml 4-溴联苯的THF溶液,反应引发后,在50~60℃加入剩余的4-溴联苯的THF溶液,加毕,保温4h。然后将体系将至室温,加入5.1g碘化亚铜。再将体系冷却至-10~-20℃,加入含50.0g (S)-(2-氧代恶唑烷-4-基)甲基- 4-甲基苯磺酸酯(0.18mol)的200ml THF溶液,加毕,保温反应2h。将反应体系倒入150.0g 4M盐酸中,搅拌,静置,分液。保留有机相。将有机相在40~50℃减压浓缩溶剂,得类白色固体,直接投下一步。
实施例
向三口瓶中加入100ml THF和5.6g(1.2eq)镁粉,同时将49.0g对溴联苯溶于100mlTHF中。氮气保护下将镁粉体系加热至45~55℃,在45~55℃加入少量碘和30ml 4-溴联苯的THF溶液,反应引发后,在45~55℃加入剩余的4-溴联苯的THF溶液,加毕,保温4h。然后将体系将至室温,加入4.8g碘化亚铜。再将体系冷却至-20~-30℃,加入含50.0g (S)-(2-氧代恶唑烷-4-基)甲基- 4-甲基苯磺酸酯(0.18mol)的200ml THF溶液,加毕,保温反应2h。将反应体系倒入150.0g 4M盐酸中,搅拌,静置,分液。保留有机相。将有机相在40~50℃减压浓缩溶剂,得类白色固体,直接投下一步。
步骤3:D-N-BOC-联苯丙胺醇的合成
向第二步所得产物中加入200mL 乙醇,搅拌溶解,再加入53.0g盐酸(0.45mol),加入至回流反应4h。将体系降至室温,将21.6g NaOH(0.54mol)用100.0ml水溶解后加入体系中。再将41.3g BOC酸酐(0.19mol)用100.0ml乙醇溶解加入体系中。将体系加热至35~45℃保温2h,再加入300.0ml水于40~45℃保温1h,然后降至20~25℃保温1h,过滤,固体于60~70℃烘干,得56.6g 白色固体,收率96%,HPLC纯度99.8%,对映异构体未检出。
Claims (7)
1.一种沙库巴曲中间体的制备方法,其特征在于:
i (R)-4-(羟甲基)恶唑烷-2-酮与对甲苯磺酰氯反应生成(S)-(2-氧代恶唑烷-4-基)甲基- 4-甲基苯磺酸酯;
ii 第i步产物与联苯溴化镁反应得到(R)-(2-氧代噁唑烷-4-基)甲基联苯;
iii第ii步产物再经盐酸水解,氨基上BOC得到D-N-BOC-联苯丙胺醇;
。
2.根据权利要求1所述的制备方法,其特征在于ii步的反应温度为-10~-20℃。
3.根据权利要求1所述的制备方法,其特征在于(S)-(2-氧代恶唑烷-4-基)甲基- 4-甲基苯磺酸酯的THF溶液加入到联苯溴化镁的THF溶液进行反应。
4.根据权利要求3所述的制备方法,其特征在于在反应中加入碘化亚铜。
5.根据权利要求1所述的制备方法,其特征在于第iii步中将第ii步产物溶于乙醇,加入盐酸回流,得到水解产物。
6.根据权利要求5所述的制备方法,其特征在于水解产物加入NaOH溶液和BOC酸酐反应。
7.根据权利要求6所述的制备方法,其特征在于反应温度是35~45℃保温2h,再加入水于40~45℃保温1h,然后将至20~25℃保温1h。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311329984.3A CN117402085A (zh) | 2023-10-16 | 2023-10-16 | 一种合成d-n-boc-联苯丙胺醇的新方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311329984.3A CN117402085A (zh) | 2023-10-16 | 2023-10-16 | 一种合成d-n-boc-联苯丙胺醇的新方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN117402085A true CN117402085A (zh) | 2024-01-16 |
Family
ID=89488181
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311329984.3A Pending CN117402085A (zh) | 2023-10-16 | 2023-10-16 | 一种合成d-n-boc-联苯丙胺醇的新方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117402085A (zh) |
-
2023
- 2023-10-16 CN CN202311329984.3A patent/CN117402085A/zh active Pending
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105330569A (zh) | 一种(r)-2-(n-叔丁氧羰基氨基)联苯丙醇的制备方法 | |
CN102627573B (zh) | 5-氨基酮戊酸盐酸盐的合成方法 | |
CN104370755B (zh) | 一种光学活性的3‑氨基丁醇和3‑氨基丁酸的制备方法 | |
CA1077057A (en) | Process for the preparation of acetic acid derivatives | |
CN111018767B (zh) | 一种d-脯氨酸衍生物及其中间体的制备方法 | |
JP2016528271A (ja) | □新規な中間体を経由するビフェニルアラニノールの合成 | |
CN106459014A (zh) | 雷迪帕韦及其衍生物的制备方法及用于制备雷迪帕韦的中间体化合物 | |
US9771317B2 (en) | Process for preparing lacosamide and related compounds | |
CN107602399B (zh) | 一种脑啡肽酶抑制剂中间体的制备方法 | |
CN111170878B (zh) | 一种制备d-型或l-型叔亮氨酸的方法 | |
CN117402085A (zh) | 一种合成d-n-boc-联苯丙胺醇的新方法 | |
CN106748966A (zh) | 一种雷米普利关键中间体的合成方法 | |
CN114702425B (zh) | (s)-2-氨基-(s)-3-[吡咯烷酮-2’]丙氨酸衍生物及中间体的制备方法 | |
CN109096098B (zh) | 一种反式-1,3-二羟基环丁烷-1-羧酸的制备方法 | |
JPS6120547B2 (zh) | ||
CN109265385B (zh) | 一种手性催化剂的合成工艺 | |
CN102070468B (zh) | β-肾上腺激动素莱克多巴胺的合成方法 | |
CN108203396B (zh) | 一种脑啡肽酶抑制剂的合成 | |
CN109836373B (zh) | 一种维生素b6的环保制备及尾气循环利用的方法 | |
CN115784922B (zh) | 一种(2s)-2-氨基-4-(环丙基/环丁基)丁酸的制备方法 | |
CN116082192B (zh) | 一种反式4-(叔丁氧羰氨基)环己烷羧酸的制备方法 | |
CN110511183B (zh) | 一种3,4-环烷基喹啉-2(1h)-酮类化合物的制备方法 | |
JP3144920B2 (ja) | α−アシルアミノケトン誘導体、その製造方法及びその利用 | |
KR101059275B1 (ko) | 개선된 4-[2-(디-엔-프로필아미노)에틸]-1,3-디하이드로-2에이치-인돌-2-온의 제조 방법 | |
JP3144921B2 (ja) | ベンジルエステル誘導体及びその製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |