JP2014525408A - R−ビフェニルアラニノールの合成 - Google Patents
R−ビフェニルアラニノールの合成 Download PDFInfo
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- JP2014525408A JP2014525408A JP2014525452A JP2014525452A JP2014525408A JP 2014525408 A JP2014525408 A JP 2014525408A JP 2014525452 A JP2014525452 A JP 2014525452A JP 2014525452 A JP2014525452 A JP 2014525452A JP 2014525408 A JP2014525408 A JP 2014525408A
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- biphenylalaninol
- aryl
- boc
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- 0 CC(C1)C(C[C@@](*)C(O*)=O)=CC=C1c1ccccc1 Chemical compound CC(C1)C(C[C@@](*)C(O*)=O)=CC=C1c1ccccc1 0.000 description 1
- RCAIWVIQRMDTAV-OAHLLOKOSA-N N[C@H](Cc(cc1)ccc1-c1ccccc1)CO Chemical compound N[C@H](Cc(cc1)ccc1-c1ccccc1)CO RCAIWVIQRMDTAV-OAHLLOKOSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/73—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
-
- 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
- C07C269/04—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 from amines with formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
-
- 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
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/36—One oxygen atom
- C07D263/42—One oxygen atom attached in position 5
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
本発明は、薬学的に活性な化合物、例えば中性エンドペプチダーゼ(NEP)阻害剤の合成における重要な中間体である、N−Boc保護ビフェニルアラニノールを製造する方法に関する(例えば、米国特許第4722810号明細書および欧州特許第00590442号明細書参照)。
を有する、鏡像異性的に富化されたキラルホスホルアミダイト単座配位子であり、
上記式中、2個のO原子およびP原子と共にCnは、C原子2〜4個を有する置換または非置換環を形成し、R1およびR2はそれぞれ独立して、H、任意に置換されているアルキル、アリール、アラルキルまたはアルカリール基を表し、あるいは、それらが結合しているN原子と共に(複素環式)環を形成してもよく、Xは対イオンであり、Sは配位子であり、aは0.5〜3の範囲であり、bおよびcはそれぞれ独立して、0〜2の範囲である。好ましくはR1およびR2はそれぞれ独立して、アルキル基、例えばC原子1〜6個、特にC原子1〜3個を有するアルキル基を表し、最も好ましくはC1およびC2はメチル基を表す。アルキル、アリール、アラルキルおよびアルカリール基は好ましくは、C原子1〜20個を有し、例えば1つまたは複数のヒドロキシ、アルコキシ、ニトリルまたはカルボン酸エステル基、またはハロゲンで任意に置換されていてもよい。R1および/またはR2は、ポリマー主鎖の一部であり得る。
を製造する方法であって:
a)触媒活性、光学活性な金属錯体の存在下にて、式IIの化合物
(式中、R=H、直鎖状または分岐状アルキル、アリールアルキルまたはアリール基である)を不斉水素化して、式IIIの化合物
が得られる工程と、
b)続いて、化合物IIIを還元して、式IVの化合物
が得られる工程と、
c)続いて、化合物IVを水素化分解して、式Vの化合物
が得られる工程と、
d)化合物VのBoc保護を行い、式Iの化合物が得られる工程と、
e)任意に、式Iの化合物を単離する工程と、
を含む方法である。
この方法では、有利なことに、工程数が減少し、中間体Vの単離が省かれる。
[実施例1a]:化合物3の合成
CH2Cl2中のビス(1,5−シクロオクタジエン)ロジウム(I)テトラフルオロボレート(7.5mg;20μmol)および(S)−1−(ジナフト[2,1−d:1’,2’−f][1,3,2]ジオキサホスフェピン−4−イル)ピペリジン(S−PiPhos)(17.6mg;44μmol)から触媒を製造した。この溶液のうち500μlを、CH2Cl25ml中の化合物2 360mgの溶液に添加した。このようにして得られた混合物を、完全に転化されるまで(HPLCおよび1HNMRに基づく)水素化し(H225バール;25℃)、化合物3を定量的収率で得た(キラルHPLCで決定されたe.e.(光学純度)>99.5%,:Chiralpak IA−3;n−ヘプタン:エタノール85:15(体積比);30℃,1mL/分)。
触媒の製造:無水および酸素不含ジクロロメタン(5mL)に、Rh(NBD)2BF4(94.0mg;0.25mmol)を溶解した。この溶液に、(S)−1−(ジナフト[2,1−d:1’,2’−f[1,3,2]ジオキサホスフェピン−4−イル]ピペリジン(S−PiPhos)(201mg;0.50mmol)を数回に分けて添加した。その色がオレンジ色にゆっくりと変化した。1時間攪拌した後、無水および酸素不含n−ヘプタン(10mL)を添加することによって、触媒を沈殿させた。沈殿物を濾過除去し、無水および酸素不含n−ヘプタンで洗浄し、減圧下にて乾燥させて、触媒278mgが得られた。
乾燥した50ml丸底フラスコに、化合物3 1029mg(2.87mmol)および無水THF10mlを添加した。得られた溶液に、LiAIH4を数回に分けて添加した(合計290mg;7.63mmol)。続いて、反応混合物を加熱還流し、2時間攪拌した。20℃に冷却した後、THF/水(3:1)を添加して反応を停止した。得られた物質を水(2ml)およびTHF(10ml)で希釈した。沈殿した塩を濾過によって除去し、濾液を真空内で濃縮して、定量的収率で化合物4が得られた。
THF(5ml)中の化合物4 125mg、Pd/C(Escat 1961;BASF)50mgおよびBoc2O172mgを18時間水素化した(30℃,5バール)。濾過によって触媒を除去し、濾液を真空内で濃縮した。CHCl3で油状残留物を粉砕すると、化合物5が結晶化した(e.e.>99%)。
Claims (6)
- 式Iの化合物
(式中、Boc=ブトキシカルボニルである)
を製造する方法であって、
a)触媒活性、光学活性な金属錯体の存在下にて、式IIの化合物
(R=H、C1〜C12直鎖状または分岐状アルキル、C1〜C12アリールアルキルまたはC1〜C12アリールであり、前記アリール環が任意に、ヘテロ原子を含んでいてもよく、Rは任意に置換されていてもよく、Bz=ベンゾイルである)を不斉水素化して、式IIIの化合物
が得られる工程と、
b)続いて、化合物IIIを還元して、式IVの化合物
(式中、Bn=ベンジルである)
が得られる工程と、
c)続いて、化合物IVを水素化分解して、式Vの化合物
が得られる工程と、
d)続いて、化合物VのBoc保護を行い、式Iの化合物が得られる工程と、
e)任意に、式Iの化合物を単離する工程と、
を含み、
Boc2Oの存在下にて水素分解を行うことによって、工程c)および工程d)を合わせて、化合物Iを直接提供する、方法。 - 前記触媒活性、光学活性な金属錯体が、Rh(I)錯体および鏡像異性的に富化された光学活性ホスホルアミダイト単座配位子から形成される、請求項1に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11178182 | 2011-08-19 | ||
EP11178182.9 | 2011-08-19 | ||
PCT/EP2012/066038 WO2013026773A1 (en) | 2011-08-19 | 2012-08-16 | Synthesis of r-biphenylalaninol |
Related Child Applications (1)
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JP2017061069A Division JP2017132793A (ja) | 2011-08-19 | 2017-03-27 | R−ビフェニルアラニノールの合成 |
Publications (2)
Publication Number | Publication Date |
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JP2014525408A true JP2014525408A (ja) | 2014-09-29 |
JP6150179B2 JP6150179B2 (ja) | 2017-06-21 |
Family
ID=46704627
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JP2014525452A Expired - Fee Related JP6150179B2 (ja) | 2011-08-19 | 2012-08-16 | R−ビフェニルアラニノールの合成 |
JP2017061069A Pending JP2017132793A (ja) | 2011-08-19 | 2017-03-27 | R−ビフェニルアラニノールの合成 |
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JP2017061069A Pending JP2017132793A (ja) | 2011-08-19 | 2017-03-27 | R−ビフェニルアラニノールの合成 |
Country Status (6)
Country | Link |
---|---|
US (1) | US9139515B2 (ja) |
EP (1) | EP2744779A1 (ja) |
JP (2) | JP6150179B2 (ja) |
CN (2) | CN103764624B (ja) |
BR (1) | BR112014003878A2 (ja) |
WO (1) | WO2013026773A1 (ja) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
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AR092278A1 (es) * | 2012-08-31 | 2015-04-08 | Novartis Ag | Proceso de obtencion de derivados n-acilicos de bifenil-alanina e intermediarios relacionados |
WO2015024991A1 (en) * | 2013-08-21 | 2015-02-26 | Dpx Holdings B.V. | Synthesis of biphenylalaninol via novel intermediates |
WO2015037460A1 (ja) * | 2013-09-10 | 2015-03-19 | 住友化学株式会社 | 光学活性な3-(ビフェニル-4-イル)-2-[(t-ブトキシカルボニル)アミノ]プロパン-1-オールの製造方法 |
CN104926704B (zh) * | 2014-03-18 | 2019-03-05 | 浙江九洲药物科技有限公司 | 氮杂环丙烷类化合物及其制备方法 |
CN105017082B (zh) * | 2015-07-31 | 2017-09-19 | 上海皓元医药股份有限公司 | 一种心衰药Entresto 关键中间体(R)‑叔丁基 (1‑([1,1`‑联苯]‑4‑基)‑3‑羟基丙烷‑2‑基)氨基甲酸酯的制备方法 |
CN105085322B (zh) * | 2015-08-15 | 2017-10-03 | 浙江永宁药业股份有限公司 | Ahu‑377中间体的制备方法及其中间体和中间体的制备方法 |
CN106349087B (zh) * | 2015-09-02 | 2018-12-28 | 四川瑞希康生物医药有限公司 | (r)-2-氨基-3-(联苯基-4-基)-1-丙醇的合成 |
CN105330569A (zh) * | 2015-09-11 | 2016-02-17 | 天台宜生生化科技有限公司 | 一种(r)-2-(n-叔丁氧羰基氨基)联苯丙醇的制备方法 |
CN105198775B (zh) | 2015-10-10 | 2017-11-14 | 凯瑞斯德生化(苏州)有限公司 | 一种手性N‑Boc联苯丙氨醇的制备方法 |
CN105622460B (zh) * | 2016-01-08 | 2017-12-05 | 浙江大学 | (r)‑n‑叔丁氧羰基联苯丙氨醇的合成方法 |
WO2017141193A1 (en) * | 2016-02-16 | 2017-08-24 | Sun Pharmaceutical Industries Limited | Process for the preparation of sacubitril or salts thereof |
KR20170119447A (ko) | 2016-04-19 | 2017-10-27 | 주식회사 아미노로직스 | Dl-4,4'-바이페닐알라닌 알킬에스터로부터 d-4,4'-바이페닐알라닌 알킬에스터 또는 l-4,4'-바이페닐알라닌 알킬에스터를 제조하는 방법 |
US20190256454A1 (en) | 2016-07-05 | 2019-08-22 | Novartis Ag | New process for early sacubitril intermediates |
EP3500549B1 (en) | 2016-08-17 | 2020-12-16 | Novartis AG | New processes and intermediates for nep inhibitor synthesis |
US10774036B2 (en) | 2016-12-23 | 2020-09-15 | Novartis Ag | Process for early sacubitril intermediates |
CN106905192A (zh) * | 2017-03-09 | 2017-06-30 | 常州沃腾化工科技有限公司 | 一种沙库必曲中间体的纯化方法 |
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2012
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WO2013026773A1 (en) | 2013-02-28 |
JP2017132793A (ja) | 2017-08-03 |
CN106977418A (zh) | 2017-07-25 |
US9139515B2 (en) | 2015-09-22 |
JP6150179B2 (ja) | 2017-06-21 |
CN103764624B (zh) | 2017-07-28 |
US20140296559A1 (en) | 2014-10-02 |
EP2744779A1 (en) | 2014-06-25 |
CN103764624A (zh) | 2014-04-30 |
BR112014003878A2 (pt) | 2017-03-21 |
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