JP5259048B2 - デュロキセチン(duloxetine)を調製するための方法およびその中で使用するための中間体 - Google Patents
デュロキセチン(duloxetine)を調製するための方法およびその中で使用するための中間体 Download PDFInfo
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- JP5259048B2 JP5259048B2 JP2004561607A JP2004561607A JP5259048B2 JP 5259048 B2 JP5259048 B2 JP 5259048B2 JP 2004561607 A JP2004561607 A JP 2004561607A JP 2004561607 A JP2004561607 A JP 2004561607A JP 5259048 B2 JP5259048 B2 JP 5259048B2
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- duloxetine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
- C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
- Steroid Compounds (AREA)
Description
(i)ラセミの(±)デュロキセチンをキラル酸で分割して、実質的に(-)デュロキセチンを含まない前記キラル酸と(+)デュロキセチンの塩を得ることと;および、
(ii)必要に応じて、前記工程(i)で調製した塩を遊離塩基またはさらに酸付加塩に変換することと、
を含む方法が提供される。
(i)ラセミの(±)デュロキセチンをジ-p-トルイル酒石酸で分割して、実質的に(-)デュロキセチンを含まないジ-p-トルイル酒石酸(+)デュロキセチンを得ることと;および、
(ii)工程(i)で調製したジ-p-トルイル酒石酸(+)デュロキセチンを塩酸(+)デュロキセチンに変換することと、
を含む。
(i)ラセミの(±)デュロキセチンをキラル酸で分割して、(-)デュロキセチンの濃縮された母液を得ることと;
(ii)工程(i)から得た(-)デュロキセチンを(±)デュロキセチンに変換することと;および、
(iii)必要に応じて、実質的に先に記載したとおりの本発明に従った方法において、工程(ii)から得た(±)デュロキセチンを使用することと、
を含む。
(i)ラセミの(±)デュロキセチンをジ-p-トルイル酒石酸で分割することによって、工程(ii)で得た(±)デュロキセチンを (+)デュロキセチンに変換し、実質的に(-)デュロキセチンを含まないジ-p-トルイル酒石酸(+)デュロキセチンを得ることと、および、
(ii)前記(ジ-p-トルイル酒石酸+)デュロキセチンを塩酸(+)デュロキセチンに変換することとを含むことが特に好ましい。
N,N-ジメチル-γ-(1-ナフタレニルオキシ)-2-チオフェンプロパンアミンオキサレート
2-(1-N,N-ジメチル-3-ヒドロキシ)プロピルアミノ)-チオフェン(12.4gms)をDMSO(70m1)に溶解した。水酸化カリウム(18.7gms)およびテトラブチル臭化アンモニウムを添加した(O.1gms)。反応混合物を60℃で1時間撹拌し、4-フルオロナフタレン(11.7gms)を2時間かけてゆっくり添加した。反応が完了したあと、これを氷水でクエンチし、トルエン中に抽出した。トルエン層を乾燥し、減圧下で濃縮した。残渣を100mlの酢酸エチルに溶解し、シュウ酸(7gms)を添加した。反応混合物を1時間撹拌し、濾過した(15.5gms、76%収率)。
(±)-N-メチル-γ-(1-ナフタレニルオキシ)-2-チオフェンプロパンアミン((±)デュロキセチン)
N,N-ジメチル-γ-(1-ナフタレニルオキシ)-2-チオフェンプロパンアミン(50gms)をトルエン(250m1)に溶解した。反応混合物にジイソプロピルエチルアミン(24.5gms)を添加し、クロロギ酸フェニル(3Ogms)をゆっくり添加した。反応混合物を6O℃まで加熱し、2時間撹拌した。反応の完了後、混合物を50mlの5%の炭酸水素ナトリウム溶液中でクエンチした。トルエン層を分離し、乾燥し、濃縮して残渣を得た。
(+)-N-メチル-γ-(1-ナフタレニルオキシ)-2-チオフェンプロパンアミン((+)デュロキセチン)
(±)デュロキセチン(20gms)をメタノール(20m1)に溶解し、(-)ジ-p-トルイル酒石酸(6.5grns)を添加した。反応液を還流下で1時間撹拌し、真空下でメタノール濃縮し、アセトン(150m1)を充填し、5℃に冷却した。得られた固体を濾過し、4O℃で減圧下において乾燥させて、(+)デュロキセチンの(-)ジ-p-トルイル酒石酸塩を得た(12.5g)。
シュウ酸(S)-N,N-ジメチル-γ-(1-ナフタレニルオキシ)-2-チオフェンプロパンアミン
(S)-2-(1-N,N-ジメチル-3-ヒドロキシ)プロピルアミノ)-チオフェン(12.5gms)をDMSO(60ml)に溶解した。水酸化カリウム(20.5gms)および18-クラウン-6(0.l2gms)を添加した。反応混合物を60℃で1時間撹拌し、4-フルオロナフタレン(11.9gms)を2時間にわたってゆっくり添加した。反応が完了したあと、これを氷水中でクエンチし、トルエン中に抽出した。トルエン層を乾燥し、減圧下で濃縮した。残渣を100mlの酢酸エチルに溶解し、シュウ酸(7.5gms)を添加した。反応混合物を1時間撹拌し、濾過して88%の収率で標記化合物を得た。
塩酸(+)-N-メチル-γ-(1-ナフタレニルオキシ)-2-チオフェンプロパンアミン(塩酸(+)デュロキセチン)。
Claims (10)
- (+)デュロキセチンまたはこれらの酸付加塩を調製するための方法であって:
(i)ラセミの(±)デュロキセチンをジ-p-トルイル酒石酸で分割して、(-)デュロキセチンを含まない、ジ-p-トルイル酒石酸(+)デュロキセチンを得ること;および、
(ii)必要に応じて、前記工程(i)で調製した塩を遊離塩基またはさらなる酸付加塩に転換すること、
を含むことを特徴とする方法。 - 工程(ii)が、(i)で調製した塩を塩酸と反応させて塩酸(+)デュロキセチンを得ることを含む、請求項1記載の方法。
- 以下を含む方法:
(i)請求項1又は2記載の方法でラセミの(±)デュロキセチンをジ-p-トルイル酒石 酸で分割して、(-)デュロキセチンの濃縮された母液を得ること;
(ii)工程(i)から得た(-)デュロキセチンを(±)デュロキセチンに転換すること;および、
(iii)必要に応じて、請求項1又は2記載の方法で工程(ii)から得た(±)デュロキセチンを使用すること。 - (+)デュロキセチンまたはこれらの酸付加塩を作製する方法であって:
(i)水酸化アルカリ金属、炭酸アルカリ金属、及び重炭酸アルカリ金属から成る群より選択される塩基および相間移動触媒の存在下において、式(I)および(II)の中間化合物を反応させて、式(III)の中間化合物またはこれらの酸付加塩を得ること
(ii)式(III)の化合物または酸付加塩を脱メチル化して(±)デュロキセチンを得ること;および、
(iii)請求項1又は2記載の方法を使用して、工程(ii)で得た(±)デュロキセチンを(+)デュロキセチンまたはこれらの酸付加塩に対する転換すること、
を含む方法。 - 塩酸(+)デュロキセチンを作製する方法であって:
(i)水酸化アルカリ金属、炭酸アルカリ金属、及び重炭酸アルカリ金属から成る群より選択される塩基および相間移動触媒の存在下において、式(I)および(II)の中間化合物(式中、Xはヒドロキシであり、Yはフルオロである)を、続いてシュウ酸を反応させて、式(III)の中間化合物のシュウ酸塩を得ること;
(iii)ラセミの(±)デュロキセチンをジ-p-トルイル酒石酸で分割することによって、工程(ii)で得た(±)デュロキセチンを(+)デュロキセチンに転換し、(-)デュロキセチンを含まないジ-p-トルイル酒石酸(+)デュロキセチンを得て、前記ジ-p-トルイル酒石酸(+)デュロキセチンを塩酸(+)デュロキセチンに転換すること、
を含む方法。 - 前記塩基が、炭酸カリウム、炭酸ナトリウム、および炭酸水素ナトリウムからなる群より選択される、請求項4又は5に記載の方法。
- 前記相間移動触媒が、クラウンエーテル、第四級アンモニウム塩、およびホスホニウム塩からなる群より選択される、請求項4〜6のいずれか1項記載の方法。
- 前記脱離基がハロである、請求項4に記載の方法。
- 前記脱離基がフルオロである、請求項8に記載の方法。
- ジ-p-トルイル酒石酸(+)デュロキセチン。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0229583.0A GB0229583D0 (en) | 2002-12-19 | 2002-12-19 | A process for preparing duloxetine and intermediates for use therein |
GB0229583.0 | 2002-12-19 | ||
PCT/GB2003/005357 WO2004056795A1 (en) | 2002-12-19 | 2003-12-10 | A process for preparing duloxetine and intermediates for use therein |
Publications (3)
Publication Number | Publication Date |
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JP2006514030A JP2006514030A (ja) | 2006-04-27 |
JP2006514030A5 JP2006514030A5 (ja) | 2007-02-01 |
JP5259048B2 true JP5259048B2 (ja) | 2013-08-07 |
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JP2004561607A Expired - Fee Related JP5259048B2 (ja) | 2002-12-19 | 2003-12-10 | デュロキセチン(duloxetine)を調製するための方法およびその中で使用するための中間体 |
Country Status (24)
Country | Link |
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US (1) | US7645890B2 (ja) |
EP (2) | EP1587801B1 (ja) |
JP (1) | JP5259048B2 (ja) |
KR (1) | KR100926723B1 (ja) |
CN (2) | CN100579975C (ja) |
AT (1) | ATE353081T1 (ja) |
AU (2) | AU2003292396B2 (ja) |
BR (1) | BR0316902A (ja) |
CA (1) | CA2510750A1 (ja) |
DE (1) | DE60311599T2 (ja) |
ES (1) | ES2279971T3 (ja) |
GB (1) | GB0229583D0 (ja) |
HR (1) | HRP20050657A2 (ja) |
IL (1) | IL169232A (ja) |
IS (1) | IS7915A (ja) |
MA (1) | MA27706A1 (ja) |
MX (1) | MXPA05006659A (ja) |
NZ (2) | NZ569874A (ja) |
PL (1) | PL377380A1 (ja) |
PT (1) | PT1587801E (ja) |
RU (1) | RU2351594C2 (ja) |
TN (1) | TNSN05167A1 (ja) |
WO (1) | WO2004056795A1 (ja) |
ZA (1) | ZA200505656B (ja) |
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2002
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