JP2020509019A - 3,7−ビス(ジメチルアミノ)フェノチアジン−5−イリウムヨウ化物の製造方法 - Google Patents
3,7−ビス(ジメチルアミノ)フェノチアジン−5−イリウムヨウ化物の製造方法 Download PDFInfo
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- JP2020509019A JP2020509019A JP2019547078A JP2019547078A JP2020509019A JP 2020509019 A JP2020509019 A JP 2020509019A JP 2019547078 A JP2019547078 A JP 2019547078A JP 2019547078 A JP2019547078 A JP 2019547078A JP 2020509019 A JP2020509019 A JP 2020509019A
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- phenothiazine
- bis
- dimethylamino
- ylium
- reaction medium
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- 229910052753 mercury Inorganic materials 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- OYEVFSJZQTUDDN-UHFFFAOYSA-N methanol;n-methylmethanamine Chemical compound OC.CNC OYEVFSJZQTUDDN-UHFFFAOYSA-N 0.000 description 1
- GSJRUEBQWPLHSN-UHFFFAOYSA-N n-methylmethanamine;oxolane Chemical compound CNC.C1CCOC1 GSJRUEBQWPLHSN-UHFFFAOYSA-N 0.000 description 1
- 239000007783 nanoporous material Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- LTOOVISGEYEBFR-UHFFFAOYSA-N phenothiazin-5-ium Chemical class C1=CC=CC2=NC3=CC=CC=C3[S+]=C21 LTOOVISGEYEBFR-UHFFFAOYSA-N 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000008363 phosphate buffer Chemical class 0.000 description 1
- 230000000886 photobiology Effects 0.000 description 1
- 229920000642 polymer Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000002824 redox indicator Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
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- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
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- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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Abstract
Description
a)フェノチアジンをヨウ素分子で処理する工程、
b)工程a)から直接的に得られる反応媒体をジメチルアミンで処理する工程、
を含む、方法に関する。
i)先に記載され、以下で詳細に記載される方法により3,7−ビス(ジメチルアミノ)フェノチアジン−5−イリウムヨウ化物を製造することと、
ii)上記3,7−ビス(ジメチルアミノ)フェノチアジン−5−イリウムヨウ化物を、3,7−ビス(ジメチルアミノ)フェノチアジン−5−イリウム塩化物へと変換することと、
を含む、方法に関する。
a)フェノチアジンをヨウ素分子で処理することと、
b)工程a)から直接的に得られる反応媒体をジアルキルアミンで処理することと、
を含む。
この製造方法は、3,7−ビス(ジメチルアミノ)フェノチアジン−5−イリウムヨウ化物を高純度で得ることを可能にする一方で、同時に実施が非常に簡単であり、かつ高収率がもたらされる。
出発物は、市販製品であるフェノチアジンである。
本発明によれば、工程a)及び工程b)は、溶剤又は溶剤の混合物中で実施される。
30℃〜90℃の範囲の温度で15分間〜6時間の期間にわたり、
好ましくは30℃〜90℃の範囲の温度で30分間〜4時間の期間にわたり、
有利には40℃〜80℃の温度で1時間〜3時間の期間にわたり、
実施される。
有利には溶剤中の溶液の形で導入されるジメチルアミンNH(CH3)2は、工程a)の後に反応媒体に添加される。
I−材料及び方法:
1)出発材料及び機器
ヨウ素分子は、TCI社から購入した。
ACROS ORGANICS社から、40重量%のジメチルアミン水溶液(Dimethylamine 40%wt solution in water)という商品名として、
ACROS ORGANICS社から、2MのジメチルアミンTHF溶液(Dimethylamine 2M solution in THF)という商品名として、
TCI社から、2MのジメチルアミンMeOH溶液(Dimethylamine, 2M solution in MeOH)という商品名として、
購入した。
HPLC/MS
方法:2015年に発行された欧州薬局方8.6
装置:HPLC Agilent 1260+MS Agilent 6120
カラム:Waters XBridge Phenyl 100×4.6−3.5μm
検出:246nm
試料濃度:1000ppm
試料溶解溶剤:水性TFA0.1%/ACN(70/30)
溶出溶剤:アセトニトリル/水中0.1%(容量/容量)のトリフルオロ酢酸
MSのためのイオン化源:エレクトロスプレー(ESI)
MSのための分析装置:単純な四重極
MSのための検出器:電子倍増管
データ処理のためのコンピュータシステム:Agilent Chemstation Open Lab
実施例1(比較):3,7−ビス(ジメチルアミノ)フェノチアジン−5−イリウムヨウ化物の2工程合成(Anita Gollmer, et al., Photochem. Photobiol. Sci.; 2014; DOI: 10.1039/C4PP00309H; p.1-47による):
1)フェノチアジン−5−イリウム四ヨウ化物の合成(1294−X15)
10gのフェノチアジン(50mmol、1.0当量)及び200mlのジクロロメタンを、500ml容の三ツ口フラスコ中に導入する。該混合物を周囲温度で撹拌する。
4.5gのフェノチアジン過ヨウ化物(7.1mmol、1.0当量)を、500ml容の三ツ口フラスコ中に導入し、メタノール(180ml)及びジクロロメタン(22.5ml)の混合物中に撹拌しながら周囲温度で溶解させる。
88gのヨウ素分子(346.2mmol、3.0当量)及び1.15lのトルエンを、2l容の三ツ口フラスコ中で混合する。23gのフェノチアジン(115.4mmol、1.0当量)を、撹拌しながら周囲温度で添加する。
5gのフェノチアジン(25.1mmol、1.0当量)及び100mlのアセトニトリルを、250ml容の三ツ口フラスコへと添加する。反応媒体を40℃に加熱する。
該方法は、実施例3と同様に行われるが、以下の違いがある:反応媒体を10℃と15℃との間に維持しながらジメチルアミンを導入する。
該方法は、実施例3と同様に行われるが、以下の違いがある:反応媒体を35℃と40℃との間に維持しながらジメチルアミンを導入する。
該方法は、実施例3と同様に行われるが、以下の違いがある:反応媒体を60℃と70℃との間に維持しながらジメチルアミンを導入する。
5gのフェノチアジン(25.1mmol、1.0当量)及び100mlのアセトニトリルを、500ml容の三ツ口フラスコ中に導入する。反応媒体を40℃に加熱する。
5gのフェノチアジン(25.1mmol、1.0当量)及び100mlのアセトニトリルを、500ml容の三ツ口フラスコ中に導入する。反応媒体を40℃に加熱する。
100gのフェノチアジン(502mmol、1.0当量)、394.8gのヨウ素分子(1555mmol、3.1当量)、及び2lのアセトニトリルを、6リットル容の反応器中に導入する。
実施例9で調製された30gの3,7−ビス(ジメチルアミノ)フェノチアジン−5−イリウムヨウ化物(72.9mmol、1.0当量)を、2l容の三ツ口フラスコ中の600mlの水へと導入する。その混合物を、N2流下で完全な溶解が得られるまで撹拌し、次いで12℃に冷却する。44.8gの85%のヒドロ亜硫酸ナトリウム(218.7mmol、3.0当量)を、次いでその溶液に撹拌しながら5分間をかけて添加する。
脱ベンゾイル化:
500ml容の三ツ口フラスコ中で、実施例10において得られた5gの3,7−ビス(ジメチルアミノ)−10−ベンゾイルフェノチアジン(12.8mmol、1.0当量)を、200mlのアセトニトリルへと導入する。反応媒体を、−20℃に冷却する。2.97gの2,3−ジクロロ−5,6−ジシアノ−1,4−ベンゾキノン(DDQ)のアセトニトリル溶液(13.1mmol、1.02当量)13.4mlを調製し、−20℃に調節する。
得られた固体を、40mlのEA中に取る。その混合物を−20℃に冷却し、39mlの酢酸エチル/HCl(4.3M)(165.12mmol、12.9当量)を素早く添加する。反応媒体を、−20℃で3時間にわたり撹拌したままにする。得られた沈殿物を、フリット(ポア3)上で濾別する。得られた固体を、75mlの酢酸エチル中に取る。その混合物を−20℃で30分間にわたり撹拌し、次いでフリット(ポア3)上で濾過する。
pHの測定を、20mlの水中の100mgの沈殿物で実施し、次いでpHを200μLの0.2MのNaOHで3.8に調整する。得られた生成物を、50mlのアセトン中に取り、次いで−15℃に冷却する。容量を事前に測定した2.3mlの2MのNaOHを添加し、次いで得られた混合物を−15℃で2時間にわたり撹拌する。得られた沈殿物を、フリット(ポア3)上で濾別する。その固体を、20mlのアセトン中に取る。その媒体を−15℃で30分間にわたり撹拌し、フリット(ポア3)上で濾過し、次いでpHの測定を、上記と同じ条件下で実施する。沈殿物を、通風オーブンにて40℃で一晩乾燥させる。
100ml容の三ツ口フラスコ中で、2.67gの塩化されたメチレンブルーを、43mlのDCM/EtOH混合物(50/50)へと導入する。その媒体を、撹拌しながら43℃に加熱し、次いでフリット(ポア3)上で熱時濾過する。1.33mlの水を、濾液に添加し、次いでジクロロメタンを真空下で蒸発除去する。75mlの酢酸エチルをその媒体に添加し、−20℃に冷却し、次いで一晩撹拌したままにする。得られた沈殿物を、フリット(ポア3)上で濾別し、次いで40mlのTHF/EA溶液(75/25)中に再スラリー化させる。濾過し、オーブンにて40℃で2日間にわたり乾燥させた後に、1.45gのメチレンブルーが得られる。
Claims (11)
- 3,7−ビス(ジメチルアミノ)フェノチアジン−5−イリウムヨウ化物の製造方法であって、出発物としてフェノチアジンを使用し、以下の工程:
a)フェノチアジンをヨウ素分子で処理する工程と、
b)工程a)から直接的に得られる反応媒体をジメチルアミンで処理する工程と、
を含む、方法。 - 前記ヨウ素分子での処理を、フェノチアジンを基準にして2.5モル当量〜3.5モル当量の範囲のヨウ素分子の量で実施する、請求項1に記載の方法。
- 工程b)の前に、工程a)から得られる反応媒体を、5℃〜50℃、好ましくは10℃〜45℃、なおも更に良好には20℃〜35℃の範囲の温度に調節する、請求項1又は2に記載の方法。
- 前記ジメチルアミンでの処理を、フェノチアジンを基準にして少なくとも7モル当量のジメチルアミンを用いて実施する、請求項1〜3のいずれか一項に記載の方法。
- 工程a)において、前記溶剤は、芳香族溶剤若しくはアセトニトリル、又はそれらの混合物、好ましくはトルエン若しくはアセトニトリル、又はそれらの混合物から選択される、請求項1〜4のいずれか一項に記載の方法。
- 工程b)において、前記ジメチルアミンは、水溶液の形で前記反応媒体へと導入される、請求項1〜5のいずれか一項に記載の方法。
- 工程b)の処理の後に沈殿物が形成し、該沈殿物を、濾過により回収する、請求項1〜6のいずれか一項に記載の方法。
- 3,7−ビス(ジアルキルアミノ)フェノチアジン−5−イリウムヨウ化物を含む組成物の製造のための、請求項1〜7のいずれか一項に記載の方法の使用であって、前記3,7−ビス(ジアルキルアミノ)フェノチアジン−5−イリウムヨウ化物は、前記組成物の少なくとも95%(その%は、HPLCにより246nmでの検出により測定される)に相当する、使用。
- 3,7−ビス(ジメチルアミノ)フェノチアジン−5−イリウム塩化物の製造方法であって、
a)請求項1〜7のいずれか一項に記載の方法により3,7−ビス(ジメチルアミノ)フェノチアジン−5−イリウムヨウ化物を製造すること、
b)前記3,7−ビス(ジメチルアミノ)フェノチアジン−5−イリウムヨウ化物を、3,7−ビス(ジメチルアミノ)フェノチアジン−5−イリウム塩化物へと変換すること、
を含む、方法。 - 3,7−ビス(ジメチルアミノ)フェノチアジン−5−イリウム塩化物を含む医薬の製造方法であって、請求項9に記載の方法により3,7−ビス(ジメチルアミノ)フェノチアジン−5−イリウム塩化物を製造することと、それを薬学的に許容可能な媒体へと導入することとを含む、方法。
- タウオパチー、タウタンパク質凝集疾患、ピック病、進行性核上性麻痺(PSP)、前頭側頭型認知症(FTD)、FTD及び17番染色体に関連するパーキンソニズム(FTDP−17)、脱抑制−認知症−パーキンソニズム−筋萎縮複合(DDPAC)、淡蒼球橋黒質変性症(PPND)、グアム−ALS症候群、淡蒼球黒質ルイ体変性症(PNLD)、大脳皮質基底核変性症(CBD)、軽度認知障害(MCI)、皮膚癌、黒色腫、メトヘモグロビン血症、ウイルス感染、細菌感染、原虫感染、寄生虫感染、マラリア、内臓リーシュマニア症、アフリカ睡眠病、トキソプラズマ症、ジアルジア症、シャーガス病、C型肝炎ウイルス(HCV)感染、ヒト免疫不全ウイルス(HIV)感染、西ナイルウイルス(WNV)感染、シヌクレイノパチー、パーキンソン病(PD)、レビー小体型認知症(DLB)、多系統萎縮症(MSA)、薬剤性パーキンソニズム、純粋自律神経不全症(PAF)、敗血症性ショック、過度の血行動態反応、乳癌、躁鬱病、アルツハイマー病(AD)から選択される病的状態の予防又は治療、より一般的には中枢神経系の変性疾患の治療を目的とする医薬の製造のための、請求項10に記載の方法。
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US11078169B2 (en) | 2021-08-03 |
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