JP6640297B2 - Jak阻害剤の製造方法及びその中間体 - Google Patents
Jak阻害剤の製造方法及びその中間体 Download PDFInfo
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- JP6640297B2 JP6640297B2 JP2018164563A JP2018164563A JP6640297B2 JP 6640297 B2 JP6640297 B2 JP 6640297B2 JP 2018164563 A JP2018164563 A JP 2018164563A JP 2018164563 A JP2018164563 A JP 2018164563A JP 6640297 B2 JP6640297 B2 JP 6640297B2
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- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000004489 tear production Effects 0.000 description 1
- VMKIXWAFFVLJCK-UHFFFAOYSA-N tert-butyl 3-oxoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=O)C1 VMKIXWAFFVLJCK-UHFFFAOYSA-N 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000009772 tissue formation Effects 0.000 description 1
- JMXKSZRRTHPKDL-UHFFFAOYSA-N titanium ethoxide Chemical compound [Ti+4].CC[O-].CC[O-].CC[O-].CC[O-] JMXKSZRRTHPKDL-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 108091006106 transcriptional activators Proteins 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/26—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24
- B01J31/28—Catalysts comprising hydrides, coordination complexes or organic compounds containing in addition, inorganic metal compounds not provided for in groups B01J31/02 - B01J31/24 of the platinum group metals, iron group metals or copper
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
Description
式中、
ZはH又は保護基であり;
P1は保護基であり;
X1はハロであり;及び
R1及びR2はそれぞれ独立してH又はC1−6アルキルであり;又は
R1及びR2はそれらが結合する2個の酸素原子及び当該酸素原子が結合しているホウ素原子と共に1、2、3又は4個のC1−4アルキル基で置換されていてもよい5から6員のヘテロシクロアルキル環である
を生成することを含む式IIの化合物の合成方法を提供する。
鈴木カップリング条件は式IIIaの化合物、式IVaの化合物、[1,1’−ビス(ジシクロヘキシルホスフィノ)フェロセン]ジクロロパラジウム(II)、フッ化セシウム並びに水及びtert−ブタノールを含む溶媒成分を含む反応混合物を加熱する工程を含む。
また、本発明は式Vの化合物又はその塩と式VI
式中、
R1及びR2はそれぞれ独立してH又はC1−6アルキルであり;又は
R1及びR2はそれらが結合する2個の酸素原子及び当該酸素原子が結合しているホウ素原子と共に1、2、3又は4個のC1−4アルキル基で置換されていてもよい5から6員のヘテロシクロアルキル環である
又はその塩を提供する。
式中、
R1及びR2はそれぞれ独立してH又はC1−6アルキルであり;又は
R1及びR2はそれらが結合する2個の酸素原子及び当該酸素原子が結合しているホウ素原子と共に1、2、3又は4個のC1−4アルキル基で置換されていてもよい5から6員のヘテロシクロアルキル環である
をカップリング剤の存在下で反応させ、式VIIの化合物を生成する工程を含む式VIIの化合物の合成方法を提供する。
なお、鈴木カップリング条件は式VII又はVIIaの化合物、式IVaの化合物、鈴木カップリング触媒、塩基及び溶媒成分からなる反応混合物を加熱する工程を含む。
本発明は更に式VIII
式中、R1及びR2はそれぞれ独立してH又はC1−6アルキルであり;又は
R1及びR2はそれらが結合する2個の酸素原子及び当該酸素原子が結合しているホウ素原子と共に1、2、3又は4個のC1−4アルキル基で置換されていてもよい5から6員のヘテロシクロアルキル環である
をカップリング剤の存在下で反応させ、式IIIの化合物又はその塩を生成する工程を含む式IIIの化合物の合成方法を提供する。
本発明はとりわけ式Iの化合物を合成するための方法及び中間体を提供する。その結果、一態様において本発明は式III
式中、
ZはH又は保護基であり;
P1は保護基であり;
X1はハロであり;及び
R1及びR2はそれぞれ独立してH又はC1−6アルキル;又は
R1及びR2はそれらが結合している2個の酸素原子及び当該酸素原子が結合しているホウ素原子と共に1、2、3又は4個のC1−4アルキル基で置換されていてもよい5から6員のヘテロシクロアルキル環である
の合成方法を提供する。
一部の実施形態において、パラジウム触媒添加量は約1×10−4から約0.1当量である。一部の実施形態において、パラジウム触媒添加量は約0.0010から約0.0015当量である。
なお、鈴木カップリング条件は式IIIaの化合物、式IVaの化合物、[1,1’−ビス(ジシクロヘキシルホスフィノ)フェロセン]ジクロロパラジウム(II)、フッ化セシウム並びに水及びtert−ブタノールを含む溶媒成分を含む反応混合物を加熱する工程を含む。
式中、
R1及びR2はそれぞれ独立してH又はC1−6アルキルであり;又は
R1及びR2はそれらが結合する2個の酸素原子及び当該酸素原子が結合しているホウ素原子と共に1、2、3又は4個のC1−4アルキル基で置換されていてもよい5から6員のヘテロシクロアルキル環である
又はその塩を提供する。
式中、
R1及びR2はそれぞれ独立してH又はC1−6アルキルであり;又は
R1及びR2はそれらが結合する2個の酸素原子及び当該酸素原子が結合しているホウ素原子と共に1、2、3又は4個のC1−4アルキル基で置換されていてもよい5から6員のヘテロシクロアルキル環である
と反応させ式VIIの化合物を生成する工程を含む式VIIの化合物の合成方法を提供する
なお、鈴木カップリング条件は式VIIaの化合物、式IVaの化合物、鈴木カップリング触媒、塩基及び第2溶媒成分を含む反応混合物を加熱する工程を含む。
なお、鈴木カップリング条件は式VIIaの化合物、式IVaの化合物、テトラキス(トリフェニルホスフィン)パラジウム(0)、炭酸水素ナトリウム並びに水及び1,4−ジオキサンを含む第2溶媒成分からなる反応混合物を加熱する工程を含む。
R1及びR2はそれぞれ独立してH又はC1−6アルキルであり;又は
R1及びR2はそれらが結合する2個の酸素原子及び当該酸素原子が結合しているホウ素原子と共に1、2、3又は4個のC1−4アルキル基で置換されていてもよい5から6員のヘテロシクロアルキル環である
の化合物又はその塩を特徴とする。
式中、
R1及びR2はそれぞれ独立してH又はC1−6アルキルであり;又は
R1及びR2はそれらが結合する2個の酸素原子及び当該酸素原子が結合しているホウ素原子と共に1、2、3又は4個のC1−4アルキル基で置換されていてもよい5から6員のヘテロシクロアルキル環である
をカップリング剤の存在下で反応させ式IIIの化合物を生成する工程を含む式IIIの化合物の合成方法を特徴とする。
式Iの化合物、{1−{1−[3−フルオロ−2−(トリフルオロメチル)イソニコチノイル]ピペラジン−4−イル}−3−[4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル]アゼチジン−3−イル}アセトニトリルはJAK(例えば、JAK1、JAK2)の阻害剤である。JAK阻害剤はJAKが関連する様々な疾患や障害の治療に有効である。JAKが関連する疾患の例として、例えば臓器移植拒否反応(例えば、同種移植片拒絶及び移植片対宿主拒絶反応)を含む免疫系が関与する疾患が含まれる。JAK関連疾患の更なる例として、多発性硬化症、リウマチ性関節炎、若年性関節炎、乾癬性関節炎、I型糖尿病、紅斑性狼瘡、乾癬、炎症性腸疾患、潰瘍性結腸炎、クローン病、重症筋無力症、免疫グロブリン腎症、心筋炎、自己免疫性甲状腺疾患、慢性閉塞性肺疾患(COPD)等の自己免疫疾患が含まれる。一部の実施形態において、自己免疫疾患は尋常性天疱瘡(PV)又は水疱性類天疱瘡(BP)等の自己免疫水疱性皮膚症である。
式Iの化合物のJAKターゲットの阻害活性をPark et al.,Analytical Biochemistry 1999,269,94−104に記載の以下のin vitroアッセイにより評価した。N末端にHisタグを付したヒトJAK1の活性領域(a.a.837−1142)及びJAK2の活性領域(a.a.828−1132)を昆虫細胞でバキュロウイルスにより発現させ、精製した。JAK1及びJAK2の触媒活性はビオチン化ペプチドのリン酸化を測定し、アッセイ行った。リン酸化ペプチドは均一時間分解蛍光法(HTRF)により検出した。化合物のIC50を各キナーゼについて、100mM NaCl、5mM DTT及び0.1mg/mL(0.01%)BSAを含む50mMトリス(pH7.8)バッファー中に酵素、ATP並びに500nMペプチドを含む40microLの反応で測定した。1mMのIC50測定の際、反応中のATP濃度は1mMであった。反応は室温で1時間行い、20μLの45mM EDTA、300nM SA−APC、6nM Eu−Py20を含むアッセイバッファー(Perkin Elmer、Boston、MA)により反応を停止した。ユーロピウム標識した抗体への結合を40分間行い、HTRFシグナルをフュージョンプレートリーダー(Perkin Elmer、Boston、MA)で測定した。式Iの化合物及びアジピン酸塩のJAK1に対するIC50は≦5nM(1mM ATPで測定)で、JAK2/JAK1比は>10(1mM ATPで測定)であった。
癌細胞株はサイトカイン依存性であるのでJAK/STATシグナル伝達が増殖に必要で、10%FBS及び1nG/mLの適切なサイトカインを含むRPMI1640培地中、6000細胞/ウェル(96穴プレートフォーマット)を蒔いた。化合物はDMSO/培地(終濃度0.2%DMSO)中の細胞に添加し、37℃、5%CO2で72時間インキュベートした。細胞生存率に対する化合物の影響をCellTiter−Glo Luminescent Cell Viability Assay(Promega)とそれに続くTopCount(Perkin Elmer、Boston、MA)定量により評価した。化合物の潜在的なオフターゲット効果を非JAK由来細胞株を使って同様のアッセイ出力にて同時に測定した。全ての実験は通常2つ組で行った。
本明細書記載の化合物は免疫低下マウスにヒト腫瘍を異種移植したモデルで評価可能である。例えば、INA−6形質細胞腫細胞株の発癌性変異体はSCIDマウスへ皮下移植するために使用できる(Burger,R.,et al. Hematol J.2:42−53,2001)。そして、腫瘍のある動物を薬剤又は溶剤投与群に無作為に別け、異なる用量の化合物を経口、腹腔内又は埋め込みポンプを用いた持続注入を含む任意の一般的な経路により投与する。腫瘍の成長はキャリパーを用いて経時的に観察した。更に、JAK活性及び下流のシグナリング経路に対する化合物の影響を評価する上記(実施例B)の解析のため、腫瘍サンプルは治療開始後何れのタイミングで採取してもよい。また、化合物の選択性はK562腫瘍モデル等の他の既知のキナーゼ(例えば、Bcr−Abl)由来の異種移植腫瘍モデルを使って評価できる。
本明細書記載の化合物のJAKターゲット阻害効果はT細胞由来のマウス遅延型過敏テストモデルを用いて評価可能である。マウス皮膚接触性遅延型過敏(DTH)反応は臨床接触性皮膚炎及び乾癬等の他のT細胞介在性の皮膚免疫疾患の有効なモデルと見なされる(Immunol Today.1998Jan;19(1):37−44)。マウスDTHは、免疫浸潤、炎症性サイトカインの増加を伴い、ケラチノサイトの過増殖など乾癬と多くの共通点がある。更に、臨床において乾癬の治療に有効である様々な種類の薬剤はマウスのDTH反応にも効果的な阻害剤である(Agents Actions.1993Jan;38(1−2):116−21)。
本明細書記載の化合物は、単一又は複合炎症応答を模したげっ歯類又は非げっ歯類モデルで評価可能である。例えば、関節炎のげっ歯類モデルは予防的又は治療的に投与された化合物の治療効果の評価に使用可能である。これらのモデルにはマウス又はラットのコラーゲン誘導型関節炎、ラットの補助剤誘導型関節炎及びコラーゲン抗体誘導関節炎等が含まれるがこれらに限定されない。多発性硬化症、I型糖尿病、網膜ぶどう膜炎、甲状腺炎、重症筋無力症、免疫グロブリン腎症、心筋炎、気道感作(喘息)、狼瘡又は大腸炎を含む自己免疫疾患も本明細書記載の化合物の治療効果の評価対象になり得る。当研究分野でこれらのモデルは確立されており、当業者に周知である(Current Protocols in Immunology,Vol3.,Coligan,J.E.et al,Wiley Press.;Methods in Molecular Biology:Vol.225,Inflammation Protocols.,Winyard,P.G.and Willoughby,D.A.,Humana Press,2003.)。
薬剤は、ウサギコンカナバリンA(ConA)涙腺モデル、スコポラミンマウスモデル(皮下又は経皮)、ボツリヌスマウス涙腺モデル又は目の分泌腺異常を引き起こす全ての自然発症のげっ歯類自己免疫疾患モデル(例えば、NOD−SCID、MRL/lpr又はNZB/NZW)を含むがこれらに限定されない、当業者に周知の1つ又は複数のドライアイ前臨床モデルにて評価可能である(Barabino et al.,Experimental Eye Research 2004,79,613−621及びSchrader et al.,Developmental Opthalmology,Karger2008,41,298−312,何れも参照することでその全てが本願に組み込まれる)。これらのモデルに対する評価項目には目の分泌腺及び目(角膜等)の組織病理学並びに場合により涙の生成を測定する典型又は改良型シルマー試験(Barabino et al.)が含まれる。活性測定は複数の投与経路(例えば、全身若しくは局所)を介して、測定可能な疾患が発症する以前又は以後に投与してもよい。
化合物は当業者に周知のオステオペニア、骨粗鬆症又は骨吸収の様々な前臨床モデルで評価可能である。例えば、卵巣を摘出したげっ歯類は骨のリモデリング及び/又は密度の兆候並びにマーカーに対する化合物の影響を評価するために利用できる(W.S.S.Jee and W. Yao,J Musculoskel.Nueron.Interact.,2001,1(3),193−207、その全ては参照することによって本願に組み込まれる)。逆に、骨の密度及び構造は対照群と化合物処理群の治療(例えば、グルココルチコイド)誘発型オステオペニアのげっ歯類モデルで評価可能である(Yao,et al.Arthritis and Rheumatism,2008,58(6),3485−3497;and id.58(11),1674−1686、何れもその全ては参照することで本願に組み込まれる)。更に、骨吸収及び密度に対する化合物の効果は上記関節炎のげっ歯類モデル(実施例E)にて評価可能である。これら全てのモデルの評価項目は多岐にわたるが、一般的には組織学的又は放射線評価に加え、免疫組織学的及び骨リモデリングの適切な生化学マーカーを含む。
[発明1]
鈴木カップリング条件下で式III
(式中、ZはH又は保護基であり;
P1は保護基であり;
X1はハロであり;
R1及びR2はそれぞれ独立してH又はC1−6アルキル;又は
R1及びR2はそれらが結合している2個の酸素原子及び当該酸素原子が結合しているホウ素原子と共に、1、2、3又は4個のC1−4アルキル基で置換されていてもよい5から6員のヘテロシクロアルキル環である)
を生成させる方法。
[発明2]
P1がベンシルオキシカルボニル(Cbz)、2,2,2−トリクロロエトキシカルボニル(Troc)、2−(トリメチルシリル)エトキシカルボニル(Teoc)、2−(4−トリフルオロメチルフェニルスルホニル)エトキシカルボニル(Tsc)、t−ブトキシカルボニル(BOC)、1−アダマンチルオキシカルボニル(Adoc)、2−アダマンチルカルボニル(2−Adoc)、2,4−ジメチルペンタ−3−イルオキシカルボニル(Doc)、シクロヘキシルオキシカルボニル(Hoc)、1,1−ジメチル−2,2,2−トリクロロエトキシカルボニル(TcBOC)、ビニル、2−クロロエチル、2−フェニルスルホニルエチル、アリル、ベンジル、2−ニトロベンジル、4−ニトロベンジル、ジフェニル−4−ピリジルメチル、N’,N’−ジメチルヒドラジニル、メトキシメチル、t−ブトキシメチル(Bum)、ベンジルオキシメチル(BOM)、2−テトラヒドロピラニル(THP)、1,1−ジエトキシメチル、(トリメチルシリル)エトキシメチル(SEM)、N−ピバロイルオキシメチル(POM)又はtert−ブトキシカルボニルである、発明1に記載の方法。
[発明3]
P1がtert−ブトキシカルボニルである、発明1に記載の方法。
[発明4]
[発明5]
式IIIの化合物が式IIIa
[発明6]
X1がクロロである、発明1ないし4の何れか1つに記載の方法。
[発明7]
ZがHである、発明1ないし4の何れか1つに記載の方法。
[発明8]
式IVの化合物が式IVa
[発明9]
鈴木カップリング条件が式IIIの化合物、式IVの化合物、鈴木カップリング触媒、塩基及び溶媒成分を含む反応混合物を加熱する工程を含む、発明1ないし8の何れか1つに記載の方法。
[発明10]
鈴木カップリング触媒がPd(dppf)2Cl2、[1,1’−ビス(ジシクロヘキシルホスフィノ)フェロセン]ジクロロパラジウム(II)、テトラキス(トリフェニルホスフィン)パラジウム(0)又はテトラキス(トリ(o−トリル)ホスフィン)パラジウム(0)である、発明9に記載の方法。
[発明11]
鈴木カップリング触媒が[1,1’−ビス(ジシクロヘキシルホスフィノ)フェロセン]ジクロロパラジウム(II)である、発明9に記載の方法。
[発明12]
塩基が炭酸ナトリウム、炭酸カリウム又はフッ化セシウムである、発明9ないし11の何れか1つに記載の方法。
[発明13]
塩基がフッ化セシウムである、発明9ないし11の何れか1つに記載の方法。
[発明14]
式IVの化合物に対してフッ化セシウムが3当量以上存在している、発明13に記載の方法。
[発明15]
溶媒成分がtert−ブタノール及び水を含む、発明9ないし14の何れか1つに記載の方法。
[発明16]
式III及びIVの化合物が約1:1のモル比で存在している、発明1ないし15の何れか1つに記載の方法。
[発明17]
式IIの化合物を脱保護し、式Vの化合物又はその塩を生成することを更に含む、発明1ないし16の何れか1つに記載の方法。
脱保護が第2溶媒成分中で式IIの化合物を塩酸と反応させることを含む、発明17に記載の方法。
[発明19]
式IIの化合物に対して塩酸が5から8当量存在している、発明18に記載の方法。
[発明20]
式IIIa
鈴木カップリング条件は式IIIaの化合物、式IVaの化合物、[1,1’−ビス(ジシクロヘキシルホスフィノ)フェロセン]ジクロロパラジウム(II)、フッ化セシウム並びに水及びtert−ブタノールを含む溶媒成分を含む反応混合物を加熱する工程を含む、発明1ないし16のいずれか1つに記載の方法。
[発明21]
式IIaの化合物を脱保護し、式V
脱保護は式IIaの化合物と塩酸を第2溶媒成分中で反応させる工程を含む、発明20に記載の方法。
[発明22]
式Vの化合物又はその塩と式VI
[発明23]
式Vの化合物又はその塩が2−(3−(4−(7H−ピロロ[2,3−d]ピリミジン−4−イル)−1H−ピラゾール−1−イル)アゼチジン−3−イル)アセトニトリル二塩酸塩である、発明22に記載の方法。
[発明24]
前記反応が2当量以上の第2塩基の存在下で行われる、発明22又は23に記載の方法。
[発明25]
第2塩基が第3級アミンである、発明24に記載の方法。
[発明26]
第2塩基がトリエチルアミンである、発明24に記載の方法。
[発明27]
還元剤が水素化シアノホウ素ナトリウム又はトリアセトキシ水素化ホウ素ナトリウムである、発明22ないし26の何れか1つに記載の方法。
[発明28]
還元剤がトリアセトキシ水素化ホウ素ナトリウムである、発明22ないし26の何れか1つに記載の方法。
[発明29]
式Vの化合物又はその塩に対して1当量を超えるトリアセトキシ水素化ホウ素ナトリウムを使用する、発明28に記載の方法。
[発明30]
式Vの化合物又はその塩に対して1当量を超える式VIの化合物を使用する、発明22ないし29の何れか1つに記載の方法。
[発明31]
反応をジクロロメタン溶媒中で行う、発明22ないし30の何れか1つに記載の方法。
[発明32]
式Iの化合物をアジピン酸と反応させ式Iの化合物のアジピン酸塩を生成する反応を更に含む、発明22ないし31の何れか1つに記載の方法。
[発明33]
式VII
R1及びR2はそれらが結合する2個の酸素原子及び当該酸素原子が結合しているホウ素原子と共に、1、2、3又は4個のC1−4アルキル基で置換されていてもよい5から6員のヘテロシクロアルキル環である)
の化合物又はその塩。
[発明34]
式VIIa
[発明35]
カップリング剤の存在下で、式VIII
(式中、R1及びR2はそれぞれ独立してH又はC1−6アルキルであり;又は
R1及びR2はそれらが結合する2個の酸素原子及び当該酸素原子が結合しているホウ素原子と共に、1、2、3又は4個のC1−4アルキル基で置換されていてもよい5から6員のヘテロシクロアルキル環である)
を反応させる工程を含む、発明33に記載の化合物の生成方法。
[発明36]
カップリング剤が1,8−ジアザビシクロ[5,4,0]ウンデセンである、発明35に記載の方法。
[発明37]
式VIIIの化合物に対して1.05から約1.2当量のカップリング剤を使用する、発明35ないし36の何れか1つに記載の方法。
[発明38]
式VIIIの化合物と式IXの化合物をアセトニトリルを含む溶媒成分中で反応させる、発明35ないし37の何れか1つに記載の方法。
[発明39]
式VIIIの化合物と式IXの化合物を約40℃から約60℃の温度でアセトニトリルを含む溶媒成分中で反応させる、発明35ないし37の何れか1つに記載の方法。
[発明40]
式VIIIの化合物に対して1から1.2当量の式IXの化合物を使用する、発明35ないし39の何れか1つに記載の方法。
[発明41]
カップリング剤存在下で式VIII
[発明42]
カップリング剤が1,8−ジアザビシクロ[5,4,0]ウンデセンである、発明41に記載の方法。
[発明43]
式VIIIの化合物に対して1.05から約1.2当量のカップリング剤を使用する、発明41又は42に記載の方法。
[発明44]
式VIIIの化合物と式IXaの化合物をアセトニトリルを含む溶媒成分中で反応させる、発明41ないし43の何れか1つに記載の方法。
[発明45]
式VIIIの化合物と式IXaの化合物を約40℃から約60℃の温度でアセトニトリルを含む溶媒成分中で反応させる、発明41ないし43の何れか1つに記載の方法。
[発明46]
式VIIIの化合物に対して1から1.2当量の式IXaの化合物を使用する、発明41ないし45の何れか1つに記載の方法。
[発明47]
鈴木カップリング条件下で式VIIaの化合物を式IVa
[発明48]
触媒がテトラキス(トリフェニルホスフィン)パラジウム(0)である、発明47に記載の方法。
[発明49]
塩基が炭酸水素ナトリウムである、発明47又は48に記載の方法。
[発明50]
式VIIaの化合物に対して4当量以上の炭酸水素ナトリウムが存在している、発明49に記載の方法。
[発明51]
第2溶媒成分が1,4−ジオキサン及び水を含む、発明47ないし50の何れか1つに記載の方法。
[発明52]
1,4−ジオキサン及び水が1:1の体積比で存在している、発明51に記載の方法。
[発明53]
式VIIa及び式IVaの化合物が約1:1のモル比で存在している、発明47ないし52の何れか1つに記載の方法。
[発明54]
式VIIaの化合物と式IVa
[発明55]
式VIII
[発明56]
式VI
[発明57]
式Xの化合物又はその塩が2−(アゼチジン−3−イリデン)アセトニトリル塩酸塩である、発明56に記載の方法。
[発明58]
還元剤が水素化シアノホウ素ナトリウム又はトリアセトキシ水素化ホウ素ナトリウムである、発明56又は57に記載の方法。
[発明59]
還元剤がトリアセトキシ水素化ホウ素ナトリウムである、発明56又は57に記載の方法。
[発明60]
式Xの化合物又はその塩に対して約1.5から約2.5当量の還元剤を使用する、発明56ないし59の何れか1つに記載の方法。
[発明61]
式Xの化合物又はその塩に対して約2当量の還元剤を使用する、発明56ないし59の何れか1つに記載の方法。
[発明62]
式VIの化合物及び式Xの化合物又はその塩をジクロロメタンを含む溶媒成分中で反応させる、発明56ないし61の何れか1つに記載の方法。
しかし、本発明の精神と範囲から逸脱することなく、様々な改良が可能なことを理解されたし。同様に、他の実施形態についても以下の発明の範囲内である。
Claims (28)
- 式VII
R1及びR2はそれらが結合している2個の酸素原子及び当該酸素原子が結合しているホウ素原子と共に、1、2、3又は4個のC1−4アルキル基で置換されていてもよい5から6員のヘテロシクロアルキル環を形成する)
の化合物又はその塩。 - 式VIIa
- 1,8−ジアザビシクロ[5,4,0]ウンデセンであるカップリング剤の存在下で、式VIII
(式中、R1及びR2はそれぞれ独立してH又はC1−6アルキルであるか;又は
R1及びR2はそれらが結合している2個の酸素原子及び当該酸素原子が結合しているホウ素原子と共に、1、2、3又は4個のC1−4アルキル基で置換されていてもよい5から6員のヘテロシクロアルキル環を形成する)
を反応させる工程を含む、請求項1記載の化合物の生成方法。 - 式VIIIの化合物に対して1.05から1.2当量のカップリング剤を使用する、請求項3記載の方法。
- 式VIIIの化合物と式IXの化合物をアセトニトリルを含む溶媒成分中で反応させる、請求項3又は4記載の方法。
- 式VIIIの化合物と式IXの化合物を40℃から60℃の温度でアセトニトリルを含む溶媒成分中で反応させる、請求項3又は4記載の方法。
- 式VIIIの化合物に対して1から1.2当量の式IXの化合物を使用する、請求項3ないし6の何れか1項記載の方法。
- 1,8−ジアザビシクロ[5,4,0]ウンデセンであるカップリング剤の存在下で式VIII
- 式VIIIの化合物に対して1.05から1.2当量のカップリング剤を使用する、請求項8記載の方法。
- 式VIIIの化合物と式IXaの化合物をアセトニトリルを含む溶媒成分中で反応させる、請求項8又は9記載の方法。
- 式VIIIの化合物と式IXaの化合物を40℃から60℃の温度でアセトニトリルを含む溶媒成分中で反応させる、請求項8又は9記載の方法。
- 式VIIIの化合物に対して1から1.2当量の式IXaの化合物を使用する、請求項8ないし11の何れか1項記載の方法。
- 鈴木カップリング条件下で式VIIaの化合物を式IVa
- 触媒がテトラキス(トリフェニルホスフィン)パラジウム(0)である、請求項13記載の方法。
- 塩基が炭酸水素ナトリウムである、請求項13又は14記載の方法。
- 式VIIaの化合物に対して4当量以上の炭酸水素ナトリウムが存在している、請求項15記載の方法。
- 第2溶媒成分が1,4−ジオキサン及び水を含む、請求項13ないし16の何れか1項記載の方法。
- 1,4−ジオキサン及び水が1:1の体積比で存在している、請求項17記載の方法。
- 式VIIa及び式IVaの化合物が1:1のモル比で存在している、請求項13ないし18の何れか1項記載の方法。
- 式VIIaの化合物と式IVa
- 式VIII
- 式VI
- 式Xの化合物又はその塩が2−(アゼチジン−3−イリデン)アセトニトリル塩酸塩である、請求項22記載の方法。
- 還元剤が水素化シアノホウ素ナトリウム又はトリアセトキシ水素化ホウ素ナトリウムである、請求項22又は23記載の方法。
- 還元剤がトリアセトキシ水素化ホウ素ナトリウムである、請求項22又は23記載の方法。
- 式Xの化合物又はその塩に対して1.5から2.5当量の還元剤を使用する、請求項22ないし25の何れか1項記載の方法。
- 式Xの化合物又はその塩に対して2当量の還元剤を使用する、請求項22ないし25の何れか1項記載の方法。
- 式VIの化合物及び式Xの化合物又はその塩をジクロロメタンを含む溶媒成分中で反応させる、請求項22ないし27の何れか1項記載の方法。
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