JP7408635B2 - Mdm2阻害剤を調製する方法 - Google Patents
Mdm2阻害剤を調製する方法 Download PDFInfo
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- JP7408635B2 JP7408635B2 JP2021510396A JP2021510396A JP7408635B2 JP 7408635 B2 JP7408635 B2 JP 7408635B2 JP 2021510396 A JP2021510396 A JP 2021510396A JP 2021510396 A JP2021510396 A JP 2021510396A JP 7408635 B2 JP7408635 B2 JP 7408635B2
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- chlorophenyl
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- 239000002904 solvent Substances 0.000 claims description 25
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- 230000035945 sensitivity Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
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- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
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- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 208000001608 teratocarcinoma Diseases 0.000 description 1
- UJJLJRQIPMGXEZ-UHFFFAOYSA-N tetrahydro-2-furoic acid Chemical compound OC(=O)C1CCCO1 UJJLJRQIPMGXEZ-UHFFFAOYSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
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- 238000003354 tissue distribution assay Methods 0.000 description 1
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- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
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- 229940116362 tragacanth Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
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- 210000003932 urinary bladder Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
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Images
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-
- 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
- C07D263/10—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/12—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals containing only hydrogen and carbon atoms
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- 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
- C07D263/10—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D263/14—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 only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with radicals substituted by oxygen atoms
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- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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, directly attached to ring carbon atoms
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- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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Description
選択された中間体を調製する方法
0℃のクロロベンゼン(170L、1684mol)、3-クロロフェニル酢酸(50Kg、293mol)、及びジメチルホルムアミド(0.7L、9mol)の混合物にチオニルクロリド(39.1Kg、329mol)を30分の経過にわたり加えた。混合物を15℃に温め、6h撹拌した。混合物を0℃に冷却し、塩化アルミニウム(43Kg、322mol)を1.5hの経過にわたり加えた。混合物を20℃に温め、15h撹拌した。水(200L)及びエタノール(200L)を混合物に加え、二相混合物を2h撹拌した。相を分離させ、有機相を、水性エチレンジアミンテトラ酢酸四ナトリウム塩(3重量%、200L)を用いて2回、及び水(200L)を用いて1回洗浄した。ヘプタン(1600L)を有機相に15分の経過にわたり加えた。懸濁液を30分間撹拌し、-5℃に冷却し、濾過した。濾過された材料を40℃で20h乾燥させた。2-(3-クロロフェニル)-1-(4-クロロフェニル)エタノンが83.6%の収率(67.4Kg)で単離された。1H NMR(500MHz,DMSO-d6,δ ppm):8.05(m,2H),7.62(m,2H),7.33(m,3H),7.21(br d,J=7.3Hz,1H),4.45(s,2H).MS(ESI)=265.1[M+H]+.
<ステップB:メチル4-(3-クロロフェニル)-5-(4-クロロフェニル)-2-メチル-5-オキソペンタノエート>
<ステップC:(3S,5R,6R)-5-(3-クロロフェニル)-6-(4-クロロフェニル)-3-メチルテトラヒドロ-2H-ピラン-2-オン及び(3R、5R,6R)-5-(3-クロロフェニル)-6-(4-クロロフェニル)-3-メチルテトラヒドロ-2H-ピラン-2-オン>
<ステップD。(3S,5R,6R)-3-アリル-5-(3-クロロフェニル)-6-(4-クロロフェニル)-3-メチルテトラヒドロ-2H-ピラン-2-オン>
<(3S,5R,6R)-3-アリル-5-(3-クロロフェニル)-6-(4-クロロフェニル)-3-メチルテトラヒドロ-2H-ピラン-2-オンを調製するための代替的な手順>
<ステップ2。(3S,5R,6R)-3-アリル-5-(3-クロロフェニル)-6-(4-クロロフェニル)-3-メチルテトラヒドロ-2H-ピラン-2-オン>
<化合物Aを作るファースト・イン・ヒューマンの方法及び商用の方法の間の差異>
DLACのグラムスケール合成が以前に報告されている。Sun et al.,J.Med.Chem.2014,57,1454を参照。この研究に基づいて、化合物Aをスキーム1に示されるファースト・イン・ヒューマン(FIH)合成方法により調製した。中間体OXOSをこの方法のための規制的な出発材料として使用した。高温で過剰なL-バリノール(3当量)を使用するDLACの開環はアミドABAをもたらし、これをジクロロメタンに抽出した。過剰なL-バリノールを、水性塩酸洗浄を使用して除去し、生成物溶液を精製無しでその後のステップに用いた。この変換において使用されたL-バリノールの量の低減をこの原材料の高いコストを考慮して将来的な開発目的として同定した。顕著なことに、化合物Aのカルボン酸と同じ酸化状態の基を含有する側鎖を持つ対応するDLACアナログDLAC1又はDLAC2からのABAアナログABA1又はABA2の調製は、望ましくないスクシンイミドSUC1又はSUC2の形成に起因して成功しなかった。所望の生成物ABA1-ABA2の形成及び副生成物SUC1-SUC2へのそれらの変換について観察された類似した速度を考慮して、許容される収率でアミドABA1-ABA2を単離することはできなかった。
<中間体OXOSを調製する商用の方法の開発>
L-バリノールを用いたDLACのABAへの熱アミド化は、中間体エステルESTを介する複数ステップの機構を通じて進行した(スキーム5)。DLACのESTへの初期エステル交換反応は、アミド生成物ABAへの転位の前のESTの蓄積に繋がる可逆的な過程(2当量のL-バリノールを用いてk1>k-1)であることが決定された。60℃で反応を行うと、DLACのESTへの急速な変換が反応の開始において観察され、続いて数日の経過にわたるESTのABAへの遅い変換が起こる(k1>k2)(図1)。高温(115℃)において(図2)、ESTのより安定なABAへの転位はより速く、ESTの濃度を増加させることにより反応の全体的な速度における増加を結果としてもたらす。
又は、中間体DHO-OMsをOXOSへの変換前に分離及び精製することができる。
1H NMR(400MHz,CHLOROFORM-d)δ ppm:7.31(d,J=8.4Hz,2H)、7.24-7.18(m,2H)、7.16(s,1H)、7.08(d,J=8.2Hz,2H)、7.07-7.01(m,1H)、5.59-5.43(m,2H)、5.01-4.83(m,2H)、3.84(dd,J=8.1,9.5Hz,1H)、3.55-3.45(m,1H)、3.42-3.34(m,1H)、3.24-3.13(m,1H)、2.46(s,3H)、2.39-2.28(m,1H)、2.28-2.14(m,1H)、1.98(br dd,J=7.8,13.6Hz,1H)、1.72(dd,J=2.4,14.3Hz,1H)、1.26(br s,1H)、1.06(s,3H)、0.88(d,J=6.7Hz,3H)、0.71(d,J=6.7Hz,3H).13C NMR(101MHz,CHLOROFORM-d)δ ppm:169.69、141.54、135.61、134.98、133.92、133.43、129.82、129.30、128.81、128.47、127.82、127.34、118.21、87.02、77.22、69.78、47.99、44.57、39.96、39.31、38.46、32.80、21.85、19.40、18.26.
<最後から2番目の中間体SULを調製するための商用の方法の開発>
高温でのイソプロピルスルフィン酸塩を用いるOXOSの処理は、熱力学的により安定な生成物SULに転位するスルフィネートエステルSULFIのジアステレオマー対の形成に繋がる(スキーム4)。この種類のスルフィネート-スルホン転位は、ベンズヒドリルスルフィネートエステルのイオン対形成及び転位機構を介して起こることが従来の方法において記載されている。しかしながら、本方法において、スキーム11に示されるクロスオーバー実験の結果は、転位は解離したイオンを伴うことを明らかにする。OXOSは70℃より高い温度で水と定量的に反応することを考慮すると、アルコールALCが生成される十分な機会がある。OXOSがALCから再生成され得ない場合、水は反応混合物から厳密に除外されなければならない。この目的を達成するための1つの経路は、共沸乾燥条件に対して安定であり、高純度で単離することができ、OXOSと効率的に反応してSULを生成するイソプロピルスルフィン酸の塩を調製することである。
<化合物Aを調製するための商用の方法の開発>
SULのアルケン基のオゾン分解、続いて結果としてもたらされるアルデヒドの、亜塩素酸ナトリウムを用いる化合物Aの対応するカルボン酸基への酸化は、化合物Aの初期製造のために使用される酸化ルテニウム/ナトリウムペリオデート法に対するより環境に優しい代替を示す。追加的に、オゾン分解経路は、結晶化を介して除去することが困難ないくつかの望ましくない二量体不純物の形成を排除する可能性があるため、生成物の単離を単純化する。
<DABCO塩としての化合物Aの単離>
不純物の堅牢な除去を可能にする薬物物質制御点は遊離酸のために利用可能でなかったことを考慮して、化合物Aのいくつかの塩を調製し、不純物の簡易な除去を可能とするために有効な候補を発見するための試験を行った。化合物Aの30を超える有機塩及び5を超える無機塩をその目的のために評価したところ、有望な競争者としてのヘミDABCO塩及びヘミカルシウム塩の同定が促された。しかしながら、ヘミカルシウム塩は、出発材料SUL又は不純物HACの中等度の除去のみを表し示した一方、ヘミDABCOイソプロピル酢酸塩(232-DAB)の使用は、両方の種の効率的な除去を可能とした(IPAC=イソプロピルアセテート)。
5LC面積%のSUL及び1LC面積%のHACは、典型的なオゾン分解-ピニック酸化反応混合物において観察されるよりも有意に高いレベルで、後者の塩の単離の間に完全に除去されることができた。232-DABは、TGA及び1H NMRにより安定な結晶性の一溶媒和物(イソプロピルアセテート)ヘミDABCO塩であることが観察された。材料の単一の多形体が同定された。材料の多型形態及びイソプロピルアセテートレベルは、0~90%の相対湿度で実行された動的蒸気収着実験により変化しなかった。追加的に、温度及び貧溶媒の使用に基づく堅牢な結晶化プロトコールを、イソプロピルアセテート及びヘプタンを使用してヘミDABCOイソプロピル酢酸塩について設計することができた。
<化合物Aの単離>
結晶化232-DABは有機溶媒中で行われたことを考慮して、直交精製処理を介して化合物Aを単離するために水性結晶化プロトコールが望まれた。フィッシャーエステル化及び結晶化を介するエステル不純物の除去ができないことに起因して、20~30℃より高い温度でのアルコール溶媒中の化合物Aの一般的な不安定性を考慮すれば、アルコール-水溶媒混合物は結晶化のために利用できなかった。水混和性溶媒を有する他の水性混合物は、結晶化設計の助けにならない急な溶解度曲線を示した。対照的に、酢酸及び水は、上記に詳述される欠点を有さずに良好な成長特徴を有して、材料を結晶化させるために好適であった。堅牢な温度及び貧溶媒ベースの結晶化をこの溶媒混合物を使用して設計し、それを水性塩酸(2当量)/イソプロピルアセテート混合物中での塩切断、2Mの水性ナトリウムホスフェート(pH6)を用いた有機層の2回のその後の洗浄、1.1Mの水性塩化ナトリウムを用いた洗浄、及びイソプロピルアセテートから酢酸への溶媒交換後に稼働した。
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EP3843733A4 (en) | 2022-08-24 |
JP2024037957A (ja) | 2024-03-19 |
AU2019327555A1 (en) | 2021-03-18 |
MX2021002397A (es) | 2021-04-29 |
KR20210052497A (ko) | 2021-05-10 |
EP3843733A1 (en) | 2021-07-07 |
CN112912080B (zh) | 2024-05-10 |
SG11202101886VA (en) | 2021-03-30 |
CN112912080A (zh) | 2021-06-04 |
WO2020047424A9 (en) | 2020-04-30 |
MX2023015251A (es) | 2024-01-19 |
EA202190632A1 (ru) | 2021-06-16 |
JP2021535130A (ja) | 2021-12-16 |
CA3110525A1 (en) | 2020-03-05 |
IL281040A (en) | 2021-04-29 |
WO2020047424A1 (en) | 2020-03-05 |
US20210347743A1 (en) | 2021-11-11 |
US11753386B2 (en) | 2023-09-12 |
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