JP2020147573A - 製造方法及びmdm2阻害剤の結晶形 - Google Patents
製造方法及びmdm2阻害剤の結晶形 Download PDFInfo
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- 239000000312 peanut oil Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000001144 powder X-ray diffraction data Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000861 pro-apoptotic effect Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- SWMZVAYYFXQTPO-LCMMRXEZSA-N propan-2-yl (4r,5r)-4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoate Chemical compound C1([C@H](O)[C@H](CC(C)C(=O)OC(C)C)C=2C=C(Cl)C=CC=2)=CC=C(Cl)C=C1 SWMZVAYYFXQTPO-LCMMRXEZSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- KJRCEJOSASVSRA-UHFFFAOYSA-N propane-2-thiol Chemical compound CC(C)S KJRCEJOSASVSRA-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 208000023958 prostate neoplasm Diseases 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 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
- 238000010583 slow cooling Methods 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
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000000638 solvent extraction Methods 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
- 241000894007 species Species 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- PJANXHGTPQOBST-UHFFFAOYSA-N stilbene Chemical compound C=1C=CC=CC=1C=CC1=CC=CC=C1 PJANXHGTPQOBST-UHFFFAOYSA-N 0.000 description 1
- 150000001629 stilbenes Chemical class 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- CBXCPBUEXACCNR-UHFFFAOYSA-N tetraethylammonium Chemical compound CC[N+](CC)(CC)CC CBXCPBUEXACCNR-UHFFFAOYSA-N 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 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
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 210000003932 urinary bladder Anatomy 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
- 238000005303 weighing Methods 0.000 description 1
- 125000005853 β-dimethylaminoethyl group Chemical group 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- 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
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
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- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
-
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/25—Sulfonic acids having sulfo groups bound to carbon atoms of rings other than six-membered aromatic rings of a carbon skeleton
-
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/33—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems
- C07C309/34—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems formed by two rings
- C07C309/35—Naphthalene sulfonic acids
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- C07D491/04—Ortho-condensed systems
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Abstract
Description
酸化がRuCl3及びNaIO4を用いて達成され、
実施形態23に記載の方法を提供する。
本発明の別の具体的実施形態において、一日量を使用用途の順にひとつずつ分注するように設計されたディスペンサーが提供される。好ましくは、ディスペンサーには、レジメンの投薬遵守をさらに容易にするために、メモリーエイドが備えられる。こうしたメモリーエイドの例は、分注した一日量の数を示す機械的なカウンターである。こうしたメモリーエイドの別の例は、たとば、一日量が最後に摂取された日を読み出す、かつ/または次の用量を摂取すべき日を思い出させる、液晶読み出しまたは可聴合図シグナルと連動した電池式のマイクロチップメモリーである。
例を挙げると、本発明の化合物がカルボン酸官能基を含むので、プロドラッグは、カルボン酸基の水素原子を(C1〜C8アルキル、(C2〜C12)アルカノイルオキシメチル、4〜9個の炭素原子を有する1−(アルカノイルオキシ)エチル、5〜10個の炭素原子を有する1−メチル−1−(アルカノイルオキシ)エチル、3〜6個の炭素原子を有するアルコキシカルボニルオキシメチル、4〜7個の炭素原子を有する1−(アルコキシカルボニルオキシ)エチル、5〜8個の炭素原子を有する1−メチル−1−(アルコキシカルボニルオキシ)エチル、3〜9個の炭素原子を有するN−(アルコキシカルボニル)アミノメチル、4〜10個の炭素原子を有する1−(N−(アルコキシカルボニル)アミノメチル、3−フタリジル、4−クロトノラクトニル、ガンマ−ブチロラクトン−4−イル、ジ−N,N−(C1〜C2)アルキルアミノ(C2〜C3)アルキル(β−ジメチルアミノエチルなど)、カルバモイル−(C1〜C2)アルキル、N,N−ジ(C1〜C2)アルキルカルバモイル−(C1〜C2)アルキル及びピペリジノ−、ピロリジノ−またはモルホリノ−(C2〜3)アルキルなどの基で置換することによって形成されたエステルを含むことができる。
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0℃の混合物に、塩化チオニル(39.1Kg、329mol)を30分間にわたって添加した。混合物を15℃まで温め、6時間かき混ぜた。混合物を0℃まで冷却し、塩化アルミニウム(43Kg、322mol)を1.5時間にわたって添加した。混合物を20℃まで温め、15時間かき混ぜた。水(200L)及びエタノール(200L)を混合物に添加し、二相混合物を2時間かき混ぜた。相を分離し、有機相をエチレンジアミン四酢酸四ナトリウム塩水溶液(3wt%、200L)で2回洗浄し、水(200L)で1回洗浄した。ヘプタン(1600L)を有機相に15分間にわたって添加した。懸濁液を30分間かき混ぜ、−5℃まで冷却し、濾過した。濾過物を40℃にて20時間乾燥させた。2−(3−クロロフェニル)−1−(4−クロロフェニル)エタノンを収率83.6%(67.4Kg)で単離した。
1H NMR(500MHz,DMSO−d6,δ ppm):8.05(m,2H),7.62(m,2H),7.33(m,3H),7.21(br
d,J=7.3 Hz,1H),4.45(s,2H).MS(ESI)= 265.1 [M+H]+。
1H NMR(400MHz,CDCl3,δ ppm):7.87(m,2H),7.38(m,2H),7.27−7.14(一連のm、4H),4.61(m,1H),3.69(s,1.5H),3.60(s,1.5
H),2.45(m,1H),2.34(m,1H),2.10(ddd,J=13.9,9.4,5.5 Hz,0.5H),1.96(ddd,J=13.7,9.0,4.3
Hz,0.5H),1.22(d,J=7.0 Hz,1.5H),1.16(d,J=7.0,1.5 H).MS(ESI)= 387.0 [M+23]+。
1H NMR(400MHz,CDCl3,δ ppm):7.22−6.98(一連のm、5H),6.91(dt,J=7.4,1.2
Hz,0.3H),6.81(m,2H),6.73(dt,J=7.6,1.4 Hz,0.7H),5.76(d,J=4.1 Hz,0.3 H),5.69(d,J=4.7
Hz,0.7H),3.67(dt,J=6.6,4.3 Hz,0.3H),3.55(td,J=7.8,4.7 Hz,0.7 H),2.96(クインテットのd,J=13.5,6.7
Hz,0.7 H),2.81(m,0.3 H),2.56(dt,J=14.3,8.0 Hz,0.7 H),2.32(dt,J=13.69,7.0 Hz,0.3
H),2.06(ddd,J=13.7,8.4,4.1,0.3 H),1.85(ddd,J=14.1,12.5,7.4,0.7 H),1.42(d,J=7.0 Hz,0.9
H),1.41(d,J=6.7 Hz,2.1H).MS(ESI)= 357.0 [M+23] +. [α]D(22
℃,c=1.0,CH2Cl2)= −31.9°;m.p.98−99 ℃。
1H NMR(400MHz,CDCl3,δ ppm):7.24(ddd,J=8.0,2.0,1.2
Hz,1H),7.20−7.15(一連のm、3H),6.91(t,J=2.0 Hz,1H),6.78(br d,J=7.6 Hz,1H),6.60(m,2H),5.84(ddt,J=17.6,10.2,7.4
Hz,1H),5.70(d,J=5.3 Hz,1H),5.21−5.13(一連のm、2H),3.82(dt,J=11.7,4.5 Hz,1H),2.62(ABX
JAB=13.7 Hz,JAX=7.6 Hz,1H),2.53(ABX,JAB=13.9 Hz,JBX=7.2
Hz,1H).1.99(dd,J=14.1,11.9 Hz,1H),1.92(ddd,J=13.9,3.9,1.2 Hz,1H).13C
NMR(CDCl3,100MHz,δ ppm):175.9,140.2,134.5,134.3,134.0,132.2,129.8,128.6,128.0,127.9,127.8,126.4,119.9,83.9,44.5,42.4,40.7,31.8,26.1.MS(ESI)=
375.2 [M+H]+.IR=1730 cm−1. [α]D(24 ℃,c=1.0,CH2Cl2)=
−191°.m.p.111−114 ℃。
1H NMR(400MHz,CDCl3,δ ppm):7.70−7.80(m,2H),7.22−7.28(m,2H),7.00−7.18(一連のm、4H),4.78−4.96(m,1H),4.42−4.50(m,1H),2.02−2.30(m,2H),1.80−1.95(m,1H),0.99−1.19(m,15H)。
2−((3R,5R,6S)−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチル−2−オキソピペリジン−3−イル)酢酸
2−((3R,5R,6S)−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチル−2−オキソピペリジン−3−イル)酢酸
2−((3R,5R,6S)−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチル−2−オキソピペリジン−3−イル)酢酸
実験1
2−((3R,5R,6S)−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチル−2−オキソピペリジン−3−イル)酢酸(100mg)を13mm試験管中に置き、水中の1mLの40%エタノールを室温で添加した。還流加熱をした後でも、物質は溶解しなかった。水中の2mLの40%エタノールを追加で添加したが、還流後でも物質は完全に溶解しなかった。物質が溶液になるまで、エタノールを滴加した。溶液をゆっくり冷却した。室温に達する前に、物質が油状化した。
2−((3R,5R,6S)−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチル−2−オキソピペリジン−3−イル)酢酸(100mg)を13mm試験管中に置き、エタノール1mL中に溶解し、還流加熱した。水を滴加し、添加時に形成された曇りが数秒で消失するまで行った(合計で水1mLを添加した)。溶液をゆっくり冷却した。室温に達する前に、油状化した。追加のエタノール(0.2mL)を添加し、混合物を加熱還流した。室温までゆっくり冷却すると、物質が油状化した。追加のエタノール(0.2mL)を添加し、混合物を加熱還流した。混合物は、室温まで冷却しても油状化しなかったが、結晶も形成しなかった。1.5時間室温に置いた後、溶液を冷凍器に置くと、物質が油状化した。
2−((3R,5R,6S)−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチル−2−オキソピペリジン−3−イル)酢酸(100mg、白色発泡体)を13mm試験管中に置き、水中の1mLの60%エタノールを室温で添加した。発泡体は完全に溶解するか、ほとんど溶解した後、白色固体として沈殿した。この固体を真空濾過により回収した。分析により、この固体が出発材料よりも純粋であることが示された。2−((3R,5R,6S)−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチル−2−オキソピペリジン−3−イル)酢酸(100mg、白色発泡体)を13mm試験管中に置き、水中の1mLの60%エタノールを添加した。添加中、混合物を室温で撹拌すると、物質は短時間で溶解した後、白色固体として沈殿した。混合物を還流加熱して物質を溶解し、室温までゆっくり冷却した。室温で一晩撹拌後、結晶は形成されなかった。前述の実験で調製した固体を溶液に種晶として添加すると、固体が即座に形成された。結晶を真空濾過によって回収し、水中の60%エタノールの冷溶液で洗浄して白色結晶性固体を得た。分析により純度のさらなる向上が示され、X線回折では本物質が結晶性であることが示された。XRPDは化合物Aのエタノール付加物と一致した(図6)。
2−((3R,5R,6S)−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチル−2−オキソピペリジン−3−イル)酢酸(100mg、白色発泡体)を13mm試験管中に置き、水中の0.75mLの60%エタノールを添加した。添加中、混合物を室温で撹拌すると、数分後、発泡体が白色結晶性固体に置き換わった。混合物を還流加熱し、撹拌せずに室温までゆっくり冷却した。数日後、大きな結晶が形成された。これを真空濾過により回収して表題化合物を無色針状結晶として得た。単一の結晶X線構造が得られ、化合物Aのエタノール付加物と一致した(図6)。
2−((3R,5R,6S)−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチル−2−オキソピペリジン−3−イル)酢酸
以下の一般手順に従って、試料を調製した。約20mgの化合物Aのエタノール付加物を計量し、1ドラムバイアルに添加した。溶媒1mLをバイアルに添加した。試料をスラリー化した。試験した溶媒は、水/エタノール(80/20、v/v)、水/エタノール(70/30、v/v)、水/エタノール(60/40、v/v)、水/1−プロパノール(90/10、v/v)、水/1−プロパノール(80/20、v/v)、水/1−プロパノール(70/30、v/v)、水/アセトニトリル(95/5、v/v)、水/アセトニトリル(90/10、v/v)、水/アセトン(95/5、v/v)、水/アセトン(90/10、v/v)、ヘプタン、ヘプタン/イソプロピルアセテート(99/1、v/v)、シクロヘキサン、シクロヘキサン/イソプロピルアセテート(99/1、v/v)であった。実験の開始時、3日、7日、10日、13日及び19日に観察結果を記した。試料を7日及び10日、13日または19日にXRPDにより分析した。結果を表3に示す。XRPDは、化合物Aのエタノール付加物(図6)、化合物Aのプロパノール溶媒和物(図7)、化合物Aの無水結晶(図1)または化合物Aの非晶質(図2)と一致した。
2−((3R,5R,6S)−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチル−2−オキソピペリジン−3−イル)酢酸
(3S,5R,6S)−3−アリル−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチルピペリジン−2−オン(80.6g、146mmol)をアセトニトリル(280mL)及び酢酸エチル(280mL)中に溶解し、2Lの3首モートンフラスコに移した。水(418mL)を添加した。フラスコに熱電対を取り付け、水浴に浸した。ルテニウム(III)クロリド水和物(0.726g、3.22mmol)を添加し、続いて過ヨウ素酸ナトリウム(31.25g)を添加した。温度は17℃から24℃に上昇し、氷を水浴に加えて温度を調節した。15分後、過ヨウ素酸ナトリウムの第2のアリコート(31.25g)を添加し、温度は18℃から20℃に上昇した。15分後、過ヨウ素酸ナトリウムの第3のアリコート(31.25g)を添加し、温度は18℃から25.6℃に上昇した。追加の氷を水浴に加えた。10分後、過ヨウ素酸ナトリウムの第4のアリコート(31.25g)を添加した。2時間撹拌後、過ヨウ素酸ナトリウム(15g)を添加し、90分後、過ヨウ素酸ナトリウム(6g)を再び添加した。1時間後、液体を大きな分液漏斗中にデカントした。固体物質を酢酸エチル(1.5L)ですすぎ、分液漏斗に添加し、10%亜硫酸水素ナトリウム(1L)で洗浄した。有機層をブラインで洗浄し、相を一晩分離させた。固体物質を酢酸エチル(300mL)で再度スラリー化し、濾過した。濾液を10%亜硫酸水素ナトリウム及びブラインで洗浄した。合わせた有機層を硫酸ナトリウムで乾燥させ、濾過し、濃縮した。粗製物質をフラッシュカラムクロマトグラフィー(1.5kgシリカゲルカラム、ヘキサン中0%〜50%イソプロパノールの勾配溶出)によって精製し、表題化合物を得た。
(3S,5R,6S)−3−アリル−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチルピペリジン−2−オン(90.4g、162mmol)をアセトニトリル(308mL)及び酢酸エチル(308mL)中に溶解し、2Lの3首モートンフラスコに移した。水(463mL)を添加した。フラスコに熱電対及び機械式撹拌子を取り付けた。ルテニウム(III)クロリド水和物(0.803g、3.56mmol)を添加し、反応容器を低温水浴中に浸した。過ヨウ素酸ナトリウムを何回かに分けて添加し(第1の部分:34.0g)、反応混合物を25℃未満に保つように温度をモニターした。温度調節しやすいように、氷を水浴に定期的に加えた。
(3S,5R,6S)−3−アリル−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチルピペリジン−2−オン(131.8g、239mmol)をアセトニトリル(402mL)及び酢酸エチル(402mL)中に溶解し、2Lの3首モートンフラスコに移した。水(603mL)を添加した。フラスコに熱電対及び機械式撹拌子を取り付けた。ルテニウム(III)クロリド水和物(1.079g、4.79mmol)を添加し、反応容器を低温水浴中に浸した。過ヨウ素酸ナトリウムを何回かに分けて添加し(第1の部分:59g)、反応混合物を25℃未満に保つように温度をモニターした。温度調節しやすいように、氷を水浴に定期的に加えた。
(3S,5R,6S)−3−アリル−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチルピペリジン−2−オン(87.3g、159mmol)をアセトニトリル(302mL)及び酢酸エチル(302mL)中に溶解し、2Lの3首モートンフラスコに移した。水(453mL)を添加した。フラスコに熱電対及び機械式撹拌子を取り付けた。ルテニウム(III)クロリド水和物(0.786g、3.49mmol)を添加し、反応容器を低温水浴中に浸した。過ヨウ素酸ナトリウムを何回かに分けて添加し(第1の部分:34.5g)、反応混合物を25℃未満に保つように温度をモニターした。温度調節しやすいように、氷を水浴に定期的に加えた。
バッチ1から4の純粋でない画分を、複数回のフラッシュカラムクロマトグラフィー(シリカゲル量は330g〜1.5kgで変動、ヘキサン中0%〜20%イソプロパノールの勾配溶出)によって再精製し、表題化合物を得た。
バッチ1〜5の物質を別の合成による物質の一部(18g)と混ぜ合わせた。2−((3R,5R,6S)−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチル−2−オキソピペリジン−3−イル)酢酸(400g)をエタノール中に溶解し、真空下で濃縮し、白色結晶性固体を得た。水(1900mL)中の60%エタノール溶液を添加し、大気圧でロータリーエバポレーターで回転させながら、混合物を80℃まで加熱した。物質を溶解した後、フラスコを機械的に撹拌させながら、溶液をゆっくり冷却した。3時間後、温度を50℃まで冷却し、結晶性2−((3R,5R,6S)−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチル−2−オキソピペリジン−3−イル)酢酸を種晶として物質に添加した。固体は完全に溶解した。30分後、溶液に再度種晶を入れると(45℃)、物質がゆっくりと結晶化し始めた。混合物が室温まで冷却したら、それを冷凍器内に一晩置いた。結晶をブフナー漏斗を通す真空濾過によって回収した。濾過ケーキを水中の氷冷した60%エタノールで洗浄し、ブフナー漏斗で真空下にて乾燥させ、白色固体を得た。NMR分析により、7.8wt%のエタノールが存在することが示された(1モル当量)。水(脱イオン化し濾過したもの(Milli−Q filtration system,EMD Millipore,Billerica,MA))を固体に添加し、混合物を室温で一晩機械的に撹拌した。アリコートを定期的に取り、固体のエタノール含有量をモニターした。3日後、物質をブフナー濾過を通して真空濾過し、水(上述の脱イオン化し濾過したもの)で洗浄し、濾過ケーキを通して真空引きによって3時間乾燥させた。濾過ケーキを漏斗内で2日間空気乾燥させ、次いで、白色固体としてこれを2Lフラスコに移し、真空下で一晩乾燥させた。NMR分析により、6.2wt%のエタノールが存在することが示された。
1H NMR(500MHz,DMSO−d6,δ
ppm):12.43(br s,1H),7.72(br,1H),7.37(br,2H),7.23(t,J=7.8 Hz,1H),7.17(d,J=8.1 Hz,1H),7.02(t,J=1.9,1.9
Hz,1H),6.99(br,1H),6.98(dt,J=7.7,1.4,1.4 Hz,1H),5.01(d,J=11.2 Hz,1H),3.84(dd,J=14.0,10.1
Hz,1H),3.59(ddd,J=13.7,11.3,2.9 Hz,1H),3.39(m,1H),3.18(dd,J=13.9,1.3 Hz,1H),3.06(ddd,J=10.6,8.1,1.6
Hz,1H),2.95(d,J=13.7 Hz,1H),2.50(d,J=13.8 Hz,1H),2.12(t,J=13.5 Hz,1H),2.10(m,1H),2.03(dd,J=13.3,3.0
Hz,1H),1.29(d,J=6.8 Hz,3H),1.29(d,J=6.8 Hz,3H),1.23(s,3H),0.55(d,J=6.6 Hz,3H),0.37(d,J=6.9
Hz,3H);mS(ESI)= 568.2 [M+H]+。
テトラヒドロフラン(20L)を反応容器に添加し、容器の温度を−50℃まで冷却した。二酸化硫黄(3.5kg、54.6mol)を反応容器内で−50℃にて濃縮した。イソプロピルマグネシウムクロリド(テトラヒドロフラン中2M、21L、42mol)を溶液に添加した。反応混合物を−10℃で30分間かき混ぜ、2.5N塩酸水溶液(18.5l、46.2mol)を添加した。反応混合物を20℃まで温め、t−ブチルメチルエーテル(10L)を添加した。相を分離し、水相をt−ブチルメチルエーテル(10L)で2回抽出した。合わせた有機抽出物を塩化ナトリウム水溶液(12wt%、20mL)で洗浄し、減圧下で濃縮して、所望のスルフィン酸を収率82%(3.7Kg)で得た。
酢酸エチル(8.4L)、アセトニトリル(8.6L)及び水(6.5L)中の(3S,5R,6S)−3−アリル−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチルピペリジン−2−オン(2.4Kg、4.4mol)の溶液にルテニウムクロリド水和物(20.5g、0.09mol)を添加した。混合物の温度を20℃から28℃の間に維持しながら、過ヨウ素酸ナトリウム(5.0kg、23.2mol)を4つの等量部分にして1.5時間にわたって添加した。混合物を2.5時間かき混ぜ、珪藻土(3.33Kg)の層に通して濾過した。得られた珪藻土ケーキをイソプロピルアセテート(10.4L)及び水(3L)で洗浄した。濾液を相分離した。有機相を塩化ナトリウム水溶液(25wt%、5.5L)で2回洗浄し、塩化ナトリウム及び亜硫酸水素ナトリウムの水溶液(25wt%塩化ナトリウム及び20wt%亜硫酸水素ナトリウム、7.8L)で2回洗浄し、塩化ナトリウム水溶液(25wt%、6.5L)で1回洗浄した。イソプロピルアセテート(12.4L)を同時に添加しながら、有機相を減圧下で蒸留した。バッチを濾過した。炭(680g)を添加し、混合物を13時間かき混ぜた。混合物を珪藻土(1.5Kg)の層に通して濾過し、珪藻土ケーキをイソプロピルアセテート(8L)で洗浄した。エタノール(16L)を同時に添加しながら、溶液を減圧下で蒸留すると、24.5Kgの留出量が生じた。ヘプタン(8.5L)を添加し、溶液に化合物Aのエタノール付加物を種晶として添加した(種晶物質は、先に実施した小規模実験と同じ手順によって調製した)(95g)。混合物を20℃で40分間かき混ぜ、ヘプタン(8.8L)を同時に添加しながら、減圧下で蒸留すると、10.9Kgの留出量が生じた。混合物を12時間かき混ぜ、濾過した。生成物をエタノール(0.4L)とヘプタン(1.6L)との混合物で洗浄した。生成物を窒素下で乾燥させ、化合物Aのエタノール付加物(1.99Kg)を収率70%で得た。
化合物Aのエタノール付加物(1.0Kg、1.62mol)をメタノール(8.5L)中に溶解し、得られた溶液を濾過した。この溶液を35℃まで温め、水(2.5L)を添加した。溶液に化合物Aの無水結晶(50g、0.074mol)を種晶として添加し、4時間にわたって20℃まで冷却した(種晶物質は、先に実施した小規模実験と同じ手順によって調製した)。水(2L)を30分間にわたって添加した。混合物を30分間かき混ぜ、濾過した。生成物を窒素下で乾燥させ、化合物Aの無水結晶(0.86Kg)を収率93%で得た。
1H NMR(400MHz,DMSO−d6)d 12.37(s,1H),7.36(bs,4H),7.23(t,1H,J=7.9
Hz),7.16(ddd,1H,J=7.9,1.9,1.0 Hz),7.02(t,1H,J=1.9 Hz),6.98(bd,1H,J=7.9 Hz),5.02(d,1H,J=7.9
Hz),3.84(dd,1H,J=13.4,10.2 Hz),3.58(ddd,1H,J=13.5,11.3,3.0 Hz),3.39(spt,1H,J=6.8
Hz),3.17(bd,1H,J=13.4 Hz),3.07(bt,1H,J=8.6 Hz),2.95(d,1H,J=13.9 Hz),2.51(d,1H,J=13.9
Hz),2.13(bt,1H,J=13.5 Hz),2.11(spt,1H,J=6.8 Hz),2.04(dd,1H,J=13.5,3.0 Hz),1.30(2x
d,6H,J=6.8 Hz),1.24(s,3H),0.56(d,3H,J=6.8 Hz),0.38(d,3H,J=6.8 Hz);精密質量[C28H36
Cl2NO5S]+:計算値=568.1691、実測値M/Z [M+1]=568.1686。
テトラヒドロフラン(20L)を反応容器に添加し、容器の温度を−50℃まで冷却した。二酸化硫黄(3.5kg、54.6mol)を反応容器内で−50℃にて濃縮した。イソプロピルマグネシウムクロリド(テトラヒドロフラン中2M、21L、42mol)を溶液に添加した。反応混合物を−10℃で30分間かき混ぜ、2.5N塩酸水溶液(18.5l、46.2mol)を添加した。反応混合物を20℃まで温め、t−ブチルメチルエーテル(10L)を添加した。相を分離し、水相をt−ブチルメチルエーテル(10L)で2回抽出した。合わせた有機抽出物を塩化ナトリウム水溶液(12wt%、20mL)で洗浄し、減圧下で濃縮して、所望のプロパン−2−スルフィン酸を収率82%(3.7Kg)で得た。このプロパン−2−スルフィン酸をエタノール(37L)中に溶解し、水(7.2L)中の酢酸カルシウム一水和物(3.0Kg、17.1mol)溶液を添加した。得られた混合物を1時間かき混ぜ、濾過した。生成物をエタノール(10.8L)と水(1.1L)との混合物で洗浄した。生成物を窒素下で乾燥させ、プロパン2−スルフィン酸カルシウム二水和物を収率86%(4.26Kg)で得た。1H NMR(400MHz,DMSO−d6)d 3.37(s,4H),1.88(spt,2H,J=7.0 Hz),0.92(d,12H,J=7.0
Hz)。
プロパン−2−スルフィン酸カルシウム二水和物(2943616)(2.7Kg、9.36mol)及びトルエン(22L)を60L容器に添加した。反応混合物を110℃まで温め、トルエン(43L)を同時に添加しながら、減圧下で蒸留すると、50Kgの留出量が生じた。反応混合物を40℃まで冷却し、(3S,5S,6R,8S)−8−アリル−6−(3−クロロフェニル)−5−(4−クロロフェニル)−3−イソプロピル−8−メチル−2,3,5,6,7,8−ヘキサヒドロオキサゾロ[3,2−a]ピリジン−4−イウムナフタレン−1−スルホネートヘミトルエン溶媒(3.6Kg、5.2mol)及びトルエン(9.0L)を添加した。反応混合物を110℃まで温め、ジメチルアセトアミド(10.9L)を同時に添加しながら、大気圧下で蒸留すると、15.8Kgの留出量が生じた。混合物を約120℃で14時間かき混ぜ、40℃まで冷却した。t−ブチルメチルエーテル(9.1L)及び水(14.5L)を混合物に添加し、二相混合物を固体が見えなくなるまでかき混ぜた。相を分離した。有機相を水(2×7.3L)で2回、飽和重炭酸ナトリウム水溶液(7.1L)で1回、塩化ナトリウム水溶液(12wt%、7.1L)で1回洗浄した。有機相を20℃まで冷却し、濾過し、アセトニトリル(21.3L)を同時に添加しながら、減圧下で蒸留すると、15Kgの留出量が生じた。水(2L)を添加した。(3S,5R,6S)−3−アリル−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチルピペリジン−2−オン(160g、0.29mol)を種晶として溶液に25℃で添加した。混合物を25℃で25分間かき混ぜ、約45分間にわたって20℃まで冷却した(種晶物質は、先に実施した小規模実験と同じ手順によって調製した)。アセトニトリル(3.0L)と水(7.0L)の混合物を反応混合物に1.5時間にわたって添加した。得られた混合物を1時間かき混ぜ、濾過した。生成物をアセトニトリル(3.6L)と水(2.4L)との混合物で洗浄した。生成物を窒素下で乾燥させ、(3S,5R,6S)−3−アリル−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチルピペリジン−2−オン(2.8Kg)を収率83%で得た。
水(2.4L)及びアセトニトリル(21.6L)の混合物中の(3S,5R,6S)−3−アリル−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチルピペリジン−2−オン(1.6Kg、2.9mol)溶液を連続撹拌式タンク反応装置のオゾン容器(1L容器)に60mL/分の流量で20℃にて流した(あるいは、オゾンスパージャを用いて反応容器内でオゾン分解を行った)。反応混合物を水(5.6L)中の亜塩素酸ナトリウム(80wt%、1.0Kg、11.6mol)溶液に6時間にわたって添加した(あるいは、亜塩素酸ナトリウム水溶液を反応混合物に添加した)。反応混合物を16時間かき混ぜ、水(5.6L)中の亜硫酸水素ナトリウム(1.2Kg、11.6mol)溶液を2時間にわたって添加した。混合物を1時間かき混ぜ、相を分離した。有機相にイソプロピルアセテート(8L)及び水(8L)を添加した。混合物を30分間かき混ぜ、相を分離した。有機相を塩化ナトリウム水溶液(6wt%、8L)で1回、1Mリン酸ナトリウム水溶液(pH6、8L)で3回、塩化ナトリウム水溶液(6wt%、8L)で1回洗浄した。有機相を濾過した。イソプロピルアセテート(32L)を同時に添加しながら、混合物を減圧下で蒸留すると、35Kgの留出量が生じた。エタノール(32L)を同時に添加しながら、混合物を減圧下で蒸留すると、36Kgの留出量が生じた。ヘプタンを添加し(9.6L)、混合物を減圧下で蒸留すると、5Kgの留出量が生じた。混合物に化合物Aのエタノール付加物(80g、0.13mol)を種晶として添加した(種晶物質は、先に実施した小規模実験と同じ手順によって調製した)。ヘプタン(6.4L)を1時間にわたって添加し、混合物を12時間かき混ぜ、15℃まで冷却し、濾過した。生成物をエタノール(90mL)とヘプタン(4.8L)との混合物で洗浄した。生成物を窒素下で乾燥させ、化合物Aのエタノール付加物(1.33Kg)を収率81%で得た。
化合物Aのエタノール付加物(1.0Kg、1.62mol)をメタノール(8.5L)中に溶解し、得られた溶液を濾過した。この溶液を35℃まで温め、水(2.5L)を添加した。溶液に化合物Aの無水結晶(50g、0.074mol)を種晶として添加し、4時間にわたって20℃まで冷却した(種晶物質は、先に実施した小規模実験と同じ手順によって調製した)。水(2L)を30分間にわたって添加した。混合物を30分間かき混ぜ、濾過した。生成物を窒素下で乾燥させ、化合物Aの無水結晶(0.86Kg)を収率93%で得た。
1H NMR(400MHz,DMSO−d6)d 12.37(s,1H),7.36(bs,4H),7.23(t,1H,J=7.9 Hz),7.16(ddd,1H,J=7.9,1.9,1.0 Hz),7.02(t,1H,J=1.9 Hz),6.98(bd,1H,J=7.9 Hz),5.02(d,1H,J=7.9 Hz),3.84(dd,1H,J=13.4,10.2
Hz),3.58(ddd,1H,J=13.5,11.3,3.0 Hz),3.39(spt,1H,J=6.8 Hz),3.17(bd,1H,J=13.4
Hz),3.07(bt,1H,J=8.6 Hz),2.95(d,1H,J=13.9 Hz),2.51(d,1H,J=13.9
Hz),2.13(bt,1H,J=13.5 Hz),2.11(spt,1H,J=6.8 Hz),2.04(dd,1H,J=13.5,3.0
Hz),1.30(2x d,6H,J=6.8 Hz),1.24(s,3H),0.56(d,3H,J=6.8 Hz),0.38(d,3H,J=6.8 Hz);精密質量[C28H36
Cl2NO5S]+:計算値=568.1691、実測値M/Z [M+1]=568.1686。化合物Aの無水結晶の代表的なXRPDパターンを図1に示す。
水(6L)及びアセトニトリル(54L)の混合物中の(3S,5R,6S)−3−アリル−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチルピペリジン−2−オン(4.0Kg、7.27mol)の撹拌溶液に、Hastelloy C22内層スパージャを用いてオゾンを20℃で10時間にわたって供給した。混合物の温度を40℃未満に維持しながら、水(14L)中の亜塩素酸ナトリウム(80wt%、2.5Kg、29mol)水溶液を1時間にわたって添加した。反応混合物の温度を40℃未満に維持しながら、反応混合物を12時間かき混ぜ、水(14L)中の亜硫酸水素ナトリウム(3.0Kg、29mol)溶液を2時間にわたって添加した。混合物を1時間かき混ぜ、相を分離した。有機相にイソプロピルアセテート(IPAC)(20L)及びpH6の1Mリン酸ナトリウム水溶液(8L)を添加した。混合物を30分間かき混ぜ、相を分離した。有機相をpH6の1Mリン酸ナトリウム水溶液(20L)で洗浄し、1M塩化ナトリウム水溶液(20L)で洗浄した。イソプロピルアセテート(80L)を同時に添加しながら、混合物を減圧下で蒸留すると、75Kgの留出量が生じた。カールフィッシャーによる溶液の含水量は、1パーセント未満であった。有機相を濾過した。溶液をさらに蒸留して、約16Lの容量にした。溶液を55℃まで加熱して、1,4−ジアザビシクロ[2.2.2]オクタン(DABCO、424g、3.65mol)を添加した。(3S,5R,6S)−3−アリル−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチルピペリジン−2−オンの1,4−ジアザビシクロ[2.2.2]オクタン(DABCO)塩の種晶(136g、0.18mol)をイソプロピルアセテート及びヘプタン(1/1、800mL)中にスラリーとして添加した。混合物を55℃で20分間かき混ぜ、20℃まで2時間にわたって冷却した。ヘプタン(16.8L)を1時間にわたって添加し、混合物を20℃で12時間かき混ぜた。生成物を濾過し、濾過ケーキをイソプロピルアセテートとヘプタンの混合物(2/3、21L)で1回、イソプロピルアセテートとヘプタンの混合物(1/4、21L)で1回洗浄した。生成物を窒素下で乾燥させ、化合物AのDABCO塩(4.64Kg)を収率87%で得た(液体クロマトグラフィー面積率(LCAP)100%、化合物A78.9wt%)。化合物AのDABCO塩は、スキーム3によるイソプロピルアセテート(IPAC)の溶媒和物である。化合物AのDABCO塩は、原薬(化合物A)の純度をより高める精製基準点である。通常、粗反応混合物の純度が液体クロマトグラフィー面積率の純度で97〜99である場合、DABCO塩の結晶化を用いて、液体クロマトグラフィー面積率の純度を100まで向上させられる(0.05よりも大きい液体クロマトグラフィー面積率の不純物なし)。比較のために、化合物Aのエタノール付加物を基準点に用いて原薬(化合物A)の純度を高めると、粗反応混合物の97〜99の液体クロマトグラフィー面積率純度を99.5〜99.6の液体クロマトグラフィー面積率純度まで改善させられる(濾過物中には、複数の不純物が0.05よりも大きい液体クロマトグラフィー面積率で存在する)。
1H NMR(400MHz,CDCl3):δ ppm 0.49(
d,J=6.8 Hz,6H),0.64(d,J=6.4 Hz,6H),1.23(d,J=6.0 Hz,12H),1.41(s,6H),1.43(d,J=7.6
Hz,12H),2.02(s,6H),2.05−2.00(m,2H),2.30−2.15(m,4H),2.71(d,J=13.2,2H),2.84(dd,J=2.0,13.6,2H),2.90(d,J=13.6
Hz,2H),2.96(s,12H),3.11(ペント,J=6.8 Hz,2H),3.67−3.22(m,2H),3.55−3.48(m,2H),4.07(dd,J=10.4,13.2
Hz,2H),4.99(sept,J=6.4 Hz,2H),5.13(d,J=11.2 Hz,2H),7.10−6.98(m,8H),7.35−7.10(m,8H),13.2(br,2H).13C
NMR(101MHz,CDCl3)δ ppm 15.3,15.7,20.3,21.0,21.4,21.8,25.6,32.6,39.6,41.5,44.5,44.6,44.8,47.0,54.8,58.4,67.6,69.2,76.7,77.0,77.4,125.7,126.9,128.2,128.5,129.8,133.9,134.0,137.5,143.8,170.7,174.6,176.3.m.p.103℃。
(3S,5R,6S)−3−アリル−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチルピペリジン−2−オンの1,4−ジアザビシクロ[2.2.2]オクタン(DABCO)塩(8.28Kg、5.79mol)にイソプロピルアセテート(41.4L)及び水(41.4L)を添加した。この混合物に4M塩酸水溶液(3L、12.1mol)を添加し、二相混合物を30分間かき混ぜた。相を分離し、有機相をpH6の1Mリン酸ナトリウム水溶液(25L)で2回洗浄し、塩化ナトリウム水溶液(7wt%、33L)で1回洗浄した。イソプロピルアセテート(42L)を同時に添加しながら、混合物を減圧下で蒸留すると、56Kgの留出量が生じた。イソプロピルアセテート含有量とカールフィッシャーによる含水量の両方を測定すると、溶液中1パーセント未満であった。有機相を濾過した。酢酸(45L)を同時に添加しながら、有機相を減圧下で蒸留すると、20kgの留出量が生じた。溶液を60℃まで加熱し、脱イオン水(29L)を30分間にわたって添加した。(3S,5R,6S)−3−アリル−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチルピペリジン−2−オンの種晶(320g、0.56mol)を酢酸及び脱イオン水(3/2、1L)中にスラリーとして添加した。混合物を60℃で3時間かき混ぜ、20℃まで6時間にわたって冷却した。混合物を20℃で12時間かき混ぜた。脱イオン水(7mL)を1時間にわたって添加し、混合物をさらに1時間かき混ぜた。生成物を濾過し、濾過ケーキを酢酸と脱イオン水の混合物(1/1、13L)で1回、脱イオン水で3回(3×65L)洗浄した。生成物を窒素下で乾燥させ、(3S,5R,6S)−3−アリル−5−(3−クロロフェニル)−6−(4−クロロフェニル)−1−((S)−1−(イソプロピルスルホニル)−3−メチルブタン−2−イル)−3−メチルピペリジン−2−オン(6.3Kg)を収率92%で得た(LCAP100%、100.3wt%、酢酸320ppm、水<100ppm)。
スキームFに従って、L−バリノール(2.6Kg、25.2mol)を50℃で溶解し、(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(3.6Kg、84.0wt%、80.8%ee,7.9mol)を添加した。混合物を110℃まで加熱し、当該温度で5時間かき混ぜた。混合物を20℃まで冷却し、ジクロロメタン(17.9L)を添加した。1N塩酸水溶液(18.5L)を添加し、二相混合物を10分間かき混ぜた。相を分離し、有機相を塩化ナトリウム水溶液(20wt%、7L)で洗浄した。ジクロロメタン(3.3L)を同時に添加しながら、有機相を大気圧下で蒸留すると、13.7Kgの留出量が生じた。有機相をp−トルエンスルホン酸無水物(5.9Kg、18mol)のジクロロメタン(23.0L)中溶液に10分間にわたって添加した。混合物の温度を25℃未満に維持しながら、2,6−ルチジン(3.56Kg、33.2mol)を1時間にわたって添加した。混合物を20℃で40分間かき混ぜた。混合物を大気圧下かつ40℃で蒸留すると、13.0Kgの留出量が生じた。温度を20℃未満に維持しながら、混合物を2N硫酸水溶液(19.5Kg)に15分間にわたって添加した。混合物を15分間かき混ぜ、相を分離した。有機相を1−ナフタレンスルホン酸ナトリウム水溶液(10wt%、19.4Kg)で2回、重炭酸ナトリウム水溶液(5wt%、19.5Kg)で1回洗浄した。1−ナフタレンスルホン酸二水和物(64g、0.26mol)を添加した。
1H NMR(400MHz,DMSO−d6)d 8.03−8.00(m,1H),7.93−7.90(m,3H),7.56−7.42(m,6.5
H),7.33(s,1H),7.27−7.13(m,6H),5.85(m,1H),5.35(m,3H),5.02(m,1H),4.93(t,1H,J=9.98
Hz),4.3(m,1H),4.09(m,1H),2.79(m,2H),2.39(t,1H,J=13.3 Hz),2.3(s,1.5 H),2.01(dd,1H,J=13.69,3.13
Hz),1.34(s,3H),0.61(d,3H,J=6.46 Hz),0.53(d,3H,J=6.85 Hz),0.41(m,1H)
オキソイミニウム塩のトルエン溶媒和物(1g)をクロロホルム(10mL)中に溶解し、この溶液を減圧下で濃縮した。得られた残留物にクロロホルム(10mL)を添加し、溶液を減圧下で再度濃縮した。最後に、得られた残留物にクロロホルム(10mL)を添加し、溶液を減圧下で濃縮した。
1H NMR(400MHz,CDCl3)d 9.13(d,1H,J=8.61
Hz),8.35(d,1H,J=7.24 Hz),7.86(t,2H,J=9.0 Hz),7.57(m,1H),7.48(m,2H),7.28(m,5H),7.09(m,3H),6.11(d,1H,J=11.15
Hz),5.81(m,1H),5.54(m,1H),5.32(m,2H),4.79(m,1H),4.64(dd,1H,J=9.00,4.89 Hz),3.56(m,1H),2.89(t,1H,J=13.69
Hz),2.65(m,2H),1.97(dd,1H,J=14.08,3.33 Hz),1.54(s,3H),0.66(s,3H),0.36(m,1H),0.59(s,3H)
Claims (38)
- 前記脱水条件が、トルエンとの共沸蒸留である、請求項13に記載の方法。
- 前記酸化がオゾンを用いて達成される、請求項18に記載の方法。
- 前記酸化がオゾンと、それに続くピニック酸化を用いて達成される、請求項18に記載の方法。
- 前記塩基がナトリウムtert−ブトキシドである、請求項24に記載の方法。
- 前記酸化がRuCl3及びNaIO4を用いて達成される、請求項23に記載の方法。
- 前記酸化剤がオゾンであり、前記酸が塩酸である、請求項37に記載の方法。
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