SA111320775B1 - عملية لتحضير مثبطات pan-CDK من الصيغة (I)، والمركبات الوسطية من المستحضر - Google Patents
عملية لتحضير مثبطات pan-CDK من الصيغة (I)، والمركبات الوسطية من المستحضر Download PDFInfo
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- SA111320775B1 SA111320775B1 SA111320775A SA111320775A SA111320775B1 SA 111320775 B1 SA111320775 B1 SA 111320775B1 SA 111320775 A SA111320775 A SA 111320775A SA 111320775 A SA111320775 A SA 111320775A SA 111320775 B1 SA111320775 B1 SA 111320775B1
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000000543 intermediate Substances 0.000 title claims abstract description 5
- 238000000034 method Methods 0.000 title claims description 12
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims 7
- PZHMENGEVRZXBN-UHFFFAOYSA-N imino-nitro-oxo-phenyl-$l^{6}-sulfane Chemical compound [O-][N+](=O)S(=N)(=O)C1=CC=CC=C1 PZHMENGEVRZXBN-UHFFFAOYSA-N 0.000 claims 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 5
- 150000003839 salts Chemical class 0.000 claims 5
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 4
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- 230000001590 oxidative effect Effects 0.000 claims 3
- CMIBUZBMZCBCAT-HOTGVXAUSA-N (2s,3s)-2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)O[C@H](C(O)=O)[C@@H](C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-HOTGVXAUSA-N 0.000 claims 2
- MXWVNAOIXKIIJK-UHFFFAOYSA-N 1-nitro-2-(2-nitrophenyl)sulfanylbenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1SC1=CC=CC=C1[N+]([O-])=O MXWVNAOIXKIIJK-UHFFFAOYSA-N 0.000 claims 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims 2
- 150000008059 anilinopyrimidines Chemical class 0.000 claims 2
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 claims 2
- 238000003776 cleavage reaction Methods 0.000 claims 2
- VRLDVERQJMEPIF-UHFFFAOYSA-N dbdmh Chemical compound CC1(C)N(Br)C(=O)N(Br)C1=O VRLDVERQJMEPIF-UHFFFAOYSA-N 0.000 claims 2
- FCIGYBRSRRKJJD-UHFFFAOYSA-N imino-nitro-phenyl-$l^{4}-sulfane Chemical compound [O-][N+](=O)S(=N)C1=CC=CC=C1 FCIGYBRSRRKJJD-UHFFFAOYSA-N 0.000 claims 2
- 230000003647 oxidation Effects 0.000 claims 2
- 238000007254 oxidation reaction Methods 0.000 claims 2
- 229910052763 palladium Inorganic materials 0.000 claims 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims 2
- 125000006239 protecting group Chemical group 0.000 claims 2
- 230000007017 scission Effects 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- IWWLVWWEZSOTJH-IUCAKERBSA-N (2S,3S)-2,3-dihydroxy-4-(4-methylbenzoyl)oxy-4-oxobutanoic acid Chemical compound C1(=CC=C(C=C1)C(=O)OC([C@@H](O)[C@H](O)C(=O)O)=O)C IWWLVWWEZSOTJH-IUCAKERBSA-N 0.000 claims 1
- KELZBYQXUNVXEU-RKDXNWHRSA-N (4r,5r)-4,5-dimethyl-2-phenyl-1,3-dioxolane Chemical compound O1[C@H](C)[C@@H](C)OC1C1=CC=CC=C1 KELZBYQXUNVXEU-RKDXNWHRSA-N 0.000 claims 1
- OWBTYPJTUOEWEK-QWWZWVQMSA-N (R,R)-butane-2,3-diol Chemical compound C[C@@H](O)[C@@H](C)O OWBTYPJTUOEWEK-QWWZWVQMSA-N 0.000 claims 1
- NRKYWOKHZRQRJR-UHFFFAOYSA-N 2,2,2-trifluoroacetamide Chemical compound NC(=O)C(F)(F)F NRKYWOKHZRQRJR-UHFFFAOYSA-N 0.000 claims 1
- IDRUEHMBFUJKAK-UHFFFAOYSA-N 2,4-dichloro-5-(trifluoromethyl)pyrimidine Chemical compound FC(F)(F)C1=CN=C(Cl)N=C1Cl IDRUEHMBFUJKAK-UHFFFAOYSA-N 0.000 claims 1
- AXBVSRMHOPMXBA-UHFFFAOYSA-N 4-nitrothiophenol Chemical compound [O-][N+](=O)C1=CC=C(S)C=C1 AXBVSRMHOPMXBA-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- RHRVBJCIQVHJAL-UHFFFAOYSA-N N(C1=CC=CC=C1)S(=O)=N Chemical class N(C1=CC=CC=C1)S(=O)=N RHRVBJCIQVHJAL-UHFFFAOYSA-N 0.000 claims 1
- 230000029936 alkylation Effects 0.000 claims 1
- 238000005804 alkylation reaction Methods 0.000 claims 1
- 238000005576 amination reaction Methods 0.000 claims 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims 1
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 claims 1
- 239000003054 catalyst Substances 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 claims 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims 1
- JZBWUTVDIDNCMW-UHFFFAOYSA-L dipotassium;oxido sulfate Chemical compound [K+].[K+].[O-]OS([O-])(=O)=O JZBWUTVDIDNCMW-UHFFFAOYSA-L 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 238000005984 hydrogenation reaction Methods 0.000 claims 1
- 229910052742 iron Inorganic materials 0.000 claims 1
- 229910052744 lithium Inorganic materials 0.000 claims 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical group [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims 1
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 claims 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 102000016736 Cyclin Human genes 0.000 abstract 1
- 108050006400 Cyclin Proteins 0.000 abstract 1
- 102000003903 Cyclin-dependent kinases Human genes 0.000 abstract 1
- 108090000266 Cyclin-dependent kinases Proteins 0.000 abstract 1
- 239000003112 inhibitor Substances 0.000 abstract 1
- 229940126062 Compound A Drugs 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N Sec-butyl alcohol Natural products CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000010923 batch production Methods 0.000 description 1
- 230000010013 cytotoxic mechanism Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members 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
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- 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
- C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C381/00—Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
- C07C381/10—Compounds containing sulfur atoms doubly-bound to nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Hydrogenated Pyridines (AREA)
- Peptides Or Proteins (AREA)
- Pyrrole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
يتعلق الاختراع الحالي بعملية جديدة لتحضير مثبطات كل kinase معتمدة على cyclin (cyclin dependent kinase) (pan-CDK) من الصيغة (I)، والمركبات الوسطية من المستحضر.
Description
ل عملية لتحضير مثبطات pan-CDK من الصيغة ()؛ والمركبات الوسطية من المستحضر Process for the preparation of pan-CDK inhibitors of the formula (I), and intermediates of the preparation الوصف الكامل خلفية الاختراع يتعلق الاختراع الحالي بعملية جديدة لتحضير مثبطات pan-CDK من الصيغة ()؛ والمركبات الوسطية من المستحضر. الطلب الدولي رقم ١١ 70١٠0/04750708 تذكر مركبات من الصيغة العامة ()؛ تحديدا Lad ٠ المركب A والعملية لتحضيره ؛ التي يشكل كشفها أقرب فن سابق. تكون العملية طبقا للطلب الدولي رقم 70٠0047650728 أ١ هي عملية متجمعة لها ٠١ مراحل مع إنتاجية كلية 77 للترتيب الأطول. الوصف العام للاختراع تتعلق العملية الجديدة بمركبات من الصيغة oT) تحديدا المركب (2R,3R)-3- {[2- {[4-(S-cyclopropylsulphonimidoyl) phenyl] amino} -5- Ve (trifluoromethyl) pyrimidin-4-ylJoxy}butan-2-ol (المركب (A ؛ الذي تم تطوير نشاطه المضاد للورم عن طريق آلية سامة للخلايا (cytotoxic) لقد تم الآن الحصول على عملية تحضير لأجل مركب من الصيغة العامة oD) NH 0 لا HN Ny CH, 0) AL OH XY F F Hs F a sa R? مجموعة C1-Ce-alkyl أو «C3-C7-cycloalkyl dda المناسبة على نطاق أكبر والتي تتغلب على عيوب عمليات التحضير من الفن السابق لهذا الصنف من المواد.
Claims (1)
- . ov عناصر_ الحماية (I) لتحضير مركب من الصيغة العامة (process) عملية -١ ١ 0, NH لبلاS., 4 re HN Ny CH, 0 A OH F F | oH ; Y Cua VF «C3-Cr-cycloalkyl أو حلقة C;-Cg-alkyl هو مجموعة R* 4 تتميز بواحدة على الأقل من الخطوات التالية: © في وجود كربونات بوتاسيوم في 4-nitrothiophenol لأجل Alkylation SN (La) 1 (I-1) من الصيغة nitrophenyl-sulphide لإعطاء (NMP) N-methyl-pyrrolidinone ١ X SH ~N~4 R _— O,N 2 O,N 1-1 A «0-SO,-(4-methylphenyl) 5} 0-SO,-CH; ل «Cl Br مرو X Cua 4 من nitrophenyl-sulphide JaY oxidative amination أمينية مؤكسدة le (Ib) Ye من الصيغة trifluoroacetate محمي مع nitrophenyl-sulphilimine لإعطاء (I-1) الصيغة ١١ 0-10( OY 9 [oxidizing امال عامل Sa pd ae ld 1 R or = SL ON Lr ON al 1-10 11 من trifluoroacetate محمي مع nitrophenyl-sulphilimine عملية أكسدة لأجل (Lo) Vé من trifluoroacetate محمي مع nitrophenyl-sulphoximine لإعطاء (I-10) الصيغة ٠ (I-11) من الصيغة nitrophenyl-sulphoximine الصيغة (3-) وازالة حماية لاحقة لإعطاء 1 of 9 0 N A CF, A 0 NH 1 ol 3 لا 5 Ss م5 O,N 10 oN 3 oN 1-1 لال مع (I-11) من الصيغة nitrophenyl-sulphoximine لأجل racemate انشقاق (1d) YA (+)-di-O-p-toluoyl-D-tartaric acid مساعدة 40. NH Os O, NH How" Q ON 2s I-11-R-D-Tol-Tart م١ — ٠ ON 1-11 (rac.) cs Oo. NH 0: ال 1:9 4 or " Lr ; a ON ٠-3-5 I-11-R Y. من الصيغة nitrophenyl-sulphoximine من R حيث يطلق بعد ذلك إنانتيومر AR مرة أخرى لتشكيل trifluoroacetate من } لأملاح ويتم إدخال مجموعة حماية (I-11-R) ٠" من الصيغة trifluoroacetate محمي مع nitrophenyl-sulphoximine من R إنانتيومر YY «(I-3-R) ٠4 trifluoroacetate محمي مع nitrophenyl-sulphoximines تتم الهدرجة لأجل (Le) Yo : من trifluoroacetate محمي مع anilino-sulphoximines لإعطاء (-3-R) من الصيغة ١ الصيغة (1-4-8 مع حفاز بلاديوم مدمم مع حديد YY CF, 0 »لا CF, . 0. MN Nv AO 4 0 NZ I=" —— مع R ار ? I-3-R HN I4-R YAده (LH) 4 تحضير (I-5-A) (2R,3R)-3-(benzyloxy)butan-2-0l في عملية من مرحلتين ٠ - عبر (4R,5R)-4,5-dimethyl-2-phenyl-1,3-dioxolane (ذ-1-12؛ حيث نتمم ١ المرحلة الأولى مع pyridinium p-toluenesulphonate في toluene ثم يحدث اختزال diisobutylaluminium hydride YY في ‘toluene I 00 A 0_0 3 : الكل م 1 سس يج Ho Ny" ب HO” : (2R,3R)-Butane-2,3-diol112-A I-5-A 79 لإعطاء 2 4-dichloro-5-trifluoromethylpyrimidine مع (I-5-A) اقتران (Lg) ve 4-{[(2R,3R)-3~(benzyloxy)butan-2-ylJoxy}-2-chloro-5-(trifluoro methyl) pyrimidine Yo ethereal مذيبات ALi مع قاعدة (-7-A) ا i A NHo” © + را UL انكل ز 8 “AA cl “AA 0 ببح 0 CF, CF, : I-5-A 17-A2,4-Dichloro-5-trifluoromethylpyrimidine vy anilino-pyrimidines من benzenesulphonic acid تحضير أملاح (Lh) YA ١ بواسطة اقتران محفز مع (I-8-R-BSA) المحمي بصورة مزدوجة من الصيغة 1 (I-4-R) 5s (I-7-A) من benzenesulphonic acid ٠1 أل «+ لا لم SN : Ss 0 “AA AO + و 0 + H,N 2 2 CF, 7 I-7-A I4-R مع 0 ب“ 4 X SO,H R Benzenesulphonic acid HN ———————— © جمد “Ao ALO CF, : 1-8-R-BSA £9 من benzenesulphonic acid إزالة مجموعات الحماية بالاتشقاق في أملاح (Li) رد بواسطة هدرجة مع (I-8-R-BSA) محمية بصورةٌ مزدوجة من الصيغة anilino-pyrimidines £Y بلاديوم على كربون منشط وهيدروجين في 0608001 وأيضا بالمعالجة مع كربونات بوتاسيوم tf )( لإعطاء مركبات من الصيغة methanol في 8 CF, - Cs oN ~ CF 8 SOH ld r= ميحد 0 لخر © HN a > 1 2 ١ : لك BN “hoo " بر : CF, 2 “AA 0 AN OH CF, : 1-8-R-BSA OL NH معي HN ١ —_— N A N = “AA ° 2 OH CF, : 0 £1 ¢) طبقا لعنصر الحماية (process) 7؟- عملية ١ oxidizing كعامل 1 ,3-dibromo-5,5-dimethylhydantoin يستخدم (Lb) حيث في الخطوة 7 كعامل كاشف. trifluoroacetamide ويستخدم " ١ طبقا لعنصر الحماية (process) عملية -١ ١ ov + potassium peroxomonosulphate تحدث الأكسدة مع (Lc) حيث في الخطوة ¥ ٠ طبقا لعنصر الحماية (process) ؛- عملية ١ - مع -ل0-( (I-11) من الصيغة notrophenyl-sulphoximine يتبلور «(I.d) حيث في الخطوة 00010016 0 acetonitrile في O-p-toluoyl-D-tartaric acid ~~ ¥ ١ طبقا لعنصر الحماية (process) Adee —0 ١ المستخدمة همي lithium حيسث في الخطوة (ع1» تكون قاعدة tetrahydrofuran المستخدم هو ethereal ويكون المذيب lithium hexamethyldisilazide Y من nitrophenyl-sulphoximines من (I-11-R-D-Tol-Tatr.) من الصيغة (salts) أملاح -١ ١ وا من الصيغة (+)-di-O-p-toluoyl-D-tartaric acid ([-11-R) الصيغة ¥ مع (I-11-A-R-D-Tol-Tatr.) ¥ “Os نح “OH on rr upd ب <2 0: How و 9 © NH دا )ضضم rv ON 11-R-D-Tol-Tart I-11-A-R-D-Tol-Tart ¢ .C3-C-cycloalkyl أو حلقة Ci-Ce-alkyl حيث 1283 هو مجمرعة © (I-8-R-BSA) 5 (I-8-R-BSA) من الصيغة (intermediates) المركبات الوسطية -# ١ CF, CF, 0 Nv N 0 2 هد oF ope ATO AVG Gand Qed CF, : CF, : I-8-R-BSA I-8-A-R-BSA ¥ .C3-Cy-cycloalkyl أو حلقة C-Co-alkyl هو مجموعة Rf Cua ¥
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| DE102010046720A DE102010046720A1 (de) | 2010-09-23 | 2010-09-23 | Verfahren zur Herstellung von pan-CDK-Inhibitoren der Formel (l), sowie Intermediate der Herstellung |
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| WO2014173815A1 (en) * | 2013-04-23 | 2014-10-30 | Bayer Pharma Aktiengesellschaft | Use of (rs)-s-cyclopropyl-s-(4-{[4-{[(1r, 2r)-2-hydroxy-1-methylpropyl]oxy}-5- (trifluoromethyl)pyrimidin-2-yl]amino}phenyl)sulphoximide for the treatment of specific tumours |
| CN111433203B (zh) | 2017-10-05 | 2024-02-13 | 创新分子股份有限公司 | 作为抗病毒化合物的取代噻唑的对映异构体 |
| KR20200119800A (ko) | 2018-02-13 | 2020-10-20 | 바이엘 악티엔게젤샤프트 | 미만성 거대 b-세포 림프종을 치료하기 위한 5-플루오로-4-(4-플루오로-2-메톡시페닐)-n-[4-[(s-메틸술폰이미도일)메틸]피리딘-2-일]피리딘-2-아민의 용도 |
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| DE10349423A1 (de) * | 2003-10-16 | 2005-06-16 | Schering Ag | Sulfoximinsubstituierte Parimidine als CDK- und/oder VEGF-Inhibitoren, deren Herstellung und Verwendung als Arzneimittel |
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