CN112759535B - Preparation method of PF-06651600 intermediate - Google Patents
Preparation method of PF-06651600 intermediate Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 88
- 238000000034 method Methods 0.000 claims abstract description 49
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 24
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- 150000001412 amines Chemical class 0.000 claims description 20
- 239000002585 base Substances 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 19
- 239000003054 catalyst Substances 0.000 claims description 16
- 230000035484 reaction time Effects 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- -1 p-methoxybenzyl Chemical group 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical group NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 4
- IDPURXSQCKYKIJ-UHFFFAOYSA-N 1-(4-methoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1 IDPURXSQCKYKIJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- IZDROVVXIHRYMH-UHFFFAOYSA-N methanesulfonic anhydride Chemical compound CS(=O)(=O)OS(C)(=O)=O IZDROVVXIHRYMH-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 3
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 abstract description 5
- 239000002184 metal Substances 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000004440 column chromatography Methods 0.000 abstract description 3
- 238000000746 purification Methods 0.000 abstract description 3
- 238000007363 ring formation reaction Methods 0.000 abstract description 3
- 238000007142 ring opening reaction Methods 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 230000009467 reduction Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- FZVQRSWZWHKIDC-LLVKDONJSA-N C(C)OC([C@@H](CCC(C)=C=O)NC(=O)OC(C)(C)C)=O Chemical compound C(C)OC([C@@H](CCC(C)=C=O)NC(=O)OC(C)(C)C)=O FZVQRSWZWHKIDC-LLVKDONJSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- 208000004631 alopecia areata Diseases 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- MIEJVQLUIIUQIQ-GOEBONIOSA-N tert-butyl n-[(3r,6s)-1-benzyl-6-methylpiperidin-3-yl]carbamate Chemical compound C[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CN1CC1=CC=CC=C1 MIEJVQLUIIUQIQ-GOEBONIOSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 3
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- YWWWGFSJHCFVOW-MRVPVSSYSA-N 1-o-tert-butyl 2-o-ethyl (2r)-5-oxopyrrolidine-1,2-dicarboxylate Chemical compound CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C YWWWGFSJHCFVOW-MRVPVSSYSA-N 0.000 description 2
- 201000004384 Alopecia Diseases 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 206010009900 Colitis ulcerative Diseases 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 230000003676 hair loss Effects 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 1
- JXUWZXFVCBODAN-UHFFFAOYSA-N 5-methylpyridin-3-amine Chemical compound CC1=CN=CC(N)=C1 JXUWZXFVCBODAN-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 210000003780 hair follicle Anatomy 0.000 description 1
- 208000024963 hair loss Diseases 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- QARBMVPHQWIHKH-KHWXYDKHSA-N methanesulfonyl chloride Chemical group C[35S](Cl)(=O)=O QARBMVPHQWIHKH-KHWXYDKHSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- WSJJUZNTRZTWIN-UHFFFAOYSA-N phenylmethanamine Chemical compound NCC1=CC=CC=C1.NCC1=CC=CC=C1 WSJJUZNTRZTWIN-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- 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
- C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
- C07D211/36—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 no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
-
- 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
Abstract
The invention relates to a preparation method of a PF-06651600 intermediate, belonging to the field of pharmaceutical chemistry. The method takes D-Boc-pyroglutamic acid ethyl ester as a raw material, and obtains a target compound 04 through format ring opening, metal chiral reduction, hydroxysulfonylation and cyclization. The method of the invention avoids chiral column resolution or resolution agent resolution, has mild reaction, easily obtained reagent, high product purity, high yield, safe operation, and no column chromatography purification, and is beneficial to industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of a PF-06651600 intermediate.
Background
Alopecia areata is an autoimmune disease that is primarily characterized by the loss of hair throughout the head, face, and body. The symptoms are caused by the attack of the patient's immune cells on the autologous hair follicles, primarily circular local hair loss. Alopecia areata has an average age of between 25 and 35 years, but can also affect children and adolescents and can occur in both men and women and all ethnicities.
PF-06651600 is a potent, selective inhibitor of JAK3 and has previously been identified as a breakthrough therapy in the FDA for the treatment of alopecia areata. Currently, it is subjected to a phase 3 clinical trial for the treatment of moderate to severe alopecia areata, while continuing the trial for the treatment of Rheumatoid Arthritis (RA), crohn's Disease (CD) and Ulcerative Colitis (UC); the structure of PF-06651600 is shown in the following formula:
in the prior art, 5-methyl-3-aminopyridine is used as a raw material, and as disclosed in WO2010048012, a rhodium metal catalyst is used for reducing a pyridine ring into a piperidine ring; WO2016112298 discloses the use of PtO 2 The pyridine ring is reduced as a catalyst. However, metal catalysts are expensive, generally reduced with hydrogen, heated and hydrogenated at high pressure for a long period of time, and the reaction conditions are severe. For example, ptO is used 2 The platinum black produced is flammable and dangerous to produce. In the prior art, the multi-step reaction needs column chromatography purification, and is difficult to realize large-scale production. In the prior art, (R) -N-3, 5-dinitrobenzoyl phenylglycine is used as a resolving agent, which is expensive, and the document (Organic Process Research)&Development (2019) records that the splitting agent has a severe exothermic phenomenon when in use, and potential safety hazards still exist when the splitting agent is not well controlled during production.
Therefore, there is an urgent need to find a new intermediate, or to research a new method for preparing an intermediate of PF-06651600, so as to obtain a method with simple operation, easy implementation, high yield, high purity, low cost, and environmental friendliness, thereby better preparing the obtained compound PF-06651600.
Disclosure of Invention
The invention provides a preparation method of a PF-06651600 intermediate, which takes D-Boc-pyroglutamic acid ethyl ester as a raw material to obtain a target compound 04 through format ring opening, metal chiral reduction, hydroxysulfonylation and cyclization. The compound 04 can continue to react to obtain the compound PF-06651600.
In a first aspect, the present invention provides a process for preparing compound 02 comprising: in a first solvent, the compound 01 reacts under the action of a catalyst, acid and first alkali to prepare a compound 02,
wherein,
R 1 one of Boc, cbz and Ts;
R 2 is one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl.
In some embodiments, the first solvent is at least one of DMF, DMSO, methanol, ethanol. In some embodiments, the first solvent is DMF.
In some embodiments, the acid is at least one of formic acid, acetic acid, ammonium formate. As a hydrogen source, the reaction is facilitated to proceed better.
In some embodiments, the molar ratio of the acid to compound 01 is from 10:1 to 1:1. In some embodiments, the molar ratio of the acid to compound 01 is from 8:1 to 3:1. In some embodiments, the molar ratio of the acid to compound 01 is from 6:1 to 5:1.
In some embodiments, the first base is at least one of TEA, ammonia water. In some embodiments, the first base is TEA.
In some embodiments, the molar ratio of the first base to compound 01 is from 4:1 to 1:1. In some embodiments, the molar ratio of the first base to compound 01 is from 3:1 to 2:1.
In some embodiments, the catalyst is at least one of the structures represented by the following formulas CAT 01-CAT 04:
in some embodiments, the catalyst is
Is favorable for better catalyzing and preparing the compound 02, and obtains the product with high chiral purity. .
In some embodiments, the molar ratio of catalyst to compound 01 is from 0.001:1 to 0.01:1. In some embodiments, the molar ratio of catalyst to compound 01 is 0.003:1 to 0.007:1. In some embodiments, the molar ratio of catalyst to compound 01 is 0.005:1.
In some embodiments, the reaction temperature of the reaction is from 10 ℃ to 80 ℃. In some embodiments, the reaction temperature of the reaction is from 20 ℃ to 50 ℃. In some embodiments, the reaction temperature of the reaction is from 30 ℃ to 40 ℃.
In some embodiments, the reaction time of the reaction is from 2h to 48h. In some embodiments, the reaction time of the reaction is from 4 hours to 24 hours. In some embodiments, the reaction time of the reaction is from 8h to 12h.
In a second aspect, the present invention provides a process for preparing compound 03 comprising reacting compound 02 with a sulfonylating agent in a solvent and in the presence of a base to give compound 03,
wherein,
R 1 one of Boc, cbz and Ts;
R 3 is one of Ms, ts and Tf.
In some embodiments, the second solvent is at least one of DCM, 2Me-THF, toluene. In some embodiments, the second solvent is DCM.
In some embodiments, the second base is at least one of TEA, DIPEA, pyridine, potassium carbonate. In some embodiments, the second base is TEA.
In some embodiments, the molar ratio of the second base to compound 2 is from 6:1 to 1:1. In some embodiments, the molar ratio of the second base to compound 2 is from 5:1 to 2:1. In some embodiments, the molar ratio of the second base to compound 02 is from 4:1 to 3:1.
In some embodiments, the sulfonylating agent is one of methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride. Facilitating better leaving for ring formation in subsequent reactions for the preparation of compound 04. In some embodiments, the sulfonylating agent is methanesulfonyl chloride.
In some embodiments, the molar ratio of sulfonylating agent to compound 02 is 4:1 to 1:1. In some embodiments, the molar ratio of sulfonylating agent to compound 02 is 3:1-2:1.
In some embodiments, the reaction temperature of the compound 02 with the sulfonylating agent is from-10 ℃ to 10 ℃. In some embodiments, the reaction temperature at which the compound 02 is reacted with the sulfonylating agent is from-5 ℃ to 5 ℃.
In some embodiments, the reaction time for the compound 02 to react with the sulfonylating agent is from 0.5h to 7h. In some embodiments, the reaction time for the compound 02 to react with the sulfonylating agent is from 1h to 5h. In some embodiments, the reaction time for the compound 02 to react with the sulfonylating agent is from 2h to 4h.
In a third aspect, the invention provides a process for preparing compound 04, comprising: the compound 03 is reacted with an amine reagent in a third solvent to give compound 04,
wherein,
R 1 one of Boc, cbz and Ts;
R 3 is one of Ms, ts and Tf;
R 4 is one of benzyl and p-methoxybenzyl.
In some embodiments, the third solvent is at least one of acetonitrile, DME, THF, 2Me-THF, toluene, water. In some embodiments, the third solvent is 2Me-THF. In some embodiments, the third solvent is benzylamine. In some embodiments, the third solvent is p-methoxybenzylamine, which facilitates more convenient preparation of compound 04.
In some embodiments, the molar ratio of amine reagent to compound 03 is from 10:1 to 1:1. In some embodiments, the molar ratio of amine reagent to compound 03 is from 8:1 to 2:1. In some embodiments, the molar ratio of amine reagent to compound 03 is from 6:1 to 4:1.
In some embodiments, the reaction temperature of the reaction with the amine reagent is from 20 ℃ to 80 ℃. In some embodiments, the reaction temperature of the reaction with the amine reagent is from 40 ℃ to 60 ℃.
In some embodiments, the reaction time for the reaction with the amine reagent is from 8 hours to 48 hours. In some embodiments, the reaction time for the reaction with the amine reagent is 12h to 36h. In some embodiments, the reaction time for the reaction with the amine reagent is 24 hours.
In a fourth aspect, the present invention provides a process for preparing compound 04, comprising: ring-opening the compound 00 through a format reaction to prepare a compound 01, catalyzing the compound 01 through a metal chiral catalyst, carrying out a reduction reaction to obtain a compound 02, carrying out a sulfonylation reaction on hydroxyl of the compound 02 to obtain a compound 03, and reacting the compound 03 with an amine reagent to obtain a target compound 04;
in the base, the base is used for the preparation of a compound,
R 1 one of Boc, cbz and Ts;
R 2 is one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl;
R 3 is one of Ms, ts and Tf;
R 4 is one of benzyl and p-methoxybenzyl.
The preparation method of the PF-06651600 intermediate provided by the invention avoids chiral column resolution or resolution agent resolution, has the advantages of mild reaction, easily obtained reagent, high product purity, high yield, safe operation, and no column chromatography purification, and is beneficial to industrial production.
In the description of the present invention, it should be understood that the terms "first," "second," and the like are used for descriptive purposes only and are not to be construed as indicating or implying a relative importance or number of technical features indicated. Thus, a feature defining "a first" or "a second" may explicitly or implicitly include one or more such feature. In the description of the present invention, the meaning of "a plurality" is two or more, unless explicitly defined otherwise.
In the description of the present specification, the descriptions of the terms "some implementations," "some embodiments," "examples," "particular examples," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
In the present invention, the expressions "compound 01" and "compound represented by formula (01)" mean the same compound.
Detailed Description
In order to better understand the technical solution of the present invention, the following further discloses some non-limiting examples, which are further described in detail.
The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
In the present invention, mmol means millimoles, h means hours, g means grams, ml means milliliters, eq means equivalent, M means mol/L, THF means tetrahydrofuran2Me-THF means 2-methyltetrahydrofuran, meOH means methanol, etOH means ethanol, CH 3 CN represents acetonitrile, DCM represents dichloromethane, DMF represents N, N-dimethylformamide, DMSO represents dimethyl sulfoxide, EA represents ethyl acetate, boc 2 O represents di-tert-butyl dicarbonate, TLC represents thin-layer chromatography, naOH represents sodium hydroxide, ms represents methanesulfonyl, ts or Tos represents p-toluenesulfonyl, NH 4 Cl represents ammonium chloride, naHCO 3 Represents sodium bicarbonate, na 2 CO 3 Sodium carbonate, DME, ethylene glycol dimethyl ether, TEA, triethylamine, meMgBr and methyl magnesium bromide.
EXAMPLE 1 preparation of (R) -2- (N-Boc-amino) -5-carbonyl-hexanoic acid ethyl ester (Compound 01-1)
Under the protection of nitrogen, 60g (1.0 eq,233.2 mmol) of Boc-D-pyroglutamic acid ethyl ester (compound 00-1) and 500ml of THF are sequentially added into a 1000ml three-port bottle, the temperature is reduced to minus 40 ℃ after stirring and clearing at room temperature, 110ml (1.4 eq,330 mmol) of MeMgBr format reagent is slowly added dropwise, after the dropwise addition, the temperature is slowly increased to minus 20 ℃ after the dropwise addition, TLC monitors the reaction, and 300ml of saturated NH is dropwise added after the raw material reaction is completed 4 The Cl solution was quenched, the aqueous phase was separated, extracted with 300ml of ethyl acetate, the combined organic phases were washed once with 500ml of water, dried under reduced pressure, added with 300ml of N-heptane, cooled down, stirred, filtered and dried to give 63.7g of an off-white solid of ethyl (2R) -2- (N-Boc-amino) -5-carbonyl-hexanoate (Compound 01-1) in 93% yield. Analysis data:
GC-MS:m/z:274.1(M+)；
1 H NMR(400MHz,CDCl 3 )δ5.16(d,J＝6.5Hz,1H),4.15(q,J＝7.1Hz,3H),2.61–2.41(m,2H),2.16–2.02(m,4H),1.84(td,J＝14.4,8.0Hz,1H),1.40(s,9H),1.24(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ207.32,172.27,155.42,79.76,61.33,52.92,39.29,29.85,28.22,26.46,14.07。
EXAMPLE 2 preparation of (2S, 5R) -2- (N-Boc-amino) -1, 5-hexanediol (Compound 02-1)
To a 100ml two-port flask, 10.92g (1.0 eq,40 mmol) of compound 01-1 and 40ml of DMF were added, and the mixture was stirred and dissolved, 13.7ml (6 eq,120 mmol) of glacial acetic acid, 13.3ml (2.4 eq,96 mmol) of TEA and 0.124g (0.005 eq,0.2 mmol) of Ru chiral catalyst (CAT 01) were added under nitrogen protection, the reaction was monitored by TLC at 20℃to 50℃for 24h, the reaction was complete, after the reaction was completed, the starting material was neutralized with saturated NaHCO3 solution, 80ml of EA was added for three times, 160ml of water was used for washing, the organic phase was dried over anhydrous sodium sulfate, the organic phase was dried under reduced pressure to give a colorless oil, N-heptane was added for Wen Xijing, and the solid was suction-filtered to give 7.46g of white solid (2S, 5R) -2- (N-Boc-amino) -1, 5-hexanediol (compound 02-1) in 80% yield. Analysis data:
GC:99％；
LC-MS:m/z(ESI):256.3(M+Na + ) + ；
1 H NMR(400MHz,CDCl 3 )δ5.07(s,1H),3.81(dd,J＝11.1,5.0Hz,1H),3.70(dd,J＝13.9,7.0Hz,1H),3.59(s,2H),3.18(d,J＝27.1Hz,1H),2.70(s,1H),1.77–1.46(m,4H),1.44(s,9H),1.19(d,J＝6.1Hz,3H)。
example 3 preparation of (2R, 5S) -1, 5-dimethyl-sulfo-2- (N-Boc-amino) hexane (Compound 03-1)
To a 100ml two-port flask, under nitrogen protection, 6g (1.0 eq,25.7 mmol) of compound 02-1 and 36ml of DCM were added, dissolved by stirring at room temperature, cooled to 0℃and 6.5g (2.5 eq,64.3 mmol) of TEA were added, stirred for 0.5h, the reaction temperature was controlled to less than 0℃and 6.5g (2.2 eq,56.7 mmol) of a solution of MsCl in DCM was added dropwise, the reaction was monitored by TLC after completion of the dropwise addition, the reaction was completed (about 1-2 h), 40ml of water was added for quenching, the separated liquid, the DCM layer was washed once with 40ml of saturated NaHCO3 and aqueous solution each, and evaporated to dryness under reduced pressure at room temperature to give 9.8g of (2R, 5S) -1, 5-dimethyl-sulfo-2- (N-Boc-amino) hexane (compound 03-1) as a yellow oil in 98% yield. Analysis data:
LC-MS:m/z(ESI):412.0(M+Na + ) + ；
1 H NMR(400MHz,CDCl 3 )δ4.82(d,J＝8.8Hz,2H),4.20(dd,J＝14.4,10.6Hz,2H),3.86(d,J＝28.2Hz,1H),3.02(d,J＝10.6Hz,6H),1.70(dd,J＝23.5,14.0Hz,4H),1.50–1.36(m,12H)。
example 4 (2S, 5R) -5- (N-Boc-amino) -2-methyl-1-benzylpiperidine (Compound 04-1)
To a 100mL two-necked flask under nitrogen protection, 9.8g (1.0 eq,25.1 mmol) of compound 03-1 was added, dissolved in 30mL of 2MeTHF, 13.5g (5.0 eq,126 mmol) of benzylamine (benzylamine) was slowly dropped under nitrogen protection, the temperature was raised to 60℃after the dropping was completed, the reaction was monitored by TLC, the reaction was completed, the solvent was distilled off under reduced pressure, 30mL of toluene was added, the temperature was lowered to 0℃and the glacial acetic acid adjusting system was added dropwise to neutrality, the aqueous phase was separated, extracted twice with toluene, the toluene layers were combined, the toluene layer was washed once with 90mL of water, and the toluene phase was dried under reduced pressure to give 6.5g of (2S, 5R) -5- (N-Boc-amino) -2-methyl-1-benzylpiperidine (compound 04-1) as a yellow oil, yield 84.8%. Analysis data:
LC-MS:m/z(ESI):305.3(M+H) + ；
1 H NMR(400MHz,CDCl 3 )δ7.41–7.30(m,5H),5.48(d,J＝5.7Hz,1H),4.52(s,1H),4.06(d,J＝13.5Hz,1H),3.76(s,1H),3.32(d,J＝13.5Hz,1H),2.71(d,J＝11.2Hz,1H),2.41(dd,J＝12.3,6.1Hz,1H),2.25(d,J＝10.4Hz,1H),1.76(d,J＝11.7Hz,1H),1.60(dd,J＝10.4,6.5Hz,2H),1.44(s,9H),1.24(d,J＝5.8Hz,3H)。
while the methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and combinations of the methods and applications described herein can be made and applied within the spirit and scope of the invention. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention.
Claims (39)
1. A method of preparing compound 02, comprising: in a first solvent, the compound 01 reacts under the action of a catalyst, acid and first alkali to prepare a compound 02,
wherein,
R 1 one of Boc, cbz and Ts;
R 2 is one of methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl;
the catalyst is of the formula CAT01,
2. the method of claim 1, wherein the first solvent is at least one of DMF, DMSO, methanol, ethanol.
3. The method of claim 1, wherein the acid is at least one of formic acid, acetic acid, ammonium formate.
4. The method of claim 1, wherein the molar ratio of acid to compound 01 is from 10:1 to 1:1.
5. The method of claim 1, wherein the molar ratio of acid to compound 01 is from 8:1 to 3:1.
6. The method of claim 1, wherein the molar ratio of acid to compound 01 is from 6:1 to 5:1.
7. The method of claim 1, wherein the first base is at least one of TEA, ammonia, and aqueous ammonia.
8. The method of claim 1, wherein the molar ratio of the first base to compound 01 is from 4:1 to 1:1.
9. The method of claim 1, wherein the molar ratio of the first base to compound 01 is from 3:1 to 2:1.
10. The method of claim 1, wherein the molar ratio of catalyst to compound 01 is from 0.001:1 to 0.01:1.
11. The method of claim 1, wherein the molar ratio of catalyst to compound 01 is from 0.003:1 to 0.007:1.
12. The process of claim 1, wherein the molar ratio of catalyst to compound 01 is 0.005:1.
13. The method according to claim 1, wherein the reaction temperature of the reaction is 10 ℃ to 80 ℃.
14. The method according to claim 1, wherein the reaction temperature of the reaction is 20 ℃ to 50 ℃.
15. The method according to claim 1, wherein the reaction temperature of the reaction is 30-40 ℃.
16. The method according to claim 1, wherein the reaction time of the reaction is 2h to 48h.
17. The method according to claim 1, wherein the reaction time of the reaction is 4h to 24h.
18. The method according to claim 1, wherein the reaction time of the reaction is 8-12 h.
19. A process for preparing compound 03, which comprises preparing compound 02 according to the process of any one of claims 1 to 18, then reacting compound 02 with a sulfonylating agent in a second solvent in the presence of a second base to give compound 03,
wherein,
R 1 is one of Boc, cbz and Ts;
R 3 is one of Ms, ts and Tf.
20. The method of claim 19, wherein the second solvent is at least one of DCM, 2Me-THF, toluene.
21. The method of claim 19, wherein the second base is at least one of TEA, DIPEA, pyridine, and potassium carbonate.
22. The method of claim 19, wherein the molar ratio of the second base to compound 02 is from 6:1 to 1:1.
23. The method of claim 19, wherein the molar ratio of the second base to compound 02 is from 5:1 to 2:1.
24. The method of claim 19, wherein the molar ratio of the second base to compound 02 is from 4:1 to 3:1.
25. The method of claim 19, wherein the sulfonylating agent is one of methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, and trifluoromethanesulfonic anhydride.
26. The method of claim 19, wherein the molar ratio of sulfonylating agent to compound 02 is from 4:1 to 1:1.
27. The method of claim 19, wherein the molar ratio of sulfonylating agent to compound 02 is 3:1-2:1.
28. A method of preparing compound 04, comprising: the process according to any one of claims 19-27 for preparing compound 03, then reacting compound 03 with an amine reagent in a third solvent to obtain compound 04,
wherein,
R 1 one of Boc, cbz and Ts;
R 3 is one of Ms, ts and Tf;
R 4 is one of benzyl and p-methoxybenzyl.
29. The method according to claim 28, wherein the third solvent is at least one of acetonitrile, DME, THF, 2Me-THF, toluene, water.
30. The method of claim 28, wherein the third solvent is benzylamine or p-methoxybenzylamine.
31. The method of claim 28, wherein the amine reagent is one of benzylamine, p-methoxybenzylamine.
32. The method of claim 28, wherein the molar ratio of amine reagent to compound 03 is from 10:1 to 1:1.
33. The method of claim 28, wherein the molar ratio of amine reagent to compound 03 is from 8:1 to 2:1.
34. The method of claim 28, wherein the molar ratio of amine reagent to compound 03 is from 6:1 to 4:1.
35. The method of claim 28, wherein the reaction temperature with the amine reagent is from 20 ℃ to 80 ℃.
36. The method of claim 28, wherein the reaction temperature with the amine reagent is from 40 ℃ to 60 ℃.
37. The method of claim 28, wherein the reaction time for the reaction with the amine reagent is from 8h to 48h.
38. The method of claim 28, wherein the reaction time for the reaction with the amine reagent is from 12h to 36h.
39. The method of claim 28, wherein the reaction time for the reaction with the amine reagent is 24 hours.
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