CN104672179A - Preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate - Google Patents
Preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate Download PDFInfo
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- CN104672179A CN104672179A CN201510083602.2A CN201510083602A CN104672179A CN 104672179 A CN104672179 A CN 104672179A CN 201510083602 A CN201510083602 A CN 201510083602A CN 104672179 A CN104672179 A CN 104672179A
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- BRMIWZWAGRRHEN-NSHDSACASA-N CC(C)C[C@@H](C(C(C)=C)=O)NC(OC(C)(C)C)=O Chemical compound CC(C)C[C@@H](C(C(C)=C)=O)NC(OC(C)(C)C)=O BRMIWZWAGRRHEN-NSHDSACASA-N 0.000 description 1
- DDMPMIMTLBGEHT-IINYFYTJSA-N CC(C)C[C@@H](C([C@]1(C)OC1)=O)NC(OC(C)(C)C)=O Chemical compound CC(C)C[C@@H](C([C@]1(C)OC1)=O)NC(OC(C)(C)C)=O DDMPMIMTLBGEHT-IINYFYTJSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/19—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic hydroperoxides
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Abstract
The invention relates to a preparation method of a carfilzomib intermediate: [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate. The preparation method comprises the following step: adding triphenylphosphine and tert-butyl alcohol hydroperoxide to a compound (III) to carry out catalytic reaction in the presence of an asymmetric chiral catalyst (R)-La-BINOL. The compound (III) is shown in a formula in the specification. The carfilzomib intermediate (I) can be synthesized with a starting material (III) by adopting the preparation method. The preparation method is accessible in used raw materials and simple in reaction conditions, is simple and convenient to operate, is simple in aftertreatment, has good selectivity, is good in yield and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of Ka Feizuo meter intermediate: the preparation method of [(1S)-3-methyl isophthalic acid-[[(2R)-2-methyl epoxy ethyl] carbonyl] butyl] t-butyl carbamate.
Background technology
Ka Feizuo meter (Carfilzomib), chemistry (S)-2-((S)-2-(2-(2H-1 by name, 4-oxazines-4 (3H)-Ji) kharophen)-4-phenylbutanamides)-4-methyl-N-((S)-1-((S)-4-methyl isophthalic acid-((R)-2-methyl oxirane-2-base)-1-oxo-pentane-2-base is amino)-1-oxo-3-phenyl third-2-base) valeramide, be the proteinoid enzyme body inhibitor developed by Proteolix, be used for the treatment of the multiple myeloma of recurrence refractory.Before on July 20th, 2012 is ratified to be used for the treatment of by FDA (Food and Drug Adminstration) (FDA), accept multiple myeloma (MM) patient of at least 2 kinds of medicines (comprising Velcade and immunomodulator treatment), its chemical structure is as follows:
Compound shown in formula (I) is the intermediate of Synthesis Card Fei Zuo meter, chemical name is [(1S)-3-methyl isophthalic acid-[[(2R)-2-methyl epoxy ethyl] carbonyl] butyl] t-butyl carbamate, and compound shown in formula (I) is through linked reaction i.e. obtained Ka Feizuo meter.As key intermediate, compou nd synthesis shown in formula (I) is shown in the earliest and is reported in Bioorg.Med.Chem.Lett.1999,9,2283, and synthetic route is as follows:
Obtain the mixture of formula (I) and formula (II) with the productive rate of 76% in this route, compound (I): the weight ratio of compound (II) is 1.7:1, this reaction is wayward, selectivity is poor, and the crystal property of compound (I), compound (II) is poor, the two is not easily separated.
Based on pharmacy value and the good market outlook of Ka Feizuo meter, find a kind of easy and simple to handle, cost is lower, and yield is higher, and the method for the applicable suitability for industrialized production compound (I) that controllability is strong is imperative.
Summary of the invention
The object of the invention is the defect for prior art, provide a kind of cost low, yield is good, the novel method of the intermediate of the applicable suitability for industrialized production Ka Feizuo meter that controllability is strong.
The present invention relates to a kind of Ka Feizuo meter intermediate: [(1S)-3-methyl isophthalic acid-[[(2R)-2-methyl epoxy ethyl] carbonyl] butyl] t-butyl carbamate (shown in formula I compound) preparation method, comprise the steps: under asymmetric chiral catalyst (R)-La-BINOL exists, add triphenylphosphine in compound (III), peroxy tert-butyl alcohol carries out catalyzed reaction
Described (R)-La-BINOL is the compound with following structure:
Further, catalytic reaction process also comprises solvent phase, and its consumption is consumption well known to those skilled in the art, such as, be 5-10 times of reactant, the wherein optional tetrahydrofuran (THF) of solvent phase, methylene dichloride, toluene, sherwood oil, Virahol, ethyl acetate, acetone, preferred toluene.
Preferably, the consumption of (R)-La-BINOL is the 1-10mol% of compound (III), most preferably 2mol%.
Preferably, the consumption of triphenylphosphine is no less than the 20mol% of compound (III), most preferably 20mol%.
Preferably, the consumption of peroxy tert-butyl alcohol is 2-5 times of compound (III), and more preferably 2-3 doubly, most preferably 3 times.
Mol% described in this patent refers to the molar percentage relative to starting material compound (III).
Described temperature of reaction is 0-50 DEG C, and preferred room temperature condition reaction, react under room temperature condition, react completely required shortest time.
The present invention can realize by starting raw material (III) Synthesis Card Fei Zuo meter intermediate (I).Use raw material to be all easy to get, reaction conditions is simple, easy and simple to handle, and aftertreatment is simple, and selectivity is good, and yield is good, is applicable to suitability for industrialized production.
The present inventor also finds, when solvent is toluene, (R) consumption of-La-BINOL is the 2mol% of compound (III), the consumption of triphenylphosphine is the 20mol% of compound (III), when the mole dosage of peroxy tert-butyl alcohol is 3 times of compound (III), efficiently solve the drawback that in background technology, prior art exists, reaction yield reaches 85%, and ee value reaches 93%, and strengthening the consumption of (R)-La-BINOL, triphenylphosphine or peroxy tert-butyl alcohol, yield and ee value there is no growth.
The present invention relates to a kind of Ka Feizuo meter intermediate: the preparation method of [(1S)-3-methyl isophthalic acid-[[(2R)-2-methyl epoxy ethyl] carbonyl] butyl] t-butyl carbamate, adopt asymmetric chiral catalyst, triphenylphosphine, peroxy tert-butyl alcohol catalyzed reaction, the ee value of the product finally obtained reaches 93%, and yield reaches 85%.Present method is simple to operate, and cost is low, and product purity is high, and yield is high, is applicable to industrial production preparation.
Embodiment
Set forth the present invention further below in conjunction with specific embodiment, should be understood that following examples are only not used in for illustration of the present invention and limit the scope of the invention.
In the following example, method therefor if no special instructions, is ordinary method.Material required in following examples or reagent, be market if no special instructions and buy.
Embodiment 1
Compound III (102g, 0.4mol) is added, asymmetric chiral catalyst (R)-La-BINOL (3.24g in the reaction flask of 1L, 2mol%), triphenylphosphine (14.8g, 20mol%), 500mL toluene, stirring at room temperature.Then, peroxy tert-butyl alcohol (108g, 1.2mol) is dripped slowly. after reaction 0.5h, TLC monitors, and after reacting completely, filtering reacting liquid, collects filtrate.Filtrate is with the cancellation of 300mL saturated sodium bisulfite solution, decompression rotary evaporation tetrahydrofuran (THF), then add ethyl acetate 400mL and carry out extraction treatment, organic phase uses 100mL water washing successively, the water washing of 100ml saturated common salt, anhydrous sodium sulfate drying, decompression is spin-dried for obtain 92g pale yellow oil, be Compound I, yield 85.0%, ee value is 93%.
Compound I
1h NMR (400MHz, DMSO) δ 7.11 (d, J=7.6Hz, 1H), 4.08 (dd, J=14.1,7.3Hz, 1H), 3.16 (d, J=5.2Hz, 1H), 2.99 (d, J=5.2Hz, 1H), 1.75 – 1.58 (m, 1H), 1.41 (s, 3H), 1.36 (s, 9H), 1.31 – 1.24 (m, 2H), 0.87 (t, J=6.6Hz, 6H).
Embodiment 2
Reaction solvent changes to tetrahydrofuran (THF) by toluene, and all the other, with embodiment 1, finally obtain Compound I, and yield 84.1%, ee value is 91%.
Embodiment 3
Reaction solvent changes to methylene dichloride by toluene, and all the other, with embodiment 1, finally obtain Compound I, and yield 80.0%, ee value is 85%.
Embodiment 4
Reaction solvent changes to sherwood oil by toluene, and all the other, with embodiment 1, finally obtain Compound I, and yield 82.3%, ee value is 90%.
Embodiment 5
Reaction solvent changes to Virahol by toluene, and all the other, with embodiment 1, finally obtain Compound I, and yield 80.6%, ee value is 86%.
Embodiment 6
Reaction solvent changes to ethyl acetate by toluene, and all the other, with embodiment 1, finally obtain Compound I, and yield 82.5%, ee value is 79%.
Embodiment 7
Reaction solvent changes to acetone by toluene, and all the other, with embodiment 1, finally obtain Compound I, and yield 86.2%, ee value is 76%.
Embodiment 8
By changing the add-on of (R)-La-BINOL and triphenylphosphine, all the other finally obtain test-results shown in table 1 with embodiment 1:
Table 1 difference amount R)-La-BINOL and triphenylphosphine composite reaction gained testing data table
As can be seen from Table 1, when solvent is toluene, (R) consumption of-La-BINOL is the 2mol% of compound (III), the consumption of triphenylphosphine is the 20mol% of compound (III), when the mole dosage of peroxy tert-butyl alcohol is 3 times of compound (III), reaction yield reaches 85%, and ee value reaches 93%, and strengthening the consumption of (R)-La-BINOL, triphenylphosphine or peroxy tert-butyl alcohol, yield and ee value there is no growth.
Embodiment 9
The mole dosage of peroxy tert-butyl alcohol is 2 times of compound (III), and all the other, with embodiment 1, finally obtain Compound I, and yield 81.7%, ee value is 86%.
Embodiment 10
The mole dosage of peroxy tert-butyl alcohol is 4 times of compound (III), and all the other, with embodiment 1, finally obtain Compound I, and yield 84.2%, ee value is 92%.
Embodiment 11
The mole dosage of peroxy tert-butyl alcohol is 5 times of compound (III), and all the other, with embodiment 1, finally obtain Compound I, and yield 82.5%, ee value is 90%.
Above content is only to present invention process route example and explanation; affiliated those skilled in the art make various amendment to described specific embodiment or supplement or adopt similar mode to substitute; only otherwise depart from the design of invention or surmount this scope as defined in the claims, protection scope of the present invention all should be belonged to.
Claims (10)
1. the preparation method of one kind [(1S)-3-methyl isophthalic acid-[[(2R)-2-methyl epoxy ethyl] carbonyl] butyl] t-butyl carbamate, comprise the steps:, under asymmetric chiral catalyst (R)-La-BINOL exists, to add triphenylphosphine in compound (III) and peroxy tert-butyl alcohol carries out catalyzed reaction
2. preparation method according to claim 1, is characterized in that, catalytic reaction process also comprises solvent phase, and wherein solvent phase is tetrahydrofuran (THF), methylene dichloride, toluene, sherwood oil, Virahol, ethyl acetate, acetone.
3. preparation method according to claim 2, is characterized in that, solvent phase is toluene.
4. the preparation method according to claim 1-3 any one, is characterized in that, the consumption of (R)-La-BINOL is the 1-10mol% of compound (III).
5. preparation method according to claim 4, is characterized in that, the consumption of (R)-La-BINOL is the 2mol% of compound (III).
6. preparation method according to claim 1 and 2, is characterized in that, the consumption of triphenylphosphine is no less than the 20mol% of compound (III).
7. preparation method according to claim 6, is characterized in that, the consumption of triphenylphosphine is the 20mol% of compound (III).
8. preparation method according to claim 1 and 2, is characterized in that, the mole dosage of peroxy tert-butyl alcohol is 2-5 times of compound (III).
9. preparation method according to claim 8, is characterized in that, the mole dosage of peroxy tert-butyl alcohol is 2-3 times of compound (III).
10. preparation method according to claim 9, is characterized in that, the consumption of peroxy tert-butyl alcohol is 3 times of compound (III).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108373456A (en) * | 2018-02-06 | 2018-08-07 | 中国科学院兰州化学物理研究所苏州研究院 | A kind of synthetic method of Carfilzomib intermediate |
| US10364269B2 (en) | 2015-05-21 | 2019-07-30 | Laurus Labs Limited | Processes for the preparation of carfilzomib or pharmaceutically acceptable salts thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103360348A (en) * | 2013-07-25 | 2013-10-23 | 苏州鹏旭医药科技有限公司 | Carfilzomib intermediate and preparation method thereof, and preparation method of Carfilzomib |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103360348A (en) * | 2013-07-25 | 2013-10-23 | 苏州鹏旭医药科技有限公司 | Carfilzomib intermediate and preparation method thereof, and preparation method of Carfilzomib |
Non-Patent Citations (3)
| Title |
|---|
| KAZUHIRO DAIKAI ET AL.: "Remarkable Ligand Effect on the Enantioselectivity of the Chiral Lanthanum Complex-Catalyzed Asymmetric Epoxidation of Enones", 《TETRAHEDRON LETTERS》 * |
| MASAHIRO BOUGAUCHI ET AL.: "Catalytic Asymmetric Epoxidation of α,β-Unsaturated Ketones Promoted by Lanthanoid Complexes", 《J. AM. CHEM. SOC.》 * |
| TETSUHIRO NEMOTO ET AL.: "Catalytic Asymmetric Epoxidation of α,β-Unsaturated Carbonyl Compounds", 《JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY, JAPAN》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10364269B2 (en) | 2015-05-21 | 2019-07-30 | Laurus Labs Limited | Processes for the preparation of carfilzomib or pharmaceutically acceptable salts thereof |
| US10800809B2 (en) | 2015-05-21 | 2020-10-13 | Laurus Labs Limited | Processes for the preparation of carfilzomib or pharmaceutically acceptable salts thereof |
| CN108373456A (en) * | 2018-02-06 | 2018-08-07 | 中国科学院兰州化学物理研究所苏州研究院 | A kind of synthetic method of Carfilzomib intermediate |
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