CN104672180A - Chiral preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate - Google Patents
Chiral preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate Download PDFInfo
- Publication number
- CN104672180A CN104672180A CN201510083612.6A CN201510083612A CN104672180A CN 104672180 A CN104672180 A CN 104672180A CN 201510083612 A CN201510083612 A CN 201510083612A CN 104672180 A CN104672180 A CN 104672180A
- Authority
- CN
- China
- Prior art keywords
- compound
- iii
- ptc
- chiral method
- preparing according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 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
Classifications
-
- 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
-
- 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
- C07D301/12—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with hydrogen peroxide or inorganic peroxides or peracids
Abstract
The invention relates to a chiral preparation method of a carfilzomib intermediate: [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate. The preparation method comprises the step that a compound (III) carries out catalytic reaction with a phase transfer catalyst (PTC) and hydrogen peroxide under alkaline conditions. 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 available 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 chiral method for preparing 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, there is provided a kind of cost low, yield is good, the novel method of midbody compound (I) [(1S)-3-methyl isophthalic acid-[[(the 2R)-2-methyl epoxy ethyl] carbonyl] butyl] t-butyl carbamate of the applicable suitability for industrialized production Ka Feizuo meter that controllability is strong.
The present invention relates to the chiral method for preparing of one [(1S)-3-methyl isophthalic acid-[[(2R)-2-methyl epoxy ethyl] carbonyl] butyl] t-butyl carbamate, comprising: compound (III) carries out catalyzed reaction with phase-transfer catalyst PTC and hydrogen peroxide in the basic conditions
Described PTC is the compound with following structure:
X group in described PTC can be iodine, bromine, chlorine or nitro.
According to substituent different, X group is PTC called after PTC A, PTC B, PTC C, the PTC D successively of iodine, bromine, chlorine or nitro by the present invention, as shown in following structural:
The preferred iodine of X group in PTC described in the present invention, i.e. PTC A.
Further, the consumption of described PTC is preferably the 2-3mol% of compound (III), is more preferably 3mol%.
Mol% described in the present invention refers to the molar percentage relative to starting material compound (III).
PTC described in the present invention directly can buy commercially available prod or synthesize voluntarily, and such as, filter after cinchonine, 4-substituting group-bromotoluene and tetrahydrofuran (THF) mix and blend being reacted completely, filter cake benzene washs, recrystallizing methanol, obtains corresponding PTC.
Substituting group in described 4-substituting group-bromotoluene comprises halogen, hydrogen, nitro.
Preferably, described alkaline condition is alkaline reagents, optional lithium hydroxide, potassium hydroxide, hydrated barta or sodium hydroxide, more preferably potassium hydroxide.
Further, the mole dosage of alkaline condition is preferably the 1-2 of compound (III) doubly, is more preferably 2 times.
Preferably, the mole dosage of described hydrogen peroxide is 2-5 times of compound (III), more elects 2-3 as doubly, most preferably is 2 times.
Further, catalytic reaction process also comprises solvent phase, and its consumption is consumption well known to those skilled in the art, such as, be 5-15 times of reactant, the wherein optional n-butyl ether of solvent phase, tetrahydrofuran (THF), methylene dichloride, toluene, sherwood oil, Virahol, ethyl acetate, acetone, preferred n-butyl ether.
Described temperature of reaction is preferably higher than 0 DEG C and lower than 4 DEG C, and 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, compound (III) is the potassium hydroxide of 2 times of compound (III) in mole dosage, 3mol%PTC A and mole dosage are carry out catalyzed reaction under the existence of 2 times of hydrogen peroxide of compound (III), temperature of reaction is higher than 0 DEG C and lower than presenting best beneficial effect when 4 DEG C, efficiently solve the drawback that in background technology, prior art exists, reaction yield reaches 97.0%, ee value and reaches 84%.
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
Phase-transfer catalyst 8.85g PTC A (0.015mol, 3mol%) is added successively, 56g potassium hydroxide (1.0mol in 1L reaction flask, 2.0eq), 500mL n-butyl ether, under stirring at room temperature, add 127g compound III (0.5mol, 1.0eq).Be cooled to 0 DEG C, slowly drip 113.3g 30% hydrogen peroxide (1.0mol, 2.0eq), temperature keeps not higher than 4 DEG C.Add insulation make temperature higher than 0 DEG C and react 36h lower than 4 DEG C.
TLC monitors, filter after reacting completely, filtrate, with the cancellation of 300mL saturated sodium bisulfite solution, separates upper organic phase, be evaporated to dry, resistates 600mL acetic acid ethyl dissolution, the water washing of 150mL saturated common salt, anhydrous sodium sulfate drying, decompression is spin-dried for obtain pale yellow oil 131g, be Compound I, yield is 97.0%, ee value is 84%.
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).
PTC A in the present embodiment is obtained by self-control, concrete grammar is: cinchonine (1.47g, 5.0mmol) and 4-iodobenzyl bromide (1.48g, 5.0mmol) mix in 20ml tetrahydrofuran (THF), stirring reaction 133h, filter, filter cake 10ml benzene washs 2 times, then adds recrystallizing methanol, obtain colourless to pale yellow crystals powder (1.04g, 35%), be PTC A, purity is 95.1%.
Embodiment 2
Use PTC B to substitute PCT A and participate in reaction, all the other are with embodiment 1, and finally obtaining yield 94.1%, ee value is 80%.
Embodiment 3
Use PTC C to substitute PCT A and participate in reaction, all the other are with embodiment 1, and finally obtaining yield 95.2%, ee value is 76%.
Embodiment 4
Use PTC D to substitute PCT A and participate in reaction, all the other are with embodiment 1, and finally obtaining yield 93.4%, ee value is 77%.
Can draw from embodiment 1-4: the same terms, the X group in PTC is iodine (PCT A), and reaction yield is the highest, and selectivity is better.
Embodiment 5
PCT A consumption becomes the 1mol% of compound (III), and all the other are with embodiment 1, and finally obtaining yield 65.8%, ee value is 60%.
Embodiment 6
PCT A consumption becomes the 2mol% of compound (III), and all the other are with embodiment 1, and finally obtaining yield 85.7%, ee value is 80%.
Embodiment 7
PCT A consumption becomes the 4mol% of compound (III), and all the other are with embodiment 1, and finally obtaining yield 80.2%, ee value is 79.5%.
Embodiment 8
PCT A consumption becomes the 5mol% of compound (III), and all the other are with embodiment 1, and finally obtaining yield 80.0%, ee value is 80.5%.
Can draw from embodiment 1 and 5-8: the same terms, when PCT A consumption becomes the 2-3mol% of compound (III), effect is better, and during 3mol%, effect is best; Be greater than 3mol% or be less than 2mol%, yield all can reduce a lot.
Embodiment 9
Alkaline condition selects lithium hydroxide, and all the other are with embodiment 1, and finally obtaining yield 95.8%, ee value is 83%.
Embodiment 10
Alkaline condition selects hydrated barta, and all the other are with embodiment 1, and finally obtaining yield 90.2%, ee value is 79%.
Embodiment 11
Alkaline condition selects sodium hydroxide, and all the other are with embodiment 1, and finally obtaining yield 90.1%, ee value is 80%.
Embodiment 12
Potassium hydroxide consumption becomes 1 times of compound (III), and all the other are with embodiment 1, and finally obtaining yield 93.8%, ee value is 78%.
Can draw from embodiment 1 and 9-12: the same terms, during alkaline condition employing potassium hydroxide, effect is better, and when employing mole dosage is the potassium hydroxide of 2 times of compound (III), effect is best.
Embodiment 13
Hydrogen peroxide consumption becomes 3 times of compound (III), and all the other are with embodiment 1, and finally obtaining yield 91.2%, ee value is 81%.
Embodiment 14
Hydrogen peroxide consumption becomes 5 times of compound (III), and all the other are with embodiment 1, and finally obtaining yield 87.5%, ee value is 76%.
Embodiment 15
Hydrogen peroxide consumption becomes 1 times of compound (III), and all the other are with embodiment 1, and finally obtaining yield 75.8%, ee value is 78%.
Embodiment 16
Hydrogen peroxide consumption becomes 6 times of compound (III), and all the other are with embodiment 1, and finally obtaining yield 72.5%, ee value is 70%.
Can draw from embodiment 1 and 13-16: the same terms, hydrogen peroxide consumption is compound (III)) 2-5 times time effect better, especially best with effect when 2 times.
Embodiment 17
Temperature of reaction is 5-10 DEG C, and the time that reacts completely needs about 48h, and all the other are with embodiment 1, and finally obtaining yield 64.9%, ee value is 71%.
Embodiment 18
Temperature of reaction is-10-0 DEG C, and the time that reacts completely needs about 60h, and all the other are with embodiment 1, and finally obtaining yield 74.2%, ee value is 76%.
Can draw from embodiment 1 and 17-18: the same terms, temperature of reaction is higher than 0 DEG C and lower than 4 DEG C constantly, the reaction times is the shortest, and yield is best simultaneously.
As can be seen from described embodiment data, compound (III) is the potassium hydroxide of 2 times of compound (III) in mole dosage, 3mol%PTC A and mole dosage are carry out catalyzed reaction under the existence of 2 times of hydrogen peroxide of compound (III), temperature of reaction is higher than 0 DEG C and lower than presenting best beneficial effect when 4 DEG C, reaction yield reaches 97.0%, ee value and reaches 84%.Be far longer than the yield of 76% of prior art, and chiral selectivity is good.
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 chiral method for preparing of one kind [(1S)-3-methyl isophthalic acid-[[(2R)-2-methyl epoxy ethyl] carbonyl] butyl] t-butyl carbamate, it is characterized in that, described compound (III) carries out catalyzed reaction with phase-transfer catalyst PTC and hydrogen peroxide in the basic conditions
The structural formula of described PTC is as follows:
Wherein, the X group in PTC structural formula is iodine, bromine, chlorine or nitro.
2. chiral method for preparing according to claim 1, is characterized in that, the X group in described PTC is iodine.
3. chiral method for preparing according to claim 1 and 2, is characterized in that, described alkaline condition is lithium hydroxide, potassium hydroxide, hydrated barta or sodium hydroxide.
4. chiral method for preparing according to claim 3, is characterized in that, described alkaline condition is potassium hydroxide.
5. chiral method for preparing according to claim 1 and 2, is characterized in that, the mole dosage of described alkaline condition is 1-2 times of compound (III).
6. chiral method for preparing according to claim 1 and 2, is characterized in that, the consumption of described PTC is the 2-3mol% of compound (III).
7. chiral method for preparing according to claim 6, is characterized in that, the consumption of described PTC is the 3mol% of compound (III).
8. chiral method for preparing according to claim 1 and 2, is characterized in that, the mole dosage of described hydrogen peroxide is 2-5 times of compound (III).
9. chiral method for preparing according to claim 1 and 2, is characterized in that, described temperature of reaction is higher than 0 DEG C and lower than 4 DEG C.
10. chiral method for preparing according to claim 1, it is characterized in that, compound (III) is the potassium hydroxide of 2 times of compound (III) in mole dosage, 3mol% iodine replaces PTC and mole dosage is carry out catalyzed reaction under the existence of 2 times of hydrogen peroxide of compound (III), and temperature of reaction is higher than 0 DEG C and lower than 4 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510083612.6A CN104672180B (en) | 2015-02-15 | 2015-02-15 | Chiral preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510083612.6A CN104672180B (en) | 2015-02-15 | 2015-02-15 | Chiral preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104672180A true CN104672180A (en) | 2015-06-03 |
| CN104672180B CN104672180B (en) | 2017-01-18 |
Family
ID=53307822
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510083612.6A Active CN104672180B (en) | 2015-02-15 | 2015-02-15 | Chiral preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104672180B (en) |
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 (3)
| 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 |
| WO2014018807A1 (en) * | 2012-07-26 | 2014-01-30 | Centrax International, Inc. | Peptide epoxyketone compounds |
| CN104086624A (en) * | 2014-03-21 | 2014-10-08 | 河南海汇药物研究有限公司 | Preparation method for carfilzomib |
-
2015
- 2015-02-15 CN CN201510083612.6A patent/CN104672180B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014018807A1 (en) * | 2012-07-26 | 2014-01-30 | Centrax International, Inc. | Peptide epoxyketone compounds |
| 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 |
| CN104086624A (en) * | 2014-03-21 | 2014-10-08 | 河南海汇药物研究有限公司 | Preparation method for carfilzomib |
Non-Patent Citations (3)
| Title |
|---|
| SHIGERU ARAI ET AL.: "Catalytic asymmetric epoxidation of enones under phase-transfer catalyzed conditions", 《TETRAHEDRON》 * |
| 孔爱娣: "手性相转移催化剂的合成及其在不对称催化反应中的应用", 《中国优秀博硕士学位论文全文数据库(硕士) 工程科技I辑》 * |
| 宫斌 等: "有机催化的不对称氧化反应", 《有机化学》 * |
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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104672180B (en) | 2017-01-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103951627B (en) | Method for synthesizing sulfentrazone midbody and sulfentrazone | |
| CN105254589B (en) | A method of preparing heart failure drugs intermediate | |
| CN104520275A (en) | Process and intermediates for preparing integrase inhibitors | |
| CN102391184A (en) | Synthesis method of celecoxib | |
| CN102766050A (en) | Method for synthesizing dimethyl fumarate | |
| CN104876956A (en) | One-pot synthesis process for boron-amine compounds | |
| JP5815507B2 (en) | Process for purification of 1-methylpyrazole-4-carboxylic acid ester | |
| CN107056756A (en) | A kind of method for preparing high-purity Losartan | |
| CN102351808A (en) | New method for synthesizing fenoxaprop-P-ethyl | |
| CN104672180A (en) | Chiral preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate | |
| CN100999483B (en) | Preparation process of p-nitro phenyl hydrazine hydrochloride | |
| CN102285937B (en) | Method for synthesizing febuxostat | |
| CN102558095B (en) | Method for preparing aromatic amine compound | |
| CN107954882A (en) | A kind of preparation method of 2- amino -2- (the 4- tert-butyl group -2- ethoxyl phenenyls) ethanol | |
| CN104045596B (en) | Method for preparing etoricoxib intermediate 1-(6-methylpyridyl-3-yl)-2-[4-(mesyl)-phenyl]-ethyl-one | |
| CN103588765A (en) | Synthesis method for azilsartan medoxomil or salt thereof, intermediate of azilsartan medoxomil or salt thereof and synthesis method for intermediate | |
| CN106565531A (en) | Synthesis method for pharmaceutically acceptable salt of alkylhydrazine | |
| CN104672179B (en) | Preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate | |
| CN110698467A (en) | Synthetic method of engagliflozin | |
| CN103717580A (en) | Method for preparing amino-triazolinone | |
| CN103787968A (en) | Preparation method of compound | |
| CN101891693A (en) | New method for preparing fluconazole | |
| CN101591328A (en) | The chemical synthesis process of a kind of 2-bromothiophene and derivative thereof | |
| CN104854085A (en) | Method for producing bis(3-aminophenyl)disulfides and 3-aminothiols | |
| CN110028448B (en) | Preparation method of 3-hydroxy-2,3-dihydroisoquinoline-1, 4-diketone compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |