CN107098827A - A kind of preparation method of ubenimex intermediate (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid - Google Patents
A kind of preparation method of ubenimex intermediate (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid Download PDFInfo
- Publication number
- CN107098827A CN107098827A CN201610094657.8A CN201610094657A CN107098827A CN 107098827 A CN107098827 A CN 107098827A CN 201610094657 A CN201610094657 A CN 201610094657A CN 107098827 A CN107098827 A CN 107098827A
- Authority
- CN
- China
- Prior art keywords
- acid
- compound
- preparation
- hydroxy
- organic base
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/16—Preparation of optical isomers
- C07C231/20—Preparation of optical isomers by separation of optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Analytical Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides one kind and ubenimex intermediate (2S is prepared as resolution reagent using organic base, 3R) the method for the phenylbutyric acid of 3 acetylamino, 2 hydroxyl 4, wherein organic base are selected from the naphthalene ethylamines of S 1, (S) 1 (2 naphthyl) ethamine, L benzene glycinol, L phenylalaninols.Ubenimex intermediate purity prepared by the present invention is good, high income, simple to operate, favorable reproducibility, is suitable for industrialized production.
Description
Technical field
The present invention relates to organic chemistry filed, and in particular to a kind of ubenimex intermediate (2S, 3R) -3-
The preparation method of acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid.
Background technology
Ubenimex (Ubenimex), chemical name is N- [(2S, 3R) -4- phenyl -3- amino -2- hydroxyls
Base butyryl]-L-Leu, structural formula is as follows：
Ubenimex is a kind of antineoplastic of peptides, and it is H.Umezawa (US 4052449) etc.
What people had found from the zymotic fluid of the netted streptomycete of olive, it can promote organism immune response and suppression
Aminopeptidase B and leucine aminopeptidase.
Clinical studies show, ubenimex is the cytotoxic activity for suppressing antineoplastic by improving,
So as to realize its curative effect in treatment of cancer.This product is used for the chemotherapy of tumor patient, the auxiliary of radiation
The disease such as treatment and senile immunodeficiency.Indication include leukaemia, multiple bone marrow cancer,
RAEB, and other body knurls.
Ubenimex it is complicated, contain 3 chiral centres, it is different in the presence of 7 solids in theory
How structure body, therefore, ensure to properly form 3 chiral centres, and optical purity meets quality and wanted
Ask, be the top priority for synthesizing ubenimex.
Journal of Antibiotics, 1983,36 (6)：It is beautiful that 659-699 reports a practical black benzene
Sigong skill, including using acetophenone as raw material, according to this through bromination, amination, acetylation, aldol condensation,
Black benzene is made in hydro-reduction, fractionation, deacetylation, amido protecting, amide condensed and deprotection reaction
Department of U.S..Wherein, resolution reaction use S-1- phenyl ethylamines for resolution reagent to racemic modification (chemical combination
Thing 1) split, selectively obtain ubenimex intermediate (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxyls -4-
Phenylbutyric acid, but the product of high-optical-purity that this resolution process can not be stably obtained, and yield is low,
It is unfavorable for industrialized production.
Patent CN101891647 A are disclosed using 1B, L-arginine, L-Histidine pair
The method that compound 1 is split, obtains (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxyl -4- benzene of high-purity
Base butyric acid, but this method needs progress to be repeatedly beaten purifying and crystallize, and complex operation is unfavorable for industry
Metaplasia is produced.
Therefore, find in the middle of a kind of ubenimex of viable commercial method to prepare high-optical-purity
Body (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid is necessary.
The content of the invention
The purpose of the present invention be improved in view of the shortcomings of the prior art there is provided one kind it is more stable, pure
Degree is high, ubenimex intermediate (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid of favorable reproducibility
Preparation method.Using suitable organic base as resolution reagent, from racemic modification (compound 1)
In isolated (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid (compound 1a), wherein having
Machine alkali is selected from S-1- naphthalene ethylamines, (S) -1- (2- naphthyls) ethamine, L- benzene glycinol, L- phenylalaninols.Its
Middle compound 1 is by enantiomter (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid (compounds
1a) constituted with (2R, 3S) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid (compound 1b).
Specifically comprise the steps of：
1) compound 1 and organic base are mixed into salt in a solvent.
2) by step 1) in obtained mixture cool, make salt crystallization precipitation, separation is obtained
Compound 1a and organic base salt.
3) by step 2) in obtained by salt be dissolved in the aqueous solution, add appropriate acid, make compound
1a is free to be separated out, and separation obtains (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxyls -4- of high-purity
Phenylbutyric acid.
Further, step 1) described in solvent be selected from C1~C10Alcohols, esters, ketone, ethers,
One or more in nitrile, aromatic hydrocarbons and alkane.
Further, step 1) described in the mol ratio of compound 1 and organic base be 1:0.2~1:10.0,
It is preferred that 1:0.5~1:2.The weight ratio of compound 1 and solvent is 1:1~1:100, preferably 1:5~1:50.
Also, step 1) in compound 1 with the temperature range that organic base is mixed in a solvent be 0~150 DEG C,
It is preferred that 20~120 DEG C.Step 2) in the cooling scope of mixture be -20~50 DEG C, preferably 0~40 DEG C.
Step 3) described in acid be Bronsted acid.
Using the technology of the present invention, using selected from S-1- naphthalene ethylamines, (S) -1- (2- naphthyls) ethamine, L- benzene
Glycinol, the organic base of L- phenylalaninols are split for resolving agent, can disposably obtain high-purity
Ubenimex intermediate (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid, without crystallizing again,
Optical purity more than 99.5%, yield more than 35%, not only increases production capacity, while also more green
Environmental protection.Therefore, this method is easy to operate, favorable reproducibility, environmental protection, is more suitable for industrialization
Production.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described, but protection scope of the present invention is not
It is limited by the following examples.
1a optical purity is detected with HPLC in embodiment, and provides area percent.
Liquid-phase condition：
Chromatographic column：The Chiralpak AY-H (250*4.6mm, 5 μm) of Daicel chemical company
Mobile phase：N-hexane：Isopropanol：Trifluoroacetic acid=60%：40%：0.1%
Sample preparation：50mg samples are dissolved in 100ml mobile phases
Sample size：10μl
Flow velocity：1ml/min
Column temperature：35℃
Detection wavelength：220nm.
Embodiment 1
(1.8 grams) of compound 1 (2.4 grams) and S-1- naphthalene ethylamines are added in ethanol (10 milliliters),
60 DEG C of stirring dissolved clarifications.Above-mentioned solution is cooled to 25 DEG C, 1.5 grams of white solid is filtrated to get, is
The S-1- naphthalene ethylamine salt of (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid, water is added to by this salt
In solution (10 milliliters), dissolved clarification is stirred, reagent hydrochloric acid (2 milliliters) is added, stirring separates out solid,
Separation, obtains 0.85 gram of (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyls butyric acid, yield 35.4%, ee
Value 99.8%.
Embodiment 2
By (1.8 grams) of compound 1 (2.4 grams) and S-1- naphthalene ethylamines add ethanol (10 milliliters) and
In acetonitrile (3 milliliters), 60 DEG C of stirring dissolved clarifications.Above-mentioned solution is cooled to 25 DEG C, is filtrated to get white
Color solid, is the S-1- naphthalene ethylamine salt of (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid, will
This salt is added in the aqueous solution (10 milliliters), stirs dissolved clarification, adds reagent hydrochloric acid (2 milliliters),
Stirring separates out solid, and separation obtains 0.89 gram of (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyls butyric acid,
Yield 37.1%, ee values 99.6%.
Embodiment 3
By (1.8 grams) addition tetrahydrofurans (20 of compound 1 (2.4 grams) and (S) -1- (2- naphthyls) ethamine
Milliliter) in, 60 DEG C of stirring dissolved clarifications.Above-mentioned solution is cooled to 25 DEG C, white solid is filtrated to get,
As the S-1- naphthalene ethylamine salt of (2S, 3R) -3- acetylaminohydroxyphenylarsonic acids 2- hydroxy-4-phenyl butyric acid, this salt is added
Into the aqueous solution (10 milliliters), dissolved clarification is stirred, reagent hydrochloric acid (2 milliliters) is added, stirring is separated out
Solid, separation, obtains 0.88 gram of (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyls butyric acid, yield 36.7%,
Ee values 99.6%.
Embodiment 4
By (1.8 grams) of compound 1 (2.4 grams) and S-1- naphthalene ethylamines add ethanol (10 milliliters) and
In acetone (3 milliliters), 60 DEG C of stirring dissolved clarifications.Above-mentioned solution is cooled to 25 DEG C, is filtrated to get white
Color solid, is the S-1- naphthalene ethylamine salt of (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid, will
This salt is added in the aqueous solution (10 milliliters), stirs dissolved clarification, adds reagent hydrochloric acid (2 milliliters),
Stirring separates out solid, and separation obtains 0.89 gram of (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyls butyric acid,
Yield 37.1%, ee values 99.6%.
Embodiment 5
(1.8 grams) of compound 1 (2.4 grams) and L- benzene glycinol are added into isopropanol (10 milliliters)
In isopropyl acetate (3 milliliters), 60 DEG C of stirring dissolved clarifications.Above-mentioned solution is cooled to 25 DEG C, mistake
Filter obtains white solid, is the S-1- naphthalene second of (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid
Amine salt, this salt is added in the aqueous solution (10 milliliters), stirs dissolved clarification, adds reagent hydrochloric acid (2
Milliliter), stirring separates out solid, and separation obtains (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid
0.87 gram, yield 36.3%, ee values 99.7%.
Embodiment 6
(1.8 grams) of compound 1 (2.4 grams) and L- phenylalaninols are added into isopropanol (20 milliliters)
In toluene (5 milliliters), 60 DEG C of stirring dissolved clarifications.Above-mentioned solution is cooled to 25 DEG C, is filtrated to get
White solid, is the S-1- naphthalene ethylamine salt of (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid,
This salt is added in the aqueous solution (10 milliliters), dissolved clarification is stirred, reagent hydrochloric acid (2 milliliters) is added,
Stirring separates out solid, and separation obtains 0.87 gram of (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyls butyric acid,
Yield 36.3%, ee values 99.6%.
Claims (7)
1. a kind of preparation side of ubenimex intermediate (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid
Method, it is characterised in that using organic base as resolution reagent, from racemic modification (compound 1)
Isolated (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid (compound 1a).Described
Organic base is selected from S-1- naphthalene ethylamines, (S) -1- (2- naphthyls) ethamine, L- benzene glycinol, L- phenylalaninols.
Described compound 1 is by enantiomter (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid
(compound 1a) and (2R, 3S) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid (compound 1b) structure
Into.
2. preparation method according to claim 1, it is characterised in that comprise the steps of：
1) compound 1 and organic base are mixed into salt in a solvent.
2) by step 1) in obtained mixture cool, make salt crystallization precipitation, separation is obtained
Compound 1a and organic base salt.
3) by step 2) in obtained by salt be dissolved in the aqueous solution, add appropriate acid, make compound
1a is free to be separated out, and separation obtains (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxyls -4- of high-purity
Phenylbutyric acid.
3. preparation method according to claim 2, it is characterised in that step 1) described in solvent choosing
From C1~C10Alcohols, esters, ketone, ethers, nitrile, aromatic hydrocarbons and alkane in one kind or many
Kind.
4. preparation method according to claim 2, it is characterised in that step 1) described in compound
1 is 1 with the mol ratio of organic base:0.2~1:10.0, preferably 1:0.5~1:2.Compound 1 and the weight of solvent
Amount is than being 1:1~1:100, preferably 1:5~1:50.
5. preparation method according to claim 1, it is characterised in that step 1) in compound 1 with having
The temperature range that machine alkali is mixed in a solvent is 0~150 DEG C, preferably 20~120 DEG C.
6. preparation method according to claim 1, it is characterised in that step 2) in mixture cooling
Scope is -20~50 DEG C, preferably 0~40 DEG C.
7. preparation method according to claim 1, it is characterised in that step 3) described in acid be matter
Sub- acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610094657.8A CN107098827A (en) | 2016-02-19 | 2016-02-19 | A kind of preparation method of ubenimex intermediate (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610094657.8A CN107098827A (en) | 2016-02-19 | 2016-02-19 | A kind of preparation method of ubenimex intermediate (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN107098827A true CN107098827A (en) | 2017-08-29 |
Family
ID=59658718
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610094657.8A Pending CN107098827A (en) | 2016-02-19 | 2016-02-19 | A kind of preparation method of ubenimex intermediate (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107098827A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109115914A (en) * | 2018-10-03 | 2019-01-01 | 淮安安莱生物科技有限公司 | A kind of efficient liquid-phase chromatography method separating Ramosetron HCl and its S type enantiomter |
| CN109115913A (en) * | 2018-10-03 | 2019-01-01 | 淮安安莱生物科技有限公司 | A kind of HPLC method based on conventional phenyl chromatography post separation Ramosetron HCl He its S type enantiomter |
| CN115594606A (en) * | 2022-12-16 | 2023-01-13 | 成都傲科新技术有限责任公司（Cn） | Asymmetric synthesis method of threo-2-hydroxy-3-acetamido-4-phenylcarbonyl butyric acid |
-
2016
- 2016-02-19 CN CN201610094657.8A patent/CN107098827A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109115914A (en) * | 2018-10-03 | 2019-01-01 | 淮安安莱生物科技有限公司 | A kind of efficient liquid-phase chromatography method separating Ramosetron HCl and its S type enantiomter |
| CN109115913A (en) * | 2018-10-03 | 2019-01-01 | 淮安安莱生物科技有限公司 | A kind of HPLC method based on conventional phenyl chromatography post separation Ramosetron HCl He its S type enantiomter |
| CN109115914B (en) * | 2018-10-03 | 2021-06-04 | 四川中科微纳科技有限公司 | High performance liquid chromatography method for separating ramosetron hydrochloride and S-type enantiomer thereof |
| CN109115913B (en) * | 2018-10-03 | 2021-08-06 | 济南迪安医学检验中心有限公司 | HPLC method for separating ramosetron hydrochloride and S-type enantiomer thereof based on conventional phenyl chromatographic column |
| CN115594606A (en) * | 2022-12-16 | 2023-01-13 | 成都傲科新技术有限责任公司（Cn） | Asymmetric synthesis method of threo-2-hydroxy-3-acetamido-4-phenylcarbonyl butyric acid |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107098827A (en) | A kind of preparation method of ubenimex intermediate (2S, 3R) -3- acetylaminohydroxyphenylarsonic acid 2- hydroxy-4-phenyl butyric acid | |
| KR100666423B1 (en) | Process for the preparation of 2r-2-propyloctanoic acid | |
| US7449589B2 (en) | Process for purifying (-)-Δ9-trans-tetrahydrocannabinol | |
| JP7186460B2 (en) | Co-crystal of 2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol | |
| CN103467475A (en) | Purification method for 1, 8-cineole | |
| US10752571B2 (en) | Method for purification of 4-hydroxyacetophenone | |
| CN110642706B (en) | Preparation method of high-purity phenoxyethanol | |
| CA2542788C (en) | Process for producing bicalutamide and method of purifying intermediate thereof | |
| US8461347B2 (en) | Process for preparing form A of atazanavir sulfate | |
| TW200909406A (en) | Process for enantioselectively preparing optically active 4-hydroxy-2,6,6-trimethylcyclohex-2-enone derivatives | |
| US20120108554A1 (en) | PROCESS FOR PREPARING HIGH PURITY 1alpha-HYDROXY VITAMIN D2 | |
| CN113024434A (en) | Preparation method of brivaracetam intermediate | |
| CN113735874B (en) | Method for selectively extracting and separating artemisinin/arteannuin by using hydrophobic ionic liquid | |
| CN110668922B (en) | Refining method of musk camphor | |
| US20210395197A1 (en) | Crystalline form of sofpironium bromide and preparation method thereof | |
| US20040176637A1 (en) | Process for preparation of 2-chlorophenylglycine derivatives and enantiomerically separation | |
| JPH08198836A (en) | Production of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide | |
| CN111484418B (en) | Preparation method of 4-amino-2-cyclopentene-1-methanol hydrochloride | |
| JP5092289B2 (en) | Process for producing optically active N-tert-butylcarbamoyl-L-tert-leucine | |
| WO2007080470A2 (en) | A method for the purification of levetiracetam | |
| EP3068746B1 (en) | Process for the preparation of enantiomerically pure 1-aminoindan | |
| EP1785412A1 (en) | Tramadol recovery process | |
| KR101916956B1 (en) | Novel Solid form of Ticagrelor and methods of preparing therof | |
| CN104926699B (en) | A kind of preparation method of high-optical-purity tamsulosin hydrochloride | |
| CN105985408A (en) | Purifying method for carfilzomib |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170829 |