CN107129437A - The preparation method of 4- [(2- chloroethyl -2- ethoxys) amino -]-L-phenylalanine hydrochloride and application - Google Patents
The preparation method of 4- [(2- chloroethyl -2- ethoxys) amino -]-L-phenylalanine hydrochloride and application Download PDFInfo
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- CN107129437A CN107129437A CN201610112196.2A CN201610112196A CN107129437A CN 107129437 A CN107129437 A CN 107129437A CN 201610112196 A CN201610112196 A CN 201610112196A CN 107129437 A CN107129437 A CN 107129437A
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- Prior art keywords
- preparation
- melphalan
- hydrochloric acid
- monohydroxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/38—Separation; Purification; Stabilisation; Use of additives
- C07C227/40—Separation; Purification
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N2030/022—Column chromatography characterised by the kind of separation mechanism
- G01N2030/027—Liquid chromatography
Abstract
The present invention relates to the preparation method of the 4 of a kind of formula 2 [(ethoxy of 2 chloroethyl 2) amino] L phenylalanine Hydrochlorides and application.Its preparation method is that melphalan is hydrolyzed, then is obtained through column chromatography purifying.The compound of formula 2 can be as the relevant material detection reference substance of hydrochloric acid melphalan, for hydrochloric acid melphalan raw material or the Pureness control of preparation.
Description
Technical field
The present invention relates to 4- [(2- chloroethyl -2- ethoxys) amino -], (i.e. monohydroxy is American and French for-L-phenylalanine hydrochloride
Logical sequence hydrochloride) preparation method and application, monohydroxy melphalan hydrochloride is the weight in hydrochloric acid melphalan raw material or preparation process
Want impurity.
Background technology
Melphalan (Melphalan), is called 4- (double (2- chloroethyls)-amino)-L-phenylalanine) and its hydrochloride be
The antineoplastic known.On January 17th, 1964,2mg melphalans tablet is listed in the U.S., and its active component is melphalan；1992
November 18, hydrochloric acid melphalan injection ALKERAN is listed in the U.S., and active component is melphalan hydrochloride.Due to phenylpropyl alcohol ammonia
The presence of acid groups, it easily enters in tumour cell and had an effect, so as to effectively suppress and prevent malignant cell
Hyperplasia and maturation.The application of melphalan and its salt of hydrochloric acid one is quite varied, available for Huppert's disease, breast cancer, oophoroma,
Chronic lymphocytic and granulocyte type leukaemia, malignant lymphoma, Huppert's disease.
The chemical structural formula of hydrochloric acid melphalan is as shown in Equation 1：
Chlorine atom in melphalan and the like structure belongs to easy leaving group, complex operation and manufacturing cycle is long easily
Chloroethyl is degraded into ethoxy, the double hydroxyl melphalans (shown in formula 3) of generation or monohydroxy melphalan hydrochloride (shown in formula 2)；
So that end product quality is difficult to ensure that.
Quality control to melphalan, hydrochloric acid melphalan raw material and preparation, it is necessary to have up-to-standard impurity reference substance.Close
In monohydroxy melphalan hydrochloride (compound shown in formula 2), the specific preparation of the compound is not retrieved temporarily at present.Therefore having must
Develop a kind of high method for preparing monohydroxy melphalan of stabilization, convenient, purity.
4- [(2- chloroethyl -2- ethoxys) amino -]-L-phenylalanine hydrochloride of the present invention is miscellaneous for hydrochloric acid melphalan
Matter, can control the purity of hydrochloric acid melphalan raw material or preparation as impurity reference substance.
The content of the invention
One aspect of the present invention provides the preparation method of the compound of formula 2, and as shown in Equation 2, chemistry is entitled for its chemical structural formula
4- [(2- chloroethyl -2- ethoxys) amino -]-L-phenylalanine hydrochloride.
Patent US3032584 is related to melphalan compound patent, its preparation method, disclose with 4- nitrophenylalanines or
L-4- nitrophenylalanines are Material synthesis melphalan.In the synthetic method, the amino acid moiety progress to raw material is first had to
Protect (ethyl esterified protection carboxyl；Phthalic anhydride protects amino) a full guard thing relatively stablized is obtained, the nitro moiety of contraposition is repaiied
After decorations, then reduced by hydrogenation, hydroxyethylation, chlorination three-step reaction obtains effective group mustargen of melphalan, finally uses
The method of hydrochloric acid reflux is deprotected to amino acid moiety, obtains melphalan product.
The present invention is the salt developed on the basis of hydrochloric acid melphalan is prepared with reference to above-mentioned patent US3032584
The new synthetic method of sour melphalan impurity-monohydroxy melphalan hydrochloride, obtains monohydroxy American and French by an one-step hydrolysis and purifying
Logical sequence, solves the convenience and stability of impurity acquisition；It is of particular importance that the present invention is to monohydroxy melphalan purification process
It is studied in detail, has filtered out more stable column chromatography for separation condition, monohydroxy melphalan HPLC purity is up to 95%
More than.The preparation condition of the present invention is gently controllable, can efficiently and easily prepare monohydroxy melphalan.
The preparation process of monohydroxy melphalan：(1) reaction is hydrolyzed in the melphalan of formula 1 in reaction solution；(2) water
Again by the isolated monohydroxy melphalan of column chromatography method after solution reaction, concentration, freeze-drying obtain monohydroxy melphalan salt
Hydrochlorate.
Further, the reaction solution described in step (1) is water or alkaline solution.
Further, described alkaline solution is selected from potassium carbonate, sodium carbonate, cesium carbonate, saleratus, sodium acid carbonate, hydrogen
One or more of aqueous solution of potassium oxide or sodium hydroxide, alkaline solution concentration expressed in percentage by weight is not more than 5%.
Further, hydrolysising reacting temperature described in step (1) is 25-70 DEG C, and the reaction time is 1-3h.
Further, column chromatography method described in step (2) uses octadecylsilane chemically bonded silica (ODS-C18) carry out
Separation, mobile phase is selected from the mixed liquor of acetonitrile and watery hydrochloric acid, methanol and hydrochloric acid.
Further, the pH of hydrochloric acid is 1~5.
Further, the pH of hydrochloric acid is 2~3.
Compound 4- [(2- chloroethyl -2- ethoxys) amino -]-L-phenylalanine hydrochloride prepared by the present invention can conduct
The relevant material detection reference substance of hydrochloric acid melphalan, the quality control for hydrochloric acid melphalan and its related preparations.
Heretofore described watery hydrochloric acid is hydrochloride aqueous solution resulting after concentrated hydrochloric acid and water mixing, its molar concentration
No more than 12mol/L.The control of watery hydrochloric acid concentration is 10 in the present invention-1~10-5Between mol/L, its pH value is 1~5.
The beneficial effect of the technical solution adopted by the present invention is simple operation, and reaction condition is gently controllable, is greatly improved anti-
The stability answered, reaction product high income, purity are high.
Embodiment
The present invention will be in hereafter by embodiment more detailed description, these embodiments are exemplarily used for furtherly
It is bright, and be not construed as limiting the present invention.
The preparation of monohydroxy melphalan hydrochloride
Embodiment 1：
The compound of formula 1 (1g) and 5%K2CO315ml is mixed, and is heated to 25 DEG C, is reacted 1 hour, with 3mol/L salt
Acid solution adjust pH to 5, add acetonitrile, filtering, mother liquor concentrations to it is a small amount of when, purified using column chromatography method.Specific column chromatography
Condition：Silica gel is octadecylsilane chemically bonded silica (ODS-C18), mobile phase is hydrochloric acid (pH is 5)：Acetonitrile=3:1 (volume
Than), flow velocity is 2ml/ minutes, collects corresponding component, is freeze-dried after being concentrated under reduced pressure below 10 DEG C, obtains 0.35g compounds
2, yield is 36.7%, HPLC purity 96.5%.
The compound structure of formula 2 is through nuclear magnetic resoance spectrum and mass spectrum confirmation, and specific data are：Mass spectrum (MS)：M/z=286 [M+H
]+, m/z=284 [M-H]+；1H NMR(DMSO-d6)δ11.02(s,1H),7.13(d,2H),6.61(d,2H),5.11(s,
2H),4.21(t,2H),4.10(s,1H),3.73(d,2H),3.65(s,1H),3.61(m,4H),,3.18(m,2H)；13C-NMR
(DMSO-d6)δ173.5,146.8,128.3,128.2,126.1,111.6,111.5,60.8,58.6,56.9,53.6,43.9,
37.3。
Embodiment 2：
The compound of formula 1 (4g) and 5%NaHCO332ml is mixed, and is heated to 35 DEG C, is reacted 2 hours, with 3mol/L's
Hydrochloric acid solution adjust pH to 2, add acetonitrile, filtering, mother liquor concentrations to it is a small amount of when, purified using column chromatography method.Specific post layer
Analysis condition：Silica gel is octadecylsilane chemically bonded silica (ODS-C18), mobile phase is hydrochloric acid (pH is 2)：Acetonitrile=3:1 (volume
Than), flow velocity is 5ml/ minutes, collects corresponding component, is freeze-dried after being concentrated under reduced pressure below 10 DEG C, obtains 0.72g compounds
2, yield is 25.2%, HPLC purity 96.1%.
Embodiment 3：
The compound of formula 1 (0.8g) and 0.5%NaOH 5ml are mixed, and are heated to 25 DEG C, are reacted 1 hour, are used 3mol/L
Hydrochloric acid solution regulation pH to 1, add methanol, filtering, mother liquor concentrations to it is a small amount of when, purified using column chromatography method.Specific post
Chromatography condition：Silica gel is octadecylsilane chemically bonded silica (ODS-C18), mobile phase is hydrochloric acid (pH is 3)：Acetonitrile=3:1 (body
Product ratio), flow velocity is 1ml/ minutes, collects corresponding component, is freeze-dried after being concentrated under reduced pressure below 10 DEG C, obtains 0.13g chemical combination
Thing 2, yield is 27.4%, HPLC purity 95.2%.
Embodiment 4：
The compound of formula 1 (7.5g) and water 50ml are mixed, and are heated to 70 DEG C, are reacted 3 hours, cooling, and adding methanol makes
After solid dissolving, by concentration, purified using column chromatography method.Specific column chromatography condition：Silica gel is bonded for octadecylsilane
Silica gel (ODS-C18), mobile phase is hydrochloric acid (pH is 2.8)：Acetonitrile=3:1 (volume ratio), flow velocity is 6ml/ minutes, collects corresponding
Component, after being concentrated under reduced pressure below 10 DEG C be freeze-dried, obtain 3.42g compounds 2, yield is 36.3%, HPLC purity
96.3%.
Claims (9)
1. the preparation method of the monohydroxy melphalan hydrochloride of a kind of formula 2, it is characterised in that comprise the following steps：
(1) it is starting material by the hydrochloric acid melphalan shown in formula 1, reaction is hydrolyzed in reaction solution；
(2) separated again by column chromatography method after hydrolysis, concentration, freeze-drying obtain monohydroxy melphalan hydrochloride；
。
2. preparation method according to claim 1, it is characterised in that：Reaction solution described in step (1) is molten for alkalescence
Liquid or water.
3. preparation method according to claim 2, it is characterised in that：Described alkaline solution be selected from potassium carbonate, sodium carbonate,
Cesium carbonate, saleratus, sodium acid carbonate, one or more of aqueous solution of potassium hydroxide or sodium hydroxide, solution weight percentage
Concentration is not more than 5%.
4. preparation method according to claim 1, it is characterised in that：Reaction solution described in step (1) is selected from water.
5. preparation method according to claim 2, is additionally included in the pH for adjusting reaction solution in step (1) after hydrolysis
It is worth 2~5.
6. the preparation method according to any one of claim 1-4, it is characterised in that：The temperature of hydrolysis in step (1)
Spend for 25-70 DEG C, the reaction time is 1-3h.
7. preparation method according to claim 1, it is characterised in that：Column chromatography method described in step (2) uses 18
Alkyl silane bonded silica gel is isolated and purified, and mobile phase is selected from the mixed liquor of acetonitrile and hydrochloric acid.
8. preparation method according to claim 7, it is characterised in that：The pH value of the hydrochloric acid is 1~5, preferably 2~3.
9. monohydroxy melphalan hydrochloride described in claim 1 is as reference substance, in the raw material or preparation of hydrochloric acid melphalan
Application in quality control.
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| CN201610112196.2A CN107129437A (en) | 2016-02-29 | 2016-02-29 | The preparation method of 4- [(2- chloroethyl -2- ethoxys) amino -]-L-phenylalanine hydrochloride and application |
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| CN201610112196.2A CN107129437A (en) | 2016-02-29 | 2016-02-29 | The preparation method of 4- [(2- chloroethyl -2- ethoxys) amino -]-L-phenylalanine hydrochloride and application |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114315866A (en) * | 2020-09-30 | 2022-04-12 | 烟台药物研究所 | Synthesis method of levamisole hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101380307A (en) * | 2006-12-12 | 2009-03-11 | 济南帅华医药科技有限公司 | Anticancer sustained-release formulation loaded with anti-cancer medicine and synergist thereof |
| CN105085405A (en) * | 2014-05-06 | 2015-11-25 | 江苏先声药业有限公司 | Preparation method and application of 4-[1-methyl-5-(2-chloroethyl-2-ethoxyl)amino-2-benzimidazolyl]butyric acid hydrochloride |
-
2016
- 2016-02-29 CN CN201610112196.2A patent/CN107129437A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101380307A (en) * | 2006-12-12 | 2009-03-11 | 济南帅华医药科技有限公司 | Anticancer sustained-release formulation loaded with anti-cancer medicine and synergist thereof |
| CN105085405A (en) * | 2014-05-06 | 2015-11-25 | 江苏先声药业有限公司 | Preparation method and application of 4-[1-methyl-5-(2-chloroethyl-2-ethoxyl)amino-2-benzimidazolyl]butyric acid hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| JENS TEICHERT，等: "Identification and Quantitation of the N-Acetyl-L-cysteine S-Conjugates of Bendamustine and Its Sulfoxides in Human Bile after Administration of Bendamustine Hydrochloride", 《DRUG METABOLISM AND DISPOSITION》 * |
| WANG XIN PING，等: "A Validated Chiral HPLC Method for the Enantiomeric Separation of Melphalan HCl", 《ADVANCED MATERIALS RESEARCH》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114315866A (en) * | 2020-09-30 | 2022-04-12 | 烟台药物研究所 | Synthesis method of levamisole hydrochloride |
| CN114315866B (en) * | 2020-09-30 | 2023-10-31 | 烟台药物研究所 | Synthesis method of levamisole hydrochloride |
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Effective date of registration: 20201230 Address after: 570311 No. 2 Yaogu No. 3 Road, Xiuying District, Haikou City, Hainan Province Applicant after: Hainan Simcere Pharmaceutical Co.,Ltd. Applicant after: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Address before: 210042 699 Xuanwu Road, Xuanwu District, Nanjing, Jiangsu -18 Applicant before: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. |
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Application publication date: 20170905 |