CN110437261A - The synthetic method of bendamustine impurity G - Google Patents
The synthetic method of bendamustine impurity G Download PDFInfo
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- CN110437261A CN110437261A CN201810408524.2A CN201810408524A CN110437261A CN 110437261 A CN110437261 A CN 110437261A CN 201810408524 A CN201810408524 A CN 201810408524A CN 110437261 A CN110437261 A CN 110437261A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Abstract
The invention discloses the synthetic methods of bendamustine impurity G.
Description
Technical field:
It is predominantly a kind of to prepare bendamustine impurity G the present invention relates to organic synthesis fields such as medicine, pesticide and dyestuffs
Method.
Background technique:
Bendamustine most earlier than the initial stage sixties 19th century by Ozegowski and its general formula Jena, Germany microorganism
Association is tested to develop.It year is produced with the trade name of Cytostasan by Jenapharm GmbH & Co. KG from 1971 to 1992.From 1993
Afterwards, this cytostatic agent is by Ribosepharm GmbH company with the trade name list marketing of Ribomustine.2008
March in year, the bendamustine that U.S. FDA ratifies Cephalon company are used for chronic lymphocytic leukemia.
The hydrolysis of two -2- chloroethyl amino groups of bendamustine in water, which will lead to drug effect, reduces and is formed impurity,
Bendamustine can also generate impurity in synthesis phase, and impurity G is exactly one of impurity common in bendamustine product.At present
There is not yet open source information reported the synthetic method of impurity G, and bendamustine is when carrying out quality analysis, it is necessary to have qualification
Impurity G as standard reference material, it is therefore desirable to a kind of easy to operate, easy purification can obtain the synthesis side of high yield impurity G
Method.
Summary of the invention:
The object of the present invention is to provide a kind of methods for preparing impurity G.
The method of the present invention includes the following steps:
(i) compound B is prepared by compound A-1 and compound A-2；
Wherein, M is selected from lithium, sodium, potassium；
R is selected from C1-10Alkyl；It preferably is selected from substituted or non-substituted methyl, substituted or non-substituted ethyl, substitution or non-
Substituted isopropyl, substituted or non-substituted amyl, substituted or non-substituted n-hexane base, takes substituted or non-substituted butyl
Generation or non-substituted constructed from normal heptyl, substituted or non-substituted normal octane base, substituted or non-substituted n -nonane base, substitution non-take
The n-decane base in generation, wherein substituent group is selected from C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl；More preferably certainly
Ethyl；
Reaction reagent is selected from sodium iodide, potassium iodide, tetrabutylammonium iodide, lithium iodide, silver iodide or iodine；
Reaction dissolvent be selected from alcohols, DMF, acetone, cyclohexanone, acetonitrile, toluene, dimethyl ether, N-Methyl pyrrolidone,
DMSO, dimethyl acetamide；Preferably be selected from methanol, ethyl alcohol, propyl alcohol, butanol, DMF, acetone, cyclohexanone, acetonitrile, toluene, dimethyl ether,
N-Methyl pyrrolidone, DMSO, dimethyl acetamide；
Reaction temperature is selected from 20 DEG C~150 DEG C；It preferably is selected from 60 DEG C~150 DEG C；More preferably from 80 DEG C~150 DEG C；
In another embodiment, reaction temperature is selected from 40 DEG C, 45 DEG C, 50 DEG C, 55 DEG C, 60 DEG C, 65 DEG C, 70 DEG C, 75 DEG C, 80
℃、85℃、90℃、95℃、100℃、105℃、110℃、115℃、120℃、125℃、130℃、135℃、140℃、145
℃,150℃；
Reaction time is 1-10h；It preferably is selected from 1-5h.
(ii) impurity G is prepared under hydrolysising condition in compound B；
Wherein, R is selected from C1-10Alkyl；It preferably is selected from substituted or non-substituted methyl, substituted or non-substituted ethyl, replaces
Or non-substituted isopropyl, substituted or non-substituted butyl, substituted or non-substituted amyl, substituted or non-substituted n-hexane
Base, substituted or non-substituted normal octane base, substituted or non-substituted n -nonane base, replaces substituted or non-substituted constructed from normal heptyl
Or non-substituted n-decane base, wherein substituent group is selected from C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl；More
It preferably is selected from ethyl；
Hydrolysising condition is acid catalyzed hydrolysis；
Acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, Loprazolam or p-methyl benzenesulfonic acid in hydrolysising condition；It preferably is selected from hydrochloric acid；
Solvent is selected from methanol, ethyl alcohol, acetonitrile or hydrochloride aqueous solution in hydrolysising condition；It preferably is selected from hydrochloride aqueous solution.
The present invention also provides a kind of methods for synthesizing compound B, include the following steps；
The following steps are included:
(i) compound B is prepared by compound A-1 and compound A-2；
Wherein, M is selected from lithium, sodium, potassium；
R is selected from C1-10Alkyl；It preferably is selected from substituted or non-substituted methyl, substituted or non-substituted ethyl, substitution or non-
Substituted isopropyl, substituted or non-substituted amyl, substituted or non-substituted n-hexane base, takes substituted or non-substituted butyl
Generation or non-substituted constructed from normal heptyl, substituted or non-substituted normal octane base, substituted or non-substituted n -nonane base, substitution non-take
The n-decane base in generation, wherein substituent group is selected from C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl；More preferably certainly
Ethyl；
Reaction reagent is selected from sodium iodide, potassium iodide, tetrabutylammonium iodide, lithium iodide, silver iodide or iodine；
Reaction dissolvent be selected from alcohols, DMF, acetone, cyclohexanone, acetonitrile, toluene, dimethyl ether, N-Methyl pyrrolidone,
DMSO, dimethyl acetamide；Preferably be selected from methanol, ethyl alcohol, propyl alcohol, butanol, DMF, acetone, cyclohexanone, acetonitrile, toluene, dimethyl ether,
N-Methyl pyrrolidone, DMSO, dimethyl acetamide；
Reaction temperature is selected from 20 DEG C~150 DEG C；It preferably is selected from 60 DEG C~150 DEG C；More preferably from 80 DEG C~150 DEG C；
In another embodiment, reaction temperature is selected from 40 DEG C, 45 DEG C, 50 DEG C, 55 DEG C, 60 DEG C, 65 DEG C, 70 DEG C, 75 DEG C, 80
℃、85℃、90℃、95℃、100℃、105℃、110℃、115℃、120℃、125℃、130℃、135℃、140℃、145
℃,150℃；
Reaction time is 1-10h；It preferably is selected from 1-5h.
Another object of the present invention is to provide a kind of midbody compound,
Wherein R is selected from C1-10Alkyl；Preferably be selected from selected from substituted or non-substituted methyl, substituted or non-substituted ethyl,
Substituted or non-substituted isopropyl, substituted or non-substituted butyl, substituted or non-substituted amyl, it is substituted or non-substituted just oneself
Alkyl, substituted or non-substituted normal octane base, substituted or non-substituted n -nonane base, takes substituted or non-substituted constructed from normal heptyl
Generation or non-substituted n-decane base, wherein substituent group is selected from C1-6Alkyl, C1-6Alkoxy, C2-6Alkenyl, C2-6Alkynyl；
More preferably from ethyl.
In the present invention, unless otherwise indicated, the meaning that used term represents is as described below.
Group carbon atom number representation method, such as C1-10, refer to that the group can contain 1 carbon atom, 2 carbon atoms, 3
A carbon atom etc., until including 10 carbon atoms；Term "or" can be used interchangeably with term "and/or", unless the context otherwise
Clearly indicate.
Alkyl indicates the aliphatic group with the saturation of the carbon atom, including straight chain and branched hydrocarbyl, wraps without limitation
Include methyl, ethyl, propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, n-pentyl, n-hexyl etc..
Alcoxyl basis representation-O- alkyl, wherein alkyl is as defined herein.It without limitation include methoxyl group, ethyoxyl etc..
Alkenyl indicates the alkyl with one or more carbon-to-carbon double bonds, including straight chain and branch, without limitation includes second
Alkenyl, acrylic, cyclohexenyl group etc..
Alkynyl indicates the alkyl with one or more carbon-carbon triple bonds, including straight chain and branch, without limitation includes second
Alkynyl, propinyl etc..
Specific implementation method:
Below by nonlimiting examples, the present invention will be described, it should be appreciated that preferred reality described herein
Apply example only for the purpose of illustrating and explaining the present invention and is not intended to limit the present invention.
Embodiment 1:
Step 1: the synthesis and optimization of compound B
Table -1
| Test number | Reaction reagent | Reaction dissolvent | Reaction temperature | Conversion ratio |
| 1 | Sodium iodide | DMF | 40℃ | About 20% |
| 2 | Sodium iodide | DMF | 60℃ | About 40% |
| 3 | Sodium iodide | DMF | 100℃ | About 95% |
| 4 | Sodium iodide | Methanol | 60℃ | About 50% |
| 5 | Sodium iodide | Methylene chloride | 40℃ | It is unconverted |
Preparation manipulation process: being added A-1-1 (5g, 12.9mmol) in tri- mouthfuls of reaction flasks of 250ml, A-2-1 (4.39g,
19.4mmol), sodium iodide (4.39g, 19.4mmol) and reaction dissolvent.Above-mentioned reaction unit is heated to table -1 under nitrogen protection
In each reaction temperature, TLC monitoring reaction conversion situation.Wherein under the conditions of 100 DEG C of reaction temperatures, using DMF as solvent, raw material turns
Rate is up to 95% or more.
Post-processing: stopping reaction, and reaction solution is transferred to separatory funnel, liquid separation, organic phase concentration, column chromatograph yellow is solid
Body, i.e. compound B.
1H NMR (400MHz, CDCl3) δ 6.92 (d, J=8.7Hz, 1H), 6.77 (d, J=8.7Hz, 1H), 4.12 (q, J
=7.1Hz, 2H), 3.75-3.66 (m, 2H), 3.69 (s, 3H), 3.65-3.57 (m, 4H), 3.13-3.07 (m, 2H), 2.94
(t, J=8.0Hz, 2H), 2.45 (t, J=8.0Hz, 2H), 2.17-2.05 (m, 2H), 1.25 (t, J=7.1Hz, 3H)
Step 2: the synthesis of impurity G
Preparation manipulation process: compound B (0.90g, 2.36mmol) is added in 25ml stand up reaction bottle, concentrated hydrochloric acid
(9.0ml), heating stirring stop reaction after 2.5h.
Post-processing: after reaction solution concentration, deionized water is added, stirs 15min under ice-water bath.Filtering, acetone are washed, and 35 DEG C true
Empty dry pale solid impurity G 0.71g, yield 77.2%, HPLC:98.03%.
MS:[M+H]+=354.1
1H NMR (400MHz, DMSO-d6) δ 14.44 (s, 1H), 12.24 (s, 1H), 7.46 (d, J=9.1Hz, 1H),
7.12 (d, J=9.2Hz, 1H), 3.88 (s, 3H), 3.85-3.78 (m, 2H), 3.77-3.67 (m, 4H), 3.19-3.08 (m,
4H), 2.39 (t, J=8.0Hz, 2H), 2.01-1.93 (m, 2H)
Finally, it should be noted that being not limited to this hair the foregoing is merely part preferred embodiment of the invention
It is bright, it, still can be to preceding for those skilled in the art although describing the invention in detail with reference to the foregoing embodiments
It states technical solution documented by embodiment to modify, or some technical characteristics therein is equivalently replaced.It is all this
Within the spirit and principle of invention, any modification, equivalent substitution, improvement and etc. done should be included in protection model of the invention
Within enclosing.
Claims (17)
1. a kind of method for synthesizing impurity G, it is characterised in that: impurity G is prepared under hydrolysising condition in (ii) compound B；
Wherein R is selected from C1-10Alkyl.
2. the method for synthesis impurity G according to claim 1, it is characterised in that: (i) compound B is by compound A-1 and change
Object A-2 is closed to be prepared；
Wherein, M is selected from lithium, sodium, potassium；R is selected from C1-10Alkyl.
3. the method for synthesis impurity G according to claim 2, it is characterised in that: the reaction reagent of step (i) is selected from iodate
Sodium, potassium iodide, tetrabutylammonium iodide, lithium iodide, silver iodide or iodine.
4. the method for synthesis impurity G according to claim 2, it is characterised in that: the reaction dissolvent of step (i) is selected from alcohol
Class, DMF, acetone, cyclohexanone, acetonitrile, toluene, dimethyl ether, N-Methyl pyrrolidone, DMSO, dimethyl acetamide.
5. the method for synthesis impurity G according to claim 2, it is characterised in that: the reaction temperature of step (i) is selected from 20 DEG C
~150 DEG C；It preferably is selected from 60 DEG C~150 DEG C；More preferably from 80 DEG C~150 DEG C.
6. the method for synthesis impurity G according to claim 1, it is characterised in that: the hydrolysising condition of step (ii) is urged for acid
The hydrolysis of change.
7. the method for synthesis impurity G according to claim 6, it is characterised in that: acid can in the hydrolysising condition of step (ii)
To be hydrochloric acid, sulfuric acid, phosphoric acid, Loprazolam or p-methyl benzenesulfonic acid.
8. the method for synthesis impurity G according to claim 6, it is characterised in that: solvent in the hydrolysising condition of step (ii)
Selected from methanol, ethyl alcohol, acetonitrile or hydrochloride aqueous solution etc..
9. the method for synthesis impurity G according to claim 1 or 2, wherein R is selected from substituted or non-substituted methyl, replaces
Or it non-substituted ethyl, substituted or non-substituted isopropyl, substituted or non-substituted butyl, substituted or non-substituted amyl, takes
Generation or non-substituted n-hexane base, substituted or non-substituted constructed from normal heptyl, substituted or non-substituted normal octane base, substitution non-take
The n -nonane base in generation, substituted or non-substituted n-decane base, wherein substituent group is selected from C1-6Alkyl, C1-6Alkoxy, C2-6's
Alkenyl, C2-6Alkynyl.
10. a kind of method for synthesizing compound B, it is characterised in that: (i) compound B is prepared by compound A-1 and compound A-2
It obtains；
Wherein, M is selected from lithium, sodium, potassium；R is selected from C1-10Alkyl.
11. the method for synthesis compound B according to claim 10, wherein R is selected from substituted or non-substituted methyl, replaces
Or it non-substituted ethyl, substituted or non-substituted isopropyl, substituted or non-substituted butyl, substituted or non-substituted amyl, takes
Generation or non-substituted n-hexane base, substituted or non-substituted constructed from normal heptyl, substituted or non-substituted normal octane base, substitution non-take
The n -nonane base in generation, substituted or non-substituted n-decane base, wherein substituent group is selected from C1-6Alkyl, C1-6Alkoxy, C2-6's
Alkenyl, C2-6Alkynyl.
12. the method for synthesis compound B according to claim 10, it is characterised in that: the reaction reagent of step (i) is selected from
Sodium iodide, potassium iodide, tetrabutylammonium iodide, lithium iodide, silver iodide or iodine.
13. the method for synthesis compound B according to claim 10, it is characterised in that: the reaction dissolvent of step (i) is selected from
Alcohols, DMF, acetone, cyclohexanone, acetonitrile, toluene, dimethyl ether, N-Methyl pyrrolidone, DMSO, dimethyl acetamide.
14. the method for synthesis compound B according to claim 10, it is characterised in that: the reaction temperature of step (i) is selected from
20 DEG C~150 DEG C；It preferably is selected from 60 DEG C~150 DEG C；More preferably from 80 DEG C~150 DEG C.
15. a kind of midbody compound,
Wherein R is selected from C1-10Alkyl.
16. midbody compound according to claim 15, wherein R is selected from substituted or non-substituted methyl, substitution or non-
Substituted ethyl, substituted or non-substituted isopropyl, substituted or non-substituted butyl, substituted or non-substituted amyl, replace or
It is non-substituted n-hexane base, substituted or non-substituted constructed from normal heptyl, substituted or non-substituted normal octane base, substituted or non-substituted
N -nonane base, substituted or non-substituted n-decane base, wherein substituent group is selected from C1-6Alkyl, C1-6Alkoxy, C2-6Alkene
Base, C2-6Alkynyl.
17. midbody compound according to claim 16, wherein R is selected from ethyl.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102292073A (en) * | 2008-12-03 | 2011-12-21 | 安斯泰来德国有限公司 | Solid dosage forms of bendamustine |
| WO2014208354A1 (en) * | 2013-06-25 | 2014-12-31 | Takeuchi Tsutomu | Pharmaceutical composition for treatment or prophylaxis of inflammatory diseases |
-
2018
- 2018-05-02 CN CN201810408524.2A patent/CN110437261A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102292073A (en) * | 2008-12-03 | 2011-12-21 | 安斯泰来德国有限公司 | Solid dosage forms of bendamustine |
| WO2014208354A1 (en) * | 2013-06-25 | 2014-12-31 | Takeuchi Tsutomu | Pharmaceutical composition for treatment or prophylaxis of inflammatory diseases |
Non-Patent Citations (2)
| Title |
|---|
| JING JING，等: "Rational design of ZnSalen as a single and two photon activatable fluorophore in living cells", 《CHEMICAL SCIENCE》 * |
| R. GUST，等: "Investigations on the Stability of Bendamustin, a Cytostatic Agent of the Nitrogen Mustard Type, I. Synthesis, Isolation, and Characterization of Reference Substances", 《MONATSHEFTE FIIR CHEMIE》 * |
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Application publication date: 20191112 |