CN108358848A - A kind of synthetic method of bendamustine hydrochloride intermediate - Google Patents
A kind of synthetic method of bendamustine hydrochloride intermediate Download PDFInfo
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- CN108358848A CN108358848A CN201810038788.3A CN201810038788A CN108358848A CN 108358848 A CN108358848 A CN 108358848A CN 201810038788 A CN201810038788 A CN 201810038788A CN 108358848 A CN108358848 A CN 108358848A
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- bendamustine hydrochloride
- synthetic method
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- nitroanilines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of synthetic methods of bendamustine hydrochloride intermediate; using 2 chlorine, 5 nitroaniline as raw material; acylation reaction is carried out with glutaric anhydride; obtain intermediate 1; the intermediate 1 is subjected to substitution reaction in methylamine water solution, intermediate 2 is made; the intermediate 2 and ethyl alcohol are subjected to cyclization, esterification under the conditions of sulfuric acid, obtain 1 methyl of target product, 5 nitro 1H benzimidazoles, 2 ethyl butyrate.Method provided by the invention has the characteristics that simple synthetic route, high income, wastewater flow rate are few.
Description
Technical field
The present invention relates to a kind of synthetic methods of bendamustine hydrochloride intermediate, belong to chemosynthesis technical field.
Background technology
1- methyl-5-nitros -1H- benzimidazolyl-2 radicals-ethyl butyrate is the important intermediate of bendamustine hydrochloride.Hydrochloric acid
Bendamustine is a kind of bifunctional alkylating agents, has antitumor action.2003, with trade name Ribomustine in Germany
Listing, for treating breast cancer, chronic lymphocytic leukemia, in the bendamustine hydrochloride trade name of U.S.'s listing
Treanda proposes application for quotation by Cephalon companies, and obtains FDA approvals by preferential examination and approval procedures.In March, 2008,
FDA ratifies bendamustine hydrochloride for treating chronic lymphocytic leukemia (CLL) first.October in the same year, FDA ratify again
2nd idicatio of the medicine, i.e., in Rituximab (rituximab, Mabthera) or the mistake of Regimen Chemotherapy containing Rituximab
Cheng Zhong, or treat in 6 months, inertia B cell non-Hodgkin lymphoma (NHL) patient that the state of an illness is still in progress.Hydrochloric acid benzene reaches
Mo Siting plasma protein binding rates are 94%~96%, and data show that the medicine generally will not be mutual with other high protein combination drugs
Displacement.Bendamustine hydrochloride average steady state distribution volume is about 25L, and whole blood/plasma concentration ratio is 0.84~0.86.Hydrochloric acid
Bendamustine is mainly metabolized by hydrolysis, and the lower metabolite of cytotoxicity is formed simultaneously.1- methyl -5- nitre
The synthesis of base -1H- benzimidazolyl-2 radicals-ethyl butyrate is mainly made by the synthetic route of patent CN101948436, and synthetic route is such as
Under：
The route is four-step reaction, which is to use vulcanized sodium selective reduction nitro in second step reaction
For amino, a large amount of vulcanized sodium waste water is will produce in post-processing, it is more serious to the damage ratio of environment, and the selectivity restored is not
Height, patent CN101948436 yields are 73.5%.Route is there is also the relatively low problem of yield, and total recovery is in 44%-55%.
Invention content
The few hydrochloric acid of simple, high income that the technical problem to be solved by the invention is to provide a kind of synthetic routes, wastewater flow rate
The synthetic method of bendamustine intermediate.
In order to solve the above technical problems, the technical solution adopted by the present invention is：
A kind of synthetic method of bendamustine hydrochloride intermediate, using the chloro- 5- nitroanilines of 2- as raw material, with glutaric anhydride
Acylation reaction is carried out, intermediate 1 is obtained, the intermediate 1 is carried out substitution reaction in methylamine water solution is made intermediate 2, will
The intermediate 2 carries out cyclization, esterification with ethyl alcohol under the conditions of sulfuric acid, obtains target product 1- methyl-5-nitros -1H-
Benzimidazolyl-2 radicals-ethyl butyrate, synthetic route are as follows：
It is 1 that the chloro- 5- nitroanilines of 2-, which react molar ratio with the glutaric anhydride,:1.
The chloro- 5- nitroanilines of 2- are 80 DEG C with the glutaric anhydride reaction temperature.
The chloro- 5- nitroanilines of 2- are 3h with the glutaric anhydride reaction time.
It is 4 that the methylamine, which reacts molar ratio with the chloro- 5- nitroanilines of the 2-,:1.
The reaction temperature of the substitution reaction is 50 DEG C.
The reaction time for stating substitution reaction is 3h.
The advantageous effect that the present invention is reached：The synthetic method route provided in the present invention is short, avoids using vulcanized sodium
The step of reaction, greatly reduces the generation of waste water；Total recovery is increased to 79% by former route 44%-55%, improves reaction
Yield shortens the production cycle, reduces cost.
Specific implementation mode
The invention will be further described below.Following embodiment is only used for clearly illustrating the technical side of the present invention
Case, and not intended to limit the protection scope of the present invention.
Embodiment 1：
It takes the chloro- 5- nitroanilines of 51.6g 2- to be added in there-necked flask, 500ml toluene is added, 36g penta is added at room temperature
Dicarboxylic anhydride is heated to 80 DEG C and reacts 3 hours, be cooled to room temperature, filters, and filter cake is dried at 70 DEG C, obtains yellow solid intermediate 1
45g, yield 95%.
Above-mentioned obtained intermediate 1 is added in 40% methylamine water solutions of 150ml, 50 DEG C is heated to and reacts 3 hours, it is cold
But yellow solid is precipitated with 2N hydrochloric acid tune PH=4-5 to room temperature, after stirring 1h, filtering, filter cake is eluted with toluene, 70 DEG C of bakings
It is dry, obtain 2 40.5g yields 91.7% of yellow solid intermediate.
Above-mentioned obtained intermediate 2 is added in there-necked flask, is added in 365ml absolute ethyl alcohols, lower dropwise addition 12ml is stirred
98% concentrated sulfuric acid drips and is heated to 80 DEG C of reflux 3h, is cooled to 45-50 DEG C, reaction solution is poured into unsaturated carbonate aqueous solutions of potassium
In (500ml), a large amount of white solids are precipitated, filter, filter cake is washed to neutrality, and 70 DEG C of drying obtain white powder 1- methyl-
5- nitros -1H- benzimidazolyl-2 radicals-ethyl butyrate 40g, yield 90.7%, purity 99.8%, fusing point：110-114℃.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, without departing from the technical principles of the invention, several improvement and deformations can also be made, these improvement and deformations
Also it should be regarded as protection scope of the present invention.
Claims (7)
1. a kind of synthetic method of bendamustine hydrochloride intermediate, which is characterized in that using the chloro- 5- nitroanilines of 2- as raw material,
Acylation reaction is carried out with glutaric anhydride, obtains intermediate 1, the intermediate 1 is carried out substitution reaction in methylamine water solution to be made
The intermediate 2 and ethyl alcohol under the conditions of sulfuric acid are carried out cyclization, esterification, obtain target product 1- methyl-by intermediate 2
5- nitros -1H- benzimidazolyl-2 radicals-ethyl butyrate, synthetic route are as follows：
2. a kind of synthetic method of bendamustine hydrochloride intermediate as described in claim 1, which is characterized in that the 2-
It is 1 that chloro- 5- nitroanilines, which react molar ratio with the glutaric anhydride,:1.
3. a kind of synthetic method of bendamustine hydrochloride intermediate as described in claim 1, which is characterized in that the 2-
Chloro- 5- nitroanilines are 80 DEG C with the glutaric anhydride reaction temperature.
4. a kind of synthetic method of bendamustine hydrochloride intermediate as described in claim 1, which is characterized in that the 2-
Chloro- 5- nitroanilines are 3h with the glutaric anhydride reaction time.
5. a kind of synthetic method of bendamustine hydrochloride intermediate as described in claim 1, which is characterized in that the methylamine
It is 4 that molar ratio is reacted with the chloro- 5- nitroanilines of the 2-:1.
6. a kind of synthetic method of bendamustine hydrochloride intermediate as described in claim 1, which is characterized in that the substitution
The reaction temperature of reaction is 50 DEG C.
7. a kind of synthetic method of bendamustine hydrochloride intermediate as described in claim 1, which is characterized in that the substitution
The reaction time of reaction is 3h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810038788.3A CN108358848A (en) | 2018-01-16 | 2018-01-16 | A kind of synthetic method of bendamustine hydrochloride intermediate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810038788.3A CN108358848A (en) | 2018-01-16 | 2018-01-16 | A kind of synthetic method of bendamustine hydrochloride intermediate |
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| CN201810038788.3A Pending CN108358848A (en) | 2018-01-16 | 2018-01-16 | A kind of synthetic method of bendamustine hydrochloride intermediate |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004106363A2 (en) * | 2003-05-30 | 2004-12-09 | Css-Albachem Limited | A tag for purification of peptides |
| CN101948437A (en) * | 2010-06-28 | 2011-01-19 | 江苏奥赛康药业有限公司 | Refining method of bendamustine hydrochloride |
| CN101948436A (en) * | 2010-06-28 | 2011-01-19 | 江苏奥赛康药业有限公司 | Method for preparing high-purity bendamustine hydrochloride |
-
2018
- 2018-01-16 CN CN201810038788.3A patent/CN108358848A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004106363A2 (en) * | 2003-05-30 | 2004-12-09 | Css-Albachem Limited | A tag for purification of peptides |
| CN101948437A (en) * | 2010-06-28 | 2011-01-19 | 江苏奥赛康药业有限公司 | Refining method of bendamustine hydrochloride |
| CN101948436A (en) * | 2010-06-28 | 2011-01-19 | 江苏奥赛康药业有限公司 | Method for preparing high-purity bendamustine hydrochloride |
Non-Patent Citations (1)
| Title |
|---|
| 高丽梅，等: "盐酸苯达莫司汀的合成", 《中国新药杂志》 * |
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Application publication date: 20180803 |
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