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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- China
- Prior art keywords
- bendamustine hydrochloride
- synthetic method
- reaction
- nitroanilines
- chloro
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- ZHSKUOZOLHMKEA-UHFFFAOYSA-N 4-[5-[bis(2-chloroethyl)amino]-1-methylbenzimidazol-2-yl]butanoic acid;hydron;chloride Chemical compound Cl.ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 ZHSKUOZOLHMKEA-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 229960001215 bendamustine hydrochloride Drugs 0.000 title claims abstract description 16
- 238000010189 synthetic method Methods 0.000 title claims abstract description 14
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 claims abstract description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000006467 substitution reaction Methods 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 6
- 235000019441 ethanol Nutrition 0.000 claims abstract description 4
- LFETXMWECUPHJA-UHFFFAOYSA-N methanamine;hydrate Chemical compound O.NC LFETXMWECUPHJA-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000005917 acylation reaction Methods 0.000 claims abstract description 3
- 230000032050 esterification Effects 0.000 claims abstract description 3
- 238000005886 esterification reaction Methods 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 11
- ZRQSYIAOCGKOJI-UHFFFAOYSA-N n-chloro-3-nitroaniline Chemical class [O-][N+](=O)C1=CC=CC(NCl)=C1 ZRQSYIAOCGKOJI-UHFFFAOYSA-N 0.000 claims description 9
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- KWIXNFOTNVKIGM-UHFFFAOYSA-N 2-chloro-5-nitroaniline Chemical class NC1=CC([N+]([O-])=O)=CC=C1Cl KWIXNFOTNVKIGM-UHFFFAOYSA-N 0.000 claims 2
- 239000002351 wastewater Substances 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 2
- HNAGHMKIPMKKBB-UHFFFAOYSA-N 1-benzylpyrrolidine-3-carboxamide Chemical compound C1C(C(=O)N)CCN1CC1=CC=CC=C1 HNAGHMKIPMKKBB-UHFFFAOYSA-N 0.000 abstract 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 1
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 abstract 1
- 229910052801 chlorine Inorganic materials 0.000 abstract 1
- 239000000460 chlorine Substances 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- VBEGHXKAFSLLGE-UHFFFAOYSA-N n-phenylnitramide Chemical compound [O-][N+](=O)NC1=CC=CC=C1 VBEGHXKAFSLLGE-UHFFFAOYSA-N 0.000 abstract 1
- -1 nitro 1H benzimidazoles Chemical class 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 229960004641 rituximab Drugs 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- XKJMBINCVNINCA-UHFFFAOYSA-N Alfalone Chemical compound CON(C)C(=O)NC1=CC=C(Cl)C(Cl)=C1 XKJMBINCVNINCA-UHFFFAOYSA-N 0.000 description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 description 2
- 229960002707 bendamustine Drugs 0.000 description 2
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 208000028564 B-cell non-Hodgkin lymphoma Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 description 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- JUMGOLYNZBZPKE-UHFFFAOYSA-N ethyl 4-(5-amino-1-methylbenzimidazol-2-yl)butanoate Chemical compound NC1=CC=C2N(C)C(CCCC(=O)OCC)=NC2=C1 JUMGOLYNZBZPKE-UHFFFAOYSA-N 0.000 description 1
- 125000005909 ethyl alcohol group Chemical group 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940066958 treanda Drugs 0.000 description 1
Classifications
-
- 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
Landscapes
- 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.
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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 |
Applications Claiming Priority (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 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108358848A true CN108358848A (en) | 2018-08-03 |
Family
ID=63006117
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810038788.3A Pending CN108358848A (en) | 2018-01-16 | 2018-01-16 | A kind of synthetic method of bendamustine hydrochloride intermediate |
Country Status (1)
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|---|---|
| CN (1) | CN108358848A (en) |
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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