CN105111238A - Method for producing minodronic acid monohydrate by using water as solvent - Google Patents
Method for producing minodronic acid monohydrate by using water as solvent Download PDFInfo
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- CN105111238A CN105111238A CN201510383153.3A CN201510383153A CN105111238A CN 105111238 A CN105111238 A CN 105111238A CN 201510383153 A CN201510383153 A CN 201510383153A CN 105111238 A CN105111238 A CN 105111238A
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- 0 *OC(CC(CCl)=O)=O Chemical compound *OC(CC(CCl)=O)=O 0.000 description 6
- ICSNLGPSRYBMBD-UHFFFAOYSA-N Nc1ncccc1 Chemical compound Nc1ncccc1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- ZVBVKRNOISRONE-UHFFFAOYSA-N OC(Cc1cnc2[n]1cccc2)=O Chemical compound OC(Cc1cnc2[n]1cccc2)=O ZVBVKRNOISRONE-UHFFFAOYSA-N 0.000 description 2
- MGDWUTQKXCZNAJ-UHFFFAOYSA-N CCOC(CC(CBr)=O)=O Chemical compound CCOC(CC(CBr)=O)=O MGDWUTQKXCZNAJ-UHFFFAOYSA-N 0.000 description 1
- LNMNFOZLNGOOGB-UHFFFAOYSA-N COC(Cc1cnc2[n]1cccc2)=O Chemical compound COC(Cc1cnc2[n]1cccc2)=O LNMNFOZLNGOOGB-UHFFFAOYSA-N 0.000 description 1
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Abstract
The present invention discloses a method for producing a minodronic acid monohydrate by using water as a solvent. According to the method, ethyl 4-bromoacetoacetate or methyl 4-bromoacetoacetate is adopted as a raw material and reacts with 2-aminopyridine by adopting water as a solvent under the effect of a catalytic amount of an organic alkali so as to highly-selectively obtain 2-(imidazo[1,2-a]pyridine-3-yl)ethyl acetate, the 2-(imidazo[1,2-a]pyridine-3-yl)ethyl acetate (methyl acetate) is hydrolyzed with an alkali solution to obtain 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid, the 2-(imidazo[1,2-a]pyridine-3-yl)acetic acid, phosphorous acid and phosphorus trichloride react to obtain minodronic acid, and refining is performed to obtain the minodronic acid monohydrate. According to the present invention, the process has characteristics of simple reaction operation, easily available raw materials, easy post-treatment, high yield, application of the water as the solvent, and environmental protection, and is suitable for mass production.
Description
Technical field
The present invention relates to a kind of method using water as solvent production Minodronic acid hydrate, belong to chemosynthesis technical field.
Background technology
Osteoporosis osteoporosis is a kind of general metabolism osteopathy, and it is a kind of bone forming and the unbalanced disease of bone resorption, namely with bone amount reduce and osseous tissue fine structure destroy for feature and cause bone fragility increase and fracture disease.Diphosphonate can reduce osteoclast activity, direct or induction osteocyte, and produces osteoclast supressor.
The minodronic acid developed by Astellas company is third generation azepine aryl biphosphonate derivative, can as oral and injection formulations use.Pharmacological evaluation shows that its anti-bone resorption activity is 2,10,100 times of incadronate disodium disodiumincadronate, alendronate sodium alendronate and Pamidronate Disodium disodiumpamidronate.
Minodronic acid hydrate, English name: MinodronicAcidHydrate, chemical name is [1-hydroxyl-2-(imidazo [1,2-a] pyridin-3-yl) ethylidene] 1,1-bis phosphoric acid monohydrate, molecular formula: C
9h
14n
2o
8p
2, molecular weight: 340.16, structural formula is as follows:
The synthetic method of minodronic acid monohydrate is reported in European patent EP 0354806, but not about the synthetic method of its raw material 2-[imidazo (1,2-a) pyridin-3-yl] acetic acid.
2004, Pi Shiqing, Zhao Guoqing; At Chinese Journal of Pharmaceuticals, 2004,35 (4), 193-193; Report with imidazo [1,2-a] pyridine is raw material, 3-[(N is obtained by reacting with paraformaldehyde and dimethylamine hydrochloride, N dimethylamine base) methyl] imidazo [1,2-a] pyridine (2), react with haloalkane and form quaternary ammonium salt 3, after cyano group replacement obtains 4, directly hydrolysis obtains 5 in the basic conditions, reacts to obtain minot phosphoric acid with phosphorus trichloride and phosphorous acid in appropriate solvent.Its synthetic route is as follows:
This technique employs the sodium cyanide of severe toxicity, and operational hazards, step is long, and starting raw material is more expensive, is not suitable for industrialization.
2011, Tian Jian, Zhong Jianfeng, Guo Wei; University Of Shanxi's journal (natural science edition) 34 (s2): 55 ~ 56,2011; Disclose a new reaction scheme, with ethyl formate and o-aminopyridine for raw material, be obtained by reacting target compound through condensation, bromination, pass ring and willgerodt-kindler.Its synthesis is as follows:
This route uses bromine, very not convenient to production, and route is long, purification difficult, and is not suitable for suitability for industrialized production.
2013, Chai Huifang, Zhao Chunshen; Shenyang Pharmaceutical University's journal, 2013,30 (6), 439-441; Disclose with PA and MALEIC ANHYDRIDE as raw material, compound 2-[imidazo (1 is obtained through cyclization, esterification, chloro, reduction, hydrolysis ester group, 2-a) pyridin-3-yl] acetic acid, then obtain minodronic acid monohydrate after reacting with phosphorous acid.Synthetic route is as follows:
This operational path is long, and wherein two steps use phosphorus oxychloride or phosphorus trichloride carries out chlorination, a step hydrogenation, and step is longer; Cost is higher, as seen this technique be not suitable for industrial production.
It is starting raw material that patent CN1020101860 discloses with GBL, and through open loop, oxidation, is hydrolyzed and obtains compound 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid after bromo with after PA cyclization.But oxidation step needs very low temperature to react in this route, the at substantial energy, and use bromine, production operation is inconvenient, is therefore not suitable for suitability for industrialized production.Synthetic route is as follows:
Patent CN102020676 discloses one with 2; 2-dimethoxy acetaldehyde and phosphine acyl acetic acid three ethyl are starting raw material; with PA ring synthetic compound 2-(imidazo [1 after condensation; 2-a] pyridin-3-yl) ethyl acetate; 2-[imidazo (1 is obtained after hydrolysis; 2-a) pyridin-3-yl] acetic acid, more phosphorated obtained Minodronic acid hydrate.Synthetic route is as follows:
This route is comparatively succinct, and yield is higher.But raw material 2,2-dimethoxy acetaldehyde price is more expensive, is not easy to obtain, causes production cost higher.
In patent CN101531681, reporting one with ethy succinyl chloride is starting raw material, with PA ring synthetic compound 2-(imidazo [1 after reduction, bromination, 2-a] pyridin-3-yl) ethyl acetate, 2-[imidazo (1 is obtained after hydrolysis, 2-a) pyridin-3-yl] acetic acid, more phosphorated obtained Minodronic acid hydrate.Relate to reduction reaction in this route and use three tert.-butoxy Li-Al hydrogens, need to react at low temperatures.And ethy succinyl chloride price is higher, adds production cost.Also bromine has been used in reaction process, unfriendly to environment, so this route is not suitable for suitability for industrialized production.
Synthetic route is as follows:
In patent CN102153585 and patent CN101973993,4-ethyl bromoacetoacetate (4-chloroacetyl acetacetic ester) and PA cyclization under the effect of acid binding agent is used to obtain 2-(imidazo [1 respectively, 2-a] pyridin-3-yl) ethyl acetate, 2-[imidazo (1 is obtained after hydrolysis, 2-a) pyridin-3-yl] acetic acid, more phosphorated obtained Minodronic acid hydrate.But when this patent experiment carries out repetition to above-mentioned reaction, find ring-closure reaction time with 4-chloroacetyl acetacetic ester for raw material obtains 2-(imidazo [1,2-a] pyridine-2-base) ethyl acetate is principal product, when with 4-ethyl bromoacetoacetate for raw material obtains 2-[imidazo (1,2-a) pyridin-3-yl] mixture of acetic acid and 2-(imidazo [1,2-a] pyridine-2-base) ethyl acetate.And two products can not separate, and cause this route not to be used for suitability for industrialized production.Flow process is as follows:
In order to avoid 2-(imidazo [1; 2-a] pyridine-2-base) generation of ethyl acetate impurity; in patent CN102875602, compound 4-chloro methyl aceto acetate is carried out ketone group and protect (2-chloromethyl-[1; 3]-dioxolane-2-base) ethyl acetate; react with PA again; obtain 2-[imidazo (1; 2-a) pyridin-3-yl] ethyl acetate; through sodium hydroxide hydrolysis; obtain 2-[imidazo (1; 2-a) pyridin-3-yl] acetic acid, more phosphorated obtained Minodronic acid hydrate.Synthetic route is as follows:
Although this technique overcomes the generation of chemical isomer, need experience protection and two steps of deprotection, increase cost undoubtedly, and make troubles to production technique.For this reason, urgent exploitation one is applicable to industrialized production process.
Summary of the invention
The object of the invention is the above-mentioned shortcoming overcoming prior art, there is provided that a kind of operation is simple, cheaper starting materials is easy to get, with water to replace organic solvent, environmentally friendly, aftertreatment is easy, productive rate is high, be suitable for the method for suitability for industrialized production minodronic acid monohydrate.
For achieving the above object, the present invention adopts following scheme:
Produce a method for minodronic acid monohydrate with water as solvent, it is characterized in that comprising the following steps:
A, with 4-ethyl bromoacetoacetate or 4-acetobrom methyl acetate for raw material, under water solvent, organic bases effect, react with PA, highly selective obtain 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate;
B, 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate (methyl esters) alkaline solution is hydrolyzed into 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid;
C, 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid and phosphorous acid, phosphorus trichloride react, and obtain minodronic acid, minodronic acid monohydrate of re-refining to obtain.
Produce a method for minodronic acid monohydrate as above with water as solvent, it is characterized in that the specific practice of steps A:
In reaction vessel, add 4-ethyl bromoacetoacetate or 4-acetobrom methyl acetate, PA and organic bases K successively, wherein 4-ethyl bromoacetoacetate or 4-acetobrom methyl acetate are 1:0.8 ~ 2.0 with the amount of substance ratio of PA; The ratio of the amount of substance of organic bases K and 4-ethyl bromoacetoacetate or 4-acetobrom methyl acetate is 0.01 ~ 1.0:1, is dissolved in the water of 20 ~ 50 times of volumes; React at 35 ~ 85 DEG C, TLC monitors; React complete, extract with organic solvent E, merge organic layer, saturated NaCl washing, dry, concentrating under reduced pressure, obtain 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate or 2-(imidazo [1,2-a] pyridin-3-yl) methyl acetate crude product, obtain fine work through recrystallizing and refining.
Produce a method for minodronic acid monohydrate as above with water as solvent, it is characterized in that the specific practice of step B:
2-(the imidazo [1 that step a is prepared into, 2-a] pyridin-3-yl) ethyl acetate or 2-(imidazo [1,2-a] pyridin-3-yl) methyl acetate is dissolved in the alcoholic solvent F of 5 ~ 10 times of volumes, drip the sodium hydroxide solution of 1 ~ 10N at 0 ~ 50 DEG C, dropwise; Insulated and stirred, TLC detection reaction is complete, be evaporated to volume and 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate or 2-(imidazo [1,2-a] pyridin-3-yl) methyl acetate mass ratio is 2 ~ 4, add sour G in ice-water bath, regulate pH to be 2 ~ 3; Separate out light yellow to brown solid in a large number, filtration, vacuum-drying obtain 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid.
Produce a method for minodronic acid monohydrate as above with water as solvent, it is characterized in that the specific practice of step C:
2-(imidazo [1,2-a] pyridin-3-yl) acetic acid is dissolved in the solvent H of 10 ~ 50 times of volumes, adds phosphorous acid, be heated to 80 ~ 85 DEG C, react 1 ~ 2 hour; Drip phosphorus trichloride, be warming up to back flow reaction 5 ~ 8 hours; Cooling, incline supernatant liquid, the residuum hydrochloric acid reflux 2 ~ 5 hours of 6 ~ 12N; Activated carbon decolorizing, filters, evaporated under reduced pressure filtrate, residuum ethanol or methyl alcohol stirring and crystallizing, separates out white solid; Filter to obtain minodronic acid crude product; By the salt acid treating of crude product water or 0.5 ~ 2N, obtain minodronic acid monohydrate.HPLC purity >99%, single assorted < 0.1%.
Produce a method for minodronic acid monohydrate as above with water as solvent, it is characterized in that described organic bases K be triethylamine, DIPEA, DABCO, in one or more mixture.
Produce a method for minodronic acid monohydrate as above with water as solvent, it is characterized in that described organic bases K preferentially selects DABCO.
Produce a method for minodronic acid monohydrate as above with water as solvent, it is characterized in that described organic bases K consumption preferably 10%.
Produce a method for minodronic acid monohydrate as above with water as solvent, it is characterized in that described organic solvent E is one or more the mixture in ethyl acetate, methylene dichloride, toluene.
Produce a method for minodronic acid monohydrate as above with water as solvent, it is characterized in that described organic solvent E preferentially selects ethyl acetate, methylene dichloride.
Produce a method for minodronic acid monohydrate as above with water as solvent, it is characterized in that in steps A, recrystallization solvent for use is the two or more mixture in sherwood oil, ethyl acetate, normal hexane, heptane, ether, tetrahydrofuran (THF).
Produce a method for minodronic acid monohydrate as above with water as solvent, it is characterized in that the mixture of the preferred sherwood oil of recrystallization solvent for use and ethyl acetate in steps A, sherwood oil and ethyl acetate ratio are 1:4 ~ 4:1, preferred 3:2.
Produce a method for minodronic acid monohydrate as above with water as solvent, it is characterized in that step B alcoholic solvent F is one or more the mixture in methyl alcohol, ethanol, Virahol.
Produce a method for minodronic acid monohydrate as above with water as solvent, it is characterized in that step B alcoholic solvent F preferred alcohol.
Produce a method for minodronic acid monohydrate as above with water as solvent, it is characterized in that sour G described in step B is organic acid or mineral acid, as the mixture of one or more in acetic acid, formic acid, hydrochloric acid, sulfuric acid.Preferred acetic acid and hydrochloric acid.
Produce a method for minodronic acid monohydrate as above with water as solvent, it is characterized in that the H of solvent described in step C is one or more the mixture in toluene, dimethylbenzene, chlorobenzene.Preferred toluene.
The structural formula of minodronic acid monohydrate:
In the present invention, 4-ethyl bromoacetoacetate and PA are in organic solvent, and mineral alkali is made acid binding agent ShiShimonoseki ring and obtained 2-(imidazo [1,2-a] pyridine-2-base) ethyl acetate; And 4-ethyl bromoacetoacetate and PA with water as solvent time, organic bases is made acid binding agent ShiShimonoseki ring and is obtained 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate.As follows:
4-ethyl bromoacetoacetate and PA are at 60-70 DEG C, and close ring with different solvents and acid binding agent, products therefrom ratio is as follows:
As can be seen from the table with organic solvent and organic bases do react time, product is mixture M, N; With organic solvent and mineral alkali do react time, product is main with 2-(imidazo [1,2-a] pyridine-2-base) ethyl acetate; Make acid binding agent ShiShimonoseki ring with organic bases and obtain 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate is main, particularly with water as solvent, when DABCO is alkali, obtain 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate with the ratio of more than 98%.
Reaction mechanism of the present invention is as follows:
The preferred technical solution of the present invention is as follows:
The present invention compared with prior art, has following advantage and beneficial effect:
1, select raw material cheap and easy to get, cost is lower, environmentally friendly with water as solvent;
2, target product can be obtained compared with highly selective, improve pharmaceutical purity;
3, operational path is more easy, and the more existing technique of production cost is low, can create significant economic worth.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but embodiments of the present invention are not limited thereto.
In following embodiment, nucleus magnetic resonance is by BrukerAMX-400 type nmr determination, and TMS is interior mark, and chemical shift unit is ppm; High performance liquid phase (HPLC) is detected by Agilent1100; TLC silica-gel plate GF254 is that Haiyang Chemical Plant, Qingdao produces, and adopts ultraviolet lamp colour developing; If do not particularly point out working method in embodiment, described concentrating under reduced pressure refers to be steamed by the solvent prepared in compound solution with Rotary Evaporators; Described drying refers to anhydrous sodium sulphate or magnesium sulfate, and described vacuum-drying refers to prepare compound with vacuum-drying in vacuum drying oven.
The english abbreviation related in literary composition
MeOH=methyl alcohol
TLC=tlc analysis
DIPEA=N, N-diisopropylethylamine
DABCO=1,4-diazabicylo [2.2.2] octane
Embodiment 1
The preparation of step a:2-[imidazo (1,2-a) pyridin-3-yl] ethyl acetate (B)
Take A:2-aminopyridine 9.4g and 0.1mol, 4-ethyl bromoacetoacetate 20.9g and 0.1mol and DABCO1.1g and 0.01mol, be dissolved in 400mL water.Be heated to 60-70 DEG C, TLC monitors reaction, within about 1 hour, reacts completely.Extract 3 times with ethyl acetate 200mL, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, obtain crude product.By the mixture recrystallization of crude product by 100mL sherwood oil and ethyl acetate, wherein the volume ratio of sherwood oil and ethyl acetate is 1:3, obtains light yellow solid 18g, yield 88.1%.
ESI-MS:[M+H]
+＝205.1
Nuclear magnetic resonance data:
1h-NMR (CDCl
3, 400MHz): δ (ppm)=8.06 (d, J=6.8Hz, 1H), 7.62 (d, J=8.8Hz, 1H), 7.56 (s, 1H), 7.20 (t, 1H), 4.14-4.20 (dd, J=7.2Hz, 2H), 3.94 (s, 2H), 1.25 (t, 3H).
The preparation of step b:2-[imidazo (1,2-a) pyridin-3-yl] ethyl acetate (C)
B:2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate 10.2g and 50mmol is dissolved in 70mL ethanol, drips 5mol/L sodium hydroxide solution 40mL at 35 DEG C, dropwise.Insulated and stirred, TLC detection reaction is complete, is evaporated to volume and is about 20mL, drip acetic acid in ice-water bath, regulates pH to be 2 ~ 3.Separate out a large amount of yellow brown solid, filtration, filter cake little water are washed.Vacuum-drying obtains C:2-(imidazo [1,2-a] pyridin-3-yl) acetic acid, is directly used in next step reaction without the need to purifying.
ESI-MS:[M+H]
+＝177.1
Nuclear magnetic resonance data:
1h-NMR (d
6-DMSO, 400MHz): δ (ppm)=7.58-7.56 (t, 1H), 7.48 (d, 1H), 7.27-7.23 (q, 1H), 6.92-6.96 (t, 1H), 4.04 (d, J=6.0Hz, 2H).
Step C: the preparation of minot phosphoric acid monohydrate
By C:2-(imidazo [1,2-a] pyridin-3-yl) acetic acid 17.6g, namely 0.1mol is dissolved in 400mL toluene, adds phosphorous acid 18.8g, i.e. 0.23mol, is heated to 80 DEG C, reacts 1 hour.Temperature maintains 80 DEG C and drips phosphorus trichloride 44g, i.e. 0.32mol, dropwises, and is warming up to back flow reaction 8 hours.Cooling, leave standstill, incline supernatant liquid, and the hydrochloric acid 500mL of residuum 6mol/L refluxes 5 hours.Add 10g activated carbon decolorizing, filter, evaporated under reduced pressure filtrate, impouring methyl alcohol 250mL stirring and crystallizing in residuum, separate out white solid, filter to obtain minodronic acid crude product, off-white color pressed powder.
By crude product 20g 2L water recrystallization, obtain minodronic acid monohydrate, HPLC purity 99.6%, single assorted < 0.1%.
Embodiment 2
The preparation of step a:2-[imidazo (1,2-a) pyridin-3-yl] methyl acetate (B)
Take A:2-aminopyridine 128g, i.e. 1.36mol, 4-acetobrom methyl acetate 318g, i.e. 1.63mol and DABCO30.5g, i.e. 0.272mol, be dissolved in 2.5L water.Be heated to 60-70 DEG C, TLC monitors reaction, within about 1.5 hours, reacts completely.Extract 3 times with ethyl acetate 2L, merge organic layer, saturated aqueous common salt 750mL washs, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, obtain crude product.By the mixture recrystallization of crude product by 470mL sherwood oil and ethyl acetate, wherein the volume ratio of sherwood oil and ethyl acetate is 2:5, obtains light yellow solid 135g, yield 52.2%.
ESI-MS:[M+H]
+＝191.1
Nuclear magnetic resonance data:
1h-NMR (CDCl
3, 400MHz): δ (ppm)=8.06 (d, J=6.8Hz, 1H), 7.62 (d, J=8.8Hz, 1H), 7.56 (s, 1H), 7.20 (t, 1H), 4.25 (s, 3H), 3.94 (s, 2H).
The preparation of step b:2-[imidazo (1,2-a) pyridin-3-yl] methyl acetate (C)
By B:2-(imidazo [1,2-a] pyridin-3-yl) methyl acetate 95g, namely 0.5mol is dissolved in 670mL methyl alcohol, drips 5mol/L sodium hydroxide solution 400mL, dropwise at 25 DEG C.Insulated and stirred, TLC detection reaction is complete, is evaporated to volume and is about 300mL, drip concentrated hydrochloric acid in ice-water bath, regulates pH to be 2 ~ 3.Separate out a large amount of light yellow solid, filtration, filter cake little water are washed.Vacuum-drying obtains C:2-(imidazo [1,2-a] pyridin-3-yl) acetic acid, is directly used in next step reaction without the need to purifying.
Step C: the preparation of minot phosphoric acid monohydrate
By C:2-(imidazo [1,2-a] pyridin-3-yl) acetic acid 126g, namely 0.716mol is dissolved in 2.6mL toluene, adds phosphorous acid 146g, i.e. 1.79mol, is heated to 85 DEG C, reacts 1 hour.Temperature maintains 85 DEG C and drips phosphorus trichloride 324g, i.e. 2.36mol, dropwises, and is warming up to back flow reaction 5 hours.Cooling, leave standstill, incline supernatant liquid, and the hydrochloric acid 2.5L of residuum 6mol/L refluxes 5 hours.Add 100g activated carbon decolorizing, filter, evaporated under reduced pressure filtrate, impouring methyl alcohol 2.0L stirring and crystallizing in residuum, separate out white solid, filter to obtain minodronic acid crude product, off-white color pressed powder.
By crude product 185g 0.5N hydrochloric acid 1.2L recrystallization, obtain minodronic acid monohydrate 135g, HPLC purity 99.2%, single assorted < 0.1%.
Embodiment 3
The preparation of step a:2-[imidazo (1,2-a) pyridin-3-yl] ethyl acetate (B)
Take A:2-aminopyridine 18.8g, i.e. 0.2mol, 4-ethyl bromoacetoacetate 42.9g, namely 0.22mol and triethylamine 20.2g, i.e. 0.2mol, be dissolved in 380mL water.Be heated to 60-70 DEG C, TLC monitors reaction, within about 5 hours, reacts completely.Extract 3 times with ethyl acetate 150mL, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, obtain crude product.By the mixture recrystallization of crude product by 100mL sherwood oil and ethyl acetate, wherein the volume ratio of sherwood oil and ethyl acetate is 1:3, obtains light yellow solid 25.2g, yield 61.2%.
The preparation of step b:2-[imidazo (1,2-a) pyridin-3-yl] ethyl acetate (C)
By B:2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate 75g, namely 0.367mol is dissolved in 375mL ethanol, drips 10mol/L sodium hydroxide solution 150mL, dropwise at 0 DEG C.Insulated and stirred, TLC detection reaction is complete, is evaporated to volume and is about 300mL, drip acetic acid in ice-water bath, regulates pH to be 2 ~ 3.Separate out a large amount of brown solid, filtration, filter cake little water are washed.Vacuum-drying obtains C:2-(imidazo [1,2-a] pyridin-3-yl) acetic acid, is directly used in next step reaction without the need to purifying.
Step c: the preparation of minot phosphoric acid monohydrate
By C:2-(imidazo [1,2-a] pyridin-3-yl) acetic acid 67g, namely 0.38mol is dissolved in 3.35L dimethylbenzene, adds phosphorous acid 62.2g, i.e. 0.76mol, is heated to 80 DEG C, reacts 1 hour.Temperature maintains 80 DEG C and drips phosphorus trichloride 167g, i.e. 1.216mol, dropwises, and is warming up to back flow reaction 8 hours.Cooling, leave standstill, incline supernatant liquid, and the hydrochloric acid 2.5mL of residuum 8mol/L refluxes 5 hours.Add 10g activated carbon decolorizing, filter, evaporated under reduced pressure filtrate, impouring ethanol 1.0L stirring and crystallizing in residuum, separate out white solid, filter to obtain minodronic acid crude product, off-white color pressed powder.
By the hydrochloric acid 1L recrystallization of crude product 89g 1.0mol/, obtain minodronic acid monohydrate 76g, yield 58.8%.HPLC purity 99.5%, single assorted < 0.1%.
Embodiment 4
The preparation of step a:2-[imidazo (1,2-a) pyridin-3-yl] ethyl acetate (B)
Take A:2-aminopyridine 23.5g, i.e. 0.25mol, 4-ethyl bromoacetoacetate 104.52g, i.e. 0.5mol and DIPEA16.15g, i.e. 0.125mol, be dissolved in 500mL water.Be heated to 35 ~ 40 DEG C, TLC monitors reaction, within about 5 hours, reacts completely.Extract 3 times with ethyl acetate 200mL, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.Remove solvent under reduced pressure, obtain crude product.By the mixture recrystallization of crude product by 200mL sherwood oil and ethyl acetate, wherein the volume ratio of sherwood oil and ethyl acetate is 1:3, obtains light yellow solid 26g, yield 78.4%.
The preparation of step b:2-[imidazo (1,2-a) pyridin-3-yl] ethyl acetate (C)
By B:2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate 10.2g, namely 50mmol is dissolved in 100mL ethanol, drips 4.0mol/L sodium hydroxide solution 50mL, dropwise at 20 DEG C.Insulated and stirred, TLC detection reaction is complete, is evaporated to volume and is about 20mL, drip acetic acid in ice-water bath, regulates pH to be 2 ~ 3.Separate out a large amount of light yellow solid, filtration, filter cake little water are washed.Vacuum-drying obtains C:2-(imidazo [1,2-a] pyridin-3-yl) acetic acid, is directly used in next step reaction without the need to purifying.
Step C: the preparation of minot phosphoric acid monohydrate
By C:2-(imidazo [1,2-a] pyridin-3-yl) acetic acid 17.6g, namely 0.1mol is dissolved in 180mL chlorobenzene, adds phosphorous acid 18.8g, i.e. 0.23mol, is heated to 80 DEG C, reacts 2 hours.Temperature maintains 80 DEG C and drips phosphorus trichloride 44g, i.e. 0.32mol, dropwises, and is warming up to back flow reaction 8 hours.Cooling, leave standstill, incline supernatant liquid, and the hydrochloric acid 300mL of residuum 6mol/L refluxes 5 hours.Add 10g activated carbon decolorizing, filter, evaporated under reduced pressure filtrate, impouring ethanol 300mL stirring and crystallizing in residuum, separate out white solid, filter to obtain minodronic acid crude product, off-white color pressed powder.
By crude product 19g 2L water recrystallization, obtain minodronic acid monohydrate, HPLC purity 99.5%, single assorted < 0.1%.
More than show and describe ultimate principle of the present invention and principal character and advantage of the present invention.The technician of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; without departing from the spirit and scope of the present invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.
Claims (10)
1. produce a method for minodronic acid monohydrate with water as solvent, it is characterized in that comprising the following steps:
A, with 4-ethyl bromoacetoacetate or 4-acetobrom methyl acetate for raw material, under water solvent, organic bases effect, react with PA, highly selective obtain 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate;
B, 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate (methyl esters) alkaline solution is hydrolyzed into 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid;
C, 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid and phosphorous acid, phosphorus trichloride react, and obtain minodronic acid, minodronic acid monohydrate of re-refining to obtain.
2. a kind of method of producing minodronic acid monohydrate with water as solvent according to claim 1, is characterized in that the specific practice of steps A:
In reaction vessel, add 4-ethyl bromoacetoacetate or 4-acetobrom methyl acetate, PA and organic bases K successively, wherein 4-ethyl bromoacetoacetate or 4-acetobrom methyl acetate are 1: 0.8 ~ 2.0 with the amount of substance ratio of PA; The ratio of the amount of substance of organic bases K and 4-ethyl bromoacetoacetate or 4-acetobrom methyl acetate is 0.01 ~ 1.0: 1, is dissolved in the water of 20 ~ 50 times of volumes; React at 35 ~ 85 DEG C, TLC monitors; React complete, extract with organic solvent E, merge organic layer, saturated NaCl washing, dry, concentrating under reduced pressure, obtain 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate or 2-(imidazo [1,2-a] pyridin-3-yl) methyl acetate crude product, obtain fine work through recrystallizing and refining.
3. a kind of method of producing minodronic acid monohydrate with water as solvent according to claim 1 and 2, is characterized in that the specific practice of step B:
2-(the imidazo [1 that step a is prepared into, 2-a] pyridin-3-yl) ethyl acetate or 2-(imidazo [1,2-a] pyridin-3-yl) methyl acetate is dissolved in the alcoholic solvent F of 5 ~ 10 times of volumes, drip the sodium hydroxide solution of 1 ~ 10N at 0 ~ 50 DEG C, dropwise; Insulated and stirred, TLC detection reaction is complete, be evaporated to volume and 2-(imidazo [1,2-a] pyridin-3-yl) ethyl acetate or 2-(imidazo [1,2-a] pyridin-3-yl) methyl acetate mass ratio is 2 ~ 4, add sour G in ice-water bath, regulate pH to be 2 ~ 3; Separate out light yellow to brown solid in a large number, filtration, vacuum-drying obtain 2-(imidazo [1,2-a] pyridin-3-yl) acetic acid.
4. a kind of method of producing minodronic acid monohydrate with water as solvent according to claim 3, is characterized in that the specific practice of step C:
2-(imidazo [1,2-a] pyridin-3-yl) acetic acid is dissolved in the solvent H of 10 ~ 50 times of volumes, adds phosphorous acid, be heated to 80 ~ 85 DEG C, react 1 ~ 2 hour; Drip phosphorus trichloride, be warming up to back flow reaction 5 ~ 8 hours; Cooling, incline supernatant liquid, the residuum hydrochloric acid reflux 2 ~ 5 hours of 6 ~ 12N; Activated carbon decolorizing, filters, evaporated under reduced pressure filtrate, residuum ethanol or methyl alcohol stirring and crystallizing, separates out white solid; Filter to obtain minodronic acid crude product; By the salt acid treating of crude product water or 0.5 ~ 2N, obtain minodronic acid monohydrate.
5. a kind of method of producing minodronic acid monohydrate with water as solvent according to claim 2, it is characterized in that described organic bases K be triethylamine, DIPEA, DABCO, in one or more mixture.
6. a kind of method of producing minodronic acid monohydrate with water as solvent according to claim 2, is characterized in that described organic solvent E is one or more the mixture in ethyl acetate, methylene dichloride, toluene.
7. a kind of method of producing minodronic acid monohydrate with water as solvent according to claim 2, is characterized in that in steps A, recrystallization solvent for use is the two or more mixture in sherwood oil, ethyl acetate, normal hexane, heptane, ether, tetrahydrofuran (THF).
8. a kind of method of producing minodronic acid monohydrate with water as solvent according to claim 2, is characterized in that step B alcoholic solvent F is one or more the mixture in methyl alcohol, ethanol, Virahol.
9. a kind of method of producing minodronic acid monohydrate with water as solvent according to claim 2, is characterized in that sour G described in step B is organic acid or mineral acid, as the mixture of one or more in acetic acid, formic acid, hydrochloric acid, sulfuric acid.
10. a kind of method of producing minodronic acid monohydrate with water as solvent according to claim 2, is characterized in that having described in step C solvent H to be one or more mixture in toluene, dimethylbenzene, chlorobenzene.
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