CN104610357A - Preparation method for sodium zoledronic acid - Google Patents
Preparation method for sodium zoledronic acid Download PDFInfo
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- CN104610357A CN104610357A CN201510001167.4A CN201510001167A CN104610357A CN 104610357 A CN104610357 A CN 104610357A CN 201510001167 A CN201510001167 A CN 201510001167A CN 104610357 A CN104610357 A CN 104610357A
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- QAFBDRSXXHEXGB-UHFFFAOYSA-N OC(C[n]1cncc1)=O Chemical compound OC(C[n]1cncc1)=O QAFBDRSXXHEXGB-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a preparation method for sodium zoledronic acid, and belongs to the technical field of medicine synthesis. The technical scheme key point is that the preparation method for sodium zoledronic acid comprises the following steps: using a reaction medium as an ionic liquid, using imidazole-1-group acetic acid hydrochloride as a raw material, condensing with phosphoric acid and phosphorus trichloride, then hydrolyzing to prepare zoledronic acid monohydrate, and then carrying out reaction between zoledronic acid monohydrate and sodium hydroxide for salification so as to obtain the sodium zoledronic acid, wherein the ionic liquid is 1-n-butyl-3-methyl imidazolium tetrafluoroborate, N-ethyl pyridine tetrafluoroborate, 1-n-butyl-3-methyl imidazolium hexafluorophosphate, 1-ethoxyl-2,3-dimethyl imidazolium chloride, 1-nitrile propyl-3-methyl imidazolium chloride or 1-carboxyethyl-3-methyl imidazolium chloride. The preparation method has the advantages that the raw materials are highly available; the operation is simple and convenient; the yield and the product purity are high; the requirements of environmental protection and medicine production are met; the suitability for industrialized production is realized.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of preparation method of Zoledronic Acid.
Background technology
Zoledronic Acid (Zoledronate sodium,
i), chemistry [1-hydroxyl-2-(1H-imidazoles-1-base) ethylidene] di 2 ethylhexyl phosphonic acid list sodium salt monohydrate by name, it is the imidazolyl heterocycle diphosphonate researched and developed by Novartis Co., Ltd of Switzerland (Novartis), belong to third generation bisphosphonates, in the l0 month in 2000 in Canadian Initial Public Offering.Get the Green Light in more than 80 country such as European Union, the U.S. subsequently, trade(brand)name Zometa, is used for the treatment of the Bone tumour of hypercalcemia caused by malignant tumour (HCM) and multiple myeloma and solid tumor.This medicine effectively can treat HCM caused by malignant tumour, late tumor Bone tumour and scleromalacia, and reduce the generation of bone dependent event, relief of symptoms, improves the quality of living, and is also expected to the treatment for osteoporosis.Compared with other similar drugs, the advantages such as effective in cure height, dosage are little, convenient drug administration, security are better, be also current FDA ratify unique to the effective biphosphonates of metastatic bone tumor.Current biphosphonates is still in the starting stage of clinical application in China, but achieves the progress of advancing by leaps and bounds in recent years, and market application foreground is wide.
In prior art, the synthesising method reacting condition of Zoledronic Acid is harsher, and uses the larger methyl alcohol of toxicity, chloroform and chlorobenzene, Determination of Residual Organic Solvents easily exceeds standard, and productive rate is low, and product purity is low, contaminate environment, does not meet medicinal standard, is unfavorable for suitability for industrialized production.Day by day be subject to today of common people's concern at problem of environmental pollution, developing the effective pharmaceutical synthesis method of new green is the important topic that pharmaceutical synthesis institute faces.In recent years, ionic liquid at room temperature, as a kind of novel environment-friendly reaction medium, is widely applied in multiple organic synthesis.Compared with traditional organic solvent, ionic liquid has that vapour pressure is extremely low, nonflammable, Heat stability is good, not only can make reaction medium but also play the plurality of advantages such as katalysis, recycling capable of circulation.
Summary of the invention
The present invention overcomes the preparation method that the deficiencies in the prior art provide a kind of Zoledronic Acid, and this preparation method's raw materials technology is easy to get, and easy and simple to handle, yield is high, and product purity is high, environmental friendliness and meet the requirement of pharmaceutical production, is applicable to suitability for industrialized production.
Technical scheme of the present invention is: a kind of preparation method of Zoledronic Acid, it is characterized in that: take ionic liquid as solvent, with imidazoles-1-guanidine-acetic acid hydrochloride for raw material, by with phosphoric acid and phosphorus trichloride condensation, then the obtained Zoledronic acid monohydrate of hydrolysis, react salify with sodium hydroxide again and obtain Zoledronic Acid, wherein ionic liquid is 1-normal-butyl-3-methyl imidazolium tetrafluoroborate, N-ethylpyridine a tetrafluoro borate, 1-normal-butyl-3-Methylimidazole hexafluorophosphate, 1-hydroxyethyl-2, 3-methylimidazole villaumite, 1-nitrile propyl group-3-Methylimidazole villaumite or 1-propyloic-3-Methylimidazole villaumite.
The preparation method of Zoledronic Acid of the present invention, is characterized in that:
Synthetic route is:
，
Concrete synthesis step is:
(1) synthesis of imidazoles-1-ethyl
Imidazoles and ionic liquid 1-normal-butyl-3-methyl imidazolium tetrafluoroborate is added successively in reaction vessel, stirring heating is warming up to 60 DEG C, ethyl chloroacetate is dripped under insulation backflow, drip to finish and keep return stirring 16h, TLC monitors reaction end display without raw material point, reaction is finished, and is down to room temperature, obtains imidazoles-1-ethyl crude product;
(2) synthesis of imidazoles-1-guanidine-acetic acid hydrochloride
Imidazoles-1-ethyl crude product step (1) obtained joins in reaction vessel, add concentrated hydrochloric acid, exotherm to 85 DEG C, continue to be heated to backflow, stirring reaction 10h at reflux, reaction is finished, and evaporated under reduced pressure solvent, adds dehydrated alcohol in resistates, stir 2h, suction filtration, then by filter cake in 80 DEG C of constant pressure and dries, obtain white solid imidazoles-1-guanidine-acetic acid hydrochloride;
(3) synthesis of Zoledronic acid monohydrate
Imidazoles-1-guanidine-acetic acid hydrochloride is added successively in reaction vessel, ionic liquid 1-normal-butyl-3-methyl imidazolium tetrafluoroborate and mass concentration are the phosphoric acid solution of 85%, be heated to 60 DEG C and drip phosphorus trichloride, then in 60-70 DEG C of back flow reaction 4h, reaction is complete is cooled to 40 DEG C, suction filtration, filter cake being added to volumetric molar concentration is in the hydrochloric acid of 9mol/L, heating reflux reaction 6h under the state stirred, reaction terminates, heat filter, it is in the hydrochloric acid of 9mol/L that filter cake adds to volumetric molar concentration, continue heating reflux reaction 6h under the state stirred, merging filtrate, evaporated under reduced pressure, obtain yellow oil residue, the acetone-ethanol mixed solution that volume ratio is 1:1 is slowly added in resistates, stir, separate out solid, after 15min, suction filtration, filter cake is recrystallization in deionized water, suction filtration, obtain white solid Zoledronic acid monohydrate,
(4) synthesis of Zoledronic Acid
After Zoledronic acid monohydrate water dissolution step (3) obtained, add sodium hydroxide, reflux 30min altogether, crystallisation by cooling, filters, obtains crude product Zoledronic Acid, crude product again after mother liquor concentrations half, adding distil water and Virahol after merging, heating for dissolving, add activated carbon decolorizing, cross elimination charcoal, crystallisation by cooling, filter, washing, obtains Zoledronic Acid in 40-60 DEG C of drying.
Further preferably, in reaction vessel, add imidazoles-1-guanidine-acetic acid hydrochloride, 1-normal-butyl-3-methyl imidazolium tetrafluoroborate and mass concentration in step (3) is successively the phosphoric acid solution of 85%, and being heated to 60 DEG C of times dripping phosphorus trichloride is 4-4.5h.
Further preferably, in step (3), after dropping phosphorus trichloride, best back flow reaction temperature is 65 DEG C.
Further preferably, in step (4), the mol ratio of Zoledronic acid monohydrate and sodium hydroxide is 1.6:1.
Further preferably, described ionic liquid reaction medium can recirculation use.
The present invention is that reaction medium has synthesized new drug Zoledronic Acid with ionic liquid, the method has reaction conditions gentleness, simple to operate, product is easy to separation and purification, convenient post-treatment, productive rate is high, purity is high, and related substance and Determination of Residual Organic Solvents are very little, meets modern pharmaceutical medicinal standard, environmentally friendly, ionic liquid not only can be made reaction medium but also plays the advantages such as katalysis; And reaction terminate after, ionic liquid can reclaim and effectively repeatedly reuse.This synthetic method is that pharmaceutical synthesis provides a green and effectively synthesizes new way, simultaneously, what ionic liquid had can reclaim and reusable special performance, not only solve because discharging the problem of environmental pollution brought, but also avoid the wasting of resources that the disposable consumption of reaction medium in chemical reaction causes, these advantages make this green reaction medium of ionic liquid meet the requirement of modern pharmaceutical industry, for the synthesis of this type of medicine opens up a new way.
Embodiment
Be described in further details foregoing of the present invention by the following examples, but this should be interpreted as that the scope of the above-mentioned theme of the present invention is only limitted to following embodiment, all technology realized based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
The synthesis of Zoledronic Acid
(1) synthesis of imidazoles-1-ethyl
Imidazoles (13.62g, 0.2mol) and [bmim] BF is added successively in there-necked flask
4(100mL), stirring heating is warming up to 60 DEG C, under insulation backflow, slow dropping ethyl chloroacetate (24.51g, 0.2mol), time for adding is about 2h, drip and finish, keep return stirring 16h, TLC monitors reaction end display without raw material point, reaction is finished, be down to room temperature, obtain imidazoles-1-ethyl crude product, about 24g, crude product, without the need to refining, is directly used in next step reaction.
(2) synthesis of imidazoles-1-guanidine-acetic acid hydrochloride
24g imidazoles-1-ethyl the crude product of above-mentioned preparation is added in there-necked flask, adds concentrated hydrochloric acid (34mL), exotherm to 85 DEG C, continue to be heated to backflow, stirring reaction 10h at reflux, reaction is finished, evaporated under reduced pressure solvent, 20ml dehydrated alcohol is added in resistates, vigorous stirring 2h, suction filtration, finally by filter cake in 80 DEG C of normal pressure forced air dryings, obtain white solid imidazoles-1-guanidine-acetic acid hydrochloride and be about 25.65g, total recovery 79.4%.
(3) synthesis of Zoledronic acid monohydrate
In there-necked flask, adding imidazoles-1-guanidine-acetic acid hydrochloride (17.26g, 0.137mol) successively, adding ionic liquid 1-normal-butyl-3-methyl imidazolium tetrafluoroborate [bmim] BF when stirring
4(40mL) and mass concentration be 85% phosphoric acid solution (16mL), be heated to 60 DEG C and drip phosphorus trichloride (30mL), about 4h drips complete, continue back flow reaction 4h at 65 DEG C, reaction is finished, be cooled to 40 DEG C, suction filtration, filter cake being added to 80mL volumetric molar concentration is in the hydrochloric acid of 9mol/L, heating reflux reaction 6h under the state stirred, reaction terminates, heat filter, it is in the hydrochloric acid of 9mol/L that filter cake adds to 80mL volumetric molar concentration, continue to repeat aforesaid operations, merging filtrate, evaporated under reduced pressure, obtain yellow oil residue, the acetone-ethanol mixed solution 240mL that volume ratio is 1:1 is slowly added in resistates, stir, separate out solid, after 15min, suction filtration, filter cake is recrystallization in 30mL deionized water, suction filtration, obtain white solid and be Zoledronic acid monohydrate, about 35.8g, yield 90.1%, measure through HPLC, purity > 98.5%.
(4) synthesis of Zoledronic Acid
By Zoledronic acid monohydrate (46.4g obtained above, after 0.16mol) dissolving with water (450mL), add sodium hydroxide (5.6g, 0.10mol), reflux 30min altogether, crystallisation by cooling, filter, obtain crude product Zoledronic Acid, crude product again after mother liquor concentrations half, adding distil water (410mL) after merging, Virahol (60mL), heating for dissolving, add activated carbon decolorizing, cross elimination charcoal, crystallisation by cooling, filter, washing, about being dried to containing a crystal water in 40-60 DEG C, obtain Zoledronic Acid (42.4g, 85%), total recovery is more than 60%, measure through HPLC, purity is 99.8%, mp239 DEG C.IR:711cm
-1, 671cm
-1for the stretching vibration peak of P-C, 1643cm
-1for the stretching vibration peak of C=C, 3011cm
-1for the stretching vibration peak of=C-H, 1406cm
-1for the stretching vibration peak of C-N, 1643cm
-1for the stretching vibration peak of C=N, 3447cm
-1, 3485cm
-1for the stretching vibration peak of O-H, 1459cm
-1for the symmetric curvature of C-H is vibrated, 2830cm
-1for the stretching vibration of C-H, 1324cm
-1for the stretching vibration peak of P=O, 1094cm
-1for the stretching vibration peak of P-O.
1HNMR (400MHz，D
2O)，δ:8.68(1H,s)，7.48 (1H,s)，7.34(1H,s)，4.67 (2H,t)。
Embodiment 2
Phosphorus trichloride time for adding is on the impact of reaction yield
Fix other conditions constant, only change the rate of addition of phosphorus trichloride, rate of addition on the impact of Zoledronic Acid yield in table 1, test-results shows, when phosphorus trichloride drips too fast, produces a large amount of gas instantaneously, it is very fierce to react, liquid splash, temperature raises fast, and result causes low yield, if slowly drip, speed of response is too slow, and elapsed time is oversize, and therefore 4h is best time for adding.
Table 1 phosphorus trichloride rate of addition is on the impact of reaction yield
| Time for adding (h) | Yield (%) |
| 2.5 | 51.7 |
| 3.5 | 71.6 |
| 4.0 | 90.1 |
| 4.5 | 90.1 |
| 5.5 | 88.5 |
Embodiment 3
Temperature of reaction is on the impact of Zoledronic Acid yield
Fix other condition constant, the temperature of reaction of imidazoles-1-guanidine-acetic acid hydrochloride and phosphoric acid and phosphorus trichloride condensation, on the impact of Zoledronic acid monohydrate yield, the results are shown in Table 2.Test-results shows, along with temperature raises, productive rate increases gradually, but when reflux temperature is higher, yield is on a declining curve, is the cause because phosphorus trichloride decomposes, causes reactant to reduce.In addition, when temperature is too high, solvent evaporates and solvent leakage losses must increase, and when reflux temperature is lower, speed of reaction is slow, reacts insufficient, so yield is low, therefore best temperature of reaction is about 65 DEG C.
Table 2 temperature of reaction is on the impact of yield
| Temperature (DEG C) | Yield (%) |
| 55 | 63.4 |
| 60 | 78.5 |
| 65 | 90.1 |
| 70 | 87.3 |
| 80 | 62.7 |
Embodiment 4
Ionic liquid reuses the impact of number of times on Zoledronic Acid yield
Can reaction medium used reclaim and reuse is the important content that " Green Chemistry " is paid close attention to, and the present embodiment examines ionic liquid and reuses situation for the synthesis of Zoledronic Acid, and experimental result is in table 3.From table 3, ionic liquid is after 5 times use, and product yield just starts to reduce, and this explanation ionic liquid is recyclable and effectively reuse, and reuse 5 times functional, therefore ionic liquid is a kind of green and environment-friendly solvent that can be recycled in the present reaction.
Table 3 ionic liquid reuses the impact of number of times on yield
| Reuse number of times | Yield (%) |
| 1 | 90.1 |
| 2 | 90.0 |
| 3 | 89.2 |
| 4 | 88.3 |
| 5 | 87.7 |
Embodiment 5
Different ionic liquid is on the impact of Zoledronic Acid yield
Different ionic liquid 1-normal-butyl-3-methyl imidazolium tetrafluoroborate ([bmim] BF is examined respectively under the same terms
4), N-ethylpyridine a tetrafluoro borate ([EPy] BF
4), 1-normal-butyl-3-Methylimidazole hexafluorophosphate ([bmim] PF
6), 1-hydroxyethyl-2,3-methylimidazole villaumite (LOH), 1-nitrile propyl group-3-Methylimidazole villaumite (LCN) and 1-propyloic-3-Methylimidazole villaumite (LOOH) are on the impact of Zoledronic Acid yield, the results are shown in Table 4, test-results shows that the yield impact of different ionic liquid on synthesis is little.
Table 4 different ionic liquid is on the impact of reaction yield
| Ionic liquid | Yield/% |
| [bmim]BF 4 | 90.1 |
| [EPy]BF 4 | 90.6 |
| [bmim]PF 6 | 90.2 |
| LOH | 92.33 |
| LCN | 92.41 |
| LOOH | 92.12 |
Above embodiment is only and technological thought of the present invention is described, can not limit protection scope of the present invention with this, and every technological thought proposed according to the present invention, any change that technical scheme basis is done, all falls within scope.
Claims (6)
1. the preparation method of a Zoledronic Acid, it is characterized in that: take ionic liquid as reaction medium, with imidazoles-1-guanidine-acetic acid hydrochloride for raw material, by with phosphoric acid and phosphorus trichloride condensation, then the obtained Zoledronic acid monohydrate of hydrolysis, react salify with sodium hydroxide again and obtain Zoledronic Acid, wherein ionic liquid is 1-normal-butyl-3-methyl imidazolium tetrafluoroborate, N-ethylpyridine a tetrafluoro borate, 1-normal-butyl-3-Methylimidazole hexafluorophosphate, 1-hydroxyethyl-2, 3-methylimidazole villaumite, 1-nitrile propyl group-3-Methylimidazole villaumite or 1-propyloic-3-Methylimidazole villaumite.
2. the preparation method of Zoledronic Acid according to claim 1, is characterized in that:
Synthetic route is:
，
Concrete synthesis step is:
(1) synthesis of imidazoles-1-ethyl
Imidazoles and ionic liquid 1-normal-butyl-3-methyl imidazolium tetrafluoroborate is added successively in reaction vessel, stirring heating is warming up to 60 DEG C, ethyl chloroacetate is dripped under insulation backflow, drip to finish and keep return stirring 16h, TLC monitors reaction end display without raw material point, reaction is finished, and is down to room temperature, obtains imidazoles-1-ethyl crude product;
(2) synthesis of imidazoles-1-guanidine-acetic acid hydrochloride
Imidazoles-1-ethyl crude product step (1) obtained joins in reaction vessel, add concentrated hydrochloric acid, exotherm to 85 DEG C, continue to be heated to backflow, stirring reaction 10h at reflux, reaction is finished, and evaporated under reduced pressure solvent, adds dehydrated alcohol in resistates, stir 2h, suction filtration, then by filter cake in 80 DEG C of constant pressure and dries, obtain white solid imidazoles-1-guanidine-acetic acid hydrochloride;
(3) synthesis of Zoledronic acid monohydrate
Imidazoles-1-guanidine-acetic acid hydrochloride is added successively in reaction vessel, ionic liquid 1-normal-butyl-3-methyl imidazolium tetrafluoroborate and mass concentration are the phosphoric acid solution of 85%, be heated to 60 DEG C and drip phosphorus trichloride, then in 60-70 DEG C of back flow reaction 4h, reaction is complete is cooled to 40 DEG C, suction filtration, filter cake being added to volumetric molar concentration is in the hydrochloric acid of 9mol/L, heating reflux reaction 6h under the state stirred, reaction terminates, heat filter, it is in the hydrochloric acid of 9mol/L that filter cake adds to volumetric molar concentration, continue heating reflux reaction 6h under the state stirred, merging filtrate, evaporated under reduced pressure, obtain yellow oil residue, the acetone-ethanol mixed solution that volume ratio is 1:1 is slowly added in resistates, stir, separate out solid, after 15min, suction filtration, filter cake is recrystallization in deionized water, suction filtration, obtain white solid Zoledronic acid monohydrate,
(4) synthesis of Zoledronic Acid
After Zoledronic acid monohydrate water dissolution step (3) obtained, add sodium hydroxide, reflux 30min altogether, crystallisation by cooling, filters, obtains crude product Zoledronic Acid, crude product again after mother liquor concentrations half, adding distil water and Virahol after merging, heating for dissolving, add activated carbon decolorizing, cross elimination charcoal, crystallisation by cooling, filter, washing, obtains Zoledronic Acid in 40-60 DEG C of drying.
3. the preparation method of Zoledronic Acid according to claim 2, it is characterized in that: in reaction vessel, add imidazoles-1-guanidine-acetic acid hydrochloride, 1-normal-butyl-3-methyl imidazolium tetrafluoroborate and mass concentration in step (3) is successively the phosphoric acid solution of 85%, being heated to 60 DEG C of times dripping phosphorus trichloride is 4-4.5h.
4. the preparation method of Zoledronic Acid according to claim 2, is characterized in that: the back flow reaction temperature dripped in step (3) after phosphorus trichloride is 65 DEG C.
5. the preparation method of Zoledronic Acid according to claim 2, is characterized in that: in step (4), the mol ratio of Zoledronic acid monohydrate and sodium hydroxide is 1.6:1.
6. the preparation method of Zoledronic Acid according to claim 1, is characterized in that: described ionic liquid reaction medium can recirculation use.
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| CN111303040A (en) * | 2020-03-25 | 2020-06-19 | 武汉工程大学 | Method for preparing imidazole-1-acetic acid by one-pot method |
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| CN111303040A (en) * | 2020-03-25 | 2020-06-19 | 武汉工程大学 | Method for preparing imidazole-1-acetic acid by one-pot method |
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Application publication date: 20150513 |