CN1048984C - Preparation of form 1 ranitidine hydrochloride - Google Patents
Preparation of form 1 ranitidine hydrochloride Download PDFInfo
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- CN1048984C CN1048984C CN93109329A CN93109329A CN1048984C CN 1048984 C CN1048984 C CN 1048984C CN 93109329 A CN93109329 A CN 93109329A CN 93109329 A CN93109329 A CN 93109329A CN 1048984 C CN1048984 C CN 1048984C
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- Prior art keywords
- ranitidine hydrochloride
- solution
- ranitidine
- mixed solvent
- alkanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
Abstract
With the existence of 1 ranitidine hydrochloride crystals which are used as crystal seeds and form a pure crystal shape, ranitidine hydrochloride is separated in a crystallization mode from the solution of mixed solvent of the ranitidine hydrochloride, and 1 ranitidine hydrochloride which forms a crystal shape is obtained, wherein the mixed solvent contains one portion of at least one kind of low-grade alkanol by volume, such as ethanol, and 1 to 2 portions of C6 to C10 aromatic hydrocarbon by volume, such as toluene. According to the method of the present invention, a preferable method for preparing ranitidine hydrochloride comprises the following steps: with the existence of crystal seeds, hydrochloric acid is added into the solution of free alkali in the mixed solvent, which leads ranitidine hydrochloride in the mixed solvent to be generated in an original position.
Description
The present invention relates to be called the medical compounds of ranitidine (ranitidine) hydrochloride and the preparation and the segregation of specific crystalline form body thereof.
The chemical name of ranitidine is N-[2-[[[5-[(dimethyl-amino)-methyl]-the 2-furyl] methyl] sulfo-] ethyl]-N '-methyl-2-nitro-1, the 1-quadrol, its chemical structural formula is:
The ranitidine hydrochloride salt has obtained using widely as the medicine of treatment Peptic Ulcers.
According to relevant patented technology bibliographical information, the ranitidine hydrochloride exists with two kinds of different crystalline forms, crystalline form 1 and crystalline form 2.That announced on April 1st, 1986 authorizes Crookes the Canadian Patent No.1 of (transferring GlaxoGrop limited), and 202,638, the preparation and the characteristic of commercial crystalline form 2 ranitidine hydrochlorides have been described.In this patent documentation, disclosed ranitidine has been dissolved in the industrial methylated spirit that contains HCl, in this solution, add ethyl acetate then, after precipitation and crystallization, the generation form 1 ranitidine hydrochloride.Also disclosed the strainability and the drying property instability of the form 1 ranitidine hydrochloride of preparation as stated above in this patent documentation, and it seems that from the viewpoint of producing crystalline form 2 ranitidine hydrochlorides have more advantage and better properties.It is reported that crystalline form 2 ranitidine hydrochlorides make by suitably selective freezing method.One of them is for to be dissolved in its free alkali in hydroxylic solvent such as the 2-propyl alcohol, and with this solution of salt acid treatment, at high temperature by add more 2-propyl alcohol in solution its crystallization is separated out then.Another kind method is to be dissolved in form 1 ranitidine hydrochloride in methyl alcohol or the ethanol under warm, by cooling crystalline form 2 salt crystallizations are separated out then, selectively in solution, add anti-solvent (anti-solvent) simultaneously or add crystalline form 2 ranitidine hydrochloride crystal and make crystal seed.
The invention provides a kind of crystallization method of new preparation form 1 ranitidine hydrochloride.And crystalline form 2 ranitidine hydrochlorides are usually by its precipitation and crystallization preparation in alcohol.
According to the present invention, we find, if (wherein said mixed solvent be by the pure and mild aromatic hydrocarbon of lower aliphatic in specific ratio preparation) separated out in the crystallization from the solution of the mixed solvent that contains the pure and mild a kind of aromatic hydrocarbon of one or more lower aliphatic of ranitidine hydrochloride, in this solution, add pure form 1 ranitidine hydrochloride crystal simultaneously as crystal seed, the crystal that obtains is defined as pure form 1 ranitidine hydrochloride through infrared and X-ray powder diffraction analysis.In addition, form 1 ranitidine hydrochloride prepared according to the methods of the invention has good filtration and dry stability.
Therefore, the invention provides a kind of method for preparing form 1 ranitidine hydrochloride, this method comprises the ranitidine hydrochloride is dissolved in the mixed solvent makes solution, and described mixed solvent comprises at least a C
1-C
4Alkanol and a kind of C
6-C
10Aromatic hydrocarbon, the volume ratio of alkanol and aromatic hydrocarbon are from 1: 1 to 1: 2, and have in solution in the presence of the pure form 1 ranitidine hydrochloride crystal as crystal seed, cause form 1 ranitidine hydrochloride crystallization from described solution and separate out.
Preferred aromatic hydrocarbon is toluene in the inventive method.
At room temperature, the ranitidine free alkali is soluble in the low-level chain triacontanol, but the solubleness of the hydrochloride salt of ranitidine in alkanol is very little.Therefore, preferred mode of operation according to the inventive method is, free alkali is dissolved in makes solution in the mixed solvent, in this solution, add an amount of hydrochloric acid then, described hydrochloric acid is preferably to be dissolved in a kind of low-level chain triacontanol, a kind of alkanol in the mixed solvent as described, the form of the solution of middle formation adds, so that original position generates the ranitidine hydrochloride salt in the solution of mixed solvent.Whenever the used acid amount of amount free alkali is preferably from 0.8 to 1.15 equivalent, more preferably from 0.95 to 1.0 equivalent.In the presence of the form 1 ranitidine hydrochloride crystal as crystal seed, when generating hydrochloride salt in the solution, form 1 ranitidine hydrochloride crystallization is simultaneously separated out.When hydrochloride salt generates, can the accelerate crystallisation process by solution stirring and cooling.
The employed alkanol of the inventive method is preferably ethanol and Virahol, more preferably ethanol.
The reaction that free alkali generates the ranitidine hydroxide salt is thermopositive reaction, and in the reaction process, the viscosity of solution increases.Therefore, when reaction is carried out, preferably use extra similar solvent mixture or isopropanol solution, so that solution is easy to stir.The solvent volume ratio of the specific volume ratio of solvent for use with reference at the beginning of the crystallization time.Though dilution can make the volume ratio of mixed solvent be different from above-mentioned specific ratio, crystallization Once you begin, pure crystalline form 1 ranitidine just constantly crystallization is separated out.Preferably operation at room temperature, and avoid that temperature is elevated to more than 40 ℃ in the operating process.
According to the present invention, preferably crystalline product is carried out last washing with Virahol.Below room temperature, form 1 ranitidine hydrochloride is difficult to be dissolved in the Virahol.Product prepared according to the methods of the invention, after washed with isopropyl alcohol, its outward appearance is improved greatly.
Certainly, preferably use anhydrous reagent and solvent in the said process, and in inert atmosphere, as in nitrogen atmosphere, carrying out.
Referring to following examples, the inventive method is further described.These embodiment are only used for illustrating the present invention.Embodiment 1
All operations all carries out in nitrogen atmosphere, and all reagent and solvent are all not moisture.
Under certain nitrogen flow, the ranitidine free alkali of 106g (purity is 85%, 0.29 mole) is dissolved in the 130ml ethanol, and uses the 240ml dilution with toluene.In room temperature and under stirring, the form 1 ranitidine hydrochloride crystal is added in this solution as crystal seed, in this solution, add the solution of hydrochloric acid in ethanol of 32ml (0.29 mole) 8.9M then.Stirred reaction mixture is used 50ml, 1: 1.5 ethanol/toluene mixture diluted when generating viscous suspension.Stir after 1 hour, in this solution, add the 200ml Virahol.Reaction mixture restir 1 hour filters then, and the filter cake that obtains is with washed with isopropyl alcohol three times, and each Virahol consumption is 100ml, and dry cake under 50 ℃ and vacuum state obtains the product of the off-white of 95g (90%).Infrared analysis confirms that product is pure form 1 ranitidine hydrochloride.Embodiment 2
At room temperature reach in the presence of the form 1 ranitidine hydrochloride crystal, the solution of 50ml hydrochloric acid in ethanol that will contain 9.5gHCl (0.26 mole) joins 100g ranitidine free alkali, and (purity is 85%, 0.27 mole) at 525ml, the ethanol/toluene ratio is in the solution in 1: 2 the mixed solvent.Stir after 1 hour, in this solution, add 1: 1.5 the ethanol/toluene mixed solution of 100ml.After during restir 1, in this solution, add the Virahol of 200ml.With the silt oar restir that obtains 1 hour, filter then.Use the washed with isopropyl alcohol filter cake, obtain 85g, confirm that through infrared and X-ray powder diffraction analysis the gained solid is pure form 1 ranitidine hydrochloride near pure white solid.Embodiment 3
In nitrogen atmosphere, the thick ranitidine free alkali of 49g (0.14 mole) is dissolved in the 102ml Virahol.Toluene with 150ml dilutes then.Solution is chilled to 10 ℃ in ice bath.To wherein adding the form 1 ranitidine hydrochloride crystal, and then add the solution of HCl in Virahol of 47.6ml (10 moles), 2.12M.The product that generates is an oily matter.This mixture stirred spend the night, then the solids that generates is filtered, the filter cake that obtains 500ml washed with isopropyl alcohol under 50 ℃ and vacuum, with filtration cakes torrefaction, obtains the pure form 1 ranitidine hydrochloride of 32g (65%).
Claims (7)
1, prepare the method for form 1 ranitidine hydrochloride, comprising:
The ranitidine free alkali is dissolved in the mixed solvent makes solution, wherein said mixed solvent comprises at least a C
1-C
4Alkanol and a kind of C
6-C
10Aromatic hydrocarbon, the volume ratio of alkanol and aromatic hydrocarbon are 1: 1 to 1: 2;
In above-mentioned solution, add the solution of spirit of salt in a low-level chain triacontanol;
Adding causes form 1 ranitidine hydrochloride crystallization from described solution and separates out as the pure form 1 ranitidine hydrochloride crystal of crystal seed.
2, the method for claim 1 adds 0.8 to 1.15 normal spirit of salt in wherein every normal free alkali.
3, method as claimed in claim 1 or 2, wherein aromatic hydrocarbon is toluene.
4, method as claimed in claim 1 or 2, wherein alkanol is ethanol or propyl alcohol or its mixture.
5, method as claimed in claim 1 or 2 at the beginning of crystallization, is the mixed solution diluted system of 1: 1.5 alkanol and aromatic hydrocarbon with volume ratio.
6, method as claimed in claim 1 or 2 comprises other subsequent step, promptly with the step of the form 1 ranitidine hydrochloride that washed with isopropyl alcohol generated.
7, method as claimed in claim 1 or 2, wherein alkanol is an ethanol.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/041,354 US5338871A (en) | 1991-12-20 | 1993-04-01 | Preparation of form 1 ranitidine hydrochloride |
| CN93109329A CN1048984C (en) | 1991-12-20 | 1993-08-10 | Preparation of form 1 ranitidine hydrochloride |
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81114391A | 1991-12-20 | 1991-12-20 | |
| EP93304182A EP0626381B1 (en) | 1993-04-01 | 1993-05-28 | Preparation of form 1 ranitidine hydrochloride |
| CA002099530A CA2099530C (en) | 1993-04-01 | 1993-07-02 | Preparation of form 1 ranitidine hydrochloride |
| AU41794/93A AU674006B2 (en) | 1993-04-01 | 1993-07-06 | Preparation of form 1 ranitidine hydrochloride |
| HU9301980A HU214334B (en) | 1993-04-01 | 1993-07-08 | Process for production crystall form 1 of ranitidine |
| ZA934995A ZA934995B (en) | 1993-04-01 | 1993-07-12 | Preparation of form 1 ranitidine hydrochloride |
| CN93109329A CN1048984C (en) | 1991-12-20 | 1993-08-10 | Preparation of form 1 ranitidine hydrochloride |
| NZ260551A NZ260551A (en) | 1993-04-01 | 1994-05-18 | Preparation of form 1 ranitidine hcl crystals |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1098720A CN1098720A (en) | 1995-02-15 |
| CN1048984C true CN1048984C (en) | 2000-02-02 |
Family
ID=36843633
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93109329A Expired - Fee Related CN1048984C (en) | 1991-12-20 | 1993-08-10 | Preparation of form 1 ranitidine hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1048984C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432147B (en) * | 2015-05-26 | 2018-04-17 | 烟台市华文欣欣医药科技有限公司 | A kind of method for the medicine ranitidine hydrochloride compound for preparing treatment stomach trouble |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86100111A (en) * | 1985-01-11 | 1986-11-26 | 格德昂·理查德化学工厂股份公司 | The preparation method of basic thioether and salt thereof |
| US4672133A (en) * | 1980-10-01 | 1987-06-09 | Glaxo Group Limited | Process for forming Form 2 ranitidine hydrochloride |
-
1993
- 1993-08-10 CN CN93109329A patent/CN1048984C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4672133A (en) * | 1980-10-01 | 1987-06-09 | Glaxo Group Limited | Process for forming Form 2 ranitidine hydrochloride |
| CN86100111A (en) * | 1985-01-11 | 1986-11-26 | 格德昂·理查德化学工厂股份公司 | The preparation method of basic thioether and salt thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1098720A (en) | 1995-02-15 |
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