CN107056706A - A kind of method for preparing hydrochloric acid Ivabradine alpha-crystal form - Google Patents
A kind of method for preparing hydrochloric acid Ivabradine alpha-crystal form Download PDFInfo
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- CN107056706A CN107056706A CN201611164488.7A CN201611164488A CN107056706A CN 107056706 A CN107056706 A CN 107056706A CN 201611164488 A CN201611164488 A CN 201611164488A CN 107056706 A CN107056706 A CN 107056706A
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- hydrochloric acid
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- 0 C*(CCCN(CCc(cc1*)c(C2)cc1OC)C2=O)C[C@](C1)c(cc2OC)c1cc2OC Chemical compound C*(CCCN(CCc(cc1*)c(C2)cc1OC)C2=O)C[C@](C1)c(cc2OC)c1cc2OC 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
The present invention relates to a kind of method for preparing hydrochloric acid Ivabradine alpha-crystal form.Specifically, the present invention relates to the preparation method of the hydrochloric acid Ivabradine alpha-crystal form shown in Formulas I, it is characterized in that amorphous or other crystal formations of hydrochloric acid Ivabradine turn crystalline substance in the stirring of the higher boiling poor solvent high temperatures such as toluene, butyl acetate or the pentanone of 4 methyl 2.Hydrochloric acid Ivabradine alpha-crystal form is prepared using this law, operating process is easy, and product yield is high, easy drying.
Description
Technical field
The present invention relates to a kind of method for preparing hydrochloric acid Ivabradine alpha-crystal form, using hydrochloric acid made from this law she
The production of pharmaceutical preparation can be used for as active component surely by cutting down mine-laying.
Background technology
Hydrochloric acid Ivabradine (Ivabradine hydrochloride), chemical name 3- [3- [[[(7S) -3,4- diformazans
The ring of epoxide two [4.2.0] octyl- 1,3,5- triolefin -7- bases] methyl] methylamino] propyl group] -1,3,4,5- tetrahydrochysene -7,8- dimethoxies
Base -2H-3- benzazepine -2- keto hydrochlorides, shown in structural formula such as formula (I)：
Hydrochloric acid Ivabradine, which has, is worth high pharmacological properties and therapeutic action, the especially property to heart rate decrease
Can so that it can be used for the various clinical symptoms for treating or preventing myocardial ischaemia, such as angina pectoris, miocardial infarction and occurring together
Rhythm disorder, and can be used for treating or preventing and various be related to the symptom that rhythm disorder is particularly supraventricular rhythm disorder.
The patent that report is prepared about the compound earliest is EP0534859 (Patents are US5296482), the patent
Describe Ivabradine and its preparation method with pharmaceutically acceptable sour addition salts, the especially system including its hydrochloride
Preparation Method, but any crystal formation application protection of the patent not to being related to.Because hydrochloric acid Ivabradine has high medicinal valency
Value, later patents application discloses substantial amounts of correlative study technology, including multinomial crystal formation patent application.
CN1305856C discloses hydrochloric acid Ivabradine alpha-crystal form, using toluene/1-Methyl-2-Pyrrolidone mixture as
Solvent, Crystallization Separation is obtained.
CN1827600B discloses hydrochloric acid Ivabradine beta crystal, and hydrochloric acid Ivabradine is in water or water and isopropanol
In the mixed solvent dissolve by heating, crystallisation by cooling, collect crystal, be tetrahydrate.
CN100404512C discloses hydrochloric acid Ivabradine β d crystal formations, and beta crystal is heated into 80 DEG C of dehydrations with 5 DEG C/min
Formed.
CN100402502C discloses hydrochloric acid Ivabradine γ crystal formations, and hydrochloric acid Ivabradine is in cellosolvo
Dissolve by heating, crystal is collected by filtration in crystallisation by cooling, is monohydrate.
CN100432057C discloses hydrochloric acid Ivabradine γ d crystal formations, and γ crystal formations are heated into 80 DEG C with 5 DEG C/min takes off
Water is formed.
CN1948292A discloses hydrochloric acid Ivabradine δ crystal formations, and hydrochloric acid Ivabradine is dissolved by heating in acetonitrile, cold
But crystallize, crystal is collected by filtration, product water content is 2.8%.
CN1948293A discloses hydrochloric acid Ivabradine δ d crystal formations, and δ crystal formations are heated into 85 DEG C of dehydrations with 10 DEG C/min
Formed.
EP2460797A discloses the crystal formation of hydrochloric acid Ivabradine I, and Ivabradine free alkali is in HCl/ acetonitriles into salt
Crystallization.
EP2780327A discloses hydrochloric acid Ivabradine II, III two kind of crystal formation, and hydrochloric acid Ivabradine is respectively first and second
In ketone/tetrahydrofuran mixed solvent and MEK, dissolving, cooling crystallization, filtration drying.
EP2773620A discloses the crystal formation of hydrochloric acid Ivabradine IV, and hydrochloric acid Ivabradine is in toluene, acetone, first and second
Ketone, methyl iso-butyl ketone (MIBK), ethanol, ethyl acetate, isopropyl acetate or their in the mixed solvent mashing, are collected by filtration crystal,
Dry.
EP2534135A discloses tri- kinds of crystal formations of hydrochloric acid Ivabradine Z, X, K, and hydrochloric acid Ivabradine is dissolved in isopropanol
In, crystallization obtains crystal formation Z, and crystal formation Z is dried in vacuo at 22 DEG C and obtains crystal formation X, and crystal formation Z is dried in vacuo at 70 DEG C and obtains crystal formation
K。
WO2012025940 discloses hydrochloric acid Ivabradine ζ crystal formations, and hydrochloric acid Ivabradine is recrystallized in acetonitrile, receives
Collect after crystal, controlled humidity drying.
EP2781509A discloses hydrochloric acid Ivabradine ε crystal formations, and hydrochloric acid Ivabradine is in aqueous propione or 2-
It is beaten in butanone, crystal is collected by filtration, is dried.
CN101805289A discloses hydrochloric acid Ivabradine ω crystal formations, and hydrochloric acid Ivabradine is dissolved in after water, freezes.
CN101768117B discloses hydrochloric acid Ivabradine W crystal formations, and hydrochloric acid Ivabradine is mixed methanol and acetone
Dissolved by heating in bonding solvent, stand crystallization, filtering.
CN103864690A discloses hydrochloric acid Ivabradine S crystal formations, and hydrochloric acid Ivabradine δ or δ d crystal formations are in tetrahydrochysene furan
Middle mashing of muttering turns crystalline substance.
CN101353325B discloses Novel ivabradine hydrochloride crystal form, and hydrochloric acid Ivabradine heats molten in 2- butanone
Solution, stands crystallization, filtering.
CN102731400A discloses Novel ivabradine hydrochloride crystal form, and hydrochloric acid Ivabradine is in ethanol or ethanol and second
The in the mixed solvent of acetoacetic ester is dissolved by heating, cooling crystallization.
CN103012269B discloses hydrochloric acid Ivabradine C crystal form, and hydrochloric acid Ivabradine is dissolved by heating in ethanol,
Add ethyl acetate cooling crystallization.
CN103183639A discloses II crystal formation of the hydrochloric acid Ivabradine containing 0.5 crystallization water, hydrochloric acid Ivabradine
Flowed back in the in the mixed solvent of acetone or tetrahydrofuran and ethyl acetate, drop is dissolved in water, cooling crystallization.
CN102304088B discloses hydrochloric acid Ivabradine monohydrate, and hydrochloric acid Ivabradine is dissolved in hot water, by
Step is cooled to low temperature crystallization, collects crystal, and control humiture is dried.
EP2773621A discloses the preparation method of hydrochloric acid Ivabradine δ crystal formations, hydrochloric acid Ivabradine in ethanol and
The in the mixed solvent crystallization of pentane, normal heptane or hexamethylene.
CN102050784B discloses the unbodied preparation method of hydrochloric acid Ivabradine, and hydrochloric acid Ivabradine is in ethanol
Or dissolving forms solution in acetone, is then added in ether or hexamethylene, stirring, cooling.
It is well known that the solid drugs of different crystal forms can cause different bioavilabilities, medicine is eventually affected in machine
The therapeutic effect of body.The solubility of stable type crystal formation is small, and dissolution rate is slow, and bioavilability is not high；The property of instability mode crystal formation
Matter is opposite；And metastable type crystal formation then falls between.Generally, according to Thermodynamic Law, unstable crystal formation can be to
Meta-stable transformation of crystal, meta-stable crystal formation can be converted to stable crystal form.In view of solid drugs crystal formation and its stability for its
Importance in clinical treatment, for pharmaceuticals researcher, is found suitable for the advantage solid drugs raw material of preparation patent medicine just
It is particularly important.
At present, it has been found that hydrochloric acid Ivabradine crystal formation in, alpha-crystal form is to generally acknowledge more stable crystal formation, and original, which is ground, applies dimension
Refined company is i.e. with the production of raw medicine pharmaceutical preparation of this crystal formation.But according to existing public technology, the preparation of alpha-crystal form is in toluene and N-
Methyl pyrrolidone in the mixed solvent is dissolved by heating, cooling crystallization, because 1-METHYLPYRROLIDONE boiling point is very high (about 203 DEG C),
Cause product dry when, residual solvent be difficult remove, in order to meet dissolvent residual quality requirement, it is necessary to higher temperature and compared with
Dry for a long time, and prolonged high temperature action, easily make product purity step-down.
In view of the high pharmacy value of hydrochloric acid Ivabradine alpha-crystal form pharmaceutical preparation and stable pharmacy characteristic, deeply grind
It is necessary to study carefully and develop a kind of technique of efficient production alpha-crystal form hydrochloric acid Ivabradine.
The content of the invention
Present invention aims at a kind of preparation method of hydrochloric acid Ivabradine alpha-crystal form is provided, to overcome prior art
Weak point.
The invention provides a kind of preparation method of the hydrochloric acid Ivabradine alpha-crystal form shown in Formulas I, it is characterized in that hydrochloric acid she
Cut down fixed amorphous or other crystal formations of mine-laying and turn crystalline substance in the stirring of higher boiling poor solvent high temperature, then cool down, shape is collected by filtration
Into crystal and drying.
Wherein, higher boiling poor solvent is that boiling point is more than 100 DEG C and hydrochloric acid Ivabradine solid is difficult to dissolve wherein
The solvent of (slightly soluble, indissoluble or insoluble), preferably boiling point are 100-200 DEG C of solvent, including toluene, dimethylbenzene (ortho position, meta,
Contraposition), the aromatic hydrocarbons such as ethylo benzene, in and esters such as butyl acetate, and the ketone, and Isosorbide-5-Nitrae-dioxane such as 4-methyl-2 pentanone
Amorphous or other crystal formations hydrochloric acid Ivabradines can be transformed into alpha-crystal form by one or more, due to the too high meeting of solvent boiling point
Product is caused to be difficult to drying, so when selecting solvent, the preferably toluene of moderate boiling point, butyl acetate and 4-methyl-2 pentanone
In one or more, more preferably toluene.
This law solvent for use consumption is appropriate, preferably 10-100 times (V/W) of hydrochloric acid Ivabradine quality, more preferably
10-50 times (V/W)；Described turns mixture of the brilliant process for hydrochloric acid Ivabradine and solvent at 100-200 DEG C, preferably 100-
Stirred at 150 DEG C, last cold filtration；The mixing time of described turn of brilliant process is more than 0.5h, preferably 0.5-2h.
Term " V/W " refers to the ratio of solvent volume (unit is mL) and material quality (unit is g).
Full and accurate experimental data and certain experimental result, draw gratifying conclusion, have confirmed the present inventor initial
Imagination, ultimately form technology disclosed by the invention.
Hydrochloric acid Ivabradine alpha-crystal form is prepared using this law, it is efficiently convenient.Because reaction raw materials are to be suspended in solvent substantially
In and do not dissolve, raw material is heated evenly so that other crystal formations can be fully converted into alpha-crystal form, high income, turn it is brilliant after product
Residual solvent is easily removed, convenient post-treatment.For example, the δ d crystal formations of hydrochloric acid Ivabradine are in reflux in toluene 0.5h, solid
Alpha-crystal form is completely transformed into, the crystal formation degree of purity of products therefrom is good, solid decentralization is high, does not lump, easily dried.
This law dexterously solves existing technical problem, for hydrochloric acid Ivabradine alpha-crystal form preparation provide one it is green
Colour circle is protected, saves efficient new way.
Brief description of the drawings
Fig. 1：The XRD spectrum of hydrochloric acid Ivabradine alpha-crystal form.
Embodiment
The present invention is explained in detail below with reference to instantiation so that this hair is more fully understood in those skilled in the art
Bright, instantiation is merely to illustrate technical scheme, and the present invention is not limited in any way.
Embodiment 1：
Add what is obtained according to method described in patent specification EP0534859 into 100mL (10 times, V/W) toluene
10.0g hydrochloric acid Ivabradines (δ crystal formations), are heated to backflow, stir 0.5h, are cooled to room temperature, are filtered under diminished pressure, Ran Houyu
6h is dried under 60 DEG C of vacuum conditions, white solid powder 9.7g, yield 97.0% is obtained.
Analyze measurement result
Embodiment 2：
Add what is obtained according to method described in patent specification EP0534859 into 100mL (10 times, V/W) toluene
10.0g hydrochloric acid Ivabradines (δ d crystal formations), are heated to backflow, stir 0.5h, are cooled to room temperature, are filtered under diminished pressure, then
In drying 6h under 60 DEG C of vacuum conditions, white solid powder 9.8g, yield 98.0% are obtained.
Analyze measurement result
Embodiment 3：
Add what is obtained according to method described in patent specification CN1827600B into 100mL (10 times, V/W) toluene
10.0g hydrochloric acid Ivabradines (beta crystal), are heated to backflow, stir 1.5h, are cooled to room temperature, are filtered under diminished pressure, Ran Houyu
6h is dried under 60 DEG C of vacuum conditions, white solid powder 9.8g, yield 98.0% is obtained.
Analyze measurement result
Embodiment 4：
Add what is obtained according to method described in patent specification EP2534135A into 100mL (10 times, V/W) toluene
10.0g hydrochloric acid Ivabradines (K crystal formations), are heated to backflow, stir 0.5h, are cooled to room temperature, are filtered under diminished pressure, Ran Houyu
6h is dried under 60 DEG C of vacuum conditions, white solid powder 9.7g, yield 97.0% is obtained.
Crystal formation measurement result：XRD is shown as alpha-crystal form.
Embodiment 5：
Add what is obtained according to method described in patent specification EP0534859 into 100mL (10 times, V/W) dimethylbenzene
10.0g hydrochloric acid Ivabradines (δ crystal formations), are heated to 120 DEG C, stir 0.5h, are cooled to room temperature, are filtered under diminished pressure, then
In drying 6h under 60 DEG C of vacuum conditions, white solid powder 9.6g, yield 96.0% are obtained.
Crystal formation measurement result：XRD is shown as alpha-crystal form.
Embodiment 6：
Add what is obtained according to method described in patent specification EP0534859 into 100mL (10 times, V/W) ethylo benzene
10.0g hydrochloric acid Ivabradines (δ crystal formations), are heated to 120 DEG C, stir 0.5h, are cooled to room temperature, are filtered under diminished pressure, then
In drying 6h under 60 DEG C of vacuum conditions, white solid powder 8.5g, yield 85.0% are obtained.
Crystal formation measurement result：XRD is shown as alpha-crystal form.
Embodiment 7：
Added into 100mL (10 times, V/W) 4-methyl-2 pentanone according to method described in patent specification EP0534859
The 10.0g hydrochloric acid Ivabradines (δ crystal formations) of acquisition, are heated to backflow, stir 0.5h, are cooled to room temperature, are filtered under diminished pressure,
Then in drying 6h under 60 DEG C of vacuum conditions, white solid powder 8.0g, yield 80.0% are obtained.
Crystal formation measurement result：XRD is shown as alpha-crystal form.
Embodiment 8：
Add and obtained according to method described in patent specification EP0534859 into 100mL (10 times, V/W) butyl acetate
10.0g hydrochloric acid Ivabradines (δ crystal formations), be heated to backflow, stir 1h, be cooled to room temperature, be filtered under diminished pressure, Ran Houyu
6h is dried under 60 DEG C of vacuum conditions, white solid powder 9.4g, yield 94.0% is obtained.
Crystal formation measurement result：XRD is shown as alpha-crystal form.
Embodiment 9：
Add what is obtained according to method described in patent specification EP0534859 into 100mL (10 times, V/W) toluene
10.0g hydrochloric acid Ivabradines (δ crystal formations), are heated to 100 DEG C, stir 1h, are cooled to room temperature, are filtered under diminished pressure, Ran Houyu
6h is dried under 60 DEG C of vacuum conditions, white solid powder 9.7g, yield 97.0% is obtained.
Crystal formation measurement result：XRD is shown as alpha-crystal form.
Embodiment 10：
Add what is obtained according to method described in patent specification EP0534859 into 100mL (10 times, V/W) toluene
10.0g hydrochloric acid Ivabradines (δ crystal formations), are heated to 80 DEG C, stir 0.5h, are cooled to room temperature, are filtered under diminished pressure, Ran Houyu
6h is dried under 60 DEG C of vacuum conditions, white solid powder 9.8g, yield 98.0% is obtained.
Crystal formation measurement result：XRD shows consistent with beta crystal.
Embodiment 11：
10.0g hydrochloric acid Ivabradines are added into 20ml absolute methanols, heating makes solid dissolving, is concentrated under reduced pressure into solvent
It is dry, obtain foaming solid.
Crystal formation measurement result：XRD is shown as amorphous.
100ml toluene (10 times, V/W) is added into above-mentioned solid, backflow is heated to, 0.5h is stirred, is cooled to room
Temperature, is filtered under diminished pressure, and then in drying 6h under 60 DEG C of vacuum conditions, obtains white solid powder 9.3g, yield 93.0%.
Analyze measurement result
Embodiment 12：
According to the information disclosed in patent specification CN1305856C, to 100mL toluene and 40mL N- methyi-pyrrofidiniums
The in the mixed solvent of ketone (NMP) adds the 10.0g hydrochloric acid that is obtained according to method described in patent specification EP0534859, and she cuts down cloth
Lei Ding, is heated to backflow dissolved clarification, stirs 0.5h, and cooling crystallization is filtered under diminished pressure, then in dry under 60 DEG C of vacuum conditions
6h, obtains white solid powder 8.6g, yield 86.0%.
Analyze measurement result：
Claims (7)
1. the preparation method of the hydrochloric acid Ivabradine alpha-crystal form shown in a kind of Formulas I, it is characterized in that the nothing of hydrochloric acid Ivabradine is determined
Shape or other crystal formations turn crystalline substance in the stirring of higher boiling poor solvent high temperature, then cool down, the crystal to be formed is collected by filtration,
2. the preparation method of hydrochloric acid Ivabradine alpha-crystal form according to claim 1, the higher boiling poor solvent is selected from boiling point
For 100-200 DEG C of solvent.
3. the preparation method of hydrochloric acid Ivabradine alpha-crystal form according to claim 2, the higher boiling poor solvent is selected from first
In benzene, ortho-xylene, meta-xylene, paraxylene, ethylo benzene, butyl acetate, 4-methyl-2 pentanone and 1,4- dioxane
It is one or more of.
4. the preparation method of hydrochloric acid Ivabradine alpha-crystal form according to claim 3, the higher boiling poor solvent is selected from first
One or more in benzene, butyl acetate and 4-methyl-2 pentanone, preferably toluene.
5. the preparation method of hydrochloric acid Ivabradine alpha-crystal form according to claim 1, the consumption of the higher boiling poor solvent is
10-100 times (V/W) of hydrochloric acid Ivabradine quality, preferably 10-50 times (V/W).
6. the preparation method of hydrochloric acid Ivabradine alpha-crystal form according to claim 1, the temperature that the high-temperature stirring turns brilliant is
100-200 DEG C, preferably 100-150 DEG C.
7. the preparation method of hydrochloric acid Ivabradine alpha-crystal form according to claim 1, the stirring turn the brilliant time for 0.5h with
On, preferably 0.5-2h.
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Cited By (1)
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115286577A (en) * | 2022-08-25 | 2022-11-04 | 江苏永安制药有限公司 | Preparation method of ivabradine hydrochloride and intermediate thereof |
| CN115286577B (en) * | 2022-08-25 | 2023-10-20 | 江苏永安制药有限公司 | Preparation method of ivabradine hydrochloride and intermediate thereof |
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