CN106831441B - A kind of preparation method of cinacalcet hydrochloride - Google Patents
A kind of preparation method of cinacalcet hydrochloride Download PDFInfo
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- CN106831441B CN106831441B CN201710048884.1A CN201710048884A CN106831441B CN 106831441 B CN106831441 B CN 106831441B CN 201710048884 A CN201710048884 A CN 201710048884A CN 106831441 B CN106831441 B CN 106831441B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
Abstract
The invention discloses a kind of preparation methods of cinacalcet hydrochloride, belong to chemicals and are synthetically prepared field.The present invention for raw material, prepares m-trifluoromethyl propenone (IV) by coupling reaction with bromine trifluoromethylbenzene (II) and acryloyl chloride (III)；(IV) (R) -3- (1- (1- naphthalene) ethylamino) -1- (3- (trifluoromethyl) phenyl) propyl- 1- ketone (VI) is generated with (R) -1- (1- naphthalene) ethamine (V) addition reaction, (VI) N- ((1R) -1- (1- naphthalene) ethyl) -3- (3- (trifluoromethyl) phenyl) propyl- 1- amine (cinacalcet) (VII) is prepared by reduction, salt-forming reaction obtains N- ((1R) -1- (1- naphthalene) ethyl) -3- (3- (trifluoromethyl) phenyl) -1- propylamin hydrochloride to cinacalcet again, that is cinacalcet hydrochloride (I).The route use it is cheap and easy to get between bromine trifluoromethylbenzene (II) and acryloyl chloride (III) for raw material, step is shorter, avoids compound and metallic reducing agent LiAlH using heavy metal Pd4、NaBH4Deng, it is safe and environment-friendly, economical, it is suitble to large-scale industrial production.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, especially a kind of cinacalcet hydrochloride synthetic method.
Background technique
Cinacalcet hydrochloride (I), structural formula are, it is by U.S. NPS
A kind of Sensipar of Pharmaceuticals company research and development, FDA approval listing in 2004, for treating nephrosis dialysis patient
Secondary hyperparathyroidism and thyroid cancer caused by hypercalcinemia.
Cinacalcet hydrochloride synthetic method mainly has following three kinds at present:
First is that using 3- (3- (trifluoromethyl) phenyl) propionic acid and its derivative as starting material, such as patent document
US2007259964A1, WO2008058235A2, CN102718662A, CN103739500A report 3- (3- (trifluoromethyl)
Phenyl) propionic acid and its derivative (mixed acid anhydride, carboxylic acid halides or alcoxyl ester) and (R) -1- (1- naphthalene) ethamine passes through condensation reaction
It restores to obtain the method for cinacalcet hydrochloride after obtaining amide.Patent document US6211244B1, CN103467304A by with
3- (3- (trifluoromethyl) phenyl) propionic aldehyde carries out reduction amination and obtains cinacalcet hydrochloride.Patent document WO2006125026,
CN101180261A, CN101941911A, CN103044267A, CN103450027A report 3- (3- (trifluoromethyl) benzene
Base) propanol derivative (halides or sulphonic acid ester) etc. is alkylated reaction and obtains cinacalcet hydrochloride.However this method is anti-
It should be both needed in the process using 3- (3- (trifluoromethyl) phenyl) propionic acid and its derivative, 3- (3- (trifluoromethyl) phenyl) third
Sour preparation step is cumbersome, and time-consuming and needs to use heavy metal Pd compound.
Second is that using heavy metal coupling method.Such as: patent document US7250533 discloses the fluorine-based benzene of 3- bromine three and acrylic acid second
3- (3-(trifluoromethyl) phenyl is made in the reactions such as ester is coupled through Heck, reduction) propyl alcohol, hydroxyl is converted to easy leaving group,
The method for preparing cinacalcet through condensation reaction with (R)-(1- naphthalene) ethamine in the presence of alkali.Patent document CN 101993379
A is reported using 1- acetonaphthone as raw material, introduces chiral reagent, with sodium borohydride reduction, is then reacted with 3- propiolic halide, then
With a halogen benzotrifluoride coupling reaction, last reduction reaction is simultaneously acidified, obtains cinacalcet hydrochloride.Patent document
WO2009002427A2, US20110306794A1 disclose what 3- bromine trifluoromethylbenzene was formed with (R)-(1- naphthalene) ethamine
Acrylamide coupling, then reduction, acidified obtain cinacalcet hydrochloride.Patent document WO2009002427A2 also reported alkene
The method that propyl aminating reaction prepares cinacalcet hydrochloride.But such method uses heavy metal Pd compound to participate in coupling substantially,
Higher cost, and Pd compound is difficult to completely remove in the reaction system.
Third is that such as: patent document US6211244B1 reports 1- (1- naphthalene) ethyl ketone and is using mesotomy method
Beginning raw material carries out reductive amination process with 3- (3- (trifluoromethyl) phenyl) propyl- 1- amine and obtains the racemization of cinacalcet hydrochloride
Body, then the method for chiral resolution obtains cinacalcet hydrochloride.But the starting material 3- of this method (3- (trifluoromethyl) benzene
Base) propyl- 1- amine value lattice are higher；It first obtains raceme to split again, the optical isomer of half is discarded, and production cost is higher.
Therefore it provides a kind of synthetic route is short, cost of material is low, avoids discarding the cinacalcet hydrochlorides of a large amount of intermediate products
Synthetic method, it has also become urgent technical problem to be solved in the field.
Summary of the invention
In view of the above-mentioned problems, the present invention provides one kind with bromine trifluoromethylbenzene (II) and acryloyl chloride (III) as raw material conjunction
The method of hydrochloric acid cinacalcet (I) is avoided having used valuable Pd metallic compound, also be avoided using LiAlH4, NaBH4Deng
Risk metal compound reducing agent, synthesis under normal pressure, safe operation, the present invention is implemented as follows:
A kind of preparation method of cinacalcet hydrochloride, including following four step:
Step 1: with bromine trifluoromethylbenzene (II) and acryloyl chloride (III) for raw material, pass through magnesium metal under catalysis of iodine
Coupling reaction occurs.
Specifically: suitable solvent I (ethyl acetate, tetrahydrofuran, ether etc.) is added in bromine trifluoromethylbenzene (II) by between
Dissolution is added iodine grain and magnesium powder reaction generates Grignard Reagent, then react again with acryloyl chloride (III) under the conditions of 50 ~ 60 DEG C
It generates m-trifluoromethyl propenone (IV), structural formula is
；
In the step, the molar ratio of iodine grain and bromine trifluoromethylbenzene is 0.01 ~ 0.05:1, magnesium powder and bromine trifluoromethyl
The molar ratio of benzene (II) is 1 ~ 2:1, and the molar ratio of acryloyl chloride (III) and bromine trifluoromethylbenzene (II) is 1 ~ 2:1.
Step 2: be added in the m-trifluoromethyl propenone (IV) prepared to step 1 appropriate solvent II (such as ethyl acetate,
Methylene chloride, acetonitrile etc.) it makes it dissolve, at a temperature of 20 ~ 30 DEG C, suitable acid, and (R) -1- (1- naphthalene) ethamine is added
(V) Isosorbide-5-Nitrae-addition reaction occurs, is prepared into (R) -3- (1- (1- naphthalene) ethylamino) -1- (3- trifluoromethyl) phenyl) propyl-
1- ketone (VI), structural formula are
；
VI is that cinacalcet hydrochloride alkali-alpha-methylene aoxidizes products therefrom；
In the step, the molar ratio of acid and m-trifluoromethyl propenone (IV) are 0.05 ~ 0.20:1, (R) -1- (1- naphthalene
Base) molar ratio of ethamine (V) and m-trifluoromethyl propenone (IV) is 0.8 ~ 1:1,
Step 3: gained compound (R) -3- (1- (1- naphthalene) ethylamino) -1- (3- (trifluoro is prepared to step 2
Methyl) phenyl) propyl- 1- ketone (VI) is added appropriate solvent III (such as ethyl alcohol, ethylene glycol, glycerine etc.) and makes it dissolve, be added suitable
The hydrazine hydrate and potassium hydroxide of amount, in 90 ~ 180 DEG C of progress back flow reactions, N- ((1R) -1- (1- naphthalene) second is prepared in reduction
Base) -3- (3- (trifluoromethyl) phenyl) propyl- 1- amine (cinacalcet) (VII), structural formula is；
In the step, hydrazine hydrate that mass fraction is 80% and VI molar ratio are 1 ~ 2.5:1, and potassium hydroxide rubs with VI
You are than being 1.5 ~ 2.5:1.
Step 4: by N- ((1R) -1- (1- naphthalene) ethyl) -3- (3- (trifluoromethyl) phenyl) propyl- 1- obtained by step 3
Amine (cinacalcet, VII) is dissolved in suitable solvent IV (such as methanol, ethyl alcohol, isopropanol, ethyl acetate etc.), in 50 ~ 60 DEG C
Hydrochloric acid is added, after being stirred to react 1h, is cooled to 0 ~ 10 DEG C, then stirring and crystallizing 5h or more is filtered, 65 DEG C of dry 12h are obtained
White crystalline solid powder, as target product cinacalcet hydrochloride (I)；
In this step, hydrochloric acid be added and VII molar ratio are 1.5 ~ 3:1.
Further, in the preparation method of cinacalcet hydrochloride of the present invention, acid described in step 2 includes hydrochloric acid, sulphur
Acid, nitric acid, the inorganic acids such as phosphoric acid also include alchlor, boron trifluoride, the lewis acids such as ferric trichloride.
Reaction equation of the present invention is as follows:
Compared with the existing technology, the present invention has following technical effect that
(1) it avoids using (3- (trifluoromethyl) phenyl) propionic acid of 3- involved in general synthetic routes and its derivative,
The acid and its derivative synthesis step are longer, and process route is complicated.The present invention uses industrialized material m-trifluoromethyl propylene
Ketone and acryloyl chloride are starting material, (R) -3- (1- (1- naphthalene) ethylamino) -1- (3- (trifluoromethyl) phenyl) propyl-
1- ketone (VI) prepares cinacalcet by a step reduction, and reaction step is shorter.
(2) it avoids using precious metals pd compound and metallic reducing agent LiAH4, NaBH4Deng, using hydrazine hydrate reduction agent,
It is safe and environment-friendly, economical.
(3) product yield is higher, and impurity is few, purity is high, and the cinacalcet hydrochloride purity prepared in embodiment is greater than
99.50%, maximum single impurity is suitble to large-scale production, economic value with higher less than 0.10%.
Detailed description of the invention
Fig. 1 is that 1 step of inventive embodiments (4) prepares cinacalcet hydrochloride H-NMR map.
Fig. 2 is that 1 step of inventive embodiments (4) prepares cinacalcet hydrochloride C-NMR map.
Fig. 3 is that 1 step of inventive embodiments (4) prepares cinacalcet hydrochloride IR map.
Fig. 4 is that 1 step of inventive embodiments (4) prepares cinacalcet hydrochloride Ms map.
Specific embodiment
Technical idea of the invention is further illustrated below by way of specific embodiment combination attached drawing, following embodiments are not
It is the limitation to technical scheme.
Reaction reagent involved in following embodiment, raw material are commercially available.
Embodiment 1
Cinacalcet hydrochloride preparation method in the present embodiment, includes the following steps
(1) 450 ml ethyl acetate, bromine trifluoromethylbenzene between 0.20mol (about 45.0g) are added in 1000ml reaction flask
(II), 0.20mol(about 4.8g) magnesium powder, 0.002mol(about 0.5g) iodine grain, 55 DEG C, insulated and stirred 8h are slowly heated to, is stopped
0.20mol(about 18.2g is slowly added dropwise to 0 ~ 10 DEG C in heating, slow cooling) acryloyl chloride (III), it is added dropwise within 60 minutes.
After being added dropwise, 0 ~ 10 DEG C is stirred overnight, and is slowly added to 180ml mixture of ice and water, is stirred 30 minutes, and reaction solution turns
Enter in 1000ml separatory funnel, give up the solid not being completely dissolved, mixed liquor stands 15 minutes, and lower layer's water phase is given up in liquid separation.
180ml purified water is added in separatory funnel, oscillation shakes up, and stands 15 minutes, lower layer's water phase is given up in liquid separation.It has taken
Machine mutually uses the dry 6h of 15g anhydrous sodium sulfate, filters, and 40 ~ 50 DEG C of reduced pressures remove ethyl acetate, obtain faint yellow thick object
As m-trifluoromethyl propenone (IV) 38.2g, yield 95.4%.
(2) take gained trifluoromethyl propenone (IV) 0.191mol in step (1) that 400ml ethyl acetate is added,
0.172mol(about 29.4g) (R) -1- (1- naphthalene) ethamine, 0.0184mol(about 1.8g) sulfuric acid, 6h is stirred at room temperature；Then
100ml purified water is added into reaction solution, with 10% sodium hydrate regulator solution pH to 12, mixed liquor is transferred to 1000ml liquid separation leakage
Liquid separation in bucket, organic phase are purified with 200ml after water washing, with the dry 6h of 20g anhydrous sodium sulfate, are filtered, filtrate is concentrated into without molten
The outflow of agent ethyl acetate, obtains yellow oil (R) -3- (1- (1- naphthalene) ethylamino) -1- (3- (trifluoromethyl) phenyl)
Propyl- 1- ketone (VI) 60.8g, yield 95.3%.
(3) 300ml dehydrated alcohol is added in gained clear yellow viscous object (VI) 0.164mol in step (2), 0.265mol(is about
14.8g) hydrazine hydrate (mass fraction 80%), 0.32mol(about 17.9g) potassium hydroxide, 90 ~ 180 DEG C are heated to reflux 2h, stop adding
Heat is cooled to room temperature.
200ml purified water is added, mixed liquor is extracted with 200ml toluene, and toluene solution is dry with 20g anhydrous sodium sulfate, is taken out
Filter, filtrate are concentrated to dryness, and obtain the white solid N- of class ((1R) -1- (1- naphthalene) ethyl) -3- (3- (trifluoromethyl) phenyl) propyl- 1-
Amine (cinacalcet, VII) 48.3g, yield 82.6%, purity 99.67%(is in terms of area normalization method), largest single impurity 0.08%.
(4) preparation gained cinacalcet (VII) 0.112mol(40.0g in step (3) is taken) it is added in 1000ml reaction flask,
320ml dehydrated alcohol is added, is heated to 50 ~ 60 DEG C, then 0.24mol concentrated hydrochloric acid is added dropwise in stirring and dissolving, stir 1h, be cooled to 5
DEG C, crystallization 6h is kept the temperature, is filtered, 65 DEG C of drying 12h of filter cake obtain white crystalline solid powder 35.2g, as hydrochloric acid Xi Naka
(I).Yield is 79.9%, purity 99.93%(area normalization method), largest single impurity 0.03%.
Fig. 1-Fig. 4 is respectively H-NMR map, C-NMR map, the IR map for the hydrochloric acid Xi Naka (I) that the present embodiment obtains
With Ms map.
By the H-NMR map of Fig. 1 it is found that signal hydrogen number is 23, belong to hydrochloric acid hydrogen, secondary amine hydrogen, arylamine hydrogen, Asia respectively
Methyl hydrogen and methyl hydrogen and target molecule cinacalcet hydrochloride C22H23ClF3N hydrogen number is consistent；
By the C-NMR map of Fig. 2 it is found that signal carbon potential moves δ (ppm): 142.66,134.54,133.85,132.77,
130.83、130.09、129.71、129.38、128.74、127.37、126.56、126.03、125.16、124.98、123.18、
123.10,120.62,52.41,45.26,32.04,27.61,20.53 with target molecule cinacalcet hydrochloride molecular formula
C22H23ClF3N is consistent；
By the IR map of Fig. 3 it is found that 2960cm-1There are the hydrocarbon antisymmetric stretching vibration of methyl, 2709 cm-1、2512
cm-1、1586 cm-1There are the stretching vibration of secondary amino nitrogen hydrogen and nitrogen hydrogen in-plane bending vibration, 1517 cm-1、1449 cm-1There are virtues
Ring carbon carbon stretching vibration, 1325 cm-1、1167 cm-1、1120 cm-1There are trifluoromethyl carbon fluorine stretching vibration, 795 cm-1、
773 cm-1There are the hydrocarbon out-of-plane bending vibration of naphthalene nucleus, 703 cm-1There are 1,3- di-substituted aryl ring bending vibrations；
By the Ms map of Fig. 4 it is found that charge-mass ratio m/z358.2 may be molecular ion peak, signal m/z358.2 is hydrochloric acid west
That card plug removes the molecular ion peak [M+H] of cinacalcet after demineralizing acid+。
The structure elucidation of Fig. 1-Fig. 4 shows that carbon, hydrogen and the functional group ownership of the present embodiment product support target molecule salt
Sour cinacalcet.
Embodiment 2
Cinacalcet hydrochloride preparation method in the present embodiment, includes the following steps
(1) be added 450 ml tetrahydrofurans in 1000ml reaction flask, 0.20mol(about 45.0g be added) between bromine trifluoromethyl
Benzene (II), 0.213mol(about 5.1g) magnesium powder, 0.00236mol(about 0.6g) iodine grain, 50 ~ 60 DEG C are slowly heated to, insulated and stirred
8h generates green reagent, then stops heating, and 0.212mol(about 19.2g is slowly added dropwise to 0 ~ 10 DEG C in slow cooling) acryloyl
Chlorine (III) is added dropwise for 60 minutes.
After being added dropwise, 0 ~ 10 DEG C is stirred overnight.It next day, is slowly added to 180ml mixture of ice and water, stirs 30 minutes, instead
It answers liquid to be transferred in 1000ml separatory funnel, gives up the solid not being completely dissolved, mixed liquor stands 15 minutes, liquid separation, under giving up
Layer water phase.
180ml purified water is added in separatory funnel, oscillation shakes up, and stands 15 minutes, lower layer's water phase is given up in liquid separation.It is organic
It mutually with the dry 6h of 15g anhydrous sodium sulfate, filters, 40 ~ 50 DEG C of reduced pressures remove ethyl acetate, obtain between faint yellow thick object
Trifluoromethyl propenone (IV) 38.6g, yield 96.4%.
(2) 400ml methylene chloride is added in gained m-trifluoromethyl propenone (IV) 0.193mol in step (1),
0.172mol(about 29.4g) (R) -1- (1- naphthalene) ethamine, 6h is stirred at room temperature in 0.0102mol phosphoric acid；Then into reaction solution
100ml purified water is added, with 10% sodium hydrate regulator solution pH to 12, mixed liquor is transferred to liquid separation in 1000ml separatory funnel, has
Machine is mutually purified after water washing with 200ml, with the dry 6h of 20g anhydrous sodium sulfate, is filtered, filtrate is concentrated into solvent-free ethyl acetate stream
Out, yellow oil (R) -3- (1- (1- naphthalene) ethylamino) -1- (3- (trifluoromethyl) phenyl) propyl- 1- ketone (VI) is obtained
61.4g, yield 96.2%.
(3) 300ml ethylene glycol is added in gained clear yellow viscous object (VI) 0.165mol in step (2), 0.265mol(is about
14.8g, 18ml) hydrazine hydrate (mass fraction 80%), 0.32mol(about 17.9g) potassium hydroxide, 90 ~ 180 DEG C are heated to reflux 2h, stop
It only heats, is cooled to room temperature.
200ml purified water is added, mixed liquor is extracted with 200ml toluene, and toluene solution is dry with 20g anhydrous sodium sulfate, is taken out
Filter, filtrate are concentrated to dryness, and obtain the white solid N- of class ((1R) -1- (1- naphthalene) ethyl) -3- (3- (trifluoromethyl) phenyl) propyl- 1-
Amine (cinacalcet, VII) 49.7g, yield 84.1%, purity 99.54%(is in terms of area normalization method), largest single impurity 0.07%.
(4) preparation gained cinacalcet (VII) 0.112mol (40.0g) in step (3) is added in 1000ml reaction flask,
320ml ethyl acetate is added, is heated to 55 DEG C, then 0.24mol is added dropwise in stirring and dissolving, concentrated hydrochloric acid stirs 1h, is cooled to 3
DEG C, crystallization 6h is kept the temperature, is filtered, 65 DEG C of drying 12h of filter cake obtain white crystalline solid powder 36.3g, as hydrochloric acid Xi Naka
(I).
Calculating product yield is 82.3%, purity 99.91%(area normalization method), largest single impurity 0.06%.
Embodiment 3
Cinacalcet hydrochloride preparation method in the present embodiment, includes the following steps
(1) 450 ml ether, 0.20mol(about 45.0g are added in 1000ml reaction flask) between bromine trifluoromethylbenzene (II),
0.242mol(about 5.8g) magnesium powder, 0.00256mol(about 0.65g) iodine grain, 55 DEG C, insulated and stirred 8h are slowly heated to, stops adding
0.23mol(about 20.9g, 18.8ml is slowly added dropwise to 0 ~ 10 DEG C in heat, slow cooling) acryloyl chloride (III), it drips within 60 minutes
Finish.
After being added dropwise, 0 ~ 10 DEG C is stirred overnight.It next day, is slowly added to 180ml mixture of ice and water, stirs 30 minutes, instead
It answers liquid to be transferred in 1000ml separatory funnel, gives up the solid not being completely dissolved, mixed liquor stands 15 minutes, liquid separation, under giving up
Layer water phase.
180ml purified water is added in separatory funnel, oscillation shakes up, and stands 15 minutes, lower layer's water phase is given up in liquid separation.It is organic
It mutually with the dry 6h of 15g anhydrous sodium sulfate, filters, 40 ~ 50 DEG C of reduced pressures remove ethyl acetate, obtain between faint yellow thick object
Trifluoromethyl propenone (IV) 38.9g, yield 97.2%.
(2) 400ml acetonitrile, 0.172mol is added in gained m-trifluoromethyl propenone (IV) 0.194mol in step (1)
6h is stirred at room temperature in (about 29.4g) (R) -1- (1- naphthalene) ethamine, 0.0204 mol hydrochloric acid；Then it is added into reaction solution
100ml purified water, with 10% sodium hydrate regulator solution pH to 12, mixed liquor is transferred to liquid separation in 1000ml separatory funnel, organic phase
Being purified after water washing with 200ml, with the dry 6h of 20g anhydrous sodium sulfate, is filtered, filtrate is concentrated into solvent-free ethyl acetate outflow,
Obtain yellow oil (R) -3- (1- (1- naphthalene) ethylamino) -1- (3- (trifluoromethyl) phenyl) propyl- 1- ketone (VI)
62.0g, yield 97.2%.
(3) 300ml glycerine is added in gained clear yellow viscous object 0.167mol in step (2), 0.265mol(is about
14.8g, 18ml) hydrazine hydrate (mass fraction 80%), 0.32mol(about 17.9g) potassium hydroxide, 90 ~ 180 DEG C are heated to reflux 2h, stop
It only heats, is cooled to room temperature.
200ml purified water is added, mixed liquor is extracted with 200ml toluene, and toluene solution is dry with 20g anhydrous sodium sulfate, is taken out
Filter, filtrate are concentrated to dryness, and obtain the white solid N- of class ((1R) -1- (1- naphthalene) ethyl) -3- (3- (trifluoromethyl) phenyl) propyl- 1-
Amine (cinacalcet, VII) 49.1g, yield 82.3%, purity 99.47%(is in terms of area normalization method), largest single impurity 0.05%.
(4) preparation gained cinacalcet (VII) 0.112mol(40.0g in step (3)) is added in 1000ml reaction flask,
320ml anhydrous methanol is added, is heated to 55 DEG C, then 0.24mol(about 23.6g, 20ml is added dropwise in stirring and dissolving) concentrated hydrochloric acid, is stirred
1h is mixed, is cooled to 6 DEG C, keeps the temperature crystallization 6h, is filtered, 65 DEG C of drying 12h of filter cake obtain white crystalline solid powder 37.6g, as
Hydrochloric acid Xi Naka (I).Yield is 85.3%, purity 99.86%(area normalization method), largest single impurity 0.04%.
Embodiment 4
Cinacalcet hydrochloride preparation method in the present embodiment, includes the following steps
(1) 450 ml ethyl acetate, 0.20mol(about 45.0g are added in 1000ml reaction flask) between bromine trifluoromethylbenzene
(II), 0.267mol(about 6.4g) magnesium powder, 0.00354mol(about 0.9g) iodine grain, 60 DEG C are slowly heated to, insulated and stirred 8h stops
Only heating, 0.247mol(about (22.4g, 20.1ml) acryloyl chloride (III) is slowly added dropwise to 0 ~ 10 DEG C in slow cooling, and 60 minutes
It is added dropwise.
After being added dropwise, 0 ~ 10 DEG C is stirred overnight.It is slowly added to 180ml mixture of ice and water, is stirred 30 minutes, reaction solution turns
Enter in 1000ml separatory funnel, give up the solid not being completely dissolved, mixed liquor stands 15 minutes, and lower layer's water phase is given up in liquid separation.
180ml purified water is added in separatory funnel, oscillation shakes up, and stands 15 minutes, lower layer's water phase is given up in liquid separation.It is organic
It mutually with the dry 6h of 15g anhydrous sodium sulfate, filters, 40 ~ 50 DEG C of reduced pressures remove ethyl acetate, obtain between faint yellow thick object
Trifluoromethyl propenone (IV) 39.4g, yield 98.4%.
(2) gained m-trifluoromethyl propenone (IV) 0.197mol in step (1) is dissolved in 400ml ethyl acetate, added
Enter 0.172mol(about 29.4g) (R) -1- (1- naphthalene) ethamine, 6h is stirred at room temperature in 0.0255mol alchlor；Then to anti-
Addition 100ml purified water in liquid is answered, with 10% sodium hydrate regulator solution pH to 12, mixed liquor is transferred in 1000ml separatory funnel
Liquid separation, organic phase are purified with 200ml after water washing, with the dry 6h of 20g anhydrous sodium sulfate, are filtered, filtrate is concentrated into solvent-free second
Acetoacetic ester outflow, obtains yellow oil (R) -3- (1- (1- naphthalene) ethylamino) -1- (3- (trifluoromethyl) phenyl) propyl-
1- ketone (VI) 62.6g, yield 98.2%.
(3) 300ml dehydrated alcohol, 0.265mol is added in gained clear yellow viscous object (VI) 0.169mol in step (2)
(about 14.8g, 18ml) hydrazine hydrate (mass fraction 80%), 0.32mol(about 17.9g) potassium hydroxide, 90 ~ 180 DEG C are heated to reflux
2h stops heating, is cooled to room temperature.
200ml purified water is added, mixed liquor is extracted with 200ml toluene, and toluene solution is dry with 20g anhydrous sodium sulfate, is taken out
Filter, filtrate are concentrated to dryness, and obtain the white solid N- of class ((1R) -1- (1- naphthalene) ethyl) -3- (3- (trifluoromethyl) phenyl) propyl- 1-
Amine (cinacalcet, VII) 50.3g, yield 83.5%, purity 99.44%(is in terms of area normalization method), largest single impurity 0.07%.
(4) preparation gained cinacalcet (VII) 0.112mol (40.0g) in step (3) is added in 1000ml reaction flask,
320ml anhydrous isopropyl alcohol is added, is heated to 55 DEG C, then 0.24mol is added dropwise in stirring and dissolving, concentrated hydrochloric acid stirs 1h, is cooled to 8
DEG C, crystallization 6h is kept the temperature, is filtered, 65 DEG C of drying 12h of filter cake obtain white crystalline solid powder 38.9g, as cinacalcet hydrochloride
(I).Yield is 88.2%, purity 99.83%(area normalization method), largest single impurity 0.08%.
Although illustrating and describing the present invention with specific embodiment, it will be apparent to those skilled in the art that
, many other change and modification can be made without departing from the spirit and scope of the invention.Therefore, this is meaned
In the following claims include belonging to all such changes and modifications in the scope of the invention.
Claims (2)
1. a kind of preparation method of cinacalcet hydrochloride, which is characterized in that specific step is as follows:
1) bromine trifluoromethylbenzene is dissolved in solvent I by between, 50~60 DEG C, iodine grain is added and magnesium powder generates green reagent, is added dropwise
Acryloyl chloride, 0~10 DEG C is stirred overnight, and next day, which filters, obtains compound IV, structural formula are as follows:
2) the compound IV that step 1) obtains is dissolved in solvent II, 20~30 DEG C, acid and (1R) -1- (1- naphthalene) second is added
Amine, adjusts pH to 12, and reaction generates product VI, structural formula are as follows:
The acid is one of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or lewis acid or a variety of；
3) product VI is dissolved in solvent III, hydrazine hydrate and potassium hydroxide is added, in 90~180 DEG C of back flow reaction 2h, product
Dry after being extracted with toluene, suction filtration, obtains cinacalcet；
4) cinacalcet is dissolved in solvent IV, 50~60 DEG C, after addition hydrochloric acid is stirred to react 1h, is cooled to 0~10 DEG C, stirs
Crystallization at least 5h is mixed, then filters, is dry, that is, obtaining the cinacalcet hydrochloride；
Wherein, the solvent I is one of ethyl acetate, tetrahydrofuran or ether or a variety of；
The solvent II is one of ethyl acetate, methylene chloride or acetonitrile or a variety of；
The solvent III is one of dehydrated alcohol, ethylene glycol or glycerine or a variety of；
The solvent IV is one of anhydrous methanol, dehydrated alcohol, isopropanol or ethyl acetate or a variety of；
In step 1), the molar ratio of the iodine grain and bromine trifluoromethylbenzene is 0.01~0.05:1, magnesium powder and bromine fluoroform
The molar ratio of base benzene is 1~2:1；The molar ratio of the acryloyl chloride and bromine trifluoromethylbenzene is 1~2:1；
In step 2), the molar ratio of acid and compound IV are 0.05~0.20:1, (1R) -1- (1- naphthalene) ethamine and compound IV
Molar ratio be 0.8~1:1；
In step 3), the mass fraction of the hydrazine hydrate is 80%, and the molar ratio with product VI is 1~2.5:1, the hydrogen-oxygen
The molar ratio for changing potassium and product VI is 1.5~2.5:1.
2. the preparation method of cinacalcet hydrochloride according to claim 1, which is characterized in that in step 2), the Louis
Acid includes one of alchlor, boron trifluoride or ferric trichloride or a variety of.
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