CN106831441A - A kind of preparation method of cinacalcet hydrochloride - Google Patents
A kind of preparation method of cinacalcet hydrochloride Download PDFInfo
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- CN106831441A CN106831441A CN201710048884.1A CN201710048884A CN106831441A CN 106831441 A CN106831441 A CN 106831441A CN 201710048884 A CN201710048884 A CN 201710048884A CN 106831441 A CN106831441 A CN 106831441A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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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- C07—ORGANIC CHEMISTRY
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- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
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- 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 method of cinacalcet hydrochloride, belong to the synthetically prepared field of chemicals.The present invention is with a bromine trifluoromethylbenzene（Ⅱ）And acryloyl chloride（Ⅲ）It is raw material, m-trifluoromethyl propenone is prepared by coupling reaction（Ⅳ）；（Ⅳ）With (R) 1 (1 naphthyl) ethamine（Ⅴ）Addition reaction generation (R) 3 (1 (1 naphthyl) ethylamino) 1 (3 (trifluoromethyl) phenyl) the third 1 ketone（Ⅵ）,（Ⅵ）The amine of N ((1R) 1 (1 naphthyl) ethyl) 3 (3 (trifluoromethyl) phenyl) the third 1 is prepared by reduction（Cinacalcet）（Ⅶ）, salt-forming reaction obtains (3 (trifluoromethyl) phenyl) 1 propylamin hydrochlorides, i.e. cinacalcet hydrochloride of N ((1R) 1 (1 naphthyl) ethyl) 3 to cinacalcet again（Ⅰ）.The route is using bromine trifluoromethylbenzene between cheap and easy to get（Ⅱ）And acryloyl chloride（Ⅲ）It is raw material, step is shorter, it is to avoid use the compound of heavy metal Pd, and metallic reducing agent LiAlH4、NaBH4Deng safe and environment-friendly, economy, suitable large-scale industrial production.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, particularly a kind of cinacalcet hydrochloride synthetic method.
Background technology
Cinacalcet hydrochloride（Ⅰ）, its structural formula is, it is by U.S. NPS
A kind of Sensipar of Pharmaceuticals companies research and development, FDA approval listings in 2004, for treating ephrosis dialysis patient
SHPT, and the hypercalcinemia caused by thyroid cancer.
Current cinacalcet hydrochloride synthetic method mainly has following three kinds：
One is such as patent document with 3- (3- (trifluoromethyl) phenyl) propionic acid and its derivative as starting material
US2007259964A1, WO2008058235A2, CN102718662A, CN103739500A report 3- (3- (trifluoromethyl)
Phenyl) propionic acid and its derivative（Mixed acid anhydride, carboxylic acid halides or alcoxyl ester）Pass through condensation reaction with (R) -1- (1- naphthyls) ethamine
The method for obtaining cinacalcet hydrochloride is restored after obtaining acid amides.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）Cinacalcet hydrochloride is obtained etc. reaction is alkylated.But the method is anti-
It is both needed to use 3- (3- (trifluoromethyl) phenyl) propionic acid and its derivative, 3- (3- (trifluoromethyl) phenyl) third during answering
Sour preparation process is cumbersome, and time-consuming and needs to use heavy metal Pd compounds.
Two is using heavy metal coupling method.Such as：Patent document US7250533 discloses the fluorine-based benzene of 3- bromines three and acrylic acid second
The reactions such as ester is coupled through Heck, reduction are obtained 3- (3-（Trifluoromethyl）Phenyl) propyl alcohol, hydroxyl changes into easy leaving group,
In the presence of alkali with（R）-（1- naphthyls）The method that ethamine prepares cinacalcet through condensation reaction.Patent document CN 101993379
A is reported with 1- acetonaphthones as raw material, introduces chiral reagent, with sodium borohydride reduction, is then reacted with 3- propiolic halides, then
With a halogen benzotrifluoride coupling reaction, last reduction reaction is simultaneously acidified, obtains cinacalcet hydrochloride.Patent document
WO2009002427A2, US20110306794A1 disclose 3- bromines trifluoromethylbenzene and（R）-（1- naphthyls）What ethamine was formed
Acrylamide is coupled, then reduction, acidified obtain cinacalcet hydrochloride.Patent document WO2009002427A2 also reported alkene
The method that propyl group aminating reaction prepares cinacalcet hydrochloride.But such method uses heavy metal Pd compounds to participate in coupling substantially,
It is relatively costly, and Pd compounds are difficult to remove completely in reaction system.
Three is to use mesotomy method, such as：Patent document US6211244B1 reports 1- (1- naphthyls) ethyl ketone
Beginning raw material, the racemization that reductive amination process obtains cinacalcet hydrochloride is carried out with 3- (3- (trifluoromethyl) phenyl) propyl- 1- amine
Body, then the method for chiral resolution obtain cinacalcet hydrochloride.But the initiation material 3- of the method (3- (trifluoromethyl) benzene
Base) propyl- 1- amine value lattice are higher；First obtain raceme to split again, the optical isomer of half goes out of use, and production cost is higher.
Therefore it provides a kind of synthetic route is short, cost of material is low, avoid discard a large amount of intermediate products cinacalcet hydrochloride
Synthetic method, it has also become this area technical barrier urgently to be resolved hurrily.
The content of the invention
Regarding to the issue above, the present invention provides one kind with a bromine trifluoromethylbenzene（Ⅱ）And acryloyl chloride（Ⅲ）For raw material is closed
Hydrochloric acid cinacalcet（Ⅰ）Method, it is to avoid used valuable Pd metallic compounds, also avoided using LiAlH4, NaBH4Deng
Dangerous metal compound reducing agent, synthesis under normal pressure, safe operation, what the present invention was realized in：
A kind of preparation method of cinacalcet hydrochloride, including following four step：
Step one：With a bromine trifluoromethylbenzene（Ⅱ）And acryloyl chloride（Ⅲ）It is raw material, occurs by magnesium metal under catalysis of iodine
Coupling reaction.
Specially：The bromine trifluoromethylbenzene by between（Ⅱ）Add appropriate solvent I（Ethyl acetate, tetrahydrofuran, ether etc.）
Dissolving, under the conditions of 50 ~ 60 DEG C, add iodine grain and magnesium powder reaction generation RMgBr, then again with acryloyl chloride（Ⅲ）Reaction
Generation m-trifluoromethyl propenone（Ⅳ）, its structural formula is
；
In the step, the mol ratio of iodine grain and a bromine trifluoromethylbenzene is 0.01 ~ 0.05:1, magnesium powder and a bromine trifluoromethylbenzene
（Ⅱ）Mol ratio be 1 ~ 2:1, acryloyl chloride（Ⅲ）With a bromine trifluoromethylbenzene（Ⅱ）Mol ratio be 1 ~ 2:1.
Step 2：To m-trifluoromethyl propenone prepared by step one（Ⅳ）It is middle to add appropriate solvent II（Such as ethyl acetate,
Dichloromethane, acetonitrile etc.）It is dissolved, at a temperature of 20 ~ 30 DEG C, appropriate acid, and (R) -1- (1- naphthyls) ethamine is added
（Ⅴ）Generation Isosorbide-5-Nitrae-addition reaction, is prepared into (R) -3- (1- (1- naphthyls) ethylamino) -1- (3- trifluoromethyls) phenyl) propyl-
1- ketone (VI), its structural formula is
；
VI is cinacalcet hydrochloride alkali-alpha-methylene oxidation products therefrom；
In the step, sour and m-trifluoromethyl propenone（Ⅳ）Mol ratio be 0.05 ~ 0.20：1, (R) -1- (1- naphthyls) second
Amine（Ⅴ）With m-trifluoromethyl propenone（Ⅳ）Mol ratio be 0.8 ~ 1:1,
Step 3：Gained compound (R) -3- (1- (1- naphthyls) ethylamino) -1- (3- (trifluoromethyl) benzene is prepared to step 2
Base) the appropriate solvent III of propyl- 1- ketone (VI) additions（Such as ethanol, ethylene glycol, glycerine etc.）It is dissolved, appropriate hydration is added
Hydrazine and potassium hydroxide, back flow reaction is carried out in 90 ~ 180 DEG C, and reduction prepares N- ((1R) -1- (1- naphthyls) ethyl) -3- (3-
(trifluoromethyl) phenyl) propyl- 1- amine（Cinacalcet）（Ⅶ）, its structural formula is；
In the step, mass fraction is 80% hydrazine hydrate and VI mol ratio is 1 ~ 2.5：1, potassium hydroxide and VI mol ratio
It is 1.5 ~ 2.5：1.
Step 4：By step 3 gained N- ((1R) -1- (1- naphthyls) ethyl) -3- (3- (trifluoromethyl) phenyl) propyl- 1-
Amine（Cinacalcet, VII）It is dissolved in appropriate solvent IV（Such as methyl alcohol, ethanol, isopropanol, ethyl acetate etc.）In, in 50 ~ 60 DEG C
Add hydrochloric acid, after stirring reaction 1h, be cooled to 0 ~ 10 DEG C, more than stirring and crystallizing 5h, then suction filtration, 65 DEG C dry 12h, obtain
White crystalline solid powder, as target product cinacalcet hydrochloride（Ⅰ）；
In this step, it is 1.5 ~ 3 to add hydrochloric acid and VII mol ratio：1.
Further, in the preparation method of cinacalcet hydrochloride of the present invention, the acid described in step 2 includes hydrochloric acid, sulphur
The inorganic acids such as acid, nitric acid, phosphoric acid, also including alchlor, boron trifluoride, the lewis acid such as ferric trichloride.
Reaction equation of the present invention is as follows：
Relative to prior art, the present invention has following technique effect：
（1）Avoid using 3- (3- (trifluoromethyl) phenyl) propionic acid and its derivative being related in general synthetic routes, the acid
And its derivative synthesis step is more long, process route is complicated.The present invention using industrialized material m-trifluoromethyl propenone and
Acryloyl chloride is starting material, (R) -3- (1- (1- naphthyls) ethylamino) -1- (3- (trifluoromethyl) phenyl) propyl- 1- ketone
（Ⅵ）Cinacalcet is prepared by a step reduction, reactions steps are shorter.
（2）Avoid using precious metals pd compound and metallic reducing agent LiAH4, NaBH4Deng, using hydrazine hydrate reduction agent,
Safe and environment-friendly, economy.
（3）Product yield is higher, and impurity is few, and purity is high, and the cinacalcet hydrochloride purity prepared in embodiment is more than
99.50%, maximum single impurity is less than 0.10%, is adapted to large-scale production, with economic worth higher.
Brief description of the drawings
Fig. 1 is the step of inventive embodiments 1（4）Prepare cinacalcet hydrochloride H-NMR collection of illustrative plates.
Fig. 2 is the step of inventive embodiments 1（4）Prepare cinacalcet hydrochloride C-NMR collection of illustrative plates.
Fig. 3 is the step of inventive embodiments 1（4）Prepare cinacalcet hydrochloride IR collection of illustrative plates.
Fig. 4 is the step of inventive embodiments 1（4）Prepare cinacalcet hydrochloride Ms collection of illustrative plates.
Specific embodiment
Technological thought of the invention is further illustrated below by way of specific embodiment combination accompanying drawing, following embodiments are not
It is the limitation to technical scheme.
The reaction reagent that is related in following examples, raw material are commercially available.
Embodiment 1
Cinacalcet hydrochloride preparation method in the present embodiment, comprises the following steps
（1）Bromine trifluoromethylbenzene between 450 ml ethyl acetate, 0.20mol (about 45.0g) is added in 1000ml reaction bulbs（Ⅱ）,
0.20mol（About 4.8g）Magnesium powder, 0.002mol（About 0.5g）Iodine grain, is slowly heated to 55 DEG C, and insulated and stirred 8h stops heating,
Slow cooling is slowly added dropwise 0.20mol to 0 ~ 10 DEG C（About 18.2g）Acryloyl chloride（Ⅲ）, 60 minutes completion of dropping.
After completion of dropping, 0 ~ 10 DEG C is stirred overnight, and is slowly added to 180ml mixture of ice and water, stirs 30 minutes, and reaction solution turns
Enter in 1000ml separatory funnels, give up the solid not being completely dissolved, mixed liquor stands 15 minutes, point liquid gives up lower floor's water phase.
180ml purified waters are added in separatory funnel, vibration shakes up, and stands 15 minutes, and point liquid gives up lower floor's water phase.Take
Machine mutually use 15g anhydrous sodium sulfate drying 6h, suction filtration, 40 ~ 50 DEG C be concentrated under reduced pressure, remove ethyl acetate, obtain faint yellow thick thing
As m-trifluoromethyl propenone（Ⅳ）38.2g, yield is 95.4%.
（2）Take step（1）Middle gained trifluoromethyl propenone（Ⅳ）0.191mol adds 400ml ethyl acetate,
0.172mol（About 29.4g) (R) -1- (1- naphthyls) ethamine, 0.0184mol（About 1.8g）Sulfuric acid, is stirred at room temperature 6h；Then
To 100ml purified waters are added in reaction solution, with 10% sodium hydrate regulator solution pH to 12, mixed liquor is transferred to 1000ml points of liquid leakage
Point liquid in bucket, organic phase is purified after water washing with 200ml, and with 20g anhydrous sodium sulfate drying 6h, suction filtration, filtrate is concentrated into without molten
Agent ethyl acetate flows out, and obtains yellow oil (R) -3- (1- (1- naphthyls) ethylamino) -1- (3- (trifluoromethyl) phenyl)
Propyl- 1- ketone（Ⅵ）60.8g, yield 95.3%.
(3) by step（2）Middle gained clear yellow viscous thing (VI) 0.164mol adds 300ml absolute ethyl alcohols, 0.265mol（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 waters are added, mixed liquor is extracted with 200ml toluene, and toluene solution 20g anhydrous sodium sulfate dryings are taken out
Filter, filtrate is concentrated to dryness, and obtains the white solid N- of class ((1R) -1- (1- naphthyls) ethyl) -3- (3- (trifluoromethyl) phenyl) propyl- 1-
Amine（Cinacalcet, VII）48.3g, yield is 82.6%, purity 99.67%（In terms of area normalization method）, maximum single miscellaneous 0.08%.
(4) step is taken（3）Middle preparation gained cinacalcet（Ⅶ）0.112mol（40.0g）In addition 1000ml reaction bulbs,
320ml absolute ethyl alcohols are added, 50 ~ 60 DEG C are heated to, then stirring and dissolving is added dropwise 0.24mol concentrated hydrochloric acids, stirs 1h, is cooled to 5
DEG C, crystallization 6h is incubated, suction filtration, 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）, maximum single miscellaneous 0.03%.
Fig. 1-Fig. 4 is respectively the hydrochloric acid Xi Naka of the present embodiment acquisition（Ⅰ）H-NMR collection of illustrative plates, C-NMR collection of illustrative plates, IR collection of illustrative plates
With Ms collection of illustrative plates.
From the H-NMR collection of illustrative plates of Fig. 1, signal hydrogen number is 23, and hydrochloric acid hydrogen, secondary amine hydrogen, arylamine hydrogen, Asia are belonged to respectively
Methyl hydrogen and methyl hydrogen and target molecule cinacalcet hydrochloride C22H23ClF3N hydrogen numbers are consistent；
From the C-NMR collection of illustrative plates of Fig. 2, 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、
123.10th, 120.62,52.41,45.26,32.04,27.61,20.53 with target molecule cinacalcet hydrochloride molecular formula
C22H23ClF3N is consistent；
From the IR collection of illustrative plates of Fig. 3,2960cm-1There is the hydrocarbon antisymmetric stretching vibration of methyl, 2709 cm-1、2512 cm-1、
1586 cm-1There is the stretching vibration of secondary amino nitrogen hydrogen and nitrogen hydrogen in-plane bending vibration, 1517 cm-1、1449 cm-1There is aromatic ring carbon
Carbon stretching vibration, 1325 cm-1、1167 cm-1、1120 cm-1There is trifluoromethyl carbon fluorine stretching vibration, 795 cm-1、773
cm-1There is the hydrocarbon out-of-plane bending vibration of naphthalene nucleus, 703 cm-1There are 1,3- di-substituted aryl ring flexural vibrations；
From the Ms collection of illustrative plates of Fig. 4, charge-mass ratio m/z358.2 may be molecular ion peak, and signal m/z358.2 is hydrochloric acid Xi Naka
Plug removes the molecular ion peak [M+H] of cinacalcet after demineralizing acid+。
The structure elucidation of Fig. 1-Fig. 4 shows, the carbon of the present embodiment product, hydrogen and functional group's ownership support target molecule salt
Sour cinacalcet.
Embodiment 2
Cinacalcet hydrochloride preparation method in the present embodiment, comprises the following steps
（1）450 ml tetrahydrofurans are added in 1000ml reaction bulbs, 0.20mol is added（About 45.0g）Between bromine trifluoromethylbenzene
（Ⅱ）, 0.213mol（About 5.1g）Magnesium powder, 0.00236mol（About 0.6g）Iodine grain, is slowly heated to 50 ~ 60 DEG C, insulated and stirred
8h, generates green reagent, then stops heating, and slow cooling is slowly added dropwise 0.212mol to 0 ~ 10 DEG C（About 19.2g）Acryloyl
Chlorine（Ⅲ）, 60 minutes completion of dropping.
After completion of dropping, 0 ~ 10 DEG C is stirred overnight.Next day, it is slowly added to 180ml mixture of ice and water, stirs 30 minutes, instead
Answer liquid to be transferred in 1000ml separatory funnels, give up the solid not being completely dissolved, mixed liquor stands 15 minutes, point liquid, under giving up
Layer water phase.
180ml purified waters are added in separatory funnel, vibration shakes up, and stands 15 minutes, and point liquid gives up lower floor's water phase.It is organic
Mutually with 15g anhydrous sodium sulfate drying 6h, suction filtration, 40 ~ 50 DEG C are concentrated under reduced pressure, and ethyl acetate are removed, between obtaining faint yellow thick thing
Trifluoromethyl propenone（Ⅳ）38.6g, yield is 96.4%.
（2）By step（1）Middle gained m-trifluoromethyl propenone（Ⅳ）0.193mol adds 400ml dichloromethane,
0.172mol（About 29.4g）(R) -1- (1- naphthyls) ethamine, 0.0102mol phosphoric acid is stirred at room temperature 6h；Then in reaction solution
100ml purified waters are added, with 10% sodium hydrate regulator solution pH to 12, mixed liquor is transferred to point liquid in 1000ml separatory funnels, has
Machine is purified after water washing with 200ml, and with 20g anhydrous sodium sulfate drying 6h, suction filtration, filtrate is concentrated into solvent-free ethyl acetate stream
Go out, obtain yellow oil (R) -3- (1- (1- naphthyls) ethylamino) -1- (3- (trifluoromethyl) phenyl) propyl- 1- ketone (VI)
61.4g, yield 96.2%.
(3) by step（2）Middle gained clear yellow viscous thing（Ⅵ）0.165mol adds 300ml ethylene glycol, 0.265mol（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
Only heat, be cooled to room temperature.
200ml purified waters are added, mixed liquor is extracted with 200ml toluene, and toluene solution 20g anhydrous sodium sulfate dryings are taken out
Filter, filtrate is concentrated to dryness, and obtains the white solid N- of class ((1R) -1- (1- naphthyls) ethyl) -3- (3- (trifluoromethyl) phenyl) propyl- 1-
Amine（Cinacalcet, VII）49.7g, yield is 84.1%, purity 99.54%（In terms of area normalization method）, maximum single miscellaneous 0.07%.
(4) by step（3）Middle preparation gained cinacalcet（Ⅶ）0.112mol (40.0g) is added in 1000ml reaction bulbs,
320ml ethyl acetate is added, 55 DEG C are heated to, then stirring and dissolving is added dropwise 0.24mol, and concentrated hydrochloric acid stirs 1h, is cooled to 3
DEG C, crystallization 6h is incubated, suction filtration, 65 DEG C of drying 12h of filter cake obtain white crystalline solid powder 36.3g, as hydrochloric acid Xi Naka
（Ⅰ）.
It is 82.3%, purity 99.91% to calculate product yield（Area normalization method）, maximum single miscellaneous 0.06%.
Embodiment 3
Cinacalcet hydrochloride preparation method in the present embodiment, comprises the following steps
（1）450 ml ether, 0.20mol are added in 1000ml reaction bulbs（About 45.0g）Between bromine trifluoromethylbenzene（Ⅱ）,
0.242mol（About 5.8g）Magnesium powder, 0.00256mol（About 0.65g）Iodine grain, is slowly heated to 55 DEG C, and insulated and stirred 8h stops adding
Heat, slow cooling is slowly added dropwise 0.23mol to 0 ~ 10 DEG C（About 20.9g, 18.8ml）Acryloyl chloride（Ⅲ）, drip within 60 minutes
Finish.
After completion of dropping, 0 ~ 10 DEG C is stirred overnight.Next day, it is slowly added to 180ml mixture of ice and water, stirs 30 minutes, instead
Answer liquid to be transferred in 1000ml separatory funnels, give up the solid not being completely dissolved, mixed liquor stands 15 minutes, point liquid, under giving up
Layer water phase.
180ml purified waters are added in separatory funnel, vibration shakes up, and stands 15 minutes, and point liquid gives up lower floor's water phase.It is organic
Mutually with 15g anhydrous sodium sulfate drying 6h, suction filtration, 40 ~ 50 DEG C are concentrated under reduced pressure, and ethyl acetate are removed, between obtaining faint yellow thick thing
Trifluoromethyl propenone（Ⅳ）38.9g, yield is 97.2%.
（2）By step（1）Middle gained m-trifluoromethyl propenone（Ⅳ）0.194mol adds 400ml acetonitriles, 0.172mol
（About 29.4g）(R) -1- (1- naphthyls) ethamine, 0.0204 mol hydrochloric acid, are stirred at room temperature 6h；Then added in reaction solution
100ml purified waters, with 10% sodium hydrate regulator solution pH to 12, mixed liquor is transferred to point liquid, organic phase in 1000ml separatory funnels
Purified after water washing with 200ml, with 20g anhydrous sodium sulfate drying 6h, suction filtration, filtrate is concentrated into solvent-free ethyl acetate outflow,
Obtain yellow oil (R) -3- (1- (1- naphthyls) ethylamino) -1- (3- (trifluoromethyl) phenyl) propyl- 1- ketone (VI)
62.0g, yield 97.2%.
(3) by step（2）Middle gained clear yellow viscous thing 0.167mol adds 300ml glycerine, 0.265mol（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
Only heat, be cooled to room temperature.
200ml purified waters are added, mixed liquor is extracted with 200ml toluene, and toluene solution 20g anhydrous sodium sulfate dryings are taken out
Filter, filtrate is concentrated to dryness, and obtains the white solid N- of class ((1R) -1- (1- naphthyls) ethyl) -3- (3- (trifluoromethyl) phenyl) propyl- 1-
Amine（Cinacalcet, VII）49.1g, yield is 82.3%, purity 99.47%（In terms of area normalization method）, maximum single miscellaneous 0.05%.
(4) by step（3）Middle preparation gained cinacalcet（Ⅶ）0.112mol（40.0g）In addition 1000ml reaction bulbs,
320ml absolute methanols are added, 55 DEG C are heated to, then stirring and dissolving is added dropwise 0.24mol（About 23.6g, 20ml）Concentrated hydrochloric acid, stirs
1h is mixed, 6 DEG C are cooled to, crystallization 6h is incubated, suction filtration, 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）, maximum single miscellaneous 0.04%.
Embodiment 4
Cinacalcet hydrochloride preparation method in the present embodiment, comprises the following steps
（1）450 ml ethyl acetate, 0.20mol are added in 1000ml reaction bulbs（About 45.0g）Between bromine trifluoromethylbenzene（Ⅱ）,
0.267mol（About 6.4g）Magnesium powder, 0.00354mol（About 0.9g）Iodine grain, is slowly heated to 60 DEG C, and insulated and stirred 8h stops adding
Heat, slow cooling is slowly added dropwise 0.247mol to 0 ~ 10 DEG C（About (22.4g, 20.1ml) acryloyl chloride（Ⅲ）, it is added dropwise within 60 minutes
Finish.
After completion of dropping, 0 ~ 10 DEG C is stirred overnight.180ml mixture of ice and water is slowly added to, is stirred 30 minutes, reaction solution turns
Enter in 1000ml separatory funnels, give up the solid not being completely dissolved, mixed liquor stands 15 minutes, point liquid gives up lower floor's water phase.
180ml purified waters are added in separatory funnel, vibration shakes up, and stands 15 minutes, and point liquid gives up lower floor's water phase.It is organic
Mutually with 15g anhydrous sodium sulfate drying 6h, suction filtration, 40 ~ 50 DEG C are concentrated under reduced pressure, and ethyl acetate are removed, between obtaining faint yellow thick thing
Trifluoromethyl propenone（Ⅳ）39.4g, yield is 98.4%.
（2）By step（1）Middle gained m-trifluoromethyl propenone（Ⅳ）0.197mol is dissolved in 400ml ethyl acetate, plus
Enter 0.172mol（About 29.4g）(R) -1- (1- naphthyls) ethamine, 0.0255mol alchlors are stirred at room temperature 6h；Then to anti-
Addition 100ml purified waters in liquid are answered, with 10% sodium hydrate regulator solution pH to 12, mixed liquor is transferred in 1000ml separatory funnels
Divide liquid, organic phase is purified after water washing with 200ml, and with 20g anhydrous sodium sulfate drying 6h, suction filtration, filtrate is concentrated into solvent-free second
Acetoacetic ester flows out, and obtains yellow oil (R) -3- (1- (1- naphthyls) ethylamino) -1- (3- (trifluoromethyl) phenyl) propyl-
1- ketone（Ⅵ）62.6g, yield 98.2%.
(3) by step（2）Middle gained clear yellow viscous thing (VI) 0.169mol adds 300ml absolute ethyl alcohols, 0.265mol
（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 waters are added, mixed liquor is extracted with 200ml toluene, and toluene solution 20g anhydrous sodium sulfate dryings are taken out
Filter, filtrate is concentrated to dryness, and obtains the white solid N- of class ((1R) -1- (1- naphthyls) ethyl) -3- (3- (trifluoromethyl) phenyl) propyl- 1-
Amine（Cinacalcet, VII）50.3g, yield is 83.5%, purity 99.44%（In terms of area normalization method）, maximum single miscellaneous 0.07%.
(4) by step（3）Middle preparation gained cinacalcet（Ⅶ）0.112mol (40.0g) is added in 1000ml reaction bulbs,
320ml anhydrous isopropyl alcohols are added, 55 DEG C are heated to, then stirring and dissolving is added dropwise 0.24mol, and concentrated hydrochloric acid stirs 1h, is cooled to 8
DEG C, crystallization 6h is incubated, suction filtration, 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）, maximum single miscellaneous 0.08%.
Although the present invention is illustrated and describes with specific embodiment, but it will be apparent to those skilled in the art that
, many other changes and modification can be made without departing from the spirit and scope of the invention.Therefore, this meaning
Includes all such changes and modifications belonged in the scope of the invention in the following claims.
Claims (7)
1. a kind of preparation method of cinacalcet hydrochloride, it is characterised in that comprise the following steps that：
1）Bromine trifluoromethylbenzene is dissolved in solvent I by between, 50 ~ 60 DEG C, adds iodine grain and magnesium powder to generate RMgBr, dropwise addition third
Alkene acyl chlorides, 0 ~ 10 DEG C is stirred overnight, and suction filtration obtains m-trifluoromethyl propenone；
2）By step 1）The m-trifluoromethyl propenone of acquisition is dissolved in solvent II, 20 ~ 30 DEG C, adds acid and (R) -1- (1-
Naphthyl) ethamine, after reaction terminates, adjust pH to 12, reaction generation product VI；
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 with
Dry, suction filtration after toluene extraction, obtains cinacalcet；
4）Cinacalcet is dissolved in solvent IV, 50 ~ 60 DEG C, after adding hydrochloric acid stirring reaction 1h, is cooled to 0 ~ 10 DEG C, stirring
Crystallization at least 5h, then suction filtration, drying, that is, obtain the cinacalcet hydrochloride；
Wherein, the solvent I is one or more in ethyl acetate, tetrahydrofuran or ether；
The solvent II is one or more in ethyl acetate, dichloromethane or acetonitrile；
The solvent III is one or more in absolute ethyl alcohol, ethylene glycol or glycerine；
The solvent IV is one or more in absolute methanol, absolute ethyl alcohol, isopropanol or ethyl acetate.
2. the preparation method of cinacalcet hydrochloride according to claim 1, it is characterised in that step 1）In, iodine grain with
Between bromine trifluoromethylbenzene mol ratio be 0.01 ~ 0.05：1, the mol ratio of magnesium powder and a bromine trifluoromethylbenzene is 1 ~ 2：1.
3. the preparation method of cinacalcet hydrochloride according to claim 2, it is characterised in that step 1）In, the acryloyl
The mol ratio of chlorine and a bromine trifluoromethylbenzene is 1 ~ 2：1.
4. the preparation method of cinacalcet hydrochloride according to claim 3, it is characterised in that step 2）In, a sour and trifluoro
The mol ratio of methyl-prop ketenes is 0.05 ~ 0.20：The mol ratio of 1, (R) -1- (1- naphthyls) ethamine and m-trifluoromethyl propenone
It is 0.8 ~ 1：1.
5. the preparation method of cinacalcet hydrochloride according to claim 4, it is characterised in that step 3）In, the hydrazine hydrate
Mass fraction be 80%, its mol ratio with product VI is 1 ~ 2.5：1, the potassium hydroxide is 1.5 with the mol ratio of product VI
~2.5：1.
6. according to the preparation method of one of the claim 1-5 cinacalcet hydrochlorides, it is characterised in that step 2）In, it is described
Acid is one or more in hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or lewis acid.
7. the preparation method of cinacalcet hydrochloride according to claim 6, it is characterised in that step 2）In, the Louis
Acid is to include one or more in alchlor, boron trifluoride or ferric trichloride.
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