CN109535006A - It is a kind of to prepare cinacalcet hydrochloride intermediate and method - Google Patents
It is a kind of to prepare cinacalcet hydrochloride intermediate and method Download PDFInfo
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- CN109535006A CN109535006A CN201811454868.3A CN201811454868A CN109535006A CN 109535006 A CN109535006 A CN 109535006A CN 201811454868 A CN201811454868 A CN 201811454868A CN 109535006 A CN109535006 A CN 109535006A
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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
- C07C209/60—Preparation of compounds containing amino groups bound to a carbon skeleton by condensation or addition reactions, e.g. Mannich reaction, addition of ammonia or amines to alkenes or to alkynes or addition of compounds containing an active hydrogen atom to Schiff's bases, quinone imines, or aziranes
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- 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
- C07C209/74—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 by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C211/00—Compounds containing amino groups bound to a carbon skeleton
- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
- C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
- C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
Abstract
The present invention provides a kind of midbody compound for preparing cinacalcet hydrochloride and preparation method, which has structure shown in formula (I):
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of intermediate for preparing cinacalcet hydrochloride and method.
Background technique
Cinacalcet is known as first drug in the new class compound of Sensipar (calcimimetics), can swash
Calcium receptor in parathyroid gland living, to reduce the secretion of parathormone (PTH).The chemical name of cinacalcet hydrochloride is N-
((1R) -1- (1- naphthalene) ethyl) -3- (3- (trifluoromethyl) phenyl) propyl- 1- amine hydrochlorate, molecular formula C22H22F3N·HCl
(No. CAS: 364782-34-3), also referred to as CNC-HCl, structure are as follows:
It is reported that there is following several method to can be used for preparing cinacalcet hydrochloride at present:
Scheme one: preparing cinacalcet hydrochloride using reductive amination process, with m-trifluoromethyl benzenepropanal and R-1- (1-
Naphthalene) ethamine is raw material, through titanium tetraisopropylate catalyst at schiff bases, then through sodium cyanoborohydride reduction imines, hydrochloric acid is at salt
It is made (such as United States Patent (USP) US 6211244).Its reaction route is as follows:
But use the reduction impurity content contained in this method products obtained therefrom higher, the stabilization of product during keeping sample
Property decline it is very fast.In addition, this route side reaction is more, the titanium tetraisopropylate used is expensive, and reaction cost is high, cyano hydroboration
Sodium has severe toxicity, is not suitable for industrialized production.
Scheme two:, as raw material, hydroxyl is converted to easy leaving group using 3- [3- (trifluoromethyl) phenyl] propyl alcohol, is deposited in alkali
Cinacalcet is prepared through condensation reaction with R- (1- naphthalene) ethamine lower, raw material 3- [3- (trifluoromethyl) phenyl] propyl alcohol passes through
3- bromine trifluoromethylbenzene and ethyl acrylate react and be made through Heck coupling, reduction etc. (such as WO2006125026 or the U.S. it is special
Sharp US7250533).Its reaction route is as follows:
But the ethyl acrylate used in the reaction is carcinogenic, and it is inflammable and unstable, and reaction route is too long, it is uncomfortable
Close industrialized production.
Scheme three: a series of methods for preparing cinacalcet by reduction scheme relate generally to reaction route:
The reaction is again different because of the selection of reaction system, is broadly divided into following several, and reaction is both needed in heating or high below
Temperature, the lower progress of reflux:
(1)
This method prepares cinacalcet hydrochloride with borane reduction.But BH3/ THF solution toxicity is big, stability is poor, price
Valuableness is not suitable for industrialized production.
(2)
This method prepares cinacalcet hydrochloride with borine/dimethyl sulphide, and boron trifluoride ether reagent is toxic articles, and after
A large amount of toxic gas can be discharged in treatment process, pollutes environment, be not suitable for a large amount of industrialization preparations.
(3)
This method its cinacalcet hydrochloride prepared with sodium borohydride/boron trifluoride ether reduction system.Make in preparation process
It is toxic articles with a large amount of boron trifluoride ether, and a large amount of toxic gas can be released in last handling process, it is dirty
Environment is contaminated, a large amount of industrialization preparations are not suitable for.
(4)
This method prepares cinacalcet hydrochloride with lithium aluminium hydride reduction.In LiAlH4The reactant of/THF, HCl/ normal heptane
Under system, lithium aluminium hydride reduction is too vivaciously easy over-reduction or reduction not exclusively, and dangerous, is not suitable for a large amount of industrialization preparations.
(5)
This method is using red aluminum as reducing agent, although red aluminum is relatively inexpensive, stability is also good, use when for the ease of
Storage and transport, need wiring solution-forming, and iron needs to be unfavorable for a large amount of through special pipeline in industrialized production
Production is with the realization of industrialization.
Summary of the invention
To solve the above problems, the present invention provides a kind of new intermediate and method for preparing cinacalcet hydrochloride, it should
Method is easy, raw material is easy to get, is at low cost, high income, purity are good, route is short, environmentally friendly and easy to industrialized production.
Specifically, the present invention is achieved through the following technical solutions:
In the first aspect of the present invention, it to be the bromo- N- (1- of (R) -3- that the present invention provides a kind of midbody compounds
(naphthalene -1- base) ethyl) propyl- 1- amine, there is structure shown in formula (I):
Wherein, X is selected from Cl and Br, preferably Br.
Preferably, formula (I) compound is the bromo- N- of (R) -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine.
In the second aspect of the present invention, the present invention provides a kind of method for preparing formula (I) compound, the method includes
Using the halogenated propionic aldehyde of 3- and (R) -1- naphthalene ethylamine as reactant.
Preferably, the reaction route are as follows:
Wherein X is Cl or Br, preferably Br.
Preferably, the method includes the halogenated propionic aldehyde of 3- and (R) -1- naphthalene ethylamine to be added in anhydrous methanol, ice-water bath
Stirring, is added portionwise sodium cyanoborohydride, continues to stir, and hydrochloric acid reaction is added dropwise, is concentrated under reduced pressure, after water dilution is added, with
Ethyl acetate extraction, separates organic layer, and anhydrous sodium sulfate drying is added, filters, is concentrated under reduced pressure and obtains.
Preferably, the halogenated propionic aldehyde of the 3- is selected from 3- chlorine propionic aldehyde and 3- bromine propionic aldehyde, preferably 3- bromine propionic aldehyde.
Preferably, the molar ratio of the halogenated propionic aldehyde of the 3-, (R) -1- naphthalene ethylamine and sodium cyanoborohydride is 1-1.5:1:3-
5, preferably 1:1:5.
Preferably, the concentration of hydrochloric acid is 2mol/L.
Preferably, the sodium cyanoborohydride is added in three times, and the ratio between mole being added three times is 2:2:1.
In the third aspect of the present invention, the present invention provides a kind of method for preparing cinacalcet hydrochloride, the method packets
It includes using formula (I) compound as midbody compound.
Preferably, the method includes using the halogenated propionic aldehyde of 3- and (R) -1- naphthalene ethylamine as initial compounds, through intermediate
It closes object formula (I) and prepares cinacalcet hydrochloride.
Preferably, the reaction route of the method are as follows:
Preferably, it the described method comprises the following steps:
(1) the halogenated propionic aldehyde of 3- and (R) -1- naphthalene ethylamine are added in anhydrous methanol, cyano is added portionwise in ice-water bath stirring
Sodium borohydride continues to stir, and hydrochloric acid reaction is added dropwise, is concentrated under reduced pressure, and after water dilution is added, is extracted, is separated with ethyl acetate
Organic layer is added anhydrous sodium sulfate drying, filters, acquisition formula (I) compound is concentrated under reduced pressure；
(2) by aluminum trichloride (anhydrous) adding into dichloromethane, ice-water bath, control temperature of reaction system dropwise addition formula (I) change
The dichloromethane solution of object is closed, the dichloromethane solution of benzotrifluoride is then added dropwise, after stirring, reaction solution is poured into ice water,
Organic layer is separated, is washed with saturated sodium chloride solution, anhydrous sodium sulfate drying is added, filters, concentrated hydrochloric acid is added dropwise, is vigorously stirred,
It is concentrated under reduced pressure, obtains faint yellow solid, the mashing of ethyl acetate-hexane mixed liquor is added, filters, it is dry, obtain cinacalcet hydrochloride.
Preferably, in step (1), the halogenated propionic aldehyde of 3- is selected from 3- chlorine propionic aldehyde and 3- bromine propionic aldehyde, preferably 3- bromine propionic aldehyde.
Preferably, in step (1), the molar ratio of the halogenated propionic aldehyde of the 3-, (R) -1- naphthalene ethylamine and sodium cyanoborohydride is
1-1.5:1:3-5 preferably 1:1:5.
Preferably, in step (1), the concentration of hydrochloric acid is 2mol/L.
Preferably, in step (1), the sodium cyanoborohydride is added in three times, and the ratio between mole being added three times is 2:
2:1.
Preferably, in step (2), temperature of reaction system is controlled at 0-10 DEG C, preferably 0-5 DEG C, most preferably 0 DEG C.
Preferably, in step (2), the molar ratio of aluminum trichloride (anhydrous), formula (I) compound and benzotrifluoride is 1-1.2:1-
1.2:1 preferably 1.1:1:1.
Preferably, in step (2), reaction dissolvent is methylene chloride.
Preferably, in step (2), the volume ratio of n-hexane and ethyl acetate is 1 in ethyl acetate-hexane mixed liquor:
1。
In one more preferred embodiment, it is described prepare method that cinacalcet hydrochloride obtains the following steps are included:
(1) the halogenated propionic aldehyde of 3-, (R) -1- naphthalene ethylamine are added in anhydrous methanol, ice-water bath stirs 2h, is added in three times
Sodium cyanoborohydride, the ratio between mole of sodium cyanoborohydride being added three times are 2:2:1, wherein the halogenated propionic aldehyde of 3-, (R) -1-
The molar ratio of naphthalene ethylamine and sodium cyanoborohydride is 1-1.5:1:3-5, preferably 1:1:5；Continue to stir 2h, 2mol/L salt is added dropwise
Sour quenching reaction is concentrated under reduced pressure, and after water dilution is added, is extracted with ethyl acetate, separates organic layer, it is dry that anhydrous sodium sulfate is added
It is dry, it filters, the bromo- N- of (R) -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine is concentrated under reduced pressure；
(2) by aluminum trichloride (anhydrous) adding into dichloromethane, ice-water bath controls temperature of reaction system at 0-10 DEG C, excellent
The dichloromethane solution for selecting the 0-5 DEG C of bromo- N- of dropwise addition (R) -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine, is then added dropwise benzotrifluoride
Dichloromethane solution, wherein the molar ratio of aluminum trichloride (anhydrous), formula (I) compound and benzotrifluoride be 1-1.2:1-1.2:
1, preferably 1.1:1:1；After stirring 2h, reaction solution is poured into ice water, organic layer is separated, is washed with saturated sodium chloride solution,
It is dry that anhydrous sodium sulfate is added, filters, concentrated hydrochloric acid is added dropwise, is vigorously stirred, is concentrated under reduced pressure, obtains faint yellow solid, volume ratio is added
It is beaten, filters for the ethyl acetate-hexane mixed liquor of 1:1, it is dry, obtain cinacalcet hydrochloride.
And in the fourth aspect of the present invention, the present invention provides compounds shown in formula (I) as intermediate is preparing salt
Application in sour cinacalcet.
Compared with prior art, the method for the present invention is easy, and raw material is easy to get and low in raw material price, with the halogenated propionic aldehyde of 3- and
(R) -1- naphthalene ethylamine is initial reactant, only needs two steps through the bromo- N- of intermediate (R) -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine
Reaction can synthetic hydrochloric acid cinacalcet, and entire reaction process mild condition, yield are up to 95.6%, the hydrochloric acid being prepared
Cinacalcet purity is up to 99.9%, is easy to industrialization.
Specific embodiment
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are merely to illustrate the present invention
Rather than it limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to conventional strip
Part or according to the normal condition proposed by manufacturer.
Unless otherwise defined, it anticipates known to all professional and scientific terms as used herein and one skilled in the art
Justice is identical.All reagents or raw material as used herein unless otherwise instructed or preparation, can pass through commercially available approach purchase obtain.
In addition, any method similar to or equal to what is recorded and material can be applied to the method for the present invention.It is described in the text
Preferred implement methods and materials are for illustrative purposes only.
Embodiment 1(R) preparation of the bromo- N- of -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine
By 3- bromine propionic aldehyde (13.6g, 0.1mol), (R) -1- naphthalene ethylamine (17.1g, 0.1mol) is added to anhydrous methanol
In (100mL), ice-water bath stirs 2h, and sodium cyanoborohydride (0.5mol) is added in three times, and dosage molar ratio three times is 2:
2:1 continues to stir 2h, 2mol/L hydrochloric acid (20mL) quenching reaction is added dropwise, is concentrated under reduced pressure, after the dilution of 100mL water is added, with acetic acid
Ethyl ester extraction, separates organic layer, and anhydrous sodium sulfate drying is added, filters, the bromo- N- of (R) -3- (1- (naphthalene -1- base) is concentrated under reduced pressure
Ethyl) propyl- 1- amine (23.26g, 0.08mol), yield 79.65%.1HNMR(400MHz,CDCl3)8.02-7.95(m,2H),
7.84-7.79 (m, 1H), 7.54-7.45 (m, 3H), 7.15 (d, J=7.2Hz, 1H), 4.01 (m, 1H), 3.62 (t, J=
7.6Hz, 2H), 2.78 (m, 2H), 1.89 (m, 2H), 1.32 (d, J=7.6Hz, 3H).m/z:292.07.
Embodiment 2(R) preparation of the bromo- N- of -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine
By 3- bromine propionic aldehyde (13.6g, 0.1mol), (R) -1- naphthalene ethylamine (17.1g, 0.1mol) is added to anhydrous methanol
In (100mL), ice-water bath stirs 2h, is added at one time sodium cyanoborohydride (0.5mol), continues to stir 2h, 2mol/L salt is added dropwise
Sour (20mL) quenching reaction, is concentrated under reduced pressure, and after the dilution of 100mL water is added, is extracted with ethyl acetate, separates organic layer, nothing is added
Aqueous sodium persulfate is dry, filters, be concentrated under reduced pressure the bromo- N- of (R) -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine (14.6g,
0.05mol), yield 50%.
Embodiment 3(R) preparation of the bromo- N- of -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine
By 3- bromine propionic aldehyde (13.6g, 0.1mol), (R) -1- naphthalene ethylamine (17.1g, 0.1mol) is added to anhydrous methanol
In (100mL), ice-water bath stirs 2h, and sodium cyanoborohydride (0.5mol) is added in three times, and dosage molar ratio three times is 1:
1:1 continues to stir 2h, 2mol/L hydrochloric acid (20mL) quenching reaction is added dropwise, is concentrated under reduced pressure, after the dilution of 100mL water is added, with acetic acid
Ethyl ester extraction, separates organic layer, and anhydrous sodium sulfate drying is added, filters, the bromo- N- of (R) -3- (1- (naphthalene -1- base) is concentrated under reduced pressure
Ethyl) propyl- 1- amine (17.52g, 0.06mol), yield 60%.
Embodiment 4(R) preparation of the bromo- N- of -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine
By 3- bromine propionic aldehyde (13.6g, 0.1mol), (R) -1- naphthalene ethylamine (17.1g, 0.1mol) is added to anhydrous methanol
In (100mL), ice-water bath stirs 2h, and sodium cyanoborohydride (0.3mol) is added in three times, and dosage molar ratio three times is 2:
2:1 continues to stir 2h, 2mol/L hydrochloric acid (20mL) quenching reaction is added dropwise, is concentrated under reduced pressure, after the dilution of 100mL water is added, with acetic acid
Ethyl ester extraction, separates organic layer, and anhydrous sodium sulfate drying is added, filters, the bromo- N- of (R) -3- (1- (naphthalene -1- base) is concentrated under reduced pressure
Ethyl) propyl- 1- amine (18.98g, 0.065mol), yield 65%.
Embodiment 5(R) preparation of the bromo- N- of -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine
By 3- bromine propionic aldehyde (20.4g, 0.15mol), (R) -1- naphthalene ethylamine (17.1g, 0.1mol) is added to anhydrous methanol
In (100mL), ice-water bath stirs 2h, and sodium cyanoborohydride (0.3mol) is added in three times, and dosage molar ratio three times is 2:
2:1 continues to stir 2h, 2mol/L hydrochloric acid (20mL) quenching reaction is added dropwise, is concentrated under reduced pressure, after the dilution of 100mL water is added, with acetic acid
Ethyl ester extraction, separates organic layer, and anhydrous sodium sulfate drying is added, filters, the bromo- N- of (R) -3- (1- (naphthalene -1- base) is concentrated under reduced pressure
Ethyl) propyl- 1- amine (20.44g, 0.07mol), yield 46.7%.
Embodiment 6(R) preparation of the chloro- N- of -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine
By 3- chlorine propionic aldehyde (9.25g, 0.1mol), (R) -1- naphthalene ethylamine (17.1g, 0.1mol) is added to anhydrous methanol
In (100mL), ice-water bath stirs 2h, and sodium cyanoborohydride (0.5mol) is added in three times, and dosage molar ratio three times is 2:
2:1 continues to stir 2h, 2mol/L hydrochloric acid (20mL) quenching reaction is added dropwise, is concentrated under reduced pressure, after the dilution of 100mL water is added, with acetic acid
Ethyl ester extraction, separates organic layer, and anhydrous sodium sulfate drying is added, filters, the chloro- N- of (R) -3- (1- (naphthalene -1- base) is concentrated under reduced pressure
Ethyl) propyl- 1- amine (17.34g, 0.07mol), yield 69.98%.1HNMR(400MHz,CDCl3)8.02-7.95(m,2H),
7.84-7.79 (m, 1H), 7.54-7.45 (m, 3H), 7.13 (d, J=7.2Hz, 1H), 4.01 (m, 1H), 3.65 (t, J=
7.6Hz, 2H), 2.75 (m, 2H), 1.90 (m, 2H), 1.32 (d, J=7.6Hz, 3H).m/z:247.11.
Embodiment 7(R) preparation of the fluoro- N- of -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine
By 3- fluorine propionic aldehyde (7.6g, 0.1mol), (R) -1- naphthalene ethylamine (17.1g, 0.1mol) is added to anhydrous methanol
In (100mL), ice-water bath stirs 2h, and sodium cyanoborohydride (0.5mol) is added in three times, and dosage molar ratio three times is 2:
2:1 continues to stir 2h, 2mol/L hydrochloric acid (20mL) quenching reaction is added dropwise, is concentrated under reduced pressure, after the dilution of 100mL water is added, with acetic acid
Ethyl ester extraction, separates organic layer, and anhydrous sodium sulfate drying is added, filters, the fluoro- N- of (R) -3- (1- (naphthalene -1- base) is concentrated under reduced pressure
Ethyl) propyl- 1- amine (13.88g, 0.06mol), yield 60%.1HNMR(400MHz,CDCl3)8.02-7.95(m,2H),
7.84-7.79 (m, 1H), 7.54-7.45 (m, 3H), 7.15 (d, J=7.2Hz, 1H), 4.01 (m, 1H), 3.61 (t, J=
7.6Hz, 2H), 2.73 (m, 2H), 1.89 (m, 2H), 1.34 (d, J=7.6Hz, 3H).m/z:231.14.
Embodiment 8The preparation of cinacalcet hydrochloride
By 3- bromine propionic aldehyde (13.6g, 0.1mol), (R) -1- naphthalene ethylamine (17.1g, 0.1mol) is added to anhydrous methanol
In (100mL), ice-water bath stirs 2h, and sodium cyanoborohydride (0.5mol) is added in three times, and dosage molar ratio three times is 2:
2:1 continues to stir 2h, 2mol/L hydrochloric acid (20mL) quenching reaction is added dropwise, is concentrated under reduced pressure, after the dilution of 100mL water is added, with acetic acid
Ethyl ester extraction, separates organic layer, and anhydrous sodium sulfate drying is added, filters, the bromo- N- of (R) -3- (1- (naphthalene -1- base) is concentrated under reduced pressure
Ethyl) propyl- 1- amine (23.26g, 0.08mol), yield 79.65%.1HNMR(400MHz,CDCl3)8.02-7.95(m,2H),
7.84-7.79 (m, 1H), 7.54-7.45 (m, 3H), 7.15 (d, J=7.2Hz, 1H), 4.01 (m, 1H), 3.62 (t, J=
7.6Hz, 2H), 2.78 (m, 2H), 1.89 (m, 2H), 1.32 (d, J=7.6Hz, 3H).m/z:292.07.
Aluminum trichloride (anhydrous) (14.7g, 0.11mol) is added in methylene chloride (100mL), ice-water bath, control reaction
The methylene chloride of the bromo- N- of (R) -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine (29.2g, 0.1mol) is added dropwise at 0 DEG C for system temperature
Methylene chloride (50mL) solution of benzotrifluoride (14.6g, 0.1mol) is then added dropwise in solution (30mL).After stirring 2h, it will react
Liquid pours into ice water, separates organic layer, is washed with saturated sodium chloride solution, and anhydrous sodium sulfate drying is added, filters, 20mL is added dropwise
Concentrated hydrochloric acid is vigorously stirred, and is concentrated under reduced pressure, and faint yellow solid is obtained, and ethyl acetate-hexane mixed liquor (n-hexane: acetic acid second is added
Ester=1:1) mashing, it filters, it is dry, obtain cinacalcet hydrochloride (36.65g, 0.0956mol), yield 95.6%, purity
99.9%.1HNMR(400MHZ,CDCl3): 8.16 (d, J=8.2Hz, 1H), 7.89 (d, J=7.6Hz, 1H), 7.78-7.69
(m,2H),7.60-7.51(m,3H),7.42-7.38(m,4H),4.78(m,1H),3.02(s,1H),2.70-2.54(m,4H),
1.88-1.80 (m, 2H), 1.52 (d, J=6.4Hz, 3H)
Embodiment 9The preparation of cinacalcet hydrochloride
Aluminum trichloride (anhydrous) (13.33g, 0.1mol) is added in methylene chloride (100mL), ice-water bath, control reaction
System temperature is in 0 DEG C of bromo- N- of dropwise addition (R) -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine (29.2g, 0.1mol, by 1 side of embodiment
Method preparation) dichloromethane solution (30mL), then be added dropwise benzotrifluoride (14.6g, 0.1mol) methylene chloride (50mL) it is molten
Liquid.After stirring 2h, reaction solution is poured into ice water, organic layer is separated, is washed with saturated sodium chloride solution, anhydrous sodium sulfate is added
It is dry, it filters, 20mL concentrated hydrochloric acid is added dropwise, is vigorously stirred, be concentrated under reduced pressure, obtain faint yellow solid, it is mixed that ethyl acetate-hexane is added
Liquid (n-hexane: ethyl acetate=1:1) mashing is closed, is filtered, it is dry, it obtains cinacalcet hydrochloride (37.22g, 0.0945mol), receives
Rate 94.5%, purity 99.9%.
Embodiment 10The preparation of cinacalcet hydrochloride
Aluminum trichloride (anhydrous) (14.7g, 0.11mol) is added in methylene chloride (100mL), ice-water bath, control reaction
System temperature is in 0 DEG C of bromo- N- of dropwise addition (R) -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine (35.04g, 0.12mol, by embodiment 1
Method preparation) dichloromethane solution (30mL), then be added dropwise benzotrifluoride (14.6g, 0.1mol) methylene chloride
(50mL) solution.After stirring 2h, reaction solution is poured into ice water, organic layer is separated, is washed with saturated sodium chloride solution, nothing is added
Aqueous sodium persulfate is dry, filters, and 20mL concentrated hydrochloric acid is added dropwise, is vigorously stirred, and is concentrated under reduced pressure, and obtains faint yellow solid, and ethyl acetate-is added
N-hexane mixed liquor (n-hexane: ethyl acetate=1:1) mashing, filters, dry, obtain cinacalcet hydrochloride (43.72g,
0.111mol), yield 92.5%, purity 99.9%.
Embodiment 11The preparation of cinacalcet hydrochloride
Aluminum trichloride (anhydrous) (14.7g, 0.11mol) is added in methylene chloride (100mL), ice-water bath, control reaction
System temperature is in 5 DEG C of bromo- N- of dropwise addition (R) -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine (29.2g, 0.1mol, by 1 side of embodiment
Method preparation) dichloromethane solution (30mL), then be added dropwise benzotrifluoride (14.6g, 0.1mol) methylene chloride (50mL) it is molten
Liquid.After stirring 2h, reaction solution is poured into ice water, organic layer is separated, is washed with saturated sodium chloride solution, anhydrous sodium sulfate is added
It is dry, it filters, 20mL concentrated hydrochloric acid is added dropwise, is vigorously stirred, be concentrated under reduced pressure, obtain faint yellow solid, it is mixed that ethyl acetate-hexane is added
Liquid (n-hexane: ethyl acetate=1:1) mashing is closed, is filtered, it is dry, it obtains cinacalcet hydrochloride (36.04g, 0.0915mol), receives
Rate 91.5%, purity 99.9%.
Embodiment 12The preparation of cinacalcet hydrochloride
Aluminum trichloride (anhydrous) (14.7g, 0.11mol) is added in methylene chloride (100mL), ice-water bath, control reaction
System temperature is in 10 DEG C of bromo- N- of dropwise addition (R) -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine (29.2g, 0.1mol, by embodiment 1
Method preparation) dichloromethane solution (30mL), then be added dropwise benzotrifluoride (14.6g, 0.1mol) methylene chloride (50mL)
Solution.After stirring 2h, reaction solution is poured into ice water, organic layer is separated, is washed with saturated sodium chloride solution, anhydrous slufuric acid is added
Sodium is dry, filters, and 20mL concentrated hydrochloric acid is added dropwise, is vigorously stirred, and is concentrated under reduced pressure, and obtains faint yellow solid, and ethyl acetate-hexane is added
Mixed liquor (n-hexane: ethyl acetate=1:1) mashing, filters, dry, obtains cinacalcet hydrochloride (35.45g, 0.09mol), receives
Rate 90%, purity 99.9%.
Embodiment 13The preparation of cinacalcet hydrochloride
Aluminum trichloride (anhydrous) (14.7g, 0.11mol) is added in methylene chloride (100mL), ice-water bath, control reaction
System temperature is in 0 DEG C of chloro- N- of dropwise addition (R) -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine (24.78g, 0.1mol, according to embodiment
6 are prepared) dichloromethane solution (30mL), then be added dropwise benzotrifluoride (14.6g, 0.1mol) methylene chloride (50mL)
Solution.After stirring 2h, reaction solution is poured into ice water, organic layer is separated, is washed with saturated sodium chloride solution, anhydrous slufuric acid is added
Sodium is dry, filters, and 20mL concentrated hydrochloric acid is added dropwise, is vigorously stirred, and is concentrated under reduced pressure, and obtains faint yellow solid, and ethyl acetate-hexane is added
Mixed liquor (n-hexane: ethyl acetate=1:1) mashing, filters, dry, obtains cinacalcet hydrochloride (25.02g, 0.07mol), receives
Rate 70%, purity 99.9%.
Embodiment 14The preparation of cinacalcet hydrochloride
Aluminum trichloride (anhydrous) (14.7g, 0.11mol) is added in methylene chloride (100mL), ice-water bath, control reaction
System temperature is in 0 DEG C of fluoro- N- of dropwise addition (R) -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine (23.13g, 0.1mol, according to embodiment
7 are prepared) dichloromethane solution (30mL), then be added dropwise benzotrifluoride (14.6g, 0.1mol) methylene chloride (50mL)
Solution.After stirring 2h, reaction solution is poured into ice water, organic layer is separated, is washed with saturated sodium chloride solution, anhydrous slufuric acid is added
Sodium is dry, filters, and 20mL concentrated hydrochloric acid is added dropwise, is vigorously stirred, and is concentrated under reduced pressure, and obtains faint yellow solid, and ethyl acetate-hexane is added
Mixed liquor (n-hexane: ethyl acetate=1:1) mashing, filters, dry, obtains cinacalcet hydrochloride (10.72g, 0.03mol), receives
Rate 30%, purity 99.9%.The embodiment yield is lower, thus it is speculated that using F as leaving group due to the small easy and C-shaped of ionic radius
Compare concentration at the charge around stronger o ' key and F, cloud density is big, thus is not easy the progress for causing to react of leaving away
It is difficult.
Claims (10)
1. a kind of midbody compound, with structure shown in formula (I):
Wherein, X is selected from Cl and Br.
2. midbody compound according to claim 1, which is characterized in that formula (I) compound is the bromo- N- (1- of (R) -3-
(naphthalene -1- base) ethyl) propyl- 1- amine.
3. a kind of method for preparing formula (I) compound, the method includes being reaction with the halogenated propionic aldehyde of 3- and (R) -1- naphthalene ethylamine
Object；
Preferably, the method includes the halogenated propionic aldehyde of 3- and (R) -1- naphthalene ethylamine to be added in anhydrous methanol, ice-water bath stirring,
Sodium cyanoborohydride is added portionwise, continues to stir, hydrochloric acid reaction is added dropwise, is concentrated under reduced pressure, after water dilution is added, with acetic acid second
Ester extraction, separates organic layer, and anhydrous sodium sulfate drying is added, filters, is concentrated under reduced pressure and obtains.
4. according to the method described in claim 3, it is characterized in that, the halogenated propionic aldehyde of the 3- is selected from 3- chlorine propionic aldehyde and 3- bromine third
Aldehyde, preferably 3- bromine propionic aldehyde；
Preferably, the molar ratio of the halogenated propionic aldehyde of the 3-, (R) -1- naphthalene ethylamine and sodium cyanoborohydride is 1-1.5:1:3-5, excellent
It is selected as 1:1:5；
Preferably, the concentration of hydrochloric acid is 2mol/L；
Preferably, the sodium cyanoborohydride is added in three times, and the ratio between mole being added three times is 2:2:1.
5. a kind of method for preparing cinacalcet hydrochloride, the method includes using formula (I) compound as midbody compound.
6. according to the method described in claim 5, it is characterized in that, the method includes with the halogenated propionic aldehyde of 3- and (R) -1- naphthalene second
Amine is initial compounds, prepares cinacalcet hydrochloride through intermediate compound of formula (I)；
Preferably, it the described method comprises the following steps:
(1) the halogenated propionic aldehyde of 3- and (R) -1- naphthalene ethylamine are added in anhydrous methanol, cyano boron hydrogen is added portionwise in ice-water bath stirring
Change sodium, continue to stir, hydrochloric acid reaction is added dropwise, is concentrated under reduced pressure, after water dilution is added, is extracted, separated organic with ethyl acetate
Layer is added anhydrous sodium sulfate drying, filters, acquisition formula (I) compound is concentrated under reduced pressure；
(2) by aluminum trichloride (anhydrous) adding into dichloromethane, ice-water bath, control temperature of reaction system dropwise addition formula (I) compound
Dichloromethane solution, then be added dropwise benzotrifluoride dichloromethane solution, after stirring, reaction solution is poured into ice water, is separated
Organic layer is washed with saturated sodium chloride solution, and anhydrous sodium sulfate drying is added, filters, concentrated hydrochloric acid is added dropwise, is vigorously stirred, depressurizes
Concentration obtains faint yellow solid, and the mashing of ethyl acetate-hexane mixed liquor is added, filters, dry, obtains cinacalcet hydrochloride.
7. according to the method described in claim 6, it is characterized in that, the halogenated propionic aldehyde of 3- is selected from 3- chlorine propionic aldehyde in step (1)
With 3- bromine propionic aldehyde, preferably 3- bromine propionic aldehyde；
Preferably, in step (1), the molar ratio of the halogenated propionic aldehyde of the 3-, (R) -1- naphthalene ethylamine and sodium cyanoborohydride is 1-
1.5:1:3-5 preferably 1:1:5；
Preferably, in step (1), the concentration of hydrochloric acid is 2mol/L；
Preferably, in step (1), the sodium cyanoborohydride is added in three times, and the ratio between mole being added three times is 2:2:1.
8. according to the method described in claim 6, temperature of reaction system is controlled at 0-10 DEG C it is characterized in that, in step (2),
Preferably 0-5 DEG C, most preferably 0 DEG C；
Preferably, in step (2), the molar ratio of aluminum trichloride (anhydrous), formula (I) compound and benzotrifluoride is 1-1.2:1-1.2:
1, preferably 1.1:1:1；
Preferably, in step (2), reaction dissolvent is methylene chloride；
Preferably, in step (2), the volume ratio of n-hexane and ethyl acetate is 1:1 in ethyl acetate-hexane mixed liquor.
9. the method according to any one of claim 5 to 8, which is characterized in that the described method comprises the following steps:
(1) the halogenated propionic aldehyde of 3-, (R) -1- naphthalene ethylamine are added in anhydrous methanol, ice-water bath stirs 2h, and cyano is added in three times
Sodium borohydride, the ratio between mole of sodium cyanoborohydride being added three times are 2:2:1, wherein the halogenated propionic aldehyde of 3-, (R) -1- naphthalene second
The molar ratio of amine and sodium cyanoborohydride is 1-1.5:1:3-5, preferably 1:1:5；Continue to stir 2h, 2mol/L hydrochloric acid is added dropwise and quenches
It goes out reaction, is concentrated under reduced pressure, after water dilution is added, extracted with ethyl acetate, separate organic layer, it is dry to be added anhydrous sodium sulfate, takes out
Filter, is concentrated under reduced pressure the bromo- N- of (R) -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine；
(2) by aluminum trichloride (anhydrous) adding into dichloromethane, ice-water bath, control temperature of reaction system is at 0-10 DEG C, preferably 0-5
DEG C be added dropwise the bromo- N- of (R) -3- (1- (naphthalene -1- base) ethyl) propyl- 1- amine dichloromethane solution, then be added dropwise benzotrifluoride two
Chloromethanes solution, wherein the molar ratio of aluminum trichloride (anhydrous), formula (I) compound and benzotrifluoride is 1-1.2:1-1.2:1, excellent
It is selected as 1.1:1:1；After stirring 2h, reaction solution is poured into ice water, organic layer is separated, is washed with saturated sodium chloride solution, is added
Anhydrous sodium sulfate is dry, filters, and concentrated hydrochloric acid is added dropwise, is vigorously stirred, and is concentrated under reduced pressure, and obtains faint yellow solid, and addition volume ratio is 1:1
The mashing of ethyl acetate-hexane mixed liquor, filter, it is dry, obtain cinacalcet hydrochloride.
10. compound shown in formula (I) is preparing the application in cinacalcet hydrochloride as intermediate.
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| CN113620855A (en) * | 2021-08-27 | 2021-11-09 | 山东威高药业股份有限公司 | Yiwan kasai intermediate II and synthetic method thereof |
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| CN101993379A (en) * | 2010-10-22 | 2011-03-30 | 湖北能特科技股份有限公司 | Novel preparation method of cinacalcet hydrochloride |
| CN103450027A (en) * | 2012-05-29 | 2013-12-18 | 上海京新生物医药有限公司 | Preparation method of cinacalcet hydrochloride |
| CN104774134A (en) * | 2014-01-09 | 2015-07-15 | 成都自豪药业有限公司 | Synthetic method of cinacalcet hydrochloride and intermediate compound of cinacalcet hydrochloride |
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| CN101993379A (en) * | 2010-10-22 | 2011-03-30 | 湖北能特科技股份有限公司 | Novel preparation method of cinacalcet hydrochloride |
| CN103450027A (en) * | 2012-05-29 | 2013-12-18 | 上海京新生物医药有限公司 | Preparation method of cinacalcet hydrochloride |
| CN104774134A (en) * | 2014-01-09 | 2015-07-15 | 成都自豪药业有限公司 | Synthetic method of cinacalcet hydrochloride and intermediate compound of cinacalcet hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113620855A (en) * | 2021-08-27 | 2021-11-09 | 山东威高药业股份有限公司 | Yiwan kasai intermediate II and synthetic method thereof |
| CN113620855B (en) * | 2021-08-27 | 2023-12-01 | 山东威高药业股份有限公司 | Isomakava intermediate II and synthesis method thereof |
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