CN104610069A - Preparation method of high purity cinacalcet hydrochloride - Google Patents
Preparation method of high purity cinacalcet hydrochloride Download PDFInfo
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- CN104610069A CN104610069A CN201510045894.0A CN201510045894A CN104610069A CN 104610069 A CN104610069 A CN 104610069A CN 201510045894 A CN201510045894 A CN 201510045894A CN 104610069 A CN104610069 A CN 104610069A
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- naphthalene
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Abstract
The invention discloses a preparation method of high-purity cinacalcet hydrochloride. The preparation method of the high-purity cinacalcet hydrochloride comprises the following steps: performing an alkylation reaction of 3-(3-(trifluoromethyl)phenyl) propyl ester with (R)-1-(naphthyl-1-yl) ethylamine salt in the presence of a solvent and an acid-binding agent, and performing salt forming to obtain the cinacalcet hydrochloride with the purity of more than or equal to 99.5%. The (R)-1-(naphthyl-1-yl) ethylamine salt is (R)-1-(naphthyl-1-yl) ethylamine hydrochloride or (R)-1-(naphthyl-1-yl) ethylamine sulphate, the solvent is a mixed solvent of water and an aprotic organic solvent, and the aprotic organic solvent is methylbenzene or dimethylbenzene. The volume of water is 5-90% of that of the aprotic organic solvent, the weight of the aprotic organic solvent is 1-10 times that of the 3-(3-(trifluoromethyl) phenyl) propyl ester. The high-purity cinacalcet hydrochloride with the purity of more than or equal to 99.5% can be finally obtained according to the method disclosed by the invention. The method is simple in operation and applicable to the industry.
Description
Technical field
The invention belongs to field of medicine preparing technology, be specifically related to a kind of preparation method of high-purity hydrochloric acid cinacalcet.
Background technology
Cinacalcet hydrochloride is a kind of Sensipar (calcimimetics) researched and developed by NPS Pharmaceuticals company of the U.S..It can activate the calcium acceptor in parathyroid gland, thus reduce the secretion of parathyroid hormone (PTH), regulating the behavior of Parathyroid Calcium Receptor, by strengthening acceptor to the susceptibility of calcium level in blood flow, reducing the level of Rat parathyroid hormone 1-34, calcium, phosphorus and calcium-phosphorus mixture.Be mainly used in treating the secondary hyperparathyroidism of chronic nephropathy (CKD) patient and the hypercalcemia of parathyroid carcinoma patient that carry out dialysing.
The chemical name of cinacalcet hydrochloride is: (R)-N-(1-(naphthalene-1-base) ethyl)-3-(3-(trifluoromethyl) phenyl) the third-1-amine hydrochlorate, chemical formula is C
22h
22f
3nHCl, structural formula is as follows:
。
The preparation method of cinacalcet hydrochloride mainly comprises following three major types:
(1) reductive ammonification (see american documentation literature US6211244B1): by 3-(3-(trifluoromethyl) phenyl) propylamine and acetonaphthone or be condensed into imines by 3-(3-(trifluoromethyl) phenyl) propionic aldehyde and naphthalene ethylamine, is then reduced to cinacalcet.The deficiency of reductive ammonification is: the expensive and facile hydrolysis of dewatering agent tetraisopropoxy titanium that (1) condensation reaction adopts, is not suitable for industrialized production.(2) reduction reaction is according to itrile group sodium borohydride, then toxicity is higher; According to catalytic hydrogenation, be then difficult to avoid the impurity of over reduction to produce.
(2) reduction of amide method (see world patent document WO2007127445, WO2008058235A2, american documentation literature US2007259964A1, Chinese patent literature CN102718662A, CN103739500A etc.): use 3-(3-(trifluoromethyl) phenyl) propionic acid to be starting raw material, first make acyl chlorides or mixed acid anhydride, be condensed into acid amides with naphthalene ethylamine again, then borine or Lithium Aluminium Hydride reduction obtain cinacalcet.This technique uses borane reagent or aurin tricarboxylic acid, and operation and aftertreatment have certain difficulty, is unfavorable for amplifying production, and due to reaction system impurity more, bring the problem of Control of Impurities and purifying aspect.
(3) alkylation process (see world patent document W02006125026, Chinese patent literature CN101941911A, CN103044267A, CN103450027A etc.): use 3-(3-(trifluoromethyl) phenyl) propyl alcohol to be starting raw material, first make halides or sulphonate, then carry out alkylated reaction with naphthalene ethylamine and obtain cinacalcet.Alkylation process synthesis is comparatively easy, is easy to industrialization, but existing technique still also has many areas for improvement, such as product purity aspect.
Summary of the invention
The object of the invention is to solve the problem, a kind of preparation method of high-purity hydrochloric acid cinacalcet of purity >=99.5% is provided.
The technical scheme realizing the object of the invention is: a kind of preparation method of high-purity hydrochloric acid cinacalcet, it first under the existence of solvent and acid binding agent, carries out alkylated reaction by 3-(3-(trifluoromethyl) phenyl) propyl diester and (R)-1-(naphthalene-1-base) ethylamine salt, and then salify obtains the cinacalcet hydrochloride of purity >=99.5%.
Described 3-(3-(trifluoromethyl) phenyl) propyl diester is 3-(3-(trifluoromethyl) phenyl) propyl Methanesulfonate, 3-(3-(trifluoromethyl) phenyl) propyl group p-toluenesulfonic esters, 3-(3-(trifluoromethyl) phenyl) propyl group triflate or 3-(3-(trifluoromethyl) phenyl) propyl group trifluoro-acetate, is preferably 3-(3-(trifluoromethyl) phenyl) propyl Methanesulfonate.
Described (R)-1-(naphthalene-1-base) ethylamine salt is (R)-1-(naphthalene-1-base) ethylamine hydrochloride, (R)-1-(naphthalene-1-base) ethamine vitriol, (R)-1-(naphthalene-1-base) ethamine tosilate, (R)-1-(naphthalene-1-base) ethamine tartrate or (R)-1-(naphthalene-1-base) ethamine mandelate, is preferably (R)-1-(naphthalene-1-base) ethylamine hydrochloride or (R)-1-(naphthalene-1-base) ethamine vitriol.Compared with (R)-1-(naphthalene-1-base) ethamine free alkali, (R) after-1-(naphthalene-1-base) ethamine salify, character is more stable, quality is more controlled and the advantage such as resistance to accumulating, and especially applicant surprisingly finds: (R)-1-(naphthalene-1-base) ethylamine salt effectively can suppress the generation of alkylate by-product (compound of formula I).
（Ⅰ）。
Described acid binding agent is diisopropyl ethyl amine, Trimethylamine 99, triethylamine, three n-propyl amine, triisopropylamine or tri-n-butyl amine, is preferably diisopropyl ethyl amine.
Applicant surprisingly finds: in aprotic organic solvent, add appropriate water, can not only fast reaction speed, and effectively can suppress the generation of carbamate by product (compound of formula II).Therefore, the solvent that abovementioned alkylization reaction adopts is preferably the mixed solvent that water and aprotic organic solvent form.Wherein the volumetric usage of water is 5 ~ 90% of aprotic organic solvent, is preferably 10 ~ 30%.The weight consumption of aprotic organic solvent is 1 ~ 10 times of 3-(3-(trifluoromethyl) phenyl) propyl diester, is preferably 3 ~ 5 times.Described aprotic organic solvent is methyl tertiary butyl ether, methyltetrahydrofuran, hexanaphthene, toluene, dimethylbenzene or methylene dichloride, is preferably toluene or dimethylbenzene.
（Ⅱ）。
The positively effect that the present invention has: (1) the present invention adopts (R)-1-(naphthalene-1-base) ethylamine salt to substitute (R)-1-(naphthalene-1-base) ethamine free alkali and 3-(3-(trifluoromethyl) phenyl) propyl diester carries out alkylated reaction, not only raw material (R)-1-(naphthalene-1-base) ethylamine salt is more stable, and effectively can suppress the generation of alkylate by-product, thus improve product purity.(2) the present invention adopts water and aprotic organic solvent to form mixed solvent, like this can not only fast reaction speed, and effectively can suppress the generation of carbamate by product, further increases product purity.(3) method of the present invention finally can obtain the high-purity hydrochloric acid cinacalcet of purity >=99.5%, and simple to operate, is suitable for suitability for industrialized production.
Embodiment
(embodiment 1)
The preparation method of the high-purity hydrochloric acid cinacalcet of the present embodiment is as follows:
The toluene (866g) of 1L and the deionized water of 0.2L is first added in four-hole boiling flask; 3-(3-(trifluoromethyl) phenyl) propyl Methanesulfonate (1.0mol) of the naphthalene ethylamine hydrochloride (1.1mol) of 228.5g, the diisopropyl ethyl amine (1.6mol) of 207.3g and 282.3g is added successively under stirring; under nitrogen protection; be heated to back flow reaction; control in sampling, until reaction terminates (about 24h).
After reaction terminates, stop heating, leave standstill, separatory, aqueous phase discarded; Organic phase adds the dilute hydrochloric acid 1500mL of 1mol/L, stirs, and leaves standstill, separatory, aqueous phase discarded; Organic phase slow cooling to 0 ~ 5 DEG C, separate out white crystal, suction filtration, the cold toluene (0 ~ 5 DEG C) of filter cake 100mL rinses, off-white color solid 280.1g is obtained after vacuum drying oven drying, yield is 71.2%, HPLC purity is that 99.62%(by product I and by product II amount are respectively 0.31% and 0.03%).
(embodiment 2 ~ embodiment 4)
Each embodiment is substantially the same manner as Example 1, and difference is in table 1.
Table 1
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | |
| Aprotic organic solvent | Toluene | Methyl tertiary butyl ether | Dimethylbenzene | Methyltetrahydrofuran |
| Naphthalene ethylamine salt | Naphthalene ethylamine hydrochloride | Naphthalene ethylamine tartrate | Naphthalene ethylamine vitriol | Naphthalene ethylamine mandelate |
| Products weight | 280.1g | 275.1g | 283.1g | 270.7g |
| Yield | 71.2% | 69.9% | 71.9% | 68.8% |
| Purity | 99.62% | 99.55% | 99.61% | 99.53% |
| By product I | 0.31% | 0.35% | 0.32% | 0.36% |
| By product II | 0.03% | 0.07% | 0.04% | 0.08% |
(embodiment 5 ~ embodiment 8)
Each embodiment is substantially the same manner as Example 1, and difference is in table 2.
Table 2
| Embodiment 1 | Embodiment 5 | Embodiment 6 | Embodiment 7 | Embodiment 8 | |
| Water | 0.2L | 0.5L | 0.1L | 0.6L | 0.3L |
| Toluene | 1L | 1L | 1L | 3L | 1.5L |
| Products weight | 280.1g | 276.8g | 279.3g | 273.5g | 282.7g |
| Yield | 71.2% | 70.3% | 71.0% | 69.5% | 71.8% |
| Purity | 99.62% | 99.52% | 99.63% | 99.56% | 99.60% |
| By product I | 0.31% | 0.33% | 0.30% | 0.32% | 0.33% |
| By product II | 0.03% | 0.12% | 0.04% | 0.09% | 0.04% |
(comparative example 1 ~ comparative example 5)
Each embodiment is substantially the same manner as Example 1, and difference is in table 3.
Table 3
| Embodiment 1 | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 | Comparative example 5 | |
| Naphthalene ethylamine hydrochloride | Naphthalene ethylamine hydrochloride | Naphthalene ethylamine hydrochloride | Naphthalene ethylamine | Naphthalene ethylamine | Naphthalene ethylamine | |
| Water | 0.2L | 1.2L | - | 0.2L | 1.2L | - |
| Toluene | 1L | - | 1.2L | 1L | - | 1.2L |
| Products weight | 280.1g | 281.3g | 280.5g | 285.3g | 286.1g | 285.7g |
| Yield | 71.2% | 71.5% | 71.3% | 72.5% | 72.7% | 72.6% |
| Purity | 99.62% | 99.21% | 99.15% | 98.67% | 98.23% | 98.31% |
| By product I | 0.31% | 0.39% | 0.41% | 1.15% | 1.32% | 1.24% |
| By product II | 0.03% | 0.30% | 0.35% | 0.08% | 0.34% | 0.37% |
Claims (10)
1. the preparation method of a high-purity hydrochloric acid cinacalcet, it is characterized in that: first under the existence of solvent and acid binding agent, carry out alkylated reaction by 3-(3-(trifluoromethyl) phenyl) propyl diester and (R)-1-(naphthalene-1-base) ethylamine salt, then salify obtains the cinacalcet hydrochloride of purity >=99.5%.
2. the preparation method of high-purity hydrochloric acid cinacalcet according to claim 1, is characterized in that: described (R)-1-(naphthalene-1-base) ethylamine salt is (R)-1-(naphthalene-1-base) ethylamine hydrochloride, (R)-1-(naphthalene-1-base) ethamine vitriol, (R)-1-(naphthalene-1-base) ethamine tosilate, (R)-1-(naphthalene-1-base) ethamine tartrate or (R)-1-(naphthalene-1-base) ethamine mandelate.
3. the preparation method of high-purity hydrochloric acid cinacalcet according to claim 2, is characterized in that: described (R)-1-(naphthalene-1-base) ethylamine salt is (R)-1-(naphthalene-1-base) ethylamine hydrochloride or (R)-1-(naphthalene-1-base) ethamine vitriol.
4. according to the preparation method of the high-purity hydrochloric acid cinacalcet one of claims 1 to 3 Suo Shu, it is characterized in that: described acid binding agent is diisopropyl ethyl amine, Trimethylamine 99, triethylamine, three n-propyl amine, triisopropylamine or tri-n-butyl amine.
5. the preparation method of high-purity hydrochloric acid cinacalcet according to claim 4, is characterized in that: described acid binding agent is diisopropyl ethyl amine.
6. according to the preparation method of the high-purity hydrochloric acid cinacalcet one of claims 1 to 3 Suo Shu, it is characterized in that: described solvent is the mixed solvent that water and aprotic organic solvent form; The volumetric usage of described water is 5 ~ 90% of aprotic organic solvent; The weight consumption of described aprotic organic solvent is 1 ~ 10 times of 3-(3-(trifluoromethyl) phenyl) propyl diester.
7. the preparation method of high-purity hydrochloric acid cinacalcet according to claim 6, is characterized in that: described aprotic organic solvent is methyl tertiary butyl ether, methyltetrahydrofuran, hexanaphthene, toluene, dimethylbenzene or methylene dichloride.
8. the preparation method of high-purity hydrochloric acid cinacalcet according to claim 7, is characterized in that: described aprotic solvent is toluene or dimethylbenzene.
9. the preparation method of high-purity hydrochloric acid cinacalcet according to claim 6, is characterized in that: the volumetric usage of described water is 10 ~ 30% of aprotic organic solvent.
10. the preparation method of high-purity hydrochloric acid cinacalcet according to claim 6, is characterized in that: the weight consumption of described aprotic organic solvent is 3 ~ 5 times of 3-(3-(trifluoromethyl) phenyl) propyl diester.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010067204A1 (en) * | 2008-12-08 | 2010-06-17 | Actavis Group Ptc Ehf | Highly pure cinacalcet or a pharmaceutically acceptable salt thereof |
| WO2010103531A2 (en) * | 2009-03-09 | 2010-09-16 | Megafine Pharma (P) Ltd. | A new method for the preparation of cinacalcet and new intermediates thereof |
| CN102307845A (en) * | 2009-02-19 | 2012-01-04 | Zach系统股份公司 | Process for preparing 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 |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010067204A1 (en) * | 2008-12-08 | 2010-06-17 | Actavis Group Ptc Ehf | Highly pure cinacalcet or a pharmaceutically acceptable salt thereof |
| CN102307845A (en) * | 2009-02-19 | 2012-01-04 | Zach系统股份公司 | Process for preparing cinacalcet hydrochloride |
| WO2010103531A2 (en) * | 2009-03-09 | 2010-09-16 | Megafine Pharma (P) Ltd. | A new method for the preparation of cinacalcet and new intermediates thereof |
| 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 |
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