CN118955306A - A process improvement method for dapoxetine hydrochloride - Google Patents
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Abstract
本发明涉及一种盐酸达泊西汀的工艺改进方法。本发明的合成工艺以3‑硝基‑5‑三氟甲基水杨醛作为消旋化催化剂，能够实现结晶诱导不对称转化，相对于现有技术采用简单地对异构体进行拆分（理论上能达到的最大收率仅50%），产物纯度高，收率高，节约成本。同时本发明的合成工艺，操作简单，易于实现工业化。The present invention relates to a process improvement method for dapoxetine hydrochloride. The synthesis process of the present invention uses 3-nitro-5-trifluoromethyl salicylaldehyde as a racemization catalyst, can achieve crystallization-induced asymmetric transformation, and compared with the prior art, which simply splits the isomers (theoretically, the maximum yield that can be achieved is only 50%), the product purity is high, the yield is high, and the cost is saved. At the same time, the synthesis process of the present invention is simple to operate and easy to realize industrialization.
Description
Technical Field
The invention relates to the field of organic synthesis, in particular to a process improvement method of dapoxetine hydrochloride.
Background
Dapoxetine (dapoxetine) is known as (+) - (S) -N, N-dimethyl-3- (naphthyl-1-oxy) -phenylpropanamino hydrochloride and has CAS registry number 119356-77-3, mp.175-178 ℃. It is a selective 5-hydroxytryptamine reuptake inhibitor (SSRIs) which is structurally similar to fluoxetine and also has antidepressant action, and its hydrochloride is clinically used. The composition is used for treating depression and related affective disorder diseases in early stage, and is used for treating premature ejaculation in men later. Research shows that the medicine can inhibit reuptake of complex amine in blood fast, has no direct effect on neuron receptor and short half life period, and can control premature ejaculation symptoms of young men effectively. Compared with other SSRIs, dapoxetine has the advantages of quicker action, shorter half-life and lower occurrence rate of adverse reaction.
There are a great deal of literature reports on the synthesis of dapoxetine, which is mainly categorized into two categories: the first is a racemate resolution method; the second type is an asymmetric synthesis. The racemate resolution method uses chiral resolving agent to carry out resolution reaction on racemic intermediate or final product to obtain required diastereoisomer, and separates resolving agent and single isomer to finally obtain the target chiral compound with higher optical purity. Asymmetric synthesis, i.e., converting a latent chiral unit into a chiral unit, allows it to produce unequal amounts of a stereoisomer product. The method has the greatest advantages that the target product with optical purity can be directly synthesized without carrying out resolution reaction, so that the raw material loss is reduced, and the method meets the requirements of atomic economy and green chemistry.
Wheeler et al (Journal of Labelled Compounds and Radiopharmaceuticals, 1992, 31 (4): 305-315) found that, using dimethylamine and methyl cinnamate as starting reaction materials, first performing Michael addition reaction to produce intermediate methyl 3-N, N-dimethylammonium-3-phenylpropionate, then performing reduction reaction with reducing agent LiAlH4 to produce intermediate 3-N, N-dimethylammonium-3-phenylpropanol, then performing etherification reaction with 1-fluoronaphthalene to produce dapoxetine racemate, and finally performing resolution reaction with chiral resolving agent L- (+) -tartaric acid to finally obtain the target product S-dapoxetine, the reaction formula is shown below:
。
Chen Fangjun et al (CN 20121026520.5) condensation reaction of acetophenone as an initial reaction raw material with acetonitrile, subsequent esterification reaction of the intermediate 3-benzoylpropionic acid after carboxylation reaction, hydroxylation reaction, reduction reaction to produce intermediate 3-amino-3-phenylpropanol, subsequent protection of amino group on intermediate 3-amino-3-phenylpropanol by Boc, subsequent etherification reaction, final resolution reaction by using a resolving agent tartaric acid to obtain the target product S-dapoxetine, wherein the reaction formula is shown below:
。
Yin Lingli (Chinese medicinal chemistry, 2011, 1 (1): 37-39) and the like take 3-phenyl-1-propanol as initial reaction raw materials, firstly, the 3-phenyl-1- (naphthoxy) -propane is generated by Williamson reaction with 1-fluoronaphthalene, then, NBS is used for replacing hydrogen on benzene ring benzyl position of the 3-phenyl-1- (naphthoxy) -propane intermediate, namely, bromination is performed to prepare the 3-phenyl-3-bromo-1- (naphthoxy) -propane intermediate, then, the 3-phenyl-3-bromo-1- (naphthoxy) -propane intermediate and dimethylamine intermediate are used for reaction to generate a raceme of dapoxetine, and finally, the resolution reaction is performed on the raceme of the dapoxetine by using chiral resolution reagent L- (+) -tartaric acid, so that the target product S-dapoxetine is finally, the reaction formula is shown as follows:
。
Zhang Derong et al (bioprocess, 2010, 8 (2): 13-17) enzymatically split (+/-) -N-phenylacetyl-3-amino-3-phenylpropionic acid by immobilized Penicillin G Acylase (PGA) to obtain intermediate (S) -3-amino-3-phenylpropionic acid for synthesizing dapoxetine, and subjecting the (S) -3-amino-3-phenylpropionic acid to multi-step chemical synthesis such as reduction, methylation, condensation and the like to obtain the final product dapoxetine, wherein the reaction formula is as follows:
。
resolution of the racemate using chiral reagents gives higher ee values of the target compound, but such resolution typically requires multiple recrystallisation and resolution at the final stage of the reaction wastes significant amounts of starting material. The method of using the asymmetric synthesis method effectively avoids resolution, can effectively improve the ee value, but the route for synthesizing the chiral intermediate is relatively complicated, and expensive chiral catalysts and toxic or explosive reagents are used in the process of synthesizing the chiral intermediate. Therefore, developing a process suitable for industrial dapoxetine hydrochloride has important economic value.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention provides an improved process method of dapoxetine hydrochloride. The method has simple reaction steps, does not need to use expensive chiral catalysts, can reduce the loss of raw materials, and is more suitable for industrial production.
The invention provides a technological improvement method of dapoxetine hydrochloride, which comprises the following steps:
1) 3-amino-3-phenylpropionic acid is subjected to reduction reaction to obtain 3-amino-3-phenylpropanol;
2) Carrying out crystallization-induced asymmetric conversion reaction on the 3-amino-3-phenylpropanol to obtain (S) -3-amino-3-phenylpropanol;
3) Carrying out an aminomethylation reaction on the (S) -3-amino-3-phenylpropanol to obtain (S) -3-dimethylamino-3-phenylpropanol;
4) Ether is formed by (S) -3-dimethylamino-3-phenylpropanol and 1-halogenated naphthalene to obtain dapoxetine;
5) S-dapoxetine and HCl are subjected to salification reaction to prepare dapoxetine hydrochloride;
The reaction route is as follows:
；
Wherein: x is halogen;
the crystallization-induced asymmetric transformation reaction of the step 2) is carried out in the presence of a racemization catalyst, a chiral organic acid auxiliary and a solvent, wherein the racemization catalyst is 3-nitro-5-trifluoromethyl salicylaldehyde.
Preferably, the reducing agent of the reduction reaction of step 1) is selected from NaBH 4-I2,KBH4-I2,LiAlH4 or BH 3.
Preferably, the chiral organic acid aid of step 2) is in an optically pure form selected from the group consisting of: one or more of tartaric acid, mandelic acid, dibenzoyltartaric acid, p-methyldibenzoyltartaric acid and camphorsulfonic acid, more preferably D- (-) -tartaric acid.
Preferably, the solvent of step 2) is selected from isopropanol, methanol, ethanol, isobutanol.
Preferably, the molar ratio of chiral organic acid aid to 3-amino-3-phenylpropanol in step 2) is (1-2): 1.
Preferably, the reaction temperature of step 2) is from 40℃to 80℃and more preferably from 70℃to 75 ℃.
Preferably, the aminomethylation reaction of step 3) is carried out in the presence of formaldehyde and formic acid.
Preferably, the 1-halonaphthalene of step 4) is 1-fluoronaphthalene.
Preferably, step 4) is carried out under basic conditions, said base being selected from organic bases or inorganic bases.
Preferably, the salt formation reaction of step 5) is carried out in the presence of a solvent.
Preferably, the reaction solvent of step 5) is selected from methanol, ethanol, propanol or butanol.
Optical resolution by crystallization is a classical method for separating enantiomers, which is simple and effective and widely used in laboratory and industrial production. In the prior art, dapoxetine hydrochloride is synthesized, and racemic bodies are resolved usually by resolving agents such as tartaric acid and the like before salt formation reaction. However, the resolution of the isomer is simple, and the maximum yield which can be achieved theoretically is only 50%, so that huge waste is caused. The use of crystallization-induced asymmetric transformations (Crystallization-induced asymmetric transformation, CIAT) just overcomes this drawback. CIAT is a coupling of in situ racemization (or epimerization) and selective crystallization. A successful CIAT process requires (1) an environment to allow racemization (or epimerization) to proceed smoothly, (2) a stable and efficient resolution process (chiral catalyst, chiral auxiliary or enzyme is added) to allow the conversion rate V RI≠ VSI between the isomers SMR and SMS to be equal to the conversion rate constant k RI and k SI, (3) at least one isomer to crystallize out during the process, (4) separation and operation under conditions that do not decompose or degrade, and no co-crystallization between the enantiomers SMR and SMS can occur. The second point is typically the most critical and difficult part.
Racemization (epimerization) by imine forms has been widely reported for chiral resolution of amino acids, the principle of which is as follows:
。
However, the racemization of the imine form of the amino alcohol to realize chiral resolution has not been reported in the literature. The inventors of the present invention have found that the racemic catalyst 3-nitro-5-trifluoromethyl salicylaldehyde of the present invention can achieve crystallization-induced asymmetric transformation of (S) -3-amino-3-phenylpropanol with a high yield and the ee value of the product is also high, through a great deal of creative work.
Compared with the prior art, the invention has the following advantages:
1) The synthesis process of the invention takes 3-nitro-5-trifluoromethyl salicylaldehyde as racemization catalyst, can realize crystallization-induced asymmetric transformation, and has high product purity, high yield and cost saving compared with the prior art by simply splitting isomers (the maximum yield which can be achieved theoretically is only 50%).
2) The synthesis process of the invention has simple operation and is easy to realize industrialization.
Detailed Description
The following is a detailed description of the present invention by way of examples. In the present invention, the following examples are provided for better illustration of the present invention and are not intended to limit the scope of the present invention. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
Thus, before describing the present invention in detail, it is to be understood that this invention is not limited to the particular illustrated system or process parameters, which may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to limit the scope of the invention in any way. The examples used anywhere in this specification (including examples of any terms discussed herein) are illustrative only, and in no way limit the scope and meaning of the invention or any illustrated terms. Also, the present invention is not limited to the various embodiments presented in this specification. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, the present document, including definitions, will control.
Example 13 Synthesis of amino-3-phenylpropanol
3-Amino-3-phenylpropionic acid (300 g,1.82 mol), tetrahydrofuran 5L, and NaBH 4 (152 g,4.02 mol) were added to the reaction vessel under ice-bath conditions, and stirred for 20: 20 min. I 2 (462 g,1.82 mol) is dissolved in tetrahydrofuran (700 mL) and slowly added into a reaction kettle in a dropwise manner at the temperature of 0-5 ℃, after about 1.5 and H drops are finished, after the release speed of H 2 is slowed down, the temperature is increased, and the reflux reaction is carried out for 18H.
After the reaction was stopped, the reaction mixture was cooled to room temperature, 600mL of anhydrous methanol was slowly added dropwise under ice bath until the reaction solution was clear, stirred at room temperature for 60 min, and the solvent was distilled off under reduced pressure to obtain a white oily viscous material. Adding 20% KOH 3.5L, stirring at room temperature for 3-4 hours, and separating out a large amount of oily matters. Extracting with dichloromethane three times, mixing organic phases, drying with anhydrous sodium sulfate, evaporating solvent under reduced pressure to obtain white solid, adding n-hexane 500mL, stirring 3 h, filtering to obtain white solid 253 g, yield: 92.1% and 99.2% purity by HPLC.
1HNMR（400MHz,CDCl3）δ: 1.83-1.91 (m, 2H, -CH2-); 2.80 (S, 3H, -NH2, -OH); 4.08-4.12 (m, 1H, N-CH); 3.72-3.80(m, 2H, -CH2-O); 7.24-7.35(m, 5H, Ar-H).
EXAMPLE 2 Synthesis of (S) -3-amino-3-phenylpropanol
30.2 G (0.20 mol) 3-amino-3-phenylpropanol and 150 mL isopropanol are added into a three-neck flask, after the 3-amino-3-phenylpropanol is completely dissolved under stirring, 2.4 g (0.01 mol) 3-nitro-5-trifluoromethyl salicylaldehyde is added, the temperature is controlled to be 70-75 ℃, a mixed solution of 30.0 g (0.20 mol) D- (-) -tartaric acid and 150 mL isopropanol is dropwise added, 1h drops are completed, and the reaction is carried out for 2 hours under heat preservation. The reaction solution was cooled to room temperature, filtered, and the solid was rinsed with a small amount of isopropanol and dried. Adding 125 mL acetone into the dried solid, then adding NaOH to adjust the pH of the solution to about 10, filtering to obtain 26.8g of white solid (S) -3-amino-3-phenylpropanol with the yield of 88.7%,= -10.0 (C=1, meoh), optical purity > 99.5ee%.
EXAMPLE 3 Effect of racemization catalyst on preparation of (S) -3-amino-3-phenylpropanol
The same reaction conditions as in example 2 were used, except that the racemization catalysts were different, and the experimental results were as follows:
Examples 2-3 show that the 3-nitro-5-trifluoromethyl salicylaldehyde is used as a racemization catalyst, so that the resolution efficiency is good, and the purity of the product is high.
EXAMPLE 4 Synthesis of (S) -3-dimethylamino-3-phenylpropanol
3-Amino-3-phenylpropanol (20 g,0.132 mol) is added into a three-mouth bottle, 88% formic acid (36.5 g) is slowly added dropwise under ice bath, 36% formaldehyde (27.5 g,0.33 mol) is slowly added dropwise after the solid is completely dissolved, the temperature is controlled to be 0-5 ℃, and the mixture is stirred for 8-10 hours at 95-100 ℃ after the solid is completely dissolved. After the reaction, slowly dropwise adding 30% NaOH solution in ice bath until the pH is more than or equal to 13, separating out oily matters, extracting with dichloromethane three times, combining organic phases, drying with anhydrous sodium sulfate, and evaporating the solvent under reduced pressure to obtain light yellow oily matters 20.5 g, wherein the yield is as follows: 86.9%.
EXAMPLE 5 Synthesis of (S) -dapoxetine
NaH (12.1 g,0.3 mol) and dried N, N-Dimethylformamide (DMF) 150 mL are added into a three-mouth bottle provided with a drying tube, a stirrer and a nitrogen protection device, the mixture is stirred for about 30 min, 3-dimethylamino-3-phenylpropanol (17.9 g,0.10 mol) dissolved in 150 mL DMF is slowly added dropwise into the three-mouth bottle, the mixture is placed at 50-55 ℃ for reaction for 2h after the dropwise addition, and then 1-fluoronaphthalene (17.5 g,0.12 mol) is slowly added dropwise, and the mixture is placed at 100 ℃ for stirring reaction for 6 h after the dropwise addition. The reaction was stopped, ice water 600 mL was slowly added under ice bath, and extracted three times with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate (anhydrous magnesium sulfate), the solvent was distilled off under reduced pressure to give a pale yellow oil, 20ml of petroleum ether was added, and after stirring and milling, 26.3g of solid was obtained, yield: 86.2%.= +128.3 ° (C=1, methanol), e.e% > 99.8%, MS (M/z) =306.6 (m+1).
1HNMR（400MHz,CDCl 3）δ: 2.26 [s, 6H, N-(CH3)2],2.34-2.42 (m, 1H, CH2), 2.64-2.75 (m, 1H, CH2 ), 3.65-3.74 (m, 1H, Ar-CH), 3.97-4.01 ( m, 1H, CH2O), 4.11-4.23 (m, 1H, CH 2 O), 6.72-6.78 (m, 1H, Ar), 7.32-7.48 (m, 7H, Ar), 7.58-7.72 (m, 2H, Ar), 7.81-7.91 (m, 1H, Ar).
EXAMPLE 6 preparation of dapoxetine hydrochloride
S-dapoxetine (4.0 g,13.1 mmol) is placed in a three-mouth bottle, absolute ethyl alcohol 50mL is added, stirring is carried out until the solution is dissolved, hydrochloric acid-ethanol solution is slowly added dropwise until the pH value is 3-4, stirring is carried out for 15: 15 min, the solvent is distilled off under reduced pressure, the residue is added with ethyl acetate 60 mL, stirring is carried out for 20: 20 min at 60 ℃, cooling is carried out to room temperature, filtering is carried out, filter cakes are washed with a small amount of ethyl acetate, and the white powdery solid 4.3 g is obtained, the yield: 96.0%.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
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Citations (4)
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| CN101012181A (en) * | 2007-01-31 | 2007-08-08 | 上海化学试剂研究所 | Resolution method of DL-p-chlorophenylalanine |
| CN102633658A (en) * | 2011-02-15 | 2012-08-15 | 上海予利化学科技有限公司 | Method for resolving 3-amino-3-phenylpropanol |
| CN103664660A (en) * | 2013-12-04 | 2014-03-26 | 苏州永健生物医药有限公司 | Synthesis method of dapoxetine hydrochloride |
| CN104610076A (en) * | 2015-01-08 | 2015-05-13 | 湖南中医药大学 | Synthetic methods for S-dapoxetine and salts thereof |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101012181A (en) * | 2007-01-31 | 2007-08-08 | 上海化学试剂研究所 | Resolution method of DL-p-chlorophenylalanine |
| CN102633658A (en) * | 2011-02-15 | 2012-08-15 | 上海予利化学科技有限公司 | Method for resolving 3-amino-3-phenylpropanol |
| CN103664660A (en) * | 2013-12-04 | 2014-03-26 | 苏州永健生物医药有限公司 | Synthesis method of dapoxetine hydrochloride |
| CN104610076A (en) * | 2015-01-08 | 2015-05-13 | 湖南中医药大学 | Synthetic methods for S-dapoxetine and salts thereof |
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| Title |
|---|
| CYNTHIA A. MARYANOFF ET AL.: "A crystallization-induced asymmetric transformation to prepare (R)-4-chlorophenylalanine methyl ester", 《TETRAHEDRON: ASYMMETRY》, vol. 9, 31 December 1998 (1998-12-31), pages 3247 * |
| OLIVER TORRE ET AL.: "Lipase-catalyzed resolution of chiral 1, 3-amino alcohols: application in the asymmetric synthesis of (S)-dapoxetine", 《TETRAHEDRON: ASYMMETRY》, vol. 17, 23 March 2006 (2006-03-23), pages 860 - 866 * |
| 熊文说 等: "结晶诱导不对称转化在拆分手性化合物中的研究进展", 《有机化学》, vol. 30, no. 7, 31 December 2010 (2010-12-31), pages 951 - 957 * |
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