CN114685367B - Preparation method of lauroyl oxymethyl aripiprazole - Google Patents
Preparation method of lauroyl oxymethyl aripiprazole Download PDFInfo
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- CN114685367B CN114685367B CN202011613344.1A CN202011613344A CN114685367B CN 114685367 B CN114685367 B CN 114685367B CN 202011613344 A CN202011613344 A CN 202011613344A CN 114685367 B CN114685367 B CN 114685367B
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- aripiprazole
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- 229960004372 aripiprazole Drugs 0.000 title claims abstract description 75
- -1 lauroyl oxymethyl aripiprazole Chemical compound 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title abstract description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 72
- CEUORZQYGODEFX-UHFFFAOYSA-N Aripirazole Chemical compound ClC1=CC=CC(N2CCN(CCCCOC=3C=C4NC(=O)CCC4=CC=3)CC2)=C1Cl CEUORZQYGODEFX-UHFFFAOYSA-N 0.000 claims abstract description 49
- XCHDYWCWXAASER-UHFFFAOYSA-N chloromethyl dodecanoate Chemical compound CCCCCCCCCCCC(=O)OCCl XCHDYWCWXAASER-UHFFFAOYSA-N 0.000 claims abstract description 29
- 238000006467 substitution reaction Methods 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
- 230000009471 action Effects 0.000 claims abstract description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 23
- 239000003795 chemical substances by application Substances 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 31
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 238000003756 stirring Methods 0.000 description 16
- 239000000243 solution Substances 0.000 description 13
- 239000005457 ice water Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000001914 filtration Methods 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 201000000980 schizophrenia Diseases 0.000 description 6
- 238000001514 detection method Methods 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000006838 adverse reaction Effects 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- DRBBFCLWYRJSJZ-UHFFFAOYSA-N N-phosphocreatine Chemical compound OC(=O)CN(C)C(=N)NP(O)(O)=O DRBBFCLWYRJSJZ-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 208000028017 Psychotic disease Diseases 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
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- 108020003175 receptors Proteins 0.000 description 2
- 238000013341 scale-up Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 102000040125 5-hydroxytryptamine receptor family Human genes 0.000 description 1
- 108091032151 5-hydroxytryptamine receptor family Proteins 0.000 description 1
- RDYWTOWUSVAZGN-UHFFFAOYSA-N 7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-1-(hydroxymethyl)-3,4-dihydroquinolin-2-one Chemical compound C1=C2N(CO)C(=O)CCC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC(Cl)=C1Cl RDYWTOWUSVAZGN-UHFFFAOYSA-N 0.000 description 1
- 206010001540 Akathisia Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010010774 Constipation Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010028836 Neck pain Diseases 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910001516 alkali metal iodide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical group 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- DDINXHAORAAYAD-UHFFFAOYSA-N aripiprazole lauroxil Chemical compound C1=C2N(COC(=O)CCCCCCCCCCC)C(=O)CCC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC(Cl)=C1Cl DDINXHAORAAYAD-UHFFFAOYSA-N 0.000 description 1
- 229940075231 aristada Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- UXAJBSZQOZOHEI-UHFFFAOYSA-N chloromethyl decanoate Chemical compound CCCCCCCCCC(=O)OCCl UXAJBSZQOZOHEI-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-M dodecanoate Chemical compound CCCCCCCCCCCC([O-])=O POULHZVOKOAJMA-UHFFFAOYSA-M 0.000 description 1
- NWADXBLMWHFGGU-UHFFFAOYSA-N dodecanoic anhydride Chemical compound CCCCCCCCCCCC(=O)OC(=O)CCCCCCCCCCC NWADXBLMWHFGGU-UHFFFAOYSA-N 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-M iodide Chemical compound [I-] XMBWDFGMSWQBCA-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000004031 partial agonist Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000010887 waste solvent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of lauroyl oxymethyl aripiprazole. The method comprises the following steps: under the action of an alkaline reagent and a catalyst, aripiprazole and chloromethyl laurate are subjected to substitution reaction in tetrahydrofuran to obtain lauroyl oxymethyl aripiprazole; the temperature of the substitution reaction is 5-35 ℃. The preparation method of the invention has one or more of the following advantages: high yield, good reproducibility, mild reaction conditions, simple post-treatment and low production cost, and is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of lauroyl oxymethyl aripiprazole.
Background
Schizophrenia is a chronic disabling disease of complex etiology, clinically presenting heterogeneity, affecting about 1% of the population worldwide. In China, schizophrenia is always the important mental disease to prevent and treat, since 2000 years later, a series of policies and regulations for preventing and treating the important mental disease mainly comprising schizophrenia are put out. Patients with schizophrenia lose part of the social function due to impaired cognitive function, and are very prone to interruption of drug therapy, so that patient compliance is generally low, recurrence of the disease is easy to cause, and the disease condition cannot be well controlled. Therefore, the aim of the treatment of the schizophrenia is not only focused on the good or bad curative effect of the medicament, but also how to improve the compliance of patients, reduce the recurrence of the diseases and improve the social function of the patients, improve the treatment satisfaction of the patients and enable the patients to return to social life better. Compared with the frequent administration of oral medicines, the long-acting injection greatly improves the compliance of patients and effectively prevents the recurrence of diseases by reducing the administration times.
Aripiprazole derivative (Aipiprazole Luroxil) long-acting injection approved by FDA (Alkemes) of Alkems at 10 month 5 2015The main component is lauroyl oxymethyl aripiprazole prepared by adopting a prodrug technology. Lauroyloxymethyl aripiprazole is a prodrug of aripiprazole, which is functionally dopamine D 2 、D 3 Receptors, 5-HT 1A Partial agonists of the receptor and 5-HT 2A Receptor antagonists, p alpha 1 、H 1 Receptors also have good antagonism. Aripiprazole dodecanoate is enzymatically hydrolyzed in vivo to form N-hydroxymethyl aripiprazole, which is then hydrolyzed to Cheng Ali piperazine, thereby exerting an anti-schizophrenia effect. Aristada is a novel long-acting injection, has good tolerance and safety, has a powerful therapeutic effect on serious psychotic patients, and has the advantages of rapid improvement of symptoms, low recurrence rate, small side effect and less adverse reaction after administration. The obvious characteristics are long duration of action, less dosage and only once injection per month. Currently only for adult psychotics. The disadvantage of single dosage form and large adverse reaction of first injection is that the dosage form is insufficient. Common adverse reactions of the medicine include akathisia, insomnia, anxiety, nausea, constipation, diarrhea, body weight increase, cervicodynia, creatine phosphate kinase increase and the like. The chemical structural formula is as follows:
the preparation of this compound is mainly described in WO2010151689A1, which describes two synthetic methods: the method comprises the steps of firstly preparing the aripiprazole into the hydroxymethyl aripiprazole, and then reacting with lauric anhydride to obtain the lauroyl oxymethyl aripiprazole, wherein the method has incomplete reaction in one step of preparing the hydroxymethyl aripiprazole, long reaction time and low yield (21 percent); the method has the defects of high reaction temperature, poor safety, waste of a large amount of reaction reagents and raw materials and the like, and the method comprises the steps of dissolving the biapiprazole in 1, 4-dioxane (20 times of volume), extracting hydrogen through NaH (9 times of molar ratio), reacting with chloromethyl caprate (3 times of molar ratio) at 90 ℃, and finally preparing the decanoyloxymethyl biapiprazole (Y=70%) through a silica gel column. This method has the following disadvantages: a. the reaction temperature is higher, which is unfavorable for experimental operation to a certain extent, a large amount of NaH (9 mol) is used in the reaction process, and a certain danger exists, which is unfavorable for industrial scale-up production; b. aiming at the problem that the thermal stability of the side chain chloromethyl laurate is poor, the water content in the reaction needs to be strictly controlled in the reaction process, a small amount of water reacts with NaH to release hydroxide anions, so that the hydrolysis of the side chain chloromethyl laurate is caused, a large amount of impurities are generated, the temperature of 90 ℃ is relatively high in the reaction process, the stability of the side chain is not facilitated, the post-treatment difficulty is increased, the consumption of chloromethyl laurate is relatively large, and the production cost is increased to a certain extent. These two disadvantages directly lead to high production cost and lower yield, and are not beneficial to industrial scale-up production.
In addition, when the applicant repeats the experiment of WO2010151689A1, the same operation conditions, the same feeding method and the same feeding ratio are adopted, but no corresponding experiment result is obtained, and the reproducibility of the method is poor.
Disclosure of Invention
The invention aims to overcome one or more defects of low yield, high reaction temperature, poor reproducibility, high impurity content, post-treatment operation needing column chromatography and high production cost of lauroyl oxymethyl aripiprazole in the prior art. This approach has one or more of the following advantages: high yield, good reproducibility, mild reaction conditions, simple post-treatment and low production cost, and is suitable for industrial production.
The invention provides a preparation method of lauroyl oxymethyl aripiprazole, which comprises the following steps: under the action of an alkaline reagent and a catalyst, aripiprazole and chloromethyl laurate are subjected to substitution reaction in tetrahydrofuran to obtain lauroyl oxymethyl aripiprazole; the temperature of the substitution reaction is 5-35 ℃;
in the substitution reaction, the alkaline reagent may be a conventional alkaline reagent for such reaction in the art, preferably NaH.
The molar ratio of the basic agent to the aripiprazole in the substitution reaction may be conventional in the art, preferably 2.0:1 to 4.0:1, for example 2.0:1, 3.0:1, 3.2:1 or 4.0:1.
In the substitution reaction, the catalyst may be a catalyst conventional in the art such as, preferably, an alkali metal iodide salt, further KI or NaI, for example KI.
The molar ratio of the catalyst to the aripiprazole in the substitution reaction may be conventional in the art, preferably 0.11:1 to 0.27:1, for example 0.11:1, 0.27:1.
In the substitution reaction, the molar ratio of chloromethyl laurate to aripiprazole may be a molar ratio conventional in such reactions in the art, preferably 1.5:1 to 4.0:1 (e.g., 1.5:1 to 2.0:1, 2.0:1 to 4.0:1), more preferably 2.0:1 to 3.0:1, e.g., 2.0:1.
In the substitution reaction, the ratio of the volume to mass of the tetrahydrofuran to the aripiprazole may be a volume to mass ratio which is conventional in such a reaction in the art, and is preferably 11.0 to 21.0ml/g, for example 11.0 to 16.0ml/g, further for example 16.0 to 20.0ml/g (for example 16.0ml/g, 21.0 ml/g), further for example 20.0 to 21.0ml/g, further for example 11.0ml/g, 16.0ml/g, 20.0ml/g, 21.0ml/g.
The temperature of the substitution reaction is preferably 26 to 31℃such as 26℃28℃29℃or 31 ℃.
The progress of the substitution reaction can be monitored using detection methods conventional in the art (e.g., TLC) with the aripiprazole no longer reacting as the endpoint of the reaction. The time for the substitution reaction is preferably 1 to 3 hours, for example 1.5 hours, 2.5 hours.
The post-treatment of the substitution reaction may be conventional in the art for such reactions. The post-treatment preferably comprises the steps of: quenching, salt washing, concentrating and recrystallizing.
Preferably, the post-treatment does not include a column chromatography step.
In the post-treatment, the reagent used for the quenching is preferably water.
In the post-treatment, the number of salt washes is preferably 2 or more.
In the post-treatment, the salt solution of the salt wash is preferably a NaCl solution (e.g., saturated NaCl solution).
In the post-treatment, the concentration mode can be distillation.
In the post-treatment, the solvent used in the recrystallization is acetone.
In a preferred embodiment of the present invention, said solution of chloromethyl laurate in tetrahydrofuran is added dropwise to a solution of aripiprazole in tetrahydrofuran containing said alkaline agent, said catalyst and said aripiprazole, said dropwise addition being at a temperature of 5-35 ℃.
Preferably, the temperature of the dripping is 5-25 ℃, for example 10 ℃, 20 ℃.
In a preferred embodiment of the present invention, the molar ratio of said basic agent to said aripiprazole is from 2.0:1 to 4.0:1;
the reaction temperature is 26-31 ℃.
In a preferred embodiment of the present invention, the molar ratio of said basic agent to said aripiprazole is from 2.0:1 to 4.0:1;
in the substitution reaction, the molar ratio of the chloromethyl laurate to the aripiprazole is 2.0:1-3.0:1;
the reaction temperature is 26-31 ℃.
In a preferred embodiment of the present invention, the solution of chloromethyl laurate in tetrahydrofuran is added dropwise to a solution of aripiprazole in tetrahydrofuran containing the alkaline agent, the catalyst and the aripiprazole; the dropping temperature is 5-25 ℃;
the alkaline reagent is alkali metal iodized salt;
the molar ratio of the alkaline reagent to the aripiprazole is 2.0:1-4.0:1;
in the substitution reaction, the molar ratio of the chloromethyl laurate to the aripiprazole is 2.0:1;
the reaction temperature is 26-31 ℃.
In the present invention, "room temperature" means 5 to 35 ℃.
The above preferred conditions can be arbitrarily combined on the basis of not deviating from the common knowledge in the art, and thus, each preferred embodiment of the present invention can be obtained.
The reagents and materials used in the present invention are commercially available.
The invention has the positive progress effects that: the preparation method of lauroyl oxymethyl aripiprazole has the advantages of high yield, mild reaction conditions (no need of high-temperature reaction) and simple post-treatment; and the direct salt washing in the post-treatment does not need to remove the reaction solvent, and tetrahydrofuran can be recovered by distillation, so that the production of waste solvent is reduced, the waste liquid amount is reduced, the production cost is reduced, the environment-friendly concept is met, and the method is suitable for industrial production.
Detailed Description
The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Purity in the following examples was measured by High Performance Liquid Chromatography (HPLC) under the following conditions:
the chromatographic column isC8 (150 mm. Times.4.6 mm,5 μm); the detection wavelength is 249nm; the mobile phase is aqueous phase (0.15% triethylamine solution, glacial acetic acid adjusts pH to 3.5) organic phase (acetonitrile) =20:80 (v/v); the flow rate is 1.0mL/min; column temperature: 40 ℃, sample injection amount: 10 mu L.
Example 1
In a 2L four-necked flask, 100 g of aripiprazole (commercially available, HPLC content: 98%) was added, after 1.5L of THF was added to dissolve, 27 g of NaH (60%) was added in portions, the system was completely light gray, 4g of KI was added after stirring for 5min, the ice water bath was cooled to about 10℃after the addition, 110 g of chloromethyl laurate was slowly added dropwise to 50ml of THF (50 min was completely dropwise), the internal temperature was controlled to be lower than 25℃and was completely dropwise at 26℃after the completion of the dropwise, TLC (developing agent: ethyl acetate) was stirred for about 1h, after the reaction was completed, the reaction was quenched, poured into 1L of ice water mixture, stirred for 20min and separated, the organic layer was washed twice with (2X 700 ml) saturated NaCl solution to neutrality, and the solvent was recovered by distillation after drying, to obtain about 240 g of crude product of lauryloxymethyl aripiprazole as oily white solid. The crude product is heated to reflux by adding 500ml of acetone, refluxing is carried out for 10min, hot filtration is carried out, filtrate is heated to reflux solution for 15min, the temperature is slowly reduced, stirring is carried out at room temperature overnight, the filtration is carried out the next day, the solid is washed by 40ml of cold acetone and dried, 136 g of white solid is obtained, the yield is 92%, the purity is more than 99% (HPLC detection, the retention time is 27.469 mm).
Example 2
In a 5L four-necked flask, 200 g of aripiprazole (commercially available, HPLC content is more than or equal to 98%), 3L of THF is added to dissolve, 57 g of NaH (60%) is added in batches after the addition of the solution, the system is light gray, 8 g of KI is added after stirring for 5min, the temperature is reduced to about 10 ℃ after the addition, 220 g of chloromethyl laurate is slowly added dropwise to 100ml of THF (after 50 min), the internal temperature is controlled to be lower than 25 ℃, the solution is stirred at about 31 ℃ after the dropwise addition, TLC (developing agent: ethyl acetate) is stirred for about 1h, after the reaction is ensured to be complete, the reaction is quenched, poured into 2L of ice water mixture, stirred for 20min and separated, the organic layer is washed twice with (2X 1.5L) saturated NaCl to be neutral, and then the solvent is distilled and recovered after drying, about 420 g of oily white solid crude lauroyl oxymethyl aripiprazole is obtained. The crude product is added with 1L of acetone and heated to reflux, the reflux is carried out for 10min, the hot filtration is carried out, the filtrate is heated to reflux solution for 15min, the temperature is slowly reduced, the mixture is stirred at room temperature for overnight, the filtration is carried out the next day, the solid is washed with 50ml of cold acetone and then dried, 265 g of white solid is obtained, the yield is 89%, the purity is more than 99% (HPLC detection, the retention time is 27.296 mm).
Example 3
In a 5L four-necked flask, 200 g of aripiprazole (commercially available, HPLC content: 98%) was added, after 3L of THF was added to dissolve, 54 g of NaH (60%) was added in portions, the system was light gray after stirring for 5min, 8 g of KI was added, after the addition was completed, the ice water bath was cooled to about 10℃and 220 g of chloromethyl laurate was slowly added dropwise to dissolve in 100ml of THF (50 min) and the internal temperature was controlled to be lower than 25℃and the reaction was quenched after the dropwise addition, stirring was carried out at 28℃for about 1.5h, TLC (developer: ethyl acetate) was carried out after the dropwise addition was completed, the reaction was quenched after ensuring the completion of the reaction, the reaction was poured into 1.5L of ice water mixture, after stirring for 20min, the organic layer was washed twice with (2X 1.5L) saturated NaCl to neutrality, the solvent was recovered by distillation after drying, and about 440 g of crude lauroyl-methyl aripiprazole was obtained as a white solid with oil. The crude product is heated to reflux by adding 1L of acetone, refluxing is carried out for 10min, hot filtration is carried out, filtrate is heated to reflux solution for 15min, the temperature is slowly reduced, stirring is carried out at room temperature overnight, the filtration is carried out the next day, the solid is washed by 50ml of cold acetone and dried, 262 g of white solid is obtained, the yield is 88%, the purity is more than 99% (HPLC detection, the retention time is 27.424 mm).
Example 4
In a 100ml four-necked flask, 5g of aripiprazole (commercially available HPLC content: 98%) was added, 50ml (10V) of THF (which was dissolved and clarified by slight heating) was added, 1.35 g (3 eq) of NaH (60%) was added in portions, the system was light gray, 500mg of KI was added after stirring for 5min, the ice-water bath was cooled to about 5℃after the addition, 5.5 g (2 eq) of chloromethyl laurate was slowly added dropwise to 5ml of THF (5 min was completely added), and the subsequent procedure was identical to that of example 1 with a yield of 91%.
Example 5
In a 100ml four-necked flask, 5g of aripiprazole (commercially available, HPLC content: 98%) was added, 100ml (20V) of THF (slightly heated to dissolve for clarification) was added, 1.35 g (3 eq) of NaH (60%) was added in portions, the system was light gray after the addition, 500mg of KI was added after stirring for 5min, the temperature was controlled to about 20℃and 5.5 g (2 eq) of chloromethyllaurate was slowly added dropwise to 5ml of THF (5 min was completely added), and the subsequent procedure was identical to that of example 1, with a yield of 87%.
Example 6
In a 100ml four-necked flask, 5g of aripiprazole (commercially available, HPLC content: 98%) was added, after 75ml of THF was added to dissolve, 1.35 g (3 eq) of NaH (60%) was added in portions, the system was light gray after the addition was completed, 500mg of KI was added after stirring for 5min, the temperature was controlled to about 35℃and 4.13 g (1.5 eq) of chloromethyl laurate was slowly added dropwise to dissolve in 5ml of THF (5 min was completed), and the subsequent operation was identical to the operation of example 1, with a yield of 78%.
Example 7
In a 100ml four-necked flask, 5g of aripiprazole (commercially available, HPLC content: 98%) was added, after 75ml of THF was added to dissolve, 1.35 g (3 eq) of NaH (60%) was added in portions, the system was light gray after the addition was completed, 500mg of KI was added after stirring for 5min, the ice-water bath was cooled to about 10℃after the addition, 11 g (4 eq) of chloromethyllaurate was slowly added dropwise to dissolve in 5ml of THF (5 min was completed), and the subsequent procedure was identical to that of example 1, with a yield of 82%.
Example 8
In a 100ml four-necked flask, 5g of aripiprazole (commercially available, HPLC content: 98%) was added, after 75ml of THF was added to dissolve, 0.9 g (2 eq) of NaH (60%) was added in portions, the system was light gray after stirring for 5min, 500mg of KI was added, after the addition, the ice-water bath was cooled to about 5℃and chloromethyl laurate 5.5 g (2 eq) was slowly added dropwise to dissolve 5ml of THF (5 min was completed), and the subsequent procedure was identical to that of example 1 (more raw materials remained than in example 1) and the yield was 91%.
Example 9
In a 100ml four-necked flask, 5g of aripiprazole (commercially available, HPLC content: 98%) was added, after 75ml of THF was added to dissolve, 1.8 g (4 eq) of NaH (60%) was added in portions, the system was light gray after the addition was completed, 500mg of KI was added after stirring for 5min, the ice-water bath was cooled to about 10℃after the addition, 5.5 g (2 eq) of chloromethyllaurate was slowly added dropwise to dissolve in 5ml of THF (5 min was completed), and the subsequent procedure was identical to the procedure of example 1, with a yield of 90%.
Example 10
In a 100ml four-necked flask, 5g of aripiprazole (commercially available, HPLC content: 98%) was added, after 75ml of THF was added to dissolve, 1.35 g (3 eq) of NaH (60%) was added in portions, the system was light gray, 500mg of KI was added after stirring for 5min, the ice-water bath was cooled to about 5℃after the addition, chloromethyl laurate 4.13 g (1.5 eq) was slowly added dropwise to 5ml of THF (5 min was completely) and the temperature was slowly raised to 30℃after the dropwise addition, the subsequent operation was consistent with the operation of example 1 and the yield was 80%.
Comparative example 1
In a 50mL three-necked flask, 0.5 g of aripiprazole (commercially available, HPLC content: 98%) was added, 15mL of 1, 4-dioxane was added, 0.15 g (3 eq) of NaH (60%) was added in portions at room temperature (12 ℃) to complete the addition of the system as a milky white turbid liquid, 84mg of NaI was added after stirring for 15min, 0.55 g (2 eq) of chloromethyl laurate was slowly added dropwise, the temperature was raised to 90℃and the reaction was carried out for 2h, the system was gradually changed to brown yellow, and TLC (DCM: meOH=30:1) showed almost no production of the objective compound.
Comparative example 2
In a 1L three-necked flask, 15g of aripiprazole (commercially available HPLC content: 98%) was added, 300ml of 1, 4-dioxane was added, and after ultrasonic stirring to dissolve the aripiprazole, 5.4 g (4 eq) of NaH (60%) was added in portions at room temperature (11 ℃) and stirred for 15 minutes to give a milky white turbid liquid. 2.4g NaI was added and chloromethyl laurate 20.6g (2.5 eq) was slowly added dropwise in ice water bath and the reaction stirred at 40℃for 6h, the system was gradually off-white, TLC (DCM: meOH=30:1) showed more of the target compound. The subsequent procedure was identical to that of example 1, with a yield of 49%.
Claims (9)
1. A method for preparing lauroyloxymethyl aripiprazole, comprising the steps of: under the action of an alkaline reagent and a catalyst, aripiprazole and chloromethyl laurate are subjected to substitution reaction in tetrahydrofuran to obtain lauroyl oxymethyl aripiprazole; the temperature of the substitution reaction is 5-35 ℃;
the alkaline reagent is NaH;
the catalyst is KI;
the molar ratio of the chloromethyl laurate to the aripiprazole is 1.5:1-4.0:1;
the molar ratio of the alkaline reagent to the aripiprazole is 2.0:1-4.0:1;
the molar ratio of the catalyst to the aripiprazole is 0.11:1-0.27:1;
the volume-mass ratio of the tetrahydrofuran to the aripiprazole is 11.0-21.0ml/g.
2. The process for preparing lauroyloxymethyl aripiprazole according to claim 1, wherein the temperature of the substitution reaction is 26-31 ℃.
3. The method for preparing lauroyloxymethyl aripiprazole according to claim 1, wherein in said substitution reaction, the molar ratio of said chloromethyl laurate to said aripiprazole is 2.0:1 to 3.0:1;
and/or, in the substitution reaction, the molar ratio of the alkaline reagent to the aripiprazole is 2.0:1, 3.0:1, 3.2:1 or 4.0:1;
and/or, in the substitution reaction, the molar ratio of the catalyst to the aripiprazole is 0.11:1 or 0.27:1;
and/or, in the substitution reaction, the volume-mass ratio of the tetrahydrofuran to the aripiprazole is 11.0-16.0ml/g, 16.0-20.0ml/g or 20.0-21.0ml/g;
and/or the substitution reaction temperature is 26 ℃, 28 ℃, 29 ℃ or 31 ℃.
4. The method for preparing lauroyloxymethyl aripiprazole according to claim 3, wherein in said substitution reaction, the molar ratio of said chloromethyl laurate to said aripiprazole is 2.0;
and/or, in the substitution reaction, the volume-mass ratio of the tetrahydrofuran to the aripiprazole is 11.0ml/g, 16.0ml/g, 20.0ml/g or 21.0ml/g.
5. The process for preparing lauroyloxymethyl aripiprazole according to any one of claims 1 to 4, wherein the post-treatment of the substitution reaction comprises the steps of: quenching, salt washing, concentrating and recrystallizing.
6. The method for preparing lauroyloxymethyl aripiprazole according to claim 5, wherein said post treatment does not comprise a column chromatography step; the solvent used in the recrystallization is acetone.
7. The method for preparing lauroyloxymethyl aripiprazole according to claim 1, characterized in that said solution of chloromethyl laurate in tetrahydrofuran is added dropwise to a solution of said basic agent, said catalyst and said aripiprazole in tetrahydrofuran at a temperature of 5-35 ℃.
8. The method for preparing lauroyl oxymethyl aripiprazole according to claim 7, wherein the temperature of said dropping is 5-25 ℃.
9. The process for preparing lauroyloxymethyl aripiprazole according to claim 1, characterized in that said solution of chloromethyl laurate in tetrahydrofuran is added dropwise to a solution of aripiprazole in tetrahydrofuran containing said basic agent, said catalyst and said aripiprazole; the dropping temperature is 5-25 ℃;
the molar ratio of the alkaline reagent to the aripiprazole is 2.0:1;
in the substitution reaction, the molar ratio of the chloromethyl laurate to the aripiprazole is 2.0:1;
the temperature of the substitution reaction is 26-31 ℃.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107628999A (en) * | 2017-10-25 | 2018-01-26 | 苏州华健瑞达医药技术有限公司 | The preparation method of Aripiprazole dodecylate |
| WO2018104953A1 (en) * | 2016-12-07 | 2018-06-14 | Msn Laboratories Private Limited, R&D Center | Improved process for the preparation of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]butoxy}-2oxo-3,4-dihydro-2h-quinolin-1-yl)methyl dodecanoate |
| CN110204488A (en) * | 2018-02-28 | 2019-09-06 | 四川科伦药物研究院有限公司 | A kind of preparation method of lauroyl Aripiprazole |
| CN111315722A (en) * | 2017-07-28 | 2020-06-19 | 因特奎姆私人控股公司 | Process for preparing lauroyl aripiprazole |
-
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018104953A1 (en) * | 2016-12-07 | 2018-06-14 | Msn Laboratories Private Limited, R&D Center | Improved process for the preparation of 7-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]butoxy}-2oxo-3,4-dihydro-2h-quinolin-1-yl)methyl dodecanoate |
| CN111315722A (en) * | 2017-07-28 | 2020-06-19 | 因特奎姆私人控股公司 | Process for preparing lauroyl aripiprazole |
| CN107628999A (en) * | 2017-10-25 | 2018-01-26 | 苏州华健瑞达医药技术有限公司 | The preparation method of Aripiprazole dodecylate |
| CN110204488A (en) * | 2018-02-28 | 2019-09-06 | 四川科伦药物研究院有限公司 | A kind of preparation method of lauroyl Aripiprazole |
Non-Patent Citations (1)
| Title |
|---|
| 田铁牛.《有机合成单元过程》.化学工业出版社,2006,114-115. * |
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