CN111087358B - Preparation method of Prisamod - Google Patents
Preparation method of Prisamod Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
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- C07F5/04—Esters of boric acids
Abstract
The invention discloses a preparation method of a Pusaimod, which takes bromobenzene and benzene as starting materials to prepare the Pusaimod by a convergent synthesis route.
Description
Technical Field
The invention relates to a novel method for preparing previosmod, belonging to the technical field of medicines.
Background
Prisamod is a novel S1P1 receptor immunosuppressant developed by Chinese medical academy of sciences, is a novel medicament for treating rheumatoid arthritis as shown in formula 1, and is currently in a phase I clinical test stage. From the experimental data obtained in the early stage, the compound has good pharmacological activity and can be possibly applied to clinical treatment.
The conventional preparation of the prisimod and the hydrochloride thereof is shown as a formula 1, and the prisimod and the hydrochloride thereof are finally obtained by taking biphenyl as a starting material through friedel-crafts acylation, coupling, reduction, friedel-crafts acylation, esterification, cyclization, reduction, hydrolysis and hydrochlorination by adopting a linear synthesis method. The route was followed by nine steps to give the final product in a total yield of 9.9% (see Tianyulin et al, MedChemcomm, 2013, 4, 1267-.
The synthetic route of the prisimod and the hydrochloride thereof disclosed by the above documents adopts a 'linear' synthetic method, the synthetic route is long, the yield is low, and in the synthetic process, column chromatography is required, so that the cost is increased. And a large amount of solvent and Lewis acid are used, so that the environmental pollution is large.
Disclosure of Invention
Brief description of the invention
Based on the problems of the above routes, we designed a new preparation route of the general formula.
The preparation route of the prisimod is shown as a formula 2, in the first step, a key intermediate 5 and an intermediate 6 are subjected to suzuki coupling reaction under the catalysis of a palladium catalyst to generate a compound 7, in the second step, ester group reduction is carried out to obtain a compound 8, in the third step, amide hydrolysis is carried out to obtain a compound 9 (prisimod), and in the last step, a final product of prisimod hydrochloride is obtained by hydrochlorination. Starting from bromobenzene, obtaining a key intermediate 5 through four-step reaction (formula 3), and then obtaining the total yield of the prisimod hydrochloride by coupling, hydrolyzing and hydrochlorinating, wherein the total yield is 31.1%.
The intermediate 5 can be obtained by coupling the intermediate 4 with bis-pinacol borate in one step to obtain an intermediate 6, taking benzene as an initial raw material, performing Friedel-crafts acylation on the benzene to obtain an intermediate 13, performing condensation on the intermediate 13 to obtain an intermediate 14, performing ketonic carbonyl reduction on the intermediate 14 to obtain an intermediate 15, and brominating the intermediate 15 to obtain the intermediate 6.
The optimization of the coupling conditions of the intermediates 5 and 6 comprises that the catalyst used in the step (I) is a palladium catalyst capable of catalyzing the coupling reaction of bromide and boron ester, preferably, di-bromo-bis (tri-tert-butylphosphine) dipalladium (I) (Pd-Dimer) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (Pd (dppf)2Cl2) Tetratriphenylphosphine palladium (Pd (PPh)3)4) 1,1' -di-tert-butylphosphino ferrocene palladium dichloride (Pd (dppf) Cl2-CH2Cl2) Palladium acetate (Pd (OAc)2) Palladium dichloride (PdCl)2) (ii) a More preferred is di-bromobis (tri-tert-butylphosphino) dipalladium (I) (Pd-Dimer). ② Pd-Dimer, Pd (dppf) Cl2-CH2Cl2、Pd(OAc)2、Pd(PPh3)4、Pd(dptf)2Cl2、PdCl2The molar amount of the palladium catalyst is 0.1-6.0%. Preferably 0.1% to 1.0%, more preferably 0.1% to 0.5%. ③ catalystThe reaction of chemical coupling also requires the presence of a salt, including a carbonate, fluoride or acetate; potassium carbonate and potassium fluoride are preferred; more preferably potassium carbonate. Fourthly, the reaction is carried out in organic solvent or water which is commonly used for palladium catalytic coupling reaction, and can also be carried out by using mixed solvent; the solvent is selected from toluene, ethanol, tetrahydrofuran and water, or their mixture; toluene-ethanol-water and tetrahydrofuran-water are preferred as reaction solvents. The mol ratio of the intermediate 5 to the intermediate 6 is 1: 0.65-1:1.5, preferably 1: 0.8-1:1.2, more preferably 1: 1.1.
The key intermediate 5 needs to be prepared in the route.
Detailed Description
The technical problem to be solved by the invention is to provide a synthesis method of prisimod, which is simple to operate, high in yield, low in cost and low in pollution.
The technical scheme for realizing the aim of the invention is to provide a novel preparation method of the Prussimod, which comprises the following synthetic steps: the preparation route of the key intermediate 5 is shown as a formula 3, starting from bromobenzene, carrying out Friedel-crafts acylation reaction on bromobenzene to generate a compound 2, carrying out esterification reaction on the compound 2 and butyric acid to generate a compound 3, and carrying out cyclization reaction on the compound 3 and butyramide to generate a compound 4. And in the fourth step of reaction, the compound 4 and the bis (pinacolato) borate are subjected to coupling reaction under the catalysis of a palladium catalyst to generate a compound 5.
a. Bromobenzene (compound 1) and chloroacetyl chloride are dissolved in anhydrous dichloromethane, and anhydrous aluminum trioxide is added in batches under ice bath, and the reaction is finished within about 0.5-3 hours. The reaction solution was poured into a 1mol/L ice-water mixture of hydrochloric acid. Extraction, drying and solvent removal to yield compound 2.
b. Dissolving the compound 2 in anhydrous acetonitrile, adding butyric acid, adding triethylamine under stirring, heating and refluxing for 1-6 hours, extracting with ethyl acetate-water, drying, and removing the organic solvent to obtain a compound 3.
c. Placing the solid compound 3 and butyramide in the same reaction bottle, adding boron trifluoride diethyl etherate complex, heating at the external temperature of 130 ℃ and 150 ℃, carrying out solvent-free reaction under the protection of inert gas, reacting for 4-5 hours, adding n-heptane-methanol-water, heating and stirring, carrying out n-heptane-methanol-water thermal extraction, drying, evaporating the solvent, and recrystallizing to obtain the compound 4.
d. Heating the refined compound 4 and bis-pinacol borate at an external temperature of 50-100 ℃ for reacting for 4-6 hours under the catalysis of palladium, extracting with ethyl acetate-water, drying, and evaporating to remove the solvent to obtain a key intermediate 5 to be put into the next step.
② the synthesis of the compound 6 comprises the following two methods:
A. the preparation is shown in formula 4, and is prepared by starting from p-bromophenyl alcohol and performing iodination and condensation reaction.
a. Dissolving p-bromophenyl alcohol in anhydrous dichloromethane, adding iodine, triphenylphosphine and imidazole in ice bath, protecting with inert gas, and cooling in ice bath. After the addition is finished, slowly heating to room temperature, after the reaction is finished, extracting by a methanol-water-n-heptane system, and evaporating to remove the organic solvent to obtain a compound 11.
b. Dissolving sodium hydride in DMF, dropwise adding a DMF solution of diethyl acetylaminomalonate into a reaction system under the protection of ice bath inert gas, reacting for 2 hours, adding the DMF solution of the compound 11 in ice bath, slowly heating to room temperature, continuing to react for a period of time, extracting with ethyl acetate, and evaporating to remove the solvent to obtain a compound 6.
B. The preparation is shown as a formula 5, benzene is used as a raw material, coupling with acetylaminomalonic acid diethyl ester is carried out through Friedel-crafts acylation reaction, benzyl carbonyl is reduced, and bromination is carried out to obtain a compound 6.
a. Benzene (compound 12), chloroacetyl chloride were dissolved in anhydrous dichloromethane, and anhydrous aluminum trioxide was added in portions in an ice bath, and the reaction was completed in about 1 hour. The reaction solution was poured into a 1mol/L ice-water mixture of hydrochloric acid. The reaction solution was extracted, dried and evaporated to obtain compound 13.
b. Dissolving sodium hydride in tetrahydrofuran, dropwise adding a tetrahydrofuran solution of diethyl acetamidomalonate into a reaction system under the protection of ice bath inert gas, heating to room temperature for reacting for a period of time, continuously adding a sodium iodide solution in ice bath, adding a tetrahydrofuran solution of a compound 13 in ice bath after a period of time, slowly heating to room temperature for continuously reacting for a period of time, extracting, and evaporating a solvent to obtain a compound 14.
c. Dissolving the compound 14 in ethanol, adding perchloric acid to react with palladium-carbon, reacting with medium-pressure hydrogen, filtering and extracting to obtain the compound 15.
d. Dissolving the compound 15 in acetic acid, adding sodium acetate and liquid bromine, reacting for a period of time, extracting, and evaporating the solvent to obtain an intermediate 6.
Dissolving the key intermediate 5 and the compound 6 in a solvent, wherein the feeding molar ratio is 0.65-1.5. Adding potassium carbonate and palladium catalyst, carrying out suzuki coupling reaction under strict oxygen-free condition, evaporating reaction liquid after 2-4 hours, and further refining to obtain a compound 7.
And fourthly, reducing the compound 7 in a buffer salt system by sodium borohydride, and refining to obtain a compound 8.
Fifthly, dissolving the compound 8 in absolute methanol, adding NaOH, heating and refluxing for 5-7 hours, cooling to room temperature, stirring for 8-24 hours, filtering, and washing with ice methanol to obtain the compound 9, namely the prisimod.
Sixthly, dissolving the compound 9 in an ethanol-water solution, dropwise adding concentrated hydrochloric acid until the pH value is 1-5, heating and refluxing for 3-4 hours, filtering, washing with glacial ethanol-water, crystallizing and filtering to obtain the final product, namely the prisimod hydrochloride.
Advantageous technical effects
The new synthesis method has the following advantages:
the yield is high, namely the original reaction route is a linear route, the total yield is 14.4% after nine steps of reaction, and the new reaction route is a convergent reaction route, so that the total yield is increased to 31.1%.
The purity of the compound 7 is equivalent to that of the compound in the original route, but the new route is different from the original route and does not use column chromatography and other methods for purification.
The three wastes are less, the route contains one to two steps of anhydrous Lewis acid reaction, and the dosage is less (each kilogram of product needs to be consumed)
Kilogram of lewis acid), and the dosage is larger (19.2 kilograms of lewis acid are consumed per kilogram of product) compared with the original route in which lewis acid is used for three times, so that less industrial three wastes are generated, and the method is more environment-friendly.
Detailed Description
Preparation example 1
Synthesis of 2-propyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) oxazole (Compound 5)
a.Synthesis of 1- (4-bromophenyl) -2-chloro-1-one (Compound 2): 20.0g of bromobenzene is dissolved in dichloromethane (200mL) solution and placed in a three-necked flask for cooling at external temperature
10.6mL of chloroacetyl chloride was dissolved in dichloromethane (50mL) with stirring and slowly added dropwise to a three-necked flask. 20.4g of anhydrous aluminum chloride was added to the reaction flask in three portions while maintaining the low temperature (7.0 g for the first portion, 7.0g for the second portion, and 6.4g for the third portion). After 1 hour the reaction was substantially complete and the reaction was poured into 250mL of dilute hydrochloric acid-ice water mixture and stirred for half an hour until the reaction turned pale yellowish green. The resulting mixture was extracted with dichloromethane (200 mL. times.3), washed with saturated brine (200 mL. times.1), dried over anhydrous sodium sulfate, and evaporated to removeOrganic solvent to obtain 2' -chloro-4-bromoethyl ketone (compound 2) with a yield of 93.3%. HRMS (ESI) M/z 254.9184[ M + Na ]]+
Synthesis of 2- (4-bromophenyl) -2-oxoethylbutyrate (compound 3): dissolving 10.0g of compound 2 and 4.9mL of butyric acid in anhydrous acetonitrile (80mL), dropping 9.6mL of triethylamine in anhydrous acetonitrile (20mL) in a reaction bottle under the protection of inert gas while stirring, and heating to the external temperature
The reaction was carried out for about 3 hours. Water was added, extraction was performed with ethyl acetate (80 mL. times.3), washing was performed with a saturated sodium carbonate solution (100 mL. times.1), washing was performed with a saturated brine (100 mL. times.1), the organic phase was dried over anhydrous sodium sulfate, and the organic solution was distilled off to obtain Compound 3, which was directly charged to the next step. HRMS (ESI) M/z 285.0127[ M + H ]]+
c.Synthesis of 2-propyl-4- (4-bromophenyl) oxazole (Compound 4): 11.4g of compound 3 and 8.6g of butyramide are placed in a 100mL reaction flask, 5.0mL of boron trifluoride diethyl etherate is added, and the mixture is stirred and heated under the protection of inert gas until the mixture is heated
The reaction was carried out for about 6 hours. The reaction solution is cooled to
30% methanol-water solution (100mL) was added followed by an equal volume of n-heptane, stirred vigorously, and the mixture was extracted three times with n-heptane heat. The organic layers were dried over anhydrous sodium sulfate, and the organic layers were combined and evaporated to dryness to give compound 4. Adding 100mL ethanol and 1% active carbon, heating to 60 deg.C for 30min, filtering with diatomaceous earth, and removing the reaction solution by evaporation. Compound 4 was obtained in a yield of about 67.9% for two consecutive steps. Hrms (esi) M/z 266.0176.[ M + H]+
Synthesis of 2-propyl-4- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) oxazole (compound 5): 3.0g of Compound 4,2.9g of Bipinacolato borate, 3.3g of potassium acetate and 18.5mg of [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (PdCl)2(pddf)-CH2Cl2) Adding into a reaction bottle, adding DMF (20mL) for dissolving, heating to room temperature under the protection of inert gas
The reaction is carried out for about 3-5h, and the heating is stopped. Cooled to room temperature, water was added, filtered while hot, extracted with ethyl acetate (50mL × 3), the organic solvent was evaporated off, and the mixture was cooled with petroleum ether: filtering the pad with ethyl acetate at a volume ratio of 12:1, and spin-drying the organic phase to obtain a key intermediate 5 with a yield of 87.0% for the next step. HRMS (ESI) M/z 314.1950[ M + H ]]+
Preparation example 2
2-acetylamino-2- (4-bromophenylethyl) malonic acid diethyl ester (key intermediate 6) synthesis:
a Synthesis of 1-bromo-4- (2-iodoethyl) benzene (Compound 11): 31.6g of iodine, 33.9g of triphenylphosphine and 22.4mg of imidazole were dissolved in anhydrous dichloromethane (100mL), and after cooling in an ice bath for 30 minutes, 20.0g of p-bromophenethyl alcohol was dissolved in anhydrous dichloromethane (50mL) and rapidly added dropwise to the reaction flask. The ice bath was removed and the reaction was allowed to proceed at room temperature for about 6 hours. Methylene chloride was distilled off, a water-methanol mixed solution (400mL, water: methanol volume ratio 1:3) was added, the mixture was transferred to a separatory funnel, n-heptane was added for extraction (200 mL. times.3), the mixture was vigorously shaken until the whole system was colorless and transparent, and organic layers were combined. Drying with anhydrous sodium sulfate, evaporating to remove organic solvent to obtain colorless transparent solid, i.e. compound 11, storing the product in dark place, with a yield of 93.2%.
Synthesis of diethyl 2-acetylamino-2- (4-bromophenylethyl) malonate (key intermediate 6) by dissolving 8.4g diethyl acetylaminomalonate in anhydrous DMF (40mL) and allowing the reaction solution to warm in ice bath
2.1g of sodium hydride are added in portions under a gas blanket and the ice bath is continued, keeping the temperature at not more than 5 ℃. After the addition is finished, the ice bath is removed, and the mixture is stirred at room temperature and continuously invertedShould be about
And (4) hours. 10.0g of Compound 11 was dissolved in anhydrous DMF (10mL), and slowly added dropwise to the reaction flask in an ice bath, after completion of the dropwise addition, the ice bath was removed. The reaction is continued to be carried out
And (4) hours. The reaction solution was poured into a separatory funnel, ethyl acetate was added to extract (100 mL. times.3), and the mixture was washed with 1mol/L hydrochloric acid (100 mL. times.3), once with saturated saline (100 mL. times.3), dried, and then the organic solvent was distilled off to obtain Compound 6 in 55.8% yield. HRMS (ESI) M/z 400.0746[ M + H ]]+
Example 1
2-acetylamino-2- (4-bromophenylethyl) malonic acid diethyl ester (key intermediate 6) synthesis:
synthesis of 2-chloro-1-phenylethane-1-one (compound 13): 20.0g of benzene was dissolved in a dichloromethane (200mL) solution and placed in a three-necked flask for cooling at ambient temperature
22.4mL of chloroacetyl chloride was dissolved in dichloromethane (50mL) with stirring and slowly dropped into a three-necked flask. 41.0g of anhydrous aluminum chloride was added to the reaction flask in three portions while maintaining the low temperature (13.7 g for the first portion, 13.6g for the second portion, and 13.6g for the third portion). After 1 hour the reaction was substantially complete and the reaction was poured into 300mL of hydrochloric acid-ice water mixture and stirred for half an hour until the reaction turned pale yellow-green. The resulting mixture was extracted with dichloromethane and separated (200 mL. times.3), washed with saturated brine (200 mL. times.1), dried over anhydrous sodium sulfate, and the solvent was evaporated to give phenacyl chloride (Compound 13) in a yield of 90.6%. HRMS (ESI) M/z 155.0256[ M + H ]]+
Synthesis of diethyl 2-acetylamino-2- (2-oxo-2-phenylethyl) malonate (compound 14): 30.9g of diethyl acetamidomalonate is dissolved in 200mL of tetrahydrofuran, ice-bath is carried out, and 6.2g of NaH is added in three portions to keep the temperature of the system at
After the addition was complete, the ice bath was continued for 20 min. Slowly warmed to room temperature and stirred for 30 min. Adding NaI under ice bath condition, removing ice bath, and stirring for 20 min. A solution of 18.3g of Compound 13 in tetrahydrofuran (50mL) was added dropwise rapidly under ice-bath conditions. After the addition was complete the ice bath was removed. The reaction was completed in about 6 hours, and the reaction mixture was poured into ice water, extracted with ethyl acetate (200 mL. times.3), washed with 1mol/L dilute hydrochloric acid (200 mL. times.1), and washed with saturated brine (200 mL. times.1). After drying, the solvent was distilled off to obtain a crude compound 14. N-heptane (100mL) was added for slurrying, filtered and dried to give compound 14 in 85.2% yield. HRMS (ESI) M/z 336.1452[ M + H ]]+
c.Synthesis of diethyl 2-acetylamino-2-phenylethylmalonate (Compound 15): 10.0g of Compound 14 was dissolved in ethanol (100mL), and 1.0g of palladium-carbon and 0.1mL of an aqueous perchloric acid solution were added. And carrying out medium-pressure hydrogenation reaction for 48-72 hours. After the reaction, the reaction mixture was filtered through celite, and the reaction mixture was distilled off to obtain a crude compound 15. The crude product was recrystallized using 50% methanol-water. Crystallization was carried out in an ice bath for 2 hours, and filtration gave purified compound 15 in a yield of 72.1%. HRMS (ESI) M/z 322.1648[ M + H ]]+
d.2-acetamido-2- (4-bromophenylethyl) malonic acid diethyl ester (intermediate 6) synthesis 10.0g of compound 15 was dissolved in acetic acid (100mL), 4.1g of sodium acetate was added, and 1.8mL of liquid bromine was added dropwise to the reaction system under ice-bath cooling. And continuing to perform ice bath for half an hour after the dropwise addition is finished, and removing the ice bath to slowly rise to room temperature. The reaction was monitored by TLC and was complete for about 6 hours. The reaction mixture was extracted with ethyl acetate (200 mL. times.3), washed with saturated sodium carbonate (200 mL. times.3), washed with saturated brine (200 mL. times.3), dried over anhydrous sodium sulfate, and the solvent was distilled off. Crude compound 6 was obtained and slurried with n-heptane (50 mL). Filtration afforded compound 6 in 75.8% yield. HRMS (ESI) M/z 400.0746[ M + H ]]+
Example 2
2-acetylamino-2- (2- (4'- (2-propyloxazol-4-yl) - [1,1' -biphenylyl)]-4-yl) ethyl) malonic acid diethyl ester (compound 7) synthesis: adding compound 5 and compound 6 into 50mL of solvent, adding palladium catalyst and base (3 times of molar weight), and heating to the temperature under the protection of inert gas
After 4 hours of reaction, crude compound 7 was obtained by extraction with ethyl acetate-water and drying. Is then used
Ethanol-water recrystallization to obtain purified compound 7. HRMS (ESI) M/z 507.2514[ M + H ]]+
The reaction conditions and results are detailed in Table 1.
TABLE 1
Example 3
N- (4- (4'- (2-ethyloxazol-4-yl) - [1,1' -biphenyl)]-synthesis of 4-yl) -1-hydroxy-2- (hydroxymethyl) butan-2-yl) acetamide (compound 8): 710.1 g of the compound was charged into a reaction flask, and ethanol (100mL) was further added thereto and stirred. Then, 9.1g of dipotassium hydrogenphosphate trihydrate was dissolved in 20mL of water, and was added dropwise to the reaction system. 6.8g of sodium borohydride and 680mg of sodium hydroxide were dissolved in water (20mL) and added dropwise to the system. Keeping the temperature of the system at
The temperature is kept and stirring is continued for 2 hours, the refrigeration system is closed, the temperature is naturally raised to room temperature, the reaction is stirred for about 18 hours, and TLC monitors that the conversion of the raw materials is complete. Cooling the system to
Adjusting the pH to about
Then adding water into the mixture, and adding water into the mixture,
then the crude product is crystallized by stirring. Adding the crude product into 500mL of reaction, heating the mixture to slightly reflux the system by using ethyl acetate and water, completely dissolving the mixture, and stopping stirring. Separating, washing the organic phase with water, heating to evaporate ethyl acetate, adding 3.80L n-heptane, cooling to 5 deg.C under stirring, maintaining for 2 hr, and filtering to obtain compound 8 with yield of 94.2%. HRMS (ESI) M/z 423.2290[ M + H ]]+
Example 4
2-amino-2- {2- (4'- (2-propyloxazol-4-yl) - [1,1' -biphenyl]-synthesis of 4-yl) ethyl } -1, 3-propanediol (compound 9): 78.0g of Compound 8, 780mL of anhydrous methanol were added successively to a three-necked flask, 11.1g of sodium hydroxide were added with stirring, and then heated to reflux for 6 hours, monitored by TLC until the starting material was reacted completely. The temperature was lowered to room temperature (about 20 ℃ C.), and the mixture was stirred for about 14 hours. And (3) carrying out suction filtration, drying a filter cake to obtain 53.0g of white solid, refluxing for 2h by using 530mL of methanol, cooling and crystallizing (controlling the temperature of a system to be 0-5 ℃), carrying out suction filtration, and drying to obtain the compound 9 with the yield of 73.3%. HRMS (ESI) M/z 381.2183[ M + H ]]+
Example 5
2-amino-2- {2- (4' - (2-propane)Oxazol-4-yl) - [1,1' -biphenyl]-synthesis of 4-yl) ethyl } -1, 3-propanediol hydrochloride (pricisimod hydrochloride): 10.0g of the compound was charged into a 250mL three-necked round-bottomed flask, 100mL of ethanol was added, 2.2mL of concentrated hydrochloric acid was added dropwise until the pH of the system became 3 to 4, followed by heating under reflux, filtration and removal of insoluble impurities. Cooling and crystallizing, controlling the temperature of the system to be 0-5 ℃, stirring for 2 hours, and filtering. The filter cake was washed with about 10mL of 90% ethanol solution and dried at 35-45 deg.C under vacuum to constant weight to give the final product in 92.0% yield. HRMS (ESI) M/z 381.2183[ M + H ]]+。
Claims (15)
1. The synthesis method of the Prisaimod as shown in the formula 1 is characterized in that the intermediate 5 and the intermediate 6 are coupled through palladium catalysis to synthesize a key intermediate 7, and the Prisamod is obtained through subsequent reduction and hydrolysis reaction
2. The process of claim 1 wherein intermediate 5 is obtained from intermediate 4 by a one-step coupling with a bis-pinacolato boronic acid ester
3. The synthesis process according to claim 1, characterized in that said intermediate 6 is obtainable from benzene as starting material, benzene is subjected to Friedel-crafts acylation to obtain intermediate 13, intermediate 13 is subjected to condensation to obtain intermediate 14, intermediate 14 is subjected to ketocarbonyl reduction to obtain intermediate 15, intermediate 15 is subjected to bromination to obtain intermediate 6
4. A synthesis process according to claim 1, characterized in that the coupling of intermediates 5 and 6 is carried out using a palladium catalyst capable of catalysing the coupling reaction between bromide and boron ester.
5. The synthesis process according to claim 4, characterized in that the palladium catalyst is selected from the group consisting of di-bromobis (tri-tert-butylphosphino) dipalladium (I), [1,1 '-bis (diphenylphosphino) ferrocene ] dichloropalladium, tetratriphenylphosphine palladium, 1' -di-tert-butylphosphino ferrocene dichloropalladium, palladium acetate, palladium dichloride.
6. The synthesis process according to claim 4, characterized in that the palladium catalyst is used in a molar percentage ranging from 0.1% to 6.0%.
7. The synthesis process according to claim 4, characterized in that the palladium catalyst is used in a molar percentage ranging from 0.1% to 1.0%.
8. The synthesis process according to claim 4, characterized in that the palladium catalyst is used in a molar percentage ranging from 0.1% to 0.5%.
9. The synthesis process according to claim 1, characterized in that the catalytic coupling reaction also requires the presence of a salt, which is a carbonate, fluoride or acetate.
10. The synthesis process according to claim 1, characterized in that the catalytic coupling reaction also requires the presence of salts, potassium carbonate and potassium fluoride.
11. The synthesis process according to claim 1, characterized in that the reaction is carried out in an organic solvent or water, which is commonly used for palladium-catalyzed coupling reactions, or in a mixed solvent; the solvent is selected from toluene, ethanol, tetrahydrofuran and water, or their mixture.
12. The synthesis process according to claim 1, wherein the reaction is carried out in an organic solvent or water, as is customary for palladium-catalyzed coupling reactions, or in a mixture of solvents; the solvent used is selected from toluene-ethanol-water and tetrahydrofuran-water as reaction solvent.
13. The synthesis method according to claim 1, wherein the molar ratio of the intermediate 5 to the intermediate 6 is 1: 0.65-1:1.5.
14. The synthesis method according to claim 1, wherein the molar ratio of the intermediate 5 to the intermediate 6 is 1: 0.8-1:1.2.
15. The synthesis method according to claim 1, wherein the molar ratio of intermediate 5 to intermediate 6 is 1: 1.1.
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| WO2013004190A1 (en) * | 2011-07-06 | 2013-01-10 | 中国医学科学院药物研究所 | Amino-propylene-glycol derivatives, preparation method and pharmaceutical composition and use thereof |
| CN104529734A (en) * | 2014-11-29 | 2015-04-22 | 湖北金赛药业有限公司 | Preparation method and preparation intermediate of fingolimod hydrochloride |
| CN104844486A (en) * | 2014-02-17 | 2015-08-19 | 中国医学科学院药物研究所 | Amino propanediol derivatives, preparation method, drug compositions and uses thereof |
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2018
- 2018-10-24 CN CN201811244302.8A patent/CN111087358B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013004190A1 (en) * | 2011-07-06 | 2013-01-10 | 中国医学科学院药物研究所 | Amino-propylene-glycol derivatives, preparation method and pharmaceutical composition and use thereof |
| CN104844486A (en) * | 2014-02-17 | 2015-08-19 | 中国医学科学院药物研究所 | Amino propanediol derivatives, preparation method, drug compositions and uses thereof |
| CN104529734A (en) * | 2014-11-29 | 2015-04-22 | 湖北金赛药业有限公司 | Preparation method and preparation intermediate of fingolimod hydrochloride |
Non-Patent Citations (2)
| Title |
|---|
| Design, synthesis and docking-based 3D-QSAR study of novel 2-substituted 2-aminopropane-1,3-diols as potent and selective agonists of sphingosine-1-phosphate 1 (S1P1) receptor;Yulin Tian et al.;《Med. Chem. Commun.》;20130703;第4卷;第1267-1274页 * |
| Synthesis, identification, and biological activity of metabolites of two novel selective S1P1 agonists;Qiong Xiao et al.;《Bioorganic & Medicinal Chemistry》;20160331;第24卷;第2273-2279页 * |
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