CN111302997B - Method for preparing Raatinib intermediate by one-pot method - Google Patents
Method for preparing Raatinib intermediate by one-pot method Download PDFInfo
- Publication number
- CN111302997B CN111302997B CN202010293708.6A CN202010293708A CN111302997B CN 111302997 B CN111302997 B CN 111302997B CN 202010293708 A CN202010293708 A CN 202010293708A CN 111302997 B CN111302997 B CN 111302997B
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- temperature
- acid
- pot
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Crystallography & Structural Chemistry (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention discloses a method for preparing a Laretinib intermediate by a one-pot method; the technical key points are as follows: step 1): dissolving a compound VI serving as a raw material in a solvent, and then adding isopropyl magnesium chloride to generate a Grignard reagent; and then reacting with N-Boc-pyrrolidone to obtain a compound I: step 2): adding acid into the reaction liquid, carrying out Boc removal reaction on the compound I, and obtaining a compound II after the reaction is finished; step 3), adding alkali into the reaction liquid, carrying out ring closing reaction on the compound II, and obtaining a compound III after the reaction is finished; step 4), in the reaction solution, reducing the compound III to obtain a compound IV; step 5): salifying the compound IV and D-malic acid, and recrystallizing to obtain a compound V.
Description
Technical Field
The invention relates to the field of organic synthesis, and discloses a simplified process for preparing a key intermediate of broad-spectrum targeting tumor drug Raatinib (R) -2- (2, 5-difluorophenyl) pyrrolidine (R) -2-hydroxysuccinate by a one-pot method.
Background
The current preparation methods for synthesizing the compound are three types:
the method comprises the following steps: CN108218754A:
the process is complex, the yield of four steps is about 72 percent, and the solvent in each step is different in type and difficult to recover. Each step of post-treatment produces a large amount of wastewater.
The second method comprises the following steps: CN102224153A:
the synthesis process uses expensive reagents such as laburnine, palladium acetate and the like, and has higher synthesis cost price; the process needs low temperature (-78-65 ℃), has high requirement on industrial equipment and large energy consumption;
the third method comprises the following steps: US2014371217a1
The yield of the first three steps of the process is 55.51%, and the solvents of the three steps are different in types and difficult to recover. A large amount of wastewater is generated in each step of post-treatment;
in order to simplify the process, facilitate solvent recovery and avoid the generation of large amounts of wastewater, it is necessary to develop a simplified process suitable for industrial scale-up to accomplish the above chemical preparation.
Disclosure of Invention
The invention aims to provide a method for preparing a erlotinib intermediate by a one-pot method aiming at the defects of the prior art.
The invention discloses a simplified preparation process of a broad-spectrum targeting tumor drug Raatinib intermediate (R) -2- (2, 5-difluorophenyl) pyrrolidine (R) -2-hydroxysuccinate, which reduces a large amount of wastewater generated by post-reaction treatment and reduces the types of solvents.
The compound IV is prepared by using 2, 5-difluorobromobenzene as a raw material through a one-pot method. Wherein the compounds I, II, III do not have to be treated. Only the reaction solution needs to be put into the next reaction, the operation process is greatly simplified, and complex post-treatments such as washing, drying, filtering, purifying and the like are not needed. And the use of various organic solvents and the generation of excessive waste water do not exist. The recovery of the solvent is facilitated. And carrying out salt formation and resolution on the crude product IV and D-malic acid, and recrystallizing the obtained solid to obtain a pure product V.
The synthetic route is as follows:
a process for the preparation of the intermediate of erlotinib, (R) -2- (2, 5-difluorophenyl) pyrrolidine (R) -2-hydroxysuccinate in a "one-pot" process comprising the steps of:
step 1): dissolving a compound VI serving as a raw material in a solvent, and then adding isopropyl magnesium chloride to generate a Grignard reagent; and then reacting with N-Boc-pyrrolidone to obtain a compound I:
step 2): adding acid into the reaction liquid, carrying out Boc removal reaction on the compound I, and obtaining a compound II after the reaction is finished;
step 3), adding alkali into the reaction liquid, carrying out ring closing reaction on the compound II, and obtaining a compound III after the reaction is finished;
step 4), in the reaction solution, reducing the compound III to obtain a compound IV;
step 5): salifying the compound IV and D-malic acid, and recrystallizing to obtain a compound V;
the synthetic route is as follows:
the compound names in the above synthetic routes are:
a compound I: 4- (2, 5-difluorophenyl) -4-oxybutylcarbamate.
Compound ii: 4-amino-1- (2, 5-difluorophenyl) butan-1-one hydrochloride.
Compound iii: 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole.
A compound IV: 2- (2, 5-difluorophenyl) pyrrolidine.
Compound v: (R) -2- (2, 5-difluorophenyl) pyrrolidine (R) -2-hydroxysuccinate.
Compound VI: 2, 5-difluorobromobenzene.
Further, the reaction temperature in the step 1) is-10-15 ℃, and the solvent adopted in the step 1) is: any one of diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran and methyl tert-butyl ether; the equivalent weight of the isopropyl magnesium chloride is 1.2-2.0; preferably, the equivalent weight of isopropyl magnesium chloride is 1.2-1.5.
Further, the equivalent of the N-Boc-pyrrolidone in the step 1) is 0.8 to 1.0.
Further, step 1) also includes: after adding N-Boc-pyrrolidone into the reaction solution, dropwise adding acid to quench the reaction solution after the reaction is finished, standing the reaction solution for layering, and directly carrying out the reaction of the step 2) on an organic layer; wherein the acid is HCl, H2SO4，HNO3Any one of them.
Further, the reaction temperature in step 2) is 20 to 65 ℃, and the acid added in step 2) is HCl or trifluoroacetic acid, and the equivalent thereof is 2.0 to 3.0, preferably, the calculated equivalent is 2.0 to 2.6.
Further, in the step 3), the alkali is NaOH, KOH or Na2CO3、K2CO32.0-3.0 equivalent weight; the preferred equivalent weight is between 2.2 and 2.6.
Further, step 4) further comprises: adding a reduction catalyst, wherein the reduction catalyst is Pd/C or Pt/C or Raney Ni; the reaction temperature in step 4) is 0-25 ℃.
Further, step 4) also includes: adding a reducing agent, wherein the reducing agent is NaBH4，KBH4And the equivalent weight is 2.0-3.0.
Further, the equivalent of the D-malic acid in the step 5) is 0.5-1.5.
Further, the step 5) is specifically as follows: dissolving the crude product IV obtained in the step 4) in a solvent, adding D-malic acid, salifying at the temperature of 0-50 ℃ to obtain a solid, and recrystallizing in the solvent to obtain a pure product V; wherein the solvent used in the recrystallization is methanol or ethanol or tetrahydrofuran.
The invention has the beneficial effects that:
the first invention relates to a key intermediate of the Rotinib, and a simplified process of (R) -2- (2, 5-difluorophenyl) pyrrolidine (R) -2-hydroxysuccinate; can facilitate the solvent recovery and avoid generating a large amount of waste water.
Specifically, compared with the prior art: compared with CN108218754A, CN102224153A and US2014371217A1, various solvents can be recycled (the environment-friendly effect is better, the waste water is less), the yield of the compound is higher, and therefore, the scheme of the application has relatively lower production cost in all aspects; meanwhile, as the waste water is less, the cost required for treating the waste water is also controlled, and the economic value and the social value are better.
Secondly, the applicant searches in a sopcat database and an EPO database, and no related report on the one-pot method for preparing 'the intermediate (R) -2- (2, 5-difluorophenyl) pyrrolidine (R) -2-hydroxysuccinate of rolitinib' is reported in the existing literature; according to the application, toxic and harmful substances are avoided in the synthesis process, the production cost is reduced from 8600/kg to 3800 yuan/kg (the cost is reduced by more than half), and the cheap and high-quality key intermediate (R) -2- (2, 5-difluorophenyl) pyrrolidine (R) -2-hydroxysuccinate of the erlotinib can be provided for designing and screening new drugs.
The basic inventive concept of the application is that a 'one-pot method', specifically, the same solvent is adopted in the steps 1) to 4), and a reaction container does not need to be replaced, so that the process is simplified, and the cost is reduced; and the simplified process can still obtain the (R) -2- (2, 5-difluorophenyl) pyrrolidine (R) -2-hydroxysuccinate with better purity, namely the process is simplified and the quality of the final product is not reduced.
Fourthly, the application starts from the scheme of the embodiment 1 (which can not be called as a 'one-pot method'), goes through the embodiment 2 (which can not be called as a 'one-pot method'), the embodiment 3 and the embodiment 4, and the continuous updating of the four-generation process, reduces the cost from 5800 to 3800, namely reduces the production cost by 34 percent, and has great economic benefit and social benefit.
Detailed Description
The following examples will help those skilled in the art to understand the gist of the preparation technique of the present invention, but are not intended to limit the scope of the present invention.
Comparative example 1: 29g of 2, 5-difluorobromobenzene were dissolved in 116ml of THF and cooled to about 5 ℃.70g of a 2.0M iPrMgCl solution was slowly added dropwise to the mixture while controlling the temperature below 25 ℃. After addition was cooled to about 5 ℃ and stirred for 1 hour (GC analysis confirmed Grignard formation). Temperature controlled below 25 deg.C, 18.5g N-Boc-pyrrolidone (diluted with 18.5ml THF) was slowly added dropwise. After the addition was completed, the mixture was stirred for 90min at about 5 deg.C (N-Boc-pyrrolidone was monitored to be less than 0.5% (by HPLC)). The reaction was quenched with 105g of 2M aqueous HCl while maintaining the reaction temperature below 45 ℃. The reaction was then transferred to a separatory funnel, 185ml heptane was added and the aqueous layer was removed. The organic layer was washed with 70ml of saturated aqueous NaCl solution, followed by addition of a volume of 37ml of saturated aqueous NaCl solution. The solvent of the organic layer was replaced with heptane (< l% wt THF, confirmed by GC), the distillation temperature was 35-55 ℃ and the distillation pressure was 100-200mmHg instead of adding 37ml x4 volumes of heptane and the minimum distillation volume was about 7 volumes. The mixture was then diluted to 10 volumes with heptane while heating to about 55 ℃ to give a dense solid and the mixture was allowed to cool to room temperature overnight. The slurry was cooled to less than 5 ℃ and filtered through a polypropylene filter cloth. The wet cake was washed with 37ml x 2 volume of heptane. The solid was dried under vacuum at 55 ℃ until weight was constant, yielding 24g of tert-butyl (4- (2, 5-difluorophenyl) -4-oxobutyl) -carbamate in 80% yield.
30g of tert-butyl (4- (2, 5-difluorophenyl) -4-oxobutyl) -carbamate are dissolved in 150ml of toluene and 40g of concentrated HCl (2.2eq) are added, a slight exotherm and gas evolution being observed. The reaction was heated to 65 ℃ and held for 12-24 hours and monitored by HPLC. After completion, the reaction was cooled to below 15 ℃ with an ice/water bath. The pH was adjusted to about 14 with 250ml of 2M aqueous NaOH solution. The reaction was stirred at room temperature for 1-2 hours. The mixture was transferred to a separatory funnel with toluene. The aqueous layer was removed and the organic layer was washed with 3 volumes of saturated aqueous NaCl solution. The organic layer was concentrated to an oil and redissolved in 1.5 volumes of heptane. The resulting suspension was filtered through GF/F filter paper and concentrated to give 16.5g of 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole as a pale yellow oil in 91% yield.
1.34g of chloro-1, 5-cyclooctadiene iridium dimer (0.2 mol%) and 1.5g of (R) -2- (2- (diphenylphosphino) phenyl) -4-isopropyl-4, 5-dihydrooxazole (0.4 mol%) were suspended in 925ml of MTBE at room temperature. The mixture was stirred for 1 hour and most of the solid dissolved and the solution turned dark red. The catalyst formation was monitored using an HPLC/PDA detector. The reaction was cooled to less than 5 ℃ and 182g of 5- (2, 5-difluorophenyl) -3, 4-dihydro-2H-pyrrole (1.0eq) were added, rinsing with 91ml MTBE. After controlling the temperature below 10 ℃, 276g of diphenylsilane was added dropwise. The temperature is controlled below 10 ℃, the mixture is stirred for 30 minutes and then the temperature is raised to the room temperature. The reaction was stirred at room temperature overnight. Completion of the reaction was confirmed by HPLC and then cooled to less than 5 ℃. The temperature was controlled below 20 ℃ and the reaction was quenched by addition of 910ml of 2M aqueous HCl. After 10 minutes, the ice/water bath was removed, the reaction was allowed to warm to room temperature and stirred for 2 hours. The mixture was transferred to a separatory funnel with 546ml MTBE. The aqueous layer was washed with 637ml of MTBE, 910ml of MTBE was added to the aqueous layer, and 136ml of 50% aqueous NaOH solution was added to adjust the pH to about 14. The organic layer was washed with 910ml of saturated aqueous NaCl solution, then concentrated to an oil and diluted with 546ml of MTBE. The solution was filtered through a polypropylene filter cloth and rinsed with 182ml MTBE. The filtrate was concentrated to give 175g of (R) -2- (2, 5-difluorophenyl) pyrrolidine as an oil in 95% yield and 75-85% ee.
18.3g of (R) -2- (2, 5-difluorophenyl) pyrrolidine (1.0 equivalent) were transferred to a round-bottomed flask filled with 275ml (corrected for potency) of EtOH (200 prf). 13.6g D-malic acid (1.05 eq.) was added and the mixture was heated to 65 ℃. The solids were all dissolved at about 64 ℃. The solution was allowed to cool to room temperature. The solution was crystallized from (R) -2- (2, 5-difluorophenyl) pyrrolidine (R) -2 hydroxy-succinate (about 50mg, > 97% ee) at about 55 ℃ and stirred at room temperature overnight. The suspension was then filtered through a polypropylene filter cloth and washed with 36.6ml of EtOH (200 prf). Drying under vacuum at 55 ℃ gave (R) -2- (2, 5-difluorophenyl) -pyrrolidine (R) -2-hydroxy-succinate in 84% yield with 96% ee.
Example 1: under nitrogen atmosphere, 127g of 2, 5-difluorobromobenzene was added into a 2000mL four-necked flask, 510mL of tetrahydrofuran was added, the temperature was reduced to 0-5 ℃, and 393.86mL of isopropyl magnesium chloride solution was added dropwise. After the dripping is finished, the temperature is controlled between 0 and 5 ℃ for reaction for 0.5 h. And (5) sampling and monitoring by HPLC (high performance liquid chromatography) to detect the exhaustion of the raw materials, and finishing format conversion. The temperature was controlled at 0-5 deg.C, 102g N-Boc-pyrrolidone was mixed with 100ml tetrahydrofuran solution and added dropwise to the reaction system. And (4) controlling the temperature to be 0-5 ℃ for reaction for 1h after the dripping is finished, and stopping the reaction after the sampling HPLC monitors and detects the consumption of the raw materials. 102.28ml of 2N dilute hydrochloric acid are added dropwise at the temperature of 5-10 ℃ until the pH value is 3-4, and after half an hour, the pH value is determined again. After dropping, standing for layering, and separating out an organic phase. The organic layer was dried and concentrated to give a viscous solid, to which 834.63g of n-heptane was added, and after heating to dissolve it, it was cooled and crystallized to give 143.80g of compound I. The yield thereof was found to be 87%
The compound I thus obtained was dissolved in 484ml of dichloromethane, and 273.9g of trifluoroacetic acid was added dropwise to the above organic phase while controlling the temperature at 20 to 30 ℃. After the addition, the temperature is raised to 30-35 ℃, the reaction is stopped until the liquid phase detection compound I is exhausted. After dichloromethane was removed by rotation, 2152ml of ethyl acetate was added thereto, and the mixture was heated to dissolve and clear, and then crystallized by cooling. Obtaining a compound III: 87.05 g. The yield is 100 percent
The compound iii obtained above: 87.05g of the product is dissolved in 843ml of methanol and cooled to 0-5 ℃. In this temperature range, 36.35g of NaBH4 as a solid was added to the system in portions. After the addition, the temperature is raised to 20-25 ℃. Reacting until the compound III is exhausted. The reaction was stopped. 700ml of 2N HCl solution was added dropwise to the system while controlling the temperature at 20-25 ℃ until the pH was 3-4. Stirring for 0.5h, and re-measuring the pH value. After the condition is ensured to be unchanged, methanol is removed by decompression and rotation. 365.6g of 30% NaOH was added dropwise to the system while controlling the temperature at 20-25 ℃ until the pH became 9-10. Stirring for 0.5h, and re-measuring the pH value to ensure that the pH value is unchanged. The system was extracted three times in succession with 464ml of DCM. The extracts were combined and washed twice with water. Dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to a constant weight to obtain 74.37g of a pale yellow liquid. The yield was 84.5%, and the purity was 94.33%.
A500 mL four-necked flask was charged with 74.37g of Compound IV and 43.55g D-malic acid and 315.0mL of absolute ethanol. After the addition, heating and stirring are carried out. After dissolution and clarification, slowly cooling. After the temperature is reduced to 0-5 ℃, no solid is separated out. After addition of seed crystals, a large amount of white solid precipitated. Stirring for 1h at the temperature, and performing suction filtration to obtain a filter cake. The filter cake was dried in vacuo to give 59.2g of crude 1.
The crude product 1 and 600.0ml of absolute ethanol were added to a 1000ml four-necked flask, and heated and stirred until the mixture became clear. After keeping the temperature for 0.5h, closing the heating, and slowly cooling for crystallization. After a large amount of crystals are separated out, the temperature is slowly reduced to 0-5 ℃ by a cold bath, and the temperature is kept for 1 h. Suction filtration and vacuum drying are carried out to obtain solid, and 39.86g of pure product V is obtained repeatedly. Yield 30.9% (relative to compound IV), purity 99.96%, ee value 99.11%.
Example 2: under nitrogen atmosphere, 30.95g of 2, 5-difluorobromobenzene was added into a 500mL four-necked flask, 100mL of tetrahydrofuran was added, the temperature was reduced and controlled to 0-5 ℃, and 100.22mL of isopropyl magnesium chloride solution was added dropwise. After the dripping is finished, the temperature is controlled between 0 and 5 ℃ for reaction for 0.5 h. And (5) sampling and monitoring by HPLC (high performance liquid chromatography) to detect the exhaustion of the raw materials, and finishing format conversion. The temperature was controlled at 0-5 deg.C, and 25.5g N-Boc-pyrrolidone and 25ml tetrahydrofuran solution were mixed and added dropwise to the reaction system. And (4) controlling the temperature to be 0-5 ℃ for reaction for 1h after the dripping is finished, and stopping the reaction after the sampling HPLC monitors and detects the consumption of the raw materials. Controlling the temperature to be 5-10 ℃, dropwise adding 105ml of 2N diluted hydrochloric acid until the PH value is 3-4, and repeatedly measuring the PH value after half an hour. After dropping, standing for layering, and separating out an organic phase. 37ml of concentrated hydrochloric acid was added dropwise to the organic phase while controlling the temperature at 20 to 30 ℃. After the addition, the temperature is raised to 45-50 ℃, the reaction is stopped until the liquid phase detection compound I is exhausted. The temperature was reduced to 10-15 ℃ and 50.0g of 30% NaOH was added dropwise to a pH of 8-9. Stirring for 0.5h, and re-measuring the pH value. After the reaction is ensured to be unchanged, the 2-methyltetrahydrofuran is removed by decompression until the system weight is constant. 200.0ml of absolute ethanol is added into the system. The temperature was controlled to 0-5 ℃ and 8.84g of NaBH4 as a solid was added to the system in portions. After the addition, the temperature is raised to 20-25 ℃. Reacting until the compound III is exhausted. The reaction was stopped. The temperature was controlled at 20-25 ℃ and 186ml of 2N HCl solution was added dropwise to the system until the pH was 3-4. Stirring for 0.5h, and re-measuring the pH value. After the condition is ensured to be unchanged, ethanol is removed by decompression and spin-out. A large amount of solid is separated out, and 50ml of water is added into the system for dissolving. 47.29g of 30% NaOH was added dropwise to the system while controlling the temperature at 20-25 ℃ until the pH became 9-10. Stirring for 0.5h, and re-measuring the pH value to ensure that the pH value is unchanged. The system was extracted three times in succession with 100ml of DCM. The extracts were combined and washed twice with water. Dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to a constant weight to obtain 22.12g of a pale yellow liquid. The yield was 87.7% and the purity was 95.55%.
A250 mL four-necked flask was charged with 20.82g of Compound IV, 11.95g D-malic acid, and 104.0mL of absolute ethanol. After the addition, heating and stirring are carried out. After dissolution and clarification, slowly cooling. After the temperature is reduced to 0-5 ℃, no solid is separated out. After addition of seed crystals, a large amount of white solid precipitated. Stirring for 1h at the temperature, and performing suction filtration to obtain a filter cake. The filter cake was dried in vacuo to give 20.50g of crude 1.
The crude product 1 and 200.0ml of absolute ethanol were added to a 500ml four-necked flask, and the mixture was heated and stirred until it was clear. After keeping the temperature for 0.5h, closing the heating, and slowly cooling for crystallization. After a large amount of crystals are separated out, the temperature is slowly reduced to 0-5 ℃ by a cold bath, and the temperature is kept for 1 h. Suction filtration and vacuum drying are carried out to obtain solid, and the steps are repeated to obtain 12.99g of pure product V. Yield 36.09% (relative to compound IV), purity 99.95%, ee value 99.34%.
Example 3: under nitrogen atmosphere, 30.95g of 2, 5-difluorobromobenzene was added into a 500mL four-necked flask, then 100mL of tetrahydrofuran was added, the temperature was reduced and controlled to 0-5 ℃, and 100.22mL of isopropylmagnesium chloride tetrahydrofuran solution was added dropwise. After the dripping is finished, the temperature is controlled between 0 and 5 ℃ for reaction for 0.5 h. And (5) sampling and monitoring by HPLC (high performance liquid chromatography) to detect the exhaustion of the raw materials, and finishing format conversion. The temperature was controlled at 0-5 deg.C, and 25.5g N-Boc-pyrrolidone and 25ml tetrahydrofuran solution were mixed and added dropwise to the reaction system. And (4) controlling the temperature to be 0-5 ℃ for reaction for 1h after the dripping is finished, and stopping the reaction after the sampling HPLC monitors and detects the consumption of the raw materials. Controlling the temperature to be 5-10 ℃, dropwise adding 105ml of 2N diluted hydrochloric acid until the PH value is 3-4, and repeatedly measuring the PH value after half an hour. After dropping, standing for layering, and separating out an organic phase. 37ml of concentrated hydrochloric acid was added dropwise to the organic phase while controlling the temperature at 20 to 30 ℃. After the addition, the temperature is raised to 45-50 ℃, the reaction is stopped until the liquid phase detection compound I is exhausted. The temperature was reduced to 10-15 ℃ and 50.0g of 30% NaOH was added dropwise to a pH of 7-8. Stirring for 0.5h, and re-measuring the pH value. After the reaction is ensured to be unchanged, 0.2g of 5 percent Pd/C is directly added into the system, and the temperature is controlled to be 15-20 ℃ for hydrogenation until the compound III is exhausted. The catalyst was filtered off and THF was removed under reduced pressure until the weight of the system was constant. Standing and layering to obtain 23.9 light yellow liquid. The yield is 94.5%, and the purity is 98.09%.
A250 mL four-necked flask was charged with 22.93g of Compound IV and 13.18g D-malic acid and 115.0mL of absolute ethanol. After the addition, heating and stirring are carried out. After dissolution and clarification, slowly cooling. After the temperature is reduced to 0-5 ℃, no solid is separated out. After addition of seed crystals, a large amount of white solid precipitated. Stirring for 1h at the temperature, and performing suction filtration to obtain a filter cake. The filter cake was dried in vacuo to give 23.70g of crude 1.
In a 500ml four-necked flask, crude product 1 and 230.0ml of absolute ethanol were added, and the mixture was heated and stirred until it was clear. After keeping the temperature for 0.5h, closing the heating, and slowly cooling for crystallization. After a large amount of crystals are separated out, the temperature is slowly reduced to 0-5 ℃ by a cold bath, and the temperature is kept for 1 h. Suction filtration and vacuum drying to obtain solid, and repeating the above steps to obtain 14.33g of pure product V. Yield 36.1% (relative to compound IV), purity 99.92%, ee value 99.04%.
Example 4: under nitrogen atmosphere, 30.95g of 2, 5-difluorobromobenzene was added into a 500mL four-necked flask, then 100mL of tetrahydrofuran was added, the temperature was reduced and controlled to 0-5 ℃, and 100.22mL of isopropylmagnesium chloride tetrahydrofuran solution was added dropwise. After the dripping is finished, the temperature is controlled between 0 and 5 ℃ for reaction for 0.5 h. And (5) sampling and monitoring by HPLC (high performance liquid chromatography) to detect the exhaustion of the raw materials, and finishing format conversion. The temperature was controlled at 0-5 deg.C, and 25.5g N-Boc-pyrrolidone and 25ml tetrahydrofuran solution were mixed and added dropwise to the reaction system. And (4) controlling the temperature to be 0-5 ℃ for reaction for 1h after the dripping is finished, and stopping the reaction after the sampling HPLC monitors and detects the consumption of the raw materials. Controlling the temperature to be 5-10 ℃, dropwise adding 105ml of 2N diluted hydrochloric acid until the PH value is 3-4, and repeatedly measuring the PH value after half an hour. After dropping, standing for layering, and separating out an organic phase. 37ml of concentrated hydrochloric acid was added dropwise to the organic phase while controlling the temperature at 20 to 30 ℃. After the addition, the temperature is raised to 45-50 ℃, the reaction is stopped until the liquid phase detection compound I is exhausted. The temperature was reduced to 10-15 ℃ and 50.0g of 30% NaOH was added dropwise to a pH of 7-8. Stirring for 0.5h, and re-measuring the pH value. After the reaction is ensured to be unchanged, 0.2g of 5 percent Pt/C is directly added into the system, and the temperature is controlled to be 15-20 ℃ for hydrogenation until the compound III is exhausted. The catalyst was filtered off and THF was removed under reduced pressure until the weight of the system was constant. Standing for layering to obtain 24.3g of light yellow liquid. The yield is 96.1 percent, and the purity is 98.85 percent.
A250 mL four-necked flask was charged with 23g of Compound IV and 14.5g D-malic acid and 115.0mL of absolute ethanol. After the addition, heating and stirring are carried out. After dissolution and clarification, slowly cooling. After the temperature is reduced to 0-5 ℃, no solid is separated out. After addition of seed crystals, a large amount of white solid precipitated. Stirring for 1h at the temperature, and performing suction filtration to obtain a filter cake. The filter cake was dried in vacuo to give 24.9g of crude 1.
The crude product 1 and 250.0ml of absolute ethanol were added to a 500ml four-necked flask, and the mixture was heated and stirred until it was clear. After keeping the temperature for 0.5h, closing the heating, and slowly cooling for crystallization. After a large amount of crystals are separated out, the temperature is slowly reduced to 0-5 ℃ by a cold bath, and the temperature is kept for 1 h. Suction filtration and vacuum drying are carried out to obtain solid, and 14.8g of pure product V is obtained by repeating the steps. Yield 37.2% (relative to compound IV), purity 99.96%, ee value 99.02%.
The costs of the above examples 1, 2, 3 and 4 are as follows:
the cost of producing (R) -2- (2, 5-difluorophenyl) pyrrolidine (R) -2-hydroxysuccinate of comparative example 1 was around 8652.11 yuan/kg.
The cost of producing (R) -2- (2, 5-difluorophenyl) pyrrolidine (R) -2-hydroxysuccinate of example 1 is around 5860.84 yuan/kg.
The cost of producing (R) -2- (2, 5-difluorophenyl) pyrrolidine (R) -2-hydroxysuccinate of example 2 is around 3887.16 yuan/kg.
Example 3 the cost of producing (R) -2- (2, 5-difluorophenyl) pyrrolidine (R) -2-hydroxysuccinate is around 3827.39 RMB/kg;
the cost of producing (R) -2- (2, 5-difluorophenyl) pyrrolidine (R) -2-hydroxysuccinate of example 4 is around 3814.88 yuan/kg;
from the above, the schemes of examples 3 and 4 are optimal.
The above-mentioned processes from comparative example 1 to example 2 to example 3 to example 4 are also the development routes of the applicant's technology.
The above-mentioned embodiments are only for convenience of description, and are not intended to limit the present invention in any way, and those skilled in the art will understand that the technical features of the present invention can be modified or changed by other equivalent embodiments without departing from the scope of the present invention.
Claims (5)
- A process for the preparation of a Larotenib intermediate in a one-pot process comprising the steps of:step 1): dissolving a compound VI serving as a raw material in a solvent, and then adding isopropyl magnesium chloride to generate a Grignard reagent; and then reacting with N-Boc-pyrrolidone to obtain a compound I:step 2): adding acid into the reaction liquid, carrying out Boc removal reaction on the compound I, and obtaining a compound II after the reaction is finished;step 3), adding alkali into the reaction liquid, carrying out ring closing reaction on the compound II, and obtaining a compound III after the reaction is finished;step 4), in the reaction solution, reducing the compound III to obtain a compound IV;step 5): salifying the compound IV and D-malic acid, and recrystallizing to obtain a compound V;the synthetic route is as follows:the reaction temperature in the step 1) is-10-15 ℃, and the solvent adopted in the step 1) is as follows: tetrahydrofuran;the step 1) further comprises the following steps: after adding N-Boc-pyrrolidone into the reaction solution, dropwise adding acid to quench the reaction solution after the reaction is finished, standing the reaction solution for layering, and directly carrying out the reaction of the step 2) on an organic layer; wherein the acid is HCl, H2SO4，HNO3Any one of the above;the reaction temperature in the step 2) is 20-65 ℃, the acid added in the step 2) is HCl or trifluoroacetic acid, and the equivalent weight is 2.0-3.0;in the step 3), the alkali is NaOH, KOH or Na2CO3、K2CO32.0-3.0 equivalent weight;the step 4) further comprises the following steps: adding a reduction catalyst, wherein the reduction catalyst is Pd/C or Pt/C or Raney Ni; the reaction temperature of the step 4) is 0-25 ℃;step 4) also comprises the following steps: adding a reducing agent, wherein the reducing agent is NaBH4，KBH4And the equivalent weight is 2.0-3.0.
- 2. The process for the preparation of a rasotinib intermediate in a "one-pot" process according to claim 1, wherein the equivalent weight of isopropyl magnesium chloride in step 1) is 1.2-2.0.
- 3. The process for the "one-pot" preparation of a rasotinib intermediate of claim 1, wherein the equivalent weight of the N-Boc-pyrrolidone in step 1) is 0.8-1.0.
- 4. The process for preparing a rasotinib intermediate in a "one-pot" process according to claim 1, wherein the equivalent weight of D-malic acid in step 5) is 0.5-1.5.
- 5. The method for preparing the intermediate of erlotinib by the one-pot method according to claim 1, wherein step 5) is specifically: dissolving the crude product IV obtained in the step 4) in a solvent, adding D-malic acid, salifying at the temperature of 0-50 ℃ to obtain a solid, and recrystallizing in the solvent to obtain a pure product V; wherein the solvent used in the recrystallization is methanol or ethanol or tetrahydrofuran.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010293708.6A CN111302997B (en) | 2020-04-15 | 2020-04-15 | Method for preparing Raatinib intermediate by one-pot method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010293708.6A CN111302997B (en) | 2020-04-15 | 2020-04-15 | Method for preparing Raatinib intermediate by one-pot method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111302997A CN111302997A (en) | 2020-06-19 |
| CN111302997B true CN111302997B (en) | 2022-03-29 |
Family
ID=71151900
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010293708.6A Active CN111302997B (en) | 2020-04-15 | 2020-04-15 | Method for preparing Raatinib intermediate by one-pot method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111302997B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107207514A (en) * | 2014-12-15 | 2017-09-26 | 康联制药有限公司 | Fused ring heteroaryl compound and its purposes as TRK inhibitor |
| CN107428760A (en) * | 2014-11-16 | 2017-12-01 | 阵列生物制药公司 | (S) crystal formation of the formamide disulfate of N (base of 5 (base of (R) 2 (2,5 difluorophenyl) pyrrolidines 1) pyrazolo [1,5 A] pyrimidine 3) 3 hydroxyl pyrrolidine 1 |
| CN109310694A (en) * | 2016-04-04 | 2019-02-05 | 洛克索肿瘤学股份有限公司 | Methods of treating pediatric cancers |
| CN109456331A (en) * | 2017-12-22 | 2019-03-12 | 深圳市塔吉瑞生物医药有限公司 | A kind of substituted pyrazolo [1,5-a] pyrimidine compound and its pharmaceutical composition and purposes |
-
2020
- 2020-04-15 CN CN202010293708.6A patent/CN111302997B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107428760A (en) * | 2014-11-16 | 2017-12-01 | 阵列生物制药公司 | (S) crystal formation of the formamide disulfate of N (base of 5 (base of (R) 2 (2,5 difluorophenyl) pyrrolidines 1) pyrazolo [1,5 A] pyrimidine 3) 3 hydroxyl pyrrolidine 1 |
| CN107207514A (en) * | 2014-12-15 | 2017-09-26 | 康联制药有限公司 | Fused ring heteroaryl compound and its purposes as TRK inhibitor |
| CN109310694A (en) * | 2016-04-04 | 2019-02-05 | 洛克索肿瘤学股份有限公司 | Methods of treating pediatric cancers |
| CN109456331A (en) * | 2017-12-22 | 2019-03-12 | 深圳市塔吉瑞生物医药有限公司 | A kind of substituted pyrazolo [1,5-a] pyrimidine compound and its pharmaceutical composition and purposes |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111302997A (en) | 2020-06-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111315742B (en) | Process for preparing aminopyrimidine derivatives | |
| CN111592467A (en) | Nilaparib intermediate, preparation method and application thereof, and synthesis method of nilapab | |
| CN114096529A (en) | Chemical process | |
| US3644380A (en) | Preparation of 3-cyanopyridine | |
| CN111302997B (en) | Method for preparing Raatinib intermediate by one-pot method | |
| CN112679498B (en) | Quaternary ammonium sulfonate compound and preparation method and application thereof | |
| CA2570833C (en) | Process for producing (z)-1-phenyl-1-diethylaminocarbonyl-2-aminomethylcyclopropane hydrochloride | |
| CN102010353B (en) | Method for preparing rasagiline mesylate | |
| CN110218189B (en) | Abelide intermediate and simple preparation method of Abelide | |
| CN113336761B (en) | Preparation method of JAK inhibitor key intermediate | |
| CN102477019A (en) | Novel method for producing S-3-hydroxytetrahydrofuran | |
| AU2021404731B2 (en) | Synthesis method for cyclopropyl-containing chiral amine hydrochloride | |
| CN110790708B (en) | Preparation method of Ailixipine intermediate | |
| CN110724098A (en) | Synthetic method of 5, 7-dichloro-1, 2,3, 4-tetrahydroisoquinoline-6-carboxylic acid hydrochloride | |
| CN100383144C (en) | Intermediate of olanzapine, preparation and application thereof | |
| CN114213323B (en) | New process for synthesizing procaterol hydrochloride | |
| CN110483402B (en) | Synthetic method of 3-bromo-5-phenyl-1H-pyrazole | |
| CN110746367B (en) | Synthesis method of 1,2, 4-triazole-3-methyl carboxylate | |
| CN111018734B (en) | Synthesis method of cinacalcet hydrochloride intermediate | |
| CN110590641B (en) | Green preparation method of 3-hydroxyisoindole-1-ketone series compounds | |
| CN109748885B (en) | Ceritinib intermediate and preparation method of ceritinib | |
| CN109836373B (en) | Environment-friendly preparation method of vitamin B6 and tail gas recycling method | |
| CN112778193A (en) | Synthesis method of (S) -3- (4-chlorphenyl) -piperidine | |
| CN110092749A (en) | A kind of antidepressants NSI189 and its phosphatic synthetic method | |
| CN113372254A (en) | Preparation method of 3-chloro-4-amino N-phenylmaleimide compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |