CN110615753A - Synthesis method of (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid - Google Patents
Synthesis method of (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid Download PDFInfo
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- CN110615753A CN110615753A CN201910822037.5A CN201910822037A CN110615753A CN 110615753 A CN110615753 A CN 110615753A CN 201910822037 A CN201910822037 A CN 201910822037A CN 110615753 A CN110615753 A CN 110615753A
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Abstract
The invention discloses a synthetic method of (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid, which comprises the following steps: reacting N-R-3-pyrroline with NBS to prepare an intermediate compound 2; adding the compound 2 into ethyl magnesium chloride or ethyl magnesium bromide for reaction to obtain an intermediate product compound 3; carrying out oxidation reaction on the intermediate compound 3 to obtain an N-site protected intermediate product compound 4; reacting the intermediate compound 4 with a trifluoromethanesulfonylation reagent to prepare an intermediate product compound 5; introducing carbon monoxide gas into the intermediate compound 5, and reacting to obtain an intermediate compound 6; hydrolyzing the intermediate compound 6 to synthesize an intermediate compound 7; and (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid with high chiral purity is prepared by carrying out asymmetric reduction reaction on the intermediate compound 7. According to the synthesis method of (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid, the target product is prepared by adopting the low-cost reaction raw materials, and the economic cost of the product process is reduced.
Description
Technical Field
The invention relates to a synthesis method of (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid, belonging to the technical field of chiral compound synthesis.
Background
JAK inhibitors selectively inhibit JAK kinases, blocking the JAK/STAT pathway. The JAK-STAT signal pathway is a signal transduction pathway stimulated by cytokines discovered in recent years and is involved in a plurality of important biological processes such as proliferation, differentiation, apoptosis, immunoregulation and the like of cells. JAK is a widely recognized target in the industry. Tofacitinib, pfeiffer, currently has been approved for the treatment of rheumatoid arthritis and has reached $ 9.27 billion in 2016. Norwalk/Incyte ruxolitinib (ruxolitinib) was approved for the treatment of myelofibrosis, polycythemia vera, and a global sale of $ 14.34 million in 2016 also reached.
The new drug, upadacetitinib (code ABT-494) of AbbVie company, is a new oral selective JAK-1 inhibitor, and phase III research on the treatment of rheumatoid arthritis and psoriatic arthritis is underway. In addition, upadacitinib has also been developed to treat crohn's disease, ulcerative enteritis, and ankylosing spondylitis. On 7 days 9/2017, AbbVie announced that upadacetitinib (ABT-494), a randomized, placebo-controlled, dose-range IIb study for the treatment of atopic dermatitis, reached the end point, and the results showed that clinical trials of various dose groups of empatinib showed excellent effects, which data would have a great positive effect on the promotion of empatinib to further clinical trials or to the market. The Upactinib is expected to have wide market value, and the Upactinib bulk drug also has wide industrial value.
The bulk drug of the lapatinib is a chiral heterocyclic compound containing two chiral centers, and the synthesis difficulty is very high. The MCD website shows that the maximum 25mg specification of sepianib compounds reaches 1620 memantine. The synthetic route of the lapatinib reported in the literature is that two fragments are synthesized and then the reaction is carried out for at least 4 steps. Wherein, the intermediate compound of the hand-type fragment is the key of the process and the synthesis difficulty thereof, and plays a decisive influence on the overall process and the final product property of the compound, and the synthetic route reported by Upactinib is as follows:
the yield of the intermediate compound of the hand fragment is lower (the total yield is less than 15%) in the prior art, the process is mainly used for controlling the purity of the hand fragment by preparing and obtaining a racemate and then splitting the racemate for a plurality of times, or the process route is too long, the reaction conditions of individual steps are harsh, and the process has environment-friendly conditions at the same time. How to improve the overall yield of the process under the condition of ensuring that the purity of the hand is more than 99 percent, shorten the process steps and reduce the process cost will have important influence on the quality and price of the final product of the sepitinib.
The patent CN104370909A// US2011/0311474A1// WO201106888A1 reports the following route:
2-ethyl alkynylpentanoate is used as a starting material, alkyne is reduced into alkene by hydrogenation under the catalysis of Lindlar catalyst, a racemic intermediate is prepared by ring closure, and then CBZ on the debenzyl is removed
The main disadvantage of the process is that racemic precursor is synthesized, and then the racemic precursor is split again, the theoretical highest yield is 50%, and the actual yield is about 14.75% (calculated by combining yield data disclosed in each step of the document with the split yield of 100%).
The patent publication No. CN109705011A discloses the following synthetic route:
the route reports that the same starting material of 2-alkyne ethyl valerate is used as that in the patent CN104370909A// US2011/0311474A1// WO201106888A1, except that ring formation is carried out firstly and then reduction is carried out, the process route is shortened, the problem of low boiling point and low volatility is avoided, and the overall process yield is improved. But the key disadvantages of the route are as follows: the starting material 2-propargyl ethyl valerate is expensive, and the preparation and production process needs butyne and bromine to carry out ultralow temperature high-risk reaction. The price of butyne in hundred kilograms is still very expensive, and bromine is a dangerous product. The high-risk reaction and the expensive raw material price cause the high price of the final product, which is not beneficial to the industrial production of the route.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a synthetic method of (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid, which avoids ultralow-temperature high-risk reaction, avoids the use of expensive starting materials and reduces the economic cost of the product process.
The technical purpose of the invention is realized by the following technical scheme:
a method for synthesizing (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid comprises the following steps:
s1, adding N-R-3-pyrroline into a first solvent formed by organic solvent/water, and adding NBS (N-bromosuccinimide) to react under the catalysis of alkali to prepare an intermediate compound (2), wherein R is a protecting group;
s2, adding the compound (2) into a second solvent, adding ethyl magnesium chloride or ethyl magnesium bromide for reaction, and reacting to obtain an intermediate product compound (3);
s3, adding the intermediate compound (3) into a third solvent, adding an oxidant, and performing oxidation reaction to obtain an N-position protection intermediate product compound (4);
s4, adding the intermediate compound (4) into a fourth solvent, and reacting with a trifluoromethanesulfonylation reagent under the condition of alkali to prepare an intermediate product compound (5);
s5, adding the intermediate compound (5) into a fifth solvent, and introducing carbon monoxide gas in the presence of a catalyst to react to obtain an intermediate compound (6);
s6, adding the intermediate compound (6) into a sixth solvent, and hydrolyzing under alkaline conditions to synthesize an intermediate compound (7);
s7, carrying out asymmetric reduction reaction on the intermediate compound (7) under hydrogen and a catalyst to prepare a high-chiral-purity product (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid;
the reaction process is as follows:
by adopting the technical scheme, the (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid is prepared by adopting cheap reaction raw materials, the ultralow-temperature high-risk reaction is avoided, the use of expensive starting raw materials is avoided, and the preparation method is simple and easy to control.
Preferably, the protecting group R in the N-R-3-pyrroline in the S1 is one of tert-butoxycarbonyl or benzyloxycarbonyl.
Preferably, the molar ratio of N-R-3-pyrroline to NBS in S1 is 1: 1-2; the organic solvent in the solvent of the first solvent in the S1 is any one or combination of DMSO, DMF, ethyl acetate, acetonitrile, toluene, acetone, dichloromethane, trichloromethane and 1, 2-dichloroethane; the alkali in the S1 is any one or the combination of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, DBU and diethylamine; the reaction temperature in the S1 is-5-25 ℃.
Preferably, the second solvent in S2 is any one of toluene, dichloromethane, chloroform, tetrahydrofuran, 1, 2-dichloroethane, 1, 4-dioxane, or a combination thereof; the molar ratio of the compound (2) in the S2 to the ethyl magnesium bromide or ethyl magnesium chloride is 0.8-1: 1-5; the reaction temperature in the S2 is 0-90 ℃.
Preferably, the third solvent in S3 is any one of ethyl acetate, acetonitrile, toluene, acetone, dichloromethane, or a combination thereof; the oxidant in the S3 is one of m-chloroperoxybenzoic acid or Dess-Marting oxidant; the molar ratio of the compound (3) to the oxidant in S3 is 1: 1-3; the reaction temperature in the S3 is 0-25 ℃.
Preferably, the fourth solvent in S4 is any one of toluene, dichloromethane, tetrahydrofuran 1, 2-dioxane, or a combination thereof; the base in S4 is any one or combination of sodium hydride, LiHMDS, LDA, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and DBU; the molar ratio of the compound (4) to the base in S4 is 1: 1-3; the trifluoromethanesulfonylation reagent in the S4 is one of N-phenyl bis (trifluoromethanesulfonyl) imide and trifluoromethanesulfonic anhydride; the reaction temperature in the S4 is-78-80 ℃.
Preferably, the fifth solvent in S5 is any one of methanol, ethanol, or a combination thereof; the reaction temperature in the S5 is preferably 10-50 ℃, the reaction pressure is 0.1-1 MPa, and the reaction time is 1-24 h; the reaction catalyst in the S5 is a palladium catalyst.
Preferably, the sixth solvent in S6 is an aqueous solvent, and the kind of the solvent is one or a combination of dioxane, tetrahydrofuran, methanol, ethanol and isopropanol; the alkali in the S6 is one or the combination of potassium hydroxide, sodium hydroxide, lithium hydroxide and sodium methoxide.
Preferably, the solvent in S7 is any one or combination of toluene, acetone, dichloromethane, 1, 2-dioxane, methanol, ethanol, isopropanol, benzyl alcohol, and water; the base in the S7 is any one or the combination of triethylamine, diisopropylethylamine, diisopropylamine, DBU, potassium hydroxide and lithium hydroxide; the molar ratio of compound (7) to base in S7 is 1: 1-10; the reaction temperature in the S7 is 20-50 ℃, the reaction time is 1-24 h, and the reaction pressure range is 0.1-6 MPa; the catalyst in S7 is S-segphos Ru (OAc)2, and the molar ratio of the compound (7) to the S-segphos Ru (OAc)2 is 1: 0.001 to 0.3.
In conclusion, the invention has the following beneficial effects:
(1) according to the synthetic method of the (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid, the (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid is prepared by adopting low-cost reaction raw materials and a mild reaction mode, ultralow-temperature high-risk reaction is avoided, expensive starting raw materials are avoided, and the economic cost of the product process is reduced;
(2) the synthesis method of (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid provided by the invention has the advantages that the total yield is increased to 59.82% under the condition that the product hand purity is more than 99%, the total yield is greatly increased, and a positive effect is provided for the industrial production of the lapatinib bulk drug.
Drawings
FIG. 1 is a drawing of Compound 2b of the present invention1A HNMR map;
FIG. 2 is a drawing of Compound 3b of the present invention1A HNMR map;
FIG. 3 preparation of Compound 6b of the present invention1A HNMR map;
FIG. 4 preparation of Compound 7b of the present invention1A HNMR map;
FIG. 5 preparation of Compound 8b of the present invention1A HNMR map;
FIG. 6 preparation of Compound 6a of the present invention1A HNMR map;
FIG. 7 preparation of Compound 7a of the present invention1A HNMR map;
FIG. 8 preparation of Compound 8a of the present invention1HNMR map.
Detailed Description
The invention is further described below. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
Example 1
First-step reaction (1 b-2 b):
the method comprises the following operation steps:
weighing 500.0g (2.95mol,1.0eq) of the raw material 1b, adding the raw material into a clean reaction bottle, adding 2.5L of solvent DMSO and 2.5L of water, stirring to form a uniform solution, cooling in an ice-water bath, and controlling the internal temperature to be 0-5 ℃. 650.0g (3.65mol,1.24eq) of NBS solid was weighed out and added to the above solution in portions, with exotherm occurring and controlled internal temperature not higher than 10 ℃. After the NBS addition, the reaction was carried out by heating to 25 ℃ for 4 hours, and then sampling was carried out to monitor the completion of the reaction. 176.0g of sodium hydroxide is added into 900ml of water to prepare a sodium hydroxide aqueous solution, the sodium hydroxide aqueous solution is added into the solution after the reaction, the reaction is kept at room temperature for 3 hours, and the reaction is monitored by sampling.
And adding 5L of ethyl acetate into the reaction system, stirring, extracting, layering and removing the water phase. Adding 5L of sodium thiosulfate aqueous solution with the mass fraction of 10% into the organic phase, stirring and extracting, adding 4L of water into the obtained organic phase, extracting once, adding anhydrous sodium sulfate into the obtained organic phase, drying, filtering, concentrating at 35-40 ℃ to obtain 525.12g of product oily matter, wherein the yield is 96.0%, and the product oily matter is used for the next reaction.
Second reaction (2 b-3 b):
the method comprises the following operation steps:
in a dry clean reaction vessel, 525.0g (2.83mol,1.0eq) of the epoxy compound 2b was weighed, 2.6L of anhydrous dichloromethane was added as a solvent, and the mixture was replaced with nitrogen gas 3 times under nitrogen protection. Cooling, and controlling the internal temperature at 10 ℃. Ethyl magnesium bromide was added to tetrahydrofuran to form a 2.16mol/L solution of ethyl magnesium bromide. 1.44L (3.11mol,1.1eq) of the ethyl magnesium bromide solution is slowly dripped into a dichloromethane solution of an epoxy compound 2b, the heat release is obvious, the internal temperature is controlled to be not higher than 15 ℃ for dripping, the reaction is kept at 10-15 ℃ for 2h, and the reaction is tracked by sampling detection. Adding 1L of ammonium chloride aqueous solution (10% content) into the reacted solution, extracting and demixing, removing the aqueous phase, extracting the organic phase with 1L of water once again to obtain an organic phase, and performing reduced pressure concentration, azeotropic dehydration to obtain about 567.90g of product oily matter with yield of 93.21%. TLC single spot, purity is better.
The third reaction step (3 b-4 b):
the method comprises the following operation steps:
567.90g (2.64mol,1.0eq) of the 3b compound was put into a reaction flask, 2.84L of a dichloromethane solvent was added under nitrogen protection, and an ice-water bath was carried out with the internal temperature controlled at about 0 to 5 ℃. 683.33g (3.96mol,1.5eq) of m-chloroperoxybenzoic acid is weighed and added into a dichloromethane solution of a compound 3b, the addition is finished for about 20min, the reaction is kept at 0-5 ℃, the TLC tracking reaction is carried out, and the reaction is finished for 3 hours. The reaction solution was quenched by adding 2.84L (5v \ w) of water and filtered to remove insoluble white solid. The mother liquor is layered, the organic phase is taken and added with 1.42L (10 percent, 2.5v \ w) of sodium thiosulfate aqueous solution for extraction, and the organic phase is taken. The organic phase was extracted with 1.42L of water to give an organic phase, which was concentrated at 35 ℃ to give an oil, and then 4.96L (10 v/w) of dichloromethane was added to conduct azeotropic concentration and dehydration (35 ℃) to give 523.64g of an oil with a yield of 93%. Used for the next reaction.
The fourth reaction step (4 b-5 b):
the method comprises the following operation steps:
(1) in a dry clean reaction flask, 500.0g (2.34mol,1.0eq) of 4b compound was added, 2.5L of anhydrous tetrahydrofuran as a solvent was added, the mixture was stirred to dissolve, the air in the reactor was removed by nitrogen substitution 3 times, and the temperature was lowered to-70 ℃ in an acetone dry ice bath.
(2) LiHMDS is added to tetrahydrofuran to form a 1mol/L solution of LiHMDS. And (2) dropwise adding 2.46L (2.46mol,1.05eq) of LiHMDS solution into the tetrahydrofuran solution of the compound 4b in the step (1), controlling the internal temperature in the dropwise adding process to be not higher than-65 ℃, and after the dropwise adding is finished, keeping the internal temperature to be lower than-65 ℃ and reacting for 1 h.
(3) 357.25g (2.34mol,1.0eq) of N-phenyl bis (trifluoromethanesulfonyl) imide is dissolved in 1L of solvent anhydrous tetrahydrofuran, the internal temperature is controlled to be not higher than-60 ℃, the solution is dripped into the solution in the step (2), and after the dripping is finished, the temperature is kept to be not higher than-60 ℃ for reaction for 2 hours.
After TLC detection reaction, adding 2.5L ammonium chloride aqueous solution into the reaction system, stirring for about 5min, heating to room temperature, layering, extracting the water phase with 5L ethyl acetate, and removing the water phase to obtain ethyl acetate phase. The ethyl acetate phase and the tetrahydrofuran phase are combined, 2.5L of water is added for extraction once, the obtained organic phase is decompressed and concentrated at the temperature of less than or equal to 35 ℃ to obtain 719.27g of oily matter, the yield is 89.01 percent, and the oily matter is used for the next reaction.
Fifth reaction (5 b-6 b):
the method comprises the following operation steps:
100g (0.29mol,1.0eq) of the 5b compound was put in a clean 5L autoclave, 500ml of methanol was added and stirred uniformly, 3.26g (0.0145mol,0.05eq) of palladium acetate and 85.38g (0.87mol,3.0eq) of potassium acetate were added and stirred uniformly at room temperature, nitrogen gas was substituted for 3 times, and nitrogen gas was purged under reduced pressure to make the inside of the reactor negative. Introducing gas carbon monoxide, increasing the pressure to enable the internal pressure to reach 0.2MPa, and keeping the reaction at room temperature for 17 hours to finish the conversion. Discharging redundant carbon monoxide gas, replacing 3 times with nitrogen gas to fully replace and remove residual carbon monoxide, filtering reaction liquid, washing filter cake with 200ml of methanol to obtain filtered mother liquor, and directly using the filtered mother liquor for next reaction.
Sixth reaction step (6 b-7 b):
the method comprises the following operation steps:
adding 100g of the compound 6b into 500ml of methanol, stirring and dissolving uniformly, cooling to an internal temperature of 0-5 ℃, dropwise adding 300ml of 1N lithium hydroxide aqueous solution, controlling the internal temperature to be not higher than 15 ℃, stirring and keeping the room temperature for reaction for about 4 hours after dropwise adding; TLC detection reaction is complete; evaporating most of methanol at 40 ℃ under reduced pressure, adding 500mL of ethyl acetate and 100mL of water, stirring for 10 minutes, demixing, and removing an ethyl acetate phase; adding 600mL of ethyl acetate into the aqueous phase in an ice bath, and adjusting the pH value of the aqueous phase to 4 by using concentrated hydrochloric acid; layering, extracting the water phase once with 200mL ethyl acetate, combining the organic phases, concentrating the organic phases under reduced pressure until no fraction is produced to obtain 57.09g of light yellow oily matter with the total yield of the two steps of 81.7%;
seventh reaction (7 b-8 b):
adding 57.09g (1.0eq,0.2376mol) of the 7b compound into a hydrogen reaction kettle, adding 2.06g (0.025eq,0.0059mol) of a catalyst (S-segphos Ru (OAc)2, adding 250ml (4.38 v/w) of solvent methanol, uniformly stirring, adding 72.01g (3.0eq,0.713mol) of diisopropylamine, uniformly stirring, performing nitrogen replacement for 3 times, performing hydrogen replacement for 3 times, increasing the hydrogen pressure to 2.0MPa, reacting for 6 hours at the temperature of 30 ℃, after the sampling reaction is completed, replacing nitrogen to remove hydrogen, filtering diatomite, washing a filter cake with methanol (100ml 3) for three times, and evaporating the mother liquor to dryness under reduced pressure to obtain 56.07g of colorless to light yellow liquid (3R,4S) -1-tert-butoxycarbonyl-4-ethylpyrrole-3-carboxylic acid oily with the yield of 97%.
Example 2
First-step reaction (1 b-2 b):
the method comprises the following operation steps:
500.0g (2.95mol,1.0eq) of the raw material 1b was weighed into a clean reaction flask, 2.5L of the solvent 1, 2-dichloroethane and 2.5L of water were added, stirred to form a homogeneous solution, cooled in an ice-water bath, and the internal temperature was controlled at-5 ℃. 525.5g (2.95mol,1.0eq) of NBS solid was weighed out and added to the above solution in portions, with exotherm occurring and internal temperature controlled not to rise above 10 ℃. After the completion of NBS addition, the reaction was carried out at 10 ℃ for 4 hours, and the completion of the reaction was monitored by sampling. Adding 142.3g of sodium hydroxide into 700ml of water to prepare a sodium hydroxide aqueous solution, adding the sodium hydroxide aqueous solution into the solution after the reaction, keeping the room temperature for reacting for 3 hours, and sampling to monitor the completion of the reaction.
And adding 5L of ethyl acetate into the reaction system, stirring, extracting, layering and removing the water phase. Adding 5L of sodium thiosulfate aqueous solution with the mass fraction of 10% into the organic phase, stirring and extracting, adding 4L of water into the obtained organic phase, extracting once, adding anhydrous sodium sulfate into the obtained organic phase, drying, filtering, concentrating at 35-40 ℃ to obtain 519.65g of product oily matter, wherein the yield is 95.0%, and the product oily matter is used for the next reaction.
Second reaction (2 b-3 b):
the method comprises the following operation steps:
in a dry clean reaction vessel, 525.0g (2.83mol,1.0eq) of the epoxy compound 2b was weighed, 2.6L of anhydrous dichloromethane was added as a solvent, and the mixture was replaced with nitrogen gas 3 times under nitrogen protection. Cooling, and controlling the internal temperature at 10 ℃. Ethyl magnesium bromide was added to tetrahydrofuran to form a 2.16mol/L solution of ethyl magnesium chloride. 2.62L (5.65mol,2eq) of the ethyl magnesium bromide solution is slowly dripped into a dichloromethane solution of an epoxy compound 2b, the heat release is obvious, the internal temperature is controlled not to be higher than 15 ℃, the reaction is kept at 50 ℃ for 2 hours, and the sampling detection tracks the completion of the reaction. Adding 1L of ammonium chloride aqueous solution (10% content) into the reacted solution, extracting and demixing, removing the aqueous phase, extracting the organic phase with 1L of water again, and performing azeotropic dehydration on the obtained organic phase by reduced pressure concentration to obtain about 576.49g of product oily matter with the yield of 94.62%. TLC single spot, purity is better.
The third reaction step (3 b-4 b):
the method comprises the following operation steps:
567.90g (2.64mol,1.0eq) of the 3b compound was put into a reaction flask, 2.84L of a dichloromethane solvent was added under nitrogen protection, and an ice-water bath was carried out with the internal temperature controlled at about 0 to 5 ℃. 683.33g (3.96mol,1.5eq) of m-chloroperoxybenzoic acid is weighed and added into a dichloromethane solution of a compound 3b, the addition is finished for about 20min, the reaction is kept at 0-5 ℃, the TLC tracking reaction is carried out, and the reaction is finished for 3 hours. The reaction solution was quenched by adding 2.84L (5v \ w) of water and filtered to remove insoluble white solid. The mother liquor is layered, the organic phase is taken and added with 1.42L (10 percent, 2.5v \ w) of sodium thiosulfate aqueous solution for extraction, and the organic phase is taken. The organic phase was extracted with 1.42L of water to give an organic phase, which was concentrated at 35 ℃ to give an oil, and then 4.96L (10 v/w) of dichloromethane was added to conduct azeotropic concentration and dehydration (35 ℃) to give 523.64g of an oil with a yield of 93%. Used for the next reaction.
The fourth reaction step (4 b-5 b):
the method comprises the following operation steps:
(1) 100g (0.47mol,1.0eq) of 4b compound was added to a dry clean reaction flask, 500ml of anhydrous tetrahydrofuran as a solvent was added, the mixture was stirred to dissolve, the air in the reactor was removed by nitrogen substitution 3 times, and the temperature was lowered to an internal temperature of less than-40 ℃ in an acetone dry ice bath.
(2) LiHMDS is added to tetrahydrofuran to form a 1mol/L solution of LiHMDS. And (2) dropwise adding 520ml (0.52mol,1.1eq) of LDA solution into the tetrahydrofuran solution of the compound 4b in the step (1), controlling the internal temperature in the dropwise adding process to be not higher than-45 ℃, and after the dropwise adding is finished, keeping the internal temperature to be lower than-40 ℃ for reacting for 1 h.
(3) Dissolving 71.45g (0.47mol,1.0eq) of N-phenyl bis (trifluoromethanesulfonyl) imide with 200ml of solvent anhydrous tetrahydrofuran, controlling the internal temperature to be not higher than-30 ℃, dropwise adding the solution into the solution in the step (2), and after dropwise adding, keeping the temperature to be not higher than-30 ℃ for reacting for 2 hours.
After TLC detection reaction, adding 500ml of ammonium chloride aqueous solution into the reaction system, stirring for about 5min, heating to room temperature, layering, extracting the aqueous phase with 1L of ethyl acetate, and removing the aqueous phase to obtain an ethyl acetate phase. The ethyl acetate phase and the tetrahydrofuran phase are combined, 500ml of water is added for extraction once, the obtained organic phase is decompressed, concentrated and dried at the temperature of less than or equal to 35 ℃ to obtain 138.04g of oily matter, the yield is 85 percent, and the oily matter is used for the next reaction.
Fifth reaction (5 b-6 b):
the method comprises the following operation steps:
5b 100g (0.29mol,1.0eq) of the compound was charged in a clean 5L autoclave, 500ml of methanol was added, 5.43g (0.007mol,0.025eq) of palladium bis (triphenylphosphine) acetate and 85.38g (0.87mol,3.0eq) of potassium acetate were added, the mixture was stirred at room temperature until homogeneous, nitrogen gas was substituted for 3 times, and nitrogen gas was purged under reduced pressure to make the pressure inside the reactor negative. Introducing gas carbon monoxide, increasing the pressure to enable the internal pressure to reach 0.15MPa, and keeping the reaction at room temperature for 17 hours to finish the conversion. Discharging redundant carbon monoxide gas, replacing 3 times with nitrogen gas to fully replace and remove residual carbon monoxide, filtering reaction liquid, washing filter cake with 200ml of methanol to obtain filtered mother liquor, and directly using the filtered mother liquor for next reaction.
Sixth reaction step (6 b-7 b):
the method comprises the following operation steps:
adding 100g of the compound 6b into 500ml of methanol, stirring and dissolving uniformly, cooling to an internal temperature of 0-5 ℃, dropwise adding 300ml of 1N lithium hydroxide aqueous solution, controlling the internal temperature to be not higher than 15 ℃, stirring and keeping the room temperature for reaction for about 4 hours after dropwise adding; TLC detection reaction is complete; evaporating most of methanol at 40 ℃ under reduced pressure, adding 500mL of ethyl acetate and 100mL of water, stirring for 10 minutes, demixing, and removing an ethyl acetate phase; adding 600mL of ethyl acetate into the aqueous phase in an ice bath, and adjusting the pH value of the aqueous phase to 4 by using concentrated hydrochloric acid; layering, extracting the water phase once with 200mL ethyl acetate, combining the organic phases, concentrating the organic phases under reduced pressure until no fraction is produced to obtain 57.09g of light yellow oily matter with the total yield of the two steps of 81.7%;
seventh reaction (7 b-8 b):
adding 57.09g (1.0eq,0.2376mol) of the 7b compound into a hydrogen reaction kettle, adding 2.06g (0.025eq,0.0059mol) of a catalyst (S-segphos Ru (OAc)2, adding 250ml (4.38 v/w) of solvent methanol, uniformly stirring, adding 72.01g (3.0eq,0.713mol) of diisopropylamine, uniformly stirring, performing nitrogen replacement for 3 times, performing hydrogen replacement for 3 times, increasing the hydrogen pressure to 2.0MPa, reacting for 6 hours at the temperature of 30 ℃, after the sampling reaction is completed, replacing nitrogen to remove hydrogen, filtering diatomite, washing a filter cake with methanol (100ml 3) for three times, and evaporating the mother liquor to dryness under reduced pressure to obtain 56.07g of colorless to light yellow liquid (3R,4S) -1-tert-butoxycarbonyl-4-ethylpyrrole-3-carboxylic acid oily with the yield of 97%.
Example 3
First-step reaction (1 b-2 b):
the method comprises the following operation steps:
weighing 500.0g (2.95mol,1.0eq) of the raw material 1b, adding the raw material into a clean reaction bottle, adding 2.5L of solvent DMSO and 2.5L of water, stirring to form a uniform solution, cooling in an ice-water bath, and controlling the internal temperature to be 0-5 ℃. 1048.39g (5.9mol,2eq) of NBS solid was weighed out and added to the above solution in portions, with an exotherm occurring, and the addition was completed with an internal temperature of not higher than 10 ℃. After the NBS addition was completed, the reaction was carried out at-5 ℃ for 6 hours, and the completion of the reaction was monitored by sampling. The preparation method comprises the steps of adding 187.0g of sodium hydroxide into 900ml of water to prepare a sodium hydroxide aqueous solution, adding the sodium hydroxide aqueous solution into the reacted solution, keeping the room temperature for reacting for 3 hours, and sampling to monitor the completion of the reaction.
And adding 5L of ethyl acetate into the reaction system, stirring, extracting, layering and removing the water phase. Adding 5L of sodium thiosulfate aqueous solution with the mass fraction of 10% into the organic phase, stirring and extracting, adding 4L of water into the obtained organic phase, extracting once, adding anhydrous sodium sulfate into the obtained organic phase, drying, filtering, concentrating at 35-40 ℃ to obtain 514.18g of product oily matter, wherein the yield is 94.0%, and the product oily matter is used for the next reaction.
Second reaction (2 b-3 b):
the method comprises the following operation steps:
in a dry clean reaction flask, 463.78g (2.50mol,1.0eq) of the epoxy compound 2b was weighed in, 2.5L of chloroform solvent was added, and nitrogen was replaced 3 times with nitrogen protection. Cooling, and controlling the internal temperature at 10 ℃. Ethyl magnesium bromide was added to tetrahydrofuran to form a 2.16mol/L solution of ethyl magnesium bromide. 5.79L (12.5mol,5.0eq) of the above ethyl magnesium bromide solution is slowly dripped into a dichloromethane solution of an epoxy compound 2b, the heat release is obvious, the internal temperature is controlled to be not higher than 15 ℃ for dripping, the reaction is kept at 90 ℃ for 2h, and the sampling detection tracks the completion of the reaction. Adding 1L of ammonium chloride aqueous solution (10% content) into the reacted solution, extracting and demixing, removing the aqueous phase, extracting the organic phase with 1L of water once again to obtain an organic phase, and performing reduced pressure concentration, azeotropic dehydration to obtain about 517.83g of product oily matter with yield of 96.21%. TLC single spot, purity is better.
The third reaction step (3 b-4 b):
the method comprises the following operation steps:
567.90g (2.64mol,1.0eq) of the 3b compound was put into a reaction flask, 2.84L of a dichloromethane solvent was added under nitrogen protection, and an ice-water bath was carried out with the internal temperature controlled at about 0 to 5 ℃. 683.33g (3.96mol,1.5eq) of m-chloroperoxybenzoic acid is weighed and added into a dichloromethane solution of a compound 3b, the addition is finished for about 20min, the reaction is kept at 0-5 ℃, the TLC tracking reaction is carried out, and the reaction is finished for 3 hours. The reaction solution was quenched by adding 2.84L (5v \ w) of water and filtered to remove insoluble white solid. The mother liquor is layered, the organic phase is taken and added with 1.42L (10 percent, 2.5v \ w) of sodium thiosulfate aqueous solution for extraction, and the organic phase is taken. The organic phase was extracted with 1.42L of water to give an organic phase, which was concentrated at 35 ℃ to give an oil, and then 4.96L (10 v/w) of dichloromethane was added to conduct azeotropic concentration and dehydration (35 ℃) to give 523.64g of an oil with a yield of 93%. Used for the next reaction.
The fourth reaction step (4 b-5 b):
the method comprises the following operation steps:
(1) 100g (0.47mol,1.0eq) of the 4b compound was added to a dry clean reaction flask, 500ml of anhydrous tetrahydrofuran as a solvent was added thereto, the mixture was stirred to dissolve the compound, air in the reactor was removed by nitrogen substitution 3 times, and the temperature of the mixture was lowered to an internal temperature of less than-70 ℃ in an acetone dry ice bath.
(2) LiHMDS is added to tetrahydrofuran to form a 1mol/L solution of LiHMDS. 490ml (0.49mol,1.05eq) of LiHMDS solution is added dropwise into the tetrahydrofuran solution of the compound 4b in the step (1), the internal temperature in the dropwise adding process is controlled to be not higher than-65 ℃, and after the dropwise adding is finished, the internal temperature is kept to be lower than-65 ℃ for reaction for 1 h.
(3) 132.60g (0.47mol,1.0eq) of trifluoromethanesulfonic anhydride was diluted with 200ml of anhydrous tetrahydrofuran as a solvent, and then the mixture was added dropwise thereto while controlling the internal temperature to be not higher than-60 ℃ and then the temperature was maintained at not higher than-60 ℃ for 2 hours after the addition.
After TLC detection reaction, adding 500ml of ammonium chloride aqueous solution into the reaction system, stirring for about 5min, heating to room temperature, layering, extracting the aqueous phase with 1L of ethyl acetate, and removing the aqueous phase to obtain an ethyl acetate phase. The ethyl acetate phase and the tetrahydrofuran phase are combined, 500ml of water is added for extraction once, the obtained organic phase is decompressed, concentrated and dried at the temperature of less than or equal to 35 ℃ to obtain 132.04g of oily matter, the yield is 81.31 percent, and the oily matter is used for the next reaction.
Fifth reaction (5 b-6 b):
the method comprises the following operation steps:
5b 100g (0.29mol,1.0eq) of the compound was charged in a clean 5L autoclave, 500ml of methanol was added, 5.43g (0.007mol,0.025eq) of palladium bis (triphenylphosphine) acetate and 85.38g (0.87mol,3.0eq) of potassium acetate were added, the mixture was stirred at room temperature until homogeneous, nitrogen gas was substituted for 3 times, and nitrogen gas was purged under reduced pressure to make the pressure inside the reactor negative. Introducing gas carbon monoxide, increasing the pressure to enable the internal pressure to reach 0.15MPa, and keeping the reaction at room temperature for 17 hours to finish the conversion. Discharging redundant carbon monoxide gas, replacing 3 times with nitrogen gas to fully replace and remove residual carbon monoxide, filtering reaction liquid, washing filter cake with 200ml of methanol to obtain filtered mother liquor, and directly using the filtered mother liquor for next reaction.
Sixth reaction step (6 b-7 b):
the method comprises the following operation steps:
adding 100g of the compound 6b into 500ml of methanol, stirring and dissolving uniformly, cooling to an internal temperature of 0-5 ℃, dropwise adding 300ml of 1N lithium hydroxide aqueous solution, controlling the internal temperature to be not higher than 15 ℃, stirring and keeping the room temperature for reaction for about 4 hours after dropwise adding; TLC detection reaction is complete; evaporating most of methanol at 40 ℃ under reduced pressure, adding 500mL of ethyl acetate and 100mL of water, stirring for 10 minutes, demixing, and removing an ethyl acetate phase; adding 600mL of ethyl acetate into the aqueous phase in an ice bath, and adjusting the pH value of the aqueous phase to 4 by using concentrated hydrochloric acid; layering, extracting the water phase once with 200mL ethyl acetate, combining the organic phases, concentrating the organic phases under reduced pressure until no fraction is produced to obtain 57.09g of light yellow oily matter with the total yield of the two steps of 81.7%;
seventh reaction (7 b-8 b):
adding 57.09g (1.0eq,0.2376mol) of the 7b compound into a hydrogen reaction kettle, adding 2.06g (0.025eq,0.0059mol) of a catalyst (S-segphos Ru (OAc)2, adding 250ml (4.38 v/w) of solvent methanol, uniformly stirring, adding 72.01g (3.0eq,0.713mol) of diisopropylamine, uniformly stirring, performing nitrogen replacement for 3 times, performing hydrogen replacement for 3 times, increasing the hydrogen pressure to 2.0MPa, reacting for 6 hours at the temperature of 30 ℃, after the sampling reaction is completed, replacing nitrogen to remove hydrogen, filtering diatomite, washing a filter cake with methanol (100ml 3) for three times, and evaporating the mother liquor to dryness under reduced pressure to obtain 56.07g of colorless to light yellow liquid (3R,4S) -1-tert-butoxycarbonyl-4-ethylpyrrole-3-carboxylic acid oily with the yield of 97%.
Example 4
N-Cbz-3-pyrroline is used as a starting material to synthesize a target product (3R,4S) -1-benzyloxycarbonyl-4-ethylpyrrole-3-carboxylic acid, and the first step to the seventh step of the reaction are carried out in the same manner as in the steps of example 1(1b to 8 b).
The reaction process is as follows:
the above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above embodiments, and all technical solutions belonging to the idea of the present invention belong to the protection scope of the present invention. It should be noted that modifications and embellishments within the scope of the invention may occur to those skilled in the art without departing from the principle of the invention, and are considered to be within the scope of the invention.
Claims (9)
1. A synthetic method of (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid is characterized by comprising the following steps:
s1, adding N-R-3-pyrroline into a first solvent formed by an organic solvent/water, and adding NBS for reaction under the catalysis of alkali to prepare an intermediate compound (2), wherein R is a protecting group;
s2, adding the compound (2) into a second solvent, adding ethyl magnesium chloride or ethyl magnesium bromide for reaction, and reacting to obtain an intermediate product compound (3);
s3, adding the intermediate compound (3) into a third solvent, adding an oxidant, and performing oxidation reaction to obtain an N-position protection intermediate product compound (4);
s4, adding the intermediate compound (4) into a fourth solvent, and reacting with a trifluoromethanesulfonylation reagent under the condition of alkali to prepare an intermediate product compound (5);
s5, adding the intermediate compound (5) into a fifth solvent, and introducing carbon monoxide gas in the presence of a catalyst to react to obtain an intermediate compound (6);
s6, adding the intermediate compound (6) into a sixth solvent, and hydrolyzing under alkaline conditions to synthesize an intermediate compound (7);
s7, carrying out asymmetric reduction reaction on the intermediate compound (7) under hydrogen and a catalyst to prepare a high-chiral-purity product (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid;
the reaction process is as follows:
2. the method for synthesizing (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid according to claim 1, wherein the protecting group R in N-R-3-pyrroline in S1 is one of tert-butoxycarbonyl group and benzyloxycarbonyl group.
3. The method for synthesizing (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid according to claim 1 or 2, wherein the molar ratio of N-R-3-pyrroline to NBS in S1 is 1: 1-2;
the organic solvent in the solvent of the first solvent in the S1 is any one or combination of DMSO, DMF, ethyl acetate, acetonitrile, toluene, acetone, dichloromethane, trichloromethane and 1, 2-dichloroethane;
the alkali in the S1 is any one or the combination of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, DBU and diethylamine;
the reaction temperature in the S1 is-5-25 ℃.
4. The method for synthesizing (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid according to claim 1, wherein the second solvent in S2 is any one or combination of toluene, dichloromethane, chloroform, tetrahydrofuran, 1, 2-dichloroethane, 1, 4-dioxane;
the molar ratio of the compound (2) in the S2 to the ethyl magnesium bromide or ethyl magnesium chloride is 0.8-1: 1-5;
the reaction temperature in the S2 is 0-90 ℃.
5. The method for synthesizing (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid according to claim 1, wherein the third solvent in S3 is any one or combination of ethyl acetate, acetonitrile, toluene, acetone, and dichloromethane;
the oxidant in the S3 is one of m-chloroperoxybenzoic acid or Dess-Marting oxidant;
the molar ratio of the compound (3) to the oxidant in S3 is 1: 1-3;
the reaction temperature in the S3 is 0-25 ℃.
6. The method for synthesizing (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid according to claim 1, wherein the fourth solvent in S4 is any one or combination of toluene, dichloromethane, tetrahydrofuran 1, 2-dioxane;
the base in S4 is any one or combination of sodium hydride, LiHMDS, LDA, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and DBU;
the molar ratio of the compound (4) to the base in S4 is 1: 1-3;
the trifluoromethanesulfonylation reagent in the S4 is one of N-phenyl bis (trifluoromethanesulfonyl) imide and trifluoromethanesulfonic anhydride;
the reaction temperature in the S4 is-78-80 ℃.
7. The method for synthesizing (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid according to claim 1 or 2, wherein the fifth solvent in S5 is any one of methanol and ethanol or a combination thereof;
the reaction temperature in the S5 is preferably 10-50 ℃, the reaction pressure is 0.1-1 MPa, and the reaction time is 1-24 h;
the reaction catalyst in the S5 is a palladium catalyst.
8. The method for synthesizing (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid according to claim 1 or 2, wherein the sixth solvent in S6 is an aqueous solvent, and the solvent is one or a combination of dioxane, tetrahydrofuran, methanol, ethanol and isopropanol;
the alkali in the S6 is one or the combination of potassium hydroxide, sodium hydroxide, lithium hydroxide and sodium methoxide.
9. The method for synthesizing (3R,4S) -1-substituted-4-ethylpyrrole-3-carboxylic acid according to claim 1 or 2, wherein the solvent in S7 is any one or combination of toluene, acetone, dichloromethane, 1, 2-dioxane, methanol, ethanol, isopropanol, benzyl alcohol, and water;
the base in the S7 is any one or the combination of triethylamine, diisopropylethylamine, diisopropylamine, DBU, potassium hydroxide and lithium hydroxide;
the molar ratio of compound (7) to base in S7 is 1: 1-10;
the reaction temperature in the S7 is 20-50 ℃, the reaction time is 1-24 h, and the reaction pressure range is 0.1-6 MPa;
the catalyst in S7 is S-segphos Ru (OAc)2, and the molar ratio of the compound (7) to the S-segphos Ru (OAc)2 is 1: 0.001 to 0.3.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112778189A (en) * | 2020-04-23 | 2021-05-11 | 北京海步医药科技股份有限公司 | (3R,4S) -N-substituent-3-carboxylic acid-4-ethyl pyrrolidine, intermediate and lapatinib |
| CN114315679A (en) * | 2022-01-21 | 2022-04-12 | 杭州新博思生物医药有限公司 | Preparation method of Upactinib chiral intermediate |
| CN114516866A (en) * | 2021-12-06 | 2022-05-20 | 南京卓康医药科技有限公司 | Preparation method of chiral 4-alkyl-pyrrole-3-formic acid compound |
| CN115124447A (en) * | 2022-08-29 | 2022-09-30 | 山东诚创蓝海医药科技有限公司 | Preparation method of 3-azetidinone hydrochloride |
| WO2022242278A1 (en) * | 2021-05-16 | 2022-11-24 | 上海鼎雅药物化学科技有限公司 | Preparation methods for upadacitinib and intermediate thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304552A (en) * | 2012-03-09 | 2013-09-18 | 广东东阳光药业有限公司 | Substituted pyridine compound as well as application method and usage thereof |
| CN108271371A (en) * | 2015-10-30 | 2018-07-10 | 卡里塞拉生物科学股份公司 | For inhibiting the composition of arginase activities and method |
| CN108368121A (en) * | 2015-10-16 | 2018-08-03 | 艾伯维公司 | The method for preparing (3S, 4R) -3- ethyls -4- (3H- imidazos [1,2-a] pyrrolo- [2,3-e] pyrazine -8- bases)-N- (2,2,2- trifluoroethyl) pyrrolidines -1- formamides and its solid-state form |
| CN110117245A (en) * | 2019-06-21 | 2019-08-13 | 浙江师范大学 | A kind of synthetic method of JAK inhibitor intermediate |
| CN110183367A (en) * | 2019-06-11 | 2019-08-30 | 南京新酶合医药科技有限公司 | A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization |
-
2019
- 2019-09-02 CN CN201910822037.5A patent/CN110615753A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103304552A (en) * | 2012-03-09 | 2013-09-18 | 广东东阳光药业有限公司 | Substituted pyridine compound as well as application method and usage thereof |
| CN108368121A (en) * | 2015-10-16 | 2018-08-03 | 艾伯维公司 | The method for preparing (3S, 4R) -3- ethyls -4- (3H- imidazos [1,2-a] pyrrolo- [2,3-e] pyrazine -8- bases)-N- (2,2,2- trifluoroethyl) pyrrolidines -1- formamides and its solid-state form |
| CN108271371A (en) * | 2015-10-30 | 2018-07-10 | 卡里塞拉生物科学股份公司 | For inhibiting the composition of arginase activities and method |
| CN110183367A (en) * | 2019-06-11 | 2019-08-30 | 南京新酶合医药科技有限公司 | A kind of synthetic method of (3R, 4S) -1- benzyloxycarbonyl group -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization |
| CN110117245A (en) * | 2019-06-21 | 2019-08-13 | 浙江师范大学 | A kind of synthetic method of JAK inhibitor intermediate |
Non-Patent Citations (1)
| Title |
|---|
| ARI M.P. KOSKINEN ET AL.,: "A Simple Route To 4-Substituted-3,4-Didehydreprolines. Mechanistic Probes For The Inhibition of Prolyl-4-Hydroxylase", 《TETRAHEDRON LETTERS》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112778189A (en) * | 2020-04-23 | 2021-05-11 | 北京海步医药科技股份有限公司 | (3R,4S) -N-substituent-3-carboxylic acid-4-ethyl pyrrolidine, intermediate and lapatinib |
| WO2022242278A1 (en) * | 2021-05-16 | 2022-11-24 | 上海鼎雅药物化学科技有限公司 | Preparation methods for upadacitinib and intermediate thereof |
| CN114516866A (en) * | 2021-12-06 | 2022-05-20 | 南京卓康医药科技有限公司 | Preparation method of chiral 4-alkyl-pyrrole-3-formic acid compound |
| CN114516866B (en) * | 2021-12-06 | 2024-02-20 | 南京卓康医药科技有限公司 | Preparation method of chiral 4-alkyl-pyrrole-3-formic acid compound |
| CN114315679A (en) * | 2022-01-21 | 2022-04-12 | 杭州新博思生物医药有限公司 | Preparation method of Upactinib chiral intermediate |
| CN114315679B (en) * | 2022-01-21 | 2024-08-30 | 杭州新博思生物医药有限公司 | Martinib chiral preparation method of intermediate |
| CN115124447A (en) * | 2022-08-29 | 2022-09-30 | 山东诚创蓝海医药科技有限公司 | Preparation method of 3-azetidinone hydrochloride |
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