A method for synthesizing Ivankaser

Abstract

This invention belongs to the field of medicinal chemistry, specifically relating to a method for synthesizing ivcarboxylate. The specific technical solution includes: a method for synthesizing ivcarboxylate, comprising: reductive amination of a chiral amine with a benzyl-protected nitrogen atom with a pyrrolidone, followed by catalytic hydrogenation to remove the protecting group, thereby obtaining ivcarboxylate. The preparation method provided by this invention has a short synthetic route, relatively mild preparation conditions, and great application potential.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, and specifically relates to a method for synthesizing icvancasce. Background Technology

[0002] Evocalcet, chemically named 4-[(3S)-3-[[(R)-1-(1-naphthyl)ethyl]amino]-1-pyrrolyl]phenylacetic acid, is a novel oral calcimimetic agent. Its mechanism of action involves allosteric binding to and inhibition of the activity of calcium-sensitive receptors (CaSRs) on parathyroid cells, thereby suppressing serum parathyroid hormone (PTH) production and preventing PTH-mediated calcium outflow from bone, thus helping to normalize calcium levels. Evocalcet is primarily used to treat secondary hyperparathyroidism (SHPT) by lowering serum calcium, phosphorus, and parathyroid hormone levels.

[0003] Currently, there are few reported methods for synthesizing icvancase in the literature, mainly including: Bioorganic & Medicinal Chemistry Letters, 2018, 28, 2055-2060; CN108484469A and CN113620855A. These existing preparation methods are all cumbersome and difficult to implement.

[0004] Therefore, providing a simple, quick, economical, and practical method would be of great significance to the promotion and application of Ivankassa. Summary of the Invention

[0005] The purpose of this invention is to provide a method for synthesizing Ivancasere.

[0006] To achieve the above-mentioned objectives, the technical solution adopted by the present invention is: a method for synthesizing ivcarboxylic acid, wherein the method uses a chiral amine with a benzyl-protected N atom to undergo reductive amination with pyrrolidone, and then removes the protecting group (benzyl) by catalytic hydrogenation to obtain ivcarboxylic acid.

[0007] Preferably, the reaction equation for preparing the chiral amine with benzyl-protected N atom is as follows:

[0008]

[0009] The R group can be any one of tert-butyl, adamantyl, benzyl, 4-methoxyphenyl, 3,4-difluorophenyl, 3,5-dimethylphenyl, 2,6-diisopropylphenyl, or naphthyl.

[0010] Preferably, the reaction equation for the reductive amination of the chiral amine with benzyl-protected N atom and pyrrolidone is as follows:

[0011]

[0012] Preferably, the molar ratio is chiral amine: pyrrolidone: sodium borohydride triacetate = 1:1:(2-6).

[0013] Preferably, in the reductive amination reaction of a chiral amine with benzyl-protected N atom and pyrrolidone, the reaction solvent is any one of tetrahydrofuran, dichloromethane, chloroform, or 1,2-dichloroethane.

[0014] Preferably, the reaction equation for the catalytic hydrogenation removal of the protecting group is as follows:

[0015]

[0016] In the equation, Ⅱ refers to palladium catalyst Ⅱ.

[0017] Preferably, the palladium catalyst II is selected from Pd / C or Pd(OH)2 / C with a content of 5-20%.

[0018] Preferably, by mass ratio, compound 4:palladium catalyst II = 1:(0.01-0.2)

[0019] Preferably, in the catalytic hydrogenation reaction to remove the protecting group, the reaction solvent is methanol or ethanol.

[0020] Preferably, in the catalytic hydrogenation reaction for removing the protecting group, the reaction temperature is 25°C to 80°C, and / or the hydrogen pressure is 1 to 50 bar.

[0021] This invention offers the following advantages: It provides a novel method for preparing ivcarboxylic acid, and for the first time applies asymmetric small-molecule organic catalysis to the synthesis of a key chiral amine intermediate in the ivcarboxylic acid synthesis. This invention utilizes the highly efficient and selective asymmetric catalytic reduction of an N-tert-butylsulfinylproline amide Lewis base catalyst to prepare a chiral amine intermediate with benzyl protection on the nitrogen atom. This intermediate is then reductively aminationd with a pyrrolidone fragment to quickly and easily obtain an ivcarboxylic acid precursor with both the carboxyl and nitrogen atoms protected by benzyl groups. Finally, catalytic hydrogenation removes both protecting groups in a single step, thus completing the efficient preparation of ivcarboxylic acid.

[0022] The preparation method provided by this invention has a short synthesis route, relatively mild preparation conditions, and great application potential. Detailed Implementation

[0023] This invention provides a novel method for synthesizing icvancascene, specifically comprising the following steps:

[0024] 1. Under an inert gas (e.g., nitrogen) atmosphere, using toluene, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, chloroform, or acetonitrile as the reaction solvent, trichlorosilane as the reducing agent, and chiral Lewis base I as the catalyst, imine 1 is subjected to asymmetric catalytic hydrogen transfer reduction at -20℃ to 25℃ to prepare chiral amine intermediate 2. The molar ratio of imine 1 to catalyst I is 1:(0.005–0.2). The reaction equation is as follows:

[0025]

[0026] The chiral Lewis base I is derived from the N-tert-butylsulfinylproline amide Lewis base catalyst described in patent PCT / CN2009 / 001257. In the catalyst, the R group can be any one of: tert-butyl, adamantyl, benzyl, 4-methoxyphenyl, 3,4-difluorophenyl, 3,5-dimethylphenyl, 2,6-diisopropylphenyl, or naphthyl.

[0027] 2. Under an inert gas atmosphere, using tetrahydrofuran, dichloromethane, chloroform, or 1,2-dichloroethane as the reaction solvent and sodium triacetate borohydride as the reducing agent, a reductive amination reaction is carried out between chiral amine intermediate 2 and pyrrolidone 3 to prepare intermediate 4. The molar ratio of chiral amine 2, pyrrolidone 3, and sodium triacetate borohydride is 1:1:(2-6). The reaction equation is as follows:

[0028]

[0029] 3. Under the action of palladium catalyst II, intermediate 4 was subjected to catalytic hydrogenation to remove the benzyl protecting group, yielding crude icarceline 5. Palladium catalyst II was selected from Pd / C or Pd(OH)₂ / C with a content of 5–20%. The mass ratio of intermediate 4 to catalyst II was 1:(0.01–0.2). The solvent was methanol or ethanol. The reaction temperature was 25℃–80℃, and the hydrogen pressure was 1–50 bar (using hydrogen to replace the inert gas). The reaction equation is as follows:

[0030]

[0031] 4. Recrystallize the crude icarceptin 5 to obtain pure icarceptin. The recrystallization solvent can be methanol, ethanol, isopropanol, or a mixture of tert-butanol and water (1:10 to 20:1, V / V).

[0032] It should be noted that the chiral Lewis base catalyst I used in this invention was synthesized according to the synthesis methods described in Chem. Eur. J. 2008, 14, 8789-8792 and Chem. Eur. J. 2011, 17, 2846-2848.

[0033] The imine 1 of the present invention is synthesized according to the synthetic methods described in Chem. Eur. J. 2002, 8, 2955 and J. Org. Chem. 1999, 64, 4204.

[0034] The pyrrolidone 3 of the present invention was synthesized according to the synthetic method described in Bio. Med. Chem. 2003, 11, 145-157.

[0035] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Unless otherwise specified, the technical means used in the embodiments are conventional means well known to those skilled in the art. All data obtained are average values ​​obtained after at least three repetitions, and each repetition yields valid data. All raw materials used in the present invention are conventional materials that can be purchased from the market. In the present invention, unless otherwise specified, all quantities and percentages are in units of weight.

[0036] Example 1: Synthesis of chiral amine intermediate 2

[0037] 1. Synthesis Method 1: Under normal pressure and nitrogen protection, N-tert-butylsulfinylproline-tert-butylamine amide catalyst (Ia, 1.0 mmol) and imine 1 (10 mmol) were dissolved in dichloromethane (20 mL), cooled to 0 °C, and trichlorosilane (25 mmol) was slowly added. The reaction was then carried out at 0 °C. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added for quenching, and the pH was adjusted to 8-9. The mixture was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to dryness. The crude product was purified by silica gel column chromatography to obtain pure (R)-N-benzyl-1-(naphthyl-1)ethylamine with a yield of 92% and an enantioselectivity of 95% ee.

[0038] The NMR data of the prepared chiral amine intermediate 2 are as follows: 1 HNMR(400MHz, CDCl3),7.97-8.01(m,3H),7.55(m,2H),7.28-7.35(m,6H),6.99(m,1H),5.00(brs,1H),4.01(d,1H),3.82(s,2H),1.40(d,3H).

[0039] In this embodiment, the subsequent synthesis methods all prepared chiral amine intermediate 2, and the NMR data were the same, so they will not be described again.

[0040] 2. Synthesis Method 2: Under normal pressure and nitrogen protection, N-tert-butylsulfinylproline-adamantaneamine amide catalyst (Ib, 0.5 mmol) and imine 1 (10 mmol) were dissolved in chloroform (25 mL), cooled to -10 °C, and trichlorosilane (18.2 mmol) was slowly added, followed by reaction at -10 °C. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added for quenching, and the pH was adjusted to 8-9. Extraction was performed with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to dryness. The crude product was purified by silica gel column chromatography to obtain pure (R)-N-benzyl-1-(naphthyl-1)ethylamine with a yield of 95% and an enantioselectivity of 96% ee.

[0041] 3. Synthesis Method 3: Under normal pressure and nitrogen protection, N-tert-butylsulfinylproline-benzylamine amide catalyst (Ic, 2.0 mmol) and imine 1 (10 mmol) were dissolved in 1,2-dichloroethane (25 mL), and trichlorosilane (18.2 mmol) was slowly added. The reaction was then carried out at room temperature. After the reaction was completed, saturated sodium bicarbonate aqueous solution was added for quenching and the pH was adjusted to 8-9. The product was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to dryness. The crude product was purified by silica gel column chromatography to obtain pure (R)-N-benzyl-1-(naphthyl-1)ethylamine with a yield of 96% and an enantioselectivity of 90% ee.

[0042] 4. Synthesis Method 4: Under normal pressure and nitrogen protection, N-tert-butylsulfinylproline-p-methoxyaniline amide catalyst (Id, 2.0 mmol) and imine 1 (10 mmol) were dissolved in carbon tetrachloride (25 mL), and trichlorosilane (18.2 mmol) was slowly added. The reaction was then carried out at room temperature. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added for quenching and the pH was adjusted to 8-9. The product was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to dryness. The crude product was purified by silica gel column chromatography to obtain pure (R)-N-benzyl-1-(naphthyl-1)ethylamine with a yield of 92% and an enantioselectivity of 93% ee.

[0043] 5. Synthesis Method 5: Under normal pressure and nitrogen protection, N-tert-butylsulfinylproline-3,4-difluoroaniline amide catalyst (Ie, 2.0 mmol) and imine 1 (10 mmol) were dissolved in acetonitrile (25 mL), cooled to 0 °C, and trichlorosilane (18.2 mmol) was slowly added, followed by reaction at 0 °C. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added for quenching and pH was adjusted to 8–9. Extraction was performed with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to dryness. The crude product was purified by silica gel column chromatography to obtain pure (R)-N-benzyl-1-(naphthyl-1)ethylamine with a yield of 92% and an enantioselectivity of 92% ee.

[0044] 6. Synthesis Method 6: Under normal pressure and nitrogen protection, N-tert-butylsulfinylproline-3,5-dimethylaniline amide catalyst (If, 0.1 mmol) and imine 1 (10 mmol) were dissolved in toluene (25 mL), cooled to -20 °C, and trichlorosilane (18.2 mmol) was slowly added, followed by reaction at -20 °C. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added for quenching and the pH was adjusted to 8-9. Extraction was performed with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to dryness. The crude product was purified by silica gel column chromatography to obtain pure (R)-N-benzyl-1-(naphthyl-1)ethylamine with a yield of 95% and an enantioselectivity of 98% ee.

[0045] 7. Synthesis Method 7: Under normal pressure and nitrogen protection, N-tert-butylsulfinylproline-2,6-diisopropylaniline amide catalyst (1g, 0.05mmol) and imine 1 (10mmol) were dissolved in toluene (25mL), cooled to -20℃, and trichlorosilane (18.2mmol) was slowly added, followed by reaction at -20℃. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added for quenching and pH was adjusted to 8-9. Extraction was performed with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to dryness. The crude product was purified by silica gel column chromatography to obtain pure (R)-N-benzyl-1-(naphthyl-1)ethylamine with a yield of 98% and an enantioselectivity of 99% ee.

[0046] 8. Synthesis Method 8: Under normal pressure and nitrogen protection, N-tert-butylsulfinylproline-(naphthyl-1')amine amide catalyst (Ih, 1.0 mmol) and imine 1 (10 mmol) were dissolved in toluene (25 mL), cooled to -20 °C, and trichlorosilane (18.2 mmol) was slowly added, followed by reaction at -20 °C. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added for quenching and pH was adjusted to 8-9. Extraction was performed with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to dryness. The crude product was purified by silica gel column chromatography to obtain pure (R)-N-benzyl-1-(naphthyl-1)ethylamine with a yield of 95% and an enantioselectivity of 98% ee.

[0047] Example 2: Synthesis of Ivancasere

[0048] 1. Synthesis Method 1: Under normal pressure and nitrogen protection, sodium triacetate (44.4 mmol) was added in portions to a tetrahydrofuran (60 mL) solution of chiral amine intermediate (compound 2, 22.2 mmol) and N-(4'-benzyloxycarbonylmethylene-phenyl)-pyrrolidine-3-one (compound 3, 22.2 mmol) to prevent excessive exothermic reaction. The reaction was then stirred at room temperature for 8 hours. After the reaction was allowed to proceed overnight, a saturated sodium bicarbonate aqueous solution was added to quench the reaction and adjust the pH to 8-9. The mixture was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to dryness to give the initial product: Benzyl2-(4-((S)-3-(benzyl((R)-1-(naphthalen-1-yl)ethyl)amino)pyrrolidin-1-yl)phenyl)acetate, compound 4, with a yield of 90%.

[0049] Under atmospheric pressure and nitrogen protection, a methanol solution (50 mL) of compound 4 (11.8 g, 20.0 mmol) was added to a stainless steel reactor, along with Pd / C (1.18 g, 10% by weight). The nitrogen gas was replaced with hydrogen, and the reaction was stirred for 3 hours at room temperature and 5 bar. After the reaction was complete, the mixture was filtered, the solvent was evaporated, and the crude product was recrystallized from a methanol-water mixture (10:1 volume ratio) to obtain 5.98 g of pure ivcarboxylic acid, with a yield of 80%.

[0050] The nuclear magnetic resonance data of Ivancasce obtained during preparation are as follows: 1 HNMR(400MHz,d6-DMSO),12.39(brs,1H),7.97-8.01(m,3H),7.55(m,2H),7.26-7.28(m,3H),6.99(d,1H),6.68(d,2 H),4.16(brs,1H),4.01(m,1H),3.57(s,2H),3.31(m,1H),3.06-3.15(m,3H),2.72(m,1H),1.79(d,3H),1.54(m,2H).

[0051] Subsequent synthetic methods were used to prepare Ivancase, and the NMR data were the same, so they will not be described in detail here.

[0052] 2. Synthesis Method 2: Under normal pressure and nitrogen protection, sodium triacetate borohydride (210.5 mmol) was added in portions to a dichloromethane (200 mL) solution of compound 2 (42.1 mmol) and compound 3 (42.1 mmol), and the reaction was stirred at room temperature for 8 hours. After the reaction was complete, saturated sodium bicarbonate aqueous solution was added to quench the reaction and adjust the pH to 8-9. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to dryness to obtain compound 4, with a yield of 95%.

[0053] Under atmospheric pressure and nitrogen protection, an ethanol solution (80 mL) of compound 4 (23.6 g, 40.0 mmol) was added to a stainless steel reactor, along with Pd / C (1.18 g, 5% by weight). The nitrogen gas was replaced with hydrogen, and the reaction was stirred for 3 hours at room temperature and 20 bar. After the reaction was complete, the mixture was filtered, the solvent was evaporated, and the crude product was recrystallized from the crude product using a 5:1 (ethanol to water) mixture to obtain 12.75 g of pure icarpases, with a yield of 85%.

[0054] 3. Synthesis Method 3: Under normal pressure and nitrogen protection, sodium triacetate borohydride (43.4 mmol) was added in portions to a chloroform (50 mL) solution of compound 2 (21.7 mmol) and compound 3 (21.7 mmol), and the mixture was stirred at room temperature for 8 hours. After the reaction was complete, a saturated sodium bicarbonate aqueous solution was added to quench the reaction and adjust the pH to 8-9. The mixture was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to dryness to give compound 4, with a yield of 92%.

[0055] Under atmospheric pressure and nitrogen protection, a 100.0 mL isopropanol solution of compound 4 (11.8 g, 20.0 mmol) was added to a stainless steel reactor, along with 0.56 g of Pd(OH)₂ / C (5% by weight). The nitrogen gas was replaced with hydrogen, and the reaction was stirred for 3 hours at room temperature and 10 bar. After the reaction was complete, the mixture was filtered, the solvent was evaporated, and the crude product was recrystallized from the crude product using a 1:1 volume ratio of isopropanol and water to obtain 6.73 g of pure icarpases, with a yield of 90%.

[0056] 4. Synthesis Method 4: Under normal pressure and nitrogen protection, sodium triacetate borohydride (62.4 mmol) was added in portions to a solution of compound 2 (20.8 mmol) and compound 3 (20.8 mmol) in 1,2-dichloroethane (60 mL). The mixture was stirred at room temperature for 8 hours until the reaction was complete. The reaction was then quenched with saturated sodium bicarbonate solution, and the pH was adjusted to 8–9. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and rotary evaporated to dryness to give compound 4, with a yield of 96%.

[0057] Under atmospheric pressure and nitrogen protection, a 50.0 mL solution of compound 4 (11.8 g, 20.0 mmol) in tert-butanol was added to a stainless steel reactor, along with Pd / C (1.18 g, 10% by weight). The nitrogen was replaced with hydrogen, and the reaction was stirred for 3 hours at room temperature and 5 bar. After the reaction was complete, the mixture was filtered, the solvent was evaporated, and the crude product was recrystallized from the crude product using a 1:10 volume ratio of tert-butanol to water to obtain 5.98 g of pure irvancascet, with a yield of 80%.

[0058] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Any modifications, alterations, substitutions, or variations made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention shall fall within the protection scope defined by the claims of the present invention.

Claims

1. A method for synthesizing icvancascene, characterized in that: The method uses a chiral amine with a benzyl-protected N atom to undergo reductive amination with pyrrolidone, followed by catalytic hydrogenation to remove the benzyl group, in order to prepare icvancalcet.

2. The method according to claim 1, characterized in that: The reaction equation for preparing the chiral amine with benzyl-protected N atom is as follows: The R group can be any one of tert-butyl, adamantyl, benzyl, 4-methoxyphenyl, 3,4-difluorophenyl, 3,5-dimethylphenyl, 2,6-diisopropylphenyl, or naphthyl.

3. The method according to claim 1, characterized in that: The reaction equation for the reductive amination of the chiral amine with benzyl-protected N atom and pyrrolidone is as follows:

4. The method according to claim 3, characterized in that: The molar ratio is chiral amine: pyrrolidone: sodium borohydride triacetate = 1:1:(2-6).

5. The method according to claim 3, characterized in that: In the reductive amination reaction of a chiral amine with a benzyl-protected N atom with pyrrolidone, the reaction solvent is any one of tetrahydrofuran, dichloromethane, chloroform, or 1,2-dichloroethane.

6. The method according to claim 1, characterized in that: The reaction equation for the catalytic hydrogenation removal of benzyl groups is as follows: In the equation, Ⅱ refers to palladium catalyst Ⅱ.

7. The method according to claim 6, characterized in that: The palladium catalyst II is selected from Pd / C or Pd(OH)2 / C with a content of 5-20%.

8. The method according to claim 6, characterized in that: By mass ratio, compound 4:palladium catalyst II = 1:(0.01-0.2).

9. The method according to claim 6, characterized in that: In the catalytic hydrogenation reaction to remove benzyl groups, the reaction solvent is methanol or ethanol.

10. The method according to claim 6, characterized in that: In the catalytic hydrogenation reaction for removing benzyl, the reaction temperature is 25℃~80℃, and / or the hydrogen pressure is 1~50 bar.

Images