Preparation method of (S)-3-[t-butyloxycarboryl (isopropyl) amino]-2-(4-chlorphenyl) propionic acid
Through the phase transfer catalytic reaction of p-chlorobenzene acetonitrile and paraformaldehyde, combined with the treatment of isopropylamine, hydrochloric acid and sulfuric acid, the synthesis of patacetin intermediate was successfully simplified by using the chiral proline benzophenone resolving agent. The process solves the problems of difficult preparation and high price of catalysts in existing methods, achieves high yield and high purity production, and reduces costs.
Patent Information
- Application Number
- CN202411452398.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-10-17
- Publication Date
- 2025-01-21
AI Technical Summary
The existing Pataseri intermediate synthesis method has the problem that catalysts are difficult to construct, expensive, and are not suitable for industrial production.
Use p-chlorophenylacetonitrile to react with paraformaldehyde in the presence of a phase transfer catalyst, and then conduct a series of reactions with isopropylamine, hydrochloric acid and sulfuric acid, and finally perform salt-forming separation through the chiral proline benzophenone pyridine ligand. (S)-3-[tert-butoxycarbonyl(isopropyl)amino]-2-(4-chlorophenyl)propionic acid is obtained.
The synthesis steps are simplified, the yield and optical purity are improved, the use of expensive metal catalysts is avoided, the production cost is reduced, and it is suitable for industrial production.
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Figure CN119330859A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to a method for preparing (S)-3-[tert-butyloxycarbonyl (isopropyl) amino]-2-(4-chlorophenyl) propionic acid, belonging to the technical field of drug synthesis. Background Art
[0002] Ipatasertib is a highly selective PAN-Akt inhibitor that targets Akt1 / 2 / 3 with an IC50 of 5nM / 18nM / 8nM in a cell-free assay, which is 620 times more selective than PKA. Ipatasertib selectively inhibits cell cycle progression and Akt signaling-driven cancer cell viability, including tumor suppressor gene PTEN deficiency, PIK3CA oncogene mutation, and HER2 amplification. + The strongest effect is in the luminal and luminal subtypes. Combination therapy can also be used to treat prostate cancer. Currently, ATK inhibitors Ipatasertib and Capivasertib (AZD5363) targeting the PI3K-AKT signaling pathway have been developed clinically to inhibit the activation of the PI3K-AKT signaling pathway and inhibit tumor growth.
[0003] (S)-3-[tert-Butyloxycarbonyl (isopropyl) amino]-2-(4-chlorophenyl) propionic acid, the compound is a key intermediate of the selective PAN-AKT inhibitor patasertib, CAS: 1001179-33-4; the main synthesis methods in the literature include:
[0004] The literature [Organic Letters, 2017, vol. 19, #18, 4806-4809] and [Organic Process Research and Development, 2014, vol. 18, #1, 135-141] uses (E)-3-(tert-butoxycarbonyl)(isopropyl)amino-2-(4-chlorophenyl) acrylic acid as a raw material to obtain (S)-3-[tert-butoxycarbonyl(isopropyl)amino]-2-(4-chlorophenyl) propionic acid through asymmetric hydrogenation, with a yield of more than 90%. However, the catalyst of this method is not easy to obtain and is expensive, which is not suitable for industrial production. The reaction route is shown as follows:
[0005]
[0006] The literature [Organic Process Research and Development, 2014, vol. 18, #12, 1652-1666] uses chlorophenylacetic acid as a raw material, (R)-benzyl-2-oxazolidinone, toluene and triethylamine are mixed, and pivaloyl chloride is added dropwise to react to obtain (R)-4-benzyl-3-[2-(4-chlorophenyl)acetyl]oxazolidin-2-one; then it is mixed with titanium tetrachloride and toluene, DIPEA is added dropwise, and N-isopropyl-N-(methoxymethyl) The reaction is carried out with tert-butyl (S)-3-[(R)-4-benzyl-2-oxoxazolidin-3-yl]-2-(4-chlorophenyl)-3-oxopropyl-(isopropyl)carbamate, followed by quenching with ammonium chloride to obtain tert-butyl (S)-3-[(R)-4-benzyl-2-oxoxazolidin-3-yl]-2-(4-chlorophenyl)-3-oxopropyl-(isopropyl)carbamate; followed by reaction with lithium hydroxide and hydrogen peroxide to obtain a crude product of (S)-3-[tert-butyloxycarbonyl (isopropyl)amino]-2-(4-chlorophenyl)propionic acid, and then Boc removal with hydrochloric acid and Boc purification to obtain a qualified product. The literature achieves a scale of several tens of kilograms, but the raw material N-isopropyl-N-(methoxymethyl)carbamic acid tert-butyl ester is not easy to purchase, purification is complicated, and the overall yield is not high; the reaction route is shown as follows:
[0007]
[0008] In view of the shortcomings of the above literature, it is necessary to redesign the synthesis route and find a preparation method that is simple and easy to operate and convenient for industrial production. Summary of the invention
[0009] In order to overcome the defects of the above-mentioned technology, the present invention provides a method for preparing a patase intermediate. Using p-chlorophenylacetonitrile as a raw material, it reacts with paraformaldehyde in the presence of a phase transfer catalyst to obtain compound 2; then it reacts with isopropylamine for nucleophilic addition to obtain compound 3; then hydrochloric acid and sulfuric acid are added to make cyano water to obtain compound 4; then the amine group is protected with di-tert-butyl dicarbonate to obtain compound 5; finally, it is subjected to salt formation and separation with a chiral proline benzophenone pyridine ligand to obtain (S)-3-[tert-butyloxycarbonyl (isopropyl) amino]-2-(4-chlorophenyl) propionic acid. The preparation method of the present invention has mild reaction conditions in each step, is easy to purify, is simple to operate, has high yield and chiral purity, avoids the use of expensive catalysts in the production process, and reduces production costs.
[0010] The preparation method of (S)-3-[tert-butyloxycarbonyl(isopropyl)amino]-2-(4-chlorophenyl)propionic acid of the present invention comprises the following steps:
[0011]
[0012] Step A: using p-chlorophenylacetonitrile and paraformaldehyde as raw materials, reacting in the presence of a phase transfer catalyst and a base to obtain compound 2;
[0013] Step B: reacting compound 2 with isopropylamine at low temperature to obtain compound 3;
[0014] Step C: heating compound 3 in the presence of an acid to hydrolyze to obtain compound 4; Step D: reacting compound 4 with di-tert-butyl dicarbonate in an organic solvent to obtain compound 5;
[0015] Step E: Compound 5 is salified with a resolving agent 6 in an organic solvent and then liberated to obtain (S)-3-[tert-butoxycarbonyl(isopropyl)amino]-2-(4-chlorophenyl)propionic acid.
[0016] Furthermore, in step A of the above technical solution, the phase transfer catalyst is selected from tetrabutylammonium bromide or benzyltriethylammonium chloride; and the base is selected from potassium acetate.
[0017] Furthermore, in step A of the above technical solution, the molar ratio of p-chlorophenylacetonitrile, potassium acetate and paraformaldehyde is 1:0.055-0.060:1.2-1.25.
[0018] Furthermore, in step B of the above technical solution, the molar ratio of compound 2 to isopropylamine is 1:1.2-1.25.
[0019] Furthermore, in step C of the above technical solution, the acid is selected from a mixed acid of hydrochloric acid and sulfuric acid.
[0020] Furthermore, in step D of the above technical solution, the organic solvent is selected from methanol or ethanol; and triethylamine is added during the reaction.
[0021] Furthermore, in step D of the above technical scheme, the molar ratio of compound 4, triethylamine and Boc2O is 1:1.05-1.10:1.10-1.15.
[0022] Furthermore, in step E of the above technical solution, the molar ratio of the compound 5 to the resolving agent 6 is 1:0.45-0.55.
[0023] Furthermore, in step E of the above technical solution, the organic solvent is selected from ethanol.
[0024] Advantageous Effects of the Invention
[0025] The invention uses p-chlorophenylacetonitrile to perform continuous reactions, simplifies the synthesis steps of the key intermediate of patasertib, improves the yield, has a fast reaction speed, is more convenient to operate, improves the production efficiency, avoids the use of expensive metal catalysts in the process, adopts a chiral proline benzophenone resolving agent to increase the optical purity to more than 99.8%, and the resolving agent can be recycled, thereby further reducing the production cost of the key intermediate of patasertib, and is more in line with industrial production. BRIEF DESCRIPTION OF THE DRAWINGS
[0026] Figure 1 This is the HNMR spectrum of (S)-3-[tert-butoxycarbonyl(isopropyl)amino]-2-(4-chlorophenyl)propanoic acid obtained in Example 7. DETAILED DESCRIPTION
[0027] The specific implementation of the present invention is described in detail below. The present invention can be implemented in many other ways than those described herein, and those skilled in the art can make similar improvements without violating the connotation of the present invention, so the present invention is not limited by the specific embodiments disclosed.
[0028] Example 1
[0029]
[0030] 5 kg (33 mol) of p-chlorobenzeneacetonitrile, 30 L of toluene, 290 g of benzyltriethylammonium chloride, 1.76 kg (1.8 mol) of potassium acetate and 1.2 kg (40 mol) of paraformaldehyde were mixed and stirred, the temperature was raised to reflux, the temperature was lowered to 10-15°C, 25 L*4 of water was added for washing, and the organic phase was concentrated under reduced pressure to obtain 4.927 kg of compound, with a yield of 91.3%, and HPLC 95.1%. 1 HNMR(400MHz, CDCl3):7.53(d,2H),7.39(d,2H),6.32(s,1H),6.12(s,1H).
[0031] Example 2
[0032]
[0033] 5 kg of p-chlorobenzeneacetonitrile (33 mol), 30 L of toluene, 220 g of tetrabutylammonium bromide, 1.76 kg of potassium acetate (1.8 mol) and 1.2 kg of paraformaldehyde (40 mol) were mixed and stirred, the temperature was raised to reflux, the temperature was lowered to 10-15°C, 25 L of water*4 was added for washing, and the organic phase was concentrated under reduced pressure to obtain 4.9 kg of the compound, with a yield of 90.8%, and HPLC 94.9%.
[0034] Example 3
[0035]
[0036] 4.9 kg of compound 2 (29.95 mol) and 20 L of toluene were mixed and stirred, cooled to -10°C, 2.213 kg (37.44 mol) of isopropylamine were added, and then the temperature was raised to 10°C for reaction overnight, 15 kg of water was added, 3N hydrochloric acid was added to adjust the pH to 9-9.5, and the mixture was allowed to stand for stratification. The organic phase was washed with 10 kg*2 of water, and the organic phase was concentrated under reduced pressure to obtain 5.71 kg of compound 3 with a yield of 85.6% and an HPLC value of 96.7%. 1 HNMR(400MHz, CDCl3):7.38(d,2H),7.22(d,2H),6.51(s,1H),3.89(dd,1H),3.40-3.32(m,2H),2.61-2.55(m,1H),1.11-0.99(m,6H).
[0037] Example 4
[0038]
[0039] 5.7 kg of compound 3 (25.6 mol) was dissolved in 15 L of toluene, and the mixture was added dropwise to a pre-mixed mixture of 1.3 kg (12.8 mol) of 36% hydrochloric acid and 5.38 kg (38.4 mol) of 70% sulfuric acid. The mixture was heated to 65°C for reaction for 7 hours, and the layers were allowed to stand for stratification. The aqueous phase was retained, and the aqueous phase was cooled to 0°C. Aqueous potassium carbonate solution was added to adjust the pH to 6.5-6.8, and the mixture was extracted with ethyl acetate and washed with saturated sodium chloride water. The organic phase was concentrated under reduced pressure, and then n-heptane was added to precipitate the solid. The solid was filtered, and the filter cake was rinsed with n-heptane and dried to obtain 5.7 kg of compound 4 with a yield of 92.1% and an HPLC value of 99.3%. 1 H NMR (400MHz, DMSO-d6): 12.59(s,1H),7.39(d,2H),7.26(d,2H),6.71(s,H),3.83(dd,1H),3.29-3.23(m,2H),2.58-2.52(m,1H),1.10-0.98(m,6H).
[0040] Example 5
[0041]
[0042] 5.7 kg of compound 4 (23.6 mol) was mixed with 14.3 L of methanol and 14.3 L of water, triethylamine (25 mol) was added, and then a methanol solution containing 5.675 kg (26 mol) of di-tert-butyl dicarbonate was added dropwise, and the reaction was allowed to proceed overnight at room temperature. Hydrochloric acid was added to adjust the pH to 3-4, and the mixture was extracted with ethyl acetate. The organic phase was washed with water and saturated sodium chloride, and then the organic phase was concentrated under reduced pressure and recrystallized by adding MTBE to obtain 7.16 kg of compound 5; the yield was 88.7%, and the HPLC was 99.2%.
[0043] Example 6
[0044]
[0045] 5.7 kg of compound 4 (23.6 mol), 14.3 L of ethanol and 14.3 L of water were mixed, triethylamine (26 mol) was added, and then an ethanol solution containing 5.675 kg (26 mol) of di-tert-butyl dicarbonate was added dropwise, and the reaction was allowed to react at room temperature overnight. Hydrochloric acid was added to adjust the pH to 3-4, and ethyl acetate was used for extraction. The organic phase was washed with water and saturated sodium chloride, and then the organic phase was concentrated under reduced pressure and MTBE was added for recrystallization to obtain 7.01 kg of compound 5; the yield was 86.9%, and the HPLC was 99.4%.
[0046] Example 7
[0047]
[0048] 7 kg of compound 5 (20.48 mol) was mixed with 56 L of ethanol, heated to reflux, and 3.804 kg (10.24 mol) of (S)-N-(3-benzoylphenyl)-2-(pyridin-3-yl)-5-pyrrolidineamide was added, and reflux was continued for 5-6 hours, then the temperature was slowly lowered to 10-15° C., filtered, the filter cake (white needle-shaped crystals) was rinsed with ethanol, the filter cake was put back into the kettle, ethyl acetate was added, the temperature was lowered to 0° C., hydrochloric acid was added dropwise to adjust the pH to 2.0-2.5, and the mixture was allowed to stand for stratification, the organic phase was retained, the aqueous phase could recover the resolving agent, the organic phase was washed with water, and the organic phase was concentrated to dryness under reduced pressure to obtain 3.234 kg of compound 6. The yield was 46.2%, HPLC 99.5%, and chiral purity was 99.8%. 1 H NMR (400MHz, DMSO-d6): 12.60 (s, 1H), 7.40 (d, 2H), 7.31 (d, 2H), 3.86 (bs, 1H), 3.63 (dd, 1H), 3.35 (dd, 1H), 1.36 (s, 9H), 1.01 (d, 3H), 0.90 (d, 3H). The aqueous phase was adjusted to pH = 11-12 by adding alkali, extracted with dichloromethane, concentrated, and re-obtained by adding n-heptane for slurrying, with a yield of 88-89%.
[0049] Resolving agent (S)-N-(3-benzoylphenyl)-2-(pyridin-3-yl)-5-pyrrolidineamide preparation method:
[0050]
[0051] Compound 7 was obtained using the literature method [European Journal of Organic Chemistry, 2014, vol. 2014, #6, 1202-1211].
[0052] Then, compound 7 (12.3 g, 50 mmol), triethylamine (13.1 g, 130 mmol) and 110 mL of dichloromethane were mixed, the temperature was controlled to -20°C to -15°C, and ethyl chloroformate (5.94 g, 55 mmol) / 40 mL of dichloromethane solution was added dropwise, and the mixture was stirred for reaction for 1 hour. Then, compound 8 (10.2 g, 52 mmol) / 40 mL of dichloromethane solution was added dropwise, and the mixture was naturally heated to room temperature for reaction for 3 hours. After the reaction was completed, the mixture was washed with saturated sodium bicarbonate and saturated brine, the solvent was evaporated, and MTBE and n-heptane (1 / 3) were added for pulping and purification to obtain 15.6 g of compound 6 as an off-white solid. 1 HNMR (400MHz, CDCl3): 10.02(s,1H),8.05(d,1H),7.34-7.85(m,10H),6.63-6.73(m,2H),4.20(m,1H),3.05-3.16(m,2H),1.81-2.05(m,4H).
[0053] The technical features of the above-mentioned embodiments can be combined arbitrarily. To make the description concise, all possible combinations of the technical features in the above-mentioned embodiments are not exhaustively listed. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification. For ordinary technicians in this field, several modifications and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention, and the protection scope of the present invention shall be subject to the attached claims.
Claims
1. A method for preparing (S)-3-[tert-butyloxycarbonyl(isopropyl)amino]-2-(4-chlorophenyl)propionic acid, characterized in that: The steps include: Step A: using p-chlorophenylacetonitrile and paraformaldehyde as raw materials, reacting in the presence of a phase transfer catalyst and a base to obtain compound 2; Step B: reacting compound 2 with isopropylamine at low temperature to obtain compound 3; Step C: heating compound 3 in the presence of an acid to hydrolyze the compound 4; Step D: reacting compound 4 with di-tert-butyl dicarbonate in an organic solvent to obtain compound 5; Step E: Compound 5 is salified with a resolving agent 6 in an organic solvent and then liberated to obtain (S)-3-[tert-butoxycarbonyl(isopropyl)amino]-2-(4-chlorophenyl)propionic acid.
2. The method for preparing (S)-3-[tert-butyloxycarbonyl (isopropyl) amino]-2-(4-chlorophenyl) propionic acid according to claim 1, characterized in that: In step A, the phase transfer catalyst is selected from tetrabutylammonium bromide or benzyltriethylammonium chloride; and the base is selected from potassium acetate.
3. The method for preparing (S)-3-[tert-butyloxycarbonyl(isopropyl)amino]-2-(4-chlorophenyl)propionic acid according to claim 2, characterized in that: In step A, the molar ratio of p-chlorophenylacetonitrile, potassium acetate and paraformaldehyde is 1:0.055-0.060:1.2-1.
25.
4. The method for preparing (S)-3-[tert-butyloxycarbonyl(isopropyl)amino]-2-(4-chlorophenyl)propionic acid according to claim 1, characterized in that: In step B, the molar ratio of compound 2 to isopropylamine is 1:1.2-1.
25.
5. The method for preparing (S)-3-[tert-butyloxycarbonyl(isopropyl)amino]-2-(4-chlorophenyl)propionic acid according to claim 1, characterized in that: In step C, the acid is selected from a mixed acid of hydrochloric acid and sulfuric acid.
6. The method for preparing (S)-3-[tert-butyloxycarbonyl (isopropyl) amino]-2-(4-chlorophenyl) propionic acid according to claim 1, characterized in that: In step D, the organic solvent is selected from methanol or ethanol; and triethylamine is added during the reaction.
7. The method for preparing (S)-3-[tert-butyloxycarbonyl(isopropyl)amino]-2-(4-chlorophenyl)propionic acid according to claim 6, characterized in that: In step D, the molar ratio of compound 4, triethylamine and Boc2O is 1:1.05-1.10:1.10-1.
15.
8. The method for preparing (S)-3-[tert-butyloxycarbonyl(isopropyl)amino]-2-(4-chlorophenyl)propionic acid according to claim 1, characterized in that: In step E, the molar ratio of compound 5 to resolving agent 6 is 1:0.45-0.
55.
9. The method for preparing (S)-3-[tert-butyloxycarbonyl(isopropyl)amino]-2-(4-chlorophenyl)propionic acid according to claim 1, characterized in that: In step E, the organic solvent is selected from ethanol.