CN115724781A - Method for synthesizing empatinib key chiral intermediate - Google Patents
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Abstract
The application provides a method for synthesizing a key chiral intermediate II-a of Uppitinib by Ru (OAc) 2 The- (R) -OSDP can catalyze the asymmetric hydrogenation of the unsaturated carboxylic acid I-a to synthesize the chiral carboxylic acid II-a, and the chiral carboxylic acid II-a can form a salt with tert-butylamine and obtain the IV-a with high optical purity after recrystallization. The asymmetric hydrogenation catalyst related to the method provided by the application has an independent patent (CN 109503659B), is high in catalytic efficiency, high in enantioselectivity, simple and convenient to operate, and beneficial to industrial production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing a key chiral intermediate of lapatinib and tert-butylamine salt thereof by an asymmetric catalytic hydrogenation method.
Technical Field
Upadacitinib (Upatinib) is an adult developed by Albervia (Abbvie) for the treatment of moderate to severe active rheumatoid arthritis with inadequate or intolerant aminopterin response and is approved by the FDA to market in 8 months of 2019. In addition to the treatment of rheumatoid arthritis, the new drug is also used in multiple phase 3 clinical trials for the treatment of various inflammatory diseases such as ulcerative enteritis, psoriatic arthritis, crohn's disease, and atopic dermatitis. Therefore, its indications are expected to expand further.
In the synthetic process of the lapatinib, the structure III-a is a key chiral fragment, and in addition, the fragment III-a has great demand in the development of the drug imitation and other new drugs of the lapatinib. However, the quality and cost of the fragment III-a are mainly controlled by the synthesis process of the key chiral intermediate II-a, so that the optimization of the synthesis process route of II-a is crucial in the synthesis process of Upagtinib. (Scheme 1)
At present, the synthesis process route of the structure II-a also has some progress, and the main strategies are chemical resolution method and asymmetric synthesis method. Patent Route WO2019016745 A1, dr. Reddy's Laboratories Limited (leidy-boshi) company reports resolution of rac-II-a compounds (Route 1) with chiral 1-naphthylethylamine, the Route raw materials are cheap and easy to obtain, the Route is long, multiple steps require column separation and purification, the yield of the target product is low, and 1-naphthylethylamine with two different configurations needs to be used as a resolving agent. The cycloaddition reaction of 3+2 in Route II can shorten the reaction steps, but the alkyne ester as the raw material is expensive, and the method requires column separation and purification, and also has high resolution cost. Route III uses chiral camphor sulfonamide as chiral auxiliary group, amide is generated by condensation with alkynoic acid, then key enamide intermediate is generated by cycloaddition of 3+2, corresponding chiral compound is obtained by diastereoselective hydrogenation, and then product II-a with single configuration and chiral auxiliary agent are obtained by hydrolysis. This route avoids the losses associated with resolution, but also uses the expensive alkynoic acids, and subsequent recovery of the chiral auxiliary adds to the cost. (Scheme 2)
Patent route US 10550126 B2, alberweico, first reported Ru (OAc) 2 The- (S) -SegPhos complex (S/C = 1000) catalyzes the asymmetric hydrogenation of an unsaturated tetra-substituted carboxylic acid compound I-a to synthesize a key intermediate II-a of the lapatinib, and forms a salt with dicyclohexylamine, and the compound II-a is obtained by recrystallization with 90% yield and 99% enantioselectivity. Patent route WO2020/202183A1, mylan Laboratories Limited (Milan pharmaceuticals Co., ltd., U.S.A.) also reports a similar asymmetric hydrogenation of the pathway to synthesize the tetrasubstituted carboxylic acid compound II-a, followed by the same use of Ru (OAc) 2 - (S) -SegPhos (S/C = 425) complex. (Scheme 3) in which the synthesis of the substrate is carried out using more valuable reagents such as ethylboronic acid (ester), palladium acetate and Pd (dppf) Cl 2 Catalysts and the like, and the subsequent asymmetric hydrogenation conversion number (TON) is not high, so that the synthesis cost is still high.
Patent line CN 109369659B, li Xinsheng et al Zhejiang university also report Ru (OAc) 2 The- (S) -SegPhos complex (S/C = 200) catalyzes the asymmetric hydrogenation of an unsaturated tetra-substituted carboxylic acid compound I-a to synthesize a key intermediate of the lapatinib, and the compound II-a is obtained with 83% of yield and 99% of enantioselectivity after recrystallization. This route gives low yields of synthesis of the substrate I-a, also using Ru (OAc) in the asymmetric hydrogenation of the compound I-a 2 The- (S) -SegPhos complex is used as a catalyst and the number of asymmetric hydrogenation conversion is not high, and the method is in the patent protection period. Patent route CN 109705011A, CN 110117245B, subsequent report of Li Xinsheng et al Ru (OAc) 2 The compound II-a is synthesized by catalytic asymmetric hydrogenation of- (S) -BINAP complex (S/C = 40-333), although the catalyst is commercially available, the catalytic efficiency is low, and the metal content of the product is easily exceeded due to a large amount of Ru metal catalyst residues. In addition, in the synthetic substrate I-a route, the actual yield of the Grignard addition route is very low, and the post-treatment is complicated; although the cost can be reduced by nickel (instead of palladium) catalyzed coupling, ethylboronic acid is still expensive and cost is difficult to control. (Scheme 4)
The patent route CN 110615753A, nanjing New Enzymatics pharmaceutical science and technology Limited, discloses a method for synthesizing chiral carboxylic acid II, which comprises the steps of carrying out epoxidation, grignard ring opening, oxidation, trifluoromethanesulfonylation, palladium-catalyzed decarbonylation esterification and hydrolysis on N-R-3-pyrroline to obtain unsaturated tetra-substituted carboxylic acid I, and finally carrying out asymmetric hydrogenation to obtain chiral carboxylic acid II. The method has long synthesis route, low efficiency, large amount of high-risk oxidation reagent, expensive sulfonylation reagent and metal palladium, and finally, ru (OAc) reported in the patent is used for asymmetric hydrogenation 2 - (S) -SegPhos, the catalyst is expensive and the catalytic efficiency is not high.
Patent line CN 111217819A, zhengxuu spring et al (Ru (benzane) Cl) reported by Hangzhou Ke Chao Biotechnology Co., ltd 2 ] 2 The- (S) -SunPhos complex (S/C = 1000) catalyzes the asymmetric hydrogenation of an unsaturated tetra-substituted carboxylic acid compound I-a to synthesize a key intermediate of the lapatinib, and then the key intermediate and (S) or (R) -1-phenylethylamine are subjected to reaction to obtain a corresponding salified compound. The method comprises the following steps: TON is only 1000, chiral amine is needed to be added for salification, and 81-90% yield and 99% enantioselectivity are obtained after recrystallization. (Scheme 6)
Patent route CN 112778189A, the synthesis of unsaturated tetra-substituted carboxylic acid compounds I-a by partial reduction of pyrrolidine intermediates, finally using likewise Ru (OAc) 2 Asymmetric hydrogenation of the- (S) -SegPhos complex gives the compound II-a. (Scheme 7) this route requires large amounts of highly toxic NaBH 3 CN reducing agent, cbz as protecting group, low yield, difficult separation, and final use of Ru (OAc) 2 The (S) -SegPhos complex (S/C = 1257) has a low asymmetric hydrogenation efficiency,but also in the patent protection period.
Patent route (CN 111072543B) construction of vinyl-substituted unsaturated alkene esters by Pd-catalyzed Suzuki coupling using Ru (OAc) 2 The- (S) -DM-SegPhos complex catalyzes asymmetric hydrogenation to obtain the corresponding ester, and finally hydrolysis to obtain the deprotected chiral carboxylic acid. (Scheme 8) the route also uses expensive vinylboron reagent, metallic palladium and the like, and the chiral catalyst (S) -DM-SegPhos is expensive and has low catalytic efficiency.
Disclosure of Invention
The invention provides a synthetic method of a key chiral intermediate II-a of Upactinib, which uses independently developed chiral Ru (OAc) 2 The- (R) -OSDP complex efficiently catalyzes asymmetric hydrogenation of unsaturated tetra-substituted carboxylic acid I-a to obtain a key chiral intermediate II-a, and the chiral carboxylic acid II-a can form a salt with tert-butylamine and obtain IV-a with high optical purity after repulping or recrystallization. The invention breaks Ru (OAc) 2 The patent barriers of the- (S) -SegPhos complex in the asymmetric hydrogenation synthesis of the key chiral intermediate II-a and the technical bottlenecks of low conversion efficiency of other chiral ligands.
The invention aims to provide a compound of general formula I, which is synthesized into a compound of general formula II through asymmetric hydrogenation, wherein the synthetic route comprises the following steps:
wherein, the group PG is a nitrogen atom protecting group, preferably benzyloxycarbonyl (Cbz), tert-butoxycarbonyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl and the like, and the structure of the compound I-a, I-b is as follows:
the structure of the compound II-a, II-b is as follows:
the chiral catalyst Ru (OAc) for asymmetric hydrogenation 2 - (R) -OSDP Structure:
wherein-PPh in (R) -OSDP 2 Other derivatives are possible (e.g.:
etc.).
The chiral catalyst is preferably Ru (OAc) 2 - (R) -OSDP, the amount of the chiral catalyst to be added is 0.00005 to 0.01 molar equivalent, more preferably 0.0001 to 0.001 molar equivalent, to the reaction substrate; the hydrogen pressure in the asymmetric hydrogenation reaction is 30 to 90atm, and more preferably 50 to 80atm; the reaction temperature in the asymmetric hydrogenation reaction is 30-90 ℃, and more preferably 40-80 ℃; the reaction solvent for asymmetric hydrogenation reaction is generally an alcohol solvent, such as methanol, ethanol, propanol, etc., or a mixture of two solvents, preferably methanol; the asymmetric hydrogenation can be carried out with or without the addition of a base, which is an organic base (triethylamine, diisopropylethylamine, 1, 4-diazabicyclo [2, 2)]Octane, 4-dimethylaminopyridine, etc.), and one of inorganic bases (sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium phosphate, potassium phosphate, etc.) in an amount of 0.001-1.0 molar equivalent to the substrate.
Compared with the prior art, the synthetic method of the empatinib key chiral intermediate II-a has the following benefits:
1. catalyst used Ru (OAc) 2 - (R) -OSDP having autonomyPatent application
2.Ru(OAc) 2 - (R) -OSDP having high catalytic activity and enantioselectivity
3. The key chiral intermediate II-a obtained by asymmetric hydrogenation can form a salt with tert-butylamine to obtain IV-a, and the compound IV-a is a new compound and is easy to dissociate to obtain the II-a with high optical purity.
Drawings
FIG. 1 is a hydrogen spectrum of compound IV-a;
FIG. 2 is a carbon spectrum of compound IV-a.
The specific implementation mode is as follows:
example 1: synthesis method of compounds II-a and IV-a
Unsaturated carboxylic acid I-a (275mg, 1mmol) was charged in a hydrogenation flask under an inert gas atmosphere, and Ru (OAc) was added 2 - (R) -OSDP (8 mg, 0.001mmol), deoxygenated methanol (1 mL), and then transferred to an autoclave, set to a hydrogen pressure (60 atm), reacted at 60 ℃ for 24 hours, cooled to room temperature, and the solvent was spin-dried to give an oil II-a (274 mg,99% yield in ieel, 96% ee). 1 HNMR(600MHz,CDCl 3 )δ7.40–7.28 (m,5H),6.94(s,1H),5.14(ddd,J＝18.0,12.5,5.9Hz,2H),3.78(ddd,J＝35.7,11.5, 3.6Hz,1H),3.67–3.51(m,2H),3.35–3.23(m,1H),3.17–3.04(m,1H),2.44– 2.28(m,1H),1.58–1.47(m,1H),1.39(dt,J＝13.7,7.1Hz,1H),0.98(dd,J＝13.0, 7.2Hz,3H). 13 C NMR(151MHz,CDCl 3 )δ177.9,155.0,136.8,128.5,128.0,127.9, 67.0,49.9,48.4,46.6,43.6,22.0,12.6.Rotamer: 13 C NMR(151MHz,CDCl 3 )δ 177.6,154.9,136.7,128.5,128.0,127.8,67.09,49.6,47.6,45.6,42.6,22.0,12.6. MS(ESI):276.1[M-H] +
The oily substance II-a (274mg, 96% ee) was dissolved in acetonitrile (5 mL), and tert-butylamine (0.96 eq.) was added dropwise to give a large amount of a white solidSeparating out, heating to 70 ℃, pulping or recrystallizing to obtain IV-a (305mg, 88 percent yield,>99％ee)。 1 H NMR(600MHz,d 6 -DMSO)δ7.38–7.25(m,1H),5.09–4.98 (m,1H),3.49(ddd,J＝20.0,10.6,4.7Hz,1H),3.41–3.25(m,1H),3.22–3.15(m, 1H),2.75(ddd,J＝26.3,11.9,6.7Hz,1H),2.14–2.03(m,1H),1.53–1.44(m,1H), 1.27–1.22(m,1H),1.20(s,2H),0.88(td,J＝7.3,3.1Hz,1H). 13 C NMR(151MHz, d 6 -DMSO)δ175.9,154.5,137.8,128.8,128.1,127.9,66.0,50.7,50.2,49.8,49.0, 43.4,28.3,22.2,13.2.rotamer: 13 C NMR(151MHz,d 6 -DMSO)δ175.7,154.4,137.8, 128.8,128.1,127.8,65.9,50.7,50.2,49.5,48.5,42.5,28.3,22.1,13.2.
example 2: synthesis method of compounds II-a and IV-a
Unsaturated carboxylic acid I-a (1.38g, 5mmol) was charged in a hydrogenation flask under an inert gas atmosphere, and Ru (OAc) was added 2 - (R) -OSDP (1.6 mg, 0.002mmol), deoxygenated methanol (3 mL), then transferred to an autoclave, set to a hydrogen pressure (80 atm), reacted at 60 ℃ for 48h, cooled to room temperature, and the solvent was spin-dried to give oil II-a (1.34g, 97% yield, 95% ee); after beating with tert-butylamine in acetonitrile or recrystallization, IV-a (1.46g, 86% yield,>99％ee)。
example 3: synthesis method of compounds II-a and IV-a
Unsaturated carboxylic acid I-a (1.38g, 5mmol) was charged in a hydrogenation flask under an inert gas atmosphere, and Ru (OAc) was added 2 - (R) -OSDP (0.8mg, 0.001mmol), deoxygenated methanol (3 mL), and then transferred to a pressure vessel, set to a hydrogen pressure (80 atm), reacted at 60 ℃ for 70 hours, cooled to room temperature, and the solvent was spin-dried to obtain an oil II-a (1.01g, 90% yield,94% ee), which was slurried or recrystallized with tert-butylamine in acetonitrile to obtain IV-a (1.32g, 84% yield,>99％ee)
example 4: synthesis method of compounds II-a and IV-a
Unsaturated carboxylic acid I-a (275mg, 1mmol), et was added to a hydrogenation flask under an inert gas atmosphere 3 N (140. Mu.L, 1.0 eq.) Ru (OAc) was added 2 - (R) -OSDP (0.8mg, 0.001mmol), deoxygenated methanol (1.0 mL), and then transferred to a pressure vessel, and reacted at 60 ℃ under a hydrogen pressure (60 atm) of 14h, cooled to room temperature, solvent dried by spinning, dissolved in DCM, pH adjusted to acidity, organic phase extracted, washed with saturated brine, dried over anhydrous sodium sulfate, spun dried to give oil II-a (271mg, 98% yield,90% ee), slurried or recrystallized with tert-butylamine in acetonitrile to give IV-a (268mg, 78% yield,>99％ee)。
example 5: synthesis method of compound II-b
Unsaturated carboxylic acid I-b (121mg, 0.5mmol) was charged in a hydrogenation flask under an inert gas atmosphere, and Ru (OAc) was added 2 - (R) -OSDP (0.8mg, 0.001mmol), deoxygenated methanol (1 mL), and then transferred to an autoclave, reacted at 60 ℃ for 24 hours under a hydrogen pressure (60 atm), cooled to room temperature, and the solvent was dried by spinning to obtain an oily substance II-b (119mg, 98% yield,94% ee), and slurried or recrystallized with tert-butylamine in acetonitrile to obtain IV-b (128mg, 83% yield,>99％ee)。 1 H NMR(600MHz,CDCl 3 )δ6.40(brs, 1H),3.67(ddd,J＝15.4,11.4,3.2Hz,1H),3.58–3.44(m,2H),3.20(dt,J＝19.2, 9.1Hz,1H),3.12–3.05(m,1H),2.33(dd,J＝14.2,7.2Hz,1H),1.56–1.48(m,1H), 1.47(s,9H),1.38(dt,J＝16.0,7.7Hz,1H),0.98(dt,J＝10.7,5.3Hz,3H). MS(ESI):242.1[M-H] + 。
Claims (9)
1. an asymmetric hydrogenation catalytic reaction, wherein the reaction is represented by the following formula:
wherein PG is a nitrogen atom protecting group.
2. The asymmetric hydrogenation catalytic reaction according to claim 1, wherein PG represents a nitrogen atom-protecting group, and is not limited to Cbz (benzyloxycarbonyl), but may be a t-butoxycarbonyl group, allyloxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, or the like.
3. The asymmetric hydrogenation catalytic reaction of claim 1, wherein the asymmetric hydrogenation reaction isThe catalyst is Ru (OAc) 2 - (R) -OSDP, structural formula:
Ru(OCOCF 3 ) 2 -PPh in- (R) -OSDP, (R) -OSDP 2 Other derivatives are possible (e.g.:
4. The asymmetric hydrogenation catalytic reaction of claim 1, wherein the catalyst Ru (OAc) 2 The amount of- (R) -OSDP used is from 0.0001 to 0.001 molar equivalent to the substrate.
5. The asymmetric hydrogenation catalytic reaction according to claim 1, wherein the hydrogen pressure of the asymmetric hydrogenation reaction is 50 to 80atm.
6. The asymmetric hydrogenation catalytic reaction according to claim 1, wherein the reaction temperature of the asymmetric hydrogenation reaction is 40 to 80 ℃.
7. The asymmetric hydrogenation catalytic reaction as claimed in claim 1, wherein the reaction solvent for asymmetric hydrogenation is alcohol solvent such as methanol, ethanol, isopropanol, etc., or a mixture of two thereof.
8. The asymmetric hydrogenation catalytic reaction according to claim 1, wherein the asymmetric hydrogenation reaction can be carried out with or without addition of a base, and if a base is added, the base used is one of an organic base (triethylamine, diisopropylethylamine, 1, 4-diazabicyclo [2, 2] octane, 4-dimethylaminopyridine, etc.), an inorganic base (sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, sodium phosphate, potassium phosphate, etc.); wherein the base is used in an amount of 0.001 to 1.0 molar equivalent to the substrate.
9. The asymmetric hydrogenation catalytic reaction of claim 1, wherein the chiral intermediate II-a obtained by asymmetric hydrogenation can be salified with tert-butylamine, and further slurried or recrystallized to obtain the structure IV-a:
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| Application Number | Priority Date | Filing Date | Title |
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| CN202111004942.3A CN115724781A (en) | 2021-08-30 | 2021-08-30 | Method for synthesizing empatinib key chiral intermediate |
| PCT/CN2021/132941 WO2023029236A1 (en) | 2021-08-30 | 2021-11-25 | Method for synthesizing key chiral intermediate of upadacitinib |
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| CN202111004942.3A CN115724781A (en) | 2021-08-30 | 2021-08-30 | Method for synthesizing empatinib key chiral intermediate |
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| CN110128471B (en) * | 2018-02-08 | 2021-01-15 | 凯特立斯（深圳）科技有限公司 | Synthesis and application of oxaspiro diphosphine ligand |
| WO2019153203A1 (en) * | 2018-02-08 | 2019-08-15 | 凯特立斯（深圳）科技有限公司 | Synthesis and application of oxaspirocyclodiphosphine ligand |
| CN111217819B (en) * | 2018-11-27 | 2021-05-14 | 杭州科巢生物科技有限公司 | Synthetic method of sepiatinib |
| CN109503659B (en) * | 2019-01-03 | 2021-06-18 | 凯特立斯（深圳）科技有限公司 | Oxaspiro diphosphine ligand and application thereof in asymmetric hydrogenation of alpha, beta-unsaturated carboxylic acid |
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