CN115260074A - Preparation method of Paxlovid intermediate of oral antiviral drug - Google Patents
Preparation method of Paxlovid intermediate of oral antiviral drug Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title abstract description 14
- LIENCHBZNNMNKG-OJFNHCPVSA-N nirmatrelvir Chemical compound CC1([C@@H]2[C@H]1[C@H](N(C2)C(=O)[C@H](C(C)(C)C)NC(=O)C(F)(F)F)C(=O)N[C@@H](C[C@@H]3CCNC3=O)C#N)C LIENCHBZNNMNKG-OJFNHCPVSA-N 0.000 title abstract description 12
- 229940125675 paxlovid Drugs 0.000 title abstract description 12
- 239000003443 antiviral agent Substances 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 86
- 238000006243 chemical reaction Methods 0.000 claims abstract description 45
- 238000000034 method Methods 0.000 claims abstract description 29
- RPMXALUWKZHYOV-UHFFFAOYSA-N nitroethene Chemical group [O-][N+](=O)C=C RPMXALUWKZHYOV-UHFFFAOYSA-N 0.000 claims abstract description 18
- 230000035484 reaction time Effects 0.000 claims abstract description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- 239000000203 mixture Substances 0.000 claims description 52
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 27
- 239000003153 chemical reaction reagent Substances 0.000 claims description 20
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 16
- 239000003960 organic solvent Substances 0.000 claims description 16
- 238000006138 lithiation reaction Methods 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 13
- 239000003054 catalyst Substances 0.000 claims description 11
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical group C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 claims description 2
- -1 lithium diamine Chemical class 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 7
- QNSPKWUAZQIIGZ-QMMMGPOBSA-N dimethyl (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanedioate Chemical compound COC(=O)CC[C@@H](C(=O)OC)NC(=O)OC(C)(C)C QNSPKWUAZQIIGZ-QMMMGPOBSA-N 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 5
- 230000000840 anti-viral effect Effects 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 150000002431 hydrogen Chemical class 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000008399 tap water Substances 0.000 description 3
- 235000020679 tap water Nutrition 0.000 description 3
- 241000711573 Coronaviridae Species 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 150000004985 diamines Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 208000025721 COVID-19 Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of an oral antiviral drug Paxlovid intermediate, belonging to the field of pharmacy. The invention provides a Paxlovid intermediate for preparing an oral antiviral medicament, which takes N-Boc-L-glutamic acid dimethyl ester and nitroethylene as initial raw materials: novel process for the preparation of compound 2s. The method has the advantages of easily available reaction raw materials, easily controlled reaction conditions, short reaction time, high total product yield and high purity, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a preparation method of an oral antiviral drug Paxlovid intermediate.
Background
The compound 2s is an important medical intermediate. The literature (J.org.chem.2021, 86,18, 13104-13110) reports that compound 2s is an important intermediate for the preparation of the oral antiviral drug Paxlovid. Paxlovid is an oral small-molecule new coronavirus therapeutic drug developed by the company pfeiffe, and is used for treating adult patients with light to moderate novel coronavirus pneumonia (COVID-19) with severe high risk factors. Therefore, the industrial production of the compound 2s is of great significance.
Chinese patent application publication No. CN1374947A discloses a method for preparing an optical isomer of compound 2s (i.e., compound 9 in the scheme), which is as follows. However, on the one hand, this process does not give the target product compound 2s, but only its optical isomer, and cannot be used for the preparation of Paxlovid; on the other hand, the method takes long time, and needs 3 to 4 days; in addition, the method has low total yield of only 34.8 percent, and is not suitable for industrial production.
It is of great significance to develop a process for the preparation of compound 2s which is short in time consumption and high in overall product yield.
Disclosure of Invention
The invention aims to provide a method for preparing an oral antiviral drug Paxlovid intermediate.
The invention provides a method for preparing an oral antiviral drug Paxlovid intermediate compound 2S, which comprises the following steps:
(1) Reacting the compound SM with nitroethylene to obtain a mixture of a compound 1S and a compound 1R;
(2) Reacting a mixture of the compound 1S and the compound 1R in the presence of a palladium catalyst in a hydrogen atmosphere to obtain a mixture of a compound 2S and a compound 2R;
(3) Resolving a mixture of compound 2S and compound 2R to give compound 2S.
Further, in the step (1), the reaction is carried out in the presence of a lithiation reagent, and the molar ratio of the compound SM, the nitroethylene and the lithiation reagent is 1 (1.2-3) to (1.2-3); the solvent of the reaction is an organic solvent; the feeding mode of the step (1) is as follows: firstly, dropwise adding a lithiation reagent solution into a solution of a compound SM, reacting for 0.3-3 hours after dropwise adding, then continuously dropwise adding nitroethylene, and reacting for 1-5 hours after dropwise adding.
Further, in the step (1), the molar ratio of the compound SM to the nitroethylene to the lithiation reagent is 1; the lithiation reagent is one or a mixture of two of lithium diamine and lithium diisopropylamide, and the organic solvent is tetrahydrofuran; the temperature of the reaction system is-80 ℃ to-40 ℃ when the lithiation reagent solution is dripped, and the optimal temperature is-50 ℃; the reaction temperature is-80 to-40 ℃ after the lithiation reagent solution is dripped, the reaction temperature is preferably-50 ℃, and the reaction time is 0.5 to 1.5 hours, preferably 1 hour; the temperature of the reaction system is-80 ℃ to-40 ℃ when the nitroethylene is dripped, and the preferential temperature is-50 ℃; the reaction temperature after the dropping of nitroethylene is-40-0 deg.c, preferably-20 deg.c, and the reaction time is 2-4 hr, preferably 3 hr.
Further, in the step (1), after the reaction is finished, the method further comprises the following steps: adding acid into the reaction system to quench the reaction, then adding water and methyl tert-butyl ether, extracting, separating, taking an organic phase, washing and drying to obtain a mixture of the compound 1S and the compound 1R.
Further, in the step (2), the palladium catalyst is palladium carbon; the mass ratio of the mixture of the compound 1S and the compound 1R to the palladium catalyst is (5-20): 1; the pressure of the hydrogen atmosphere is 0.5-2.5Mpa; the solvent for the reaction is an organic solvent, the temperature for the reaction is 35-55 ℃, and the reaction time is 16-32 hours.
Further, in the step (2), the palladium carbon is 5% palladium carbon; the mass ratio of the mixture of the compound 1S and the compound 1R to the palladium catalyst is 10, and the pressure of the hydrogen atmosphere is 1.0-2.0MPa; the organic solvent is one or a mixture of two of methanol and chloroform, and in the mixture of methanol and chloroform, the volume ratio of methanol to chloroform is preferably 7; the reaction temperature was 45 ℃ and the reaction time was 24 hours.
Further, in the step (2), after the reaction is finished, the method further comprises the following steps: adding an alkaline reagent into the reaction system, and continuously reacting for 6-10 hours; preferably, the alkaline reagent is one or a mixture of two of sodium acetate and potassium carbonate, and the molar ratio of the mixture of the compound 1S and the compound 1R to the alkaline reagent is 1 (1-3), preferably 1.
Further, in step (3), the splitting method is: adding a mixture of a compound 2S and a compound 2R into an organic solvent, dissolving at 45-75 ℃, then cooling to 15-35 ℃, stirring, and separating out a solid, namely the compound 2S;
the organic solvent is one or a mixture of more than two of methanol, methyl tert-butyl ether, dichloromethane and n-hexane.
Further, in the step (3), the organic solvent is selected from a mixture of methanol and methyl tert-butyl ether, a mixture of dichloromethane and n-hexane; in the mixture of methanol and methyl tert-butyl ether, the volume ratio of the methanol to the methyl tert-butyl ether is 1 (5-10); in the mixture of dichloromethane and n-hexane, the volume ratio of dichloromethane to n-hexane is 1 (5-10).
Further, in the step (3), the mass-to-volume ratio of the mixture of the compound 2S and the compound 2R to the organic solvent is 1 (8-12) g/mL, preferably 1;
the dissolving temperature is 45-65 ℃, the stirring temperature is 25 ℃, and the stirring time is more than 2 hours.
The invention provides a Paxlovid intermediate for preparing an oral antiviral medicament, which takes N-Boc-L-glutamic acid dimethyl ester and nitroethylene as initial raw materials: novel process for the preparation of compound 2s. The method has the advantages of easily available reaction raw materials, easily controlled reaction conditions, short reaction time, high total product yield and high purity, and is suitable for industrial production.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
Examples 1-3 the route for the preparation of compound 2s is as follows:
example 1: preparation of Compound 2s
Step 1:
dissolving N-Boc-L-glutamic acid dimethyl ester (27.5g, 0.1mol) in 275mL of anhydrous tetrahydrofuran, cooling to-78 ℃, slowly dropwise adding LiHMDS (diamine lithium, 205.0mL,1.0M in THF), and after dropwise adding, continuing to perform heat preservation reaction for 1 hour; controlling the temperature to be 50 ℃ below zero, dropwise adding nitroethylene (8.76g, 0.12mol), and after dropwise adding, returning the temperature to 20 ℃ below zero to react for 3 hours; after the reaction was completed, the reaction solution was quenched with 20mL of acetic acid, 275mL of tap water and 137.5mL of methyl tert-butyl ether were added, and the mixture was extracted, separated, the organic phase was washed with 55mL of 1N hydrochloric acid, dried over sodium sulfate and concentrated to obtain 27.8g of a mixture of compound 1S and 1R in a yield of 80%; [ M +1] =349.2.
H NMR(400M,CDCl3):δ＝5.01(br,1H),4.42(m,3H),3.75-3.69(d,6H),2.61(m,1H),2.31(m,2H),2.05(m,1H),1.42(s,9H),1.25(m,1H).
And 2, step:
dissolving a mixture (34.8g, 0.1mol) of a compound 1S and 1R in 350mL of methanol, adding 5% palladium carbon (3.48g, 0.1w/w), uniformly stirring, replacing hydrogen, pressurizing to 1.0-2.0Mpa, heating to 45 ℃, reacting for 24 hours, cooling to 20-25 ℃, carrying out suction filtration to recover a catalyst, concentrating a filtrate to dryness to obtain 24.3g of a mixture of a compound 2S and a compound 2R, wherein the yield is 85%; [ M +1] =287.3.
And 3, step 3:
a mixture (28.6 g, 0.1mol) of the compound 2S and 2R is dissolved in 50mL of methanol, heated to 60 ℃, stirred and dissolved, 250mL of methyl tert-butyl ether is slowly added dropwise, then the temperature is reduced to 25 ℃, stirring is continued for 2 hours, and suction filtration is carried out to obtain 17.1g of compound 2S solid, the yield is 60%, and the HPLC purity is 99.1%.
HNMR(400M,CDCl3):δ＝5.86(br,1H),5.48(br,1H),4.32(m,1H),3.74(s,3H),3.37(m,2H),2.46(m,2H),2.14(m,2H),1.87(m,1H),1.42(s,9H).
Example 2: preparation of Compound 2s
Step 1:
dissolving N-Boc-L-glutamic acid dimethyl ester (27.5g, 0.1mol) in 275mL of anhydrous tetrahydrofuran, cooling to-50 ℃, slowly dropwise adding LiHMDS (diamine lithium, 215.0mL,1.0M in THF), and after dropwise adding, continuing to perform heat preservation reaction for 1 hour; controlling the temperature to be 50 ℃ below zero, dropwise adding nitroethylene (14.6 g, 0.2mol), and after dropwise adding, returning the temperature to 20 ℃ below zero to react for 3 hours; after the reaction is completed, the reaction solution is quenched by 20mL of acetic acid, 275mL of tap water and 137.5mL of methyl tert-butyl ether are added for extraction, liquid separation is carried out, an organic phase is washed by 55mL of 1N hydrochloric acid, the organic phase is dried by sodium sulfate and then concentrated, and a mixture of 29.6 compounds 1S and 1R is obtained, wherein the yield is 85%; [ M +1] =349.2.
H NMR(400M,CDCl 3 ):δ＝5.01(br,1H),4.42(m,3H),3.75-3.69(d,6H),2.61(m,1H),2.31(m,2H),2.05(m,1H),1.42(s,9H),1.25(m,1H).
Step 2:
dissolving a mixture (34.8g, 0.1mol) of a compound 1S and 1R in a mixed solution of 350mL of methanol and 50mL of chloroform, adding 5% palladium carbon (3.48g, 0.1w/w), uniformly stirring, replacing hydrogen, pressurizing to 1.0-2.0Mpa, heating to 45 ℃, reacting for 24 hours, adding sodium acetate (16.4g, 0.2mol), continuously stirring and reacting for 8 hours, cooling to 20-25 ℃, carrying out suction filtration and recovering a catalyst, and concentrating a filtrate to be dry to obtain 27.1g of a mixture of a compound 2S and a compound 2R, wherein the yield is 95%; m +1] =287.3.
And step 3:
a mixture of the compound 2S and 2R (28.6 g, 0.1mol) was dissolved in a mixed solution of 25mL of methanol and 250mL of methyl t-butyl ether, heated to 65 ℃ and stirred to dissolve, then slowly cooled to 25 ℃ and stirred for 2 hours, followed by suction filtration to obtain 18.5g of a compound 2S solid, with a yield of 65% and an HPLC purity of 99.3%.
H NMR(400M,CDCl 3 ):δ＝5.86(br,1H),5.48(br,1H),4.32(m,1H),3.74(s,3H),3.37(m,2H),2.46(m,2H),2.14(m,2H),1.87(m,1H),1.42(s,9H).
Example 3: preparation of Compound 2s
Step 1:
dissolving N-Boc-L-glutamic acid dimethyl ester (27.5g, 0.1mol) in 275mL of anhydrous tetrahydrofuran, cooling to-50 ℃, slowly dropwise adding LDA (lithium diisopropylamide, 215.0mL,1.0M in THF), and after dropwise adding, continuing to perform heat preservation reaction for 1 hour; controlling the temperature to be 50 ℃ below zero, dropwise adding nitroethylene (14.6 g, 0.2mol), and after the dropwise adding is finished, returning the temperature to 20 ℃ below zero to react for 3 hours; after the reaction was completed, the reaction solution was quenched with 20mL of acetic acid, 275mL of tap water was added, 137.5mL of dichloromethane was extracted, liquid separation was performed, the organic phase was washed with 55mL of 1N hydrochloric acid, and the organic phase was dried over sodium sulfate and concentrated to obtain 27.8g of a mixture of compound 1S and 1R with a yield of 80%; [ M +1] =349.2.
HNMR(400M,CDCl3):δ＝5.01(br,1H),4.42(m,3H),3.75-3.69(d,6H),2.61(m,1H),2.31(m,2H),2.05(m,1H),1.42(s,9H),1.25(m,1H).
Step 2:
dissolving a mixture (34.8g, 0.1mol) of a compound 1S and 1R in 350mL of methanol and 50mL of chloroform, adding 5% palladium-carbon (3.48g, 0.1w/w), uniformly stirring, replacing hydrogen, pressurizing to 1.0-2.0Mpa, heating to 45 ℃, reacting for 24 hours, adding potassium carbonate (27.6g, 0.2mol), continuously stirring and reacting for 8 hours, cooling to 20-25 ℃, carrying out suction filtration to recover a catalyst, concentrating a filtrate to dryness to obtain 25.7g of a mixture of a compound 2S and a compound 2R, wherein the yield is 90%; m +1] =287.3.
And 3, step 3:
a mixture (28.6 g,0.1 mol) of the compound 2S and 2R is dissolved in a mixed solution of 25mL of dichloromethane and 250mL of n-hexane, the temperature is raised to 45 ℃, the mixture is stirred and dissolved, then the temperature is slowly lowered to 25 ℃, the stirring is continued for 2 hours, and the suction filtration is carried out, so that 15.6g of the compound 2S solid is obtained, the yield is 55%, and the HPLC purity is 99.1%.
HNMR(400M,CDCl3):δ＝5.86(br,1H),5.48(br,1H),4.32(m,1H),3.74(s,3H),3.37(m,2H),2.46(m,2H),2.14(m,2H),1.87(m,1H),1.42(s,9H).
In conclusion, the invention provides an intermediate for preparing an oral antiviral drug Paxlovid by taking N-Boc-L-glutamic acid dimethyl ester and nitroethylene as initial raw materials: novel process for the preparation of compound 2s. The method has the advantages of easily available reaction raw materials, easily controlled reaction conditions, short reaction time, high total product yield and high purity, and is suitable for industrial production.
Claims (10)
1. A process for preparing compound 2S, characterized in that: the method comprises the following steps:
(1) Reacting the compound SM with nitroethylene to obtain a mixture of a compound 1S and a compound 1R;
(2) Reacting a mixture of a compound 1S and a compound 1R in the presence of a palladium catalyst in a hydrogen atmosphere to obtain a mixture of a compound 2S and a compound 2R;
(3) Resolving a mixture of compound 2S and compound 2R to give compound 2S.
2. The method of claim 1, wherein: in the step (1), the reaction is carried out in the presence of a lithiation reagent, and the molar ratio of the compound SM, the nitroethylene and the lithiation reagent is 1 (1.2-3) to (1.2-3); the solvent for the reaction is an organic solvent; the feeding mode of the step (1) is as follows: firstly, dropwise adding a lithiation reagent solution into a solution of a compound SM, reacting for 0.3-3 hours after dropwise adding, then continuously dropwise adding nitroethylene, and reacting for 1-5 hours after dropwise adding.
3. The method of claim 2, wherein: in the step (1), the molar ratio of the compound SM to the nitroethylene to the lithiation reagent is 1; the lithiation reagent is one or a mixture of two of lithium diamine and lithium diisopropylamide, and the organic solvent is tetrahydrofuran; the temperature of the reaction system is-80 ℃ to-40 ℃ when the lithiation reagent solution is dripped, and the optimal temperature is-50 ℃; the reaction temperature is-80 to-40 ℃ after the lithiation reagent solution is dripped, the reaction temperature is preferably-50 ℃, and the reaction time is 0.5 to 1.5 hours, preferably 1 hour; the temperature of the reaction system is-80 ℃ to-40 ℃ when the nitroethylene is dripped, and the preferential temperature is-50 ℃; the reaction temperature after the dropping of nitroethylene is-40-0 deg.c, preferably-20 deg.c, and the reaction time is 2-4 hr, preferably 3 hr.
4. The method of claim 1, wherein: in the step (1), after the reaction is finished, the method further comprises the following steps: adding acid into the reaction system to quench the reaction, then adding water and methyl tert-butyl ether, extracting, separating, taking an organic phase, washing and drying to obtain a mixture of the compound 1S and the compound 1R.
5. The method of claim 1, wherein: in the step (2), the palladium catalyst is palladium carbon; the mass ratio of the mixture of the compound 1S and the compound 1R to the palladium catalyst is (5-20): 1; the pressure of the hydrogen atmosphere is 0.5-2.5Mpa; the solvent for the reaction is an organic solvent, the temperature for the reaction is 35-55 ℃, and the reaction time is 16-32 hours.
6. The method of claim 5, wherein: in the step (2), the palladium carbon is 5% palladium carbon; the mass ratio of the mixture of the compound 1S and the compound 1R to the palladium catalyst is 10; the organic solvent is one or a mixture of two of methanol and chloroform, and in the mixture of methanol and chloroform, the volume ratio of methanol to chloroform is preferably 7; the reaction temperature was 45 ℃ and the reaction time was 24 hours.
7. The method of claim 1, wherein: in the step (2), after the reaction is finished, the method further comprises the following steps: adding an alkaline reagent into the reaction system, and continuously reacting for 6-10 hours; preferably, the alkaline reagent is one or a mixture of two of sodium acetate and potassium carbonate, and the molar ratio of the mixture of the compound 1S and the compound 1R to the alkaline reagent is 1 (1-3), preferably 1.
8. The method according to any one of claims 1 to 7, wherein: in the step (3), the splitting method comprises the following steps: adding a mixture of a compound 2S and a compound 2R into an organic solvent, dissolving at 45-75 ℃, then cooling to 15-35 ℃, stirring, and separating out a solid, namely the compound 2S;
the organic solvent is one or a mixture of more than two of methanol, methyl tert-butyl ether, dichloromethane and n-hexane.
9. The method of claim 8, wherein: in the step (3), the organic solvent is selected from a mixture of methanol and methyl tert-butyl ether, and a mixture of dichloromethane and n-hexane; in the mixture of methanol and methyl tert-butyl ether, the volume ratio of the methanol to the methyl tert-butyl ether is 1 (5-10); in the mixture of the dichloromethane and the normal hexane, the volume ratio of the dichloromethane to the normal hexane is 1 (5-10).
10. The method of claim 9, wherein: in the step (3), the mass-to-volume ratio of the mixture of the compound 2S and the compound 2R to the organic solvent is 1 (8-12) g/mL, preferably 1;
the dissolving temperature is 45-65 ℃, the stirring temperature is 25 ℃, and the stirring time is more than 2 hours.
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