CN114591299A - Paroviride intermediate and preparation and application thereof - Google Patents
Paroviride intermediate and preparation and application thereof Download PDFInfo
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- CN114591299A CN114591299A CN202111596071.9A CN202111596071A CN114591299A CN 114591299 A CN114591299 A CN 114591299A CN 202111596071 A CN202111596071 A CN 202111596071A CN 114591299 A CN114591299 A CN 114591299A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention provides a structure of a compound (IV), a synthesis method of the compound (IV) and a synthesis method for preparing a paroxetine intermediate (I) by using the compound (IV) as a raw material. The compound (IV) can be obtained by splicing reaction of cyclopropyl proline methyl ester (V) and L-tert-leucine (VI) protected by phthaloyl; removing phthaloyl protection from the compound (IV) to obtain an intermediate (III); and (3) hydrolyzing the intermediate (III) in the presence of inorganic base to obtain an acid intermediate (II), and finally protecting the intermediate (II) by trifluoroacetyl to obtain the compound (I). The invention adopts phthaloyl to protect L-tert-leucine (VI) fragment, has wide selection range of condensation reaction conditions, is easy to purify the intermediate, and provides a new method for preparing the intermediate (I) of the Parovidey.
Description
Technical Field
The invention relates to the technical field of synthesis of Parovide and a main component PF-07321332 thereof, in particular to the technical field of an intermediate (1R,2S,5S) -3- ((S) -3, 3-dimethyl-2- (2,2, 2-trifluoroacetamide) butoxycarbonyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-formic acid (I).
Background
Pairovird (Paxlovid) is an oral new crown specific drug developed by Pfizer, U.S. the company of Peverizer, and the code of the main component of the drug is PF-07321332, and the palofvird is a mixture of PF-07321332 and ritonavir. In 11 months 2021, pfeixuan oral perovewed was successful in the mild disease trial at stage three, reducing the risk of hospitalization or death in 89% of patients with mild new coronary disease compared to placebo. The structure of PF-07321332 is shown in formula 1, and the compound (1R,2S,5S) -3- ((S) -3, 3-dimethyl-2- (2,2, 2-trifluoroacetamido) butyloxycarbonyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid (I) is one of key intermediates for synthesizing PF-07321332.
The synthesis of PF-07321332 is disclosed in Supplement Information of Science (DOI:10.1126/Science. abl4784) by Peui corporation as shown in formula 2.
The method comprises the steps of taking L-tert-leucine protected by Boc as a raw material, condensing with a cyclopropyl proline intermediate (V) in the presence of HATU to obtain a condensation product, hydrolyzing methyl ester to obtain an intermediate acid, removing a Boc protecting group to obtain an intermediate amino acid hydrochloride, and reacting with ethyl trifluoroacetate to obtain a compound (1R,2S,5S) -3- ((S) -3, 3-dimethyl-2- (2,2, 2-trifluoroacetamide) butoxycarbonyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-formic acid (I).
Disclosure of Invention
Considering that Boc-protected L-tert-leucine and cyclopropylproline intermediate (V) are condensed in the presence of HATU, HATU is costly and unsuitable for mass production, which greatly increases the production cost of compound (I). Therefore, the invention provides a structure of a compound (1R,2S,5S) -3- ((S) -2- (1, 3-dioxoisoindol-2-yl) -3, 3-dimethylbutyloxycarbonyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid methyl ester (IV).
The amino group in the compound (IV) is protected by phthaloyl, and the amino group does not contain naked hydrogen, so that methods such as acyl chloride, mixed anhydride, condensing agent and the like can be considered when splicing two fragments, and reaction conditions with low cost and easy operation can be preferably selected to realize the splicing reaction.
The spectrum data of compound (IV) are as follows:
1H NMR(400MHz,DMSO-d6)δ7.88(dd,J=10.5,1.7Hz,4H),4.38(d,J=12.5Hz,1H),4.13(d,J=101.2Hz,1H),3.69(dd,J=10.2,5.4Hz,1H),3.64(s,3H),2.89–2.75(m,1H),1.75–1.39(m,1H),1.36–1.26(m,1H),0.99(d,J=12.2Hz,9H),0.83(d,J=7.5Hz,3H),0.42(s,3H).
MS(ESI)m/z=413(M++H).
the invention provides a synthesis method of a compound (IV), which takes (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-methyl formate (V) and phthaloyl protected L-tert-leucine (VI) as raw materials to obtain the compound (IV) through splicing reaction. Compound (V) comprises an acceptable salt thereof, such as the hydrochloride salt.
Wherein the compound methyl (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate (V) comprises an acceptable salt thereof, such as the hydrochloride salt.
Preferably, the splicing reaction comprises the steps of reacting the phthaloyl protected L-tert-leucine (VI) with a chlorinated reagent to generate an acyl chloride or mixed anhydride intermediate, and then reacting with the compound (V) to obtain the compound (IV), wherein the chlorinated reagent contains thionyl chloride, oxalyl chloride, triphosgene, pivaloyl chloride and p-toluenesulfonyl chloride.
Preferably, the splicing reaction comprises a process of direct condensation of compound (V) with compound (VI) in the presence of condensing agents including combinations of T3P, HATU, EDCI/HOBT, EDCI/HOPO, and the like.
The invention also provides a synthesis method of the intermediate (1R,2S,5S) -3- ((S) -3, 3-dimethyl-2- (2,2, 2-trifluoroacetamide) butoxycarbonyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-formic acid (I) of the paluvir. The method comprises the following two steps:
a) removing phthaloyl protection by using a compound (IV) as a raw material to obtain an intermediate (III);
b) the intermediate (II) is hydrolyzed in the presence of an inorganic base to give an intermediate (II).
c) The intermediate (III) is protected by upper trifluoroacetyl group to obtain the compound (I).
Wherein intermediate (III) comprises an acceptable salt thereof, such as the hydrochloride salt; the reagent used for removing the phthaloyl protection comprises hydrazine hydrate, ammonia gas, ethanolamine and diethanolamine.
Wherein the inorganic base comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate and sodium potassium carbonate.
Wherein the conditions for the upper trifluoroacetyl group comprise conducting the reaction in the presence of ethyl trifluoroacetate and a base.
Preferably, the base comprises sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine.
The invention has the advantages that:
1. the phthaloyl is adopted to protect the L-tert-leucine fragment, the condensation reaction condition selection range is wide, the intermediate is easy to purify, the manufacturing cost of the compound (I) is reduced, and the method is suitable for industrial mass production.
2. Provides a new method for preparing the intermediate (I) of the paluvir.
Detailed Description
For a better understanding of the present invention, reference will now be made to the following examples. It should be understood that the following specific examples are illustrative of the invention only and are not limiting.
Example 1: preparation of phthaloyl protected L-tert-leucine (1-2)
Adding 25g of L-tert-leucine (1-2), 28.2g of phthalic anhydride, 2.0g of triethylamine and 500mL of toluene into a 1000mL reaction bottle, heating to reflux, and carrying out water separation reaction for 4 hours until the raw materials are reacted completely. Adding 150mL of 5% hydrochloric acid, stirring, separating liquid, extracting the water phase once by using 300mL of ethyl acetate, and washing the combined organic phase once by using 200mL of water; concentrating and drying the organic phase, dissolving the obtained crude product in 95mL ethyl acetate, slowly dripping 240mL n-hexane, filtering the separated solid, rinsing a small amount of n-hexane, and drying to obtain 31.0g of white crystal phthaloyl protected L-tert-leucine (1-2) with the yield of 62.3%.1H NMR(400MHz,DMSO-d6)δ12.90(s,1H),8.17–7.61(m,4H),4.47(s,1H),1.08(s,9H).MS(ESI)m/z=262(M++1).
Example 2: preparation of compound (2-2) by acid chloride method
Under the protection of nitrogen, dissolving 12.7g of phthaloyl protected L-tert-leucine (1-2) in 178mL of dichloromethane, adding 0.1g of DMF, slowly dropwise adding oxalyl chloride at 0-10 ℃, and keeping the temperature for 5 hours until the raw materials disappear; the dichloromethane was removed by concentration and the residue was dissolved in 100mL of tetrahydrofuran until use.
Under the protection of nitrogen, 10.0g of dimethylcyclopropylproline methyl ester hydrochloride (2-1), 15.13g of diisopropylethylamine and 100mL of tetrahydrofuran are added into another reaction bottle, and the mixture is stirred at room temperature for 20 minutes; cooling to 0-10 deg.c in ice bath, and dropping the acyl chloride solution; after the addition is finished, the temperature is raised to 5-15 ℃ for reaction for 6 hours, and the reaction is controlled to be complete. Adding 100mL of dichloromethane and 100mL of water into the reaction solution, and stirring and separating the solution; washing the organic phase by using 100mL of 0.5N hydrochloric acid and 100mL of water; the solvent was removed by concentration to obtain 18.8g of a white solid compound (2-2) in a yield of 94%.1H NMR(400MHz,DMSO-d6)δ7.88(dd,J=10.5,1.7Hz,4H),4.38(d,J=12.5Hz,1H),4.13(d,J=101.2Hz,1H),3.69(dd,J=10.2,5.4Hz,1H),3.64(s,3H),2.89–2.75(m,1H),1.75–1.39(m,1H),1.36–1.26(m,1H),0.99(d,J=12.2Hz,9H),0.83(d,J=7.5Hz,3H),0.42(s,3H).MS(ESI)m/z=413(M++H).
According to the above procedures, different chlorinating agents were used to prepare acid chlorides, and the experimental results obtained are as follows:
watch 1
Serial number | Acyl chlorides | Yield of |
1 | Oxalyl chloride | 94% |
2 | Thionyl chloride | 92% |
3 | Triphosgene | 95% |
Example 3: preparation of Compound (2-2) by Mixed anhydride Process
Adding 26.2g of tetrahydrofuran and phthaloyl protected L-tert-leucine (1-2) into a 250mL reaction bottle, adding 20.0g of DIPEA and 1.0g of DMAP under the protection of nitrogen, cooling to 0-10 ℃, slowly dropwise adding 18.8g of p-toluenesulfonyl chloride, raising the temperature to room temperature after dropwise adding is finished, and reacting for 3 hours until the raw materials disappear; then 21.0g of dimethylcyclopropyl proline methyl ester hydrochloride (2-1) is added, and the mixture is stirred for 24 hours at room temperature until the reaction is finished; adding 200mL of dichloromethane and 200mL of water, and stirring and separating liquid; washing the organic phase with 200mL of 0.5N hydrochloric acid and 200mL of water; the solvent was removed by concentration to obtain 36.6g of a white solid compound (2-2) in a yield of 94%. The spectral data are given in example 2.
According to the operation steps, different acyl chloride and solvents are adopted, and the obtained experimental results are as follows:
watch two
Example 4: preparation of compound (2-2) by active ester method
Adding 13.1g of tetrahydrofuran and phthaloyl protected L-tert-leucine (1-2) into a 250mL reaction bottle, adding 10.0g of DIPEA and 0.5g of DMAP under the protection of nitrogen, cooling to 0-10 ℃, slowly dropwise adding 8.7g of methyl chloroformate, heating to room temperature after dropwise adding is finished, and reacting for 3 hours until the raw materials disappear; then 10.5g of dimethylcyclopropyl proline methyl ester hydrochloride (2-1) is added, and the mixture is stirred for 24 hours at room temperature until the reaction is finished; adding 200mL of dichloromethane and 200mL of water, and stirring and separating liquid; washing the organic phase by using 100mL of 0.5N hydrochloric acid and 100mL of water; the solvent was removed by concentration to obtain 24.2g of a white solid compound (2-2) in a yield of 94%. The spectral data are given in example 2.
According to the above operation steps, different chloroformates and solvents are used, and the obtained experimental results are as follows: watch III
Serial number | Solvent(s) | Activating agent | Yield of |
1 | Tetrahydrofuran (THF) | Chloroformic acid methyl ester | 85% |
2 | Tetrahydrofuran (THF) | Chloroformic acid ethyl ester | 87% |
3 | Tetrahydrofuran (THF) | Isopropyl chloride | 86% |
4 | Tetrahydrofuran (THF) | Isobutyl chloroformate | 88% |
5 | DMF | Chloroformic acid methyl ester | 75% |
6 | Methylene dichloride | Chloroformic acid ethyl ester | 68% |
7 | Methyl tetrahydrofuran | Isopropyl chloroformate | 66% |
8 | DMA | Isobutyl chloroformate | 72% |
Example 5: condensation method for preparing compound (2-2)
Adding 52.2g of tetrahydrofuran and phthaloyl protected L-tert-leucine (1-2) 300mL into a 500mL reaction bottle, adding 40.0g of DIPEA and 2.0g of DMAP under the protection of nitrogen, cooling to 0-10 ℃, slowly dropwise adding 36.0g of T3P (n-propyl triphosphate anhydride), heating to room temperature after dropwise adding is finished, and reacting for 3 hours until the raw materials disappear; then 42.0g of dimethylcyclopropyl proline methyl ester hydrochloride (2-1) is added, and the mixture is stirred for 24 hours at room temperature until the reaction is finished; adding 300mL of dichloromethane and 300mL of water, and stirring and separating liquid; washing the organic phase with 300mL of 0.5N hydrochloric acid and 300mL of water; the solvent was removed by concentration to obtain 78.3g of a white solid compound (2-2) in 92% yield. The spectral data are given in example 2.
According to the operation steps, different combinations of condensing agents and solvents are adopted, and the obtained experimental results are as follows:
watch four
Serial number | Solvent(s) | Condensing agent combination | Yield of |
1 | Tetrahydrofuran (THF) | T3P | 92% |
2 | Tetrahydrofuran (THF) | EDCI/HOBT | 83% |
3 | Tetrahydrofuran (THF) | EDCI/HOPO | 85% |
4 | Tetrahydrofuran (THF) | HATU | 90% |
5 | DMF | T3P | 88% |
6 | Methylene dichloride | EDCI/HOBT | 80% |
7 | Methyl tetrahydrofuran | EDCI/HOPO | 81% |
8 | DMA | HATU | 89% |
Example 6: preparation of Compound (6-1)
Adding 20.6g of the compound (2-2) and 200mL of methanol into a 500mL reaction bottle, cooling to 0-10 ℃, adding 10.0g of 85% hydrazine hydrate, and after dropwise addition, heating to 40 ℃ for reaction for 4 hours until the raw materials disappear; concentrating to remove the solvent, adding 300mL of dichloromethane and 300mL of water, and stirring for liquid separation; the organic phase was washed with 100mL of 0.5N aqueous sodium bicarbonate solution and 100mL of water, and the solvent was removed by concentration to give 12.3g of a white solid compound (6-1) in 87% yield. The crude product can be directly put into the next reaction. MS (ESI) M/z 283 (M)++H).
According to the above operation steps, different reagents and reaction conditions are changed, and the obtained experimental results are shown in the following table five: watch five
Serial number | Reagent | Reaction conditions | Yield of |
1 | Hydrazine hydrate | At 40 ℃ for 4 hours | 87% |
2 | Ammonia methanol | Refluxing for 10 hours | 45% |
4 | Ethanolamine | Refluxing for 8 hours | 76% |
5 | Diethanolamine (DEA) | Refluxing for 8 hours | 70% |
Example 7: preparation of Compound (7-1)
In a 250mL reaction vessel, 28g of compound (6-1) and 100mL of tetrahydrofuran were added and dissolved with stirring. Keeping the temperature at 15-20 ℃, slowly adding 12g of triethylamine, stirring for 1 hour, adding 5g of lithium hydroxide and 50mL of water, and stirring for reacting for 4 hours at 15-20 DEG CWhen the reaction of the raw materials is finished, the central control monitors the completion of the reaction of the raw materials. The reaction solution was concentrated to remove the solvent, 0.5N hydrochloric acid was added to adjust pH to 7.0 to 7.5, extraction was performed with ethyl acetate, and the organic phase was concentrated to remove the solvent, to obtain 28.9g of the compound (7-1), yield: 95 percent. Can be directly put into the next reaction.1H NMR(400MHz,DMSO-d6)δ4.15(s,1H),3.77(q,J=5.1Hz,2H),3.69(d,J=10.8Hz,1H),1.94(s,1H),1.53(dd,J=7.7,5.2Hz,1H),1.43(d,J=7.7Hz,1H),1.01(s,9H),1.00(s,3H),0.93(s,3H).MS(ESI)m/z=156(M++1).
According to the operation steps, different inorganic bases and solvents are changed, and the obtained experimental results are shown in the following table six:
watch six
Serial number | Solvent(s) | Inorganic base | Yield of |
1 | Tetrahydrofuran (THF) | Lithium hydroxide | 95% |
2 | Tetrahydrofuran (THF) | Sodium hydroxide | 93% |
3 | Tetrahydrofuran (THF) | Potassium hydroxide | 90% |
4 | Tetrahydrofuran (THF) | Sodium carbonate | 88% |
5 | Tetrahydrofuran (THF) | Potassium carbonate | 89% |
6 | Methanol | Lithium hydroxide | 91% |
7 | Ethanol | Lithium hydroxide | 90% |
Example 8: preparation of Compound (8-1)
In a 250mL reaction vessel, 10g of sodium methoxide and 100mL of methanol were added, and after stirring and dissolving, 15.2g of compound (7-1) was added and dissolved with stirring. Raising the temperature to 40 ℃, starting to dropwise add 30g of trifluoroacetic acid ethyl ester, and stirring for 6 hours after the addition is finished to finish the reaction. And concentrating the reaction solution to remove the solvent, adding 90mL of isopropyl acetate for dissolving, cooling to 0-5 ℃, adding 100mL of 2mol/mL diluted hydrochloric acid until the pH value is 3-4, stirring for liquid separation, extracting the water phase once again by using 50mL of isopropyl acetate, washing the combined organic phase with water, drying and concentrating. Adding n-hexane into the residueDissolving 90g, stirring in ice bath for crystallization for about 2 hours, filtering and drying to obtain 15.6g of the compound (8-1), wherein the yield is as follows: 86 percent.1H NMR(400MHz,DMSO-d6)δ12.73(s,1H),9.43(d,J=8.5Hz,1H),4.42(d,J=8.5Hz,1H),4.13(s,1H),3.83(dd,J=10.5,5.3Hz,1H),3.70(d,J=10.5Hz,1H),1.51(dd,J=7.5,5.1Hz,1H),1.41(d,J=7.6Hz,1H),0.99(s,3H),0.98(s,9H),0.80(s,3H).MS(ESI)m/z=387(M++Na).
According to the above operation steps, different reagents and reaction conditions are changed, and the obtained experimental results are shown in the following table seven: watch seven
Serial number | Solvent(s) | Alkali | Yield of |
1 | Methanol | Sodium methoxide | 86% |
2 | Ethanol | Sodium ethoxide | 83% |
4 | Methanol | Sodium tert-butoxide | 77% |
5 | Methanol | Potassium tert-butoxide | 79% |
6 | Methanol | Triethylamine | 85% |
In this specification, the invention has been described with reference to specific embodiments thereof. It will, however, be evident that various modifications and changes may be made thereto without departing from the broader spirit and scope of the invention. The description is thus to be regarded as illustrative instead of limiting.
Claims (9)
3. The process according to claim 2, wherein the compound methyl (1R,2S,5S) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylate (V) comprises an acceptable salt thereof, such as the hydrochloride salt.
4. The method according to claim 2, wherein the splicing reaction comprises reacting the phthaloyl protected L-tert-leucine (VI) with a chlorinating reagent to generate an acid chloride or a mixed anhydride intermediate, and then reacting with the compound (V) to obtain the compound (IV), wherein the chlorinating reagent contains thionyl chloride, oxalyl chloride, triphosgene, pivaloyl chloride and p-toluenesulfonyl chloride.
5. The process of claim 2 wherein the splicing reaction comprises a direct condensation of compound (V) with compound (VI) in the presence of a condensing agent comprising a combination of T3P, HATU, EDCI/HOBT, EDCI/HOPO, and the like.
6. A method for synthesizing a palovir dipivoxil intermediate (1R,2S,5S) -3- ((S) -3, 3-dimethyl-2- (2,2, 2-trifluoroacetamido) butoxycarbonyl) -6, 6-dimethyl-3-azabicyclo [3.1.0] hexane-2-carboxylic acid (I), the method comprising the following three steps:
a) removing phthaloyl protection by using a compound (IV) as a raw material to obtain an intermediate (III);
b) hydrolyzing the intermediate (II) in the presence of an inorganic base to obtain an intermediate (II);
c) and protecting the intermediate (III) by using upper trifluoroacetyl to obtain a compound (I).
7. The process according to claim 6a, wherein intermediate (III) comprises an acceptable salt thereof, such as the hydrochloride; the reagent used for removing the phthaloyl protection comprises hydrazine hydrate, ammonia gas, ethanolamine and diethanolamine.
8. The process according to claim 6b, wherein the inorganic base comprises lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium potassium carbonate.
9. The process of claim 6c, wherein the upper trifluoroacetyl group conditions comprise reaction in the presence of ethyl trifluoroacetate and a base comprising sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, triethylamine.
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