CN114736151A - Preparation method of parefovir dipivoxil key intermediate and structural formula of compound - Google Patents
Preparation method of parefovir dipivoxil key intermediate and structural formula of compound Download PDFInfo
- Publication number
- CN114736151A CN114736151A CN202210389871.1A CN202210389871A CN114736151A CN 114736151 A CN114736151 A CN 114736151A CN 202210389871 A CN202210389871 A CN 202210389871A CN 114736151 A CN114736151 A CN 114736151A
- Authority
- CN
- China
- Prior art keywords
- compound
- key intermediate
- boc
- preparation
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 15
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 claims abstract description 14
- 229940125898 compound 5 Drugs 0.000 claims abstract description 13
- 229940125782 compound 2 Drugs 0.000 claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 9
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 9
- ZEOVXNVKXIPWMS-UHFFFAOYSA-N 2,2-dichloropropane Chemical compound CC(C)(Cl)Cl ZEOVXNVKXIPWMS-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 8
- 229960001153 serine Drugs 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000002140 halogenating effect Effects 0.000 claims abstract description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- -1 tert-butyl dimethyl silicon oxygen acetaldehyde Chemical compound 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 5
- TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 claims description 4
- 239000007822 coupling agent Substances 0.000 claims description 4
- 238000007363 ring formation reaction Methods 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 3
- JITPDUHVEYEXBV-UHFFFAOYSA-N 3-O-tert-butyl 1-O-[3-[(2-methylpropan-2-yl)oxy]-3-oxopropanoyl] propanedioate Chemical compound C(C)(C)(C)OC(=O)CC(=O)OC(CC(=O)OC(C)(C)C)=O JITPDUHVEYEXBV-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000003223 protective agent Substances 0.000 claims description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims 1
- 229910052710 silicon Inorganic materials 0.000 claims 1
- 239000010703 silicon Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
- WGCNASOHLSPBMP-UHFFFAOYSA-N Glycolaldehyde Chemical compound OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 abstract description 4
- 230000006340 racemization Effects 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 abstract description 2
- NABIUKOOBGHKIX-UHFFFAOYSA-N 2-dimethylsilyloxy-3,3-dimethylbutanal Chemical compound C[SiH](C)OC(C=O)C(C)(C)C NABIUKOOBGHKIX-UHFFFAOYSA-N 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 238000001035 drying Methods 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000005457 ice water Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 4
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- MEBFFOKESLAUSJ-UHFFFAOYSA-N 2-[tert-butyl(dimethyl)silyl]oxyacetaldehyde Chemical compound CC(C)(C)[Si](C)(C)OCC=O MEBFFOKESLAUSJ-UHFFFAOYSA-N 0.000 description 2
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000005888 cyclopropanation reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- DCVICHWBECIALB-UHFFFAOYSA-N tert-butyl 2,3-dihydropyrrole-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC=C1 DCVICHWBECIALB-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 229940102001 zinc bromide Drugs 0.000 description 2
- MSOMFHPQDYWNEZ-ZETCQYMHSA-N (2s)-1-cyclopropylpyrrolidine-2-carboxylic acid Chemical compound OC(=O)[C@@H]1CCCN1C1CC1 MSOMFHPQDYWNEZ-ZETCQYMHSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- YMGUBTXCNDTFJI-UHFFFAOYSA-N cyclopropanecarboxylic acid Chemical class OC(=O)C1CC1 YMGUBTXCNDTFJI-UHFFFAOYSA-N 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 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 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 229940125675 paxlovid Drugs 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 229910052611 pyroxene Inorganic materials 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000006104 solid solution Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
- C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
- C07C309/66—Methanesulfonates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/63—Esters of sulfonic acids
- C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
-
- 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 preparation method of a Paroviride key intermediate and a structural formula of a compound, wherein amino of L-serine is protected by BOC and reacts with trimethoxy phosphine to generate a compound 4; compound 4 reacts with tert-butyl dimethyl siloxy acetaldehyde to obtain compound 5, which is cyclopropanated with 2, 2-dichloropropane to obtain compound 6; halogenating hydroxyl of a compound 7 obtained by desiliconizing the compound 6 to obtain a compound 8, cyclizing the compound 8 to obtain a compound 9, and removing BOC protection to obtain a compound 2 of a pareto intermediate. The invention takes cheap L-serine and hydroxy acetaldehyde protected by tert-butyl dimethyl silicon as raw materials, and obtains a key intermediate for preparing the Parovirid by constructing Z-type double bonds, cyclopropanating, desiliconizing and finally cyclizing. The method has the advantages of simple operation, cheap raw materials, simple synthesis steps, effective avoidance of the problems of double bond position isomerism and chiral racemization, and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of organic matter synthesis pharmacy, in particular to a preparation method of a parefovir dipivoxil key intermediate and a compound structural formula.
Background
Parevirtide (Paxlovid), a drug developed by pyroxene for treating new coronary pneumonia, has been approved to be on the market by multiple countries, and the main active ingredient structure of the drug is shown as compound 1.
In the synthesis process of the compound 1, the compound 2 (proline fragment of cyclopropyl) is a key intermediate, and is also a key point for controlling the main synthesis technical difficulty and restricting the product cost, and in the prior art, the synthesis method of the compound is as follows:
the method comprises the following steps: synthesis (1982,753) starts from chiral hydroxyproline by methyl esterification, Boc protection of the amino group, followed by leaving of the hydroxyl group as a leaving group, e.g. iodine, sulphonyl, trifluoromethanesulphonyl, phenylseleno; then eliminating with alkali to obtain double bond, cyclopropanating to obtain cyclopropyl proline. The method has long route, position isomerism can be generated when double bonds are eliminated, the benzene seleno is used for eliminating the double bonds, although the position isomerism cannot be generated, the selenium reagent is extremely toxic, and chiral racemization can also occur when the trifluoromethanesulfonyl is eliminated, and the formula is as follows:
the second method comprises the following steps: synthesis (2001,46) in the literature synthesizes Boc-dihydropyrrole, then synthesizes racemic Boc-dihydroproline methyl ester, and carries out enzymatic hydrolysis resolution to obtain proline, and then methyl esterification and cyclopropanation are carried out. The disadvantages of this process are that Boc-dihydropyrrole synthesis is not easy, half of the isomers are useless after chiral resolution, and the carboxyl group is further methyl esterified as follows:
the third method comprises the following steps: the Journal of Medicinal Chemistry (2006, 6074) starts from pyroglutamic acid, reduces the carboxyl group to the hydroxyl group, benzaldehyde protects, constructs an olefin, cyclopropanates, then reduces the amide, protects the amino group, oxidizes the hydroxyl group to a carboxylic acid and esterifies. The route is long, and high-risk operations such as low temperature operation, lithium aluminum hydride operation and the like are adopted, and the following formula is shown:
disclosure of Invention
Aiming at the defects and problems in the prior art, the invention provides a preparation method of a pareto key intermediate and a structural formula of a compound.
In order to achieve the purpose, the invention provides the following technical scheme:
a preparation method of a Parovirid key intermediate comprises the following steps:
protecting amino of L-serine with BOC, and reacting with trimethoxy phosphine to generate a compound 4;
step two, reacting the compound 4 with tert-butyl dimethyl silicon oxygen acetaldehyde to obtain a compound 5;
step three, cyclopropanating the compound 5 and 2, 2-dichloropropane to obtain a compound 6;
step four, desiliconizing protection is carried out on the compound 6 to obtain a compound 7;
fifthly, halogenating the hydroxyl of the compound 7 to obtain a compound 8;
step six, cyclizing the compound 8 to obtain a compound 9;
and seventhly, removing BOC protection from the compound 9 to obtain a compound 2 of a Parrovirde key intermediate.
In the technical scheme, the BOC protective agent comprises Boc-acetic anhydride (Boc)2O。
In the technical scheme, the trimethoxy phosphine is replaced by triethoxy phosphorus.
In the technical scheme, in the third step, the compound 5 and 2, 2-dichloropropane form a ring under the action of a zinc-copper coupling agent to obtain a compound 6.
In the above technical scheme, in the fourth step, tetrabutylammonium fluoride is used to remove the silyl protection in the compound 6.
In the above technical scheme, in the sixth step, the ring formation reaction mode from the compound 8 to the compound 9 is as follows: adding powdered sodium carbonate into anhydrous tetrahydrofuran to form ring.
The invention also discloses a structural formula for synthesizing the compound 2, wherein the structural formula is as follows:
wherein: x1Including halogen group, and amino ring-forming group; x2Is an alkanyl group; x3Is a protecting group for protecting the structure of an amino group.
In the above technical solution, X is1comprises-OMs, -OTs, -Cl, -Br, -I and-OTf, protective groups comprise BOC and FMOC, and chain alkyl groups comprise methyl, ethyl and propyl.
The invention takes cheap L-serine and hydroxy acetaldehyde protected by tert-butyl dimethyl silicon as initial raw materials, and obtains a key intermediate for preparing the Parovideby through constructing Z-type double bonds, cyclopropanation, desiliconization protection and final cyclization. The method has the advantages of simple operation, cheap raw materials, simple synthesis steps, effective avoidance of the problems of double bond position isomerism and chiral racemization, and suitability for industrial production.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the following embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
A preparation method of a Parovirid key intermediate comprises the following steps:
protecting amino of L-serine with BOC, and reacting with trimethoxy phosphine to generate a compound 4;
step two, reacting the compound 4 with tert-butyl dimethyl silicon oxygen acetaldehyde to obtain a compound 5;
step three, cyclopropanating the compound 5 and 2, 2-dichloropropane to obtain a compound 6;
step four, desiliconizing protection is carried out on the compound 6 to obtain a compound 7;
fifthly, halogenating the hydroxyl of the compound 7 to obtain a compound 8;
step six, cyclizing the compound 8 to obtain a compound 9;
and seventhly, removing BOC protection from the compound 9 to obtain a compound 2 of a Parrovirde key intermediate.
The specific synthetic route is shown as the following formula:
specific example 1:
adding 50g of serine and 100g of sodium carbonate into 300g of water, stirring at room temperature to dissolve and clarify, then dropwise adding 115g of Boc anhydride, stirring at room temperature for 24 hours, adding acetic acid to adjust the pH value to 6-7, then adding 300ml of ethyl acetate to extract a product, extracting twice, drying anhydrous sodium sulfate, and concentrating to dryness to obtain 101.1g of a crude product.
Adding 101.1g of the crude product obtained in the step (1), 88.5g of trimethoxy phosphine and 274.5g of triphenylphosphine into 1000ml of tetrahydrofuran, stirring, dissolving, clarifying, cooling to below-10 ℃, slowly dropwise adding 182.3g/100ml of tetrahydrofuran solution of diethyl azodicarboxylate, preserving heat for 2 hours after dropwise adding, then concentrating under reduced pressure, and purifying by a column to obtain 74.5g of a compound 4.
11.2g of potassium tert-butoxide is dissolved in 300ml of anhydrous tetrahydrofuran, 31.1g of a solution of a compound 4 dissolved in 50ml of anhydrous tetrahydrofuran is slowly dropped in an ice water bath, the temperature is controlled not to exceed 10 ℃, the solution is stirred for half an hour after the addition, 17.4g of a solution of tert-butyldimethylsilyloxyacetaldehyde dissolved in 50ml of anhydrous tetrahydrofuran is then dropped in, the temperature is slowly raised to 25 ℃, the reaction is shown to be complete by stirring until TLC, the solution is slowly dropped in ice water for liquid separation, aqueous phase ethyl acetate is extracted, organic phases are combined, dried and concentrated, and column chromatography is carried out to obtain 31.5g of a compound 5.
Adding 3.2g of zinc-copper coupling agent, 17.9g of compound 5, 6.35g of zinc powder and 11.18g of zinc bromide into 100ml of anhydrous tetrahydrofuran respectively, stirring at 25 ℃ for half an hour, slowly dropwise adding 11.3g of 2, 2-dichloropropane, stirring at 25 ℃ until the detection reaction is complete, adding ice water, filtering, separating liquid, extracting with water-phase ethyl acetate, combining organic phases, drying, concentrating, and carrying out column chromatography to obtain 16.6g of compound 6.
Dissolving 16g of compound 6 in 80ml of dichloromethane, adding 10.44g of tetrabutylammonium fluoride, stirring until the reaction is finished, washing the organic phase with sodium bicarbonate solution, drying, concentrating and drying to obtain compound 7, adding 100ml of tetrahydrofuran, 13.28g of carbon tetrabromide and 10.48g of triphenylphosphine, stirring until the raw materials disappear, filtering, concentrating to dryness, and performing column chromatography to obtain 12.8g of compound 8.
Dissolving 12g of the compound 8 in 50ml of anhydrous tetrahydrofuran, adding 13.8g of powdered potassium carbonate, stirring until the reaction is completed, filtering, and concentrating and carrying out column chromatography to obtain 8.5g of a compound 9.
8g of compound 9 was dissolved in 50ml of anhydrous methanol, 6g of concentrated hydrochloric acid was added thereto, and the mixture was stirred until the reaction was completed, filtered, and concentrated to dryness to obtain 6.8g of compound 2.
Specific example 2:
adding serine 50g and sodium carbonate 100g into water 300g, stirring at room temperature to dissolve and clarify, and adding dropwise (Boc)2And 106g of O, stirring at room temperature for 20 hours, adding acetic acid to adjust the pH value to 6-7, adding 300ml of ethyl acetate to extract a product, extracting twice, drying with anhydrous sodium sulfate, and concentrating to obtain a crude product of 100.4 g. Adding 100.4g of the crude product obtained above, 88.1g of triethoxyphosphine and 272.3g of triphenylphosphine into 1000ml of tetrahydrofuran, stirring, dissolving, clarifying, cooling to below-10 ℃, slowly dropwise adding 181.1g/100ml of tetrahydrofuran solution of diethyl azodicarboxylate, preserving heat for 2 hours after dropwise adding, then concentrating under reduced pressure, and purifying by a column76.3.6g of solid were obtained.
Dissolving 20g of potassium tert-butoxide in 300ml of anhydrous tetrahydrofuran, slowly adding 36g of the solid solution in 50ml of anhydrous tetrahydrofuran dropwise in an ice-water bath, controlling the temperature to be not more than 10 ℃, stirring for half an hour after the addition, then adding 19.6g of tert-butyldimethylsilyloxyacetaldehyde in 50ml of anhydrous tetrahydrofuran dropwise, slowly heating to 25 ℃, stirring until TLC shows that the reaction is complete, slowly pouring into the ice-water, separating, extracting with aqueous phase ethyl acetate, combining organic phases, drying, concentrating, and carrying out column chromatography to obtain 34.1g of the compound 5.
Adding 3.2g of zinc-copper coupling agent, 17.9g of compound 5, 6.35g of zinc powder and 11.18g of zinc bromide into 100ml of anhydrous tetrahydrofuran respectively, stirring at 25 ℃ for half an hour, slowly dropwise adding 11.3g of 2, 2-dichloropropane, stirring at 25 ℃ until the detection reaction is complete, adding ice water, filtering, separating liquid, extracting with water-phase ethyl acetate, combining organic phases, drying, concentrating, and carrying out column chromatography to obtain 16.6g of compound 6.
Dissolving 16g of compound 6 in 80ml of dichloromethane, adding 10.44g of tetrabutylammonium fluoride, stirring until the reaction is finished, washing the organic phase with sodium bicarbonate solution, drying, concentrating and drying to obtain compound 7, adding 100ml of tetrahydrofuran, 13.28g of carbon tetrabromide and 10.48g of triphenylphosphine, stirring until the raw materials disappear, filtering, concentrating to dryness, and performing column chromatography to obtain 12.8g of compound 8.
Dissolving 12g of the compound 8 in 50ml of anhydrous tetrahydrofuran, adding 13.8g of powdered potassium carbonate, stirring until the reaction is completed, filtering, and concentrating and carrying out column chromatography to obtain 8.5g of a compound 9.
8g of compound 9 was dissolved in 50ml of anhydrous methanol, 6g of concentrated hydrochloric acid was added thereto, and the mixture was stirred until the reaction was completed, filtered, and concentrated to dryness to obtain 6.8g of compound 2.
The invention also provides an intermediate structural formula for synthesizing the compound 2, the structural formula is shown as a compound 10, wherein X1 is a halogen group or other groups capable of forming a ring with amino, preferably-OMs, -OTs, -Cl, -Br, -I and-OTf; x2 is a methyl, ethyl, propyl or other chain hydrocarbon group; x3 is a protecting group for protecting the structure of amino group, preferably BOC, FMOC. The compound 10 can be prepared into the compound 2 through simple cyclization reaction, and is a key intermediate for synthesizing the compound 2.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the claims.
Claims (8)
1. A preparation method of a Parovirid key intermediate is characterized by comprising the following steps: the method comprises the following steps:
protecting amino of L-serine with BOC, and reacting with trimethoxy phosphine to generate a compound 4;
step two, reacting the compound 4 with tert-butyl dimethyl silicon oxygen acetaldehyde to obtain a compound 5;
step three, cyclopropanating the compound 5 and 2, 2-dichloropropane to obtain a compound 6;
step four, desiliconizing protection is carried out on the compound 6 to obtain a compound 7;
fifthly, halogenating the hydroxyl of the compound 7 to obtain a compound 8;
step six, cyclizing the compound 8 to obtain a compound 9;
and seventhly, removing BOC protection from the compound 9 to obtain a compound 2 of a Parrovirde key intermediate.
2. The process of claim 1 for the preparation of a parrowed key intermediate, wherein: in the first step, the BOC protective agent comprises Boc-acetic anhydride, (Boc)2O。
3. A process for the preparation of a parrowed key intermediate according to claim 1 or 2, characterised in that: in the first step, the trimethoxy phosphine is replaced by triethoxy phosphorus.
4. The method for preparing a parrowed key intermediate according to claim 3, wherein: in the third step, the compound 5 and 2, 2-dichloropropane form a ring under the action of a zinc-copper coupling agent to obtain a compound 6.
5. The process of claim 4, wherein the intermediate is prepared by the following steps: in the fourth step, tetrabutylammonium fluoride is used for removing the silicon-based protection in the compound 6.
6. The method for preparing a Parowerdie key intermediate according to claim 5, wherein: in the sixth step, the ring formation reaction modes of the compounds 8 to 9 are as follows: adding powdered sodium carbonate into anhydrous tetrahydrofuran to form ring.
7. A compound having the formula: a process for the synthesis of a Paroviride key intermediate according to claims 1 to 6, of the formula:
wherein: x1Including halogen group, and amino ring-forming group; x2Is an alkanyl group; x3Is a protecting group for protecting the structure of amino.
8. The structural formula of a compound according to claim 7, wherein: said X1comprises-OMs, -OTs, -Cl, -Br, -I and-OTf, protective groups comprise BOC and FMOC, and chain alkyl groups comprise methyl, ethyl and propyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210389871.1A CN114736151B (en) | 2022-04-13 | 2022-04-13 | Preparation method of Pa Luo Weide key intermediate and structural formula of compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210389871.1A CN114736151B (en) | 2022-04-13 | 2022-04-13 | Preparation method of Pa Luo Weide key intermediate and structural formula of compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN114736151A true CN114736151A (en) | 2022-07-12 |
| CN114736151B CN114736151B (en) | 2023-04-21 |
Family
ID=82282662
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210389871.1A Active CN114736151B (en) | 2022-04-13 | 2022-04-13 | Preparation method of Pa Luo Weide key intermediate and structural formula of compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114736151B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115286559A (en) * | 2022-07-15 | 2022-11-04 | 上海再启生物技术有限公司 | Preparation method of anti-new crown drug Parovirid key intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102206247A (en) * | 2000-07-21 | 2011-10-05 | 先灵公司 | Novel peptides as NS3-serine protease inhibitors of hepatitis C virus |
| CN112574189A (en) * | 2019-09-27 | 2021-03-30 | 海创药业股份有限公司 | EP300/CBP inhibitor |
| CN114057627A (en) * | 2022-01-18 | 2022-02-18 | 南京桦冠生物技术有限公司 | Preparation method of hepatitis C and neocorolla drug intermediate and salt thereof |
-
2022
- 2022-04-13 CN CN202210389871.1A patent/CN114736151B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102206247A (en) * | 2000-07-21 | 2011-10-05 | 先灵公司 | Novel peptides as NS3-serine protease inhibitors of hepatitis C virus |
| CN112574189A (en) * | 2019-09-27 | 2021-03-30 | 海创药业股份有限公司 | EP300/CBP inhibitor |
| CN114057627A (en) * | 2022-01-18 | 2022-02-18 | 南京桦冠生物技术有限公司 | Preparation method of hepatitis C and neocorolla drug intermediate and salt thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115286559A (en) * | 2022-07-15 | 2022-11-04 | 上海再启生物技术有限公司 | Preparation method of anti-new crown drug Parovirid key intermediate |
| CN115286559B (en) * | 2022-07-15 | 2023-11-17 | 上海再启生物技术有限公司 | Preparation method of key intermediate of anti-new crown drug Pa Luo Weide |
Also Published As
| Publication number | Publication date |
|---|---|
| CN114736151B (en) | 2023-04-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN111170855B (en) | Compound and method for synthesizing 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid by using same | |
| CN103025727B (en) | The preparation method of HMG-CoA reductase inhibitor and intermediate thereof | |
| CN114736151A (en) | Preparation method of parefovir dipivoxil key intermediate and structural formula of compound | |
| CN112645833A (en) | Synthesis method of (S) -2, 6-diamino-5-oxohexanoic acid | |
| JP5301676B2 (en) | Process for producing (3S, 4S) -4-((R) -2- (benzyloxy) tridecyl) -3-hexyl-2-oxetanone and novel intermediate used therefor | |
| CN106520892A (en) | 7-amino-3-vinyl cephalosporanic acid preparation method | |
| CN103073525B (en) | Method for synthesizing (S)-(3,4-difluorophenyl)hexamethylene oxide | |
| CN106518944A (en) | Preparation method of methylprednisone | |
| EP1669353B1 (en) | Process for preparing alpha, beta - unsaturated esters | |
| CN110551123A (en) | Preparation method of 5- (tert-butyloxycarbonyl) -2-methyl-4, 5,6, 7-tetrahydro-2H-pyrazolo [4,3-C ] pyridine-7-carboxylic acid | |
| SU976846A3 (en) | Method of producing derivatives of prostacycline or salts thereof | |
| CN104781231A (en) | Process for the preparation of travoprost | |
| CN112939814B (en) | Preparation method of deuterated dacarbazine intermediate | |
| CN114933523A (en) | Process for the preparation of caronic acid and its derivatives | |
| CN111675660B (en) | Preparation method for synthesizing palbociclib intermediate and method for synthesizing palbociclib | |
| CN103804414A (en) | Intermediate compound for preparing rosuvastatin calcium and method for preparing rosuvastatin calcium from rosuvastatin calcium | |
| CN103709132A (en) | Method for preparing nebivolol midbody | |
| CN110498762B (en) | Synthesis method of (2S,5R) -5- [ (benzyloxy) amino ] -piperidine-2-ethyl formate | |
| CN109761868A (en) | A kind of synthetic method of optical voidness cloprostenol | |
| CN106478439B (en) | A kind of preparation method of O- tertiary butyls-L-threonine tert-butyl ester | |
| CN101486691B (en) | Method for synthesizing N-(benzyloxycarbonyl)-amino-epoxy-phenyl butane | |
| KR100249134B1 (en) | New process for preparing 2-[(2,6-dichlorophenyl)amino]phenyl acetoxyacetic acid | |
| CN106674096A (en) | Synthesis method of 2, 3-bis-substituted pyridine derivative | |
| KR100543172B1 (en) | A Process for Preparing Terrein Compounds | |
| JP3876079B2 (en) | Process for producing 1,24-dihydroxycholesterols |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: A key intermediate preparation method for Parovide and structural formula of its compound Granted publication date: 20230421 Pledgee: Agricultural Bank of China Xiangtan County Branch Pledgor: Hunan Furui Biomedical Technology Co.,Ltd. Registration number: Y2024980000042 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |