CN116283623A - Intermediate for synthesizing dextromethorphan as well as preparation method and application thereof - Google Patents
Intermediate for synthesizing dextromethorphan as well as preparation method and application thereof Download PDFInfo
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- CN116283623A CN116283623A CN202310334003.8A CN202310334003A CN116283623A CN 116283623 A CN116283623 A CN 116283623A CN 202310334003 A CN202310334003 A CN 202310334003A CN 116283623 A CN116283623 A CN 116283623A
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- compound
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- dextromethorphan
- solvent
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- MKXZASYAUGDDCJ-SZMVWBNQSA-N LSM-2525 Chemical compound C1CCC[C@H]2[C@@]3([H])N(C)CC[C@]21C1=CC(OC)=CC=C1C3 MKXZASYAUGDDCJ-SZMVWBNQSA-N 0.000 title claims abstract description 32
- 229960001985 dextromethorphan Drugs 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 229940125773 compound 10 Drugs 0.000 claims abstract description 12
- 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 claims abstract description 12
- 239000000126 substance Substances 0.000 claims abstract description 3
- 239000003054 catalyst Substances 0.000 claims description 34
- 239000002904 solvent Substances 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 claims description 18
- 239000002585 base Substances 0.000 claims description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- 229940125782 compound 2 Drugs 0.000 claims description 13
- 239000000654 additive Substances 0.000 claims description 12
- 230000000996 additive effect Effects 0.000 claims description 12
- 238000003786 synthesis reaction Methods 0.000 claims description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 11
- 229940125898 compound 5 Drugs 0.000 claims description 11
- 238000007363 ring formation reaction Methods 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 9
- 229940126214 compound 3 Drugs 0.000 claims description 9
- DKGAVHZHDRPRBM-UHFFFAOYSA-N tertiry butyl alcohol Natural products CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- 238000006722 reduction reaction Methods 0.000 claims description 8
- -1 tert-butyl alcohol alkali metal salt Chemical class 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- OILAIQUEIWYQPH-UHFFFAOYSA-N cyclohexane-1,2-dione Chemical compound O=C1CCCCC1=O OILAIQUEIWYQPH-UHFFFAOYSA-N 0.000 claims description 7
- 229910052783 alkali metal Inorganic materials 0.000 claims description 6
- 239000003638 chemical reducing agent Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 claims description 5
- 238000005899 aromatization reaction Methods 0.000 claims description 5
- 238000006317 isomerization reaction Methods 0.000 claims description 5
- 238000007069 methylation reaction Methods 0.000 claims description 5
- 229940079593 drug Drugs 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical group OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical group [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical group [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 claims description 3
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 3
- 239000011259 mixed solution Substances 0.000 claims description 3
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical group C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 claims description 3
- 235000006408 oxalic acid Nutrition 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical group CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 3
- TWSWWTQEYGSYFZ-SECBINFHSA-N (2s)-1-n,1-n-diethyl-3,3-dimethylbutane-1,2-diamine Chemical group CCN(CC)C[C@@H](N)C(C)(C)C TWSWWTQEYGSYFZ-SECBINFHSA-N 0.000 claims description 2
- AFPHTEQTJZKQAQ-UHFFFAOYSA-N 3-nitrobenzoic acid Chemical group OC(=O)C1=CC=CC([N+]([O-])=O)=C1 AFPHTEQTJZKQAQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000006845 Michael addition reaction Methods 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- MOIPGXQKZSZOQX-UHFFFAOYSA-N carbonyl bromide Chemical group BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 238000010511 deprotection reaction Methods 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 2
- 238000005907 ketalization reaction Methods 0.000 claims description 2
- 125000000468 ketone group Chemical group 0.000 claims description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 2
- 229920001296 polysiloxane Polymers 0.000 claims description 2
- 150000003141 primary amines Chemical class 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- 230000021736 acetylation Effects 0.000 claims 1
- 238000006640 acetylation reaction Methods 0.000 claims 1
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 230000035484 reaction time Effects 0.000 description 13
- 239000011521 glass Substances 0.000 description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 229940125797 compound 12 Drugs 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 5
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000000852 hydrogen donor Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 206010011224 Cough Diseases 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical group [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 2
- 230000000954 anitussive effect Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical group O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 2
- 238000011924 stereoselective hydrogenation Methods 0.000 description 2
- YQSHYGCCYVPRDI-UHFFFAOYSA-N (4-propan-2-ylphenyl)methanamine Chemical compound CC(C)C1=CC=C(CN)C=C1 YQSHYGCCYVPRDI-UHFFFAOYSA-N 0.000 description 1
- RRQYJINTUHWNHW-UHFFFAOYSA-N 1-ethoxy-2-(2-ethoxyethoxy)ethane Chemical compound CCOCCOCCOCC RRQYJINTUHWNHW-UHFFFAOYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 238000006824 Eschweiler-Clarke methylation reaction Methods 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- ODWXUNBKCRECNW-UHFFFAOYSA-M bromocopper(1+) Chemical compound Br[Cu+] ODWXUNBKCRECNW-UHFFFAOYSA-M 0.000 description 1
- 150000001793 charged compounds Chemical class 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006704 dehydrohalogenation reaction Methods 0.000 description 1
- 229960003782 dextromethorphan hydrobromide Drugs 0.000 description 1
- JAQUASYNZVUNQP-PVAVHDDUSA-N dextrorphan Chemical compound C1C2=CC=C(O)C=C2[C@@]23CCN(C)[C@@H]1[C@H]2CCCC3 JAQUASYNZVUNQP-PVAVHDDUSA-N 0.000 description 1
- 229940019778 diethylene glycol diethyl ether Drugs 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000004081 narcotic agent Substances 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UYLUJGRCKKSWHS-UHFFFAOYSA-N prop-1-en-1-one Chemical compound CC=C=O UYLUJGRCKKSWHS-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/14—Antitussive agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/31—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing rings other than six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/40—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by doubly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/28—Morphinans
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/14—All rings being cycloaliphatic
- C07C2602/26—All rings being cycloaliphatic the ring system containing ten carbon atoms
- C07C2602/28—Hydrogenated naphthalenes
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides an intermediate for synthesizing dextromethorphan, and a preparation method and application thereof. The chemical structure of the intermediate is shown in formula 10:
Description
Technical Field
The invention relates to the technical field of synthesis of morphinan ring compounds, in particular to an intermediate for synthesizing dextromethorphan, and a preparation method and application thereof.
Background
Dextromethorphan (also known as dextromethorphan) is widely used clinically to treat cough because of its central antitussive effect and lack of narcotics and addiction. Dextromethorphan is mainly applied to medicines in the form of hydrobromide, and common cold antitussive medicines in the market such as Meikao, meikovia pseudoephedra tablet, przewal tablet, parker's, children's cough water and the like all contain dextromethorphan hydrobromide.
Currently, the synthesis method of dextromethorphan is mostly carried out by adopting a Grewe cyclization method. For example, chinese patent CN103044327a discloses a preparation method of dextromethorphan: the (+) -N-methyl-1- (4-methoxy) benzyl-1, 2,3,4,5,6,7, 8-octahydroisoquinoline a is cyclized under the high temperature (130-140 ℃ or reflux) acidic condition to obtain (+) -3-hydroxy-N-methyl morphinan b, and finally methoxy is introduced on the benzene ring to obtain dextromethorphan c. In the method, the cyclization reaction is carried out under the condition of strong acid and high temperature, the equipment requirement is high, byproducts are more after the cyclization, the yield is low, methoxy groups are easy to remove at high temperature, and the methylation treatment is needed again, so that the method is not beneficial to environmental protection.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides an intermediate for synthesizing dextromethorphan, and a preparation method and application thereof, which solve the problems of more byproducts, low yield and unfavorable environmental protection existing in the prior art.
In one aspect of the invention, an intermediate for synthesizing dextromethorphan is provided, wherein the chemical structure of the intermediate is shown as formula 10:
in another aspect of the invention, a preparation method of an intermediate for synthesizing dextromethorphan is provided, which comprises the steps of taking cyclohexanedione 1 as a raw material, and carrying out acetonitrile substitution reaction to obtain a compound 2; carrying out a Wilde-Michelson synthesis reaction on the compound 2 to obtain a compound 4; performing mono ketal protection on the compound 4 to obtain a compound 5; carrying out Robinson cyclization reaction on the compound 5 to obtain a compound 6; carrying out aromatization reaction and methylation reaction on the compound 6 to obtain a compound 7; deprotection of compound 7 over a ketone group to afford compound 8; carrying out double bond isomerization reaction on the compound 8 to obtain a compound 9; carrying out reduction reaction on the compound 9 to obtain a compound 10; the reaction process is as follows:
further, the method comprises the following steps:
s1: in the presence of a first base, carrying out nucleophilic substitution reaction on cyclohexanedione and bromoacetonitrile in a first solvent to generate a compound 2;
s2: the compound 2 and butenone undergo Michael addition reaction under the action of a first catalyst to generate a compound 3;
s3: carrying out asymmetric Robinson cyclization reaction on the compound 3 under the action of a second catalyst and a first additive to generate a compound 4;
s4: in a second solvent, carrying out ketalization reaction on the compound 4 and ethylene glycol under the action of a third catalyst and a second additive to generate a compound 5;
s5: in a third solvent, the compound 5 is reacted with tetrahydropyrrole and butenone in sequence, and then reflux cyclization reaction is carried out under an acidic condition to generate a compound 6;
s6: in a fourth solvent, carrying out aromatization reaction on the compound 6 under the action of a fourth catalyst, and then carrying out methylation reaction in the presence of a second base to generate a compound 7;
s7: in a fifth solvent, the compound 7 undergoes hydrolysis reaction under the action of acid to generate a compound 8;
s8: in a sixth solvent, carrying out isomerization reaction on the compound 8 and the tert-butyl alcohol alkali metal salt to generate a compound 9;
s9: the compound 9 is subjected to cyano reduction, primary amine acylation, carbonyl reduction and acetyl removal under the action of a fifth catalyst, an acylating agent and a reducing agent to obtain a compound 10.
Further, the first base is a quaternary ammonium base, preferably, the first base is benzyltrimethylammonium hydroxide, and the second base is potassium carbonate.
Further, the first solvent is methanol and water, the second solvent is dichloromethane, the third solvent is toluene, the fourth solvent is acetonitrile, the fifth solvent is a mixed solution of dichloromethane and water, and the sixth solvent is tert-butanol.
Further, the first catalyst is triethylamine; the second catalyst is (S) -N1, N1-diethyl-3, 3-dimethyl-1, 2-butanediamine and trifluoromethanesulfonic acid; the third catalyst is trimethyl silicone triflate, the fourth catalyst is bromoketone, and the fifth catalyst is Raney-Ni.
Further, the first additive is m-nitrobenzoic acid; the second additive is triethyl orthoformate.
Further, the acid is oxalic acid, the alkali metal tert-butoxide is potassium tert-butoxide, the acylating agent is acetic anhydride, and the reducing agent is hydrazine hydrate.
Further, the molar ratio of cyclohexanedione to bromoacetonitrile to the first base is 1:1:0.4; the molar ratio of the compound 2 to the butenone to the first catalyst is 1:1:0.01; in the step S3, the mol ratio of the compound 3 to the second catalyst to the first additive is 1:0.1:0.05; the mol ratio of the compound 4 to the glycol to the third catalyst to the second additive is 1:5.5:0.02:1.1; the molar ratio of the butenone to the tetrahydropyrrole is 1:1.05:1.2; the molar ratio of the compound 6 to the fourth catalyst is 1:0.05; the molar ratio of the compound 7 to the acid is 1:3.2; the molar ratio of the compound 8 to the alkali metal tert-butoxide is 1:1; the molar ratio of the compound 9 to the fifth catalyst to the acylating agent to the reducing agent is 1:0.1:1.05:1.1.
Preferably, in the step S1, the reaction temperature is room temperature, and the reaction time is 20-24 hours; in the step S2, the reaction temperature is room temperature, and the reaction time is 2-3h; in the step S3, the reaction temperature is room temperature, and the reaction time is 2-3h; in the step S4, the reaction temperature is-15 to-10 ℃ and the reaction time is 5-7h; in the step S5, the reaction temperature is 110-115 ℃ and the reaction time is 16-20h; in the step S6, the reaction temperature is room temperature, and the reaction time is 16-20h; in the step S7, the reaction temperature is room temperature, and the reaction time is 2-5h; in the step S8, the reaction temperature is 20-25 ℃ and the reaction time is 2-4h; in the step S9, the acylation temperature is room temperature, and the acylation time is 6-8 hours; the reduction temperature is 160-180 ℃, and the reduction reaction time is 6-8h.
In still another aspect of the present invention, there is provided an application of an intermediate for synthesizing dextromethorphan in preparing a morphinan ring drug, preferably dextromethorphan.
In one embodiment of the present invention, the method for synthesizing dextromethorphan of compound 10 comprises the steps of:
s10: in a seventh solvent, cyclizing the compound 10 under the action of bromine, and then dehydrohalogenating the compound in the presence of a third base to obtain a compound 11;
s11: in an eighth solvent, the compound 11 and a hydrogen donor undergo stereoselective hydrogenation reaction under a sixth catalyst to obtain a compound 12;
s12: under the action of formic acid and formaldehyde, carrying out Eschweiler-Clarke methylation reaction on the compound 12 to obtain dextromethorphan;
in an embodiment of the present invention, the seventh solvent is dichloromethane, the eighth solvent is methanol, the third base is sodium carbonate, the sixth catalyst is palladium hydroxide, and the hydrogen donor is ammonium formate.
In one embodiment of the present invention, in step S10, the molar ratio of the compound 10 to the bromine to the third base is 1:1:2, the cyclization reaction temperature is 0-5 ℃, and the cyclization reaction time is 0.5-1h; the dehydrohalogenation reaction temperature is 135-150 ℃ and the reaction time is 1-1.5h;
in one embodiment of the present invention, in step S11, the molar ratio of the compound 11 to the sixth catalyst to the hydrogen donor is 1:0.1:5, the reaction temperature is 135-145 ℃, and the reaction time is 5-7 hours;
in one embodiment of the present invention, in step S12, the molar ratio of compound 12 to formaldehyde is 1:2; the dosage ratio of the compound 12 to the formic acid is 0.3:4 in g/ml; the reaction temperature is 70-100 ℃ and the reaction time is 2-4h.
Compared with the prior art, the invention has the following beneficial effects:
(1) The invention discloses the compound 10 for the first time and uses the compound for preparing dextromethorphan, so that not only is the yield improved, but also the purity is improved.
(2) The new synthetic route of the invention does not use expensive starting materials, and the reaction condition is mild, thereby being beneficial to industrial production.
(3) The invention avoids harsh process conditions, greatly reduces three wastes and is environment-friendly.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
Example 1 preparation of (3- (2, 6-dioxocyclohexyl) acetonitrile) (Compound 2)
In a standard glass bottle, cyclohexanedione (900 mg,8.03 mmol), bromoacetonitrile (8.03 mmol,1.0 eq.) and benzyltrimethylammonium hydroxide (3.21 mmol,0.4 eq.) were dissolved in 10ml of a mixed solution of methanol and water in a volume ratio of 20:1 and reacted at room temperature for 24h; methanol was concentrated, isopropyl acetate was added to the residue, which was washed with water, dried, and concentrated to give compound 2 (840 mg) in 70% yield.
Example 2 preparation of Compound 3
In a standard glass bottle, compound 2 (5 g,33.08 mmol), methyl vinyl ketone (33.08 mmol,1.0 eq.) and 1% triethylamine (TEA, 335 mg) were added and reacted at 25℃for 2h without solvent. Compound 3 (7.32 g) was obtained in 100% yield.
EXAMPLE 3 preparation of Compound 4
Under the condition of no solvent at room temperature,to compound 3 (2.0 g,9.04 mmol) was added the catalyst (S) -N1, N1-diethyl-3, 3-dimethyl-1, 2-butanediamine triflic acid (0.9 mmol,0.1 eq.) m-NO 2 C 6 H 4 CO 2 H (0.45 mmol,0.05 eq.) for 2H. The reaction mixture was chromatographed to give compound 4 (1.66 g), 90% yield, 96% enantioselectivity.
Example 4 preparation of Compound 5
Compound 4 (2.0 g,9.84 mmol), 1, 2-ethanediol (54.12 mmol,5.5 eq.) and dichloromethane (20 ml) were added to the reaction flask, and trimethylsilicone triflate (TMSOTF, 0.2mmol,0.02 eq.) and triethylorthoformate (10.82 mmol,1.1 eq.) were added simultaneously, and reacted at-10℃for 5h to give compound 5 (2.16 g) in 89% yield.
EXAMPLE 5 preparation of Compound 6
Into a standard glass bottle were charged tetrahydropyrrole (4.37 mmol,1.2 eq.) and toluene 20ml, compound 5 (900 mg,3.64 mmol) was added dropwise, reflux water splitting reaction was performed at 110-115℃for 6h, then methylketene (4.37 mmol,1.05 eq.) was added, and reflux reaction was performed at 110-115℃for 5h. The organic phase was separated and concentrated. The concentrate was added to 8ml of a mixture of acetic acid and water in a volume ratio of 2:1, and the mixture was refluxed at 100℃for 5 hours, separated, and distilled under reduced pressure to give Compound 6 (0.71 g) in 65% yield.
EXAMPLE 6 preparation of Compound 7
Compound 6 (800 mg,2.67 mmol) and copper bromide (0.14 mmol,0.05 eq.) were dissolved in acetonitrile 10ml in a standard glass bottle, aromatization was performed at room temperature for 13h, then methyl iodide (3.47 mmol,1.3 eq.) and potassium carbonate (3.47 mmol,1.3 eq.) were added and reacted at room temperature for 3h to give compound 7 (0.774 g) in 93% yield.
Example 7 preparation of (R) -2- (6-methoxy-2-carbonyl-2, 3, 4a,9, 10-hexahydrophenanthren-4 a-yl) acetylnitrile (Compound 8)
In a standard glass bottle 10ml of a mixed solvent of water and Dichloromethane (DCM) in a volume ratio of 1:1 was added, and compound 7 (1.0 g,3.21 mmol), oxalic acid (10.28 mmol,3.2 eq.) were added and reacted at room temperature for 2 hours to give compound 8 (729 mg) by column chromatography in 85% yield.
Example 8 preparation of (S) -2- (6-methoxy-2-carbonyl-1, 2,3, 4a, 9-hexahydrophenanthren-4 a-yl) acetylnitrile (Compound 9)
In a standard glass bottle, 8ml of t-butanol, and compound 8 (850 mg,3.18 mmol) and potassium t-butoxide (3.18 mmol,1 eq.) were added, and the isomerization reaction was carried out at room temperature for 2 hours to give compound 9 (638 mg) in 75% yield.
Example 9 preparation of (S) -2- (6-methoxy-1, 2,3, 4a, 9-hexahydrophenanthren-4 a-yl) ethylamine (Compound 10)
In a standard glass bottle, compound 9 (1.0 g,3.74 mmol), THF 10mL, raney-Ni (0.37 mmol,0.1 eq.) and acetic anhydride (3.93 mmol,1.05 eq.) were added, hydrogen was replaced, and the reaction was carried out at 25℃for 6h. After that, filtration was carried out, and the filtrate was concentrated to obtain a concentrate, 10mL of diethylene glycol diethyl ether and hydrazine hydrate (4.11 mmol,1.1 eq.) were added, and the reaction was carried out at 180℃for 6 hours to obtain compound 10. The yield thereof was found to be 86%.
EXAMPLE 10 preparation of Compound 11
To 20ml of a methylene chloride solution were added compound 10 (2.0 g,7.77 mmol), bromine (7.77 mmol,1.0 eq.) and intramolecular cyclization reaction was carried out at 0-5℃for 0.5 hours, followed by washing with water twice, drying, concentrating, adding N, N-dimethylformamide (DMF, 20 ml), sodium hydrogencarbonate (15.54 mmol,2.0 eq.) and reaction at 135℃for 1.0 hour to give compound 11. The yield thereof was found to be 73%.
EXAMPLE 11 preparation of Compound 12
To 10ml of methanol was added 11 (500 mg,1.96 mmol), palladium hydroxide (0.2 mmol,0.1 eq.) and ammonium formate (9.79 mmol,5 eq.) and the mixture was subjected to stereoselective hydrogenation at 135℃for 5 hours to give 12. The yield thereof was found to be 90%.
EXAMPLE 12 preparation of dextromethorphan
In a reaction glass flask was charged compound 12 (1.5 g,5.83 mmol), formic acid 20ml and formaldehyde (11.66 mmol,2.0 eq.) and reacted at 100℃under reflux for 2h to give dextromethorphan. The yield thereof was found to be 95%.
Finally, it is noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the same, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications and equivalents may be made thereto without departing from the spirit and scope of the technical solution of the present invention, which is intended to be covered by the scope of the claims of the present invention.
Claims (10)
1. An intermediate for synthesizing dextromethorphan, which is characterized in that: the chemical structure of the intermediate is shown in formula 10:
2. a process for the preparation of an intermediate for the synthesis of dextromethorphan as set forth in claim 1, wherein: comprises the steps of taking cyclohexanedione 1 as a raw material, and carrying out acetonitrile substitution reaction to obtain a compound 2; carrying out a Wilde-Michelson synthesis reaction on the compound 2 to obtain a compound 4; performing mono ketal protection on the compound 4 to obtain a compound 5; carrying out Robinson cyclization reaction on the compound 5 to obtain a compound 6; carrying out aromatization reaction and methylation reaction on the compound 6 to obtain a compound 7; deprotection of compound 7 over a ketone group to afford compound 8; carrying out double bond isomerization reaction on the compound 8 to obtain a compound 9; carrying out reduction reaction on the compound 9 to obtain a compound 10; the reaction process is as follows:
3. a process for the preparation of an intermediate for the synthesis of dextromethorphan as claimed in claim 2, wherein: the method comprises the following steps:
s1: in the presence of a first base, carrying out nucleophilic substitution reaction on cyclohexanedione and bromoacetonitrile in a first solvent to generate a compound 2;
s2: the compound 2 and butenone undergo Michael addition reaction under the action of a first catalyst to generate a compound 3;
s3: carrying out asymmetric Robinson cyclization reaction on the compound 3 under the action of a second catalyst and a first additive to generate a compound 4;
s4: in a second solvent, carrying out ketalization reaction on the compound 4 and ethylene glycol under the action of a third catalyst and a second additive to generate a compound 5;
s5: in a third solvent, the compound 5 is reacted with tetrahydropyrrole and butenone in sequence, and then reflux cyclization reaction is carried out under an acidic condition to generate a compound 6;
s6: in a fourth solvent, carrying out aromatization reaction on the compound 6 under the action of a fourth catalyst, and then carrying out methylation reaction in the presence of a second base to generate a compound 7;
s7: in a fifth solvent, the compound 7 undergoes hydrolysis reaction under the action of acid to generate a compound 8;
s8: in a sixth solvent, carrying out isomerization reaction on the compound 8 and the tert-butyl alcohol alkali metal salt to generate a compound 9;
s9: under the action of a fifth catalyst, an acylating agent and a reducing agent, the compound 9 undergoes cyano reduction, primary amine acetylation, carbonyl reduction and acetyl removal to obtain a compound 10.
4. A process for the preparation of an intermediate for the synthesis of dextromethorphan as claimed in claim 3, wherein: the first base is a quaternary ammonium base, preferably, the first base is benzyltrimethylammonium hydroxide and the second base is potassium carbonate.
5. A process for the preparation of an intermediate for the synthesis of dextromethorphan as claimed in claim 3, wherein: the first solvent is methanol and water, the second solvent is dichloromethane, the third solvent is toluene, the fourth solvent is acetonitrile, the fifth solvent is a mixed solution of dichloromethane and water, and the sixth solvent is tertiary butanol.
6. A process for the preparation of an intermediate for the synthesis of dextromethorphan as claimed in claim 3, wherein: the first catalyst is triethylamine; the second catalyst is (S) -N1, N1-diethyl-3, 3-dimethyl-1, 2-butanediamine and trifluoromethanesulfonic acid; the third catalyst is trimethyl silicone triflate, the fourth catalyst is bromoketone, and the fifth catalyst is Raney-Ni.
7. A process for the preparation of an intermediate for the synthesis of dextromethorphan as claimed in claim 3, wherein: the first additive is m-nitrobenzoic acid; the second additive is triethyl orthoformate.
8. A process for the preparation of an intermediate for the synthesis of dextromethorphan as claimed in claim 3, wherein: the acid is oxalic acid, the alkali metal tert-butoxide is potassium tert-butoxide, the acylating agent is acetic anhydride, and the reducing agent is hydrazine hydrate.
9. A process for the preparation of an intermediate for the synthesis of dextromethorphan as claimed in claim 3, wherein: the molar ratio of cyclohexanedione to bromoacetonitrile to the first base is 1:1:0.4; the molar ratio of the compound 2 to the butenone to the first catalyst is 1:1:0.01; in the step S3, the mol ratio of the compound 3 to the second catalyst to the first additive is 1:0.1:0.05; the mol ratio of the compound 4 to the glycol to the third catalyst to the second additive is 1:5.5:0.02:1.1; the molar ratio of the butenone to the tetrahydropyrrole is 1:1.05:1.2; the molar ratio of the compound 6 to the fourth catalyst is 1:0.05; the molar ratio of the compound 7 to the acid is 1:3.2; the molar ratio of the compound 8 to the alkali metal tert-butoxide is 1:1; the molar ratio of the compound 9 to the fifth catalyst to the acylating agent to the reducing agent is 1:0.1:1.05:1.1.
10. Use of an intermediate for the synthesis of dextromethorphan as set forth in claim 1 in the preparation of a morphinan ring drug, preferably dextromethorphan.
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