CN114380819A - Zolpidem intermediate compound - Google Patents
Zolpidem intermediate compound Download PDFInfo
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- CN114380819A CN114380819A CN202011134867.8A CN202011134867A CN114380819A CN 114380819 A CN114380819 A CN 114380819A CN 202011134867 A CN202011134867 A CN 202011134867A CN 114380819 A CN114380819 A CN 114380819A
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- Prior art keywords
- reaction
- methyl
- methylphenyl
- imidazo
- zolpidem
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 28
- 229960001475 zolpidem Drugs 0.000 title claims abstract description 18
- ZAFYATHCZYHLPB-UHFFFAOYSA-N zolpidem Chemical compound N1=C2C=CC(C)=CN2C(CC(=O)N(C)C)=C1C1=CC=C(C)C=C1 ZAFYATHCZYHLPB-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 78
- 238000000034 method Methods 0.000 claims abstract description 25
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229930040373 Paraformaldehyde Natural products 0.000 claims abstract description 16
- 229920002866 paraformaldehyde Polymers 0.000 claims abstract description 16
- OLZONQCQODMZSS-UHFFFAOYSA-N 2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetonitrile Chemical compound C1=CC(C)=CC=C1C1=C(CC#N)N2C=C(C)C=CC2=N1 OLZONQCQODMZSS-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 14
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- VNDYJBBGRKZCSX-UHFFFAOYSA-L Zinc bromide Inorganic materials Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 25
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 235000011056 potassium acetate Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000011541 reaction mixture Substances 0.000 claims 1
- AWEWSJJCANQFRB-UHFFFAOYSA-N 6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine Chemical compound C1=CC(C)=CC=C1C1=CN(C=C(C)C=C2)C2=N1 AWEWSJJCANQFRB-UHFFFAOYSA-N 0.000 abstract description 13
- GOTRQUOBHPXTLU-UHFFFAOYSA-N CC(C=C1)=CC=C1C1=C(CBr)N(C=C(C)C=C2)C2=N1 Chemical compound CC(C=C1)=CC=C1C1=C(CBr)N(C=C(C)C=C2)C2=N1 GOTRQUOBHPXTLU-UHFFFAOYSA-N 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 230000015572 biosynthetic process Effects 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 6
- 238000001308 synthesis method Methods 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 230000009471 action Effects 0.000 abstract description 2
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 231100000053 low toxicity Toxicity 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
- 239000008213 purified water Substances 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 21
- 239000000706 filtrate Substances 0.000 description 18
- 238000001914 filtration Methods 0.000 description 18
- 238000001514 detection method Methods 0.000 description 17
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical group Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 16
- 239000012295 chemical reaction liquid Substances 0.000 description 16
- 238000001035 drying Methods 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- 230000008569 process Effects 0.000 description 16
- 238000003756 stirring Methods 0.000 description 14
- 238000000605 extraction Methods 0.000 description 12
- 239000005457 ice water Substances 0.000 description 12
- 230000007935 neutral effect Effects 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000002904 solvent Substances 0.000 description 10
- 238000005406 washing Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 8
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- XWSCOGPKWVNQSV-UHFFFAOYSA-N 5-bromo-2,3-dichloropyridine Chemical compound ClC1=CC(Br)=CN=C1Cl XWSCOGPKWVNQSV-UHFFFAOYSA-N 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229960005111 zolpidem tartrate Drugs 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 4
- 206010022437 insomnia Diseases 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 229960001701 chloroform Drugs 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000013341 scale-up Methods 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 2
- 150000008051 alkyl sulfates Chemical class 0.000 description 2
- 125000005997 bromomethyl group Chemical group 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000011941 photocatalyst Substances 0.000 description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 2
- 229940095064 tartrate Drugs 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- IGJYZHOQYHTURH-UHFFFAOYSA-N 2-(2,4-dimethylphenyl)-1h-imidazole Chemical compound CC1=CC(C)=CC=C1C1=NC=CN1 IGJYZHOQYHTURH-UHFFFAOYSA-N 0.000 description 1
- XMNIXWIUMCBBBL-UHFFFAOYSA-N 2-(2-phenylpropan-2-ylperoxy)propan-2-ylbenzene Chemical compound C=1C=CC=CC=1C(C)(C)OOC(C)(C)C1=CC=CC=C1 XMNIXWIUMCBBBL-UHFFFAOYSA-N 0.000 description 1
- REXUYBKPWIPONM-UHFFFAOYSA-N 2-bromoacetonitrile Chemical compound BrCC#N REXUYBKPWIPONM-UHFFFAOYSA-N 0.000 description 1
- VODKOOOHHCAWFR-UHFFFAOYSA-N 2-iodoacetonitrile Chemical compound ICC#N VODKOOOHHCAWFR-UHFFFAOYSA-N 0.000 description 1
- YDHIMEXEGOCNHU-UHFFFAOYSA-N 2-pyridin-3-ylacetamide Chemical compound NC(=O)CC1=CC=CN=C1 YDHIMEXEGOCNHU-UHFFFAOYSA-N 0.000 description 1
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- VHURNHRWSLJJDL-UHFFFAOYSA-N C(C1=CC=CC=C1)S(=O)(=O)C1=CC=NC=C1 Chemical compound C(C1=CC=CC=C1)S(=O)(=O)C1=CC=NC=C1 VHURNHRWSLJJDL-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 229940121985 Non-benzodiazepine hypnotic Drugs 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- SEACYXSIPDVVMV-UHFFFAOYSA-L eosin Y Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C([O-])=C(Br)C=C21 SEACYXSIPDVVMV-UHFFFAOYSA-L 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 231100000171 higher toxicity Toxicity 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 229940043267 rhodamine b Drugs 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 208000020685 sleep-wake disease Diseases 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a zolpidem intermediate compound. The invention takes 6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine as a starting material, and reacts with paraformaldehyde and a brominating reagent under the action of a catalyst to obtain a new zolpidem intermediate 3-bromomethyl-6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine. Meanwhile, the invention provides a method for preparing the zolpidem intermediate 2- (6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine-3-yl) acetonitrile by using the novel intermediate compound: 3-bromomethyl-6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine reacts with trimethylsilyl cyanide under the catalysis of alkali to obtain 2- (6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridin-3-yl) acetonitrile. The new intermediate provided by the invention is simple in synthesis method, and the preparation of 2- (6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine-3-yl) acetonitrile by using the intermediate has the advantages of low toxicity, mild use conditions, high conversion rate and simplicity and convenience in operation.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a zolpidem intermediate compound.
Background
Zolpidem tartrate (Zolpidem tartrate), chemical name 2- (4-methylphenyl) -N, N, 6-trimethylimidazo [1,2-a ]]Pyridine-3-acetamide tartrate, a non-benzodiazepine
Hypnotics, trade name
Originally developed by Synthelabo, France, and first marketed in France in 1988. The traditional Chinese medicine composition is clinically used for treating serious sleep disorder diseases, such as occasional insomnia and temporary insomnia; in addition, the product has obvious curative effect on primary insomnia, depression and insomnia caused by psychosis; has quick action and low addictionAnd the like. The chemical structural formula is as follows:
currently, many reports on the synthesis process of zolpidem are reported, such as Chinese patent applications CN106946876A, CN1413212A (same family EP1259509, WO2001038327), CN1668617A (same family US20040010146, WO20040010146), CN1729188A (same family WO2004058758), CN106749237A, CN106866661A, CN101336242A (same family WO 64444), green synthesis process research of zolpidem tartrate, 200702007064444, synthesis of zolpidem tartrate, New processes of synthesis of zolpidem tartrate, New Chinese medicine industries, 2014,23(5),16-17, and Zopidem tartrate, Chinese medicine industries, 2017,48(12), 1726-0, Angew. chem.2010. Ed, 49,2743-2746, chem.Sci, 2013,4,764, 769, Eur J.201769, Heteroct J.2019, and Heteroct J.20142; 445, J.Med.chem.,1997,40,3109, 3118, Journal of Pharmacy and Pharmacology,2018,79(9),1164, 1173, Org.Lett.,2012,14(17),4580, 4583, Organic Preparations and products International The New Journal for Organic Synthesis,43:2,260, 264, 2004CH00125, 2007MU00160, 2009CH00904, 2003MU01081, DE A, EP B, EP A, EP B, EP01809627 (family US A), PL196300B, US A, US B, US20040010146, WO A, and WO A.
Furthermore, German patents GB9915489, GB1076089, EP0050563, US4492695, US4382938, US20070027180 and the document Arkivoc,2009(ii) 315-:
however, the process route has long reaction steps and is complicated to operate. Meanwhile, the method is applied to a genotoxic substance formaldehyde for reaction in a Mannich reaction, iodomethane with high toxicity and low boiling point is used in the N-alkylation step, and the quaternary ammonium salt is subjected to nucleophilic substitution by a highly toxic substance sodium cyanide to prepare a cyano intermediate 2- (6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridin-3-yl) acetonitrile, so that the whole reaction operation process is dangerous and low in safety. In addition, when the cyano group is converted into the amide, the dry HC1 gas needs to be introduced into the reaction system for a long time under the heating condition, so the operation is complicated, and the industrial production is not facilitated. And finally, the amidation is carried out by using sensitive and unstable CDI and phosphorus oxychloride or phosphorus pentachloride with higher toxicity.
From the above, it is known that 2- (6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridin-3-yl) acetonitrile, as a key intermediate in the synthesis of zolpidem, directly affects the production, market supply and quality of the drug. The chemical structural formula is as follows:
as for the preparation method of 2- (6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridin-3-yl) acetonitrile, in addition to the above reports, the following synthetic routes are disclosed:
contrary to the above process, US4492695A discloses formylating 6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine on the aromatic ring, reducing it to hydroxymethyl, treating it with tosyl chloride (TsCl) in the presence of pyridine, and nucleophilic substitution with sodium cyanide to obtain the corresponding cyanide intermediate:
although the synthesis method avoids the use of highly toxic iodomethane, the synthesis method is applied to sodium borohydride (NaBH) which is harmful to human bodies in the aldehyde group reduction process4) The operation is dangerous, and the yield is not high; more importantly, the use of a virulent reagent sodium cyanide cannot be avoided in the reaction, so that the operation safety is low and the scale-up production is difficult.
The Der Pharma Chemica,2012,4(6):2466-2469 and the patents IN288884 and WO2009007995a1 use chloroformates instead of methyl iodide for the reaction, but do not avoid the use of methyl iodide, but do not avoid the use of sodium cyanide, a highly toxic reagent:
③ indian patent 2013MU02428 and WO2015011722a2 adopt alkyl sulfate instead of methyl iodide for reaction, and although the use of methyl iodide is avoided, the use of virulent reagent sodium cyanide cannot be avoided:
the Chinese patent application CN106866661A and the document J.org.chem.,2017,5391-5397 are directly prepared by using 6-methyl-2- (4-methylphenyl) imidazole [1,2-a ]]Pyridine is used as starting material, under the protection of inert gas and photocatalyst [ fac-Ir (ppy)3、Ir(ppy)2(dtbbpy)PF6、Ru(bpy)3Cl2·6H2O, eosin Y or rhodamine B]And visible light (a light source is a 5W blue LED lamp) and bromoacetonitrile or iodoacetonitrile under an alkaline condition. Although the process greatly simplifies the operation steps, the photocatalyst is required to be used for reaction in Schlenk under the irradiation of visible blue light under the protection of inert gas, the process is limited to the mg level in a laboratory, and the industrial scale-up production is difficult:
the document Organic Letters,2017,19,9, 2226-ion 2229 is prepared by reacting 6-methyl-2- (4-methylphenyl) imidazole [1,2-a ] under the protection of inert gas]Pyridine with acetonitrile in FeCp2And under the catalysis of dicumyl peroxide, directly dehydrogenating and coupling to obtain the target product. However, the process needs to react peroxide at high temperature (100 ℃) for a long time (20 hours), so that the process is high in danger, the process is limited to a laboratory milligram level, and the target product is obtained by column chromatography for purification, so that the industrial scale-up production is difficult:
in summary, the existing preparation method of 2- (6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine-3-yl) acetonitrile has many defects in the aspects of safe process, complex operation, production scale and the like, so that the research and search of a reaction route which has mild reaction conditions, safe and simple operation process, high product yield and high purity and is suitable for industrial production of 2- (6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine-3-yl) acetonitrile still needs to be solved at present.
Disclosure of Invention
Aiming at the problems of the existing preparation technology of 2- (6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine-3-yl) acetonitrile, the invention provides a novel intermediate compound and a preparation method thereof on the one hand, and provides a method for preparing 2- (6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine-3-yl) acetonitrile by using the novel intermediate on the other hand. The method has mild reaction conditions, safe and simple operation process, and the prepared target product has higher purity and yield.
The invention provides a zolpidem intermediate compound, which has a structural formula shown as a formula I-1:
in a second aspect, the present invention provides a process for the preparation of compound I-1, comprising the steps of:
at room temperature, adding a compound SM-1, paraformaldehyde, a brominating reagent and concentrated sulfuric acid into an organic solvent A, and controlling the temperature until the reaction is finished to obtain an intermediate I-1, wherein the synthetic route is as follows:
preferably, the brominating reagent is selected from HBr or ZnBr2The HBr may be hydrogen bromide gas or a commercially available 33% HBr/acetic acid solution.
Preferably, the feeding molar ratio of the compound SM-1, paraformaldehyde and brominating reagent is 1: 1.0-1.5: 1.0 to 2.0, wherein 1: 1.05: 1.5.
preferably, the feeding mass-volume ratio of the compound SM-1 to concentrated sulfuric acid is 1: 1.5 to 3.0, the mass is in g and the volume is in ml, wherein the mass is 1: 2.0.
preferably, the organic solvent A is selected from one or the combination of trichloromethane, 1, 2-dichloroethane and acetonitrile.
Preferably, the reaction temperature is 35-60 ℃, and particularly preferably 45-50 ℃.
In a preferred scheme, after the reaction is finished, post-treatment operation is required, and the method comprises the following specific steps: pouring the reaction solution into purified water, adding dichloromethane or ethyl acetate for extraction until the organic layer is washed to be neutral, evaporating the organic solvent, adding the obtained solid into ice water, stirring and crystallizing to obtain the compound I-1.
In a third aspect, the invention provides a use of compound I-1 for preparing zolpidem intermediate 2- (6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridin-3-yl) acetonitrile.
A process for preparing zolpidem intermediate 2- (6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridin-3-yl) acetonitrile from compound I-1 comprising the steps of: adding a compound I-1, trimethylsilyl cyanide and alkali into a reaction solvent B at room temperature, controlling the temperature until the reaction is finished, and performing post-treatment to obtain a target product I, wherein the reaction route is as follows:
preferably, the alkali is selected from one of potassium carbonate, sodium phosphate, potassium acetate, sodium acetate and sodium carbonate, wherein potassium carbonate is particularly preferred.
Preferably, the reaction solvent B is selected from one or a combination of 1, 4-dioxane, acetonitrile, tetrahydrofuran and toluene, wherein 1, 4-dioxane is particularly preferred.
Preferably, the feeding molar ratio of the compound I-1 to the trimethylsilyl cyanide and the base is 1: 1.2-2.0: 1.0 to 2.0, wherein 1: 1.5: 1.3.
preferably, the reaction temperature is 60-100 ℃, and particularly preferably 80-85 ℃.
Preferably, the post-treatment step is: and cooling the reaction solution to room temperature, filtering, pouring the filtrate into purified water, extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the obtained filtrate under reduced pressure to dryness to obtain the target product I.
The invention has the beneficial effects that:
1. the invention provides a new intermediate compound of zolpidem and a method for preparing 2- (6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine-3-yl) acetonitrile by using the new intermediate, the whole synthesis method is simple and convenient to operate, and the reaction yield and the purity are high;
2. according to the invention, bromomethyl is introduced on SM-1 by adopting Blanc bromomethylation reaction, wherein bromine is taken as a leaving group, and compared with the leaving groups in the prior art, such as quaternary ammonium salt, p-toluenesulfonylpyridine positive ion, chloroformate, alkyl sulfate and the like, the bromomethyl has the characteristics of short preparation path, simplicity and convenience in operation and high atom economy;
3. the invention adopts trimethyl silane cyanide as an excellent reagent to introduce cyano, and compared with the traditional cyaniding reagent sodium cyanide, the trimethyl silane cyanide has the advantages of low toxicity, mild use conditions and high conversion rate;
4. meanwhile, the process can effectively avoid the use of a highly toxic product, namely methyl iodide, and improves the operation safety.
Detailed Description
The invention is further illustrated by the following examples, which should be properly understood: the examples of the present invention are merely illustrative and not restrictive, and therefore, the present invention may be modified in a simple manner without departing from the scope of the invention as claimed.
The structure of the compound obtained by the invention is confirmed as follows:
ESI-HRMS(m/z)：315.0495[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.21(s,1H),7.62(d,J＝9.2Hz,2H),7.52(d,J＝8.1Hz,1H),7.34-7.24(m,1H),7.16(d,J＝8.6Hz,2H),4.99(s,2H),2.44(s,3H),2.39(s,3H)；13C NMR(100MHz,DMSO-d6)δ150.35,140.55,137.99,133.35,129.89,129.57,129.33,126.69,124.78,123.48,119.00,24.61,21.13,15.47。
ESI-HRMS(m/z)：262.1337[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),7.62(d,J＝9.4Hz,1H),7.58(d,J＝8.1Hz,2H),7.30(d,J＝7.9Hz,2H),7.17(dd,J＝1.4Hz,J＝9.1Hz,1H),4.10(s,2H),2.43(s,3H),2.40(s,3H)；13C NMR(100MHz,DMSO-d6)δ141.45,140.60,138.26,133.34,129.85,129.54,129.35,126.72,123.46,119.03,117.26,111.74,21.15,15.48,15.26。
in the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Example 1
At room temperature, mixing 6-methyl-2- (4-methylphenyl) imidazo [1,2-a]Pyridine (SM-1, 22.23g, 0.10mol), paraformaldehyde (3.15g, 0.105mol), ZnBr2(33.75g, 0.15mol) is added into 1, 2-dichloroethane (200ml), the temperature is controlled to 45-50 ℃ for reaction under stirring, concentrated sulfuric acid (45ml) is added for continuous temperature control reaction, after the detection reaction is finished, the reaction solution is poured into purified water for washing, dichloromethane is added for extraction until an organic layer is washed to be neutral, the solid obtained after the solvent is evaporated is added into ice water (200ml), and the intermediate I-1 is obtained after stirring, crystallization and drying, the yield is 86.6%, and the HPLC purity is 99.82%.
Example 2
At room temperature, mixing 6-methyl-2- (4-methylphenyl) imidazo [1,2-a]Pyridine (SM-1, 22.23g, 0.10mol), paraformaldehyde (3.00g, 0.10mol), ZnBr2(33.75g, 0.15mol) is added into 1, 2-dichloroethane (200ml), the temperature is controlled to 55-60 ℃ for reaction, concentrated sulfuric acid (45ml) is added for continuous temperature control reaction, after the detection reaction is finished, the reaction liquid is poured into purified water for washing, dichloromethane is added for extraction until an organic layer is washed to be neutral, the solid obtained after the solvent is evaporated is added into ice water (200ml), and the mixture is stirred, crystallized and dried to obtain the intermediate I-1, wherein the yield is 83.2%, and the HPLC purity is 99.52%.
Example 3
At room temperature, mixing 6-methyl-2- (4-methylphenyl) imidazo [1,2-a]Pyridine (SM-1, 22.23g, 0.10mol), paraformaldehyde (13.51g, 0.15mol), ZnBr2(33.75g, 0.15mol) is added into acetonitrile (200ml), the temperature is controlled to 40-45 ℃ for reaction, concentrated sulfuric acid (45ml) is added for continuous temperature control reaction, after the detection reaction is finished, reaction liquid is poured into purified water for washing, dichloromethane is added for extraction until an organic layer is washed to be neutral, solid obtained after the solvent is removed through evaporation is added into ice water (200ml), and the mixture is stirred, crystallized and dried to obtain an intermediate I-1, wherein the yield is 82.6%, and the HPLC purity is 99.48%.
Example 4
At room temperature, mixing 6-methyl-2- (4-methylphenyl) imidazo [1,2-a]Pyridine (SM-1, 22.23g, 0.10mol), paraformaldehyde (15.32g, 0.17mol), ZnBr2(33.75g, 0.15mol) is added into trichloromethane (110ml), the temperature is controlled to be 35 to 40 ℃ for reactionAdding concentrated sulfuric acid (45ml) to continue temperature control reaction, pouring the reaction liquid into purified water to be washed to be neutral after detection reaction is finished, adding dichloromethane (100ml) to extract, adding the solid obtained after solvent evaporation into ice water (200ml), stirring, crystallizing and drying to obtain the intermediate I-1, wherein the yield is 76.5%, and the HPLC purity is 98.96%.
Example 5
At room temperature, mixing 6-methyl-2- (4-methylphenyl) imidazo [1,2-a]Pyridine (SM-1, 22.23g, 0.10mol), paraformaldehyde (3.15g, 0.105mol), ZnBr2(22.52g, 0.1mol) is added into acetonitrile (110ml), the temperature is controlled to 50-55 ℃ for reaction, concentrated sulfuric acid (45ml) is added for continuous temperature control reaction, after the detection reaction is finished, reaction liquid is poured into purified water for washing, ethyl acetate is added for extraction until an organic layer is washed to be neutral, solid obtained after the solvent is removed by evaporation is added into ice water (200ml), and the mixture is stirred, crystallized and dried to obtain an intermediate I-1, wherein the yield is 83.6%, and the HPLC purity is 99.66%.
Example 6
At room temperature, mixing 6-methyl-2- (4-methylphenyl) imidazo [1,2-a]Pyridine (SM-1, 22.23g, 0.10mol), paraformaldehyde (3.15g, 0.105mol), ZnBr2(45.04g, 0.2mol) is added into acetonitrile (110ml), the temperature is controlled to 40-45 ℃ for reaction, concentrated sulfuric acid (45ml) is added for continuous temperature control reaction, after the detection reaction is finished, reaction liquid is poured into purified water for washing, ethyl acetate is added for extraction until an organic layer is washed to be neutral, solid obtained after the solvent is removed by evaporation is added into ice water (200ml), and the mixture is stirred, crystallized and dried to obtain an intermediate I-1, wherein the yield is 82.8%, and the HPLC purity is 99.55%.
Example 7
At room temperature, mixing 6-methyl-2- (4-methylphenyl) imidazo [1,2-a]Pyridine (SM-1, 22.23g, 0.10mol), paraformaldehyde (3.15g, 0.105mol), ZnBr2(49.54g, 0.22mol) is added into 1, 2-dichloroethane (200ml), the temperature is controlled to 50-55 ℃ for reaction under stirring, concentrated sulfuric acid (45ml) is added for continuous temperature control reaction, after the detection reaction is finished, the reaction liquid is poured into purified water for washing, dichloromethane is added for extraction until an organic layer is washed to be neutral, the solid obtained after the solvent is evaporated is added into ice water (200ml), and the intermediate I-1 is obtained after stirring, crystallization and drying, the yield is 76.7%, and the HPLC purity is 98.92%.
Example 8
Adding 6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine (SM-1, 22.23g, 0.10mol), paraformaldehyde (3.15g, 0.105mol), HBr/AcOH (omega 33%, 36.78g) into 1, 2-dichloroethane (200ml) at room temperature, stirring, controlling the temperature to be 45-50 ℃ for reaction, adding concentrated sulfuric acid (34ml) for reaction, pouring the reaction liquid into purified water, washing, adding dichloromethane for extraction until an organic layer is washed to be neutral, adding ice water (200ml) into the solid obtained after the solvent is removed by evaporation, stirring, crystallizing and drying to obtain an intermediate I-1, wherein the yield is 82.9%, and the HPLC purity is 99.52%.
Example 9
Adding 6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine (SM-1, 22.23g, 0.10mol), paraformaldehyde (3.15g, 0.105mol), HBr/AcOH (omega 33%, 36.78g) into acetonitrile (200ml) at room temperature, stirring, controlling the temperature to 45-50 ℃ for reaction, adding concentrated sulfuric acid (45ml) for continuous temperature control reaction, after the detection reaction is finished, pouring a reaction solution into purified water, washing, adding dichloromethane for extraction until an organic layer is washed to be neutral, adding a solid obtained after the solvent is removed into ice water (200ml), stirring, crystallizing and drying to obtain an intermediate I-1, wherein the yield is 81.6%, and the HPLC purity is 99.46%.
Example 10
Adding 6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine (SM-1, 22.23g, 0.10mol), paraformaldehyde (3.15g, 0.105mol), HBr/AcOH (omega 33%, 36.78g) into acetonitrile (200ml) at room temperature, stirring, controlling the temperature to be 60-65 ℃ for reaction, adding concentrated sulfuric acid (27ml) for reaction at a controlled temperature, pouring the reaction liquid into purified water for washing, adding dichloromethane for extraction until an organic layer is washed to be neutral, adding a solid obtained after evaporation of a solvent into ice water (200ml), stirring, crystallizing and drying to obtain an intermediate I-1, wherein the yield is 77.6%, and the HPLC purity is 99.02%.
Example 11
Adding 6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine (SM-1, 22.23g, 0.10mol), paraformaldehyde (3.15g, 0.105mol), HBr/AcOH (omega 33%, 36.78g) into trichloromethane (200ml) at room temperature, stirring, controlling the temperature to be 30-35 ℃ for reaction, adding concentrated sulfuric acid (49ml) for continuous temperature control reaction, after the detection reaction is finished, pouring a reaction solution into purified water, washing, adding dichloromethane for extraction until an organic layer is washed to be neutral, adding a solid obtained after the solvent is removed into ice water (200ml), stirring, crystallizing and drying to obtain an intermediate I-1, wherein the yield is 75.3%, and the HPLC purity is 98.84%.
Preparation of Compound I
Example 12
Adding 3-bromomethyl-6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine (I-1, 15.76g, 0.05mol), trimethylsilyl cyanide (TMSCN, 7.44g, 0.075mol) and potassium carbonate (5.42g, 0.065mol) into 1, 4-dioxane (100ml) at room temperature, controlling the temperature to be 80-85 ℃ for reaction, cooling the reaction liquid to room temperature after detection reaction is finished, filtering, pouring the filtrate into purified water (150ml), adding dichloromethane (40ml multiplied by 3) for extraction, combining organic phases, drying an organic layer by anhydrous sodium sulfate, filtering, and concentrating the obtained filtrate under reduced pressure to dryness to obtain the target product I, wherein the yield is 92.3%, and the purity is 99.84%.
Example 13
Adding 3-bromomethyl-6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine (I-1, 15.76g, 0.05mol), trimethylsilyl cyanide (TMSCN, 5.95g, 0.06mol) and sodium phosphate (10.66g, 0.065mol) into 1, 4-dioxane (100ml) at room temperature, controlling the temperature to be 100-105 ℃ for reaction, cooling the reaction liquid to room temperature after detection reaction is finished, filtering, pouring the filtrate into purified water (150ml), extracting dichloromethane (40ml multiplied by 3), combining organic phases, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the obtained filtrate under reduced pressure to dryness to obtain the target product I, wherein the yield is 88.6%, and the purity of HPLC is 99.44%.
Example 14
Adding 3-bromomethyl-6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine (I-1, 15.76g, 0.05mol), trimethylsilyl cyanide (TMSCN, 4.96g, 0.05mol) and potassium phosphate (13.80g, 0.065mol) into toluene (100ml) at room temperature, controlling the temperature to 100-105 ℃ for reflux reaction, cooling the reaction liquid to room temperature after detection reaction is finished, filtering, pouring the filtrate into purified water (150ml), extracting dichloromethane (40ml multiplied by 3), combining organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, and concentrating the obtained filtrate under reduced pressure to dryness to obtain the target product I, wherein the yield is 84.5%, and the HPLC purity is 98.98%.
Example 15
Adding 3-bromomethyl-6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine (I-1, 15.76g, 0.05mol), trimethylsilyl cyanide (TMSCN, 9.92g, 0.1mol) and sodium carbonate (6.89g, 0.065mol) into butanone (100ml) at room temperature, controlling the temperature to be 75-80 ℃ for reflux reaction, cooling the reaction liquid to room temperature after detection reaction is finished, filtering, pouring the filtrate into purified water (150ml), extracting dichloromethane (40ml multiplied by 3), combining organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, and concentrating the obtained filtrate under reduced pressure to dryness to obtain the target product I, wherein the yield is 89.0%, and the HPLC purity is 99.54%.
Example 16
Adding 3-bromomethyl-6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine (I-1, 15.76g, 0.05mol), trimethylsilyl cyanide (TMSCN, 10.91g, 0.11mol) and potassium acetate (6.38g, 0.065mol) into tetrahydrofuran (100ml) at room temperature, controlling the temperature to 65-70 ℃ for reflux reaction, cooling the reaction liquid to room temperature after detection reaction is finished, filtering, pouring the filtrate into purified water (150ml), extracting dichloromethane (40ml multiplied by 3), combining organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, and concentrating the obtained filtrate under reduced pressure to dryness to obtain the target product I, wherein the yield is 85.1%, and the purity of HPLC is 98.85%.
Example 17
Adding 3-bromomethyl-6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine (I-1, 15.76g, 0.05mol), trimethylsilyl cyanide (TMSCN, 7.44g, 0.075mol) and potassium carbonate (6.91g, 0.05mol) into 1, 4-dioxane (100ml) at room temperature, controlling the temperature to 100-105 ℃ for reflux reaction, cooling the reaction liquid to room temperature after detection reaction is finished, filtering, pouring the filtrate into purified water (150ml), extracting dichloromethane (40ml multiplied by 3), combining organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, and concentrating the obtained filtrate under reduced pressure to dryness to obtain the target product I, wherein the yield is 88.5% and the purity is 99.20%.
Example 18
Adding 3-bromomethyl-6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine (I-1, 15.76g, 0.05mol), trimethylsilyl cyanide (TMSCN, 7.44g, 0.075mol) and potassium carbonate (13.82g, 0.1mol) into acetonitrile (100ml) at room temperature for reaction at 75-80 ℃, cooling the reaction liquid to room temperature after detection reaction is finished, filtering, pouring the filtrate into purified water (150ml), extracting dichloromethane (40ml multiplied by 3), combining organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, and concentrating the obtained filtrate under reduced pressure to dryness to obtain the target product I with yield of 88.1% and HPLC purity of 99.14%.
Example 19
Adding 3-bromomethyl-6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine (I-1, 15.76g, 0.05mol), trimethylsilyl cyanide (TMSCN, 7.44g, 0.075mol) and potassium carbonate (15.21g, 0.11mol) into acetonitrile (100ml) at room temperature for reaction at 60-65 ℃, cooling the reaction liquid to room temperature after detection reaction is finished, filtering, pouring the filtrate into purified water (150ml), extracting dichloromethane (40ml multiplied by 3), combining organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, and concentrating the obtained filtrate under reduced pressure to dryness to obtain the target product I with yield of 84.6% and HPLC purity of 98.80%.
Claims (10)
1. A zolpidem intermediate compound is characterized by having a structure shown as a formula I-1:
2. a process for preparing zolpidem intermediate compound I-1 of claim 1, comprising the steps of: at room temperature, adding a compound SM-1, paraformaldehyde, a brominating reagent and concentrated sulfuric acid into an organic solvent A, and controlling the temperature until the reaction is finished to obtain an intermediate I-1, wherein the reaction route is as follows:
3. the method according to claim 2, wherein the reaction mixture is heated to a temperature in the reaction mixtureIn that, the brominating reagent is selected from HBr or ZnBr2One kind of (1).
4. The preparation method according to claim 2, wherein the compound SM-1, paraformaldehyde and brominating agent are fed in a molar ratio of 1: 1.0-1.5: 1.0 to 2.0.
5. The preparation method according to claim 2, wherein the mass-to-volume ratio of the compounds SM-1 to concentrated sulfuric acid is 1: 1.5 to 3.0, the mass is in g and the volume is in ml.
6. The preparation method according to claim 2, wherein the organic solvent A is selected from one or a combination of chloroform, 1, 2-dichloroethane, and acetonitrile; the reaction temperature is 35-60 ℃, and preferably 45-50 ℃.
7. Use of the zolpidem intermediate compound of claim 1, for the preparation of zolpidem intermediate 2- (6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridin-3-yl) acetonitrile.
8. Use of the zolpidem intermediate compound of claim 7 for the preparation of zolpidem important intermediate 2- (6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridin-3-yl) acetonitrile, comprising the steps of:
adding a compound I-1, trimethylsilyl cyanide and alkali into a reaction solvent B at room temperature, controlling the temperature until the reaction is finished, and performing post-treatment to obtain a target product I, wherein the synthetic route is as follows:
9. the use according to claim 8, wherein the base is selected from one of potassium carbonate, sodium phosphate, potassium acetate, sodium carbonate; the reaction solvent B is selected from one or the combination of 1, 4-dioxane, acetonitrile, tetrahydrofuran and toluene; the reaction temperature is 60-100 ℃, and particularly preferably 80-85 ℃.
10. The use according to claim 8, wherein the molar ratio of compound I-1 to trimethylsilyl cyanide and base is 1: 1.2-2.0: 1.0 to 2.0.
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| 唐除痴等: "不对称反应概论", 31 October 2017, 南开大学出版社, pages: 234 * |
| 魏荣宝: "有机化学", 31 August 2003, 天津大学出版社, pages: 174 - 175 * |
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