CN114621217A - Preparation method of zolpidem - Google Patents
Preparation method of zolpidem Download PDFInfo
- Publication number
- CN114621217A CN114621217A CN202011464057.9A CN202011464057A CN114621217A CN 114621217 A CN114621217 A CN 114621217A CN 202011464057 A CN202011464057 A CN 202011464057A CN 114621217 A CN114621217 A CN 114621217A
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- zolpidem
- filtrate
- temperature
- Prior art date
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- 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 52
- 229960001475 zolpidem Drugs 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 128
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 238000000034 method Methods 0.000 claims abstract description 32
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 74
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 49
- 239000011261 inert gas Substances 0.000 claims description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 25
- 239000008213 purified water Substances 0.000 claims description 25
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 239000002585 base Substances 0.000 claims description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 3
- 229910000406 trisodium phosphate Inorganic materials 0.000 claims description 3
- QPIOVNJLOVNTMW-UHFFFAOYSA-N 2-bromo-n,n-dimethylacetamide Chemical compound CN(C)C(=O)CBr QPIOVNJLOVNTMW-UHFFFAOYSA-N 0.000 abstract description 25
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 238000009776 industrial production Methods 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 6
- 230000009471 action Effects 0.000 abstract description 2
- DAJLHNABGVYSOO-UHFFFAOYSA-N boric acid;2,3-dimethylbutane-2,3-diol Chemical compound OB(O)O.CC(C)(O)C(C)(C)O DAJLHNABGVYSOO-UHFFFAOYSA-N 0.000 abstract 1
- 239000000706 filtrate Substances 0.000 description 65
- 239000000243 solution Substances 0.000 description 59
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 46
- 238000001914 filtration Methods 0.000 description 43
- 238000001514 detection method Methods 0.000 description 42
- 235000011056 potassium acetate Nutrition 0.000 description 35
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 31
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 230000002829 reductive effect Effects 0.000 description 24
- BMQDAIUNAGXSKR-UHFFFAOYSA-N (3-hydroxy-2,3-dimethylbutan-2-yl)oxyboronic acid Chemical compound CC(C)(O)C(C)(C)OB(O)O BMQDAIUNAGXSKR-UHFFFAOYSA-N 0.000 description 23
- 229910052786 argon Inorganic materials 0.000 description 23
- 239000012074 organic phase Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 21
- 238000001035 drying Methods 0.000 description 21
- 238000002156 mixing Methods 0.000 description 18
- 230000008569 process Effects 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- -1 heteroaryl acetamides Chemical class 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 206010022437 insomnia Diseases 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000005660 chlorination reaction Methods 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- 231100000331 toxic Toxicity 0.000 description 3
- 230000002588 toxic effect Effects 0.000 description 3
- XWSCOGPKWVNQSV-UHFFFAOYSA-N 5-bromo-2,3-dichloropyridine Chemical compound ClC1=CC(Br)=CN=C1Cl XWSCOGPKWVNQSV-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000012790 confirmation Methods 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 229960005111 zolpidem tartrate Drugs 0.000 description 2
- XQRILQRMHDAYOF-UHFFFAOYSA-N 2,2-dimethoxy-n,n-dimethylacetamide Chemical compound COC(OC)C(=O)N(C)C XQRILQRMHDAYOF-UHFFFAOYSA-N 0.000 description 1
- 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
- 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 description 1
- JNQVLKWNKVMFBN-UHFFFAOYSA-N 2-hydroxy-n,n-dimethylacetamide Chemical class CN(C)C(=O)CO JNQVLKWNKVMFBN-UHFFFAOYSA-N 0.000 description 1
- TZGPACAKMCUCKX-UHFFFAOYSA-N 2-hydroxyacetamide Chemical class NC(=O)CO TZGPACAKMCUCKX-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
- 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 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 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 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical group CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- PUHKYHYSAKNRMK-UHFFFAOYSA-N BrC1=C(N=C2N1C=C(C=C2)C)C1=CC=C(C=C1)C Chemical compound BrC1=C(N=C2N1C=C(C=C2)C)C1=CC=C(C=C1)C PUHKYHYSAKNRMK-UHFFFAOYSA-N 0.000 description 1
- 206010051625 Conjunctival hyperaemia Diseases 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 239000012448 Lithium borohydride Substances 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
- 206010068319 Oropharyngeal pain Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 208000028017 Psychotic disease Diseases 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000002009 allergenic effect Effects 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
- 238000007098 aminolysis reaction Methods 0.000 description 1
- SWLVFNYSXGMGBS-UHFFFAOYSA-N ammonium bromide Chemical compound [NH4+].[Br-] SWLVFNYSXGMGBS-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910001622 calcium bromide Inorganic materials 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- VBXDEEVJTYBRJJ-UHFFFAOYSA-N diboronic acid Chemical compound OBOBO VBXDEEVJTYBRJJ-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- MOOYVEVEDVVKGD-UHFFFAOYSA-N oxaldehydic acid;hydrate Chemical compound O.OC(=O)C=O MOOYVEVEDVVKGD-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006042 reductive dechlorination reaction Methods 0.000 description 1
- 238000012958 reprocessing Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- XWGJFPHUCFXLBL-UHFFFAOYSA-M rongalite Chemical compound [Na+].OCS([O-])=O XWGJFPHUCFXLBL-UHFFFAOYSA-M 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 238000013341 scale-up Methods 0.000 description 1
- 208000013220 shortness of breath Diseases 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
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- KKVTYAVXTDIPAP-UHFFFAOYSA-M sodium;methanesulfonate Chemical compound [Na+].CS([O-])(=O)=O KKVTYAVXTDIPAP-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Substances ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 238000005292 vacuum distillation Methods 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 field of pharmaceutical chemicals, and particularly relates to a preparation method of zolpidem. The invention utilizes the compound I-1 and the boric acid pinacol to obtain an intermediate compound I-2 under the action of a catalyst; the intermediate compound I-2 and 2-bromo-N, N-dimethylacetamide act in a catalyst to obtain zolpidem. Compared with the prior art, the method has the advantages that the reaction steps can be obviously shortened, the production cost is low, the operation is simple and convenient, and the prepared zolpidem has higher purity and yield, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of zolpidem.
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 the characteristics of quick response, low addiction and the like. The chemical structural formula is as follows:
the synthesis processes of zolpidem are reported in many ways, and patents GB9915489, GB1076089, EP0050563, US4492695, US4382938, US20070027180A1 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. The final amidation is carried out using CDI (CDI is a very expensive, toxic, allergenic and hygroscopic compound and is therefore very difficult to use on an industrial scale, and the other is that the desired target product obtained by this process is contaminated by the decomposition products of CDI and thus only with the aid of a complicated purification process is it possible to obtain zolpidem which meets the strict requirements of the pharmacopoeia) and also phosphorus oxychloride or phosphorus pentachloride which is more toxic.
To eliminate the disadvantages of the above-mentioned processes, a number of processes for preparing heteroaryl acetamides have been proposed. In general, they differ in the method used for introducing the acetamide side chain and in the reagents used, mainly in the following three strategies:
(ii) 6-methyl-2- (4-methylphenyl) imidazole [1,2-a ] as described in US patents US4794185, FR2600650 and EP251589]Pyridine as key intermediate or starting material, and N, N-dimethyl-2, 2-dimethoxy-acetamideThe alpha-hydroxy-N, N-dimethyl-acetamide derivative should be prepared and then subjected to SOCl2After chlorination, by NaBH4、Zn(BH4)2、KBH4、LiBH4Reduction dechlorinated zolpidem:
although the synthesis method avoids using highly toxic sodium cyanide, SOCl which has strong corrosivity and irritation and can cause burn of human body is used in the process of reducing hydroxyl2The chlorination reaction is carried out, borohydride which is harmful to human bodies (symptoms such as sore throat, cough, shortness of breath, headache, abdominal pain, diarrhea, dizziness, conjunctival congestion, pain and the like after the borohydride is contacted with sodium borohydride) is used in the reduction reaction, the activity of the borohydride is high, hydrogen can be released in the reaction process, the operation is dangerous, and the borohydride is difficult to be used in the field of drug synthesis.
In addition, the process also needs to prepare side chain intermediates respectively, so that the total number of steps required for preparing zolpidem is large, the production period is increased, and the process is not suitable for large-scale production; meanwhile, the side chain N, N-dimethyl-2, 2-dimethoxyacetamide can be prepared only with the aid of special equipment, cannot be produced on an industrial scale, and is sensitive to trace amounts of water and acid, so that the route is difficult to scale up.
U.S. Pat. No. 4, 4808594A (family FR8615533, EP0267111A1) synthesized zolpidem derivatives using the same strategy, but performed during reductive dechlorination using a clump of a strong carcinogen that was highly damaging to the human lungs, liver and kidneys, making the procedure less safe.
In Chinese patents CN1972939A (same family EP01172364, US2007213537, WO2006007289) and CN1729188A (same family WO2004058758, EP01809627, US20070213537A1), EP01809627 heteroaryl α -hydroxyacetamides, strong acids (sulfuric acid, perchloric acid or mixtures thereof), halides (LiBr, NaBr, KBr, MgBr, etc.)2、CaBr2Or NH4Br), catalyst (platinum, palladium, ruthenium, osmium, iridium, or rhodium catalyzed)A reagent) and a water removal agent (carboxylic anhydride, carboxylic acid chloride or magnesium sulfate, a molecular sieve) are contacted with a hydrogen source (hydrogen gas, 1-4 atmospheric pressures) to prepare zolpidem. Although the process reduces the chlorination process, the reaction still needs to be carried out under the catalysis of noble metal, and the reaction pressure is high, and the operation is dangerous:
chinese patent CN1668617A (same family US20040010146, WO20040010146) uses hydroxyacetamide derivative as reagent to proceed side chain extension preparation, but the reagent is not easy to obtain, and the reduction reagent PBr is used3Burns are easily caused and irritative to the respiratory system, and therefore it is difficult to perform during the amplification operation:
② patents EP1038875T1 and EP1038875A2 adopt (condensed) glyoxylic acid monohydrate as a side chain for extension to prepare corresponding acid derivatives, then reduce hydroxyl, and finally react with dimethylamine to prepare zolpidem. However, this process uses very corrosive and difficult to handle chemicals (such as formic acid) and also involves filtration and vacuum distillation operations, and in addition, this process uses precious metal catalysts which need to be recovered after reprocessing, making it difficult to implement the process on a large scale:
③ WO0008021A2, WO0008021A3 and US6407240B1 adopt methyl glyoxylate or methyl hemiacetal thereof as a side chain to extend and prepare corresponding ester derivatives, then hydroxyl is reduced after being chlorinated, and finally zolpidem is prepared by dimethylamine hydrolysis. Although the method adopts the direct dimethyl aminolysis mode of ester to introduce dimethylamino, the use of CDI, phosphorus oxychloride or phosphorus pentachloride can be saved, but the side chain extension reagent used by the method is not easy to obtain, and the reducing hydroxyl is used in the sodium methane sulfonate which is not easy to obtain or the sodium formaldehyde sulfoxylate with larger toxicity, so that the method is not suitable for industrial amplification production:
in conclusion, the existing preparation method of zolpidem has many defects in the aspects of safe process, complex operation, low yield, high production cost and the like, so that the research and search of a reaction route which has mild reaction conditions, simple and convenient operation process, high product yield, high purity and low production cost and is suitable for industrial production of zolpidem still remains the problem to be solved at present.
Disclosure of Invention
Aiming at the problems of long route, complex operation, low yield, low purity, high technical requirement, high production cost and the like of the existing zolpidem preparation technology, the invention provides a novel zolpidem synthesis method. The zolpidem prepared by the method has higher purity and yield, and is suitable for industrial production.
The specific technical scheme of the invention is as follows:
a preparation method of zolpidem comprises the following steps:
the compound I-1 and the diboronic acid pinacol are reacted under the action of a catalyst to obtain an intermediate compound I-2; the compound I-2 and 2-bromo-N, N-dimethylacetamide act in a catalyst to obtain zolpidem I;
the reaction synthesis route is as follows:
preferably, the above steps are described in further detail in the following sections:
preparation of Compound I-2:
the preparation method of the compound I-2 comprises the following steps: under the protection of inert gas, adding the compound I-1, pinacol borate, alkali and a catalyst into a reaction solvent at room temperature, and controlling the temperature until the reaction is finished to obtain a reaction solution containing the product I-2.
Preferably, the catalyst is selected from Pd (PPh)3)4、Pd(PPh3)2Cl2、Pd(dppf)Cl2Of (1), Pd (dppf) Cl is particularly preferred2。
Preferably, the base is selected from K2CO3、Na2CO3、K3PO4、Na3PO4One of NaOAc and KOAc, and KOAc is particularly preferable.
Preferably, the feeding molar ratio of the compound I-1 to the pinacol borate, the base and the catalyst is 1: 1.1-1.4: 1.2-1.8: 0.03 to 0.08, particularly preferably 1: 1.2: 1.5: 0.05.
preferably, the reaction solvent is selected from one of dimethyl sulfoxide, N-dimethylformamide, 1, 4-dioxane and N, N-dimethylacetamide, and particularly preferably is dimethyl sulfoxide.
Preparation of compound I:
the preparation method of the compound I comprises the following steps: and (3) under the protection of inert gas, continuously adding alkali, purified water and a compound SM-3, namely 2-bromo-N, N-dimethylacetamide into the reaction solution containing the product I-2, controlling the temperature until the reaction is finished, and carrying out post-treatment on the reaction to obtain the zolpidem.
Preferably, the catalyst is selected from Pd (PPh)3)4、Pd(PPh3)2Cl2、Pd(dppf)Cl2Of these, Pd (PPh) is particularly preferred3)2Cl2。
Preferably, the base is selected from K2CO3、Na2CO3、K3PO4、Na3PO4One of NaOAc and KOAc, and K is particularly preferable3PO4。
Preferably, the feeding molar ratio of the continuously added alkali, the 2-bromo-N, N-dimethylacetamide and the compound I-1 is 0.8-1.5: 1.2-1.5: 1, particularly preferably 1.2: 1.3: 1.
in a preferable scheme, the post-treatment step is to control the temperature until the reaction is finished, filter, add the filtrate into purified water, extract with an extracting agent, combine organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure until the filtrate is dried to obtain zolpidem I; preferably, the extractant is selected from one of dichloromethane, chloroform, ethyl acetate and methyl tert-butyl ether, and ethyl acetate is particularly preferred.
In the present invention, the inert gas used in the process for preparing compounds I-2 and I is generally selected from nitrogen, argon, and particularly preferably argon; the reaction temperature is 80-110 ℃, and particularly preferably 95-100 ℃.
The invention has the beneficial effects that:
1. the invention provides a novel preparation method of zolpidem, and the zolpidem prepared by the process has higher purity and yield;
2. in the invention, the zolpidem side chain is constructed by the 2-bromo-N, N-dimethylacetamide reagent, compared with the prior art, the reaction steps can be obviously shortened, the operation is simple and convenient, and the method is suitable for industrial production;
in conclusion, the invention provides a novel method for preparing zolpidem, which can avoid the use of dangerous chemical reagents, does not generate new impurities in a synthesized intermediate, has high yield and purity, and is suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
All such modifications are intended to be included within the scope of this invention.
The structure confirmation data of the intermediate compound I-1 obtained by the invention are as follows:
ESI-HRMS(m/z)：301.0342[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.30(s,1H),7.56(d,J＝7.4Hz,2H),7.51(d,J＝7.6Hz,1H),7.25(d,J＝7.6Hz,1H),7.16(d,J＝7.4Hz,2H),2.435(s,3H),2.36(s,3H)；13C NMR(101MHz,DMSO-d6)δ154.12,138.30,137.52,134.10,129.73,129.55,128.35,123.350,119.12,118.03,94.32,21.10,15.48。
the structure confirmation data of the intermediate compound I-2 obtained by the invention are as follows:
ESI-HRMS(m/z)：349.2082[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.60～7.54(d,J＝7.4Hz,2H),7.50～7.45(d,J＝6.8Hz,1H),7.21～7.10(m,3H),2.44(s,3H),2.37(s,3H),1.30(s,12H)；13C NMR(101MHz,DMSO-d6)δ145.66,140.12,136.77,134.42,129.90,129.54,128.23,128.03,123.50,122.04,119.02,86.45,24.71,21.12,15.45。
the structure of the zolpidem compound obtained by the invention is confirmed as follows:
mp.：195.2～196.1℃；ESI-HRMS(m/z)：308.1756[M+H]+；1H NMR(400MHz,CD3OD-d4)δ9.52(s,1H),7.62～7.85(m,2H),7.38(d,J＝7.4Hz,2H),7.32(d,J＝7.4Hz,2H),4.47(d,J＝5.4Hz,2H),2.80(s,3H),2.48(s,3H),2.41(s,3H),2.36(s,3H)；13C NMR(101MHz,CD3OD-d4)δ176.73,140.55,138.15,137.99,133.35,129.89,129.57,129.33,126.69,124.78,119.91,119.00,36.93,36.73,21.13,15.47。
the purity of zolpidem is measured by HPLC, and the chromatographic conditions are as follows:
a chromatographic column: YMC Triart-C18A column (4.6mm x 250mm, 5 μm) or a chromatography column of comparable performance;
mobile phase: mobile phase A: aqueous sodium sulfate solution (2.84 g of anhydrous sodium sulfate and 1ml of trifluoroacetic acid were taken, dissolved in water and diluted to 1000ml), mobile phase B: acetonitrile, gradient elution;
column temperature: 35 ℃;
detection wavelength: 248 nm;
flow rate: 1.0 ml/min;
sample introduction amount: 20 mu l of the mixture;
wherein the retention time of zolpidem is about 18.7 min.
The elution gradient is shown in table 1:
TABLE 1 elution gradiometer
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Synthesis of intermediate I-1:
example 1
Adding 6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine (SM-1, 44.46g, 0.2mol) and trifluoroacetic acid (1.14g, 0.01mol) into dichloromethane (350ml) at room temperature, uniformly stirring, adding NBS (42.72g, 0.24mol) into a reaction solvent at the temperature of 0-5 ℃, reacting at the temperature of 10-15 ℃, filtering after detecting the reaction, washing the filtrate with a 10% sodium sulfite aqueous solution (200ml multiplied by 2), washing with purified water (200ml multiplied by 2), drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain the 3-bromo-6-methyl-2- (4-methylphenyl) imidazo [1,2-a ] pyridine (I-1), wherein the yield is 94.6% and the purity is 99.95%.
Synthesis of Compound I:
example 2
Under the protection of argon at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), potassium acetate (14.72g, 0.15mol), Pd (dppf) Cl2(3.66g, 5.0mmol) is added into dimethyl sulfoxide (250ml), the temperature is controlled to be 95-100 ℃ for reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (11.77g, 0.12mol) and 2-bromo-N, N-dimethylacetamide (21.58g, 0.13mol) into the reaction solution, stirring and uniformly mixing, controlling the temperature to be 95-100 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting by using ethyl acetate (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain zolpidem (I), wherein the yield is 90.2%, and the purity is 99.93%.
Example 3
Under argon protection at room temperature, compound I-1(30.12g, 0.10 m)ol), pinacol borate (15.84g, 0.11mol), potassium carbonate (20.73g, 0.15mol), Pd (PPh)3)4(5.78g, 5.0mmol) is added into dimethyl sulfoxide (250ml), the temperature is controlled to be 100-105 ℃ for reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (11.77g, 0.12mol) and 2-bromo-N, N-dimethylacetamide (21.58g, 0.13mol) into the reaction solution, stirring and uniformly mixing, controlling the temperature to be 95-100 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting by using dichloromethane (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain zolpidem (I), wherein the yield is 83.5%, and the purity is 99.67%.
Example 4
Under the protection of argon at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (14.40g, 0.1mol), sodium carbonate (12.90g, 0.15mol), Pd (PPh)3)2Cl2(3.51g, 5.0mmol) is added into N, N-dimethylformamide (250ml), the temperature is controlled to be 75-80 ℃ for reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (11.77g, 0.12mol) and 2-bromo-N, N-dimethylacetamide (21.58g, 0.13mol) into the reaction solution, stirring and uniformly mixing, controlling the temperature to be 95-100 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting by using chloroform (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain the zolpidem (I), wherein the yield is 78.9%, and the purity is 99.11%.
Example 5
Under argon protection at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (20.15g, 0.14mol), potassium phosphate (31.84g, 0.15mol), Pd (PPh)3)2Cl2(3.51g, 5.0mmol) is added into N, N-dimethylacetamide (250ml), the temperature is controlled to be 110-115 ℃ for reflux reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, a water (40ml) solution of potassium acetate (11.77g, 0.12mol) and 2-bromine-N, N-dimethylacetamide (21.58g, 0.13mol) is uniformly stirred, the temperature is controlled to be 95-100 ℃, after detection reaction is finished, the mixture is filtered by using kieselguhr, filtrate is added into purified water (800ml), ethyl acetate (250ml multiplied by 3) is extracted, organic phases are combined, dried by anhydrous sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure to be dry to obtain zolpidem (I), wherein the yield is 85.4%, and the purity is 99.79%.
Example 6
Under argon protection at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (24.47g, 0.17mol), sodium phosphate (57.01g, 0.15mol), Pd (dppf) Cl2(3.66g, 5.0mmol) is added into 1, 4-dioxane (250ml), the temperature is controlled to be 80-85 ℃ for reflux reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (11.77g, 0.12mol) and 2-bromo-N, N-dimethylacetamide (21.58g, 0.13mol) into the reaction solution, stirring and uniformly mixing, controlling the temperature to 90-95 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting by using methyl tert-butyl ether (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain zolpidem (I), wherein the yield is 78.5%, and the purity is 98.99%.
Example 7
Under the protection of argon at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), potassium acetate (11.78g, 0.12mol), Pd (dppf) Cl2(3.66g, 5.0mmol) is added into N, N-dimethylformamide (250ml), the temperature is controlled to be 105-110 ℃ for reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (11.77g, 0.12mol) and 2-bromo-N, N-dimethylacetamide (21.58g, 0.13mol) into the reaction solution, stirring and uniformly mixing, controlling the temperature to be 95-100 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting by using dichloromethane (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain zolpidem (I), wherein the yield is 83.5%, and the purity is 99.90%.
Example 8
Under the protection of argon at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), potassium acetate (9.81g, 0.10mol), Pd (dppf) Cl2(3.66g, 5.0mmol) is added into N, N-dimethylacetamide (250ml), the temperature is controlled to be 100-105 ℃ for reaction, and after the reaction is detected, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (11.77g, 0.12mol) and 2-bromo-N, N-dimethylacetamide (21.58g, 0.13mol) into the reaction solution, stirring and uniformly mixing, controlling the temperature to be 95-100 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting by using chloroform (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain the zolpidem (I), wherein the yield is 78.4%, and the purity is 99.15%.
Example 9
Under the protection of argon at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), potassium acetate (17.67g, 0.18mol), Pd (dppf) Cl2(3.66g, 5.0mmol) is added into 1, 4-dioxane (250ml), the temperature is controlled to be 75-80 ℃ for reflux reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (11.77g, 0.12mol) and 2-bromo-N, N-dimethylacetamide (21.58g, 0.13mol) into the reaction solution, stirring and uniformly mixing, controlling the temperature to 90-95 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting by using ethyl acetate (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain zolpidem (I), wherein the yield is 85.1%, and the purity is 99.74%.
Example 10
Under the protection of argon at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), potassium acetate (20.61g, 0.21mol), Pd (dppf) Cl2(3.66g, 5.0mmol) is added into dimethyl sulfoxide (250ml), the temperature is controlled to be 110-105 ℃ for reflux reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of an inert gas, potassium acetate (11.77g,0.12mol) of water (40ml) and 2-bromo-N, N-dimethylacetamide (21.58g, 0.13mol), stirring and mixing uniformly, controlling the temperature to 95-100 ℃, after detection reaction is finished, filtering by using diatomite, adding filtrate into purified water (800ml), extracting methyl tert-butyl ether (250ml multiplied by 3), combining organic phases, drying by anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain zolpidem (I), wherein the yield is 78.8%, and the purity is 98.98%.
Example 11
Under the protection of argon at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), sodium acetate (12.31g, 0.15mol), Pd (dppf) Cl2(2.20g, 3.0mmol) is added into dimethyl sulfoxide (250ml), the temperature is controlled to be 100-105 ℃ for reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (11.77g, 0.12mol) and 2-bromo-N, N-dimethylacetamide (21.58g, 0.13mol) into the reaction solution, stirring and uniformly mixing, controlling the temperature to be 95-100 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting by using dichloromethane (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain zolpidem (I), wherein the yield is 86.2%, and the purity is 99.59%.
Example 12
Under argon protection at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), potassium carbonate (20.73g, 0.15mol), Pd (dppf) Cl2(0.73g, 1.0mmol) is added into dimethyl sulfoxide (250ml), the temperature is controlled to be 75-80 ℃ for reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (11.77g, 0.12mol) and 2-bromo-N, N-dimethylacetamide (21.58g, 0.13mol) into the reaction solution, stirring and uniformly mixing, controlling the temperature to be 95-100 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting by using chloroform (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain the zolpidem (I), wherein the yield is 80.4%, and the purity is 98.93%.
Example 13
Under the protection of argon at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), sodium carbonate (12.60g, 0.15mol), Pd (dppf) Cl2(5.85g, 8.0mmol) is added into dimethyl sulfoxide (250ml), the temperature is controlled to be 95-100 ℃ for reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (11.77g, 0.12mol) and 2-bromo-N, N-dimethylacetamide (21.58g, 0.13mol) into the reaction solution, stirring and uniformly mixing, controlling the temperature to be 95-100 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting by using ethyl acetate (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain the zolpidem (I), wherein the yield is 85.6%, and the purity is 99.72%.
Example 14
Under the protection of argon at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), potassium acetate (15.90g, 0.15mol), Pd (dppf) Cl2(7.33g, 10mmol) is added into dimethyl sulfoxide (250ml), the temperature is controlled to be 110-105 ℃ for reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (11.77g, 0.12mol) and 2-bromo-N, N-dimethylacetamide (21.58g, 0.13mol) into the reaction solution, stirring and uniformly mixing, controlling the temperature to be 95-100 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting by using methyl tert-butyl ether (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain zolpidem (I), wherein the yield is 79.4%, and the purity is 99.48%.
Example 15
Under the protection of argon at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), potassium acetate (14.72g, 0.15mol), Pd (dppf) Cl2(3.66g, 5.0mmol) is added into dimethyl sulfoxide (250ml), the temperature is controlled to be 95-100 ℃ for reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; continuing to add potassium acetate (under the protection of inert gas)7.85g, 0.08mol) of water (40ml) and 2-bromo-N, N-dimethylacetamide (21.58g, 0.08mol), stirring, uniformly mixing, controlling the temperature to be 80-85 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding filtrate into purified water (800ml), extracting by using dichloromethane (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to dryness to obtain the zolpidem (I), wherein the yield is 81.7%, and the purity is 99.33%.
Example 16
Under the protection of argon at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), potassium acetate (14.72g, 0.15mol), Pd (dppf) Cl2(3.66g, 5.0mmol) is added into toluene (250ml), the temperature is controlled to be 95-100 ℃ for reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (5.89g, 0.06mol) and 2-bromo-N, N-dimethylacetamide (21.58g, 0.13mol) into the reaction solution, stirring and uniformly mixing, controlling the temperature to be 85-90 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting by using chloroform (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain the zolpidem (I), wherein the yield is 75.5%, and the purity is 99.07%.
Example 17
Under the protection of argon at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), potassium acetate (14.72g, 0.15mol), Pd (dppf) Cl2(3.66g, 5.0mmol) is added into N, N-dimethylformamide (250ml), the temperature is controlled to be 95-100 ℃ for reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (14.72g, 0.15mol) and 2-bromo-N, N-dimethylacetamide (21.58g, 0.13mol) into the reaction solution, stirring and uniformly mixing, controlling the temperature to be 100-105 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting by using ethyl acetate (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain zolpidem (I), wherein the yield is 83.4%, and the purity is 99.49%.
Example 18
Under the condition of argon protection at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), potassium acetate (14.72g, 0.15mol), Pd (dppf) Cl2(3.66g, 5.0mmol) is added into dimethyl sulfoxide (250ml), the temperature is controlled to be 95-100 ℃ for reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (16.68g, 0.17mol) and 2-bromo-N, N-dimethylacetamide (21.58g, 0.13mol) into the reaction solution, uniformly stirring, controlling the temperature to be 105-110 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting by using methyl tert-butyl ether (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain zolpidem (I), wherein the yield is 81.8%, and the purity is 99.35%.
Example 19
Under the protection of argon at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), potassium acetate (14.72g, 0.15mol), Pd (dppf) Cl2(3.66g, 5.0mmol) is added into toluene (250ml), the temperature is controlled to be 95-100 ℃ for reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (11.77g, 0.12mol) and 2-bromo-N, N-dimethylacetamide (16.6g, 0.1mol) into the reaction solution, stirring and uniformly mixing, controlling the temperature to 90-95 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting dichloromethane (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain zolpidem (I), wherein the yield is 77.9%, and the purity is 99.41%.
Example 20
Under the protection of argon at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), potassium acetate (14.72g, 0.15mol), Pd (dppf) Cl2(3.66g, 5.0mmol) is added into N, N-dimethylformamide (250ml), the temperature is controlled to be 95-100 ℃ for reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of an inert gas, potassium acetate (11.77g,0.12mol) of water (40ml) and 2-bromo-N, N-dimethylacetamide (19.92g, 0.12mol), uniformly stirring, controlling the temperature to 85-90 ℃, after the detection reaction is finished, filtering by using diatomite, adding the filtrate into purified water (800ml), extracting by using chloroform (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain the zolpidem (I), wherein the yield is 81.3%, and the purity is 99.68%.
Example 21
Under the condition of argon protection at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), potassium acetate (14.72g, 0.15mol), Pd (dppf) Cl2(3.66g, 5.0mmol) is added into dimethyl sulfoxide (250ml), the temperature is controlled to be 95-100 ℃ for reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (11.77g, 0.12mol) and 2-bromo-N, N-dimethylacetamide (24.9g, 0.15mol) into the reaction solution, stirring and uniformly mixing, controlling the temperature to be 95-100 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting by using ethyl acetate (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain zolpidem (I), wherein the yield is 83.9%, and the purity is 99.81%.
Example 22
Under the protection of argon at room temperature, compound I-1(30.12g, 0.10mol), pinacol borate (17.28g, 0.12mol), potassium acetate (14.72g, 0.15mol), Pd (dppf) Cl2(3.66g, 5.0mmol) is added into toluene (250ml), the temperature is controlled to be 95-100 ℃ for reaction, and after the detection reaction is finished, a reaction solution containing a compound I-2 is obtained; under the protection of inert gas, continuously adding a water (40ml) solution of potassium acetate (11.77g, 0.12mol) and 2-bromo-N, N-dimethylacetamide (28.22g, 0.17mol) into the reaction solution, stirring and uniformly mixing, controlling the temperature to 90-95 ℃, after the detection reaction is finished, filtering by using kieselguhr, adding the filtrate into purified water (800ml), extracting by using methyl tert-butyl ether (250ml multiplied by 3), combining organic phases, drying by using anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure until the filtrate is dry to obtain zolpidem (I), wherein the yield is 79.7%, and the purity is 99.65%.
Claims (7)
1. A preparation method of zolpidem is characterized by comprising the following steps:
(1) under the protection of inert gas, adding a compound I-1, a compound SM-2, alkali and a catalyst into a reaction solvent at room temperature, and controlling the temperature until the reaction is finished to obtain a reaction solution containing the compound I-2;
(2) under the protection of inert gas, continuously adding alkali, purified water and a compound SM-3 into a reaction solution containing the compound I-2, uniformly stirring, controlling the temperature until the reaction is finished, and carrying out post-treatment on the reaction to obtain zolpidem, wherein the reaction synthetic route is as follows:
2. the method according to claim 1, wherein the reaction solvent in step (1) is one selected from the group consisting of dimethylsulfoxide, N-dimethylformamide, 1, 4-dioxane, and N, N-dimethylacetamide.
3. The preparation method according to claim 1, wherein the reaction temperature in the step (1) and the step (2) is 80-110 ℃.
4. The preparation method according to claim 1, wherein the feeding molar ratio of the compound I-1 to the compound SM-2, the base and the catalyst in the step (1) is 1: 1.1-1.4: 1.2-1.8: 0.03 to 0.08.
5. The method according to claim 1, wherein the catalyst in step (1) and step (2) is selected from Pd (PPh)3)4、Pd(PPh3)2Cl2、Pd(dppf)Cl2To (3) is provided.
6. The method according to claim 1, wherein the step (1) and the step (2) are carried out in the same manner as described above) The base is selected from K2CO3、Na2CO3、K3PO4、Na3PO4NaOAc and KOAc.
7. The preparation method according to claim 1, wherein the feeding molar ratio of the base added in step (2), the compound SM-3 and the compound I-1 is 0.8-1.5: 1.2-1.5: 1.
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