CN109053726A - A kind of preparation method of zolpidem acid - Google Patents
A kind of preparation method of zolpidem acid Download PDFInfo
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- CN109053726A CN109053726A CN201811072769.9A CN201811072769A CN109053726A CN 109053726 A CN109053726 A CN 109053726A CN 201811072769 A CN201811072769 A CN 201811072769A CN 109053726 A CN109053726 A CN 109053726A
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- Prior art keywords
- acid
- oxo
- reaction
- aminomethyl phenyl
- zolpidem
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- JHGHLTNIQXXXNV-UHFFFAOYSA-N 2-[6-methyl-2-(4-methylphenyl)imidazo[1,2-a]pyridin-3-yl]acetic acid Chemical compound C1=CC(C)=CC=C1C1=C(CC(O)=O)N2C=C(C)C=CC2=N1 JHGHLTNIQXXXNV-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 48
- -1 unlike the prior art Chemical compound 0.000 claims abstract description 25
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002253 acid Substances 0.000 claims abstract description 10
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 6
- 150000002168 ethanoic acid esters Chemical class 0.000 claims abstract description 5
- BMRNMQHFDJRSMB-UHFFFAOYSA-N 1h-imidazole;toluene Chemical class C1=CNC=N1.CC1=CC=CC=C1 BMRNMQHFDJRSMB-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 28
- 235000019441 ethanol Nutrition 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- CMBSSVKZOPZBKW-UHFFFAOYSA-N 5-methylpyridin-2-amine Chemical compound CC1=CC=C(N)N=C1 CMBSSVKZOPZBKW-UHFFFAOYSA-N 0.000 claims description 10
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-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
- 239000003513 alkali Substances 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical class CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 238000007259 addition reaction Methods 0.000 claims description 4
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 3
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 2
- VNJMEFZKYZHWEO-UHFFFAOYSA-N 4-(4-methylphenyl)-4-oxobut-2-enoic acid Chemical compound CC1=CC=C(C(=O)C=CC(O)=O)C=C1 VNJMEFZKYZHWEO-UHFFFAOYSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 239000002841 Lewis acid Substances 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 2
- 229910000043 hydrogen iodide Inorganic materials 0.000 claims description 2
- 150000007517 lewis acids Chemical group 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 claims 1
- 150000001336 alkenes Chemical class 0.000 claims 1
- ZWIPGARCRSFMHK-UHFFFAOYSA-N benzene;1h-imidazole Chemical class C1=CNC=N1.C1=CC=CC=C1 ZWIPGARCRSFMHK-UHFFFAOYSA-N 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 7
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 abstract 1
- 239000012535 impurity Substances 0.000 abstract 1
- 230000020477 pH reduction Effects 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 abstract 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 9
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000002994 raw material Substances 0.000 description 5
- 230000000630 rising effect Effects 0.000 description 5
- VNHBYKHXBCYPBJ-UHFFFAOYSA-N 5-ethynylimidazo[1,2-a]pyridine Chemical compound C#CC1=CC=CC2=NC=CN12 VNHBYKHXBCYPBJ-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 238000010907 mechanical stirring Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 3
- 238000013517 stratification Methods 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
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000005554 hypnotics and sedatives Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 231100000004 severe toxicity Toxicity 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 229960005111 zolpidem tartrate Drugs 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 1
- KRVGXFREOJHJAX-UHFFFAOYSA-N 2-bromo-1-(4-methylphenyl)ethanone Chemical compound CC1=CC=C(C(=O)CBr)C=C1 KRVGXFREOJHJAX-UHFFFAOYSA-N 0.000 description 1
- 125000001340 2-chloroethyl group Chemical class [H]C([H])(Cl)C([H])([H])* 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical group CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- IUYQVEWBKZKUKI-UHFFFAOYSA-N CC1=C(C=CC(=C1)CN)C2=NC=CN2 Chemical class CC1=C(C=CC(=C1)CN)C2=NC=CN2 IUYQVEWBKZKUKI-UHFFFAOYSA-N 0.000 description 1
- BMNSGYKRSCFWKV-LREBCSMRSA-N NC(=O)CC1=CC=CN=C1.OC(=O)[C@H](O)[C@@H](O)C(O)=O Chemical compound NC(=O)CC1=CC=CN=C1.OC(=O)[C@H](O)[C@@H](O)C(O)=O BMNSGYKRSCFWKV-LREBCSMRSA-N 0.000 description 1
- 229940121985 Non-benzodiazepine hypnotic Drugs 0.000 description 1
- VDRVYAZGWHECCL-UHFFFAOYSA-N [4-(1h-imidazol-2-yl)phenyl]methanamine Chemical class C1=CC(CN)=CC=C1C1=NC=CN1 VDRVYAZGWHECCL-UHFFFAOYSA-N 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 239000000498 cooling water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 229960001475 zolpidem Drugs 0.000 description 1
- 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 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 present invention discloses a kind of synthetic method of zolpidem acid, unlike the prior art, toluene is subjected to Friedel-Crafts reaction with maleic anhydride first and obtains 4- oxo -4-(4- aminomethyl phenyl) -2- butenoic acid, addition, which is carried out, with halogen acids again obtains the halogenated -4- oxo -4-(4- aminomethyl phenyl of 3-)-butyric acid, then through being esterified, cyclization, obtaining 2-, (6- methyl -2- is to methylbenzene imidazoles [1,2- α] pyridin-3-yl) acetic acid esters, then hydrolyzed, acidification obtains zolpidem acid.Using method of the invention, the zolpidem acid of high-purity can be obtained, whole synthetic route step is few, and high income is at low cost, and impurity is few, is suitable for industrialized production.
Description
Technical field
This patent is related to chemosynthesis technical field, and in particular to a kind of preparation method of pharmaceutical intermediate zolpidem acid.
Background technique
Zolpidem acid, is the key intermediate for preparing Zolpidemtar Trate (following formula).Zolpidemtar Trate, i.e. N, N, 6-
Trimethyl-2-(4- aminomethyl phenyl)-imidazo [1,2-α] pyridine-3- acetamide-L (+)-tartrate is typical
Non-benzodiazepine hypnotic sedative agent, feature be it is rapid-action, effect is obvious, adverse reaction is small.The medicine is by France
The research and development of Synthelabo company, are widely used as hypnotic sedative agent all over the world, have and gradually replace benzodiazepine
Trend.Also there is the pharmaceutical factory Duo Jia to list this kind in China, market sale is good, and degree of recognition is high.
At present the preparation method of zolpidem acid mainly there are several types of:
1. preparation method disclosed in patent EP50563:
The route will use the Cymag and iodomethane of severe toxicity, and cyan-hydrolysis condition is more harsh, be not easy to realize industrialization
Production.
2. periodical Organic Preparations and Procedures International, 2011,43:260-
Preparation method disclosed in 264:
The route carries out cyclization and obtains 6- methyl -2- using the bromo- 4'- methyl acetophenone of 2- and 2- amino -5- picoline as raw material
(4- aminomethyl phenyl) imidazoles [1,2-a] pyridine, but the Cymag and iodomethane of severe toxicity are equally used, and cyan-hydrolysis item
Part is more harsh, is not easy to realize industrial production.
3. preparation method disclosed in patent CN 106749237A:
The patent reacts preparation 6- methyl-with 6- methyl -2- (4- aminomethyl phenyl) imidazoles [1,2-a] pyridine (1) using oxalyl chloride
2- (4- aminomethyl phenyl)-α -one base-imidazoles [1,2-a] pyridine -3- chloroacetic chloride (2), the intermediate purify without isolation, directly add
Enter basic hydrolysis, then zolpidem acid is obtained with hydrazine hydrate reduction.Although this method does not use iodomethane and Cymag, water used
Hydrazine is closed, toxicity is still larger and explosive, and storage transport is all extremely inconvenient.
Summary of the invention
The present invention provides a kind of efficiently succinct method for preparing zolpidem acid, this method have reaction condition mildly,
It is easy to operate, product purity is high, the features such as avoiding using hypertoxic raw material, be suitble to industrialized production.
Its technology path are as follows:
Taken that the technical scheme comprises the following steps:
Toluene obtains 4- oxo -4-(4- methylbenzene with maleic anhydride progress Friedel-Crafts reaction to step 1) in the presence of a catalyst
Base) -2- butenoic acid (TBEA)；
Step 2) halogen acids carries out addition to the 4- oxo -4- p-methylphenyl -2- butenoic acid (TBEA) and obtains 3- halogen
Generation -4- oxo -4-(4- aminomethyl phenyl)-butyric acid (TBXA)；
Halogenated -4- oxo -4-(4- the aminomethyl phenyl of the step 3) 3-)-butyric acid (TBXA) be esterified to obtain with alcohol it is corresponding
Ester；
Halogenated -4- oxo -4-(4- the aminomethyl phenyl of the step 4) 3-)-butyrate with 2- amino -5- picoline alkali act on
Lower cyclization obtains 2-(6-methyl-2-to methylbenzene imidazoles [1,2-α] pyridine-3-yl) acetic acid esters (ZAC-A), so
After to be hydrolyzed to obtain zolpidem sour (ZAC).
Further, the specific steps of the step 1) and technological parameter include: that maleic anhydride and toluene are added to reaction
In bottle, solvent is added, stirring and dissolving is slowly added to alchlor, reacts 0.5-6 hours, pours into quenching reaction in ice water, then
Extracted, be concentrated to get 4- oxo -4-(4- aminomethyl phenyl) -2- butenoic acid (TBEA)；Wherein, maleic anhydride: alchlor:
Toluene (molar ratio)=1:1~1.5:0.9~10；Reaction temperature is -20~80 DEG C；Solvent includes for toluene, methylene chloride, two
One of chloroethanes, carbon disulfide and nitrobenzene are a variety of；The catalyst is lewis acid.
Further, the specific steps of the step 2 and technological parameter include: by 4- oxo -4-(4- aminomethyl phenyl) -
2- butenoic acid (TBEA), solvent and halogen acids are added sequentially in reaction flask, then temperature reaction, after the completion of addition reaction, after
Continue the addition alcohol into system to be esterified to obtain the bromo- 4- oxo -4-(4- aminomethyl phenyl of 3-)-butyrate；The wherein halogen acids
For hydrogen chloride, hydrogen bromide or hydrogen iodide or any solution of former three；The alcohol is one of C1-C4 alcohol；4- oxo -4-
(4- aminomethyl phenyl) -2- butenoic acid (TBEA): halogen acids: alcohol (molar ratio) are as follows: 1:1.0~2.0:1.1-10；The solvent is
Methylene chloride, dichloroethanes, toluene and dimethylbenzene it is one or more；Reaction temperature is 50~120 DEG C.
Further, alcohol described in the step 3) is one of C1-C4 alcohol.
Further, the specific steps of the step 4) and technological parameter include: that corresponding ester is added in reaction flask,
Then stirring solvent dissolution is added, 2- amino -5- picoline and alkali is then added, with the bromo- 4- oxo -4-(4- methylbenzene of 3-
Base)-butyrate cyclization obtains 2-(6-methyl-2-to methylbenzene imidazoles [1,2-α] pyridine-3-yl) acetic acid esters,
HPLC is detected after the reaction was completed, adds water heating hydrolysis, obtains product zolpidem acid；Wherein, the bromo- 4- oxo -4-(4- first of 3-
Base phenyl)-butyrate: 2- amino -5- picoline (molar ratio)=1:0.9~1.2；Reaction temperature is 0~50 DEG C；It is described molten
Agent is one of methanol, ethyl alcohol and isopropanol or a variety of；The alkali be sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus,
One of sodium hydroxide and potassium hydroxide are a variety of.
Further, the resulting halogenated -4- oxo -4-(4- aminomethyl phenyl of 3- of step 2)-butyric acid (TBXA) warp
Separation or the reaction for carrying out step 3) afterwards without isolation.
The beneficial effects of the present invention are:
1) raw material of the present invention uses toluene, maleic anhydride and 2- amino -5- picoline, and raw material is cheap and easy to get, safety and environmental protection.
2) reaction condition of the present invention is mild, and easy to operate, raw material is easy to get, yield is higher, is suitble to industrialized production.And technique
Step is simple, easy to operate, just with industrializing implementation.
Specific embodiment
Embodiment 1:
Step 1) is added 9.8g maleic anhydride, 9.2g toluene and 200ml methylene chloride into 1L there-necked flask, under mechanical stirring in
Cold bath is cooled to 0 DEG C, and 27g alchlor is then slowly added into reaction flask, is kept for 0-10 DEG C of temperature, finished, room temperature
It is stirred to react 4h or more, HPLC detection reaction is completed, reaction solution is poured into 500g ice water and is quenched, then with 500g ethyl acetate
Extraction, takes off dry solvent, dry yellow solid 16.2g, mp. 120.8-123.1 °C; 1H-NMR (400 MHz, CDCl3)
δ 8.00 (d, J=15.5 Hz, 1H), 7.92 (d, J=8.1 Hz, 2H),7.33 (d, J=8.1 Hz, 2H),
6.89 (d, J=15.5 Hz, 1H), 2.45 (s, 3H), yield 85.0%.
Step 2 is by 19.0g 4- oxo -4-(4- aminomethyl phenyl) -2- butenoic acid, 20.2g48% hydrobromic acid and 500g bis-
Chloroethanes is added in 1000mL reaction flask, and temperature rising reflux reaction after the completion of addition reaction, is stood, and cooling separates water phase, organic
It is added in reaction flask, adds 1.0g p-methyl benzenesulfonic acid, 10.0g ethyl alcohol, reflux water-dividing reacts 3h, and HPLC display has been reacted
At., stop reaction, cooling is added 200mL water into reaction flask and stirs 15min, and stratification separates organic phase, is concentrated, obtains
Yellow solid 26.33g, yield 88.0%.
Step 3) is by the bromo- 4- oxo -4-(4- aminomethyl phenyl of 23.9g3-)-ethyl butyrate and 65g ethyl alcohol, it is added to
In 500ml reaction flask, stirring and dissolving sequentially adds the sodium bicarbonate solution that 9.0g 2- amino -5- picoline He prepared
(15g+160g water) is stirred at room temperature reaction overnight, stops reaction, be then added 9.0gKOH, 300ml water, after temperature rising reflux 3h,
HPLC display reaction is completed, and acetic acid is added, is acidified to pH4-5, a large amount of solids is precipitated, filters, dry off-white powder
18.2g, purity 99.80%, 208.7-209.7 DEG C of fusing point, yield 81.3%.
Embodiment 2
19.6g maleic anhydride and 200g toluene are added into 1L there-necked flask for step 1), are cooled under mechanical stirring in cold bath
0 DEG C, it is then slowly added to 54g alchlor into reaction flask, is kept for 0-10 DEG C of temperature, finishes, be warming up to and reaction is stirred at room temperature
4h or more, HPLC detection reaction are completed, and reaction solution is poured into 500g ice water and is quenched, then with the extraction of 500g ethyl acetate, are taken off
Dry solvent, dry yellow solid 30.0g, mp. 121.3-123.2 °C; 1H-NMR (400 MHz, CDCl3) δ 8.00
(d, J=15.5 Hz, 1H), 7.92 (d, J=8.1 Hz, 2H),7.33 (d, J=8.1 Hz, 2H), 6.89 (d, J
=15.5 Hz, 1H), 2.45 (s, 3H), yield 78.7%.
Step 2 is by 19.0g 4- oxo -4-(4- aminomethyl phenyl) -2- butenoic acid, 18.3g20% hydrogen chloride methanol solution
It is added in 1000mL reaction flask with 500g toluene, temperature rising reflux reaction, after the reaction was completed, 200mL is added into reaction flask for cooling
Water stirs 15min, and stratification separates organic phase, is concentrated, obtains yellow solid 22.4g, yield 78.6%.
Step 3) is by the bromo- 4- oxo -4-(4- aminomethyl phenyl of 22.4g3-)-methyl butyrate and 60g ethyl alcohol, it is added to
In 500ml reaction flask, stirring and dissolving, the solution of potassium carbonate (10g for sequentially adding 9.0g 2- amino -5- picoline and preparing
+ 160g water), reaction is stirred at room temperature overnight, stops reacting, then addition 9.0g potassium hydroxide, 300ml water, after temperature rising reflux 3h,
HPLC display reaction is completed, and acetic acid is added, is acidified to pH4-5, a large amount of solids is precipitated, filters, dry off-white powder
18.0g, purity 99.80%, 208.5-209.8 DEG C of fusing point, yield 81.8%.
Embodiment 3:
Step 1) is added 19.6g maleic anhydride, 18.4g toluene and 200ml dichloroethanes into 1L there-necked flask, under mechanical stirring
It is cooled to 0 DEG C in cold bath, 27g alchlor is then slowly added into reaction flask, is kept for 0-10 DEG C of temperature, finished, room
Temperature is stirred to react 4h or more, and HPLC detection reaction is completed, reaction solution is poured into 500g ice water and is quenched, then with 500g acetic acid second
Ester extraction, takes off dry solvent, dry yellow solid 32.4g, mp. 120.8-123.1 °C; 1H-NMR (400 MHz,
CDCl3) δ 8.00 (d, J=15.5 Hz, 1H), 7.92 (d, J=8.1 Hz, 2H),7.33 (d, J=8.1 Hz,
2H), 6.89 (d, J=15.5 Hz, 1H), 2.45 (s, 3H), yield 85.0%.
Step 2 is by 19.0g 4- oxo -4-(4- aminomethyl phenyl) -2- butenoic acid, 27.9g50% hydroiodic acid solution and
200g dimethylbenzene is added in 1000mL reaction flask, and heating is reacted in 110-120 DEG C, after the completion of addition reaction, stands, cools down, point
Water phase out, it is organic to be added in reaction flask, add 1.0g p-methyl benzenesulfonic acid, 10.0g ethyl alcohol, in 110-120 DEG C of reaction 3h,
HPLC display reaction is completed.Stop reaction, cooling is added 200mL water into reaction flask and stirs 15min, and stratification has separated
Machine phase, concentration, obtains yellow solid 26.33g, yield 88.0%.
Step 3) is by the bromo- 4- oxo -4-(4- aminomethyl phenyl of 22.4g3-)-ethyl butyrate and 60g ethyl alcohol, it is added to
In 500ml reaction flask, stirring and dissolving sequentially adds the sodium carbonate liquor that 9.0g 2- amino -5- picoline He prepared
(8.5g+160g water) is stirred at room temperature reaction overnight, stops reaction, 8.0g sodium hydroxide, 300ml water, temperature rising reflux is then added
After 3h, HPLC display reaction is completed, and acetic acid is added, is acidified to pH4-5, a large amount of solids is precipitated, filters, dry off-white powder
18.0g, purity 99.80%, 208.5-209.8 DEG C of fusing point, yield 81.8%.
Claims (6)
1. a kind of preparation method of zolpidem acid, which comprises the following steps:
Toluene obtains 4- oxo -4-(4- methylbenzene with maleic anhydride progress Friedel-Crafts reaction to step 1) in the presence of a catalyst
Base) -2- butenoic acid (TBEA)；
Step 2) halogen acids carries out addition to the 4- oxo -4- p-methylphenyl -2- butenoic acid (TBEA) and obtains 3- halogen
Generation -4- oxo -4-(4- aminomethyl phenyl)-butyric acid (TBXA)；
Halogenated -4- oxo -4-(4- the aminomethyl phenyl of the step 3) 3-)-butyric acid (TBXA) be esterified to obtain with alcohol it is corresponding
Ester；
The corresponding ester of step 4) (6-methyl-2-that obtain 2-of the cyclization under alkali effect with 2- amino-5- picoline
To methylbenzene imidazoles [1,2-α] pyridine-3-yl) acetic acid esters (ZAC-A), it is then hydrolyzed to obtain zolpidem acid
(ZAC).
2. the preparation method of zolpidem acid according to claim 1, it is characterised in that: the step 1) specific steps and work
Skill parameter includes: that maleic anhydride and toluene are added in reaction flask, and solvent is added, and stirring and dissolving is slowly added to alchlor, instead
Answer 0.5-6 hours, pour into quenching reaction in ice water, then extracted, be concentrated to get 4- oxo -4-(4- aminomethyl phenyl) -2- fourth
Olefin(e) acid (TBEA)；Wherein, maleic anhydride: alchlor: toluene (molar ratio)=1:1~1.5:0.9~10；Reaction temperature is -20
~80 DEG C；Solvent includes for one of toluene, methylene chloride, dichloroethanes, carbon disulfide and nitrobenzene or a variety of；It is described to urge
Agent is lewis acid.
3. the preparation method of zolpidem acid according to claim 1, it is characterised in that: the specific steps of the step 2 and
Technological parameter includes: by 4- oxo -4-(4- aminomethyl phenyl) -2- butenoic acid (TBEA), solvent and halogen acids are added sequentially to instead
It answers in bottle, then temperature reaction, after the completion of addition reaction, continues the addition alcohol into system and be esterified to obtain the bromo- 4- oxo-of 3-
4-(4- aminomethyl phenyl)-butyrate；Wherein the halogen acids is hydrogen chloride, hydrogen bromide or hydrogen iodide or any molten of former three
Liquid；The alcohol is one of C1-C4 alcohol；4- oxo -4-(4- aminomethyl phenyl) -2- butenoic acid (TBEA): halogen acids: alcohol
(molar ratio) are as follows: 1:1.0~2.0:1.1-10；The solvent be methylene chloride, dichloroethanes, toluene and dimethylbenzene one kind or
It is a variety of；Reaction temperature is 50~120 DEG C.
4. the preparation method of zolpidem acid according to claim 1, it is characterised in that: alcohol described in the step 3) is
One of C1-C4 alcohol.
5. the preparation method of zolpidem acid according to claim 1, it is characterised in that: the specific steps of the step 4) and
Technological parameter includes: that corresponding ester is added in reaction flask, and stirring solvent dissolution is then added, 2- amino -5- is then added
Picoline and alkali, with the bromo- 4- oxo-4-(4- aminomethyl phenyl of 3-)-butyrate cyclization obtains 2-(6-methyl-2-is to first
Base benzene imidazoles [1,2-α] pyridine-3-yl) acetic acid esters, HPLC detect after the reaction was completed, add water heating hydrolysis, obtain
Product zolpidem acid；Wherein, the bromo- 4- oxo -4-(4- aminomethyl phenyl of 3-)-butyrate: 2- amino -5- picoline (molar ratio)
=1:0.9~1.2；Reaction temperature is 0~50 DEG C；The solvent is one of methanol, ethyl alcohol and isopropanol or a variety of；It is described
Alkali is one of sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus, sodium hydroxide and potassium hydroxide or a variety of.
6. the preparation method of zolpidem acid according to claim 1, it is characterised in that: the resulting 3- halogen of step 2
Generation -4- oxo -4-(4- aminomethyl phenyl)-butyric acid (TBXA) through separation or without isolation after carry out step 3) reaction.
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| CN111057053A (en) * | 2018-10-17 | 2020-04-24 | 复旦大学 | Preparation method of zolpidem |
| CN114380819A (en) * | 2020-10-22 | 2022-04-22 | 鲁南制药集团股份有限公司 | Zolpidem intermediate compound |
| CN114773337A (en) * | 2022-04-22 | 2022-07-22 | 诚弘制药(威海)有限责任公司 | Method for preparing zolpidem |
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