CN102249902B - Preparation method of 1-chloroformyl-2-ethoxy naphthalene crystal - Google Patents
Preparation method of 1-chloroformyl-2-ethoxy naphthalene crystal Download PDFInfo
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- CN102249902B CN102249902B CN2011101385258A CN201110138525A CN102249902B CN 102249902 B CN102249902 B CN 102249902B CN 2011101385258 A CN2011101385258 A CN 2011101385258A CN 201110138525 A CN201110138525 A CN 201110138525A CN 102249902 B CN102249902 B CN 102249902B
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- oxyethyl group
- chloroformyl
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- group naphthalene
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- 239000013078 crystal Substances 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- ZRVFFIXOCFUHDA-UHFFFAOYSA-N 2-ethoxynaphthalene-1-carbonyl chloride Chemical compound C1=CC=CC2=C(C(Cl)=O)C(OCC)=CC=C21 ZRVFFIXOCFUHDA-UHFFFAOYSA-N 0.000 title abstract 4
- 150000001263 acyl chlorides Chemical class 0.000 claims abstract description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000010992 reflux Methods 0.000 claims abstract description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 66
- 239000007788 liquid Substances 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000010792 warming Methods 0.000 claims description 8
- 239000003921 oil Substances 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 6
- -1 1-chloroformyl Chemical group 0.000 claims description 5
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000010703 silicon Substances 0.000 claims description 5
- 229910052710 silicon Inorganic materials 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 2
- 238000009413 insulation Methods 0.000 claims description 2
- 238000000034 method Methods 0.000 abstract description 13
- 239000006227 byproduct Substances 0.000 abstract description 6
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000003912 environmental pollution Methods 0.000 abstract description 3
- MYFBSSDLYGWAHH-UHFFFAOYSA-N 2-ethoxynaphthalene-1-carboxylic acid Chemical compound C1=CC=CC2=C(C(O)=O)C(OCC)=CC=C21 MYFBSSDLYGWAHH-UHFFFAOYSA-N 0.000 abstract 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 abstract 1
- 238000010438 heat treatment Methods 0.000 abstract 1
- 239000003208 petroleum Substances 0.000 abstract 1
- 239000000047 product Substances 0.000 description 11
- 238000012512 characterization method Methods 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000008025 crystallization Effects 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- 229960001775 nafcillin sodium Drugs 0.000 description 2
- OCXSDHJRMYFTMA-KMFBOIRUSA-M nafcillin sodium monohydrate Chemical compound O.[Na+].C1=CC=CC2=C(C(=O)N[C@@H]3C(N4[C@H](C(C)(C)S[C@@H]43)C([O-])=O)=O)C(OCC)=CC=C21 OCXSDHJRMYFTMA-KMFBOIRUSA-M 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Abstract
The invention discloses a preparation method of 1-chloroformyl-2-ethoxy naphthalene crystal. The method comprises the following steps of: directly dripping sulfoxide chloride into organic solution of 2-ethoxy-1-naphthoic acid, heating to a reflux temperature, and reacting to prepare acyl chloride solution; and adding one of n-hexane, petroleum ether and silyl ether serving as an extracting agent into the acyl chloride solution to separate out the 1-chloroformyl-2-ethoxy naphthalene crystal. The method is simple in production process and low in environmental pollution, a few reaction byproducts are reduced, the 1-chloroformyl-2-ethoxy naphthalene crystal has stable quality and high purity, and the method is suitable for industrialized production.
Description
Technical field
The present invention relates to the preparation method of the preparation method of a kind of 1-chloroformyl-2-oxyethyl group naphthalene, particularly 1-chloroformyl-2-oxyethyl group naphthalene crystal.The main application of this compound is the intermediate as synthetic semisynthetic antibiotics Nafcillin sodium.
Background technology
1-chloroformyl-2-oxyethyl group naphthalene is a kind of important medicine intermediate, is mainly used in synthetic Nafcillin sodium etc.Synthetic method bibliographical information about 1-chloroformyl-2-oxyethyl group naphthalene is less, and the relevant method for preparing 1-chloroformyl-2-oxyethyl group naphthalene solid crystal yet there are no bibliographical information at present.
S.SIDNEY (J.Pharm.Sci.1963; 763), CN 101456869B and CN 101781315A related to the synthetic of 1-chloroformyl-2-oxyethyl group naphthalene 52 (8):; in these synthetic methods; all used catalyzer; S.SIDNEY (J.Pharm.Sci.1963; 52 (8): 763) and the acyl chlorides liquid for preparing of CN 101456869B do not separate out solid crystal; be directly used in the next step, after acyl chlorides liquid concentrating under reduced pressure evaporate to dryness will prepare by CN 101781315A again with after organic solvent dissolution for the next step.The main drawback of above method is the by product (for the dark oil thing) of acyl chlorides quality and productive rate that all can exert an influence in preparing the process of acyl chlorides, and the by product that reaction produces is not effectively processed, and causes the acyl chlorides prepared purity lower.
Summary of the invention
The purpose of this invention is to provide a kind of production process simple, byproduct of reaction is few, cost-saving, the preparation method of steady quality, 1-chloroformyl that purity is high-2-oxyethyl group naphthalene crystal.
The preparation method of 1-chloroformyl of the present invention-2-oxyethyl group naphthalene crystal comprises the following steps:
1) under the catalyst-free effect, in the organic solution of 2-oxyethyl group-1-naphthoic acid, directly drip sulfur oxychloride, be warming up to reflux temperature and carry out back flow reaction, prepare acyl chlorides liquid;
2) to adding a kind of as extraction agent in normal hexane, sherwood oil or silicon ether in the acyl chlorides liquid of step 1), make to separate out 1-chloroformyl-2-oxyethyl group naphthalene solid crystal.
The concrete preparation method of above-mentioned 1-chloroformyl-2-oxyethyl group naphthalene crystal is:
1) under the catalyst-free effect, mol ratio according to 2-oxyethyl group-1-Nai Jia Suan ︰ sulfur oxychloride=1 ︰ 1.0～1.2, in the organic solution of 2-oxyethyl group-1-naphthoic acid, directly drip sulfur oxychloride, be warming up to reflux temperature back flow reaction 1.5～3h, prepare acyl chlorides liquid;
2) at 20～35 ℃ of temperature, to adding a kind of as extraction agent in normal hexane, sherwood oil or silicon ether in the acyl chlorides liquid of step 1), crystallize out, be cooled to 10～20 ℃ of insulation 0.5～1h, obtains 1-chloroformyl-2-oxyethyl group naphthalene solid crystal.
Wherein, described is a kind of of methylene dichloride, ethylene dichloride, chloroform, trichloroethane, methylene bromide or tetrahydrofuran (THF) for the organic solvent that dissolves 2-oxyethyl group-1-naphthoic acid, and its weight is 2～5 times of 2-oxyethyl group-1-naphthoic acid weight.
The extraction agent volumetric usage added be described acyl chlorides liquid long-pending 1/3～1/2.
The preparation method of 1-chloroformyl of the present invention-2-oxyethyl group naphthalene crystal compared with the prior art; in the building-up process of acyl chlorides liquid, cut off and induced the catalyzer that generates dark oil thing by product; after being finished, acyl chloride reaction can directly add the target product that extraction agent is separated out the high purity good stability; avoid prior art must first separate the drawback that dark oil thing by product just can obtain up-to-standard 1-chloroformyl-2-oxyethyl group naphthalene crystal, also alleviated simultaneously operator's labour intensity.The more important thing is; because the toxicity of acylating agent sulfur oxychloride is large; prior art can not closed-loop operation when separating impurity, and temperature of reaction is high, and the hydrogen chloride gas that excessive acylating agent and reaction produce is diffused in air; increased the weight of environmental pollution; give that operator are healthy causes very big harm, the whole technological process of the present invention all can be carried out under relatively airtight condition, and environmental pollution is less; and simple to operate, be more suitable for suitability for industrialized production.
Embodiment
Embodiment 1.
In dry retort, add 100kg methylene dichloride, 40kg2-oxyethyl group-1-naphthoic acid, under room temperature, add the 22kg sulfur oxychloride, be warming up to 60 ℃ of back flow reaction 3h.Be down to 35 ℃, add normal hexane 26kg, have mass crystallization to separate out, after adding, be cooled to 20 ℃ and continue insulated and stirred 30min.Rejection filter, at 40～50 ℃ of vacuum-drying 3h, obtain 1-chloroformyl-2-oxyethyl group naphthalene white crystals, yield 90.7%, and the HPLC method is measured content 99.5%.
75 ℃ of product fusing point test values, conform to 72～75 ℃ of bibliographical information values; Results of elemental analyses is C 66.50%; H 4.68%; Cl 15.13%; O 13.69%, with the calculated value C 66.53% of 1-chloroformyl-2-oxyethyl group naphthalene; H 4.72%; Cl 15.11%; O 13.64% conforms to substantially.The product that above characterization result proof obtains is 1-chloroformyl-2-oxyethyl group naphthalene.
Embodiment 2.
In dry retort, add 150kg methylene dichloride, 40kg2-oxyethyl group-1-naphthoic acid, under room temperature, add the 23kg sulfur oxychloride, be warming up to 59 ℃ of back flow reaction 3h.Be down to 34 ℃, add normal hexane 30kg, have mass crystallization to separate out, after adding, be cooled to 20 ℃ and continue insulated and stirred 30min.Rejection filter, at 40～50 ℃ of vacuum-drying 3h, obtain 1-chloroformyl-2-oxyethyl group naphthalene white crystals, yield 90.7%, and the HPLC method is measured content 99.5%.
74.5 ℃ of product fusing point test values, conform to 72～75 ℃ of bibliographical information values; Results of elemental analyses is C 66.51%; H 4.73%; Cl 15.08%; O 13.68%, with the calculated value C 66.53% of 1-chloroformyl-2-oxyethyl group naphthalene; H 4.72%; Cl 15.11%; O 13.64% conforms to substantially.The product that above characterization result proof obtains is 1-chloroformyl-2-oxyethyl group naphthalene.
Embodiment 3.
In dry retort, add 200kg ethylene dichloride, 40kg2-oxyethyl group-1-naphthoic acid, under room temperature, add the 24.2kg sulfur oxychloride, be warming up to 70 ℃ of back flow reaction 2h.Be down to 30 ℃, add sherwood oil 35kg, have mass crystallization to separate out, after adding, be cooled to 16 ℃ and continue insulated and stirred 30min.Rejection filter, at 40～50 ℃ of vacuum-drying 3h, obtain 1-chloroformyl-2-oxyethyl group naphthalene white crystals, yield 91%, and the HPLC method is measured content 99.1%.
75 ℃ of product fusing point test values, conform to 72～75 ℃ of bibliographical information values; Results of elemental analyses is C 66.49%; H 4.70%; Cl 15.09%; O 13.72%, with the calculated value C 66.53% of 1-chloroformyl-2-oxyethyl group naphthalene; H 4.72%; Cl 15.11%; O 13.64% conforms to substantially.The product that above characterization result proof obtains is 1-chloroformyl-2-oxyethyl group naphthalene.
Embodiment 4.
In dry retort, add 160kg methylene bromide, 40kg2-oxyethyl group-1-naphthoic acid, under room temperature, add the 25.3kg sulfur oxychloride.Be warming up to 76 ℃ of back flow reaction 1.5h.Be down to 25 ℃, add silicon ether 30kg, have mass crystallization to separate out, after adding, be cooled to 13 ℃ and continue insulated and stirred 30min.Rejection filter, at 40～50 ℃ of vacuum-drying 3h, obtain 1-chloroformyl-2-oxyethyl group naphthalene white crystals, yield 91.8%, and the HPLC method is measured content 99.1%.
75 ℃ of product fusing point test values, conform to 72～75 ℃ of bibliographical information values; Results of elemental analyses is C 66.50%; H 4.76%; Cl 15.10%; O 13.64%, with the calculated value C 66.53% of 1-chloroformyl-2-oxyethyl group naphthalene; H 4.72%; Cl 15.11%; O 13.64% conforms to substantially.The product that above characterization result proof obtains is 1-chloroformyl-2-oxyethyl group naphthalene.
Embodiment 5.
In dry retort, add 200kg methylene bromide, 40kg2-oxyethyl group-1-naphthoic acid, under room temperature, add the 25.3kg sulfur oxychloride.Be warming up to 76 ℃ of back flow reaction 1.5h; be down to 20 ℃; add silicon ether 50kg; there is mass crystallization to separate out, after adding, be cooled to 10 ℃ and continue insulated and stirred 30min, rejection filter; at 40～50 ℃ of vacuum-drying 3h; obtain 1-chloroformyl-2-oxyethyl group naphthalene white crystals, yield 92%, the HPLC method is measured content 98.7%.
74 ℃ of product fusing point test values, conform to 72～75 ℃ of bibliographical information values; Results of elemental analyses is C 66.55%; H 4.71%; Cl 15.08%; O 13.66%, with the calculated value C 66.53% of 1-chloroformyl-2-oxyethyl group naphthalene; H 4.72%; Cl 15.11%; O 13.64% conforms to substantially.The product that above characterization result proof obtains is 1-chloroformyl-2-oxyethyl group naphthalene.
Claims (3)
1.1-the preparation method of chloroformyl-2-oxyethyl group naphthalene crystal, the steps include:
1) under the catalyst-free effect, mol ratio according to 2-oxyethyl group-1-Nai Jia Suan ︰ sulfur oxychloride=1 ︰ 1.0～1.2, in the organic solution of 2-oxyethyl group-1-naphthoic acid, directly drip sulfur oxychloride, be warming up to reflux temperature back flow reaction 1.5～3h, prepare acyl chlorides liquid;
2) at 20～35 ℃ of temperature, to adding a kind of as extraction agent in normal hexane, sherwood oil or silicon ether in the acyl chlorides liquid of step 1), crystallize out, be cooled to 10～20 ℃ of insulation 0.5～1h, obtains 1-chloroformyl-2-oxyethyl group naphthalene solid crystal.
2. the preparation method of 1-chloroformyl according to claim 1-2-oxyethyl group naphthalene crystal; it is characterized in that described is a kind of of methylene dichloride, ethylene dichloride, chloroform, trichloroethane, methylene bromide or tetrahydrofuran (THF) for the organic solvent that dissolves 2-oxyethyl group-1-naphthoic acid, and its weight is 2～5 times of 2-oxyethyl group-1-naphthoic acid weight.
3. the preparation method of 1-chloroformyl according to claim 1-2-oxyethyl group naphthalene crystal, the volumetric usage that it is characterized in that described extraction agent be acyl chlorides liquid long-pending 1/3～1/2.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2951839A (en) * | 1959-07-15 | 1960-09-06 | Doyle Frank Peter | Synthetic penicillins |
| US3773757A (en) * | 1971-10-01 | 1973-11-20 | Pfizer | Process for the preparation of alpha-carboxyarylmethyl-and alpha-carboaryloxy-arylmethyl penicillins |
| CN101456869A (en) * | 2008-12-30 | 2009-06-17 | 华北制药集团山西博康药业有限公司 | Synthetic method of nafcillin sodium |
| CN101906033A (en) * | 2010-08-30 | 2010-12-08 | 天津市化学试剂研究所 | Preparation method of m-methyl benzoyl formyl chloride |
-
2011
- 2011-05-26 CN CN2011101385258A patent/CN102249902B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2951839A (en) * | 1959-07-15 | 1960-09-06 | Doyle Frank Peter | Synthetic penicillins |
| US3773757A (en) * | 1971-10-01 | 1973-11-20 | Pfizer | Process for the preparation of alpha-carboxyarylmethyl-and alpha-carboaryloxy-arylmethyl penicillins |
| CN101456869A (en) * | 2008-12-30 | 2009-06-17 | 华北制药集团山西博康药业有限公司 | Synthetic method of nafcillin sodium |
| CN101906033A (en) * | 2010-08-30 | 2010-12-08 | 天津市化学试剂研究所 | Preparation method of m-methyl benzoyl formyl chloride |
Non-Patent Citations (2)
| Title |
|---|
| Sidney S.Walkenstein等.You have full text access to this contentAbsorption, metabolism, and excretion of the semisynthetic penicillin 6-(2-ethoxy-1-naphthamido)penicillanic acid (nafcillin).《Journal of Pharmaceutical Sciences》.1963,第52卷(第8期), |
| You have full text access to this contentAbsorption, metabolism, and excretion of the semisynthetic penicillin 6-(2-ethoxy-1-naphthamido)penicillanic acid (nafcillin);Sidney S.Walkenstein等;《Journal of Pharmaceutical Sciences》;19630831;第52卷(第8期);第763-767页 * |
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Effective date of registration: 20201119 Address after: No.8, Industrial Avenue, furniture base, Longling Industrial Park, Nankang District, Ganzhou City, Jiangxi Province Patentee after: LONCH GROUP JIANGXI PHARMACEUTICAL Co.,Ltd. Address before: 100176 No.1, dize North Street, Beijing Economic and Technological Development Zone, Daxing District, Beijing Patentee before: Beijing shengkejia Electronic Co.,Ltd. |