CN1323068C - Method for synthesizing N-benzyloxy-oxo-L-valine synthesizing method - Google Patents
Method for synthesizing N-benzyloxy-oxo-L-valine synthesizing method Download PDFInfo
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- CN1323068C CN1323068C CNB2005100378001A CN200510037800A CN1323068C CN 1323068 C CN1323068 C CN 1323068C CN B2005100378001 A CNB2005100378001 A CN B2005100378001A CN 200510037800 A CN200510037800 A CN 200510037800A CN 1323068 C CN1323068 C CN 1323068C
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- China
- Prior art keywords
- ethyl acetate
- temperature
- carbobenzoxy
- xie ansuan
- synthetic method
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 238000000034 method Methods 0.000 title claims abstract description 9
- 230000002194 synthesizing effect Effects 0.000 title abstract 4
- 229960004295 valine Drugs 0.000 title abstract 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 30
- 238000006243 chemical reaction Methods 0.000 claims abstract description 15
- 239000000243 solution Substances 0.000 claims abstract description 11
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000007788 liquid Substances 0.000 claims abstract description 7
- 238000010189 synthetic method Methods 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- 239000012266 salt solution Substances 0.000 claims description 4
- 238000005352 clarification Methods 0.000 claims description 3
- 238000004821 distillation Methods 0.000 claims description 3
- 238000012423 maintenance Methods 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 230000008901 benefit Effects 0.000 abstract description 4
- 238000000605 extraction Methods 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000002904 solvent Substances 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 2
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 abstract 4
- 238000011084 recovery Methods 0.000 abstract 3
- CANZBRDGRHNSGZ-NSHDSACASA-N (2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)OCC1=CC=CC=C1 CANZBRDGRHNSGZ-NSHDSACASA-N 0.000 abstract 1
- 239000012267 brine Substances 0.000 abstract 1
- 238000003889 chemical engineering Methods 0.000 abstract 1
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 abstract 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a synthesizing method for N-carbobenzoxy-L-valine in the technical field of chemical engineering. The present invention is mainly characterized in that carbobenzoxy chlorine is directly dropped in mixed liquid formed by dissolving L-valine in sodium hydroxide solutions; the temperature of reaction materials is cooled to be from 15 to 25 DEG C by brine ice without ensuring the original reaction condition of a temperature of 0 to 5 DEG C by reducing the temperature so as to save energy sources and reduce the cost. Ethyl acetate is used as an extraction solvent, and has the advantages of low toxicity, convenient sources, low cost and easy recovery. The recovery ratio of finished products is 138% measured by the L-valine and is one time higher than the recovery ratio recorded in literatures, so the economical benefit is increased. The synthesizing method has the advantages of compact process, economy, reasonableness, safe and easy operation and high productive efficiency, and is suitable for mass production.
Description
Technical field
The present invention relates to the synthetic method of a kind of N-carbobenzoxy-(Cbz) of chemical technology field-L-Xie Ansuan.
Background technology
N-carbobenzoxy-(Cbz)-L-Xie Ansuan is synthetic polypeptide, the critical materials of synthetic drugs, " the 3rd biochemical reagents of modern chemistry reagent handbook () disclose 22 gram L-Xie Ansuans have been dissolved in the sodium hydroxide of 95mL 2mol/L, the salt ice bath is cooled to 0 ℃, drip the Carbobenzoxy Chloride (excessive 10%) of 30mL 6.7mol/L, keep temperature of reaction at 0-5 ℃, the sodium hydroxide that drips 2mol/L is simultaneously kept PH=9, rise to room temperature after dropwising, stirred 2 hours, remove unreacted Carbobenzoxy Chloride with ether, to PH=3, use the ethyl acetate extracting again 3 times with hcl acidifying, dry, filter, concentrate, getting white solid 13.3 grams. this synthetic method has the following disadvantages: first, its temperature of reaction system is at 0-5 ℃, and the energy consumption that is used to lower the temperature is too big, has increased the cost of suitability for industrialized production.The second, remove in this step reaction of unreacted Carbobenzoxy Chloride, used extraction solvent is an ether.Ether toxicity is big, volatile, dangerous big, and operation has been brought inconvenience.The 3rd. product yield is 60.5% (in the L-Xie Ansuan), and yield is on the low side, and product cost is too high, is unfavorable for the commercialization sale.
Summary of the invention
Purpose of the present invention provides one can be fit to produce economical rationality, the synthetic method of N-carbobenzoxy-(Cbz)-L-Xie Ansuan that processing ease and yield are high in enormous quantities at existing N-carbobenzoxy-(Cbz)-L-Xie Ansuan synthetic method above shortcomings.
The objective of the invention is to be achieved through the following technical solutions, the synthetic method of a kind of N-carbobenzoxy-(Cbz)-L-Xie Ansuan, main raw material adopts Carbobenzoxy Chloride and L-Xie Ansuan, synthetic method comprises the L-Xie Ansuan is dissolved in the sodium hydroxide solution, dropping sodium solution in reaction process, equal 9 to keep reacting system PH value, it is characterized in that, described synthetic method also comprises: A, be dissolved in the mixed solution of sodium hydroxide solution at the L-Xie Ansuan, directly drip Carbobenzoxy Chloride, make temperature of charge maintain normal temperature; B, follow the tracks of reaction, when thin plate inclusion-free point, finish to react with thin plate; C, handling procedure; (1), be no less than twice, stay lower layer of water liquid with ethyl acetate extraction; (2), adding hydrochloric acid makes above-mentioned water liquid pH value equal 2; (3), be no less than twice, stay the upper strata ethyl acetate layer with ethyl acetate extraction; (4), use anhydrous sodium sulfate drying, make ethyl acetate layer clarification; (5), filter above-mentioned ethyl acetate clear liquor, underpressure distillation ethyl acetate; It is to adopt the icy salt solution cooling that temperature of charge maintains normal temperature, and the temperature maintenance that makes reaction system is at 15-25 ℃.
The present invention is dissolved at the L-Xie Ansuan and directly drips Carbobenzoxy Chloride in the mixed solution of sodium hydroxide solution, make the reaction mass temperature maintenance under 15-25 ℃ condition by the icy salt solution cooling, need not to guarantee original 0-5 ℃ reaction conditions by cooling, save the energy, reduce cost, the employing ethyl acetate is an extraction solvent, toxicity is little, convenient sources, cheap, reclaim easily, product yield of the present invention can reach 138% in the L-Xie Ansuan, exceed more than one times than document record yield, improved economic benefit, synthetic method craft of the present invention is succinct, be fit to produce in enormous quantities, economical rationality, operational safety is easy, the production efficiency height.
Embodiment
1, taking by weighing L-Xie Ansuan 117.5 grams is dissolved in the 450mL 2N sodium hydroxide solution;
2, take by weighing 170.6 gram Carbobenzoxy Chlorides and be added drop-wise in the above-mentioned mixed solution,, make temperature of charge maintain 15-25 ℃ with the icy salt solution cooling;
3, drip 620mL 2N sodium hydroxide solution in the process, equal 9 to keep reacting system PH value; Above chemical equation is with the chemical equation in " modern chemistry reagent handbook " described synthetic method;
4, follow the tracks of reaction with thin plate, when thin plate inclusion-free point, finish reaction;
5, handling procedure:
A: ethyl acetate extraction 2 times, stay lower layer of water liquid;
B: add hydrochloric acid and make above-mentioned water liquid pH value equal 2;
C: ethyl acetate extraction 2 times, stay the upper strata ethyl acetate layer;
D: the dry anhydrous sodium sulphate of using, the ethyl acetate clarification gets final product;
E: filter ethyl acetate, the underpressure distillation ethyl acetate;
F: dry to such an extent that product 162 restrains, yield is 137.9% (in the L-Xie Ansuan).
Claims (2)
1, the synthetic method of a kind of N-carbobenzoxy-(Cbz)-L-Xie Ansuan, main raw material adopts Carbobenzoxy Chloride and L-Xie Ansuan, synthetic method comprises the L-Xie Ansuan is dissolved in the sodium hydroxide solution, dropping sodium solution in reaction process, equal 9 to keep reacting system PH value, it is characterized in that described synthetic method also comprises:
A, be dissolved in the mixed solution of sodium hydroxide solution at the L-Xie Ansuan, directly drip Carbobenzoxy Chloride, temperature of charge maintains normal temperature;
B, follow the tracks of reaction, when thin plate inclusion-free point, finish to react with thin plate;
C, handling procedure: (1), be no less than twice with ethyl acetate extraction, stay lower layer of water liquid; (2), adding hydrochloric acid makes above-mentioned water liquid pH value equal 2; (3), be no less than twice, stay the upper strata ethyl acetate layer with ethyl acetate extraction; (4), use anhydrous sodium sulfate drying, make ethyl acetate layer clarification; (5), filter above-mentioned ethyl acetate clear liquor, underpressure distillation ethyl acetate.
2, the synthetic method of N-carbobenzoxy-(Cbz) according to claim 1-L-Xie Ansuan is characterized in that it is to adopt the icy salt solution cooling that described temperature of charge maintains normal temperature, and the temperature maintenance that makes reaction system is at 15-25 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100378001A CN1323068C (en) | 2005-02-06 | 2005-02-06 | Method for synthesizing N-benzyloxy-oxo-L-valine synthesizing method |
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|---|---|---|---|
| CNB2005100378001A CN1323068C (en) | 2005-02-06 | 2005-02-06 | Method for synthesizing N-benzyloxy-oxo-L-valine synthesizing method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1814586A CN1814586A (en) | 2006-08-09 |
| CN1323068C true CN1323068C (en) | 2007-06-27 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2005100378001A Expired - Fee Related CN1323068C (en) | 2005-02-06 | 2005-02-06 | Method for synthesizing N-benzyloxy-oxo-L-valine synthesizing method |
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| CN (1) | CN1323068C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108912016A (en) * | 2018-06-11 | 2018-11-30 | 广东肇庆星湖生物科技股份有限公司 | A method of preparing N- benzyloxy-oxo-L-valine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4293706A (en) * | 1980-06-19 | 1981-10-06 | Ppg Industries, Inc. | Preparation of N-benzyloxycarbonyl aspartic acid |
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2005
- 2005-02-06 CN CNB2005100378001A patent/CN1323068C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4293706A (en) * | 1980-06-19 | 1981-10-06 | Ppg Industries, Inc. | Preparation of N-benzyloxycarbonyl aspartic acid |
Non-Patent Citations (1)
| Title |
|---|
| N－苄氧羰基氨基酸配位萃取拆分外消旋苯丙氨酸 彭阳峰等，华东理工大学学报，第31卷第1期 2005 * |
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| Publication number | Publication date |
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| CN1814586A (en) | 2006-08-09 |
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