CN103848750A - Method for preparing alpha-cycloalanine - Google Patents
Method for preparing alpha-cycloalanine Download PDFInfo
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- CN103848750A CN103848750A CN201410137290.4A CN201410137290A CN103848750A CN 103848750 A CN103848750 A CN 103848750A CN 201410137290 A CN201410137290 A CN 201410137290A CN 103848750 A CN103848750 A CN 103848750A
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- 238000000034 method Methods 0.000 title abstract description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000004471 Glycine Substances 0.000 claims abstract description 5
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims abstract description 4
- 230000032050 esterification Effects 0.000 claims abstract description 3
- 238000005886 esterification reaction Methods 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 18
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 claims description 12
- -1 Methyl benzenesulfonyl Chemical group 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 claims description 9
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ROBXZHNBBCHEIQ-BYPYZUCNSA-N ethyl (2s)-2-aminopropanoate Chemical compound CCOC(=O)[C@H](C)N ROBXZHNBBCHEIQ-BYPYZUCNSA-N 0.000 claims description 5
- 238000010189 synthetic method Methods 0.000 claims description 5
- LLCHQRKZFHWNRT-UHFFFAOYSA-N C(C)C1=C(C([N+](C)(C)CCCCCCCCCCCCCCCC)(CC)CC)C=CC=C1 Chemical compound C(C)C1=C(C([N+](C)(C)CCCCCCCCCCCCCCCC)(CC)CC)C=CC=C1 LLCHQRKZFHWNRT-UHFFFAOYSA-N 0.000 claims description 3
- 230000031709 bromination Effects 0.000 claims description 3
- 238000005893 bromination reaction Methods 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 239000003444 phase transfer catalyst Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 abstract 1
- 238000005804 alkylation reaction Methods 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 6
- 230000035484 reaction time Effects 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 206010004954 Birth trauma Diseases 0.000 description 1
- 241000255789 Bombyx mori Species 0.000 description 1
- 208000019743 Cranial nerve injury Diseases 0.000 description 1
- MQIUGAXCHLFZKX-UHFFFAOYSA-N Di-n-octyl phthalate Natural products CCCCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCCC MQIUGAXCHLFZKX-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000009360 aquaculture Methods 0.000 description 1
- 244000144974 aquaculture Species 0.000 description 1
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 1
- BJQHLKABXJIVAM-UHFFFAOYSA-N bis(2-ethylhexyl) phthalate Chemical compound CCCCC(CC)COC(=O)C1=CC=CC=C1C(=O)OCC(CC)CCCC BJQHLKABXJIVAM-UHFFFAOYSA-N 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
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Abstract
The invention relates to a method for synthesizing alpha-cycloalanine. The method comprises the steps of performing esterification on glycine serving as a raw material, synthesizing esterified product from the former step with p-benzene sulfonyl chloride, performing alkylation reaction on the synthesized product from the former step and 1,2-dibromoethane, and finally hydrolyzing to obtain a product. The method has the advantages of low process pollution, high yield, good purity, low cost and the like, is simple to operate and is a process suitable for industrialized production.
Description
Technical field
The invention belongs to technical field of organic synthesis, be specifically related to a kind of preparation method of α-ring L-Ala.
Background technology
α-ring L-Ala is the extraordinary amino acid of a kind of natural non-albumen, and on medicine and food, purposes is very large.ACC can prevent and treat senile dementia, protection Cranial nerve injury as birth trauma and the effect such as hypotensive; In aquaculture, can regulate and control silkworm protein biology synthetic, regulation and control laying rate of poultry etc.; Cereal is had to good adjusting and controlling growth effect simultaneously, and there is sterilization, the effect such as antitumor.But synthetic is not very simple, raw material is easy to get, mild condition, the simple synthetic method of method are just more difficult.
The synthetic method of report is few at home at present, mostly also is laboratory preparation abroad, and raw material is not easy to obtain, pollute greatly, or severe reaction conditions, yield is very low.Patent US5569781 A1 report for raw material, generates needed product with hydrogenchloride, sodium hydroxide, ammonia react with 1,1-cyclopropyl dioctyl phthalate dimethyl ester, generates isomer simultaneously, affects productive rate.
Patent US4298760 A1 uses raw material through reacting in reporting, use 1,2-ethylene dichloride finally to generate product simultaneously, but the middle hexamethylphosphoramide using, n-Butyl Lithium occurs being fine in testing, but amplifying generation, will increase production cost.
Logusch, EW(Tetrahedron Letters, 1986, the first roll, 27, the 49 pages, 5935-5938) once reported: take 1-phthalimide base-1-ethylene-acetic acid methyl esters as raw material, under the condition of the logical heating installation of hydrogenchloride, react, obtain ACC.Although such reaction is a lot, there is a common shortcoming, raw material is difficult to obtain.
Although some experiment at present can be synthesized α-ring L-Ala, extensive generate extremely scarce, finds a high efficiency, pollutes the concrete significance of little, to be expected to expanding production synthetic method.
Summary of the invention
The object of the present invention is to provide a kind of raw material to be easy to get, to pollute the synthetic route little, income is high.
α-ring L-Ala synthetic method of the present invention, is characterized in that by glycine be raw material, elder generation and ethyl esterification, then with synthetic to benzene sulfonyl chloride, then carry out alkylated reaction with glycol dibromide, finally hydrolysis, obtains product, overall yield 70%～85%.
Below α-ring L-Ala syntheti c route of the present invention is described in detail:
The preparation of glycine ethyl ester of the present invention, it is prepared and obtained by glycine and ethanol, catalyzer comprises p-methyl benzene sulfonic chloride, SOCl
2, H Cl gas, dense H
2sO
4deng, being preferable over p-methyl benzene sulfonic chloride, solvent comprises and ethanol, methyl alcohol, THF etc. is preferable over ethanol, and volume doubly measures 8～10, and temperature of reaction is preferable over 70～85 ℃, and more preferably in 78～80 ℃, the reaction times is preferable over 1～4h, more preferably in 2～3h.
In the preparation of (N-is to Methyl benzenesulfonyl) of the present invention glycine ethyl ester, react with p-methyl benzene sulfonic chloride (1.0～1.1eq) with glycine ethyl ester, under highly basic catalysis, highly basic is preferable over sodium alkoxide, sodium hydride, NaOH etc., more preferably in NaOH (1.2～1.5eq), use water as solvent, volume doubly measures 5～6, and temperature of reaction is preferable over 40～55 ℃, more preferably in 45～50 ℃, reaction times is preferable over 0.5～2h, more preferably in 1～1.5h.
In the preparation of (N-is to Methyl benzenesulfonyl) of the present invention ring alanine ethyl ester, 1,2-ethylene dibromide (1.4～1.5eq) reacts with above-mentioned reaction product, under alkaline condition, react, be preferable over NaOH (2Nmol), solvent is preferable over acetone, Virahol, toluene, more preferably in acetone, volume doubly measures 5～6, phase-transfer catalyst is preferable over bromination triethyl hexadecyldimethyl benzyl ammonium, and temperature of reaction is preferable over 40～50 ℃, more preferably in 42～45 ℃, reaction times is preferable over 3～6h, more preferably in 4～5h.
In the preparation of the α-ring L-Ala described in this reaction, above-mentioned reactant and water generation hydrolysis reaction, carry out under acidic conditions, is preferable over HCl.Solvent is preferable over ethanol, and volume doubly measures 5～6, and temperature of reaction is preferable over 70～85 ℃, and more preferably, in 75～80 ℃, the reaction times is preferable over 10～13h, more preferably in 11～12h.
The advantage of technique of the present invention: raw material is easy to get, reaction conditions is not harsh, and obviously reduces cost, is applicable to expanding production.
?
Accompanying drawing explanation
Accompanying drawing is α-ring L-Ala preparation method's of the present invention reaction scheme.
Embodiment
Below embodiments of the invention are elaborated: the present embodiment is implemented under take technical solution of the present invention as prerequisite, provided at length embodiment and process, but protection scope of the present invention is not limited to following embodiment.
Embodiment 1
The preparation of glycine ethyl ester
Glycine 20g, ethanol 160 ~ 200ml, in being furnished with the 250ml there-necked flask of thermometer, being warming up to 80 ℃ of temperature controls and refluxing, and adds p-methyl benzene sulfonic chloride 55g in batches, reaction 2.5h.Reaction finishes, and underpressure distillation is inhaled crystalline substance for 0 ~ 4 ℃, filters, and dries, and obtains the about 22g of product.
Embodiment 2
The preparation of (N-is to Methyl benzenesulfonyl) glycine ethyl ester
NaOH9.5g is put into the 250ml there-necked flask of being furnished with thermometer, be dissolved in 100 ~ 120ml water, add p-methyl benzene sulfonic chloride 42g, add 20g glycine ethyl ester in batches, 50 ℃ of temperature controls, reaction 1.5h.Reaction finishes to adjust pH value to 7, extracts organic phase condensing crystal by ethyl acetate.Filter, dry, obtain the about 45g of product.
Embodiment 3
The preparation of (N-is to Methyl benzenesulfonyl) ring alanine ethyl ester
Preparation NaOH concentration 2mol/L, ice bath stirs, and claims in addition (N-is to Methyl benzenesulfonyl) glycine ethyl ester 20g to put into the 250ml there-necked flask of being furnished with thermometer, add acetone 100 ~ 120ml, be cooled to 0 ~ 5 ℃, then the NaOH solution for preparing cooling is simultaneously added in there-necked flask, again by bromination triethyl hexadecyldimethyl benzyl ammonium 18g, 45 ℃ of temperature controls, the about 4.5h of stirring reaction, reaction finishes, layering extraction, organic phase is concentrated dry, and solid is dried, weigh, obtain the about 18g of product.
Embodiment 4
The preparation of α-ring L-Ala
(N-is to Methyl benzenesulfonyl) ring alanine ethyl ester takes 20g and puts into there-necked flask, is dissolved in the ethanol of 100 ~ 120ml, passes into HCl gas, 80 ℃ of back flow reaction, and reaction times 11h, reaction finishes.Concentrated dry, obtain solid, dry, obtain the about 6g of α-ring L-Ala.
Claims (6)
1. α-ring L-Ala synthetic method of the present invention, is characterized in that by glycine esterification, more synthetic with p-methyl benzene sulfonic chloride, then carries out alkylated reaction with glycol dibromide, and finally hydrolysis, obtains product.
2. the preparation method of glycine ethyl ester according to claim 1, is characterized in that: the catalyzer of the first step reaction comprises p-methyl benzene sulfonic chloride, SOCl
2, H Cl gas, dense H
2sO
4deng, be preferable over p-methyl benzene sulfonic chloride.
3. the preparation method of (N-is to Methyl benzenesulfonyl) according to claim 2 glycine ethyl ester, it is characterized in that: second step reacts under highly basic catalysis, highly basic is preferable over sodium alkoxide, sodium hydride, NaOH etc., more preferably in NaOH (1.2～1.5eq).
4. the preparation method of (N-is to Methyl benzenesulfonyl) according to claim 3 ring alanine ethyl ester, is characterized in that: three-step reaction solvent is preferable over acetone, Virahol, toluene, and more preferably in acetone, volume doubly measures 5～6.
5. the preparation method of (N-is to Methyl benzenesulfonyl) according to claim 4 ring alanine ethyl ester, is characterized in that: three-step reaction phase-transfer catalyst is preferable over bromination triethyl hexadecyldimethyl benzyl ammonium.
6. the preparation method of α-ring L-Ala according to claim 5, is characterized in that: second step reaction, for carrying out under acidic conditions, is preferable over HCl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410137290.4A CN103848750B (en) | 2014-04-08 | 2014-04-08 | A kind of preparation method about α-ring alanine |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410137290.4A CN103848750B (en) | 2014-04-08 | 2014-04-08 | A kind of preparation method about α-ring alanine |
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| Publication Number | Publication Date |
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| CN103848750A true CN103848750A (en) | 2014-06-11 |
| CN103848750B CN103848750B (en) | 2016-08-17 |
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|---|---|---|---|
| CN201410137290.4A Active CN103848750B (en) | 2014-04-08 | 2014-04-08 | A kind of preparation method about α-ring alanine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105061288A (en) * | 2015-08-07 | 2015-11-18 | 武汉华素康生物科技有限公司 | Compound and preparation method therefore and application thereof |
| CN110483363A (en) * | 2019-08-06 | 2019-11-22 | 吉林大学珠海学院 | A kind of preparation method of tryptophan esters hydrochloride |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4298760A (en) * | 1980-08-14 | 1981-11-03 | Zoecon Corporation | Process for preparing 1-aminocyclopropane-1-carboxylic acid |
| CN1239092A (en) * | 1998-06-17 | 1999-12-22 | 浙江省医学科学院 | Process for synthesizing 1-aminocyclopropane-1-carboxylic acid |
-
2014
- 2014-04-08 CN CN201410137290.4A patent/CN103848750B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4298760A (en) * | 1980-08-14 | 1981-11-03 | Zoecon Corporation | Process for preparing 1-aminocyclopropane-1-carboxylic acid |
| CN1239092A (en) * | 1998-06-17 | 1999-12-22 | 浙江省医学科学院 | Process for synthesizing 1-aminocyclopropane-1-carboxylic acid |
Non-Patent Citations (1)
| Title |
|---|
| 张漫波等: "对甲苯磺酰甘氨酸甲基酯的合成及晶体结构", 《广西师范大学学报(自然科学版)》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105061288A (en) * | 2015-08-07 | 2015-11-18 | 武汉华素康生物科技有限公司 | Compound and preparation method therefore and application thereof |
| CN110483363A (en) * | 2019-08-06 | 2019-11-22 | 吉林大学珠海学院 | A kind of preparation method of tryptophan esters hydrochloride |
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| CN103848750B (en) | 2016-08-17 |
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Denomination of invention: A preparation method of a - cycloalanine Effective date of registration: 20201210 Granted publication date: 20160817 Pledgee: Bank of China Limited by Share Ltd. Luohe branch Pledgor: WUYANG WEISEN BIOMEDICAL Co.,Ltd. Registration number: Y2020980009103 |
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Date of cancellation: 20211125 Granted publication date: 20160817 Pledgee: Bank of China Limited by Share Ltd. Luohe branch Pledgor: WUYANG WEISEN BIOMEDICAL CO.,LTD. Registration number: Y2020980009103 |
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Denomination of invention: About a- Preparation method of cycloalanine Effective date of registration: 20211129 Granted publication date: 20160817 Pledgee: Bank of China Limited by Share Ltd. Luohe branch Pledgor: WUYANG WEISEN BIOMEDICAL CO.,LTD. Registration number: Y2021980013477 |
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