CN106187795A - A kind of synthetic method of D Phenylglycine methyl ester - Google Patents
A kind of synthetic method of D Phenylglycine methyl ester Download PDFInfo
- Publication number
- CN106187795A CN106187795A CN201610526124.2A CN201610526124A CN106187795A CN 106187795 A CN106187795 A CN 106187795A CN 201610526124 A CN201610526124 A CN 201610526124A CN 106187795 A CN106187795 A CN 106187795A
- Authority
- CN
- China
- Prior art keywords
- methyl ester
- sulphuric acid
- synthetic method
- concentrated sulphuric
- addition
- 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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- 238000010189 synthetic method Methods 0.000 title claims abstract description 9
- BHFLUDRTVIDDOR-MRVPVSSYSA-N methyl (2r)-2-amino-2-phenylacetate Chemical group COC(=O)[C@H](N)C1=CC=CC=C1 BHFLUDRTVIDDOR-MRVPVSSYSA-N 0.000 title abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 21
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 235000011149 sulphuric acid Nutrition 0.000 claims abstract description 11
- 239000001117 sulphuric acid Substances 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000003054 catalyst Substances 0.000 claims abstract description 3
- 238000001816 cooling Methods 0.000 claims abstract description 3
- 150000004702 methyl esters Chemical class 0.000 claims description 12
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims 1
- 235000011114 ammonium hydroxide Nutrition 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 abstract description 13
- 229910021529 ammonia Inorganic materials 0.000 abstract description 9
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 abstract 2
- 238000000034 method Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- -1 methyl ester hydrochloride Chemical class 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000010612 desalination reaction Methods 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 description 2
- 229960005361 cefaclor Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010033078 Otitis media Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- FLKYBGKDCCEQQM-WYUVZMMLSA-M cefazolin sodium Chemical compound [Na+].S1C(C)=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 FLKYBGKDCCEQQM-WYUVZMMLSA-M 0.000 description 1
- 229960003408 cefazolin sodium Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000000686 essence Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002148 esters Chemical class 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
- 208000015181 infectious disease Diseases 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses the synthetic method of a kind of D Phenylglycine methyl ester, comprise the steps: 1) reactor adds methanol and D phenylglycine, it is cooled to 10 15 DEG C, it is slowly added dropwise into catalyst concentrated sulphuric acid wherein, the addition of concentrated sulphuric acid is 1:20 21 with the mass ratio of D phenylglycine, and the rate of addition of concentrated sulphuric acid is 1 5kg/h；2) after completion of dropwise addition, being warmed up to 60 70 DEG C and react, after reaction terminates, be concentrated into pulpous state through cooling, add water, regulate pH to 7.5 8.0 with ammonia, crystallizing and drying obtains product D Phenylglycine methyl ester.Reaction temperature of the present invention is gentleer, and route succinctly operates safe and simple.
Description
Technical field
The invention belongs to chemosynthesis technical field, be specifically related to the synthetic method of a kind of D-PG methyl ester.
Background technology
D-PG methyl ester be the synthesis of cefaclor and the important intermediate of ammonia benzyl, cefaclor and ammonia benzyl be semi-synthetic
Second generation cephalosporin, antimicrobial spectrum and antibacterial activity are similar to cefazolin sodium, be mainly used in treat otitis media, lower respiratory tract sense
Dye, urinary tract infection, skin and skin structure infections, can suppress all hemophilus influenzas, including the bacterium to ampicillin-resistant
Strain.
The synthesis following synthetic route of patent report:
Though this technique step is simple, but end product is D-PG methyl ester hydrochloride, synthesis cephalo Lip river gram and ammonia
Benzyl needs desalination, brings loaded down with trivial details technique to follow-up synthesis, so low cost obtains D-PG methyl ester and the tool dissociated
Commercially valuable.
Summary of the invention
The present invention provides a kind of method synthesizing D-PG methyl ester, and simple to operate, the feature of environmental protection is good, and yield is high, and not
Need desalination.
In order to solve the problems referred to above, the technical solution adopted in the present invention is such that a kind of D-PG methyl ester
Synthetic method, comprises the steps:
1) reactor adds methanol and D-PG, be cooled to 10-15 DEG C, be slowly added dropwise into catalyst dense wherein
Sulphuric acid, the addition of concentrated sulphuric acid and the mass ratio of D-PG are 1:20-21, and the rate of addition of concentrated sulphuric acid is 1-5kg/h；
2) after completion of dropwise addition, it is warmed up to 60-70 DEG C and reacts, after reaction terminates, be concentrated into pulpous state through cooling, add
Water, regulates pH to 7.5-8.0 with ammonia, and crystallizing and drying obtains product D-PG methyl ester.
Preferably, step 1) described in methanol and the mol ratio of D-PG be 65-75:1.
Preferably, step 2) in, during concentration, temperature is 40 DEG C, and pressure is-0.085MPa.
Involved reaction equation is as follows:
The synthetic method of D-PG methyl ester of the present invention, relative to prior art, has the advantage that
It is 85-90% that the esterification of the most traditional chlorinated sulfoxide obtains the yield of D-PG methyl ester hydrochloride, and because has big
The acid existence of amount, D-PG impurities left is at least more than 1%, and the product purity obtained only has 98-99%, and the present invention
Yield can be made to bring up to 90-95%, and product purity reaches more than 99%.
The most with low cost: the raw material used in the method for the invention is all basic material that is cheap, that be readily available.
3. safety: reaction temperature is gentleer, easily realizes industrialized great production.
The esterification of the most traditional chlorinated sulfoxide obtains D-PG methyl ester hydrochloride, only sloughs hydrochlorate and could use directly
Obtaining synthesizing the intermediate of cephalo Lip river gram and ammonia benzyl, the present invention need not desalination and i.e. can directly use, and synthesizes cephalo for the later stage
Ammonia benzyl is supplied to good advantage.
5, thionyl chloride esterification obtains D-PG methyl ester hydrochloride reaction principle is first to synthesize sulfonic acid chloride, then and carboxyl
It is exchanged into ester, because substantial amounts of hydrogen chloride and sulfur dioxide existence can affect stablizing of ester group, to basic when of reacting last
Having a balance, raw material residual can be more than 1%, but this patent not there is problems in that.
6, route of the present invention is succinct, operates safe and simple.
Detailed description of the invention
Embodiment 1
1) reactor adds 1500kg methanol and 100kg D-PG, is cooled to 10 DEG C, drips 5kg concentrated sulphuric acid,
Dropping process duration is 1-2 hour.
2) after completion of dropwise addition, being warmed up to 60-70 DEG C of reaction, react 8 hours, reaction is cooled to 40 DEG C after terminating ,-
Being concentrated into pulpous state under 0.085MPa, add 100kg water, ammonia regulation pH to 7.5-8.0, crystallizing and drying obtains product 104kg D-
Phenylglycine methyl ester.
After testing:
Purity: 99.5% (HPLC)
Embodiment 2
1) reactor adds 300kg methanol and 20kg D-PG, is cooled to 10-15 DEG C, drips 1kg concentrated sulphuric acid,
Dropping process duration is 0.5-1 hour.
2) after completion of dropwise addition, it is warmed up to 60-70 DEG C of reaction, reacts 8 hours.Reaction is cooled to 40 DEG C after terminating ,-
Being concentrated into pulpous state under 0.085MPa, add 20kg water, ammonia regulation pH to 7.5-8.0, crystallizing and drying obtains product 20.6kgD-
Phenylglycine methyl ester.
After testing:
Purity: 99.6% (HPLC)
The present embodiment is to produce according to the amount of industrialized great production, is different from the experiment condition of laboratory, is carrying out
Through substantial amounts of experimental verification before industrialization, then carry out enlarged experiment, after 20 batches of steady production, obtain this technique.This
Bright described process stabilizing and yield are high.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all essences in the present invention
Within god and principle, any modification, equivalent substitution and improvement etc. made, should be included within the scope of the present invention.
Claims (3)
1. the synthetic method of a D-PG methyl ester, it is characterised in that comprise the steps:
Reactor adds methanol and D-PG, is cooled to 10-15 DEG C, is slowly added dropwise into catalyst concentrated sulphuric acid wherein,
The addition of concentrated sulphuric acid and the mass ratio of D-PG are 1:20-21, and the rate of addition of concentrated sulphuric acid is 1-5kg/h；
After completion of dropwise addition, it is warmed up to 60-70 DEG C and reacts, after reaction terminates, be concentrated into pulpous state through cooling, add water, use ammonia
Water regulation pH to 7.5-8.0, crystallizing and drying obtains product D-PG methyl ester.
The synthetic method of a kind of D-PG methyl ester the most according to claim 1, it is characterised in that described in step 1)
Methanol and the mol ratio of D-PG be 65-75:1.
The synthetic method of a kind of D-PG methyl ester the most according to claim 1, it is characterised in that step 2) in, dense
During contracting, temperature is 40 DEG C, and pressure is-0.085MPa.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610526124.2A CN106187795A (en) | 2016-07-05 | 2016-07-05 | A kind of synthetic method of D Phenylglycine methyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610526124.2A CN106187795A (en) | 2016-07-05 | 2016-07-05 | A kind of synthetic method of D Phenylglycine methyl ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106187795A true CN106187795A (en) | 2016-12-07 |
Family
ID=57465375
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610526124.2A Pending CN106187795A (en) | 2016-07-05 | 2016-07-05 | A kind of synthetic method of D Phenylglycine methyl ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106187795A (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004062558A2 (en) * | 2003-01-14 | 2004-07-29 | Universita' Degli Studi Di Trieste | Process for enzymatic synthesis of βετα-lactam antibiotics |
| CN101277927A (en) * | 2005-09-29 | 2008-10-01 | 帝斯曼知识产权资产管理有限公司 | Process for esterification of an organic acid |
| CN101631872A (en) * | 2007-03-09 | 2010-01-20 | 帝斯曼知识产权资产管理有限公司 | Process for the preparation of beta-lactam compounds |
| CN101631764A (en) * | 2007-03-09 | 2010-01-20 | 帝斯曼知识产权资产管理有限公司 | Process for the preparation of amino acid methyl esters |
-
2016
- 2016-07-05 CN CN201610526124.2A patent/CN106187795A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004062558A2 (en) * | 2003-01-14 | 2004-07-29 | Universita' Degli Studi Di Trieste | Process for enzymatic synthesis of βετα-lactam antibiotics |
| CN101277927A (en) * | 2005-09-29 | 2008-10-01 | 帝斯曼知识产权资产管理有限公司 | Process for esterification of an organic acid |
| CN101631872A (en) * | 2007-03-09 | 2010-01-20 | 帝斯曼知识产权资产管理有限公司 | Process for the preparation of beta-lactam compounds |
| CN101631764A (en) * | 2007-03-09 | 2010-01-20 | 帝斯曼知识产权资产管理有限公司 | Process for the preparation of amino acid methyl esters |
Non-Patent Citations (1)
| Title |
|---|
| SHENG-YU SHI ETAL: "Polypeptide-b-Poly(Phenyl Isocyanide) Hybrid Rod-Rod Copolymers: One-Pot Synthesis, Self-Assembly, and Cell Imaging", 《MACROMOL. RAPID COMMUN.》 * |
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| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20161207 |
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| RJ01 | Rejection of invention patent application after publication |