CN100519514C - Method of preparing D-p-hydroxyphenylglycine - Google Patents
Method of preparing D-p-hydroxyphenylglycine Download PDFInfo
- Publication number
- CN100519514C CN100519514C CNB2008100546250A CN200810054625A CN100519514C CN 100519514 C CN100519514 C CN 100519514C CN B2008100546250 A CNB2008100546250 A CN B2008100546250A CN 200810054625 A CN200810054625 A CN 200810054625A CN 100519514 C CN100519514 C CN 100519514C
- Authority
- CN
- China
- Prior art keywords
- phpg
- beta
- naphthalenesulfonic
- double salt
- acid double
- 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.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- LJCWONGJFPCTTL-SSDOTTSWSA-N D-4-hydroxyphenylglycine Chemical compound [O-]C(=O)[C@H]([NH3+])C1=CC=C(O)C=C1 LJCWONGJFPCTTL-SSDOTTSWSA-N 0.000 title abstract 6
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 claims abstract description 75
- 150000003839 salts Chemical class 0.000 claims abstract description 67
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000000243 solution Substances 0.000 claims abstract description 26
- 238000001914 filtration Methods 0.000 claims abstract description 21
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 15
- 238000001035 drying Methods 0.000 claims abstract description 15
- 239000007787 solid Substances 0.000 claims abstract description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 11
- 239000007864 aqueous solution Substances 0.000 claims abstract description 6
- 239000013078 crystal Substances 0.000 claims description 20
- 230000003292 diminished effect Effects 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 16
- 238000010792 warming Methods 0.000 claims description 15
- 230000003287 optical effect Effects 0.000 claims description 12
- 238000013019 agitation Methods 0.000 claims description 10
- 238000009413 insulation Methods 0.000 claims description 10
- -1 phenyl aldehyde Chemical class 0.000 claims description 9
- 238000004061 bleaching Methods 0.000 claims description 5
- 230000006340 racemization Effects 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 238000010979 pH adjustment Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 abstract description 5
- 238000001816 cooling Methods 0.000 abstract 2
- 230000000630 rising effect Effects 0.000 abstract 2
- LJCWONGJFPCTTL-UHFFFAOYSA-N 4-hydroxyphenylglycine Chemical compound OC(=O)C(N)C1=CC=C(O)C=C1 LJCWONGJFPCTTL-UHFFFAOYSA-N 0.000 abstract 1
- LJCWONGJFPCTTL-ZETCQYMHSA-N L-4-hydroxyphenylglycine Chemical compound OC(=O)[C@@H](N)C1=CC=C(O)C=C1 LJCWONGJFPCTTL-ZETCQYMHSA-N 0.000 abstract 1
- 239000003513 alkali Substances 0.000 abstract 1
- 229910052799 carbon Inorganic materials 0.000 abstract 1
- 230000006698 induction Effects 0.000 abstract 1
- 239000007788 liquid Substances 0.000 abstract 1
- 238000004321 preservation Methods 0.000 abstract 1
- 238000005406 washing Methods 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 10
- 238000005194 fractionation Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin 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=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 2
- 229960003022 amoxicillin Drugs 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- 206010019280 Heart failures Diseases 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- ARLPLMVJWOUPSH-UHFFFAOYSA-N azanium;(2-bromo-7,7-dimethyl-3-oxo-4-bicyclo[2.2.1]heptanyl)methanesulfonate Chemical compound [NH4+].C1CC2(CS([O-])(=O)=O)C(=O)C(Br)C1C2(C)C ARLPLMVJWOUPSH-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960004841 cefadroxil Drugs 0.000 description 1
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 1
- 229960004682 cefoperazone Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Abstract
The invention provides a preparing method of D-p-hydroxyphenylglycine, which comprises adding DL-p-hydroxyphenylglycine and resolving agent beta-naphthalenesulfonic acid in water to prepare solution, rising temperature and reacting under agitating, adding induction seeds, adjusting the specific totation of the solution, performing heat-preservation reaction, cooling, sufficiently crystallizing, reducing pressure, filtering and drying, thereby obatining solid D-p-hydroxyphenylglycine beta-naphthalenesulfonic acid complex salts or L-p-hydroxyphenylglycine beta naphthalenesulfonic acid complex salts; dissolving D-p-hydroxyphenylglycine beta-naphthalenesulfonic acid complex salts in water to prepare aqueous solution, rising temperature, adding active carbon to perform decoloring treatment, adjusting the PH value by alkali liquid, cooling the sollution to room temperature, filtering, washing, and drying, thereby obatining D-p-hydroxyphenylglycine. The D-p-hydroxyphenylglycine produced by the method of the invention has good quality, short reaction time and low cost.
Description
Technical field
The present invention relates to a kind of preparation method of D-D-pHPG, more specifically relate to a kind of preparation method who produces high purity D-D-pHPG by the crystal seed revulsion.
Background technology
D-pHPG is a kind of amino acid by the chemical synthesis process preparation.Have optically active D-D-pHPG and have important medicinal use, its chemical formula is as follows:
As the CN101045693A background technology put down in writing, chiral D-D-pHPG and derivative thereof have broad application prospects in field such as antimicrobial, antiviral.Wherein the D-D-pHPG can be applied to Broad spectrum antibioticss such as synthetic amoxycillin, amoxycillin cephalo, cefoperazone, cephalo Luo Qi and cefadroxil azoles, and the L-D-pHPG has the effect of diseases such as assisting therapy ischemic heart disease, heart failure, diabetes.Ordinary method synthetic DL-D-pHPG is the racemic modification with chirality, need split this racemic modification of DL-D-pHPG to prepare chiral D-D-pHPG.
At present report pass through split DL-D-pHPG racemic modification and produce the method for D-D-pHPG and mainly comprise crystal seed revulsion and asymmetric transformation approach.The crystal seed revulsion is meant by the method that adds the chirality crystal seed in oversaturated racemic modification solution induces fractionation DL-D-pHPG, because the solubleness of DL-D-pHPG in water, ethanol equal solvent is little, so generally select the salt of DL-D-pHPG or derivative to carry out the fractionation of crystal seed revulsion.The defective of existing method is that low, the resulting product of once through yield is not high because of mixing enantiomorph purity.Yamada etc. make salt with aromatic sulphonic acid and DL-D-pHPG, carry out induced crystallization with crystal seed then, and the yield of existing method is 22%～28%, and optical purity is 96.2%～98%." Chinese Journal of Pharmaceuticals " [2005 (4): 199-200, Yang Fan etc.] report, with (+)-3-bromo-camphor sulfonic acid ammonium salt is resolving agent, with the salicylic aldehyde is catalyzer, in the presence of an amount of Glacial acetic acid, adopt asymmetric transformation approach to obtain D-D-pHPG double salt, double salt neutralizes in methanol solvate and obtains the D-D-pHPG, total recovery is 70%, and optical purity reaches 99%.This method reaction times reaches 22h, has defectives such as long reaction time, yield be low.
Summary of the invention
The objective of the invention is to overcome the deficiencies in the prior art, a kind of preparation method of D-D-pHPG is provided, make the D-D-pHPG quality that adopts this preparation method to produce good, and the reaction times is short, cost is low.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A kind of preparation method of D-D-pHPG, with the beta-naphthalenesulfonic-acid is resolving agent, resolution of racemic DL-D-pHPG, obtain the D-D-pHPG, its technical scheme is that it comprises the steps: (1), both weight proportions are 1: 1.2～1.6 DL-D-pHPG and resolving agent beta-naphthalenesulfonic-acid after adding in water, be mixed with concentration and be 25%～45% solution, being warming up to 60 ℃～80 ℃ under agitation condition reacts, add and induce crystal seed, regulator solution specific optical rotation value reaches 1.5 °～2.0 °, insulation reaction 1～1.5 hour, be cooled to 20 ℃～40 ℃ sufficient crystallisings, through filtration under diminished pressure, be drying to obtain solid (D-D-pHPG beta-naphthalenesulfonic-acid double salt or) L-D-pHPG beta-naphthalenesulfonic-acid double salt.This step weight yield can reach 99.6%.(1-1), the above-mentioned L-D-pHPG beta-naphthalenesulfonic-acid double salt that makes is soluble in water, the weight proportion of the two is 1: 1～1.5, add phenyl aldehyde, the weight of phenyl aldehyde is 0.2%～0.5% of L-D-pHPG beta-naphthalenesulfonic-acid double salt weight, be warmed up to 90 ℃～140 ℃, racemization to L-D-pHPG beta-naphthalenesulfonic-acid double salt specific rotation below 10 °, be cooled to below 50 ℃, filtration under diminished pressure obtains DL-D-pHPG beta-naphthalenesulfonic-acid double salt, DL-D-pHPG beta-naphthalenesulfonic-acid double salt is soluble in water, be mixed with concentration and be 25%～45% solution, being warming up to 60 ℃～80 ℃ under agitation condition reacts, add and induce crystal seed, regulator solution specific optical rotation value reaches 1.5 °～2.0 °, insulation reaction 1～1.5 hour is cooled to 20 ℃～40 ℃ sufficient crystallisings, through filtration under diminished pressure, be drying to obtain solid D-D-pHPG beta-naphthalenesulfonic-acid double salt or L-D-pHPG beta-naphthalenesulfonic-acid double salt.
(2), the above-mentioned D-D-pHPG beta-naphthalenesulfonic-acid double salt that makes is soluble in water, make concentration and be 25%～35% the aqueous solution, be warming up to 70 ℃～90 ℃ and add the activated carbon decolorizing processing, with lye pH adjustment value to 3.8～6.0, be cooled to room temperature, filter, wash, be drying to obtain (highly purified) D-D-pHPG.Perhaps,
Technological process with resulting above-mentioned product L-D-pHPG beta-naphthalenesulfonic-acid double salt repeating step (1-1) and step (2) in the step (1-1) promptly obtains the D-D-pHPG.
In the technique scheme, before the technological process of carrying out step (2), preferably the D-D-pHPG beta-naphthalenesulfonic-acid double salt that earlier [in the step (1), in the step (1-1)] is made is soluble in water, the weight proportion of the two is 1: 1～1.5, recrystallization is cooled to room temperature, filtration under diminished pressure obtains elaboration D-D-pHPG beta-naphthalenesulfonic-acid double salt, and then carries out the technological process of step (2).The weight of used gac can be 0.2%～1.0% of D-D-pHPG beta-naphthalenesulfonic-acid double salt weight in the step (2), and bleaching time can be 20min～40min.
Compared with the prior art, beneficial effect of the present invention is as follows:
1, preparation method of the present invention adopts crystal seed to induce Split Method, with the beta-naphthalenesulfonic-acid is that resolving agent is (certain, resolving agent can also expand to alkyl aryl sulfonic acid family material), use advanced in the world water to induce Split Method, split effect and obviously improve (being higher than other method for splitting), and cost not as good as similar resolving agent 1/10th, cost is lower.
2, method for splitting specific rotation value of the present invention can be-156 °～-161 °, reaches advanced world standards.
3, the D-D-pHPG chemical purity that adopts preparation method of the present invention to produce can reach 99.6%, and quality is good; The omnidistance fractionation time is 2.5 hours, and the reaction times is short.
4, recycle material of the present invention is realized zero release, when cost falls in joint, has avoided environmental pollution.
Embodiment
Embodiment 1: preparation method of the present invention comprises the steps: (1), adds 1030g DL-D-pHPG (being the DL D-pHPG) and 1350g resolving agent beta-naphthalenesulfonic-acid in 3000ml water, is mixed with concentration and is about 44% solution.Being warming up to 60 ℃ under agitation condition reacts, add and induce crystal seed (D-D-pHPG beta-naphthalenesulfonic-acid double salt on a small quantity, 20g), regulator solution specific optical rotation value reaches 1.5 °, insulation reaction 1 hour, be cooled to 25 ℃ of sufficient crystallisings, be drying to obtain solid (white crystals shape) D-D-pHPG beta-naphthalenesulfonic-acid double salt 1730g through filtration under diminished pressure, (in the vacuum drying oven).The omnidistance fractionation time is 2.5 hours.The 1730g D-D-pHPG beta-naphthalenesulfonic-acid double salt that makes in the step (1) is dissolved in the 1730g water, and recrystallization is cooled to room temperature, and filtration under diminished pressure obtains 1640g elaboration D-D-pHPG beta-naphthalenesulfonic-acid double salt.(2), the above-mentioned 1640g that makes (elaboration) D-D-pHPG beta-naphthalenesulfonic-acid double salt is dissolved in the 3280g water, make concentration and be about 33.3% the aqueous solution, be warming up to 70 ℃ and add the 3.28g activated carbon decolorizings and handle, bleaching time can be 30min.With sodium hydroxide solution adjust pH to 3.8, be cooled to room temperature, vacuum filtration, wash, be drying to obtain 656g D-D-pHPG, [α]
20 D=-157.1 ° (c=1,1NHCl), chemical purity is 99.6%.
Embodiment 2: preparation method of the present invention comprises the steps: (1), adds 1030g DL-D-pHPG and 1350g resolving agent beta-naphthalenesulfonic-acid in 3000ml water, be mixed with concentration and be about 44% solution, being warming up to 65 ℃ under agitation condition reacts, add and induce crystal seed (L-D-pHPG beta-naphthalenesulfonic-acid double salt) on a small quantity, regulator solution specific optical rotation value reaches 1.7 °, insulation reaction 1.5 hours, be cooled to 30 ℃ of sufficient crystallisings, promptly obtain solid L-D-pHPG beta-naphthalenesulfonic-acid double salt 1610g through filtration under diminished pressure, vacuum-drying.
(1-1), the 1610g L-D-pHPG beta-naphthalenesulfonic-acid double salt that makes in the step (1) is dissolved in the 2000g water, add the 5g phenyl aldehyde, be warmed up to 120 ℃, racemization (being incubated 7 hours) to L-D-pHPG beta-naphthalenesulfonic-acid double salt specific rotation is 5 °, be cooled to 30 ℃, filtration under diminished pressure obtains 1590g DL-D-pHPG beta-naphthalenesulfonic-acid double salt.1590g DL-D-pHPG beta-naphthalenesulfonic-acid double salt is dissolved in the 3500g water, be mixed with concentration and be 31.2% solution, being warming up to 60 ℃ under agitation condition reacts, add and induce crystal seed (D-D-pHPG beta-naphthalenesulfonic-acid double salt) on a small quantity, regulator solution specific optical rotation value reaches 1.5 °, insulation reaction 1 hour is cooled to 20 ℃ of sufficient crystallisings, promptly obtains solid (white crystals shape) D-D-pHPG beta-naphthalenesulfonic-acid double salt 1360g through filtration under diminished pressure, vacuum-drying.The omnidistance fractionation time is 2.5 hours.
Then according to the technological process of resulting above-mentioned product repeating step (2) [if the crystal seed of inducing of above-mentioned adding is a L-D-pHPG beta-naphthalenesulfonic-acid double salt, then obtain solid L-D-pHPG beta-naphthalenesulfonic-acid double salt, according to the technological process of resulting above-mentioned product repeating step (1-1)].Before the technological process of carrying out step (2), can earlier the 1360gD-D-pHPG beta-naphthalenesulfonic-acid double salt that makes in the step (1-1) be dissolved in the 1360g water, recrystallization is cooled to room temperature, filtration under diminished pressure obtains 1290g elaboration D-D-pHPG beta-naphthalenesulfonic-acid double salt, and then carries out the technological process of step (2).The 1290g D-D-pHPG beta-naphthalenesulfonic-acid double salt that is about to make is dissolved in 2580 water, make concentration and be 33.3% the aqueous solution, be warming up to 70 ℃ and add the processing of 3.87g activated carbon decolorizing, with sodium hydroxide solution adjust pH to 4.0, be cooled to room temperature, filter (vacuum filtration), wash, be drying to obtain 451g D-D-pHPG, [α]
20 D=-156.8 ° (c=1,1NHCl), chemical purity is 99.6%.
Embodiment 3: preparation method of the present invention is resolving agent with the beta-naphthalenesulfonic-acid, resolution of racemic DL-D-pHPG, obtain the D-D-pHPG, it comprises the steps: (1), adding both weight proportions of back in water is the DL-D-pHPG and the resolving agent beta-naphthalenesulfonic-acid of 1: 1.2 (perhaps 1: 1.4 or 1: 1.6), be mixed with concentration and be 25% solution of (perhaps 35% or 45%), being warming up to 60 ℃ (perhaps 70 ℃ or 80 ℃) under agitation condition reacts, add and induce crystal seed (D-D-pHPG beta-naphthalenesulfonic-acid double salt), regulator solution specific optical rotation value reaches 1.5 ° (perhaps 2.0 °), insulation reaction 1.4 hours, be cooled to 20 ℃ of (perhaps 30 ℃ or 40 ℃) sufficient crystallisings, through filtration under diminished pressure, be drying to obtain solid D-D-pHPG beta-naphthalenesulfonic-acid double salt.(2), the above-mentioned D-D-pHPG beta-naphthalenesulfonic-acid double salt that makes is soluble in water, make concentration and be 25% aqueous solution of (perhaps 30% or 35%), be warming up to 70 ℃ (perhaps 80 ℃ or 90 ℃) and add the activated carbon decolorizing processing, with lye pH adjustment value to 3.8 (perhaps 5.0 or 6.0), be cooled to room temperature, filter, wash, be drying to obtain the D-D-pHPG.
Embodiment 4: preparation method of the present invention is resolving agent with the beta-naphthalenesulfonic-acid, resolution of racemic DL-D-pHPG, obtain the D-D-pHPG, it comprises the steps: (1), adding both weight proportions of back in water is the DL-D-pHPG and the resolving agent beta-naphthalenesulfonic-acid of 1: 1.2 (perhaps 1: 1.4 or 1: 1.6), be mixed with concentration and be 25% solution of (perhaps 35% or 45%), being warming up to 60 ℃ (perhaps 70 ℃ or 80 ℃) under agitation condition reacts, add and induce crystal seed (L-D-pHPG beta-naphthalenesulfonic-acid double salt), regulator solution specific optical rotation value reaches 1.5 ° (perhaps 2.0 °), insulation reaction 1.4 hours, be cooled to 20 ℃ of (perhaps 30 ℃ or 40 ℃) sufficient crystallisings, through filtration under diminished pressure, be drying to obtain solid L-D-pHPG beta-naphthalenesulfonic-acid double salt.(1-1), the above-mentioned L-D-pHPG beta-naphthalenesulfonic-acid double salt that makes is soluble in water, the weight proportion of the two is 1: 1 (perhaps 1: 1.3 or 1: 1.5), add phenyl aldehyde, the weight of phenyl aldehyde is 0.2% (perhaps 0.3% or 0.5%) of L-D-pHPG beta-naphthalenesulfonic-acid double salt weight, be warmed up to 90 ℃ (perhaps 110 ℃ or 130 ℃ or 140 ℃), racemization (6 hours) to L-D-pHPG beta-naphthalenesulfonic-acid double salt specific rotation 6 ° (racemization can select 6 hours～10 hours, specific rotation is getting final product below 10 ° or 10 °, can select 7 ° or 8 ° or 9 ° as specific rotation), be cooled to 30 ℃ (perhaps 50 ℃ or 35 ℃ or 20 ℃, preferred 30 ℃～35 ℃), filtration under diminished pressure obtains DL-D-pHPG beta-naphthalenesulfonic-acid double salt, DL-D-pHPG beta-naphthalenesulfonic-acid double salt is soluble in water, be mixed with concentration and be 25% solution of (perhaps 35% or 45%), being warming up to 60 ℃ (perhaps 70 ℃ or 80 ℃) under agitation condition reacts, add and induce crystal seed (D-D-pHPG beta-naphthalenesulfonic-acid double salt), regulator solution specific optical rotation value reaches 1.5 ° (perhaps 1.7 ° or 2.0 °), insulation reaction 1 hour (perhaps 1.5 hours), be cooled to 20 ℃ of (perhaps 30 ℃ or 40 ℃) sufficient crystallisings, through filtration under diminished pressure, be drying to obtain solid D-D-pHPG beta-naphthalenesulfonic-acid double salt.Then according to the technological process of resulting above-mentioned product repeating step (2).Before the technological process of carrying out step (2), can be earlier that the D-D-pHPG beta-naphthalenesulfonic-acid double salt that makes in the step (1-1) is soluble in water, the weight proportion of the two is 1: 1 (perhaps 1: 1.3 or 1: 1.5), recrystallization is cooled to room temperature, filtration under diminished pressure obtains elaboration D-D-pHPG beta-naphthalenesulfonic-acid double salt, and then carries out the technological process of step (2).
The weight of used gac can be 0.2% (perhaps 1.0%) of D-D-pHPG beta-naphthalenesulfonic-acid double salt weight in the step of the foregoing description 3 and embodiment 4 (2), and bleaching time can be 20min～40min.The consumption of gac and bleaching time also can be in given scopes.
Claims (3)
1, a kind of preparation method of D-D-pHPG is a resolving agent with the beta-naphthalenesulfonic-acid, and resolution of racemic DL-D-pHPG obtains the D-D-pHPG, it is characterized in that it comprises the steps:
(1), adding both weight proportions of back in water is 1: 1.2～1.6 DL-D-pHPG and resolving agent beta-naphthalenesulfonic-acid, be mixed with concentration and be 25%～45% solution, being warming up to 60 ℃～80 ℃ under agitation condition reacts, add and induce crystal seed, regulator solution specific optical rotation value reaches 1.5 °～2.0 °, insulation reaction 1～1.5 hour is cooled to 20 ℃～40 ℃ sufficient crystallisings, through filtration under diminished pressure, be drying to obtain solid L-D-pHPG beta-naphthalenesulfonic-acid double salt;
(1-1), the above-mentioned L-D-pHPG beta-naphthalenesulfonic-acid double salt that makes is soluble in water, the weight proportion of the two is 1: 1～1.5, add phenyl aldehyde, the weight of phenyl aldehyde is 0.2%～0.5% of L-D-pHPG beta-naphthalenesulfonic-acid double salt weight, be warmed up to 90 ℃～140 ℃, racemization to L-D-pHPG beta-naphthalenesulfonic-acid double salt specific rotation below 10 °, be cooled to below 50 ℃, filtration under diminished pressure obtains DL-D-pHPG beta-naphthalenesulfonic-acid double salt, DL-D-pHPG beta-naphthalenesulfonic-acid double salt is soluble in water, be mixed with concentration and be 25%～45% solution, being warming up to 60 ℃～80 ℃ under agitation condition reacts, add and induce crystal seed, regulator solution specific optical rotation value reaches 1.5 °～2.0 °, insulation reaction 1～1.5 hour is cooled to 20 ℃～40 ℃ sufficient crystallisings, through filtration under diminished pressure, be drying to obtain solid D-D-pHPG beta-naphthalenesulfonic-acid double salt or L-D-pHPG beta-naphthalenesulfonic-acid double salt;
(2), the above-mentioned D-D-pHPG beta-naphthalenesulfonic-acid double salt that makes is soluble in water, make concentration and be 25%～35% the aqueous solution, be warming up to 70 ℃～90 ℃ and add the activated carbon decolorizing processing, with lye pH adjustment value to 3.8～6.0, be cooled to room temperature, filter, wash, be drying to obtain the D-D-pHPG; Perhaps,
Technological process with resulting above-mentioned product L-D-pHPG beta-naphthalenesulfonic-acid double salt repeating step (1-1) and step (2) in the step (1-1) promptly obtains the D-D-pHPG.
2, preparation method according to claim 1, it is characterized in that before the technological process of carrying out step (2), earlier that the D-D-pHPG beta-naphthalenesulfonic-acid double salt that makes is soluble in water, the weight proportion of the two is 1: 1～1.5, recrystallization is cooled to room temperature, filtration under diminished pressure obtains elaboration D-D-pHPG beta-naphthalenesulfonic-acid double salt, and then carries out the technological process of step (2).
3, preparation method according to claim 1, the weight that it is characterized in that used gac in the step (2) are 0.2%～1.0% of D-D-pHPG beta-naphthalenesulfonic-acid double salt weight, and bleaching time is 20min～40min.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2008100546250A CN100519514C (en) | 2008-03-13 | 2008-03-13 | Method of preparing D-p-hydroxyphenylglycine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2008100546250A CN100519514C (en) | 2008-03-13 | 2008-03-13 | Method of preparing D-p-hydroxyphenylglycine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101239926A CN101239926A (en) | 2008-08-13 |
| CN100519514C true CN100519514C (en) | 2009-07-29 |
Family
ID=39931813
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2008100546250A Expired - Fee Related CN100519514C (en) | 2008-03-13 | 2008-03-13 | Method of preparing D-p-hydroxyphenylglycine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100519514C (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101863818B (en) * | 2010-06-30 | 2012-08-08 | 宜兴市前成生物有限公司 | Method for preparing DL-proline |
| US8940928B2 (en) | 2012-02-15 | 2015-01-27 | Henan Newland Pharmaceutical Co., Ltd. | Method of synthesizing levorotatory p-hydroxyphenylglycine compounds |
| CN103755581B (en) * | 2014-01-16 | 2016-05-25 | 中山百灵生物技术有限公司 | Resolution method of D, L-leucine |
-
2008
- 2008-03-13 CN CNB2008100546250A patent/CN100519514C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN101239926A (en) | 2008-08-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102718673B (en) | Novel technology for synthesis of aminomethylbenzoic acid | |
| CN109369372A (en) | A method of preparing 3-hydroxybutyrate salt | |
| CN107311875A (en) | The synthetic method of aramine | |
| CN1321121C (en) | Post processing method for preparing levo-ofloxacin | |
| CN102153567B (en) | Method for preparing cefoxitin acid | |
| CN102060860B (en) | Preparation method of Marbofloxacin | |
| CN101704766B (en) | Preparation method of arginine aspirin and powder-injection of arginine aspirin | |
| CN100519514C (en) | Method of preparing D-p-hydroxyphenylglycine | |
| CN103420891B (en) | The synthetic method of type II diabetes medicine glimepiride intermediate benzene sulfanilamide (SN) triphosgene | |
| CN108059601A (en) | A kind of technique for preparing 3- amino-1-adamantane alcohols | |
| CN101624351A (en) | Preparation method of DL-lysine | |
| CN110041261A (en) | A kind of preparation method of naphcon | |
| CN100537552C (en) | Method for preparing Repaglinide | |
| CN107880083A (en) | A kind of process for purification of clindamycin phosphate | |
| CN101781264B (en) | Production method of 1-methyl-5-mercapto-1,2,3,4-tetrazole | |
| CN103664805A (en) | Method for preparing acipimox | |
| CN102617461A (en) | Novel method for refining aripiprazole | |
| CN105130972B (en) | Benzoic acid emtricitabine salt, its preparation method and the method for preparing emtricitabine with benzoic acid emtricitabine salt | |
| CN104672114A (en) | A preparing method of 2,4-dichloro-5-sulfamoylbenzoic acid | |
| FR2544718A1 (en) | NIFLUMIC ACID MORPHOLINOETHYL ESTER DINIFLUMATE, PREPARATION, THERAPEUTIC USE AS ANALGESIC AND ANTI-INFLAMMATORY | |
| CN108129430A (en) | A kind of synthetic method of Li Tasite intermediates | |
| CN112194581A (en) | Preparation method of flurbiprofen axetil | |
| CN100363373C (en) | Preparation method of isomalto loigosaccharide sulphate (IMOS) | |
| CN109265413A (en) | A kind of preparation method and refining methd of difenidol hydrochloride | |
| CN103360365A (en) | New preparation process of medicinal raw material duloxetine hydrochloride of antidepressant drug |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| ASS | Succession or assignment of patent right |
Owner name: SHIJIAZHUANG PHARMACEUTICAL GROUP ZHONGRUN PHARMAC Free format text: FORMER OWNER: HEBEI HONGYUAN CHEMICAL CO., LTD. Effective date: 20120427 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 052165 SHIJIAZHUANG, HEBEI PROVINCE TO: 010206 HOHHOT, INNER MONGOLIA AUTONOMOUS REGION |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20120427 Address after: 010206 Inner Mongolia Togtoh Industrial Park Patentee after: ZHONGRUN PHARMACEUTICAL INNER MONGOLIA Co.,Ltd. OF CSPC Address before: 052165 No. 91, Hainan Road, Shijiazhuang economic and Technological Development Zone, Hebei, China Patentee before: HEBEI HONGYUAN CHEMICAL Co.,Ltd. |
|
| C56 | Change in the name or address of the patentee |
Owner name: INNER MONGOLIA CHANGSHENG PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: ZHONGRUN (INNER MONGOLIA) CO., LTD., SHIJIAZHUANG PHARMACEUTICAL GROUP |
|
| CP01 | Change in the name or title of a patent holder |
Address after: 010206 the Inner Mongolia Autonomous Region Togtoh Industrial Park Patentee after: INNER MONGOLIA CHANGSHENG PHARMACEUTICAL Co.,Ltd. Address before: 010206 the Inner Mongolia Autonomous Region Togtoh Industrial Park Patentee before: ZHONGRUN PHARMACEUTICAL INNER MONGOLIA Co.,Ltd. OF CSPC |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090729 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |