CN109232237A - The synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate - Google Patents
The synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate Download PDFInfo
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- CN109232237A CN109232237A CN201811061196.XA CN201811061196A CN109232237A CN 109232237 A CN109232237 A CN 109232237A CN 201811061196 A CN201811061196 A CN 201811061196A CN 109232237 A CN109232237 A CN 109232237A
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- arhalofenate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses the synthetic methods of novel anti-trioxypurine compound Arhalofenate intermediate, the novel anti-trioxypurine compound Arhalofenate intermediate is (R)-parachloromandelic acid, its specific synthesis step are as follows: using common organic solvent as resolution solvent, using racemic parachloromandelic acid as raw material, using (R)-amine as resolving agent, reflux prepares (R)-amine (R)-parachloromandelic acid, acid adding tune pH, ethyl acetate repeatedly extracts, merge organic phase, it is dry that anhydrous sodium sulfate is added, filter desalination, it is dried under reduced pressure to obtain high (the R)-parachloromandelic acid of optical purity.Having the beneficial effect that synthetic method of the present invention is easy to get with raw material, isolated speed and effect are good, and fractionation rate is high, and it is at low cost, it is easy to operate, it is not high to working condition and equipment requirement, it is easy to industrialized production.
Description
Technical field
The present invention relates to field of medicinal chemistry, more particularly, to novel anti-trioxypurine compound Arhalofenate intermediate
Synthetic method.
Background technique
Disease incidence of the gout in China is 0.17%, and rises year by year trend.Gout is by monosodium urate mineralization institute
The crystal correlation arthropathy of cause, with the direct phase of hyperuricemia caused by purine metabolic disturbance and (or) underexcretion
It closes, refers in particular to acute characteristic arthritis and chronic gout stone disease, mainly formed including acute attack arthritis, tophus,
Tophaceous chornic arthritis, urate nephropathy and uric acid lithangiuria, severe one may occur in which joint deformity and renal insufficiency.
Gout is often with the performance such as Central obesity, hyperlipidemia, hypertension, diabetes B and cardiovascular disease.Gout is more common in middle aged male
Property, women only account for 5%, mainly postmenopausal women, and gout has rejuvenation trend.Therefore, the market of anti-gout drugs needs
The amount of asking is huge, and anti-gout drugs curative for effect, that toxic side effect is small, more by the favor of medical worker and patient.
The effect of Arhalofenate anti-trioxypurine is significant, still can improve insulin sensitivity simultaneously, reduce blood glucose, triglycerides and inflammation
The drug of reaction.The most important biochemical basis of gout is hyperuricemia.Normal adult about generates uric acid 750mg daily, wherein
80% is endogenous, and 20% is exogenous uric acid, these uric acid enter uric acid metabolism pond, the uric acid about 60% in daily metabolic pool
It is metabolized, wherein 1/3 through enteron aisle catabolism, 2/3 through kidney excretion, so as to maintain the stabilization of internal uric acid level,
In any link go wrong and can lead to hyperuricemia.
Anti-gout drugs from the sales volume of Hospitals at Present antigout preparation with from the point of view of consumption sum, this kind of drug in recent years
Sale skyrocketing trend is presented, and show summer and autumn high-incidence feature, it is temporal with epidemiology onset peak
It analyzes almost the same.The current kind of gout suppressant is few, clinical treatment mainly with colchicin, non-steroid anti-inflammatory drug, hormone,
Promote uric acid excretion medicine (such as probenecid, Sulfinpyrazone and Benzbromarone) and inhibits based on uric acid synthetic drug (allopurinol).It is acute
Mainly tazettine, non-steroid anti-inflammatory drug, hormone are drunk in application to period of disease, and mainly application promoted uric acid excretion medicine, inhibited the paracmasis
Uric acid synthetic drug.These drugs are all defective in the treatment.Weak curative effect, side effect become greatly the bottleneck of its clinical application.Drop urine
Sour drug Arhalofenate is carrying out the clinical research of 3 phases, is not increase gout breaking-out wind when only one reduces blood uric acid
Danger, still can improve simultaneously insulin sensitivity, reduce blood glucose, triglycerides and inflammatory reaction drug, these will make its at
For the significant drug for treating gout.Therefore, have great importance to the synthetic route research of Arhalofenate and application.
In recent years, research and development reduce the hot spot that the drug of blood uric acid is research.But almost without the listing that can succeed
Drug, reason have two, first is that the purpose for reducing blood uric acid is not achieved in clinical test results, with blank compared with control drug
Control group compares no notable difference；Second is that these drug candidates have serious side reaction even toxicity, very to human injury
Greatly, therefore can not be tested by safety evaluatio can not list.Arhalofenate is the novel gout suppressant researched and developed in recent years,
Clinical test results show that it reduces the significant effect of blood uric acid, also while improving insulin sensitivity, reducing blood glucose, glycerol three
Ester and inflammatory reaction, and almost without serious side reaction, the clinical research of 3 phases is come at present, once listing,
Arhalofenate can become the important drugs of antigout immediately.And the research in relation to Arhalofenate synthetic route constantly increases
It is more, but summarize discovery these study used by synthetic method there are problems, such as have that the reaction time is long, reaction condition is severe
It carves, the disadvantages of yield is low, used condensation reagent is expensive, therefore, the variation route of the Arhalofenate of research synthesis early is very
It is crucial.Arhalofenate synthesis key technology is mainly the fractionation of parachloromandelic acid, by selecting resolving agent appropriate and work
Skill condition prepares high (the R)-parachloromandelic acid of optical purity.
Summary of the invention
The purpose of the present invention is to provide a kind of synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate,
The synthetic method is easy to get with raw material, and isolated speed and effect are good, and fractionation rate is high, at low cost, easy to operate, to working condition and
Equipment requirement is not high, easy to industrialized production.
The present invention in view of the above technology in the problem of mentioning, the technical solution taken are as follows:
The synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate, the novel anti-trioxypurine compound
Arhalofenate intermediate is (R)-parachloromandelic acid.Above-mentioned (R)-parachloromandelic acid be a kind of important chiral intermediate simultaneously
It is used to synthetic drug, can be used as acid resolving agent to split novel anti-trioxypurine compound Arhalofenate, raisingization
The yield and fractionation rate of object Arhalofenate are closed, and then solves compound Arhalofenate synthesising reacting time length, reaction
The disadvantages of condition is harsh, yield is low, expensive, so that compound Arhalofenate can become the important drugs of antigout.
The synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate, the specific steps of synthesis are as follows:
Step 1: being that resolution solvent is added into racemic parachloromandelic acid in 1:8-12 (g/mL) by solid-liquid ratio, be allowed to complete
Portion's dissolution, it is spare；
Step 2: it is added dropwise resolving agent under agitation, the molar ratio of racemic parachloromandelic acid and resolving agent is 1:
0.85-1.15 is heated to reflux 15-90min under conditions of reacting outer bath temperature and being 70~100 DEG C after mixing, keeps crystal salt molten
Solution, is then slowly cooled to room temperature, crude product is obtained by filtration；
Step 3: obtained crude product is recrystallized in resolving agent, obtains white, needle-shaped crystals salt, it is spare；
Step 4: it is that 1:10-15 (g/mL) is soluble in water by crystal salt by solid-liquid ratio, adjusts the pH to 0.8-1.2 of solution,
Then it is extracted with ethyl acetate 2-4 times, merges organic phase, then dry, the evaporating solvent under reduced pressure with anhydrous sodium sulfate, it is solid to obtain white
Body, as (R)-parachloromandelic acid, the synthetic method first convert racemic parachloromandelic acid to resolving agent reaction corresponding
Diastereomer, i.e. difficulty soluble salt (R)-phenyl ethylamine (R)-parachloromandelic acid and lyotropic salt (R)-amine (S)-parachloromandelic acid,
Then utilize diastereomer the difference of solubility in resolution solvent so that difficulty soluble salt (R)-amine (R)-parachloromandelic acid from
Preferential crystallization comes out in solution, achievees the effect that separation, and then (R)-amine (R)-parachloromandelic acid obtained after separation is turned
Corresponding optically-active compound (R)-parachloromandelic acid is turned to, to reach fractionation purpose, which is easy to get, yield
Height, at low cost, easy to operate, not high to working condition and equipment requirement, economy is higher, and the optics of (R)-parachloromandelic acid
Purity is greater than 99%e.e..
Preferably, resolution solvent is methanol or 95% ethanol solution or ethyl alcohol or propyl alcohol or isopropanol or second in step 1
Acetoacetic ester or toluene or methylene chloride.
Further preferably, resolution solvent is 95% ethanol solution in step 1, and the difficulty soluble salt (R)-amine (R)-is to chlorine almond
Acid and lyotropic salt (R)-amine (S)-difference in solubility of the parachloromandelic acid in the resolution solvent are larger, are conducive to chirality and tear open
Point, fractionation rate is improved, and the resolution solvent is cheap, can reduce the synthesis cost of (R)-parachloromandelic acid, and then reduce
The cost of compound Arhalofenate.
For optimisation technique scheme, the measure taken further include: contain 0.032-0.036% in above-mentioned 95% ethanol solution
N,N-diisopropylethylamine, the presence of the n,N-diisopropylethylamine can increase amino on (R)-amine and (R)-to chlorine almond
The quantity of hydrogen bond is formed between carboxyl on acid, and then forms hydrogen bond net, and it is flat to chlorine to be conducive to increase difficulty soluble salt (R)-amine (R)-
The stability of peach acid crystal structure, and then increase the stability difference of two kinds of salt, and difficulty soluble salt (R)-amine (R)-is to chlorine almond
Hydrogen bond in acid crystal structure reduces difficulty soluble salt (R)-amine (R)-parachloromandelic acid by Cl ... the Cl halogen key connection occurred
Solubility in resolution solvent improves difficulty soluble salt (R)-amine (R)-parachloromandelic acid and lyotropic salt (R)-amine (S)-to chlorine
Poor solubility of the mandelic acid in the resolution solvent improves the fractionation performance of resolution solvent, so that difficulty soluble salt (R)-amine (R)-
Parachloromandelic acid can rapid crystallization come out, and improve isolated speed and effect, final raising (R)-parachloromandelic acid it is pure
Degree.
Preferably, resolving agent is (R)-amine in step 2.
Further preferably, resolving agent is (R)-phenyl ethylamine or (R)-naphthalene ethylamine in step 2.The resolving agent dosage is few, can be with
Racemic chloro mandelic acid generates difficulty soluble salt (R)-amine (R)-parachloromandelic acid and lyotropic salt (R)-amine (S)-parachloromandelic acid,
Then utilize diastereomer the difference of solubility in resolution solvent so that difficulty soluble salt (R)-amine (R)-parachloromandelic acid from
Preferential crystallization comes out in solution, achievees the effect that separation, while the R generated)-amine (R)-parachloromandelic acid is easy to be reduced back
Enantiomer, fractionation rate are higher.
Compared with the prior art, the advantages of the present invention are as follows: 1) conjunction of the compounds of this invention Arhalofenate intermediate
It being easy to get at method raw material, high income is at low cost, and easy to operate, not high to working condition and equipment requirement, economy is higher, and
(R)-parachloromandelic acid optical purity is greater than 99%e.e.；2) resolution solvent of the invention is conducive to increase difficulty soluble salt (R)-
Amine (R)-parachloromandelic acid crystal structure stability reduces difficulty soluble salt (R)-amine (R)-parachloromandelic acid in resolution solvent
In solubility, improve poor solubility in the resolution solvent of difficulty soluble salt and lyotropic salt, improve the fractionation performance of resolution solvent,
Difficulty soluble salt (R)-amine (R)-parachloromandelic acid rapid crystallization is come out, and improves isolated speed and effect, finally
Improve the purity of (R)-parachloromandelic acid；3) present invention is few with resolving agent dosage, can generate difficulty soluble salt with racemic chloro mandelic acid
(R)-amine (R)-parachloromandelic acid and lyotropic salt (R)-amine (S)-parachloromandelic acid, achieve the effect that separation, generate simultaneously
R)-amine (R)-parachloromandelic acid is easy to be reduced back enantiomer, fractionation rate is higher.
Specific embodiment
The present invention program is described further below by embodiment:
Embodiment 1:
The synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate, the novel anti-trioxypurine compound
Arhalofenate intermediate is (R)-parachloromandelic acid.Above-mentioned (R)-parachloromandelic acid be a kind of important chiral intermediate simultaneously
It is used to synthetic drug, can be used as acid resolving agent to split novel anti-trioxypurine compound Arhalofenate, raisingization
The yield and fractionation rate of object Arhalofenate are closed, and then solves compound Arhalofenate synthesising reacting time length, reaction
The disadvantages of condition is harsh, yield is low, expensive, so that compound Arhalofenate can become the important drugs of antigout.
The synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate, reaction equation are as follows:
The synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate, the specific steps of synthesis are as follows:
Step 1: being that 1:8 (g/mL) 95% ethyl alcohol is added into racemic parachloromandelic acid by solid-liquid ratio, be allowed to all
Dissolution；
Step 2: (R)-phenyl ethylamine, mole of racemic parachloromandelic acid and (R)-phenyl ethylamine being added dropwise under agitation
Than being heated to reflux 50min under conditions of reacting outer bath temperature and being 80 DEG C after mixing, dissolving crystal salt, then for 1:1.15
It is slowly cooled to room temperature, crude product is obtained by filtration；
Step 3: obtained crude product being recrystallized in resolving agent, obtains white, needle-shaped crystals salt, as (R)-benzene second
Amine (R)-parachloromandelic acid；
Step 4: it is that 1:10 (g/mL) is soluble in water by (R)-phenyl ethylamine (R)-parachloromandelic acid crystal salt by solid-liquid ratio,
The pH to 1.0 for adjusting solution, is then extracted with ethyl acetate 3 times, merges organic phase, then dry with anhydrous sodium sulfate, and decompression is steamed
Except solvent, white solid is obtained, as (R)-parachloromandelic acid.The synthetic method first by racemic parachloromandelic acid and is split
Agent reaction is converted into corresponding diastereomer, i.e. difficulty soluble salt (R)-phenyl ethylamine (R)-parachloromandelic acid and lyotropic salt (R)-amine
(S) then-parachloromandelic acid utilizes the difference of solubility in resolution solvent of diastereomer, so that difficulty soluble salt (R)-amine
(R)-parachloromandelic acid preferential crystallization from solution comes out, and achievees the effect that separation, then (R)-amine obtained after separation
(R)-parachloromandelic acid is converted into corresponding optically-active compound (R)-parachloromandelic acid, to reach fractionation purpose, the synthesis side
Method raw material is easy to get, and high income is at low cost, easy to operate, not high to working condition and equipment requirement, and economy is higher, and (R)-
The optical purity of parachloromandelic acid is greater than 99%e.e..
Embodiment 2:
The synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate, the specific steps of synthesis are as follows:
Step 1: being that 1:10 (g/mL) 95% ethyl alcohol is added into racemic parachloromandelic acid by solid-liquid ratio, be allowed to all
Dissolution, in above-mentioned 95% ethanol solution containing 0.035% n,N-diisopropylethylamine, the presence of the n,N-diisopropylethylamine
The quantity for forming hydrogen bond between the carboxyl on the amino and (R)-parachloromandelic acid on (R)-amine can be increased, and then form hydrogen bond net,
Be conducive to increase the stability of difficulty soluble salt (R)-amine (R)-parachloromandelic acid crystal structure, and then increase the stability of two kinds of salt
Difference, and the hydrogen bond in difficulty soluble salt (R)-amine (R)-parachloromandelic acid crystal structure is connected by Cl ... the Cl halogen key occurred
It connects, reduces difficulty soluble salt (R)-amine (R)-solubility of the parachloromandelic acid in resolution solvent, improve difficulty soluble salt (R)-amine
(R)-parachloromandelic acid and lyotropic salt (R)-amine (S)-poor solubility of the parachloromandelic acid in the resolution solvent are improved and are split
The fractionation performance of solvent enables difficulty soluble salt (R)-amine (R)-parachloromandelic acid rapid crystallization to come out, and improves separation
Speed and effect, the final purity for improving (R)-parachloromandelic acid；
Step 2: (R)-phenyl ethylamine, mole of racemic parachloromandelic acid and (R)-phenyl ethylamine being added dropwise under agitation
Than being heated to reflux 20min under conditions of reacting outer bath temperature and being 85 DEG C after mixing, dissolving crystal salt, then slowly for 1:1
It is cooled to room temperature, crude product is obtained by filtration；
Step 3: obtained crude product being recrystallized in resolving agent, obtains white, needle-shaped crystals salt, as (R)-benzene second
Amine (R)-parachloromandelic acid；
Step 4: it is that 1:12 (g/mL) is soluble in water by (R)-phenyl ethylamine (R)-parachloromandelic acid crystal salt by solid-liquid ratio,
The pH to 1.0 for adjusting solution, is then extracted with ethyl acetate 3 times, merges organic phase, then dry with anhydrous sodium sulfate, and decompression is steamed
Except solvent, white solid is obtained, as (R)-parachloromandelic acid.
Embodiment 3:
The synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate, the specific steps of synthesis are as follows:
Step 1: 2.8g parachloromandelic acid being placed in the single port bottle of 100mL, it is molten that the ethyl alcohol that 30mL concentration is 95% is added
Then (R)-phenyl ethylamine of 1.9mL is added dropwise under agitation, is heated to reflux 15min after mixing for liquid, stirring to whole dissolutions,
Solid is dissolved, is then slowly cooled to room temperature, crude product 2.413g is obtained by filtration；
Step 2: the crude product that step 1 obtains being recrystallized twice in 95% ethyl alcohol, it is right to obtain (R)-phenyl ethylamine (R)-
Chloro mandelic acid 1.25g；
Step 3: (R)-phenyl ethylamine (R)-parachloromandelic acid that step 1 obtains being dissolved in 16mL water, adds hydrochloric acid to adjust molten
Then the pH to 1 of liquid is extracted with ethyl acetate three times, merge organic phase, anhydrous sodium sulfate is dry, and evaporating solvent under reduced pressure obtains white
Color solid (R)-parachloromandelic acid 0.67g.
(R)-parachloromandelic acid nmr spectrum data:1H-NMR (DMSO-d6,600MHz, ppm): 12.58 (s,
2H ,-OH ,-COOH), 7.42 (d, 4H), 5.04 (s, 1H)13C-NMR (DMSO-d6,150MHz, ppm): δ 173.7,139.2,
132.1,128.4,128.4,128.1,128.1,71.6.
Embodiment 4:
The synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate, the specific steps of synthesis are as follows:
Step 1: 2.8g parachloromandelic acid being placed in the single port bottle of 100mL, it is molten that the ethyl alcohol that 30mL concentration is 95% is added
Then (R)-phenyl ethylamine of 1.9mL is added dropwise under agitation, is heated to reflux 15min after mixing for liquid, stirring to whole dissolutions,
Solid is dissolved, is then slowly cooled to room temperature, crude product 2.413g is obtained by filtration；
Step 2: the crude product that step 1 obtains being recrystallized twice in 95% ethyl alcohol, it is right to obtain (R)-phenyl ethylamine (R)-
Chloro mandelic acid 1.25g；
Step 3: (R)-phenyl ethylamine (R)-parachloromandelic acid that step 1 obtains being dissolved in 16mL water, adds hydrochloric acid to adjust molten
Then the pH to 1 of liquid is extracted with ethyl acetate three times, merge organic phase, anhydrous sodium sulfate is dry, and evaporating solvent under reduced pressure obtains white
Color solid (R)-parachloromandelic acid 0.67g contains 0.032% ethyl cinnamate and 0.2% carbonic acid in above-mentioned ethyl acetate
The ethyl acetate of sodium, polarity very little is mainly combined with hydrone with this relatively weaker interaction of dipole-dipole, above-mentioned second
In acetoacetic ester on the one hand ethyl cinnamate and sodium carbonates' presence can be such that the polarity of water solution system further enhances, and make acetic acid
The solubility of ethyl ester is smaller, on the other hand can increase the steric hindrance of ethyl acetate, it is suppressed that (R)-parachloromandelic acid and fractionation
Agent combines, and reduces distribution coefficient and separation factor, so that (R)-parachloromandelic acid enters organic phase, obtains good separation effect
Fruit increases extraction efficiency, while can reduce the load of solvent recovery tower, reduces production cost.
Routine operation in operating procedure of the invention is well known to those skilled in the art, herein without repeating.
Technical solution of the present invention is described in detail in embodiment described above, it should be understood that the above is only
For specific embodiments of the present invention, it is not intended to restrict the invention, all any modifications made in spirit of the invention,
Supplement or similar fashion substitution etc., should all be included in the protection scope of the present invention.
Claims (10)
1. the synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate, it is characterised in that: the novel anti-trioxypurine
Compound Arhalofenate intermediate is (R)-parachloromandelic acid.
2. the synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate according to claim 1, feature
It is: the synthetic method of the intermediate are as follows:
Step 1: resolution solvent will be added in racemic parachloromandelic acid, be allowed to whole dissolutions；
Step 2: resolving agent being added dropwise under agitation, is heated to reflux after mixing, dissolves crystal salt, then slowly cool to room
Crude product is obtained by filtration in temperature；
Step 3: obtained crude product is recrystallized in resolving agent, obtains white, needle-shaped crystals salt, it is spare；
Step 4: crystal salt is soluble in water, the pH of solution is adjusted, is then extracted with ethyl acetate 2-4 times, organic phase is merged, then
Dry with anhydrous sodium sulfate, evaporating solvent under reduced pressure obtains white solid, as (R)-parachloromandelic acid.
3. the synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate according to claim 2, feature
Be: in the step 1 resolution solvent be methanol or 95% ethanol solution or ethyl alcohol or propyl alcohol or isopropanol or ethyl acetate or
Toluene or methylene chloride.
4. the synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate according to claim 2, feature
Be: resolution solvent is 95% ethanol solution in the step 1.
5. the synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate according to claim 4, feature
It is: the N containing 0.032-0.036% in 95% ethanol solution, N- diisopropylethylamine.
6. the synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate according to claim 2, feature
Be: resolving agent is (R)-amine in the step 2.
7. the synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate according to claim 2, feature
Be: resolving agent is (R)-phenyl ethylamine or (R)-naphthalene ethylamine in the step 2.
8. the synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate according to claim 2, feature
Be: the solid-liquid ratio of the racemic parachloromandelic acid and resolution solvent is 1:8-12 (g/mL), racemic to chlorine almond
The molar ratio of acid and resolving agent is 1:0.85-1.15.
9. the synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate according to claim 2, feature
Be: the heating reflux reaction time is 15-90min in the step 2, and reacting outer bath temperature is 70~100 DEG C.
10. the synthetic method of novel anti-trioxypurine compound Arhalofenate intermediate according to claim 2, feature
Be: the solid-liquid ratio of crystal salt and water is 1:10-15 (g/mL) in the step 4, and the pH of solution is adjusted to 0.8-1.2.
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|---|---|---|---|---|
| JP2001072644A (en) * | 1999-09-06 | 2001-03-21 | Yamakawa Yakuhin Kogyo Kk | Production of optically active 2-chloromandelic acid and production intermediate |
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| CN105085234A (en) * | 2015-08-31 | 2015-11-25 | 彭静 | Preparing method of (R)-(-)-4-chloromandelic acid |
| CN105130794A (en) * | 2015-09-02 | 2015-12-09 | 彭静 | Method for preparing S-4-methoxymandelic acid through splitting S-1-phenylethylamine |
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2018
- 2018-09-12 CN CN201811061196.XA patent/CN109232237A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001072644A (en) * | 1999-09-06 | 2001-03-21 | Yamakawa Yakuhin Kogyo Kk | Production of optically active 2-chloromandelic acid and production intermediate |
| CN104744231A (en) * | 2013-12-26 | 2015-07-01 | 天津药物研究院 | Method for splitting 2-hydracrylicacid racemate |
| CN105085234A (en) * | 2015-08-31 | 2015-11-25 | 彭静 | Preparing method of (R)-(-)-4-chloromandelic acid |
| CN105130794A (en) * | 2015-09-02 | 2015-12-09 | 彭静 | Method for preparing S-4-methoxymandelic acid through splitting S-1-phenylethylamine |
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Application publication date: 20190118 |