CN104892509B - Nuo get Si Ta preparation method - Google Patents
Nuo get Si Ta preparation method Download PDFInfo
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- CN104892509B CN104892509B CN201510299804.0A CN201510299804A CN104892509B CN 104892509 B CN104892509 B CN 104892509B CN 201510299804 A CN201510299804 A CN 201510299804A CN 104892509 B CN104892509 B CN 104892509B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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Abstract
Present invention is disclosed a kind of Nuo get Si Ta (Roxadustat) preparation method, its preparation process includes：Using tyrosine as raw material, through being esterified, being etherified, being cyclized, dehydrogenation, oxidation is reset and Nuo get Si Ta is made in acylation reaction.The preparation method raw material is easy to get, and concise in technology is economic and environment-friendly, is adapted to industrialized production.
Description
Technical field
It is more particularly to a kind of the invention belongs to organic synthetic route design and its bulk drug and intermediate preparing technical field
It is possibly used for treating the medicine Nuo get Si Ta of chronic anaemia preparation method.
Background technology
Nuo get Si Ta (Roxadustat) is researched and developed by Fibrogen Inc of the U.S. (FibroGen), Astellas and A Si
A kind of micromolecular inhibitor of hypoxia inducible factor (HIF) prolyl hydroxylase that Li Kang obtains the arthorization, code name FG-
4592.Brand-new oral drugs are initiated as one kind, FG-4592 is currently in the III phase clinical trial stages, for treating chronic renal
The disease anemia related to ESRD.Because the medicine does not have the Chinese translation of standard also, therefore the applicant is herein by it
Transliteration is " Nuo get Si Ta ".
Nuo get Si Ta's (Roxadustat, I) is chemical entitled：N- [(4- hydroxyl -1- methyl -7- phenoxy group -3- isoquinolin)
Carbonyl] glycine, its structural formula is：
The international monopoly WO2004108681 of Yuan Yan companies provides a kind of Nuo get Si Ta intermediates and its by the intermediate
Prepare Nuo get Si Ta synthetic route：
Preparation methods and acylation reaction of the international monopoly WO2013013609 of Zhejiang Bei Da companies to core intermediate
Further optimization is carried out, its synthetic route is：
The international monopoly WO2014014834 and WO2014014835 of Yuan Yan companies additionally provide another Nuo get Si Ta systems
Standby synthetic route：
Analyze said synthesis route, although the synthesis constantly to Nuo get Si Ta is improved and optimized, its essential conjunction
Ring mode, the i.e. formation of isoquinolin female ring are essentially identical.Especially isoquinolin changes the incorporation way of methyl or your gold is passed through
Suzuki reaction under element catalysis, otherwise realized by the reduction of amine.Moreover, the enlightenment raw material of above-mentioned reaction scheme is not easy to obtain
, repeatedly need to be protected and deprotection reaction in course of reaction.Obviously, the preparation process is relatively cumbersome, and high expensive is right
Industrialized production brings certain difficulty.
For existing defective workmanship, concise in technology, the economic and environment-friendly and technology of preparing that has good quality are developed, especially
Seek to can adapt to the technology of industrialized production, the economic and social benefit of the medicine, which is improved, has important reality to anticipate
Justice.
The content of the invention
It is easy to get it is an object of the invention to provide a kind of raw material, is concise in technology, economic and environment-friendly and suitable industrialized production
Nuo get Si Ta (Roxadustat) preparation method.
For achieving the above object, present invention employs following main technical schemes：A kind of preparation of Nuo get Si Ta (I)
Method,
It is characterized in that its preparation comprises the following steps：It is tyrosine and methanol, ethanol, propyl alcohol, isopropanol, n-butanol, different
Esterification occurs under percentage by weight 65-98% sulphuric acid catalysis and obtains corresponding tyrosine ester for butanol or the tert-butyl alcohol
(II), the tyrosine ester (II) carries out etherification reaction with chlorobenzene or bromobenzene under catalyst action and 2- amino -3- (4- benzene is made
Phenyl) propionic ester (III), 2- amino -3- (4- Phenoxyphenyls) propionic esters (III) and acetaldehyde are in acid condition
Carry out cyclization and 1- methyl -3- formic acid esters -7- phenoxy groups -1,2,3,4- tetrahydroisoquinolines (IV), the 1- methyl -3- is made
Formic acid esters -7- phenoxy groups -1,2,3,4- tetrahydroisoquinolines (IV) occur in the case where alkali accelerator acts on dehydrogenation reaction be made 1- methyl -
3- formic acid esters -7- phenoxy groups isoquinolin (V), the 1- methyl -3- formic acid esters -7- phenoxy groups isoquinolin (V) is in oxidant and right
Toluene sulfochloride participates in lower generation Oxido-rearrangement and 1- methyl -3- formic acid esters -4- hydroxyl -7- phenoxy group isoquinolin is made
(VI), the 1- methyl -3- formic acid esters -4- hydroxyl -7- phenoxy groups isoquinolin (VI) occurs with glycine under acid binding agent effect
Nuo get Si Ta (I) is made in acylation reaction.
In addition, the present invention also proposes following attached technical scheme：
During the esterification alcohol used be methanol, ethanol, propyl alcohol, isopropanol, n-butanol, isobutanol, the tert-butyl alcohol or
Benzylalcohol, preferably methanol or ethanol.
The etherification reaction raw material tyrosine ester (II) is 1: 0.5-1.5, preferably 1 with the molar ratio of chlorobenzene or bromobenzene
∶1。
The alkali accelerator of the etherification reaction is sodium methoxide, caustic alcohol or sodium hydroxide, preferably sodium methoxide.
The catalyst of the etherification reaction is that copper powder, cupric oxide, cuprous oxide, stannous chloride, cuprous bromide or iodate are sub-
Copper, preferably copper powder or cuprous bromide.
The solvent of the etherification reaction is dimethyl sulfoxide.
The temperature of the etherification reaction is 130-180 DEG C, preferably 170-175 DEG C.
The cyclization is carried out under strongly acidic conditions, thus by adding percentage by weight 33-36% concentrated hydrochloric acid
To realize its acid condition.
The temperature of the cyclization is 90-120 DEG C, preferably 100-105 DEG C.
The dehydrogenation reaction is to be used as the elimination reaction of leaving group by p-toluenesulfonyl (Ts) to realize, so
1- methyl -3- methyl formate -7- phenoxy groups -1,2,3,4- tetrahydroisoquinolines (IV) first act on paratoluensulfonyl chloride in potassium carbonate
Lower formation intermediate state N- p-toluenesulfonyl -1- methyl -3- methyl formate -7- phenoxy groups -1,2,3,4- tetrahydroisoquinolines, then
The intermediate state eliminates p-methyl benzenesulfonic acid again in the presence of alkali accelerator and realizes dehydrogenation reaction.
The alkali accelerator of the dehydrogenation reaction is pyridine, N- methylmorpholines, diisopropylethylamine, 4- dimethylamino pyrroles
Pyridine, potassium carbonate, lithium carbonate, potassium tert-butoxide, sodium hydroxide or potassium hydroxide.
The temperature of the dehydrogenation reaction is 100-160 DEG C, preferably 120-130 DEG C.
The solvent of the dehydrogenation reaction is dioxane, toluene, dimethylbenzene, DMF or dimethyl sulfoxide,
It is preferred that dimethyl sulfoxide.
The Oxido-rearrangement is by the nitrogen oxidation of isoquinolin ring, is then occurred under the catalysis of p-toluenesulfonyl
Rearrangement reaction, realize 4- positions hydroxylating.
The oxidant of the Oxido-rearrangement is benzoyl hydroperoxide, metachloroperbenzoic acid, sodium hypochlorite, ozone or double
Oxygen water, preferably hydrogen peroxide.
The solvent of the Oxido-rearrangement is glacial acetic acid.
The temperature of the Oxido-rearrangement is 25-60 DEG C, preferably 35-45 DEG C.
The acid binding agent of the acylation reaction is sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, ethanol
Sodium, sodium carbonate, potassium carbonate or cesium carbonate, preferably sodium methoxide.
Compared to prior art, Nuo get Si Ta involved in the present invention (I) preparation method, there is raw material to be easy to get, technique
The features such as succinct and economic and environment-friendly, so beneficial to the industrialized production of the bulk drug, promote the development of its economic technology.
Embodiment
Technical solution of the present invention is further non-limitingly described in detail below in conjunction with several preferred embodiments.
Embodiment one：
Adding tyrosine (18.1g, 0.1mmol) and methanol 250mL in dry reaction bottle, ice bath is cooled to 0-5 DEG C, and 1
The concentrated sulfuric acid 10g of percentage by weight 98% is added dropwise in hour.Drop finishes, and is warming up to backflow,.Stirring reaction 16-20 hours, TLC inspections
It is complete to survey reaction.Normal pressure is concentrated, and pure water 100mL is added in residue, with the sodium hydroxide of percentage by weight 10% adjust pH to
6.5-7.0, there is solid precipitation, filter, chlorine cake is washed with first alcohol and water (1: 1), is dried in vacuo to obtain white solid methyl-P-tyrosine
(II) 15.3g, yield 78.5%；EI-MS m/z：196[M+H]+。
Embodiment two：
In blanket of nitrogen and ice bath, in reaction bulb add methyl-P-tyrosine (II) (9.8g, 50mmol), potassium methoxide (3.5g,
50mmol) with methanol 50mL, after the generation of no gas, it is heated to flowing back, stirring reaction 2 hours.Normal pressure concentration removes solvent,
Dimethyl sulfoxide 25mL, the copper powder (0.2g, 3.1mmol) of brand-new are added in residue, 150-155 DEG C is to slowly warm up under stirring,
About after half an hour, bromobenzene (7.9g, 50mmol) is added dropwise, is continuously heating to 170-175 DEG C, stirring reaction 3 hours, TLC detections are instead
It should terminate.60 DEG C are cooled to, methanol is added and keeps micro-boiling, filter while hot, filter cake reusable heat ethanol washs three times, merges organic
Phase, 0 DEG C is cooled to, filtering, vacuum drying obtains white solid 2- amino -3- (4- Phenoxyphenyls) methyl propionate (III)
11.5g, yield 84.9%；EI-MS m/z：272[M+H]+。
Embodiment three：
2- amino -3- (4- Phenoxyphenyls) methyl propionate (III) (10.8g, 40mmol), weight are added in reaction bulb
The acetaldehyde of percentage 40% (20g, 0.2mol) and the concentrated hydrochloric acid 50mL that percentage by weight is 35%, back flow reaction 1 hour.Continue to add
Enter the acetaldehyde of percentage by weight 40% (10g, 0.1mol) and percentage by weight for 35% concentrated hydrochloric acid 25mL, then back flow reaction 3-5
Hour.4-7 DEG C is cooled to, adds ethyl acetate, extracting and demixing.Water layer adjusts pH to 11-12 with sodium hydroxide solution, uses acetic acid
Ethyl ester extract three times, merge organic phase, anhydrous sodium sulfate drying, be concentrated under reduced pressure to give white solid 1- methyl -3- methyl formates -
7- phenoxy groups -1,2,3,4- tetrahydroisoquinolines (IV) 8.4g, yield 70.7%；Mass spectrum (EI)：EI-MS m/z：298[M+H]+。
Example IV：
Under ice bath, 1- methyl -3- methyl formate -7- phenoxy groups -1,2,3,4- tetrahydroisoquinolines are added in reaction bulb
(IV) (5.9g, 20mmol) and dichloromethane 100mL, 0 DEG C adds down potassium carbonate (13.8g, 0.1mol) with stirring, to toluene sulphur
Acyl chlorides (11.4g, 60mmol), finishes, removes ice bath, is stirred at room temperature 3 hours.Add water 30mL, stratification after stirring, organic phase
Watery hydrochloric acid, water and saturated common salt water washing are used successively, is concentrated, and the sodium hydroxide solution of percentage by weight 30% is added in products therefrom
(8.0g, 60mmol) and dimethyl sulfoxide 60mL, 120-130 DEG C is progressively warming up to, stirring reaction 2-4 hours, TLC detection reactions are tied
Beam.Room temperature is down to, adds water 100mL, is extracted with ethyl acetate 3 times, merges organic phase, successively with water and saturated common salt water washing,
Anhydrous magnesium sulfate is dried, concentration, gained grease ethyl acetate and n-hexane (1: 3) recrystallization, is dried in vacuo to obtain off-white color
Solid 1- methyl -3- methyl formates -7- phenoxy groups isoquinolin (V) 5.25g, yield 89.6%；EI-MS m/z：294[M+H]+,1H
NMR(DMSO-d6) δ 2.85 (s, 3H), 3.97 (s, 3H), 7.16-7.24 (m, 3H), 7.49-7.60 (m, 4H), 8.35 (d, J=
9.0,1H), 8.94 (s, 1H).
Embodiment five：
1- methyl -3- methyl formate -7- phenoxy groups isoquinolin (V) (2.93g, 10mmol) and ice vinegar are added in reaction bulb
Sour 50mL, the lower hydrogen peroxide 5mL that percentage by weight 30% is added dropwise is stirred, 60-70 DEG C is warming up to, weight was slowly added dropwise in 10 hours
The hydrogen peroxide 2mL of percentage 30% and glacial acetic acid 12mL mixed liquor is measured, drop finishes, and continues to react 20-24 hours.It is concentrated under reduced pressure, adds
Enter ethanol, continue distillation to eliminate remaining glacial acetic acid.Residue is dissolved with dichloromethane, the carbonic acid of percentage by weight 5%
Hydrogen sodium washs, and separates organic phase, anhydrous sodium sulfate drying.Filtering, add in resulting solution paratoluensulfonyl chloride (3.8g,
20mmol), backflow, stirring reaction 3-4 hours are warming up to, TLC detection reactions terminate.Decompression steams solvent, is down to room temperature, adds
Methanol, there is solid precipitation, be cooled to 0 DEG C, stand overnight.Filtering, filter cake are washed twice with cold methanol, are dried in vacuo to obtain off-white color
Solid 1- methyl -3- methyl formates -4- hydroxyls -7- phenoxy groups isoquinolin (VI) 1.86g, yield 60.2%；EI-MS m/z：310
[M+H]+,1H NMR(DMSO-d6) δ 2.90 (s, 3H), 4.05 (s, 3H), 7.17-7.26 (m, 3H), 7.49-7.61 (m, 4H),
8.38 (d, J=9.0,1H), 11.7 (s, 1H).
Embodiment six：
It is different that 1- methyl -3- methyl formate -4- hydroxyl -7- phenoxy groups are added in magnetic agitation and pressure-resistant reaction bulb
The methanol solution of quinoline (VI) (1.55g, 5mmol), glycine (1.13g, 15mmol) and sodium methoxide (3.25g, 6mmol)
(30mL).Sealing, 120 DEG C are slowly heated to, stirring reaction 8-10 hours, TLC detection reactions terminate.Room temperature is cooled to, is had solid
Body separates out.Filter, gained solid recrystallizing methanol, then be beaten with acetone, gained solid is vacuum dried to obtain white solid promise
Get Si Ta 1.40g, yield 79.5%；EI-MS m/z：353[M+H]+,1H NMR(DMSO-d6) δ 2.72 (s, 3H), 3.99 (d, J
=6.0,2H), 7.18-7.28 (m, 3H), 7.49-7.63 (m, 4H), 8.31 (d, J=8.8,1H), 9.08 (s, 1H), 13.41
(brs, 1H).
It is pointed out that the technical concepts and features of above-described embodiment only to illustrate the invention, ripe its object is to allow
Present disclosure can be understood and implement according to this by knowing the personage of technique, and the protection model of the present invention can not be limited with this
Enclose.Any equivalent change or modification in accordance with the spirit of the invention, it should all be included within the scope of the present invention.
Claims (9)
1. a kind of preparation method of Nuo get Si Ta (I),
It is characterized in that its preparation comprises the following steps：Tyrosine and methanol, ethanol, propyl alcohol, isopropanol, n-butanol, isobutanol
It is described or esterification occurs under percentage by weight 65-98% sulphuric acid catalysis and obtains corresponding tyrosine ester for the tert-butyl alcohol
The catalysis of tyrosine ester and chlorobenzene or bromobenzene in copper powder, cupric oxide, cuprous oxide, stannous chloride, cuprous bromide or cuprous iodide
Effect is lower and 2- amino -3- (4- Phenoxyphenyls) propionic ester, the 2- ammonia is made in the lower progress etherification reaction of alkali accelerator effect
Base -3- (4- Phenoxyphenyls) propionic esters carry out cyclization with acetaldehyde and 1- methyl -3- formic acid esters -7- are made in acid condition
Phenoxy group -1,2,3,4- tetrahydroisoquinolines, the 1- methyl -3- formic acid esters -7- phenoxy groups -1,2,3,4- tetrahydroisoquinolines are in alkali
Accelerator effect is lower to occur the obtained 1- methyl -3- formic acid esters -7- phenoxy group isoquinolin of dehydrogenation reaction, the 1- methyl -3- formic acid
Ester -7- phenoxy groups isoquinolin occurs Oxido-rearrangement in the case where oxidant and paratoluensulfonyl chloride participate in and 1- methyl -3- first is made
Acid esters -4- hydroxyl -7- phenoxy group isoquinolin, the 1- methyl -3- formic acid esters -4- hydroxyls -7- phenoxy groups isoquinolin and glycine
Acylation reaction occurs under acid binding agent effect Nuo get Si Ta (I) is made.
2. Nuo get Si Ta as claimed in claim 1 preparation method, it is characterised in that the alkali accelerator of the etherification reaction is first
Sodium alkoxide, caustic alcohol or sodium hydroxide.
3. Nuo get Si Ta as claimed in claim 1 preparation method, it is characterised in that the temperature of the etherification reaction is 130-180
℃。
4. Nuo get Si Ta as claimed in claim 1 preparation method, it is characterised in that the temperature of the cyclization is 90-120
℃。
5. Nuo get Si Ta as claimed in claim 1 preparation method, it is characterised in that the alkali accelerator of the dehydrogenation reaction is pyrrole
Pyridine, N- methylmorpholines, diisopropylethylamine, DMAP, potassium carbonate, lithium carbonate, potassium tert-butoxide, sodium hydroxide or
Potassium hydroxide.
6. Nuo get Si Ta as claimed in claim 1 preparation method, it is characterised in that the temperature of the dehydrogenation reaction is 100-160
℃。
7. Nuo get Si Ta as claimed in claim 1 preparation method, it is characterised in that the solvent of the dehydrogenation reaction is dioxy six
Ring, toluene, dimethylbenzene, N,N-dimethylformamide or dimethyl sulfoxide.
8. Nuo get Si Ta as claimed in claim 1 preparation method, it is characterised in that the oxidant of the Oxido-rearrangement is
Benzoyl hydroperoxide, metachloroperbenzoic acid, sodium hypochlorite, ozone or hydrogen peroxide.
9. Nuo get Si Ta as claimed in claim 1 preparation method, it is characterised in that the acid binding agent of the acylation reaction is hydrogen-oxygen
Change sodium, potassium hydroxide, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, caustic alcohol, sodium carbonate, potassium carbonate or cesium carbonate.
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