CN101696174A - O-p-methoxyphenyl-N,N-ethyl dibenzyl-tyrosine and synthesizing method - Google Patents
O-p-methoxyphenyl-N,N-ethyl dibenzyl-tyrosine and synthesizing method Download PDFInfo
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- CN101696174A CN101696174A CN200910153224A CN200910153224A CN101696174A CN 101696174 A CN101696174 A CN 101696174A CN 200910153224 A CN200910153224 A CN 200910153224A CN 200910153224 A CN200910153224 A CN 200910153224A CN 101696174 A CN101696174 A CN 101696174A
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Abstract
The invention discloses an O-p-methoxyphenyl-N,N-ethyl dibenzyl-tyrosine and a synthesizing method. N,N-ethyl dibenzyl-tyrosine and para-bromoanisole are taken as raw materials; under the catalysis of blue vitriod or monohydrate cupric acetate, potassium phosphate is used as alkali, N,N-dimethylglycine hydrochloride is used as a ligand, and coupled reaction is carried out in N,N-dimethylformamide or N-methylpyrrolidone solution at 100 DEG C to obtain the O-p-methoxyphenyl-N,N-ethyl dibenzyl-tyrosine with middling yield and excellent optical purity. In the method, a cuprous salt with poor stability to air and high price is not used as a catalyst, but the potassium phosphate with low price is used as an acid-binding agent, the cheap para-bromoanisole is used as a coupling component, and inert gases for protection and a solvent for purification are not needed during reaction. The preparation method has simple and convenient operation, less equipment requirements, low reaction cost, short process flow and favorable industrialized application prospect and can be developed and used for producing dextrothyroxine sodium.
Description
Technical field
The present invention relates to organic synthesis and pharmaceutical intermediate preparation method, especially relate to organic synthesis and pharmaceutical intermediate and prepare O-p-methoxyphenyl-N, N-ethyl dibenzyl-tyrosine and synthetic method, gained compound can further be developed and be used for the synthetic of L-levothyroxine sodium.
Background technology
L-levothyroxine sodium (L-Thyroxine, L-T
4Structural formula is as shown below) be by Sando company under the U.S. Novartis Co.,Ltd and the exploitation of MOVA drugmaker joint research and development and in June, 2004 specifics through all kinds of illnesss of treatment Tiroidina of drugs approved by FDA listing, this comprises thyromegaly, cretinism, thyroid function morbid state syndromes, hyperthyroidism, thyroid function decline, thyroiditis and thyroid carcinoma etc.L-T
4But metabolism is thyroid homology synthetic hormone L-T in vivo
3, do not produce serious toxic side effect after therefore taking for a long time, be the choice drug of all kinds of thyroid diseases of treatment.
In the synthesis step of this medicine, general bifunctional protection (i.e. the protection of amino and carboxyl), the coupling that needs to experience L-tyrosine forms two aryl oxide intermediates, iodate, goes processes such as protection, salify.Although the order of these steps can have variation successively, the reaction that wherein forms two aryl oxides is a most key step.At present, known route and the method for synthetic L-Thyroxine mainly contain following several:
(1)Tetrahedron?Lett.，1998，39，2937.
Coupling step in this method adopt price very expensive be the coupling component to methoxyphenylboronic acid, and venus crystals need use stoichiometric consumption, triethylamine needs greatly excessive (5 times of amounts), reaction needed was carried out 18 hours at least.Obviously, the cost height of this route can't be realized suitability for industrialized production.
(2)J.Chem.Soc.，1949，3424.
Two aryl oxide intermediates need experience two-step reaction and could obtain in this route.In order to improve the ability of leaving away of the OTs group that forms on the intermediate, on the tyrosine substrate, increased by two strong electrophilic nitros, syntheticly brought loaded down with trivial details subsequent step and L-Thyroxine is given in the introducing of these two groups.
(3)J.Am.Chem.Soc.，1959，81，871；Tetrahedron?Lett.，1997，38，6965.
Though to generate the productive rate in two aryl oxides one step very high in coupling in this route, but the coupling component is the spiral cyclopropane of unstable chemcial property, it prepares, and not only step is tediously long, cost an arm and a leg and bigger oxygenant and the iodinating agent of toxicity but also need to use, therefore also being one can't realize industrialized route.
(4)US?Patent?2889364；2889363；5917087.
This is one the simplest and the most direct in the known synthetic L-Thyroxine route, but in the coupling step that generates two aryl oxides, exist the safety and efficiency problem that some are unfavorable for scale operation, for example needed to use highly compressed liquid-air, reaction times needs at least 24 hours, and productive rate has only 41%.
This shows that critical one step of coupling remains in many being worth and further improves and improvements in the existing synthetic L-Thyroxine route.O-p-methoxyphenyl-N, N-ethyl dibenzyl-tyrosine (structural formula is as shown below) are the important intermediate that is used to prepare L-Thyroxine that the present invention develops, through follow-up iodate, go protection, can obtain L-Thyroxine behind the salify.
O-p-methoxyphenyl-N, the N-ethyl dibenzyl-tyrosine
The purpose of selecting two benzyls that the amino on the L-tyrosine is protected is follow-up more or less freely when going to protect, and can not cause the racemization of product chiral centre during simultaneously with coupling component generation linked reaction.
The Ullmann reaction is one of important method of preparation two aryl oxides, but classical Ullmann reaction is that fragrant halogen and phenates under 250～300 ℃ of high temperature coupling are taking place under the copper powder effect, condition harshness not only, and need stoichiometry or excessive copper powder such as use, make scale operation face huge environmental stress, many functional groups cause byproduct of reaction more because of tolerating hot conditions like this simultaneously, and the principal product yield is low.People have carried out a large amount of research to improve this reaction in recent years, can realize promoted this reaction in copper source under the catalysis metering now, and find that the principal element that this reaction of promotion is effectively carried out is the kind and the character of part, and the kind of acid binding agent and character.In addition, the kind in temperature of reaction, reaction medium, coupling component and copper source etc. also has certain influence to this reaction.Therefore, the present invention adopts the Ullmann reaction, with the para-bromoanisole is coupling component, N, the N-ethyl dibenzyl-tyrosine is substrate, N, the N-dimethyl glycine hydrochloride is a part, under a cupric sulfate pentahydrate or a water cupric acetate catalyzed, is acid binding agent with potassiumphosphate, with important intermediate O-p-methoxyphenyl-N of medium chemical yield and the synthetic L-Thyroxine of good optical purity preparation, N-ethyl dibenzyl-tyrosine.
Summary of the invention
One of purpose of the present invention is to provide a kind of two new aryl oxide compounds, i.e. O-p-methoxyphenyl-N, and the N-ethyl dibenzyl-tyrosine, it can be used for the preparation of L-Thyroxine.
Two of purpose of the present invention is to provide a kind of preparation method of above-claimed cpd.
For achieving the above object, reaction mechanism of the present invention is as follows:
According to above-mentioned reaction mechanism, the present invention takes following technical scheme, it is characterized in that this method is:
With the cupric salt is catalyzer, and amount ranges is N, 15%～30% of N-ethyl dibenzyl-tyrosine consumption; With N, the N-dimethyl glycine hydrochloride is a part, and its amount ranges is N, 22～45% of N-ethyl dibenzyl-tyrosine consumption; With the potassiumphosphate is acid binding agent, and amount ranges is N, 1.05～1.8 times of N-ethyl dibenzyl-tyrosine consumption; With the para-bromoanisole is coupling component, and amount ranges is N, 1.2～2 times of N-ethyl dibenzyl-tyrosine consumption; With N, dinethylformamide or N-Methyl pyrrolidone are solvent, and amount ranges is N, 50～80 times (above ratio is mol ratio) of N-ethyl dibenzyl-tyrosine consumption; The temperature range of reaction is 90～110 ℃; The time of reacting required is 7-10 hour; The optimum amount ratio of reaction is a cupric salt: part: potassiumphosphate: para-bromoanisole: N, N-ethyl dibenzyl-tyrosine are 0.2: 0.35: 1.3: 1.3: 1; The top condition of reaction is: temperature of reaction is 100 ℃, and the reaction times is 8 hours; Described cupric salt is a cupric sulfate pentahydrate or a water venus crystals.
Reaction finishes and reaction solution is chilled to the room temperature after-filtration, uses extracted with diethyl ether after the adding suitable quantity of water in the filtrate, and filter cake washs with an amount of ether, and the organic liquor of merging washes after drying with water 2～3 times.Obtain thick product after concentrating, carry out chromatographic separation with petrol ether/ethyl acetate (10: 1) for eluent on silica gel column chromatography, the final light yellow transparent thick liquid that obtains is O-p-methoxyphenyl-N, the N-ethyl dibenzyl-tyrosine.The optical purity of product (the e.e.% value is 85.4～95.3%) is measured (Waters 600E-2487 type on high performance liquid chromatograph, Daicel OJ-H chiral capillary column, moving phase normal hexane/ethanol/trifluoroacetic acid (85: 15: 0.1 volume ratios, flow velocity 1.0mL/min, UV-detector 220nm), the specific rotation light value is measured on Autopol IV type digital display trace polarimeter.The physical data of this compound is as follows:
Molecular formula: C
32H
33NO
4Molecular weight: 495.62
Outward appearance: light yellow transparent thick liquid specific rotation light value :-47.5 ° (C=1, ethanol)
Infrared spectra (Varian Avatar-II type infrared spectrometer, KBr membrane process):
v＝3026，2933，2832，1722，1496，1228，1029，823，791，695cm-1
Nucleus magnetic resonance
1H composes (Brucker Avance II type 400MHz liquid superconduction nuclear magnetic resonance spectrometer, deuterochloroform)
δ＝1.30(t，J＝7.2Hz，3H)，2.96(m，1H)；3.06(dd，J
1＝7.2Hz，J
2＝14Hz，1H)，3.58(m，3H)，3.81(s，3H)，3.96(d，J＝14Hz，2H)，4.18(d，J＝7.2Hz，1H)，4.23(d，J＝7.2Hz，1H)，6.80～6.98(m，8H)，7.24(m，10H)ppm
Nucleus magnetic resonance
13C composes (Brucker Avance II type 100MHz liquid superconduction nuclear magnetic resonance spectrometer, deuterochloroform)
δ＝14.55，35.00，54.52，55.70，60.27，62.44，114.86，117.71，120.33，127.06，128.22，128.84，130.58，150.72，155.74，156.79，172.13ppm
Mass spectrum (HP 1198 type mass spectrometers, 70eV electron-bombardment)
m/z(％)495(M
+，2)，422(M-CO
2Et，27)，282([M+1]-CH
3OC
6H
4O-C
6H
5CH
2，100)，213(32)，181(30)，91(C
6H
5CH
2，97)，77(15)，65(25).
The beneficial effect that the present invention has is:
(1) does acid binding agent with cheap potassiumphosphate, replace expensive alkali such as cesium carbonate or cesium fluoride, reaction cost is reduced greatly;
(2) with cheapness and to the cupric salt hydrate replacement of air-stable air-sensitive and expensive cuprous salt are made catalyzer, thereby can simplify the operating process of reaction greatly and reduce the cost that product prepares;
(3) replace expensive iodide as the coupling component that generates two aryl oxides with cheap bromide, significantly saved the cost of reaction;
(4) building-up reactions need not protection of inert gas, also need not to use through removing the organic solvent of water deoxygenation purifying, has reduced reaction cost effectively and has simplified operating process;
(5) reaction product has excellent optical purity;
(6) reaction times is short, temperature is lower and operational safety, need not to use the High Temperature High Pressure synthesis condition;
(7) catalyzer and part source is abundant, cheap, and consumption is few, the catalytic efficiency height.
Above-mentioned these advantages, make the present invention have characteristics such as reaction cost is low, synthesis cycle is short, processing safety is high, equipment requirements is few, product optical purity excellence, be very suitable for suitability for industrialized production, and can further develop the scale operation that is used for the L-levothyroxine sodium.
Embodiment
Following experiment is used to set forth the present invention for example, rather than is used to limit to the present invention.
Embodiment 1:
Under the normal temperature, with para-bromoanisole (13mmol, 2.43g), N, the N-ethyl dibenzyl-tyrosine (10mmol, 4.21g), potassiumphosphate (13mmol, 2.75g), N, N-dimethyl glycine hydrochloride (3.5mmol, 0.49g) and cupric sulfate pentahydrate (2mmol 0.49g) places and fills N, in the 100mL there-necked flask of dinethylformamide (50mL).The suspension liquid of said mixture was 100 ℃ of following heated and stirred reactions 8 hours.Reaction finishes and reaction solution is chilled to the room temperature after-filtration, uses extracted with diethyl ether after the adding suitable quantity of water in the filtrate, and filter cake washs with an amount of ether, and the organic liquor of merging is spent the night with anhydrous sodium sulfate drying after washing 2～3 times with water.Siccative is filtered, and filtrate obtains thick product behind concentrating under reduced pressure on the Rotary Evaporators.On silica gel column chromatography with petrol ether/ethyl acetate (10: 1) for eluent carries out chromatographic separation, obtain light yellow transparent thick liquid and be target compound.Productive rate is 54.7%, and e.e% is 93.8%.
Embodiment 2:
Under the normal temperature, with para-bromoanisole (13mmol, 2.43g), N, the N-ethyl dibenzyl-tyrosine (10mmol, 4.21g), potassiumphosphate (13mmol, 2.75g), N, N-dimethyl glycine hydrochloride (3.5mmol, 0.49g) and a hydrated copper acetate (2mmol 0.40g) places and fills N, in the 100mL there-necked flask of dinethylformamide (50mL).The suspension liquid of said mixture was 100 ℃ of following heated and stirred reactions 8 hours.Post-processing operation obtains light yellow transparent thick liquid product with embodiment 1.Productive rate is 48.5%, and e.e% is 92.7%.
Embodiment 3:
Under the normal temperature, with para-bromoanisole (13mmol, 2.43g), N, N-ethyl dibenzyl-tyrosine (10mmol, 4.21g), potassiumphosphate (13mmol, 2.75g), N, N-dimethyl glycine hydrochloride (3.5mmol, 0.49g) and cupric sulfate pentahydrate (2mmol 0.49g) places the 100mL there-necked flask that fills N-Methyl pyrrolidone (50mL).The suspension liquid of said mixture was 100 ℃ of following heated and stirred reactions 8 hours.Post-processing operation obtains light yellow transparent thick liquid product with embodiment 1.Productive rate is 56.1%, and e.e% is 90.2%.
Embodiment 4:
Under the normal temperature, with para-bromoanisole (13mmol, 2.43g), N, the N-ethyl dibenzyl-tyrosine (10mmol, 4.21g), potassiumphosphate (13mmol, 2.75g), N, N-dimethyl glycine hydrochloride (3.5mmol, 0.49g) and cupric sulfate pentahydrate (2mmol 0.49g) places and fills N, in the 100mL there-necked flask of dinethylformamide (50mL).The suspension liquid of said mixture was 100 ℃ of following heated and stirred reactions 7 hours.Post-processing operation obtains light yellow transparent thick liquid product with embodiment 1.Productive rate is 51.9%, and e.e% is 86.1%.
Embodiment 5:
Under the normal temperature, with para-bromoanisole (13mmol, 2.43g), N, the N-ethyl dibenzyl-tyrosine (10mmol, 4.21g), potassiumphosphate (13mmol, 2.75g), N, N-dimethyl glycine hydrochloride (3.5mmol, 0.49g) and cupric sulfate pentahydrate (2mmol 0.49g) places and fills N, in the 100mL there-necked flask of dinethylformamide (50mL).The suspension liquid of said mixture was 100 ℃ of following heated and stirred reactions 10 hours.Post-processing operation obtains light yellow transparent thick liquid product with embodiment 1.Productive rate is 56.7%, and e.e% is 89.4%.
Embodiment 6:
Under the normal temperature, with para-bromoanisole (13mmol, 2.43g), N, the N-ethyl dibenzyl-tyrosine (10mmol, 4.21g), potassiumphosphate (13mmol, 2.75g), N, N-dimethyl glycine hydrochloride (3.5mmol, 0.49g) and cupric sulfate pentahydrate (2mmol 0.49g) places and fills N, in the 100mL there-necked flask of dinethylformamide (50mL).The suspension liquid of said mixture was 110 ℃ of following heated and stirred reactions 8 hours.Post-processing operation obtains light yellow transparent thick liquid product with embodiment 1.Productive rate is 52.4%, and e.e% is 90.9%.
Embodiment 7:
Under the normal temperature, with para-bromoanisole (20mmol, 3.73g), N, the N-ethyl dibenzyl-tyrosine (10mmol, 4.21g), potassiumphosphate (13mmol, 2.75g), N, N-dimethyl glycine hydrochloride (3.5mmol, 0.49g) and cupric sulfate pentahydrate (2mmol 0.49g) places and fills N, in the 100mL there-necked flask of dinethylformamide (50mL).The suspension liquid of said mixture was 100 ℃ of following heated and stirred reactions 8 hours.Post-processing operation obtains light yellow transparent thick liquid product with embodiment 1.Productive rate is 59.3%, and e.e% is 92.8%.
Embodiment 8:
Under the normal temperature, with para-bromoanisole (13mmol, 2.43g), N, the N-ethyl dibenzyl-tyrosine (10mmol, 4.21g), potassiumphosphate (18mmol, 3.81g), N, N-dimethyl glycine hydrochloride (3.5mmol, 0.49g) and cupric sulfate pentahydrate (2mmol 0.49g) places and fills N, in the 100mL there-necked flask of dinethylformamide (50mL).The suspension liquid of said mixture was 100 ℃ of following heated and stirred reactions 8 hours.Post-processing operation obtains light yellow transparent thick liquid product with embodiment 1.Productive rate is 51.8%, and e.e% is 85.4%.
Embodiment 9:
Under the normal temperature, with para-bromoanisole (13mmol, 2.43g), N, the N-ethyl dibenzyl-tyrosine (10mmol, 4.21g), potassiumphosphate (13mmol, 2.75g), N, N-dimethyl glycine hydrochloride (4.5mmol, 0.63g) and cupric sulfate pentahydrate (2mmol 0.49g) places and fills N, in the 100mL there-necked flask of dinethylformamide (50mL).The suspension liquid of said mixture was 100 ℃ of following heated and stirred reactions 8 hours.Post-processing operation obtains light yellow transparent thick liquid product with embodiment 1.Productive rate is 50.5%, and e.e% is 95.3%.
Embodiment 10:
Under the normal temperature, with para-bromoanisole (13mmol, 2.43g), N, the N-ethyl dibenzyl-tyrosine (10mmol, 4.21g), potassiumphosphate (10.5mmol, 2.22g), N, N-dimethyl glycine hydrochloride (3.5mmol, 0.49g) and cupric sulfate pentahydrate (2mmol 0.49g) places and fills N, in the 100mL there-necked flask of dinethylformamide (50mL).The suspension liquid of said mixture was 100 ℃ of following heated and stirred reactions 8 hours.Post-processing operation obtains light yellow transparent thick liquid product with embodiment 1.Productive rate is 55.1%, and e.e% is 92%.
Embodiment 11:
Under the normal temperature, with para-bromoanisole (13mmol, 2.43g), N, the N-ethyl dibenzyl-tyrosine (10mmol, 4.21g), potassiumphosphate (13mmol, 2.75g), N, N-dimethyl glycine hydrochloride (3.5mmol, 0.49g) and cupric sulfate pentahydrate (3mmol 0.74g) places and fills N, in the 100mL there-necked flask of dinethylformamide (50mL).The suspension liquid of said mixture was 100 ℃ of following heated and stirred reactions 8 hours.Post-processing operation obtains light yellow transparent thick liquid product with embodiment 1.Productive rate is 55.6%, and e.e% is 91.6%.
Claims (5)
1.O-p-methoxyphenyl-N, the N-ethyl dibenzyl-tyrosine, its structural formula is as follows:
2.O-p-methoxyphenyl-N, the synthetic method of N-ethyl dibenzyl-tyrosine is characterized in that: be catalyzer with the cupric salt, and amount ranges be N, and 15%～30% of N-ethyl dibenzyl-tyrosine consumption; With N, the N-dimethyl glycine hydrochloride is a part, and its amount ranges is N, 22～45% of N-ethyl dibenzyl-tyrosine consumption; With the potassiumphosphate is acid binding agent, and amount ranges is N, 1.05～1.8 times of N-ethyl dibenzyl-tyrosine consumption; With the para-bromoanisole is coupling component, and amount ranges is N, 1.2～2 times of N-ethyl dibenzyl-tyrosine consumption; With N, dinethylformamide or N-Methyl pyrrolidone are solvent, and amount ranges is N, 50～80 times of N-ethyl dibenzyl-tyrosine consumption, and above ratio is mol ratio; The temperature range of reaction is 90～110 ℃; The time of reacting required is 7-10 hour.
3. O-p-methoxyphenyl-N according to claim 2, the synthetic method of N-ethyl dibenzyl-tyrosine, it is characterized in that: the optimum amount ratio of reaction is a cupric salt: part: potassiumphosphate: para-bromoanisole: N, N-ethyl dibenzyl-tyrosine are 0.2: 0.35: 1.3: 1.3: 1; The top condition of reaction is: temperature of reaction is 100 ℃, and the reaction times is 8 hours.
4. O-p-methoxyphenyl-N according to claim 2, the synthetic method of N-ethyl dibenzyl-tyrosine is characterized in that: described cupric salt is a cupric sulfate pentahydrate or a water venus crystals.
5. O-p-methoxyphenyl-N according to claim 2, the synthetic method of N-ethyl dibenzyl-tyrosine is characterized in that: the optical purity e.e% value of reaction product is 85.4～95.3%.
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| CN113214132A (en) * | 2021-05-14 | 2021-08-06 | 英科新创（苏州）生物科技有限公司 | Preparation method of hapten iodoacetyl thyroxine active coupling reagent |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113214132A (en) * | 2021-05-14 | 2021-08-06 | 英科新创（苏州）生物科技有限公司 | Preparation method of hapten iodoacetyl thyroxine active coupling reagent |
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Application publication date: 20100421 |