阅读说明：本技术 屈昔多巴关键中间体的拆分方法 (Resolution method of droxidopa key intermediate ) 是由 曾秀秀 张晓娟 于 2017-12-25 设计创作，主要内容包括：本发明涉及屈昔多巴苏式关键中间体(合成路线一、二、三中的关键中间体I、关键中间体II、关键中间体III)的拆分方法,其特征在于采用非生物碱、商业化易得、价格便宜的S-二苯基脯氨醇为拆分剂,采用10倍-20倍溶剂,0.6-1.0摩尔当量的拆分剂,回流反应,于25-45℃析晶,拆分得到关键中间体I,II,III/S-二苯基脯氨醇复盐,然后在酸性条件下将复盐游离,得到L-苏式-关键中间体I,II,III。本发明的拆分方法,拆分收率高、拆分得到的目标产物手性纯度高、拆分剂商业易得、适合工业化生产。(The invention relates to a method for splitting droxidopa threo type key intermediates (key intermediate I, key intermediate II and key intermediate III in a first, a second and a third synthetic routes), which is characterized in that non-alkaloid, commercialized and easily available S-diphenyl prolinol with low price is used as a splitting agent, a 10-20 times solvent and 0.6-1.0 molar equivalent of the splitting agent are used for reflux reaction, crystallization is carried out at 25-45 ℃, key intermediates I, II, III/S-diphenyl prolinol double salt is obtained by splitting, and then the double salt is dissociated under an acidic condition to obtain L-threo type-key intermediates I, II and III. The resolution method has the advantages of high resolution yield, high chiral purity of the target product obtained by resolution, easy commercial availability of the resolving agent and suitability for industrial production.)

1. The resolution method of the droxidopa threo type key intermediate I is characterized in that S-diphenyl prolinol is adopted as a resolving agent in an organic solvent, reflux reaction and cooling crystallization are carried out to obtain a key intermediate I double salt, and then the key intermediate I double salt is dissociated under an acidic condition to obtain the L-threo type key intermediate I, wherein the reaction formula is as follows:

。

2. the resolution method according to claim 1, characterized in that the organic solvent used for resolution is selected from one or more of ethanol, methanol, isopropanol, n-butanol, n-pentanol, tetrahydrofuran, ethyl acetate, toluene, dichloromethane, chloroform and DMF, and is mixed according to any proportion.

3. The resolution solvent according to claim 2, characterized in that one or more of isopropanol, n-butanol, ethyl acetate are preferably mixed in any proportion.

4. The resolution solvent according to claim 2, characterized in that the amount of solvent used is 10-20ml per 1g of key intermediate I.

5. The resolution process according to claim 1, characterized in that the molar amount of the resolving agent is 0.6-1.0 times the molar amount of the key intermediate I.

6. Resolution process according to claim 1, characterized in that the molar amount of resolving agent is preferably 0.6 to 0.7 times the molar amount of key intermediate I.

7. The resolution process according to claim 1, characterized in that the crystallization temperature is 25-45 ℃.

Technical Field

The invention belongs to the technical field of preparation of raw material medicines, and particularly relates to a novel resolution method of a droxidopa key intermediate.

Background

Droxidopa (chemical name: L-threo-3- (3, 4-dihydroxyphenyl) serine) is a synthetic amino acid having the following chemical structural formula:

。

droxidopa can restore abnormally reduced noradrenaline concentration in brain to normal level, so that various symptoms caused by noradrenaline deficiency, such as dizziness, hypodynamia caused by orthostatic hypotension, gait rigidity of a Parkinson disease patient and the like can be improved.

There are many reports on the synthetic route and preparation method of droxidopa, and the summary shows that the following 3 routes are adopted:

route one, reference US4480109, which is a synthetic route of japanese sumitomo pharmaceutical published compound patents of the original research company. According to the patent route, piperonal is used as an initial raw material, firstly, piperonal and glycine are condensed and recrystallized by using water to obtain threo-3- (3, 4-methylenedioxyphenyl) serine, the intermediate reacts with benzyl chloroformate to carry out amino protection to obtain a key intermediate I shown as the following formula, a required L-threo-product is obtained by splitting, and a target product droxidopa is obtained by removing methylene and amino protection, wherein the specific synthetic route is as follows:

。

and a second route: reference is made to the synthetic chemistry of 2012,18,124-127, in which 3, 4-dibenzyloxybenzaldehyde is used as a starting material to replace piperonal, and then the starting material is condensed with glycine, and the product is post-treated to obtain threo-3- (3, 4-dibenzyloxy-phenyl) serine, the intermediate is reacted with benzyl chloroformate to perform amino protection to obtain a key intermediate II shown in the following formula, and the key intermediate II is resolved to obtain a desired L-threo-product, and then the protecting group is removed to obtain a target product droxidopa, specifically the synthetic route is as follows:

。

and a third route: reference WO2013142093, which is an improvement of the original synthesis route, still using piperonal as starting material, first condensing with glycine and then treating to obtain threo-3- (3, 4-methylenedioxyphenyl) serine, then performing amino protection with N-methoxycarbonylphthalimide, resolving to obtain the desired L-threo-product, and then removing the protecting group to obtain the desired droxidopa, the specific synthesis route is as follows:

。

as described above, the currently adopted main routes are route one, route two and route three, the most critical step in the three routes is the resolution of threo-key intermediates (i.e. key intermediate I, key intermediate II and key intermediate III), the resolution quality not only affects the quality of the final product droxidopa, but also the resolution yield has a significant impact on the cost of the final product droxidopa.

However, in the existing literature, most alkaloids such as quinidine, quinine, strychnine, cinchonidine, cinchonine, ephedrine, demethyl ephedrine, dehydroabietylamine and the like are adopted for the resolution of droxidopa threo-key intermediates, and the alkaloids used most are ephedrine and demethyl ephedrine, but the ephedrine and demethyl ephedrine belong to controlled drugs, are limited in commercial purchase and use, are expensive, and limit industrial large-scale use; few resolving agents of non-alkaloid are reported, but the resolution yield and the chiral purity of the resolved L-threo product far do not reach the quality requirement standard of the bulk drugs.

Disclosure of Invention

The invention aims to provide a resolving agent of droxidopa threo-key intermediate and a resolving process thereof, which have the advantages of good resolving effect, easy commercialization and purchase, low cost and suitability for industrial application, aiming at the defects in the existing resolution technology of droxidopa threo-key intermediates (key intermediate I, key intermediate II and key intermediate III).

In the earlier screening process of the droxidopa threo-type key intermediate resolving agent, a novel non-alkaloid resolving agent suitable for the droxidopa threo-type intermediate is found, the resolving agent is easy to commercialize and purchase, the price is low, the resolving effect of the resolving agent applied to the droxidopa threo-type intermediate resolving agent is obviously better than that of the prior art (see examples 1-12), the resolving yield is 40-45%, the yield and purity of an L-type target product after resolving reach 98-99.7%, and the chiral purity requirement can be met without refining raw material medicines.

The invention provides a resolution method of droxidopa threo-key intermediates (key intermediate I, key intermediate II and key intermediate III), which comprises the following reaction steps:

。

in the above reaction, the raw material for resolution is threo-key intermediates (key intermediate I, key intermediate II, key intermediate III) in the most 3 synthetic routes reported at present.

In the reaction, the resolving agent is S-diphenyl prolinol, and the molar dosage of the resolving agent is 0.6 to 1 time, preferably 0.6 to 0.7 time of that of the key intermediate I, the key intermediate II or the key intermediate III.

In the above reaction, the solvent for resolution is selected from one or more of protic solvent including ethanol, methanol, isopropanol, n-butanol, n-pentanol and tetrahydrofuran, and is mixed in any proportion; the aprotic solvent comprises one or more of ethyl acetate, toluene, dichloromethane and chloroform which are mixed according to any proportion; the polar solvent includes DMF. Wherein the protic solvent is preferably isopropanol or n-butanol, and the aprotic solvent is preferably ethyl acetate.

In the above reaction, the ratio of the amount (volume) of the solvent to the weight (g) of the starting material to be resolved is selected from 10:1 to 20:1, preferably 10: 1.

In the reaction, the reaction temperature is reflux, the crystallization temperature is different from the selected solvent and ranges from 25 ℃ to 45 ℃,

preferably 30-45 deg.C.

The advantages of the invention are as follows: the invention aims to provide a method for splitting droxidopa threo-type-key intermediates (key intermediate I, key intermediate II and key intermediate III), which overcomes the defects that alkaloid is generally adopted as a splitting agent in the prior art, commercial purchase is not easy, cost is high and industrial amplification is not easy, and compared with the prior art, the splitting agent and the splitting process adopting the technology of the invention have the following advantages:

1. compared with the tube product alkaloid commonly adopted in the prior art as the resolving agent, the resolving agent S-diphenyl prolinol adopted by the invention is a commercial product, is easy to purchase, has lower price and greatly reduced cost compared with the alkaloid, and is more suitable for industrial production;

2. compared with the resolving agent in the prior art, the resolving agent S-diphenyl prolinol has better resolving effect, the resolving yield is 40-45%, the chiral purity of the L-threo-products (L-threo-key intermediate I, L-threo-key intermediate II and L-threo-key intermediate III) after primary resolution is 98-99.5%, and the chiral purity requirement of the raw material medicaments can be met without refining the chiral purity.

Drawings

FIG. 1: example 1 resolution of the resulting L-threo-key intermediate I chiral purity HPLC profile;

FIG. 2: example 2 resolution of the resulting L-threo-key intermediate II chiral purity HPLC profile;

FIG. 3: example 3 the resulting L-threo-key intermediate III chiral purity HPLC profile was resolved.

Detailed Description

In order to make the technical problems, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the following embodiments, but the present invention is not limited thereto. Any equivalent substitutions of this area of art made in accordance with the present disclosure are intended to be within the scope of the present invention.

Example 1

Putting 3g (0.0088 mol) of the key intermediate I in the first route into a three-necked bottle, adding 30ml of isopropanol, then adding 1.34g (0.0053 mol) of S-diphenylprolinol, heating and refluxing for 30min-1h, cooling the reaction solution to 35 +/-2 ℃, crystallizing for 3h, performing suction filtration, and washing the filtrate with isopropanol to obtain 2.4g of the key intermediate I-S-diphenylprolinol double salt with the yield of 43%.

Dissolving the double salt in 20ml of ethyl acetate, cooling to 10-15 ℃, dropwise adding dilute hydrochloric acid to adjust the pH of the solution to be =2-3, stirring for 30min, layering, extracting a water layer with EA until no product exists, combining organic layers, washing with saturated saline solution, drying and concentrating to be dry, adding 20ml of methanol to dissolve residues, cooling to 10-15 ℃, dropwise adding 50ml of purified water, stirring and crystallizing for 1.5-2h, performing suction filtration, and performing vacuum drying at 45 ℃ overnight to obtain 1.2g of an L-threo-key intermediate I, wherein the yield is 40%, and the chiral purity: 98.54% (HPLC detection pattern is shown in figure 1).

Example 2

Putting 3g (0.0059 mol) of the key intermediate II in the second route into a three-necked bottle, adding 30ml of isopropanol, then adding 0.89g (0.00354 mol) of S-diphenylprolinol, heating and refluxing for 30min-1h, cooling the reaction solution to 30 +/-2 ℃, crystallizing for 3h, carrying out suction filtration, and washing the filtrate with isopropanol to obtain 2.07g of the key intermediate II-S-diphenylprolinol double salt with the yield of 46%.

Dissolving the double salt in 20ml of ethyl acetate, cooling to 10-15 ℃, dropwise adding diluted hydrochloric acid to adjust the pH of the solution to be =2-3, stirring for 30min, layering, extracting a water layer with EA until no product exists, combining organic layers, washing with saturated saline solution, drying and concentrating to be dry, adding 20ml of methanol to dissolve residues, cooling to 10-15 ℃, dropwise adding 50ml of purified water, stirring and crystallizing for 1.5-2h, performing suction filtration, and performing vacuum drying at 45 ℃ overnight to obtain 1.32g of an L-threo key intermediate II, wherein the yield is 44%, and the chiral purity: 99.35% (HPLC detection spectrum is shown in figure 2).

Example 3

Putting 3g (0.0084 mol) of the key intermediate III in the third route into a three-necked bottle, adding 30ml of isopropanol, then adding 1.28g (0.005 mol) of S-diphenyl prolinol, heating and refluxing for 30min-1h, cooling the reaction liquid to 45 +/-2 ℃, crystallizing for 3h, performing suction filtration, and washing the filtrate with isopropanol to obtain 2.19g of the key intermediate III-S-diphenyl prolinol double salt with the yield of 46%.

Dissolving the double salt in 20ml of ethyl acetate, cooling to 10-15 ℃, dropwise adding diluted hydrochloric acid to adjust the pH of the solution to be =2-3, stirring for 30min, layering, extracting a water layer with EA until no product exists, combining organic layers, washing with saturated saline solution, drying and concentrating to be dry, adding 20ml of methanol to dissolve residues, cooling to 10-15 ℃, dropwise adding 50ml of purified water, stirring and crystallizing for 1.5-2h, performing suction filtration, and performing vacuum drying at 45 ℃ overnight to obtain 1.35g of an L-threo key intermediate III, wherein the yield is 45%, and the chiral purity is as follows: 99.68% (HPLC detection pattern is shown in figure 3).

Examples 4 to 12

The yields and chiral purities of the L-target products obtained by the process described in examples 1 to 3, with variation of the resolution solvent, the amount of resolving agent and the crystallization temperature are summarized in the following table:

note: 1. the amounts of resolving agent in the table refer to: the mole multiple of the resolving agent to the resolving raw material;

2. the solvent amounts in the tables refer to: the ratio of the volume of solvent (ml) used to the weight of the starting material to be resolved (g).