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CN111004272B - Preparation method of orlistat chiral intermediate - Google Patents

Preparation method of orlistat chiral intermediate Download PDF

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CN111004272B
CN111004272B CN201911165943.9A CN201911165943A CN111004272B CN 111004272 B CN111004272 B CN 111004272B CN 201911165943 A CN201911165943 A CN 201911165943A CN 111004272 B CN111004272 B CN 111004272B
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reaction
catalyst
orlistat
preparation
chiral intermediate
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CN111004272A (en
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徐亮
蔡祥
李增
蒙发明
李苏泳
李彦雄
郭俊
毛波
丸罔啓二
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Zhongshan Enantiotech Corp ltd
Foshan Yiansai Pharmaceutical Technology Co ltd
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Foshan Yiansai Pharmaceutical Technology Co ltd
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    • B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
    • B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
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Abstract

The invention relates to a preparation method of an orlistat chiral intermediate. The preparation method comprises the following steps: carrying out a pressurized reaction on the reaction raw material 6 at 10-70 ℃ in the presence of a solvent, alkali, a catalyst and hydrogen to obtain an orlistat chiral intermediate 5; the catalyst is a ruthenium catalyst; the ligands of the ruthenium catalyst include phosphine ligands and aminobenzimidazole ligands. The preparation method of the orlistat chiral intermediate 5 has the advantages of mild reaction conditions, clean reaction system, no need of silica gel column chromatography, HPLC and other complex steps in the separation and purification process, and suitability for large-scale production.

Description

Preparation method of orlistat chiral intermediate
Technical Field
The invention relates to the field of organic synthesis, in particular to a preparation method of an orlistat chiral intermediate.
Background
Orlistat, chemical name is (3S, 4S) -3-hexyl-4- [ (2S) -2-hydroxytridecyl ] -2-oxetanone N-formyl-L-leucine ester, and its structural formula is shown as "1" in the following reaction formula. Orlistat (Orlistat) is a representative esterase inhibitor and is the only non-centrally acting weight loss drug approved by the Food and Drug Administration (FDA) in the united states, and its mechanism is to inhibit lipase activity in the pancreas, stomach and intestine, thereby reducing 30% of the fat in the diet to be absorbed by the human body, reducing fat stores in the body, and reducing body weight.
Figure BDA0002287449530000011
Orlistat comprises four chiral centers, one of which is derived from the natural product L-leucine, as shown in the above structural formula "1". The synthetic route is designed for Xu Qinyao and the like of the university of east China, and the asymmetric reduction of the 6 carbonyl group in the compound is particularly critical in the synthetic route, so that the whole chiral construction framework of orlistat is determined. The intermediate 4 is used as a key intermediate in the route, the intermediate 7 is subjected to hydroxyl protection to obtain a compound 6, and the compound is subjected to asymmetric reduction, frater-Seebach alkylation and ester hydrolysis synthesis.
Asymmetric reduction of carbonyl in the process of preparing the compound 5 from the compound 6 is one of the accepted high-efficiency asymmetric reduction methods, but the traditional method usually needs to be carried out under the severe conditions of high temperature and high pressure (100 ℃,3.3 MPa), and is difficult to scale up.
Disclosure of Invention
Based on the above, one of the purposes of the present invention is to provide a preparation method of orlistat chiral intermediate 5, which does not need high temperature and high pressure reaction conditions and is suitable for scale-up production.
The specific technical scheme is as follows:
a preparation method of an orlistat chiral intermediate comprises the following synthetic route:
Figure BDA0002287449530000021
wherein, P is P-methoxybenzyl, trimethylsilyl or methoxymethyl;
the preparation method comprises the following steps: carrying out a pressurized reaction on the reaction raw material 6 at 10-70 ℃ in the presence of a solvent, alkali, a catalyst and hydrogen to obtain an orlistat chiral intermediate 5;
the catalyst is a ruthenium catalyst; the ligands of the ruthenium catalyst comprise phosphine ligands and aminobenzimidazole ligands (English abbreviation: BIMAH).
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a preparation method of an orlistat chiral intermediate 5, which has mild reaction conditions, a clean reaction system and no need of complicated steps such as silica gel column chromatography, HPLC and the like in the separation and purification process and is suitable for large-scale production. According to the preparation method, ruthenium is selected as a catalyst central metal, a phosphine ligand and BIMAH are selected as catalyst ligands, and other reagents are combined, so that the orlistat chiral intermediate 5 can be obtained simply, conveniently and highly in yield and chiral purity.
Detailed Description
In order that the invention may be more readily understood, reference will now be made to the following more particular description of the invention, examples of which are set forth below. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. These embodiments are provided so that this disclosure will be thorough and complete.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The embodiment provides a preparation method of an orlistat chiral intermediate, and the synthetic route of the preparation method is as follows:
Figure BDA0002287449530000031
wherein, P is P-methoxybenzyl (PMB), trimethylsilyl (TMS) or methoxymethyl (MOM);
the preparation method comprises the following steps: carrying out a pressurized reaction on the reaction raw material 6 at 10-70 ℃ in the presence of a solvent, alkali, a catalyst and hydrogen to obtain an orlistat chiral intermediate 5;
the catalyst is a ruthenium catalyst; the ligands of the ruthenium catalyst include phosphine ligands and BIMAH ligands.
In some of these embodiments, the phosphine ligand is selected from at least one of DIOP (2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis (diphenylphosphino)), BINAP (1,1 '-binaphthyl-2,2' -bisdiphenylphosphine), and Josiphos.
In some of these embodiments, the catalyst is (S, S) -dioPRUCL 2 (S) -Me-BIMAH. The structural formula is
Figure BDA0002287449530000032
In some of these embodiments, the solvent is selected from at least one of ethanol, methanol, isopropanol, tetrahydrofuran, toluene, and dichloromethane.
In some of these embodiments, the base is selected from at least one of potassium tert-butoxide, potassium ethoxide, and sodium ethoxide.
The reaction reagent of the invention is simple and easy to obtain, has less three wastes and is environment-friendly.
In some of these embodiments, the temperature of the reaction is 20-50 ℃.
In some of these embodiments, the temperature of the reaction is 35-45 ℃. When the temperature is kept in this range, the yield of the reaction is higher and the isomer selectivity is better. When the temperature is higher than this range, the reaction rate is increased, but the side reactions are increased and the energy consumption is increased; when the temperature is lower than this range, the reaction rate is lowered.
In some of these embodiments, the pressurized pressure P is: p is more than 1atm and less than or equal to 30atm.
In some of these embodiments, the pressurization is at a pressure of (2-20) atm, preferably 2-10atm. The reaction conditions of the invention do not need violent reaction conditions such as high temperature, high pressure and the like, thereby greatly reducing the reaction cost and improving the safety and operability of the reaction.
In some of these embodiments, the molar ratio of the reaction feed 6 to the catalyst is: 1:0.01-0.02.
In some of these embodiments, the molar ratio of the starting material 6 to base is: 1:0.4-1.
In some of these embodiments, the method of preparation comprises the steps of: dissolving a reaction raw material 6 by using a solvent, sequentially adding a catalyst and alkali in an inert gas atmosphere, replacing the inert gas by using hydrogen, performing a pressurized reaction, and separating and purifying after the reaction is finished to obtain an orlistat chiral intermediate 5.
In some of these embodiments, the process of separation and purification comprises the steps of: and filtering the reaction system, concentrating the obtained filtrate, dissolving the concentrate with ethyl acetate, washing with a hydrochloric acid aqueous solution and a NaCl aqueous solution in sequence, and concentrating the obtained organic phase to obtain the orlistat chiral intermediate 5.
The present invention will be described in further detail with reference to specific examples.
(S,S)-diopRuCl 2 (S) -Me-BIMAH: prepared according to the literature Adv.Synth.Catal.2011.353.495-500.
Example 1
Figure BDA0002287449530000041
(1) In a 5L autoclave, in the argon atmosphere, 100g of raw material 6-1 is added from a charging port, 1L of methanol is added to fully dissolve the raw material 6-1, argon is continuously introduced for bubbling degassing, bubbling is continuously carried out for 1h, and degassing is finished. Under argon atmosphere, 0.3g of catalyst (S, S) -diop RuCl was added from a feed port 2 (S) -Me-BIMAH, 12g of potassium tert-butoxide is added finally, and after the addition is finished, the addition port is closed quickly.
(2) Replacing argon with hydrogen, slowly introducing hydrogen to 10atm, and closing the inflation valve. The reaction is carried out at 35-45 ℃ with rapid stirring. When the pressure drops to a level where it remains constant, the reaction is deemed to have stopped. Sampling and detecting liquid phase analysis to confirm the conversion rate. When the conversion is greater than 99.5%, the reaction is considered to be complete. After the reaction is finished, the system is filtered by suction. The catalyst was removed, the filtrate was concentrated under reduced pressure, the residue was dissolved in 0.3L of ethyl acetate, washed with 0.1L of 0.5N aqueous hydrochloric acid and then 0.1L of saturated brine, and the organic phase was concentrated under reduced pressure to give a pale yellow oil 5-1, with a yield of 95.2%, a purity of 99%, and a chiral purity of 99.2%.
Example 2
This example differs from example 1 in that the catalyst used was (S) -bindRuCl 2 (S) -Me-bimaH instead of (S, S) -dioPRUCL 2 (S) -Me-BIMAH. Structural formula is
Figure BDA0002287449530000051
(1) In a 5L autoclave, in an argon atmosphere, adding 100g of raw material 6-1 from a charging port, then adding 1L of methanol to fully dissolve the raw material 6-1, continuing to introduce argon for bubbling degassing, continuously bubbling for 1h, and finishing degassing. Under argon atmosphere, 3.4g of catalyst (S) -bindampRuCl was added from a feed inlet 2 (S) -Me-bimaH, and finally 12g of potassium tert-butoxide is added, and after the addition is completed, the addition port is quickly closed.
(2) Replacing argon with hydrogen, slowly introducing hydrogen to 10atm, and closing the inflation valve. The reaction is carried out at 35-45 ℃ with rapid stirring. When the pressure drops to a level where it remains constant, the reaction is deemed to have stopped. Sampling and liquid phase analysis are carried out to confirm the conversion rate. The reaction is considered complete when the conversion is greater than 99.5%. After the reaction is finished, the system is filtered by suction. The catalyst was removed, the filtrate was concentrated under reduced pressure, the residue was dissolved in 0.3L of ethyl acetate, washed with 0.1L of 0.5N aqueous hydrochloric acid and then 0.1L of saturated brine, and the organic phase was concentrated under reduced pressure to give a pale yellow oil 5-1, 91% yield, 98% purity and 98.6% chiral purity.
Example 3
This example differs from example 1 in that the solvent is toluene instead of methanol.
(1) In a 5L autoclave, in an argon atmosphere, 100g of raw material 6-1 is added from a charging port, 1L of toluene is added to fully dissolve the raw material 6-1, argon is continuously introduced for bubbling degassing, bubbling is continuously carried out for 1h, and degassing is finished. Under an argon atmosphere, 0.3g of catalyst (S, S) -diop RuCl was added from a feed port 2 (S) -Me-BIMAH, and finally 12g of potassium tert-butoxide is added, and after the addition is finished, the addition port is quickly closed.
(2) Replacing argon with hydrogen, slowly introducing hydrogen to 10atm, and closing the inflation valve. The reaction is carried out at 35-45 ℃ with rapid stirring. When the pressure drops to a level where it remains constant, the reaction is deemed to have stopped. Sampling and liquid phase analysis are carried out to confirm the conversion rate. When the conversion is greater than 99.5%, the reaction is considered to be complete. After the reaction is finished, the system is filtered by suction. The catalyst was removed, the filtrate was concentrated under reduced pressure, the residue was dissolved in 0.3L of ethyl acetate, washed with 0.1L of 0.5N aqueous hydrochloric acid and then 0.1L of saturated brine, and the organic phase was concentrated under reduced pressure to give a pale yellow oil 5-1, yield 92%, purity 98.5%, chiral purity 99.1%.
Example 4
This example differs from example 1 in that the solvent is tetrahydrofuran instead of methanol.
(1) In a 5L autoclave, in the argon atmosphere, 100g of raw material 6-1 is added from a charging port, 1L of tetrahydrofuran is added to fully dissolve the raw material 6-1, argon is continuously introduced for bubbling degassing, bubbling is continuously carried out for 1h, and degassing is finished. Under an argon atmosphere, 0.3g of catalyst (S, S) -diop RuCl was added from a feed port 2 (S) -Me-BIMAH, 12g of potassium tert-butoxide is added finally, and after the addition is finished, the addition port is closed quickly.
(2) Replacing argon with hydrogen, slowly introducing hydrogen to 10atm, and closing the inflation valve. The reaction is carried out at 35-45 ℃ with rapid stirring. When the pressure drops to a constant level, the reaction is deemed to have stopped. Sampling and liquid phase analysis are carried out to confirm the conversion rate. When the conversion is greater than 99.5%, the reaction is considered to be complete. After the reaction is finished, the system is filtered by suction. The catalyst was removed, the filtrate was concentrated under reduced pressure, the resulting solution was dissolved in 0.3L of ethyl acetate, washed with 0.1L of 0.5N aqueous hydrochloric acid and then 0.1L of saturated brine, and the organic phase was concentrated under reduced pressure to give a light yellow oil 5-1, yield 90%, purity 98.3%, chiral purity 99.3%.
Example 5
This example differs from example 1 in that the base is sodium ethoxide instead of potassium tert-butoxide.
(1) In a 5L autoclave, in an argon atmosphere, adding 100g of raw material 6-1 from a charging port, then adding 1L of methanol to fully dissolve the raw material 6-1, continuing to introduce argon for bubbling degassing, continuously bubbling for 1h, and finishing degassing. Under an argon atmosphere, 0.3g of catalyst (S, S) -diop RuCl was added from a feed port 2 (S) -Me-BIMAH, 30.28g of sodium ethoxide was added finally, and after the addition was completed, the addition port was closed quickly.
(2) Replacing argon with hydrogen, slowly introducing hydrogen to 10atm, and closing the inflation valve. The reaction is carried out at 35-45 ℃ with rapid stirring. When the pressure drops to a level where it remains constant, the reaction is deemed to have stopped. Sampling and liquid phase analysis are carried out to confirm the conversion rate. When the conversion is greater than 99.5%, the reaction is considered to be complete. After the reaction is finished, the system is filtered by suction. The catalyst was removed, the filtrate was concentrated under reduced pressure, the filtrate was dissolved in 0.3L of ethyl acetate, and then washed with 0.1L of 0.5N aqueous hydrochloric acid and 0.1L of saturated brine, and the organic phase was concentrated under reduced pressure to give 5-1 as a pale yellow oil, in which the yield of 5-1 of the compound of this example was 93.4%, the purity was 97%, and the chiral purity was 99.0%.
Example 6
(1) In a 5L autoclave, in an argon atmosphere, adding 100g of raw material 6-1 from a charging port, then adding 1L of methanol to fully dissolve the raw material 6-1, continuing to introduce argon for bubbling degassing, continuously bubbling for 1h, and finishing degassing. Under an argon atmosphere, 0.3g of catalyst (S, S) -diop RuCl was added from a feed port 2 (S) -Me-BIMAH, 12g of potassium tert-butoxide is added finally, and after the addition is finished, the addition port is closed quickly.
(2) Replacing argon with hydrogen, slowly introducing hydrogen to 10atm, and closing the inflation valve. The reaction was carried out at 65 ℃ with rapid stirring. When the pressure drops to a constant level, the reaction is deemed to have stopped. Sampling and liquid phase analysis are carried out to confirm the conversion rate. When the conversion is greater than 99.5%, the reaction is considered to be complete. After the reaction is finished, the system is filtered by suction. The catalyst was removed, the filtrate was concentrated under reduced pressure, the resulting solution was dissolved in 0.3L of ethyl acetate, washed with 0.1L of 0.5N aqueous hydrochloric acid and then 0.1L of saturated brine, and the organic phase was concentrated under reduced pressure to give a pale yellow oil 5-1, 93% yield, 97.3% purity, and 99.15% chiral purity.
Comparative example 1
This comparative example differs from example 1 in that the catalyst of this comparative example is a catalyst solution obtained as described in the documents Xu Qinyao, yu Jianghui, hu Wenhao, yangping, new scheme [ J ] for orlistat synthesis, organic chemistry, 2010,30 (08): 1177.
(1) In a 5L autoclave, in an argon atmosphere, adding 100g of raw material 6-1 from a charging port, then adding 1L of methanol to fully dissolve the raw material 6-1, continuing to introduce argon for bubbling degassing, continuously bubbling for 1h, and finishing degassing. Under argon atmosphere, a catalyst solution (molar ratio of the raw material 6-1 to the catalyst: 1: 0.005) was fed from a feed port, and after the completion of the feeding, the feed port was rapidly closed.
(2) Replacing argon with hydrogen, slowly introducing hydrogen to 10atm, and closing the inflation valve. The reaction is carried out at 35-45 ℃ with rapid stirring. When the pressure drops to a constant level, the reaction is deemed to have stopped. A sample was taken and analyzed in the liquid phase to confirm the conversion, which indicated that only a small amount of product was formed (< 5% yield).
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (10)

1. The preparation method of the orlistat chiral intermediate is characterized in that the synthetic route of the preparation method is as follows:
Figure FDA0003842268610000011
wherein, P is P-methoxybenzyl, trimethylsilyl or methoxymethyl;
the preparation method comprises the following steps: carrying out a pressurized reaction on the reaction raw material 6 at 10-70 ℃ in the presence of a solvent, alkali, a catalyst and hydrogen to obtain an orlistat chiral intermediate 5;
the catalyst is (S, S) -diphorrucl 2 (S) -Me-BIMAH or (S) -bindRuCl 2 (S) -Me-BIMAH, the catalyst (S, S) -diop RuCl 2 The structural formula of (S) -Me-BIMAH is
Figure FDA0003842268610000012
The catalyst (S) -bindaprrucl 2 The structural formula of (S) -Me-BIMAH is
Figure FDA0003842268610000013
The alkali is selected from at least one of potassium tert-butoxide, potassium ethoxide and sodium ethoxide;
the pressure for pressurization is 2-20atm.
2. The method according to claim 1, wherein the solvent is at least one selected from the group consisting of ethanol, methanol, isopropanol, toluene, tetrahydrofuran, and dichloromethane.
3. The method of claim 1 or 2, wherein the reaction temperature is 20 to 50 ℃.
4. The method according to claim 3, wherein the reaction temperature is 35 to 45 ℃.
5. The production method according to any one of claims 1 or 2, wherein the pressure of the pressurization is 2 to 10atm.
6. The production method according to claim 5, wherein the pressure of the pressurization is 10atm, and the temperature of the reaction is 35 to 45 ℃.
7. The process according to any one of claims 1 or 2, wherein the molar ratio of the starting material 6 to the catalyst is 1:0.01-0.02.
8. The method according to claim 1 or 2, wherein the molar ratio of the reaction raw material 6 to the base is 1:0.4-1.
9. The method for preparing according to claim 1 or 2, characterized in that it comprises the following steps: dissolving a reaction raw material 6 by using a solvent, sequentially adding a catalyst and alkali in an inert gas atmosphere, replacing the inert gas by using hydrogen, performing a pressurized reaction, and performing separation and purification after the reaction to obtain an orlistat chiral intermediate 5, wherein the separation and purification process does not comprise a silica gel column chromatography step and an HPLC step.
10. The method according to claim 9, wherein the separation and purification process comprises the following steps: and filtering the reaction system, concentrating the obtained filtrate, dissolving the concentrate with ethyl acetate, washing with a hydrochloric acid aqueous solution and a NaCl aqueous solution in sequence, and concentrating the obtained organic phase to obtain the orlistat chiral intermediate 5.
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