CN110128324A - A kind of chiral synthesis method of Alvimopan intermediate and its intermediate - Google Patents

Abstract

The invention discloses a chiral synthesis method of an alvimopan intermediate, which is characterized in that the compound (4) is prepared from the formula compound (2) and the compound (3) as starting materials through an asymmetric conjugate addition reaction , Compound (4) finally obtains Compound (1) Alvimopan intermediate through reduction reaction, and its reaction formula is as follows: The present invention provides a brand-new chiral synthesis method of Alvimopan intermediate, which uses relatively cheap raw materials to obtain the target product through a two-step reaction, greatly shortens the reaction steps, improves the total yield of the reaction, and reduces The cost is reduced, and the method has the advantages of high synthetic yield and good product purity.

Description

A kind of chiral synthesis method of Alvimopan intermediate and its intermediate

technical field

The invention belongs to the technical field of drug synthesis, and in particular relates to a chiral synthesis method of an alvimopan intermediate and an intermediate thereof.

Background technique

Alvimopan (common name: Alvimopan, trade name Entereg), chemical name: 2-([(2S)-2-([(3R,4R)-4-(3-hydroxyphenyl)-3, 4-Dimethylpiperidin-1-yl]methyl)-3-phenylpropionyl]amino)acetic acid. The molecular weight of Alvimopan: 424.53; CAS registration number: 156053-89-3; the structural formula is shown in Formula 5:

Alvimopan (Alvimopan) is a highly selective peripheral μ-type opioid receptor antagonist developed by GlaxoSmithKline (GSK) and Adolor (Adolor), which was listed by FDA in 2008 for the treatment of postoperative Intestinal obstruction (POI). Generally speaking, abdominal surgery, due to the use of opioid analgesics, causes gastrointestinal dysfunction, manifested as anorexia, nausea, flatulence, abdominal distension, reduced defecation, and intestinal obstruction. prolong the patient's hospital stay. The use of selective opioid receptor antagonists can effectively alleviate the above symptoms. Alvimopan’s unique peripheral mechanism of action makes it highly targeted, and it is currently the only drug with good clinical effects in this field.

At present, most of the preparation methods of Alvimopan reported at home and abroad use expensive (3R,4R)-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine as the starting material and methyl acrylate The ester undergoes N-alkylation reaction, followed by benzylation reaction, hydrolysis reaction, amidation reaction, and finally Alvimopan is obtained by hydrolysis. The reaction scheme is as follows:

Foreign literature Improved Process for Preparation of(3R,4R)-3-(3,4-Dimethyl-4-piperidinyl)phenol, A Key Intermediate for the Synthesis of Alvimopan.Org.Process Res.Dev.,2014,18(1) , pp 163–167, the published reaction scheme is as follows:

In the existing Alvimopan synthesis technology at home and abroad, the cost of raw materials is high, the reaction route is long, and more heavy metal oxides are used as catalysts, the heavy metal residues in the product are not easy to remove, and there are still low product yields and poor quality Defects.

Contents of the invention

Purpose of the invention: Aiming at the problems existing in the prior art, the present invention provides a chiral synthesis method of Alvimopan intermediate, which uses relatively cheap raw materials to obtain the target product through two-step reaction, which greatly shortens the reaction steps , the overall reaction yield is improved, the cost is reduced, and the method has the advantages of high synthesis yield, good product purity, and the like.

The present invention also provides an alvimopan intermediate compound (1), and the alvimopan intermediate compound (1) provides a new raw material for the synthesis of alvimopan.

Technical solution: In order to achieve the above object, a chiral synthesis method of Alvimopan intermediate as described in the present invention is characterized in that, the formula compound (2) and compound (3) are used as starting raw materials, through asymmetric The compound (4) is obtained by the conjugate addition reaction, and the compound (4) is finally obtained through the reduction reaction to obtain the compound (1) alvimopan intermediate, and its reaction formula is as follows:

Wherein, the molar ratio of the compound (2) to the compound (3) is 1:1.1˜1:1.5.

As a preference, the compound (2) and the compound (3) undergo asymmetric conjugated addition reaction with a reaction solvent selected from anhydrous tetrahydrofuran, anhydrous diethyl ether, anhydrous methyl tert-butyl ether, anhydrous dichloromethane, One or more of anhydrous toluene, anhydrous tert-butyl ether, anhydrous 2-methyltetrahydrofuran and anhydrous acetonitrile.

Preferably, the reaction temperature of the compound (2) and the compound (3) through the asymmetric conjugate addition reaction is -20° C. to 25° C., and the time is 6-12 hours.

Preferably, the catalyst for the compound (2) and compound (3) undergoing asymmetric conjugate addition reaction is selected from CuCl, CuCl ₂ , CuBr, CuBr ₂ , CuCN, CuBr-SMe ₂ , CuI, CuTC and CuI ₂ one or more of.

As a preference, the chiral ligand structure of the compound (2) and compound (3) undergoing asymmetric conjugated addition reaction is:

The synthetic route of chiral ligand in the present invention is as follows:

Wherein, the molar ratio of the catalyst to the compound (2) is 1:20-100.

¹ H NMR (400MHz, CDCl ₃ ), δ: 1.06-1.98(m, 22H), 1.83(m, 3H), 2.52(m, 12H), 3.46(m, 1H), 3.84(s, 5H, Fc- H), 4.22-4.37 (m, 3H, Fc-H), 7.13-7.69 (m, 6H, Ph). ESI+[M+H] ⁺ = 651.29.

Wherein, the molar ratio of the catalyst to the chiral ligand is 1:1˜1:1.2.

Preferably, the reaction solvent of the reduction reaction of the compound (4) is selected from anhydrous tetrahydrofuran, anhydrous diethyl ether, anhydrous methyl tert-butyl ether, anhydrous dichloromethane, anhydrous toluene, anhydrous tert-butyl ether And one or more of anhydrous 2-methyltetrahydrofuran.

Preferably, the reaction temperature of the reduction reaction of the compound (4) is 0° C. to 25° C., and the time is 4-6 hours.

The Alvimopan intermediate compound (1) synthesized by the chiral synthesis method of the Alvimopan intermediate of the present invention has a structural formula of:

Many processes in the prior art are based on It is the starting material for Alvimopan synthesis, which is expensive. The compound (1) obtained by designing this route in the present invention can be hydrolyzed to replace the Cl atom with -OH, thereby reducing the cost of raw materials and shortening the synthesis steps.

Beneficial effects: Compared with the prior art, the present invention has the following advantages: The present invention provides a new chiral synthesis method of Alvimopan intermediate, which is compared with the Alvimopan intermediate in the prior art The cost of synthetic raw materials is high, the reaction steps are many, the synthetic process is complex, the synthetic method is simple and easy, the cost is low, the yield is high, the product quality is good, the raw materials are cheap and easy to obtain, and it is suitable for large-scale industrial production. At the same time, the synthesized Alvimopan intermediate provides a new intermediate raw material for the preparation of Alvimopan.

Detailed ways

Below in conjunction with embodiment the present invention will be further described.

The method for the detection purity of Alvimopan intermediate HPLC of the present invention:

Test equipment: Agilent 1100 high performance liquid chromatography (DAD detector).

Chromatographic conditions: use OD-H (4.6×250 mm, 5 μm) as a chromatographic column, flow rate: 0.5 ml/min.

Mobile phase A: isopropanol; mobile phase B: n-heptane

Carry out linear gradient elution according to the following table:

time (minutes) Mobile phase A(%) Mobile phase B(%) 0 1 99 30 5 95 50 25 75 60 45 55

UV detection wavelength: 248nm.

Example 1

Preparation of compound (4)

At -20°C, 1.25kg (10.0mol) of compound (2) was added to a 50L reactor in 10L reaction solvent anhydrous dichloromethane, and 19g (0.1mol) of catalyst CuTC and 71.5g of chiral ligand ( 0.11mol), and finally slowly add compound (3) (11mol, 1M tetrahydrofuran solution, i.e. 11mol compound (3) dissolved in tetrahydrofuran, concentration 1mol/L), dropwise after 2 hours, TLC monitors the reaction process for 6-10h , after the reaction was completed, raised to about 0°C, slowly added 5L of saturated ammonium chloride aqueous solution, stirred for 30 minutes and then raised to room temperature, liquid separation, the aqueous phase was extracted with dichloromethane, and then the organic phase was combined, and the organic phase was decompressed Concentrate under low pressure (0.2 mmHg) to obtain the crude product of compound (4), which was recrystallized from ethyl acetate/petroleum ether to obtain 2.23 kg (9.42 mol) of the refined product, the molar yield was 94.2%, and the purity by HPLC was 97.3%.

¹ H NMR (400MHz, DMSO-d ⁶ ), δ7.49–7.06 (m, 5H), 6.53 (s, 1H), 3.37 (m, 2H), 2.99 (q, J=6.6Hz, 1H), 2.01 (dt,J=13.2,5.8Hz,1H),1.79(dt,J=13.2,5.7Hz,1H),1.33(s,3H),1.20(d,J=6.6Hz,3H).

ESI+[M+H] ⁺ ＝238.

Preparation of compound (1)

At 0°C, under the protection of nitrogen, add 2.13kg (9.0mol) of compound (4) to 10L reaction solvent anhydrous tetrahydrofuran into a 20L reaction kettle, slowly add 152g (4mol) of lithium tetrahydrogen, and after 1 hour After the addition is complete, TLC monitors the reaction process for 3-6 hours. After the reaction is completed, rise to room temperature, slowly add 5L saturated ammonium chloride aqueous solution, stir for 30 minutes, separate the liquids, extract the aqueous phase with dichloromethane, and then combine the organic phase and the organic phase Concentrate under reduced pressure (0.2mmHg) to obtain the crude product of compound (1), the crude product is salified with hydrogen chloride to obtain the refined product hydrochloride 2.11kg (8.11mol), and its molar yield is 90.1%, HPLC detection purity: 97.7% .

¹ H NMR (400MHz, DMSO-d ⁶ )δ7.47–7.10(m,5H), 3.17(dt,J=12.5,5.4Hz,1H),2.97–2.79(m,2H),2.62(dd,J =12.5,8.1Hz,1H),2.13(tq,J=8.2,6.5Hz,1H),1.84–1.53(m,2H),1.31(s,3H),1.23(s,1H),0.81(d, J＝6.6Hz,3H).

ESI+[M+H] ⁺ ＝224.

Comparative example 1

The comparative example adopts the same raw material and preparation method as in Example 1, the difference is that no chiral ligand is added in the synthesis of compound (4), the molar yield of compound (4) is 54.5%, and the HPLC detection purity: 80.2% .

Example 2

According to the synthesis method of Example 1, the difference is that the molar ratio of compound (2) to compound (3) is 1:1.2, the reaction temperature is 0°C, the reaction solvent is anhydrous dichloromethane, the catalyst is CuBr ₂ , the catalyst The molar ratio of the catalyst to the compound (2) is 1:60; the molar ratio of the catalyst to the chiral ligand is 1:1.2. Its molar yield is 94.5%, and the HPLC detection purity: 98.25%.

The reaction solvent of the reduction reaction of compound (4) is anhydrous diethyl ether, and the reaction temperature is 25°C. Its molar yield is 90.3%, and the HPLC detection purity: 97.5%.

Example 3

According to the synthesis method of Example 1, the difference is that the molar ratio of compound (2) to compound (3) is 1:1.5, the reaction temperature is 25°C, the reaction solvent is anhydrous acetonitrile, the catalyst is CuCl ₂ , the catalyst and the compound (2) The molar ratio is 1:20; the molar ratio of the catalyst to the chiral ligand is 1:1. Its molar yield is 92.3%, and the HPLC detection purity: 97.4%.

The reaction solvent of the reduction reaction of compound (4) is anhydrous methyl tert-butyl ether, and the reaction temperature is 20°C. Its molar yield is 90.2%, and the HPLC detection purity: 98.32%.

Claims (10)

1. a kind of Chiral Synthesis of Aiweimopan intermediate, which is characterized in that made by formula compound (2) and compound (3) It for starting material, is reacted through asymmetric conjugated reaction and compound (4) is made, chemical combination is finally made through reduction reaction in compound (4) Object (1) Aiweimopan intermediate, reaction equation are as follows:

2. the Chiral Synthesis of Aiweimopan intermediate according to claim 1, which is characterized in that the compound (2) and the molar ratio of compound (3) is 1:1.1~1:1.5.

3. the Chiral Synthesis of Aiweimopan intermediate according to claim 1, which is characterized in that the compound (2) and reaction dissolvent of the compound (3) by asymmetric conjugated reaction reaction preferably is selected from anhydrous tetrahydro furan, anhydrous ether, nothing Water methyl tertiary butyl ether(MTBE), anhydrous methylene chloride, dry toluene, anhydrous tertbutyl ether, anhydrous 2- methyltetrahydrofuran and anhydrous second One or more of nitrile.

4. the Chiral Synthesis of Aiweimopan intermediate according to claim 1, which is characterized in that the compound (2) and reaction temperature of the compound (3) by asymmetric conjugated reaction reaction is -20 DEG C~25 DEG C, time 6-10h.

5. the Chiral Synthesis of Aiweimopan intermediate according to claim 1, which is characterized in that the compound (2) and catalyst of the compound (3) by asymmetric conjugated reaction reaction is selected from CuCl, CuCl₂、CuBr、CuBr₂、CuCN、 CuBr-SMe₂, CuI, CuTC and CuI₂One or more of.

6. the Chiral Synthesis of Aiweimopan intermediate according to claim 1, which is characterized in that the compound (2) and compound (3) passes through the chiral ligand structure that asymmetric conjugated reaction reacts are as follows:

7. the Chiral Synthesis of Aiweimopan intermediate according to claim 4, which is characterized in that the catalyst with The molar ratio of compound (2) is 1:20~100.

8. the Chiral Synthesis of Aiweimopan intermediate according to claim 5, which is characterized in that the catalyst with The molar ratio of chiral ligand is 1:1~1:1.2.

9. the Chiral Synthesis of Aiweimopan intermediate according to claim 4, which is characterized in that the compound (4) reaction dissolvent of reduction reaction is selected from anhydrous tetrahydro furan, anhydrous ether, anhydrous methyl tertbutyl ether, anhydrous dichloromethane One or more of alkane, dry toluene, anhydrous tertbutyl ether and anhydrous 2- methyltetrahydrofuran, the compound (4) are gone back The reaction temperature of original reaction is 0 DEG C~25 DEG C, time 3-6h.

10. among Aiweimopan synthesized by a kind of Chiral Synthesis of Aiweimopan intermediate as described in claim 1 Body compound (1), structural formula are as follows: