CN114315679A

CN114315679A - Preparation method of Upactinib chiral intermediate

Info

Publication number: CN114315679A
Application number: CN202210070054.XA
Authority: CN
Inventors: 陈德宝; 丁建圣; 刘艳华
Original assignee: Hangzhou Simbos Pharm Co ltd
Current assignee: Hangzhou Simbos Pharm Co ltd
Priority date: 2022-01-21
Filing date: 2022-01-21
Publication date: 2022-04-12
Anticipated expiration: 2042-01-21
Also published as: CN114315679B

Abstract

The invention relates to a preparation method of a lapatinib chiral intermediate shown in formula 6, which comprises the steps of taking 6-oxa-3-azabicyclo [3.1.0] hexane-3-benzyl carboxylate as a raw material, carrying out asymmetric ring-opening reaction under the catalytic action of a pyridine bis-oxazoline ytterbium chloride complex, sequentially removing C-4-trimethylsilyl groups, forming mesylate with C-4-hydroxy, carrying out a series of reactions of configuration inversion at 4-position, and finally hydrolyzing under an alkaline condition to obtain the lapatinib chiral intermediate compound 6. The method has the advantages of cheap and easily-obtained raw materials, simple process operation, high chiral purity of the product, high atom utilization rate, easy industrialization and higher economic and industrial application values.

Description

Preparation method of Upactinib chiral intermediate

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a preparation method of a chiral intermediate of Upactinib.

Background

Upatinib (Upadacitinib) is a selective and reversible JAK1 inhibitor, is developed by Eberwei pharmaceutical company in America, and shows good curative effect in clinical tests for treating various autoimmune diseases and inflammatory diseases. In 2019, empatinib was marketed in the united states and approved for the treatment of patients with moderate and severe rheumatoid arthritis. In 2021, according to the research result of the key clinical trial, the medicine also submits the application of new indications of ankylosing spondylitis. The structural formula of the sepitinib is as follows:

the lapatinib contains two chiral centers, so the introduction of chiral groups is the key of the preparation process. The (3R,4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid (compound 6) is a key chiral intermediate for preparing the uppatinib, the chiral purity of the compound plays an important role in the quality of the final product of the uppatinib, and the structural formula is as follows:

the synthesis methods of the intermediate (6) of the lapatinib reported in the literature at present are mainly divided into a chiral catalytic synthesis method and a chemical resolution method. The main synthesis methods include the following methods:

method one (CN 110183367A/WO2017066775A1/CN 109369659A):

the method uses ethyl pentynoate or ethyl aminoacetate hydrochloride as a raw material, firstly constructs an achiral five-membered ring through two-step reaction, and then obtains the pyrroline derivative through protective group transformation or alkylation. Finally, the compound 6 is obtained by selective reduction of an expensive chiral catalyst S-segphosRu complex. The catalyst is expensive and the production cost is high.

Method two (CN 104370909A/WO 2019016745A 1):

in the above patent route, ethyl pentynoate is also used as a raw material, alkene is reduced by hydrogenation with a Lindlar catalyst, a racemic intermediate is obtained by ring closure and reduction with Raney nickel, then a Cbz protecting group on benzyl is removed, ester hydrolysis occurs, and finally a target product 6 with high chiral purity is obtained by resolution for more than 3 times. The process is subjected to repeated resolution, is complicated to operate, has the actual yield of below 20 percent, and is not beneficial to industrial production.

Therefore, the synthesis method of the Upacatinib key chiral intermediate (3R,4S) -1-benzyloxycarbonyl-4-ethylpyrrolidine-3-carboxylic acid (compound 6) is needed to be invented, so as to meet the requirements of simple and easily available raw materials, simple process operation, low product process economic cost and high chiral purity of the obtained product.

Disclosure of Invention

The invention aims to provide a preparation method of a chiral intermediate of Upactinib, which has the advantages of cheap and easily obtained raw materials, simple process operation and high chiral purity of a product and is suitable for industrial production.

In order to realize the purpose of the invention, the following technical scheme is adopted:

a method for preparing an uppertinib chiral intermediate (compound 6), comprising the steps of:

(a) reacting the compound 1 with trimethylsilyl cyanide under the catalytic action of a pyridine bis-oxazoline ytterbium chloride complex to obtain a compound 2;

；

(b) reacting the compound 2 under an acidic condition to obtain a compound 3;

；

(c) the compound 3 is subjected to the action of an acid-binding agent and methylsulfonyl chloride to obtain a compound 4;

；

(d) reacting the compound 4 with ethyl magnesium bromide under the catalysis to obtain a compound 5;

；

(e) hydrolyzing the compound 5 under alkaline conditions to obtain a compound 6;

。

wherein, in the reaction step (a), the solvent is dichloromethane or trichloromethane; the reaction temperature is-20 ℃ to 0 ℃; the reaction time is 8-24 hours.

In the reaction step (b), the solvent used is tetrahydrofuran, 2-methyltetrahydrofuran or acetonitrile.

In the reaction step (c), the acid-binding agent is triethylamine, pyridine or N, N-diisopropylethylamine.

In the reaction step (d), the catalyst is ferric acetylacetonate or aluminum acetylacetonate; the reaction temperature is-40 to-10 ℃; the reaction time is 2-8 hours.

In the reaction step (e), the alkali used is potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate; the solvent is methanol or ethanol.

The invention has the beneficial effects that:

the novel preparation method of the Upacatinib key chiral intermediate 6 overcomes the defects of harsh reaction conditions, low chiral purity of the product or high cost caused by using expensive catalysts in multiple steps in the prior art; the method has the advantages of high process efficiency, less side reaction and high economic and industrial application values.

Drawings

Fig. 1 is a high performance liquid chromatogram of the uppertinib chiral intermediate compound 6 of example 1 of the present invention.

Fig. 2 is a nuclear magnetic hydrogen spectrum of the uppertinib chiral intermediate compound 6 of example 1 of the present invention.

Detailed Description

The technical contents of the present invention will be described in detail with reference to examples, which are only for further describing the features of the present invention in detail, and are not intended to limit the scope of the present invention or the scope of the claims of the present invention.

Example 1:

preparation of compound 2: benzyl 6-oxa-3-azabicyclo [3.1.0] hexane-3-carboxylate (compound 1, 100 g, 456 mmol) was charged to a 2L four-necked flask, chloroform (800 mL), 2, 6-bis [ (4R) -4-tert-butyl-2-oxazolinyl ] pyridine (3.0 g, 9.1 mmol), and ytterbium trichloride hexahydrate (3.5 g, 9.1 mmol) were added, and the mixture was stirred at room temperature for 30 min. The temperature is reduced to-15 to-10 ℃, 100ml of trichloromethane solution of trimethylsilyl cyanide (54.3 g, 547 mmol) is slowly dropped, and the mixture is stirred for 12 hours at the temperature of-15 to-10 ℃. After the reaction, the temperature was slowly raised to about 0 ℃, and 500mL of water and 57g of sodium bicarbonate solid were added and stirred for 30 min. Filtering, standing for layering, collecting the lower organic phase, extracting the upper aqueous phase with 200mL of trichloromethane, combining the organic phases, and washing with 500mL of saturated saline solution. The organic phase is put in a water bath at 35 ℃ and decompressed and concentrated to be dry to obtain 150g of brown oily compound 2, the yield is over 100 percent, and the next step of reaction is directly carried out.

Preparation of compound 3: the oily compound 2 obtained in the above step was completely added to a 2L four-necked flask, 450mL of tetrahydrofuran was added, and the mixture was stirred at room temperature until the compound was completely dissolved. Then, the temperature is reduced to below 10 ℃, 1140mL of tetrahydrofuran solution of tetrabutylammonium fluoride (1 mol/L, 1140 mmol) is added dropwise, and the mixture is heated to room temperature and stirred for 2h after dropping. After the reaction, the reaction mixture was concentrated to dryness in a water bath at 40 ℃ and then 1000mL of ethyl acetate and 500mL of 2N HCl aq. were added and stirred for 30 min. Standing for layering, collecting an upper organic phase, washing with 2 parts of 500mL saturated saline solution, placing in a water bath at 40 ℃, and concentrating under reduced pressure until the mixture is dried to obtain 105g of yellow oily compound 3, wherein the yield of the two steps is 93.5 percent in total.

Preparation of compound 4: compound 3 (105 g, 426 mmol) was charged into a 2L four-necked flask, and 500mL of methylene chloride was added. After dissolution with stirring, methanesulfonyl chloride (73.3 g, 640 mmol) was added. After the addition, the temperature of the reaction solution is reduced to-5-0 ℃. At this temperature triethylamine (86 g, 852 mmol) was added dropwise, the temperature being controlled so as not to exceed 10 ℃. And continuously stirring for 2 hours at the temperature of 0-10 ℃ after the addition. After completion of the reaction, 250 mL of water was added to the reaction mixture and stirred for 5 min. The layers were separated by standing, and the lower organic phase was washed with 250 mL of 1N HCl aq., 250 mL of saturated aqueous sodium carbonate solution, and 250 mL of saturated brine, respectively. The organic phase was dried over anhydrous sodium sulfate and then concentrated to dryness under reduced pressure at 35 ℃ in a water bath to give 130g of compound 4 as a dark yellow oil with a yield of 94.0%.

Preparation of compound 5: compound 4 (130 g, 401 mmol) was charged into a 2L four-necked flask and 650mL of anhydrous tetrahydrofuran was added. Stirring until the mixture is dissolved, cooling to-35 to-30 ℃, adding ferric acetylacetonate (2.8 g, 8.0 mmol), and stirring for 15 min. 600mL of tetrahydrofuran solution of ethyl magnesium bromide (1 mol/L, 600 mmol) is slowly dropped under the condition of minus 35 to minus 30 ℃, and the mixture is stirred for 2 hours after dropping. After the reaction, 150mL of ethanol was added dropwise at low temperature, and the mixture was stirred for 30 min. Then, 400mL of 2N HCl aq. was added dropwise, and the mixture was warmed to room temperature and stirred for 30 min. The reaction solution was placed in a water bath at 40 ℃ and concentrated to remove most of the solvent, leaving about 500mL of solvent. To the residual solvent was added 2 parts of 500mL ethyl acetate for extraction, and the organic phases were combined and washed with 300mL saturated aqueous sodium carbonate solution and 300mL saturated brine. The organic phase was concentrated to dryness under reduced pressure in a water bath at 35 ℃ to give 88.0g of compound 5 as a pale yellow oil with a yield of 85.0%.

Preparation of compound 6: compound 5 (88.0 g, 341 mmol) above was charged into a 1L four-necked flask, and 400mL of ethanol and 40mL of water were added. After heating to 40-45 ℃ and stirring to dissolve completely, potassium hydroxide (47.7 g, 852 mmol) was added. The temperature is increased to reflux and stirring is carried out for 4 hours. After the reaction, the reaction solution was concentrated to dryness in a water bath at 40 ℃. Adding 500mL of methyl tert-butyl ether and 500mL of water into the concentrate, adjusting the pH to 2-3 by using concentrated hydrochloric acid, separating an organic phase, washing by using 500mL of water, continuing to put the mixture into a water bath at 40 ℃ and concentrating the mixture till the mixture is dry to obtain 93.0g of brown oily matter, wherein the crude yield is 98.5%.

In another 2L four-necked flask, the brown oil and 1400mL of acetonitrile were added, dicyclohexylamine (59.5 g, 330 mmol) was added, and a white solid was slowly precipitated by stirring at room temperature. Then the temperature is raised to 70 ℃ and the mixture is stirred for 1 h. Slowly cooling to about 25 ℃, and stirring for 12 hours at the temperature. Filtration and washing of the filter cake with 150ml acetonitrile. And collecting a filter cake, and drying at 60-65 ℃ to obtain 140g of white solid. And adding 500mL of methyl tert-butyl ether and 500mL of water into the solid, adjusting the pH to 6-7 by using a 15% phosphoric acid aqueous solution, and completely dissolving the solid. The organic phase was collected, washed with 300ml of saturated brine, and dried over anhydrous magnesium sulfate (30 g). Drying, placing in water bath at 40 deg.CConcentration to dryness under pressure gave 80.0g of a brown oil which, upon cooling, was a brown solid in 91% yield with a chiral purity of 99.1% (see FIG. 1). ESI-MS (m/z）：276[M-1]^-；¹H NMR(400MHz，CDCl₃) δ9.50(s，1H)，δ7.38~7.28(m，5H)，δ5.21~5.12 (m，2H)，δ3.81~3.78 (m，1H)，δ3.76~3.56 (m，2H)，δ3.33~3.24 (m，1H)，δ3.14~2.11 (m，1H)，δ2.36 (m，1H)，δ1.55~1.53(m，1H)，δ1.29~1.22 (m，1H)，δ1.02~0.97 (t，3H)。

Claims

1. A preparation method of an Upacitorib intermediate compound 6 is characterized by comprising the following steps:

；

(b) reacting the compound 2 under an acidic condition to obtain a compound 3;

；

；

；

。

2. the process of claim 1, wherein in the reaction step (a), the solvent is dichloromethane or chloroform.

3. The method for preparing the intermediate of lapatinib according to claim 1, wherein in the reacting step (a), the reaction temperature is-20 ℃ to 0 ℃; the reaction time is 8-24 hours.

4. The process of claim 1, wherein the solvent used in the reaction step (b) is selected from tetrahydrofuran, 2-methyltetrahydrofuran or acetonitrile.

5. The method for preparing an intermediate of lapatinib according to claim 1, wherein in the reacting step (c), the acid scavenger is selected from triethylamine, pyridine or N, N-diisopropylethylamine.

6. The method for preparing an intermediate of lapatinib according to claim 1, wherein in reaction step (d), the catalyst is ferric acetylacetonate or aluminum acetylacetonate.

7. The method for preparing the intermediate of uppatinib according to claim 1, wherein in the reaction step (d), the reaction temperature is-40 to-10 ℃; the reaction time is 2-8 hours.

8. The process of claim 1, wherein in the reaction step (e), the base is selected from potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate.

9. The process of claim 1, wherein in the reaction step (e), the solvent is methanol or ethanol.