CN114315679B

CN114315679B - Martinib chiral preparation method of intermediate

Info

Publication number: CN114315679B
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: 2024-08-30
Anticipated expiration: 2042-01-21
Also published as: CN114315679A

Abstract

The invention relates to a preparation method of Wu Pati-nylon chiral intermediate shown in formula 6, which takes 6-oxa-3-azabicyclo [3.1.0] hexane-3-benzyl carboxylate as a raw material, and under the catalysis of pyridine bisoxazoline ytterbium chloride complex, an asymmetric ring-opening reaction is carried out, and then a series of reactions of removing C-4 trimethylsilyl group, forming methanesulfonate with C-4 hydroxyl and carrying out configuration inversion are sequentially carried out, and finally, the Wu Pati-nylon chiral intermediate compound 6 is obtained through hydrolysis under alkaline conditions. The method has the advantages of low-cost 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

Martinib chiral preparation method of intermediate

Technical Field

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

Background

Wu Pati Ni (Upadacitinib) is a selective and reversible JAK1 inhibitor, is developed by America Eibovian pharmaceutical company, and has good curative effect in clinical trials for treating various autoimmune diseases and inflammatory diseases. In 2019, lapatinib was marketed in the united states and approved for the treatment of patients with moderate and severe rheumatoid arthritis. In 2021, the medicine has also submitted a new indication application for ankylosing spondylitis according to the research results of key clinical experiments. Wu Pa A Tinich has the following structural formula:

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

The synthesis method of Wu Pa tenib intermediate (6) reported in the current literature is mainly divided into a chiral catalytic synthesis method and a chemical resolution method. The main synthesis method comprises the following steps:

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

The patent route takes ethyl pentynoate or ethyl glycine hydrochloride as a raw material, an achiral five-membered ring is firstly constructed through two-step reaction, and then the dihydropyrrole derivative is obtained through protecting group transformation or alkylation. Finally, the compound 6 is obtained by selective reduction of an expensive chiral catalyst S-segphosRu complex. The catalyst has high price and high production cost.

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

The patent route also uses ethyl valerate as a raw material, uses a Lindlar catalyst to carry out hydrogenation reduction to obtain alkene, then closes a ring, uses Raney nickel to carry out reduction to obtain a racemization intermediate, then removes Cbz protecting group on benzyl, carries out ester hydrolysis, and finally obtains a target product 6 with higher chiral purity through resolution for more than 3 times. The process has complex operation after multiple resolution, and the actual yield is below 20%, which is not beneficial to industrial production.

Therefore, it is necessary to invent a synthesis method of the (3R, 4S) -1-carbobenzoxy-4-ethylpyrrolidine-3-carboxylic acid (compound 6) which is a key chiral intermediate of the Marpatinib, so as to meet the requirements of simple and easily obtained raw materials, simple process operation, low economic cost of the product process and high chiral purity of the obtained product.

Disclosure of Invention

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

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

a process for preparing a chiral intermediate of lapatinib (compound 6), comprising the steps of:

(a) The compound 1 reacts with trimethylsilicon cyanide under the catalysis of pyridine bisoxazoline ytterbium chloride complex to obtain a compound 2;

；

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

；

(c) Compound 3 is reacted with acid binding agent and methylsulfonyl chloride to obtain compound 4;

；

(d) The compound 4 reacts 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 chloroform; 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.

The catalyst in the reaction step (d) 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 is potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate; the solvent is methanol or ethanol.

The beneficial effects of the invention are as follows:

The novel preparation method of the lapatinib key chiral intermediate 6 overcomes the defects of harsh reaction conditions, low chiral purity of products or higher cost due to the use of expensive catalysts in multiple steps in the prior art; the invention has the advantages of higher process efficiency, less side reaction and higher economic and industrial application value.

Drawings

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

FIG. 2 is a nuclear magnetic resonance spectrum of the chiral intermediate compound 6 of Marpatinib according to example 1 of the present invention.

Detailed Description

The technical content of the present invention will be described in detail below with reference to examples, which are only to further illustrate the features of the present invention in detail, but are not limited to 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, 458 mmol) was added to a 2L four-necked flask, chloroform (800 mL), 2, 6-bis [ (4R) -4-tert-butyl-2-azolinyl ] pyridine (3.0 g,9.1 mmol) and ytterbium trichloride hexahydrate (3.5 g,9.1 mmol) were added, and stirred at room temperature for 30min. And (3) cooling to-15 to-10 ℃, slowly dropwise adding 100ml of a trichloromethane solution of trimethylcyano silane (54.3 g,547 mmol), and stirring for 12 hours at-15 to-10 ℃. After the reaction was completed, the temperature was slowly raised to about 0℃and 500mL of water and 57g of sodium hydrogencarbonate solid were added thereto and stirred for 30 minutes. The mixture was filtered, left to stand for separation, the lower organic phase was collected, the upper aqueous phase was extracted with 200mL of chloroform, and the organic phases were combined and washed with 500mL of saturated brine. The organic phase was concentrated to dryness under reduced pressure in a water bath at 35℃to give 150g of compound 2 as a brown oil in a yield exceeding 100%, which was directly taken to the next reaction.

Preparation of compound 3: the above oily compound 2 was all added to a 2L four-necked flask, and 450mL of tetrahydrofuran was added thereto, followed by stirring at room temperature until complete dissolution. Then cooling to below 10 ℃, dropwise adding 1140mL of tetrahydrofuran solution of tetrabutylammonium fluoride (1 mol/L,1140 mmol), and stirring for 2h after the completion of dropwise adding, heating to room temperature. After the reaction was completed, the reaction mixture was concentrated to dryness in a water bath at 40℃and 1000mL of ethyl acetate and 500mL of 2N HCl aq were added thereto, followed by stirring for 30 minutes. The mixture was allowed to stand for delamination, and the upper organic phase was collected, washed with 2 parts of 500mL of saturated brine, and concentrated to dryness in a water bath at 40℃under reduced pressure to give 105g of a yellow oily compound 3, the total yield of the two steps being 93.5%.

Preparation of Compound 4: compound 3 (105 g,426 mmol) above was added to 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 completion of the addition, the reaction mixture was cooled to-5~0 ℃. Triethylamine (86 g, 850 mmol) was added dropwise at this temperature, the temperature not exceeding 10 ℃. And continuing stirring at 0-10 ℃ for 2h after the addition is finished. After the reaction was completed, 250 mL parts of water was added to the reaction mixture and stirred for 5 minutes. The layers were separated by standing, and the lower organic phase was washed with 250 mL of 1N HCl aq, 250 mL saturated aqueous sodium carbonate, and 250 mL saturated brine, respectively. Anhydrous sodium sulfate was added to the organic phase to dry, and the mixture was concentrated to dryness in a water bath at 35℃under reduced pressure to give 130g of compound 4 as a deep yellow oil in 94.0% yield.

Preparation of Compound 5: compound 4 (130 g,401 mmol) is added to a 2L four-necked flask and 650mL of anhydrous tetrahydrofuran is added. After stirring until dissolution, cooling to-35 to-30 ℃, adding ferric acetylacetonate (2.8 g,8.0 mmol), and stirring for 15min. Slowly dropwise adding 600mL of tetrahydrofuran solution of ethyl magnesium bromide (1 mol/L,600 mmol) at the temperature of-35 to-30 ℃, and stirring for 2h after dropwise adding. After the reaction, 150mL of ethanol was added dropwise at low temperature, and the mixture was stirred for 30min. 400mL of 2N HCl aq were then added dropwise, and the mixture was stirred at room temperature for 30min. The reaction mixture was concentrated in a water bath at 40℃and most of the solvent was distilled off, leaving about 500mL of the solvent. To the residual solvent, 2 parts of 500mL of ethyl acetate was added, and the organic phases were combined and washed with 300mL of a saturated aqueous sodium carbonate solution and 300mL of a 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 in 85.0% yield.

Preparation of Compound 6: compound 5 (88.0 g, 3411 mmol) above was added to a 1L four-necked flask, 400mL of ethanol and 40mL of water were added. After the temperature is raised to 40-45 ℃ and stirred until the mixture is completely dissolved, potassium hydroxide (47.7 g, 850 mmol) is added. Heating to reflux and stirring for 4h. After the reaction was completed, the reaction mixture was concentrated to dryness in a water bath at 40 ℃. The concentrate was added with 500mL of methyl tert-butyl ether and 500mL of water, the pH was adjusted to 2-3 with concentrated hydrochloric acid, the organic phase was separated, washed with 500mL of water and then further concentrated to dryness in a water bath at 40℃to give 93.0g of a brown oil in a crude yield of 98.5%.

In a separate 2L four-necked flask, the above brown oil and 1400mL of acetonitrile were added, followed by dicyclohexylamine (59.5 g, 330 mmol) and stirred at room temperature to slowly precipitate a white solid. Then heating to 70 ℃ and stirring for 1h. Slowly cooling to about 25 ℃, and stirring for 12 hours at the temperature. The mixture was filtered and the filter cake was washed with 150ml of acetonitrile. The filter cake is collected and dried at the temperature of 60-65 ℃, 140g of white solid was obtained. And adding 500mL of methyl tertiary butyl ether and 500mL of water into the solid, and adjusting the pH to 6-7 by using a 15% phosphoric acid aqueous solution, wherein the solid is completely dissolved. The organic phase was collected, washed with 300ml of saturated brine, and dried over 30g of anhydrous magnesium sulfate. Drying, concentrating under reduced pressure in water bath at 40deg.C to obtain 80.0g brown oil, cooling to obtain brown solid with 91% yield and chiral purity of 99.1% (shown in figure) 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 process for the preparation of the lapatinib intermediate compound 6, comprising the steps of:

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

2. a process for the preparation of Wu Pa tenib intermediate compound 6 according to claim 1, wherein in reaction step (a) the solvent used is dichloromethane or trichloromethane.

3. The process for the preparation of Wu Pa tenib intermediate compound 6 according to claim 1, wherein in reaction step (a), the reaction temperature is from-20 ℃ to 0 ℃; the reaction time is 8-24 hours.

4. A process for the preparation of Wu Pa tenib intermediate compound 6 according to claim 1, wherein in reaction step (b) the solvent used is selected from tetrahydrofuran, 2-methyltetrahydrofuran or acetonitrile.

5. A process for the preparation of Wu Pa tenib intermediate compound 6 according to claim 1, wherein in reaction step (c) the acid-binding agent is selected from triethylamine, pyridine or N, N-diisopropylethylamine.

6. The process for the preparation of Wu Pa tenib intermediate compound 6 according to claim 1, wherein in reaction step (d) the catalyst is iron acetylacetonate or aluminum acetylacetonate.

7. The process for the preparation of Wu Pa tenib intermediate compound 6 according to claim 1, wherein in reaction step (d) the reaction temperature is-40 to-10 ℃; the reaction time is 2-8 hours.

8. A process for the preparation of Wu Pa tenib intermediate compound 6 according to claim 1, wherein in reaction step (e) the base used is selected from potassium hydroxide, sodium hydroxide, potassium carbonate or sodium carbonate.

9. A process for the preparation of Wu Pa tenib intermediate compound 6 according to claim 1, wherein in reaction step (e) the solvent used is methanol or ethanol.