CN104945404B - A kind of preparation method of N- propenecarbonyls piperidine derivative - Google Patents

Abstract

The invention relates to a preparation method of N-propylenecarbonylpiperidine derivatives, in particular to a new intermediate for the preparation of ibrutinib, a preparation method thereof and a method for preparing ibrutinib; it belongs to the technical field of pharmacy. The method involves the reaction shown in the following formula: The method is simple and convenient to operate, can reduce costs, and is beneficial to industrial production.

Description

A kind of preparation method of N-propylene carbonylpiperidine derivative

technical field

The invention relates to a preparation method of N-propylenecarbonylpiperidine derivatives, in particular to a new intermediate for the preparation of ibrutinib, a preparation method thereof and a method for preparing ibrutinib; it belongs to the technical field of pharmacy.

Background technique

Bruton's tyrosine kinase (BTK) is an important mediator of at least three key B-cell survival mechanisms that allow it to direct B-cell malignancies into lymphoid tissues, enabling tumor cells to access the necessary microenvironment for survival. Selective inhibition of Bruton's tyrosine kinase (BTK) can inhibit the proliferation of tumors, thereby achieving the effect of treating tumors.

Ibrutinib (English name Ibrutinib), is a selective inhibitor of Bruton's tyrosine kinase (BTK), which can be used to treat relapsed or refractory mantle cell lymphoma (MCL) and other diseases. Has a breakthrough status; its structure is shown in formula (1):

Contents of the invention

Summary of the invention

The present invention provides novel compounds for preparing ibrutinib and preparation methods of these novel compounds.

The present invention provides methods for preparing ibrutinib from these novel compounds.

Definition of Terms

Ibrutinib (English name Ibrutinib), refers to the chemical name 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4 -D]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one compound.

Detailed description of the invention

Through research, the inventor has developed a new intermediate, its preparation method and its method for preparing ibrutinib. This method of using a new intermediate to prepare ibrutinib is simple to operate, does not need to use reagents such as triphenylphosphine and solvents that are prone to produce peroxides, has short reaction time and low cost, and is conducive to the industrial preparation of ibrutinib. Ni.

In a first aspect, the present invention provides a new intermediate compound (3) as shown in formula (3):

Wherein, _R is p-toluenesulfonyl, 4-trifluoromethylbenzenesulfonyl, p-bromobenzenesulfonyl, 2-nitrobenzenesulfonyl, 4-nitrobenzenesulfonyl, benzenesulfonyl, methylsulfonyl, Trifluoromethanesulfonyl, tert-butyldimethylsilyl, or triethylsilyl.

Compound (3) has a chiral carbon, which can be a mixture of R and S configurations, or a single S configuration. In some embodiments, compound (3) is in the S configuration.

In a second aspect, the present invention provides a method for preparing the compound (3).

The preparation method of compound (3) comprises: the compound (2) shown in following formula (2) and the compound (4) shown in formula (4) in the presence of base B3, in organic solvent S3, carry out amide at temperature T3 chemical reaction to obtain compound (3):

The preparation method of the above-mentioned compound (2) comprises: the compound (1) shown in the formula (1) is subjected to a deprotection reaction, and the compound (2) is prepared:

The preparation method of the above-mentioned compound (1) comprises: the compound (0) represented by formula (0) is subjected to a protective group reaction, and the compound (1) is prepared:

In some embodiments, the preparation method of compound (3) comprises: carrying out a protecting group reaction on compound (0) to prepare compound (1);

Compound (1) was deprotected to prepare compound (2); compound (2) and compound (4) were subjected to amidation reaction at temperature T3 in organic solvent S3 in the presence of base B3 to obtain compound ( 3):

In the preparation method of the above compound (1), compound (2) and compound (3), LG ₁ is selected from C1-C4 alkoxycarbonyl, benzyloxycarbonyl, trifluoroacetyl, acetyl, trimethylsilyl ethyl Oxycarbonyl, p-toluenesulfonyl, trityl, 2,4-dimethoxybenzyl, p-methoxybenzyl, benzyl; _R1 is as defined above; _R2 is hydroxyl, fluorine, chlorine, Bromine, iodine, methanesulfonyloxy, p-toluenesulfonyloxy, or p-nitrobenzenesulfonyloxy; LG ₂ is selected from hydrogen, chlorine, bromine, p-toluenesulfonyl, benzenesulfonyl, methanesulfonyl; Indicates a single or double bond.

In the above-mentioned compound (1), compound (2), and compound (3), there is a chiral carbon respectively. In order to obtain the target compound of a single configuration, a raw material with a single configuration can be used for the reaction, or a compound containing two configurations can be used. A mixture of different types is reacted, and the mixture is then resolved to obtain compounds of a single configuration.

The base B3 is triethylamine, diisopropylethylamine, n-butyllithium, tetrabutylammonium hydroxide, ammonia, pyridine, 4-dimethylaminopyridine, N-methylmorpholine, potassium hydroxide, carbonic acid Potassium, potassium bicarbonate, potassium tert-butoxide, potassium phosphate, potassium hydride, sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydride, sodium borohydride, cesium carbonate, or combinations thereof.

In some embodiments, the base B3 is triethylamine, diisopropylethylamine, ammonia water, 4-dimethylaminopyridine, potassium carbonate, cesium carbonate, or a combination thereof. In some embodiments, the base B3 is potassium carbonate. In some embodiments, the base B3 is triethylamine, diisopropylethylamine, or a combination thereof.

The temperature T3 is -10°C-40°C. In some embodiments, temperature T3 is between 0°C and 30°C.

The organic solvent S3 is dichloromethane, toluene, ethyl acetate, acetonitrile, 2-methyltetrahydrofuran, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide, or a combination thereof. In some embodiments, the organic solvent S3 is dichloromethane, toluene, ethyl acetate, acetonitrile, or a combination thereof.

In some embodiments, R ₂ is chlorine, LG ₂ is hydrogen, and compound (4) is acryloyl chloride.

In some embodiments, _R2 is hydroxyl, _LG2 is hydrogen, and compound (4) is acrylic acid.

In some embodiments, R ₂ is hydroxyl, LG ₂ is chloro, and compound (4) is 1-chloropropionic acid.

In some embodiments, R ₂ is chloro, LG ₂ is chloro, and compound (4) is 1-chloropropionyl chloride.

In some embodiments, R ₂ is hydroxyl, LG ₂ is p-toluenesulfonyl, and compound (4) is 1-p-toluenesulfonylpropionic acid.

In some embodiments, R ₁ is p-toluenesulfonyl, and compound (4) is acryloyl chloride.

In some embodiments, R ₁ is p-toluenesulfonyl and compound (4) is acrylic acid.

In some embodiments, R ₁ is tert-butyldimethylsilyl, and compound (4) is acryloyl chloride.

In some embodiments, LG ₁ is tert-butoxycarbonyl; R ₁ is p-toluenesulfonyl.

In some embodiments, LG ₁ is tert-butoxycarbonyl; R ₁ is 4-trifluoromethylbenzenesulfonyl.

In some embodiments, the preparation method of compound (3) comprises: reacting 3-p-toluenesulfonyloxypiperidine with acryloyl chloride in the presence of triethylamine in dichloromethane at 20°C-25°C to prepare Compound (3), 3-p-toluenesulfonyloxy-N-propenecarbonylpiperidine, was obtained.

In some embodiments, the preparation method of compound (3) comprises: N-tert-butoxycarbonyl-3-p-toluenesulfonyloxypiperidine undergoes a deprotection reaction to obtain 3-p-toluenesulfonyloxypiperidine; 3-p-toluenesulfonyloxypiperidine is acylated with acryloyl chloride to prepare compound (3), namely 3-p-toluenesulfonyloxy-N-propylenecarbonylpiperidine.

In some embodiments, the preparation method of compound (3) comprises: N-tert-butoxycarbonyl-3-hydroxypiperidine and p-toluenesulfonyl chloride in the presence of a base, in an organic solvent, undergo an esterification reaction to prepare N -tert-butoxycarbonyl-3-p-toluenesulfonyloxypiperidine; then undergo deprotection reaction to obtain 3-p-toluenesulfonyloxypiperidine; 3-p-toluenesulfonyloxypiperidine and acryloyl chloride Compound (3) ie 3-p-toluenesulfonyloxy-N-propylenecarbonylpiperidine was prepared.

In some embodiments, the preparation method of compound (3) includes: (S)-1-tert-butoxycarbonyl-3-hydroxypiperidine and p-toluenesulfonyl chloride in the presence of a base, in an organic solvent, undergo an esterification reaction , to prepare (S)-1-tert-butoxycarbonyl-3-p-toluenesulfonyloxypiperidine; then through deprotection reaction to obtain (S)-3-p-toluenesulfonyloxypiperidine; (S )-3-p-toluenesulfonyloxypiperidine is acylated with acryloyl chloride to prepare compound (3), namely (S)-3-p-toluenesulfonyloxy-N-propylenecarbonylpiperidine.

In the third aspect, the present invention provides a new method for preparing ibrutinib represented by formula (1), which comprises: compound (3) and compound (5) represented by formula (5) in the presence of base B4, In organic solvent S4, carry out reaction at temperature T4, prepare Ibrutinib:

Wherein, R ₁ is as defined above. The above-mentioned compound (3) can be a single S configuration, or a mixture of R configuration and S configuration.

The base B4 is selected from: potassium carbonate, triethylamine, diisopropylethylamine, tetrabutylammonium fluoride, pyridine, tetrabutylammonium hydroxide, 4-dimethylaminopyridine, N-methylmorpholine, Potassium tert-butoxide, cesium carbonate, or combinations thereof.

The organic solvent S4 is selected from N,N-dimethylacetamide, N,N-dimethylformamide (DMF), dimethyl sulfoxide, or a combination thereof.

The temperature T4 is 50°C-100°C. In some embodiments, the temperature T4 is 50°C-80°C.

In some embodiments, R ₁ is p-toluenesulfonyl.

In some embodiments, the base B4 is selected from potassium carbonate, triethylamine, tetrabutylammonium fluoride, cesium carbonate, or combinations thereof. In some embodiments, the base B4 is selected from potassium carbonate. In some embodiments, the base B4 is selected from tetrabutylammonium fluoride.

In some embodiments, the organic solvent S4 is selected from N,N-dimethylformamide.

In some embodiments, the preparation method of ibrutinib comprises: compound (5) shown in formula (5) and (S)-3-p-toluenesulfonyloxy-N-propylenecarbonylpiperidine in potassium carbonate In the presence of N,N-dimethylformamide, react at 55°C-65°C to prepare ibrutinib, as shown in the following formula:

The aforementioned method for preparing compound (3) can be used in the method for preparing ibrutinib.

In some embodiments, the method for preparing ibrutinib comprises: performing amidation reaction between compound (2) and compound (4) in the presence of base B3 in an organic solvent S3 at temperature T3 to obtain compound (3) ; Compound (3) reacts with compound (5) in the presence of base B4 at temperature T4 in an organic solvent S4 to prepare compound (1) ibrutinib.

In some embodiments, the method for preparing ibrutinib comprises: compound (0) is subjected to a protective group reaction to prepare compound (1); compound (1) is subjected to deprotection reaction to prepare compound (2); compound (2) and compound (4) in the presence of base B3, in organic solvent S3, carry out amidation reaction at temperature T3 to obtain compound (3); compound (3) and compound (5) in the presence of base B4, In organic solvent S4, react at temperature T4 to prepare compound (1) ibrutinib.

Detailed ways

In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

In the present invention, g means gram, mL means milliliter, and h means hour.

Example 1: Preparation of compound (S)-3-p-toluenesulfonyloxy-N-propylenecarbonylpiperidine

Step 1: Preparation of (S)-1-tert-butoxycarbonyl-3-p-toluenesulfonyloxypiperidine

In the reactor, add (S)-1-tert-butoxycarbonyl-3-hydroxypiperidine 30.00g, triethylamine 30.17g, 4-dimethylaminopyridine 1.82g, dichloromethane 70mL, stir and mix, and the mixture Cool down to 0°C; add a mixture of 31.26g p-toluenesulfonyl chloride dissolved in 40mL of dichloromethane, drop it in 30 minutes, keep stirring at 0°C for 0.5h, then move to room temperature at 28°C and continue stirring for 3h. The reaction solution was washed 3 times with saturated sodium bicarbonate (100mL/time), the organic layer was evaporated to dryness, and then crystallized with 450mL mixed solvent ethyl acetate:cyclohexane=1:8, and the white solid compound (S)- 1-tert-butoxycarbonyl-3-p-toluenesulfonyloxypiperidine 45.36g; MS data: 733.0, 378.0, 302.0, 300.0; NMR data: ¹ H NMR (600MHz, CDCl ₃ ) δ7.82(d, J＝8.3Hz, 2H), 7.36(d, J＝8.0Hz, 2H), 4.46(s, 1H), 3.57(d, J＝12.4Hz, 1H), 3.46–3.20(m, 3H), 2.46( s, 3H), 1.91–1.71 (m, 3H), 1.44 (d, J=7.4Hz, 10H).

Step 2: Preparation of compound (S)-3-p-toluenesulfonyloxypiperidine

In the reactor, add (S)-1-tert-butoxycarbonyl-3-p-toluenesulfonyloxypiperidine 20.00g, ethyl acetate 100mL, 4mol/L hydrochloric acid 100mL, stir overnight at 24°C, thin-layer After the analysis and detection reaction (EA:MeOH=1:2, Rf=0.57), the liquid was separated, and the aqueous phase was extracted twice with 50 mL of ethyl acetate, and the ethyl acetate layers were combined and spin-dried to obtain a white solid. The solid was slurried with 50 mL of ethyl acetate:petroleum ether=1:4 mixture for 0.5 h, suction filtered, and dried at 45°C for 4 h to obtain 13.12 g of solid; MS data: 257.00, 256.00; NMR data: ¹ H NMR (600 MHz, D ₂ O)δ7.77(d,J=8.4Hz,2H),7.41(d,J=8.2Hz,2H),4.87(s,1H),3.32(ddd,J=13.6,7.6,6.0Hz, 1H), 3.27(d, J=13.0Hz, 1H), 3.20(dd, J=13.9, 2.1Hz, 1H), 2.98(td, J=12.6, 3.2Hz, 1H), 2.36(s, 3H), 1.92–1.82(m,1H),1.79–1.63(m,3H).

Step 3: Preparation of compound (S)-3-p-toluenesulfonyloxy-N-propenecarbonylpiperidine

Into the reactor, add (S)-3-p-toluenesulfonyloxypiperidine 10.00g, triethylamine 11.90g and dichloromethane 100mL, after mixing, stir at 24°C, dropwise add acryloyl chloride 3.95g, Stir for 17h; the reaction solution was washed with water (50mL×3), and the dichloromethane layer was evaporated to dryness under reduced pressure to obtain 10.09g of oily (S)-3-p-toluenesulfonyloxy-N-propylenecarbonylpiperidine; mass spectrum MS Data: 311.20, 310.20; NMR data: ¹ H NMR (600MHz, CDCl ₃ ) δ7.88–7.76 (m, 2H), 7.37 (d, J＝8.0Hz, 2H), 6.59–6.35 (m, 1H), 6.25(dd,J=16.8,1.8Hz,1H),5.69(dd,J=15.6,6.1Hz,1H),4.52(s,1H),3.81–3.60(m,2H),3.43(d,J= 52.3Hz, 2H), 2.46(s, 3H), 2.04–1.73(m, 5H), 1.52(s, 1H).

Example 2: Preparation of compound (S)-3-p-toluenesulfonyloxy-N-propylenecarbonylpiperidine

In the reactor, add (S)-3-p-toluenesulfonyloxypiperidine 10.00g, diisopropylethylamine 15.25g and toluene 100mL, after mixing, stir at 20°C, add acrylic acid 3.50g dropwise , stirred for 17 h; the reaction solution was washed with water three times (50 mL/time), and the toluene layer was spin-dried to obtain 10.04 g of oily (S)-3-p-toluenesulfonyloxy-N-propylenecarbonylpiperidine.

Embodiment 3: Preparation Ibrutinib

(S)-3-p-toluenesulfonyloxy-N-propylenecarbonylpiperidine 5.00g, 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d ] 2.45g of pyrimidine, 3.35g of potassium carbonate and 50mL of N,N-dimethylformamide, stirred, the temperature of the mixture was raised to 60°C, and stirred overnight. After the reaction solution was lowered to room temperature, 50 mL of water was added dropwise to it, and a large amount of white solids were precipitated, filtered with suction, the filter cake was beaten with 10 mL of methanol at room temperature for 1 hour, filtered with suction, and the filter cake was vacuum-dried to obtain 2.71 g of ibrutinib; MS data: 442.20, 441.20; NMR data: ¹ H NMR (400MHz, DMSO) δ8.25(s, 1H), 7.66(d, J=7.2Hz, 2H), 7.43(t, J=7.6Hz, 2H ),7.34–7.04(m,5H),6.98–6.56(m,2H),6.09(dd,J＝27.2,17.1Hz,1H),5.64(dd,J＝48.8,9.4Hz,1H),4.70( s,1H),4.55(d,J=10.9Hz,1H),4.18(d,J=10.0Hz,1H),4.06(d,J=13.1Hz,1H),3.70(s,1H),3.20( d,J=11.4Hz,1H),3.02(s,1H),2.26(d,J=9.6Hz,1H),2.13(s,1H),1.93(d,J=12.6Hz,1H),1.57( s, 1H).

Embodiment 4: Preparation of Ibrutinib

The method of Example 1 was used to prepare (S)-3-(p-nitrobenzenesulfonyloxy)-N-propylenecarbonylpiperidine; (S)-3-(p-nitrobenzenesulfonyloxy)- N-propylenecarbonylpiperidine 5.00g, 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine 2.15g, potassium carbonate 3.00g and DMF50mL, stirred, The mixture was warmed to 60°C and stirred overnight. After the reaction solution was lowered to room temperature, 50 mL of water was added dropwise to it, and a large amount of white solids precipitated out. The filter cake was pulped with 10 mL of methanol at room temperature for 1 hour, and the filter cake was vacuum-dried to obtain 2.31 g of ibrutinib.

Example 5

With reference to the method of Example 1, tert-butyldimethylsilyl chloride was used instead of p-toluenesulfonyl chloride to prepare (S)-3-tert-butyldimethylsilyloxy-N-propylenecarbonylpiperidine; then refer to According to the method of Example 3, ibrutinib was prepared.

The method of the present invention has been described through preferred embodiments, and relevant persons can obviously make changes or appropriate changes and combinations to the methods and applications described herein within the content, spirit and scope of the present invention to realize and apply the technology of the present invention . Those skilled in the art can refer to the content of this article to appropriately improve the process parameters to achieve. In particular, it should be pointed out that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims (7)

1. a kind of method for replacing Buddhist nun according to Shandong shown in formula (1), including：

In the presence of alkali B3, in organic solvent S3, amidation process, system are carried out in temperature T3 with compound (4) for compound (2) Obtain compound (3)：

Compound (3) in the presence of alkali B4, in organic solvent S4, is reacted in temperature T4, is prepared with compound (5) Buddhist nun is replaced according to Shandong：

Wherein, R₁For p-toluenesulfonyl, 4- tnBuoromethyl-benzenesulfonyls, brosyl, 2- nitrobenzenesulfonyls, 4- nitre Base benzenesulfonyl, benzenesulfonyl, mesyl, trifyl, t-Butyldimethylsilyl or triethyl group silicon substrate；Chemical combination Object (3) is the mixture of S configurations or R configurations and S configurations；R₂For hydroxyl, fluorine, chlorine, bromine, iodine, mesyloxy, to toluene sulphur Acyloxy or p-nitrophenyl sulfonyloxy；LG₂Selected from hydrogen, chlorine, bromine, p-toluenesulfonyl, benzenesulfonyl, mesyl；Indicate singly-bound or double bond.

2. according to the method described in claim 1, further including：Compound (0) carries out protection group reaction, and compound is prepared (1)；Compound (1) carries out deprotection reaction, and compound (2) is prepared：

Wherein, LG₁Selected from C1-C4 alkoxy carbonyls, benzyloxycarbonyl, trifluoroacetyl group, acetyl group, allyloxycarbonyl, trimethyl Silicon carbethoxyl group, p-toluenesulfonyl, trityl, 2,4- dimethoxy-benzyls, to methoxy-benzyl, benzyl.

3. according to the method described in claim 1, the alkali B3 be triethylamine, diisopropyl ethyl amine, ammonium hydroxide, 4- dimethylaminos Pyridine, potassium carbonate, cesium carbonate, or combinations thereof.

4. according to the method described in claim 1, the temperature T3 is -10 DEG C -40 DEG C；The organic solvent S3 is dichloromethane Alkane, toluene, ethyl acetate, acetonitrile, or combinations thereof.

5. according to the method described in claim 1, the alkali B4 be potassium carbonate, triethylamine, diisopropyl ethyl amine, tetrabutyl fluorine Change ammonium, pyridine, tetrabutylammonium hydroxide, 4-dimethylaminopyridine, N-methylmorpholine, potassium tert-butoxide, cesium carbonate, or combinations thereof.

6. according to the method described in claim 1, the organic solvent S4 be n,N-dimethylacetamide, N, N- dimethyl formyls Amine, dimethyl sulfoxide (DMSO), or combinations thereof；The temperature T4 is 50 DEG C -80 DEG C.

7. according to the method described in claim 1, including：Compound (5) and (S) -3- tolysulfonyl oxygroup-N- propenecarbonyls Piperidines is in the presence of potassium carbonate, in DMF, in 55 DEG C of -65 DEG C of reactions, is prepared and replaces Buddhist nun according to Shandong：