KR101954281B1 - Process for the stereoselective preparation of optically active 3-hydroxypiperidine or its derivatives - Google Patents

Abstract

The present invention provides a method for preparation of 3-hydroxypiperidine, which is optically active by using 1-[(1R)-(1-phenylethyl)]-(3R)-3-tosylpiperidine or 1-[(1R)-(1-phenylethyl)]-(3S)-3-tosylpiperidine, or derivatives thereof. A preparation method of the present invention can be usefully used for a stereoselective synthesis of drugs such as mepenzolate, ibrutinib and the like.

Description

TECHNICAL FIELD [0001] The present invention relates to a stereoselective preparation of optically active 3-hydroxypiperidine or a derivative thereof,

The present invention relates to a process for the selective preparation of optically active 3-hydroxypiperidine or derivatives thereof.

Such as hydroxypiperidine piperidine is methoxy penjol rate (Mepenzolate), eve Ruti nibeu (Ibrutinib) - optically active 3-hydroxypyrrolidine, piperidine, namely (3 R) - hydroxypyrrolidine and piperidine (3 S) It is used as an important intermediate in the synthesis of medicines. And The fact that the pharmacological activity of the drug may be different from well known in the art, depending on the stereochemistry, e.g., (3 R) - methoxy penjol rate is (3 S) - The bronchodilator activity significantly higher than the methoxy penjol rate It is known. Accordingly, it is very important to stereoselectively produce optically active 3-hydroxypiperidine or derivatives thereof.

Asymmetric synthesis, enzymatic asymmetric reduction, and chemical resolution methods have been known as methods for producing optically active 3-hydroxypiperidine (see, for example, Tetrahedron 2007, 63, 331-336, Process Biochemistry 2016, 51, 881-885, WO2004 / 064730, WO2004 / 072086, WO2015 / 131299, etc.). However, these conventional production methods are difficult to purify due to low water solubility of 3-hydroxypiperidine, and are difficult to mass-produce on an industrial scale, and chiral impurities exist.

On the other hand, the present inventors have found that the nucleophilic geometry and regio- and stereoselective ring opening of 1-azonibicyclo [3.1.0] hexane tosylate (MK Ji et al., Chem. Asian J. 2014, 9, 1060-1067). Supra are (2 S) -2- (3- hydroxypropyl) -1 - [(1 R) - - (1- phenylethyl) [(1 R) - ( 1- phenylethyl)] 1 from aziridine ] -1-azoniabicyclo [3.1.0] hexanoyltosylate, which comprises reacting the 1 - [( 1R ) - (1-phenylethyl)] - 1-azoniabicyclo [3.1 0.0 > [0] < / RTI > hexanoxylate is converted to piperidine or pyrrolidine derivatives via geometric and stereoselective ring opening, depending on the nature of the nucleophile applied.

The present inventors have conducted various studies to develop a novel method for producing optically active 3-hydroxypiperidine. Surprisingly, the tosyloxy group was hydrolyzed to 1 - [( 1R ) - (1-phenylethyl)] - ( 3R ) -3-tosylpiperidine synthesized as an intermediate in the prior art of the present invention, It was found that the chirality of the hydroxy group was retained when the hydroxy group was formed. When the hydrogenation reaction was continuously performed, the optically active 3-hydroxypiperidine and its derivative were obtained in a high yield ≪ / RTI > and purity.

Accordingly, the present invention is 1 - [(1 R) - (1- phenylethyl)] - (3 R) -3- tosyl piperidine or 1 - [(1 R) - (1- phenylethyl)] - ( 3 S ) -3-tosylpiperidine to prepare an optically active 3-hydroxypiperidine or a derivative thereof.

According to one aspect of the present invention, there is provided a process for preparing a compound of formula (I), comprising hydrolyzing a compound of formula (III) with a metal alkoxide to produce a compound of formula And hydrogenation of the compound of formula (2a) using (i) a palladium catalyst or (ii) hydrogenation using a palladium catalyst in the presence of an amino-protecting group forming agent to produce a compound of formula There is provided a process for the preparation of a compound of formula (I)

<Formula 1a>

&Lt; EMI ID =

&Lt; EMI ID =

Wherein TsO is tosyloxy, Ph is phenyl and R is hydrogen or an amino-protecting group.

According to another aspect of the present invention, there is provided a process for preparing a compound of formula (I), comprising: hydrolyzing a compound of formula (IIIb) with a metal alkoxide to produce a compound of formula (IIb); And (ii) hydrogenating the compound of formula (2b) with a palladium catalyst in the presence of (i) a palladium catalyst or (ii) in the presence of an amino-protecting group forming agent to produce a compound of formula There is provided a process for the preparation of a compound of formula (Ib)

&Lt; EMI ID =

(2b)

&Lt; EMI ID =

Wherein TsO is tosyloxy, Ph is phenyl and R is hydrogen or an amino-protecting group.

The present invention provides a method for stereoselectively preparing optically active 3-hydroxypiperidine or derivatives thereof via a novel synthetic route. In particular, it has been found by the present invention that the chiral nature of the hydroxy group is retained when the compound of formula (3a) or (3b) is hydrolyzed with a metal alkoxide to form a hydroxy group. Therefore, when the hydrolysis is followed by the hydrogenation reaction, the optically active 3-hydroxypiperidine and derivatives thereof can be simply produced with high yield and purity. Further, the production method of the present invention can be applied to a large-scale reaction, so that it is possible to perform a simple and economical reaction and is suitable for mass production on an industrial scale. Therefore, the production method of the present invention can be usefully used for the stereoselective synthesis of drugs such as mefenzolate, ibrutinib and the like.

The present invention relates to a process for the preparation of a compound of formula (II) by hydrolysis of a compound of formula (3a) to a metal alkoxide, And hydrogenation of the compound of formula (2a) using (i) a palladium catalyst or (ii) hydrogenation using a palladium catalyst in the presence of an amino-protecting group forming agent to produce a compound of formula Lt; RTI ID = 0.0 &gt; (Ia) &lt; / RTI &gt;

<Formula 1a>

&Lt; EMI ID =

&Lt; EMI ID =

Wherein TsO is tosyloxy, Ph is phenyl and R is hydrogen or an amino-protecting group.

The present invention also relates to a process for preparing a compound of formula (II), which comprises hydrolyzing a compound of formula (3b) to a metal alkoxide to produce a compound of formula (2b); And (ii) hydrogenating the compound of formula (2b) with a palladium catalyst in the presence of (i) a palladium catalyst or (ii) in the presence of an amino-protecting group forming agent to produce a compound of formula To provide a process for preparing a compound of formula (Ib): &lt; EMI ID =

&Lt; EMI ID =

(2b)

&Lt; EMI ID =

Wherein TsO is tosyloxy, Ph is phenyl and R is hydrogen or an amino-protecting group.

In the preparation method of the present invention, the compound of formula (3a) and the compound of formula (3b) used as a starting material were synthesized in accordance with the prior art (MK Ji et al., Chem. Asian J. 2014, 9, 1060-1067) Can be prepared according to the disclosed method. For example, the compound of formula (3a), as in the following scheme 1, (R 2) of Formula 5a - method of the aziridine-2-carboxylic acid esters known (e.g., Ji, et al M.-K. ., Chem. Asian. J. 2014, 9, 1060-1067) as converted to the compound of formula 4a, and then, the compound of formula 4a p- toluenesulfonate nilan hydride base (e.g., amine, triethyl Amine, etc.).

<Reaction Scheme 1>

The reaction formula of (2 R) compound of Formula 5a in the 1-aziridine-2-carboxylic acid ester in place of (2 S) - using aziridine-2-carboxylic acid ester in the reaction turned on in the same way to prepare a compound of formula 3b can do.

The preparation method of the present invention comprises hydrolyzing the compound of formula (3a) or the compound of formula (3b) with a strong base, i.e., a metal alkoxide, respectively, to prepare the corresponding compound of formula (2a) or the compound of formula (2b). As the metal alkoxide, potassium tert-butoxide is preferably used. The hydrolysis reaction may be carried out in an organic solvent such as ethers such as tetrahydrofuran and diethoxyethane. The resulting compound of formula (2a) or the compound of formula (2b) can be isolated through a process including neutralization, washing with an organic solvent such as dichloromethane and brine, organic layer separation, drying and the like. Alternatively, the separated organic layer may be used directly in the subsequent hydrogenation reaction without a separate drying step.

The process of the present invention can be carried out by hydrogenating the compound of formula (2a) or the compound of formula (2b) using (i) a palladium catalyst or (ii) hydrogenation using a palladium catalyst in the presence of an amino- To prepare the corresponding compound of formula (I) or the compound of formula (Ib). When the compound of formula (2a) or the compound of formula (2b) is hydrogenated using a palladium catalyst, a compound of formula (1a) or a compound of formula (1b) wherein R is hydrogen is obtained. When the compound of formula (2a) or the compound of formula (2b) is hydrogenated using a palladium catalyst in the presence of an amino-protecting group-forming agent, a compound of formula (1a) or a compound of formula (1b) wherein R is an amino- . The palladium catalyst may be Pd (OH) ₂ or Pd / C, preferably Pd (OH) ₂ . The amount of the catalyst to be used may be appropriately selected within the range of 1 to 30 mole percent. Examples of the amino-protecting group forming agent include amide forming reagents such as di-tert-butyl dicarbonate [(t-BuO) ₂ O], benzoyl chloride and acetyl chloride as well as alkyl protecting group forming reagents including various alkyl halogens , And preferably di-tert-butyl dicarbonate [(t-BuO) ₂ O] can be used. The hydrogenation reaction can be carried out by blowing hydrogen under atmospheric pressure, but is not limited thereto. The hydrogenation reaction may be carried out in a mixed solvent of ethanol and dichloromethane. The compound of formula (1a) or the compound of formula (1b) obtained according to the hydrogenation reaction can be isolated through a process including removal of solvent, washing with ethyl acetate and brine, organic layer separation, drying and the like.

The compound of formula (Ia) or the compound of formula (Ib) obtained according to the present invention can be prepared by reacting various medicines, for example, optically active mefenazolate, Can be used for manufacturing.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrating the present invention, and the present invention is not limited to these examples.

Example 1. Preparation of 1 - [(1 R ) - (1-phenylethyl)] - (3 R ) -3-tosylpiperidine

Step 1: Preparation of (2S ) -2- (3-hydroxypropyl) -1 - [( 1R ) - (1-phenylethyl)] aziridine

Ethyl (3 S) -. [( 1 R) -1- phenylethyl aziridine-2-yl] carboxylate using MK Ji et al, Chem. To carry out the reaction in the same manner to the procedure described in Asian J. 2014, 9, 1060-1067, (2 S) -2- (3- hydroxypropyl) -1 - [(1 R) - (1- phenylethyl )] &Lt; / RTI &gt; aziridine.

Yield: 90%

^{1 H-NMR (400 MHz,} CDCl 3): δ 7.39-7.15 (5H, m), 3.61 (2H, t, J = 6.4 Hz), 2.53 (1H, q, J = 6.6 Hz), 1.85-1.50 ( 5H, m), 1.44 (3H, d, J = 6.6Hz), 1.48-1.40 (2H, m).

Step 2. Preparation of 1 - [(1 R ) - (1-phenylethyl)] - (3 R ) -3-tosylpiperidine

(2 S ) -hydroxypropyl [(1 R ) -phenylethyl] aziridine (5.0 g) prepared in Step 1 was dissolved in acetonitrile (120 ml) and triethylamine (1.1 eq.) And p- Sulfonyl anhydride (8.7 g) was added. The reaction mixture was stirred at 0 &lt; 0 &gt; C for 10 minutes and then at room temperature for 4 hours. The reaction mixture was quenched by the addition of ice (100 g) to the reaction mixture and extracted three times with CH ₂ Cl ₂ (300 mL). The combined extracts were washed with NaCl saturated solution (100 mL) twice and water was removed using anhydrous magnesium sulfate. The solid was filtered off and the filtrate was distilled under reduced pressure. The resulting product (8.6 g) was purified by short silica gel flash chromatography (CH ₂ Cl ₂ / ethyl acetate / n-hexane = 1: 1: 4, v / v / v) to obtain the title compound.

Yield: 92%

¹ H-NMR (400 MHz, CDCl ₃ ):? D = 7.72 (d, J = 8.3 Hz, 2H), 7.40-7.10 = 6.8 Hz, 1H), 2.68 (m, 2H), 2.43 (s, 3H), 2.16-1.91 (m, 2H), 1.89-1.30 6.8 Hz, 3H); 13 C NMR (50 MHz, CDCl 3): d = 144.3, 134.3, 129.6, 128.0, 127.4, 127.3, 126.8, 125.8, 78.3, 63.6, 54.2, 49.2, 30.6, 23.0, 21.5, 18.2 ppm; HRMS: m / z calcd for C 2 0H 25 NO 3 S: 360.1627 [M + H] +; ^{found: 360.1630 [α] 20 =} -6.8 ° c = 1.21 in CHCl 3)

Example 2.1 - Preparation of (3 S) -3- tosyl piperidine (the compound of formula 3b) - [(1 R) - (1- phenylethyl);

Ethyl (3 S) - [(1 R) -1- phenylethyl aziridine-2-yl] carboxylate instead of ethyl (3 R) - [(1 R) -1- phenylethyl aziridine-2-yl; It was prepared - [phenyl-ethyl (1 R)] aziridine-hydroxypropyl-carboxylate for example 1 (2 R) were reacted by the same procedures as in step 1 of use. Further, the obtained (2 R) - hydroxy-propyl [(1 R) - phenylethyl] was reacted in the same manner as in Step 2 of Example 1 using aziridine 1 - [(1 R) - (1- phenylethyl )] - (3 S) -3- tosyl piperidine (the compound of formula 3b) was prepared.

Yield: 87%

^{1 H-NMR (400 MHz,} CDCl 3): δ 7.34-7.09 (5H, m), 3.21 (2H, m), 2.44 (1H, q, J = 6.4 Hz), 1.63 (1H, m), 1.55- 1.43 (3H, d, J = 6.4 Hz), 1.30-1.07 (4H, m)

Example 3. Preparation of 1- (tert-butoxy) - ( 3R ) -hydroxypiperidine (compound of formula (Ia))

Step 1: Preparation of 1 - [(1 R ) - (1-phenylethyl)] - (3 R ) -hydroxypiperidine

Example 1 was prepared in 1 - [(1 R) - ( 1- phenyl-ethyl)] - (3 R) -3- tosyl piperidine means (50 mL tetrahydro acids (compound, 1 g of formula 3a) ) Was added dropwise with slow stirring to a solution of potassium tert-butoxide (0.37 g) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 1 hour and then the temperature was lowered to 0 &lt; 0 &gt; C. The reaction mixture was neutralized with 1N HCl solution, dichloromethane (200 mL) was added to the reaction mixture, saturated NaCl solution (150 mL) was added, and the organic layer was separated. The obtained organic layer was further washed with a saturated NaCl solution (150 mL), and water was removed using anhydrous magnesium sulfate. The solid was filtered off and the filtrate was dried under reduced pressure to give 1 - [( 1R ) (1-phenylethyl)] - ( 3R ) -hydroxypiperidine (compound of formula (II)). This was used in the subsequent reaction without purification.

Step 2: Preparation of 1- (tert-butoxy) - ( 3R ) -hydroxypiperidine (compound of formula 1a)

Pd (OH) ₂ (10 mol%) was added thereto with stirring and di-tert-butyl dicarbonate (1.2 g) was added thereto. . The reaction mixture was filtered, and the filtrate was dried under reduced pressure to remove the solvent. The resulting product was dissolved in ethyl acetate (100 mL) and then washed twice with saturated NaCl solution (100 mL) and layer separated. The organic layer was washed with anhydrous magnesium sulfate to remove water, and the solid was filtered off and purified by column chromatography to give the title compound.

Yield: 76%

^{1 H-NMR (400 MHz,} CDCl 3): δ 3.77 (d, J = 10.4 Hz, 2H), 3.69-3.41 (m, 1H), 3.23-3.11 (m, 2H), 1.88 (dd, J = 12.2 , 4.2 Hz), 1.86-1.73 (m, 1H), 1.63-1.35 (m, 11H). &Lt; 13 &gt; C NMR (100 MHz, CDCl3) [delta] 154.8, 79.2, 67.2, 50.5, 43.4, 31.1, 29.3, 21.9. [[alpha]] D &lt; 20 &gt; = -23.6 (c 0.54, EtOH)

Preparation of piperidine-hydroxypiperidine (compound of formula 1b) - Example 4. 1- (ter- butoxy) - (3 S)

1 - [(1 R) - (1- phenyl-ethyl)] - (3 R) -3- tosyl-piperidine prepared in Example 2 instead of 1 - [(1 R) - (1- phenyl-ethyl)] - (3 S) -3- tosyl blood by using the piperidine the reaction in the same manner as in step 1 of example 3 1 - [(1 R) - (1- phenyl-ethyl)] - (3 S) - hydroxypyrrolidine Pyridine (compound of formula 2b). Also, the obtained 1 - [(1 R) - (1- phenyl-ethyl)] - (3 S) - hydroxypiperidine was reacted using piperidine in the same manner as step 2 of Example 3 1- (ter- portion ethoxy) - (3 S) - hydroxypiperidine piperidine (to prepare a compound of formula 1b.

Yield: 85%

^{1 H-NMR (400 MHz,} CDCl 3): δ 3.77 (d, J = 10.4 Hz, 2H), 3.69-3.41 (m, 1H), 3.23-3.11 (m, 2H), 1.88 (dd, J = 12.2 , 4.2 Hz), 1.86-1.73 (m, 1H), 1.63-1.35 (m, 11H). &Lt; 13 &gt; C NMR (100 MHz, CDCl3) [delta] 154.8, 79.2, 67.2, 50.5, 43.4, 31.1, 29.3, 21.9. [[alpha]] D &lt; 20 &gt; = -23.6 (c 0.54, EtOH)

Claims (2)

Hydrolyzing the compound of formula (3a) with a metal alkoxide to produce a compound of formula (2a); And
(I) hydrogenation using a palladium catalyst or (ii) hydrogenation using a palladium catalyst in the presence of di-tert-butyl dicarbonate to produce a compound of formula
Lt; RTI ID = 0.0 &gt; (Ia) &lt; / RTI &
<Formula 1a>

&Lt; EMI ID =

&Lt; EMI ID =

Wherein TsO is tosyloxy, Ph is phenyl and R is hydrogen or tert-butoxy. Hydrolyzing the compound of formula (3b) with a metal alkoxide to produce a compound of formula (2b); And
(I) hydrogenation of the compound of formula (2b) using a palladium catalyst or (ii) hydrogenation of the compound of formula (Ib) using a palladium catalyst in the presence of di-tert-butyl dicarbonate
Lt; RTI ID = 0.0 &gt; (Ib) &lt; / RTI &
&Lt; EMI ID =

(2b)

&Lt; EMI ID =

Wherein TsO is tosyloxy, Ph is phenyl and R is hydrogen or tert-butoxy.