Intermediate for Synthesizing Paroxetine, Method for Preparing the same, and Uses Thereof

Abstract

A paroxetine intermediate, a method for preparing the same, and uses thereof are provided. Specifically, the method includes: reacting a compound of formula I below with a compound of formula II in the presence of air organic base under the catalysis of a complex formed from a chiral amine oxide L and a rare-earth metal compound Ln(OTf).sub.3 to prepare a compound of formula III below: wherein R.sub.1 is alkyl, phenyl or benzyl; R.sub.2, R.sub.3, R.sub.4 are each independently C.sub.1-C.sub.6 alkyl or C.sub.6-C.sub.10 aryl; the chiral amine oxide L has the following structure: wherein n=1, 2; and R=Ph-, 2,6-Me.sub.2C.sub.6H.sub.3-, 2,6-Et.sub.2C.sub.6H.sub.3-, 2,6-iPr.sub.2C.sub.6H.sub.3-, Ph.sub.2CH—.

##STR00001##

Claims

1. A compound having the structure of formula I: ##STR00024## wherein R.sub.2, R.sub.3 and R.sub.4 are each independently C.sub.1-C.sub.6 alkyl or C.sub.6-C.sub.10 aryl.

2. The compound according to claim 1, wherein the compound has the following structure: ##STR00025##

3. A method of preparing a compound of formula III below, ##STR00026## obtained by reacting a compound of formula I with a compound of formula II in the presence of an organic base under the catalysis of a complex formed from a chiral amine oxide L and a rare-earth metal compound Ln(OTf).sub.3: ##STR00027## wherein R.sub.1 is alkyl, phenyl or benzyl, preferably C.sub.1-C.sub.6 alkyl, phenyl or benzyl; R.sub.2, R.sub.3, R.sub.4 are each independently C.sub.1-C.sub.6 alkyl or C.sub.6-C.sub.10 aryl; the chiral amine oxide L has the following structure: ##STR00028## wherein n=1, 2; and R=Ph-, 2,6-Me.sub.2C.sub.6H.sub.3—, 2,6-Et.sub.2C.sub.6H.sub.3—, 2,6-iPr.sub.2C.sub.6H.sub.3—, Ph.sub.2CH—; and Ln in the rare-earth metal compound Ln(OTf).sub.3 represents a lanthanide metal selected from La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu.

4. The method according to claim 3, wherein the organic base is an amine.

5. The method according to claim 3, wherein the Ln(OTf).sub.3 is gadolinium trifluoromethanesulfonate [Gd(OTf).sub.3], holmium trifluoromethanesulfonate [Ho(OTf).sub.3], ytterbium trifluoromethanesulfonate [Yb(OTf).sub.3], erbium trifluoromethanesulfonate [Er(OTf).sub.3].

6. The method according to claim 3, wherein the organic base is triethylamine, diisopropylethylamine, trimethylamine, tri-n-propylamine, tri-n-butylamine, dimethyl aniline, diethylaniline, dimethyl benzylamine, diethyl benzylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene.

7. The method according to claim 3, wherein the reaction is carried out in a solvent such as pentane, hexane, heptane, dichloroethane, chloroform, toluene, ethylbenzene, isopropyl benzene, tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, ethyl acetate or isopropyl acetate.

8. A method of preparing a compound of formula I, ##STR00029## obtained by condensing a compound of formula IV below with p-fluorocinnamic acid in the presence of a dehydrant and an organic base, ##STR00030## wherein R.sub.2, R.sub.3, R.sub.4 are the same as defined in claim 1.

9. The method according to claim 8, wherein the dehydrant is 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-(7-azabenzotriazol)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, dicyclohexylcarbodiimide, or benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.

10. The method according to claim 8, wherein the organic base is N-methylmorpholine, triethylamine, diisopropylethylamine, trimethylamine, tri-n-propylamine, tri-n-butylamine, dimethylaniline, diethylaniline, dimethyl benzylamine, diethyl benzylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene.

Description

DESCRIPTION OF DRAWINGS

[0044] FIG. 1 is an HPLC spectrum of a racemic control liquid of compound IIIa;

[0045] FIG. 2 is an HPLC spectrum of a compound IIIa prepared according to Example 2; and

[0046] FIG. 3 is a H-spectrum of a compound Ia prepared according to Example 1.

DETAILED DESCRIPTION

[0047] In order to understand the disclosure of the present invention better, the present invention is further described hereafter in combination with specific examples, but these specific examples are not intended to limit the disclosure of the present invention.

[0048] The compound of the formula I can be prepared according to the following examples:

[0049] General Method: Preparation of Compound of Formula I

[0050] Into a 250 ml round-bottomed flask were weighed the pyrazole compound IV (30 mmol), and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (30-45 mmol) and N-methylmorpholine (30-45 mmol) sequentially: 100-200 mL of dichloromethane was added to dissolve them, and then p-fluorocinnamic acid (30 mmol) was added slowly to react overnight. The product was washed with water, concentrated to dryness, and then crystallized with petroleum ether/ethyl acetate (or heptane, or hexane/ethyl acetate, or heptane/ethyl acetate, or toluene, or MTBE, etc.) to obtain 21-29 mmol of pure p-fluorocinnamoyl pyrazole compound III with a yield of 70-97%.

[0051] The compound of the formula III can be prepared according to the following method:

[0052] General Method: Preparation of Compound of Formula III

[0053] Into a dry reaction flask were weighed a metal catalyst Ln(OTf).sub.3 (0.01-0.03 mol), a chiral ligand L (0.02 mol), the p-fluorocinnamoyl pyrazole III (0.2 mol) sequentially. The flask was replaced with nitrogen for 3 times. 300 mL of dichloromethane was added to activate at 35° C. for 10-30 min. A monoamide II (0.2 mol) and Et.sub.3N (0.2-0.4 mol) were added sequentially to react at 30-50° C. for 40-100 hours, and the reaction solution was washed with dilute hydrochloric acid, concentrated to dryness, and crystallized with petroleum ether/ethyl acetate to obtain 0.016-0.0174 mol of catalysate with a yield of 80-87%.

Preferred Embodiments

EXAMPLE 1

Preparation of Compound of Formula Ia

[0054] ##STR00014##

[0055] Into a 250 ml round-bottomed flask were weighed pyrazole (30 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (30 mmol), and N-methylmorpholine (30 mmol) sequentially, 100 mL of dichloromethane was added to dissolve them, and then p-fluorocinnamic acid (30 mmol) was added slowly to react overnight. The product was washed with water, concentrated to dryness, and then crystallized with petroleum ether/ethyl acetate to obtain 7.2 g of pure p-fluorocinnamoyl-3,5-dimethylpyrazole with a yield of 97%.

[0056] .sup.1H-NMR(400 MHz,CDCl3), δ=7.858-7.861(m,2H), δ=7.646-7.68(m,2H,), δ=7.0721-7.117(m,2H), δ=6.011(s,H), δ=2.618(s,3H), δ=2.287(s,3H).

[0057] ESI-MS (m/z)=244.9[M+H]:

[0058] The melting point: 92.5-94.5° C.

EXAMPLE 2

Preparation of Compound of Formula I

[0059] ##STR00015##

[0060] Into a dry reaction flask were weighed a metal catalyst Yb(OTf).sub.3 (0.02 mol), a chiral ligand L-PiMe.sub.2 (0.02 mol), p-fluorocinnamoyl-3,5-dimethylpyrazole (0.2 mol) sequentially. The flask was replaced with nitrogen for 3 times. 300 mL of dichloromethane was added to activate at 35° C. for 20 min. A monoamide (0.2 mol) and Et.sub.3N (0.2 mol) were sequentially added to react at 30-50° C. for 60-80 hours, and the reaction solution was washed with dilute hydrochloric acid, concentrated to dryness, and crystallized with petroleum ether/ethyl acetate to obtain 51 g of catalysate with a yield of 87%. The HPLC purity of the product was 94.65%, the ee was 99.12%, and the HPLC spectrum of the product was shown in FIG. 2.

[0061] Examples 3-10 were experimental data obtained by operating according to the same method as that of Example 1:

TABLE-US-00001 [00016] [00017] Example R.sub.2 R.sub.3 R.sub.4 Organic base Dehydrant Solvent Yield  3 Me H Me N-methylmorpholine HATU THF 92.2%  4 Me H Me N-methylmorpholine DCC toluene 91.7%  5 Me Ph Me triethylamine EDCI dichloromethane 90.7%  6 Et H Me triethylamine EDCI dichloromethane 89.0%  7 Ph H Me diethylaniline PyBOP hexane 80.5%  8 4-Me—Ph Me Ph diethylaniline HATU ethyl acetate 76.3%  9 Pr 3-Et—Ph Me DBU EDCI tetrahydrofuran 70.1% 10 H H H N-methylmorpholine EDCI dichloromethane 90.3%

##STR00018##

[0062] Examples 11-18 were experimental data obtained by operating according to the same method as that of Example 2:

TABLE-US-00002 [00019] [00020] Example R1 R.sub.2 R.sub.3 R.sub.4 Ln Base Solvent Yield ee 11 Me Me H Me Yb tri-n-propylamine THF 83.4% 98.89% 12 Et Me H Me Yb Et.sub.3N toluene 85.5% 99.06% 13 Pr Me Ph Me Yb DBU dichloromethane 83.9% 98.79% 14 i-Pr Et H Me Yb Et.sub.3N dichloromethane 84.8% 98.86% 15 n-Bu Ph H Me Gd dimethylaniline hexane 80.0% 97.26% 16 Et 4-Me—Ph Me Ph Gd Et.sub.3N ethyl acetate 83.3% 97.58% 17 Et Pr 3-Et—Ph Me Ho Et.sub.3N tetrahydro furan 80.7% 97.40% 18 Me H H H Er Et.sub.3N dichloromethane 80.6% 97.61%

[0063] Examples 19-27 were experimental data obtained by operating according to the same method as that of Example 2 except that a different catalyst L was selected:

TABLE-US-00003 [00021] [00022] [00023] Example n R Yield (%) HPLC (%) ee (%) 19 1 Ph— 82.2 90.87 98.3 20 1 2,6-Me.sub.2C.sub.6H.sub.3— 85.3 94.61 98.7 21 1 2,6-Et.sub.2C.sub.6H.sub.3— 84.1 94.30 98.5 22 1 2,6-iPr.sub.2C.sub.6H.sub.3— 83.7 92.15 97.9 23 1 Ph.sub.2CH— 80.8 92.54 97.7 24 2 Ph— 83.1 90.60 97.1 25 2 2,6-Et.sub.2C.sub.6H.sub.3— 84.3 94.13 98.6 26 2 2,6-iPr.sub.2C.sub.6H.sub.3— 82.6 93.42 98.4 27 2 Ph.sub.2CH— 80.5 92.10 97.8