WO2000053569A1

WO2000053569A1 - Method for preparing 2-2[(4-alkylphenyl)-ethyl]-2-amino-propanediol and intermediates useful in such preparation

Info

Publication number: WO2000053569A1
Application number: PCT/CN2000/000046
Authority: WO
Inventors: Dali Yin; Donghui Wang; Yonghua Zhang
Original assignee: Hangzhou Zhongmei Huadong Pharmaceutical Co. Ltd.; Institute Of Materia Medica, Chinese Academy Of Medical Sciences
Priority date: 1999-03-11
Filing date: 2000-03-10
Publication date: 2000-09-14
Also published as: CN1144779C; CN1266844A; AU3142600A

Abstract

This invention relates to a method for preparing 2-2[(4-alkylphenyl)-ethyl]-2-amino-propanediol compounds of general formula (I), wherein R is C1-10 alkyl, preferably n-octyl, which comprises the following steps: reacting alkylbenzene (II) with acetyl chloride in the presence of Lewis acid; preparing p-alkyl α-halophenylethyl ketone (IV) according to a conventional method in the presence of a small amount of Lewis acid; condensing the obtained compound (IV) with 2-acylamino-malonate to give 2-acylamino-2-[2-p-alkylphenyl-2-oxo-ethyl]-malonate (VI) in the presence of a base; reducing product (VI) to 2-acylamino-2-[2-p-alkylphenyl-2-hydroxy-ethyl]-propanediol (VII); then hydrolyzing and hydrogenating compound (VII) to form compound (I). This invention also relates to the intermediates involved in the above method.

Description

Method for preparing 2- [2- (4-fluorenylphenyl) -ethyl] -2-amino-propanediol by clear book

FIELD OF THE INVENTION Field of the Invention

The present invention relates to a method for preparing 2- [2- (4-alkylphenyl) -ethyl] -2-amino-propanediol, and more particularly, to a method for preparing a compound of the following structural formula (I), and in the preparation An intermediate produced in the process.

Background technique

The compound of the following structural formula is abbreviated as FTY-720, and its chemical name is 2-amino-2- [2- (4-octylphenyl) ethyl] -1,3-propanediol hydrochloride.

This compound was originally disclosed in PCT / JP93 / 01515, has immunosuppressive activity, and is expected to become a new immunosuppressant for clinical use (see PCT / JP93 / 01515).

The method disclosed in the above PCT application uses protected phenylethanol as a starting material, and the entire synthetic route undergoes 10 steps of reaction. The main disadvantage of this method is that, due to the instability of the phenylethanol acetate compound, the Fnedle-Crafts acylation reaction of phenylethanol acetate and octanoyl chloride is low, and the total yield is lower than this. Low and not suitable for large-scale preparation. Therefore, the object of the present invention is to provide an improved method for preparing fluorenylphenylethylaminopropanediol, which overcomes the defects of the prior art, and has the advantages of low reaction cost and high yield.

It is a further object of the present invention to provide an intermediate product obtained in the method of the present invention. Invention Disclosure

According to one aspect, the present invention includes a method for preparing 2- [2- (4-fluorenylphenyl) -ethyl] -2-amino-propanediol of the following general formula (I):

In the formula: R is a C1-10 alkyl group;

The method includes the following steps:

1. Fluorenylbenzene (II) reacts with acetyl chloride in the presence of Lewis acid to form p-fluorenylacetophenone (III);

2. The product (III) is formed into p-alkyl α-haloacetophenone (IV) by conventional methods in the presence of a small amount of Lewis acid;

3. The product (IV) is condensed with 2-amidomalonate (V) under basic conditions to form 2-amido-2— [2-p-fluorenylphenyl—2-oxoethyl] malon Acid ester (VI);

4. The product (VI) is reduced to 2-amido- 2- [2-p-alkylphenyl 2-hydroxy-ethyl] propanediol (VII);

5. The product (VII) is hydrolyzed to form 2-amino-1 2- [2-p-alkylphenyl-2-hydroxylethyl] propanediol (VIII); then

6. The product (VIII) is hydrolyzed to form the compound (I). According to another aspect, the present invention includes an intermediate product obtained in the above preparation method

(VI), (VII) and (VIII).

Detailed description of the invention

The method for preparing 2- [2- (4-alkylphenylethyl] -2-amino-propanediol according to the present invention can be simply expressed as follows:

OH CH ₂ OH

Reduction Ri cH ^{_ CH} 2-Cr NHR ₂ vn

CH ₂ OH hydrolysis

The preparation method of the present invention uses fluorenylbenzene II as a starting material, wherein the fluorenyl group R is a linear or branched fluorenyl group of C1-10, preferably n-octyl. The Fnedel-Crafts reaction of II with acetyl chloride is carried out under the catalysis of a Lewis acid, preferably A1C1 ₃ , to produce the product (III). III has sufficient purity and can be used in the following reactions without purification.

Compound IV can be prepared by α-halogenation of III, and the reaction is performed according to a conventional method known to those skilled in the art, using a small amount of Lew _1S acid, preferably A1 (¾) as a catalyst for the reaction. X is Br or Cl, and Br is preferred. One

Condensation of IV and V under basic conditions to obtain the key intermediate VI of the present invention, as described above; is (: 1 to 4 acyl, preferably acetyl; but (1 to 4 alkyl, preferably Methyl and ethyl. Common bases such as sodium ethoxide, sodium methoxide, sodium hydride, potassium tert-butoxide, etc., of which sodium ethoxide and sodium methoxide are preferred. The molar ratio of reactants IV to V is 1: 1 to 1: 2. The ratio of Na to IV is 1-1.5: 1.

Reduction of a compound of formula VI with a dehydrogenated compound yields another key intermediate of the present invention

VII, and ₁₂ which, as described above. The reducing agents used are aluminum or boron rehydrides and their derivatives, preferably LiAlH ₄ , NaBH ₄ , KB ^ n LiBH ₄ , and most preferably NaBH ₄ . The solvent used in the reaction in this step is a common solvent when using a dehydrogenated compound, such as water, methanol or ethanol. It is obvious to those skilled in the art that the reaction of this step also requires the participation of a buffer of borate or phosphate.

The intermediate VII is hydrolyzed to obtain yet another important intermediate VIII of the present invention, wherein R is the same as the aforementioned ^. This step can be performed with a strong base such as NaOH, KOH, LiOH or a strong acid such as HC1, ≦ ₀₄ in water or an alcohol (eg, methanol, ethanol).

VIII Hydrogenolysis under acidic conditions can directly obtain the target compound I, in which a catalytic amount of a hydrogenolysis catalyst known to those skilled in the art, such as Pd-C, can be used, and the hydrogen pressure is 1-5 kg / cm ² o

It is obvious to a person skilled in the art that the target compound I can also be prepared by first hydrolyzing the compound VII and then hydrolyzing the N-acyl group.

According to another embodiment of the present invention, the product VI can also be subjected to hydrogenolysis as described above to form 2-amido-2- [2-p-alkylphenylmonoethyl] malonate, whose structural formula is as follows ,

-. Wherein R n R _{3 is} as described above, and then the ester is reduced and hydrolyzed as described above to finally obtain compound I.

Compound I can further form salts with acids. The acid may be HC1, H ₂ S0 ₄ ,

HC10 ₄ , HBr, HO Ac, etc.

Compared with the prior art method, the total yield is about 5% (based on the salt-forming material). The method according to the present invention not only has the characteristics of short synthetic route and simple operation, but also has a relatively high yield in each step. High, the total yield can reach about 20-25% (based on the material after salt formation). Therefore, the method of the present invention is a more economical, faster and more effective method for preparing 2- [2- (4-fluorenylphenyl) -ethyl] -2-amino-propanediol.

The present invention will be further described by examples below, but these examples are only used to illustrate the present invention and not to limit the scope of the present invention. Example 1

Preparation of 4-octyl-acetophenone

A mixture of octylbenzene (9.1 g, 48 mmol) and acetyl chloride (4.7 g, 60 mmol) was cooled in an ice bath, and anhydrous A1C1 ₃ (8.9 g, 67 mmol) was added portionwise over 1 hour with stirring. Stirring was continued for 1 hour, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with 1N HC1, washed with water to neutrality, dried over anhydrous sodium sulfate, and concentrated to obtain 9.2 g of an oil.

'HNMR (300Mhz, CDC1 ₃ ) δ 7.88 (d, J = 8.1Hz, 2H), 7,26 (d, J-8.1Hz, 2H), 2.65 (t, J = 7.2Hz, 2H), 2.60 (s , 3H), 1.62 (m, 2H), 1.26 (m, 10H), 0.87 (t, J = 6.3Hz, 3H) Example 2

Preparation of 4-octyl-a-bromoacetophenone

4-octyl-acetophenone (4.2 g, 18 mmol) was dissolved in 5 ml of ether, and the solution was cooled in an ice bath. Add A1C1 ₃ (50 mg) under stirring, add Br ₂ (2.9 g, 18 mmol) dropwise within 1 hour, continue stirring for 30 minutes, and concentrate under reduced pressure. The resulting solids were washed with ice water and ice-cold 95% ethanol. Pressure drying gave 4.8 g of 4-octyl-α-bromoacetophenone. Example 3

2-acetamido-2- [2- (4-octylphenyl) -2-oxo-ethyl] -1,3-dimalonate

Dissolve Na (0.4 g, 17.2 mmol) in 16 ml of ethanol, add diethyl acetaminomalonate (4.7 g, 21.6 mmol), and add 4-octyl-α dropwise over 40 minutes under ice cooling. -Bromoacetophenone (4.8 g, 15.4 mmol) in anhydrous ether. 0. C was stirred for 2 hours, and concentrated under reduced pressure. The residue was extracted with ethyl acetate, washed with water to neutrality, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (petroleum ether / ethyl acetate = 3: 1) to obtain 6.2. g oil, yield 95% (based on octylbenzene).

^! HNMR (300Mhz, CDC1 ₃ ) δ 7.86 (d, J = 8.1Hz, 2H), 7.26 (d, J = 8.1Hz, 2H), 7.10 (s, 1H), 4.35-4.20 (m, 6H), 2.64 (t, J = 7.8Hz, 2H), 1.93 (s, 3H), 1.60 (m, 2H), 1.40-1.18 (m, 16H), 0.86 (t, J = 6.6Hz, 3H); EI-MS m / z 448 (M + l), 217 Example 4 (reduction)

2-acetamido-2- [2- (4-octylphenyl) -2-hydroxy-ethyl H, 3-propanediol

Dissolve 2-acetamido-2- [2- (p-octylphenyl) -2-oxo-ethyl] -1,3-dimalonate (1.68 g, 3.8 mmol) in 30 ml In 95% ethanol, add K ₂ ΗΡ0 ₄ · 3Η ₂ 0 aqueous solution (6.84 g, 30 mmol), and then add NaBH ₄ NaOH aqueous solution (0.74 g NaBH, / 5 ml H ₂ O / 0.5 ml 10% NaOH), room temperature After stirring for 6 hours under reduced pressure, ethanol was removed under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N HC1, saturated NaHC0 ₃ and saturated NaCl, dried over anhydrous NaS0 ₄ and concentrated to give 1.29 g of white solid. 940 mg, The yield was 68%.

"HNMR (300Mhz, DMSO) δ 7.18 (d, J = 7.8Hz, 2H), 7.09 (d, J = 7.8Hz, 2H), 4.67 (d, J = 9.6Hz, 1H), 3.65-3.45 (m, 4H), 2.60-2.40 (m, 2H), 2.00 (d, J = 15Hz, 1H), 1.71 (dd, J -15, 9.6Hz), 1.60-1.40 (m, 2H), 1.30-1.15 (m, 10H), 0.81 (t, J = 6.9Hz, 3H) Example 5 (hydrolytic hydrogenation)

2-amino-2- [2- (4-octylphenyl) ethyl H, 3-propanediol

Dissolve 2-acetamido-2- [2- (4-octylphenyl) -2-hydroxy-ethyl] -1,3-propanediol (1.6 g, 4.38 mmol) in 15 ml of methanol and add NaOH (0.18 g, 4.5 mmol). After thermal reflux for 2 hours, the reaction solution was cooled to room temperature, and 0.4 ml of concentrated hydrochloric acid was added dropwise to make the pH of the reaction solution 5-6. After filtration, transfer the reaction solution to a hydrogenation flask, add 10% Pd-C (160 mg), 0.4 ml concentrated hydrochloric acid, and shake at 20-40 ° C under a pressure of 3 kg / cm ² of hydrogen for 20 minutes. hour. After the reaction was completed, the catalyst was removed by filtration. Sodium hydroxide was added for alkalization, and then concentrated under reduced pressure. The residue was extracted with ethyl acetate, dried and concentrated to obtain a white solid. Ethyl acetate was recrystallized to obtain 0.94 g of white flaky crystals in a yield of 70%.

'HNMR (300Mhz, DMSO, D ₂ 0 exchange) δ 7.07 (d, J = 9.3Hz, 2H), 7.03 (d, J = 7. · 37ζ, 2H), 3.27 (d, J = 10.5Hz, 2H), 3.22 (d, J = 10.5Hz, 2H), 2.55-2.40 (m, 4H), 1.55-1.40 (m, 4H), 1.30-1.10 (m, 10H), 0.80 (t, J = 6.9Hz, 3H) : EI-MS m / z 308 (M + 1), 276 Example 6 (Salt formation)

2-amino-2- [2- (4-octylphenyl) ethyl] -1,3-propanediol hydrochloride

Add 2-amino-2- [2- (4-octylphenyl) ethyl] -1,3-propanediol (0.9 g, 2.9 mmol) to 10 ml of ethanol. It is not completely soluble. Concentrated hydrochloric acid-saturated solution is added dropwise. Ether until pH reaches 4. stress reliever It was concentrated and the crude product was recrystallized from ethanol to obtain 0.5 g of white flake crystals with a yield of 50%.

'HNMR (300Mhz, DMSO) δ 7.08 (s, 4H), 3.49 (s, 4H), 2.60-2.40 (m, 4H), 1.80-1.70 (m, 2H), 1.60-1.45 (m, 2H), 1.30 -1.20 (m, 10H), 0.83 (t, J = 6.6Hz, 3H) Example 7 (Hydrolysis first)

2-acetamido-2- [2- (4-octylphenyl) ethyl H, 3-ethyl malonate

The 2-acetamido-2- [2- (4-octylphenyl) -2-oxo-ethyl] -1,3-dimalonate (1.76 g, 4.0 mmol) was dissolved in 30 ml of methanol, and 100 mg of 10% Pd-C and HC10 ₄ (0.8 g, 5.5 mmol) were added. Shake for 16 hours at 30 ° C and 2 kg / cm ² hydrogen pressure, filter the reaction solution, neutralize the filtrate with NaHC0 ₃ , concentrate under reduced pressure, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate, and column chromatography Separation (petroleum ether / ethyl acetate 3: 1) gave 11 g, yield 63%.

'HNMR (300Mhz, CDC1 ₃ ) δ 7.05 (2d, J = 8.4Hz, 4Η), 4.20 (m, 4H), 2.69 (m, 2H), 2.55 (t, J = 8.1Hz, 2H), 2.46 (m , 2H), 1.95 (s, 3H), 1.58 (m, 2H), 1.40-1.20 (m, 16H), 0.88 (t, J = 6.6Hz, 3H)

Claims

Rights request

1. Method for preparing 2- [2- (4-alkylphenyl) -ethyl] -2-amino-propylene glycol of the following general formula (I):

In the formula: R is a C1-10 alkyl group;

The method includes the following steps:

1). Alkylbenzene (II) reacts with acetyl chloride in the presence of Lewis acid to form p-alkylacetophenone (III);

2). The product (III) is formed into p-fluorenyl α-haloacetophenone (IV) by a conventional method in the presence of a small amount of Lewis acid;

3). The product (IV) is condensed with 2-amidomalonate (V) under basic conditions to form 2-amido-2- [2-p-alkylphenyl-2-oxo-ethyl] propane Diester (VI);

4). The product (VI) is reduced to 2-amido-1 2- [2-p-fluorenylphenyl 2-hydroxy-ethyl] propanediol (VII);

5), the product (VII) is hydrolyzed to form 2-amino-2- [2-p-alkylphenyl-2-hydroxylethyl] propanediol (VIII); then

6). The product (VIII) is hydrolyzed to form the compound (I).

2. The method according to claim 1, wherein R is n-octyl.

3. The method according to claim 1, wherein the reducing agent used in step 4) is aluminum or boron Of the double hydride.

4. The method according to claim 3, wherein the double hydride is LiAlH ₄ , NaBH ₄ , KBH ₄ and LiBH ₄₀

5. The method according to any one of claims 1 to 4, wherein the solvent used in step 4) is water, methanol, or ethanol, and further requires the participation of a borate or a phosphate buffer.

6. The method according to claim 1, wherein the base used in step 3) is sodium ethoxide, sodium methoxide, sodium hydride, and potassium tert-butoxide.

7. The method according to claim 6, wherein the molar ratio of reactants IV to V is 1: 1 to 1: 2, and the ratio of Na to IV is 1 to 1.5: 1.

8. The method according to claim 1, wherein the hydrogen pressure used in step 6) is 1 to 5 kg / cm ²

9. The method according to claim 1, wherein the product (VII) can also be firstly subjected to hydrogenolysis, and then hydrolyzed to finally form the compound (I).

10. The method according to claim 1, wherein the product (VI) can be firstly hydrogenolyzed to 2-yl-2- [2-p-fluorenylphenylethyl] malonate, followed by reduction and hydrolysis.

11.Compound of formula VI: o COOR ₃

Rr // wCH-CH ₂ -C--NNHHRR ₂₂

, COOR ₃ VI where 1 ^ is a fluorenyl group of CI-10; is an acyl group of CI-4; R ₃ is a fluorenyl group of C1-4

12.Compounds of formula VII:

OH CH ₂ OH

CH- CH ₂ -C-NHR ₂ VII

CH ₂ OH Among them! ^ Is an alkyl group of CI-10; R ₂ is an acyl group of C1-4.

13. The compound according to claim 11 or 12, wherein R _t is n-octyl and R ₂ is acetyl.

14. Compound of formula VIII:

OH CH ₂ OH

CH-CH ₂ -C-NH ₂

\ VIII

CH ₂ OH where R is a fluorenyl group of Cl-10 <

15. The compound according to claim 14, wherein R is n-octyl.