CN102206187A - New synthetic method for 6-benzyl-1-ethoxymethyl-5-isopropyluracil (Emivirine) and its analogues - Google Patents

Abstract

The invention relates to a new synthetic method for a compound which is represented by the general formula (IV), n thereof is 1, 2 or 3, R1 is selected from phenyl, naphthyl, cyclopentyl and cyclohexyl, R2 is selected from C1 to C4 alkyl, vinyl and formoxyl, and R3 is selected from methyl, vinyl, cyclohexyl and phenyl. The invention provides the new synthetic method which treats isopropyl cyclomalonate as a raw material. The method has the advantages of easily obtained raw materials and reagents and simple operation, and allows multi sites to be reconstructed simultaneously and easily, a large selection space in new drug molecule designation to be achieved and the officinal possibility of such compound to be increased.

Description

A New Synthetic Method for 6-Benzyl-1-Ethoxymethyl-5-Isopropyluracil (Emivirine) and Its Analogs

Technical field:

The present invention relates to a kind of preparation method of active ingredient of medicine, more specifically a kind of compound 6-benzyl-1-ethoxymethyl-5 isopropyluracil (Emivirine) with anti-HIV-1 type AIDS activity and preparation methods of analogues thereof.

Background technique:

Emivirine is a non-nucleoside reverse transcriptase inhibitor, which produces non-competitive inhibition with the reverse transcriptase of HIV-1 virus and has potent anti-HIV activity in vitro. It is compatible with AZT (zidovudine), d4T (stata Vudine) and 3TC (lamivudine) and many other major anti-HIV-1 drugs can produce a synergistic effect in combination, and there is no cross-resistance with nucleoside reverse transcriptase inhibitors. Virus strains resistant to AZT and 3TC can still fully maintain the sensitivity to the drug. The drug has excellent preclinical toxicological properties. Animal test results show that the drug does not produce long-term or cumulative toxicity, and has no significant impact on fertility. The drug has entered phase II Linchuan trials in the United States.

There are two main synthetic routes of existing Emivirine. One is to use 5-isopropyluracil as a raw material, after being substituted at the N-1 position, it undergoes a nucleophilic substitution reaction with benzaldehyde under strong alkali conditions, and finally acetylates the hydroxy group and removes it by hydrogenation to obtain the final product (Masanori B etc., Nucleosides, Nucleotides Nucleic Acids.1995, 14:575-583; Ubasawa et al., 1996, JP 08003143; Cazaux et al., 1999, FR 2779722; Otani, Hiroshi et al., 2001, JP2001114767), the route is as shown in Scheme 1.

a.1) ( _Me3Si )2NH, _{( NH4} ) _2SO4 , _CH2Cl2 ; 2) _KI , _{EtOCH2OEt.b.1} ) NaOH, _PhMe ; 2) BuLi, THF/hexane, PhCHO .c. AcOH, 4-DMAP(cat.)dH ₂ , Et ₃ N, Pd, Me ₂ CHOH.

The other one is based on 4,5-dibromo-2,6-dimethoxypyrimidine as a raw material, and the halogens at positions 5 and 6 undergo Grignard exchange reactions with isopropyl Grignard reagents respectively, and then react with acetone and Benzyl bromide reaction, in which dehydroxylation is required after reacting with acetone, and finally the protecting group is removed to obtain the final product (Paul K et al., Organic Letters. 2006, 8: 3737-3740), the route is shown in Scheme 2. Using 6-chloro-5-isopropyluracil as a raw material, a similar method was used, but no protection was required to obtain the final product (PaulK et al., Organic Letters.2007, 9: 1639-1641), and the route is as shown in Scheme 3 Show.

a.1) i-PrMgCl·LiCl, THF, rt.2) LaCl ₃ ·2LiCl, Me ₂ CO, THF, 0°C. b.1) Et ₃ N, TFA, CH ₂ Cl ₂ , rt.2) H ₂ 1bar, PtO ₂ , EtOH.

c.1) i-PrMgCl·LiCl, THF, rt.2) PhCH ₂ Br, rt.d.HCl conc.MeOH, reflux.e.1) BSA, MeCN.2) TMS triflates, CH ₂ (OEt) ₂ .

a. POCl ₃ , H ₃ PO ₄ , reflux. b. NaI, HI, rt. c. 1) MeMgCl·LiCl, -30°C. 2) i-PrMgCl·LiCl, -30°C. d. 1) CuI, BnBr, -30℃. e.1) BSA, MeCN. 2) TMS triflates, CH ₂ (OEt) ₂ .

In addition, the synthesis of Emivirine analogues can first prepare compound II as the key intermediate, and then splicing rings and replacing at the N-1 position to obtain the final product. Wherein, compound II is prepared by two ways (Erik B.P et al. 1995,8:934-936; NielsenC et al., 1996,39:2427-2431; Nielsen C et al., 2002,45:5721-5726), route as shown in Scheme 4 Show.

a.Zn,THF,reflux.b.1)Et ₃ N,MgCl ₂ 2)HCl c.1)NaOEt,EtOH,reflux.2)aq.ClCH ₂ COOH,reflux.d.BSA,LiI,MeCN.

The raw materials used in the above synthetic routes are not the easiest and easy to obtain, and involve organometallic reactions, which require relatively harsh reaction conditions, such as anhydrous, oxygen-free, low temperature, etc. In the Grignard reaction, transition elements and monovalent copper salts are used as catalysts, which are more poisonous. Reformastky Reaction requires a large excess of zinc powder, and has strict requirements on the quality of zinc powder. Therefore, there is still a need for a simpler, more economical, and easier to obtain homologue synthetic route.

Invention content:

The present invention provides a method capable of preparing the compound of formula (IV) using simple starting materials.

In the formula, n is 1, 2 or 3; _R is phenyl, naphthyl, cyclopentyl, cyclohexyl;

R ₂ is C1-C4 alkyl, vinyl, formyl;

R ₃ is methyl, vinyl, cyclohexyl, phenyl;

The present invention is implemented through the following reaction schemes:

Step (1) is the nucleophilic substitution reaction of cycloisopropyl malonate (Meldrum's Acid) and acid halide in the presence of an organic base in a reaction solvent at a certain temperature for several hours, and then reflux alcoholysis in ethanol A compound of formula (I) is obtained. More specifically, the nucleophilic substitution reaction adopts an organic base (such as triethylamine, tri-n-butylamine, pyridine, tripropylamine) as an acid removal agent in a reaction solvent (such as tetrahydrofuran, dioxane, acetone , dichloromethane, chloroform, acetonitrile), and react in the temperature range of -10 to 30°C for 1 to 6 hours. After the reaction, evaporate the solvent under reduced pressure, directly reflux in absolute ethanol for 2 to 8 hours, and alcoholyze to obtain the compound of formula (I), wherein R ₁ is the same as the compound of general formula (IV).

Step (2) is a nucleophilic substitution reaction between the compound of the formula (I) and the halide in the presence of an organic or inorganic base in an aprotic solvent at a certain temperature for several hours to obtain the compound of the formula (II). More specifically, nucleophilic substitution reactions are carried out with organic bases (such as sodium alkoxide, triethylamine, tri-n-butylamine, pyridine, tripropylamine) or inorganic bases (such as NaOH, KOH, CsOH, Ba(OH) ₂ , Mg(OH) ₂ , Ca(OH), Sr(OH) ₂ , KHCO ₃ , K ₂ CO ₃ , Na ₂ CO ₃ , CsCO ₃ ) are acid-removing agents, and in aprotic solvents (such as DMF, DMSO , tetrahydrofuran, acetone, dioxane, pyrrolidones), and react at 20-160°C for 2-10 hours to obtain the compound of formula (II), wherein R ₁ and R ₂ are the same as the compound of general formula (IV).

In step (3), the compound of formula (II) and thiourea are subjected to a ring closure reaction under the condition of sodium ethoxide/ethanol, and then hydrolyzed in an aqueous solution of chloroacetic acid under reflux conditions to obtain the compound of formula (III).

Step (4) is that the compound of formula (III) undergoes nucleophilic substitution with alkyl chloromethyl ether under the catalysis of silicon etherification reagent and Lewis base to obtain the final product (IV), wherein, R ₁ , R ₂ , R ₃ Same as the compound of general formula (IV). When _R1 is phenyl, _R2 is isopropyl and _R3 is phenyl, the final product is 1-ethoxymethyl-5-isopropyl-6 benzyluracil (Emivirine).

The present invention has the advantages of: 1. This route uses cycloisopropyl malonate (Meldrum's Acid) as raw material to synthesize 1-ethoxymethyl-5-isopropyl-6-benzyluracil or its analog. The raw materials and reagents used are all cheap and easy to obtain, and the reaction has no strict requirements on the conditions, the operation is simple, and it is easy to prepare in large quantities. 2. Through this route, it is easy to obtain derivatives modified at three important sites at the same time, complete the accumulation of compound libraries, and lay a foundation for further exploring the structure-activity relationship of such compounds and developing highly effective anti-HIV-1 AIDS drugs.

Note: Cycloisopropyl malonate can be obtained from commercial sources, and can also be prepared in one step from cheaper and readily available malonic acid (David D et al., J.Am.Chem.Soc.1948, 70:3426-3428 ).

Detailed ways:

The present invention will be further described below in conjunction with embodiment, but does not limit this description.

Embodiment 1 The preparation of 3-oxo-4-phenylbutyric acid ethyl ester (formula I compound)

Cycloisopropyl malonate (23.75g, 0.165mol) and anhydrous pyridine (32.5mL, 0.4mol) were dissolved in 100mL of dichloromethane, and then slowly dropped into phenylacetyl chloride (25.50g, 0.165mol ), continue to react at 0°C for 1 hour, and react at room temperature for 1 hour. The reaction solution was diluted with 50 mL of dichloromethane, and 100 mL of 2N hydrochloric acid was added, the organic phase was separated, the aqueous layer was extracted twice with dichloromethane (50 mL), the organic phases were combined, and the solvent was evaporated under reduced pressure to obtain a light orange solid. Rinse with a small amount of ethanol to obtain white crystals. After suction filtration, directly reflux in 250 mL of absolute ethanol for 2.5 hours. After evaporating the solvent under reduced pressure, a light yellow liquid is obtained, which can be used in the next reaction without purification. Purification by silica gel column chromatography (50:1 petroleum ether/ethyl acetate) gave 33.05 g of light yellow liquid with a yield of 98.8%.

ESI-MS: m/z=207.1[M+H] ⁺

¹ H NMR (300MHz, CDCl ₃ ) δ: 7.31-7.15 (5H, m, ArH), 5.20 (2H, s, COCH ₂ CO), 4.52 (2H, s, CH ₂ Ph), 3.61-3.56 (2H, q, OCH ₂ CH ₃ ), 1.16～1.14 (3H, t, OCH ₂ CH ₃ ).

Embodiment 2 The preparation of 3-oxo-4-cyclohexyl butyric acid ethyl ester (compound of formula I)

Cycloisopropyl malonate (23.75g, 0.165mol) and anhydrous pyridine (32.5mL, 0.4mol) were dissolved in 100mL of dichloromethane, and then cyclohexylacetyl chloride (26.40g, 0.165 mol), continue to react at 0°C for 1 hour, and react at room temperature for 1 hour. The reaction solution was diluted with 50 mL of dichloromethane, and 100 mL of 2N hydrochloric acid was added, the organic phase was separated, the aqueous layer was extracted twice with dichloromethane (50 mL), the organic phases were combined, and the solvent was evaporated under reduced pressure to obtain a light orange solid. After suction filtration, directly reflux in 250 mL of absolute ethanol for 2.5 hours, evaporate the solvent under reduced pressure to obtain a light yellow liquid, which can be used in the next reaction without purification. Purification by silica gel column chromatography (50:1 petroleum ether/ethyl acetate) gave 30.74 g of light yellow liquid with a yield of 88.3%.

ESI-MS: m/z=212.2[M+H] ⁺

¹ H NMR (300MHz, CDCl ₃ ) δ: 4.20 (2H, s, COCH ₂ CO), 3.58-3.45 (2H, q, OCH ₂ CH ₃ ), 2.61 (2H, s, CH ₂ ), 1.15-1.12 ( 3H, t, OCH ₂ CH ₃ ).

Embodiment 3 Preparation of 2-isopropyl-3-oxo-4-phenylbutyric acid ethyl ester (compound of formula II)

Ethyl 3-oxo-4-phenylbutyrate (16.5g, 0.080mol), 2-bromopropane (11.8g, 0.096mol), anhydrous potassium carbonate (26.2g, 0.24mol) and dry DMF (25mL ) were mixed and stirred at room temperature for 12 hours. Add ethyl acetate (50 mL) to dilute, wash with water, wash with saturated brine, and dry over sodium sulfate. The solvent was distilled off under reduced pressure, and purified by silica gel column chromatography (80:1 petroleum ether/ethyl acetate) to obtain 14.2 g of light yellow liquid with a yield of 71.3%.

ESI-MS: m/z=249.1[M+H] ⁺

¹ H NMR (300MHz, CDCl ₃ ) δ: 7.38~7.22 (5H, m, ArH), 5.07 (1H, s, COCHCO), 4.42~4.36 (1H, m, CHMe ₂ ), 4.21~4.16 (2H, q , OCH ₂ CH ₃ ), 4.11 (2H, s, CH ₂ Ph), 1.32～1.29 (3H, t, OCH ₂ CH ₃ ), 1.26～1.24 (6H, d, CHMe ₂ ).

¹³ C NMR (75MHz, CDCl ₃ ) δ: 172.01 (C-3), 167.84 (C-1), 138.14, 129.18, 128.14, 126.20 (C-aryl), 91.69 (CO CH HCO), 70.23 ( CH ₂ Ph), 59.37 (O CH ₂ CH ₃ ), 37.81 ( CHMe ₂ ), 21.35 (CH Me ₂ ), 14.43 (OCH ₂ CH ₃ )

Example 4 Preparation of 5-isopropyl-6-benzyluracil (compound of formula III)

Sodium metal (2.2g, 96mmol) was dissolved in 200ml of absolute ethanol, thiourea (4.96g, 64mmol) and ethyl 2-isopropyl-3-oxo-4-phenylbutyrate (6.56g, 32mmol) were added, The reaction mixture was heated to reflux for 6 hours. Rotate under reduced pressure at 40-50°C until nearly dry, and dissolve the residue in water (50ml). The pH was adjusted to 4 with 2N hydrochloric acid, and 6.12 g of precipitate was filtered out with a suction filter funnel, and the precipitate and 20% chloroacetic acid (200 ml) were heated to reflux for 8 hours. After cooling to room temperature, white crystals were precipitated, filtered with suction, washed with cold ethanol and cold ether in turn, and dried to obtain 5.48 g of 5-isopropyl-6-benzyluracil, yield 66.1%, mp 224-226°C.

ESI-MS: m/z=245.4[M+H] ⁺

¹ H NMR (300MHz, CDCl ₃ ) δ: 10.97-10.94 (2H, br s, 2NH), 7.33-7.16 (5H, m, ArH), 3.90 (2H, s, CH ₂ Ph), 2.95-2.88 (1H , m, CHMe ₂ ), 1.20～1.18 (6H, d, CHMe ₂ ).

¹³ C NMR (75MHz, CDCl ₃ ) δ: 163.77 (C-4), 150.94 (C-2), 148.45, 136.99, 128.46, 127.88 (C-aryl), 113.79 (C-5), 35.21 ( CH ₂ Ph) _, 26.29 ( CHMe2 ), _19.99 ( CHMe2 )

Example 5 6-benzyl-1-ethoxymethyl-5-isopropyluracil (compound of formula IV, Emivirine)

Dissolve 5-isopropyl-6-benzyluracil (1.2g, 5.0mmol) in dichloromethane (30ml), add N, O-bistrimethylsilylacetamide (BSA) (3.2ml, After stirring at room temperature for 40 minutes, chloromethyl ethyl ether (0.57 g, 6.0 mmol) and a catalytic amount of LiI were added, and after stirring _at room temperature for 3 hours, saturated _Na2CO3 solution was added to stop the reaction, dichloro Extracted with methane, dried over sodium sulfate, evaporated the solvent under reduced pressure, purified by silica gel column chromatography (3:1 petroleum ether/ethyl acetate), and finally obtained 1-ethoxymethyl-5-isopropyl-6-benzyluracil 1.38g, yield 91.5%, mp.105～108℃.

HRESI-MS m/z: calcd for C ₁₇ H ₂₂ N ₂ O ₃ , 303.17090 [M+H] ⁺ ; found 303.17032.

¹ H NMR (300MHz, CDCl ₃ ) δ: 8.97 (1H, br s, NH), 7.36～7.11 (5H, m, ArH), 5.13 (2H, s, NCH ₂ O), 4.18 (2H, s, CH ₂ Ph), 3.65~3.60 (2H, q, OCH ₂ Me), 2.90~2.82 (1H, m, CHMe ₂ ), 1.29~1.27 (6H, d, CHMe ₂ ), 1.20~1.17 (3H, t, OCH ₂ Me)

¹³ C NMR (75MHz, CDCl ₃ ) δ: 162.23 (C-4), 151.82 (C-2), 148.46 (C-6), 135.44, 129.19, 127.26, 127.22 (C-aryl), 119.71 (C-5 ), 72.91 (N CH ₂ O), 65.00 (O CH ₂ CH ₃ ), 33.50 ( CH ₂ Ph), 28.34 ( CHMe ₂ ), 20.39 (CH Me ₂ ), 15.03 (OCH ₂ CH ₃ )

Embodiment 6 6-benzyl-1-benzyloxymethyl-5-isopropyluracil (compound of formula IV)

Dissolve 5-isopropyl-6-benzyluracil (1.2g, 5.0mmol) in dichloromethane (30ml), add N, O-bistrimethylsilylacetamide (BSA) (3.2ml, 11.0mmol) after the reaction solution became clear, after stirring at room temperature for 40 minutes, chloromethyl benzyl ether (0.94g, 6.0mmol) and a catalytic amount of LiI were added, and after stirring at room temperature for 3 hours, saturated _Na2CO3 solution was added to stop the reaction _. Extracted with methane, dried over sodium sulfate, evaporated the solvent under reduced pressure, purified by silica gel column chromatography (3:1 petroleum ether/ethyl acetate), and finally obtained 1-benzyloxymethyl-5-isopropyl-6-benzyluracil 1.57g, yield 86.5%, mp.105～108℃.

HRESI-MS m/z: calcd for C ₂₂ H ₂₄ N ₂ O ₃ , 365.18536[M+H] ⁺ ; found 365.18597.

¹ H NMR (300MHz, CDCl ₃ ) δ: 8.87 (1H, br s, NH), 7.33-7.25 (8H, m, ArH), 7.06-7.04 (2H, d, ArH), 5.21 (2H, s, NCH ₂ O), 4.65 (2H, s, OCH ₂ Ph), 4.16 (2H, s, CH ₂ Ph), 2.88～2.81 (1H, m, CHMe ₂ ), 1.27～1.25 (6H, d, CHMe ₂ )

¹³ C NMR (75MHz, CDCl ₃ ) δ: 162.09 (C-4), 151.79 (C-2), 148.37 (C-6), 137.33, 135.29, 129.21, 128.48, 128.00, 127.78, 127.27 (C-aryl) , 119.79 (C-5), 72.96 (N CH ₂ O), 71.81 (O CH ₂ Ph), 33.48 ( CH ₂ Ph), 28.32 ( CHMe ₂ ), 20.40 (CH Me ₂ )

Claims (11)

1. the new preparation process of general formula (IV):

In the formula, n is 1,2 or 3; R ₁Be phenyl, naphthyl, cyclopentyl, cyclohexyl;

R ₂Be C1-C4 alkyl, vinyl, formyl radical;

R ₃Be methyl, vinyl, cyclohexyl, phenyl;

The preparation method of logical formula V is made up of the following step:

(1) by propanedioic acid ring isopropyl ester (Meldrum ' sAcid) and carboxylic acid halides generation nucleophilic substitution reaction, alcoholysis obtains formula I compound in ethanol again;

(2) formula I compound and halogenide generation nucleophilic substitution reaction obtain formula II compound;

(3) formula II compound and thiocarbamide carry out ring-closure reaction, and hydrolysis obtains the formula III compound in the chloroacetic aqueous solution again;

(4) the formula III compound under the catalysis of silicon etherifying reagent and Lewis alkali with monochloromethyl-ether generation nucleophilic substitution, obtain final product (IV).

2. according to the described synthetic method of claim 1, it is characterized in that synthetic 6-benzyl-1-ethoxymethyl-5-sec.-propyl uridylic (Emirivine), promptly n is 1, R ₁Be phenyl, R ₂Be sec.-propyl, R ₃Be ethyl.

3. according to the described synthetic method of claim 1, it is characterized in that step (1): key intermediate (I) by propanedioic acid ring isopropyl ester and carboxylic acid halides in the presence of organic bases, in reaction solvent, carry out the generation nucleophilic substitution reaction of a few hours under the certain temperature, the backflow alcoholysis obtains in ethanol again, wherein R ₁Identical with the compound of general formula (IV).

4. it is characterized in that according to the described synthetic method of claim 3 nucleophilic substitution reaction of step (1) is the disacidify agent with the organic bases, organic bases is selected from triethylamine, tri-n-butylamine, pyridine, tripropylamine.

5. it is characterized in that according to the described synthetic method of claim 3 solvent of step (1) is selected from tetrahydrofuran (THF), dioxane, acetone, methylene dichloride, chloroform, acetonitrile.

6. it is characterized in that according to the described synthetic method of claim 3 temperature of reaction of step (1) is-10 ℃～30 ℃, the reaction times is 1～6 hour.

7. according to the described synthetic method of claim 1, it is characterized in that step (2): in the presence of organic bases or mineral alkali, in reaction solvent, the nucleophilic substitution reaction that carries out a few hours under the certain temperature obtains key intermediate (II) by formula I compound and halogenide, wherein, R ₁, R ₂Identical with the compound of general formula (IV).

8. it is characterized in that according to the described synthetic method of claim 7 nucleophilic substitution reaction of step (2) is the disacidify agent with the organic bases, organic bases is selected from sodium alkoxide, triethylamine, tri-n-butylamine, tripropylamine.

9. it is characterized in that according to the described synthetic method of claim 7 step (2) is the disacidify agent with the mineral alkali, mineral alkali is selected from NaOH, KOH, CsOH, Ba (OH) ₂, Mg (OH) ₂, Ca (OH), Sr (OH) ₂, KHCO ₃, K ₂CO ₃, Na ₂CO ₃, CsCO ₃..

10. it is characterized in that according to the described synthetic method of claim 7 solvent of step (2) is selected from DMF, DMSO, tetrahydrofuran (THF), dioxane, pyrrolidinone compounds.

11. it is characterized in that according to the described synthetic method of claim 7 temperature of reaction of step (2) is 20 ℃～160 ℃, the reaction times is 2～10 hours.