RU2733731C1 - Method of producing intermediate products for synthesis of kalanolides and analogues thereof - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: invention relates to organic chemistry and specifically to a method of producing compound 5, a compound of general formula (II), a compound of general formula (IV), where R, in each case independently represents Calkyl.EFFECT: technical result is improved method of producing intermediate products for synthesis of analogues of anti-HIV agent kalalolid A and its analogues, as well as obtaining novel heterocyclic compounds.10 cl, 1 dwg, 3 ex

Description

The technical field to which the invention relates

The present invention relates to an improved method for the synthesis of intermediates for the synthesis of analogs of the anti-HIV agent calanolide A.

State of the art

Calanolide A is currently a promising drug candidate and is undergoing phase II clinical trials against HIV infection. However, analogs of Calanolide A were synthesized, significantly superior to the parent compound. For example, compound 6 is characterized by anti-HIV activity (EC ₅₀ = 2.85 nM, TI> 10526), which exceeds that of calanolide A (EC ₅₀ = 640 nM, TI 47-140) by about 220 times, see D1. Two schemes for the synthesis of compound 6 (D1) have been described, one of which involves exhaustive tosylation of 1 to give ditosyl derivative 2 and subsequent removal of one of the tosyl groups. Compound 3a is then converted to 6. This process requires an additional deprotection step to give 3a and, as a result, an increase in the number of steps and a decrease in yield. In addition, the described purification of compound 3a is carried out using chromatography. On the other hand, following the procedure described in D1, we found in the reaction mixture a significant amount of unreacted 2, dihydroxy derivative 1 and side isomer 3b (Scheme 1).

Scheme 1. One of the known schemes for the synthesis of an analog of calanolide A

Moreover, at the stage of annulation of the pyran ring also requires purification using chromatography.

Thus, there is a need for effective methods for the synthesis of intermediates for the preparation of analogs of calanolide A.

Cited prior art documents

D1 Ma, T. et al. J. Med. Chem. 2008, 51, 1432-1446.

Disclosure of invention

The present invention relates to an improved method for the synthesis of intermediates for the synthesis of anti-HIV analogs of the drug calanolide A. It was found that a two-step tosylation / detosylation procedure can be replaced by a one-step nicotinoylation procedure, which allows the selectively protected intermediate (I) to be obtained easily and in high yield immediately the form of a solid. The presence of the pyridyl moiety of nicotinic acid allows other advantages to be achieved as well. In particular, it is possible to carry out the pyran ring annulation step (which is usually carried out in a pyridine solvent) under "no solvent" conditions. Moreover, the product with an annelated pyran ring can be easily isolated in the form of a salt. Without wishing to be bound by theory, the authors believe that the basic pyridine nitrogen atom can be used to form solid crystalline salts, which are easily separated from the reaction mixture and can be easily purified.

Thus, in one embodiment, the present method comprises one or more of the following steps:

Stage 1 . Introduction of a protective nicotinoyl group. The compound of formula (I) is reacted

,

,

with a compound of formula (I)

,

,

where X represents –OH, –N ₃ or benzotriazolyl;

with the formation of compound (II)

.

...

Stage 2 . A compound of formula (II) is reacted with a compound of formula (III)

,

,

where Y is OR, or two Y together form a group = O; and

R, independently at each occurrence, is C _1-6 alkyl, in particular methyl or ethyl;

with the formation of compound (IV)

,

,

where R is as described above.

Stage 3. Removal of the protective nicotinoyl group from compound (IV) with acid or base to obtain compound 5.

,

,

where R is as described above.

In another embodiment, the present invention relates to a compound of formula (II)

.

...

In yet another embodiment, the present invention relates to a compound of formula (IV)

,

,

where R, at each occurrence independently, is C _1-6 alkyl, in particular methyl or ethyl.

Preferred Embodiments

Stage 1

The ratio of compounds 1 and (I) may be from 1: 5 to 5: 1, but most preferably the ratio is about 1: 1.

The reaction in stage 1 can be carried out in an inert aprotic solvent, in particular in tetrahydrofuran, acetone, acetonitrile, DMF, ethyl acetate or dioxane.

The reaction in step 1 can be carried out in the presence of a base, in particular an organic amine; for example, triethylamine, N-methylmorpholine, N-ethyldiisopropylamine, 1,4-diazabicyclo [2.2.2] octane, ethylenediamine and the like. In this case, the amount of the base can be from 0.01 to 10 equivalents. Most preferably, about 1 equivalent of base is used, for example 1.05 to 1.10 equivalents of base.

The reaction in step 1 can be carried out in the presence of coupling agents such as 1,3-dicyclohexylcarbodiimide (DDC), azabenzotriazole tetramethyl-uronium hexafluorophosphate (HATU), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC), 1,3 -diisopropylcarbodiimide and the like. The amount of the coupling agent used is not particularly limited, but it is most preferable to use 1.0-5.0 equivalents.

The reaction temperature of step 1 is not particularly limited, however, from a practical point of view, the preferred temperature is 0-60 ° C, most preferably about 25 ° C.

The reaction time of step 1 is usually from 1 hour to 72 hours, most preferably from 6 to 12 hours.

The compound (II) formed in step 1 is preferably filtered from a solution containing by-products and / or unreacted starting compounds. Compound 1, filtered from the reaction mixture, is preferably sufficiently pure, so there is no need for additional purification. However, such purification can be carried out using standard methods such as crystallization from an organic solvent.

Stage 2

The reaction in step 2 can be carried out without using a solvent or in an inert aprotic high boiling point solvent such as pyridine, DMF, toluene, xylene or the like.

The amount of compound (III) used is not particularly limited, the most preferred amount is 1-10 equivalents, for example 4-5 equivalents.

The temperature for carrying out step 2 is not particularly limited, however, from the point of view of technology, the preferred temperature is 50-200 ° C, most preferably 135-150 ° C.

The reaction time for step 2 is usually 5 minutes to 2 hours, most preferably 15 to 45 minutes.

The reaction mixture formed in step 2 containing compound (IV), after cooling, can be diluted with an inert organic diluent such as acetone or ethyl acetate in an amount of 1 to 5 volumes, after which the acid or its solution in an organic solvent such as acetone, ethyl acetate is added or a C1-C6 alkyl alcohol. After a while, a crystalline precipitate of the salt of compound (IV) with an acid precipitates from the resulting solution. A variety of organic and inorganic acids can be used in an amount of 1 to 20 equivalents, however, the preferred acid is picric acid in an amount of 1.0–2.0 equivalents, which forms a crystalline precipitate of the salt of compound (IV). The resulting salt can be collected, for example, by filtration and optionally recrystallized from a solvent such as o-xylene or 1,4-dioxane to provide the purified salt (IV).

Stage 3

The reaction in step 3 can be carried out in a suitable inert solvent, in particular C _1-6 alcohol, water, DMF, toluene, xylene or the like.

The base used can be KOH, NaOH, NH ₃ , sodium methoxide, sodium ethylate, triethylamine and the like.

The acid used may be hydrochloric acid, trifluoroacetic acid, acidic polystyrene sulfonic acid cation resin and the like.

The temperature for carrying out step 2 is not particularly limited, however, from a technological point of view, the preferred temperature is 20-100 ° C, most preferably 25-70 ° C or 50-60 ° C.

The reaction time of step 3 is usually from 1 hour to 48 hours, most preferably from 3 to 12 hours, in particular 6 hours.

The resulting compound 5 can be isolated from the reaction mixture by filtration, extraction and the like.

The completeness of the reaction can be ascertained using thin layer chromatography (TLC), nuclear magnetic resonance NMR spectroscopy, or other generally known methods.

Examples of

The examples below illustrate some preferred embodiments of the present invention, but do not limit it.

Example 1a

5-Hydroxy-4-propylcoumarin-7-yl nicotinate

To a solution of 5,7-dihydroxy-4-propylcoumarin (1 mmol, 220 mg) and triethylamine (1.1 mmol, 111 mg) in 10 ml of acetone was added 1-nicotinoylbenzotriazole (1.0 mmol, 224 mg) with stirring. A day later, the precipitate of 5-hydroxy-4-propylcumarin-7-yl nicotinate was filtered off and washed with acetone. The yield is 78%.

Example 1b

5-Hydroxy-4-propylcoumarin-7-yl nicotinate

To a solution of 5,7-dihydroxy-4-propylcoumarin (1 mmol, 220 mg) and triethylamine (1.1 mmol, 111 mg) in 10 ml acetone, 1-nicotinoyl azide (1.0 mmol, 148 mg) was added with stirring. A day later, the precipitate of 5-hydroxy-4-propylcoumarin-7-yl nicotinate was filtered off.

Example 1c

5-Гидрокси-4-пропилкумарин-7-ил никотинат

5-Hydroxy-4-propylcoumarin-7-yl nicotinate

To a solution of 5,7-dihydroxy-4-propylcoumarin (1 mmol, 220 mg) and triethylamine (1.1 mmol, 111 mg) in 10 ml of dioxane, nicotinic acid (1.0 mmol, 123 mg) was added with stirring and 1, 3-dicyclohexylcarbodiimide (1.5 mmol, 309 mg). After a week of keeping the reaction mixture at room temperature, the precipitate of 5-hydroxy-4-propylcoumarin-7-yl nicotinate and dicyclohexylurea was filtered off and recrystallized from ethyl alcohol to obtain pure 5-hydroxy-4-propylcoumarin-7-yl nicotinate.

M.p. 229-231 ° C.

¹ H-NMR: (DMSO-d ₆ + CCl ₄ ) 10.88 (s, 1H, OH-5), 9.25 (d, J = 1.5 Hz, 1H, H2 '), 8.84 ( dd, J = 1.5 Hz, J = 4.8 Hz, 1H, H6 '), 8.44 (dt, J _d = 7.6 Hz, J _t = 1.9 Hz, 1H, H4'), 7.59 (dd, J = 4.9Hz, J = 7.6Hz, 1H, H5 '), 6.73 (s, 2H, H6, H8), 5.98 (s, 1H, H3), 2.96 (m, 2H, CH ₂ ), 1.70 (m, 2H, CH ₂ ), 1.04 (m, 3H, CH ₃ );

IR: 1082, 1150, 1290, 1434, 1613, 1739 cm ^-1 .

Example 2

2,2-dimethyl-8-oxo-10-propyl-2H, 8H-pyrano [2,3-f] chromene-5-yl nicotinate picrate

A mixture of 5-hydroxy-4-propylcoumarin-7-yl nicotinate (2 mmol, 650 mg) and acrolein diethyl acetal (1.266 g, 8 mmol) was heated at 145 ° C with stirring for 40 minutes. Then the reaction mixture was diluted with 10 ml of ethyl acetate and a solution of picric acid (458 mg, 2 mmol) in 10 ml of ethyl acetate was added. The precipitated light yellow crystals of picrate were filtered off and recrystallized from o-xylene or dioxane. Yield 464 mg, 45%.

¹ H-NMR (DMSO-d ₆ + CCl ₄ ): 9.38 (br s, 1H), 8.98 (br s, 1H), 8.84 (br s, 1H), 8.65-8, 67 (m, 1H), 8.63 (s, 2H), 7.77-7.80 (m, 1H), 6.90 (s, 1H), 6.72 (s, 2H), 6.46 (d, J = 10 Hz, 1H), 6.08 (s, 1H), 5.77 (d, J = 10 Hz, 1H), 2.92-2.96 (m, 2H, CH ₂ ), 1.68-1.73 (m, 2H), 1.55 (s, 6H), 1.06-1.10 (m, 3H).

Example 3

5-Hydroxy-2,2-dimethyl-10-propyl-2H, 8H-pyrano [2,3-f] chromen-8-one

The picrate of 2,2-dimethyl-8-oxo-10-propyl-2H, 8H-pyrano [2,3-f] chromene-5-yl nicotinate (1 mmol, 621 mg) was mixed with 20 ml of methanol and polystyrene sulfonate cation exchanger, heated at 55 ° C with stirring for 8 hours. Then the reaction mixture was filtered and the filtrate was diluted with 60 ml of water. The resulting precipitate of the product was filtered off and dried in air. Yield 281 mg, 98%.

¹ H-NMR (DMSO-d ₆ + CCl ₄ ): 10.73 (s, 1H), 6.56 (d, J = 9.9Hz, 1H), 6.33 (s, 1H), 5, 90 (s, 1H), 5.64 (d, J = 9.9 Hz, 1H, H-3), 2.83-2.77 (m, 2H), 1.66-1.51 (m, 2H), 1.43 (s, 6H), 1.10-0.91 (m, 3H).

Claims (25)

1. A method of obtaining compound 5, including the following stages: step 1: in an inert aprotic solvent in the presence of a base, a compound of formula 1 and a compound of formula (I) are contacted to form a compound of formula (II):

, where X represents –OH, –N ₃ or benzotriazolyl; Step 2: contacting, in an inert solvent or without solvent, a compound of formula (II) and a compound of formula (III) to form a compound of formula (IV):

, where Y is OR, or two Y together form a group = O; and R, at each occurrence independently, is C _1-6 alkyl, in particular methyl or ethyl; after completion of the reaction, an acid or its solution in an organic solvent is added to the reaction mixture containing compound (IV) to obtain a crystalline precipitate of the acid salt of compound (IV); Step 3. In a polar solvent, a compound of formula (IV) is contacted with an acid or base to obtain compound 5:

where R, at each occurrence independently, is C _1-6 alkyl. 2. The method according to claim 1, where in step 1 the ratio of compounds 1 and (I) is about 1: 1, the solvent is acetone or dioxane, the base is triethylamine. 3. A process according to claim 1 or 2, wherein step 1 is carried out in the presence of a coupling agent such as 1,3-dicyclohexylcarbodiimide (DDC) or 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. 4. The method according to any one of claims 1 to 3, where the interaction in stage 2 is carried out without the use of a solvent at a temperature of 135-150 ° C. 5. A method according to any one of claims 1 to 4, wherein in step 2 the acid is picric acid. 6. The method according to any one of claims 1 to 5, where in stage 3 the acid is an acidic polystyrene sulfonic acid cation exchanger. 7. The method according to any one of claims 1 to 6, where stage 3 is carried out in C1-C6 alkyl alcohol, in particular in methanol at a temperature of 50-60 ° C. 8. Compound of formula (II)

... 9. Compound of formula (IV)

, or a salt thereof; where R, at each occurrence independently, is C _1-6 alkyl. 10. A compound according to claim 9 wherein R is methyl.