UA101946C2 - Process and intermediates for the preparation of integrase inhibitors - Google Patents

Abstract

The invention provides synthetic processes and synthetic intermediates that can be used to prepare 4-oxoquinolone compounds having useful integrase inhibiting properties.

Description

In accordance with another aspect, the invention relates to a method of obtaining a compound of formula 9:

BUT nn heh

CO ok g E oo

CI 9 where A is a Si-Svalkyl, which includes cyclization of the corresponding compound of formula 8:

N

Ko re; phi (9) Mn ok g EE 0 o

SI

8

In accordance with another aspect, the invention relates to a compound of formula 15:

MeOo OoMe but (

Hg

Ff si 15 or its salts.

In accordance with another aspect, the invention relates to a compound of formula 15a:

Me Ome

SIM»O. F

Me Ve

Fo

SI

15a

In accordance with another aspect, the invention relates to a compound of formula 16:

MeOo fi OMe

Hg

WITH

SI

16

In accordance with another aspect, the invention relates to a method of obtaining a compound of formula 15:

MeO OMe

Hg

Fe si 15 or its salts, which includes the transformation of the corresponding compound of formula 14: ve

Vg VI 14 in the compound of formula 15 or in its salt.

The invention also relates to other synthesis methods and synthetic intermediates useful for the preparation of 4-oxoquinone compounds described here.

Detailed description of the invention

Unless otherwise noted, the terms listed below mean the following: halogen is fluorine, chlorine, bromine, or iodine. The term alkyl includes normal and branched carbon chains. However, the names of individual radicals, such as propyl, assume only the straight chain, and branched-chain isomers, such as isopropyl, are named separately.

One skilled in the art understands that compounds with a chiral center can exist in optically active and racemic forms, and can be isolated in such forms. Some compounds may exhibit polymorphism. It should be understood that the present invention includes a description of methods for obtaining any racemic, optically active, polymorphic, tautomeric or stereoisomeric forms of the compound described herein and mixtures thereof, and it is well known in the art how to obtain optically active forms (for example, separation racemic form by methods of recrystallization, synthesis from optically active starting materials, chiral synthesis or chromatographic separation using a chiral stationary phase).

The specific and preferred values listed below for radicals, substituents, and spacers are for illustration purposes only; they do not exclude other given values or other values in given intervals for radicals and substituents.

Specifically:

C-Svalkyl can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl or hexyl.

A specific value for Ba is methyl.

The specific value for H is methyl.

The specific value for Ks is 1-imidazolyl.

A specific value for B is ethyl.

According to one aspect, the invention relates to a method of obtaining a compound of formula 3: ro) o) no fi on g EE o si

Kk or its salts, which includes the transformation of the corresponding compound of formula 2: on

Vg. o 2 or its salt into the compound of formula 3 or its salt. As shown below, the reaction can be easily carried out by mixing compound 2 with a polar aprotic solvent (eg, tetrahydrofuran) and cooling the mixture to below room temperature (eg, about -207C).

And And yo | - oh re! heh) we and oh me? dream (2 ma): n Vg m , o 9 /; o /2

VI M "1

A B2 M same MeEH, X xx head in o 3

First, the mixture is treated with an organometallic reagent (for example, dialkylmagnesium, dialkylzinc, alkylmagnesium halide, trialkylaluminum, or metal hydride) to form a carboxylate salt. For example, the mixture can be treated with about 0.5 equivalents of dibutylmagnesium or butylethylmagnesium, or about one equivalent of butylethylmagnesium-butanol adduct to give compound A. The resulting mixture can be mixed with a second organometallic reagent (eg, alkyllithium or alkylmagnesium halide) to give an organometallic compounds (compound VI! or B2). As a rule, this is done at a reduced temperature to affect the metal-halide exchange. For example, the resulting mixture can be mixed with approximately 1.2-2.2 equivalents of alkyllithium (for example, with approximately 1.8 equivalents of n-butyllithium or tert-butyllithium) at a temperature of -504507"C to obtain an organolithium compound (compound B1).According to one aspect of the invention, the metal-halogen exchange reaction can be carried out at a temperature of -20-20"С. The progress of such a reaction can be monitored by any convenient method (for example, HPLC). Upon completion of the reaction, 3-chloro-2-fluorobenzaldehyde (approximately 1.3 equivalents) can be added to the system. The progress of the addition reaction can be monitored by any suitable method (for example, by HPLC). Compound C is also isolated by any suitable method (for example, chromatography or crystallization). This approach avoids contamination and reduces the cost associated with the use of other reagents (eg, transition metals such as palladium reagents).

According to one aspect of the invention, the compound of formula 2 or its salt is prepared by bromination of 2,4-dimethoxybenzoic acid. The reaction is carried out under standard bromination conditions.

According to one aspect of the invention, a compound of formula C or a salt thereof is then converted into a compound of formula 4: p; o fi on g E o)

SI

4 or its salt. About 1-5 hydride equivalents of a silane reducing agent (eg, phenyldimethylsilane, polymethylhydrosiloxane, or chlorodimethylsilane, or a trialkylsilane, such as triethylsilane) is mixed with a suitable acid (eg, trifluoroacetic acid, trifluoromethanesulfonic acid, or acetic acid). It is convenient to carry out the reaction with approximately 1.2-2.0 hydride equivalents of triethylsilane and 5-10 equivalents of trifluoroacetic acid. A compound is added to this mixture

With or its salt. This can be conveniently done at a reduced temperature, for example, 0210°C. The progress of the reaction can be monitored by any suitable method (for example, HPLC). Upon completion of the reaction, compound 4 or its salt is also isolated by any suitable method (for example, chromatography or Compound 4 or its salt can also be prepared by adding trifluoroacetic acid to compound C in a suitable solvent and then introducing a silane reducing agent to give compound 4.

Alternatively, compound 4 or its salt can be prepared by taking the corresponding organometallic compound with compound 2 and reacting it with compound 11:

ku

IS

Ci 11 de Vu represents a suitable leaving group (eg, triflate, mesylate, tosylate, brosylate, etc.).

According to one aspect of the invention, a compound of formula 4 or a salt thereof is then converted to a compound of formula 5"

K and E i)

SI or its salt, where Ac is a suitable leaving group.

The carboxylic acid functionality of compound 4 can be activated, for example, by conversion to an acyl chloride or acyl imidazolide (compound 5) by treatment with a suitable reagent, for example, thionyl chloride, oxalyl chloride, cyanuric chloride, or 1,1-carbonylimidazole in a suitable solvent (eg, toluene or tetrahydrofuran). Any suitable leaving group can be introduced into the molecule, but the main thing is that the compound of formula 5' can then be converted into the compound of formula 6. For example, the reaction can easily be carried out using one equivalent of 1,1"-carbonyldiimidazole in tetrahydrofuran.

According to another aspect of the invention, the compound of formula 5' or its salt is then converted into the compound of formula 6: prio) o (fi ok 2 E (9) (Fe);

Si 6 or its salt where A is Si-Swalkill. For example, a compound of formula 5 can be mixed with 1-5 equivalents of a monoalkylmalonate salt and 1-5 equivalents of a magnesium salt in a suitable solvent. It is convenient to mix the compound of formula 5" with about 1.7 equivalents of potassium monoethylmalonate and about 1.5 equivalents of magnesium chloride. A suitable base, such as triethylamine or imidazole, is then added to the reaction. The reaction is then carried out at an elevated temperature (e.g. , about 100550 degrees), and its progress is monitored by any suitable method (for example, HPLC). Upon completion of the reaction, compound 6 can also be isolated by any suitable method (for example, chromatography or crystallization).

According to another aspect of the invention, the compound of formula 6 or its salt can be converted into the corresponding compound of formula 7:

Ka. K (54 g E (9) (6)

SI

7 where Na and P are independently a C-Svalkyl and A is a C-Svalkyl. Compound 6 can be converted to an activated alkylidene analog such as compound 7 by treatment with a formate group donor such as dimethylformamide dialkyl acetal (eg, dimethylformamide dimethyl acetal) or trialkyl orthoformate. The reaction is carried out at an elevated temperature (for example, approximately 100x50 degrees). The reaction can be accelerated by the introduction of an acidic catalyst such as, for example, alkanoic acid, benzoic acid, sulfonic acid or mineral acid. It is convenient to use, approximately, 500 ppt - 195 acetic acid. The progress of the reaction can be monitored by any suitable method (for example,

TOP). Compound 7 can be isolated or directly used to prepare a compound of formula 8 as described below.

According to another aspect of the invention, the compound of the formula 7 can be converted into the corresponding compound of the formula 8: where A is Si-Svalkyl. Compound 7 can be mixed with (5)-2-amino-33-methyl-1-butanol (5-valinol, ca. 1.1 equivalents) to give compound 8. The progress of the reaction can be monitored by any suitable method (e.g., HPLC ). The compound of formula 8 can be isolated or directly used to prepare the compound of formula 9 as described below.

According to another aspect, the invention relates to a method of obtaining a compound of formula 9:

BUT nn - ro) M

Fee approx

FI E o o (et) 9 where A is a C-Svalkyl, which includes the cyclization of the corresponding compound of formula 8: n she what o Mn ok

SI

8

Compound 8 can be cyclized to give Compound 9 by treatment with a silylating agent (eg, M,O-bis(trimethylsilyl)lacetamide, M,O-bis(trimethylsilyl)-trifluoroacetamide, or hexamethyldisilazane).

The reaction can be carried out in a polar aprotic solvent (for example, in dimethylformamide, dimethylacetamide, M-methylpyrrolidinone or acetonitrile). A salt (such as potassium chloride, lithium chloride, sodium chloride, or magnesium chloride) may be added to speed up the reaction. Typically, about 0.5 equivalents of a salt such as potassium chloride is added. The reaction can be carried out at an elevated temperature (for example, about 100-220 degrees), thus it is possible to achieve an acceptable completion time of the method. The progress of the reaction can be monitored by any suitable method (for example, HPLC). The introduction of an acid during the operation makes it possible to hydrolyze any silyl ether formed by the reaction of the silylating reagent with the alcohol group of compound 8. Examples of typical acids include mineral acids, sulfonic acids, and alkanoic acids. A concrete example of an acid that we can use is an aqueous solution of hydrochloric acid. Upon completion of hydrolysis, compound 9 can be isolated by any suitable method (eg, chromatography or crystallization). During the conversion described above, the silencing agent temporarily protects the alcohol group and is then removed. This eliminates the need to enter separate steps for inserting and removing protection, which increases the efficiency of the conversion.

According to another aspect of the invention, the compound of formula 9 is converted into the compound of formula 10:

but n

S ro on and EE 0 o s

Compound 9 is converted to Compound 10 by treatment with a suitable base (eg, potassium, sodium, or lithium hydroxide). For example, it is convenient to use about 1.3 equivalents of potassium hydroxide. The reaction can be carried out in any suitable solvent, such as, for example, tetrahydrofuran, methanol, ethanol, isopropanol or a mixture thereof. Water can also be used as a solvent. It is convenient to use a mixture of isopropanol and water. The progress of the reaction can be monitored in any suitable way (for example,

TOP). The initially formed carboxylate salt can be neutralized by an acid (for example, hydrochloric or acetic). For example, it is convenient to use approximately 1.5 equivalents of acetic acid. After neutralization, compound 10 is isolated by any suitable method (eg, chromatography or crystallization).

According to another aspect of the invention, a compound of formula 10 can be crystallized by adding a "seed" crystal to a solution containing a compound of formula 10. International patent application publication MO 2005/113508 discloses some special crystalline forms of 6-(3-chloro-2-fluorobenzyl)- 1-(5)-1-hydroxymethyl-2-methylpropyl|-7-methoxy-4-oxo-1,4-dihydroquinolone-3-carboxylic acid. International Patent Application Publication UMO 2005/113508 is incorporated herein in its entirety by reference (in particular, see pages 12-62 of this application). The particular crystal forms are identified there as crystal form I and crystal form PP. The powder X-ray scattering pattern for the crystalline form of FI is characterized by diffraction peaks at diffraction angles 28) equal to 6.56, 13.20, 19.86, 20.84, 21.22, and 25.22, which was measured on X-ray powder diffractometers. The powder X-ray scattering structure for Crystalline Form I is characterized by diffraction peaks at diffraction angles of 264), equal to 8.54, 14.02, 15.68, 17.06, 17.24, 24.16, and 25.74, which was measured on an X-ray powder diffractometer.

The publication of international patent application UMO 2005/113508 also describes methods of obtaining the crystalline form of 6-(3-chloro-2-fluorobenzyl)-1-((5)-1-hydroxymethyl-2-methylpropyl|-7-methoxy-4-oxo -1,4-dihydro-quinolone-3-carboxylic acid with an extrapolated melting point of about 162.1 degrees, as well as methods of obtaining a crystalline "seed" with a crystal purity of at least 7095. Accordingly, seed crystals of 6-(Z-chloro- 2-fluorobenzyl)-1-((5)-1-hydroxymethyl-2-methylpropyl|-7-methoxy-4-oxo-1,4-dihydro-quinolone-3-carboxylic acid can be obtained as described in the publication of international patent applications UUO 2005/113508.

The method presented in Scheme 1 below allows you to favorably obtain an unrefined ("crude") mixture

For compound 10, which can be directly crystallized to give Crystalline Form II without further purification (e.g., without first obtaining another polymorph such as Crystalline Form II or without some other form of prepurification), see example 6 below.

In cases where the compounds identified herein are sufficiently basic or acidic to form stable basic or acidic salts, the invention also relates to salts of such compounds. Such salts can be used as intermediates, for example, to purify these compounds. Examples of useful salts include organic acid addition salts formed with acids such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, o-ketoglutarate, and o-glycerophosphate. Suitable inorganic salts can also be prepared, including hydrochlorides, sulfates, nitrates, bicarbonates, and carbonates.

Salts can be prepared by conventional methods well known in the art, for example by reacting a sufficiently basic compound, such as an amine, with a suitable acid to provide an anion. Salts of alkali metals (eg potassium, sodium or lithium), alkaline earth metals (eg calcium or magnesium) and carboxylic acids can also be used.

Below, the invention is illustrated by the following non-limiting examples. The integrase inhibitor of formula 10 can be prepared as shown in the following Scheme 1:

Scheme I

I'm young M on J on -- on no on on

Hg

Ge) E IF) E o) : A A

SI Si

Z 4 re) (c) -E ro) o y- o) MMe» um -ya z

M-7 ог ог ) E (c) 2 E (c) Ge) gi E 6) 6) a si s

Baba ba and n NO n non sh

KU U M re; o chn ve vu - z --zyan, (fi Y ok og on si si s

Wa Za 10

Example 1: Preparation of Compound Z

Compound 2 (10 g) was added to 192 ml of THF and the mixture was cooled to -20°C. Then the mixture was successively treated with 21 ml of a 1 M solution of dibutylmagnesium in heptane and 19.2 ml of a 2.5 M solution of n-butyllithium in hexane, maintaining the temperature -20" C. 33-chloro-2-fluorobenzaldehyde (7.3 g) was added and the mixture was allowed to warm to 0°C. After 2 hours at this temperature, the reaction was quenched by the addition of 55 mL of 2 M hydrochloric acid. The organic phase was separated and extracted with 92 mL of ethyl acetate. The combined organic phases were washed with 92 mL of saturated aqueous sodium chloride solution, the organic phase was concentrated, and the product was precipitated by adding 200 mL of heptane.

The suspension was filtered and the resulting product was dried in air to give Compound 3: "H NMR (0M5O-de, 400 MHz) δ 12.15 (horn 5, 1H), 7.81 (5.1), 7.42(09- 7.2 Hz, 1), 7.264, t -6.8Hz, 1H), 7.151, -7.8 Hz, 1H), 6.77 (5, 1H), 6.09 (0, U - 4.7 Hz, 1H), 5.90 (9, U 2 4.9 Hz, 1H), 3.84 (in, ЗН), 3.80 (in, ЗН).

Alternatively, compound C can be prepared as follows.

Compound 2 (20 g) was added to 300 ml of THF and cooled to -20"C. The mixture was successively treated with 75.93 g ml of a solution of BEM-B (butylethyl magnesium and butanol adduct) in heptane and 35.08 g of 28 wt. 95 solution of tert -butyllithium in heptane, maintaining a temperature of -20"C. Then 3-chloro-2-fluorobenzaldehyde (15.80 g) was added and the mixture was allowed to warm to 0°C. After 2 hours at this temperature, the reaction was quenched by the addition of 2M hydrochloric acid. The organic phase was separated and extracted with ethyl acetate, then dried over sulfate of sodium and precipitated the product by addition of MTBE. The suspension was filtered and the product dried in air to give compound C (18.00 g, yield 69.1 95): "H NMR (0M50O-aiv, 400 MHz) 6 12.15 (horn 5, 1H), 7.81 (5, 1H), 7.42 (b y) 7.2 Hz, 1H), 7.26 (.9 2-68 Hz, 1H), 7.154, - 7.8 Hz, 1H ), 6.77 (5, 1H), 6.09 (0.9 - 4.7 Hz, 1H), 5.90 (9.9 -4.9

Hz, 1H), 3.84 (5, ЗН), 3.80 (in, ЗН).

Compound C can also be obtained by the method shown in the following scheme.

MeOo OMe

Me OMe: ve i-CRAFTSMANS siMeO (I V pil p ovo "i I

Vi Vi or REMESI then SEVA E and 8 a 1ba

Me OMe i-RIMASNSI no iya on

And nn nn nn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn

E (9) or i-RIMeSiI then so, Ff and 3

Compound 14 (10 g) was added to 28 mL of THF and 9 mL of bisdimethylaminoethyl ether precooled to 0°C. Isopropylmagnesium chloride (22.9 mL of a 2.07 M solution in THF) was added and the mixture was allowed to warm to room temperature overnight. . Before the addition of 3-chloro-2-fluorobenzaldehyde to improve the degree of conversion, an additional portion of isopropylmagnesium chloride (5 mL) was added to the reaction mixture. Then 3-chloro-2-fluorobenzaldehyde (4.4 mL) was added. After stirring at ambient temperature medium for 2 hours, to the mixture was added 38.6 g of a 14 wt 95 solution containing a complex of isopropylmagnesium chloride and lithium chloride in THF. After stirring overnight at ambient temperature, CO gas was bubbled through the reaction mixture." The reaction was stopped by adding 2 M hydrochloric acid to pHe3. The organic phase was separated and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride. The organic phase was concentrated and the precipitate or a product with the addition of MTBE. The suspension was filtered and the product dried in air to give Compound 3: "H NMR (OM50-v, 400 MG) 6 12.15 (riv, 1H), 7.81 (5, 1H), 7.42(659-7, 2 Hz, 1H), 7.269 - 6.8 Hz, 1H), 7.154, - 7.8

Hz, 1), 6.77 (5, 1H), 6.09 (9, 9) - 4.7 Hz, 1H), 5.90 (0, U 2 4.9 Hz, 1H), 3.84 (5, ZN), 3.80 (5, ZN).

Compound C can also be obtained by the method shown in the following scheme.

Me Ome

MeO OMe

Hg Hg or i-RimMYasi then E 3-xpor-2-fluorobenzaldehyde 14 "s 15

Meow. OMe i-REMESNiSI no (A on poni staged nate or i-RiMesSipotim so, F E o a

Kk)

Example 2: Preparation of Compound 4.

Triethylsilane (6.83 g) was added to trifluoroacetic acid (33.13 g), previously cooled in an ice bath. Compound C (10 g) was then added to the mixture while maintaining the temperature below 15°C. After stirring for 2 hours, MTBE was added to precipitate the product. The suspension was filtered and the product was washed with additional MTBE. After drying, 9.12 g of Compound 4 was obtained: " H NMR (0M50O-yv, 400 MHz) b 12.11 (rg 5, 1H), 7.47 (v, 1H), 7.42-7.38 (t, 1H), 7.14-7.08 (t, 2H), 6.67 (c, 1H), 3.87-3.84 (t, 8H).

Alternatively, Compound 4 may be prepared as follows.

Triethylsilane (7.50 g) was added to trifluoroacetic acid (49.02 g), previously cooled in an ice bath. Compound C (14.65 g) was added to the mixture, maintaining the temperature below 15 °C. After stirring for 1 hour, a solution of 17.63 g of sodium acetate in 147 ml of methanol was added. The mixture was boiled for 3 hours, then cooled to 0 °C. WITH. The suspension was filtered and the product was washed with additional methanol. After drying, 12.3 g of Compound 4 were obtained (yield 89.795): "H NMR (0M5O-yv, 400 MHz) 6 12.11 (riv, 1H), 7.47 (v, 1H), 7.42-7, 38 (t, 1H), 7.14-7.08 (t, 2H), 6.67 (v, 1H), 3.87-3.84 (t, 8H).

Example 3: Preparation of Compound 5a.

Imidazole (0.42 g) and 1,1"-carbonylimidazole (5.49 g) were suspended in 30 mL of THF at ambient temperature. Compound 4 (10 g) was then added in one portion and the mixture was stirred at ambient temperature until complete reaction (HPLC control). The resulting suspension was filtered and the precipitate was washed with MTBE. The precipitate was then dried to give Compound 5a: "H NMR (OM50O-av, 400

MHz) 5 7.99 (v, 1H), 7.52 (v, 1H), 7.41-7.38 (t, 1H), 7.30 (v, 1H), 7.12-7.08 (t, 2H), 7.04 (5, 1H), 6.81 (v, 1H), 3.91 (5, 2H). 3.90 (5, ZN), 3.79 (in, ZN).

Example 4: Preparation of compound ba.

Imidazole (0.42 g) and 1,1"-carbonylimidazole (5.9 g) were suspended in 30 mL of THF at ambient temperature. Compound 5a (10 g) was then added in one portion and the mixture was stirred at ambient temperature for 4 hours to form a suspension of Compound 5a. In a separate flask, 8.91 g of potassium monoethyl malonate was suspended in 40 mL of THF. Magnesium chloride (4.40 g) was added, and the resulting suspension was maintained at 55 degrees for 90 minutes. Suspension of Compound 5a was added to the magnesium chloride/potassium monoethyl malonate mixture and stirred overnight at 557 C. The mixture was then cooled to room temperature and the reaction was stopped by dropwise addition of 80 mL of a 28 wt, 95 NzRoh aqueous solution.

The organic phase was separated and successively washed with aqueous solutions of Manbo»z, KNSO»z and Masi. Then it was concentrated, obtaining an oil, which was re-evaporated with ethanol. The resulting solid was dissolved in

30 ml of ethanol and 6 ml of water. Compound ba crystallized upon cooling. The resulting crystals were separated by filtration and the product was washed with an aqueous ethanol solution. After drying, Compound ba was obtained: "H NMR (OM50-yv, 400 MHz) 5 7.51 (5, 1H), 7.42-7.38 (t, 1H), 7.12-7.10 (t, 2H), 6.70 (5, 1H), 4.06 (d, 9 - 7.0 Hz, 2H), 3.89 (5, 8H), 3.81 (5, d2H), 1.15( 1.9 - 7.0 Hz, ZN).

Alternatively, compound Ba can be prepared as follows.

Carbonyldiimidazole (10.99 g) was suspended in 60 mL of THF at ambient temperature.

Compound 4 (20 g) was then added in one portion and the mixture was stirred at ambient temperature for 30 minutes to form a suspension of compound 5a. In a separate flask, 15.72 g of potassium monoethyl malonate was suspended in 100 ml of THF. Magnesium chloride (6.45 g) was added and the resulting suspension was heated at 557°C for 5 hours. A suspension of compound 5a was added to the magnesium chloride/potassium monoethyl malonate mixture and stirred at 55°7C overnight. Then the mixture was cooled to room temperature and the reaction was stopped by adding 120 ml of 28 wt. 96 of an aqueous solution of НзРОх. The organic phase was separated and successively washed with aqueous solutions of KHSO3 and Masi. It was then concentrated to an oil and evaporated with ethanol.

The obtained solid was dissolved in 100 ml of ethanol and 12 ml of water. Compound ba crystallized upon cooling. The resulting crystals were separated by filtration and the product was washed with an aqueous ethanol solution.

After drying, 21.74 g of compound ba were obtained (yield 8995): "H NMR (0M5O-dv, 400 MHz) 5 7.51 (5, 1H), 7.42-7.38 (t, 1H), 7, 12-7.10 (t, 2H), 6.70 (5, 1H), 4.06 (4, 94 - 7.0 Hz, 2H), 3.89 (in, 8H), 3.81 (5 , 2), 1.15(69 7.0 Hz, zn).

Example 5: Preparation of Compound 9a.

Compound ba (20 g) was mixed with 6.6 g of dimethylformamide dimethyl acetal, 6 g of toluene and 0.08 g of glacial acetic acid. The mixture was heated at 907C for 4 hours. The mixture was then cooled to room temperature and 5.8 g of (5)-2-amino-3-methyl-1-butanol was added. The mixture was stirred at ambient temperature for 1 hour and then concentrated to a thick oil. After that, dimethylformamide (36 g), potassium chloride (1.8 g) and bis(trimethylsilyl)acetamide (29.6 g) were added and the mixture was heated at 90°C for 1 hour. The mixture was cooled to room temperature and diluted with 200 g of dichloromethane .

Dilute hydrochloric acid (44 g, approximately 1N) was added and the mixture was stirred at ambient temperature for 20 minutes. The organic phase was separated, successively washed with water, an aqueous solution of sodium bicarbonate and again with water. The solvent was replaced with acetonitrile and the volume of the mixture was brought up to 160 ml. The mixture was heated until clear, cooled slightly, seeded and cooled to isolate crystalline compound Za. The product was separated by filtration and additionally washed with cold acetonitrile. After vacuum drying, Compound Za was obtained: "H NMR (0M50O-div, 400 MHz) 6 8.61 (5, 1H), 7.86 (v, 1H), 7.451, 9 - 7.4 Gu, 1H), 7 .26 (5, 1H), 7.23-7.14 (t, 2H), 5.10 (riv, 1H), 4.62 (riv, 1H), 4.18 (4, U - 7.0

Hz, 2H), 4.03 (5, 2H), 3.96 (v, ЗН), 3.92-3.84 (t, 1H), 3.78-3.75 (t, 1H), 2 ... Gu, ZN).

Alternatively, Compound 9a can be prepared as follows.

Compound ba (50 g) was mixed with 17.5 g of dimethylformamide dimethyl acetal, 90 g of OME and 0.2 g of glacial acetic acid. The mixture was heated to 65°C for 3 hours. The mixture was then cooled to room temperature and 14.5 g of (5)-2-amino-3-methyl-1-butanol and 25 g of toluene were added. The mixture was stirred at room temperature overnight, then concentrated by distillation. Potassium chloride (4.5 g) and bis(trimethylsilyl)acetamide (80.2 g) were then added and the mixture was heated to 90°C for 2 hours. The mixture was cooled to room temperature and diluted with 250 g of dichloromethane. hydrochloric acid (110 g, -1M) and stirred the mixture at ambient temperature for 30 min. The organic phase was separated, washed successively with water, aqueous sodium bicarbonate solution, and again with water. The solvent was exchanged for acetonitrile by distillation. The mixture was heated until it became clear, cooled slightly, seeded and cooled to completely isolate crystalline Compound Ba. The product was separated by filtration and further washed with cold acetonitrile. After vacuum drying, 48.7 g (in exit 81905)

Compounds 9a: "H NMR (0M50O-iv, 400 MHz) 5 8.61 (5, 1H), 7.86 (in, 1H), 7.45 (Her, in) - 7.4 Hz, 1H), 7.26 (in, 1H), 7.23-7.14 (t, 2H), 5.10 (Running in, 1H), 4.62 (Bg 5, 1H), 4.18 (4.9. - 7.0 Gu, 2H), 4.03 (5, 2H), 3.96 (5, ЗН), 3.92-3.84 (t, 1H), 3.78-3.75 (t, 1H), 2.28 (bg5, 1), 1.24(9-:7.0 Hz, ZN), 1.12 (4.9 -6.4 Hz, ZN), 0.72 (4.9 6.4 Gu, ZN).

Example 6: Preparation of Compound 10.

Compound Za (6.02 g) was suspended in 36 ml of isopropanol and 24 ml of water. An aqueous solution of potassium chloride (2.04 g of 45 wt. 95 solution) was added and the mixture was heated to 40°C. After 3 hours, 1.13 g of glacial acetic acid was added and the seeds of Compound 10 (10 mg) were added to the mixture. The mixture was cooled to in an ice bath for 2 hours, and the resulting solid was separated by filtration. 1H), 8.02 (in, 1H), 7.48-7.45 (t, 2), 7.23(9U 6.8 HZ, 1H), 7.17 (9 - 7.8 Gu, 1H ), 5.18 (horn 5, 1H), 4.86 (river, 1H), 4.10 (in, 2H), 4.02 (in,

ЗН), 3.97-3.96 (t, 1Н), 3.79-3.76 (t, 1Н), 2.36 (riv, 1Н), 1.14 (0.9 -6.3 Hz , ZN), 0.71 (9.9 - 6.3 Hu, ZN).

Example 7: Preparation of Compound 13.

The synthesis of compound Za from compound 7a, described in Example 5 above, leads to the formation of another product, which, most likely, is due to the presence of an impurity of (5)-2-amino-4-methyl-1-pentanol in (5)-2 -amino-3-methyl-1-butanol. To confirm the identity of the second product, an independent synthesis of compound 13 was carried out as shown below. that another 5 re; Ge) er schu va buru os re: --zk s dk i

Eh 00 oh! he

FI g oo oo ; with A va Gei Si 12 13

Compound 13 was obtained from compound 12 by a method similar to that given above for compound 10 in example 6. After the described procedure, the product was extracted with anisole. The described product was isolated as a foam after removing the solvent: "H NMR (0M5O-yv, 400 MG) 5 8.80 (5, 1H), 8.02 (v, 1H), 7.48-7.44 (t, 2H), 7.23 (69-7.2

Hz, 1H), 7.16 (1, 9 - 7.6 Hz, 1H), 5.19 (riv, 1H), 4.09 (in, 2H), 4.00 (in, ЗН), 3, 77 (horn 5, 2H), 1.94-1.87 (t, 1H), 1.82- 1.75 (t, 1H), 1.43 (peri, U - 6.4 Hz, 1H), 0, 89 (y, U - 6.4 Hz, ZN), 0.85 (9, U - 6.8 Hz, ZN).

Intermediate compound 12 was obtained in the following way. and. Compound 12 was obtained from compound Ba by a method similar to that given above for the preparation of compound Za, except that instead of (5)-2-amino-3-methyl-1-butanol, (5)-(-)-2- amino-4-methyl-1-pentanol. The target product was isolated as a foam after the final acetonitrile solution was concentrated to dryness: 1H NMR (0M5O-iv, 400 MHz) 6 8.54 (5, 1H), 7.86 (5, 1H), 7.46- 7.43 (t, 1H), 7.25 (5, 1H), 7.22-7.14 (t, 2H), 4.97 (horn 5, 1H), 4.20-4.16 (t , 2H), 4.03 (5, 2H), 3.95 (in, ЗН), 3.7З (horn 5, 2H), 1.83-1.82 (t, 1H), 1.72-1 .69 (t, 1H), 1.43 (peri y - 64 Hz, 1H), 1.24 (1.9 -7.2 Hz, zn), 0.88 (4.9 -6.4 Hz, 3), 0.84 (40.9 -64 Hu, zn).

Compound 13 can be used as an inhibitor of HIV integrase as described in the international patent application

MO 2004/046115. Accordingly, the invention also relates to compound 13 or its salt, as well as to methods of obtaining compound 13 or its salt. The invention also relates to compositions containing compound 10 or its salt and compound 13 or its salt, as well as to compositions containing compound 9a or its salt and compound 12 or its salt. Such compositions are useful for the preparation of integrase inhibitors described in the publication of international patent application UUO 2004/046115.

Alternatively, compound 10 may be prepared from compound 2 as described in the following illustrative examples 8-12, starting from 1 kg of starting compound.

Example 8. Preparation of Compounds with formula 3.

Vg ОН 2. mV no on (in hexane) o 3. EE o

Compound 2 oh FI

SeneVO, E si

Mm.m.: 281.07.

Compound Z

S vNi«SIRO5 si m.m.: 340.73

Compound 2 was mixed with anhydrous tetrahydrofuran and heated to form a solution or thin suspension.

The mixture was cooled to a temperature of -20 to -30"C and butylethylmagnesium in heptane was added. In a separate reactor, butyllithium in hexane was mixed with cooled (to a temperature of -20 to -30"C) tetrahydrofuran. A suspension of compound 2 with butylethylmagnesium was added to the n-butyllithium solution, maintaining the temperature of the mixture in the range from -20 to -30°C. The lithium/halogen exchange reaction was monitored by HPLC. After the reaction was completed, a solution of 3-chloro-2-fluorobenzaldehyde in tetrahydrofuran was added. After 1 hour, the mixture was heated to 0"C. The completion of the reaction was monitored by HPLC. After completion, the reaction was stopped with an aqueous solution of hydrochloric acid, bringing the pH to 1-3. After phase separation, the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried with sodium sulfate at 18-257C. After the sodium sulfate was filtered, the solvent was replaced with MTBE and the resulting suspension was cooled to 0"C.

The product was separated by filtration, washed with cold MTBE and dried at 40"C, obtaining Compound 3.

ZtnsSi 77777111 Y11365 | 77070531

UAE 77777771 вв І111111171461 ІІ

MmavbOye 77777711 14204 | 77777772 11111111

MTBE 77777771 vv | 77777795. HER 77111111 1. Load 1.00 kg of Compound 2 and 8.7 kg of THF into reactor (1). 2. Heat the mixture to 45-507"C in such a way that all solids dissolve or a thin homogeneous suspension is formed and no solid particles remain at the bottom of the reactor. 3. Cool the contents of the reactor (1) to a temperature from -20 to -3070. 4 . Load into the VIEIMO reactor (1595 wt./wt. in heptane) (-1.8 kg, 0.6 equivalents) (1), maintaining the temperature of the reaction mixture below -207C throughout the addition time. 5. Into a separate reactor (2 ) load 2.6 kg of THF and cool to a temperature of -20 to -30"С. 6. Load into the reactor (2) n-Viyi (in hexane) (1.9 kg, 1.8 equivalents), maintaining the temperature below -20"C throughout the addition time. 7. Transfer the contents of the reactor (1) into the reactor (2), maintaining the temperature below -20"C throughout the addition time. 8. Load 0.5 kg of THF into the reactor (3) and cool to -20 - -3070. 9. Transfer the contents of reactor (3) to reactor (1) and then to reactor (2) for direct washing. 10. About 15 minutes after the start of synthesis, take a sample from the reaction mixture and analyze it by HPLC to determine how the lithium/halogen exchange is going. (Usually, the balance of compound 2 is 1-8 96. If the amount of compound 2 is more than 8905, take a sample after another 30 minutes and before adding an additional amount of n-Via Her). 11. Mix 0.79 kg of aldehyde and 0.79 kg of THF in a suitable container. 12. Add the contents of the container to the reactor. When adding, keep the temperature of the reaction mixture below -20 26. 13. Stir the reaction mixture at -20"7С for 1 hour, then heat to 070. 14. Stop the reaction by adding 2 M HC (-3.8 kg) to pH 1-3 15. Separate the phases. 16. Extract the aqueous phase with 2.3 kg of EtOAc. 17. Extract the aqueous phase with 2.3 kg of EtOAc. 18. Discard the aqueous phase. 19. Combine the organic phases and dry over 2 kg of Ma»25O» x for at least 1 hour. The temperature of the organic phase before the addition of Ma»5O» should be 20-2576. 20. Filter the suspension to remove Mag50Om. 21. Concentrate the combined organic phases by vacuum distillation to -1.5 L ( a thick suspension should form). 22. Add 2.8 kg of MTBE (methyl tert-butyl ether) to the suspension. 23. Concentrate the mixture to -1.5 l. 24. Add 2.8 kg of MTBE to the suspension. 25. Concentrate mixture to -1.5 l. 26. Add 1.9 kg of MTBE to the suspension. 27. Cool the suspension to -0"C and separate Compound C by filtration. 28. Wash the dishes for distillation of 1.9 kg MTBE, previously cooled to -07C. 29. Drain the precipitate until solid granules are obtained. The purity of Compound C can be increased if it is resuspended in 6 volumes of a mixture of toluene:HOAc (85:15). 30. Dry the wet sediment under vacuum at a temperature below 40"C.

Example 9. Preparation of the compound with formula 4.

y-o o 1. еЬ8IN, tFOK 220 o nenanonnnnnnnnnnnnnnnnia i no on on 2. MIBE si si

Compound 3 Compound 4

SN SEOh SivN«SIgO,

M.mM.: 340.73 M.mM.: 324.73

Compound C was mixed with trifluoroacetic acid and stirred until a solution was formed. The solution was cooled to -3 to 3°C and triethylsilane was added, maintaining the temperature at 1570. The progress of the reaction was monitored by HPLC. After completion of the reaction, MTBE was added to precipitate Compound 4 and the mixture was cooled to 0°C. The product was separated by filtration, washed with MTBE and dried at 60"C, obtaining

Compound 4. 340.73

MITBE selected | 7777777777771561 11111111

TtFOK 114.02 116.28 1. Dissolve 1.00 kg of Compound C in 1.7 kg of TFOK. 2. Cool the reaction mixture to -3 - 370.

C. Load 0.4 kg of triethylsilane into the reaction mixture. When adding, keep the temperature of the reaction mixture below 1570. 4. 30 minutes after the addition of triethylsilane, take a sample from the reaction mixture and analyze it by HPLC to determine whether the conversion of compound C to compound 4 is complete. 5. Load 4.0 kg of MTBE into the reaction mixture , while maintaining the temperature of the mixture below 1576. 6. Cool the mixture to 0"C and stir for at least 30 minutes. 7. Separate compound 4 by filtration and wash the reaction vessel with 1.6 kg MTBE. 8. Dry the obtained compound 4 under vacuum at a temperature less than 6070.

Note: The purity of compound 4 can be increased by resuspension in 4 volumes of acetone. The suspension was heated to 407"C for 2 hours, cooled for 12 hours to 18-25"C before filtration, then washed twice with 1 volume of acetone.

Example 10. Preparation of compounds with the formula ba. -0 fi o L re o onov Fa: ba -- y x

E 0 M M E O

A so "Zh ssh si si loluka ba

Compound and bow: | re; fo Ge! o ov oo Mei, -33333-- ko og EE O O 0 «em g

SI

The compound

Carbonyldiimidazole and imidazole were mixed with anhydrous tetrahydrofuran. Compound 4 was added to the mixture to form compound 5a. The reaction was monitored by HPLC. In a separate reactor, potassium monoethylmalonate and tetrahydrofuran were mixed, after which anhydrous magnesium chloride was added, maintaining the MMT temperature at 30°C. The resulting suspension was heated at 50°C for at least two hours, after which compound 5a (as part of the mixture) was added. The reaction was monitored by HPLC. After the formation of compound Ba was complete, the mixture was cooled to 18-25°C and aqueous phosphoric acid was added to stop the reaction. The organic phase was washed with aqueous sodium bisulfate, brine, potassium dihydrogen carbonate, and again with brine, and then filtered . The solvent was changed to anhydrous ethanol. Water was added and the mixture was heated to dissolve the solids, then cooled to about 40°C, seeded with compound ba and cooled to 0-57°C. The product was filtered, washed with cold aqueous ethanol, and dried at 40"C, having received Compound ba.

PL MON MON SAT NOW BUT OT MON OO

НеРОг (В5 by mass) 7777777 | 19800 | 77772311 manvoy 77777777 | 12006 | 7777774

KknSOoz 77777771 fo loma | 77777/05о777// masses 77777711 15844 | 77770487 zra2v-2EON (O,Bosheptanuui | 46.07 | (B by HER 77777771

Procedure: 1. Charge 0.55 kg CO and 0.042 kg imidazole to reactor 1. 2. Charge 2.67 kg TEF to reactor 1 and mix to form a slurry. 3. Load 1.00 kg of compound 4 in portions into reactor 1 so that the release of COg is moderate. The reaction is endothermic. 4. Load 0.89 kg of KEM into reactor 2. 5. Load 4.45 kg of TEF into reactor 2 and mix to form a slurry. b. Load 0.44 kg of MoSig into reactor 2 (can be loaded in parts to reduce heat release). 7. Heat the contents of reactor 2 to 50"C and stir at this temperature for at least two hours. 8. Transfer the contents of reactor 1 to reactor 2. If transferred too quickly, the mixture may temporarily thicken. 9. Stir the contents of reactor 2 for at least 12 hours at 5070. 10. Cool the suspension to ambient temperature. 11. Stop the reaction by introducing into the reaction mixture 7.0 kg of 28 wt. 7 kg of HgO). The reaction is exothermic. The final pH value of the aqueous phase should be 1-2. 12. Wash the organic (upper) phase with 1.2 kg of 20 wt. 95 aqueous solution of Manzboa (dissolve 0.24 kg of ManbO in 0.96 kg Hg2O). The final pH value of the aqueous phase should be 1-2. 13. Wash the organic (upper) phase with 1.2 kg of 20 wt. 95 Massi aqueous solution (dissolve 0.24 kg of mass in 0.96 kg of HgO). 14 Wash the organic (upper) phase with 5.0 kg of 10 wt. 95 aqueous KHSO3 solution (dissolve 0.50 kg of KHSO3 in 4.5 kg Hg20). The final pH value of the aqueous layer should not be 8-10. 15. Wash the organic (aqueous) phase with 1.2 kg of 20 wt. 95 of an aqueous solution of Mass (0.24 kg of mass, 0.96 kg of NEO).

The final pH value of the aqueous phase should be 7-9. 16. Concentrate the organic phase and replace the solvent with EUN. 17. Bring the concentration to --3.5 l/kg. 18. Load 0.6 volume of water. 19. Heat to 70-80"C to form a clear solution. 20. Cool to 40"C and add 0.1 wt. 95 compound 6. 21. Cool slowly to 570. 22. Hold for at least 2 hours. 23. Filter and wash the sediment twice with a mixture of ЕУН':Н2гО 50:50 (1.2 kg of ЕУН on 1.5 kg of НгО), 1.35 kg for each washing. 24. Dry the sediment at a temperature below 5070.

Example 11. Preparation of the compound of formula 9a.

ro) fi (c) DMFDMA o fi o MMe, ptn potnisnkonnnya fr o toluene 19154 o;

F) E o 0 1007s F EE 0 o a p

Compound va Compound Ta

Sobi settled SoznNovSIEMO in m.m.: 394.82 m.m. : 449.8

N n S no nn S ich I m As du nyn iny iny pet nntyutnnnn re 5-valinol 19/54 DMF, 100 b o

Toluene, KT g E 0 o and E o o si s

Compound ba and

SN SIEMO in Spoluka Za - s SIEMO, m.m. : 507.98 gato 475 54

Compound ba was mixed with toluene, M,M-dimethylformamide dimethyl acetal and glacial acetic acid, after which it was heated to 100°C. The reaction was monitored by HPLC. After the formation

Compound 7a was completed, the mixture was cooled to 18-25°C, after which (5)-(-)-valinol was added. The reaction was monitored by HPLC. After the formation of compound Za was completed, the mixture was concentrated. The residue was mixed with dimethylformamide, chloride potassium and M.O-bistrimethylsilylacetamide and heated to 1007С.

The reaction was monitored by HPLC. After the reaction, the mixture was cooled and dichloromethane was added.

After that, an aqueous solution of hydrochloric acid was added to desilylate compound 9a. The reaction was monitored by TLC. After completion of the reaction, the organic phase was washed with water, an aqueous solution of sodium bicarbonate and again with water. The solvent was changed to acetonitrile and the mixture was heated. Seeds were introduced into the mixture and cooled, crystallizing the compound Za. The product was filtered, washed with cold acetonitrile and dried at 40"C, obtaining compound 9a. ratio

LTolul.///////77777777777711111111111111111924 11111143!

ME 77777711 zmo | 77777718 11111111

Ks 11111111 i7455 | 2 sh-KHM 009... | ....YyuyuyuyuyuyuYrpov

Мне 77777771 1365 11717112 11111111 Tue Po NN: "ZK: UNI PON S TONN KO

Water. 77777777 1802 | 787777 11111111

Bbvodno MansSoz 77777777 7841 77771114 11111111

SAM 77777711 405 | 77771705... |. (Zarodkispolukida 77777 475.94 | -: 0005... | ..:KK«x/ССu 1. Load 1.00 kg of compound ba into reactor 1. 2. Load 0.33 kg of M,M-dimethylformamide of dimethyl acetal (1.1 equivalents), 0.001 kg of glacial acetic acid and 3.3 kg of toluene into reactor 1. 3. Heat the mixture to "1007 (must be because MeonH can be driven off during this process). 4. After 1 hour, the reaction should end (control by HPLC) (may remain "295 compound ba)". 5. Cool the mixture in reactor 1 to 18-2576. 6. Charge 0.29 kg of (5)-(-)-valinol (1.1 equiv.) , dissolved in 1.0 kg of toluene into reactor 1 and continue stirring at ambient temperature. 7. After 1 hour the reaction should be complete (HPLC control) (less than 195 compound ba). 8. Concentrate the contents of reactor 1 to "2 L /kg 9. Load 1.89 kg of OME, 0.09 kg of potassium chloride (0.5 equivalents) and 1.13 kg of M,0- into reactor 1

bistrimethylsilyl acetamide (2.2 equivalents). 10. Heat the mixture in reactor 1 to -100 70 11. After 1 hour, the reaction should end (595 of Compound 8a remains). 12. Cool the contents of reactor 1 to 18-2576. 13. Load 10 kg of OSM into reactor 1. 14. Load into reactor 1 within 15 minutes 2.0 kg of a 1N aqueous solution of NSI, keeping the temperature of the mixture below 3570. 15. Stir the mixture for at least 10 minutes to desilate compound 8 a (control by TLC). 16. Separate phases. 17. Wash the organic phase with 4.0 kg of water. 18. Wash the organic phase with 4.0 kg of 595% sodium bicarbonate aqueous solution. 19. Wash the organic phase with 4.0 kg of water. 20. Concentrate the organic phase by distillation to "1.5 l/kg of compound ba. 21. Replace the solvent with AFM distillation until a suspension is formed. Bring the final volume to 58 l/kg of compound ba. 22. Heat the mixture to boiling so that the solid substance dissolves. 23. Cool the solution to 75"C and load the seeds of compound 9a. 24. Cool the mixture to 0"C for at least 2 hours and keep at this temperature for at least 1 hour. 25. Separate the compound by filtration and wash the wet precipitate with 1.6 kg of cold AFM. 26. Dry the wet sediment at a temperature below 40"C under vacuum.

Notes: 1. The HPLC peak of the remaining compound ba is stretched by baseline artifact. HPLC at this stage shows only 295 compound ba in relation to compound ba. Experiments have shown that introducing an additional amount of reagents and increasing the reaction time, as a rule, does not allow to reduce the observed level of compound ba. 2. TLC method:

Eluting solvent: 10095 ethyl acetate.

Reinforced compound According to AG 0.85.

Compound 9a AG: 0.50.

Example 12. Preparation of the compound of formula 10. но Н шщщ Кк 1. 455 KOH, -- ог! 2.. Lyodyana DEON on . Compound 40 g 00 Z. Svoluk E O0 OO

FI (U) Seed and

Si Si

Compound Za Compound 10, u- form

SzhnouSIEMO" I (897761-98-1)

M.M.: 475.94 Sa NozaTyemo"

M.m.: 447.88

Compound Za was mixed with an aqueous solution of isopropyl alcohol and heated to 30-40°C. An aqueous solution of potassium hydroxide was added, while the reaction was monitored by HPLC. After completion of the reaction, glacial acetic acid was added and the mixture was heated to 60-70°C. The solution was filtered on a hot filter and cooled to 55-65"С. Germs were introduced into the solution (see the publication of the international patent application UMO 2005/113508) and cooled to 0"С. The product was separated by filtration, washed with a cold aqueous solution of isopropyl alcohol and dried at 50°C, obtaining compound 10. isopropyl alcohol |

Water 77777777 77777171 1802 | 77777740 (Seed compounds!0 | 447.88 | 7700171 HER 1. Load 1.00 kg of Compound Za into reactor 1. 2. Load 4.7 kg of isopropyl alcohol and 4.0 kg of water into reactor 1. 3. Load 0.34 kg of 4595 KOH aqueous solution into reactor 1.

4. Heat the mixture in reactor 1 to 30-40"С. 5. After the end of hydrolysis, add 0.19 kg of glacial acetic acid. 6. Heat the mixture to 60-702С and pass the solution through a barrier filter into reactor 2. 7. Cool the mixture in reactor 2 to 55-6570. 8. Introduce the seeds of compound 10 (see the publication of the international patent application UUO 2005/113508) in the form of a suspension in 0.28 volume of the isopropyl alcohol/water mixture 64. 9. Cool the mixture until 18-257C for at least 2 hours and stir to form a suspension. 10. Cool the mixture to 0"C and stir for at least 2 hours. 11. Separate compound 10 by filtration and wash the precipitate with 3x15 cold isopropyl alcohol/water mixture (6:4). 12. Dry the separated solid at a temperature below 50"7C under vacuum.

Example 13: Preparation of compound 15

Meow OMe

MeOo OoMe ; : ve I. ARIMESI SI no A shchi i nn current chnotnnnott stand nosno Du»

Vg Vg or i-RgMesI then SEVA E in 2. NS F

SI

Bisdimethylaminoethyl ether (2.84 g) was dissolved in 42 ml of THF and cooled in an ice bath.

Isopropylmagnesium chloride (8.9 mL of a 2M solution in THF) was then sequentially slowly added, followed by compound 14 (5 g dissolved in 5 mL of THF). The mixtures were allowed to warm to ambient temperature and stirred overnight. 2.1 ml of 3-chloro-2-fluorobenzaldehyde was added. After stirring for -1 hour, the reaction was stopped by adding 2N HCl to pH -7. The product was extracted with ethyl acetate and the organic phase was dried over sodium sulfate. The solvent was changed to heptane to precipitate the product, and then a mixture of heptane:Mt'BE»E (471) was added to form a slurry. After filtration, the solid was suspended in toluene, filtered, and dried under vacuum to give compound 15: 1H NMR (CO3SM, 400 MHz) 5 7.47 (v, 1H), 7.41-7.35 (t, 2H), 7 ... ,81 (5, ZN).

Example 14: Preparation of compound 15a

MeO OMe

Meo OMe; - ve ERGMeSILASI simeO In other things

A: Vg or i-VgMesi then SEVA E 14

SI

' 15a

Compound 14 (5 g), isopropylmagnesium chloride (8.9 mL of a 2M solution in THF), and THF (56 mL) were mixed at ambient temperature and then heated at 507°C for 55 h. After cooling to ambient temperature and stirring for 2.1 mL of 3-chloro-2-fluorobenzaldehyde was added dropwise overnight to form a suspension.After stirring overnight, the solid was filtered off and washed with MTBE to afford compound 15a.

Example 15: Preparation of compound 16

Meo OMe MeO OMe no fi (a

Vg diarrhea rr Vg and E o E

SI SI

15 16

Triethylsilane (1.2 mL) was added to trifluoroacetic acid (2.3 mL) cooled in an ice bath. Compound 15 (1.466 g) was added to the mixture while maintaining the temperature below 5°C. After stirring for -2 hours, ice was added to stop the reaction. The product was extracted with dichloromethane and the organic phase was washed with aqueous ManNsCO 3 . The organic phase was dried over Mag25O4 and concentrated to dryness. The product was purified by column chromatography on silica gel, obtaining 1.341 g of compound 16: "H NMR (SOCI", 400 MHz) 6 7.20 (9 7.0 Hz, 1H), 6.99-6.91 (t, ЗН), 6.46 (5, 1Н), 3.91 (in, ЗН), 3.81 (5, 5Н).

All publications, patents and patent documentation are incorporated herein by reference, thus

as if they were incorporated by reference individually.

The invention has been described with reference to various specific and preferred aspects and methods.

However, it should be understood that many different variations and modifications can be made within the spirit of the invention and without departing from its scope.