KR20110099995A - Method for preparing valaciclovir and acid addition salts thereof - Google Patents

Abstract

In the present invention, L-valine protected with an amino group is reacted with acyclovir using O, O'-diethyl chlorothiophosphate (DECTP) as an acylation activator in the presence of an organic base, thereby preparing a balaccyclober with an amino group. Thereafter, the amino protecting group is removed to prepare an antiviral compound, balaccyclovir, and an acid addition salt thereof, wherein the isomers of the D-array are reduced as well as by-products such as DCU derived from an acylating agent. Since there is no at all, a high purity balacyclovir can be manufactured efficiently.

Description

Valacyclovir and acid addition salt thereof preparation method {METHOD FOR PREPARING VALACICLOVIR AND ACID ADDITION SALTS THEREOF}

The present invention relates to a novel method for preparing an antiviral compound, valacyclovir and acid addition salts thereof.

Valaciclovir of Formula 1, which is disclosed for the first time in U.S. Patent No. 4,957,924, is an antiviral compound widely used in the treatment and prevention of infections of viruses, especially herpes virus, in particular in the form of hydrochloride, Valtrex ^® (Valtrex ^® ) is marketed under the trade name.

Valacyclovir has been disclosed as hydrochloride monohydrate crystals in U.S. Patent No. 4,957,924, followed by hydrochloride anhydrides of type 1 crystals (WO 96/22082 and WO 96/22291), hydrochloride anhydrides of type 2 crystals (International Patent Publication WO 03/040145) as well as various hydrochloride crystal forms are disclosed in WO 03/022209, WO 04/052892, WO 04/106338, WO 05/000850 and WO 05/085247. . In addition, WO 07/107696 discloses a methalate, phosphate, maleate, fumarate, tartarate and citrate and crystalline forms thereof, as well as a balaccyclovir free base.

On the other hand, the typical manufacturing method of the balaccyclober is U.S. Patent No. 4,957,924, WO 96/22082, WO 96/22291, WO 03/041647, WO 07/013645, WO 08/139539, WO 09/031576, Japanese Patent Laid-Open No. 10/195075, US Patent Publication No. 2007/0112193, and the like.

Most of the known methods for preparing balaccyclovir are known as acylation reactions of acyclovir of formula 2 and L-valine derivatives of formula 3 wherein the amino group is protected by Z, as shown in Scheme 1 below. After preparing a balacyclovir protected amino group of the formula (4), to remove the amino protecting group of the formula (4) to prepare a balaccyclovir. Wherein Z is benzyloxycarbonyl (hereinafter referred to as Cbz), t-butoxycarbonyl (hereinafter referred to as Boc), or 2-oxo-3-penten-4-yl (2-oxo-3 -penten-4-yl) group. At this time, the acylation reaction of the acyclovir of Formula 2 and the valine derivative of Formula 3 is usually N, N'-dicyclohexylcarbodiimide as an acylation activator in a polar solvent such as N, N-dimethylformamide (hereinafter referred to as DMF). (N, N'-dicyclohexylcarbodiimide; hereinafter DCC) and 4- (dimethylamino) pyridine {4- (dimethylamino) pyridine as an acylation catalyst; DMAP} below. Subsequently, in a balaccyclober in which the amino group of Formula 4 is protected, a hydrogenation reaction is carried out in the presence of palladium metal when the amino protecting group is Cbz, and an acid hydrolysis reaction when the amino protecting group is Boc or 2-oxo-3-penten-4-yl. Is carried out to prepare balaccyclovir or salts thereof.

<Scheme 1>

However, those skilled in the art who understand the characteristics of the acylation reaction using DCC as an acylation activator will well understand that Scheme 1 using DCC has the following problems.

First, acyclovir is very low in reactivity and it is very difficult to complete the reaction so that no acyclovir remains in the acylation reaction. In this case, the L-valine derivative of Formula 3 and excess DCC should be added several times until the reaction is completed. Second, N, N-dicyclohexylurea (hereinafter DCU) generated from excess DCC used as the acylation activator may remain in the balaccyclober. It is because it is very difficult to remove completely by the conventional method other than the chromatographic method by the characteristic of DCU. Third, as known in the literature (LM Beauchamp et al., Antiviral Chemistry & Chemotherapy 1992, 3, 159-164), racemicization of valine derivatives of formula 3 occurs when DCC is used as an acylation activator, resulting in 2-3 It is likely to incorporate about 30% D-configuration of the balaccyclovir isomers.

Therefore, in order to manufacture a balaccyclober in which the above-mentioned impurity DCU is removed and the isomers of the D-array are reduced, it is necessary to select very difficult reaction conditions and tedious and repetitive purification process. There is a problem of mass production of environmentally unfriendly waste liquid.

In order to solve the above problems caused by the use of DCC as an acylation activator, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (EDC), which is an easily removed acylation activator, is used. Although the method is disclosed in WO 03/041647, EDC is very expensive and industrially undesirable.

The present inventors have made diligent efforts to solve the DCU residual problem and D-array isomer formation problem caused by the conventional balaccyclovir preparation using the DCC activator. As a result, no DCU is generated by using the new acylation activator. Furthermore, the present invention was completed by confirming that a balaccyclovir or an acid addition salt thereof having reduced isomers of D-array can be produced.

It is therefore an object of the present invention to provide a novel method for producing a balacyclovir to solve the problems of the conventional method for producing balacyclovir using DCC from acyclovir.

In order to achieve the above object, the present invention provides (1) an organic base and 4- (dimethylamino) pyridine (DMAP), O, O 'as the active acylation in the presence-formula with the chloro diethyl thiophosphate (DECTP) Acylating the acyclovir of 2 with an L-valine derivative protected by the amino group of formula 3 to prepare a balaccyclovir derivative protected by the amino group of formula 4; And (2) hydrogenating the obtained balaccyclovir derivative of Formula 4 or performing an acid hydrolysis reaction to obtain a balaccyclovir of Formula 1 or an acid addition salt thereof. Provided are methods for preparing clover or acid addition salts thereof.

The present invention not only reduces the isomers of the D- configuration by using a very inexpensive acylation activator in the acylation reaction between the acyclovir and the amino-group protected L-valine derivatives, and because there are no by-products such as DCU derived from the acylating agent. High purity balacyclovir can be efficiently produced.

Hereinafter, the present invention will be described in detail.

Method of manufacturing a rub during clover or its acid addition salt according to the present invention, an organic base and 4- (dimethylamino) pyridine (DMAP), O, O 'as the active acylation in the presence-of diethyl chloro thiophosphate (DECTP) Acylation of an acyclovir of Formula 2 with an L-valine derivative protected with an amino group of Formula 3 to prepare a balaccyclovir derivative protected with an amino group of Formula 4 (step 1); And obtaining a balaccyclovir or an acid addition salt thereof by performing hydrogenation or acid hydrolysis of the obtained balaccyclovir derivative of Formula 4 to remove an amino protecting group (step 2). It is characterized by.

<Formula 1>

Where

Z is benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc) or α, β-unsaturated carbonyl represented by the following formula (5) as an amino protecting group;

Wherein R is methyl, methoxy or ethoxy.

Referring to the manufacturing method according to the present invention in detail step by step as follows.

<Step 1> Acylation Reaction

According to the present invention, step 1 is an acylation reaction of the acyclovir of Formula 2 with the L-valine derivative of Formula 3 using DECTP as an acylation activator in the presence of an organic base and DMAP. To prepare a step.

Organic bases that can be used in the acylation reaction include triethylamine, diisopropylethylamine, tributylamine, N, N, N ', N'-tetramethylethylenediamine, N-methylimidazole or N-methyl Morpholine and the like, and preferably N, N, N ', N'-tetramethylethylenediamine or tributylamine can be used. The amount of the organic base may be appropriately adjusted depending on the kind and the amino protecting group Z of the valine derivative of the formula (3). Preferably, the organic base is used in an amount of 1.5 to 4 molar equivalents based on 1 molar equivalent of the acylated activator DECTP.

DMAP (4- (dimethylamino) pyridine) used in the acylation reaction is an acylation catalyst, and it is usually preferable to use 0.01 mol to 0.2 mol equivalent to 1 mol equivalent of acyclovir.

DECTP ( O, O'-diethyl chlorothiophosphate) used as the acylation activator has never been used as an acylation activator of carboxylic acid and alcohol, and especially as in the present invention, of acyclovir and L-valine derivatives. It has never been used as an acylation activator. The acylation activator DECTP may vary depending on the amino protecting group Z, but is preferably used in 1 to 3 molar equivalents relative to 1 molar equivalent of the valine derivative of Formula 3.

Acyclovir of Formula 2, which is a starting material used in the acylation reaction, is itself a compound having antiviral activity, and may be used in the form of an anhydride or a hydrate, and if necessary, a particle size of 100 μm or less to further promote the reaction. More preferably, 10 micrometers or less can also be used.

In addition, the L-valine derivative of the formula (3) is that the amino group is protected by Z, N-Cbz-L-valine or N-Boc-L-valine wherein the amino protecting group (Z) is Cbz or Boc is commercially purchased Or prepared from L-valine according to a known method, on the other hand, when the amino protecting group (Z) is of formula (5), the method disclosed in the prior art cited herein (see WO 08/139539). L-valine in the presence of an organic base, similarly or in an improved manner, may be converted to acetylacetone (if R is methyl), methyl acetoacetate (if R is methoxy) or ethyl acetoacetate (where R is ethoxy). It is used as a compound of the formula (6) which is a kind of Dan's salt prepared by reacting. Typically, the L-valine derivative of Formula 3 may vary depending on the amino protecting group Z, but is preferably used in 1 to 2 molar equivalents relative to 1 molar equivalent of the acyclovir of Formula 2.

Wherein R is methyl, methoxy or ethoxy and B is one of the organic bases used in the acylation reaction of step 1.

The acylation reaction according to the present invention is preferably carried out in a temperature range of -10 ℃ to 60 ℃, preferably 0 ℃ to 25 ℃ in an aprotic polar organic solvent, examples of the aprotic polar organic solvent is N , N -dimethylformamide, N , N -dimethylacetamide, dimethyl sulfoxide or N-2-methylpyrrolidone, and the like, and preferably N , N -dimethylformamide can be used.

<Step 2> Deprotection  reaction

Step 2 according to the present invention is a step of preparing a balaccyclovir or a salt thereof by removing the amino protecting group Z from the balaccyclovir derivative of Formula 4 obtained in the above step 1. The deprotection reaction of step 2 can proceed as follows depending on the amino protecting group Z.

For example, when the amino protecting group Z is Cbz, the deprotection reaction is similar to or improved upon the prior art cited herein (see US Pat. No. 4,957,924 or WO 96/22082). It may be carried out in a mixed solvent with aqueous methanol or tetrahydrofuran using a palladium metal catalyst fixed to hydrogen gas and carbon or aluminum oxide (Al ₂ O ₃ ) at atmospheric pressure to 60 psi. In this case, formic acid may be used as a hydrogen source instead of hydrogen gas, and diluted hydrochloric acid may be added to the reaction solution to promote the reaction and to dissolve the starting material and the product.

When the amino protecting group Z is Boc, the deprotection reaction is carried out in water according to a method analogous to or ameliorated in the prior art cited herein (see WO 03/041647), in which water is a balaccyclovir derivative It may be carried out by adding 5 to 10 molar equivalents of hydrochloric acid relative to 1 molar equivalent. In this case, formic acid or trifluoroacetic acid may be added to the reaction solution to promote the reaction.

When the amino protecting group Z is of formula (5), the deprotection reaction can be carried out in aqueous acetone, methanol, according to methods analogous to or ameliorated in the prior art cited herein (see WO 08/139539). In the ethanol or isopropanol solution, 1 to 3 molar equivalents of hydrochloric acid may be added to 1 molar equivalent of the protected balacyclober of the amino group of formula (4).

In the present invention, when the amino protecting group Z of Formula 4 is Cbz in the reaction of Step 2, Z is a Boc or a protecting group of Formula 5 in that flammable hydrogen gas is used, and when Z is a protecting group of Formula 5 It is more preferable in that it uses less concentrated hydrochloric acid than when Z is Boc.

The reaction of removing an amino protecting group from a compound protected by an amino group with a protecting group of Cbz, Boc or Formula 5 may be somewhat different depending on each compound, but those skilled in the art will generally know PGM Wuts and Green ( TW Green) presented a number of ways (Protective Groups in Organic Synthesis, 4th Ed. It will be appreciated that this may be done according to 2007, Wiely & Sons) or a variation thereof. Therefore, although the present invention does not specifically describe the reaction conditions or the method for the step 2 of removing the amino protecting group from the balaccyclovir derivatives of the formula (4), the present invention is a method of the prior art cited above and these Include all variations.

Valacyclovir prepared according to steps 1) and 2) of the present invention may be prepared in various pharmaceutically acceptable salts or in various crystalline forms thereof, including free bases or hydrochlorides, according to treatment methods similar to the prior art cited herein. Can be switched. The process of the present invention thus comprises the valacyclovir free base, pharmaceutically acceptable salts thereof, and various crystalline forms thereof according to the prior art cited herein.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

The purity (%) of valacyclovir described in the following examples is determined by liquid chromatography (column: Capcell pak MG, inner diameter 4.6 mm x length 250 mm, particle size 5 μm, detection wavelength: 254 nm, eluent: pH 3.5 phosphate buffer) It was calculated by the following equation from the peak area of the valacyclovir separated by / acetonitrile = 5/950 (v / v%), elution rate: 1.5 mL / min).

&Quot; (1) &quot;

Purity of valacyclovir and% of acyclovir = [area of all peaks except peak / solvent peaks of valacyclovir or acyclovir] x 100.

The amount (%) of the valacyclovir D-forms described in the following examples is determined by liquid chromatography (column: Daicel crownpak CR (+), inner diameter 4.0 mm × length 150 mm, particle size 5 μm, detection wavelength: 254 nm, Eluent: 60% perchloric acid / purified water = 20/1000 (v / v%), elution rate: 1.0 mL / min) from the peak area of the balaccyclovir L-form and the peak area of the balaccyclovir D-form It was calculated by the following equation (2).

<Equation 2>

Amount (%) of the balacyclovir D-form = [(peak area of the balacyclovir D-form) / (peak area of the balacyclovir L-form + peak area of the balacyclovir D-form)] x 100.

Melting points were measured using a capillary digital melting point meter (Barnstead Electrothermal, UK). Moisture content was measured using a 795 KFT moisture meter (Metrohm, Switzerland). Infrared absorption spectrum (IR) was measured by MB-100 infrared spectrometer (Bomen, Canada). Hydrogen nuclear magnetic resonance spectroscopy ( ¹ H-NMR) was measured by Avance DPX 300 (Bruker, Germany).

Example 1 Preparation of Valacyclovir (When Z = Cbz)

<1-1> Preparation of the compound of Formula 4 (Z = Cbz) (acylation reaction)

After dissolving 14.5 g (57.7 mmol) of N- (benzyloxy) carbonyl-L-valine in 50 mL of N, N-dimethylformamide, 10.4 g (44.4 mmol, water content 3.85%), 4- (dimethyl) 0.5 g (4 mmol) of amino) pyridine and 31.4 ml (208.7 mmol) of N, N, N ', N'-tetramethylethylenediamine were added. After cooling the mixture to 5 ° C., 16.0 g (84.8 mmol) of O, O′-diethyl chlorothiophosphate was slowly added dropwise, followed by stirring at 5 ° C. for 2 hours and at room temperature for 12 hours. 200 mL of water was added to the reaction solution, heated to 90 ° C. to dissolve the contents, and then slowly cooled to 5 ° C. and stirred for 2 hours. The resulting solid was filtered and washed with water to give 22.4 g of crude product. The obtained product was recrystallized in ethanol and then dried to give 2-[(amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl N- (benzyloxy) carbonyl as white crystals. 19.1 g (94% yield from acyclovir) of -L-valinate (compound of Formula 4: Z is Cbz) were obtained.

Melting Point: 168-172 ° C

Specific luminance: [α] _D24 : -9.7 ^o ( c = 1.0, DMF)

¹ H-NMR (300 MHz, MeOD, ppm); 0.87-0.92 (m, 6H), 2.02-2.08 (m, 1H), 3.77-3.80 (m, 2H), 4.04-4.06 (d, 1H), 4.23-4.30 (m, 2H), 5.45 (s, 1H ), 6.16 (s, 2H), 7.36-7.27 (m, 5H), 7.83 (m, 1H),

IR (KBr, cm ^-1 ): υ 3324, 3187, 2965, 2720, 1729, 1631, 1540, 1488, 1390, 1102

<1-2> Preparation of Valacyclovir Hydrochloride (Deprotection Reaction)

4.0 g (8.7 mmol) of the compound of formula 4 (Z = Cbz) prepared in 1) was dissolved in 200 mL of a mixed solvent of methanol-tetrahydrofuran (1: 1), followed by 0.2 g of 10% palladium / carbon, and 0.5 M. 19.2 mL (9.6 mmol) of aqueous hydrochloric acid was added. The mixture was reacted under a hydrogen pressure of 50 psi for 6 hours in a Parr hydrogen reactor, and then the reaction solution was filtered through a pad of celite and the filtrate was concentrated to give 3.1 g of crude product. The obtained product was recrystallized in water-ethanol and then dried to give 2.4 g of white crystals of balaccyclovir hydrochloride (80% yield from acyclovir, 8.5% moisture content, 98.4% purity, 1.0% D-body).

Melting point: 196-197 ° C

Specific luminance: [α] _D ²⁴ : -8.1 ^o ( c = 1.0, H ₂ O)

¹ H-NMR (300 MHz, CD ₃ OD, ppm); 1.00-1.02 (d, 6H), 2.18-2.24 (m, 1H), 3.39-3.91 (m, 3H), 4.30-4.50 (m, 2H), 5.56 (s, 2H), 8.31 (s, 1H)

IR (KBr, cm ^-1 ): υ 3438, 3321, 2969, 1739, 1642, 1380, 1220, 1107, 1043

Example  2 to Example  6

Triethylamine, diisopropylethylamine, N-methylimidazole, N instead of N, N, N ', N'-tetramethylethylenediamine as organic bases in the acylation reaction of Example <1-1> Reaction was carried out in the same manner as in Example 1, except that methylmorpholine or tributylamine was used, thereby obtaining a balaccyclovir hydrochloride as shown in Table 1 below.

Example Organic base Yield% Purity% % Of D- sieve Example 2 Triethylamine 69 97.9 1.02 Example 3 Diisopropylethylamine 75 98.3 1.18 Example 4 N-methylimidazole 79 98.2 1.12 Example 5 N-methylmorpholine 71 98.0 1.05 Example 6 Tributylamine 79 98.5 0.95

Example  7: Valacyclovir  Manufacturing (Z = Boc If

<7-1> Compound of formula 4 (Z = Boc Manufacture of Acylation  reaction)

After dissolving 12.5 g (57.7 mmol) of N- (t-butoxy) carbonyl-L-valine in 50 mL of N, N-dimethylformamide, 10.4 g (44.4 mmol, water content 3.85%), 4- 0.5 g (4 mmol) of (dimethylamino) pyridine and 31.4 mL (208.7 mmol) of N, N, N ', N'-tetramethylethylenediamine were added. The reaction solution was cooled to 5 ° C., and then slowly added dropwise 16.0 g (84.4 mmol) of O, O′-diethyl chlorothiophosphate, followed by stirring at 5 ° C. for 2 hours and at room temperature for 12 hours. 200 mL of water was added to the reaction solution, heated to 90 ° C., and then slowly stirred to 5 ° C. for 2 hours. The resulting solid was filtered and washed with water to give 17.9 g of crude product. The obtained product was recrystallized in methanol and DMF and dried to give 2-[(amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl N- (t-butoxy) as white crystals. 16.8 g (89% yield from acyclovir) of carbonyl-L-valinate (compound of formula 4: Z is Boc) were obtained.

Melting Point: 146-148 ° C

Specific luminance: [α] _D ²⁴ : -15.0 ^o ( c = 1.0, DMF)

¹ H-NMR (300 MHz, MeOD, ppm); 0.91-0.86 (m, 3H), 1.43 (s, 9H), 2.02-2.00 (m, 1H), 3.78-3.81 (m, 2H), 3.96-3.98 (d, 1H), 4.19-4.30 (m, 2H ), 5.48 (s, 1H), 7.85 (s, 1H),

IR (KBr, cm ^-1 ): υ 3325, 3193, 2969, 2724, 1723, 1692, 1631, 1540, 1488, 1392, 1178, 1161

<7-2> Valacyclovir  Preparation of hydrochloride ( Deprotection  reaction)

5.0 g (11.7 mmol) of the compound of formula 4 (Z = Boc) prepared in step 1) was suspended in 20 mL of water, and then 12N hydrochloric acid (4.9 ml, 58.8 mmol) was added dropwise and stirred at room temperature for 5 hours. 275 mL of isopropanol was added to the reaction solution, which was then cooled to -15 ° C and stirred for 1 hour. The resulting solid was filtered, washed with isopropanol and dried to give 4.2 g of white crystals of balaccyclovir hydrochloride (81% yield from acyclovir, 9.0% moisture content, 98.4% purity, 0.7% D-form). .

Melting point: 195-197 ° C

Specific light intensity: [α] _D ²⁴ : -7.9 ^o ( c = 1.0, H ₂ O)

¹ H-NMR and IR spectra are the same as those obtained in Example <1-2>.

Example  8 to Example  12

Triethylamine, diisopropylethylamine, N-methylimidazole, N- instead of N, N, N'N'-tetramethylethylenediamine as organic base in the acylation reaction of Example <7-1> Except for using methylmorpholine or tributylamine, it was reacted in the same manner as in Example 7 to obtain a balaccyclovir hydrochloride as shown in Table 2.

Example Organic base Yield% Purity% % Of D- sieve Example 8 Triethylamine 72 98.1 1.16 Example 9 Diisopropylethylamine 71 98.5 0.96 Example 10 N-methylimidazole 76 98.2 1.15 Example 11 N-methylmorpholine 71 97.5 1.31 Example 12 Tributylamine 74 98.4 0.91

Example  13: Valacyclovir  Preparation (Z = Formula 5 (R = methyl )

<13-1> A compound of Formula 4 (Z = Formula 5; wherein R = methyl Manufacture of Acylation  reaction)

After dissolving 10 g (85.4 mmol) of L-valine in 50 mL of methanol, 11.2 mL (109.3 mmol) of acetylacetone and 18 mL (119.6 mmol) of N, N, N ', N'-tetramethylethylenediamine were added. The reaction solution was heated to 70 ° C., stirred for 2 hours, cooled to room temperature and concentrated under reduced pressure twice by addition of toluene (R is methyl and B is N, N, N′N′-tetramethylethylenediamine). Preparation of Dane's salt of formula (6).

48 mL of dimethylformamide was added to the concentrated residue and dissolved. 12.1 mL (88.1 mmol) of N, N, N ', N'-tetramethylethylenediamine, 10.0 g (42.7 mol, 3.85% of water content) and 4- ( 0.48 g (3.9 mmol) of dimethylamino) pyridine was added sequentially. After the reaction solution was cooled to 5 ° C., 16.8 mL (106.8 mmol) of O, O′-diethyl chlorothiophosphate was slowly added dropwise, followed by stirring at 5 ° C. for 2 hours and at room temperature for 12 hours. 240 mL of water was added to the reaction solution, which was then warmed up to 100 ° C., then slowly cooled to 5 ° C., stirred for 1 hour, and the resulting solid was filtered. Washed with water and dried at 40 ° C. to give 2-[(amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl N-[(2-oxo-3- Penten) -4-yl] -L-valinate [compound of formula 4: Z is Formula 5 (R = methyl)] 15.4 g (89% yield from acyclovir) was obtained.

Melting Point: 151-156 캜

¹ H-NMR (300 MHz, MeOD, ppm); 0.89-1.00 (m, 6H), 1.89 (s, 3H), 1.98 (s, 3H), 2.12-2.18 (m, 1H), 3.80-3.83 (t, 2H), 4.12-4.14 (d, 1), 4.23-4.35 (m, 2H), 5.09 (s, 1H), 5.46 (s, 2H), 7.85 (s, 1H)

IR (KBr, cm ^-1 ): υ 3459, 3319, 3187, 2965, 2719, 1732, 1619, 1574, 1310, 1182

<13-2> Valacyclovir  Preparation of hydrochloride ( Deprotection  reaction)

10.0 g (24.6 mmol) of the compound of formula (4, obtained by <13-1> (Z = Formula 5 (R = methyl))) was suspended in 50 ml of 70% acetone aqueous solution, and 10.2 mL (49.2 mmol) of 12N hydrochloric acid aqueous solution was slowly added. Added dropwise. The reaction mixture was warmed to 50 ° C. and stirred for 2.5 h. 70 mL of acetone was added dropwise to the reaction solution, cooled to 5 ° C, and stirred for 1 hour. The resulting solid was filtered, washed with acetone and dried to yield 7.2 g of white crystals of balaccyclovir hydrochloride (70% yield from acyclovir, 2.4% moisture content, 99.2% purity, 0.9% D-form). .

Melting Point: 197-199 ° C

Specific luminance: [α] _D ²⁴ : -8.1 ^o ( c = 1.0, H ₂ O)

¹ H-NMR and IR spectra were the same as those obtained in step 2 of Example 1.

Example  14: Valacyclovir  Preparation (Z = Formula 5 (R = Methoxy )

<14-1> Compound of formula 4 (Z = Formula 5; wherein R = Methoxy Manufacture of Acylation  reaction)

After dissolving 21 g (177.6 mmol) of L-valine in 63 mL of methanol, 25.8 mL (239.8 mmol) of methylacetoacetate and 40 mL (266.4 mmol) of N, N, N ', N'-tetramethylethylenediamine were added. . The reaction solution was heated to 70 ° C., stirred for 2 hours, cooled to room temperature, and concentrated under reduced pressure twice by addition of toluene (R is methoxy and B is N, N, N ′, N′-tetramethylethylene Manufactured by Dane's salt of formula (6) which is diamine.

100 mL of dimethylformamide was added to the concentrated residue to dissolve. 33.3 mL (222.0 mmol) of N, N, N ', N'-tetramethylethylenediamine, 20.8 g of acyclovir (88.8 mmol, 3.85% of water) and 4- ( 1 g (8 mmol) of dimethylamino) pyridine was added sequentially. After the reaction solution was cooled to 5 ° C, 35 mL (222.0 mmol) of O, O'-diethyl chlorothiophosphate was slowly added dropwise, followed by stirring at 5 ° C for 2 hours and at room temperature for 12 hours. After adding 200 mL of methanol to the reaction solution, the mixture was stirred for 1 hour, slowly cooled to 5 ° C, and stirred for 1 hour. The resulting solid was filtered and washed with methanol to give a wet. The wet was stirred in 200 mL of water for 1 hour and then filtered. Washed with water and hexane and dried at 40 ° C. to give 2-[(amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl N-[(1-methoxy) as an off-white crystal. Toxylcarbonylpropen) -2-yl] -L-valinate [compound of formula 4: Z is Formula 5 (R = methoxy)] yielded 31.9 g (85% yield from acyclovir).

Melting point: 132 (condensation), 178 to 186 ° C

¹ H-NMR (300 MHz, DMSO, ppm); 0.83-0.93 (m, 6H), 1.82 (s, 3H), 2.03-2.10 (m, 1H), 3.53 (s, 3H), 3.66-3.71 (m, 2H), 4.06-4.10 (m, 1H), 4.19-4.24 (m, 2H), 4.46 (s, 1H), 6.55 (s, 2H), 7.82 (s, 1H)

IR (KBr, cm ^-1 ): υ 3467, 3308, 3189, 2965, 2722, 1732, 1540, 1488, 1391, 1276

<14-2> Valacyclovir  Preparation of hydrochloride ( Deprotection  reaction)

10 g (23.6 mmol) of the compound of formula 4 (Z = Formula 5 (R = methoxy)) obtained in the above <14-1> was suspended in 60 mL of 90% aqueous methanol solution, and 3.9 mL (47.2 mmol) of 12N aqueous hydrochloric acid solution was added. Slowly added dropwise. The reaction mixture was warmed to 50 ° C. and stirred for 2.5 h. 200 mL of isopropanol was added dropwise to the reaction solution, cooled to 5 ° C, and stirred for 1 hour. The resulting solid was filtered, washed with isopropanol and dried to give 7.3 g (yield 71%, moisture content 3.1%, purity 99.4%, D-form amount 1.1%) of white crystals of balaccyclovir hydrochloride.

Melting Point: 197-199 ° C

Specific luminance: [α] _D ²⁴ : -8.2 ^o ( c = 1.0, H ₂ O)

¹ H-NMR and IR spectra are the same as those obtained in step 2 of Example 1.

Example  15: Valacyclovir  Preparation (Z = Formula 5 (R = Ethoxy )

<15-1> Compound of formula 4 (Z = Formula 5; wherein R = Ethoxy Manufacture of Acylation  reaction)

After 21 g (177.6 mmol) of L-valine was dissolved in 63 mL of methanol, 30.3 mL (239.8 mmol) of ethylacetoacetate and 40 mL (266.4 mmol) of N, N, N ', N'-tetramethylethylenediamine were added. . The reaction solution was heated to 70 ° C., stirred for 2 hours, cooled to room temperature, and concentrated under reduced pressure twice by addition of toluene (R is ethoxy and B is N, N, N'N'-tetramethylethylenediamine Manufactured by Dane's salt.

100 mL of dimethylformamide was added to the concentrated residue to dissolve. 33.3 mL (222.0 mmol) of N, N, N ', N'-tetramethylethylenediamine, 20.8 g of acyclovir (88.8 mmol, 3.85% of water) and 4- ( 1 g (8 mmol) of dimethylamino) pyridine was added sequentially. After the reaction solution was cooled to 5 ° C, 35 mL (222.0 mmol) of O, O'-diethyl chlorothiophosphate was slowly added dropwise, followed by stirring at 5 ° C for 2 hours and at room temperature for 12 hours. After adding 200 mL of methanol to the reaction solution, the mixture was stirred for 1 hour, slowly cooled to 5 ° C, and stirred for 1 hour. The resulting solid was filtered and washed with methanol to give a wet. The wet was stirred in 200 mL of water for 1 hour and then filtered. Washed with water and hexane and dried at 40 ° C. to yield 2-[(amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl N- [ Toxylcarbonylpropen) -2-yl] -L-valinate [compound of formula 4: Z is Formula 5 (R = ethoxy)] 32.2 g (83% yield from acyclovir) was obtained.

Melting point: 157 (condensation), 174-182 degreeC

¹ H-NMR (300 MHz, MeOD, ppm); 0.83-0.93 (m, 6H), 1.18-1.23 (t, 3H), 1.84 (s, 3H), 2.06-2.13 (m, 1H), 3.80-3.83 (t, 2H), 3.98-4.06 (m, 3H ), 4.25-4.29 (m, 3H), 4.48 (s, 1H), 5.53 (s, 1H), 7.76 (s, 1H)

IR (KBr, cm ^-1 ): υ 3470, 3296, 3190, 2967, 2720, 2459, 1730, 1576, 1390, 1270

<15-2> Valacyclovir  Preparation of hydrochloride ( Deprotection  reaction)

10.0 g (22.9 mmol) of the compound of formula 4 (Z = Formula 5 (R = ethoxy)) prepared in <15-1> was suspended in 60 mL of 90% aqueous methanol solution, and 3.8 mL (45.8 mmol) of 12N hydrochloric acid aqueous solution. Was slowly added dropwise. The reaction mixture was warmed to 50 ° C. and stirred for 2.5 h. 200 mL of isopropanol was added dropwise to the reaction solution, cooled to 5 ° C, and stirred for 1 hour. The resulting solid was filtered, washed with isopropanol and dried to give 6.5 g of white crystals of balaccyclovir hydrochloride (67% yield from acyclovir, 2.5% water content, 99.1% purity, 1.2% D-body).

Melting point: 196-197 ° C

Specific luminance: [α] _D ²⁴ : -8.1 ^o ( c = 1.0, H ₂ O)

¹ H-NMR and IR spectra are the same as those obtained in step 2 of Example 1.

Example  16: Valacyclovir  Preparation (Z = Formula 5 (R = Ethoxy )

<16-1> Compound of formula 4 (Z = Formula 5; wherein R = Ethoxy Manufacture of Acylation  reaction)

After dissolving 21 g (177.6 mmol) of L-valine in 105 mL of methanol, 30.3 mL (239.8 mmol) of ethylacetoacetate and 63 mL (266.4 mmol) of tributylamine were added. The reaction solution was heated to 70 ° C. and stirred for 2 hours. After cooling the reaction solution to room temperature, toluene was added and concentrated under reduced pressure (preparation of Danes salt of formula 6 wherein R is ethoxy and B is tributylamine).

100 mL of dimethylformamide was added to the concentrated residue, which was then dissolved. 127 mL (532.8 mmol) of tributylamine, 20.8 g (88.8 mmol, 3.85% of water) and 1 g (8 mmol) of 4- (dimethylamino) pyridine were added in this order. Was added. After the reaction solution was cooled to 5 ° C, 35 mL (220.0 mmol) of O, O'-diethyl chlorothiophosphate was slowly added dropwise, followed by stirring at 5 ° C for 2 hours and at room temperature for 12 hours. 400 mL of methanol was added to the reaction solution, followed by stirring for 1 hour. The reaction solution was slowly cooled to 5 ° C., then stirred for 1 hour and the resulting solid was filtered. Washed with methanol and dried at room temperature to give 2-[(amino-1,6-dihydro-6-oxo-9H-purin-9-yl) methoxy] ethyl N-[(1-ethoxycarbonyl) as an off-white crystal. Propene) -2-yl] -L-valinate [compound of formula 4: Z is Formula 5 (R = ethoxy)] 32.6 g (84% yield from acyclovir) was obtained.

Melting Point: 182-187 ° C

¹ H-NMR (300 MHz, DMSO, ppm); 0.83-0.88 (m, 6H), 1.12-1.17 (t, 3H), 1.18 (s, 3H), 2.01-2.02 (m, 1H), 3.30-3.33 (m, 2H), 3.68-3.70 (m, 2H ), 4.07-4.10 (m, 1H), 4.18-4.25 (m, 2H), 4.44 (s, 1H), 5.35 (s, 1H), 7.81 (s, 1H)

IR (KBr, cm ^-1 ): υ 3472, 3291, 3190, 2967, 2713, 1730, 1655, 1606, 1267, 1102

<16-2> Valacyclovir  Preparation of hydrochloride ( Deprotection  reaction)

10.0 g (22.9 mmol) of the compound of formula 4 (Z = Formula 5 (R = ethoxy)) prepared in <16-1> was suspended in 60 mL of 90% aqueous methanol solution, and 3.8 mL (45.8 mmol) of 12N hydrochloric acid aqueous solution. Was slowly added dropwise. The reaction mixture was warmed to 50 ° C. and stirred for 2.5 h. 200 mL of isopropanol was added dropwise to the reaction solution, cooled to 5 ° C, and stirred for 1 hour. The resulting solid was filtered, washed with isopropanol and dried to give 6.7 g of white crystal balaccyclovir hydrochloride (70% yield from acyclovir, 8.2% moisture content, 99.2% purity, 0.9% D-form). .

Melting point: 196-197 ° C

Specific luminance: [α] _D ²⁴ : -8.1 ^o ( c = 1.0, H ₂ O)

¹ H-NMR and IR spectra are the same as those obtained in step 2 of Example 1.

According to the results exemplified in the above examples, the amount of D-body contained in the balaccyclovir hydrochloride prepared according to the method of the present invention was found to be 1.31% or less without purification, and the conventional method (LM Beauchamp et al. , Antiviral Chemistry & Chemotherapy 1992, 3, 159-164). In addition, the purity of the balaccyclovir hydrochloride prepared according to the method of the present invention was found to be 97.5% or more, in particular as a protected L- valine as in Examples 13 to 16 (Dane's salt), the purity was higher than 99%.

Claims (14)

(1) Protecting the acyclovir of formula (2) using O, O'-diethyl chlorothiophosphate (DECTP) as an acylation activator in the presence of an organic base and 4- (dimethylamino) pyridine (DMAP) Acylating the L-valine derivative to prepare a balaccyclovir derivative protected by the amino group of Formula 4; And
(2) obtaining a balaccyclovir or a salt thereof by hydrogenating the obtained balaccyclovir derivative of Formula 4 or performing an acid hydrolysis reaction to remove an amino protecting group
Method for preparing a valacyclovir or acid addition salts thereof of Formula 1 comprising:
<Formula 1>

<Formula 2>

<Formula 3>

<Formula 4>

In the above formula
Z is benzyloxycarbonyl (Cbz), t-butoxycarbonyl (Boc) or α, β-unsaturated carbonyl represented by the following formula (5) as an amino protecting group;
<Formula 5>

In which R is methyl, methoxy or ethoxy.
The method of claim 1, wherein the organic base of step 1 is triethylamine, diisopropylethylamine, tributylamine, N, N, N ', N'-tetramethylethylenediamine, N-methylimidazole and N A method for producing a balaccyclovir or an acid addition salt thereof, which is selected from the group consisting of methylmorpholine.
The method according to claim 2, wherein the organic base is N, N, N ', N'-tetramethylethylenediamine or tributylamine.
The method according to claim 1, wherein the organic base is used in 1.5 to 4 molar equivalents relative to 1 molar equivalent of O, O' -diethyl chlorothiophosphate.
The method according to claim 1, wherein the DMAP is used in an amount of 0.01 mol to 0.2 mol equivalent to 1 mol equivalent of acyclovir.
The method of claim 1, wherein O, O' -diethyl chlorothiophosphate is used in 1 to 3 molar equivalents to 1 molar equivalent of valine derivative of Formula 3, Valacyclovir or acid addition salt thereof Manufacturing method.
The method according to claim 1, wherein the L-valine derivative of Chemical Formula 3 is used in 1 to 2 molar equivalents to 1 molar equivalent of the acyclovir of Chemical Formula 2.
The method of claim 1, wherein R in the α, β-unsaturated carbonyl represented by Chemical Formula 5 is methoxy, a method for producing a balaccyclovir or an acid addition salt thereof.
The method of claim 1, wherein in the α, β-unsaturated carbonyl represented by Formula 5, R is ethoxy.
According to claim 1, wherein the acylation reaction of step 1 N, N-aprotic polar selected from dimethylacetamide, dimethyl sulfoxide and N-2- methylpyrrolidin group consisting of a money-dimethylformamide, N, N Method for producing a balaccyclober or acid addition salts thereof, characterized in that carried out in an organic solvent.
The method according to claim 10, wherein the acylation reaction of step 1 is carried out in N , N -dimethylformamide.
According to claim 1, wherein when the amino protecting group (Z) of the balaccyclovir derivative of Formula 4 is benzyloxycarbonyl (Cbz), the removal of the amino protecting group in step 2 is carried out in a mixed solvent with aqueous methanol or tetrahydrofuran. A method for producing a balacyclovir or an acid addition salt thereof, characterized in that the reaction is carried out by reacting a balacyclovir derivative of formula (4) with hydrogen gas and formic acid in the presence of a palladium metal catalyst fixed to carbon or aluminum oxide.
According to claim 1, wherein when the amino protecting group (Z) of the balaccyclovir derivatives of the formula (4) is t-butoxycarbonyl (Boc), the amino protecting group removal in step 2 is carried out in the water To react with hydrochloric acid, characterized in that the balaccyclovir or acid addition salt thereof.
According to claim 1, wherein when the amino protecting group (Z) of the balaccyclovir derivative of Formula 4 is α, β-unsaturated carbonyl of Formula 5, the removal of the amino protecting group in step 2 is achieved with aqueous acetone, methanol, ethanol or isopropanol. A method for producing a balacyclovir or an acid addition salt thereof, characterized in that it is carried out by reacting a balacyclovir derivative of Formula 4 with hydrochloric acid in a solution.