RU2805661C2 - New method for synthesis of phenoxydiaminopyrimidine compound - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: options for obtaining the free base of compound A of formula 1 are proposed, including the stage of converting 2-isopropylphenol into a co-crystal of 4-bromo-2-isopropylphenol and hemi-DABCO, additionally including the stage of converting a co-crystal of 4-bromo-2-isopropylphenol and hemi-DABCO into a methoxyphenol compound, further comprising the step of reacting 2-isopropyl-4-methoxyphenol with ClCH₂CN to produce a cyanoether compound, 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile.

EFFECT: development of a simple method for obtaining the free base of compound A with high yield.

11 cl, 11 dwg, 1 ex

Description

Field of invention

The present invention relates to a new method for preparing a phenoxydiaminopyrimidine compound or a pharmaceutically acceptable salt thereof that is useful for the potential treatment of diseases associated with purinergic P2X receptors, for example, respiratory and pain-related diseases, conditions and disorders.

BACKGROUND OF THE INVENTION

P2X receptor subunits are found on afferent fibers in the urothelium of the rodent and human bladder. There is evidence indicating that ATP may be released from epithelial/endothelial cells of the bladder or other hollow organs as a result of distension (Burnstock (1999) J. Anatomy 194:335-342; and Ferguson et al. (1997) J. Physiol 505:503-511). The ATP thus released may play a role in transmitting information to sensory neurons located in subepithelial components, such as the suburothelial lamina propria (Namasivayam, et al. (1999) BJU Intl. 84:854-860). P2X receptors have been studied in a number of neurons, including sensory, sympathetic, parasympathetic and central neurons (Zhong, et al. (1998) Br. J. Pharmacol. 125:771-781). These studies indicate that purinergic receptors may play a role in afferent neurotransmission from the bladder, and that P2X receptor modulators are potentially useful for the treatment of bladder disorders and other genitourinary diseases or conditions.

Recent evidence also suggests a role for endogenous ATP and purinergic receptors in nociceptive responses in mice (Tsuda, et al. (1999) Br. J. Pharmacol. 128:1497-1504). ATP-induced activation of P2X receptors on dorsal root ganglion nerve terminals has been shown to stimulate the release of glutamate, a key neurotransmitter involved in nociceptive signaling (Gu and MacDermott, Nature 389:749-753 (1997)). P2X3 receptors have been identified on nociceptive neurons in the dental pulp (Cook et al., Nature 387:505-508 (1997)). Thus, ATP released from damaged cells may cause pain through activation of P2X3 and/or P2X2/3, including receptors on nociceptive sensory nerve endings. This is consistent with the induction of pain by intradermal ATP in the blister base model (Bleehen, Br J Pharmacol 62:573-577 (1978)). P2X antagonists have been shown to be analgesic in animal models (Driessen and Starke, Naunyn Schmiedebergs Arch Pharmacol 350:618-625 (1994)). These data indicate that P2X2 and P2X3 are involved in nociception and that P2X receptor modulators have potential utility as analgesics.

Other investigators have shown that P2X3 receptors are expressed in the human colon and are expressed at higher levels in inflamed colon than in normal colon (Y. Yiangou et al, Neuroastroenterol Mot (2001) 13:365-69). Others have suggested that the P2X3 receptor is involved in sensing distension or intraluminal pressure in the intestine and initiating reflex contractions (X. Bian et al., J Physiol (2003) 551.1:309-22), and have linked it to colitis (G. Wynn et al. al., Am J Physiol Gastrointest Liver Physiol (2004) 287:G647-57); Inge Brouns et al. (Am J Respir Cell Mol Biol (2000) 23:52–61) found that P2X3 receptors are expressed in pulmonary neuroepithelial bodies (NEBs), implying involvement of the receptor in pain transmission in the lung. Researchers have also suggested that P2X2 and P2X3 receptors are involved in pO2 sensing in the lung NEB (W. Rong et al., J Neurosci (2003) 23(36):11315-21).

Thus, there is a need for improved methods for producing compounds that are effective modulators of P2X receptors, including P2X3 and P2X2/3 receptors.

US Patent Nos. 7,858,632 and 7,741,484 describe methodology and synthetic methods that can be used to prepare phenoxydiaminopyrimidine derivatives. However, currently known methods have various disadvantages, including complex chemistry and/or low yield. There remains a need for improved synthetic methods to produce phenoxydiaminopyrimidine derivatives with simplified chemistry and/or higher yield.

SUMMARY OF THE INVENTION

Described herein is a new process for the preparation of Compound A, a phenoxydiaminopyrimidine compound of the following formula, or a pharmaceutically acceptable salt thereof:

Compound A.

Also described herein are various salts and solvates of Compound A.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1. XRPD profile of a cocrystal of 4-bromo-2-isopropylphenol and hemi-DABCO.

Figure 2. XRPD profile of a cocrystal of 4-bromo-2-isopropylphenol and mono-DABCO.

Figure 3. XRPD profile of 2-isopropyl-4-methoxyphenol form 1.

Figure 4. XRPD profile of a cocrystal of 2-isopropyl-4-methoxyphenol and DMAP.

Figure 5. XRPD profile of 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine Form 1.

Figure 6. XRPD profile of 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine solvate 1 in NMP.

Figure 7. XRPD profile of compound A free base solvate 1 in acetonitrile.

Figure 8. XRPD profile of compound A citrate solvate 1 in methanol.

Figure 9. XRPD profile of compound A citrate solvate 1 in IPA.

Figure 10. XRPD profile of compound A citrate hydrate solvate 1 in methanol.

Figure 11. XRPD profile of compound A glycolate form 1.

DETAILED DESCRIPTION OF THE INVENTION

A process for preparing the free base of Compound A or a pharmaceutically acceptable salt thereof with simplified chemistry and higher yield is described herein.

In one embodiment, Compound A citrate is prepared by a process comprising synthesis and isolation of a cocrystal of 4-bromo-2-isopropylphenol and DABCO, synthesis of 2-isopropyl-4-methoxyphenol and 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile, synthesis and isolation 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine, synthesis of the free base of compound A, 5-((2,4-diaminopyrimidin-5-yl)oxy)-4-isopropyl-2-methoxybenzenesulfonamide, and finally converting the free base of compound A to the corresponding citrate as shown in Scheme 1.

Scheme 1

In one embodiment, 2-isopropylphenol is treated with NBS in the presence of MSA to form 4-bromo-2-isopropylphenol. This compound is treated with DABCO to obtain a solid cocrystal of 4-bromo-2-isopropylphenol with DABCO.

In one embodiment, a cocrystal of 4-bromo-2-isopropylphenol and DABCO is converted to 2-isopropyl-4-methoxyphenol in the presence of copper(I) bromide, DMF and sodium methoxide. In one embodiment, both DMF and DABCO are required in this reaction to prevent dimerization of the product.

In an alternative embodiment, 2-isopropyl-4-methoxyphenol is synthesized from mequinol in the presence of direnium decarbonyl and propylene at high temperatures and pressures.

In one embodiment, 2-isopropyl-4-methoxyphenol is treated with an alkylating agent to produce the desired 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile. In one embodiment, this reaction is carried out with potassium carbonate in acetonitrile. In another embodiment, this reaction is carried out with sodium hydroxide in a mixture of toluene and NMP. These reaction conditions allow complete conversion of phenol to 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile, whereas previous methods were unable to achieve complete conversion of phenol to 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile.

In one embodiment, 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile is treated with ethyl formate in NMP and this mixture is added to a solution of potassium tert-butoxide in NMP. This order of addition allows the formation of the desired bond; while addition of reactants in an alternative order may result in dimerization of the starting material as cyanomethyl ether and the formation of carbon monoxide. The resulting enolate is treated with guanidine to obtain 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine.

In one embodiment, 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine is treated with chlorosulfonic acid in the presence of acetonitrile to produce a sulfonyl chloride intermediate. In acetonitrile, this reaction is homogeneous and can be directly quenched with aqueous ammonium hydroxide to give the free base of Compound A, 5-((2,4-diaminopyrimidin-5-yl)oxy)-4-isopropyl-2-methoxybenzenesulfonamide.

In one embodiment, the free base of Compound A, 5-((2,4-diaminopyrimidin-5-yl)oxy)-4-isopropyl-2-methoxybenzenesulfonamide, is treated with glycolic acid in methanol to form a glycolate. The addition of citric acid converts the glycolate to citrate in a mixture of methanol and isopropanol to form Compound A citrate. This new salt exchange approach for isolation allows for the desired form and control of impurities.

The technique according to Scheme 1 provides several important advantages. The synthesis of the intermediate 2-isopropyl-5-methoxyphenol is carried out in one or two steps instead of the sequence of multiple steps required for previous synthetic methods. The desired alkylation is carried out in a safe, controlled manner without extreme exotherms. 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine is synthesized directly from 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile without any intermediates or isolations, and without the use of anilines, which can complicate purification of the desired compound. The chlorosulfonylation reaction is carried out in acetonitrile to directly produce the sulfonyl chloride without the need for phosphorus oxychloride. The free base 5-((2,4-diaminopyrimidin-5-yl)oxy)-4-isopropyl-2-methoxybenzenesulfonamide is isolated from a mixture of water and acetonitrile, allowing easy crystallization of several forms of the desired product. This method provides simplified chemistry, higher yields and uses standard manufacturing equipment, thereby providing a productive, environmentally friendly and portable manufacturing process.

In one embodiment, the method includes the step of converting 2-isopropylphenol into a co-crystal of 4-bromo-2-isopropylphenol and DABCO:

In one embodiment, the above conversion is carried out in the presence of NBS, MSA and a solvent such as MeCN. In another embodiment, hydrogen peroxide and hydrobromic acid can be used. In another embodiment, pyridinium tribromide is used. In another embodiment, other bromination reagents can be used.

In one embodiment, the conversion described above is carried out at a temperature of from about -5°C to 10°C, or more specifically from about -5°C to 0°C.

In one embodiment, the cocrystal of 4-bromo-2-isopropylphenol and DABCO is isolated as a cocrystal of 4-bromo-2-isopropylphenol and hemi-DABCO. In another embodiment, the cocrystal is isolated as a cocrystal of 4-bromo-2-isopropylphenol and mono-DABCO.

In one embodiment, the process for preparing a co-crystal of 4-bromo-2-isopropylphenol and hemi-DABCO includes the following step:

.

In one embodiment, the method further includes the step of reacting a co-crystal of 4-bromo-2-isopropylphenol and DABCO with NaOMe to produce 2-isopropyl-4-methoxyphenol:

.

In one embodiment, the above reaction is carried out in the presence of copper(I) bromide as a catalyst. In other embodiments, copper(II) bromide, copper(I) iodide, and other copper(I) or copper(II) salts may be used as the catalyst.

In one embodiment, a cocrystal of 4-bromo-2-isopropylphenol and DABCO is loaded as a cocrystal of 4-bromo-2-isopropylphenol and hemi-DABCO. In another embodiment, the cocrystal is loaded as a cocrystal of 4-bromo-2-isopropylphenol and mono-DABCO.

In one embodiment, the reaction is carried out in the presence of MeOH and DMF. In other embodiments, the solvent may be dimethylacetamide, dioxane, or DMSO.

In one embodiment, 2-isopropyl-4-methoxyphenol is not isolated. In another embodiment, 2-isopropyl-4-methoxyphenol is isolated as an anhydrate. In a further embodiment, 2-isopropyl-4-methoxyphenol is isolated as a co-crystal with DMAP.

In one embodiment, the method further includes the step of reacting 2-isopropyl-4-methoxyphenol with ClCH ₂ CN to form 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile, as follows:

.

In one embodiment, the reaction described above is carried out in the presence of NMP and toluene. In another embodiment, the reaction is carried out in the presence of acetonitrile. In another embodiment, other polar aprotic solvents can be used.

In one embodiment, the reaction described above is carried out in the presence of a base. In one embodiment, the base is NaOH. In another embodiment, the base is potassium carbonate. In another embodiment, other hydroxide or carbonate bases can be used.

In one embodiment, chloroacetonitrile is used as the alkylating reagent. In another embodiment, bromoacetonitrile, iodoacetonitrile and other 2-substituted acetonitriles can be used.

In one embodiment, the above reaction is carried out at a temperature of from about 0°C to about 10°C. In another embodiment, the above reaction is carried out at a temperature of from about 25°C to about 35°C.

In one embodiment, the method further includes the step of converting a cyanoether compound having the formula below to 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine:

.

In one embodiment, the above conversion is carried out by first preparing a solution of 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile with ethyl formate in toluene to produce the intermediate 3-hydroxy-2-(2-isopropyl-4-methoxyphenoxy)acrylonitrile linolate. In other embodiments, these compounds are dissolved in NMP, DMI, or other polar aprotic solvents.

In one embodiment, a solution containing the 3-hydroxy-2-(2-isopropyl-4-methoxyphenoxy)acrylonitrile enolate intermediate is mixed with the guanidine source directly without isolating the enolate.

In one embodiment, the source of guanidine is guanidine hydrochloride. In another embodiment, other salt forms of guanidine can be used, including guanidine carbonate and guanidine hydrogen sulfate.

In one embodiment, ammonium salts are present during the addition of guanidine.

In one embodiment, toluene is distilled off from the reaction mixture prior to crystallization. In other embodiments, the toluene is not removed prior to crystallization.

In one embodiment, N-methylpyrrolidinone is used as the solvent. In another embodiment, other polar aprotic solvents are used.

In one embodiment, the above reaction between the mixture and guanidine-HCl is carried out at a temperature of from about 80°C to 98°C. In another embodiment, the reaction temperature is from about 95°C to 110°C.

In one embodiment, 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine is isolated as an anhydrate. In another embodiment, 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine is isolated as a solvate in NMP. 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine also forms solvates with acetone, DMA or DMI.

In one embodiment, the method further includes the step of reacting 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine with ClSO ₃ H and then with ammonia to produce the free base of Compound A:

In one embodiment, the ammonia is supplied as ammonium hydroxide. In another embodiment, other ammonium salts can be used. In another embodiment, ammonia is used in organic solvents.

In one embodiment, the above reaction between 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine and ClSO ₃ H is carried out in the presence of MeCN.

In one embodiment, the above reaction between 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine and ClSO ₃ H is carried out at a temperature of from about 25°C to about 35°C. In another embodiment, the reaction temperature is from about 35°C to about 45°C. In another embodiment, the reaction temperature is from about 45°C to about 70°C.

In one embodiment, methanol is present during the conversion of the sulfonyl chloride to Compound A. In another embodiment, water is present during the conversion of the sulfonyl chloride to Compound A.

In one embodiment, the free base of Compound A is prepared as an anhydrate. In another embodiment, the free base of Compound A is prepared as a solvate in acetonitrile. Compound A free base also forms solvates with DMSO, DMAc, DMF, acetone, NMP, IPA, methanol, THF, MEK, sulfolane or NMP/IPA.

In one embodiment, the free base of compound A in the above reactions is obtained in greater than 80% yield. In another embodiment, the yield is greater than 85%. In another embodiment, the yield is greater than 90%.

In one embodiment, the method further includes the step of converting the free base of Compound A to Compound A citrate.

In one embodiment, the conversion is carried out in the presence of MeOH and glycolic acid. In another embodiment, IPA is also present during the conversion.

In one embodiment, the citrate is isolated as an anhydrate. In another embodiment, the citrate is isolated as a solvate in methanol or isopropanol. Citrate also forms solvates with methanol/water, ethanol/water, IPA/water, THF or NMP.

In one embodiment, the glycolate is isolated as an anhydrate and then converted to citrate. The glycolate also forms solvates or hydrates with methanol, IPA, tert-amyl alcohol, water, or a combination of these solvents, and forms desolvated/dehydrated forms from these solvates/hydrates.

In one embodiment, the above conversion has a yield greater than 85%. In another embodiment, the yield is greater than 90%. In another embodiment, the yield is approximately 93%.

In one embodiment, a method for producing Compound A citrate includes the following steps:

(a) converting 2-isopropylphenol to a co-crystal of 4-bromo-2-isopropylphenol and DABCO:

;

(b) reaction of the resulting cocrystal of 4-bromo-2-isopropylphenol and DABCO with NaOMe to form 2-isopropyl-5-methoxyphenol:

;

(c) reaction of 2-isopropyl-5-methoxyphenol with ClCH ₂ CN to give 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile:

;

(d) converting 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile to 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine:

;

(e) reacting 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine with ClSO ₃ H and then with NH ₄ OH to give the free base of compound A, 5-((2,4-diaminopyrimidine- 5-yl)oxy)-4-isopropyl-2-methoxybenzenesulfonamide:

; And

(f) converting the free base of Compound A, 5-((2,4-diaminopyrimidin-5-yl)oxy)-4-isopropyl-2-methoxybenzenesulfonamide, to Compound A citrate in the presence of glycolic acid and MeOH:

.

In one embodiment, the overall yield of Compound A citrate from 2-isopropylphenol is greater than 50%. In another embodiment, the overall yield is greater than 55%. In another embodiment, the overall yield is greater than 60%.

EXPERIMENTAL PART

The examples below are provided for illustration purposes only and are not intended to be limiting in any way. The abbreviations used herein and in the description are abbreviations generally accepted in the art or as follows.

°C: degrees Celsius

DABCO: 1,4-diazabicyclo[2.2.2]octane

DMA: Dimethylamine

DMAP: Dimethylaminopyridine

DMF: N,N-dimethylformamide

DMI: 1,3-dimethyl-2-imidazolidinone

EtOAc: ethyl acetate

EtOH: ethanol

g: grams

h: hour(s)

IPA: isopropyl alcohol

kg: kilograms

l: liter

LC: liquid chromatography

MeOH: methanol

MSA: methanesulfonic acid

MeCN: Acetonitrile

MEK: methyl ethyl ketone

min: minutes

ml: milliliter(s)

mole: number of moles

N: normal

NBS: N-bromosuccinimide

nM: nanomolar

NMP: N-methyl-2-pyrrolidone

K.t. or room temperature: room temperature

saturated: saturated

THF: tetrahydrofuran

mass or mass: mass

XRPD: X-ray powder diffraction

In one embodiment, the free base of Compound A and its citrate are prepared by a process comprising the synthesis and isolation of a co-crystal of 4-bromo-2-isopropylphenol and DABCO, the synthesis of 2-isopropylphenyl, 2-isopropyl-5-methoxyphenol and 2-(2-isopropyl-4 -methoxyphenoxy)acetonitrile, synthesis and isolation of 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine, synthesis of Compound A free base, and final conversion of Compound A free base to the corresponding citrate as illustrated below.

Step 1. Preparation of co-crystal of 4-bromo-2-isopropylphenol and DABCO

The following cocrystal of 4-bromo-2-isopropylphenol and hemi-DABCO is obtained in greater than 99% purity and approximately 85-92% yield by the following process:

To a solution of 2-isopropylphenol (75.0 g, 550 mmol) in acetonitrile (225 ml) was added MSA (0.520 g, 5.41 mmol). The mixture was cooled to -10°C and NBS (98.01 g, 550 mmol) was added in portions while maintaining the internal temperature below 10°C. The reaction mixture was kept for 30 minutes to 1 hour and then heated to 20°C, diluted with water (450 ml) and extracted with toluene (225 ml). The organic layer was washed sequentially with 9 wt% phosphoric acid (150 ml) and 5 wt% NaCl (150 ml). The organic layers were concentrated to approximately 150 ml and filtered into a clean reactor. The mixture was heated to 30-40°C and n-heptane (28.5 ml) was added followed by DABCO (30.89 g, 275 mmol). The mixture was seeded (the seed can be synthesized from a previous batch of this procedure carried out without seed) with a cocrystal of 4-bromo-2-isopropylphenol and hemi-DABCO (75 mg, 0.277 mmol), diluted with 52.5 ml of n-heptane and stirred in for 1 hour. The slurry was cooled to 20°C over 1 hour and 370 ml of n-heptane was added over 2 hours. The slurry was cooled to 5°C over 2 hours, kept for 2 hours, filtered and washed with n-heptane ( 2×75 ml). The solid was dried at 20-25°C under vacuum to obtain a co-crystal of 4-bromo-2-isopropylphenol and hemi-DABCO (134.8 g, 90%) as a solid. ¹ H-NMR (400 MHz, DMSO- d ₆ ) δ 7.20 (d, J = 2.5 Hz, 1H), 7.13 (dd, J = 8.5, 2.6 Hz, 2H), 6.73 (d, J =8.5 Hz, 2H), 3.16 (hept, J =6.9 Hz, 2H), 2.60 (s, 12H), 1.14 (d, J =6 ,9 Hz, 12H).

Crystallization in step 1 gives a cocrystal of 4-bromo-2-isopropylphenol and hemi-DABCO, a cocrystal of bromophenol and mono-DABCO, or a mixture of a cocrystal of bromophenol and hemi-DABCO and a cocrystal of bromophenol and mono-DABCO. The XRPD profile for the cocrystal of bromophenol and hemi-DABCO is presented in Figure 1 .

The cocrystal of bromophenol and mono-DABCO can be prepared using the following procedure:

DABCO (1.7 g, 15 mmol), phenol (2.5 g, 15 mmol) and 2 ml of n-heptane were placed in a flask with a magnetic stirrer. The resulting slurry was stirred at 23°C overnight. The suspension was then filtered and the resulting wet residue was washed with 2 ml of n-heptane at a temperature of 5°C. The residue was dried under vacuum with a nitrogen purge to obtain a cocrystal of 4-bromo-2-isopropylphenol and mono-DABCO (2.9 g, 70% yield) as a solid. ¹ H-NMR (500 MHz, DMSO- d6 ) δ 9.65 (s, 1H), _7.20 (s, 1H), 7.14 (d, J =8.5 Hz, 1H), 6, 74 (d, J =8.5 Hz, 1H), 3.17 (hept, J =6.8 Hz, 1H), 2.61 (s, 12H), 1.15 (d, J =6.9 Hz, 6H).

The XRPD profile for the cocrystal of bromophenol and mono-DABCO is presented in Figure 2 .

Stage 2a. Preparation of 2-isopropyl-4-methoxyphenol

2-isopropyl-4-methoxyphenol below is obtained in approximately 92% yield by the following process:

To a solution of a cocrystal of 4-bromo-2-isopropylphenol and hemi-DABCO (120 g, 442 mmol) in 25 wt% sodium methoxide in methanol (430 g) was added 60 ml of DMF. The solution was purged with nitrogen under pressure, copper(I) bromide (3.23 g, 22.5 mmol) was added to the mixture, and the reaction mixture was heated to reflux for 12-16 hours. The reaction mixture was cooled to 0-5 °C and quenched with 6 M HCl until the pH of the solution was less than 5. The slurry was diluted with 492 ml of toluene and 720 ml of water to obtain a homogeneous solution with a layer of residues between the layers. The aqueous layer was discarded as waste. The organic layer was filtered to remove the residue layer and washed with 240 ml of water to obtain 2-isopropyl-4-methoxyphenol (491 g, 13.3 wt%, 89% yield) as a solution in toluene. ¹ H-NMR (500 MHz, DMSO- d6 ) δ 8.73 (s, 1H) _, 6.68 (d, J =8.6 Hz, 1H), 6.66 (d, J =3.0 Hz, 1H), 6.55 (dd, J =8.6, 3.1 Hz, 1H), 3.65 (s, 3H), 3.17 (hept, J =6.9 Hz, 1H), 1.14 (d, J =6.9 Hz, 6H).

Stage 2b. Preparation of 2-isopropyl-4-methoxyphenol

Alternatively, methoxyphenol is produced through the following process:

400 ml of anhydrous toluene, Re ₂ (CO) ₁₀ (3.16 g, 4.84 mmol) and mequinol (100 g, 806 mmol) were placed in a high pressure vessel at room temperature. The container was then degassed with propylene and propylene (85.0 g, 2.02 mol) was charged into the container. The container was closed and heated to 170°C. Internal pressure was measured at approximately 250 psi. inch. The reaction mixture was stirred under these conditions for 72 hours. The container was then allowed to cool to 23°C. The internal pressure was carefully reduced to 1 atmosphere and the toluene solution was analyzed as 91% and used directly in the next step or isolated as a solid.

Step 2a/2b provides anhydrous form 1 of 2-isopropyl-4-methoxyphenol. The XRPD profile of methoxyphenol form 1 is shown in Figure 3 .

In another embodiment, the product was isolated as a cocrystal with DMAP:

.

DMAP (3.67 g, 30.1 mmol), 2.5 mL of toluene, and 2-isopropyl-4-methoxyphenol (5.00 g, 30.1 mmol) were placed in a flask with a magnetic stirrer. The reaction mixture was stirred at room temperature. for 5 minutes, and a homogeneous solution was formed. The reaction mixture was then cooled to 5°C. Ten ml of n-heptane was added slowly over 20 min. The resulting slurry was stirred at 5°C overnight. The suspension was filtered and the resulting wet residue was washed with 3 ml of n-heptane at a temperature of 5°C. The residue was dried under vacuum with a nitrogen purge to obtain a cocrystal of 2-isopropyl-4-methoxyphenol and DMAP (7.01 g, 81%) as a solid. ¹ H-NMR (500 MHz, DMSO- d6 ) δ 8.78 (s, 1H), _8.10 (d, J =6.1 Hz, 2H), 6.71-6.65 (m, 2H ), 6.57 (dd, J =11.3, 6.0 Hz, 3H), 3.66 (s, 3H), 3.17 (hept, J =6.8 Hz, 1H), 2.95 (s, 6H), 1.14 (d, J =6.9 Hz, 6H).

Crystallization provides an anhydrous crystal of 2-isopropyl-4-methoxyphenol with DMAP. The XRPD profile of the cocrystal of 2-isopropyl-4-methoxyphenol and DMAP is presented in Figure 4 .

Stage 3a. Preparation of cyanoether, 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile

The cyanoether is obtained in approximately 95% yield by the following process:

A 12-15 wt% solution of 2-isopropyl-4-methoxyphenol (314.3 g, 12 wt%, 226.8 mmol) was concentrated to over 50 wt% 2-isopropyl-4-methoxyphenol in toluene in vacuo at 40-50°C. 189 ml of NMP was added to the solution and the mixture was cooled to 5°C. Sodium hydroxide (27.2 g, 50 wt% in water, 340 mmol) and chloroacetonitrile (36 g, 340 mmol) were sequentially added to the mixture while maintaining the internal temperature below 10°C. The reaction mixture was kept for 2 hours and then diluted with 150 ml of toluene and 226 ml of water while maintaining the temperature below 10°C. The mixture was heated to 20-25°C, the layers were separated and the organic layer was washed with 75 ml of 20 wt.% NaCl (aq). The organic layer was filtered to obtain 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile (56.8 g, 74.6 wt%) as a solution in toluene. The filter was washed with NMP to obtain additional 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile (27.1 g, 5.0 wt%) as a solution in NMP. The cumulative yield was approximately 94%. ¹ H-NMR (500 MHz, DMSO- d6 ) δ 7.05 (d, J =8.8 Hz, 1H), 6.81 (d, J =3.0 _Hz , 1H), 6.78 ( dd, J =8.8, 3.1 Hz, 1H), 5.11 (s, 2H), 3.73 (s, 3H), 3.20 (hept, J =6.9 Hz, 1H), 1.17 (d, J =6.9 Hz, 6H).

Stage 3b. Preparation of cyanoether, 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile

Alternatively, the cyanoether presented below was prepared in approximately 92% yield by the following process:

A solution of 2-isopropyl-4-methoxyphenol in toluene (491 g, 13.3 wt%, 393 mmol) was concentrated and the solvent was replaced with acetonitrile in vacuo at 40-50°C. Potassium carbonate (164.5 g, 1190 mmol) and tetrabutylammonium hydrogen sulfate (1.5 g, 4.42 mmol) were added to a separate container and the container was purged with nitrogen gas under pressure. A solution of phenol in acetonitrile and chloroacetonitrile was sequentially added to the reaction vessel. The container was heated to 40°C and held for 4 hours. The mixture was allowed to cool to 25°C and diluted with 326 ml of water. The layers were separated and the organic layer was washed with 130 ml of 10 wt.% NaCl. The solvent was changed to toluene under vacuum and the organic layer was filtered through two 16D Cuno #5 cassettes. The organic layer was concentrated to give 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile in toluene (128.2 g, 58 wt%, 92% yield).

Step 4. Preparation of diaminopyrimidine, 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine

Diaminopyrimidine is obtained in approximately 90% yield by the following process:

A solution of potassium tert-butoxide (44.8 g, 0399 mmol) in NMP (180 ml) was cooled to -10°C. A solution of 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile cyanoether (59.3 g, 61.4 wt%, 177 mmol) in toluene and ethyl formate (26.3 g, 355 mmol) was added to the main solution. while maintaining the internal temperature between -12°C and -8°C. After standing for 3 hours, guanidine hydrochloride (136 g, 1420 mmol) was added to the mixture and the reaction mixture was heated to 115°C for 6 hours. The mixture was allowed to cool to 90°C, diluted with 200 ml of water and kept until the reaction the mixture did not become homogeneous (approximately 30-45 minutes). After all solids had dissolved, a vacuum (400 mmHg) was applied to the reactor to remove the toluene. The vacuum was released and the solution was allowed to cool to 85°C. A seed of 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine (49.8 mg) was added (the seed can be synthesized by the method described in US patent 7741484), the solution was left for 2 hours, 200 ml of water was added and the batch was allowed to cool to 20°C over 6 hours. The slurry was kept for 10 hours at 20°C, filtered, washed with a mixture of water:NMP 2:1 (3x100 ml) and water (3x100 ml), and dried in vacuo at 50°C to obtain the title compound (42.2 g, 88%) as a solid. ¹ H-NMR (500 MHz, DMSO- d6 ) δ 7.23 (s, 1H) _, 6.83 (d, J= 3.0 Hz, 1H), 6.70 (dd, J= 8.9 , 3.0 Hz, 1H), 6.63 (d, J= 8.8 Hz, 1H), 6.32 (s, 2H), 5.75 (s, 2H), 3.71 (s, 3H ), 3.28 (hept, J= 6.9 Hz, 1H), 1.20 (d, J= 6.9 Hz, 6H); ¹³ C-NMR (126 MHz, DMSO- d6 ) δ 159.7, 157.2 _, 155.1, 148.4, 144.2, 139.0, 130.4, 116.9, 112.5, 111.3, 55.4, 26.57, 22.83.

Crystallization in step 4 provides Form 1 of anhydrous 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine. The XRPD profile for Form 1 of 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine is presented in Figure 5.

In one embodiment, 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine solvate 1 in NMP is prepared by adding an excess amount of 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4- form 1 diamine in NMP into a closed container to obtain a suspension. The suspension is stirred at room temperature. until the form transition is complete. Crystals of 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine solvate 1 in NMP can be collected by filtration and immediately measured by XRPD to prevent desolvation. The XRPD profile of 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine solvate 1 in NMP is presented in Figure 6.

Step 5: Preparation of the free base of compound A

The free base of compound A is obtained in approximately 91% yield through a process comprising the steps:

Chlorosulfonic acid (63.1 mL, 942 mmol) while maintaining the internal temperature below 25°C. The solution was kept for 1 hour at 25°C and then heated to 45°C for 12 hours. The solution was allowed to cool to 20°C and 235 ml of ammonium hydroxide and 71 ml of acetonitrile were added to the solution at -10°C while maintaining the internal temperatures below 15°C. The slurry was kept at 10°C for 1 hour, heated to 25°C and held for 1 hour. The slurry was diluted with 564 ml of water and 188 ml of 50 wt.% sodium hydroxide to obtain a homogeneous solution, which was heated to 35°C for 2 hours. The solution was allowed to cool to 22°C and the pH of the solution was adjusted to 12.9 with 2 M citric acid solution. The solution was seeded with the free base of compound A (470 mg, 1.19 mmol) (the seed can be synthesized by the method described in US patent 7741484), incubated for 2 hours, acidified to pH 10.5-11.3 with 2 M citric acid solution acid for 5-10 hours, and then kept for 2 hours. The suspension was filtered, the resulting residue was washed with a mixture of water:acetonitrile 90:10 (2×118 ml) and water (2×235 ml), and dried at 55°C in vacuo to give Compound A free base (50.9 g, 91%) as a solid. ^1H -NMR (500 MHz, DMSO- d6 ) δ 7.36 (s, 1H), _7.07 (s, 1H), 7.05-6.89 (m, 3H), 6.37 (s , 2H), 5.85 (s, 2H), 3.89 (s, 3H), 3.41 (hept, J =6.6 Hz, 1H), 1.27 (d, J =6.8 Hz , 6H).

Crystallization in step 5 provides free base form 1 of compound A.

In one embodiment, Compound A Free Base Solvate 1 in Acetonitrile can be prepared by adding an excess amount of Compound A Free Base Form 1 to acetonitrile in a closed container to form a suspension. The suspension is stirred at 50°C until the shape transition is complete. Crystals of Compound A free base solvate 1 in acetonitrile can be collected by filtration and immediately measured by XRPD to prevent desolvation. The XRPD profile of Compound A free base solvate 1 in acetonitrile is presented in Figure 7.

Stage 6a. Preparation of Compound A Citrate

Compound A citrate was prepared through a process comprising the steps:

Compound A free base (30.0 g, 84.9 mmol) and glycolic acid (22.6 g, 297 mmol) were added to methanol (360 ml). The solution was heated to 60°C, kept for 1 hour and filtered through a 0.6-μm filter into a clean container. A solution of citric acid (32.6 g, 170 mmol) in 2-propanol (180 ml) at room temperature. filtered through a 0.6-μm filter into the methanol solution for 30 min while maintaining the temperature of the methanol solution between 58-62°C. The solution was seeded with compound A citrate (450 mg, 0.825 mmol) (the seed can be synthesized by the method described in patent application number PCT/US17/66562), incubated for 1 hour and diluted with 180 ml of 2-propanol for 3 hours while maintaining temperatures between 58-62°C. The slurry was cooled to 50°C for 3 hours. The slurry was filtered at 50°C, washed with a mixture of methanol:2-propanol 1:1 (120 ml) and 2-propanol (120 ml) at 50°C, and dried in vacuum at 35°C to obtain Compound A citrate (45.1 g, 97%) as a solid. ¹ H-NMR (400 MHz, DMSO- d6 ) δ 10.89 (s, 3H), 7.33 (s, 1H ₎ , 7.10 (s, 1H), 7.07 (s, 3H), 7.04 (s, 2H), 6.44 (s, 2H), 3.91 (s, 3H), 3.34 (hept, J =6.7 Hz, 1H), 2.69 (d, J =15.3 Hz, 2H), 2.60 (d, J =15.3 Hz, 2H), 1.26 (d, J =6.9 Hz, 6H).

Stage 6b. Alternative Method for Preparation of Compound A Citrate

Alternatively, Compound A citrate is prepared by a process comprising the steps of:

To a suspension of Compound A citrate (4.5 g, 8.25 mmol) in methanol (72 ml) and 2-propanol (36 ml) at 50°C, a solution of Compound A free base ( 30.0 g, 84.9 mmol) and glycolic acid (22.6 g, 297 mmol) in 360 ml methanol at 50°C and a solution of citric acid (19.5 g, 101 mmol) in 180 ml 2-propanol at 25°C for 8 hours while maintaining the seed solution temperature at 60°C. After completion of the simultaneous addition, citric acid (13.2 g, 68.7 mmol) in 180 mL 2-propanol was added to the slurry over 8 h while maintaining the temperature at 60°C. The suspension was allowed to cool to 50°C and kept for 1 hour, filtered at 50°C, washed with a mixture of methanol:2-propanol 1:1 (2×120 ml) and 2-propanol (120 ml), and dried in vacuum at 35°C to obtain Compound A citrate (45.1 g, 88%) as a solid.

Crystallization in step 6a/6b provides Compound A anhydrous citrate form 1.

In another embodiment, Compound A Citrate Form 1 in methanol can be prepared via a saturated solution of Compound A Citrate Form 1 in methanol at 50°C. The solution is cooled naturally to ambient temperature or evaporated at ambient temperature to obtain crystals of compound A citrate solvate 1 in methanol. The XRPD profile for compound A citrate solvate 1 in methanol is presented in Figure 8.

In another embodiment, Compound A Citrate Solvate 1 in IPA can be prepared by adding an excess amount of Compound A Citrate Solvate 1 in methanol to the IPA in a closed container to form a slurry. The suspension is stirred at 5°C or lower until the shape transition is complete. Compound A citrate solvate 1 crystals in IPA can be collected by filtration and immediately measured by XRPD to prevent desolvation. The XRPD profile for compound A citrate solvate 1 in IPA is presented in Figure 9.

In another embodiment, Compound A Citrate Hydrate Solvate 1 in Methanol 1 can be prepared by adding an excess amount of Compound A Citrate Form 1 to a 3:1 (v/v) methanol:water mixture in a closed container to form a slurry. The suspension is stirred at room temperature. until the form transition is completed. Crystals of Compound A citrate hydrate solvate 1 in methanol can be collected by filtration and immediately measured by XRPD to prevent desolvation. The XRPD profile for Compound A citrate hydrate solvate 1 in methanol is presented in Figure 10.

In another embodiment, Compound A Free Base Form 1 can be prepared by adding an excess amount of Compound A Free Base Form 1 and 4-5 equiv of glycolic acid to a 3:1 (v/v) methanol:IPA mixture in a closed container to form a slurry. The suspension is stirred at 50°C until the shape transition is complete. Compound A glycolate Form 1 crystals can be collected by filtration at 50°C, washed with hot IPA at 50°C, and vacuum dried at 50°C. The XRPD profile of compound A glycolate form 1 is presented in Figure 11.

While the foregoing description describes the principles of the present invention, with examples provided for illustration only, the practice of the present invention covers all typical variations, adaptations and/or modifications that come within the scope of the appended claims. All publications, patents and patent applications cited herein are incorporated by reference in their entirety.

Claims (33)

1. A method for preparing the free base of compound A having the following formula: , comprising the step of converting 2-isopropylphenol into a co-crystal of 4-bromo-2-isopropylphenol and hemi-DABCO, as follows: ; further comprising the step of converting the co-crystal of 4-bromo-2-isopropylphenol and hemi-DABCO into a methoxyphenol compound being 2-isopropyl-4-methoxyphenol, as follows: ; further comprising the step of reacting 2-isopropyl-4-methoxyphenol with ClCH ₂ CN to produce the cyanoether compound, 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile, as follows: ; further comprising the step of converting the cyanoether compound, 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile, into the diaminopyrimidine compound, 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine: And further comprising the step of reacting 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine with ClSO ₃ H and then with NH ₄ OH to provide the free base of Compound A, 5-((2,4-diaminopyrimidine- 5-yl)oxy)-4-isopropyl-2-methoxybenzenesulfonamide as shown below: 2. The method according to claim 1, where the conversion into a cocrystal of 4-bromo-2-isopropylphenol and hemi-DABCO is carried out in the presence of NBS and MSA. 3. The method according to claim 1, where the conversion to 2-isopropyl-4-methoxyphenol is carried out in the presence of NaOMe and with CuBr as a catalyst. 4. The method according to claim 3, where the conversion is carried out in the presence of MeOH and DMF. 5. The method of claim 1, wherein the reaction to produce the cyanoether compound is carried out at a temperature of from about 20°C to about 60°C. 6. The method according to claim 1, where the conversion to 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine is carried out in the presence of potassium tert-butoxide in NMP and the cyanoether compound are in solution in ethyl formate and toluene. 7. The method according to claim 6, where the conversion to 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine is additionally carried out in the presence of guanidine hydrochloride. 8. The method according to claim 1, where the reaction between 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine and ClSO ₃ H is carried out in the presence of MeCN. 9. A method for preparing the free base of compound A, comprising the following steps: (a) converting 2-isopropylphenol to a cocrystal of 4-bromo-2-isopropylphenol and hemi-DABCO: ; (b) converting the cocrystal of 4-bromo-2-isoprophylphenol and hemi-DABCO to 2-isopropyl-4-methoxyphenol shown below in the presence of NaOMe: ; (c) reaction of 2-isopropyl-5-methoxyphenol with ClCH ₂ CN to give 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile: ; (d) converting 2-(2-isopropyl-4-methoxyphenoxy)acetonitrile to 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine: ; And (e) reacting 5-(2-isopropyl-4-methoxyphenoxy)pyrimidine-2,4-diamine with ClSO ₃ H and then with NH ₄ OH to give the free base of compound A, 5-((2,4-diaminopyrimidine- 5-yl)oxy)-4-isopropyl-2-methoxybenzenesulfonamide: . 10. The method of claim 9, further comprising converting the free base of compound A to citrate of compound A in the presence of glycolic acid and MeOH: . 11. The method according to claim 10, where the total yield of compound A citrate from 2-isopropylphenol exceeds 50%.

Images