FI107255B - O-[4-(4-Pyridyl)butyl]-N-butylsulphonyl-(L)-tyrosine, process for preparing it and its use for preparing corresponding O-[4-(4-piperidinyl)butyl] derivatives - Google Patents

Abstract

The invention relates to O-[4-(4-pyridyl)butyl]-N- butylsulphonyl-(L)-tyrosine of the formula I' <IMAGE>; to a process for preparing a compound of the formula I <IMAGE> by means of selectively hydrogenating a compound of the formula I', and to a process for preparing a compound of the formula I'.

Description

107255 O- [4- (4-Pyridyl) butyl] -N-butylsulfonyl- (L) -tyrosine, process for its preparation and use thereof for the preparation of the corresponding O- [4- (4-piperidinyl) butyl] derivative 5

BACKGROUND OF THE INVENTION In U.S. Patent Application Serial No. 750,647, filed Aug. 30, 1991, (= U. S. Patent Publication No. 914534, Pub.

March 28, 1992) describes fibrinogen receptor antagonists and methods for making fibrinogen receptor antagonists. In particular, a compound of formula ho2 cr "'' Inhs2 n-Bu is prepared according to a 11 step process which involves the formation of a potentially hazardous NaH / DMF to form an ether which requires purification by chromatography.

Singerman et al. . J. Heterocyclo Chem. (1966), 3, 74, describes a process for the preparation of 4- (4-pyridinyl) butyl chloride, which requires six steps. 25 weeks. The process of the invention requires only one step to prepare this compound.

Solar et al. . J. Orq. Chem. (1966), 31, 1996 describe O-alkylation of tyrosine. There are no precedents for the selective O-alkylation of N-sulfonylated tyrosine described in this application.

Summary of the Invention

The invention relates to the synthesis of a compound of the formula / = 1, 1 -CCH 2) nrO-yT |

COjH

For the preparation of crude compounds wherein R 1 is a six membered saturated or unsaturated heterocyclic ring containing one or two heteroatoms wherein the heteroatoms are N or NR 6 wherein R 6 is H or C 5 alkyl, m is an integer from 2 to 6, and R4 is aryl, C1-4 alkyl or C4.10 aralkyl.

Detailed Description of the Invention

The invention relates to a compound of the formula 10c2h ssJJAS1A ', iNHSO2C4H915, and pharmaceutically acceptable salts thereof.

The pharmaceutically acceptable salt is preferably the hydrochloride salt.

The invention also relates to a process for the preparation of the aforementioned compound and pharmaceutically acceptable salts thereof, wherein the compound of the formula

H CO 2 H

1 H 2 X 4 H 2 O 2 C 4 H 9 is phenol-O-alkylated with a compound of formula 30 Q 2 in aqueous alkali hydroxide in a highly polar aprotic solvent.

3, 107255

In a preferred embodiment, the phenol-O-alkylation is carried out in a highly polar aprotic solvent which is 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone or methylsulfoxide in 3 N KOH ° C.

The invention further relates to a compound

C02H

The use of NHSO2C * H310 or a pharmaceutically acceptable salt thereof and the pharmaceutically acceptable salts thereof by the selective hydrogenation of the above compound of formula 15 15 / = ν ^ '^ ^ γγ (( f-NHSO2C4H9 20 or a pharmaceutically acceptable salt thereof.

The compound of the invention is thus useful as a starting material in the above-described application.

The invention relates to a multistep process for the preparation of N- (n-butylsulfonyl) -O- [4- (4-piperidyl) butyl] tyrosine of the formula ...

L · n

s — 1 H 11 O

107 · · 4 107255 or pharmaceutically acceptable salts thereof. Compounds (I) are antagonists of the fibrinogen receptor.

This multistep process for the preparation of compounds (I) comprises the following steps: a)

1) BSTFA

H ° - <\ //} ~ -7-- ^ CO, - 2) pyr / R 4 SO 2 Cl ± 3) water. KHSO ^ 0-1) "O = W ^ H502R4 15 N-" co2h ¢ 1-2) wherein the tyrosine or tyrosine derivative (1-1) is subjected to bis-trimethylsilyl trifluoroacetamide (BSTFA) mediated sulfonylation using R4SO2Cl, wherein R 4 is n-butyl in acetonitrile to give the corresponding sulfonamide (1-2), 25 b), 1) nBuLi.

P -ch3 -R1CCH2) -C1-2) BrCCH3-4Cl0-3) (1-4) 30 Methylated R1 (1-3) is reacted with nBuLi to quench with a straight chain alkyl group having Br at one end and Cl at the other end to give R 1 (CH 2) mCl (1-4) where R 1 is pyridyl and m is 4,35 · 5,7 5 5 5 5 5 5 5 5 5 5 5 5 - 5 - (nhsosr 4 + R t CCH 2) n F 1 CO 3 H 1 - 4 ) Ä r'cch2) "-r & f *" 0 * - * N— 'co2h

Solvent C1-5) 10 (1-2) is added to (1-4) and subjected to phenol-O-alkylation in alkali hydroxide, preferably 3 N KOH, in polar aprotic solvents such as 1,3-dimethyl-3,4 , 5,6-Tetrahydro-2 (1H) -pyrimidinone (DMPU), Methylsulfoxide (DMSO), N-Methyl-pyrrolidinone (N-MP), 1,3-Dimethyl-2-imidazolidinone (DMEU) , tetramethylurea (TMU) or Ν, Ν-dimethylacetamide (DMA), preferably in highly aprotic solvents such as DMPU or DMSO, more preferably DMSO, preferably at about 65 ° C.

Selective hydrogenation is achieved by use

Pd / C in acetic acid: tt = \ - rm Ί 0 _ / ^ = V'V'wlsc * K '' 5 Pd / c.

25 t h acoh t 2) HCl HN ^) - C CH2) m- o—

C02H

HCl wherein R4 is n-butyl and m is 4.

The synthesis utilizes trimethylsilyl groups as a temporary protection that allows selective sulfonylation to be carried out in a single vessel synthesis using L-tyrosine itself.

Preferably, 1) 4-picoline is used in the synthesis as the latent form of piperidine, which eliminates the need for a protecting group on three carbon atoms, and formation of a shared homolog with 3-bromo-1-chloropropane via 4-picolyllithium, 2) temporary bis-( , Ο 'silylation with BSTFA to provide selective N-suI-phosphorylation with n-BuSO 2 Cl to give the sulfonamide in high yield and free from racemization, in one step, 3) selective high yield formation of phenyl ether using a simple reagent: 15 alkaline bases (NaOH or KOH, preferably 3 N KOH), DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H-pyrimidinone) or DMSO, and 4) pyridine ring selective hydrogenation in the presence of a tyrosine ring using Pd / C in acetic acid.

The synthesis of the invention employs inexpensive starting materials and reagents and avoids prior art process steps employing potentially hazardous NaH / DMF mixtures to induce ether formation, which necessitates chromatographic purification. No such chromatographic purification is required for the synthesis of the present invention.

Example 1

The following was prepared

i.i \ CO I

hd2ct '' * jhso2- / ^ 35 compound. The four process steps are outlined below:. · · 7 107255

Lie 1 5 1) BSTFA ^ 3δ10ν ^ Ν

xx - XX

10 -02C ^ "" "NH3 * Μ ^ ίΟ, Ο

HO

2) pyr / n-BuS02Cl jT

3) 15% KHSO4 · H2O C NH-SO2 (n-Bu) B4% 2 Step 2. σ - [cr- 2) Br (CH 2) 3 Cl 3) HCl XX 3 VaPa base 30 92% 4 HCl salt 1072 ^ 5

8 I

Step 3 5

1) 3N KOH, DM 5 O at 65 ° C

+ 3 2) Crystallizations 80% x 77% ”cr ^ tx 4 H02 C '^ ////// NH- S 02 ζ n- Bu) 15

Step 4

1) H2Pd / C, Ac OH

4 --- 2) water HCl 94% 20 HN 4 O

HCl J

H2 ° 5 H02C- ^ Xnh-S02: 25 2 ί e 9 107255

Step 1: Nn-BuSO 2 - (L) Tyrosine (2) A 50 L four neck round bottom flask equipped with a mechanical stirrer, condenser, nitrogen inlet, HCl trap, heating unit and 5 thermometer probes was purged with nitrogen overnight and it was then charged with (L) -tyrosine (1040 g, 5.74 mol) 1, CH 3 CN (20.8 L), N, O-bis-trimethylsilyl trifluoromethylacetamide (3103 g, 12.054 mol). The suspension was heated at 85 ° C to mild reflux for 10 hours. The resulting clear solution, which, based on 41 NMR, was * predominantly O, O'-bis-trimethylsilyl- (L) -tyrosine, was cooled to 40 ° C and pyridine (544.84 g, 6.888 mol) and -BuSO 2 Cl (989.0 g, 6314 mol) was added slowly over 30 minutes. The reaction mixture was then stirred at 70 ° C for 3 hours and at room temperature for 14 hours. Almost all of the solvent was removed in a batch concentrator and the resulting oily residue was treated with 15% KHSO 4 (20.8 L) and stirred vigorously for 1 hour. The mixture was extracted with i-propyl acetate (3x20 6.2 L). The combined organic layer was treated with Ecosorb ™ S-402 (3.12 kg) and stirred at room temperature overnight. The Ecosorb ™ was removed by filtration and the filter cake was washed with i-propyl acetate (4.2 L). The filtrate was evaporated to dryness and the resulting yellow oil was dissolved in hot. 25 mL of EtOAc (45-50 ° C, 1.25 L). Hexane (3.74 L) was added slowly to the stirred solution and the resulting slurry was stirred at room temperature overnight. The solid was collected by filtration and the filter cake was washed with EtOAc / Hexane (0.2 L / 1.89 L). After drying in vacuo, 3057 g (84%) of 2 were obtained as a white solid.

HPLC experiment: 99.6 A%, RT = 7.55 min; Zorbax RX-C8 column, 4.6 mm x 25 cm ID, 220 nm, 1.5 ml / min, linear gradient from 10 to 90% A over 10 minutes, A = CH 3 CN, 10 107255 B = 0 , 1% aqueous H 3 PO 4. Sp. 125-16.5 ° Z, [α] 25 D = -25.2 ° (c 0.80, MeOH), MS (EI) m / z 301 (M +) 1 H NMR (CD 3 OD) δ 0.81 (t, J = 7.2 Hz, 3H), 1.24 (m, 2H), 1.45 (m, 2H), 2.61 (t, J = 7.9 Hz, 2H), 2.73 (ABX , JM = δ 13.8 Hz, JH = 9.8 Hz, 1H), 3.07 (B from ABX, JBA = 13.8 Hz,

Jbx = 4.7Hz, 1H), 4.07 (X from ABX, JXA = 9.8Hz, JXB = 4.7Hz, 1H), 6.72 (d, J = 8.4Hz, 2H) ), 7.10 (d, J = 8.4 Hz, 2H).

13 C NMR (CD 3 OD) δ 13.9, 22.5, 26.5, 39.1, 54.1, 59.5, 116.3, 129.2, 131.6, 157.5, 175.3.

Analysis: Calculated for C13H1905SN: C 51.81, H 6.35, N 4.65, S 10.64 Found: C 51.73, H 6.28, N 4.60, S 10.82.

Step 2: 4- (4-Pyridinyl) butyl chloride HCl salt (4) In the preparation of 4- (4-pyridinyl) butyl chloride, it was necessary to heat 4-picoline and n-BuLi at 40 ° C for 2 hours to provide complete n-BuLi consumption. If not heated, a portion of the unreacted n-BuLi is transmetallized with 3-bromo-1-chloropropane to give n-butyl bromide which is then reacted with 4-picolyllithium to give 4-per-ylpyridine. The opposite addition of 4-picolyllithium to 3-bromo-1-chloropropane at £ -65 ° C was critical to avoid the bis-alkylation product, 1,5-. Formation of bis- (4-pyridinyl) pentane. Complete removal of THF and water were important for the smooth formation of the HCl salt because THF reacts with HCl to give 4-chlorobutanol which increases the solubility of the HCl salt and reduces its yield, and the presence of water makes filtration of the HCl salt very difficult due to the rubbery nature of the hydrate. Taking these precautions into account, the 4- (4-pyridinyl) butyl chloride hydrochloride salt (4) was prepared in 92% yield and 98% purity.

• · 11,107,255 22 l four-neck round bottom flasks equipped with a mechanical stirrer, a condenser, a side-feed addition funnel, and a thermometer probe were purged with nitrogen overnight. THF (4.1 L) and 5 4-picoline (838.2 g, 9.0 mol) were added and the batch was cooled to -70 ° C. n-Butyllithium (7.02 L, 1.41 M) in hexane was added slowly while maintaining an internal temperature of -50 ° C.

It took about 1 hour to add 10 orange-colored solutions with little precipitate. When the reaction was carried out at 0 ° C, a significant decrease in yield and an increase in impurity formation was observed.

The dry ice bath was removed and the batch was allowed to warm to room temperature and then heated at 40-45 ° C for 2 hours.

Heating at 40-45 ° C was the optimum temperature for performing complete lithiation of 4-picoline without decomposition. Without this heating, the unreacted 20 n-BuLi transmetallated with 3-bromo-1-chloropropane to give 1-n-butyl bromide. It then reacted with 4-picolyl lithium to give 4-pentylpyridine which could not be separated from the desired product. Heating at higher temperature resulted in significant decomposition.

THF (4.1 L) was added to dissolve the 4-picolyl lithium slurry to give a strong orange solution. The batch was cooled to 0 ° C, then carefully added through a polypropylene tube using a 30 pneumatic pump to a -75 ° C solution of 3-bromo-1-chloropropane in THF (1.5 L) in a dry 50 L three neck in a round-bottomed bottle fitted with a mechanical stirrer, a nitrogen inlet and outlet, and a thermometer probe, while maintaining an internal temperature of 35 ° C-65 ° C.

The reaction of 4-picolyllithium and 3-bromo-1-chloropropane was exothermic. It was very critical to keep the internal temperature below -65 ° C to avoid reaction of the desired product with 4-picolyllithium to form 1,5-5 bis- (4-pyridinyl) pentane. The addition took about 2 hours.

The batch was allowed to gradually warm to 0 ° C overnight and then worked up by adding 9 L of water, stirring for 10 minutes, separating the layers and extracting the 10 aqueous layer with i-propyl acetate (5 L). The combined organic layers were concentrated in vacuo at 40 ° C to one third of the original volume in a batch concentrator fitted with two additional stoppers between the tank and the internal vacuum line, then i-propyl acetate (6 L) was added and again concentrated to one third of the original volume.

Complete removal of THF and water with i-propyl acetate azeotrope was critical to the smooth formation of the HCl salt. THF reacts with HCl to give 4-chlorobutanol, which increases the solubility of the HCl salt and reduces its yield. The presence of water gives a gummy solid which makes filtration of the HCl salt very difficult.

The batch was cooled to -10 ° C and treated. Followed by a solution of 9.0 moles of HCl in 3 L of 3a i-propyl acetate.

HCl in i-propyl acetate was prepared the day before by bubbling HCl gas with i-propyl acetate: Ln at -10 ° C until 9.1 moles of HCl had accumulated (30% by weight) and stored at room temperature. The loss of HCl was about 1%. Addition of HCl to the batch was exothermic. The temperature rose to +35 ° C.

After stirring for 1 hour, the resulting slurry was transferred through a polypropylene hose using a pneumatic-35 pump to a nitrogen-filled, sealed coarse filter • ♦ 13 107255 data funnel that was placed in a vacuum. The solid was washed several times with THF (4.5 L total volume) and dried under a stream of nitrogen under reduced pressure to give 1710.4 g (92%) of 4 as a white solid.

HPLC assay: 98% area; RT = 2.40 min; Zorbax RX Column, 4.6mm x 25cm ID, 220nm, 1.5ml / min, Isocratic 50% / 50% A / B, A = CH 3 CN, B = 0.01M Decanesulfonic Sodium 0.1% aqueous H 3 PO 4. For 4-picoline, RT = 1.7 min.

10 M.p. 119-120.5 ° C, MS (CI) m / z 169 (M + - HCl).

1 H NMR (CD 3 OD) δ 1.79-2.00 (m, 4H), 3.01 (t, J = 7.3 Hz, 2H), 3.36 (t, J = 6.1 Hz, 2H) , 8.00 (d, J = 6.7 Hz, 2H), 8.75 (d, J = 6.7 Hz, 2H), 13 C NMR (CD 3 OD) δ 28.1, 33.0, 36.1 , 45.3, 128.6, 142.2, 15,166.1;

Analysis: Calculated for C 9 H 13 NCl 2: C 52.45, H 6.36, N 6.80, Cl 34.40.

Found: C, 52.22; H, 6.40; N, 6.51; Cl, 34.11.

Step 3: Formation of Phenyl Ether 5 in a 20 KOH mediated coupling reaction with urea based solvents (DMPU, DMEU, TMU) and DMSO gave the best experimental yields, 85-96%. DMA and N-MP gave test yields slightly above 80. DMPU was found to be the optimal solvent to minimize the formation of the bisalkylated product. 25 (1%), while DMSO gave the largest amount of bisalkylated product (2%).

> «T 14 107I> 55 H0 5 * fTYv ^ cl HOC ^ '^ NH-SOjCn-Bu) N' ^ '2 1 HC1 3

3N KOH, 75 ° C

10 Solvent N '^ T

H 2 CO 2 "" "NH-SO 2 (n-Bu) 15 ho 2 C SO 2 (n-Bu)

A direct diffusion process for the coupling product was developed, which avoided the large use of methylene chloride for extraction. Treatment and filtration of the water-diluted reaction mixture Ecosorb followed by adjustment of the pH to its isoelectric point (pH 4.8) provided hydrocarbon 80% yield in 93-95 A% purity. Subsequent pH adjustment (pH 5.5) and two rinses in 10% AcOH / water removed unreacted n-BuS0; - Tyr and bis impurity to give 99+ A% pure beige solid in 77% isolation yield. If the bis impurity is still present in a non-flammable amount (? 0.1 A%), further rinsing in 10% AcOH / water should be performed. Alternatively, the pH may be adjusted to 5.5 rather than pH 4.8 after treatment with Ecosorb and filtration so that the precipitation of the product and the elimination of n-BuSO 2 -Tyr are combined in the same step. This eliminates a single insulation.

15 107255

Formation and purification of ether

Step 3a: A 50 L four neck round bottom flask equipped with a mechanical stirrer, a condenser, a nitrogen inlet, and a thermometer probe was charged with Nn-butanesulfonyl (L) tyrosine (1386.3 g, 4.6 mol). , 4- (4-pyridinyl) butyl chloride.HCl (1137.8 g, 5.52 mol) and DMSO (16.56 L). Under vigorous stirring, 3N aqueous KOH (5.52 L, 10 16.56 mol) was added over 15 minutes.

The mixing of 3 N aqueous KOH with the rest of the material was slightly exothermic. The temperature was maintained between 30-40 ° C during this operation using cooling water.

Potassium iodide (7.64 g, 46.0 mmol) was added and the mixture was heated at 65 ° C for 24 hours and 60 ° C for 12 hours (or until the reaction was 95% complete as determined by HPLC analysis). ). After cooling to room temperature, the mixture was diluted with 0.25 N NaOH (46 L) and extracted once with t-butyl methyl ether (23 L). The aqueous layer was treated with Ecosorb S-402 (2.0 kg) and Nuchar SA (150 g) and the resulting mixture (~ 67 L) was mechanically stirred for 1 hour. The mixture was filtered through a coarse porous sintered glass funnel and the filter cake washed. 25 were made with 69 of D1 water. The combined filtrate ("136 L) was placed in a 200 L vessel equipped with a pH meter and mechanical stirrer. With vigorous stirring, NaCl (2.5 kg) was added, stirred for 30 minutes and then 50% was added. aqueous acetic acid (~ 4 L) until the pH was 4.80 and stirring was continued for 2-3 hours.

The pH was initially about 13.3. At a pH of about 4.8, a slightly brown gum formed with a beige solid. An extended 16,107,255 mixing times were required for complete conversion to crystalline material. If the pH is below 4.8, dilute NaOHru should be added.

The resulting slurry was filtered through a coarse-porous sintered glass funnel and the cake washed with 23 L of D1 water. The iron product was dried at 40 ° C under an internal vacuum at positive nitrogen pressure for 20 hours to give 1599 g (80%) of a brown to beige solid with 95% w / w purity.

The main impurities are the tyrosine starting material 10 (0.75 A%) and the bisalkylated product (2.75 A%). The mother liquors and the washing solutions combined contained about 10% product by LC analysis. HPLC experiment: product 5, 96% area, RT = 6.76 min, tyrosine 1, RT = 7.66 min, bis-alkylated product, RT = 6.20 min; Zorbax RX-C8 column, 4.6 mm x 25 cm 2, 15 220 nm, 1.5 ml / min, linear gradient from 10 to 90% A over 10 minutes, A = CH 3 CN, B = 0.1 % aqueous h3po4.

Step 3b:

The solid was further purified to 99.4 A% purity by the following methods.

Removal of both impurities at this stage is critical before the substance is subjected to hydrogenation because hydrogenated bis impurity and tyrosine 1 are extremely difficult to remove.

. To a 50 L RB flask equipped with a thermometer probe and addition funnel was charged crude 5 (1.50 kg, 3.45 mol) and 0.25 N NaOH (19.33 L, 4.83 mol). ). After complete dissolution of the solid by gentle heating at 60-70 ° C for a few minutes, 0.25 N NaHCO 3 (4.83 L, 1.21 mol) is added. The solution was cooled to room temperature and the pH adjusted to 7 by the slow addition of 1 N HCl (~ 2.65 L). The pH of the solution was further lowered to 5.5 by slowly adding 0.5 N HCl (~ 5.10 L). Stirring was continued for 1 hour, after which the slurry-35 was slurried through a coarse funnel covered with a · · •; «17 107255 with" shark "sheet of paper and a polypropylene pad (10 μπι) and the cake was washed with DI-H2O (10 L). The solid was dried under an internal vacuum under a stream of nitrogen to give 1.42 kg of a beige solid.

This treatment removed most of the tyrosine I. At this point, the sample should contain ≤ 0.1% by weight of 1. Successive rinses in 10% AcOH / H 2 O removed the bis-alkylated impurity. Filtration of solid slurry using an M-porous sintered glass funnel is not recommended due to the extremely low flow rate. A C-porous sintered glass funnel should not be used due to low throughput.

The solid was suspended in 10% acetic acid in water (1 g / 15 mL) and heated with steam to 80 ° C for 15 minutes, then allowed to cool slowly to room temperature overnight. After stirring for 18 hours, the solid was collected on a coarse funnel covered with a "shark" sheet of paper and a polypropylene filler (10 μιη), washed with D1 water (20 L), and dried partially using an internal vacuum and a stream of nitrogen for several hours. I drive. This rinse was repeated and the solid was washed with D1 water (20 L), methanol (3 x 41) and dried in vacuo at 35 ° C under a stream of nitrogen for two days. 1.16 kg (77%, 62% by weight) of 25 dirty white solids were obtained.

• ·

Subsequent research showed that methanolic washes were not necessary. About 5% of the material was lost in this operation. If the level of the bis-alkylated impurity is greater than 0.1%, a second acetic acid-30 po / water rinse should be performed.

HPLC experiment: product 5, 99.8% area, RT = 6.76 min, tyrosine 1, RT = 7.66 min, bis-alkylated product, RT = 6.20 min; Zorbax RX-C8 column, 4.6 mm x 25 cm ID, 220 nm, 1.5 ml / min, linear gradient from 10 to 90% A over 10 minutes, A = 35 CH 3 CN, B = 0.1 % aqueous H3PO4.

♦ · ·· 18 107255

Sp. 137-138 ° C, [α] 25 D = -14.7 ° (c 0.91, MeOH), MS (Cl) m / z 435 (MH +).

1 H NMR (CD 3 OD) δ 0.86 (t, J = 7.3 Hz, 3H), 1.33 (hex, J = 7.3

Hz, 2H), 1.68 (m, 2H), 1.83 (m, 2H), 2.82 (m, 2H), 3.06 (δ from ABX, Jm = 13.9 Hz, JM). = 6.3 Hz, 1H), 3.16 (B from ABX, JBA = 13.9 Hz, Jbx = 5.0 Hz, 1H), 3.90 (t, J = 5.7 Hz, 2H) , 4.32 (X from ABX, Jxa = 6.3 Hz, J = 5.0 Hz, 1H), 6.72 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 6.3 Hz, 2H), 8.19 (d, J = 6.3 Hz, 2H), δ 13 C NMR (CDCl 3) δ 13, 5, 21.5, 25.4, 26.5, 28.6, 35.1, 38.9, 53.0, 57.9, 67.0, 114.3, 125.0, 128.7, 130.8, 145.3, 155.8, 157.7, 175.0,

Analysis: Calculated for C 22 H 30 O 5 SN 2: C 60.81, H 6.96, N 6.45, S 7.38 Found: C 60.53, H 6.88, N 6.26, S 7.65.

Step 4: Hydrogenation

Finally, selective hydrogenation of the pyridine ring to the piperidine ring was carried out using 5 wt% 10% Pd / C in AcOH at 60 ° C to give the desired product 20 purely without reduction of the phenol ring. Hydrogenation was closely monitored by HPLC and 1HNMR at close to theoretical hydrogen uptake. As soon as the consumption of starting materials is complete, hydrogenation should be stopped. Filtration of the reaction mixture, evaporation of acetic acid followed by crystallization of the product from 6% AcOH / water gave 6 free bases. Traces of starting material were removed by rinsing in 6% AcOH / water. Treatment of the free base with 2.5 vol.% Concentrated HCl (2.1 eq.) In i-propyl acetate gave 5 (hydrc-30 chloride) monohydrate in 94% overall yield as a white to off-white solid> At a purity of 99.7 A%, with two impurities each at a level of 0.1 A%.

«· 19 107255

Step 4a:

Phenyl ether 5 (1.051 kg, 2.42 mol) and 10% Pd / C (53 g, 5 wt.%) In acetic acid (14 L) were hydrogenated in a 5 gallon stainless steel vessel at 40 psi: and 60 ° C. The reaction was sampled once an hour near the end of the reaction and stopped as soon as complete consumption of starting material was observed (5.5 hours). The longer reaction time resulted in the formation of impurities.

A 10 mL sample was filtered through a thin pad of Solka-Flock (washed with acetic acid), washed with acetic acid, and evaporated to dryness in a rotary evaporator. The resulting oil was treated with a few milliliters of water to precipitate a solid and then returned to the rotary evaporator to dry. The resulting white solid was analyzed by 1HNMR (CD30D) and HPLC. The whole process took about 30 minutes to complete. In 1HNMR (CD3OD), the complete disappearance of the pyridine peaks at 7.32 and 8.40 ppm indicates complete consumption of the starting material. HPLC (using the linear gradient conditions described above) was used to monitor the amount of impurity at RT = ~ 8.9 minutes, this impurity increasing significantly with longer hydrogenation. The peaks of the starting material and the product came very close to each other, with retention times of 6.76 and 6.80, respectively.

The reaction mixture was filtered through Solka-Flock (820 g, washed with 5 L acetic acid) and washed with acetic acid (14 L). The filtrate was concentrated to a thick oil containing about 1 kg of acetic acid in a batch concentrator fitted with two additional drains between the collection tank and the internal vacuum line at 60 ° C (about 5 hours). D1 water (15 L) was added to a concentration of 1 g / 15 mL of 6% acetic acid in water and the resulting slurry was stirred for 18 hours at room temperature. The solid was collected in a Buchner funnel covered with a shark membrane • 10 725255 peril strip and polypropylene filler (10 μπι), washed with DI water (10 L) and dried under vacuum in a nitrogen jet to give 1.03 kg (97%) ) white solid.

If the amount of 5 is even higher than the reference value, 5 should be rinsed again with 6% acetic acid in water (1 g / 15 ml) (at least 6 hours). A typical yield is about 92% with a 5-fold reduction of 3. HPLC experiment: 6. Free base, 99.5%, RT = 6.94 min, 5. RT = 6.72 min, 1 RT = 7.39 min; Zorbax RX-C8 column, 4.6 mm x 10 25 cm ID, 220 nm, 1.5 ml / min, linear gradient from 20 to 70% A over 12 minutes, A = CH 3 CN, B = 0.1% aqueous H3PO4. Sp. 223-225 ° C.

1 H NMR (CD 3 OD) δ 0.88 (t, J = 7.3 Hz, 3H), 1.33 (m, 6H), 1.58 (m, 5H), 1.76 (m, 2H), 1 , 81 (m, 2H), 2.77 (t, J = 7.5, 2H), 2.80 (m, 1H), 2.88 (m, 2H), 3.03 (ABB from B) , JBA = 13.9 Hz,

Jbx = 4.6 Hz, 1H), 3.30 (m, 2H), 3.90-4.0 (m, 3H), 6.80 (cj, J = 8.5 Hz, 2H), 7, 18 (d, J = 8.5 Hz, 2H). |

Found: C, 59.98; H, 8.40; N, 6 Found: C, 59.98; H, 8.40; N, 6.34; 40, S 7.24. j

Step 4b: A 6 L free base (316.0 g, 0.717 mol) and isopropyl acetate (9.5 L) were charged to a 22 L three-neck RB flask equipped with a mechanical stirrer, nitrogen inlet and addition funnel. The mixture was stirred at room temperature (19 ° C) for 10-15 minutes, after which concentrated hydrochloric acid (120 ml) was added dropwise. The addition took about 40 minutes and the temperature remained at 19 ° C during the addition. The mixture was then stirred at room temperature (19 ° C) for a further 5 hours.

The product was isolated by filtration under a nitrogen atmosphere. The solid product was washed with isopropyl acetate (2 x 11) and aspirated under nitrogen overnight to give 6 µl HCl monohydrate (348 g) in 98% yield.

I · 21 107255 HPLC experiment: 6.99.8%, RT = 6.79 min; Zorbax RX-C8 column, 4.6 mm x 25 cm ID, 220 nm, 1.5 ml / min, linear gradient from 10 to 90% A over 10 minutes, A = CH 3 CN, B = 0.1 aqueous H 3 PO 4%, or L-700,462, 99.8 5%, RT = 6.94 min; 5, RT = 6.72 min; 1, RT = 7.39 min; Zorbax RX-C8 column, 4.6mm x 25cm ID, 220nm, 1.5ml / min, linear gradient from 20-70% A over 12 minutes, A = CH3CN, B = 0.1% aqueous H3P04. Chiral HPLC: L-isomer,> 99.9%, RT = 10 min; D-isomer, <0.1%, RT = 8.5 min; ULTRON-ES-OVM column, 4.6 mm ✓ x 25 cm, 5 m, "guard" column, 220 nm, 0.7 ml / min, iso-chromate, 90% buffer (6 g ammonium formate, pH adjusted to 4.1 L with formic acid), 10% MeOH.

15 Spl. 87-88 ° C, m.p. 131-132 ° C, [α] 25 D = -4.4 ° (c 0.92, MeOH), 1 H NMR (CD 3 OD) δ 0.84 (t, J = 7.3 Hz, 3H), 1.23 (hex, J = 7.3 Hz, 2H), 1.30-1.70 (m, 9H), 1.75 (m, 2H), 1.95 (m, 2H), 2.64 (t, J = 7.4, 2H), 2.77 (A of ABX, JAB = 13.9Hz, JAX = 9.8 20Hz, 1H), 2.95 (m, 2H), 3.11 (B of ABX) , JBA = 13.9 Hz, JBX = - 4.6 Hz, 1H), 3.47 (m, 2H), 3.95 (t, J = 6.2 Hz, 2H), 4.09 (X ABX of JXA = 9.8 Hz, JXB = 4.6 Hz, 1H), 6.84 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.6 Hz, 2H) ).

13 C NMR (CD 3 OD) δ 14.0, 22.5, 24.0, 26.5, 30.0, 30.4, 34.8, 25. 36.8, 39.0, 45.3, 54.1 , 59.4, 68.7, 115.5, 130.4, 131.7, 159.6, 175.2.

IR (Nujol, cm -1) 3520, 3208, 3166, 2800-2300, 1727, 1610, 1595, 1324, 1256, 1141, 1119, 829.

HRMS calcd for C22H37N2O5S 441.2423, found 441.2423 (MH + -30 H2O-C1)

Analysis: Calculated for C 22 H 39 O 6 ClN 2 S: C, 53.37; H, 7.94; N, 5.66; Cl, 7.16; S, 6.48.

Found: C, 53.56; H, 8.04; N, 5.62; Cl, 7.36; S, 6.53. 1 ·> «

Claims (6)

1. A compound of the formula: 5 ° C 2 H lsc 3 As 2 NH 4 SO 2 C 4 H 9 and pharmaceutically acceptable salts thereof. ίο A compound according to claim 1, wherein the salt is a hydrochloride salt. 3. A process for the preparation of a compound of the formula c NHSO2C4Hs is subjected to phenol-O-alkylation with a compound having the formula 30 in an aqueous acyl hydroxide in a highly polar aprostatic solvent. 4. A process according to claim 3, characterized in that the phenol-O-alkylation is carried out in a highly polar aprotic solvent, which is 1,3-107,55 dimethyl-3,4,5,6-tetrahydro-hydrochloride. 2 (1H) -pyrimidinone or methylsulfoxide, in 3N KOH at a temperature of about 65 ° C. 5. Use of the compound n \ ° 2H \ -yy 1 4 4> -> - Nhso acceptable site thereof, characterized in that the aforementioned compound is 0 ° to> 3-25 or a pharmaceutically acceptable site thereof is selectively hydrogenated. Use according to claim 5, characterized in that the starting compound is in the form of a hydrochloride salt. «• · '· ·