CS200168B2 - Method of producing substituted carboxanide-triphenyl-phosphonium-bromide - Google Patents

Description

The present invention relates to a process for the manufacture of substituted carboxamide triphenylphosphonium bromides which are useful as starting materials for the preparation of novel analogs of naturally occurring prostaglandins. In particular, the invention relates to the production of starting materials for the preparation of novel N-substituted prostaglandin carboxamides.

A process for the preparation of a substituted carboxamide triphenylphosphonium bromide of the formula II

Br ® F 2 C ₆ H _{s) 3} PC H _of CH _of CH _of CH _of cnhr (II) (II) wherein

R is C 2 -C 8 alkanoyl or C 4 -C 8 cycloalkanoyl, aroyl or substituted C 7 -C 11 aroyl in which the substituent is methyl, halogen or methoxy, C 1 -C 7 alkylsulfonyl, thiophene 2 sulfonyl, benzenesulfonyl or toluenesulfonyl, characterized in that the compound of formula X is present

O

II

Br — CH2 — CH2 — CH '- CH2 — C — NHR (X) where

R is as defined above and reacted with triphenylphosphine.

It is to be understood that the term "alkyl" as used herein includes branched chain alkyl groups as well as straight chain alkyl groups.

The compounds produced by the process of the invention are used in the synthesis of the prostaglandin derivatives shown in Reaction Schemes A and B below, wherein THP is 2-tetrahydropyranyl and R is as defined above.

Reaction Scheme A

(Π ())

Reaction Scheme B

W> 3

O ll

PCH2CH2CH2CH2CH3 CNHR->

(Knows) ()

The use of the compound of formula II is shown in Reaction Scheme A, wherein the hemiacetal of formula I is reacted with a novel reagent of formula II to give the product of formula III which is the N-substituted carboxamide analogs of bls-THP-PGF ' _2k .

A further use of the compounds of formula (II) is shown in Reaction Scheme B, wherein the hemiacetal of formula (VI) is reacted with a novel reagent of formula (II) to give the product of formula (VII), the N-substituted carboxamide analogues of bis-THP ether -dihydro-PGF _2ff .

The following examples illustrate and do not limit the scope of the appended claims. All temperatures are in degrees Celsius and the melting and boiling points are uncorrected.

Example 1

A stirred solution of 100 g (0.55 mol) of 5-bromvaleramide, 62.4 g (0.61 mol) of acetic anhydride and 5.4 g (0.055 mol) of concentrated sulfuric acid was heated on a steam bath under nitrogen for 1.5 hours (internal The mixture is then cooled to room temperature and diluted with 250 ml of water, the resulting granulated precipitate is filtered off and diluted with 600 ml of methylene chloride, and the solution is washed with 100 ml of saturated sodium bicarbonate solution, 100 ml of saturated brine solution, dried over anhydrous. magnesium sulfate, treated with Darco and filtered, hexane was added to effect crystallization to give 64.8 g (53.0% yield) of N-acetyl-5-bromovalerainide, m.p. 88-90 ° C.

The IR spectrum (CDCl 3) of the product shows absorption bands at 5.72 µm (attenuated strong), 5.8 μΐη (strong) attributed to carbonyl groups.

The NMR spectrum (CDCl 3) shows a triplet center at 3.46 δ (J = 6 cps) for

BrCH2, triplet center at 2.63 δ (J = 6 cps) for

CHzC—,

O singlet at 2.36 δ for

CHsC—

II o

a multiplet at 1.67 to 2.17 δ for —CH2 — CH2 — and a broad singlet at 9.00 to 9.58 δ for —N — H.

A solution of 50.5 g (0.227 mol) of N-acetyl-5-bromvaleramide and 64.6 g (0.274 mol) of triphenylphosphine in 250 ml of xylene was refluxed under nitrogen for 4 hours and then allowed to cool to room temperature. The xylene is decanted from the resulting oil, which is recrystallized from methylene chloride and ethyl acetate. Colorless needles of [4- (acetylaminocarbonyl) butyl] triphenylphosphonium bromide (50.2 g, 45.7% yield), m.p. 164-165 ° C, are obtained.

The IR spectrum (CHCl3) of the product shows absorption bands at 5.72 μπι (attenuated strong) and 5.80 μm (strong) attributed to carbonyl groups.

The NMR spectrum (CDCl 3) shows a multiplet at 3.42 to 3.98 δ for P-CH 2, a multiplet at 2.44 to 2.96 δ for

CH2CNH—,

O singlet at 2.23 δ for

O

II ch ₃ c, multiplet at 1.48 to 2.13 δ for CH 2 CH 2 and multiplet at 7.60 to 8.14 for aromatic protons.

Example 2

A mixture of 10.0 g (55.6 mmol) of 5-bromvaleramide propionic acid and 5 drops of concentrated sulfuric acid was heated in an oil bath at 110 ° C for 5 hours. The mixture was then cooled and diluted with 50 mL of water. The aqueous layer was washed three times with methylene chloride and the combined organic extracts were dried over anhydrous magnesium sulfate and evaporated to give a semi-solid. The crude semi-solid was purified by chromatography on silica gel using benzene and then chloroB form as eluates. The desired N-propionyl-5-bromvaleramide was obtained as a white solid of 7.71 g (59.0% yield). The product was recrystallized from methylene chloride and hexane as white microcrystals, m.p. 94-97 ° C.

The IR spectrum (CHCl3) of the product shows carbonyl absorption at 1695 cm @ ^-1 (strong) and 1730 cm @ ^-1 (attenuation).

The NHR spectrum (CDCl 3) of the product shows a triplet at 3.44 δ (J = 6 cps) for CH 2 Br, a multiplet at 2.90 to 2.41 δ for

CH2CONHCOCH2, * multiplet at 2.10 to 1.68 δ for CH'2-CH2 and triplet at 1.19 δ (J = 7 cps) for CH3.

A solution of 7.40 g (31.8 mmol) of N-propionyl-5-bromvaleramide prepared above and

12.5 g (47.8 mmol) of triphenylphosphine in 74 ml of acetonitrile were heated under reflux overnight under nitrogen. The reaction mixture was cooled and evaporated on a rotary evaporator. The resulting white foam was triturated six times with benzene and then further purified by silica gel chromatography using chloroform and then 10% methanol in chloroform as eluents. The desired (4-propionylaminocarbonylbutyl) triphenylphosphonium bromide was obtained as a white hygroscopic solid weighing 9.24 g (58.4% yield).

The NMR spectrum (CDCl 3) shows a singlet at 10.3 δ for NH, a multiplet at 8.14 to 7.27 δ for aromatic protons, a multiplet at 3.97 to 3.33 α for CH 2, a multiplet at 2.92 to 2, 30 <5 for

CH2CONHCOCH2, multiplet at 2.21 to 1.40 δ for CH2 — CH2 and triplet at 1.03 δ (J = 8 cps) for CH3. Example 3

A solution of 7.96 g of 5-bromvaleric acid chloride, 3.40 g of cyclopropanecarboxamide, 3.16 g of pyridine and 20 ml of 1,2-dimethoxyethane was heated to reflux under nitrogen.

1.5 hours, then evaporated on a rotary evaporator. The resulting semi-solid was extracted twice with methylene chloride. The combined methylene chloride layers were washed with saturated brine, dried over anhydrous magnesium sulfate, treated with charcoal, and filtered. The filtrate was evaporated on a steam bath with the addition of hexane until crystallization began. There was thus obtained 3.98 g (40% yield) of white crystalline N-cyclopropanecarbonyl-5-bromovaleramide having a melting point of 114-115 ° C.

The NMR spectrum (CDCl3) of the crystalline product shows a singlet at 9.60 δ for NM, a multiplet at 3.73 to 3.26 δ for —CH2 Br, a multiplet at 2.95 to 2.51 δ for —CH2 C,

II o

multiplet at 2.27 to 1.60 δ for CH2CH2 and

CHC

0 and multiplet at 1.20 to 0.68 δ for the remaining cyclopropyl protons.

A mixture of 4.96 g (20 mmol) of N-cyclopropanecarbonyl-5-bromvaleramide prepared above, 7.86 g (30 mmol) of triphenylphosphine and 50 ml of acetonitrile was heated under reflux for 112 hours. The mixture was then evaporated and the resulting white foam was purified by silica gel column chromatography using 5% methanol in methylene chloride as eluent. Removal of the starting materials and less polar impurities gave the desired [4- (cyclopropanecarbonylaminocarbonyl) butyl] triphenylphosphonium bromide as a white hygroscopic foam weighing 2.42 g (23.8% yield).

A solution of 7.40 g (31.8 mmol) of N-propionyl-5-bromvaleramide prepared above and 12.5 g (47.8 mmol) of triphenylphosphine in 74 ml of acetonitrile was refluxed under nitrogen overnight. The reaction mixture was cooled and evaporated on a rotary evaporator. The resulting white foam was triturated six times with benzene and then purified by silica gel chromatography using chloroform and then 10% methanol in chloroform as eluents. The desired (4-propionylaminocarbonylbutyl) triphenylphosphonium bromide 9.24 g (58.4% yield) was obtained as a white hygroscopic solid.

The NMR spectrum (CDCH) shows a singlet at 10.3 δ for NH, a multiplet at 8.14 to 7.27 δ for aromatic protons, a multiplet at 3.97 to 3.33 δ for CH2P, a multiplet at 2.92 to 2, 30 δ pro

CH2CONHCOCH2, a multiplet of 2.21 to 1.40 δ for CH2 — CH2 and a triplet at 1.03 δ (J = 8 cps) for CH3.

The above product can be reacted with the known χ-hemiacetal 2- [5.alpha.-hydroxy-3 &apos;-( tetrahydropyran-2-yloxy) -2/3/3 - (tetrahydropyran-2-yloxy) -trans- 1cis-5-octadien-1-yl / cyclopent-1a-yl] -acetaldehyde [EJ Corey et al: J. Am. Chem. Soc., 93, 1490 (1971)] to prepare N-acetyl-α- hydroxy-11a, 15'-bis (tetrahydropyran-2-yloxy) -cis-5-trans-13-cis-17-prostatrienamide, which can be converted by known reactions [EJ Correy, ibid.] to carboxamide

N-cyclopropanecarbonylprostaglandin F _3a or N-cyclopropanecarbonylprostaglandin E3 carboxamide.

Example 4

A mixture of 3.6 g (20 mmol) of 5-bromvaleramide and 12.0 g (0.10 mol) of trimethylacetyl chloride was heated to reflux under nitrogen.

4.5 hours. Excess acid chloride was removed under reduced pressure and the remaining oil was recrystallized from hexane as white needles weighing 1.83 g (28.8% yield), mp 53-57 ° C.

The NMR spectrum (CDCl3) shows a singlet at 1.16 δ for C (CH3) 3, a multiplet at 1.56 to 2.08 δ for —CH2CH2—, a multiplet at 2.47 to 3.03 δ for —CH2C, and

0 multiplet at 3.15 to 3.65 δ for —CH2 Br.

A solution of 1.82 g (6.80 mmol) of N-trimethylacetyl-5-bromvaleramide prepared above and 2.67 g (10.2 mmol) of triphenylphosphine in 18 ml of acetonitrile was refluxed under nitrogen for 96 hours. The solution was evaporated and the resulting solid was triturated four times with benzene. The triturated solid was purified on silica gel by column chromatography using first ethyl acetate to remove high Rf impurities and then a 9: 1 mixture of methylene chloride and ethyl acetate. The salt, (4-trimethylaminocarhonylbutyl) triphenylphosphonium bromide, 0.750 g, m.p. 133.5-138 ° C, is obtained from methylene chloride and ethyl acetate as a crystal.

The IR spectrum (CDCl 3) of the product shows a strong absorption at 1734 cm ^-1 attributed to carbonyl groups.

The NMR spectrum (CDCl3) shows a singlet at 1.25 δ for C (CH3) 3, a multiplet at 1.57 to 2.10 δ for —CH2CH2—, a multiplet at 2.63 to 3.10 δ for —CH2C—, broad multiplet at 3.37 to 3.97 δ for —CH2P, multiplet at 7.50 to 7.98 δ for 03P, and singlet at 9.52 δ for N — H.

Example 5

A mixture of methanesulfonamide (23.5 g, 0.25 mol) and 5-bromo-valeric acid chloride (49.8 g, 0.25 mol) was heated at 85 DEG C. in an oil bath for 45 minutes. The brown reaction mixture was allowed to cool and dissolved in ethyl acetate. The organic solution was washed with water and saturated brine, dried over anhydrous sodium sulfate, evaporated and cooled to give a white crystalline N-methanesulfonyl-5-bromvaleramide of 48.2 g (74.8% yield), m.p. to 98 ° C.

NMR spectrum (CDCl 3) shows a broad singlet at 4.26-3.95 SN-H, multiplet at 3.66-3.23 δ for —CH2 Br, singlet at 3.31 S for SO2 —CH3, multiplet at 2.63 up to 2.20 δ for —CH2CO and a multiplet at 2.12 to 1.52 6 CH'2 — CH2.

The IR spectrum (CHCl 3) shows a strong absorption at 1720 cm ^-1 attributed to the carbonyl group.

A solution of 48.2 g (0.187 mol) of N-methanesulfonyl-5-bromvaleramide prepared above, 53.8 g (0.208 mol) of triphenylphosphine and 120 ml of xylene was heated to reflux under nitrogen for 2 hours. The solution was then allowed to cool to room temperature and the resulting solid was collected by filtration. Recrystallization of the crude solid from methylene chloride and ethylene acetate gave white crystalline [(4-methanesulfonylaminocarbonyl) butyl] triphenylphosphonium bromide 42.5 g (43.8% yield), melting at 188-190 degrees Celsius.

The IR spectrum (KBr) of the product showed a strong absorption at 5.85 μτη attributed to the carbonyl group.

The NMR spectrum (CDCl 3) shows a complex multiplet at 8.14 to 7.27 δ for aromatic protons, multiplet at 4.00 to 3.30 δ for —CH2P, singlet at 3.12 δ for —SO2CH3, multiplet at 3.00 up to 2.38 δ for CH2CO and a multiplet at 2.23 to 1.38 δ for CH2CH2.

Titration of the solid product shows a pKai / 2 of 5.25.

Example 6

A solution of benzenesulfonamide (3.14 g, 20.0 mmol) and 5-bromvaleric acid chloride (4.38 g, 22.0 mmol) in acetonitrile (10 mL) was heated at reflux under nitrogen for 1.5 h. The reaction mixture was then evaporated to give a crude brown solid which was recrystallized from methylene chloride and hexane. The prepared N-benzenesulfonyl-5-bromvaleramide is obtained as colorless needles weighing 5.39 g (84.5% yield), m.p. 95-97 ° C.

The IR spectrum (CHCl 3) shows strong absorption at 1720 cm ^-1 attributed to the carbonyl group.

The NMR spectrum (CDCl 3) shows a broad singlet at 9.05 δ for NH.

two multiplets at 8.07 to 7.82 δ and

7.61 to 7.23 δ for aromatic protons, multiplet at 3.40 to 3.08 δ for CIMSr, multiplet at 2.43 to 2.07 δ for CH2CO, and multiplet at 1.85 to 1.48 δ for CH2 —CH.

A solution of 4.81 g (15.0 mmol) of N-benzenesulfonyl-5-bromvaleramide prepared above and 5.89 g (22.5 mmol) of triphenylphosphine in 50 ml of acetonitrile was heated at reflux for 140 hours and then evaporated to give an oil. white foam was obtained. The white foam was triturated three times with ether and then recrystallized from methylene chloride and benzene. The desired (4-benzenesulfonylaminocarbonylbutyl) triphenylphosphonium bromide was obtained as colorless needles of 5.33 g (61.2% yield), m.p. 176-179 ° C.

The IR spectrum showed a strong absorption at 1720 cm ^-1 attributed to the carbonyl group.

The NMR spectrum (CDCl 3) of the product shows a multiplet at 8.15 to 7.27 δ for aromatic protons, a broad multiplet at 3.85 to 3.14 <5 for

CH 2 P, multiplet at 2.87 to 2.47 <S for CH 2 CO, and multiplet at 2.04 to 1.38 δ for CH 2 CH 2.

Example 7

A mixture of 2.57 g (15 mmol) of p-toluenesulfonamide and 2.99 g (15 mmol) of 5-bromovaleric chloride was heated on a steam bath for 20 minutes. The resulting solid N-p-toleunsulfonyl-5-bromvaleramide was allowed to cool and was recrystallized twice from methylene chloride and hexane as white needles, 4.63 g (92.0% yield), m.p. 116-117 ° C.

The NMR spectrum (CDCl 3) of the crystalline product shows a singlet at 9.68? S for N-H, two doublets at 7.95 and 7.35 (J = 8 cps) for aromatic protons, multiplet at 3.50 to 3.18? for —CH2Br, multiplet at 2.53 to 2.18 δ for CH2CO, singlet at 2.45 δ for —CH3 and multiplet at 1.94 to 1.54 <5 for —CH2CH2—.

The IR spectrum (CHCl 3) shows a strong absorption at 1720 cm ^-1 attributed to the carbonyl group.

A solution of 3.34 g (10 mmol) of the bromosulfonamide prepared above and 3.93 g (15 mmol) of triphenylphosphine in 50 ml of acetonitrile was heated at reflux overnight. The solution was then evaporated and the resulting solid was triturated three times with benzene and then recrystallized from ethanol and ether to give white crystals of [4- (p-toluenesulfonylaminocarbonyl) butyl] triphenylphosphonium bromide (IV) weighing 3.87 g ( 64% yield) having a melting point of 134-141 ° C.

The NMR spectrum (CDCl 3 of the crystalline product shows a broad singlet at 11.8 δ for NH, multiplets at 8.10 to 7.13 δ for aromatic protons, multplet at 3.96 to 3.29 <5 for —CH2P, multiplet at 2, 92 to 2.56 Å for —CH2CO, a shinglet at 2.38 δ for —CH3, and a multiplet at 2.16 to 1.40 for —CH2CH2—.

The IR spectrum (CHCl 3) showed strong absorption at 5.82 µm attributed to the carboxyl group.

Example 1 a d 8

A solution of 4.26 g (20.0 mmol of 2-thiophenesulfonamide) and 4.38 g (22.0 mmol of 5-bromvaleric acid chloride in 10 ml of acetonitrile) was heated at reflux for 7.5 hours. The reaction mixture was then evaporated and the resulting dark The solid was dissolved in methylene chloride, treated with Darco and filtered, and hexane was added to induce crystallization to give the desired N- (2-thiophenesulfonyl) -5-bromvaleramide as white needles weighing 5.92 g (90 g). (8% yield) having a melting point of 85-88 ° C.

The IR spectrum (CDCl 3) of the product shows strong absorption at 1720 cm ^-1 attributed to carbonyl groups.

The NMR spectrum (CDCl 3) shows three complex multiplets at 7.96 to 7.75 δ,

7.75 to 7.53 and 7.25 to 6.93 δ for thiophene protons, multiplet at 3.60 to 3.20 δ for CH2Br, multiplet at 2.59 to 2.20 δ for CH2CO and multiplet at 1 97 to 1.53 <5 for CH 2 - CH 2.

A solution of 4.88 g (15.0 mmol) of N- (2-thiophenylsulfonyl) -5-bromovaleramide prepared above and 5.89 g (22.5 mmol) of triphenylphosphine in 60 ml of acetonitrile are heated at reflux for 6 days and The white foam was triturated with ether three times and then recrystallized from methanol and ether to give the desired [4- (2-thiophosphoryl) aminocarbonylbutyl] triphenylphosphonium bromide as colorless cubes of 4. 97 g (56.3% yield) having a melting point of 215-218 ° C.

The IR spectrum (KBr) showed strong absorption at 5.85 µm attributed to the carbonyl group.

The NMR spectrum (CF 3 CO 2 H) shows multiplets at 8.13 to 7.13 δ for phenyl and thiophene protons, broad multiplet at 3.58 to 2.99 δ for

CH2, multiplet at 2.85 to 2.54 δ for CH2CO and wide multiplet at 2.25 to 1.75 δ for

CH2CH2

Example 9

A mixture of 3.98 g (20 mmol of 5-bromvaleric acid chloride) and 2.42 g (20 mmol of benzamide) was heated on a steam bath under nitrogen for 45 minutes, allowed to cool, and the resulting solid was recrystallized from ethanol as colorless needles. 2.46 g (44.8% yield), mp 122-123 ° C.

The NMR spectrum (CDCl3) of the product shows multiplets at 8.03 to 7.44 δ for aromatic protons, a triplet at 3.47 δ (J = 6 cps) for CH2 Br, a triplet at 3.08 δ (J = 7 cps} for CH2CO and a multiplet at 2.10 to 1.80 δ for CH 2 CH 2.

The IR spectrum (CHCl3) of the product shows a strong absorption at 5.90 μηι for carbonyl groups.

A solution of 2.84 g (10 mmol) of N-benzoyl-5-bromvaleramide prepared above and 3.93 g (15 mmol) of triphenylphosphine in 50 ml of acetonitrile was heated to reflux under nitrogen for 72 hours. The acetonitrile was removed by rotary evaporation. was triturated three times with benzene and then recrystallized from methylene chloride and ethyl acetate to give the desired (4-benzoylaminocarbonylbutyl) triphenylphosphonium bromide, 2.38 g (43.7% yield), mp 193-194 ° C.

The NMR spectrum (CDCl 3) of the product shows multiplets at 8.31 to 7.26 δ for aromatic protons, multiplet at 3.97 to 3.42 δ for CH 2 P, multiplet at 3.25 to 2.91 δ for CH 2 CO, and multiplets at 2.18 to 1.57 δ for CH 2 CH 2.

The IR spectrum (CHCl 3) of the product showed a strong absorption at 1725 cm ^-1 for carbonyl groups.

Claims (1)

OBJECT OF THE INVENTION A process for the preparation of a substituted carboxamide triphenylphosphonium bromide of the formula II 11 carbon atoms in which the substituent is methyl, halogen or methoxy, alkylsulfonyl of 1 to 7 carbon atoms, thiophenesulfonyl, bezensulfonyl or toluenesulfonyl; ® 2 (C ₆ H ₅ ) ₃ PC H _from CH _from CH _from CH _from CNHR nyl, characterized in that the compound of the general formula X 0 Br - CH 2 - CH 2 - CH 2 - CH 2 - C - NHR (II) (X), where where R is C 2 -C 8 alkanoyl or C 4 -C 8 cycloalkanoyl, aroyl or substituted aroyl of 7 to 8 carbon atoms R is as defined above reacted with triphenylphosphine. Severography, n. P., Plant 7, Most