BE712744A - - Google Patents

Description

  

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  Process for the preparation of therapeutic agents.



   The present invention relates to a new series of basic chemicals and their acid addition salts which are useful as analgesics and muscle relaxants, and more especially, it relates to
 EMI1.1
 some 1 - arylth3.othy.-2-methyl-6,7-d.mthoxy -., 23s.tètrahydro4t.soquînoldines.



   The present invention provides a member selected from the group consisting of compounds of formula

 <Desc / Clms Page number 2>

 
 EMI2.1
 (where FR is a member selected from the group consisting of
 EMI2.2
 in which W, X and Y are each chosen from a hydrogen atom ,. a chloro, bromo, fluoro, trifluoromethyl, nitro, lower alkyl or lower alkoxy radical); and their non-toxic and pharmaceutically acceptable acid addition salts.



   Preferred embodiments of the present invention are compounds of formula:
 EMI2.3
 (in which X and Y have the meaning given above) and their non-toxic and pharmaceutically

 <Desc / Clms Page number 3>

 acceptable, and in particular, the two compounds (and their salts) of formula:
 EMI3.1
 wherein X represents a hydrogen or chlorine atom, which are exceptionally effective analgesic agents.



   The present invention encompasses within its scope the acid addition salts prepared by reacting these basic compounds with organic and mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, acid. phosphoric acid, acetic acid, maleic acid, tartaric acid, citric acid, sulfuric acid, glycolic acid, succinic acid, ascorbic acid, & c.



     The term "lower alkyl as used herein" denotes straight chain and branched saturated monovalent aliphatic hydrocarbon radicals having one to ten carbon atoms inclusive, for example radicals. methyl, ethyl, propyl, isopropyl, butyl, normal, secondary and tertiary butyl, amyl, decyl, etc.



   The compounds of the present invention are prepared as shown schematically below by reacting an appropriate ss-arylthiopropionic acid with 3,4-dimethoxyphenethylamine to form the amide, cyclizing the amide, for example with sodium chloride. phosphoryl, dihydrodisquinoline

 <Desc / Clms Page number 4>

 substituted in position 1, by reducing the latter, for example with a borohydride, to the corresponding tztrahydroisoquinoline and finally by methylation in position 2; and we
 EMI4.1
 can write:

   OCR "FR - S - CH2CH2COOH + .j, H2NCH2CHz-Q- OCH
 EMI4.2
     
An alternative process is given below as an example and follows the diagram:

 <Desc / Clms Page number 5>

 
 EMI5.1
 
Ainsion can prepare the starting ss-arylmercaptopropionic acids by the methods indicated in the literature, for example according to Krollpfeiffer and his co-workers, "Ber. 3, 58, 1654-1680 (1925) or according to Stewart and his co-workers," J .

   Org. Chem., @ 14. 1111-1117 ,, (1949), and the ss-arylthiopropionaldehydes which are

 <Desc / Clms Page number 6>

 other starting compounds according to "Chemical Abstracts", 59 8635e (1963).
 EMI6.1
 



  The p-arylmercaptopropionic acids are used to acylate 3,4-dim-thoxyphc-nitliylamlne in the normal way and the amide thus produced is cyclized, for example with oxides or chlorides of phosphorus, and reduced, for example with a hydride or aluminum borohydride
 EMI6.2
 minimum.

   and alkali metal to tetrahydro-soluminum, as illustrated below, or following the procedures set forth on pages 250 and 254 of Volume IV of The Chemistry of Carbon Compounds, de Bicher, Elsevier Publishing Co., Inc., New York, NY, 1947. , and at pages 347-353 of Volume IV of "Heterocyclic Compounds" by Eliierfield, Viley, New York, 1952, and in US Pat. No. 2,683,146 and in British Patent No. 926,493.
 EMI6.3
 The tetrahydroisoquinoline is then methylated in position 2 by the usual techniques used to methylate secondary aliphatic amines, - 'for example
 EMI6.4
 with formic acid and formaldehyde9 Thus,

   the introduction of the methyl group can be carried out according to known methods, for example by treating the decomposition material
 EMI6.5
 part, that is to say 1,2,3,4-tetrahydroisoquino14ine substituted in 1, 6 and 7 with a molar equivalent of a reactive ester of methanol.

   A reactive ester of methanol is in particular that formed with a strong mineral acid, for example hydrochloric, hydrobromic, hydriodic, sulfuric, etc., or a strong organic sulfonic acid, for example
 EMI6.6
 example methanesulphonic, ethanesulphonic, 2-hydroxyethane-stli, fonic, p-toluenesulphonic, etc; therefore, the reactive esters are, for example,

 <Desc / Clms Page number 7>

 methyl halides, eg chloride, bromide
 EMI7.1
 or lylodure, dimethyl sulfate and methyl p-toluenesulfate, etc.

   The reactive ester is preferably reacted with the starting material in the form of a metal compound, in particular an alkali metal, for example lithium, sodium or the like; the latter is prepared by treating with a suitable reagent capable of forming such a compound, for example with an alkali metal hydride, for example sodium hydride. etc., or any other equivalent reagent.

   The formation of the metal compound, as well as the treatment of the latter with the reactive ester, is preferably carried out in the presence of a suitable inert solvent, if necessary, while cooling, or at an elevated temperature, and / or in a container. closed, . and / or in the atmosphere of an inert gas, for example nitrogen.



   It is also possible to introduce the methyl group. by other methods, for example by treating the
 EMI7.2
 ? , 2,,. -T trazydro, saqu3noline substituted in 1,6, 7 starting with formaldehyde in the presence of a reducing reagent, for example formic acid, hydrogen in the presence of a hydrogenation catalyst such as palladium, etc., or any other suitable reducing reagent.



   According to another very interesting process, the compounds of the present invention are prepared by reacting a compound of formula HS FR where FR has the meaning given above (and preferably its metal salt such as sodium or potassium salt) with a reagent of formula! @

 <Desc / Clms Page number 8>

 
 EMI8.1
 where 2 # is an equivalent of an inert anion, The anions will include halides (chloride, bromide and iodide), a sulfate, a (lower alkyl) sulfate and sulfonates, for example p-toluene sulfonate and p-bromobenzeneaulfonate,

   but other anions are also useful and do not even have to be non-toxic since Iranian does not appear in the final pharmaceutical product prepared by reacting this reagent with, for example, a compound of the formula FR- S-Na, as shown in Example 8 below.



   These quaternary intermediate salts are prepared, following a process, by treatment with an alkali, for example Na2CO3, of the reaction product of the alcohol of the formula:
 EMI8.2
 with SOCl2, SOBr2, (CH3) 2SO4, p-CH3C6H4SO2Cl, p-BrC6H4SO2Cl, etc. the Z # anion is of little consequence in these active intermediates, since the chemical reactivity resides in the cation. The Z # anion is defined to be an inert anion to exclude unusual anions containing other substituents, for example phenolic hydroxyl groups, capable of further reacting with

 <Desc / Clms Page number 9>

 these quaternary salts.

   Thus prepared, Z # can be a chloride, a bromide, a methanesulphonate, an ethanesulphonate, a p-toluene-sulphonate, a p-bromobenzene-sulphonate, and the like.



   By exchange reactions of the conventional type, Z # can be replaced by other anions, for example the phosphate, fluoride, malate, succinate, fumarate, oleate, etc. ions. The salts obtained by these variations of Z # may, in certain cases, present particular advantages due to their solubility, their ability to crystallize, etc., but all this is secondary to the chemical reactivity of the compound which is independent of the nature of Z #.



   In a preferred embodiment, the compounds of the present invention are prepared by reacting a compound of formula FR-SH where FR is as defined above (and preferably its metal salt such as sodium or potassium salt. ) with a reagent 'of formula:
 EMI9.1
 where X and Y each represent a hydrogen, chlorine, bromine or fluorine atom, a trifluoromethyl, nitro, lower alkyl or lower alkoxy radical. This reaction is preferably carried out in an inert organic solvent, for example ethanol, at a temperature between 20 and 100 ° C.



   The preparation of this reagent is illustrated for the case where X represents a hydrogen atom and Y a radical

 <Desc / Clms Page number 10>

 
 EMI10.1
 para-bromo1 as follows:
 EMI10.2
 
 EMI10.3
 OX31nte 'estr êth .a, xe d3aede 6 7-dimetho -, tTah, yroisonuinoln.3.'achtidcxe) ± 7A. L.



  Bluhm and W.J. Gens-ler, n'e Orge Chem. ", 21, 336-339 (19567.

 <Desc / Clms Page number 11>

 
 EMI11.1
 To a stirred solution of 216.9 g (1 mole) of diethyl ethyl ester distilled in 1 liter of absolute ethanol is slowly added 181.2 g (1 mole) of homoveratrylamine distilled in a nitrogen atmosphere. We stir the mixture
 EMI11.2
 reaction for 16 hours at room temperature, then concentrated to dryness. The resulting oil is taken up in 2 liters of 24% hydrochloric acid, heated on a boiling bajn-marie for 4 hours, then concentrated to dryness to obtain a yellow oil.
 EMI11.3
 



  This oil is taken up in 1 liter of absolute alcohol, filtered to remove the LiMl3, .n trarsA'ttin1 ea is saturated with hydrochloric gas while cooling, stored at room temperature for one day, then concentrated to to dryness to obtain an oil: This oil is taken up in a liter of absolute ethanol, it is saturated with hydrochloric gas while cooling, it is stored at room temperature for a Court, and it is again concentrated to dryness.

   The brown oil thus obtained was made basic with an aqueous solution of sodium carbonate, extracted with chloroform, dried over sodium sulfate, and concentrated to obtain an oil which gave a crystalline oxalate with 90 g of oxalic acid in acetone. Recrystallization from
 EMI11.4
 95% ethanol provides 2,:. 6? .diaatho-, 3, ¯ttxaild o isoquinolin-1-acetic acid etn> "dyoxdate (61%). Several recrystallizations from Z'thano to bzz produced a melting analytical sample. at 136-J.54 C (mesa fusion defined). ftlyeî. Calculates for 's,'. i. ', h.a'2aÉÎ4: C, 55.23 Ls' 6.26; N, 3.79 Find: C, 55.28; He 6t5; N, 3.81.

 <Desc / Clms Page number 12>

 
 EMI12.1
 



  .Chl0.l: b1.! 1.te ester, ethY, .l: 1, '1llê de Vac1de ..A.: Ld "" thoy -? - ^ th7.-i., 2, 3, , r¯ "-t: strxhydroI souf no.inr-1-, iuc (1) fAo Brossi and colleagues," Helv.



  Chem. Acta.x: ..9 533-593 1''96te A 3.8 g (eye, 35 mole) of bfi7-d acid ethyl ester: t; thrty-.1,23,1-ttrahydrolsoquinoline- l-acetate, obtained from leoxalate
 EMI12.2
 by neutralization with sodium carbonate, one adds
 EMI12.3
 1.2 ml of 40% formaldehyde and 36 ml of 838% diacid. The reaction mixture was heated on a ouiZLa <water bath for 2 hours. 3 ml hydrochloric diacid 6 R are added and the solution is concentrated to dryness.
 EMI12.4
 to obtain 4.5 g (100%) of ethyl ester hydrochloride
 EMI12.5
 than crude crystalline 6,7-izethoxy-2-ethyl-1,2,3,4-tetrahydroisoquinoixze-1-sct3que acid. Recrystallization from absolute ethanol affords an analytical material melting at.? R-.3.3 G.



  Calcula for C16H23NO4.aCl: c, 58p26; 9 7.34? N, HW'J Found: '58e36; He ''33 Ne 432.



  B 7-Ci rnethoc- -i- -hsdro hydrochloride, eth i- .. -'rv-T, -βtA ahydxoi scauino3: e tzlx¯). a stirred suspension of 7.6 g (oe2 mole) of lithiums3.urr-Inium hydride in 100 µl of tt.rahydroxuran? 58.5 g (0.2 mol) of the ethyl ester of 6.7-dimel, -, hoxy-2-mt7, iyl-lx2e3e4-t6trC.ydroisoquine, inel-aCQ1Ue (obtained from the hydrochloride by neutral-
 EMI12.6
 sation with sodium carbonate) in 150 ml of tetra-
 EMI12.7
 hydrofuran <The suspension is heated under reflux for four hours. Carefully add 25 n of water and stir the suspension with heating until it becomes

 <Desc / Clms Page number 13>

 white.

   Anhydrous sodium sulfate is added and the solids are removed by filtrate :! we. Concentrate the filtrate
 EMI13.1
 to dryness to obtain 199 g (99.3%) of an oil which produces b, 7-dimthoxy.-1-s-.hydro: y- ethyl-2-methyl-1,2 hydrochloride, Crystalline 3,4-tetrallydroisoquinoline in acetone. Recrystallization from absolute ethanol gives 42.6 g of analytical material, mp 179-182 ° C.
 EMI13.2
 na11sa: Calculated for GiHN03.HZ C, 58.43! H, 7e7l; 11a 487 Found: in, 58e26; dï f, OCi Ne H'i / (2 l.-a azti D-bromobenzenesulfonate, dinc-6?. dimethoy-2-methyl,., 2,3, .- ttrahdro3soruinoéi.nitzr ILrj.



  To a stirred solution at room temperature of 5.3 g (0.021 mol) of 6,7-dimethoxy-lp-hydroxyethyl-2-methylir2,3, t * -ttrahydroisoqv.ir.oline (obtained from hydrochloride by neutralization with sodium carbonate) in 100 ml of chloroform, 5.5 g are added
 EMI13.3
 (t, Ci? J..6 mol) of p-bromobenxeraestl.fonyl.e chloride. Stirring is continued for four hours. 11.2 g of anhydrous sodium carbonate was added and stirring continued for 16 hours. The mixture was filtered and the filtrate was concentrated to obtain 9.6 g (97%) of crude crystalline material.

   Several recrystallizations in
 EMI13.4
 lisopropanol gives p-bromobonzenesulfonate, 2, z -... aze # idino-6,7-dim4thoxy-2-methyl-1,2,3,4-tetrahydroisoquinoleinium analytically pure and melting at 182-184.5 C , Analysis: Calculated for, C20H24BrNO5S: e, 51.07; H, 5114; N, 2.98 Found: Ce 51.01; FI, 5th29; N, 2.92.

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   The compounds of the present invention contain an asymmetric carbon atom and thus are normally found as a racemic mixture of the two optical isomers. Both isomers are active and these two isomers and mixtures thereof are within the scope of the present invention.



   In the form of its hydrochloride, the preferred compound of the present invention has the structure:
 EMI14.1
 and may be called 1- (p-chlorothio- hydrochloride
 EMI14.2
 p: znoxythy.- j 7-d: mthoy -? - thyL-1, 2,3, lttra.hydri sn.quinoline of 1 --- (p-ChlorophénY1ercapto) hydrochloride thy ..6r7-ditho: ry-. -.tnyl-1,2,.-ttrahydroi soquâno. leine. This compound was tested for analgesic action by the phenylquinone test of Sigmund et al.
 EMI14.3
 co-workers, "Proc. Soc. Expiai * Biol, and 'd. n, 2je 729 (1957) in which an analgesic reduces wriggling induced in mice.

   At doses of 150 to 50 mg / kg orally in mice, administered 50 minutes
 EMI14.4
 before the injection of the phenyl-p-quinone, it is observed that the reduction in the wriggling caused is, at the end of the first hour, 9 and 72% respectively for this compound. This compound was also found to be a potent pain reliever in the classic rat tail tapping test.

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   As shown in detail below, the compounds of the present invention are resolved very efficiently to their optical isomers using certain novel optically active acids. These optically active acids have the formula:
 EMI15.1
 in which R1 represents an atom of hydrogen, chlorine or bromine., or a nitro group and R2 represents a hydrogen, chlorine or bromine atom but R1 and R2 do not each represent a hydrogen tern .

   The preferred acids are those having the formulas:
 EMI15.2
 
The anines used to illustrate the resolution of the compounds of the present invention have the structures:

 <Desc / Clms Page number 16>

 
 EMI16.1
 The first is a potent analgesic and muscle relaxant.

   The. Optical isomers of the latter are converted into optical isomers of the former and the other amines of the present invention, as described in detail below by the following series of reactions:
 EMI16.2
 
 EMI16.3
 ! la is 1'1 somère (+) Ilb is 1 sound (-)
 EMI16.4
 CH 3 ü '' N -0- 111 1l1a is the (-) isomer 111b is the (+) / t 'Cl ### (\, ### SU CzH50H; NaOH

 <Desc / Clms Page number 17>

 
 EMI17.1
 
 EMI17.2
 Va is .a3somer (-) lob is the isomer z Poduot1on dèS resolution aênts Acid J +) - 2, '- nitrottll'tran111o \ tè ...- 44 g (0.2 mole) of anhydride (- a3dacéty.succrique and 35 g (0.25 mole) of 2-nitroaniline with 300 ml of methyl chloride and refluxed for 3 and a half hours.



  This solution is cooled to room temperature and treated dropwise while stirring with a solution of 39 g of potassium hydroxide (86% pellets; 0.6 mol) in 400 ml of water. Stirred for 1 hour at room temperature. The layers are separated and the methylene chloride layer is extracted with an additional 100 ml of water. The aqueous layers are mixed, heated on a boiling water bath, treated with decolorizing charcoal, filtered through
 EMI17.3
 hot. through diatomaceous earth (ttCeliten) ,. they are acidified with 50 ml of concentrated hydrochloric acid and cooled to 5 ° C. for 16 hours. The crystals were collected and washed with 100 ml of cold water to obtain 32 g of yellow crystals.

   This material is taken up in 300 ml of hot water and treated with. 15 ml of concentrated hydrochloric acid and cool it. 28 g (52%) of 2-nitrotartranilic acid crystals are collected. We

 <Desc / Clms Page number 18>

 
 EMI18.1
 recrystallize a 6chontillon in n-prop9Rol for analysis, mp 196.0-198.00C, -a-75 +? lt3o (c 2.5, αtiianoi>, -a-7 B5 + 89ego (0 o, 83, B20).



  .: '\ rllÜysç .: C8lculê for CI "10107 Ce 44e45; H, 3e73; N, 10e37 Found: Ce 44.41; lie 3e79; Ne 10.31.



  .AcM ('t34-nchlorotartranil 22 g (mole eye) of (+) - 2, j-aiacôtylà uccinic anhydride and 18 g (0.11 mole) of 2,4-dichloroaniline are stirred together for 2 hours in 150 ml of methylene chloride A solution of 21 g of potassium hydroxyl is added.
 EMI18.2
 (87 µg 0.32 mole pellets) in 2.00 ml of water and the two-phase system is stirred vigorously for 1 hour. The methylene chloride layer is separated, extracted with 100 ml of water and discarded. The aqueous extracts are mixed, heated on a boiling water bath, filtered, acidified with 35 ml of concentrated hydrochloric acid, and cooled to produce the crystal.
 EMI18.3
 tallization.

   When collected, this material weighs 17 g (59%) colorless diacid (+) - 2 ', 4'-aichlorotartraniliqàe. several crystallizations from water produced an analytical sample, melting at 182.5-192.5 C, -a-7 + 100e7O (c 1.6, 95% ethylianol).



  Analysis: Calculated for ClOH9NO4: C, 40.84; H, 3, OS? N, 4.76.



     Found: C, 40.84. E, 3.21; N, 4.57.



   The following examples are given by way of illustration, but not limitation, of the present invention.

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 EMI19.1
 g.xm! PLE 1.
 EMI19.2
 

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 EMI20.1
 ioroJrratryla icr.-ci: loreth3o; hcroxv xo ionicue (1). It is heated to reflux for 4 and a half days in
 EMI20.2
 using an oan-tark collector to remove the water, a Solange stirred 12 g (0.59 mole) of p-p-chloro acid -
 EMI20.3
 thiophenoxypropionic (F. KroJ.lpfe: 1.f'fer, H.

   Schultze, 2 * schlumbolin and 2.somnle-meyer, "Ber.",, .51 (1925)) and 108 g (0.59 mole) of homoveratrylfuine in 1.5 liters of toluene * The solution is cooled to At about 40 ° C, diluted with 500 ml of hot anhydrous Srellysolve Zut (mixed lower alkanes), then cooled to 5 ° C to produce crystallization. The crystals collected produced 178 g of crude material. A small portion is recrystallized from a mixture of acetone and water containing a few drops of acetic acid to obtain an analytical sample melting at 82-84 C.
 EMI20.4
 



  Analysis: Calculated for C19fi22C71r0S: C, 60.07; H, 5.84; N, 3.68
 EMI20.5
 Found: C, 60.05; B, 5.89; N, s, lE.2.



  Α- (pTI-chlorothioDhenox.YélYl) -6.7-d1hPxY.3.4 = dihycio3.soaur.o.ine (il). A stirred solution of 10 g (0.026 mol) of homoveratrylamide -p (chlorothiopheno-propionic acid and 25 ml of phosphoryl chloride in 50 ml of toluene is refluxed for one hour. The solution is allowed to cool to or-4 to temperature. stirring continuously for two hours 100 ml of water are slowly added The aqueous layer is separated, the
 EMI20.6
 makes sodium carbonate eiec basic and extracts it with ethyl acetate. Ethyl acetate extracts, after dehydration over anhydrous sodium sulfate and concentration to dryness, provide 6.7 g of product.

 <Desc / Clms Page number 21>

 raw crystalline.

   Two recrystallizations from acetone produced an analytical sample melting at 110-111 C.



  Analyze Calculate for C19H20ClNO2S:
 EMI21.1
 C, 63rdO5; H, 5th57; N, 3.87 Found: C, 63.30; H, 5> 74; Ne 3.60.



  ? -l .chlorothio hlr¯o. êth 1 -b -dimê-haac P-. 2 -têtz, hvdra3 socuinalF ine I. with a stirred suspension of 9.0 g (0.025 mol) of 1- (µ-p-chlorothioph4nozzY- etiy.) .. b, 7-d: ethaxy -, .- dhydro: onurdwne II in 100 ml of ethanol absolute, maintained in a water bath at 60-65 C, slowly added 1 g of sodium borohydride. Stirring is continued at 60-65 C for 1.5 hours after the addition. After cooling the solution to room temperature, hydrochloric acid is added.
 EMI21.2
 , 6 until the evolution of hydrogen ceases.

   Most of the solvent is evaporated off under reduced pressure. The residue is neutralized with 10% sodium carbonate solution, and extracted with ethyl acetate. The ethyl acetate layers were washed with saturated sodium chloride solution, dried over anhydrous potassium carbonate and concentrated to dryness to obtain a crude oil which crystallized spontaneously. The yield is less than 50%. The crude material is recrystallized from methanol to obtain an analytical sample which melts at 79-80 ° C.
 EMI21.3
 



  Analysis:,. Calculated for C19H ;;. ZCIN .zS: C, 62.71; H, 6.09; N, 3.85
 EMI21.4
 Found: C, 62.96; Hue 6e2O; N, 3, he ..

 <Desc / Clms Page number 22>

 
 EMI22.1
 



  1 - (- f, -p-chlorotiohénovéthYl) -67-d1M0thoxy'- 1.2.3,4tcityhYdofsoouinolf.jne 1. (another process # ti.lisant LIAIS,). fez. a stirred suspension of 0.33 g (0.009 mol) of lithium aluminum hydride in 50 ml of tarx'wlx: y.x'odux anne, 10 g (0.028 mol) are added over a period of half an hour ) of 1- (pp-chlorothiôphenoxyethyl) l, r-dimtho.xy-; r, of hydx o3.soq, uâncâ .: donkey It dissolved in 75 Ri of tetrahydrofuran. The suspension is stirred for 3.5 hours at room temperature. Carefully add 10 µl of saturated sodium sulfate solution to decompose any excess hydride; the suspension is stirred until it is completely white. Solid sodium sulfate is added and the solids are removed.
 EMI22.2
 by filtration.

   The solution is concentrated to the site. cited to obtain 10 g of crude crystalline material. Recrystallization from isopropanol gives 7.2 g of product, melting at 81-82 C. Its infrared ray absorption spectrum is identical to that of the product obtained using sodium borohydride.
 EMI22.3
 



  2 -..-- chloxoth3opnnox hydrochloride; r.lth â. ntnoxyv -; - rncthvi-.2,, iyttxshvdroisocuinol3ne (IV). Is heated on a boiling water bath for two hours, a solution of 25 ml of 88% formic acid, 7 ml of
 EMI22.4
 formaldehyde at 1.0 ;, and 8e5 9 (0.023 mol) of 1- (g-pckaloxo tuophE: x.o: cythyl.) -6,? 'dimetho: y-? ,, 3 s, tf trahydr- isoquindéine 111., 6 ml of concentrated hydrochloric acid are added and the solution is concentrated to dryness to obtain the crude product which is recrystallized from methanol to obtain 9.2 g of material analytically. pure melting at 197-199 C (decomposition).

 <Desc / Clms Page number 23>

 
 EMI23.1
 



  Analysis: Calculated for C20H24ClNO2S.EC1; C, 57.06; H, 6x22; N, 3.3 Found: C, 57.88; H, 6.29; N, 3.08.
EXAMPLE 2
 EMI23.2
 V
 EMI23.3
 1- (fl-p-chlorot? Iionhénozy hydrate hydrate = ttm. -6 '-dih dro. -2rr, eth 1-1 2 tL- trahrdxcnsoauino-! Fine (V). Heated together in a bath. oil maintained at 200-220 C for 25 minutes a mixture of 20 g of pyridine hydrochloride (wet weight melted at 190 C in anhydrous N2 before use) and 3.5 g
 EMI23.4
 J, 001 mol) of 1- (¯ ck: orothiophenaxy .. ethyl) -6,7-dimethoxy-2-methyl-1,2,3,-tetrahydroisoqu ± nollein IV hydrochloride. The residue, cooled, is treated with 50 ml of water and 5 g of sodium bromide.

   The crystals were collected and washed with water to obtain 3.5 g of crude dark material. Several crystallizations in a mixture of methanol and water containing a slight amount of acid
 EMI23.5
 bronchial and illorite treatment give a colorless analytical sample melting at 100.0-104.00c.



  Analysis: Calculated for C18H20C102S.HBr.H2o: C, 4.1 ?; HP'5y! 6; N, 3.12; H2Oe 4.02 Found: C, 4825; H, 5.12; idp 2.92; HZOE? 4.38-

 <Desc / Clms Page number 24>

 
 EMI24.1
 EXAMPLE
 EMI24.2
 
 EMI24.3
 -thiophno: propiona1dhYde (Vl). (Ksenija Sirotanovic, mika Büjlon-Rocen and Dragica Galovic, Glasinic Hem. Drustva, Beograd 226 (8, '9, 10), 509-18 (1960-61) ùe c, fi., 22, S635e (1963). 7 ml of acrol (0.1 mol) containing 0.1 g of hydrated cupric acetate cooled to -Joe are slowly treated for 45 minutes with

 <Desc / Clms Page number 25>

   11.0 g (0.1 mol) of thiophenol while maintaining the temperature
 EMI25.1
 turem below OOC. Stirring is continued at 00 ^ 1 for one hour.

   The mixture is diluted with 10 µl of toluene, dried over sodium sulfate and filtered. Removal of the toluene under reduced pressure and distillation of the residue gives 9 g (54%) of a colorless oil,
 EMI25.2
 having a boiling point of 94-99 C at 0a'7 mm / Hg. The infrared absorption spectrum shows a strong absorption at 5.81 microns attributable to the presence of the carbonyl group of the aldehyde function and two distinct weaker bands at 3.56 microns and 3.69 microns attributable to vibration. carbon-hydrogen spacing of the aldehyde function.
 EMI25.3
 



  Hydrochloride ¯de 6 7-dimthox -1-- -tY.io hénoxvf.thyl) -1.2.3.4-t8trahYdroisoquinoline. (VI1-L; 9, g (0.054 mol) of -thiophenoxyprop1onaldehyde VI and 110 g (0.061 are placed together mole) of homovra.trylamane in isopropanol and heated on a boiling water bath.The isopropanol is removed under reduced pressure, leaving a pale yellow oil.The absorption spectrum of infrared rays by this The oil revealed complete disappearance of absorption at 5.81 microns in the region characterizing the aldehyde and the appearance of a new band at 6.00 microns of only medium intensity.



   The above oil is treated with 75 ml of 24% hydrochloric acid and heated on a boiling water bath for 1 hour and a half. We dilute the mixture
 EMI25.4
 3.soproganol3 reaction mixture, treat it with "Norit", filter and wash it with methanol and concentrate to dryness under reduced pressure. We take the residue

 <Desc / Clms Page number 26>

 in hot 95% ethanol, then cool it in the lace. We collect the crystals and wash them intimately
 EMI26.1
 with cold 95% ethanol and dried to obtain 4.6 g (23%) of colorless material.

   Recrystallization from eth.no2-water-actan combination gives an analytical sample, melting at 214-216 ° C.
 EMI26.2
 Analysis: Calculate for CHx '(S, IiC1:
C, 62.36; H, 6.61. N, 3.83 Found: C, 62.50; H, 6.79; N, 4.07.
 EMI26.3
 



  Ioiït <lrate ce 6t'7-dymthoYye - ,; th1-.wthohr rocvttzyl -. ' z3 trahydroi soau3r¯drane JVIl1 t.



  3.0 g (0.0082 mole) of 6,7-dimethoy hydrochloride --.- (- t? I ophNnayé thyl) -1p 2a 3,.-Earlyrahydrai socluino = lein V11 is treated with a dilute solution of carbonate sodium and extracted twice with ethyl acetate. These extracts are dried over potassium carbonate and concentrated to dryness to obtain the free base in form. of an oil (yield, 100%). This oil is treated with 10 ml of 88% formic acid and 3 ml of 40% formaldehyde and heated on a boiling water bath for 2 and a half hours. The reaction mixture is concentrated to dryness. The residue is taken up in an ethanol mixture and treated with 3 g of potassium iodide.

   The crystals are collected and recrystallized from
 EMI26.4
 '? aeth.noi. at 93% to obtain 1.6 g (42) of analytical material, melting at 111.0%, 5 ° C.



    Analysis: Calculated for C20H25NO2S.HI:
C, 50.95; H, 5.56; N, 2.97
 EMI26.5
 Found: C, 51.30; ' 51.18; H, 5.72; 5.64j Ne 2.97.



   This compound is a potent muscle relaxant.

 <Desc / Clms Page number 27>

 EXAMPLE 4
 EMI27.1
 XII

 <Desc / Clms Page number 28>

 
 EMI28.1
 lli? rlQ.y.! '.. t.r "' y'1 .d, ', D" ci.sLe. b'ic5.-di !: 1 thyl-2zoly, 1) ccantoQrop1t1o, i). It is heated to reflux in an apparatus comprising a Dean-Stark collector
 EMI28.2
 for 96 hours a solution of 102 g '(0.17 sole) of acid - {., 5-.dâthy3.w2-thiazoLyl) -: aercaptoprorionlque (Stewart and Mathes, "J. Ogg. Chem." 14, 1111 (1949))
 EMI28.3
 and 85 g (0.47 mol) of homoveratrylin in one liter of toluene. 77% of the theoretical amount of water is obtained.



    The reaction mixture is cooled and concentrated to obtain an oil which is crystallized from an acetone-water mixture. The product is collected and dried to obtain 46 g.
 EMI28.4
 (26%) Ide p- (, 5-ài methyl -? - tlià azolylmprcaptopropionique. Recrystallization from an acatone-water mixture gives an analytical sample melting at 113.5-IlyC 4 - Calculated for C18 II 24N20362-
C, 56.83; H, 6.36. N, 7.37.



  Found: C, 57.32; H, 6.55; N, 7.25.
 EMI28.5
 b, -dimt: oxy-1 - {1,5.di .: t'r.yl-2-th.azoly7.) nercaptotr1-î, dihdroisor.ieinol.ine Y In a solution of 10 g (2, 6 x 10 2 moles) dehonov6-atrylamide i {,,, 5-.d $ thy.- 2-thiazclyL) icercaptopropionic IX in 50 ml of chloroform, gradually added 6.7 g (3.2 x 10-2 moles ) phosphorus pentachloride with stirring. The orange solution is refluxed for an hour and a half, cooled and concentrated to obtain an oil to which are added 30 ml of water and a sufficient quantity of saturated sodium carbonate solution to bring the pH to 9.

   We extract the m-
 EMI28.6
 basic mixture with two portions of 50 ùù of dry chloroform -Cn

 <Desc / Clms Page number 29>

 chloroform on magnesium sulphate, filter and concentrate it to obtain an oil which is crystallized
 EMI29.1
 by trituration in IISkellJ1sol ve Bn. The crystals were collected to obtain 6 g (67%) of product which was recrystallized from a methanol-ethyl acetate mixture to obtain an analytical sample melting at 145-148 ° C.



  (decomposition).



    Analyze Calculated for C18H22N2O2S2
 EMI29.2
 C, 59.66; Rp b, 2N, 7.73 Found; C, 59.37; H, 6.12, N, 7.96.



  6, -dirthoxy --- (I ° 5-d-imthv ..



  --tbaov-'crcatrréth.yl-l, 2, 3, d .- 'ttraydroisoauIrzo.tne .HIM. 0.42 g (1.1 x 10-2 moles) of sodium borohydride is gradually added to a suspension of 4 g
 EMI29.3
 (1.1 x 10-2 moles) of b, i-di.l'ilOXy ..: ¯3 .- (, p5-di: nthy .-- thiazolyl) mercaptoethYl-1,2-dihydroisoquinol ine X in 50 ml of absolute ethanol heated in a water bath at 70 C.



  There is a violent reaction and dissolution.



  The mixture is warmed to 60 ° C. for half an hour, then it is cooled. A small amount of 6N hydrochloric acid is added to decompose the excess borohydride and the mixture is concentrated. The residue is separated into 50 ml of chloroform and 50 ml of water. The chloroform is separated and dried over magnesium sulfate, filtered and concentrated to obtain a foam which gives 2.2 g (50%) of crystalline hydrochloride in an ethanol-hydrochloric acid mixture.



  Recrystallization from acetone-water produces an analytical sample melting at greater than 220 ° C.
 EMI29.4
 



  Analysis: Calculated for C3HZNZOSC3. :
C, 53.91; H, 6.28; N, 6.99 Found: C, 54.25; H, 6.29; N, 6.75.

 <Desc / Clms Page number 30>

 
 EMI30.1
 



  1., ^ "? Drate âe 6.7-a'i: ttc: v-3-: 3-1..5-di: ntth .tlti :: ^ yrtcrcartot3;, r1¯2¯ ^ Acah'L 1 2. ttûxahYxroisa-. auvno'ian: (X11), to a mixture of 8 g (2.2 x 10 - '".... moles) of, r¯d, ithax, y -.-- (3,% - âi: nftxây, -2-thazo.y) mercapta-,: â; x: L-3.pp, 3, of - ttr'ydroisocuiPâo..in XI and 1.8 ml (2.4 x 10- 2 moles) of 40% formaldehyde, 4.1 ml (11 x 10 "'' N) of 8% fornic acid are added. There is a severe drawback of carbon dioxide. The Slangs are warmed on the surface. water bath, boiling for one hour and more and concentrating it. Addition of one equivalent of hydrochloric acid and another concentration gives 5.2 C (? 7%) of a crystalline hydrochloride. twice in an acetone-water mixture provides a
 EMI30.2
 analytical sample melting at 180-184 C (decomposition).
 EMI30.3
 



  Analysis: Calculated for C19H26N2O2S2-HCl: C, 54.98; H, 6.56; ii, 6.75.



  Found: firp 55.05; I, 6.62; îÎ, C7, $ 7 ..
 EMI30.4
 



  EXAMPLE $ Replacement of p-p-chlorothiophenoxy acid
 EMI30.5
 propioniqua (also called µ-p-chlorophenylmercaptopropion1que acid) 'of Example 1 by wn equinola weight, ire: acid - (p-n3.ropïny.mercapto) propioniquL, acid - (o-trJ.fluoroEiethylphnyl3! ercapto) propionic diacid - (:

  , p-dichloronhenyl, ercapto) prop3.oniquey. - (o-fluolph6nylmercapto) propionic acid, -o-brarophnylnercapto) prop3onic acid, -e-chlorophenylmercapto) propionic acid, (a, o-di.chlorophcn, y3.rercapto) prop3onic acid, acid - (p-thyîphcny.raercapto) propi.on3.çue,

 <Desc / Clms Page number 31>

 
 EMI31.1
 p- (p-1sopropylphenylmercapto) propionic acid, fi- (p-methoxyphenyltercapto) proploniqàe acid, - (m, D-dimethophenylmercapto) propionic acid, P- (o - n, 'Ltroph6nylmprcapto) diacid - (- pyridylnercapto) proponic acid, µ- (4-pyridylmercapto) propaonic acid, p- (2-thienylmercapto) propionic acid, deaedde - (3-thinylmercapto) proplonic. p- (2-chlorothienyl-3-marcapto) propionic acid and 9- (3-chlorothienyl-2-morcapto) p.-oplonic acid,
 EMI31.2
 produces respectively the:

   
 EMI31.3
 lL - (p-nitrophenylmercapto) ethyl17- 6.7-dinethoxy-2-micit'.nyl-l, 2,3, .4-t ,, trdiydrol soquinol4ine hydrochloride, l - / -. (o - trifluorom4thylphnnylmereapto hydrochloride ) thy-b, '-di mthoYy-2-mthy-l, 2, 3, l * -Vtr ahydroi soqui-
 EMI31.4
 nolein,
 EMI31.5
 1 - p- (m, p-dichlorophenylmercapto) ethyl 7-6,? - din thoxy-2-m thyl-1 hydrochloride 2, 39 .-- t trahydroi soauinciiine, l --- (o-fluorophenYlmercapto) ethyl17- 6,7-dimetÀoxy-2 - = - ethyl-1,2,3,4-tetrahyàroàsoquinoline hydrochloride, 1-- hydrochloride - (o-brornophénYlmercapto) ethy17-6,7- 'dj mth.oxy .-: nthyl-1, 2, 3, * têtra: ydxox soquir.o.é.nsp hydrochloride de l-'p- (o-. chlorophenyliNercapto) ethy7- 6, '- di:

  thoy'-2-m.Ethyl-i,, 3,.-ttrahydrai oouinoiines hydrochloride of 1-fp- (o, o-dichlorophenylmercapto) ± thy 7-, "ï-dimthaxy-2 rathyl - .., 2,, . ttra, hydrvi, aoqui no.3.re, hydrochloride of 1 (p methy7.phnJ3.mareaptothy.



  1a? -À: ethox = y 2-: xétry3-, 2, ,, f * ttrai; droïsoquinoi.inc, hydrochloride of 1 --- (p-1soprüpy1phenylmercapto) 0thy17G, '.- â,: ét.oy-? methyl.-L, 2r 3, .trahydrai soqazinoßin,

 <Desc / Clms Page number 32>

 
 EMI32.1
 1-ffl- (p-nettioxyphén> 'lmercapto) hydrochloride 4thy fi- 6, 7-d3; nthot -'.-: thy .-- ,, 2, 3, īßvtrahydroi soçtzînoêne, hydrochloride of 1 - ( , p-dimethoxyph6nylmercapto) thyy7-6,7-dii4hox, - a; ethyl-1,2,1. ttr..ydrosoquinoline, hydrochloride of 1 - p- (o-n1trcph nylmeroapto) éthy17b a'-d itzo.1 -: ahy3..1., 2, 3,, .ttraa'ydra3 saquntr, donkey, hydrochloride of l-, CP- (2-pyridylmarcapto) ethyl ¯7 -6,7dtrathafy--:

  a thy.-x, 2, 3a -ttz 'raydroâ soauirsolne, hydrochloride do. s-4-? β i .dy.n ercapto thy-6, 7 .. dmctzoay-2-taZyl.-. 2, s .mt'trahydxoi scaqunolne, 1-fµ- (2-thienyInercapto) ethyl Ù-6,7diratho.c, -2-thy1-I, 2, 3, l-ttrahydroß soqzinoâne hydrochloride, hydrochloride of 1- fs 3-thi ny: neraapéo) thy = b, idimét: oxy-w-mpthyl-., 2 J 3,! A.-k trahydxa soqunol.â ne hydrochloride de?., I - (- chloroth.nyï -3-mercapta? Thyb, ¯? EYthcyr-.w-netiyl-3,, 2,3,4-vtrahydroisocuino .; eine, and hydrochloride of. -3-aia7.oroth, ny3.-2-mereapta) thyb, 7-d: tho: y -? - thy.-? ,, 3,, .- t'trhydxo: F saq, o.ï ne EXAMPLE 6.
 EMI32.2
 
 EMI32.3
 he

 <Desc / Clms Page number 33>

 
 EMI33.1
   IV
 EMI33.2
 e 13- (p-fluorothiophenoxy) proion: 1Que - (11.

   20 g (0.156 mol) of p-fluorothiophenol are dissolved in 50 ml of water containing 12.5 g (0.312 mol) of sodium hydroxide.
 EMI33.3
 P-Bronoproplonic acid (23 g (0.15 μm) is added and the resulting solution is warmed on the boiling water bath for one and a half hours. The mixture is cooled and acidified with 15 ml of concentrated hydrochloric acid after which the product separates out as an oil.

   The oil is crystallized by scraping, collected and dried to obtain 31 g (100%) of acid
 EMI33.4
 - (, 9?. 'Wflrotâl. ^ PhÉrOà:' propiorz.que, Recrystallization from ethyl acetate gives an analytical sample melting at 70-72 C.

 <Desc / Clms Page number 34>

 
 EMI34.1
 Annivno: Calculated for C 9 1-1 9 FO 2 s C, 53.98H, 4.53 Found: C, 54.00; H., 4.43.
 EMI34.2
 



  P.on.ov4ratr lpmtde of i.-i acid,? - fluaro'h¯3o; hnoxynronionicue 11 ', we mix 27 g (, 3.30 mole.) Diacid - {p¯i'luorothiophézzoxyj propioniqueand 24.4 g (0.135 mol) d9ho; r.ovratry.ar.tine in 125 ml of toluene, and the solution is refluxed for 42 hours with a Dan-Stark collector until the theoretical amount of d has been collected. water, i.e., 2.4 ml. The solution is filtered and concentrated. The resulting oil is crystallized by scraping from an acetone-water mixture. We collect the
 EMI34.3
 product and dried to obtain 29 g (61%) of homovf, p- (p-fluorothiophenoxy) propionic acid ratryi-amide. Recrystallization from a mixture of t: ny.ettSkellysolve Dut acetate gives an analytical sample melting at. vs.



  4n * lV '* #' Calcl * lle for l, a2N3S: C. 62.79; H, 6.10; N, 3e85 Found: C, 62.65; H, 6.06; N, 3.76.
 EMI34.4
 dimt.> thaIuoroÇh3obhnoxrthyl 'j.- 1,2,3,4-tetrahydroisoquineleine (111). 4.5 g (0.025 mole) of phosphorus pentachloride are slowly added to a so-
 EMI34.5
 solution of 5 g (0.0136 mole; of p, - (p-11aorot1'iophenoxy) propioniou in 50 ml of chloroform. The mixture is heated under reflux for one hour and twenty minutes, and concentrated to A red oil is obtained The oil is suspended in 25 ml of water and made besic to a pH of 9 with a 20% solution of sodium carbonate.

   The basic suspension is extracted with two 40 ml portions of ethyl acetate. We

 <Desc / Clms Page number 35>

 ethyl acetate is dehydrated over magnesium sulfate, filtered and concentrated to obtain 5 g of a red oil which crystallizes but which refuses to crystallize ,,
 EMI35.1
 The crude dihydroisoquinoline is suspended in 50 ml of ethanol warmed in a water bath at 60 C. 1.9 g (0.05 mole) of sodium borohydride are gradually added, with stirring. The resulting solution is stirred for 45 minutes at 65 ° C., then cooled.



  Addition of a drop of hydrochloric acid does not give off hydrogen which indicates that all of the sodium borohydride has been consumed. The mixture is concentrated, the residue is treated with water and the residue is treated with water. 'extracted with two portions of ethyl acetate. Ethyl acetate is dehydrated over magnesium sulfate, filtered, and concentrated to obtain a yellow oil which immediately crystallizes. The product is isolated by trituration
 EMI35.2
 in an ethyl acetate-TTSkellysolve Bn mixture and then collecting it by filtration to obtain 1.3 g of 6.7-dimetiioxy-1 - (- p-fluorothlophenoxyethyl) -11.213, /, tetrahydroisoquinoline.

   Recrystallization from ethyl acetate-ttSkellysalve Bt 'gives a. analytical sample melting at 95.5-97.5 C.



    Analysis: Calculated for C19H22FNO2S:
C, 65.68; H, 6.38; N, 4.03
 EMI35.3
 Find? 65.80; He 6e38; ! 9 4.02. hlarhy; spleen of 6, '7-d: L: ét'axy -.---- fLaorothio- .hénaaéthvl -2 -: eth 1-. 2 ^, -tetrahvdraiso ino'1 é3ne (IV). 0.9 ml (0.017 mol) of an 88% aqueous solution of fornic acid is added to a mixture of 1.7 g

 <Desc / Clms Page number 36>

 
 EMI36.1
 10, .OCàIk? mole) of b, 7-dieRt'r.o; y.-19 (-p-f.uorot: iophhnox; l- 4ihyi.j-1. ,, 3, l-ttraaydroisoquino: eine and 0.4 ml.

   (more than 0.005 mol) of a 40% aqueous solution of formaldehyde. The mixture was warmed on the water bath for two and a half hours, and concentrated. The residual oil was diluted with one equivalent of concentrated hydrochloric acid, cooled and scraped to obtain a crystalline solid. The latter is isolated by trituration in a mixture of acetone-ethyl acetate and then collecting it by filtration to obtain 1.7 g of 6,7- hydrochloride.
 EMI36.2
 dica, ZO? c, -Z - (- p-fhuaro thiophénoxyçthy2 - = ¯thyl- ,, 2, 3, J * t & trahydrolsoquinoline. Recrystallization first in an ethanol-nethanol mixture, then in acetonitrile gives a analytical sample showing two melting points.

   The first is at about 130 C after which solidification occurs, then a second melting point at about 160 C. The melting points are not clearly defined.
 EMI36.3
 



  Analysis: Calculated for C20H24FNOZS.IICl;
C, 60.36; H, 6.33; N, 3.52 Found: C, 60.18; H, 6.58; N, 3.87.



    EXAMPLE 7
 EMI36.4
 II

 <Desc / Clms Page number 37>

 
 EMI37.1
 
V
Ss- (p-trifluoromethylthiophenoxy) propionic acid (I). 24.4 g (0.159 mole) of ss-bromopropionic acid is added to a mixture of 30 g (0.159 mole) of p-trifluoromethylthicphenol (indicated by F. Gadient et al in "Helv. Chim. Acta". , 1860-1870 (1962). See CA, 58,4575a (1963); the preparation process is that of "Org. Syn. Coll. Vol. 1, John Wiley & Sons, Inc.

   N.Y., P. 504, (1941)), in 50 ml of a 25.6% solution of sodium hydroxide. The resulting solution is warmed for one hour and derated on the boiling water bath, it is

 <Desc / Clms Page number 38>

 cooled and acidified with 32 ml of concentrated hydrochloric acid. The product crystallizes and is collected by wire.
 EMI38.1
 tration to obtain 40 g (89%) of p (p-trifluorom6thylthlophér.oxy) proplonîcue acid. Recrystallization from "Skelly-joist Bit gives a sample, analytical melting at 63-a, C.



  .nai, yse: Calculated for C1oH9F; 02S:
C, 47.99; H, 3.63 Found: C, 48.16; H, 3.82.
 EMI38.2
 



  Homov.:érat .r, yl ar.1i de .d'ac <, àe, $ trifluoraméthy, lr thiotlhenoxyp: r'o, pion: 1aue (l1L. A solution of 32 g (0, L2a mole) of 3 P trifluoromthyl.th3ophéna acid,) pr. pionic in 150 l of toluene, 2le8 g (0.12 mol) of horwovératrylamàne are added. The mixture is heated at reflux for 24 hours with a Deantark collector to obtain the theoretical amount of water. Cooling the solution provides 27 g (54%) of homo-
 EMI38.3
 crystalline veratrylamide diacid - (p-tr1fluoromJthylthiophenoxy) propionic. Concentration of the mother liquor provides a second harvest. Recrystallization
 EMI38.4
 in a mixture of dedt7.iyl acetate- "Skellysolve B" provides an analytical sample, melting at 81-83 C.



  Analysis: Calculated for C20H22F3NO3S:
C, 58.09; H, 5.36; N, 3.39
Found: C, 57.90; H, 5.53; N, 3.32.
 EMI38.5
 Ciloi, 6.7-diuzét .vdrp-te: iōv.l. p: ¯ :: rfLuera !!. '.. {thv1; thQPÈ'nothYl) - 3, A-di hydrot: i. which noltin {1111 ..



  Is suspended 5 g (0.012 mol) of the acid homovetatrylanide (1,> - trif - '. Noro tl-lî oph (., Noxy) pro pi oni that in 50 ml of toluene and added 9 , 2 g (0.06 mole) of oxy-

 <Desc / Clms Page number 39>

 phosphorus chloride. The mixture is heated to reflux for three hours and fifteen minutes, cooled and concentrated to obtain an oil which is suspended in 50 ml of ae and warmed below the temperature. reflux temperature for 16 hours. The mixture and the extract are cooled with two 50 ml portions of chloroform.

   The chloroform extracts are dried over magnesium sulfate. filters them. and the con
 EMI39.1
 center to obtain 3 g of white crystalline $ -d3.mthoxy- 1- (µ-p-trafl, aoromethylthiophenoxyethyl) -3, ± -dihydroisoquinoline hydrochloride. Recrystallization from acetone-ethanol gives an analytical sample melting at 152.5-154 ° C.
 EMI39.2
 



  Analysis: Calculated for CZOHZoF, NO2S.HCl: Ce 55.61; ki, 4.90 N, 3, Found: C, 55.62; i3, J, 93N, 2.95.



  6.7-d1methoxY-1 hydrochloride (r, -p-trifloromethy.thi othno.ythya.) - I, 2, 3, r 'ç¯étra? Ay dro soauineinq flfl. 7 g (0.0177 mol) of S = -dimethoxy-i.¯ (-p-triflcaoromethylth3 aphnaxythyLl -3, l-.d.hydro, saquinoline, obtained from the hydrochloride by neutralization with sodium carbonate, suspended in 100 ml of ethanol and heated to 55 C using
 EMI39.3
 of a 'bai11-maI'1e. Is added p! 'Ogre3siveinent Op75 g (0.02 mol) of sodium borohydride, while stirring and warmed!: 161nBe for 45 minutes at 10C.

   Hydrochloric acid is added until all of the excess hydride is decomposed and the mixture is concentrated. The residue is treated with water and extracted with chloroform. The chloroform is dried over magnesium sulfate.

 <Desc / Clms Page number 40>

   sium, filter and concentrate it to obtain an oil
 EMI40.1
 which provides 4.6 g of crystalline hydrochloride from an ethyl acetate-ether mixture. Recrystallization from ethyl acetate gives an analytical sample)
 EMI40.2
 mp 110-165 ° C, 6,7-dimethoxy-1- ¯awtri '.ub r o; thylt: nâ cpitnay xahyij -1 p 2 p p, - .. et rahydr-- 1soquinol: 1ne hydrochloride.



  A: 1 sc: Calculated for CON (32S.C,: C,: tp0 H, z343 N, 3W3 Found: Ce 54.18; H, 5p6 .; Ne 3p.5 Clilorhvdrate de 6, 'i-drnthoxY-1 - (G tr'fluorom hy? T.orl ^ t> ncxv, thvl -.2-: ncth 1-.2 .I ,, - ttrahYdrcisoR.u.1oleine - (V). 0.7 m1 (0.093 mole) of 40% aqueous solution of flormaldehyde to a mixture of 3e6 g (0.0083 mole) of 6y7-diin6thoxy-1- (pp-tr''fluoronethylthiophna., Ethy.) -. pp3p, t-ttrhydrosoq hydrochloride Uirioline in lp5 al (0.029%) of an 88% aqueous solution of fornic acid and one equivalent of sodium hydroxide There is a violent evolution of carbon dioxide.

   The reaction mixture is warmed for one and a half hours on the boiling water bath and diluted with two equivalents of hydrochloric acid. The addition of water, provides: 3 g of hydrochloride
 EMI40.3
 6,7-dimethoxiP-1- (fi-p-trafluoromethylthiophenoxythy,) -H--cthyl-, 2,3p, -têtxahydroisoquino2.rae lens. Recrystall: tsat: 1on in mdthauoi produces an analytical sample melting at 198-212 C (decomposition).



  ., nn. # es Calculated for C21HZ4F, 3NO2S.HC1: C, 56.30; H, 5th63; N, pZ 4 Found: C, 56.13 He 5e63; N, 2.97.

 <Desc / Clms Page number 41>

 EXAMPLE 8
 EMI41.1
 
 EMI41.2
 1.- ± -. Hromothiorhnō th 7. - 6 '-dimthoxv-mt.h 7.-2.-TfNr7hyroâsonui.nâ.irce hydrate.



  A solution of Oe3 g (0007 mole) of sodium hydroxide and 1.4 g (00074 mole) of p-hromoth1ophenol in 30 ml of ethanol is mixed with 3.5 g (. 007 mole) of 2, - aztidirl0-c, '7-dimetAOSCy-2¯-1,2,3-methyl-p-hromobenzenesulfonate, (- tetrahydroisoquinolinium) and heated for an hour and a half on a boil.



    The mixture is concentrated to dryness under reduced pressure. The residue is treated with water and the extract with chloroform. The chloroform extracts are dried over magnesium sulfate, filtered and concentrated to dryness to obtain an oil which gives 2.6 g (76%) of crystalline product from an acetone-anhydrous hydrochloric acid mixture. Recrystallization from methanol affords the analytically pure hydrochloride of
 EMI41.3
 .- (-a-bromothi ophnoxyrthyi) -, 7.dimt.ho: y - ,. thy.-, 2,3G, -rtrF, hydroisoqu3nane melting at 192200oC (not clearly defined).



  Analysis: Calculated for C22BrâOS.iC7. : C, 52.55; H, 5.49; N, 3.05 Found: C, G.,. Jt7j fi, 5.69, N, 304.



   By analogous procedures, the compounds of the following Examples 9 to 12 are prepared according to the amounts

 <Desc / Clms Page number 42>

 indicated and the properties established: EXAMPLE
 EMI42.1
 
 EMI42.2
 Chlor.h.vdr.::tte de 1 - (;; - n-chlo: roth1oph0noy. :( thy.l) t., 'Iwd3.rtho.-Fm.; hvl-.1 2.' G.- tetzzYavdroisoou3rio.fine (for comparison with the same compound previously prepared by another process).



   80.5 mg (0.002 moles) of sodium hydroxide.
 EMI42.3
 



  310mz (0.002 mole) of p-chloTothiophenol 1 g (0.0021 mole) of p-bromobenzenesulfonate of / C2,1-g7-azetadino-6,? - dir; 4thoxy-2-methyll, 2,3,4-t4trabydroàso '= inolinium. providing 560mg (67% l- (p-poa7, orohophc.-nart: hyl).-b, 'ï-d3mF.hoxy.-2-rC hyl, 39 ra t3roà.socfuincl3ne hydrochloride having an absorption spectrum infrared rays identical to that of the same compound prepared by the process of Example 1.



   EXAMPLE 10
 EMI42.4
 
 EMI42.5
 . ' a% '- <..' T ': S1C33i-r ¯ ;;,' "'whVl-1 w .., t7-: ï'tPb. ionhtnox5 - -'w1 -. ^ x3, I4- ^ rFa, = .rosoaur.lane.

 <Desc / Clms Page number 43>

 
 EMI43.1
 



  0.212 g (0.0053 sole) sodium hydroxide
 EMI43.2
 z2 g (0.0053 mol) of p-nitrothiophenol 2y0 g (0.0042 mnle) of p-bromopcnzènesulfonate de, 2, 3. -azt3 dïno-b, '- dimhocy-2-mthy'! I, 2,3,, -ttrarydroid soûuinal-inius providing 1.0 g (61%) of 6,7-diiRëthoxy-2-sethyl-1- (6-pn, trothiophcroyl) --1, 2, 3, h- Ltrs.rydroi soquinc.inc, after recreating in ethyl acetate, the melting point is 129-1310C.



  Analysis: Calculated for CzoB.Z4NZ04S: C, 61e83; H, 6.23; N, 7.21 Found: C, 61.50; 3, 6, 2g; N, 7, 50.



  EXAMPLE 11
 EMI43.3
 
 EMI43.4
 Axa onoethanolate fie de 6,7dàmetho hydrochloride -2- # ôthvl-1- N-oxvde .de ... p.-2-pvri dyle) - !: 1erc! -Nj; o- eth '! -. at .'?. dy-ttrahydra3 seasi na.ie.



  0.94 g (C3, OOb3 mol) of sodium salt of 2-mercaptopyridine N-oxide 2, g (0.0053 mol) of p-bromobenzenesulfonate, 2.1 L.s. ^% - aetid; na-, ^ wd1 m tha: y-- uahy.- 1,, 3,1.-ttral> ydrai soeuialci: itm fou1'n: issent 1, S g (71%) of 6, V - dihydrochloride monoethanolate di: 6thoXY-2-methyl-l'-L (tJo: \. "Yde of p-2-pyridyl.e) -mercapta thy-, qz 's, ¯ 4 ± trahycï, rof sanuinal3ne

 <Desc / Clms Page number 44>

 
 EMI44.1
 in an ac-to, ie-ac4-do hydrochloric mixture. Recrystallization from ethanol-hydrochloric acid melanze provides an analytical sample melting at 11 -135 ° C. (from the position).



  Analysis: Calculated for 1H2h0.2HC '., C21OF: C, 52.60; H3 6.73; N, 5.85 Found: C, 52.94; He 6.93; N, 5.86.



  B. lono6thanol: te of dichlorhvdratē.de6,, 7M.tloxv ..; - rth 1-1-- <s-2 .. vrivl -: ^ .: ercr tofthvï) -1d23t = -tétre 'hdroJJoquinQ10ine. A stirred and cooled solution of 4 g (0.011%) of 6e7-direthoxy-2-m6thyll- ± 7 (3-2-ryri; yl 11-oxide) .. m Onrcap: oéthy., 2? 3 is treated. , I tetrahydroisoqu1noline in 30 ml, of chloroform with 2.2 ml of tri-phosphorus chloride * The solution is heated
 EMI44.2
 at reflux for an hour and a half. The solution is neutralized
 EMI44.3
 chloroflormic toz and washed with dilute sodium carbonate, dehydrated over magnesium sulfate, ìl-
 EMI44.4
 tre and concentrate it to dryness to obtain an oil
 EMI44.5
 which provides 2 g (.0%) of α, 7-dim4tho> dihydrochloride monoethanolate: y-2-methyl-1- (p-2-pyridyl-mercaptoethyl) - 1;?, 3, / + - t6trc -hyô.roisoquinq14à> the crystalline in hydrochloric acid ethanolic.

   Recrystallization from ethanolic hydrochloric acid produces an analytical sample melting at 118-135 ° C (decomposition).



  Analysis: Calculated for ty5.2ai..C: .H1: C, 54.42; RJ 6.96; N, 6.05 Found: Ce, 54.50; H, 7.00; N, 5.95.

 <Desc / Clms Page number 45>

 
 EMI45.1
 



  EXAMPLES
 EMI45.2
 
 EMI45.3
 6,? - d3r.:étha.cY-2-réhy3 -ï.-N-oxide of 1- ür3 dy3e wrr <erGaT3toéh'1 -2,! -W'trahvdrOisortlino.eins 0.0098 mole of the sodium salt of N -O7de of 4-mercaptopyridine Z-Prgparé in crude form by hydrolysis of 2 g (0.0098 mole) of (4-pyridlne N-oxide) -thiouron1 chloride in sodium hydroxide-7; z5 g (0.0053 mole) of 2, .- a, y% - azétiâ3.nob p-bronobenzenesulfonate $ 7> cY i.e hox, -2-r, ^, ethyl-L,, 3, .-té-rahydro. t soaui noiéin.ium producing 1.6 g (85%) of 6,7-dàmethoxy-2-methyl-1-. (1-o-.yde de -, - pyridyle) -mercapoéhy3-, 2, s, -terahydro1soquir.olein. An ana- sample is recrystallized.
 EMI45.4
 lytic in a mixture of methanol-ethyl acetate, ion-
 EMI45.5
 dant to .âb,.-25i, 5 C.



  Analysis: Calculated for C19H24N20JS: C, 63.30; H, 6.71; N, 7.77 Found: Ce 63e2O; H, 6.88; N, 7.84.



  B. 6, i-dineho: cv ----; Eā hyl-1. En-trridylrereatoFtYyl) - =, 2,3, ¯-- Lrahydro3ûocuir¯yine By a process analogous to that of Example '11, 3.1 g (0.0086 mol-) of b9? - di are reacted ; ethox.y-2-eth; Z-1 -, (I.oxyâ.e de -: - pyr. i dyle) -rerc apo é hyl7- '',, 3,, .trahydroi soaui no-. skimp with 2 ml of phosphorus trichloride to obtain 3 g (100%) of b, 'i-di.nF: hoxy -.'- éhy3 .-. (- ..' ,, - pyx3dyl) ¯

 <Desc / Clms Page number 46>

 
 EMI46.1
 iaercaptOGthyl) -. 123 .- 'y'c'soquinoline. Recrystllization from ethyl acetate-IISkellysolve BI 'gives an analytical ÓchDl1t.Illon, mp 95-96 ° C. afja: Calculated for C'9H-4N2O2S: ce 66.24; 11, 7eO2; Ne 8e13 Found: C, 65.74; H, 7.06; N, 8.23.
 EMI46.2
 



  EXAMPLE 13
 EMI46.3
 
 EMI46.4
 Hydrochloride 3 ..- (E -?,! - c? IeYt.orth3oahnovéthy ..- ü g7-CÊ.iPt tii03: y -T. ".: 'rIV, .- Z 2. -Ttrt: h' ' : O SC5 unOZ.C: 23.e.



  02 .. (0.0053 ', mole) of sodium hydroxide. 0.95 g (0.0053 mole) of 3, .- d.c'¯zloroth.ophW oI ,, S g (OCQ53 mole) of ,, 1.-a, ..- azt3dino-é p-broobcnz0nesulfonate ,? - d3ratholr-; G Vhy, -i,, 3,, .. tctrahydroi soquins.cnum produce 2 g (92 10 of 1 - (- 3, .- dich? orothi ophcnoy thy1) -b,? - dimF tkaoxy - -rcthyl-I ,, 2,, 3, l-ttrahyàro. soquincFüne yes gives crystalline hydrochloride in ethyl acetate. Recrystallization from an acetone-ethanol mixture gives a snalytic sample melting at 160-165 C ( deccomrosltlon).



  Analysis: Calculated for CZollZ3N02SCIZ.fCl: cy 53.52; H, 5.39; N, 3.12 Found. VS; 53.63; 11, 5.5g; N, 3, 26, 3.21.
 EMI46.5
 



  This compound has been shown to be a very pain reliever '
 EMI46.6
 acti '; a: ns: 9 it exhibits analgesic action at a dose as low as 1 i "g / ks subcutaneously during
 EMI46.7
 rat tail tapping test.

 <Desc / Clms Page number 47>

   EXAMPLE
 EMI47.1
 
 EMI47.2
 h2orhvdrate of 1- 8-r.:-.c:aâorothio héno. ehv! - âinetho v2-nâéh -I -érah droisaouinoléires 0.264 g (0.0066 mole) of sodium hydroxide. 9 0.96 g (0.0066 mole) of m-chlorothiophenol, z0 g. (0.006. mole) of p -brorcbensnesltlfonat4 de j2, .- û "/ aétidina-f,? - diméhrxy-2-éhy3 ..-?, 2, 3s 4-tctß a.hydroi. ^ - ¯oq, zinoiéiniu provided ssent la 1- (pn- chlorothiopheno; yethy:

  1) -6.7 * -diméthomty-2 éhy -. ,, 3, .¯tétxahydxoisouino.éixae under fcr!? A of an oil which produces 1.5 g (58%) of a crystalline hydrochloride in a ethyl acetate-anhydrous hydrochloric acid mixture. Two recrystallizations from ethyl acetate ethanol provide an analytical sample melting at 156-158 ° C.
 EMI47.3
 



  Analysis: 'Calculated for C20HZ4CIN02S.HC1:
C, 57.96; (H, 6.22; N, 3.38 Found: C, 57.85; H, 6.19; N, 3.21.



   EXEMOLE 15
 EMI47.4
 

 <Desc / Clms Page number 48>

 
 EMI48.1
 rorrtlydra'e. of b.7-d3rthxr.-2-mt2.-1. ..s .. n thyl th i o ph noxv4hyI) .At, rnhxdrqsortuncl ejine.



  0.212 g (0.0053 mole) sodium hydroxide, 0.66 (0.0053 mole) of p - :; thy3.th3ophnol, 2.5 g (0.0053 mole) of 2, .- aaztldino p-bromobenzcnesulfonate -6,7mdim thoxy-2-métiy7.1, 2,, l - tetrahydroi soqui no.einium produce 1.1 (89%) of 6 ,, 'dâmct? .Or.y.-¯nêtTy-1- - (- p -: thyltniophnofyt; ay.) -., 2,3, / - ttrahydro3soçuino, ine which produces bromhdrate in an isopropanol-water mixture. Recrystallization from acetone-water provides an analytical sample melting at 190-194 C.
 EMI48.2
 



  Anq1xs: Calculated for C21R27N02S.HBr:
C, 57.53; H, 6.44; N, 3.20 Found: C, 57.29; H, 6.55; N, 3.12.



   EXAMPLE 16
 EMI48.3
 
 EMI48.4
 % 7-dimot; ioxv-2-m <'thvl-1 -2 J 5-tri <ilorothiophnoxythyl) -1,2.3 t4t gg¯J¯Ldroisoauinol, 4ine (process previously described).



     0.254 g (0.0064 mole) sodium hydroxide
 EMI48.5
 1.4 g (0.0064 mol) of 2,4,5-tricixlorothiophenol and 3eO g (0.0064 mol) of -2,1-α-! Azét1dino-6,7-dimethoÁ7-2 p-broaobenxenesulfonate -methyl-1,2,3,4-tetrahydrdSoqu1nolsinium

 <Desc / Clms Page number 49>

 
 EMI49.1
 provide 6, 'i-dihoxy-2-: i thv'! - I-i-; s, a5.-tr3chlo- .roh3ophnaxr r hyï.) - ï., 2, 3, l-térs.hydroi.saquinoline in the form of a crystalline solid which is recrystallized in a mixture of acetate dsêhyier.Ske? 7; s. re Bn to obtain 1.3 g (46%) of a. analytical sample melting at 100-101 C.
 EMI49.2
 Analvseô Calculated for C? 2C: fQZa;
C, 53.76; H, 4.96; N, 3.14 Found: C, 53.91; H, 4.96; N, 3.03.



   EXAMPLE 17
 EMI49.3
 Resolution of (+) - 6.7-dimethoXY-1-8.hy.dO cthrâ.-2-; i; h ï. ï. 2 3 lrahydaaisoruinol, 3r.P 11 a '& b ..



  To a hot solution of 73.1 g (0.292 mol) of () - & y7di nhoxya.-hydoxp-éhyl -2 hyï.wl y 29 3,, -trahydra.isoquind6ine in 375 ml of 95% ethanol, is added a hot solution of 39,, g (0.146 mol) of (+) - 2'nitrotartrani11ic acid in 375 ml of 95% ethanol. 75.9 g of octals are collected after a storage of 20
 EMI49.4
 hrs at 500. Recrystallization from 750 ml ds hr at 80% yields 69.8 g (92%) of material melting at 193.5-195.5 C.



   This material is converted to its free base by neutralization with aqueous sodium carbonate solution and extraction with ethyl acetate. Concentration of the ethyl acetate extracts provides 30.0 g of oil.



  This oil provides a crystalline hydrochloride in isopropanol and 10 ml of concentrated hydrochloric acid. Recrystallization from 150 ml of absolute ethanol gives
 EMI49.5
 22.3 g (55%) -) - 6,7-d3: nhcxyt¯3-- hydrochloride

 <Desc / Clms Page number 50>

 
 EMI50.1
 hydro) ..- yethyl-2-methyl-1,2,3, J + -tetrahydroi soquind61ne (11 a), melting at 177-130 C, fa Jµ5 + 22.7 (c 2.05 chloroform).



  Anill: Calculated for 1 / f213'C, 58.43; H. 7e7lé N, / ,, 87 ..



   Found: C, 58.67; H, 7.81; N, 4.63.



   The mother liquor from the initial cris is concentrated up to 1/5 of its initial volume and
 EMI50.2
 the treatment with leO g (diacid (+) - 2initrotartranàlifiue in 25 l of 95% ethanol. The solution is concentrated to dryness and the oil thus obtained is taken in ethyl acetate, OR, filter, wash With aqueous sodium carbonate solution, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain 33.6 g of an oil This oil produced a crystalline hydrochloride in an acetone-anhydrous hydrochloric acid mixture.



  Recrystallization from 95% ethanol gives 24.4 g
 EMI50.3
 (60%) hydrochloride (-) -6,7-dimetino; ty-1-fi-hydroxyethyl-2-atethyl-1) .3-tetrahydroisoquinol4ine (IIb); melting at 177-179 C, -a-75 -22.8 (c 2eO2, chloroform).



  An.Tlys # -: Calculated for lJf2l 3 *
C, 58.43; H, 7.71; N, 4.87 Found: C, 58.41; H, 7.81; N, 4.67.
 EMI50.4
 (-) -. l-a 7aztd) n-brooben7ènslfcnate no- 6, 7-d1.m6: t ;; hoxV'-2-methyl-l. 2. 3., - k-t6t.rahydroi.sooill..nolf :: lniu !! 1.



  11I. 23.8% (0.083 mole) of (+) - 6.,7-dimethyl-2-m ,, thyl-1,2,3,4-tetrahydrolsocuinoline hydrochloride is converted to its free base by neutralization with sodium carbonate and extraction with 200 ml of chloroform.
 EMI50.5
 



  1-Oxluralt, eh "Lorofor., Is dehydrated over sodium sulfate.

 <Desc / Clms Page number 51>

 sodium and filtered. This solution is then treated with 23.2 g (0.091 mol) of p-bromobenzenesulfonyl chloride and stirred for 4 hours at room temperature. 44 g of anhydrous sodium carbonate are then added and stirring is continued for 16 hours. The reaction mixture is filtered and the filtrate is concentrated to obtain 38 g of crude crystalline material. A recruit
 EMI51.1
 tallisatlon in isopropano1 gives 26.8 g (69%) of analytical material (IIIa), melting at 178-128 C, - 25 ¯ 115 713 (c 2.02, chloroform) Analysis: Calculated for C20H24BrNO5S:
 EMI51.2
 ; p, 5, p? â H, 5.14? N, gRB Found: Ce, 51.24; binds 5.24? Ne 2.85.



  -hroobenr.énesu.anate e + - 1a aactr3inoo; mtpYl-1.2,3! At? trahdroisoauinolt.iniu- i11JJiL. 22.6 g (0.079 mole) of {¯>) ¯, #? Hydrochloride are converted. dimt.'oxy -.'.- métnyl-., 2, 3,, tctxaaydroi soq.zino .. lein to its free base by neutralization with sodium carbonate and extraction with 200 ml of chloroform.



  The chloroform extract is dried over sodium sulfate and filtered. This solution is then treated with
 EMI51.3
 ; 2.8 (5.085 mole) of p-broMbenzenesulfonyl chloride and stirred for 4 hours at room temperature. 41.5 g of anhydrous sodium carbonate are added and stirring is continued for 16 hours. The reaction mixture is filtered and the filtrate is concentrated to afford 39 g of crude crystalline material.

   Recrystallization
 EMI51.4
 deus isopropanol gives 26.0 g (70.3%) of analytical material, l! l, melting at 179.5-1g0.5 C, ra jµ5 -i-114.2 (c 2.00, chloroform) .

 <Desc / Clms Page number 52>

 
 EMI52.1
 An.vse: Calculated for C20H24BrNO, S:
C, 51.07; H, 5.14; N, 2.98 Found: C, 51.11; H, 5.12; N, 2.75.
 EMI52.2
 i :-( 'clorothloplëno: {vethv: L -6r7-di, m <.thax-.



  2 - :, ethyl3. '1-ttraay isoquinol3ine IVa. A solution of 0.3 g (0.0075 mole) of sodium hydroyide and 1.09 g (0.0075 mole) of p-chlorothiophenol in 30 ml of absolute ethanol is treated with 3.53 g ( 0.0075 mol) of p-bro-
 EMI52.3
 robenmènesalfonate de (-). ,,, â.-a "avétdâno-6,7-dmétho 2-: ét.yw, 2.3 ,. -'vétxa., ydxoisaquinoléinâut llla and heated on a boiling water bath for 5 minutes The reaction mixture is cooled, diluted with an equal volume of ethyl ether, and filtered.
 EMI52.4
 trat until an oil is obtained which recrystallizes on standing.

   Recrystallization from 95% ethanol gives 1.65 g (58%) of analytical material (IVa) ,, having a dot
 EMI52.5
 Melt of 54.5-55.5 C, --75 - 365 (c 2> 05, chloroform).



  1b1? Lvse: Calculated for C20ll24CINOZS:
C, 63.56; H, 6.40; N, 3.71 Found: C, 63.71; H, 6.45; N, 3.56.
 EMI52.6
 



  , (') - I - (.-- chloxathohénaxyétl -6,7.-dimêt: oxy- 2-m <thYl-1.¯2¯, µ, <oé / ttahyd #? Isoauinollinēlvb. A solution is treated 0.3 g (0.0075 mole) of sodium hydroxide and 1.09 g (0.0075 mole) of p-'chlorothic'phenol in 30 ml of absolute ethanol with 3.53 g (0, 0075 mol) of p-'Dromobenzcnesulfonte of (+) -. L 2, ia, ¯,% azet: i.dino-6, 'd3methoxy-2. Mt: ißl.l, 2,3,1-tc5trahydroisoquirnniart (Illb ) and heat on a boiling water bath for 5 minutes *

 <Desc / Clms Page number 53>

 cool the reaction mixture, dilute it with an equal volume of ethyl ether, and filter. The filtrate is concentrated until an oil is obtained which crystallizes on standing.



  Recrystallization from 95% ethanol gives 0.85 g (30%) of analytical material having a melting point of
 EMI53.1
 53-54 C, -a-7B5 + J7.00 (c, 1.62, chloroform). Analysis: Calculated for C20H24ClNO2S:
 EMI53.2
 C, 63.56; H, 6.10; N, 3.11 Found: C, 63.87; aig C7gj.Oj 1> 3.78. f 18 gegolution of 'la (+) -1- (beta-p-chlorot, hi ophÁp.o: W-: th I -6' -dir.rétho. --mth 1-1.2 5 ty-ttrah dro3soaixinol3ne IV a & b. 8.7 g (0.0495 mol) of (:) - 1bêta-p ch7oxothi.onï: noxythyl) -b, 'I-àimrthoxy - atlayJ 1g2g3,1-ttrahydroisoquimoéine and 8, are taken up. 4 g (0.0286 mol) of (+) - 24 "-dichlorotartranilic acid in 125 ml of hot ethyl acetate, filtered and cooled to cause crystallization.

   The crystals are collected and washed with 25 ml of cold ethyl acetate.
 EMI53.3
 the mother liquor, for the isolation of the (+) isomer, is recreated 15 g of the crystals in 125 ml of ethyl acetate to obtain 14.3 g of the pure (-) isomer salt, melting at: Ll ;, â - .. 3.6g 5 Cw L-a1Pha-75 + 42.60 (c 1.8, GHCl3). This material is shaken with 50 ml of water containing 2.5 g of sodium hydroxide and 50 ml of methylene chloride.
 EMI53.4
 The solid material is removed by filtration and the methylene chloride layer is separated. The aqueous layer is extracted once more with methylene chloride.



  The extracts are mixed, they are dehydrated over K2CO3,

 <Desc / Clms Page number 54>

   filtered through diatomaceous earth (“Celite”) and concentrated to dryness to obtain 7.5 g of a colorless oil which crystallizes as a residue. Recrystallization of this material from an 85% methanol-water mixture
 EMI54.1
 gives 4.1 g of pure 3.soraLre (-), melting at 54.0 -55.0 ° C., aj75 -38.4 (2.0 c, CaCl.). Its infrared ray absorption spectrum is identical to that of the material prepared in Example 17.



   This is the (S) isomer in the nomenclature of
 EMI54.2
 Calzrn, Ingold and Prelog "Lxperientiatt, XII (3), 81-94 (March 15, 1956).



   This (S) isomer is converted to its acidic fumarate in the following manner. We take back. 189 mg of (-) -1- (beta
 EMI54.3
 p-chlorath 'ophfzioxy thylj.-6, 7-d: mtxiax-y-2-.methyl -1,2,3,4tt5trah, dra.socu: nc.:, ne and 58 mg fumaric diacid in 2.5 ml of hot isopropyl alcohol which, after cooling slowly to 5 ° C. deposits the crystalline (S) isomer acid fumarate which is collected by centrifugation, which is dried and weighs 240 mg, and melts
 EMI54.4
 ? ; 6, -.;, 5 C. (corrects) and shows Ca-Y) + 21.9 (c 2.0Q, 95% ethanol).



  Analysis: Calculated for C20H24C1NQ2S.C41I404: C, 5835; H, 5, 1 ,; N, 2.84.



  Found: C, 58.73; 59, / y9; 57.99; 8.90H, 5J'76; 6.0 5'a57; 5.99; N, 2.79
 EMI54.5
 The isol: 1clre (+) is obtained from the same liquor from the first crystallization of the salt. The ethyl acetate solution is cooled in a water bath.

 <Desc / Clms Page number 55>

   iced, it is treated with bleaching charcoal and filtered through "Celite". It was washed with 50 ml of 10% potassium carbonate, filtered and concentrated to dryness to give 9.4 g of an oil as a residue.

   This oil is crystallized in mixed lower alkanes ("Skellysolve B") then in
 EMI55.1
 methanol at 85% to obtain 5.4 g of aatiere rich in isomer (+), a-75 + 23, aO (c 2, o, CHC13). From the mother liquors of these crystallizations, 2 g of material are recovered which, after crystallization in a mixture
 EMI55.2
 5-cau methanol, gives 1,, g of pure sor, era (+) having a melting point of 53.5-55.0, [[alpha]] 25D + 37.8 (c 1.9, CHCl3).



   This isomer (R) is converted to its acidic fumarate as follows. 2.00 g (0.0053 mol) of
 EMI55.3
 (+) - 1- (µ-p-chloiothiôpheno? Yethyl) -6,? - dimethoxç / -2-m4thyll, 2,3,4-tardrahydrossoqu3noléi; e and 0.615 g (0.0053 mole) of fumaric acid and take them up in 35 ml of isopropyl alcohol. The solution is filtered, evaporated to about 30 ml in a stream of nitrogen and stored at room temperature to allow crystallization of the R-isomer acid fumarate which is collected and separated.
 EMI55.4
 che at 56% / 0.05 mm; it weighs 2.0 g and has a melting point of 129.0-13l.0oC. (corrects) and presents.



  -a-7; ' -2l, po (c 2.02, 95% eth 10l).



  Analysis: Calculated for C20L24C1Id0zS.C? 0 C; \, 58.3 ;; H, 5.71; II, 2.8 Found: C, 5s,? OjH, 5.6; N, 3, 02.



   All or substantially all of the analgesic inaction resides in this (R) isomer, whether in the form of. free base or a single addition of diacids.

 <Desc / Clms Page number 56>

 



   The acidic fumarates of (R) and (S) isorers prepared above exhibit different melting points because they have been isolated in diferent crystalline forms; this is indicated by their infrared ray absorption spectra which are identical when taken in solution, ie in a 9: 1 mixture of chloroform and methanol (cf. 2000 cm-1- 1250 cm-1).



   Mixing equal weights of acid fumarate of (R) and (S) isomers in hot isopropyl alcohol; cooling produces the crystalline racemic acid fumarate of compound 1V, melting at 120.0-121.0 C. (corrected), which also exhibits the same infrared absorption spectrum in solution as a sample of this salt prepared directly from the racy base.



   The partially resolved material is purified as follows. 4 g ([[alpha]] 25D + 23) of this material are taken up in 50 ml of isopropanol and treated with 0.5 ml of concentrated hydrochloric acid, concentrated to 25 ml and cooled. The crystalline material is removed by filtration (racemic HCl salt). The filtrate is concentrated, taken up in 1: ethyl acetate, filtered, washed with dilute sodium carbonate solution, dried over sodium sulphate, and concentrated to dryness.

   This residue is crystallized from an 85% methanol - water mixture to obtain 1.2 g of pure (+) isomer (1Vb), melting at 53.0-55.0 C., [[alpha]] 25D + 37 , 5 (c 1.9, CHCl3). The infrared absorption spectra of these two samples are identical to that of the material prepared in Example 17.

 <Desc / Clms Page number 57>

 



   Although, in the above discussion, various embodiments of the present invention have been presented with precise and circumstantial details for the purpose of illustrating, it will be apparent to experts in this field that the present invention is likely to apply. apply according to other embodiments, and which can be varied widely in many details without departing from the fundamental concept, or the spirit or scope of the invention.

 

Claims (1)

R E V E N D I C A T I O N S. 1. A process for preparing compounds of general formula: EMI58.1 or. FR represents EMI58.2 (where W, X and Y each represent a hydrogen, chlorine, bromine, or fluorine atom, or a trifluoromethyl, nitro, lower alkyl; or lower alkoxy radical) and their non-acid addition salts pharmaceutically acceptable toxicants, a process which is chosen by: A - the reaction of a compound of formula: EMI58.3 (where FR is as defined above), or a metal salt of said compound, in an inert solvent, with at least about one equivalent, of a methylating agent, and <Desc / Clms Page number 59> B - The reaction of a compound of formula: EMI59.1 where Z represents an equivalent of an inert anion, in an inert solvent, with at least approximately one equivalent of a compound of formula FR - S - H where FR is as defined above, or a metal salt thereof. 2. A compound of formula '. : EMI59.2 where FR represents EMI59.3 (where W, X and Y each represent a hydrogen atom, or chlorine, bromine or fluorine or a tri- radical EMI59.4 fluoromethyl., nitro, lower alkyl or inner alkoxy), and its non-toxic acid addition salts EMI59.5 pharmaceutically acceptable. <Desc / Clms Page number 60> 3. A compound of formula: EMI60.1 (where. W, X and Y each represent an atony of hydrogen, or of a chlorine, bromine or fluorine group, or a radical EMI60.2 triiluorozethyl, nitro, lower alkyl or alkoxy, Lower), and its non-toxic diacid addition salts EMI60.3 pharmaceutically acceptable. 4. A compound according to paragraph, 3 in which W, X and Y each represent a hydrogen or chlorine atom, and its non-toxic acid addition salts EMI60.4 pharmaceuticals acceptable. 5. 6,7-Dimethoxy-1- (beta-p-chlorothiophenoxythyl) --- methyl-1., 2., 3 -t Etrahydro soquinoline and its pharmaceutically acceptable non-toxic acid addition salts. 6.- 6,7-dàmé ± hoxy "-1- (bôta-3,4-dichloTothiophnox.yethyl) -2-mthyl-, l,, 3,.-Tetrahydro soqulnoline and its non-toxic diacid addition salts pharmaceutically acceptable. EMI60.5 7.- A compound of 1st <Desc / Clms Page number 61> EMI61.1 or. FR represents EMI61.2 (where W, X and Y each represent a hydrogen or chlorine, bromine, or fluorine atom or a trifluoromethyl, nitro, lower alkyl or lower alkoxy radical) and its diacid addition salts * @ 8. A compound of formula: EMI61.3 (where W, X and Y each represent a hydrogen atom of chlorine, bromine or fluorine or a trifluoromethyl, nitro, lower alkyl or lower alkoxy radical) and its pharmaceutically acceptable acid addition salts. <Desc / Clms Page number 62> 9. A compound according to paragraph 8 in which EMI62.1 :, X and 'each represent a hydroene or chlorine atom, and its diacid addition salts. 10. 6, 1-Cimhoxy-3.-beta-p-chlozo? Aouhinoxy .. thyi; - '!, Z, 3, .- té4ratyàroisoqunaline and its acid additives. ; .1.- La &, -dâethoxy-.labs.-3, / -. Dichlorotaiohcno: -, rhy3.) - 1,2,3, 'r = aydâo.soqino3.: Ine and its addition salts acids. 12.- A compound of formula EMI62.2 EMI62.3 where Ze represents an equivalent of an an1on'inerte. 13. A compound according to paragraph 12 in which Z # is a halide ion. EMI62.4 14th comi> ose, according to paragraph 'in 14. A compound according to 1 paragraph 12 in which Z # is an anion of formula: EMI62.5 where X and Y each represent a hydrogen, chlorine, bromine or fluorine atom, or a trifluoromethyl) nitro, lower alkyl or lower alkoxy radical. 15. - A compound according to paragraph 12 in which EMI62.6 2 represents Iranian p-bronobenzenesulfonate.