DE2011024A1 - Patentwesen, Ost-Berlin WP138598 Process for the production of new 3-carbalkoxy-1-thia-isochroman-1, 1-dioxide derivatives - Google Patents

Description

Fta lÖ / Ü-

Process for the production of new 3-0arbalkQxy-1-thia - is ochroman-1 :, 1 ~ dioxide derivatives

The invention relates to a process for the production of nsuen "-3-carballs: öxy ~ i-tbiia-iso" cliio · * ·· man-ii-dioxide derivatives of the all-earth formula I, τ / or in IL and R ^ eij-i ^ n lower IU Alkylresty a Wasserst off atom or a lower Alltylrest and R ₁ is a branched or unverzv / _eigte: saturated od3r unsaturated alkylene group by halogen or by aryl or heterocyclic · i!

cyclic radicals can be substituted, o-.ler mean a cycloalkyl radical,

Of compounds of this Hing system, which is also called as "(. B-Hydro2tyalkyl) be called Λ-sultone of 2 ~ -.- benzolsulfoiisäuren were only few · representatives made" So-erhlel- "th G" R "- and CIjMO . J, H «TIJBiJEtJLL [J.chem.Socv

0098 39/2268

BATH ORIGINAL

(London) 194 ?, 124-127] by. Bsha; .i & lung of 0-methylsugenol or, O-acetyleugenol with concentrated sr sulfuric acid the sultones of the 4th

or the 4-metaoxy-5 ^ hyaroxy --- 2 ~ (ß ~ h ^ droxy ~ npropyl) ~ benzenesulfonic acid in extensions of less than 10% of the QÜheorie, in much better The above-mentioned compounds could yield by sulfonating .ß-bromodihydroeugenol methyl ether or, '0-acetyl ~ .3-bromodihydroeusenol and then heating the diluted with water p.n sulphonic acid solutions of sulfuric acid -

will be

Compounds obtainable according to the invention can be used as remedies, they show pronounced pharmacodynamic properties in animal experiments. • Jirkuiigsn on the central nervous system ^. taming ^: Sffektss bessztihebonj

^x:;. ntsprsch9'.id dsr invention has the n.-m ^ n-3 Carbal ^1: oxy-1 ~ thia-isochroman-1, i ~ dio: ~ tid Dsrivate of general formula I produced in that mc; a either

a) Compounds of the general formula II, where the radicals R., R ₀ and R _{0 have} the meaning given above, with an alcohol of the formula R ^ OH, where R ^ has the meaning given above, in known V / eise var ^ ste-rt or "'

b) Compounds of the general formula II, in which the radicals R., Rg and R ^ dio have the meaning mentioned above, with inorganic acid halogensnidane v / ia thionyl chloride to form carboxylic acid halide of the general formula III, in which the radicals R ^ ₁ Rg and R ^ the above go-

009839/2266 _BAD original

and Hal means, reacts or reacts the denominations of the general formula III with an alcohol of the general formula R ₂ J _- OH, in which R ₂ ^ has the meaning given above

o) Compounds of: ■ general formula IV, in which IU, IU f Ra and R ₂ ^ have the abovementioned meaning, heated to melt under normal pressure or in vacuo

d) Connections. the general formula V, the Re they R *, -ELg ₁ -RW and R ₂ ^ have the meaning given above, with concentrated sulfur ΐ |

Feisäure expediently treated at Zim, -iertemp-33? 8.tux, :

The esterification by process a) can be both without a catalyst as well as in the presence of a catalysts, such as mineral acids odsr acid salts of these, chlorosulfonic acid, boron trifluoride, Thionyl chloride, acetyl chloride or chlorariic acid ester carried out.

The reaction is expediently carried out under! -Ürhita-en-, to the. D '.? Is between the boiling point of the alcohol in question Alcohols also suffice for rcalntioiastexiperatures between

see 9o and Ί2ο ⁰ C * When using catalysts such as thionyl chloride or Ohl, orameisGiisäureestsr, the esterification can also be carried out at room temperature.

From the reaction niches obtained from the Verfa.lu- * ena) Sntwodsir the out &fallnen carboxylic acid esters of the general formula I sucked off or the excess alcohol is removed. and

009839/2266

the crude carboxylic acid esters obtained as a residue to dissolve unpoured carboxylic acid with aqueous sodium hydrosene carbonate solution Treated o The then with water Washed crude products are made by customary methods, for example by recrystallization from organic solvents or corresponding solvent mixtures, finely purified.

In the process b), after be3iideter reaction of the compounds of the general formula II with inorganic Säurehalogonidcn to Vorbindungen represents general "groves formula III, first the excess of acid halide, suitably by distillation, removed hs d implementation D5R ^{compounds:.?.;} In general, Porrael III takes place with the alcohols to give compounds of the general formula I. The compounds of the general formula I obtained by process b) often precipitate in pure form already in the heat or during the cooling of the reaction mixture.

The according to method c) he hold and powdered Raw products are cleaned by washing with water and alcohol and if necessary crystallized from organic solvents.

^ according to de: .i Verfc.hrsnsv / ~ isen a) and b) as final products, boiiötijten connections of the general form; V3l II is obtained to L ispi ^ .l entv? cd & r by B - h <.v. : dlu: ig from Verbi: - _A dung: n dor general formula VI, \ / orin R ^, ^ and R ^ di-2 above bod'attuig have and R _r a Carballroxy] .-, Ccrbaiaoyl- odsr eiiiu groupG ui-'d lk \ l r.lii halo ₀ eMatoiu bcdt.-ui; cii _/ initially

t \

τ Gohi / ofclsäaco ar.-e-ciinäBlg bai

BATH ORIGINAL

2011Q24

Room temperature and a

with water Schwef elsaAiran diluted to about 9o Vobis ⁰ C odor by verse eleven mig of compounds of general Forrioi IfIIy wherein Ry. , Rp u ^ L Eo have the meaning given above, with dilute mineral acids.,

The compounds of the general formula IV used as starting materials according to process c) can be prepared by treating compound Dn of the general formula VIIX ₁ . wherein

R3 and shark the ones given above and En have an Oarbonitril- or a Carbamoylsruppa means with concentrated Sulfuric acid at hauia temperature, 'then, brief heating of the mixture diluted with .. "water and subsequent esterification of the isolated 2 "- (B-Halogon * .ß-carbaxyätliyl) -4.5-dialkoxy-benzolaminoniumsulfona.t-Doriväte by heating in the appropriate alcohol,

■■■. ■■ "-»

Example 1:

2.9 S 3 ~ carboxy-6.7-dimethoxy-1-thia-isochroBian · -1.1-dioxide and 5o ml of methanol were turned into · Go ^ en- ^ ^; Wait for 1-2 drops of concentrated sulfuric acid to boil for 6 hours. The cooled reaction mixture is sucked off and the crude _ 3-C's * ^ o ^ t.h9 ^^ - 6: «7 ^ iniothoxy-1 ^ thia-riso- · chroftian-LI-dioxide (3 s). from a mixture of methanol and acetone umlp? is; ^ llisi0rt (m.p .: 211r; up to 214 ⁰ C),. ■■■. ■; ... .; .; ■■■. ■. : '■ ".''■' ■■ '■■ ..

Exploiter 2.8 s = 92.7% dor Thoorio aa 3-

Carbomethoxy-6,7-d.imethoxy-1-thia-.

isochroman-1.1 «» dioxide \

OO9'8 ^ S / 2 2 66 bad orjqinäl

Analysis for molecular weight: 3o2.3

GHS bo-calculates: 47.68 4.57 1o, 61 found: 47.71 4.58 10.73

Example 2:

A mixture of 2.9 S 3-C2Jboxy-6,7-dlmothaxyi-thia-isochroman-LI-dioicid and Ίο s thionyl chloride is refluxed in a water bath for 8 hours ο after removal of excess thionyl chloride from the reaction ". The raw 3-chlorocarbo: iyl-6.7-dimethoxy-1-thia-isochromic: .i-1.1-dioxide is mixed with 60 ml of methanol and the mixture is heated to the boil for 1 to 3 2 hours 3-carbomethoxy-6.7-dim thoxy £-1-thi - isochroman-1.1-dioxide Tird osaugt according ATaloihlung of RocJ-rtionsgoni- schss from ^, with methanol Gcwasch · '· :! and dried (m.p. 211 to 214 ⁰ C. Hatching: 2.8 3 = 92.7% of theory

Example 3:

2.9 3 3-0arboxy-S, 7-dinv / bhoxy-i-thia-isochroi) ian-1.1-diozid are added with 130 ml of absolute ethanol for 20 hours. Boiling is heated, and the excess ethane is distilled off from the reaction, the residue is poured out with aqueous sodium hydrosanocarbon detachment, and this is treated with water. The dried raw 3 ~ 0arbätho: £ y-6. 'J' DIMC-thoxy-i-thia-isochroman-i .i-dioxide v / ill be from a mixture of ethanol and · Acoton umkristallisicrt (Fp; - 2o8-21o ⁰ C), yield: 2.5 g = 78 , 7 % of the theoria on 3-

0arbätho3cy-6.7-dirdv-; t hoxy-1 -t hiais 0 chroman-1.1-dloxid

009839/2266

BAP ORIGINAL

Analysis for
Molecular weight: 316.3

σ η

calculated: 49.37 5 found: 49.57 5.2 o 10.24

M acidifying the aqueous Uatriumhydroäencarbonatlösung with dilute sulfuric acid falling o "2 g unumgesefztas 3 ~ Carbo2cy-6 * 7-di-

274 to 276 X out.

Example 4:

A mixture of 2.9 g 3-0arboxy-6.7-dimetho2cy-1 "thia ~ isocoroman-1.1-dioxide, 3NC ml of absolute ethanol, and O, 3 g of thionyl chloride is S4- hours at Rr.umtempora.tur ö- ^r ührt. Afterward. the crude 3-Carbäthox7-6.7-dimctho3 ^ 7-1-thiaisQChroman-1.1-diozid is suctioned off, treated with aqueous sodium hydrogen carbonate solution, washed with water and recrystallized from acetone (pp: 208 to 21o T).
Yield: 2 ': g = 76 % of theory of 3-0arb ^

ät ho2 £ y-6 7-dime t h 02iy ~ 1 -t h ia- i s ochr ο nan-

1.1-dioside.

Example 5:

) 3in Geaiscjh of 2.9 g

1.-thia-isochroroan-1.1-dioxide, 30 ml of absolute ethanol and 0.3 δ Ohloranieisensaureathylsster is heated to boiling for 3 hours with stirring.

After cooling the reaction mixture to the edge temperature the crude ethyl ester is filtered off with suction, washed with ethanol, treated with T / aq triuinhyärogencarbönatilösung; treated, a;:. schlic.ßn: "ad with Waters washed and dried (! Fps 2o8 to

SAD

■ - ■ <~ J

Yield: 2.9 g = 9117% of theory απ 3 ~ Oarb ~

Example 6:

0.9s 2 »- (B-0hlor-fl» -carbäthoxyäJhyl) ~ 4 .. 5-dimethoxybenzolainraoniumsulfonat are ^{brought to melt in a vacuum (12 mm Hg) at a temperature of 200 ~ 21o 0} C for a few minutes. The cooled melt is crushed in a mortar, washed out with water and ethanol and dried. 3-Carbethoxy-6.7-dimethoicy-1-thia ~ isochrono.n-1.1-dioside is obtained, mp: 2o8 ~ 21o ^C C,

Yield: 0.6 g = 78 % of theory »

The 8.1s Aus3, aii3sprodukt b ^ necessary ^ te 2- (JE5-Chlor-ß-

is created xrie fol ^ t

12 sa ~ -Ohlor ~ J3- (3..4 ~ diEietho2cyphenyl) -propionäure ~ nitrile and 12 ml concentrated sulfuric acid are combined at 0 ⁰ C and left to stand overnight at room temperature. Then 4-0 g of ice are added to the sulfuric acid solution and the mixture is heated to boiling for a few minutes. Thoxy-benzolaminoiiiurasulfonat is filtered off with suction (10.8 g) and then refluxed for 2 hours with 50 ml of absolute methylene. After distilling off the pine part of the solvent crystallize after cooling the ethanolic solution 7.5 g of 2 -. 2o4 to 214 ⁰ C, dec,),

009839/2 2 66

8AD ORIGINAL

The following connections were also established: "

SFame

Sunnien
fornel

Melting point ⁰ C

3-C; ~ rbo-n-hexy loxy-6 * 7 ~ di methoxy-1-thia-isochronane 1.1-dioxide

3-carbisopropoxy-S.7-dim t ho: s7-1-t hia-iso chroüian 1.1-dioxide

3y ^

met b.oxy-1 - ΐ h ia- i s 0 c br oiaan-1.1-dioxide

yy

methoxy-1-uhia-isochroria: idii

3-carbobenzyloxy -:., 7-dimethoxy-1-thia-isochroHan- 1.1-dioxide

3-Carbotetrahydrofnrfuryloxy-6 7-diue t ίιο: ς7-1 -b aiaiiiiaii-i .1-dioxide

3-Carbo-.ß-chloroethoxy-S, 7-d iaie t hoxy-1 -t h la- is oc hr oraaia « 1.1-dioxide

y
1.1-dioxide

3-methyl-3-carb is propoxy-δ. 7-diiii3t; laox3'-1 - i; hia-iso-Liaii-i .1-dioxide

3-Me-thy 1-3-c arbomet hoxy-6 · 7-diEiet hoxy-1 - ΐ hia-isochromaii-i .T-dioxide

3-Methy l-3-Gaa? I) ät ho: rj ⁷ -6.7-diraethcxy-i-thia-isochroxian-1 * 1-dio :: id

9 * - 95

176-178

108-11ο

165-16?

170-172

136-133

99-101

9o - 92

OO9839 / 2266 BADOR) GlNAi,

Claims (2)

.Patent claim *
I. Process for the preparation of 3-Carbalko2cy-1-thia-isochronaii ^ «i-dioxide derivatives of the general formula I, in which R ^ and Rg are a lower alkyl radical, R is a hydrogen atom or an alkyl radical thereof and R ₂ , a branched or unbranched, saturated or unsaturated Alley 1 group, which can also be substituted by halogen or by aryl or heterocyclic radicals, or a cycloalkyl radical, in that one a) VsrbindtLicisn der allo ~ ne formula II, - .. orin the radicals R _x ., Rp and R-, which have above mentioned Bsdrutunj, with an alcohol dor general formula R ^ OH, ■ Orin R ^ the above mentioned Has meaning, esterified or b) Compounds of the general formula II, - / orin the radicals R>., Rg and R- have the meaning given above, with inorganic acid halogonidoη such as thionyl chloride to form carboic acid halosenides of formula III, in which the radicals R- , Rg and R-the abovementioned meaning bcsitaen ur.d Hai means a halogen atom, and the compounds of the allgr-msinsn Forsiiel III with eiii3ii alcohol of the general formula R ^ OH, where R ^ the ob on gona'.T: ^s .te meaning _o has, lets odsr react o) Compound 311 of the general formula IV, before in R ^ j, R2 »Ro and R ^ the above Meaning b? Sitz3n, untor Horrialdruok odnr heated odor in Valcuun to Sclii'ielz? n d) compounds dsr al Ig "■ my η Foicracl V in which the radicals IL, Rg, R, and R, the above genajvato Bedeutimg own, with l: o: iz - ntriortcr Sch \ 7v fr.lsäure zv / eclcmäßig boi Ziai aortic tumor treated -009839/2266 BATH 2. 3 ^ 0arbalko2 ^ - 1'-tliia- »isochroraan - 1 _e '1 ~ dio; i: ia ~ derivatives of the general formula I, τ-jorin R _x . and Rg is a lower alkyl radical, Ro is a hydrogen atom or a lower allyl radical and 3λ is a versrarei ^ tG or unpaid, saturated or unsaturated alkyl group, which can also be substituted by halogen or by aryl or heterocyclic radicals, or a cycloalkyl radical » -Τ ,, Ι-dioxide 1.1-diotide 5 «3-öarTDO-n- chroiaan-i «
6. 3-Oarbisopropo: cy-6 _# 7-dimottio2 ^)? - i ^ tliia-i chroman 1.1 dioxide
7 · 3 ~ Oarbisoarü3 ⁷ loxy-6, 7 ~ dimetho: cy-1 -thia-'iso- chroi! ian-1,1-aio2: id 8. 3 ~ man-1.1- ^ di oxide thia-isocbrona: 2-1.1-11-3-Car "bo-ß-chloräthosy ~» 6-7 ~ dimstho2 {^ - 1-thia- 12, 3-Cai ^l chroiaan-1.1-dios: id
13 3 ~ Mothy 1-3-carb is op: eopo3cy ~ S., 7-cti3vietlio: qy - 1 ~ thia- isochrojiian-1.1-d 14. 3-MGthyl ~ i so ehr orian-1 # 1-di oa: id 15 * 3-methyl'-3-carbätlioüä: yisocliroinan-i .1-dioxide ο ο 9 β a 9/2 iß 6 (ID V ■ ν (n> Γ ' t, o - RjC ti » OB ₂ χΤ3 ' ^ .XX). Hal ^ y i Hal III 9/167-Jd-G-52/70 09839/2266 -12- 201102A (VIII) R ₁ O- Hal 00983972266