US2302671A - Halogenated derivatives of aceto propane - Google Patents

Halogenated derivatives of aceto propane Download PDF

Info

Publication number
US2302671A
US2302671A US353505A US35350540A US2302671A US 2302671 A US2302671 A US 2302671A US 353505 A US353505 A US 353505A US 35350540 A US35350540 A US 35350540A US 2302671 A US2302671 A US 2302671A
Authority
US
United States
Prior art keywords
aceto
ether
propyl
alcohol
chlor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US353505A
Inventor
Edwin R Buchman
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Research Corp
Original Assignee
Research Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US296817A external-priority patent/US2218350A/en
Application filed by Research Corp filed Critical Research Corp
Priority to US353505A priority Critical patent/US2302671A/en
Application granted granted Critical
Publication of US2302671A publication Critical patent/US2302671A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
    • C07C43/04—Saturated ethers
    • C07C43/12—Saturated ethers containing halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • C07C45/676—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton by elimination of carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups

Definitions

  • This invention relates to the production of halogenated derivatives of aceto propane and has for its object the provision of new and useful de'-' rivativ'es of this nature and useful and effective methods-of making-them.
  • I-Ialogenated derivatives of the-type-to which this invention relates are useful in the synthesis of vitamin B1, which has extremely valuable therapeutic and nutritional properties.
  • ketonic form II enelic form
  • In innerether, lactone, or tehahydroiurane form
  • a solution containing halogenated aceto propyl alcohol is obtained. Since the principal intended use of the product is in the synthesis of the thiazole portion of vitamin B1 and in such synthesis Water is present or is formed in the course of the reaction, the particular product isolated is more or less immaterial except from a theoretical standpoint. Because the ether is more stable than the alcohol, it is preferable from a practical standpoint to employ the ether.
  • a halogenated derivative of aceto propane may be prepared by the halogenation of 'y aceto propyl alcohol with one of the elemental halogens bromine, chlorine and iodine or with sulphuryl bromide or sulphuryl chloride.
  • the same halogenated derivative may likewise be made by halogenating a aceto v butyro lactone with the same halogenating agent and then subjecting the resulting a halogenated butyrolactone to a combined hydrolysis and decarboxylation.
  • reaction product is then treated in a suitable manner to remove the desired product, or products, which may be a halogen derivative of 'y aceto propyl alcohol, a halogen derivative of aceto propyl ether, or both, depending upon the isolation process.
  • 'y aceto propyl alcohol maybe halogenated by treatment with a suitable halogenating agent, such as a halogen or a sulfuryl halide.
  • 7 brom 'y aceto propyl alcohol which may also be designated 3-brom-3-acetopropan-l-ol, may be prepared by dissolving grams of 7 aceto propyl alcohol in 150 cc. of water and vigorously stirring the solution while 48 grams of bromine are added drop by drop at such a rate that the color imparted to the solution by one drop of the bromine disappears before the next drop is added.
  • the aqueous solution which results contains impure 'y brom v aceto propyl alcohol.
  • One method of purifying the product is to separate the small amount of insoluble oil which is formed as a by-product, from the aqueous solution and to extract the aqueous solution repeatedly with ordinary ethyl ether to dissolve the remainder of the brominated product.
  • the insoluble oil and the ethereal extracts are combined and dried over a suitable dehydrating agent such as anhydrous sodium sulphate.
  • the ethyl ether is then distilled ofi and the residue is practically pure di (bromo aceto propyl) ether which is hereinafter designated from aceto propyl ether.
  • This material may be further purified, if desired, by distilling it in vacuo at less than 1 mm. of mercury.
  • the product is a colorless oil, which is soluble in hot water, ether and alcohol and which may be distilled though not without some decomposition.
  • the brom aceto propyl ether thus prepared is sparingly soluble in Water but freely soluble in organic solvents such as petroleum ether. It may be converted into '7 brom 'y aceto propyl alcohol by making a dilute water solution thereof, for it hydrolizes readily into the brominated alcohol.
  • the solution of the ether in water may be most readily efiected by mild heating at a temperature of 50 to 60 C.
  • the brom alcohol has not been isolated as such because it goes over into the ether too readily. However, the presence of the alcohol in a water solution of the brom ether has been established by freezing point depression of the aqueous solution.
  • the corresponding chlorine derivatives may likewise be made by direct reaction of chlorine upon 7 aceto propyl alcohol.
  • This reaction may be carried out by treating 12 grams of 'y aceto propyl alcohol, dissolved in 60 cc. of water, with a stream of gaseous chlorine, the reaction mixture being stirred and cooled if necessary so that the temperature remains between 20 C. and 40 C. This is continued until the increase in weight of the reaction mixture reaches 8 grams.
  • the mixture is cooled to about 15 C. and allowed to stand 15 minutes during which time a small, heavy, oily layer separates at the bottom of the vessel. This oily layer is removed and washed twice with water.
  • the aqueous layer and the aqueous washings are extracted with ethyl ether. Then the ethereal extracts are combined with the above oily layer and dried over a suitable dehydrating agent, such as sodium sulfate.
  • a suitable dehydrating agent such as sodium sulfate.
  • the ethyl ether is evaporated off leaving an oil boiling at 87 C. to C. at about 2 mm. pressure, This material is a stable, colorless oil which is soluble in ether, alcohol and hot water and is slightly soluble in cold water.
  • This product consists principally of chlor aceto propyl ether having the properties described in Example 5 below.
  • the invention also contemplates the production of the related iodine derivatives in a similar manner, although iodine is not so reactive as bromine or chlorine and the yield of the iodine compounds is not so great.
  • sulfuryl halides such as sulfuryl chloride or sulfuryl bromide may be employed.
  • Example 3 In practicing one process of this nature, 27 grams of sulfuryl chloride are added slowly to 20.4 grams of v aceto propyl alcohol and the reaction mixture is kept at 0 C. for one-half hour. At the end of that time, 50 added and the mixture is heated to expel the sulfur dioxide and the hydrogen chloride remaining in the mixture. The mixture is then cooled and poured onto crushed ice and the excess acidity is neutralized with a potassium carbonate solution. The resulting mixture is repeatedly extracted with petroleum ether and the ether extract is treated first with anhydrous sodium sulfate and finally with anhydrous potassium carbonate. After the extract is dried,
  • the residue is distilled in vacuo to remove the petroleum ether v and the residue is fractionally distilled .vacuo, whereupon a product havin a boiling point at;2 mm. pressure of about 90 to 120 C, is obtained.
  • This product also consists predominantly of the aforementioned chlor aceto propyl ether.
  • the corresponding brom compounds may be prepared in a similar manner by reacting upon 7 aceto propyl alcohol with an equivalent amount of sulfuryl bromide and purifying the product obtained by a similar procedure.
  • the brom, chlor and iodo derivatives of aceto propane described hereinbefore may also be made by simultaneously hydrolizing and decarboxylating the corresponding a halogen derivative of 0c aceto v butyro lactone.
  • the a aceto 'y butyrolactone employed in this reaction has the formula ,dium ethylate or sodium methylate, the latter being preferred.
  • Chlor aceto propyl ether may be obtained by first preparing a chlor oz aceto 'y butyro lactone by treating on aceto v butyro lactone with sulfuryl chloride, in accordance with the method described in my aforesaid application Serial No. 118,573, now Patent No. 2,193,858, issued March 19, 1940.
  • solutionbf' an alkaliinstead of the dilute acid.
  • the acid and allgali are both examples of pH modifying agents.
  • the reaction mixture is then extracted several times with small-portions of ethyl ether and the combined ethereal solution is driedover a dehydrating material, such .as sodium sulphate.
  • a dehydrating material such .as sodium sulphate.
  • the dried solution is then distilled in vacuo and the portion boiling at to C. at 2 to 3 mm. pressure is, collected.
  • the collected material is principally chlor aceto propyl ether and is substantially identical with the product obtained by direct chlorination of 'y aceto propyl alcohol and distillation of the reaction product as described in Example 2.
  • Example 5 410 grams of the chlorinated lactone prepared as described in Example 4 are heated on a steam bath with 410 cc. of water and 12 cc. of 38% hydrochloric acid until decarboxylation is complete. This operation requires about 7 hours. On cool ing the reaction mixture an oily layer separates which is removed by repeated extraction of the mixture with petroleum-ether. The ether extracts are then shaken with solid potassium carbonate and 01:27.81. Found: mol. wt. 259 (dioxane);
  • This chlor aceto propyl ether is a colorless and almost odorless liquid which is soluble withdifliculty in water but which is readily soluble in organic solvents.
  • Example 6 If the only liquid described in Example 5 is fractionally distilled at 1.7 mm. pressure and that fraction which is obtained at 68 to 70 C. is redistilled at 3 10 mm. at 20 to 24 (3., a fraction is obtained consisting of 'y chlor y aceto propyl alcohol. Calcd for Cal-190201; mol. Wt.:136.54; (3:43.95; 11:6.64; and Cl:25.96. mol. wt.:l46 (dioxane); 0:44.64; 11:62.9 and 01:26.43. d-"*:1.210 gm./cc.; n :1.4684. This chlor aceto propyl alcohol is insoluble in petroleum ether, whereas the chlor aceto propyl ether is soluble therein.
  • Aqueous solutions of chlor aceto propyl ether give molecular weight values indicating complete hydrolysis into chlor aceto propyl alcohol.
  • the ether goes into Water solution readily when the mixtures are warmed, 60 C. having proved to be a satisfactory temperature to employ.
  • Example 7 with500 cc.- of water at 60C: for-about six hours and the mixture is allowed to stand. All of the resulting oily layer will dissolve upon shaking the mixture.
  • the mixture is extracted repeatedly with ether, the ethereal extracts are dried over a suitable dehydrating agent, such as sodium sulfate, and the solvent is then removed in a water pump at 200 C, The residual oil is then fractionally distilled in a molecular still and 'y chlor aceto propyl alcohol, boiling at 27 C. at 0.01 mm. pressure is obtained.
  • a suitable dehydrating agent such as sodium sulfate
  • the bromine compound which corresponds to the chlorinated lactone described hereinabove in Example 4 may be made in an analogous manner by treating a aceto 'y butyrolactone with sulphuryl-bromide or in aqueous suspension with bromine.
  • the bromide compound corresponding to the above described chlorinated aceto propyl alcohol may then be prepared by treating the brominated lacetone with a suitable pI-I regulating agent, such as dilute hydrobromic acid.
  • Example 8 These reactions may be carried out by suspending 32 grams of a aceto 'y butyrolactone in '70 cc. of water and adding 40 grams of bromine thereto drop by drop, meanwhile vigorously stirring the mixture with a mechanical stirrer. This will produce a bromo a aceto 'y butyr'olactone and in the reaction which occurs hydrobromic acid is also produced. This brominated lactone may be hydrolyzed and decarboxylated by means of a dilute solution of hydrobromic acid.
  • the simplest way to hydrolyze the brominated lactone is to continue to stir the mixture after the bromine has been added, until the hydrolysis and decarboxylation are completed.
  • the brominated product resulting from the hydrolysis is extracted from the mixture with ether, and the ethereal extract is dried.
  • the dried extract is freed from ethyl ether and is then distilled in vacuo at about 1 mm. pressure and the brom aceto propyl ether is collected.
  • This material is an oil which is colorless when freshly made, but it is not as stable as the corresponding chlorine compound and darkens on standing,
  • the corresponding 7 iodo 'y aceto propyl alcohol and iodo aceto propyl ether may be produced in smaller yields than the related chlor and brom compounds by employing elemental iodine instead of the chlorinating and brominating agents mentioned previously in the several reactions described hereinabove.
  • the iodo compounds may also be prepared in more substantial yields, by treating one of the chlor or brom alcohols or ethers with sodium iodide.
  • the halogenated aceto propyl ethers obtained may assume the structures indicated by Formulae VI, VII, and VIII outlined hereinabove. If VI were the correct structure, one would expect that two molecules of phenyl hydrazine would react with 1 molecule of the di-halo-aceto-propyl ether. If the correct structure were VII phenyl hydrazine would not react with this ether at all. Actually, in full agreement with structure VIII, only 1 molecule of phenyl hydrazine reacts with 1 molecule of the ether. When a second molecule of phenyl hydrazine is present, it separates from the reaction mixture as phenyl hydrazine hydrochloride.
  • the product of the action of phenyl hydrazine on 'y chloro 'y aceto propyl ether having the properties described in Example 5 is a yellowish crystalline powder melting at about C., insoluble in water or petroleum ether, but soluble in other usual organic solvents, such as alcohol, acetone or ether. It has a composition corresponding to the formula C16H2102N2C1 According to the later ideas of Bodforss, its structure is as follows:
  • halogenated aceto propyl ethers produced as described hereinbefore contain at least one tetrahydrofurane group and that in all probability they contain only one such group.
  • the appended claims are intended to embrace all forms of the ether unless specifically limited to cover only certain ones of such ethers.
  • the chlorine, bromine and iodine derivatives of 'y aceto propyl alcohol and ether produced in accordance with the invention may be condensed with thio formamide to produce salts of the thiazole derivative known as 4-methyl-5-(fihydroxy-ethyl) thiazole in accordance with the method outlined in Patent No. 2,133,966 granted October 25, 1938.
  • This thiazole derivative may in turn be caused to enter into other reactions to produce synthethic compounds having the characteristic physiological and therapeutic properties of the antineuritic vitamin.
  • R and R are groups of the class consisting of CHaCOCHXCI-IzCHzand wherein X is one of the halogenes bromine, chlorine and iodine.
  • R. and R are groups of the class consisting of CH3COCHXCH2CH2 and wherein X is one of the halogens bromine, chlorine and iodine, and in which at least one of the groups represented by R and R is CH; oni-o- CH2-CHX 6.
  • R. and R are groups of the class consisting of CH3COCHXCH2CH2 and wherein X is one of the halogens bromine, chlorine and iodine, and in which at least one of the groups represented by R and R is CH; oni-o- CH2-CHX 6.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

Patented Nov. 24-, 1942 UNITED STATES PATENT OFFICE-l HALooENATEn DERIVATIVES 0F AoETo PROPANE Edwin R. Buchnian, Pasadena, Calif., assign'or to Research Corporation, New York, N. Y., a cor poration of New York No Drawing; Original application September2l,
1939, Serial No. 296,817.
Divided and this 'ap plication August 21, 1940, Serial No. 353,505 6 Claims. (01. zoo-e45) This invention relates to the production of halogenated derivatives of aceto propane and has for its object the provision of new and useful de'-' rivativ'es of this nature and useful and effective methods-of making-them. I-Ialogenated derivatives of the-type-to which this invention relates are useful in the synthesis of vitamin B1, which has extremely valuable therapeutic and nutritional properties.
This application'is a division of my copendin'g application Serial No. 296,817 filed September 27,
1939, for Halogenated derivatives of 'aceto propane, which in turn was filed as a continuation in part of my applications, Serial Nof118,5 '73, filed December 31, 1936, and Serial No. 171,905,
filed October '30, 1937. Application Serial No; 118,573 was'a division of application Serial No. 98,929; which I filed September 1, 1936, while application Serial No.171,'905 was a continuation in part of application Serial No. 11,683, which I filed March 18, 1935, and of said application Serial In the'foregoing'applications the product obtained'by halogena'tingv aceto propyl alcohol or by hydrolysing halogenated a aceto y butyrolactone is describedas 'y halogen aceto propyl alcohol but it has been subsequently found that molecules of a 'y halogen 'y aceto propyl alcohol tend to react spontaneously with one another to form"'halogenated a'oeto propyl others with 'sur-.
prising LeaseJ These ethers when in aqueous solutions hydrolyze into the halogenated alcohol more or less completely according to the concentration and temperature. When 'y halogen 'y aceto propyl alcohol is distilled, the resulting product may consist predominately of either the'alcohol or the ether depending upon the temperature, pressure and/or speed of the distillation. The conditions for isolation described in the above mentioned applications are such as to produce,
in whole or in part, the ether rather than the alcohol.
There are threepossible forms in which 7 aceto propyl alcohol may existQthe formulae of which may be written:
(ketonic form) II (enelic form) and In (innerether, lactone, or tehahydroiurane form) It is probablethat any solution'of this product contains some orall'of these "formsin equilib-"- rium. The above outlined ketonic'iorm undoubtedly is in tautomeric equilibrium with the enolic" These; tautomertic' forms form of the molecule. are, however, so readily mony with enolketo" inter'convertible', in 'har-j ignored in" th'following discussion.
The sveialhaldgen derivatives of 'y' aceto pro:
pyl alcohol? likewise may exist in similar forms having the structures:
O i V mo' -on'it onkcmon in which X one'o'f the' halogens chlorine," bro mine anaiod ueig v It is Obvious that'When'tWo moleculso'f one of these halogenated aceto'pi'opyl alcohols react 'aneth'e'r; the-resulting ether'inay have" to form I any one ofthe fonowinjg structures? QHs--CO-CHX-CI-Iz-CHz o-oHz-' cHzoHX-co-cH3 VI c113 3111 onko-o-o-C-O-om cuterm orix ong v vn' and,: 1
' ona oo cnx onz oru o-o oon, onir om VIII in which formulae, X has thesame-significance as befo'reL It is difiiciilt'to determine which of the'sjef'forr'ns "the "ether will assume under any givensetof conditionsfbut'it appears that the form usuauy obtained underordinary conditions, as in the specific examples'giveii hereinafter, possess'es' one tetraliydrofuraneradical and-has the "structure indicated by Formula VII Il v In the :aforementioned application Serial No. 171,905/1 have described several methods of making' halogenfderivatives of 7 aceto propyl-alcohol 'ahd' have described the properties of the resulting products. sev'eral products of reaction" which'boil'over the range from' 84 to 120 C. at
1 to 2 mmQpressure are described therein and,
while halogen derivatives of 'y aceto propylalcohol undoubtedly are-present-in the reaction mix--' tures obtained by halogenation of v aceto propyl I tamorhrsm general, that for the sake of simplicity the enolic forms will be alcohol, one of the above described halogenated ethers is the principal product obtained upon distillation under'the conditions described, instead of the corresponding halogenated alcohol as stated in my previous applications referred to hereinabove. However, for all practical purposes, the desired result is obtained no matter which compound is secured because in the presence of traces of Water the ether reacts as if the alcohol were used. For example, if the product is dissolved in water, a solution containing halogenated aceto propyl alcohol is obtained. Since the principal intended use of the product is in the synthesis of the thiazole portion of vitamin B1 and in such synthesis Water is present or is formed in the course of the reaction, the particular product isolated is more or less immaterial except from a theoretical standpoint. Because the ether is more stable than the alcohol, it is preferable from a practical standpoint to employ the ether.
In accordance with the present invention, a halogenated derivative of aceto propane may be prepared by the halogenation of 'y aceto propyl alcohol with one of the elemental halogens bromine, chlorine and iodine or with sulphuryl bromide or sulphuryl chloride. The same halogenated derivative may likewise be made by halogenating a aceto v butyro lactone with the same halogenating agent and then subjecting the resulting a halogenated butyrolactone to a combined hydrolysis and decarboxylation. The reaction product is then treated in a suitable manner to remove the desired product, or products, which may be a halogen derivative of 'y aceto propyl alcohol, a halogen derivative of aceto propyl ether, or both, depending upon the isolation process.
The invention will be fully understood from the following detailed description of specific embodiments thereof. As an example of how the invention may be practiced, 'y aceto propyl alcohol maybe halogenated by treatment with a suitable halogenating agent, such as a halogen or a sulfuryl halide.
Example 1 In accordance with one specific embodiment of the invention, 7 brom 'y aceto propyl alcohol, which may also be designated 3-brom-3-acetopropan-l-ol, may be prepared by dissolving grams of 7 aceto propyl alcohol in 150 cc. of water and vigorously stirring the solution while 48 grams of bromine are added drop by drop at such a rate that the color imparted to the solution by one drop of the bromine disappears before the next drop is added. The aqueous solution which results contains impure 'y brom v aceto propyl alcohol.
One method of purifying the product is to separate the small amount of insoluble oil which is formed as a by-product, from the aqueous solution and to extract the aqueous solution repeatedly with ordinary ethyl ether to dissolve the remainder of the brominated product. The insoluble oil and the ethereal extracts are combined and dried over a suitable dehydrating agent such as anhydrous sodium sulphate. The ethyl ether is then distilled ofi and the residue is practically pure di (bromo aceto propyl) ether which is hereinafter designated from aceto propyl ether. This material may be further purified, if desired, by distilling it in vacuo at less than 1 mm. of mercury. The product is a colorless oil, which is soluble in hot water, ether and alcohol and which may be distilled though not without some decomposition. The pure substance can be readily distilled in a molecular still at 40 C. bath temperature and at 0.008 mm. pressure. Calcd. for: CwHrsOsBrz, mol. Wt.=343.96;
0:34.89; H=4.69. Found: mol. wt.=316 (di oxane); C=34.84; H-=4.56. d =1.592 gm./cc'.- n =1.4989.
The brom aceto propyl ether thus prepared is sparingly soluble in Water but freely soluble in organic solvents such as petroleum ether. It may be converted into '7 brom 'y aceto propyl alcohol by making a dilute water solution thereof, for it hydrolizes readily into the brominated alcohol. The solution of the ether in water may be most readily efiected by mild heating at a temperature of 50 to 60 C. The brom alcohol has not been isolated as such because it goes over into the ether too readily. However, the presence of the alcohol in a water solution of the brom ether has been established by freezing point depression of the aqueous solution.
Eztample 2 The corresponding chlorine derivatives may likewise be made by direct reaction of chlorine upon 7 aceto propyl alcohol. This reaction may be carried out by treating 12 grams of 'y aceto propyl alcohol, dissolved in 60 cc. of water, with a stream of gaseous chlorine, the reaction mixture being stirred and cooled if necessary so that the temperature remains between 20 C. and 40 C. This is continued until the increase in weight of the reaction mixture reaches 8 grams. The mixture is cooled to about 15 C. and allowed to stand 15 minutes during which time a small, heavy, oily layer separates at the bottom of the vessel. This oily layer is removed and washed twice with water. The aqueous layer and the aqueous washings are extracted with ethyl ether. Then the ethereal extracts are combined with the above oily layer and dried over a suitable dehydrating agent, such as sodium sulfate. The ethyl ether is evaporated off leaving an oil boiling at 87 C. to C. at about 2 mm. pressure, This material is a stable, colorless oil which is soluble in ether, alcohol and hot water and is slightly soluble in cold water. This product consists principally of chlor aceto propyl ether having the properties described in Example 5 below.
The invention also contemplates the production of the related iodine derivatives in a similar manner, although iodine is not so reactive as bromine or chlorine and the yield of the iodine compounds is not so great.
Instead of using halogens as the halogenating agents, sulfuryl halides, such as sulfuryl chloride or sulfuryl bromide may be employed.
Example 3 In practicing one process of this nature, 27 grams of sulfuryl chloride are added slowly to 20.4 grams of v aceto propyl alcohol and the reaction mixture is kept at 0 C. for one-half hour. At the end of that time, 50 added and the mixture is heated to expel the sulfur dioxide and the hydrogen chloride remaining in the mixture. The mixture is then cooled and poured onto crushed ice and the excess acidity is neutralized with a potassium carbonate solution. The resulting mixture is repeatedly extracted with petroleum ether and the ether extract is treated first with anhydrous sodium sulfate and finally with anhydrous potassium carbonate. After the extract is dried,
the residue is distilled in vacuo to remove the petroleum ether v and the residue is fractionally distilled .vacuo, whereupon a product havin a boiling point at;2 mm. pressure of about 90 to 120 C, is obtained. This product also consists predominantly of the aforementioned chlor aceto propyl ether.
The corresponding brom compounds may be prepared in a similar manner by reacting upon 7 aceto propyl alcohol with an equivalent amount of sulfuryl bromide and purifying the product obtained by a similar procedure.
The brom, chlor and iodo derivatives of aceto propane described hereinbefore may also be made by simultaneously hydrolizing and decarboxylating the corresponding a halogen derivative of 0c aceto v butyro lactone. The a aceto 'y butyrolactone employed in this reaction has the formula ,dium ethylate or sodium methylate, the latter being preferred.
Example 4 Chlor aceto propyl ether may be obtained by first preparing a chlor oz aceto 'y butyro lactone by treating on aceto v butyro lactone with sulfuryl chloride, in accordance with the method described in my aforesaid application Serial No. 118,573, now Patent No. 2,193,858, issued March 19, 1940.
In carrying out this reaction 68 grams of the a aceto 'y butyrolactone are placed in a flask equipped with a mechanical stirrer and 68 grams of sulfuryl chloride are added with continual stirring over a period of one and a half hours. After the reaction is completed the reaction product is washed with water, taken up in ether and dried over a suitable dehydrating agent, such as calcium chloride. distilled at a reduced pressure and the fraction distilling at approximately 85 C. and 2 or 3 mm. pressure is collected. This product is substantially pure or chlor a aceto v butyrolactone having the formula:
CHsO O OHClCHaCHzOH-l-fi 02 A similar result is obt'ained by using-a dilute The etheral extract is then 3 Found:
solutionbf' an alkaliinstead of the dilute acid. The acid and allgali are both examples of pH modifying agents.
The reaction mixture is then extracted several times with small-portions of ethyl ether and the combined ethereal solution is driedover a dehydrating material, such .as sodium sulphate. The dried solution is then distilled in vacuo and the portion boiling at to C. at 2 to 3 mm. pressure is, collected. The collected material is principally chlor aceto propyl ether and is substantially identical with the product obtained by direct chlorination of 'y aceto propyl alcohol and distillation of the reaction product as described in Example 2.
Example 5 410 grams of the chlorinated lactone prepared as described in Example 4 are heated on a steam bath with 410 cc. of water and 12 cc. of 38% hydrochloric acid until decarboxylation is complete. This operation requires about 7 hours. On cool ing the reaction mixture an oily layer separates which is removed by repeated extraction of the mixture with petroleum-ether. The ether extracts are then shaken with solid potassium carbonate and 01:27.81. Found: mol. wt. 259 (dioxane);
(3:47.13; .H:6.13; and ,Cl:28.07. d -1.2175 gm./cc.; n :l.4748. This chlor aceto propyl ether is a colorless and almost odorless liquid which is soluble withdifliculty in water but which is readily soluble in organic solvents.
Example 6 If the only liquid described in Example 5 is fractionally distilled at 1.7 mm. pressure and that fraction which is obtained at 68 to 70 C. is redistilled at 3 10 mm. at 20 to 24 (3., a fraction is obtained consisting of 'y chlor y aceto propyl alcohol. Calcd for Cal-190201; mol. Wt.:136.54; (3:43.95; 11:6.64; and Cl:25.96. mol. wt.:l46 (dioxane); 0:44.64; 11:62.9 and 01:26.43. d-"*:1.210 gm./cc.; n :1.4684. This chlor aceto propyl alcohol is insoluble in petroleum ether, whereas the chlor aceto propyl ether is soluble therein.
If, however, this low boiling fraction 1s redistilled at 1.7 mm. pressure, most of the distillate boils in the ether range, that is about C. with splitting off of water, which can be collected in a carbon dioxide trap. Thus, it is evident that both chlor aceto propyl alcohol and chlor aceto propyl ether may be obtained from the same reaction mixture and that the product isolated depends upon the conditions which exist during the isolation step.
Aqueous solutions of chlor aceto propyl ether give molecular weight values indicating complete hydrolysis into chlor aceto propyl alcohol. The ether goes into Water solution readily when the mixtures are warmed, 60 C. having proved to be a satisfactory temperature to employ.
Example 7 with500 cc.- of water at 60C: for-about six hours and the mixture is allowed to stand. All of the resulting oily layer will dissolve upon shaking the mixture. The mixture is extracted repeatedly with ether, the ethereal extracts are dried over a suitable dehydrating agent, such as sodium sulfate, and the solvent is then removed in a water pump at 200 C, The residual oil is then fractionally distilled in a molecular still and 'y chlor aceto propyl alcohol, boiling at 27 C. at 0.01 mm. pressure is obtained. Calcd for CH902C12 mol. wt.=136.54; 0:43.95; II=6.64, and 01:25.97. Found: apparent mol. wt.=1l8.5 corrected for mol. of Water consumed in the hydrolysis would give mol. wt.=127.5; 0:44.35; H=6.48. d =1.210 gm./cc. n D=l.4684. The chlor aceto propyl alcohol is insoluble in petroleum ether, while chlor aceto propyl ether dissolves therein readily.
The bromine compound which corresponds to the chlorinated lactone described hereinabove in Example 4 may be made in an analogous manner by treating a aceto 'y butyrolactone with sulphuryl-bromide or in aqueous suspension with bromine. The bromide compound corresponding to the above described chlorinated aceto propyl alcohol may then be prepared by treating the brominated lacetone with a suitable pI-I regulating agent, such as dilute hydrobromic acid.
Example 8 These reactions may be carried out by suspending 32 grams of a aceto 'y butyrolactone in '70 cc. of water and adding 40 grams of bromine thereto drop by drop, meanwhile vigorously stirring the mixture with a mechanical stirrer. This will produce a bromo a aceto 'y butyr'olactone and in the reaction which occurs hydrobromic acid is also produced. This brominated lactone may be hydrolyzed and decarboxylated by means of a dilute solution of hydrobromic acid. Since hydrobromic acid is present in the reaction mixture resulting from the bromination oi the lactone, the simplest way to hydrolyze the brominated lactone is to continue to stir the mixture after the bromine has been added, until the hydrolysis and decarboxylation are completed. The brominated product resulting from the hydrolysis is extracted from the mixture with ether, and the ethereal extract is dried. The dried extract is freed from ethyl ether and is then distilled in vacuo at about 1 mm. pressure and the brom aceto propyl ether is collected. This material is an oil which is colorless when freshly made, but it is not as stable as the corresponding chlorine compound and darkens on standing,
The corresponding 7 iodo 'y aceto propyl alcohol and iodo aceto propyl ether may be produced in smaller yields than the related chlor and brom compounds by employing elemental iodine instead of the chlorinating and brominating agents mentioned previously in the several reactions described hereinabove. If desired, the iodo compounds may also be prepared in more substantial yields, by treating one of the chlor or brom alcohols or ethers with sodium iodide.
As stated previously, the halogenated aceto propyl ethers obtained may assume the structures indicated by Formulae VI, VII, and VIII outlined hereinabove. If VI were the correct structure, one would expect that two molecules of phenyl hydrazine would react with 1 molecule of the di-halo-aceto-propyl ether. If the correct structure were VII phenyl hydrazine would not react with this ether at all. Actually, in full agreement with structure VIII, only 1 molecule of phenyl hydrazine reacts with 1 molecule of the ether. When a second molecule of phenyl hydrazine is present, it separates from the reaction mixture as phenyl hydrazine hydrochloride. The product of reaction of phenyl hydrazine with v halogen 'y aceto propyl ether is analogous in structure to "tetraphenyltetracarbazon described by Sven Bodforss in Berichte der deutschen chemischen Gesellschaft, vol. 52, p. 1762 and 1767 (1919) and V0]. 72, p. 468 (1939). The reaction involved is also analogous to that of Bodforss, but only one side of the molecule undergoes reaction with phenyl hydrazine. Thus the product of the action of phenyl hydrazine on 'y chloro 'y aceto propyl ether having the properties described in Example 5 is a yellowish crystalline powder melting at about C., insoluble in water or petroleum ether, but soluble in other usual organic solvents, such as alcohol, acetone or ether. It has a composition corresponding to the formula C16H2102N2C1 According to the later ideas of Bodforss, its structure is as follows:
If an excess of phenyl hydrazine is used in the above reaction and an inert solvent is employed, the excess of the reagent is unchanged showing the presence of one and only one a chlor keto group in the molecule of the 'y chloro 'y aceto propyl ether. This is further confirmed by the action of iodine on an aqueous alkaline solution of 'y chloro 'y aceto propyl ether. If this reaction is carried out with a cold water solution only half as much iodine is consumed as is the case when the 'y chloro 'y aceto propyl ether is first warmed with water for a few minutes before carrying out the iodine reaction. This is evidence that the ether has only one COCH3 group and that another such group is formed when the ether is hydrolyzed into the related alcohol.
From the foregoing, it is apparent that the halogenated aceto propyl ethers produced as described hereinbefore contain at least one tetrahydrofurane group and that in all probability they contain only one such group. However, the appended claims are intended to embrace all forms of the ether unless specifically limited to cover only certain ones of such ethers.
The chlorine, bromine and iodine derivatives of 'y aceto propyl alcohol and ether produced in accordance with the invention may be condensed with thio formamide to produce salts of the thiazole derivative known as 4-methyl-5-(fihydroxy-ethyl) thiazole in accordance with the method outlined in Patent No. 2,133,966 granted October 25, 1938. This thiazole derivative may in turn be caused to enter into other reactions to produce synthethic compounds having the characteristic physiological and therapeutic properties of the antineuritic vitamin.
What is claimed is:
1. The process of converting a 'y halogen 1 aceto propyl alcohol into the corresponding ether which comprises dehydrating the alcohol.
2. The process of converting a 7 halogen '7 aceto propyl alcohol into the corresponding ether which comprises distilling the alcohol under reduced pressure.
3. The chemical compound diby-halogen-yaceto'propyl) ether wherein the halogen is a member of the group consisting of bromine, chlorine and iodine,
4. A chemical compound having the formula Rr-O'R in which R and R are groups of the class consisting of CHaCOCHXCI-IzCHzand wherein X is one of the halogenes bromine, chlorine and iodine.
5. A chemical compound having the formula R-O-R' in which R. and R are groups of the class consisting of CH3COCHXCH2CH2 and wherein X is one of the halogens bromine, chlorine and iodine, and in which at least one of the groups represented by R and R is CH; oni-o- CH2-CHX 6. The compound having the formula,
on, mire OCHXCHT- 0H,- 0- 0-011, CHIC-CH, EDWIN R. BUCHMAN.
US353505A 1939-09-27 1940-08-21 Halogenated derivatives of aceto propane Expired - Lifetime US2302671A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US353505A US2302671A (en) 1939-09-27 1940-08-21 Halogenated derivatives of aceto propane

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US296817A US2218350A (en) 1939-09-27 1939-09-27 Halogenated derivatives of aceto propane
US353505A US2302671A (en) 1939-09-27 1940-08-21 Halogenated derivatives of aceto propane

Publications (1)

Publication Number Publication Date
US2302671A true US2302671A (en) 1942-11-24

Family

ID=26969834

Family Applications (1)

Application Number Title Priority Date Filing Date
US353505A Expired - Lifetime US2302671A (en) 1939-09-27 1940-08-21 Halogenated derivatives of aceto propane

Country Status (1)

Country Link
US (1) US2302671A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4009157A (en) * 1974-03-21 1977-02-22 Pennwalt Corporation Primary-aliphatic α-hydroxy azoalkanes

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4009157A (en) * 1974-03-21 1977-02-22 Pennwalt Corporation Primary-aliphatic α-hydroxy azoalkanes

Similar Documents

Publication Publication Date Title
US2519190A (en) Polyhalogenated polycyclic hydrocarbons and insecticides thereof
Swallen et al. THE SYNTHESIS OF BETA-BROMO-ALKYL ETHERS AND THEIR USE IN FURTHER SYNTHESES1, 2
Mowry Mucochloric acid. I. Reactions of the pseudo acid group
US2462433A (en) Preparation of organic thiocyanates and isothiocyanates
Summerbell et al. Studies in the Dioxane Series. II. Aryl Substituted Dioxanes Synthesis of p-Dioxene1
US2302671A (en) Halogenated derivatives of aceto propane
CLAUSON-KAAS et al. The Preparation of 2, 5-Diacetoxy-2, 5-Dihydrofuran, 2, 5-Diacetoxytetrahydrofuran and Pyridazine
US2218349A (en) Halogenated derivatives of aceto propyl alcohol
Coonradt et al. The Chlorination of Thiophene. I. Addition Products
US2314571A (en) Process for producing gamma-halogen gamma-aceto propyl alcohol
US2218350A (en) Halogenated derivatives of aceto propane
Plummer et al. An improved procedure for preparing primary nitroalkanes by the Victor Meyer reaction
US2193858A (en) Halogenated organic compounds
JP4467890B2 (en) Chloromethylation of thiophene
DE3314029C2 (en)
McCubbin et al. The oxidation of “di-isobutylene” by ozone
JPH0223535B2 (en)
US4057585A (en) Method of preparing 2,3-dichloroanisole
C-CN Studies on Succinic Acids V. The Preparation and Properties of Diastereoisomers of Tetraalkylsuccinic Acids
US2740810A (en) Preparation of 2-methyl-4-chlorophenoxyacetic acid
US2443388A (en) Protection
US3251884A (en) Bis(haloalkyl)disulfides
Fuson et al. The Action of Methylmagnesium Halides on 2, 4, 6-Trisubstituted Benzoyl Chlorides
US2927134A (en) Preparation of cyclohexenone
US2654760A (en) Preparation of 4-methyl-5-(beta-hydroxyethyl)-thiazole