CA1070710A - Synthesis of d-2-amino-1-butanol - Google Patents
Synthesis of d-2-amino-1-butanolInfo
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- CA1070710A CA1070710A CA244,749A CA244749A CA1070710A CA 1070710 A CA1070710 A CA 1070710A CA 244749 A CA244749 A CA 244749A CA 1070710 A CA1070710 A CA 1070710A
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- butanol
- amino
- propyl
- chloromethyl
- acetamide
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Abstract
ABSTRACT
d-2-Amino-1-butanol, for the synthesis of ethambutol hydrochloride, d,d'-2,2'-(ethylenediimino)di-1-butanol dihydro-chloride, is produced in high purity and good yields by the reaction of butene-l, a nitrile, preferably an excess of acetonitrile, and chlorine to form N-[l-(chloromethyl)propyl]-acetimidoyl chloride which is hydrolyzed to d1-2-amino-1-bu-tanol, which can be isolated as the hydrochloride, or free base, or a mixture resolved with L(+)-tartaric acid and the d-2-amino-1-butanol reacted with ethylene dichloride and then hydrochloric acid to form ethambutol hydrochloride. A minimum of by-products which are conveniently split out permits the economical synthesis of a pharmaceutical grade product.
d-2-Amino-1-butanol, for the synthesis of ethambutol hydrochloride, d,d'-2,2'-(ethylenediimino)di-1-butanol dihydro-chloride, is produced in high purity and good yields by the reaction of butene-l, a nitrile, preferably an excess of acetonitrile, and chlorine to form N-[l-(chloromethyl)propyl]-acetimidoyl chloride which is hydrolyzed to d1-2-amino-1-bu-tanol, which can be isolated as the hydrochloride, or free base, or a mixture resolved with L(+)-tartaric acid and the d-2-amino-1-butanol reacted with ethylene dichloride and then hydrochloric acid to form ethambutol hydrochloride. A minimum of by-products which are conveniently split out permits the economical synthesis of a pharmaceutical grade product.
Description
~5,261 7~ :
dl-2-Amino-l-butanol is produced by adding butene-l and chlorine to acetonitrile, preferably simul-taneously, to yield N-[l-(chloromethyl)propyl]acetimidoyl chloride together with a certain amount of by-product 1,2-dichlorobutane; the N-[l-(chloromethyl)propyl]acet-imidoyl chloride is hydrolyzed conveniently in situ to N-ll-(chloromethyl)propyl]acetamide, which is further hydrolyzed with convenient removal of excess acetoni-trile and 1,2-dichlorobutane with presumably a ring closing and reopening steps to dl-2-amino-1-hutanol, conveniently as the hydrochloride. dl-2-Amino-l-butanol has many uses as such, including resolution to d-2- :
-amino-l-butanol which is reacted with ethylene dichlor-ide to produce ethambutol hydrochloride, d,d'-2,2'--~ethylenediimino)di-l-butanol dihydrochlorideD The dl-30 -2-amino-1-butanol from the present process yielcls a ~:
~ .
7~
.: .
1 pharmaceutically elegant grade of ethambutol hydrochlor~
ide. .~:
This gives d-2-amino-1-butanol in a form .
which is particularly acceptable for reaction with ethyl-ene dichloride to yield a pharmacelltically elegant grade of d,d'-2,2'-(ethylenediimino)di-1-butanol dihydrochlor-de .
These equations may be written~
CH3CH2CH=cH2 + C12 + ~ CH3CN
10 butene-l acetonitrile CH3cH2cHcH2cL '' N=CClCH3 N-[l-chloromethyl)propylJacetimidoyl chloride or N-[1-(chloromethyl)propyl]ethanimidoyl chloride ..
I ~ CH3cH2cHcH2~l + HCl H20 ' . ::
N-l-(chloromethyl)propyl]acetamide II~ CH3cH2cH CH2 Heat l l HN + O
Cl 4-ethyl-2-methyl-2-oxazoline hydrochloride or 4,5-dihydro~4-ethyl-2-methyl-oxazole hydrochloridb ~2 III -~ C~3CH2CH-CH20H + CH3COOCH3 ~ NH3C1 IV
dl-2-amino-1-butanol hydrochloride methyl acetate . ~ - 3 -- ~7~7~
This invention is concerned with the preparation of ~ 2,2'~(ethylenediimino)di-1-butanol which comprises mixing dl-2-amino-1-butanol containing dl-l amino-2-butanol with L(+)- tartaric acid in anhydrous methanol, separating the crystalline acid L(+)-tartrate of _-2-amino-1-butanol from the salts of dl-2-amino-1-butanol and d- and 1- l-amino-
dl-2-Amino-l-butanol is produced by adding butene-l and chlorine to acetonitrile, preferably simul-taneously, to yield N-[l-(chloromethyl)propyl]acetimidoyl chloride together with a certain amount of by-product 1,2-dichlorobutane; the N-[l-(chloromethyl)propyl]acet-imidoyl chloride is hydrolyzed conveniently in situ to N-ll-(chloromethyl)propyl]acetamide, which is further hydrolyzed with convenient removal of excess acetoni-trile and 1,2-dichlorobutane with presumably a ring closing and reopening steps to dl-2-amino-1-hutanol, conveniently as the hydrochloride. dl-2-Amino-l-butanol has many uses as such, including resolution to d-2- :
-amino-l-butanol which is reacted with ethylene dichlor-ide to produce ethambutol hydrochloride, d,d'-2,2'--~ethylenediimino)di-l-butanol dihydrochlorideD The dl-30 -2-amino-1-butanol from the present process yielcls a ~:
~ .
7~
.: .
1 pharmaceutically elegant grade of ethambutol hydrochlor~
ide. .~:
This gives d-2-amino-1-butanol in a form .
which is particularly acceptable for reaction with ethyl-ene dichloride to yield a pharmacelltically elegant grade of d,d'-2,2'-(ethylenediimino)di-1-butanol dihydrochlor-de .
These equations may be written~
CH3CH2CH=cH2 + C12 + ~ CH3CN
10 butene-l acetonitrile CH3cH2cHcH2cL '' N=CClCH3 N-[l-chloromethyl)propylJacetimidoyl chloride or N-[1-(chloromethyl)propyl]ethanimidoyl chloride ..
I ~ CH3cH2cHcH2~l + HCl H20 ' . ::
N-l-(chloromethyl)propyl]acetamide II~ CH3cH2cH CH2 Heat l l HN + O
Cl 4-ethyl-2-methyl-2-oxazoline hydrochloride or 4,5-dihydro~4-ethyl-2-methyl-oxazole hydrochloridb ~2 III -~ C~3CH2CH-CH20H + CH3COOCH3 ~ NH3C1 IV
dl-2-amino-1-butanol hydrochloride methyl acetate . ~ - 3 -- ~7~7~
This invention is concerned with the preparation of ~ 2,2'~(ethylenediimino)di-1-butanol which comprises mixing dl-2-amino-1-butanol containing dl-l amino-2-butanol with L(+)- tartaric acid in anhydrous methanol, separating the crystalline acid L(+)-tartrate of _-2-amino-1-butanol from the salts of dl-2-amino-1-butanol and d- and 1- l-amino-
2-butanol which remain in solution in the methanol)dissolving said _-2-amino-1-butanol L(+)- tartrate in water, adding an alkali or alkaline earth hydroxide, separating out the resultant alkali or alkaline earth L(+)- tartrate, thus isolating _-2-amino-1-butanol, evaporating off remaining water, adding ethylene dichloride, and reacting to form d, -2,2'-(ethylenediimino)di-1-butanol, and isolating the thus formed d,d-2,2'-(ethylenediimino)di-1-butanol as the dihydrochloride salt.
The dl-2-amino-1-butanol used in the invention may be conveniently synthesized by heating N-[l-(chloromethyl) propyl]-acetamide in the presence of a lower alkanol and water whereby the N-[l-(chloromethyl)propyl]acetamide is hydrolyzed to dl-2-amino-1-butanol, and distilling off the coproduced alkanol acetate, whereby side reactions are suppressed, and the hydrolysis to dl-2-amino-1-butanol is essentially quantitative.
~7~7::~0 1 Surprisingly, best results are obtained in the reaction with acetonitrile if an excess oE acetoni-trile is used. Acetonitrile is the expensive compon-ent and routinely it is customary to attempt to use less of the expensive component.
Here, chlorine also reacts with butene-l to yield 1,2-dichlorobutene. ~n excess of acetonitrile shifts the reaction towards N-[l-~chloromethyl)propyl]-acetimidoyl chloride. An amount of water corresponding to that required for the hydrolysis of N-[l-(chloromethyl)-propyl]acetimidoyl chloride may be added before, with vr after the addition of the chlorine and butene to the re-action mixture to hydrolyze the N-[l-chloromethyl)propyll-acetimidoyl chloride to N-[l-(chloromethyl)propyl~acet-amide. The reaction o~ acetonitrile with hydrochloricacid formed in the hydrolysis is sufficiently slow that at least 95% of the excess of acetonitrile may be dis-tilled under reduced pressure from the reaction mixture and recycled. The economical recovery of the acetoni-trile in 5uch form that it may be recycled to the pro-cess is essential to the low cost production being sought.
Too great an excess of acetonitrile requires too large a reaction vessel. A continuous reaction may be used, which permits smaller equipment, and a large excess of acetonitrile, which is recycled to the start-ing materials.
After stripping the acetonitrile, if hydroly-sis of N-[l-(chloromethyl)propyl]acetimidoyl chloride to N-[l-(chloromethyl)propyl~]acetamide has not been com-pleted during the reaction, hydrolysis is completed by ~7~7~
1 adding water to the pot residue. Production of N-[l--(chloromethyl)propyl]acetamide by hydrolysis of N-[l--(chloromethyl)propyl]acetimidoyl chloride, is avored by the presence of a weak base such as calcium carbon-ate, calcium oxide, calcium hydroxide, sodium carbonate,sodil~m bicarbonate, potassium carbonate or bicarbonate, barium carbonate, or strontium carbonate. The base is not necessary if the M-[l-(chloromethyl)propyl]acetamide is to be processed by fur~her hydrolysis to d}-2-amino--l-butanol. After hydrolysis, 1-2-dichlorobutane :Ls stripped by distillation under reduced pressure.
After removal of the acetonitrile and 1,2-di- ~ ;
chlorobutane, the purity of the N-[l-(chloromethyl)-propyl]acetamide is sufficiently high for convenient processing through to dl-2-amino-1-butanol hydrochloride of a grade which may be used in a resolution step, or other purposes.
The N-[l-(chloromethyl)propyl]acetimidoyl chloride may be recovered and utilized after its forma-tion. Conveniently, water is added to the reactor tohydrolyze N-[l-(chloromethyl)propyl]acetimidoyl chloride to N-[l-(chloromethyl)-propyl]acetamide, so that, in ef-fect, the first two steps are simultaneously accomplish-.
ed, exotherms are better controlled, and the processing steps are simultaneous, Baving time and manipulation. A
slight excess over the calculated quantity of water nec-essary for hydrolysis of M-[l-~chloromethyl)propyl~acet-imidoyl chloride to N-[l-(chloromethyl)propyl~acetamide may be added after the completion of chlorination.
The acetonitrile may be separated from the N-~7~
1 -[l-(chloromethyl)propyl]acetimidoyl chloride or N-[l--~chloromethyl)propyl]acetamide. Conveniently, it is separated after the hydrolysis to N-[l-(chloromethyl)-propyl]acetamide. The 1,2-dichlorobutane may be separ-ated in whole or in part by distillation after the syn-thesis of N-[l-(chloromethyl)propyl]acetimidoyl chloride, or after hydrolysis to N-[l-(chloromethyl)propyl]acet-amide. At least part of the 1,2-di~hlorobutane may be retained until the syn~hesis of the dl-2-amino-1-butanol hydrochloride is completed. It is usually more conven ient to separate the 1,2-dichlorobutane after the hy-drolysis to the N-[l-(chloromethyl)propyl]acet~mide, as the reaction mixture is then smaller, and more compact equipment may be used for the reaction of the N-[l-~chlor-omethyl)propyl~acetamide to ~ amino-l-butanol hydro-chloride. Azeotropic distillation with water permits convenient and effective complete removal of the 1,2--dichlorobutane from the dl-2 amino-l-butanol.
Subsequently, methanol is added to the aqueous reaction ~ixture containing N-~l-(chloromethyl)propyl]-acetamide, preferably with catalytic amounts of hydro-chloric acid, which is refluxed to hydrolyze to dl-2--amino-~-butanol hydrochloride with by-product methyl acetate. The methyl acetate is removed by distillation leaving dl-2-amino-1-butanol hydrochloride.
For the production o~ N-[l-(chloromethyl)propyl~-acetimidoyl chloride, the presence of water is to be avoided, and vacuum distillation to remove acetonitrile and l,2-dichlorobutane is necessary. If hydrolyzed to N-[l~(chloromethyl)propyllacetamide, mild conditions for 71~
1 the removal of both acetonitrile and 1,2-dichlorobutane are preferred. A weak base aids in controlled hydroly-sis. Where hydrolysis to dl-2-amino-1-butanol is desir-ed, the acid produced in h~drolysis can be used to form the hydrochloride salts of the product.
In the production of dl-2-amino-1-butanol hy-drochloride, the acetonitrile should be vacuum distilled out at the N-[l-(chloromethly)propyl]acetamide stage, for recycling. If the acetonitrile is perr~litted to remain during the hydrolysis to dl-2-amino-1-butanol hydro-chloride, the acetonitrile tends to hydrolyze to acetic acid with production of ammonia, usually as the ammonium chloride. The acetic acid from the hydrolysis of aceto-nitrile is readily removed as the methyl ester, but the 15 loss of acetonitrile reduces the efficiency of the pro- ~;
cess 1,2-Dichlorobutane is preferably at least partially removed by vacuum distillation at the N-[l--(chloromethyl)propyl]acetamide stage. It causes no com-plications other than increasing the size of the reactorrequired. Conveniently, the last of the 1,2-dichloro-butane is removed by azeotropic distillation from dl-2 -amino-l-butanol hydrochloride at the time acetic acid is removed as the methyl ester. Conveniently, the inter~
mediate reactions to dl 2-amino-1-butanol hydrochloride may overlay without the isolation of N-[l-~chloromethyl)-propyl]acetimidoyl chloride and N-[l-(chloromethyl)propyl]-acetamide.
By dissolving in methyl alcohol, or isopropanol, or mixtures thereof, a solution of the dl-2-amino-:L-but-. " ~ . . ~ ., ~ .
1 anol, predominantly as the hydrochloride, is obtainedwhich can be partially neutralized with ammonia to form a mixture of dl-2-amino-1-butanol and dl-2-amino-1-but-anol hydrochloride, with ammonium chloride being filtered out. The mixture is approximately two parts dl-2-amino--l-butanol and one part dl-2-amino-1-butanol hydrochlor-ide, a ratio which is close to the optimum desired for reacting with L(+~- tartaric acid in the presence of an-hydrous methanol to permit the separation of the d-2--amino-l-butanol tartrate as is set forth in detail in United States Patent 3,553,257.
This process has unique and unexpected advant-ages in the present system because part of the butene-l adds chlorine and acetonitrile in the reverse of the de lS sired position so that about 3 to 10~ dl-1-amino-2-butanol is found in the dl-2-amino-1-butanol as an impurity. In separation of the d- and l-isomers of dl-2-amino-1-but-anol, both isomers of dl~l-amino-2-butanol remain with the mother liquor, and a much purified d-2-amino-1-but-anol separates out as the L(+)- tartrate saIt.
A starting material containing up to about 10%
of dl-l~amino-2-butanol yields a purified d-2~amino-1--butanoI, as the tartrate, having a content of less than 0.01~ of dl-1-amino-2-butanol, as its tartrate salts.
If washing is less thorough, up to 0.1% may be present.
A purity is readily obtained which can be used as a starting material for ethambutol which is of pharmaceut-ical grade with a minimum of addi~ional purification.
The facility of separating out impurities and by-products is unobvious and of the essence of the pres-~ 8 --~707~(~
1 ent system of reactions.
Exa~ e 1 Preparation of dl-2-Amino~l-butanol Hydrochloricle .
Acetonitrile (164 g., 4 moles) is placed in a tared 500 ml. 4-necked Morton flask equipped with a mechanical stirrer, a thermometer, two fritted glass gas-inlet tubes, a syringe needle (attached to a syringe pump), and a dry-ice condenser. The flask is cooled in an ice-water bath to 3-5C. Chlorine (71 g., 1 mole) 10 and butene-l (56 g., 1 mole~ are passed through the well- ;~
-stirred acetonitrile at a ra*e of about 400 ml./min.
each while water (10 g., 0.55 mole) is added ~imultane-ously at a linear rate with the syringe pump during the course of the reaction (1 hour).
The reaction temperature rises to 20C. within 8 minutes and stays constant through the course of the reaction. The reaction mixture is stirred for an addi-tional 15-30 minutes. The reaction mixture is weighed to insure that proper amounts of the gaseous reactants have been introduced. Excess acetonitrile (b.p. 36-41C./-150-170 mm.) is remo~ed by distillation (bath temperat-ure up to 100C.) while using a 10-plate distillation col-umn. A sudden temperature drop indicates the end of acetonitrile distillation.
Th~ acetonitrile fraction conta ~s 1-2% HCl and about 6% 1,2-dichlorobutane and can be recycled, without further treatment to a subse~uent batch, or can be purified before recycling.
The hsat temperature rises to 70 and by-prod-uct lt2-diehlorobutane is distilled off between 70-40C~
g _ :
07~
1 at 150 to 25 mm. A dry-ice trap attached to the vacuum line contains 15-25 g. of a material which consisted of 35% HCl, 10% 1,2-dichlorobutane and a crystalline solid derived from the reaction of acetonitrile with anhydrous H~l.
The residue in the flask, predominantly N-[l--(chloromethyl)propyl]acetamide, is mixed with water (45 g., 2.5 moles) and the mixture is brought ~o reflux. The residual 1,2-dichlorobutane is removed by azeotropic distillation (Dean-Stark trap) while the mixture is re-fluxed for 2 hours. The water and some acetic acld (formed during hydrolysis with water~ are removed at 80 (under reduced pressure (15-20 mm.) to leave a viscous residue consisting of N-~l-(chloromethyl)propyl~acetamide, and its hydrolysis products.
- Methanol (48 gO, 1.5 moles) and concentrated hydrochloric acid (0.5 ml.) are added to the residue and the reaction mixture is refluxed for 2 hours. After removal of the volatiles tH20, methyl acetate, etc.), - 20 the dl-2-amino-1-butanol hydrochloride is obtained as a colorless viscous material which crystallizes on stand-ing.
Example 2 dl-2-amino-1 butanol A 30 g. portion of the crude dl-2-amino-1 -butanol hydrochloride from Example 1 is susper.ded in a mixture o 100 ml. of toluene and 20 ml. of isopropanol.
Anhydrous ammonia tlO.2 g., 0.6 mole~ is introduced over the sur~ace of the well-stirred suspension at 25C.
A dry-ice-acetone condenser controls ammonia loss during ~0707~L~
1 reaction. Crystalline ammonium chloride starts precipi-tatlng immediately and stirring is continued for 15 20 minutes to insure completion of the reaction. The dry--ice-acetone condenser is removed and excess NH3 is al-lowed to volatilized (15~20 minutes). The precipitatedNH4Cl is filtered off and washed with a small amount of toluene.
The filtrate and washings are combined and the solvents evaporated under reduced pressure to obtain d,1-2-amino-1-butanol (210 0 g. ) . The product by gas liquid chromatography is 63% pure, and contains about 8%
of dl~l-amino-2-butanol. The same process can be used to obtain the d- or 1- optical isomer as a free base from its hyrochloride salt.
Example 3 .
d-2~amino-1-butanol tartrate from dl-2-amino-1-butanol hydrochloride A 50 g. sample of dl-2-amino-1-butanol hydro-chloride from Example 1 is dissolved in 100 ml. of anhy-drous methanol. One mole of anhydrous NH3 is condensed in over a period of 40 minutes~ (A dry-ice-acetone con-denser is used to prevent ammonLa loss during reaction.) After stirring for 0.5 hour, the dry-ice-acetone conden~
ser is removed and excess NH3 is allowed to volatilize (20-30 minutes). The precipitated NH4Cl is filtered off tl3.2 gm., 0.246 mole, 62~) and the filtrate i~ concen-trated to leave a viscous oil (43 gm.) which contains 58% by weight free dl-2-amino-1-butanol (the remainder being unreacted dl-2-amino-1-butanol hydrochloride).
The mixture (42 g.) is dissolved in 120 ml. of ~L~7~)7:~LO
1 anhydrous Methanol and the solution is treated with 35 g. (0.233 mole) of L(~)- tartarlc acid. The reaction temperature rises to 45-47C. during addition of tar-taric acid. The solution is maintained at this temper-ature for 1 hour and then cooled to 25C. over a periodof 4-5 hours. Crystallization can be expedited by seed-ing the solution with d-2-amino-1-butanol L(~)- tartrate to induce crystallization of the salt, The precipi~ated salt is filtered off and wash-ed four times with cold methanol and then dried in an inert atmosphere. The salt i9 obtained as colorless crystalline solid [30 g., 0.125 mole, 63%) m.p. 133-140C.
[a]D6= 23.52 (c = 5~, H2O) and in a typical run was in-distinguishable rom authentic d-2-amino-1-butanol L(+)-tartrate [m p. 137-141C.; [al26=23.74 (c = 5%, H2O)].
Up to about 8% of dl-1-amino-2-butanol may be formed in the reactions from the addition of the imido group to the 1 position in butene-l, in effect, the reverse of that desired. By analogous reactions, this is converted to , dl-1-amino-2-butanol. Both the d and 1 isomers remain with the mother liquor in the crystallization, and per-mit the separatian of d~2-amino-1-butanol L(~)- tartrate substantially free from impurities.
The isolation of d 2-amino l-butanol from the salt has been described in United States Patent No.
The dl-2-amino-1-butanol used in the invention may be conveniently synthesized by heating N-[l-(chloromethyl) propyl]-acetamide in the presence of a lower alkanol and water whereby the N-[l-(chloromethyl)propyl]acetamide is hydrolyzed to dl-2-amino-1-butanol, and distilling off the coproduced alkanol acetate, whereby side reactions are suppressed, and the hydrolysis to dl-2-amino-1-butanol is essentially quantitative.
~7~7::~0 1 Surprisingly, best results are obtained in the reaction with acetonitrile if an excess oE acetoni-trile is used. Acetonitrile is the expensive compon-ent and routinely it is customary to attempt to use less of the expensive component.
Here, chlorine also reacts with butene-l to yield 1,2-dichlorobutene. ~n excess of acetonitrile shifts the reaction towards N-[l-~chloromethyl)propyl]-acetimidoyl chloride. An amount of water corresponding to that required for the hydrolysis of N-[l-(chloromethyl)-propyl]acetimidoyl chloride may be added before, with vr after the addition of the chlorine and butene to the re-action mixture to hydrolyze the N-[l-chloromethyl)propyll-acetimidoyl chloride to N-[l-(chloromethyl)propyl~acet-amide. The reaction o~ acetonitrile with hydrochloricacid formed in the hydrolysis is sufficiently slow that at least 95% of the excess of acetonitrile may be dis-tilled under reduced pressure from the reaction mixture and recycled. The economical recovery of the acetoni-trile in 5uch form that it may be recycled to the pro-cess is essential to the low cost production being sought.
Too great an excess of acetonitrile requires too large a reaction vessel. A continuous reaction may be used, which permits smaller equipment, and a large excess of acetonitrile, which is recycled to the start-ing materials.
After stripping the acetonitrile, if hydroly-sis of N-[l-(chloromethyl)propyl]acetimidoyl chloride to N-[l-(chloromethyl)propyl~]acetamide has not been com-pleted during the reaction, hydrolysis is completed by ~7~7~
1 adding water to the pot residue. Production of N-[l--(chloromethyl)propyl]acetamide by hydrolysis of N-[l--(chloromethyl)propyl]acetimidoyl chloride, is avored by the presence of a weak base such as calcium carbon-ate, calcium oxide, calcium hydroxide, sodium carbonate,sodil~m bicarbonate, potassium carbonate or bicarbonate, barium carbonate, or strontium carbonate. The base is not necessary if the M-[l-(chloromethyl)propyl]acetamide is to be processed by fur~her hydrolysis to d}-2-amino--l-butanol. After hydrolysis, 1-2-dichlorobutane :Ls stripped by distillation under reduced pressure.
After removal of the acetonitrile and 1,2-di- ~ ;
chlorobutane, the purity of the N-[l-(chloromethyl)-propyl]acetamide is sufficiently high for convenient processing through to dl-2-amino-1-butanol hydrochloride of a grade which may be used in a resolution step, or other purposes.
The N-[l-(chloromethyl)propyl]acetimidoyl chloride may be recovered and utilized after its forma-tion. Conveniently, water is added to the reactor tohydrolyze N-[l-(chloromethyl)propyl]acetimidoyl chloride to N-[l-(chloromethyl)-propyl]acetamide, so that, in ef-fect, the first two steps are simultaneously accomplish-.
ed, exotherms are better controlled, and the processing steps are simultaneous, Baving time and manipulation. A
slight excess over the calculated quantity of water nec-essary for hydrolysis of M-[l-~chloromethyl)propyl~acet-imidoyl chloride to N-[l-(chloromethyl)propyl~acetamide may be added after the completion of chlorination.
The acetonitrile may be separated from the N-~7~
1 -[l-(chloromethyl)propyl]acetimidoyl chloride or N-[l--~chloromethyl)propyl]acetamide. Conveniently, it is separated after the hydrolysis to N-[l-(chloromethyl)-propyl]acetamide. The 1,2-dichlorobutane may be separ-ated in whole or in part by distillation after the syn-thesis of N-[l-(chloromethyl)propyl]acetimidoyl chloride, or after hydrolysis to N-[l-(chloromethyl)propyl]acet-amide. At least part of the 1,2-di~hlorobutane may be retained until the syn~hesis of the dl-2-amino-1-butanol hydrochloride is completed. It is usually more conven ient to separate the 1,2-dichlorobutane after the hy-drolysis to the N-[l-(chloromethyl)propyl]acet~mide, as the reaction mixture is then smaller, and more compact equipment may be used for the reaction of the N-[l-~chlor-omethyl)propyl~acetamide to ~ amino-l-butanol hydro-chloride. Azeotropic distillation with water permits convenient and effective complete removal of the 1,2--dichlorobutane from the dl-2 amino-l-butanol.
Subsequently, methanol is added to the aqueous reaction ~ixture containing N-~l-(chloromethyl)propyl]-acetamide, preferably with catalytic amounts of hydro-chloric acid, which is refluxed to hydrolyze to dl-2--amino-~-butanol hydrochloride with by-product methyl acetate. The methyl acetate is removed by distillation leaving dl-2-amino-1-butanol hydrochloride.
For the production o~ N-[l-(chloromethyl)propyl~-acetimidoyl chloride, the presence of water is to be avoided, and vacuum distillation to remove acetonitrile and l,2-dichlorobutane is necessary. If hydrolyzed to N-[l~(chloromethyl)propyllacetamide, mild conditions for 71~
1 the removal of both acetonitrile and 1,2-dichlorobutane are preferred. A weak base aids in controlled hydroly-sis. Where hydrolysis to dl-2-amino-1-butanol is desir-ed, the acid produced in h~drolysis can be used to form the hydrochloride salts of the product.
In the production of dl-2-amino-1-butanol hy-drochloride, the acetonitrile should be vacuum distilled out at the N-[l-(chloromethly)propyl]acetamide stage, for recycling. If the acetonitrile is perr~litted to remain during the hydrolysis to dl-2-amino-1-butanol hydro-chloride, the acetonitrile tends to hydrolyze to acetic acid with production of ammonia, usually as the ammonium chloride. The acetic acid from the hydrolysis of aceto-nitrile is readily removed as the methyl ester, but the 15 loss of acetonitrile reduces the efficiency of the pro- ~;
cess 1,2-Dichlorobutane is preferably at least partially removed by vacuum distillation at the N-[l--(chloromethyl)propyl]acetamide stage. It causes no com-plications other than increasing the size of the reactorrequired. Conveniently, the last of the 1,2-dichloro-butane is removed by azeotropic distillation from dl-2 -amino-l-butanol hydrochloride at the time acetic acid is removed as the methyl ester. Conveniently, the inter~
mediate reactions to dl 2-amino-1-butanol hydrochloride may overlay without the isolation of N-[l-~chloromethyl)-propyl]acetimidoyl chloride and N-[l-(chloromethyl)propyl]-acetamide.
By dissolving in methyl alcohol, or isopropanol, or mixtures thereof, a solution of the dl-2-amino-:L-but-. " ~ . . ~ ., ~ .
1 anol, predominantly as the hydrochloride, is obtainedwhich can be partially neutralized with ammonia to form a mixture of dl-2-amino-1-butanol and dl-2-amino-1-but-anol hydrochloride, with ammonium chloride being filtered out. The mixture is approximately two parts dl-2-amino--l-butanol and one part dl-2-amino-1-butanol hydrochlor-ide, a ratio which is close to the optimum desired for reacting with L(+~- tartaric acid in the presence of an-hydrous methanol to permit the separation of the d-2--amino-l-butanol tartrate as is set forth in detail in United States Patent 3,553,257.
This process has unique and unexpected advant-ages in the present system because part of the butene-l adds chlorine and acetonitrile in the reverse of the de lS sired position so that about 3 to 10~ dl-1-amino-2-butanol is found in the dl-2-amino-1-butanol as an impurity. In separation of the d- and l-isomers of dl-2-amino-1-but-anol, both isomers of dl~l-amino-2-butanol remain with the mother liquor, and a much purified d-2-amino-1-but-anol separates out as the L(+)- tartrate saIt.
A starting material containing up to about 10%
of dl-l~amino-2-butanol yields a purified d-2~amino-1--butanoI, as the tartrate, having a content of less than 0.01~ of dl-1-amino-2-butanol, as its tartrate salts.
If washing is less thorough, up to 0.1% may be present.
A purity is readily obtained which can be used as a starting material for ethambutol which is of pharmaceut-ical grade with a minimum of addi~ional purification.
The facility of separating out impurities and by-products is unobvious and of the essence of the pres-~ 8 --~707~(~
1 ent system of reactions.
Exa~ e 1 Preparation of dl-2-Amino~l-butanol Hydrochloricle .
Acetonitrile (164 g., 4 moles) is placed in a tared 500 ml. 4-necked Morton flask equipped with a mechanical stirrer, a thermometer, two fritted glass gas-inlet tubes, a syringe needle (attached to a syringe pump), and a dry-ice condenser. The flask is cooled in an ice-water bath to 3-5C. Chlorine (71 g., 1 mole) 10 and butene-l (56 g., 1 mole~ are passed through the well- ;~
-stirred acetonitrile at a ra*e of about 400 ml./min.
each while water (10 g., 0.55 mole) is added ~imultane-ously at a linear rate with the syringe pump during the course of the reaction (1 hour).
The reaction temperature rises to 20C. within 8 minutes and stays constant through the course of the reaction. The reaction mixture is stirred for an addi-tional 15-30 minutes. The reaction mixture is weighed to insure that proper amounts of the gaseous reactants have been introduced. Excess acetonitrile (b.p. 36-41C./-150-170 mm.) is remo~ed by distillation (bath temperat-ure up to 100C.) while using a 10-plate distillation col-umn. A sudden temperature drop indicates the end of acetonitrile distillation.
Th~ acetonitrile fraction conta ~s 1-2% HCl and about 6% 1,2-dichlorobutane and can be recycled, without further treatment to a subse~uent batch, or can be purified before recycling.
The hsat temperature rises to 70 and by-prod-uct lt2-diehlorobutane is distilled off between 70-40C~
g _ :
07~
1 at 150 to 25 mm. A dry-ice trap attached to the vacuum line contains 15-25 g. of a material which consisted of 35% HCl, 10% 1,2-dichlorobutane and a crystalline solid derived from the reaction of acetonitrile with anhydrous H~l.
The residue in the flask, predominantly N-[l--(chloromethyl)propyl]acetamide, is mixed with water (45 g., 2.5 moles) and the mixture is brought ~o reflux. The residual 1,2-dichlorobutane is removed by azeotropic distillation (Dean-Stark trap) while the mixture is re-fluxed for 2 hours. The water and some acetic acld (formed during hydrolysis with water~ are removed at 80 (under reduced pressure (15-20 mm.) to leave a viscous residue consisting of N-~l-(chloromethyl)propyl~acetamide, and its hydrolysis products.
- Methanol (48 gO, 1.5 moles) and concentrated hydrochloric acid (0.5 ml.) are added to the residue and the reaction mixture is refluxed for 2 hours. After removal of the volatiles tH20, methyl acetate, etc.), - 20 the dl-2-amino-1-butanol hydrochloride is obtained as a colorless viscous material which crystallizes on stand-ing.
Example 2 dl-2-amino-1 butanol A 30 g. portion of the crude dl-2-amino-1 -butanol hydrochloride from Example 1 is susper.ded in a mixture o 100 ml. of toluene and 20 ml. of isopropanol.
Anhydrous ammonia tlO.2 g., 0.6 mole~ is introduced over the sur~ace of the well-stirred suspension at 25C.
A dry-ice-acetone condenser controls ammonia loss during ~0707~L~
1 reaction. Crystalline ammonium chloride starts precipi-tatlng immediately and stirring is continued for 15 20 minutes to insure completion of the reaction. The dry--ice-acetone condenser is removed and excess NH3 is al-lowed to volatilized (15~20 minutes). The precipitatedNH4Cl is filtered off and washed with a small amount of toluene.
The filtrate and washings are combined and the solvents evaporated under reduced pressure to obtain d,1-2-amino-1-butanol (210 0 g. ) . The product by gas liquid chromatography is 63% pure, and contains about 8%
of dl~l-amino-2-butanol. The same process can be used to obtain the d- or 1- optical isomer as a free base from its hyrochloride salt.
Example 3 .
d-2~amino-1-butanol tartrate from dl-2-amino-1-butanol hydrochloride A 50 g. sample of dl-2-amino-1-butanol hydro-chloride from Example 1 is dissolved in 100 ml. of anhy-drous methanol. One mole of anhydrous NH3 is condensed in over a period of 40 minutes~ (A dry-ice-acetone con-denser is used to prevent ammonLa loss during reaction.) After stirring for 0.5 hour, the dry-ice-acetone conden~
ser is removed and excess NH3 is allowed to volatilize (20-30 minutes). The precipitated NH4Cl is filtered off tl3.2 gm., 0.246 mole, 62~) and the filtrate i~ concen-trated to leave a viscous oil (43 gm.) which contains 58% by weight free dl-2-amino-1-butanol (the remainder being unreacted dl-2-amino-1-butanol hydrochloride).
The mixture (42 g.) is dissolved in 120 ml. of ~L~7~)7:~LO
1 anhydrous Methanol and the solution is treated with 35 g. (0.233 mole) of L(~)- tartarlc acid. The reaction temperature rises to 45-47C. during addition of tar-taric acid. The solution is maintained at this temper-ature for 1 hour and then cooled to 25C. over a periodof 4-5 hours. Crystallization can be expedited by seed-ing the solution with d-2-amino-1-butanol L(~)- tartrate to induce crystallization of the salt, The precipi~ated salt is filtered off and wash-ed four times with cold methanol and then dried in an inert atmosphere. The salt i9 obtained as colorless crystalline solid [30 g., 0.125 mole, 63%) m.p. 133-140C.
[a]D6= 23.52 (c = 5~, H2O) and in a typical run was in-distinguishable rom authentic d-2-amino-1-butanol L(+)-tartrate [m p. 137-141C.; [al26=23.74 (c = 5%, H2O)].
Up to about 8% of dl-1-amino-2-butanol may be formed in the reactions from the addition of the imido group to the 1 position in butene-l, in effect, the reverse of that desired. By analogous reactions, this is converted to , dl-1-amino-2-butanol. Both the d and 1 isomers remain with the mother liquor in the crystallization, and per-mit the separatian of d~2-amino-1-butanol L(~)- tartrate substantially free from impurities.
The isolation of d 2-amino l-butanol from the salt has been described in United States Patent No.
3,553,257, supra~
Conversion to ethambutol is described in United States Patent 3,769,347.
Examvle 4 -d-2~Amino-l butanol - 12 ~
7~
1 d-2-Amino-l-butanol tartrate (150 g.) (0.63 mole) from Æxample 3 is added with stirrin~ to an aque-ous solution of KOH prepared by dissolving 76 ~. KOH in 115 ml. of distilled water. d-2-Amino l-butanol which forms the upper layer is extracted wit:h tetrahydrofuran (100 ml. x 2). The tetrahydrofuran extract is dried ~Na2SO4) and concentrated under reduced pressure. The crude, oily residue is distilled under reduced pressure to give _-2-amino-1-butanol (b.p. 99-103 at 30 mm.).
The material is further fractionated to give pure d-2--amino-l-butanol having a b.p. of 174, and lal25- 9.9.
The yield of the distilled material is about 50% to 76%
and can be improved substantially if additional extrac-tions are carried out with tetrahydrofuran.
Example 5 Ethambutol Hydrochloride -Following the procedure described in Example 1 of United States Patent 3,769,347, a mixture of 462 g.
of d-2-amino-1-butanol, produced in accordance with the procedure of Example A, and 32 g. of ethylene dichloride is heated to 80C. and the temperature is allowed to rise exothermally to about 130C. After 1 hour, the mix-ture is cooled to about 95C.~ 22.5 g. of sodium hydrox-ide is slowly added, and a temperature of about 112 is maintained for 1 hour. The sodium hydroxide is in the form of prills of about 4 nm. diameter. The mixture is cooled to 70C. and unreacted d-2-amino~l-butanol is recovered by vacuum distillation. The distillation is at a pressure below 20 mm. mercury, and below 130Co ~
heat being applied at a rate within the capacity of the ~0~707~
1 condenser.
Isopropamol (290 g.) is added to the distilla-tion residue at a temperature not above 90C., and fol-lowed by a refluxing period of 30 minutes. The mixture is cooled to and filtered at 60C~ to remove sodium chloride, and the filter cake is washed with 47 g. of isopropanol, at 60C. The volume of the filtrate is diluted to 430 ml. with isopropanol and the temperature is adjusted to 40-45C., 2 g. of diatomaceous earth filt~
er aid is added, and a second filtration is carried out.
To the clear filtrate there is added 120 g.
of methanol and 15 g. of water. The vessel is closed and hydrogen chloride tabout 25 g.) is introduced over the surface of the charge at a gas pressure of 5-7 psig while the temperature is allowed to rise to 55C., to a pH of 2 to 2.5. The charge is cooled very slowly to 28C.
and is stirred for about 1 hour.
Conveniently, a small aliquot is titrated, and a calculated quantity of hydrogen chloride added. Proper final p~ is confirmed by testing as acid to wet Congo Red test paper. Other methods of measuring the pH can be used. The white crystalline product, d,d'-2,2'-tethyl-enediimino)-di-l-butanol dihydrochloride is separated by filtration and washed with isopropanol. The product, carefully dried at al!maximum temperature of 75~C., is about 70 g., has a decomposition range of 198.5-204C., and an ash content of 0.1%.
This is a pharmaceutically acceptable, elegant grade of ethambutol hydrochloride without further treat-- 30 ment or refinement. The produck may be tabletted or en-~ ~t~ 7 ~
1 capsulated by conventional procedures.
Example 6 N-[l-(Chloromethyl)propyl]acetamide Into a 250 ml. 3-necked flask fitted with a stirrer, dry-ice-acetone trap, a gas outlet, and a gas inlet is charged 41.05 g. (1.0 mole) acetonitrile, 25 g.
(0.25 mole) CaCO3, 13.5 ml. (0.75 mole) water and 26.8 g. (0.475 mole) l-butene. The mixture is cooled to -5 to -8C. and chlorine added over 2 hours maintaining the temperature at below 7C. until the reaction mixture turns yellow indicating a slight excess of chlorine. The mixture is filtered and the solvents distilled under re-duced pressure to yield 28.6 g. of N-[l-(chloromethyl)-propyl]acetamide (40.2% yield based on l-butene).
~ æ e 7 N-[l-(Chloromethyl)propyl]acetamide A 500 ml. 3-necked flask fitted with a stirrer and dry-ice-acetone trap is charged with 82.1 g. (2.0 moie) acetonitrile, 27.4 g. (1.52 mole) water, 27 g.
(0.25 mole) Na2CO3 and 28.1 g. (0.50 mole) l-butene and cooled to 0C. Chlorine (0~50 mole) is added over 1/2 hour, the reaction temperature reaching a high of 32C~
After stirring for 2 hours at 25C., the reaction mix-ture is filtered. The acetonitrile washings of the solid phase and filtrate is combined and the solvents removed by vacuum distillation to leave 33.0 g. of the N-El-~chloromethyl)propyl]acetamide (44.0% yield based on l-butene~
Example 8 dl-2-Amino-1-butanol ~7(~7~
1 Sodium hydroxide pels (97~ pure, 18. a g., 0.45 mole) are stirred with 100 ml. of anhydrous methanol and crude dl-2-amino-1-butanol hydrochloride, 50 g.
(87% real, 0.35 mole) from a run similar to that of Ex-ample 1 is added with stirring over a period of O.S
hour. The reaction mixture warms up and precipitated sodium chloride is removed by filtration, washed with methanol and the washings combined with the main fil-trate. Methanol and water (formed during neutralizationj are removed under reduced pressure and the residual oil distilled to yield dl-2-amino-1-butanol (b.p. 95-100%/-30-35 mm.), 26.68 g. (86% of theory). The material con-tains about 9.6~ of dl-1-amino-2-butanol.
dl-2-Amino-l-butanol can be used as a catalyst as described in United States Patent 3,539,652 (CA 74, 23499) as a component of organosilicone compositions, French P~tent No. 1,556,008 (CH 71, 115) or as a compon-ent in a flame retardant composition, United States Patent No. 3,413,380 (CA 70, 40).
~
dl-2-Amino-l-butanol _ Sodium hydroxide pels (97% pure, 18.8 g~, 0.45 mole) are stirred with 100 ml. of isopropanol con-taining 0.7 ml. of water. A part of the sodium hydrox-ide goes into solution. Crude dl-2-amino-1-butanol hy drochloride 50 g. (70~ real, 0.28 mole) is added with stirri~.g over a period of 0.5 hour. The reaction mix-ture warms up to about 45C. and crystalline sodium chloride precipitates out of the reaction mixture. The salt is removed by filtration, washed with isopropanol 7~
1 and the washings are combined with the main filtrate.
The filtrate is distilled under reduced pressure. Iso-propanol and water are removed as a fore-run and dl-2--amino-l-butanol (25 g., 88.3~ yield) is distilled at 95-105 at 30 mm. Gas liquid chromatographic analysis of this product showed lt to contain about 10% l-amino--2-butanol.
Example 10 _-2-Amino-l-butanol ;
10To a 15 g. portion of undistilled crude dl-2--amino-l-butanol (59% real, Ool mole) from a run similar to that of Example 2, dissolved in 48 ml. of methanol is added with stirring 17.5 g. (0.117 mole) of L(+)-tartaric acid while the temperature is maintained at 45.
The solution is seeded with a small amount of crystals of the L(+)- tartrate of d-2-amino l-butanol and the temperature maintained at 45C. for 0.5 hour. An addi- , tional 4.2 g. ~0.028 mole) of tartaric acidlis added and the mixture held at 45-47C. for an additional 0~5 hour.
The temperature is then lowered to 16-18 over a 4-hour period and held at this temperature for 1 hour. The crys-talline L(+~- tartrate of d-2-amino-1-butanol is removed by filtration, washed with cold methanol (3 ml. x 3) and dried in an inert atmosphere~ In one such run the d 2--amino~l-butanol L(+)- tartrate weighed 8.5 (0.035 mole, 71.0%~, melted at 137-138 and had a specific rotation la]D6= 23.74 (c 5%, H2O). The crude feed dl-2-amino--l-butanol contained about 8% of dl-1-amino-2-butanol as an impurity. This impurity is not carried through the resolution process. The L)~)- tartrate salt o d-2-07~0 1 -amino-l-butanol obtained a~ter resolution is found to contain no detectable quantities of l--amino-2-butanol, by gas liquid chromatography, which iS sensitive to about 0.01% of the 1-amino-2-butanol.
Example 11 d-2-Amino-l butanol .~
To 15 g. of distilled dl-2-amino-1-butanol (38.5% pure by gas liquid chromatography), from a run similar to Example 2, dissolved in 48 ml. of anhydrous methanol is added with stirring 17.5 g. (0.117 mole) of L(+)- tartaric acid while maintaining the temperature below 47C. The resulting solution is stirred at 45-47 for 0.5 hour and an additional 4.21 g. (0.028 mole) of tartaric acid is added and the solution stirred for an additional 0.5 hour at 45-47~. The solution is seeded with a small amount of the L(~)- tartrate of d-2-amino--1-butanol. The mixture is slowly cooled to 16-17C.
over a 4~hour period and the crystalline L(+)- tartrate salt of d-2-amino-1-butanol is removed by filtration, washed with cold methanol (3 ml. x 3) and dried in an inert atmosphere. The white crystalline material (14.5 g., 0.061 mole, 81.9% yield) melts at 136-140 and has a specific rotation of la]D = 23.74 (c = 5%, H20). The feed dl-2-amino-1-butanol used for resolution contains about 8% of dl-1-amino-2-butanol as an impurity. This impurity is, however, not carried through the resolution process. The ~(+~- tartrate salt of d-2-amino l-butanol obtained after resolution is found to contain no detect-able quantities of either d or 1 l~amino-2-butanol by gas liquid chromatography which is sensitive to 0.01% of ~17[)7~L~
1 1-amino-2-butallol. ~pparently, all o~ the dl-l-amino--2-butanol remains with the mother liquor, and is re-jected along with the 1-2-amino-1-butanol in the meth-anol.
Example 12 dl-2-Amino-l-butanol A A 137 g. sample of crude dl-2-amino-1-butanol hydrochloride from a run similar to Example 1 is treat-ed with a solution of 137 g. KOH in 200 ml. of water.
The mixture is extracted three times with tetrahydro furan and the combined extracts dried (Na2SO~). The solvent is removed under reduced pressure to give 95 g.
of a crude oil (60.6% dl-2-amino-1-butanol and 6% dl-l--amino-2-butanol).
B In a separate experiment a 250 g. sample of a similar crude dl-2-amino-1-butanol hydrochloride dis-solved in 200 ml. of anh~drous methanol is trea~ed with 3 moles of anhydrous ammonia. After a few hours stirr-ing, the excess ammonia is allowed to evaporate. The precipitated ammonium chloride is removed by filtration and the filtrate concentrated gives 174.5 gm. of an oil which contains both dl-2-amino-1-butanol and its hydro-chloride together with some quantities of dl-l-amino-2--butanol and its hydrochloride ~total 5809~ dl-2-amino--l-butanol by gas liquid chromatography~
C A 7.5 gm. sample of crude dl-2-amino-1-butanol from the fixst experiment (A) is mixed with a 7.5 gm.
portion of the material (dl-2-amino-1-butanol and its hydrochloride) from the second experiment and the mix-ture is dissolved in a mixture of 80 parts of anhydrous lQ7~7~
1 methanol and 20 parts of lsopropanol (v/v) (tile solu-tion con-tains 0.1 mole of real dl-2-amino 1 butanol of which 0.097 mole is ~resent as the free base. (L(~
tartaric acid (15 g., 0.1 mole) is added slowly keeping S the temperature below 45C. unti1 the exotherm ceases.
After stirring the solution for an hour at 45C., the temperature is lowered slowly and at 40C. the mixture is seeded with a small amount of the L(~)- tartrate salt of d~2-amino-1-butanol and then gradually cooled to 18 over a period of 4 hours. The crystalline L(+)- tar-trate salt of _-2-amino-1-butanol formed in the reaction mixture is removed by filtration, washed with cold meth-anol (3 ml. x 3) and pumped dry. The yield of the ma-terial is 9.0 g. (0.036 mole, 75.2~); m.p. 137.5-139.5;
[a]D5= 23.84 (c = 5%, H2O).
Example 13 N-[l-(Chloromethyl)propyl]acetimidoyl chlorlde Reagent grade acetonitrile (S2 g., 2 moles) is placed in a 500 ml. three-necked flask equipped with a mechanical stirrer, a low-temperature thermometer and two fritted inlet tubes. With vigorous stirring and cooling (-20C.), butene-l (28 g., 0.5 mole) and chlor-ine (35.5 g., 0.5 mole) are added simultaneously both at a rate of about 375-400 ml./min. The addition is com-plete in about 37 minutes and the reaction temperatureat the end of this period rises to -10C. (bath/20C.), The mixture is fractionated to ~ive: Fraction I, as g.
(mostly acetonitrile) distilling under 20 mm. pressure at a bath temperature of 50C.; Fraction II, 12.5 g.
distilling under 20 mm. pressure at a bath tem~erature -- ~0 --~LCl 7~:)73Lo 1 of 65C., 70~ 1,2-dichlorobutane, 30~ N-[l-chloromethyl)-propyl]-acetimidoyl chloride; Fraction III, 35.9 g. dis-tillin~ under 2 mm. pressure at a bath temperaturP of 60, about 90% N-[l-(chloromethyl)prop~l]acetimidoyl chloride residue, 6.7 g. dark brown viscous oil. Based on Fractions II and III, the yield of N-ll-(chloromethyl)-oropyl]ace~imidoyl chloride is 39.7 g. (48%). A portion of Fraction III is redistilled to yive a pale yellow oil with a characteristic odor resembling that of thionyl chloride. The product, N~ (chloromethyl)propyl]acet-imidoyl chloride displays strong infrared bands at 3000, 1705, 1430, 1370, 1085, 960, 920, 840 and 740 cm~l.
NMR(CDC13): 0.88 ppm (t, 3H), 1.4-1~8 ppm (m, 2H), 245 ppm (s, 3H), 3.62 ppm (m, 2H, -CH2Cl), and about 3.9 ppm 15 (m, lH, CH).
Occasionally, a solid isomer of N-[l-(chloro-methyl)propyl~acetimidoyl chloride ~often the ma~or prod-uct is also obtained. The two forms seem to be intercon-vertible in certain solvents. On reaction with water, both hydrolyze to N-[l-(chloromethyl)propyl]acetamide.
The solid form has infrared bands at 3000, 1650, 1550, 1480, 1365, 1280, 1045, and 740 cm~l.
Example_14 N-[l-(Chloromethyl ? propyl]acetamide A sample of N-[l-chloromethyl)propyl]acetimi-doyl chloride from Example 8 is treated with an excess of 10~ aqueous sodium carbonate solution at room temp-erature. The organic material is extracted with ether and dried over Mg504. Removal of the solvent under re-duced pressure leaves N-[l-~chloromethyl)propyl]acetamide ~07[1710 1 as a crystalline solid in nearly quantitative yield. An in~rared spectrum shows peaks at 3300(M), 3100(W), 1650(S), and 550~S) cm l; nuclear magnetic resonanc~ (CDC13) shows peaks 0.95 ppm (t, 3H0, 1.4-1.8 ppm (m, 2H), 2.03 ppm (s~
3EI), 3.67 ppm (d, 2H, CH2Cl), 3.8-4.4 ppm (m, lH).
The effects of conditions on yield~ is shown in the following examples in which the chlorination re- -actions were carried out at initial temperatures of -3 to ~23 and the acetonitrile to C12 ratio was varied from 2 to 4. Additionally, the initial concentration of butene-l was varied by either passing butene-l and C12 simultaneously (low initial butene-l concentration) ~ :
into acetonitrile or by first condensing butene at -SC.
into acetonitrile and then passing C12 through the mlx-ture (high initial butene-l concentration). The results of these experiments in Table I show that the yield of .
N-~l-(chloromethyl)propyl]acetimidoyl chloride is depend- ~
ent primarily on the mole ratio of acetonitrile to C12 - : -and amounts to about 50--55% when this ratio approaches
Conversion to ethambutol is described in United States Patent 3,769,347.
Examvle 4 -d-2~Amino-l butanol - 12 ~
7~
1 d-2-Amino-l-butanol tartrate (150 g.) (0.63 mole) from Æxample 3 is added with stirrin~ to an aque-ous solution of KOH prepared by dissolving 76 ~. KOH in 115 ml. of distilled water. d-2-Amino l-butanol which forms the upper layer is extracted wit:h tetrahydrofuran (100 ml. x 2). The tetrahydrofuran extract is dried ~Na2SO4) and concentrated under reduced pressure. The crude, oily residue is distilled under reduced pressure to give _-2-amino-1-butanol (b.p. 99-103 at 30 mm.).
The material is further fractionated to give pure d-2--amino-l-butanol having a b.p. of 174, and lal25- 9.9.
The yield of the distilled material is about 50% to 76%
and can be improved substantially if additional extrac-tions are carried out with tetrahydrofuran.
Example 5 Ethambutol Hydrochloride -Following the procedure described in Example 1 of United States Patent 3,769,347, a mixture of 462 g.
of d-2-amino-1-butanol, produced in accordance with the procedure of Example A, and 32 g. of ethylene dichloride is heated to 80C. and the temperature is allowed to rise exothermally to about 130C. After 1 hour, the mix-ture is cooled to about 95C.~ 22.5 g. of sodium hydrox-ide is slowly added, and a temperature of about 112 is maintained for 1 hour. The sodium hydroxide is in the form of prills of about 4 nm. diameter. The mixture is cooled to 70C. and unreacted d-2-amino~l-butanol is recovered by vacuum distillation. The distillation is at a pressure below 20 mm. mercury, and below 130Co ~
heat being applied at a rate within the capacity of the ~0~707~
1 condenser.
Isopropamol (290 g.) is added to the distilla-tion residue at a temperature not above 90C., and fol-lowed by a refluxing period of 30 minutes. The mixture is cooled to and filtered at 60C~ to remove sodium chloride, and the filter cake is washed with 47 g. of isopropanol, at 60C. The volume of the filtrate is diluted to 430 ml. with isopropanol and the temperature is adjusted to 40-45C., 2 g. of diatomaceous earth filt~
er aid is added, and a second filtration is carried out.
To the clear filtrate there is added 120 g.
of methanol and 15 g. of water. The vessel is closed and hydrogen chloride tabout 25 g.) is introduced over the surface of the charge at a gas pressure of 5-7 psig while the temperature is allowed to rise to 55C., to a pH of 2 to 2.5. The charge is cooled very slowly to 28C.
and is stirred for about 1 hour.
Conveniently, a small aliquot is titrated, and a calculated quantity of hydrogen chloride added. Proper final p~ is confirmed by testing as acid to wet Congo Red test paper. Other methods of measuring the pH can be used. The white crystalline product, d,d'-2,2'-tethyl-enediimino)-di-l-butanol dihydrochloride is separated by filtration and washed with isopropanol. The product, carefully dried at al!maximum temperature of 75~C., is about 70 g., has a decomposition range of 198.5-204C., and an ash content of 0.1%.
This is a pharmaceutically acceptable, elegant grade of ethambutol hydrochloride without further treat-- 30 ment or refinement. The produck may be tabletted or en-~ ~t~ 7 ~
1 capsulated by conventional procedures.
Example 6 N-[l-(Chloromethyl)propyl]acetamide Into a 250 ml. 3-necked flask fitted with a stirrer, dry-ice-acetone trap, a gas outlet, and a gas inlet is charged 41.05 g. (1.0 mole) acetonitrile, 25 g.
(0.25 mole) CaCO3, 13.5 ml. (0.75 mole) water and 26.8 g. (0.475 mole) l-butene. The mixture is cooled to -5 to -8C. and chlorine added over 2 hours maintaining the temperature at below 7C. until the reaction mixture turns yellow indicating a slight excess of chlorine. The mixture is filtered and the solvents distilled under re-duced pressure to yield 28.6 g. of N-[l-(chloromethyl)-propyl]acetamide (40.2% yield based on l-butene).
~ æ e 7 N-[l-(Chloromethyl)propyl]acetamide A 500 ml. 3-necked flask fitted with a stirrer and dry-ice-acetone trap is charged with 82.1 g. (2.0 moie) acetonitrile, 27.4 g. (1.52 mole) water, 27 g.
(0.25 mole) Na2CO3 and 28.1 g. (0.50 mole) l-butene and cooled to 0C. Chlorine (0~50 mole) is added over 1/2 hour, the reaction temperature reaching a high of 32C~
After stirring for 2 hours at 25C., the reaction mix-ture is filtered. The acetonitrile washings of the solid phase and filtrate is combined and the solvents removed by vacuum distillation to leave 33.0 g. of the N-El-~chloromethyl)propyl]acetamide (44.0% yield based on l-butene~
Example 8 dl-2-Amino-1-butanol ~7(~7~
1 Sodium hydroxide pels (97~ pure, 18. a g., 0.45 mole) are stirred with 100 ml. of anhydrous methanol and crude dl-2-amino-1-butanol hydrochloride, 50 g.
(87% real, 0.35 mole) from a run similar to that of Ex-ample 1 is added with stirring over a period of O.S
hour. The reaction mixture warms up and precipitated sodium chloride is removed by filtration, washed with methanol and the washings combined with the main fil-trate. Methanol and water (formed during neutralizationj are removed under reduced pressure and the residual oil distilled to yield dl-2-amino-1-butanol (b.p. 95-100%/-30-35 mm.), 26.68 g. (86% of theory). The material con-tains about 9.6~ of dl-1-amino-2-butanol.
dl-2-Amino-l-butanol can be used as a catalyst as described in United States Patent 3,539,652 (CA 74, 23499) as a component of organosilicone compositions, French P~tent No. 1,556,008 (CH 71, 115) or as a compon-ent in a flame retardant composition, United States Patent No. 3,413,380 (CA 70, 40).
~
dl-2-Amino-l-butanol _ Sodium hydroxide pels (97% pure, 18.8 g~, 0.45 mole) are stirred with 100 ml. of isopropanol con-taining 0.7 ml. of water. A part of the sodium hydrox-ide goes into solution. Crude dl-2-amino-1-butanol hy drochloride 50 g. (70~ real, 0.28 mole) is added with stirri~.g over a period of 0.5 hour. The reaction mix-ture warms up to about 45C. and crystalline sodium chloride precipitates out of the reaction mixture. The salt is removed by filtration, washed with isopropanol 7~
1 and the washings are combined with the main filtrate.
The filtrate is distilled under reduced pressure. Iso-propanol and water are removed as a fore-run and dl-2--amino-l-butanol (25 g., 88.3~ yield) is distilled at 95-105 at 30 mm. Gas liquid chromatographic analysis of this product showed lt to contain about 10% l-amino--2-butanol.
Example 10 _-2-Amino-l-butanol ;
10To a 15 g. portion of undistilled crude dl-2--amino-l-butanol (59% real, Ool mole) from a run similar to that of Example 2, dissolved in 48 ml. of methanol is added with stirring 17.5 g. (0.117 mole) of L(+)-tartaric acid while the temperature is maintained at 45.
The solution is seeded with a small amount of crystals of the L(+)- tartrate of d-2-amino l-butanol and the temperature maintained at 45C. for 0.5 hour. An addi- , tional 4.2 g. ~0.028 mole) of tartaric acidlis added and the mixture held at 45-47C. for an additional 0~5 hour.
The temperature is then lowered to 16-18 over a 4-hour period and held at this temperature for 1 hour. The crys-talline L(+~- tartrate of d-2-amino-1-butanol is removed by filtration, washed with cold methanol (3 ml. x 3) and dried in an inert atmosphere~ In one such run the d 2--amino~l-butanol L(+)- tartrate weighed 8.5 (0.035 mole, 71.0%~, melted at 137-138 and had a specific rotation la]D6= 23.74 (c 5%, H2O). The crude feed dl-2-amino--l-butanol contained about 8% of dl-1-amino-2-butanol as an impurity. This impurity is not carried through the resolution process. The L)~)- tartrate salt o d-2-07~0 1 -amino-l-butanol obtained a~ter resolution is found to contain no detectable quantities of l--amino-2-butanol, by gas liquid chromatography, which iS sensitive to about 0.01% of the 1-amino-2-butanol.
Example 11 d-2-Amino-l butanol .~
To 15 g. of distilled dl-2-amino-1-butanol (38.5% pure by gas liquid chromatography), from a run similar to Example 2, dissolved in 48 ml. of anhydrous methanol is added with stirring 17.5 g. (0.117 mole) of L(+)- tartaric acid while maintaining the temperature below 47C. The resulting solution is stirred at 45-47 for 0.5 hour and an additional 4.21 g. (0.028 mole) of tartaric acid is added and the solution stirred for an additional 0.5 hour at 45-47~. The solution is seeded with a small amount of the L(~)- tartrate of d-2-amino--1-butanol. The mixture is slowly cooled to 16-17C.
over a 4~hour period and the crystalline L(+)- tartrate salt of d-2-amino-1-butanol is removed by filtration, washed with cold methanol (3 ml. x 3) and dried in an inert atmosphere. The white crystalline material (14.5 g., 0.061 mole, 81.9% yield) melts at 136-140 and has a specific rotation of la]D = 23.74 (c = 5%, H20). The feed dl-2-amino-1-butanol used for resolution contains about 8% of dl-1-amino-2-butanol as an impurity. This impurity is, however, not carried through the resolution process. The ~(+~- tartrate salt of d-2-amino l-butanol obtained after resolution is found to contain no detect-able quantities of either d or 1 l~amino-2-butanol by gas liquid chromatography which is sensitive to 0.01% of ~17[)7~L~
1 1-amino-2-butallol. ~pparently, all o~ the dl-l-amino--2-butanol remains with the mother liquor, and is re-jected along with the 1-2-amino-1-butanol in the meth-anol.
Example 12 dl-2-Amino-l-butanol A A 137 g. sample of crude dl-2-amino-1-butanol hydrochloride from a run similar to Example 1 is treat-ed with a solution of 137 g. KOH in 200 ml. of water.
The mixture is extracted three times with tetrahydro furan and the combined extracts dried (Na2SO~). The solvent is removed under reduced pressure to give 95 g.
of a crude oil (60.6% dl-2-amino-1-butanol and 6% dl-l--amino-2-butanol).
B In a separate experiment a 250 g. sample of a similar crude dl-2-amino-1-butanol hydrochloride dis-solved in 200 ml. of anh~drous methanol is trea~ed with 3 moles of anhydrous ammonia. After a few hours stirr-ing, the excess ammonia is allowed to evaporate. The precipitated ammonium chloride is removed by filtration and the filtrate concentrated gives 174.5 gm. of an oil which contains both dl-2-amino-1-butanol and its hydro-chloride together with some quantities of dl-l-amino-2--butanol and its hydrochloride ~total 5809~ dl-2-amino--l-butanol by gas liquid chromatography~
C A 7.5 gm. sample of crude dl-2-amino-1-butanol from the fixst experiment (A) is mixed with a 7.5 gm.
portion of the material (dl-2-amino-1-butanol and its hydrochloride) from the second experiment and the mix-ture is dissolved in a mixture of 80 parts of anhydrous lQ7~7~
1 methanol and 20 parts of lsopropanol (v/v) (tile solu-tion con-tains 0.1 mole of real dl-2-amino 1 butanol of which 0.097 mole is ~resent as the free base. (L(~
tartaric acid (15 g., 0.1 mole) is added slowly keeping S the temperature below 45C. unti1 the exotherm ceases.
After stirring the solution for an hour at 45C., the temperature is lowered slowly and at 40C. the mixture is seeded with a small amount of the L(~)- tartrate salt of d~2-amino-1-butanol and then gradually cooled to 18 over a period of 4 hours. The crystalline L(+)- tar-trate salt of _-2-amino-1-butanol formed in the reaction mixture is removed by filtration, washed with cold meth-anol (3 ml. x 3) and pumped dry. The yield of the ma-terial is 9.0 g. (0.036 mole, 75.2~); m.p. 137.5-139.5;
[a]D5= 23.84 (c = 5%, H2O).
Example 13 N-[l-(Chloromethyl)propyl]acetimidoyl chlorlde Reagent grade acetonitrile (S2 g., 2 moles) is placed in a 500 ml. three-necked flask equipped with a mechanical stirrer, a low-temperature thermometer and two fritted inlet tubes. With vigorous stirring and cooling (-20C.), butene-l (28 g., 0.5 mole) and chlor-ine (35.5 g., 0.5 mole) are added simultaneously both at a rate of about 375-400 ml./min. The addition is com-plete in about 37 minutes and the reaction temperatureat the end of this period rises to -10C. (bath/20C.), The mixture is fractionated to ~ive: Fraction I, as g.
(mostly acetonitrile) distilling under 20 mm. pressure at a bath temperature of 50C.; Fraction II, 12.5 g.
distilling under 20 mm. pressure at a bath tem~erature -- ~0 --~LCl 7~:)73Lo 1 of 65C., 70~ 1,2-dichlorobutane, 30~ N-[l-chloromethyl)-propyl]-acetimidoyl chloride; Fraction III, 35.9 g. dis-tillin~ under 2 mm. pressure at a bath temperaturP of 60, about 90% N-[l-(chloromethyl)prop~l]acetimidoyl chloride residue, 6.7 g. dark brown viscous oil. Based on Fractions II and III, the yield of N-ll-(chloromethyl)-oropyl]ace~imidoyl chloride is 39.7 g. (48%). A portion of Fraction III is redistilled to yive a pale yellow oil with a characteristic odor resembling that of thionyl chloride. The product, N~ (chloromethyl)propyl]acet-imidoyl chloride displays strong infrared bands at 3000, 1705, 1430, 1370, 1085, 960, 920, 840 and 740 cm~l.
NMR(CDC13): 0.88 ppm (t, 3H), 1.4-1~8 ppm (m, 2H), 245 ppm (s, 3H), 3.62 ppm (m, 2H, -CH2Cl), and about 3.9 ppm 15 (m, lH, CH).
Occasionally, a solid isomer of N-[l-(chloro-methyl)propyl~acetimidoyl chloride ~often the ma~or prod-uct is also obtained. The two forms seem to be intercon-vertible in certain solvents. On reaction with water, both hydrolyze to N-[l-(chloromethyl)propyl]acetamide.
The solid form has infrared bands at 3000, 1650, 1550, 1480, 1365, 1280, 1045, and 740 cm~l.
Example_14 N-[l-(Chloromethyl ? propyl]acetamide A sample of N-[l-chloromethyl)propyl]acetimi-doyl chloride from Example 8 is treated with an excess of 10~ aqueous sodium carbonate solution at room temp-erature. The organic material is extracted with ether and dried over Mg504. Removal of the solvent under re-duced pressure leaves N-[l-~chloromethyl)propyl]acetamide ~07[1710 1 as a crystalline solid in nearly quantitative yield. An in~rared spectrum shows peaks at 3300(M), 3100(W), 1650(S), and 550~S) cm l; nuclear magnetic resonanc~ (CDC13) shows peaks 0.95 ppm (t, 3H0, 1.4-1.8 ppm (m, 2H), 2.03 ppm (s~
3EI), 3.67 ppm (d, 2H, CH2Cl), 3.8-4.4 ppm (m, lH).
The effects of conditions on yield~ is shown in the following examples in which the chlorination re- -actions were carried out at initial temperatures of -3 to ~23 and the acetonitrile to C12 ratio was varied from 2 to 4. Additionally, the initial concentration of butene-l was varied by either passing butene-l and C12 simultaneously (low initial butene-l concentration) ~ :
into acetonitrile or by first condensing butene at -SC.
into acetonitrile and then passing C12 through the mlx-ture (high initial butene-l concentration). The results of these experiments in Table I show that the yield of .
N-~l-(chloromethyl)propyl]acetimidoyl chloride is depend- ~
ent primarily on the mole ratio of acetonitrile to C12 - : -and amounts to about 50--55% when this ratio approaches
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1~7~171~) 1 Hydrolysis of l~-[l-(chloromethyl)pro~yl]acet-imidoyl chloride is highl pH dependent. It has now been found that a simple hydrolysis procedure is effective.
On re1uxing with water N-[l-(chloromethyl)propyl]acet-imidoyl chloride is transformed into a mixture of dl~2 -amino-l-butanol (77~), dl-2-amino-1-butanol acetate hydrochloride (17%), the N-[1-(hydroxymethyl)propyl]acet-amide (7%) and acetic acid within one hour. The product ratios appear to represent equilibrium compositions be-cause additional heating (14 hrs) does not materially change their distribution. If, however, the hydrolysis is carried out with aqueous methanol or ethanol, it is complete within 2 hours and the acetyl component of the product can be removed as methyl or ethyl acetate by distillation. This procedure not only decreases hydroly-sis time, it also avoids the accumulation of salts in the reaction mixture, gives essentially quantitative yields of dl-2-amino-1-butanol from N-[l-(chloromethyl)propyl]-acetimidoyl chloride through N-[l-(chloromethyl)propyl]-acetamide, and facilitates product work~up. Methyl ace-tate boils at 57C., and is readily distilled off~
In order to make this process as economical as possible, excessively large volumes of aqueous meth- ~ ~
anol should be avoided. If insufficient quantities of water are used (less than N-[l-(chloromethyl)propyl]acet-imidoyl chloride:H2O:MeOH mole ratio 1:3:3) and espec-ially if the hydrolysis is carried out in the presence of the l,2-dichlorobutane by-product, a small fraction (3-15~) of N~[l-(chloromethyl)propyl]acetimidoyl chlor-ide hydrolyzes to 2-amino-1-chlorobutane hydrochloride~
~07~
l The formation of 2-amino-l-chlorobutane hydrochloride can be totally suppressed if water and methanol are add-ed sequentially/ and in that order, rather than together in one step. Addition of water to N-[l-(chloromethyl)-S propyl~acetimidoyl chloride almost instantaneously con-verts it to the N-[l-(chloromethyl)propyl]acetamide which then hydrolyzes via the oxazoline intermediate.
Three series of reactions (A, B and C) were completed using as-is acetonitrile (water conc. (Karl--Fisher) = 0.059-0.2%). In each of these series, reac-tions were carried out using 0.5 mole of butene, 0.5 mole of chlorine, and the acetonitrile:Cl2 mole ratio (identical to the acetonitrile:butene) was varied from l to 8.
In a series A (reaction time = l hr.) the re-action temperature was maintained at 0C. while chlor-ine and butene were passed simultaneously into acetoni-trile in one hour. After removal of acetonitrile (40--50, 50 mm.), the crude reaction mixture con~aining N-[l-(chloromethyl)propyl]acetimidoyl chloride and 1,2--dichlorobutane was hydrolyzed by refluxing with aqueous methanol.
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~L~'7(1~0 1 I~ is significant to note that N-~l (chloro-methyl)propyl]acetimidoyl chloride can be hydrolyz~d substantially quantitatively to ~-[l-(chlorom~tyl)-propyl]acetamide, and then to dl-2-amino-1-butanol. Re-porting as dl-2-amino-1-butanol hydrochlorlde is a very convenient method of showing yields. Errors due to vol-atile components are avoided. Small quantities of dl-l--amino-2-butanol report with the c -2-amino-1-butanol.
Even at a low acetonitrile:C12 ratio of one, the yield 0 of _-2-amino-1-butanol HCl is as high as 31%. Increas-ing the acetonitrile:C12 mole ratio from 1 to 2 improves the yield to 43%,~an increase of 12%. Further increases in the acetonitrile:C12 ratios also improve the yields, For each additional mole of acetonitrile (up to a total of 5 moles (AN:C12 ratios 3 to 5) the yield o~ dl-2--amino-l-butanol HCl increases on average about 6 Still further addition of acetonitrile (AN:C12 mole ratios 6 to 8) is considerably less effective; the aver-age incremental yield of dl-2-amino-1-butanol ~Cl being of the order of about 3% pex mole of acetonitrile. A
ratio of about 4:1 is a good compromise between yield and a reasonable size reaction vessel and recycle ratio of acetonitrile.
In both series B and C, the gaseous reactants were run into acetonitrile over a period of 0.5 hr. The initial reaction temperature was 0. This was allowed to rise to a maximum of 35 during the course of the re-action. Additionally, in series B, chlorin was passed through a solution of butene in acetonitrile to maintain - 30 a high initial concentration of butene. In series C
7~7~L~
1 both chlorine and butene were passed simultaneously through acetonitrile allowing a-ttainment of a low in-itial concentration of butene. The results of simultan-eous and sequential additions of butene and chlorine on the yield of N-[l-(chloromethyl)propy:l]acetimidoyl chlor-ide at different acetonitrile/C12 mole ratios are sum-- marized in Table III.
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1~7[37~L0 1 In series B and C ma-terial balances show con-version and recovery data on acetonitrile. In each case the dis-tillate 1,2-dichlorobutane + acetoni-trile was analyzed for 1,2-dichlorobutane and acetonitrile by gas li~uid chromatography.
A less pure product is obtained if the N-[l--(chloromethyl)propyl]acetimidoyl chloride is allowed to stand for 40-50 hours prior to work-up.
The data in the table shows that:
1. The yield of crude dl-2-amino-1-butanol HCl (or N-[l-~(chloromethyl)propyl]acetimidoyl chloride) is primarily dependent on the mole ratio of acetonitrile:C12 and var-ies between 31 and 66% as the acetonitrile:C12:butene mole ratio changes from 1:1:1 to 8:1:1.
2. Simultaneous addition of chlorine and butene to acetonitrile rather than the alternate procedure of add-ing chlorine to a mixture of butene and acetonitrile is advantageous. The reaction is less exothermic; conse~
quently easier to control, and the yields of dl-2-amino--l-butanol HCl are somewhat better. A reaction time of one hour generally appears to permit more con~rol over the reaction exothermicity.
3. The reaction temperature does not appear to be a controlling factor in determining the overall yield.
~owever, in view of the thermal instability of N-[l--(chloromethyl)propyl]acetimidoyl chloride above 50, reaction temperatures between 0-25 are more desirable.
The process can vary depending on the size of batches. Whereas the Examples are exemplary, for large scale production, the process may be run continuously, 1~7~7~
l with the butene~l and chlorine being fed continuously to a stirred continuous reactor. The recycle acetoni- .
trile is dis-tilled off and recycled continuously. Such a continuous system permi-ts a higher ratio of acetoni-trile to the butene-l and chlorine. Whereas, for a batch process, a molar ratio of at least 2 of acetoni-trile to butene-l and chlorine is preferred, more than a ratio of 16 can require an uneconomically large reac-tor. With a continuous process even higher ratios are convenient.
Whereas both butene-l and chlorine are gaseous at room temperature of about 20C., so that low temper-atures, around 0C. and lower are convenient, a higher temperature to reduce the need for cooling may be used if a pressurized reactor i5 available.
The trade-off of the cost of a pressure reac-tor against additional refrigeration can vary with equipment available.
Other modifications within the scope of this invention as defined by the appended claims are, of course, obvious to those skilled in the arts.
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1~7~171~) 1 Hydrolysis of l~-[l-(chloromethyl)pro~yl]acet-imidoyl chloride is highl pH dependent. It has now been found that a simple hydrolysis procedure is effective.
On re1uxing with water N-[l-(chloromethyl)propyl]acet-imidoyl chloride is transformed into a mixture of dl~2 -amino-l-butanol (77~), dl-2-amino-1-butanol acetate hydrochloride (17%), the N-[1-(hydroxymethyl)propyl]acet-amide (7%) and acetic acid within one hour. The product ratios appear to represent equilibrium compositions be-cause additional heating (14 hrs) does not materially change their distribution. If, however, the hydrolysis is carried out with aqueous methanol or ethanol, it is complete within 2 hours and the acetyl component of the product can be removed as methyl or ethyl acetate by distillation. This procedure not only decreases hydroly-sis time, it also avoids the accumulation of salts in the reaction mixture, gives essentially quantitative yields of dl-2-amino-1-butanol from N-[l-(chloromethyl)propyl]-acetimidoyl chloride through N-[l-(chloromethyl)propyl]-acetamide, and facilitates product work~up. Methyl ace-tate boils at 57C., and is readily distilled off~
In order to make this process as economical as possible, excessively large volumes of aqueous meth- ~ ~
anol should be avoided. If insufficient quantities of water are used (less than N-[l-(chloromethyl)propyl]acet-imidoyl chloride:H2O:MeOH mole ratio 1:3:3) and espec-ially if the hydrolysis is carried out in the presence of the l,2-dichlorobutane by-product, a small fraction (3-15~) of N~[l-(chloromethyl)propyl]acetimidoyl chlor-ide hydrolyzes to 2-amino-1-chlorobutane hydrochloride~
~07~
l The formation of 2-amino-l-chlorobutane hydrochloride can be totally suppressed if water and methanol are add-ed sequentially/ and in that order, rather than together in one step. Addition of water to N-[l-(chloromethyl)-S propyl~acetimidoyl chloride almost instantaneously con-verts it to the N-[l-(chloromethyl)propyl]acetamide which then hydrolyzes via the oxazoline intermediate.
Three series of reactions (A, B and C) were completed using as-is acetonitrile (water conc. (Karl--Fisher) = 0.059-0.2%). In each of these series, reac-tions were carried out using 0.5 mole of butene, 0.5 mole of chlorine, and the acetonitrile:Cl2 mole ratio (identical to the acetonitrile:butene) was varied from l to 8.
In a series A (reaction time = l hr.) the re-action temperature was maintained at 0C. while chlor-ine and butene were passed simultaneously into acetoni-trile in one hour. After removal of acetonitrile (40--50, 50 mm.), the crude reaction mixture con~aining N-[l-(chloromethyl)propyl]acetimidoyl chloride and 1,2--dichlorobutane was hydrolyzed by refluxing with aqueous methanol.
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~L~'7(1~0 1 I~ is significant to note that N-~l (chloro-methyl)propyl]acetimidoyl chloride can be hydrolyz~d substantially quantitatively to ~-[l-(chlorom~tyl)-propyl]acetamide, and then to dl-2-amino-1-butanol. Re-porting as dl-2-amino-1-butanol hydrochlorlde is a very convenient method of showing yields. Errors due to vol-atile components are avoided. Small quantities of dl-l--amino-2-butanol report with the c -2-amino-1-butanol.
Even at a low acetonitrile:C12 ratio of one, the yield 0 of _-2-amino-1-butanol HCl is as high as 31%. Increas-ing the acetonitrile:C12 mole ratio from 1 to 2 improves the yield to 43%,~an increase of 12%. Further increases in the acetonitrile:C12 ratios also improve the yields, For each additional mole of acetonitrile (up to a total of 5 moles (AN:C12 ratios 3 to 5) the yield o~ dl-2--amino-l-butanol HCl increases on average about 6 Still further addition of acetonitrile (AN:C12 mole ratios 6 to 8) is considerably less effective; the aver-age incremental yield of dl-2-amino-1-butanol ~Cl being of the order of about 3% pex mole of acetonitrile. A
ratio of about 4:1 is a good compromise between yield and a reasonable size reaction vessel and recycle ratio of acetonitrile.
In both series B and C, the gaseous reactants were run into acetonitrile over a period of 0.5 hr. The initial reaction temperature was 0. This was allowed to rise to a maximum of 35 during the course of the re-action. Additionally, in series B, chlorin was passed through a solution of butene in acetonitrile to maintain - 30 a high initial concentration of butene. In series C
7~7~L~
1 both chlorine and butene were passed simultaneously through acetonitrile allowing a-ttainment of a low in-itial concentration of butene. The results of simultan-eous and sequential additions of butene and chlorine on the yield of N-[l-(chloromethyl)propy:l]acetimidoyl chlor-ide at different acetonitrile/C12 mole ratios are sum-- marized in Table III.
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1~7[37~L0 1 In series B and C ma-terial balances show con-version and recovery data on acetonitrile. In each case the dis-tillate 1,2-dichlorobutane + acetoni-trile was analyzed for 1,2-dichlorobutane and acetonitrile by gas li~uid chromatography.
A less pure product is obtained if the N-[l--(chloromethyl)propyl]acetimidoyl chloride is allowed to stand for 40-50 hours prior to work-up.
The data in the table shows that:
1. The yield of crude dl-2-amino-1-butanol HCl (or N-[l-~(chloromethyl)propyl]acetimidoyl chloride) is primarily dependent on the mole ratio of acetonitrile:C12 and var-ies between 31 and 66% as the acetonitrile:C12:butene mole ratio changes from 1:1:1 to 8:1:1.
2. Simultaneous addition of chlorine and butene to acetonitrile rather than the alternate procedure of add-ing chlorine to a mixture of butene and acetonitrile is advantageous. The reaction is less exothermic; conse~
quently easier to control, and the yields of dl-2-amino--l-butanol HCl are somewhat better. A reaction time of one hour generally appears to permit more con~rol over the reaction exothermicity.
3. The reaction temperature does not appear to be a controlling factor in determining the overall yield.
~owever, in view of the thermal instability of N-[l--(chloromethyl)propyl]acetimidoyl chloride above 50, reaction temperatures between 0-25 are more desirable.
The process can vary depending on the size of batches. Whereas the Examples are exemplary, for large scale production, the process may be run continuously, 1~7~7~
l with the butene~l and chlorine being fed continuously to a stirred continuous reactor. The recycle acetoni- .
trile is dis-tilled off and recycled continuously. Such a continuous system permi-ts a higher ratio of acetoni-trile to the butene-l and chlorine. Whereas, for a batch process, a molar ratio of at least 2 of acetoni-trile to butene-l and chlorine is preferred, more than a ratio of 16 can require an uneconomically large reac-tor. With a continuous process even higher ratios are convenient.
Whereas both butene-l and chlorine are gaseous at room temperature of about 20C., so that low temper-atures, around 0C. and lower are convenient, a higher temperature to reduce the need for cooling may be used if a pressurized reactor i5 available.
The trade-off of the cost of a pressure reac-tor against additional refrigeration can vary with equipment available.
Other modifications within the scope of this invention as defined by the appended claims are, of course, obvious to those skilled in the arts.
.
~;
Claims (4)
1. The process of the synthesis of d,d-2,2'-(ethy-lenediimino)di-1-butanol which comprises mixing d1-2-amino-1-butanol containing d1-1-amino-2-butanol with L(+)- tartaric acid in anhydrous methanol, separating the crystalline acid L(+)- tartrate of d-2-amino-1-butanol from the salts of d1-2-amino-1-butanol and d- and 1- 1-amino-2-butanol which remain in solution in the methanol, dissolving said d-2-amino-1-butanol L(+)- tartrate in water, adding an alkali or alkaline earth hy-droxide, separating out the resultant alkali or alkaline earth L(+)- tartrate, thus isolating d-2-amino-1-butanol, evaporating off remaining water, adding ethylene dichloride, and reacting to form d,d-2,2'-(ethylenediimino)di-1-butanol, and isolating the thus formed d,d-2,2'-(ethylenediimino)di-1-butanol as the dihydrochloride salt.
2. The process of Claim 1 in which the d1-2-amino-1-butanol is synthesized by heating N-[1-(chloromethyl)propyl]-acetamide in the presence of a lower alkanol and water whereby the N-[1-chloromethyl)propyl]acetamide is hydrolyzed to d1-2-amino-1-butanol, and distilling off the coproduced alkanol acetate, whereby side reactions are suppressed, and the hydrol-ysis to d1-2-amino-1-butanol is essentially quantitative.
3. The process of Claim 2 in which the N-[1-chloro-methyl)propyl]acetamide is synthesized by reacting at least about 2 moles of acetonitrile with about 1 mole of chlorine and about l mole of butene-l, to produce N-[1-(chloromethyl)-propyl]acetimidoyl chloride with the concurrent production of 1,2-dichlorobutane, adding water, thereby hydrolyzing said N [l-(chloromethyl)propyl]acetimidoyl chloride to N-[1-chloro-methyl)propyl]acetamide, and after the synthesis of said N-[l-(chloromethyl)propyl]acetamide, distilling off under reduced pressure and recovering the excess acetonitrile.
4. The process of Claim 3 in which water is added at about the same rate as N-[1-(chloromethyl)propyl]acetimidoyl chloride is produced, thereby hydrolyzing N-[1-(chloromethyl)-propyl]acetamide before said N-[1-(chloromethyl)propyl]acetimi-doyl chloride can be additionally chlorinated, and also re-leasing the heat of hydrolysis over the course of the reaction, thus controlling isothermal temperature rise.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA244,749A CA1070710A (en) | 1976-02-02 | 1976-02-02 | Synthesis of d-2-amino-1-butanol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA244,749A CA1070710A (en) | 1976-02-02 | 1976-02-02 | Synthesis of d-2-amino-1-butanol |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1070710A true CA1070710A (en) | 1980-01-29 |
Family
ID=4105107
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA244,749A Expired CA1070710A (en) | 1976-02-02 | 1976-02-02 | Synthesis of d-2-amino-1-butanol |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1070710A (en) |
-
1976
- 1976-02-02 CA CA244,749A patent/CA1070710A/en not_active Expired
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