IE43823B1 - Synthesis of d1-2-amino-1-butanol hydrochloride and derivatives thereof - Google Patents

Description

This invention relates to a process for the synthesis of dl - 2 - amino - 1 - butanol hydrochloride, and to the subsequent processing of the product thus obtained. dl - 2 - Amino - 1 - butanol has many uses. For example it is an intermediate in the preparation of the anti-tubercular drug ethambutol.

In accordance with the present invention there is provided a process for the synthesis of dl - 2 - amino - 1 - butanol hydrochloride which comprises heating H - (1 - (chloromethyl)propy1Jacetamide in the presence of a (C-j-Cg) alkanol and water, and preferably also a catalytic amount of hydrochloric acid, whereby the N (1 - (chloromethyl)propyl) - acetamide is hydrolyzed to dl - 2 amino - 1 - butanol hydrochloride and distilling off the coproduced alkanol acetate.

The present invention also provides a process for preparing cH - 2 - amino - 1 - butanol, which comprises neutralizing dl - 2 amino - 1 - butanol hydrochloride which has been synthesized by the process of this invention.

Further, the present invention provides a process for the preparation of d - 2 - amino - 1 - butanol, which comprises mixing d1_ - 2 - amino - 1 - butanol which has been prepared by the process defined in the preceding paragraph with L(+)-tartaric acid in anhydrous methanol, separating the crystalline acid L(+)-tartrate of d. - 2 amino - 1 - butanol from the methanol, dissolving said tartrate salt in water, adding an alkali or alkaline earth hydroxide, and separating out the resultant alkali or alkaline earth L(+)-tartrate thereby isolating^ - 2 - amino - 1 - butanol in aqueous solution.

In another aspect, the present invention relates to d, d' - 2,2' ethylenediimino - di - 1 - butanol which has been prepared from the d - 2 - amino - 1 - butanol product of the process of the preceding paragraph by a reaction with ethylene dichloride. 2 8 2 3 The starting material for the present process of synthesizing dl - 2 amino - 1 - butanol hydrochloride, viz. N - (1 - (chloromethyl)-propyl) acetamide may be synthesized by reacting N - (1 - (chloromethyl)propy1)acetimidoyl chloride wjth water, optionally in the presence of a weak base, thereby hydrolyzing N - (1 - (chloromethyl)propyl)acetimidoyl chloride to N - (1 (chloromethyl)propyl)-acetamide.

More particularly, it is preferred that the N - (1 -(chloromethyl)propyl) acetamide be synthesized by reacting at least 2 moles of acetonitrile with about 1 mole of chlorine and about 1 mole of butene-Ι-, to produce N - (1 10 (chloromethyl)propoyl)acetimidoyl chloride with the concurrent production of 1,2-dichlorobutane, adding water, thereby hydrolyzing said N - (1 - chloromethyl )-propyl)acetimidoyi chloride to N - (1 - (chloromethyl)propyl)acetamide, and after the synthesis of said N - (1 - (chloromethyl)propyl)acetamide, distilling off acetonitrile under reduced pressure and recovering the excess acetonitrile. The overall reaction may be represented as follows: CH3CH2CH = CH2 + Cl2 + CHgCN butene-1 acetonitrile ch3ch2chch„cl N - [l - chloromethyl )propyl] acetimidoyl chloride or N - Ll - (chloromethyl )propyj]ethaninridoyl chloride NHC0CH3 II III - ethyl - 2 - methyl - 2 - oxazoline hydrochloride or 4,5 - dihydro - 4 - ethyl - 2 - methyloxazole hydrochloride III--> CHgOH ©NHgCl dl-2-amino-l-butanol hydrochloride methyl acetate S S 2 3 Surprisingly, best results are obtained in the reaction with acetonitrile if an excess of acetonitrile is used. Acetonitrile is the expensive component and routinely it is customary to attempt to use less of the expensive component.

Here, chlorine also reacts with butene-1 to yield 1,2-dichlorobutene. An excess of acetonitrile shifts the reaction towards N-[1-(chloromethyl)propyl]acetimidoyl chloride. An amount of water corresponding to that required for the hydrolysis of N-[1-(chloromethyl) propyl]acetimidoyl chloride may be added before, with or after the addition of the chlorine and butene to the reaction mixture to hydrolyze the N-(l-chloromethyl)propyl]acetimidoyl chloride to N-[l-(chloromethyl)propyl]acet15 amide. The reaction of acetonitrile with hydrochloric acid formed in the hydrolysis is sufficiently slow that at least 95% of the excess of acetonitrile may be distilled under reduced pressure from the reaction mixture and recycled. The economical recovery of the acetoni20 trile in such form that it may be recycled to the process 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 starting materials.

. After stripping the acetonitrile, if hydrolysis of N-[1-(chloromethyl)propyl]acetimidoyl chloride to N-[1-(chloromethyl)propyl]acetamide has not been com30 pleted during the reaction, hydrolysis is completed by S 3 2 3 adding water to the pot residue. Production of N - £l - (chlororoethyl)propylj acetamide by hydrolysis of N - Ql - (chloromethyl Jpropyljacetimidoyl chloride, is favoured by the presence of a weak base such as calcium carbonate, calcium oxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or bicarbonate, barium carbonate, or strontium carbonate. The base is not however necessary since the N - j_l - (chloromethyl) propyl j -acetamide is to be processed by further hydrolysis to dl_ - 2 - amino - 1 - butanol. After hydrolysis, 1,2-dichlorobutane is stripped by distillation under reduced pressure.

After removal of the acetonitrile and 1,2-dichlorobutane, the purity of the N - [l - (chloromethyl) - propyl] acetamide is sufficiently high for convenient processing by means of the present invention to dl_ - 2 - amino - 1 - butanol hydrochloride of a grade which may be used in a resolution step, or other purposes.

Conveniently, water is added to the reactor to hydrolyze the N -[l - (chloromethyl )-propyl] acetimidoyl chloride to N - [j - (chloromethyl) - propyljacetamide at about the same rate as the former compound is reduced, so that exotherms are better controlled, the processing steps are simultaneous, saving time and manipulation and avoiding additional chlorination of the acetimidoyl chloride. A slight excess over the calculated quantity of water necessary for hydrolysis of N - [1 - chloromethyl)propylJ acetimidoyl chloride to N - jj - (chloromethyl)propylj - acetamide may be after after the completion of chlorination.

The acetonitrile may be separated from the N -[l - (chloromethyl) propyl] acetimidoyl chloride or N - [j - (chloromethyl) propyl]] acetamide. Conveniently, it is separated after the hydrolysis to aqueous reaction mixture containing N - 01 4S3 83 N - 01 - (chloromethyl )-propyl] acetamide. The 1,2-dichlorobutane may be separated in whole or in part by distillation after the synthesis of N -01 - (chloromethyl)propyl acetimidoyl chloride, or after hydrolysis to N -01 - (chloromethyl)-propyl]acetamide. At least part of the 1,2-dichlorobutane may be retained until the synthesis of the dl - 2 amino - 1 - butanol hydrochloride is completed. It is usually more convenient to separate the 1,2-dichlorobutane after the hydrolysis to the N - 01 - (chloromethyl)propyl]acetamide, as the reaction mixture is then smaller, and more compact equipment may be used for the reaction of the N -0 - (chloromethyl )propyfj acetamide to di - 2 amino - 1 - butanol hydrochloride. Azeotropic distillation with water permits convenient and effective complete removal of the 1,2-dichlorobutane from the dl - 2 - amino - 1 - butanol.

Subsequently, methanol or other (C-j-Cg) alkanol is added to the (chloromethyl)propyl]acetamide, preferably with catalytic amounts of hydrochloric acid, which is heated, preferably refluxed, to form dl - 2 - amino - 1 - butanol hydrochloride with by-product alkanol acetate. The alkanol acetate is removed by distillation leaving dl - 2 - amino — 1 - butanol - hydrochloride. For example, methyl acetate boils at 57°C and is readily distilled off.

Hydrolysis of N - 0 - (chloromethyl J-propylJacetamidoyl chloride is highly pH dependent. It has been found that on refluxing with water N - 01 - chloromethyl)-propyl]acetimidoyl chloride is transformed into a mixture of dl_ - 2 - amino - 1 - butanol (77%), dl_ - 2 - amino - 1 butanol acetate hydrochloride (17%), the N - 0 - (hydroxymethylJpropylj acetamide (7%) and acetic acid within one hour. The product ratios appear to represent equilibrium compositions because additional heating (14 hours) does not materially change their distribution. If, however, the hydrolysis is carried out with aqueous methanol or ethanol, or other (C-|-Cg) alkanol, it is complete within 2 hours and the acetyl :823 component of the product can be removed as e.g. methyl or ethyl acetate by distillation. This procedure not only decreases hydrolysis 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 - - (chloromethyl)propyl] acetamide, and facilitates product work-up. As already mentioned, methyl acetate boils at 57°C., and is readily distilled off.

In order to make this process as economical as possible, excessively large volumes of aqueous alkanol should be avoided. If insufficient quantities of water are used (less than N £l - (chioromethy1)propyljacetimidoyl chloride : HgO:ROH mole ratio 1:3:3) and especially if the hydrolysis is carried out in the presence of the 1,2-diehlorobutane by-product, a small fraction (3-15%) of N - 0 - (chloromethyl)propyl] acetamidoyl chloride hydrolyzes to 2 - amino - 1 - chlorobutane hydrochloride.

The formation of 2 - amino - 1 - chlorobutane hydrochloride can be totally suppressed if water and (Cj-Cg) alkanol are added sequentially, and in that order, rather than together in one step. Addition of water to N - [(1 - (chloromethyl) - propyl acetimidoyl chloride almost instantaneously converts it to the N - (1 - chloromethyl) propyl)acetamide which then hydrolyzes via the oxazoline intermediate.

In the present invention, the acetonitrile used in the preparation of the N -Ql - (chloromethyl)propyljacetamide is preferably distilled off under reduced pressure for recycling.

If the acetonitrile is permitted to remain during the hydrolysis to dl - 2 - amino - 1 - butanol hydrochloride, the acetonitrile tends to hydrolyze to acetic acid with production of ammonia, usually as the ammonium chloride. The acetic acid from the hydrolysis of acetonitrile is readily removed as the methyl ester, but the loss of acetonitrile reduces the efficiency of the process. 1,2-Dichlorobutane is preferably at least partially removed by vacuum distillation at the N -£l - (chloromethyl)propyf] acetamide stage. It causes no complications other than increasing the size of the reactor required. Conveniently, the last of the 1,2-dichlorobutane is removed by azeotropic distillation from di - 2 - amino - 1 - butanol hydrochloride at the time acetic is removed as the methyl ester. Conveniently, the intermediate reactions to dl - 2 - an^no - 1 - butanol hydrochloride may overlay without the isolation of N - £l - (chloromethyl )propyl] acetimidoyl chloride and N - {j - (chloromethyl)propylj acetamide.

By dissolving the reaction mixture containing N - [j - (chloromethyl)propyljacetamide in methyl alcohol, or isopropanol, or other (C-j-Cg) alkanol, or mixtures thereof, a solution of the dl - 2 - amino - 1 - butanol, 3 8 8 3 predominantly as the hydrochloride, is obtained which can, if desired, be partially neutralized with ammonia to form a mixture of dl-2-amino-l-butanol and dl-2-amino-l-butanol hydrochloride, with ammonium chloride being filtered out. The mixture is approximately two parts dl-2-amino-1-butanol and one part dl-2-amino-l-butanol hydrochloride, a ratio which is close to the optimum desired for reacting with L(+)- tartaric acid in the presence of anhydrous methanol to permit the separation of the dl - 2-amino-l-butanol tartrate as is set forth in detail in United States Patent 3,553,257.

This process has unique and unexpected advantages in the present system because part of the butene-1 adds chlorine and acetonitrile in the reverse of the desired position so that about 3 to 10% dl-l-amino-2-butanol is found in the dl-2-amino-l-butanol as an impurity. In separation of the d- and 1-isomers of dl-2-amino-l-butanol, both isomers of dl-l-amino-2-butanol remain with the mother liquor, and a much purified d-2-amino-l-butanol separates out as the L(+)- tartrate salt.

A starting material containing up to about 10% of dl-l-amino-2-butanol yields a purified d-2-amino-l-butanol, as the tartrate, having a content of less than 0.01% of dl-l-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 pharmaceutical grade with a minimum of additional purification.

The facility of separating out impurities and by-products is unobvious. - 943833 1 The invention is illustrated by the Examples which follow. Example 1 Preparation of dl-2-Amino-l-butanol Hydrochloride 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 3-5°C. Chlorine (71 g., 1 mole) and butene-1 (56 g., 1 mole) are passed through the well-stirred acetonitrile at a rate of about 400 ml./min. each while water (10 g., 0.55 mole) is added simultaneously at a linear rate with the syringe pump during the course of the reaction (1 hour).

The reaction temperature rises to 20°C. within minutes and stays constant through the course of the reaction. The reaction mixture is stirred for an additional 15-30 minutes. The reaction mixture is weighed to insure that proper amounts of the gaseous reactants have been introduced. Excess acetonitrile (b.p. 36-41°C./ x 150-170 mm.) is removed by distillation (bath temperature up to 100°C.) while using a 10-plate distillation column. A sudden temperature drop indicates the end of acetonitrile distillation.

The acetonitrile fraction conta ins 1-2% HCI and about 6% 1,2-dichlorobutane and can be recycled, without further treatment to a subsequent batch, or can be purified before recycling.

The heat temperature rises to 70° and by-prod30 uct 1,2-dichlorobutane is distilled off between 70-40°C. ~ 42823 at 150 to 25 nun. A dry-ice trap attached to the vacuum line contains 15-25 g. of a material which consisted of 38% HCl, 10% 1,2-dichlorobutane and a crystalline solid derived from the reaction of acetonitrile with anhydrous HCl.

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 to reflux. The residual 1,2-dichlorobutane is removed by azeotropic distillation (Dean-Stark trap) while the mixture is refluxed for 2 hours. The water and some acetic acid (formed during hydrolysis with water) are removed at 80° (under reduced pressure (15-20 mm.) to leave a viscous residue consisting of N-[1-(chloromethyl)propyl]acetamide, and its hydrolysis products.

Methanol (48 g., 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 (HgO, methyl acetate, etc.), the dl-2-amino-l-butanol hydrochloride is obtained as a colorless viscous material which crystallizes on standing.

Example 2 dl-2-amino-l-butanol A 30 g. portion of the crude dl-2-amino-l-butanol hydrochloride from Example 1 is suspended in a mixture of 100 ml. of toluene and 20 ml. of isopropanol. Anhydrous ammonia (10.2 g., 0.6 mole) is introduced over the surface of the well-stirred suspension at 25°C.

A dry-ice-acetone condenser controls ammonia loss during reaction. Crystalline ammonium chloride starts precipitating immediately and stirring is continued for 15-20 minutes to insure completion of the reaction. The dry-ice-acetone condenser is removed and excess NHj is al5 lowed to volatilize (15-20 minutes). The precipitated NH^Cl 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,l-2-amino-l-butanol (21.0 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-l-butanol tartrate from dl-2-amino-l-butanol hydrochloride A 50 g. sample of dl-2-amino-l-butanol hydrochloride from Example 1 is dissolved in 100 ml. of anhy20 drous methanol. One mole of anhydrous NH3 is condensed in over a period of 40 minutes. (A dry-ice-acetone condenser is used to prevent ammonia loss during reaction.) After stirring for 0.5 hour, the dry-ice-acetone condenser is removed and excess NH3 is allowed to volatilize (20-30 minutes). The precipitated NH^Cl is filtered off (13.2 gm., 0.256 mole, 62%) and the filtrate is concentrated to leave a viscous oil (43 gm.) which contains 58% by weight free dl-2-amino-l-butanol (the remainder being unreacted dl-2-amino-l-butanol hydrochloride).

The mixture (42 g.) is dissolved in 120 ml. of _ 12 z 0 »··» r> n »j υ iw w anhydrous methanol and the solution is treated with 35 g. (0.233 mole) of L(+)- tartaric acid. The reaction temperature rises to 45-47°C. during addition of tartaric acid. The solution is maintained at this temper5 ature for 1 hour and then cooled to 25°C. over a period of 4-5 hours. Crystallization can be expedited by seeding the solution with d-2-amino-l-butanol L(+)~ tartrate to induce crystallization of the salt.

The precipitated salt is filtered off and wash10 ad four times with cold methanol and then dried in an inert atmosphere. The salt is obtained as colorless crystalline solid [30 g., 0.125 mole, 63%) m.p. 138-140°C [a]p6= 23.52° (c = 5%, H20) and in a typical run was indistinguishable from authentic d-2-amino-l-butanol L(+)15 tartrate [m.p. 137-141 °C.,· [a]26=23.74° (c = 5%, H2O)).

Up to about 8% of dl-l-amino-2-butanol may be formed in the reactions from the addition of the imido group to the 1 position in butene-1, in effect, the reverse of that desired. By analogous reactions, this is converted to dl-l-amino-2-butanol. Both the d and 1 isomers remain with the mother liquor in the crystallization, and permit the separation of d-2-amino-l-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. 4SS23 Example 4 d-2-Amino-1-butanol x_. 1 d-2-Amino-l-butanol tartrate (150 g.) (0.63 mole) from Example 3 is added with stirring to an aqueous solution of KOH prepared by dissolving 76 g. KOH in 115 ml. of distilled water. d-2-Amino-l-butanol which forms the upper layer is extracted with tetrahydrofuran (100 ml. x 2). The tetrahydrofuran extract is dried (Wa2SO4) and concentrated under reduced pressure. The crude, oily residue is distilled under reduced pressure to give d-2-amino-l-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 [0,1^= 9.9. The yield of the distilled material is about 50% to 76% and can be improved substantially if additional extractions 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-l-butanol, produced in accordance with the procedure of Example 4, and 32 g. of ethylene dichloride is heated to 80°C. and the temperature is allowed to rise exothermally to about 130°C. After 1 hour, the mix ture is cooled to about 95°C., 22.5 g. of sodium hydroxide 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 70°C. and unreacted d-2-amino-l-butanol is recovered by vacuum distillation. The distillation is at a pressure below 20 mm. mercury, and below 130°C., heat being applied at a rate within the capacity of the S S 2 3 condenser.

Isopropanol (290 g.) is added to the distillation residue at a temperature not above 90°C., and followed by a refluxing period of 30 minutes. The mixture is cooled to and filtered at 60°C. to remove sodium chloride, and the filter cake is washed with 47 g. of isopropanol, at 60°C. The volume of the filtrate is diluted to 430 ml. with isopropanol and the temperature is adjusted to 40-45°C., 2 g. of diatomaceous earth filter 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 (about 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 55°C., to a pH of 2 to 2.5. The charge is cooled very slowly to 28°C. and is stirred for about 1 hour.

Conveniently, a small aliquot is titrated, and a calculated quantity of hydrogen chloride added. Proper final pH 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'-2,21 -(ethylenediimino)-di-l-butanol dihydrochloride is separated by filtration and washed with isopropanol. The product, carefully dried at a maximum temperature of 75°C., is about 70 g., has a decomposition range of 198.5-204°C., and an ash content of 0.1%.

This is a pharmaceutically acceptable, elegant grade of ethambutol hydrochloride without further treatment or refinement. The product may be tabletted or en15 capsulated by conventional procedures.

Example 6 N-Γ1-(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) 1-butene. The mixture is cooled to -5 to -8°C. and chlorine added over 2 hours maintaining the temperature at below 7°C. until the reaction mixture turns yellow indicating a slight excess of chlorine. The mixture is filtered and the solvents distilled under reduced pressure to yield 28.6 g. of N-[1-(chloromethyl)propyl]acetamide (40.2% yield based on 1-butene).

Example 7 N- [1- (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 mole) acetonitrile, 27.4 g. (1.52 mole) water, 27 g. (0.25 mole) Na2CC>3 and 28.1 g. (0.50 mole) 1-butene and cooled to 0°C. Chlorine (0.50 mole) is added over 1/2 hour, the reaction temperature reaching a high of 32°C. After stirring for 2 hours at 25 °C., the reaction mixture 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 H-[l-(chloromethyl)propyl]acetamide (44.0% yield based on 1-butene).

Example 8 dl-2-Amino-l-butano1 2 8 Ζ 3 - 1 Sodium hydroxide pels (97% pure, 18.8 g., 0.45 mole) are stirred with 100 ml. of anhydrous methanol and crude dl-2-amino-l-butanol hydrochloride, 50 g. (87% real, 0.35 mole) from a run similar to that of Ex5 ample 1 is added with stirring over a period of 0.5 hour. The reaction mixture warms up and precipitated sodium chloride is removed by filtration, washed with methanol and the washings combined with the main filtrate. Methanol and water (formed during neutralization) are removed under reduced pressure and the residual oil distilled to yield dl-2-amino-l-butanol (b.p. 95-100%/30-35 mm.), 26.68 g. (86% of theory). The material contains about 9.6% of dl-l-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 Patent No. 1,556,008 (CH 71, 115) or as a component in a flame retardant composition, United States Patent No. 3,413,380 (CATO, 40).

Example 9 dl-2-Amino-l-butanol Sodium hydroxide pels (97% pure, 18.8 g., 0.45 mole) are stirred with 100 ml. of isopropanol containing 0.7 ml. of water. A part of the sodium hydrox25 ide goes into solution. Crude dl-2-amino-l-butanol hydrochloride 50 g. (70% real, 0.28 mole) is added with stirring over a period of 0.5 hour. The reaction mixture warms up to about 45°C. and crystalline sodium chloride precipitates out of the reaction mixture. The salt is removed by filtration, washed with isopropanol 3 8 2 3 and the washings are combined with the main filtrate.

The filtrate is distilled under reduced pressure. Isopropanol 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 it to contain about 10% 1-amino-2-butanol.

Example 10 d-2-Amino-l-butanol To a 15 g. portion of undistilled crude dl-2-amino-l-butanol (59% real, 0.1 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 45°C. for 0.5 hour. An additional 4.2 g. (0.028 mole) of tartaric acid is added and the mixture held at 45-47°C. 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 tailine L(+)~ tartrate of d-2-amino-l-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-225 -amino-l-butanol L(+)- tartrate weighed 8.5 (0.035 mole, 71.0%), melted at 137-138° and had a specific rotation [a]2®= 23.74 (c - 5%, Η2θ) · The crude feed dl-2-amino-1-butanol contained about 8% of dl-l-amino-2-butanol as an impurity. This impurity is not carried through the resolution process. The 1,)+)- tartrate salt of d-218 S 8 2 3 -amino-1-butanol obtained after 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 l-amino-2-butanol.

Example 11 d-2-Amino-l-butanol To 15 g. of distilled dl-2-amino-l-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 1,(+)- tartaric acid while maintaining the temperature below 47°C. 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 16-17°C. over a 4-hour period and the crystalline 1,(+)- tartrate salt of d-2-amino-l-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 (α]θ = 23.74 (c = 5%, H2O). The feed dl-2-amino-l-butanol used for resolution contains about 8% of dl-l-amino-2-butanol as an impurity. This impurity is, however, not carried through the resolution process. The L(+)- tartrate salt of d-2-amino-l-butanol obtained after resolution is found to contain no detectable quantities of either d or 1 1-amino-2-butanol by gas liquid chromatography which is sensitive to 0.01% of l-amino-2-butanol. Apparently, all of the dl-l-amino-2-butanol remains with the mother liquor, and is rejected along with the 1-2-amino-l-butanol in the methanol.

Example 12 dl-2-Amino-l-butanol A A 137 g. sample of crude dl-2-amino-l-butanol hydrochloride from a run similar to Example 1 is treated with a solution of 137 g. KOH in 200 ml. of water.

The mixture is extracted three times with tetrahydrofuran and the combined extracts dried (l^SO^) . The solvent is removed under reduced pressure to give 95 g. of a crude oil (60.6% dl_-2-amino-l-butanol and 6% dl-1-amino-2-butanol).

B In a separate experiment a 250 g. sample of a similar crude dl-2-amino-l-butanol hydrochloride dissolved in 200 ml. of anhydrous methanol is treated with 3 moles of anhydrous ammonia. After a few hours stirring, 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-l-butanol and its hydrochloride together with some quantities of dl-l-amino-2-butanol and its hydrochloride (total 58.9% dl-2-amino25 -1-butanol by gas liquid chromatography.

C A 7.5 gm. sample of crude dl-2-amino-l-butanol from the first experiment (A) is mixed with a 7.5 gm. portion of the material (dl-2-amino-l-butanol and its hydrochloride) from the second experiment and the mix30 ture is dissolved in a mixture of 80 parts of anhydrous methanol and 20 parts of isopropanol (v/v) (the solution contains 0.1 mole of real d1-2-amino-1-butano1 of which 0.097 mole is present as the free base. (L(+)tartaric acid (15 g., 0.1 mole) is added slowly keeping the temperature below 45°C. until, the exotherm ceases. After stirring the solution for an hour at 45°C., the temperature is lowered slowly and at 40°C. the mixture is seeded with a small amount of the L(+)- tartrate salt of d-2-amino-l-butanol and then gradually cooled to 18° over a period of 4 hours. The crystalline L(+)~ tartrate salt of d-2-amino-l-butanol formed in the reaction mixture is removed by filtration, washed with cold methanol (3 ml. x 3) and pumped dry. The yield of the material is 9,0 g. (0.036 mole, 75.2%); m.p. 137.5-139.5; [α)β5= 23.84“ (c = 5%, H2O).

Example 13 N-[1-(Chloromethyl)propyl]acetimidoyl chloride Reagent grade acetonitrile (82 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 (-20“C.), butene-1 (28 g., 0.5 mole) and chlorine (35.5 g., 0.5 mole) are added simultaneously both at a rate of about 375-400 ml./min. The addition is complete in about 37 minutes and the reaction temperature at the end of this period rises to -10°C. (bath/20°C.). The mixture is fractionated to give: Fraction 1, 89 g. (mostly acetonitrile) distilling under 20 mm. pressure at a bath temperature of 50“C.; Fraction II, 12.5 g. distilling under 20 mm. pressure at a bath temperature 43833 of 65®c., 70% 1,2-dichlorobutane, 30% N-(l-chloromethyl)propyl]-acetimidoyl chloride; Fraction III, 35.9 g. distilling under 2 mm. pressure at a bath temperature of 60°, about 90% N-[l-(chloromethyl)propyl]acetimidoyl chloride residue, 6.7 g. dark brown viscous oil. Based on Fractions II and III, the yield of N-[l-(chloromethyl)propyl]acetimidoyl chloride is 39.7 g. (48%). A portion of Fraction III is redistilled to give a pale yellow oil with a characteristic odor resembling that of thionyl chloride. The product, N-(l-(ohloromethyl)propyl]acetimidoyl chloride displays strong infrared bands at 3000, 1705, 1430, 1370, 1085, 960, 920, 840 and 740 cm”1. NMR(CDC13): 0.88 ppm (t, 3H), 1.4-1.8 ppm (m, 2H), 245 ppm (s, 3H), 3.62 ppm (m, 2H, -CHjCl), and about 3.9 ppm (m, IH, CH).

Occasionally, a eolid isomer of N-[l-(ohloromethyl)propyl]acetimidoyl chloride (often the major product is also obtained. The two forms seem to be interconvertible 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”1.

Example 14 N-[1-(Chloromethyl)propyl]acetamide A sample of N-[l-chloromethyl)propyl]acetimidoyl chloride from Example 12 is treated with an excess of 10% aqueous sodium carbonate solution at room temperature. The organic material is extracted with ether and dried over MgSO4. Removal of the. solvent under re30 duced pressure leaves N-[l-(chloromethyl)propyl]acetamide as a crystalline solid in nearly quantitative yield. An infrared spectrum shows peaks at 3300(M), 3100(W), 1650 (S), and 550 (S) can-1; nuclear magnetic resonance (CDC13) shows peaks 0.95 ppm (t, 3H0, 1.4-1.8 ppm (m, 2H), 2.03 ppm (s, 3H), 3.67 ppm (d, 2H, CH2C1), 3.8-4.4 ppm (m, IH).

EXAMPLES 15-21.

N- l-(Chloromethy1)propyl acetamide chloride The effects of conditions on yields is shown in the following examples in which the chlorination reactions were carried out at initial temperatures of -3 to +23° and the acetonitrile to Cl2 ratio was varied from 2 to 4. Additionally, the initial concentration of of butene-1 was varied by either passing butene-1 and Cl2 simultaneously (low initial butene-1 concentration) into acetonitrile or by first condensing butene at -5°C. into acetonitrile and then passing Cl2 through the mixture (high initial butene-1 concentration). The results of these experiments in Table I show that the yield of N-[1-(ahloromethyl)propyl]acetimidoyl chloride is dependent primarily on the mole ratio of acetonitrile to Cl2 and amounts to about 50-55% when this ratio approaches 4.

TABLE I PRODUCTION OF N-C1-(CHLOHOMETHYL)PROPYL]ACETIMIDOYL CHLORIDE (I) Reaction of Butene-1 (0.5 mole) with. 01, (0.5 mole) in. A.cetonitrilea (AN) T°C AN/Cl Cl, Rate Reaction Time Initial Butene I Example Init. Peak (mole ratio) (ml/min) (hrs.) _cone. (% yield) COO CO o o o kocxc'-r^a 4* ΙΛ ΙΛΙΛ °qp ο’θ/Λ o SWbQtOis tri Ο Ο·Η ·Η ·Η Ο Λ rri rri 33 ,d ,£+ Η ΙΛιΛίΑΐΛφ CMCMOOOOCM Κ\0-Ο-Ο 04 U\lf\ Η C\J CM Κλ Ο Ο ^<Μ ΚλΟ Ο CM I I ω X? & 0 Α •Η Α • rri bO 03 rri Ο- Ρ •Η Ρ (1) -Ρ Α «Ρ 03 6 φ •Η ο ft θ Ά n 03 A p Α co o A 0 ο 03 rri Φ Α ft P *d Ο nJ ft •rl bD Φ tJ co A •Η rA Φ σ* > fcO P P •η •rri (0 ft rri Α Φ A Φ Φ £ fi rri 03 Ρ •rri A d <0 rri 03 h0 • 3 <0 Φ Φ ω υ A *A rW A Ό P •rri 03 •rri co •rri A A A •H 03 Ό O rri A > Φ Φ rri ft O A P fi a* Ά o o a Φ Φ Φ Ο I>i 03 P xl rri -Ρ P 03 P o S A CO O Ο « jy Oi ft 03 Ά ε 03 03 O A •rri Φ CO 1¾ a φ A rri rri 03 Ή A ft 03 P l>5 P Α 03 A P P Φ •Η 03 A o hO •rri o Φ o Φ •rri A • A Ρ A •rri A Φ A Φ m Ρ ft •P 3 ft 0 rri ο o • -p A o CO O rri rri P A ft Ά •H Φ 0 A £0 0 A O φ A A lf\ S A A O A •Η Φ | •A P Ά 03 ft Α Λ O 03 . O O Φ z—k Α ft P O A A A ΓΗ « 03 -P Φ ft h» υ o nJ A A O P B Φ tJ Φ O •rl P φ P to Φ 1 P Φ Α co A rri Ά 03 Φ s Φ CO O Φ Φ A o & P P o 03 rri b0 A co o o O A •rri A O 03 fi P a rri Α Ά 03 Φ Ά A P ο A CO rri A Φ rri A υ •Η co jg •rri (0 A o A Ρ A Φ > Φ 1 Ο to .-} P rri rri rri φ A 1 •rri 1 Φ υ UJ φ •rri Φ A Φ 02 fi A ί Α A A 0 A Ό P A !Ξ< A Φ P Φ rri rri •rri P Φ P Φ ft Ά il rri P A 0 A •rri ft A «3! 03 'd co fd 0 A Η ζ—\. zx z~\ Z~\ ζ-\ cd fi O Ά Η s-z o o <_ζ EXAMPLES 22-33.

Three series of reactions (A, B and C) were completed using as-is acetonitrile (water cone. (Karl-Fisher) = 0.059-0.2%). In each of these series, reactions 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 1 to 8.

In a series A (reaction time = 1 hour) the reaction temperature was maintained at 0°C. while chlorine and butene were passed simultaneously into acetonitrile in one hour. After removal of acetonitrile (40-50° , 50 mm.), the crude reaction mixture containing Ν- 1-(chloromethyl)propyl acetimidoyl chloride and 1,2-dichlorobutane was hydrolyzed by refluxing with aqueous methanol. 43833 <~Η Φ O Ά CS 2 co -Ρ φ o 3 Ό Α·Η I Ό O A η α o Φ·Η O •H S P Pi CO T5 _ I & i\| & Φ Ξ •H ?=-» s~> a . O W •H •PA, Ov-< CC Φ « i VD U lf\O O t-t N\CM H OLf\<0 10 ooooo Η Η Η Η H TASUS II Φ<·> P d CT-rt ng ooooo ooooo •T CM CM CU CM cu o o Φ +3 d cd φ M •P d φ Aw r*f rH rH ι—I r—1 r~t ρ—1 r-t r-i r-l r-l CJ if 'Ό 00 Φ ω d Φ Φ O LT\Lf\Lf\ir\ r4 -P · · · · · 3 Η ο Ο Ο Ο a pq O ooooo o OOOOO EH CM CQ LO LO CM 04 CM CM CM Acetonitrile CO :6 It is significant to note that N-[1-(chloromethyl) propyl]acetimidoyl chloride can be hydrolyzed substantially quantitatively to N-(1-(chlorometyl)propyl]acetamide, and then to dl-2-amino-l-butanol. Reporting as dl-2-amino-l-butanol hydrochloride is a very convenient method of showing yields. Errors due to volatile components are avoided. Small quantities of dl-1-amino-2-butanol report with the dl-2-amino-l-butanol. Even at a low acetonitrile:C12 ratio of one, the yield of dl-2-amino-l-butanol,HCl is as high as 31%. Increasing the acetonitrile:Cl2 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:Cl2 ratios 3 to 5) the yield of dl-2-amino-l-butanol*HC1 increases on average about 6%.

Still further addition of acetonitrile (AN:C12 mole ratios 6 to 8) is considerably less effective; the average incremental yield of dl-2-amino-l-butanol*HCl being of the order of about 3% per 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 reaction. Additionally, in series B, chlorine was passed through a solution of butene in acetonitrile to maintain a high initial concentration of butene. In series C both chlorine and butene were passed simultaneously through acetonitrile allowing attainment of a low initial concentration of butene. The results of simultaneous and sequential additions of butene and chlorine on the yield of N-[1-(chloromethyl)propyl]acetimidoyl chlor ide at different acetonitrile/Cl2 mole ratios are summarized in Table III. 1 Ο Φ β -PH Φ OJ-rH > ϋ ti O Φ •rH Φ <&β β I o o C\J Ο in ί if (Τ' CTCTCTCT I CTCT ITS I I Reaction of Butene-1 (0.5 mole)a with Cl? ¢0.5 mole)a in Acetonitrile (AN) Series Bb: Addition of 01, to Butene + Acetonitrile (AN) I .3 Η ϋ H h«H >5 Ο Ό Λβ I W P -rl (\) Φ 0) S **H fi’HrH O OP S h ω + ο o Η (C 9 β p I & O β Η O H £> A o & βϋ fc I o r-H ρ Φ ω ο β φ •H co r-Ι nd ρ ο I β θ CM * ο Η β I ζ~\ pH rH Ρ Ο ρ d Φ ·Η a a ο ·η β +5 ο Φ η ϋ Λ Λ φ ο -fd \_χ ι—ι ·Η I >5^ Η Qj Ο I—( Ο rH ι l d & aa ο •rH -Ρ ϋ .. φ O en Φ rH s ΐΑίΛιΑιΑ Lf\Lf\ • ♦ · I · · ΟΟΟΟ I οο d υ c\i m η σ' ιί\ \d I LfXd ΟΟΟΟ ο ο R3S& °§ fCiNMCifu I (Μι-Ι ... * I · · ΟΟΟΟ οο ΚΧφ Ο «''CO '.ο ΚΧ C'J θ'CO mCSCSd KXNXKXd ih Li\U\ d CJ CJ ΚΊι-Ι rj O' / ΰσ-: .ί O'·/ r~l ι—ί (—I (\l Cj C d IJ ooooooo r-ι in rl H CJ ί 4 O It) 0) •rH β O P Φ β Φ P CO r4 β o •H P •rl Ό W β o Φ ra Lf\Q ΙίλΚΜΓλΚΜΛ 0) CJ C4 (\I rH ‘H I | I I I I I β OOOOOOO φ >, ·*> cn o r— oj co CM ζΜ CM »Ό CO CO CO HCTCTiXT o CTCTCTCT H CO Φ H 0 a cm tb β o β ο ΐΛίΛιΓΜΛΡ Η Ο PU Ο Ρ β β & β *--> ο η a Ρ ι>* φ β a a ο βρ ο ϋ Η Ή Ρ Ρ • « 1 · « P Ο 2 «ΟΟΟΟ cj o i-ι οο O'r-IOj Φ P Φ CQ CQ β Cb Φ 1 β Η Ο t—j ·Η 1 Ρ •S5 φ Η Η Η Ο ·Η o d mind β Ρ • · · · · Φ ω ω «ΟΟΟΟ 3 Φ·Η Φ β Φ P β P OOQO'h CO TJ ω Ο Ι>5 Η Ρ φ φ Η Ρ <0 oo-3 κ\ o ο β c\j CJ (\i <\J H • · · · · Φ β Ρ •Η 0 rlOOOOrl β O a CM d β •Η Ρ ο Ο Η β Ρ ϋ Ο ·Η χί d ΟΟΉΟ o § r? . a 1 ω 04 φ * bQrH » * · » * o *d ο Ρ Η iPiHMS-d O md d mifl o Q β Ο 3 Φ Ο β Φ Φ Qj ϋ Η β β Φ > CJ Φ rH t> H φ ρ,ο d cj d co ic 0 β Ρ a l>-1J Cj CJ rr a β cd φ φ • · · · 0 β CQ β ooooo CMP Φ Φ o Γ-? β 3 ϋ •Η Φ P xl β « β S cd β Φ Ό co β CO Φ Λ β Φ ω Ρ τ} > • β·-1 rl CJ d Ο co Φ o Ο ρ β H 04 Φ a h .. Ο β Η op β·Η φ ο X β a Ό $P •Η Φ Η •rf Ρ εθ S iC'd !>-Cd H β β β Ο c., Cj Cj CJ CJ Η Ο β ρ d ι ι ι ι i Ρ Ο •Η ooooo Ρ Φ •rH ω a Οι ϋ Ρ Ό ·Η Φ β φ Η Ρ ο β φ φ ρ V •γΗ φ ΪΗ β -J ldon co co co co co co t /TS Ρ ο In series B and C material balances show conversion and recovery data on acetonitrile. In each case the distillate 1,2-dichlorobutane + acetonitrile was analyzed for 1,2-dichlorobutane and acetonitrile by gas liquid 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-l-butanol'’HCl (or N-[1 -(chloromethyl)propyl]acetimidoyl chloride) is primarily dependent on the mole ratio of acetonitrilerClj and varies between 31 and 66% as the acetonitrile:Cl2: 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 adding chlorine to a mixture of butene and acetonitrile is advantageous. The reaction is less exothermic, consequently easier to control, and the yields of dl-2-amino20 -l-butanol’HCl are somewhat better. A reaction time of one hour generally appears to permit more control over the reaction exothermicity. 3. The reaction temperature does not appear to be a controlling factor in determining the overall yield.

However, 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. 3 8 2 3 with the butene-1 and chlorine being fed continuously to a stirred continuous reactor. The recycle acetonitrile is distilled off and recycled continuously. Such a continuous system permits a higher ratio of acetoni5 trile to the butene-1 and chlorine. Whereas, for a batch process, a molar ratio of at least 2 of acetonitrile to butene-1 and chlorine is preferred, more than a ratio of 16 can require an uneconomically large reactor. With a continuous process even higher ratios are convenient.

Whereas both butene-1 and chlorine are gaseous at room temperature of about 20°C., so that low temperatures, around 0°C. and lower are convenient, a higher temperature to reduce the need for cooling may be used if a pressurized reactor is available.

The trade-off of the cost of a pressure reactor against additional refrigeration can vary with equipment available.

Claims (16)

1. A process for the synthesis of dl - 2 - amino - 1 - butanol hydrochloride, which comprises heating N - 0 - (chloromethyl) propyl]acetamide in the presence of a (C-^-Cg) alkanol and water whereby the N -01-(chloromethyl )propy1] acetamide is hydrolyzed to dl - 2 - amino - 1 - butanol hydrochloride, and distilling off the coproduced alkanol acetate.

2. A process according to Claim 1, in which the water is added first, the mixture refluxed, and then the (C-j-Cg) alkanol is added.

3. A process according to Claim 1 or Claim 2, in which the N - 01 - (chloromethyl)propyljacetamide is synthesized by reacting N -01 - (chloromethyl)propyl]-acetimidoyl chloride with water, optionally in the presence of a weak base, thereby hydrolyzing N - 01 - (chloromethyl )propyl] acetimidoyl chloride to N 1 - (chloromethyl)-propyl)acetamide.

4. A process according to Claim 3, in which the N 01 - (chloromethyl)propyl]-acetamide is synthesized by reacting at least 2 moles of acetonitrile with about 1 mole of chlorine and about 1 mole of butene-1, to product N - 01 -(chloromethyl) propylj -acetimidoyl chloride with the concurrent production of 1,2-dichlorobutane, adding water, thereby hydrolyzing said N - 01 - (chloromethyl)propyl]acetimidoyl chloride to N 01-(chloromethyl )propyl]acetamide, and after the synthesis of said N - 01 - (chloromethyl)-propyl]acetamide, distilling off acetonitrile under reduced pressure and recovering the excess acetonitrile. 4 2 8 2 3

5. A process according to Claim 4, in which water is added at about the same rate as N - [l - (chloromethyl)propyl]acetimidoyl chloride is produced, thereby hydrolyzing said N - fl - (chloromethyl) propyl] -acetimidoyl chloride before it can be additionally chlorinated, and also releasing the heat of hydrolysis over the course of the reaction, thus controlling isothermal temperature rise.

6. A process according to any preceding claim, in which said hydrolysis of N - (l-ehloromethyl)propyl)acetamide to dl_ - 2 - amino - 1 - butanol hydrochloride is carried out in the presence of catalytic amounts of hydrochloric acid.

7. A process for the synthesis of dl - 2 - amino - 1 - butanol hydrochloride, according to Claim 1 and substantially as described in Example 1 herein.

8. dl_ - 2 - Amino - 1 - butanol hydrochloride whenever synthesized by a process according to any preceding claim.

9. A process for preparing dl - 2 - amino - 1 - butanol, which comprises neutralizing dl - 2 - amino - 1 - butanol hydrochloride according to Claim 8.

10. A process according to Claim 9, wherein dl - 2 - amino - 1 butanol hydrochloride according to Claim 8 is partially neutralized with ammonia to form dl_ - 2 - amino - 1 - butanol in admixture with dl- 2 - amino - 1 - butanol hydrochloride.

11. A process for preparing dl_ - 2 - amino - 1 - butanol, according to Claim 9 and substantially as described in any one of Examples 2, 7, 8 or 11.

12. dl - 2 - Amino - 1 - butanol whenever prepared by a process according to any one of Claims 9-11.

13. A process for the preparation of d - 2 - amino - 1 - butanol, which comprises mixing dl - 2 - amino - 1 butanol according to Claim 12 3 8 3 with L(+)-tartaric acid in anhydrous methanol, separating the crystalline acid L(+)-tartrate of d. - 2 - amino - 1 - butanol from the methanol, dissolving said tartrate salt in water, adding an alkali or alkaline earth hydroxide, and separating out the 5 resultant alkali or alkaline earth L(+)-tartrate thereby isolating c[ - 2 - amino - 1 - butanol in aqueous solution.

14. A process for the preparation of d - 2 - amino - 1 - butanol, according to Claim 13 and substantially as described in any one of Examples 3, 4, 9, 10 and 11 herein. 10

15. d^ - 2 - Amino - 1 - butanol whenever prepared by a process according to Claim 13 or Claim 14.

16. c[, d' ' -2,2' - (Ethylenediimino)di - 1 - butanol prepared from - 2 - amino - 1 - butanol according to Claim 15 by a reaction with ethylene dichloride.