JPS60243055A - Synthesis of n-(1-(chloromethyl)propyl)acetamide - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION (1-butene and a base, preferably at the same time)
N-(1-(chloromethyl)propyl) along with a certain amount of by-product 1,2-dichlorobutane
N-(1-(chloromethyl)propyl)acetimidoyl chloride is conveniently hydrolyzed in situ to N-[1-(chloromethyl)propyl]acetamide and excess It is further df- possibly by a ring-closing and re-cleavage step while conveniently removing acetonitrile and 1,2-dichlorobutane.
dl-2-amino-1-butanol is prepared by hydrolysis to 2-7 minol-1-butanol, conveniently as the hydrochloride salt. dit-2-amino-1-butanol has many uses as it is, including d-2
-7mi7-1-butyl/- is also included, and when this d unit is reacted with ethylene dichloride, ethambutol hydrochloride, d, d'-2,2'-(ethylenediimide/) no 1- Produces butanol dihydrochloride. The dit-2-7 minol-1-butal 7-ol obtained in this way yields ethambutol hydrochloride of excellent quality for pharmaceutical use.

This process is a particularly acceptable form for producing d,d'''-2,2'-(ethylenediimy/)cy-1-butanol dihydrochloride of excellent quality for pharmaceutical use by reaction with ethylene dichloride. 7d-2-7mi/-1-butanol is obtained.

These equations can also be expressed as follows (1°CH3CH
3CH=CH2+ (12+CH3CN butene-1 acetonitrile N=ccItcH.

N-(1(chloromethyl)propyl]acetimidoyl chloride or N-(1,-(chloromethyl)propyl)ethanimidoyl chloride N-[1-(chloromethyl)propyl]acetamide C1-CH, <l1l) 4-Ethyl-2-methyl-2-oxazinone hydrochloride or 4,5-dihydro-4-dithyl-2-methyl-oxazole hydrochloride (: H3COOCH.

(IV) df-2-amino-1-butanol hydrochloride methyl acetate Surprisingly, in the reaction with acetonitrile), the best results are obtained when acetonitrile is used in excess. Acetonitrile is an expensive ingredient, but it is customary to try to use less of some of the expensive ingredients on a daily basis. In this case chlorine also reacts with butene-1 to form 1,2-dichlorobutane. When acetonitrile is in excess, the reaction is reduced to N-(
1(chloromethyl)propyl]acetimidoyl chloride is pushed forward. N-(1(chloromethyl)
A quantity of rat water corresponding to the amount required for the hydrolysis of the N-[:i-(chloromethyl)propyl]acetimidoino and chloride was added to the reaction mixture before, during, or after adding the base and butene. ] Acetimidoyl chloride may be hydrolyzed to N-(1(chloromethyl)propyl)acetamide. The reaction between acetonitrile and the hydrochloric acid formed in the hydrolysis is slow enough that at least 95% of the excess acetonitrile is can be distilled from the reaction mixture under reduced pressure and recycled.

Economically recovering acetonitrile in a form that can be recycled into the process at low cost! 1! It is important to try to build

Too much excess acetonitrile will require too large a reaction vessel. Continuous reactions may be used, allowing relatively small equipment and large excesses of acetonitrile, the latter of which is recycled to the starting material.

After stripping off the acetonitrile, N was added during the reaction.
-(1(chloromethyl)propyl)acetimidoyl
If the hydrolysis of chloride to N-[1-(chloromethyl)propyl]aceYamide is not complete, in b) the hydrolysis is terminated by adding water to the pot residue. N
The production of N-(1-(chloromethyl)propyl)acetamide by hydrolysis of -(1-(chloromethyl)propyl)acetimidoyl chloride includes calcium carbonate, calcium oxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, The presence of a weak base such as potassium carbonate or potassium bicarbonate, barium carbonate or strontium carbonate is advantageous.N-[1-(chloromethyl)propyl]acetamide can be further hydrolyzed to give dA'
No base is required when bringing to -2-amino-1-butanol. After hydrolysis, 1,2-dichlorobutane is distilled off under reduced pressure.

After removing the acetonitrile and 1,2-dichlorobutane, the purity of the N-(1(chloromethyl)propyl)acetamide is determined to be of a quality that can be used for resolution steps or other purposes. High enough to conveniently process into butanol hydrochloride.

N'-C1-(chloromethyl)propyl]acetimidoyl chloride may be recovered and utilized after its formation. Conveniently, water is added to the reactor to convert N-[1-(chloromethyl)propyl]acetimidoyl chloride into N
Hydrolysis to (1(chloromethyl)propyl)acetamide effectively performs the first two steps at the same time, provides better control of heat generation, and saves time and operations since the processing steps are simultaneous. After the chlorination is completed, N-(
Water may be added in slight excess of the amount calculated to hydrolyze 1-(chloromethyl)propyl]acetimidoyl chloride to N-(1-(chloromethyl)propyl)acetamide.

N-(1(chloromethyl)propyl)acetimidoyl chloride or N-[1-(chloromethyl)propyl]
Acetonitrile may be decomposed from acetamide. N
It is convenient to separate it after hydrolysis to -(1-(chloromethyl)propyl]acetamide.N-(
After the synthesis of 1-(chloromethyl)propyl J acetimidoyl chloride, or 1. tN-1-(chloromethyl)propyl] 1,2-tsukuo by hydrolysis to ayatamide followed by distillation.

The butane may be separated off in whole or in part. 1.2 until the synthesis of dl-2-ami/-1-butamer hydrochloride is completed.
- At least a portion of the dichlorobutane may be left behind. It is usually more convenient to separate the 1,2-dichlorobutane after hydrolysis to N-(1-(chloromethyl)propyl)acetamide, since the reaction mixture is partially reduced and N-(1- (chloromethyl)propyl"acetamide may be reacted to dil-2-amino-1-butyl hydrochloride by azeotropic distillation with water. df-2-
The complete removal of 1,2-dichlorobutane from amino-1-butanol is accomplished conveniently and effectively.

Methanol is then added to the aqueous reaction mixture containing N-[1-(chloromethyl)propyl]acetamide, preferably along with a catalytic amount of hydrochloric acid. Hydrochloric acid is refluxed and hydrolyzed to produce dn-2-amino-
The 3° methyl acetate that yields 1-butanol hydrochloride is removed by distillation, leaving dl-2-amino-1-butanol hydrochloride.

The presence of water should be avoided in the production of N-(1-(chloromethyl)propyl]acetimidoyl chloride;
Vacuum distillation is also required to remove acetonitrile and 1,2-dichlorobutane.

Upon hydrolysis to N-(1-(chloromethyl)propyl]acetamide, mild conditions are preferred for the removal of both acetonitrile and 1,2-dichlorobutane. A weak base aids in the controlled hydrolysis.

If hydrolysis to dl-2-7 minnow-1-butanol is desired, the acid generated in the hydrolysis is taken up for use in forming the hydrochloride salt of the product.

In the preparation of dl-2-ami/-1-butanol hydrochloride, acetonitrile should be vacuum distilled at the N-[1-(chloromethyl)propyl]acetamide stage for recycling. If acetonitrile is left behind during the hydrolysis to dl2-2-amino-1-buta7-al hydrochloride, it tends to hydrolyze to acetic acid, yielding ammonia, usually as ammonium chloride. Although the acetic acid produced in the hydrolysis of acetonitrile is easily removed as a methyl ester, the loss of acetonitrile reduces the efficiency of the process.

N-(1-(Chloromethyl) Process) In the acetamide stage, it is preferred to remove at least a portion of the 1,2-dichlorobutane by vacuum distillation. Conveniently, the last 1,2-dichlorobutane can be removed as methyl ester to form dl-2-amino-1
- removed from butanol hydrochloride by azeotropic distillation. Conveniently, the intermediate anti-J6 to dl-2-amino/-1-butanol hydrochloride is converted to N-(1-(chloromethyl)propyl).
Acetimidoyl chloride and N-[1-(chloromethyl)propyl]acetamide can be duplicated without isolation.

dl-2-amino-
A solution of 1-butanol is obtained mainly as the hydrochloride salt,
When this is partially neutralized with ammonia, a mixture of dl-2-7 mino-1-butanol, dl-2-amino-1-butanol hydrochloride and ammonium chloride is formed, but the ammonium chloride is removed. The remaining mixture is approximately 2 parts dl-amino-1-butyl and 1 part dl-2.
-amino-1-butanol hydrochloride, U.S. Pat.
As detailed in No. 553,257, the proportions were determined by reaction with [,(+)-tartaric acid in the presence of anhydrous methanol to separate d-2-7 minnow-1-buta-71-tartaric acid salt. This is close to the optimal condition desired to make uJ functional.

This method has unique and unexpected advantages. This is because some of the butene-1 adds chlorine and acetonitrile in the opposite direction to the desired position, so dj! −
Approximately 3-1 as an impurity in 2-7 minnow 1-butanol
0% dj! This is because -1-7 minnow 2-butal 7-al is found. di-2-7 minnow 1-but/-l d
- In the separation of isomers and l-isomers, both isomers of dl-1-amino-2-butanol remain with the mother liquor, leaving highly purified d-2-7 minol-1-butanol. It is separated as L(+)-tartrate.

Starting materials containing up to about 10% dl-1-7 minnow-2-butanol may have a dl-1 content of 0.01% or more.
A purified d-2-7 mino-1-butanol having -amino-2-butyl 7-ol as its tartrate salt is produced. It can be present up to 0.1% if washing is insufficient. With additional minimal purification, a purity that can be used as a starting material for pharmaceutical quality ethambutol is readily obtained.

Ease of separation of impurities and solids is not self-evident and is also the essence of this reaction system.

Example 1 DL-Shadow Minnow 1- Butt / - Le Curtain LJEλ1 Mechanical stirrer, thermometer, las gas inlet tube filled with two glass bulbs, injection needle (connected to injection pump) and dryer A seven-tonitrile (164B
, 4 mol). Cool the flask to 3-5°C in an ice water bath. Chlorine (71 g, 1 mole) and butene-1 (5
6 g, 1 mol) and about 4.6 g, 1 mol) each. (IQ + acetonate well stirred at a rate of oI/min) + water (10 Bi, 0.05 mol) at a linear rate using an injection pump simultaneously during the course of the reaction (1 hour). ) is added.

The reaction temperature rises to 20'C within 8 minutes and remains constant at this temperature during the reaction process. The reaction mixture was heated for an additional 15-30 min.
Stir for a minute. Weigh the reaction mixture to ensure that the appropriate amount of reactant has been introduced. Excess, Surplus A7tonitrile (
Boiling point 36-41℃/150-170 +o+n) 10
It is removed by distillation (bath temperature up to 100°C) using a plate distillation column. An unexpected drop in temperature marks the end of the acetonitrile distillation.

The athotonitrile fraction contains 1-2% HCl and about 6% 1
, 2-dichlorobutane and can be recycled to the next batch without further treatment or purified before recycling.

The heating temperature was raised to 10°C, and the by-product 1,2-dichlorobutane was heated at 150 to 25+aIM (apparatus between 1 and 40°C. Materials 15-258 are produced consisting of a crystalline solid derived from the reaction of 10% 1.2-dichlorobutane and acetonitrile with anhydrous HCl.

The residue in the flask is mainly N-(1-(chloromethyl)
propyl]acetamide, and water (45g12
．． 5 mol) and then refluxing the mixture.

The mixture is allowed to flow for 2 hours at 11 to remove the remaining 2-dichlorobutane by azeotropic distillation (Dean-Stark trap) with water and some acetic acid (formed during hydrolysis with water). is removed at 80 DEG (15.about.20+ oa+ vacuum) leaving a viscous residue consisting of N-(1-(chloromethyl)propyl]acetamide and its hydrolysis products.

Methanol (41 Jg, 1.5 mol) and concentrated hydrochloric acid (0,
5io/) to the residue and then the reaction mixture is refluxed for 2 hours. After removal of the volatiles (H2C, methyl acetate, etc.) d1-2-amino-1-butanol hydrochloride is obtained as a colorless viscous substance which crystallizes on standing.

Example 2 d-Lyu ζ-27-□) □4i□2L-buta/-ru-e
2-□Ya5. -b) Crude df-2- obtained in Example 1
7 minnow 1-buta 7-le mlllj M30 bi toluene 100 koma! and Improper Tool '10ml. Anhydrous ammonia (10.2 g, 0.6 mol) is introduced to the surface of the well-stirred suspension at 25°C.

A dry ice-acene condenser controls ammonia loss during the reaction. Crystallized ammonium chloride begins to precipitate immediately and stirring is continued for 1.5 to 20 minutes to ensure completion of the reaction. Mv dry ice near 7 ton cooler
Leave the excess NH to be emitted by #JI (15.~
20 minutes). Precipitated NH, Cj! Blend and wash with medium-range toluene.

When the furnace liquid and washing liquid are combined and the solvent is evaporated under reduced pressure, d
1-2-7 minnow 1-butal 7-ol (21,0g) is obtained. The product was 63% pure by gas-liquid chromatography and contained approximately 8% df-1-amino-2-butanol.
- Optical isomers can be obtained as free bases from their hydrochloride salts.

Example 3 From dl-amino-1-butanol hydrochloride to d-2-amino-7-1-butanol chloride LL-m-dl-2-amino-7-1-butanol obtained in Example 1 Dissolve 5 og of a sample of the 7-yl salt in 100 liters of anhydrous methanol. 1 mole of anhydrous NH is condensed for 40 minutes (dry ice-acetone condenser is used to prevent ammonia loss during the reaction). After stirring for 0.5 hour, the dry ice-acetone cooler was removed and the excess Nf (3) was allowed to volatilize (20 to 30 minutes). 0.24 (imol, 62%), and the furnace liquor was then concentrated to contain 58% by weight of free dl-2-amino-1-butanol (the remainder being unreacted dl-2-amino-1-butanol hydrochloride). salt) viscous oil (43g)
remains.

The mixture (42 g) was dissolved in 120 ml of anhydrous methanol and the solution was dissolved in 35 g (0,233
mol). The reaction temperature was between 45 and 45°C during the addition of tartaric acid.
The temperature rises to 47℃. The solution is kept at this temperature for 1 hour and then cooled to 25°C over 4-5 hours.

Since crystallization induces salt crystallization, d-2-ami7-
This can be facilitated by adding 1-butanol L(+)-tartrate seeds to the solution.

After washing the precipitated ground with cold methanol for 4 hours and drying in an inert atmosphere, the salt was obtained as a colorless crystalline solid (30 g, 0.125 mol.

63%);+apl 38-1 40℃; (a)”
= 23.52° (C1) = 5%, H20)] and in a typical test the true d
-2-7 minnow 1-butanol L(+)-tartrate (a
+p, 13? -14.1℃: Ca) 26=23
．． 74° (C=5%, H20)). Up to about 8% of the dl2-1-7 mino-2-but-7-al will be formed during the reaction with the addition of an imide group to the 1-position of the butene-1, effectively the opposite position to the desired one. A similar reaction converts this to dl-1-ami7-2-butanol. Both the d-isomer and the l-isomer remain with the mother liquor during crystallization, so impurities are virtually eliminated from the d-isomer.
This is the separation ability of 2-aminobutanol L(+)-tartrate.

Isolation of d-2-ami7-1-buta-7-ol from its salts is described in the aforementioned US Pat. No. 3,553,257.

Conversion to ethambutol is described in U.S. Patent No. 3°769347.
The name is listed in the name details.

Example 4 Ryu Muni Lぢf9/2'' Futo1 product - Distilled water 115+aj! d-2-7 minnow 1-buta-71 tartrate (150 g, o, 63 mol) obtained in Example 3 was added to an aqueous solution of KOH prepared by dissolving 76 g of KOH in
Add while stirring. The d-2-amino-1-butanol forming the upper layer was dissolved in tetrahydrofuran (100"ml).
Extract with X2). Dry the tetrahydro7ran extract (
Concentrate under reduced pressure with Na2SO=).

Distillation of the crude oily residue under reduced pressure yields d-2-7mi/
-1-Butanol (bp, 99-103°/30mm)
is obtained. Further fractionation of this material yields pure d-2-aminobutyl-7-al with a boiling point of 174° [,a]'' = 9.9. The yield of distilled material is approximately 50
76%, and the yield can be substantially improved by further extraction with tetrahydro-76%.

Example 5 Preparation of Tos Z-Butol Hydrochloride 462 g of d-2-ami/-1-butanol and 32 g of ethylene dichloride, prepared according to the procedure of Example 4 according to the procedure described in U.S. Pat. No. 3,769,347, Example 1. and heated the mixture to 80℃, the temperature is exothermically about 130℃
let it go up to After 1 hour, the mixture was cooled to about 95°C and hydroxylated. is gradually added and a temperature of about 112° C. is maintained for 1 hour. Sodium hydroxide is in the form of small particles approximately 41 mm in diameter. After the mixture is cooled to 70 DEG C., unreacted d-2-7 minol-1-butyl is recovered by vacuum distillation. Distillation is at pressures below 20 mm of mercury, below 130° C., and heat is applied at a rate within the capacity of the condenser.

Improper tool (290 g) is added to the distillation residue at a temperature not exceeding 90° C. and then refluxed for 80 minutes. The mixture is cooled to 60°C and filtered at this temperature to remove the sodium chloride, and the filter cake is washed at 60°C with 47 g of Improper Tools. The volume of the liquid is 430uj with Improper Tool! l: F# while watching the temperature 40-4
The temperature is adjusted to 5° C., 2 g of diatomaceous earth filter aid is added, and 1177) filtration is performed twice.

Add 120 g of methanol and 15 g of water to the clear filter. IIH2 to 2.5*t' hydrogen chloride (approx. 25 g) e approx. 0.35-0 without raising the temperature to 55°C without intervening the container.
．． 1 in 5? / am” gauge (5-7 psig) NO
Introduce above the charge surface with X pressure. Cool the charge very slowly to 28° C. and then stir for about 1 hour. It is convenient to add the calculated amount of hydrogen chloride by expelling the sample in a medium dish. The appropriate final pH is confirmed by testing as an acid on wet Congo red test paper. l) Other methods of H measurement can be used.

The white crystalline product d,d'-2,2'-(ethylene no.7)di-1-but/-lunihydrochloride is separated by filtration and washed with Improper Tool. The product, carefully dried at a maximum temperature of 75 °C, weighs approximately 70 g, with a weight of 198.5-204
It has a decomposition temperature range of °C and an ash content of 0.1%. .

This is excellent quality ethambutol hydrochloride that is pharmaceutically acceptable without further processing or purification. The product may be shaped or packaged according to conventional procedures.

Example 6 Preparation of N-(1-(chloromethyl)propyl]acetamide - □ □ Hair acetonitrile 41. in a '750...! three-necked flask equipped with a stirring rock, dry ice-acetone trap, gas outlet and port. 05[1 (1,0 mol), CaC0,
25g (0,25 (le), water 13.5+aj! (0,
75 mol) and 26.8 g (0,475 mol) of 1-butene. The mixture is cooled to -5 to -8°C and chlorine is added while maintaining the temperature above 7°F for 2 hours until the reaction mixture turns yellow, indicating a slight excess of chlorine. The mixture is filtered and the solvent is distilled under reduced pressure to give 28.6% of N-(1(chloromethyl)propyl)acetamide (4.02% yield based on 1-butene).

Example 7 N-(1-(chloromethyl)propyl]acetamide L to IE-□−−−−−−−−−−− 5 with stirring rock and dry ice-acetone trap attached
8.2 acetonitrile in a three-bottle flask of 00I111
1H (2,0-vl), 27.4 g (1,52 mol) of water
, Na, CO 327 g (0.25 mol) and 28.1 bi(0.50 mol) 1-butene and then cooled to 0°C. After adding chlorine (1,50 mol) for 172 hours, the reaction temperature reaches 32°C. After stirring for 2 hours at 25°C, the reaction mixture is filtered. The solid phase is washed with acetonitrile and the furnace liquor is removed. are combined and the solvent is removed by vacuum distillation to give 33.0 bis of N-[1-(chloromethyl)propyl]acetamide (44.0% yield based on 1-butene).

Example 8 Preparation of dl-2-7 minnow-1-butanol Small granular hydroxide (97% purity, 18.8 g, 0.45 mol) is stirred with 100 nf of anhydrous methanol. Next, 50 g of crude d1-2-amino-1-butanol hydrochloride (real part 87%, 0.35 g
mol) was added with stirring for 30 minutes. The reaction mixture is heated to remove the precipitated sodium chloride by filtration and washed with methanol, and the washings are added to the main furnace liquor. After removal of methanol and water (produced during neutralization) under reduced pressure, what remains is dl-2-amino-butanol (boiling, α
95-100'C/ 30-35 m+o) 26.68
g (86% of buried@haku). This substance is dn-1
-7 minnow contains about 9.6% 2-butanol.

dl-2-ami7-1-butanol is disclosed in U.S. Patent No. 3.5.
No. 39.652 (CA, 74.23499) as a catalyst;
CI, Nia 1,115) or as a component of silicone compositions described in US Pat.

It can be used as a component in the flame retardant composition described in No. 413.380 (CA, '7Kyo-140).

Example 9 Sodium hydroxide (97% purity, 18.8 g, 0.45 mol) was dissolved in inpropar/-ol containing 0.7II11 of water. 1
Stir with 00161. Sodium hydroxide becomes a solution. $Itdn-2-7 Minnow 1-butanol hydrochloride 50g (real part '70%, 0.□28 mol) 0.5
Add with stirring for an hour. The reaction mixture was heated to about 45°C.
Crystalline thorium chloride precipitates from the reaction mixture. The salts are removed by filtration, washed with inpropar/-ol, and the washing liquid is combined with the main furnace liquid. The furnace liquor is distilled under reduced pressure. 3011IL was added to df-2-amy/-1-butyl while removing Impropal and water as in the previous test.
11 at 95-105°C (25'g, 88.3
%yield). Analysis by gas-liquid chromatography shows that the product contains approximately 10% 1-amino/-2-butyl-7-ol.

Example 10 Production of d-2-amy/-1-butyl 7-ol Methanol 4B
15 g (real part: 59%, 0.1 mole) of undistilled crude dβ-2-amino-1-phthanol obtained in the same manner as in Example 2 was dissolved in fal and stirred while maintaining the temperature at 45°C. Add L(+)-tartaric acid 17°51H (0,117 mol) to the bottom. The solution was seeded with a small amount of d-2-7minor-1-butanol (+)-tartrate and then 0.00%.
Maintain temperature at 45°C for 5 hours. Tartaric acid 4.2g (0,
028 mol) was added for an additional 0.5 hours 45-47
'Keep the mixture at C. The temperature was then increased to 1 for 4 hours.
Lower the temperature to 6-18°C and keep at this temperature for 1 hour. The crystalline L(+)-tartrate of d-2-7my7-1-buta7-l was separated by filtration and diluted with cold methanol (3+117
3) Wash and dry in an inert atmosphere. In one operation, 8.5FK (0,035 mol, '
71%) weighed and melted at 13'7-138 °C, specific rotation (a)'' = 23.74 (C = 5%, H2O
). The crude d-2-amino-1-butanol charged contained about 8% df-1-amino-2-butanol as an impurity. This impurity is not carried through the splitting operation. d-2-amino-1- obtained after splitting
It has been found that the salt of butanol does not contain significant amounts of 1-amino/-2-butanol detectable by gas-liquid chromatography. The above gas-liquid chromatography shows 1-7 m/-2-butyl about 0.0
I can feel up to 1%.

Example 11 d-2-7+/-21-1-butanol 41-Ω-kidney 5g of distilled dl-2-ami/-1-butanol obtained in the same manner as in Example 2 (gas-liquid chromatographic purity (88.5%) dissolved in 48 ml of anhydrous methanol was added 17.5 g of L(10)-tartaric acid (0,0, Add 117 mol) 1, stir the resulting solution at 45-47°C for 0.5 hour, then add 4.21i (0,028 mol) of tartaric acid and stir the solution for another 0.5 hour November 45-47 Stir at 4-
Ru.

Add a small amount of L(deca)-tartrate of d-2-amino-1-butyl 7-l to the solution. Cook the mixture for 4 hours at 16
・Slowly cool to ~1°C and separate crystalline d-2-amino/-1-butyl 7-tartrate by filtration;
Wash with cold methanol (3II11 x 3) and dry in an inert atmosphere. White crystal shopping trade (14.5g,
0.061 mol, 81.9% yield) is 13 G □-1
It melts at 40°C, and [α) 25 = 23.74 (C =
It has a specific optical rotation of 5%, H2O O). Preparation df-2 used for division
-Amino-7-1-butyl-7-al contains about 8% d as an impurity.
Contains 1-1-amino-2-butal 7-al.

However, this impurity is not carried through the splitting operation. d-2-amino-1-buta 7 obtained after splitting
It is found that the L<10)-tartrate salt contains no detectable amounts of either d- or l-1-7 my/-2-butyl/- by gas-liquid chromatography. Gas-liquid chromatography: 1-7 minnow 2-butanol 0
．． I feel up to 01%. Apparently, df-1-ami7-2
All of the -butanol remains with the mother liquor and is therefore removed along with the f-2-amino-1-butanol in the methanol.

Example 12 dfL2-1-1-butanol (f')[1
(A) Crude d! obtained by the same operation as in Example 1. −
Sample 1 of 2-amino-1-butanol hydrochloride: 37 g is treated with a solution of 13° 7 g of KOH in 200 w1 of water. The mixture is extracted three times with tetrahydrofuran and the combined extracts are dried (Na2SO4). Removal of the solvent under reduced pressure yields 95 g of crude oil (60.6% df-2-amino-1-butanol and 6% df-1-amino-7-2-butamele).

CB) In another test, 200 ml of anhydrous methanol
A 250 g sample of similarly crude d7-2-7-butanol hydrochloride dissolved in 100 g of anhydrous ammonia is treated with 3 mol of anhydrous ammonia. After stirring for several hours, the excess ammonia is allowed to evaporate. After removing the precipitated ammonium chloride by filtration and concentrating the liquid, 174.5 g of oil was obtained, which was
f-2-7 minnow 1-buta/-ol and its hydrochloride
-Contains together with dl-ami/-2-butanol and its hydrochloride (according to gas-liquid chromatography, dl-2-amino-1-butanol accounts for a total of 58.9%)
.

(C) First trial &i: Crude dl-2- obtained in (A)
A 7.5 g sample of 7-amino-butanol was mixed with 7.5 g of the substance obtained in the second test (dl-2-amino-1-butanol and its hydrochloride) and the mixture was dissolved in 80 g of anhydrous methanol. dl-2-7 and 20 parts (v/v) of isopropanol (the solution contains 0.1 mol% of dl-2-7 and 20 parts (v/v) of 7-1-butanol). 097 moles are present as free base). Keep the temperature below 45℃ until the fever stops and add L(+)-tartaric acid (1 sg, o, methyl).
Add gradually. After the solution was stirred for 1 hour at 45°C, the temperature was gradually lowered and at 40°C a small amount of d-2-amino-1-butanol salt +)-tartrate was added to the mixture and then the mixture was stirred for 18 hours over a period of 4 hours. Cool slowly to °.

The crystalline d-2-r-m-z-1-butanol salt +)-tartrate formed in the reaction mixture is separated by filtration, washed with cold methanol (3111AX3) and then pumped dry. List of substances is 9,0B (0,036
molar, 75.2%); melting point 137.5-F9.5
;(a,)”=23.84 (C=5%, H2O)
Example 13 Preparation of N-1:1-(Chloromethyl)propyl7cetimidoyl chloride 500II11 equipped with a mechanically stirred rock, a low temperature thermometer and an inlet tube filled with two glass bulbs. Add reagent grade acetonitrile (82,2 mol) to a three-necked 7-fusco. While stirring vigorously and cooling (-20°C), heat the mixture to about 3″75
~400mj! Butene-1 (28 g, O
，! 5 mol) and chlorine (35.5 g, 0.5 mol) are added simultaneously. The addition is complete in about 3.degree. 7 minutes and at the end of this time the reaction temperature rises to -10.degree. C. (bath temperature -20'C). Fractional distillation of the mixture yields 14: Fraction 1
．． 89 g (mainly acetonitrile) 20 + fraction at bath temperature 50 °C under a black bar; fraction If + 12.51 (+ 2
011II Distillation at 11 pressure and bath temperature of 65°C, 1,2-
N-chlorobutane 70%, N-(1-(chloromethyl)propyl]acetimidoyl chloride 30%; * min IL
35.9 and a bath temperature of 60'C'C'2tnaa pressure, a dark brown viscous oil with a residual content of about 90% N-CI-(rialomenal)propyl]acetimidoyl chloride; 6.71+. Based on fraction 11 and the river, the yield of N-(1-(chloromethyl)propyl J acetimidoyl chloride is 39.7 g (48 bi). When fraction 2 is autodistilled, it is similar to thionyl chloride. A pale yellow oil is obtained with a characteristic odor.
°n 05,14.30.137(1,1085,9
60, 920, 840 and 740c Tsuru-1 have strong infrared bands. NMR (CD CI!): 0.
88ppm(t, 31-1)+1,'l-1,8p
lo++(m, 21-I L 2451+pm(s+
:(H), 3.62ppm(m, 2t1.-CH2
C/) and about 3.9 ppm (+n, I H, CH)a. Often the solid isomer 1 of N-(1-(chloromethyl)propyl]acetimidoyl chloride (often the main product) is also obtained. Both forms appear to be interchangeable in some solvents. Upon reaction with water, both forms N
- Hydrolyzes to [1~(chloromethyl)propyl]ace1amide. , +t'll-like ones are 3(10(+,
1650, 1550.1480.1365°1280.
1045. and has an infrared band at '140 cu'.

Example 14 N-(1-(chloromethyl)propyl]acetamide A sample of N-(1-(chloromethyl)propyl)7cetimidoyl chloride obtained in Example 13 was diluted with excess carbonate at room temperature). Treat with 10% aqueous solution.Extract the organics with ether and dry over Mg5O=,.l2.

Removal of the solvent under reduced pressure yields N~[1-
(chloromethyl)propyl]acetamide remains in quantitative yield. Infrared spectrum is 3300 (M), 310
0(W), 165 (+(S), and 550(S)c+
Shows a peak at +1'; both nuclear magnetism is 1! I! (CDel
*) is 0.95ppIfi(L, 3H)+1.4-
1,8pp+o(re, 2H)lx, 031p+#
(s, 3H): J, 67pp LII(d+ 21−
1, CH,, C1,), 3°8~4.41)+1
The peak of import (4n, IH) is shown.

The effect of H on the yield of various conditions is shown in the following example,
In these examples, the chlorination reaction was carried out at temperatures ranging from 3°C below the initial temperature to +23°C, and the ratio of acetonitrile to CI2 was varied from 2 to 4. Additionally, the initial concentration of butene-1 can be determined by either passing heptene-1 and 012 in acetonitrile simultaneously (low initial concentration of butene-1) or by first condensing the heptene in acetonitrile at -5°C and then passing the mixture through C12. (initial concentration of butene-1). The results of these tests in Table 1 show that the yield of N-(1-(chloromethyl)propyl]acetimidoyl chloride depends primarily on the molar ratio of acetonitrile to C/2, and that this ratio is
It shows that when it is brought close to , it becomes about 50 ・-55%.

(a) All reactions were conducted at atmospheric pressure with vigorous stirring in Molton flasks.

(1+) Butene-1 was loaded into a reaction 7 Busco by pouring the weighed sample into acetonitrile cooled to 5°C.

(e) Butene-1 and Cf2 were simultaneously passed through a corrected flow meter.

(d) The yield is the actual amount of residue remaining after removing the volatiles.
Based on TLm. The purity of the raw rIt product was determined by gas-liquid chromatography, infrared and nuclear magnetic resonance.

(1) 1=N41-(chloromethyl)propyl]acetimidoyl chloride The hydrolysis of N-(1,-(chloromethyl)propyl)acetimidoyl chloride is greatly influenced by pH.Simple hydration It has now been found that the decomposition procedure is effective. Refluxing N-El-(chloromethyl)propyl]acetimidoyl chloride with water yields dl-2-7 mino-1-butanol (17% ),
dl-2-7 minnow 1-butanol acetate-1/hydrochloric acid t
M (17%), N-[1-(hydroxymethyl)propyl]acetamide (7%) and acetic acid. The proportions of the products appear to have a uniform composition, since further heating (14 hours...1) does not essentially improve their distribution. However, when the hydrolysis is carried out in methanol or aqueous ethanol, the hydrolysis is complete within two hours and the acetyl component of the product can be removed by distillation as methyl acetate or ethyl acetate.

This procedure not only shortens the hydrolysis time but also avoids the accumulation of salts in the reaction mixture, N-(1-(
Chloromethyl)propyl”7s1imidoyl chloride to N41-(chloromethyl)propyl]acetamide to djl! It produces -2-amino/-1-butal 7-al in virtually stationary yields and facilitates work-up of the product.

Methyl acetate boils at 75°C, so it is easy to distill off.

In order to make this method as economical as possible, an excessively large 1 t.
Aqueous ethanol solutions of t should be avoided.

If an insufficient amount of water ((N-(1-(chloromethyl)butylnoacetimidoyl)
or in particular in the presence of 1,2-dichlorobutane by-product.
In the process, a small portion (3-15%) of N-(1-(chloromethyl)propyl)acetimidoyl chloride is converted into 2-
Hydrolyze to 7-1-chlorobutane hydrochloride. 2-
The formation of ami-7-1-chlorobutane hydrochloride can be completely suppressed by adding water and methanol sequentially and in this order rather than adding them together in one step. When water is added to N-(1-(chloromethyl)propyl]7cetimidoyl chloride, it is almost instantaneously converted to N-(1-(chloromethyl)propyl JaceI amide), which then converts the oxazoline intermediate. It is then hydrolyzed.

Acetonitrile [water concentration (Karl Fischer) = 0
．． 059.-〇, 2%'' was used as is to eliminate the royal series reactions (A, I', and C). These series reacted with 0.5 mole of Al2-L) and were resistant to
It was carried out using 10, s mol, and acetonitrile:C
A2 molar ratio (equal to acetonitrile:butene ratio) is 1
I changed it from 8 to 8.

In Series A (1 hour reaction time), the reaction temperature was maintained at 0° C. while simultaneously passing the r111 salt system and butene into acetonitrile for 1 hour. After removing acetonitrile (40-50°C, 50m+a), N-(1-(chloromethyl)propyl]7cetimidoyl chloride and 1
, 2-dichlorobutane was hydrolyzed by refluxing with aqueous methanol.

N-(],-(chloromethyl)propyl]acetimidoyl chloride is practically quantitatively hydrolyzed to N-(1-(chloromethyl)propyl)acetamide and then d
It is significant to mention that it can be hydrolyzed to l-2-amino-1-butanol. Expressing it as dl-2-ami7-1-butanol hydrochloride is a very convenient method that reduces yield. Errors due to volatile components are avoided. d
A small amount of J-1-amino-2-butanol is combined with dl-2-amino-1-butanol. Acetonitrile: Even at a low molar ratio of C12 of 1, dl-2-7
The yield of minnow 1-butanol.HCl is 31%. Acetonitrile: (Increasing the 1'2 molar ratio from 1 to 2 improved the yield to 43%, an increase of 12%.

Further increasing the acetonitrile:Cn2 ratio also improves the yield. For each 1 mol increase of acetonitrile up to a total of 5 mol (A N :C12 ratio 3 to 5) cH! -2
- Average yield of amino-1-butanol HC1 is about 6%
To increase. Note that increasing acetonitrile (A1'J
:C12 molar ratio 6 to 8) 4I and low efficiency (;dA'
The average increase in yield of -2-7 minnow 1-butanol/HCA is about 3% per mole of acetonyl/lyl.

The approximately 4:1 ratio is a good compromise between yield and rational J-method reactor and acetonitrile circulation rate.

In both rows B and 0, the gaseous reactants were passed through the acetonitrile for 0.5 hours. The initial reaction temperature was 0°C. This allowed A to rise up to 135°C during the course of the reaction. Additionally, in Row B, chlorine was passed through the acetonitrile solution of butene to maintain the initial concentration of butene. In row 0, both chlorine and butene were passed through the acetonitrile simultaneously to reduce the initial concentration of butene. Simultaneous cooling and sequential addition of butene and chlorine at different acetonitrile/C molar ratios
Table 3 shows the effects on the yield of -(thalolomethyl)propyl]acetimidoyl chloride.

a) Excluding Example 34. Example 34 is a mixture of 0222 moles and 2 moles of butene in 2 moles of acetonitrile.
I passed it.

b) Open during reaction: 0.5 hours: Cz, speed 40 (Lel/
Minute C) Yield based on butene. These self-percentages include the IL-(
Does not include loss of 1-(chloromethyl)propyl]acetimidoyl chloride. It will be 3-5%.

In series B and C, the mass balance includes conversion and recovery data for acetonitrile. In each case, the distillate (1,2-dichlorobutane deca-heptonitrile)
was analyzed using gas-liquid chromatography for 1,2-chlorobutane and acetonitrile.

A less pure product is obtained if N-(]-(chloromethyl)propyl'acetimidoyl chloride is allowed to stand for 40.-50 hours before aging.

From the data in the table, it is determined that the human compound is 2 or 2: (1) -2-amino-1-butanol I-I C
The yield of / (or N-(1-(chloromethyl)propyl) acetimidoyl chloride) mainly depends on the molar ratio of acetonitrile:C12, and also on the molar ratio of acetonitrile:C12.
I2nibutene molar ratio from 1:1:1 to 8:1:1
If you change it to 31% to 66%.

(2) Simultaneous addition of chlorine and butene to acetonitrile is advantageous over the alternative of adding chlorine to a mixture of butene and acetonitrile. The reaction is easier to control because it generates less heat, and d
The yield of A'-2-7 minnow 1-butanol.HCl is somewhat better. A reaction time of 1 hour generally appears to allow better control of the exotherm of the reaction.

(3) Reaction temperature does not appear to be a controlling factor determining overall yield. However, N-C1-(chloromethyl)propyl]acetimidoyl chloride! i
(Taking into consideration the thermal instability at temperatures below 1°C, a reaction temperature between 0 and 25°C is more preferred.

This method can be varied depending on batch size. Although the example is exemplary,
For production, butene is added to a stirred continuous reactor.
It may be advantageous to operate the process continuously with continuous feeds of 1 and chlorine. The recycled acetonitrile is continuously distilled and recycled. In such a continuous system, the ratio of acetonitrile to butene and chlorine is 1 to 1. On the other hand, for batch processes, it is preferred that the molar ratio of acetonitrile to butene-1 and chlorine is at least 2; molar ratios of 16 or more may require uneconomically large reactors. Continuous methods even favor trade ratios.

Both butene-1 and chlorine are gaseous at room temperature of about 20°C, so lower temperatures of about 0°C and higher are convenient, but if a pressurized vessel is available, reducing the need for cooling. Higher temperatures may also be used.

The cost of additional refrigeration and pressure vessels will depend on the equipment being used.

Patent applicant: American Cyanamid Kan and 2 others

Claims (6)

[Claims] (1) N in the presence of at least approximately molar equivalents of a weak base selected from the group consisting of calcium carbonate, calcium oxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, barium carbonate, and strontium carbonate. -[1-(ri-tetramethyl)propyl]
Acetimidoyl chloride is reacted with water, thereby hydrolyzing N-[1-(chloromethyl)propyl]acetimidoyl chloride to N-(1-(chloromethyl)propyl]°?cetamide. Characteristic method for synthesizing N-(1-(chloromethyl)propyl]acetamide. (2) reacting butene-1, chlorine and acetonitrile to form N-(1-(chloromethyl)propyl]acetimidoyl chloride with simultaneous production of the by-product 1,2-dichlorobutane; N-(1-(chloromethyl)propyl)acetimidoyl chloride
A method for synthesizing N-(1(chloromethyl)propyl)acetamide by hydrolysis to -(1-(chloromethyl)propyl)acetamide, comprising calcium carbonate, calcium oxide, calcium hydroxide, sodium carbonate, bicarbonate, N-[1-(chloromethyl)propyl]acetimidoyl chloride in the presence of at least approximately molar equivalents of a weak base selected from the group consisting of sodium, potassium bicarbonate, barium carbonate, and strontium carbonate.
An improved method characterized in that a sufficient amount of water is added to (1-(chloromethyl)propyl)acetamide for hydrolysis, and then acetonitrile and 1,2-dichlorobutane are placed under reduced pressure r. (3) reacting at least about 2 moles of acetonitrile with about 1 mole of chlorine and about 1 mole of butane-1 to produce N-[1-(chloromethyl)propyl] while simultaneously producing 1,2-dichlorobutane; acetimidoyl chloride, containing at least approximately 17 um of calcium carbonate, calcium oxide, calcium hydroxide, sodium carbonate, bicarbonate), potassium carbonate, potassium bicarbonate, barium carbonate, and strontium carbonate. Add water in the presence of an equivalent amount of weak base, thereby reducing this N.
[(Chloromethyl)propyl]acetimidoyl chloride is hydrolyzed to N'41-(lyclomethyl)propyl]acetamide, and after the formation of this N-(1-(chloromethyl)propyl)acetamide, excess acetonitrile is removed under reduced pressure. A method for synthesizing N-C1-(chloromethyl)propyl]acetamide, in which the apparatus and recovery method is performed. (4) As N-[1,-(chloromethyl)propyl]acetimidoyl chloride is formed, water is added at approximately the same rate, thereby further forming this N-(1-(chloromethyl)propyl]acetimidoyl chloride. It is hydrolyzed to N-(1(chloromethyl)propyl)acetamide before being chlorinated, and the heat of hydrolysis is released during the course of the reaction, thereby characterized by an isothermal temperature condition.
f. The method described in Section 3. (5) The method according to claim H, wherein the separated acetonitrile is recycled without further purification. 6. The method of claim 5, wherein the addition of 1-butene, chlorine, and water to the acetonitrile is a continuous step and the circulation of the acetonitrile is continuous.